The puzzle of immune phenotypes of childhood asthma.

PubMed

Landgraf-Rauf, Katja; Anselm, Bettina; Schaub, Bianca

2016-12-01

Asthma represents the most common chronic childhood disease worldwide. Whereas preschool children present with wheezing triggered by different factors (multitrigger and viral wheeze), clinical asthma manifestation in school children has previously been classified as allergic and non-allergic asthma. For both, the underlying immunological mechanisms are not yet understood in depth in children. Treatment is still prescribed regardless of underlying mechanisms, and children are not always treated successfully. This review summarizes recent key findings on the complex mechanisms of the development and manifestation of childhood asthma. Whereas traditional classification of childhood asthma is primarily based on clinical symptoms like wheezing and atopy, novel approaches to specify asthma phenotypes are under way and face challenges such as including the stability of phenotypes over time and transition into adulthood. Epidemiological studies enclose more information on the patient's disease history and environmental influences. Latest studies define endotypes based on molecular and cellular mechanisms, for example defining risk and protective single nucleotide polymorphisms (SNPs) and new immune phenotypes, showing promising results. Also, regulatory T cells and recently discovered T helper cell subtypes such as Th9 and Th17 cells were shown to be important for the development of asthma. Innate lymphoid cells (ILC) could play a critical role in asthma patients as they produce different cytokines associated with asthma. Epigenetic findings showed different acetylation and methylation patterns for children with allergic and non-allergic asthma. On a posttranscriptional level, miRNAs are regulating factors identified to differ between asthma patients and healthy controls and also indicate differences within asthma phenotypes. Metabolomics is another exciting chapter important for endotyping asthmatic children. Despite the development of new biomarkers and the discovery of new immunological molecules, the complex puzzle of childhood asthma is still far from being completed. Addressing the current challenges of distinct clinical asthma and wheeze phenotypes, including their stability and underlying endotypes, involves addressing the interplay of innate and adaptive immune regulatory mechanisms in large, interdisciplinary cohorts.

Food intake does not differ between obese women who are metabolically healthy or abnormal.

PubMed

Kimokoti, Ruth W; Judd, Suzanne E; Shikany, James M; Newby, P K

2014-12-01

Metabolically healthy obesity may confer lower risk of adverse health outcomes compared with abnormal obesity. Diet and race are postulated to influence the phenotype, but their roles and their interrelations on healthy obesity are unclear. We evaluated food intakes of metabolically healthy obese women in comparison to intakes of their metabolically healthy normal-weight and metabolically abnormal obese counterparts. This was a cross-sectional study in 6964 women of the REasons for Geographic And Racial Differences in Stroke (REGARDS) study. Participants were aged 45-98 y with a body mass index (BMI; kg/m(2)) ≥18.5 and free of cardiovascular diseases, diabetes, and cancer. Food intake was collected by using a food-frequency questionnaire. BMI phenotypes were defined by using metabolic syndrome (MetS) and homeostasis model assessment of insulin resistance (HOMA-IR) criteria. Mean differences in food intakes among BMI phenotypes were compared by using ANCOVA. Approximately one-half of obese women (white: 45%; black: 55%) as defined by MetS criteria and approximately one-quarter of obese women (white: 28%; black: 24%) defined on the basis of HOMA-IR values were metabolically healthy. In age-adjusted analyses, healthy obesity and normal weight as defined by both criteria were associated with lower intakes of sugar-sweetened beverages compared with abnormal obesity among both white and black women (P < 0.05). HOMA-IR-defined healthy obesity and normal weight were also associated with higher fruit and low-fat dairy intakes compared with abnormal obesity in white women (P < 0.05). Results were attenuated and became nonsignificant in multivariable-adjusted models that additionally adjusted for BMI, marital status, residential region, education, annual income, alcohol intake, multivitamin use, cigarette smoking status, physical activity, television viewing, high-sensitivity C-reactive protein, menopausal status, hormone therapy, and food intakes. Healthy obesity was not associated with a healthier diet. Prospective studies on relations of dietary patterns, which may be a better indicator of usual diet, with the phenotype would be beneficial. © 2014 American Society for Nutrition.

Food Intake Does Not Differ between Obese Women Who Are Metabolically Healthy or Abnormal1234

PubMed Central

Kimokoti, Ruth W; Judd, Suzanne E; Shikany, James M; Newby, PK

2014-01-01

Background: Metabolically healthy obesity may confer lower risk of adverse health outcomes compared with abnormal obesity. Diet and race are postulated to influence the phenotype, but their roles and their interrelations on healthy obesity are unclear. Objective: We evaluated food intakes of metabolically healthy obese women in comparison to intakes of their metabolically healthy normal-weight and metabolically abnormal obese counterparts. Methods: This was a cross-sectional study in 6964 women of the REasons for Geographic And Racial Differences in Stroke (REGARDS) study. Participants were aged 45–98 y with a body mass index (BMI; kg/m2) ≥18.5 and free of cardiovascular diseases, diabetes, and cancer. Food intake was collected by using a food-frequency questionnaire. BMI phenotypes were defined by using metabolic syndrome (MetS) and homeostasis model assessment of insulin resistance (HOMA-IR) criteria. Mean differences in food intakes among BMI phenotypes were compared by using ANCOVA. Results: Approximately one-half of obese women (white: 45%; black: 55%) as defined by MetS criteria and approximately one-quarter of obese women (white: 28%; black: 24%) defined on the basis of HOMA-IR values were metabolically healthy. In age-adjusted analyses, healthy obesity and normal weight as defined by both criteria were associated with lower intakes of sugar-sweetened beverages compared with abnormal obesity among both white and black women (P < 0.05). HOMA-IR–defined healthy obesity and normal weight were also associated with higher fruit and low-fat dairy intakes compared with abnormal obesity in white women (P < 0.05). Results were attenuated and became nonsignificant in multivariable-adjusted models that additionally adjusted for BMI, marital status, residential region, education, annual income, alcohol intake, multivitamin use, cigarette smoking status, physical activity, television viewing, high-sensitivity C-reactive protein, menopausal status, hormone therapy, and food intakes. Conclusions: Healthy obesity was not associated with a healthier diet. Prospective studies on relations of dietary patterns, which may be a better indicator of usual diet, with the phenotype would be beneficial. PMID:25411036

Defining constant versus variable phenotypic features of women with polycystic ovary syndrome using different ethnic groups and populations.

PubMed

Welt, C K; Arason, G; Gudmundsson, J A; Adams, J; Palsdóttir, H; Gudlaugsdóttir, G; Ingadóttir, G; Crowley, W F

2006-11-01

The phenotype of women with polycystic ovary syndrome (PCOS) is variable, depending on the ethnic background. The phenotypes of women with PCOS in Iceland and Boston were compared. The study was observational with a parallel design. Subjects were studied in an outpatient setting. Women, aged 18-45 yr, with PCOS defined by hyperandrogenism and fewer than nine menses per year, were examined in Iceland (n = 105) and Boston (n = 262). PCOS subjects underwent a physical exam, fasting blood samples for androgens, gonadotropins, metabolic parameters, and a transvaginal ultrasound. The phenotype of women with PCOS was compared between Caucasian women in Iceland and Boston and among Caucasian, African-American, Hispanic, and Asian women in Boston. Androstenedione (4.0 +/- 1.3 vs. 3.5 +/- 1.2 ng/ml; P < 0.01) was higher and testosterone (54.0 +/- 25.7 vs. 66.2 +/- 35.6 ng/dl; P < 0.01), LH (23.1 +/- 15.8 vs. 27.6 +/- 16.2 IU/liter; P < 0.05), and Ferriman Gallwey score were lower (7.1 +/- 6.0 vs. 15.4 +/- 8.5; P < 0.001) in Caucasian Icelandic compared with Boston women with PCOS. There were no differences in fasting blood glucose, insulin, or homeostasis model assessment in body mass index-matched Caucasian subjects from Iceland or Boston or in different ethnic groups in Boston. Polycystic ovary morphology was demonstrated in 93-100% of women with PCOS in all ethnic groups. The data demonstrate differences in the reproductive features of PCOS without differences in glucose and insulin in body mass index-matched populations. These studies also suggest that measuring androstenedione is important for the documentation of hyperandrogenism in Icelandic women. Finally, polycystic ovary morphology by ultrasound is an almost universal finding in women with PCOS as defined by hyperandrogenism and irregular menses.

Design of Biomedical Robots for Phenotype Prediction Problems

PubMed Central

deAndrés-Galiana, Enrique J.; Sonis, Stephen T.

2016-01-01

Abstract Genomics has been used with varying degrees of success in the context of drug discovery and in defining mechanisms of action for diseases like cancer and neurodegenerative and rare diseases in the quest for orphan drugs. To improve its utility, accuracy, and cost-effectiveness optimization of analytical methods, especially those that translate to clinically relevant outcomes, is critical. Here we define a novel tool for genomic analysis termed a biomedical robot in order to improve phenotype prediction, identifying disease pathogenesis and significantly defining therapeutic targets. Biomedical robot analytics differ from historical methods in that they are based on melding feature selection methods and ensemble learning techniques. The biomedical robot mathematically exploits the structure of the uncertainty space of any classification problem conceived as an ill-posed optimization problem. Given a classifier, there exist different equivalent small-scale genetic signatures that provide similar predictive accuracies. We perform the sensitivity analysis to noise of the biomedical robot concept using synthetic microarrays perturbed by different kinds of noises in expression and class assignment. Finally, we show the application of this concept to the analysis of different diseases, inferring the pathways and the correlation networks. The final aim of a biomedical robot is to improve knowledge discovery and provide decision systems to optimize diagnosis, treatment, and prognosis. This analysis shows that the biomedical robots are robust against different kinds of noises and particularly to a wrong class assignment of the samples. Assessing the uncertainty that is inherent to any phenotype prediction problem is the right way to address this kind of problem. PMID:27347715

Design of Biomedical Robots for Phenotype Prediction Problems.

PubMed

deAndrés-Galiana, Enrique J; Fernández-Martínez, Juan Luis; Sonis, Stephen T

2016-08-01

Genomics has been used with varying degrees of success in the context of drug discovery and in defining mechanisms of action for diseases like cancer and neurodegenerative and rare diseases in the quest for orphan drugs. To improve its utility, accuracy, and cost-effectiveness optimization of analytical methods, especially those that translate to clinically relevant outcomes, is critical. Here we define a novel tool for genomic analysis termed a biomedical robot in order to improve phenotype prediction, identifying disease pathogenesis and significantly defining therapeutic targets. Biomedical robot analytics differ from historical methods in that they are based on melding feature selection methods and ensemble learning techniques. The biomedical robot mathematically exploits the structure of the uncertainty space of any classification problem conceived as an ill-posed optimization problem. Given a classifier, there exist different equivalent small-scale genetic signatures that provide similar predictive accuracies. We perform the sensitivity analysis to noise of the biomedical robot concept using synthetic microarrays perturbed by different kinds of noises in expression and class assignment. Finally, we show the application of this concept to the analysis of different diseases, inferring the pathways and the correlation networks. The final aim of a biomedical robot is to improve knowledge discovery and provide decision systems to optimize diagnosis, treatment, and prognosis. This analysis shows that the biomedical robots are robust against different kinds of noises and particularly to a wrong class assignment of the samples. Assessing the uncertainty that is inherent to any phenotype prediction problem is the right way to address this kind of problem.

Modular control of glutamatergic neuronal identity in C.elegans by distinct homeodomain proteins

PubMed Central

Serrano-Saiz, Esther; Poole, Richard J.; Felton, Terry; Zhang, Feifan; De La Cruz, Estanisla Daniel; Hobert, Oliver

2013-01-01

The choice of using one of many possible neurotransmitter systems is a critical step in defining the identity of an individual neuron type. We show here that the key defining feature of glutamatergic neurons, the vesicular glutamate transporter EAT-4/VGLUT is expressed in 38 of the 118 anatomically defined neuron classes of the C.elegans nervous system. We show that eat-4/VGLUT expression is controlled in a modular manner, with distinct cis-regulatory modules driving expression in distinct glutamatergic neuron classes. We identify 13 different transcription factors, 11 of them homeodomain proteins, that act in specific combinations in 25 different glutamatergic neuron classes to initiate and maintain eat-4/VGLUT expression. We show that the adoption of a glutamatergic phenotype is linked to the adoption of other terminal identity features of a neuron, including cotransmitter phenotypes. Examination of mouse orthologs of these homeodomain proteins resulted in the identification of mouse LHX1 as a regulator of glutamatergic neurons in the brainstem. PMID:24243022

Desiderata for computable representations of electronic health records-driven phenotype algorithms.

PubMed

Mo, Huan; Thompson, William K; Rasmussen, Luke V; Pacheco, Jennifer A; Jiang, Guoqian; Kiefer, Richard; Zhu, Qian; Xu, Jie; Montague, Enid; Carrell, David S; Lingren, Todd; Mentch, Frank D; Ni, Yizhao; Wehbe, Firas H; Peissig, Peggy L; Tromp, Gerard; Larson, Eric B; Chute, Christopher G; Pathak, Jyotishman; Denny, Joshua C; Speltz, Peter; Kho, Abel N; Jarvik, Gail P; Bejan, Cosmin A; Williams, Marc S; Borthwick, Kenneth; Kitchner, Terrie E; Roden, Dan M; Harris, Paul A

2015-11-01

Electronic health records (EHRs) are increasingly used for clinical and translational research through the creation of phenotype algorithms. Currently, phenotype algorithms are most commonly represented as noncomputable descriptive documents and knowledge artifacts that detail the protocols for querying diagnoses, symptoms, procedures, medications, and/or text-driven medical concepts, and are primarily meant for human comprehension. We present desiderata for developing a computable phenotype representation model (PheRM). A team of clinicians and informaticians reviewed common features for multisite phenotype algorithms published in PheKB.org and existing phenotype representation platforms. We also evaluated well-known diagnostic criteria and clinical decision-making guidelines to encompass a broader category of algorithms. We propose 10 desired characteristics for a flexible, computable PheRM: (1) structure clinical data into queryable forms; (2) recommend use of a common data model, but also support customization for the variability and availability of EHR data among sites; (3) support both human-readable and computable representations of phenotype algorithms; (4) implement set operations and relational algebra for modeling phenotype algorithms; (5) represent phenotype criteria with structured rules; (6) support defining temporal relations between events; (7) use standardized terminologies and ontologies, and facilitate reuse of value sets; (8) define representations for text searching and natural language processing; (9) provide interfaces for external software algorithms; and (10) maintain backward compatibility. A computable PheRM is needed for true phenotype portability and reliability across different EHR products and healthcare systems. These desiderata are a guide to inform the establishment and evolution of EHR phenotype algorithm authoring platforms and languages. © The Author 2015. Published by Oxford University Press on behalf of the American Medical Informatics Association.

Nature and Nurture: What Determines Tumor Metabolic Phenotypes?

PubMed

Mayers, Jared R; Vander Heiden, Matthew G

2017-06-15

Understanding the genetic basis of cancer has led to therapies that target driver mutations and has helped match patients with more personalized drugs. Oncogenic mutations influence tumor metabolism, but other tumor characteristics can also contribute to their metabolic phenotypes. Comparison of isogenic lung and pancreas tumor models suggests that use of some metabolic pathways is defined by lineage rather than by driver mutation. Lung tumors catabolize circulating branched chain amino acids (BCAA) to extract nitrogen for nonessential amino acid and nucleotide synthesis, whereas pancreatic cancer obtains amino acids from catabolism of extracellular protein. These differences in amino acid metabolism translate into distinct pathway dependencies, as genetic disruption of the enzymes responsible for utilization of BCAA nitrogen limits the growth of lung tumors, but not pancreatic tumors. These data argue that some cancer metabolic phenotypes are defined by cancer tissue-of-origin and environment and that these features constrain the influence of genetic mutations on metabolism. A better understanding of the factors defining tumor nutrient utilization could be exploited to help improve cancer therapy. Cancer Res; 77(12); 3131-4. ©2017 AACR . ©2017 American Association for Cancer Research.

Heritability of tic disorders: a twin-family study.

PubMed

Zilhão, N R; Olthof, M C; Smit, D J A; Cath, D C; Ligthart, L; Mathews, C A; Delucchi, K; Boomsma, D I; Dolan, C V

2017-04-01

Genetic-epidemiological studies that estimate the contributions of genetic factors to variation in tic symptoms are scarce. We estimated the extent to which genetic and environmental influences contribute to tics, employing various phenotypic definitions ranging between mild and severe symptomatology, in a large population-based adult twin-family sample. In an extended twin-family design, we analysed lifetime tic data reported by adult mono- and dizygotic twins (n = 8323) and their family members (n = 7164; parents and siblings) from 7311 families in the Netherlands Twin Register. We measured tics by the abbreviated version of the Schedule for Tourette and Other Behavioral Syndromes. Heritability was estimated by genetic structural equation modeling for four tic disorder definitions: three dichotomous and one trichotomous phenotype, characterized by increasingly strictly defined criteria. Prevalence rates of the different tic disorders in our sample varied between 0.3 and 4.5% depending on tic disorder definition. Tic frequencies decreased with increasing age. Heritability estimates varied between 0.25 and 0.37, depending on phenotypic definitions. None of the phenotypes showed evidence of assortative mating, effects of shared environment or non-additive genetic effects. Heritabilities of mild and severe tic phenotypes were estimated to be moderate. Overlapping confidence intervals of the heritability estimates suggest overlapping genetic liabilities between the various tic phenotypes. The most lenient phenotype (defined only by tic characteristics, excluding criteria B, C and D of DSM-IV) rendered sufficiently reliable heritability estimates. These findings have implications in phenotypic definitions for future genetic studies.

Neuropathology and Animal Models of Autism: Genetic and Environmental Factors

PubMed Central

Gadad, Bharathi S.; Young, Keith A.; German, Dwight C.

2013-01-01

Autism is a heterogeneous behaviorally defined neurodevelopmental disorder. It is defined by the presence of marked social deficits, specific language abnormalities, and stereotyped repetitive patterns of behavior. Because of the variability in the behavioral phenotype of the disorder among patients, the term autism spectrum disorder has been established. In the first part of this review, we provide an overview of neuropathological findings from studies of autism postmortem brains and identify the cerebellum as one of the key brain regions that can play a role in the autism phenotype. We review research findings that indicate possible links between the environment and autism including the role of mercury and immune-related factors. Because both genes and environment can alter the structure of the developing brain in different ways, it is not surprising that there is heterogeneity in the behavioral and neuropathological phenotypes of autism spectrum disorders. Finally, we describe animal models of autism that occur following insertion of different autism-related genes and exposure to environmental factors, highlighting those models which exhibit both autism-like behavior and neuropathology. PMID:24151553

Characteristics of feed efficiency within and across lactation in dairy cows and the effect of genetic selection.

PubMed

Hurley, A M; Lopez-Villalobos, N; McParland, S; Lewis, E; Kennedy, E; O'Donovan, M; Burke, J L; Berry, D P

2018-02-01

The objective of the present study was to investigate the phenotypic inter- and intra-relationships within and among alternative feed efficiency metrics across different stages of lactation and parities; the expected effect of genetic selection for feed efficiency on the resulting phenotypic lactation profiles was also quantified. A total of 8,199 net energy intake (NE I ) test-day records from 2,505 lactations on 1,290 cows were used. Derived efficiency traits were either ratio based or residual based; the latter were derived from least squares regression models. Residual energy intake (REI) was defined as NE I minus predicted energy requirements based on lactation performance; residual energy production (REP) was defined as net energy for lactation minus predicted energy requirements based on lactation performance. Energy conversion efficiency was defined as net energy for lactation divided by NE I . Pearson phenotypic correlations among traits were computed across lactation stages and parities, and the significance of the differences was determined using the Fisher r-to-z transformation. Sources of variation in the feed efficiency metrics were investigated using linear mixed models, which included the fixed effects of contemporary group, breed, parity, stage of lactation, and the 2-way interaction of parity by stage of lactation. With the exception of REI, parity was associated with all efficiency and production traits. Stage of lactation, as well as the 2-way interaction of parity by stage of lactation, were associated with all efficiency and production traits. Phenotypic correlations among the efficiency and production traits differed not only by stage of lactation but also by parity. For example, the strong phenotypic correlation between REI and energy balance (EB; 0.89) for cows in parity 3 or greater and early lactation was weaker for parity 1 cows at the same lactation stage (0.81), suggesting primiparous cows use the ingested energy for both milk production and growth. Nonetheless, these strong phenotypic correlations between REI and EB suggested negative REI animals (i.e., more efficient) are also in more negative EB. These correlations were further supported when assessing the effect on phenotypic performance of animals genetically divergent for feed intake and efficiency based on parental average. Animals genetically selected to have lower REI resulted in cows who consumed less NE I but were also in negative EB throughout the entire lactation. Nonetheless, such repercussions of negative EB do not imply that selection for negative REI (as defined here) should not be practiced, but instead should be undertaken within the framework of a balanced breeding objective, which includes traits such as reproduction and health. Copyright © 2018 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Obstructive Sleep Apnea Phenotypes and Markers of Vascular Disease: A Review

PubMed Central

Ramos, Alberto R.; Figueredo, Pedro; Shafazand, Shirin; Chediak, Alejandro D.; Abreu, Alexandre R.; Dib, Salim I.; Torre, Carlos; Wallace, Douglas M.

2017-01-01

Obstructive sleep apnea (OSA) is a chronic and heterogeneous disorder that leads to early mortality, stroke, and cardiovascular disease (CVD). OSA is defined by the apnea–hypopnea index, which is an index of OSA severity that combines apneas (pauses in breathing) and hypopneas (partial obstructions in breathing) associated with hypoxemia. Yet, other sleep metrics (i.e., oxygen nadir, arousal frequency), along with clinical symptoms and molecular markers could be better predictors of stroke and CVD outcomes in OSA. The recent focus on personalized medical care introduces the possibility of a unique approach to the treatment of OSA based on its phenotypes, defined by pathophysiological mechanisms and/or clinical presentation. We summarized what is known about OSA and its phenotypes, and review the literature on factors or intermediate markers that could increase stroke risk and CVD in patients with OSA. The OSA phenotypes where divided across three different domains (1) clinical symptoms (i.e., daytime sleepiness), (2) genetic/molecular markers, and (3) experimental data-driven approach (e.g., cluster analysis). Finally, we further highlight gaps in the literature framing a research agenda. PMID:29259576

Molecular essence and endocrine responsiveness of estrogen receptor-negative, progesterone receptor-positive, and HER2-negative breast cancer.

PubMed

Yu, Ke-Da; Jiang, Yi-Zhou; Hao, Shuang; Shao, Zhi-Ming

2015-10-05

The clinical significance of progesterone receptor (PgR) expression in estrogen receptor-negative (ER-) breast cancer is controversial. Herein, we systemically investigate the clinicopathologic features, molecular essence, and endocrine responsiveness of ER-/PgR+/HER2- phenotype. Four study cohorts were included. The first and second cohorts were from the Surveillance, Epidemiology, and End Results database (n = 67,932) and Fudan University Shanghai Cancer Center (n = 2,338), respectively, for clinicopathologic and survival analysis. The third and fourth cohorts were from two independent publicly available microarray datasets including 837 operable cases and 483 cases undergoing neoadjuvant chemotherapy, respectively, for clinicopathologic and gene-expression analysis. Characterized genes defining subgroups within the ER-/PgR+/HER2- phenotype were determined and further validated. Clinicopathologic features and survival outcomes of the ER-/PgR+ phenotype fell in between the ER+/PgR+ and ER-/PgR- phenotypes, but were more similar to ER-/PgR-. Among the ER-/PgR+ phenotype, 30% (95% confidence interval [CI] 17-42%, pooled by a fixed-effects method) were luminal-like and 59% (95% CI 45-72%, pooled by a fixed-effects method) were basal-like. We further refined the characterized genes for subtypes within the ER-/PgR+ phenotype and developed an immunohistochemistry-based method that could determine the molecular essence of ER-/PgR+ using three markers, TFF1, CK5, and EGFR. Either PAM50-defined or immunohistochemistry-defined basal-like ER-/PgR+ cases have a lower endocrine therapy sensitivity score compared with luminal-like ER-/PgR+ cases (P <0.0001 by Mann-Whitney test for each study set and P <0.0001 for pooled standardized mean difference in meta-analysis). Immunohistochemistry-defined basal-like ER-/PgR+ cases might not benefit from adjuvant endocrine therapy (log-rank P = 0.61 for sufficient versus insufficient endocrine therapy). The majority of ER-/PgR+/HER2- phenotype breast cancers are basal-like and associated with a lower endocrine therapy sensitivity score. Additional studies are needed to validate these findings.

Defining and quantifying the social phenotype in autism.

PubMed

Klin, Ami; Jones, Warren; Schultz, Robert; Volkmar, Fred; Cohen, Donald

2002-06-01

Genetic and neurofunctional research in autism has highlighted the need for improved characterization of the core social disorder defining the broad spectrum of syndrome manifestations. This article reviews the advantages and limitations of current methods for the refinement and quantification of this highly heterogeneous social phenotype. The study of social visual pursuit by use of eye-tracking technology is offered as a paradigm for novel tools incorporating these requirements and as a research effort that builds on the emerging synergy of different branches of social neuroscience. Advances in the area will require increased consideration of processes underlying experimental results and a closer approximation of experimental methods to the naturalistic demands inherent in real-life social situations.

Differentiating Bipolar Disorder–Not Otherwise Specified and Severe Mood Dysregulation

PubMed Central

Towbin, Kenneth; Axelson, David; Leibenluft, Ellen; Birmaher, Boris

2013-01-01

Objective Bipolar Disorder–Not Otherwise Specified (BP-NOS) and Severe Mood Dysregulation (SMD) are severe mood disorders that were both defined to address questions about the diagnosis of bipolar disorder (BD) in youth. SMD and BP-NOS are distinct phenotypes that differ in clinical presentation and longitudinal course. The purpose of this review is to inform clinicians about the clinical features of the two phenotypes and about the research literature distinguishing them. Method We review the literature on SMD as studied in the National Institute of Mental Health Intramural Research Program and on BP-NOS in youth. For BP-NOS, we focus on the phenotype defined in the Course of Bipolar Youth (COBY) study, since this has received the most study. Results SMD is characterized by impairing, chronic irritability without distinct manic episodes. Most commonly, BP-NOS is characterized by manic, mixed or hypomanic episodes that are too short to meet DSM-IV-TR duration criterion. Research provides strong, albeit suggestive, evidence that SMD is not a form of BD; the most convincing evidence are longitudinal data indicating that youth with SMD are not at high risk to develop BD as they age. The BP-NOS phenotype appears to be on a diagnostic continuum with BD type I and type II. BP-NOS and BD- type I subjects have similar symptom and family history profiles, and youth with BP-NOS are at high risk to develop BD as they age. Currently, little research guides treatment for either phenotype. Conclusions Pressing research needs include identifying effective treatments for these phenotypes, ascertaining biomarkers that predict conversion from BP-NOS to BD, elucidating associations between SMD and other disorders, and defining the neural circuitry mediating each condition. PMID:23622848

On the nosology and pathogenesis of Wolf-Hirschhorn syndrome: genotype-phenotype correlation analysis of 80 patients and literature review.

PubMed

Zollino, Marcella; Murdolo, Marina; Marangi, Giuseppe; Pecile, Vanna; Galasso, Cinzia; Mazzanti, Laura; Neri, Giovanni

2008-11-15

Based on genotype-phenotype correlation analysis of 80 Wolf-Hirschhorn syndrome (WHS) patients, as well as on review of relevant literature, we add further insights to the following aspects of WHS: (1) clinical delineation and phenotypic categories; (2) characterization of the basic genomic defect, mechanisms of origin and familiarity; (3) identification of prognostic factors for mental retardation; (4) chromosome mapping of the distinctive clinical signs, in an effort to identify pathogenic genes. Clinically, we consider that minimal diagnostic criteria for WHS, defining a "core" phenotype, are typical facial appearance, mental retardation, growth delay and seizures (or EEG anomalies). Three different categories of the WHS phenotype were defined, generally correlating with the extent of the 4p deletion. The first one comprises a small deletion not exceeding 3.5 Mb, that is usually associated with a mild phenotype, lacking major malformations. This category is likely under-diagnosed. The second and by far the more frequent category is identified by large deletions, averaging between 5 and 18 Mb, and causes the widely recognizable WHS phenotype. The third clinical category results from a very large deletion exceeding 22-25 Mb causing a severe phenotype, that can hardly be defined as typical WHS. Genetically, de novo chromosome abnormalities in WHS include pure deletions but also complex rearrangements, mainly unbalanced translocations. With the exception of t(4p;8p), WHS-associated chromosome abnormalities are neither mediated by segmental duplications, nor associated with a parental inversion polymorphism on 4p16.3. Factors involved in prediction of prognosis include the extent of the deletion, the occurrence of complex chromosome anomalies, and the severity of seizures. We found that the core phenotype maps within the terminal 1.9 Mb region of chromosome 4p. Therefore, WHSCR-2 should be considered the critical region for this condition. We also confirmed that the pathogenesis of WHS is multigenic. Specific and independent chromosome regions were characterized for growth delay and seizures, as well as for the additional clinical signs that characterize this condition. With the exception of parental balanced translocations, familial recurrence is uncommon.

Heritability of Tic Disorders: a Twin-Family Study

PubMed Central

Zilhao, Nuno R.; Olthof, Maria C.; Smit, Dirk J.A.; Cath, Danielle C.; Ligthart, Lannie; Mathews, Carol A.; Delucchi, Kevin; Boomsma, Dorret I.; Dolan, Conor V.

2017-01-01

Background Genetic-epidemiological studies that estimate the contributions of genetic factors to variation in tic symptoms are scarce. We estimated the extent to which genetic and environmental influences contribute to tics, employing various phenotypic definitions ranging between mild and severe symptomatology, in a large population-based adult twin-family sample. Methods In an extended twin-family design, we analyzed lifetime tic data reported by adult mono- and dizygotic twins (n= 8,323) and their family members (n=7,164; parents and siblings) from 7,311 families in the Netherlands Twin Register (NTR). We measured tics by the abbreviated version of the Schedule for Tourette and Other Behavioral Syndromes (STOBS) (TSAICG, 2007). Heritability was estimated by genetic Structural Equation Modeling (SEM) for four tic disorder definitions: three dichotomous and one trichotomous phenotype, characterized by increasingly strictly defined criteria. Results Prevalence rates of the different tic disorders in our sample varied between 0.3 and 4.5% depending on tic disorder definition. Tic frequencies decreased with increasing age. Heritability estimates varied between .25 and .37, depending on phenotypic definitions. None of the phenotypes showed evidence of assortative mating, effects of shared environment, or non-additive genetic effects. Conclusions Heritabilities of mild and severe tic phenotypes were estimated to be moderate. Overlapping confidence intervals of the heritability estimates suggest overlapping genetic liabilities between the various tic phenotypes. The most lenient phenotype (defined only by tic characteristics, excluding criteria B, C and D of DSMIV) rendered sufficiently reliable heritability estimates. These findings have implications in phenotypic definitions for future genetic studies. PMID:27974054

The ROCK isoforms differentially regulate the morphological characteristics of carcinoma cells.

PubMed

Jerrell, Rachel J; Leih, Mitchell J; Parekh, Aron

2017-06-26

Rho-associated kinase (ROCK) activity drives cell migration via actomyosin contractility. During invasion, individual cancer cells can transition between 2 modes of migration, mesenchymal and amoeboid. Changes in ROCK activity can cause a switch between these migration phenotypes which are defined by distinct morphologies. However, recent studies have shown that the ROCK isoforms are not functionally redundant as previously thought. Therefore, it is unclear whether the ROCK isoforms play different roles in regulating migration phenotypes. Here, we found that ROCK1 and ROCK2 differentially regulate carcinoma cell morphology resulting in intermediate phenotypes that share some mesenchymal and amoeboid characteristics. These findings suggest that the ROCK isoforms play unique roles in the phenotypic plasticity of mesenchymal carcinoma cells which may have therapeutic implications.

Validated and longitudinally stable asthma phenotypes based on cluster analysis of the ADEPT study.

PubMed

Loza, Matthew J; Djukanovic, Ratko; Chung, Kian Fan; Horowitz, Daniel; Ma, Keying; Branigan, Patrick; Barnathan, Elliot S; Susulic, Vedrana S; Silkoff, Philip E; Sterk, Peter J; Baribaud, Frédéric

2016-12-15

Asthma is a disease of varying severity and differing disease mechanisms. To date, studies aimed at stratifying asthma into clinically useful phenotypes have produced a number of phenotypes that have yet to be assessed for stability and to be validated in independent cohorts. The aim of this study was to define and validate, for the first time ever, clinically driven asthma phenotypes using two independent, severe asthma cohorts: ADEPT and U-BIOPRED. Fuzzy partition-around-medoid clustering was performed on pre-specified data from the ADEPT participants (n = 156) and independently on data from a subset of U-BIOPRED asthma participants (n = 82) for whom the same variables were available. Models for cluster classification probabilities were derived and applied to the 12-month longitudinal ADEPT data and to a larger subset of the U-BIOPRED asthma dataset (n = 397). High and low type-2 inflammation phenotypes were defined as high or low Th2 activity, indicated by endobronchial biopsies gene expression changes downstream of IL-4 or IL-13. Four phenotypes were identified in the ADEPT (training) cohort, with distinct clinical and biomarker profiles. Phenotype 1 was "mild, good lung function, early onset", with a low-inflammatory, predominantly Type-2, phenotype. Phenotype 2 had a "moderate, hyper-responsive, eosinophilic" phenotype, with moderate asthma control, mild airflow obstruction and predominant Type-2 inflammation. Phenotype 3 had a "mixed severity, predominantly fixed obstructive, non-eosinophilic and neutrophilic" phenotype, with moderate asthma control and low Type-2 inflammation. Phenotype 4 had a "severe uncontrolled, severe reversible obstruction, mixed granulocytic" phenotype, with moderate Type-2 inflammation. These phenotypes had good longitudinal stability in the ADEPT cohort. They were reproduced and demonstrated high classification probability in two subsets of the U-BIOPRED asthma cohort. Focusing on the biology of the four clinical independently-validated easy-to-assess ADEPT asthma phenotypes will help understanding the unmet need and will aid in developing tailored therapies. NCT01274507 (ADEPT), registered October 28, 2010 and NCT01982162 (U-BIOPRED), registered October 30, 2013.

The phenotype of polycythemia due to Croatian homozygous VHL (571C>G:H191D) mutation is different from that of Chuvash polycythemia (VHL 598C>T:R200W)

PubMed Central

Tomasic, Nikica Ljubas; Piterkova, Lucie; Huff, Chad; Bilic, Ernest; Yoon, Donghoon; Miasnikova, Galina Y.; Sergueeva, Adelina I.; Niu, Xiaomei; Nekhai, Sergei; Gordeuk, Victor; Prchal, Josef T.

2013-01-01

Mutations of VHL (a negative regulator of hypoxia-inducible factors) have position-dependent distinct cancer phenotypes. Only two known inherited homozygous VHL mutations exist and they cause polycythemia: Chuvash R200W and Croatian H191D. We report a second polycythemic Croatian H191D homozygote distantly related to the first propositus. Three generations of both families were genotyped for analysis of shared ancestry. Biochemical and molecular tests were performed to better define their phenotypes, with an emphasis on a comparison with Chuvash polycythemia. The VHL H191D mutation did not segregate in the family defined by the known common ancestors of the two subjects, suggesting a high prevalence in Croatians, but haplotype analysis indicated an undocumented common ancestor ∼six generations ago as the founder of this mutation. We show that erythropoietin levels in homozygous VHL H191D individuals are higher than in VHL R200W patients of similar ages, and their native erythroid progenitors, unlike Chuvash R200W, are not hypersensitive to erythropoietin. This observation contrasts with a report suggesting that polycythemia in VHL R200W and H191D homozygotes is due to the loss of JAK2 regulation from VHL R200W and H191D binding to SOCS1. In conclusion, our studies further define the hematologic phenotype of VHL H191D and provide additional evidence for phenotypic heterogeneity associated with the positional effects of VHL mutations. PMID:23403324

The phenotype of polycythemia due to Croatian homozygous VHL (571C>G:H191D) mutation is different from that of Chuvash polycythemia (VHL 598C>T:R200W).

PubMed

Tomasic, Nikica Ljubas; Piterkova, Lucie; Huff, Chad; Bilic, Ernest; Yoon, Donghoon; Miasnikova, Galina Y; Sergueeva, Adelina I; Niu, Xiaomei; Nekhai, Sergei; Gordeuk, Victor; Prchal, Josef T

2013-04-01

Mutations of VHL (a negative regulator of hypoxia-inducible factors) have position-dependent distinct cancer phenotypes. Only two known inherited homozygous VHL mutations exist and they cause polycythemia: Chuvash R200W and Croatian H191D. We report a second polycythemic Croatian H191D homozygote distantly related to the first propositus. Three generations of both families were genotyped for analysis of shared ancestry. Biochemical and molecular tests were performed to better define their phenotypes, with an emphasis on a comparison with Chuvash polycythemia. The VHL H191D mutation did not segregate in the family defined by the known common ancestors of the two subjects, suggesting a high prevalence in Croatians, but haplotype analysis indicated an undocumented common ancestor ∼six generations ago as the founder of this mutation. We show that erythropoietin levels in homozygous VHL H191D individuals are higher than in VHL R200W patients of similar ages, and their native erythroid progenitors, unlike Chuvash R200W, are not hypersensitive to erythropoietin. This observation contrasts with a report suggesting that polycythemia in VHL R200W and H191D homozygotes is due to the loss of JAK2 regulation from VHL R200W and H191D binding to SOCS1. In conclusion, our studies further define the hematologic phenotype of VHL H191D and provide additional evidence for phenotypic heterogeneity associated with the positional effects of VHL mutations.

Corruption of the intra-gene DNA methylation architecture is a hallmark of cancer.

PubMed

Bartlett, Thomas E; Zaikin, Alexey; Olhede, Sofia C; West, James; Teschendorff, Andrew E; Widschwendter, Martin

2013-01-01

Epigenetic processes--including DNA methylation--are increasingly seen as having a fundamental role in chronic diseases like cancer. It is well known that methylation levels at particular genes or loci differ between normal and diseased tissue. Here we investigate whether the intra-gene methylation architecture is corrupted in cancer and whether the variability of levels of methylation of individual CpGs within a defined gene is able to discriminate cancerous from normal tissue, and is associated with heterogeneous tumour phenotype, as defined by gene expression. We analysed 270985 CpGs annotated to 18272 genes, in 3284 cancerous and 681 normal samples, corresponding to 14 different cancer types. In doing so, we found novel differences in intra-gene methylation pattern across phenotypes, particularly in those genes which are crucial for stem cell biology; our measures of intra-gene methylation architecture are a better determinant of phenotype than measures based on mean methylation level alone (K-S test [Formula: see text] in all 14 diseases tested). These per-gene methylation measures also represent a considerable reduction in complexity, compared to conventional per-CpG beta-values. Our findings strongly support the view that intra-gene methylation architecture has great clinical potential for the development of DNA-based cancer biomarkers.

[Population genetics study of functional brain asymmetry in the native and immigrant populations of northeastern USSR. I. Sex-age distribution and familial data].

PubMed

Solovenchuk, L L; Arshavskiĭ, V V

1988-05-01

Clearly definable polymorphism of hemisphere interrelations represented by three phenotypes was established by the method of EEG cross-correlation analysis. Each phenotype of the three, representing polymorphism, is characterized by marked specificity of perception and the processing of information, which determines certain integral physiological characteristics of individuals. Phenotype frequencies in aboriginal and new-come populations of the North-East of the USSR differ significantly. In comparison with the inhabitants, Moscow Russians of Magadan are significantly closer to aboriginal population, judging by their frequency distribution, and this may be due to the strategy specificity in adaptation of populations to environmental conditions. Significant difference in phenotype frequencies is shown in representatives of both sexes, this being more pronounced in the aboriginal population. The establishment of interhemispheric reaction type by approx. 10th year of individual's life is confirmed. Phenotype frequency correlations, depending on parental phenotype, were analyzed in children. The role of genetic and environmental factors in manifestation of the hemisphere relationship type is discussed. Rationality of the population analysis of hemisphere asymmetry types is grounded, according to the study of behavioural genetics and population adaptation.

Revealing plant cryptotypes: defining meaningful phenotypes among infinite traits.

PubMed

Chitwood, Daniel H; Topp, Christopher N

2015-04-01

The plant phenotype is infinite. Plants vary morphologically and molecularly over developmental time, in response to the environment, and genetically. Exhaustive phenotyping remains not only out of reach, but is also the limiting factor to interpreting the wealth of genetic information currently available. Although phenotyping methods are always improving, an impasse remains: even if we could measure the entirety of phenotype, how would we interpret it? We propose the concept of cryptotype to describe latent, multivariate phenotypes that maximize the separation of a priori classes. Whether the infinite points comprising a leaf outline or shape descriptors defining root architecture, statistical methods to discern the quantitative essence of an organism will be required as we approach measuring the totality of phenotype. Copyright © 2015 Elsevier Ltd. All rights reserved.

Tissue-Specific Profiling Reveals Transcriptome Alterations in Arabidopsis Mutants Lacking Morphological Phenotypes[C][W

PubMed Central

Simon, Marissa; Bruex, Angela; Kainkaryam, Raghunandan M.; Zheng, Xiaohua; Huang, Ling; Woolf, Peter J.; Schiefelbein, John

2013-01-01

Traditional genetic analysis relies on mutants with observable phenotypes. Mutants lacking visible abnormalities may nevertheless exhibit molecular differences useful for defining gene function. To examine this, we analyzed tissue-specific transcript profiles from Arabidopsis thaliana transcription factor gene mutants with known roles in root epidermis development, but lacking a single-gene mutant phenotype due to genetic redundancy. We discovered substantial transcriptional changes in each mutant, preferentially affecting root epidermal genes in a manner consistent with the known double mutant effects. Furthermore, comparing transcript profiles of single and double mutants, we observed remarkable variation in the sensitivity of target genes to the loss of one or both paralogous genes, including preferential effects on specific branches of the epidermal gene network, likely reflecting the pathways of paralog subfunctionalization during evolution. In addition, we analyzed the root epidermal transcriptome of the transparent testa glabra2 mutant to clarify its role in the network. These findings provide insight into the molecular basis of genetic redundancy and duplicate gene diversification at the level of a specific gene regulatory network, and they demonstrate the usefulness of tissue-specific transcript profiling to define gene function in mutants lacking informative visible changes in phenotype. PMID:24014549

Classification and prediction of toxicity of chemicals using an automated phenotypic profiling of Caenorhabditis elegans.

PubMed

Gao, Shan; Chen, Weiyang; Zeng, Yingxin; Jing, Haiming; Zhang, Nan; Flavel, Matthew; Jois, Markandeya; Han, Jing-Dong J; Xian, Bo; Li, Guojun

2018-04-18

Traditional toxicological studies have relied heavily on various animal models to understand the effect of various compounds in a biological context. Considering the great cost, complexity and time involved in experiments using higher order organisms. Researchers have been exploring alternative models that avoid these disadvantages. One example of such a model is the nematode Caenorhabditis elegans. There are some advantages of C. elegans, such as small size, short life cycle, well defined genome, ease of maintenance and efficient reproduction. As these benefits allow large scale studies to be initiated with relative ease, the problem of how to efficiently capture, organize and analyze the resulting large volumes of data must be addressed. We have developed a new method for quantitative screening of chemicals using C. elegans. 33 features were identified for each chemical treatment. The compounds with different toxicities were shown to alter the phenotypes of C. elegans in distinct and detectable patterns. We found that phenotypic profiling revealed conserved functions to classify and predict the toxicity of different chemicals. Our results demonstrate the power of phenotypic profiling in C. elegans under different chemical environments.

Social Phenotypes of Autism Spectrum Disorders and Williams Syndrome: Similarities and Differences

PubMed Central

Asada, Kosuke; Itakura, Shoji

2012-01-01

Autism spectrum disorders (ASD) and Williams syndrome (WS) both are neurodevelopmental disorders, each with a unique social phenotypic pattern. This review article aims to define the similarities and differences between the social phenotypes of ASD and WS. We review studies that have examined individuals with WS using diagnostic assessments such as the Autism Diagnostic Observation Schedule (ADOS), cross-syndrome direct comparison studies, and studies that have individually examined either disorder. We conclude that (1) individuals with these disorders show quite contrasting phenotypes for face processing (i.e., preference to faces and eyes) and sociability (i.e., interest in and motivation to interact with others), and (2) although the ADOS and a direct comparison study on pragmatic language ability suggest more deficits in ASD, individuals with WS are similarly impaired on social cognition and communicative skills. In light of these results, we discuss how cross-syndrome comparisons between ASD and WS can contribute to developmental theory, cognitive neuroscience, and the development and choice of clinical treatments. PMID:22866045

Phenotypic variation in nurse traits and community feedbacks define an alpine community.

PubMed

Michalet, Richard; Xiao, Sa; Touzard, Blaise; Smith, David S; Cavieres, Lohengrin A; Callaway, Ragan M; Whitham, Thomas G

2011-05-01

Much is known about facilitation, but virtually nothing about the underlying genetic and evolutionary consequences of this important interaction. We assessed the potential of phenotypic differences in facilitative effects of a foundation species to determine the composition of an Alpine community in Arizona. Two phenotypes of Geum rossii occur along a gradient of disturbance, with 'tight' competitive cushions in stable conditions and 'loose' facilitative cushions in disturbed conditions. A common-garden study suggested that field-based traits may have a genetic basis. Field experiments showed that the reproductive fitness of G. rossii cushions decreased with increasing facilitation. Finally, using a dual-lattice model we showed that including the cost and benefit of facilitation may contribute to the co-occurrence of genotypes with contrasting facilitative effects. Our results indicate that changes in community composition due to phenotypic differences in facilitative effects of a foundation species may in turn affect selective pressures on the foundation species. © 2011 Blackwell Publishing Ltd/CNRS.

Musculoskeletal phenotype through the life course: the role of nutrition.

PubMed

Ward, Kate

2012-02-01

This review considers the definition of a healthy bone phenotype through the life course and the modulating effects of muscle function and nutrition. In particular, it will emphasise that optimal bone strength (and how that is regulated) is more important than simple measures of bone mass. The forces imposed on bone by muscle loading are the primary determinants of musculoskeletal health. Any factor that changes muscle loading on the bone, or the response of bone to loading results in alterations of bone strength. Advances in technology have enhanced the understanding of a healthy bone phenotype in different skeletal compartments. Multiple components of muscle strength can also be quantified. The critical evaluation of emerging technologies for assessment of bone and muscle phenotype is vital. Populations with low and moderate/high daily Ca intakes and/or different vitamin D status illustrate the importance of nutrition in determining musculoskeletal phenotype. Changes in mass and architecture maintain strength despite low Ca intake or vitamin D status. There is a complex interaction between body fat and bone which, in addition to protein intake, is emerging as a key area of research. Muscle and bone should be considered as an integrative unit; the role of body fat requires definition. There remains a lack of longitudinal evidence to understand how nutrition and lifestyle define musculoskeletal health. In conclusion, a life-course approach is required to understand the definition of healthy skeletal phenotype in different populations and at different stages of life.

EG-09EPIGENETIC PROFILING REVEALS A CpG HYPERMETHYLATION PHENOTYPE (CIMP) ASSOCIATED WITH WORSE PROGRESSION-FREE SURVIVAL IN MENINGIOMA

PubMed Central

Olar, Adriana; Wani, Khalida; Mansouri, Alireza; Zadeh, Gelareh; Wilson, Charmaine; DeMonte, Franco; Fuller, Gregory; Jones, David; Pfister, Stefan; von Deimling, Andreas; Sulman, Erik; Aldape, Kenneth

2014-01-01

BACKGROUND: Methylation profiling of solid tumors has revealed biologic subtypes, often with clinical implications. Methylation profiles of meningioma and their clinical implications are not well understood. METHODS: Ninety-two meningioma samples (n = 44 test set and n = 48 validation set) were profiled using the Illumina HumanMethylation450 BeadChip. Unsupervised clustering and analyses for recurrence-free survival (RFS) were performed. RESULTS: Unsupervised clustering of the test set using approximately 900 highly variable markers identified two clearly defined methylation subgroups. One of the groups (n = 19) showed global hypermethylation of a set of markers, analogous to CpG island methylator phenotype (CIMP). These findings were reproducible in the validation set, with 18/48 samples showing the CIMP-positive phenotype. Importantly, of 347 highly variable markers common to both the test and validation set analyses, 107 defined CIMP in the test set and 94 defined CIMP in the validation set, with an overlap of 83 markers between the two datasets. This number is much greater than expected by chance indicating reproducibly of the hypermethylated markers that define CIMP in meningioma. With respect to clinical correlation, the 37 CIMP-positive cases displayed significantly shorter RFS compared to the 55 non-CIMP cases (hazard ratio 2.9, p = 0.013). In an effort to develop a preliminary outcome predictor, a 155-marker subset correlated with RFS was identified in the test dataset. When interrogated in the validation dataset, this 155-marker subset showed a statistical trend (p < 0.1) towards distinguishing survival groups. CONCLUSIONS: This study defines the existence of a CIMP phenotype in meningioma, which involves a substantial proportion (37/92, 40%) of samples with clinical implications. Ongoing work will expand this cohort and examine identification of additional biologic differences (mutational and DNA copy number analysis) to further characterize the aberrant methylation subtype in meningioma. CIMP-positivity with aberrant methylation in recurrent/malignant meningioma suggests a potential therapeutic target for clinically aggressive cases.

A comparison of the new international diabetes federation definition of metabolic syndrome to WHO and NCEP definitions in Chinese, European and South Asian origin adults.

PubMed

Unwin, Nigel; Bhopal, Raj; Hayes, Louise; White, Martin; Patel, Sheila; Ragoobirsingh, Dalip; Alberti, George

2007-01-01

To compare the prevalence, agreement and phenotypic characteristics in three ethnic groups of the new International Diabetes Federation (IDF) definition of metabolic syndrome (MS) to the World Health Organization (WHO) and national cholesterol education program (NCEP) definitions. Newcastle upon Tyne, England. Cross-sectional surveys. Chinese (171 men and 185 women), European (257 men and 301 women), and South Asian (264 men and 295 women) adults, ages 25 to 64 years. Anthropometric indices: blood pressure, fasting lipids, urine albumin-to-creatinine ratio, glucose intolerance, insulin resistance. IDF-defined MS was highly prevalent in all groups, ranging from 12.3% (95% CIs 7.4-17.2) in Chinese men to 45.5% (39.5-51.5) in South Asian men. In women, of all ethnic groups, more than 80% of those with WHO- or NCEP-defined MS also had IDF-defined MS. In men, however, agreement was less good. For example, in each ethnic group, more than a third of those with WHO-defined MS did not have IDF-defined MS. Within each ethnic group, the biological characteristics of those with MS by any definition were largely the same. However, differences existed between ethnic groups. For example, in those with IDF-defined MS, both South Asian men and women had significantly (P < .05) higher insulin resistance and significantly lower systolic and diastolic blood pressure than Europeans or Chinese. Agreement between the IDF and other definitions is better in women than men. The phenotype is similar within each ethnic group whatever the definition, but differs between groups suggesting that risks associated with MS differ by ethnic group.

Effect of Inherited Genetic Information on Stochastic Predator-Prey Model

NASA Astrophysics Data System (ADS)

Duda, Artur; Dyś, Paweł; Nowicka, Alekandra; Dudek, Mirosław R.

We discuss the Lotka-Volterra dynamics of two populations, preys and predators, in the case when the predators posses a genetic information. The genetic information is inherited according to the rules of the Penna model of genetic evolution. Each individual of the predator population is uniquely determined by sex, genotype and phenotype. In our case, the genes are represented by 8-bit integers and the phenotypes are defined with the help of the 8-state Potts model Hamiltonian. We showed that during time evolution, the population of the predators can experience a series of dynamical phase transitions which are connected with the different types of the dominant phenotypes present in the population.

Natural Variation of Drug Susceptibility in Wild-Type Human Immunodeficiency Virus Type 1

PubMed Central

Parkin, N. T.; Hellmann, N. S.; Whitcomb, J. M.; Kiss, L.; Chappey, C.; Petropoulos, C. J.

2004-01-01

Wild-type viruses from the ViroLogic phenotype-genotype database were evaluated to determine the upper confidence limit of the drug susceptibility distributions, or “biological cutoffs,” for the PhenoSense HIV phenotypic drug susceptibility assay. Definition of the natural variation in drug susceptibility in wild-type human immunodeficiency virus (HIV) type 1 isolates is necessary to determine the prevalence of innate drug resistance and to assess the capability of the PhenoSense assay to reliably measure subtle reductions in drug susceptibility. The biological cutoffs for each drug, defined by the 99th percentile of the fold change in the 50% inhibitory concentration distributions or the mean fold change plus 2 standard deviations, were lower than those previously reported for other phenotypic assays and lower than the clinically relevant cutoffs previously defined for the PhenoSense assay. The 99th percentile fold change values ranged from 1.2 (tenofovir) to 1.8 (zidovudine) for nucleoside reverse transcriptase RT inhibitors (RTIs), from 3.0 (efavirenz) to 6.2 (delavirdine) for nonnucleoside RTIs, and from 1.6 (lopinavir) to 3.6 (nelfinavir) for protease inhibitors. To evaluate the potential role of intrinsic assay variability in the observed variations in the drug susceptibilities of wild-type isolates, 10 reference viruses with different drug susceptibility patterns were tested 8 to 30 times each. The median coefficients of variation in fold change for the reference viruses ranged from 12 to 18% for all drugs except zidovudine (32%), strongly suggesting that the observed differences in wild-type virus susceptibility to the different drugs is related to intrinsic virus variability rather than assay variability. The low biological cutoffs and assay variability suggest that the PhenoSense HIV assay may assist in defining clinically relevant susceptibility cutoffs for resistance to antiretroviral drugs. PMID:14742192

Systems properties of the Haemophilus influenzae Rd metabolic genotype.

PubMed

Edwards, J S; Palsson, B O

1999-06-18

Haemophilus influenzae Rd was the first free-living organism for which the complete genomic sequence was established. The annotated sequence and known biochemical information was used to define the H. influenzae Rd metabolic genotype. This genotype contains 488 metabolic reactions operating on 343 metabolites. The stoichiometric matrix was used to determine the systems characteristics of the metabolic genotype and to assess the metabolic capabilities of H. influenzae. The need to balance cofactor and biosynthetic precursor production during growth on mixed substrates led to the definition of six different optimal metabolic phenotypes arising from the same metabolic genotype, each with different constraining features. The effects of variations in the metabolic genotype were also studied, and it was shown that the H. influenzae Rd metabolic genotype contains redundant functions under defined conditions. We thus show that the synthesis of in silico metabolic genotypes from annotated genome sequences is possible and that systems analysis methods are available that can be used to analyze and interpret phenotypic behavior of such genotypes.

Defining the landscape of adaptive genetic diversity.

PubMed

Eckert, Andrew J; Dyer, Rodney J

2012-06-01

Whether they are used to describe fitness, genome architecture or the spatial distribution of environmental variables, the concept of a landscape has figured prominently in our collective reasoning. The tradition of landscapes in evolutionary biology is one of fitness mapped onto axes defined by phenotypes or molecular sequence states. The characteristics of these landscapes depend on natural selection, which is structured across both genomic and environmental landscapes, and thus, the bridge among differing uses of the landscape concept (i.e. metaphorically or literally) is that of an adaptive phenotype and its distribution across geographical landscapes in relation to selective pressures. One of the ultimate goals of evolutionary biology should thus be to construct fitness landscapes in geographical space. Natural plant populations are ideal systems with which to explore the feasibility of attaining this goal, because much is known about the quantitative genetic architecture of complex traits for many different plant species. What is less known are the molecular components of this architecture. In this issue of Molecular Ecology, Parchman et al. (2012) pioneer one of the first truly genome-wide association studies in a tree that moves us closer to this form of mechanistic understanding for an adaptive phenotype in natural populations of lodgepole pine (Pinus contorta Dougl. ex Loud.). © 2012 Blackwell Publishing Ltd.

The polycystic ovary syndrome: a position statement from the European Society of Endocrinology.

PubMed

Conway, Gerard; Dewailly, Didier; Diamanti-Kandarakis, Evanthia; Escobar-Morreale, Héctor F; Franks, Stephen; Gambineri, Alessandra; Kelestimur, Fahrettin; Macut, Djuro; Micic, Dragan; Pasquali, Renato; Pfeifer, Marija; Pignatelli, Duarte; Pugeat, Michel; Yildiz, Bulent O

2014-10-01

Polycystic ovary syndrome (PCOS) is the most common ovarian disorder associated with androgen excess in women, which justifies the growing interest of endocrinologists. Great efforts have been made in the last 2 decades to define the syndrome. The presence of three different definitions for the diagnosis of PCOS reflects the phenotypic heterogeneity of the syndrome. Major criteria are required for the diagnosis, which in turn identifies different phenotypes according to the combination of different criteria. In addition, the relevant impact of metabolic issues, specifically insulin resistance and obesity, on the pathogenesis of PCOS, and the susceptibility to develop earlier than expected glucose intolerance states, including type 2 diabetes, has supported the notion that these aspects should be considered when defining the PCOS phenotype and planning potential therapeutic strategies in an affected subject. This paper offers a critical endocrine and European perspective on the debate on the definition of PCOS and summarises all major aspects related to aetiological factors, including early life events, potentially involved in the development of the disorder. Diagnostic tools of PCOS are also discussed, with emphasis on the laboratory evaluation of androgens and other potential biomarkers of ovarian and metabolic dysfunctions. We have also paid specific attention to the role of obesity, sleep disorders and neuropsychological aspects of PCOS and on the relevant pathogenetic aspects of cardiovascular risk factors. In addition, we have discussed how to target treatment choices based according to the phenotype and individual patient's needs. Finally, we have suggested potential areas of translational and clinical research for the future with specific emphasis on hormonal and metabolic aspects of PCOS. © 2014 European Society of Endocrinology.

MAGNAMWAR: an R package for genome-wide association studies of bacterial orthologs.

PubMed

Sexton, Corinne E; Smith, Hayden Z; Newell, Peter D; Douglas, Angela E; Chaston, John M

2018-06-01

Here we report on an R package for genome-wide association studies of orthologous genes in bacteria. Before using the software, orthologs from bacterial genomes or metagenomes are defined using local or online implementations of OrthoMCL. These presence-absence patterns are statistically associated with variation in user-collected phenotypes using the Mono-Associated GNotobiotic Animals Metagenome-Wide Association R package (MAGNAMWAR). Genotype-phenotype associations can be performed with several different statistical tests based on the type and distribution of the data. MAGNAMWAR is available on CRAN. john_chaston@byu.edu.

Exhaustive Analysis of a Genotype Space Comprising 1015 Central Carbon Metabolisms Reveals an Organization Conducive to Metabolic Innovation

PubMed Central

Hosseini, Sayed-Rzgar; Barve, Aditya; Wagner, Andreas

2015-01-01

All biological evolution takes place in a space of possible genotypes and their phenotypes. The structure of this space defines the evolutionary potential and limitations of an evolving system. Metabolism is one of the most ancient and fundamental evolving systems, sustaining life by extracting energy from extracellular nutrients. Here we study metabolism’s potential for innovation by analyzing an exhaustive genotype-phenotype map for a space of 1015 metabolisms that encodes all possible subsets of 51 reactions in central carbon metabolism. Using flux balance analysis, we predict the viability of these metabolisms on 10 different carbon sources which give rise to 1024 potential metabolic phenotypes. Although viable metabolisms with any one phenotype comprise a tiny fraction of genotype space, their absolute numbers exceed 109 for some phenotypes. Metabolisms with any one phenotype typically form a single network of genotypes that extends far or all the way through metabolic genotype space, where any two genotypes can be reached from each other through a series of single reaction changes. The minimal distance of genotype networks associated with different phenotypes is small, such that one can reach metabolisms with novel phenotypes – viable on new carbon sources – through one or few genotypic changes. Exceptions to these principles exist for those metabolisms whose complexity (number of reactions) is close to the minimum needed for viability. Increasing metabolic complexity enhances the potential for both evolutionary conservation and evolutionary innovation. PMID:26252881

Emerging molecular phenotypes of asthma

PubMed Central

Ray, Anuradha; Oriss, Timothy B.

2014-01-01

Although asthma has long been considered a heterogeneous disease, attempts to define subgroups of asthma have been limited. In recent years, both clinical and statistical approaches have been utilized to better merge clinical characteristics, biology, and genetics. These combined characteristics have been used to define phenotypes of asthma, the observable characteristics of a patient determined by the interaction of genes and environment. Identification of consistent clinical phenotypes has now been reported across studies. Now the addition of various 'omics and identification of specific molecular pathways have moved the concept of clinical phenotypes toward the concept of molecular phenotypes. The importance of these molecular phenotypes is being confirmed through the integration of molecularly targeted biological therapies. Thus the global term asthma is poised to become obsolete, being replaced by terms that more specifically identify the pathology associated with the disease. PMID:25326577

POLG1 mutations and stroke like episodes: a distinct clinical entity rather than an atypical MELAS syndrome.

PubMed

Cheldi, Antonella; Ronchi, Dario; Bordoni, Andreina; Bordo, Bianca; Lanfranconi, Silvia; Bellotti, Maria Grazia; Corti, Stefania; Lucchini, Valeria; Sciacco, Monica; Moggio, Maurizio; Baron, Pierluigi; Comi, Giacomo Pietro; Colombo, Antonio; Bersano, Anna

2013-01-15

POLG1 mutations have been associated with MELAS-like phenotypes. However given several clinical differences it is unknown whether POLG1 mutations are possible causes of MELAS or give raise to a distinct clinical and genetic entity, named POLG1-associated encephalopathy. We describe a 74 years old man carrying POLG1 mutations presenting with strokes, myopathy and ragged red fibers with some atypical aspects for MELAS such as late onset, lack of cerebral calcification and presence of frontal and occipital MRI lesions better consistent with the POLG associated-encephalopathy spectrum. The lack of available data hampers a definite diagnosis in our patient as well as makes it difficult to compare MELAS, which is a clearly defined clinical syndrome, with POLG1-associated encephalopathy, which is so far a purely molecularly defined syndrome with a quite heterogeneous clinical picture. However, the present report contributes to expand the phenotypic spectrum of POLG1 mutations underlining the importance of searching POLG1 mutations in patients with mitochondrial signs and MELAS like phenotypes but negative for common mtDNA mutations.

Validation of electronic medical record-based phenotyping algorithms: results and lessons learned from the eMERGE network.

PubMed

Newton, Katherine M; Peissig, Peggy L; Kho, Abel Ngo; Bielinski, Suzette J; Berg, Richard L; Choudhary, Vidhu; Basford, Melissa; Chute, Christopher G; Kullo, Iftikhar J; Li, Rongling; Pacheco, Jennifer A; Rasmussen, Luke V; Spangler, Leslie; Denny, Joshua C

2013-06-01

Genetic studies require precise phenotype definitions, but electronic medical record (EMR) phenotype data are recorded inconsistently and in a variety of formats. To present lessons learned about validation of EMR-based phenotypes from the Electronic Medical Records and Genomics (eMERGE) studies. The eMERGE network created and validated 13 EMR-derived phenotype algorithms. Network sites are Group Health, Marshfield Clinic, Mayo Clinic, Northwestern University, and Vanderbilt University. By validating EMR-derived phenotypes we learned that: (1) multisite validation improves phenotype algorithm accuracy; (2) targets for validation should be carefully considered and defined; (3) specifying time frames for review of variables eases validation time and improves accuracy; (4) using repeated measures requires defining the relevant time period and specifying the most meaningful value to be studied; (5) patient movement in and out of the health plan (transience) can result in incomplete or fragmented data; (6) the review scope should be defined carefully; (7) particular care is required in combining EMR and research data; (8) medication data can be assessed using claims, medications dispensed, or medications prescribed; (9) algorithm development and validation work best as an iterative process; and (10) validation by content experts or structured chart review can provide accurate results. Despite the diverse structure of the five EMRs of the eMERGE sites, we developed, validated, and successfully deployed 13 electronic phenotype algorithms. Validation is a worthwhile process that not only measures phenotype performance but also strengthens phenotype algorithm definitions and enhances their inter-institutional sharing.

Cross-validation of clinical characteristics and treatment patterns associated with phenotypes for lithium response defined by the Alda scale.

PubMed

Scott, Jan; Geoffroy, Pierre Alexis; Sportiche, Sarah; Brichant-Petit-Jean, Clara; Gard, Sebastien; Kahn, Jean-Pierre; Azorin, Jean-Michel; Henry, Chantal; Etain, Bruno; Bellivier, Frank

2017-01-15

It is increasingly recognised that reliable and valid assessments of lithium response are needed in order to target more efficiently the use of this medication in bipolar disorders (BD) and to identify genotypes, endophenotypes and biomarkers of response. In a large, multi-centre, clinically representative sample of 300 cases of BD, we assess external clinical validators of lithium response phenotypes as defined using three different recommended approaches to scoring the Alda lithium response scale. The scale comprises an A scale (rating lithium response) and a B scale (assessing confounders). Analysis of the two continuous scoring methods (A scale score minus the B scale score, or A scale score in those with a low B scale score) demonstrated that 21-23% of the explained variance in lithium response was accounted for by a positive family history of BD I and the early introduction of lithium. Categorical definitions of response suggest poor response is also associated with a positive history of alcohol and/or substance use comorbidities. High B scale scores were significantly associated with longer duration of illness prior to receiving lithium and the presence of psychotic symptoms. The original sample was not recruited specifically to study lithium response. The Alda scale is designed to assess response retrospectively. This cross-validation study identifies different clinical phenotypes of lithium response when defined by continuous or categorical measures. Future clinical, genetic and biomarker studies should report both the findings and the method employed to assess lithium response according to the Alda scale. Copyright © 2016 Elsevier B.V. All rights reserved.

The effects of graded levels of calorie restriction: IV. Non-linear change in behavioural phenotype of mice in response to short-term calorie restriction.

PubMed

Lusseau, David; Mitchell, Sharon E; Barros, Ceres; Derous, Davina; Green, Cara; Chen, Luonan; Han, Jing-Dong Jackie; Wang, Yingchun; Promislow, Daniel E L; Douglas, Alex; Speakman, John R

2015-08-25

Animals have to adjust their activities when faced with caloric restriction (CR) to deal with reduced energy intake. If CR is pronounced, allostasis can push individuals into alternate physiological states which can result in important health benefits across a wide range of taxa. Here we developed a new approach to determine the changes in behavioural phenotype associated with different levels of CR. We exposed C57BL/6 male mice to graded CR (from 0 to 40%) for three months and defined their behavioural phenotype using hidden Markov models of their movement and body temperature. All 40% CR mice exhibited a state-shift in behavioural phenotype and only some exposed to 30% CR did. We show for the first time that mice changed their activity characteristics rather than changed their activities. This new phenotyping approach provides an avenue to determine the mechanisms linking CR to healthspan.

Fold or hold: experimental evolution in vitro

PubMed Central

Collins, S; Rambaut, A; Bridgett, S J

2013-01-01

We introduce a system for experimental evolution consisting of populations of short oligonucleotides (Oli populations) evolving in a modified quantitative polymerase chain reaction (qPCR). It is tractable at the genetic, genomic, phenotypic and fitness levels. The Oli system uses DNA hairpins designed to form structures that self-prime under defined conditions. Selection acts on the phenotype of self-priming, after which differences in fitness are amplified and quantified using qPCR. We outline the methodological and bioinformatics tools for the Oli system here and demonstrate that it can be used as a conventional experimental evolution model system by test-driving it in an experiment investigating adaptive evolution under different rates of environmental change. PMID:24003997

Short communication: Cytokine profiles from blood mononuclear cells of dairy cows classified with divergent immune response phenotypes.

PubMed

Martin, C E; Paibomesai, M A; Emam, S M; Gallienne, J; Hine, B C; Thompson-Crispi, K A; Mallard, B A

2016-03-01

Genetic selection for enhanced immune response has been shown to decrease disease occurrence in dairy cattle. Cows can be classified as high (H), average, or low responders based on antibody-mediated immune response (AMIR), predominated by type-2 cytokine production, and cell-mediated immune response (CMIR) through estimated breeding values for these traits. The purpose of this study was to identify in vitro tests that correlate with in vivo immune response phenotyping in dairy cattle. Blood mononuclear cells (BMC) isolated from cows classified as H-AMIR and H-CMIR through estimated breeding values for immune response traits were stimulated with concanavalin A (ConA; Sigma Aldrich, St. Louis, MO) and gene expression, cytokine production, and cell proliferation was determined at multiple time points. A repeated measures model, which included the effects of immune response group, parity, and stage of lactation, was used to compare differences between immune response phenotype groups. The H-AMIR cows produced more IL-4 protein than H-CMIR cows at 48 h; however, no difference in gene expression of type-2 transcription factor GATA3 or IL4 was noted. The BMC from H-CMIR cows had increased production of IFN-γ protein at 48, 72, and 96 h compared with H-AMIR animals. Further, H-CMIR cows had increased expression of the IFNG gene at 16, 24, and 48 h post-treatment with ConA, although expression of the type-1 transcription factor gene TBX21 did not differ between immune response groups. Although proliferation of BMC increased from 24 to 72 h after ConA stimulation, no differences were found between the immune response groups. Overall, stimulation of H-AMIR and H-CMIR bovine BMC with ConA resulted in distinct cytokine production profiles according to genetically defined groups. These distinct cytokine profiles could be used to define disease resistance phenotypes in dairy cows according to stimulation in vitro; however, other immune response phenotypes should be assessed. Copyright © 2016 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Sarcoidosis extent relates to molecular variability.

PubMed

Monast, C S; Li, K; Judson, M A; Baughman, R P; Wadman, E; Watt, R; Silkoff, P E; Barnathan, E S; Brodmerkel, C

2017-06-01

The molecular basis of sarcoidosis phenotype heterogeneity and its relationship to effective treatment of sarcoidosis have not been elucidated. Peripheral samples from sarcoidosis subjects who participated in a Phase II study of golimumab [anti-tumour necrosis factor (TNF)-α] and ustekinumab [anti-interleukin (IL)-12p40] were used to measure the whole blood transcriptome and levels of serum proteins. Differential gene and protein expression analyses were used to explore the molecular differences between sarcoidosis phenotypes as defined by extent of organ involvement. The same data were also used in conjunction with an enrichment algorithm to identify gene expression changes associated with treatment with study drugs compared to placebo. Our analyses revealed marked heterogeneity among the three sarcoidosis phenotypes included in the study cohort, including striking differences in enrichment of the interferon pathway. Conversely, enrichments of multiple pathways, including T cell receptor signalling, were similar among phenotypes. We also identify differences between treatment with golimumab and ustekinumab that may explain the differences in trends for clinical efficacy observed in the trial. We find that molecular heterogeneity is associated with sarcoidosis in a manner that may be related to the extent of organ involvement. These findings may help to explain the difficulty in identifying clinically efficacious sarcoidosis treatments and suggest hypotheses for improved therapeutic strategies. © 2017 British Society for Immunology.

Using species distribution models to define nesting habitat of the eastern metapopulation of double-crested cormorants.

PubMed

Sheehan, Kate L; Esswein, Samuel T; Dorr, Brian S; Yarrow, Greg K; Johnson, Ron J

2017-01-01

When organisms with similar phenotypes have conflicting management and conservation initiatives, approaches are needed to differentiate among subpopulations or discrete groups. For example, the eastern metapopulation of the double-crested cormorant ( Phalacrocorax auritus ) has a migratory phenotype that is culled because they are viewed as a threat to commercial and natural resources, whereas resident birds are targeted for conservation. Understanding the distinct breeding habitats of resident versus migratory cormorants would aid in identification and management decisions. Here, we use species distribution models (SDM: Maxent) of cormorant nesting habitat to examine the eastern P. auritus metapopulation and the predicted breeding sites of its phenotypes. We then estimate the phenotypic identity of breeding colonies of cormorants where management plans are being developed. We transferred SDMs trained on data from resident bird colonies in Florida and migratory bird colonies in Minnesota to South Carolina in an effort to identify the phenotype of breeding cormorants there based on the local landscape characteristics. Nesting habitat characteristics of cormorant colonies in South Carolina more closely resembled those of the Florida phenotype than those of birds of the Minnesota phenotype. The presence of the resident phenotype in summer suggests that migratory and resident cormorants will co-occur in South Carolina in winter. Thus, there is an opportunity for separate management strategies for the two phenotypes in that state. We found differences in nesting habitat characteristics that could be used to refine management strategies and reduce human conflicts with abundant winter migrants and, at the same time, conserve less common colonies of resident cormorants. The models we use here show potential for advancing the study of geographically overlapping phenotypes with differing conservation and management priorities.

Leveraging Collaborative Filtering to Accelerate Rare Disease Diagnosis

PubMed Central

Shen, Feichen; Liu, Sijia; Wang, Yanshan; Wang, Liwei; Afzal, Naveed; Liu, Hongfang

2017-01-01

In the USA, rare diseases are defined as those affecting fewer than 200,000 patients at any given time. Patients with rare diseases are frequently misdiagnosed or undiagnosed which may due to the lack of knowledge and experience of care providers. We hypothesize that patients’ phenotypic information available in electronic medical records (EMR) can be leveraged to accelerate disease diagnosis based on the intuition that providers need to document associated phenotypic information to support the diagnosis decision, especially for rare diseases. In this study, we proposed a collaborative filtering system enriched with natural language processing and semantic techniques to assist rare disease diagnosis based on phenotypic characterization. Specifically, we leveraged four similarity measurements with two neighborhood algorithms on 2010-2015 Mayo Clinic unstructured large patient cohort and evaluated different approaches. Preliminary results demonstrated that the use of collaborative filtering with phenotypic information is able to stratify patients with relatively similar rare diseases. PMID:29854225

Leveraging Collaborative Filtering to Accelerate Rare Disease Diagnosis.

PubMed

Shen, Feichen; Liu, Sijia; Wang, Yanshan; Wang, Liwei; Afzal, Naveed; Liu, Hongfang

2017-01-01

In the USA, rare diseases are defined as those affecting fewer than 200,000 patients at any given time. Patients with rare diseases are frequently misdiagnosed or undiagnosed which may due to the lack of knowledge and experience of care providers. We hypothesize that patients' phenotypic information available in electronic medical records (EMR) can be leveraged to accelerate disease diagnosis based on the intuition that providers need to document associated phenotypic information to support the diagnosis decision, especially for rare diseases. In this study, we proposed a collaborative filtering system enriched with natural language processing and semantic techniques to assist rare disease diagnosis based on phenotypic characterization. Specifically, we leveraged four similarity measurements with two neighborhood algorithms on 2010-2015 Mayo Clinic unstructured large patient cohort and evaluated different approaches. Preliminary results demonstrated that the use of collaborative filtering with phenotypic information is able to stratify patients with relatively similar rare diseases.

Phenotypes in defined genotypes including siblings with Usher syndrome.

PubMed

Malm, Eva; Ponjavic, Vesna; Möller, Claes; Kimberling, William J; Andréasson, Sten

2011-06-01

To characterize visual function in defined genotypes including siblings with Usher syndrome. Thirteen patients with phenotypically different subtypes of Usher syndrome, including 3 families with affected siblings, were selected. Genetic analysis and ophthalmological examinations including visual fields, full-field electroretinography (ERG), multifocal electroretinography (mf ERG), and optical coherence tomography (OCT) were assessed. The patients' degree of visual handicap was evaluated by a questionnaire (ADL). Twelve of thirteen patients were genotyped as Usher 1B, 1D, 1F, 2A, 2C or 3A. In 12 of 13 patients examined with ERG the 30 Hz flickering light response revealed remaining cone function. In 3 of the patients with Usher type 1 mf ERG demonstrated a specific pattern, with a sharp distinction between the area with reduced function and the central area with remaining macular function and normal peak time. OCT demonstrated loss of foveal depression with distortion of the foveal architecture in the macula in all patients. The foveal thickness ranged from 159 to 384 µm and was not correlated to retinal function. Three siblings shared the same mutation for Usher 2C but in contrast to previous reports regarding this genotype, 1 of them diverged in phenotype with substantially normal visual fields, almost normal OCT and mf ERG findings, and only moderately reduced rod and cone function according to ERG. Evaluation of visual function comprising both the severity of the rod cone degeneration and the function in the macular region confirm phenotypical heterogeneity within siblings and between different genotypes of Usher syndrome.

Redefining Aging in HIV Infection Using Phenotypes.

PubMed

Stoff, David M; Goodkin, Karl; Jeste, Dilip; Marquine, Maria

2017-10-01

This article critically reviews the utility of "phenotypes" as behavioral descriptors in aging/HIV research that inform biological underpinnings and treatment development. We adopt a phenotypic redefinition of aging conceptualized within a broader context of HIV infection and of aging. Phenotypes are defined as dimensions of behavior, closely related to fundamental mechanisms, and, thus, may be more informative than chronological age. Primary emphasis in this review is given to comorbid aging and cognitive aging, though other phenotypes (i.e., disability, frailty, accelerated aging, successful aging) are also discussed in relation to comorbid aging and cognitive aging. The main findings that emerged from this review are as follows: (1) the phenotypes, comorbid aging and cognitive aging, are distinct from each other, yet overlapping; (2) associative relationships are the rule in HIV for comorbid and cognitive aging phenotypes; and (3) HIV behavioral interventions for both comorbid aging and cognitive aging have been limited. Three paths for research progress are identified for phenotype-defined aging/HIV research (i.e., clinical and behavioral specification, biological mechanisms, intervention targets), and some important research questions are suggested within each of these research paths.

Use of the serum anti-Müllerian hormone assay as a surrogate for polycystic ovarian morphology: impact on diagnosis and phenotypic classification of polycystic ovary syndrome.

PubMed

Fraissinet, Alice; Robin, Geoffroy; Pigny, Pascal; Lefebvre, Tiphaine; Catteau-Jonard, Sophie; Dewailly, Didier

2017-08-01

Does the use of the serum anti-Müllerian hormone (AMH) assay to replace or complement ultrasound (U/S) affect the diagnosis or phenotypic distribution of polycystic ovary syndrome (PCOS)? Combining U/S and the serum AMH assay to define polycystic ovarian morphology (PCOM) diagnoses PCOS (according to the Rotterdam classification) in more patients than definitions using one or the other of these indicators exclusively. Since 2003, PCOM, as defined by U/S, is one of the three diagnostic criteria for PCOS. As it is closely correlated with follicle excess seen at U/S, an excessive serum AMH level could be used as a surrogate for PCOM. Single-center retrospective study from a database of prospectively collected clinical, laboratory and ultrasound data from patients referred for oligo-anovulation (OA) and/or hyperandrogenism (HA) between January 2009 and January 2016. The standard Rotterdam classification for PCOS was tested against two modified versions that defined PCOM by either excessive serum AMH level alone (AMH-only) or a combination (i.e. 'and/or') of the latter and U/S. The PCOS phenotypes were defined as A (full phenotype, OA+HA+PCOM), B (OA+HA), C (HA+PCOM) and D (OA+PCOM). PCOS was more frequently diagnosed when PCOM was defined as the combination 'positive U/S' and/or 'positive AMH' (n = 639) than by either only U/S-only (standard definition, n = 612) or by AMH-only (n = 601). With this combination, PCOM was recognized in 637 of the 639 cases that met the Rotterdam classification, and phenotype B practically disappeared. In this population, U/S and AMH markers were discordant for PCOM in 103 (16.1%) cases (9% U/S-only, 7.1% AMH-only, P = 0.159). The markers used had no other significant impact on the phenotypic distribution (except for phenotype B). However, the percentage of cases positive by U/S-only was significantly higher in phenotype D than in phenotype A (14.1% vs. 5.8%, P < 0.05). Furthermore, in the discordant cases, plasma LH levels were significantly higher in the AMH-only group than in the concordant cases, and fasting insulin serum levels tended to be higher in the U/S-only group. This is a retrospective study. A referral bias explains the relatively high proportion of patients with phenotype D (28%). PCOM was defined by in-house thresholds. The AMH assay used is no longer commercially available. Our results suggest that ideally both U/S data and serum AMH level should be integrated to define PCOM in the Rotterdam classification. In a cost-effectiveness approach, the choice of one or the other has little impact on the diagnosis and the phenotyping of PCOS. No external funding. The authors have no conflict of interest to declare. © The Author 2017. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com

Defining disease phenotypes using national linked electronic health records: a case study of atrial fibrillation.

PubMed

Morley, Katherine I; Wallace, Joshua; Denaxas, Spiros C; Hunter, Ross J; Patel, Riyaz S; Perel, Pablo; Shah, Anoop D; Timmis, Adam D; Schilling, Richard J; Hemingway, Harry

2014-01-01

National electronic health records (EHR) are increasingly used for research but identifying disease cases is challenging due to differences in information captured between sources (e.g. primary and secondary care). Our objective was to provide a transparent, reproducible model for integrating these data using atrial fibrillation (AF), a chronic condition diagnosed and managed in multiple ways in different healthcare settings, as a case study. Potentially relevant codes for AF screening, diagnosis, and management were identified in four coding systems: Read (primary care diagnoses and procedures), British National Formulary (BNF; primary care prescriptions), ICD-10 (secondary care diagnoses) and OPCS-4 (secondary care procedures). From these we developed a phenotype algorithm via expert review and analysis of linked EHR data from 1998 to 2010 for a cohort of 2.14 million UK patients aged ≥ 30 years. The cohort was also used to evaluate the phenotype by examining associations between incident AF and known risk factors. The phenotype algorithm incorporated 286 codes: 201 Read, 63 BNF, 18 ICD-10, and four OPCS-4. Incident AF diagnoses were recorded for 72,793 patients, but only 39.6% (N = 28,795) were recorded in primary care and secondary care. An additional 7,468 potential cases were inferred from data on treatment and pre-existing conditions. The proportion of cases identified from each source differed by diagnosis age; inferred diagnoses contributed a greater proportion of younger cases (≤ 60 years), while older patients (≥ 80 years) were mainly diagnosed in SC. Associations of risk factors (hypertension, myocardial infarction, heart failure) with incident AF defined using different EHR sources were comparable in magnitude to those from traditional consented cohorts. A single EHR source is not sufficient to identify all patients, nor will it provide a representative sample. Combining multiple data sources and integrating information on treatment and comorbid conditions can substantially improve case identification.

Biological aspects of gender disorders.

PubMed

Corsello, S M; Di Donna, V; Senes, P; Luotto, V; Ricciato, M P; Paragliola, R M; Pontecorvi, A

2011-12-01

The scientific community is very interested in the biological aspects of gender disorders and sexual orientation. There are different levels to define an individual's sex: chromosomal, gonadic, and phenotypic sex. Concerning the psychological sex, men and women are different by virtue of their own gender identity, which means they recognize themselves as belonging to a determinate sex. They are different also as a result of their own role identity, a set of behaviors, tendencies, and cognitive and emotional attitudes, commonly defined as "male" and "female". Transsexuality is a disorder characterized by the development of a gender identity opposed to phenotypic sex, whereas homosexuality is not a disturbance of gender identity but only of sexual attraction, expressing sexual orientation towards people of the same sex. We started from a critical review of literature on genetic and hormonal mechanisms involved in sexual differentiation. We re-examined the neuro-anatomic and functional differences between men and women, with special reference to their role in psychosexual differentiation and to their possible implication in the genesis of homosexuality and identity gender disorders. Homosexuality and transsexuality are conditions without a well defined etiology. Although the influence of educational and environmental factors in humans is undeniable, it seems that organic neurohormonal prenatal and postnatal factors might contribute in a determinant way in the development of these two conditions. This "organicistic neurohormal theory" might find support in the study of particular situations in which the human fetus is exposed to an abnormal hormonal environment in utero.

Continuation-like semantics for modeling structural process anomalies

PubMed Central

2012-01-01

Background Biomedical ontologies usually encode knowledge that applies always or at least most of the time, that is in normal circumstances. But for some applications like phenotype ontologies it is becoming increasingly important to represent information about aberrations from a norm. These aberrations may be modifications of physiological structures, but also modifications of biological processes. Methods To facilitate precise definitions of process-related phenotypes, such as delayed eruption of the primary teeth or disrupted ocular pursuit movements, I introduce a modeling approach that draws inspiration from the use of continuations in the analysis of programming languages and apply a similar idea to ontological modeling. This approach characterises processes by describing their outcome up to a certain point and the way they will continue in the canonical case. Definitions of process types are then given in terms of their continuations and anomalous phenotypes are defined by their differences to the canonical definitions. Results The resulting model is capable of accurately representing structural process anomalies. It allows distinguishing between different anomaly kinds (delays, interruptions), gives identity criteria for interrupted processes, and explains why normal and anomalous process instances can be subsumed under a common type, thus establishing the connection between canonical and anomalous process-related phenotypes. Conclusion This paper shows how to to give semantically rich definitions of process-related phenotypes. These allow to expand the application areas of phenotype ontologies beyond literature annotation and establishment of genotype-phenotype associations to the detection of anomalies in suitably encoded datasets. PMID:23046705

Identification of clinical phenotypes in knee osteoarthritis: a systematic review of the literature.

PubMed

Dell'Isola, A; Allan, R; Smith, S L; Marreiros, S S P; Steultjens, M

2016-10-12

Knee Osteoarthritis (KOA) is a heterogeneous pathology characterized by a complex and multifactorial nature. It has been hypothesised that these differences are due to the existence of underlying phenotypes representing different mechanisms of the disease. The aim of this study is to identify the current evidence for the existence of groups of variables which point towards the existence of distinct clinical phenotypes in the KOA population. A systematic literature search in PubMed was conducted. Only original articles were selected if they aimed to identify phenotypes of patients aged 18 years or older with KOA. The methodological quality of the studies was independently assessed by two reviewers and qualitative synthesis of the evidence was performed. Strong evidence for existence of specific phenotypes was considered present if the phenotype was supported by at least two high-quality studies. A total of 24 studies were included. Through qualitative synthesis of evidence, six main sets of variables proposing the existence of six phenotypes were identified: 1) chronic pain in which central mechanisms (e.g. central sensitisation) are prominent; 2) inflammatory (high levels of inflammatory biomarkers); 3) metabolic syndrome (high prevalence of obesity, diabetes and other metabolic disturbances); 4) Bone and cartilage metabolism (alteration in local tissue metabolism); 5) mechanical overload characterised primarily by varus malalignment and medial compartment disease; and 6) minimal joint disease characterised as minor clinical symptoms with slow progression over time. This study identified six distinct groups of variables which should be explored in attempts to better define clinical phenotypes in the KOA population.

Topological Structure of the Space of Phenotypes: The Case of RNA Neutral Networks

PubMed Central

Aguirre, Jacobo; Buldú, Javier M.; Stich, Michael; Manrubia, Susanna C.

2011-01-01

The evolution and adaptation of molecular populations is constrained by the diversity accessible through mutational processes. RNA is a paradigmatic example of biopolymer where genotype (sequence) and phenotype (approximated by the secondary structure fold) are identified in a single molecule. The extreme redundancy of the genotype-phenotype map leads to large ensembles of RNA sequences that fold into the same secondary structure and can be connected through single-point mutations. These ensembles define neutral networks of phenotypes in sequence space. Here we analyze the topological properties of neutral networks formed by 12-nucleotides RNA sequences, obtained through the exhaustive folding of sequence space. A total of 412 sequences fragments into 645 subnetworks that correspond to 57 different secondary structures. The topological analysis reveals that each subnetwork is far from being random: it has a degree distribution with a well-defined average and a small dispersion, a high clustering coefficient, and an average shortest path between nodes close to its minimum possible value, i.e. the Hamming distance between sequences. RNA neutral networks are assortative due to the correlation in the composition of neighboring sequences, a feature that together with the symmetries inherent to the folding process explains the existence of communities. Several topological relationships can be analytically derived attending to structural restrictions and generic properties of the folding process. The average degree of these phenotypic networks grows logarithmically with their size, such that abundant phenotypes have the additional advantage of being more robust to mutations. This property prevents fragmentation of neutral networks and thus enhances the navigability of sequence space. In summary, RNA neutral networks show unique topological properties, unknown to other networks previously described. PMID:22028856

How should treatment approaches differ depending on the severity of asthma?

PubMed

Kupczyk, Maciej; Kuna, Piotr

2017-12-01

Asthma is nowadays regarded as a syndrome of various overlapping phenotypes with defined clinical characteristics, different underlying inflammatory mechanisms, identifiable genetic background, environmental risk factors and possible biomarkers. There are no doubts that due to the diversity of asthma, a 'one size fits all' management of the disease is no longer valid. Areas covered: Nowadays asthma management is based on the control of the disease, and the goals of asthma treatment are defined as good symptom control, decreased future risk of exacerbations, fixed airflow limitation, and side-effects of treatment. Alternative strategies for adjusting asthma treatment such as sputum or exhaled nitric oxide guided protocols have been evaluated and despite some effectiveness, are regarded as impractical in every-day clinical conditions. Further studies in the field of asthma phenotypes/endotypes and biomarkers are warranted with the main goal to define which of those possible subgroups will be useful in clinical practice in regards to the potential allocation of successful treatment. Expert commentary: Despite the availability of guidelines on the diagnosis and management of asthma, it seems that the disease is still not optimally controlled. Addressing unmet needs in every day care, improving education, adherence/compliance and inhalation technique may significantly improve asthma control across all severities of the disease.

Inferring fitness landscapes and selection on phenotypic states from single-cell genealogical data

PubMed Central

Kussell, Edo

2017-01-01

Recent advances in single-cell time-lapse microscopy have revealed non-genetic heterogeneity and temporal fluctuations of cellular phenotypes. While different phenotypic traits such as abundance of growth-related proteins in single cells may have differential effects on the reproductive success of cells, rigorous experimental quantification of this process has remained elusive due to the complexity of single cell physiology within the context of a proliferating population. We introduce and apply a practical empirical method to quantify the fitness landscapes of arbitrary phenotypic traits, using genealogical data in the form of population lineage trees which can include phenotypic data of various kinds. Our inference methodology for fitness landscapes determines how reproductivity is correlated to cellular phenotypes, and provides a natural generalization of bulk growth rate measures for single-cell histories. Using this technique, we quantify the strength of selection acting on different cellular phenotypic traits within populations, which allows us to determine whether a change in population growth is caused by individual cells’ response, selection within a population, or by a mixture of these two processes. By applying these methods to single-cell time-lapse data of growing bacterial populations that express a resistance-conferring protein under antibiotic stress, we show how the distributions, fitness landscapes, and selection strength of single-cell phenotypes are affected by the drug. Our work provides a unified and practical framework for quantitative measurements of fitness landscapes and selection strength for any statistical quantities definable on lineages, and thus elucidates the adaptive significance of phenotypic states in time series data. The method is applicable in diverse fields, from single cell biology to stem cell differentiation and viral evolution. PMID:28267748

Identification and characterization of near-fatal asthma phenotypes by cluster analysis.

PubMed

Serrano-Pariente, J; Rodrigo, G; Fiz, J A; Crespo, A; Plaza, V

2015-09-01

Near-fatal asthma (NFA) is a heterogeneous clinical entity and several profiles of patients have been described according to different clinical, pathophysiological and histological features. However, there are no previous studies that identify in a unbiased way--using statistical methods such as clusters analysis--different phenotypes of NFA. Therefore, the aim of the present study was to identify and to characterize phenotypes of near fatal asthma using a cluster analysis. Over a period of 2 years, 33 Spanish hospitals enrolled 179 asthmatics admitted for an episode of NFA. A cluster analysis using two-steps algorithm was performed from data of 84 of these cases. The analysis defined three clusters of patients with NFA: cluster 1, the largest, including older patients with clinical and therapeutic criteria of severe asthma; cluster 2, with an high proportion of respiratory arrest (68%), impaired consciousness level (82%) and mechanical ventilation (93%); and cluster 3, which included younger patients, characterized by an insufficient anti-inflammatory treatment and frequent sensitization to Alternaria alternata and soybean. These results identify specific asthma phenotypes involved in NFA, confirming in part previous findings observed in studies with a clinical approach. The identification of patients with a specific NFA phenotype could suggest interventions to prevent future severe asthma exacerbations. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Increased Pilus Production Conferred by a Naturally Occurring Mutation Alters Host-Pathogen Interaction in Favor of Carriage in Streptococcus pyogenes

PubMed Central

Olsen, Randall J.; Cantu, Concepcion; Pallister, Kyler B.; Guerra, Fermin E.; Voyich, Jovanka M.; Musser, James M.

2017-01-01

ABSTRACT Studies of the human pathogen group A Streptococcus (GAS) define the carrier phenotype to be an increased ability to adhere to and persist on epithelial surfaces and a decreased ability to cause disease. We tested the hypothesis that a single amino acid change (Arg135Gly) in a highly conserved sensor kinase (LiaS) of a poorly defined GAS regulatory system contributes to a carrier phenotype through increased pilus production. When introduced into an emm serotype-matched invasive strain, the carrier allele (the gene encoding the LiaS protein with an arginine-to-glycine change at position 135 [liaSR135G]) recapitulated a carrier phenotype defined by an increased ability to adhere to mucosal surfaces and a decreased ability to cause disease. Gene transcript analyses revealed that the liaS mutation significantly altered transcription of the genes encoding pilus in the presence of bacitracin. Elimination of pilus production in the isogenic carrier mutant decreased its ability to colonize the mouse nasopharynx and to adhere to and be internalized by cultured human epithelial cells and restored the virulence phenotype in a mouse model of necrotizing fasciitis. We also observed significantly reduced survival of the isogenic carrier mutant compared to that of the parental invasive strain after exposure to human neutrophils. Elimination of pilus in the isogenic carrier mutant increased the level of survival after exposure to human neutrophils to that for the parental invasive strain. Together, our data demonstrate that the carrier mutation (liaSR135G) affects pilus expression. Our data suggest new mechanisms of pilus gene regulation in GAS and that the invasiveness associated with pilus gene regulation in GAS differs from the enhanced invasiveness associated with increased pilus production in other bacterial pathogens. PMID:28264907

Human Intellectual Disability Genes Form Conserved Functional Modules in Drosophila

PubMed Central

Oortveld, Merel A. W.; Keerthikumar, Shivakumar; Oti, Martin; Nijhof, Bonnie; Fernandes, Ana Clara; Kochinke, Korinna; Castells-Nobau, Anna; van Engelen, Eva; Ellenkamp, Thijs; Eshuis, Lilian; Galy, Anne; van Bokhoven, Hans; Habermann, Bianca; Brunner, Han G.; Zweier, Christiane; Verstreken, Patrik; Huynen, Martijn A.; Schenck, Annette

2013-01-01

Intellectual Disability (ID) disorders, defined by an IQ below 70, are genetically and phenotypically highly heterogeneous. Identification of common molecular pathways underlying these disorders is crucial for understanding the molecular basis of cognition and for the development of therapeutic intervention strategies. To systematically establish their functional connectivity, we used transgenic RNAi to target 270 ID gene orthologs in the Drosophila eye. Assessment of neuronal function in behavioral and electrophysiological assays and multiparametric morphological analysis identified phenotypes associated with knockdown of 180 ID gene orthologs. Most of these genotype-phenotype associations were novel. For example, we uncovered 16 genes that are required for basal neurotransmission and have not previously been implicated in this process in any system or organism. ID gene orthologs with morphological eye phenotypes, in contrast to genes without phenotypes, are relatively highly expressed in the human nervous system and are enriched for neuronal functions, suggesting that eye phenotyping can distinguish different classes of ID genes. Indeed, grouping genes by Drosophila phenotype uncovered 26 connected functional modules. Novel links between ID genes successfully predicted that MYCN, PIGV and UPF3B regulate synapse development. Drosophila phenotype groups show, in addition to ID, significant phenotypic similarity also in humans, indicating that functional modules are conserved. The combined data indicate that ID disorders, despite their extreme genetic diversity, are caused by disruption of a limited number of highly connected functional modules. PMID:24204314

Human intellectual disability genes form conserved functional modules in Drosophila.

PubMed

Oortveld, Merel A W; Keerthikumar, Shivakumar; Oti, Martin; Nijhof, Bonnie; Fernandes, Ana Clara; Kochinke, Korinna; Castells-Nobau, Anna; van Engelen, Eva; Ellenkamp, Thijs; Eshuis, Lilian; Galy, Anne; van Bokhoven, Hans; Habermann, Bianca; Brunner, Han G; Zweier, Christiane; Verstreken, Patrik; Huynen, Martijn A; Schenck, Annette

2013-10-01

Intellectual Disability (ID) disorders, defined by an IQ below 70, are genetically and phenotypically highly heterogeneous. Identification of common molecular pathways underlying these disorders is crucial for understanding the molecular basis of cognition and for the development of therapeutic intervention strategies. To systematically establish their functional connectivity, we used transgenic RNAi to target 270 ID gene orthologs in the Drosophila eye. Assessment of neuronal function in behavioral and electrophysiological assays and multiparametric morphological analysis identified phenotypes associated with knockdown of 180 ID gene orthologs. Most of these genotype-phenotype associations were novel. For example, we uncovered 16 genes that are required for basal neurotransmission and have not previously been implicated in this process in any system or organism. ID gene orthologs with morphological eye phenotypes, in contrast to genes without phenotypes, are relatively highly expressed in the human nervous system and are enriched for neuronal functions, suggesting that eye phenotyping can distinguish different classes of ID genes. Indeed, grouping genes by Drosophila phenotype uncovered 26 connected functional modules. Novel links between ID genes successfully predicted that MYCN, PIGV and UPF3B regulate synapse development. Drosophila phenotype groups show, in addition to ID, significant phenotypic similarity also in humans, indicating that functional modules are conserved. The combined data indicate that ID disorders, despite their extreme genetic diversity, are caused by disruption of a limited number of highly connected functional modules.

Differentiating Bipolar Disorder--Not Otherwise Specified and Severe Mood Dysregulation

ERIC Educational Resources Information Center

Towbin, Kenneth; Axelson, David; Leibenluft, Ellen; Birmaher, Boris

2013-01-01

Objective: Bipolar disorder--not otherwise specified (BP-NOS) and severe mood dysregulation (SMD) are severe mood disorders that were defined to address questions about the diagnosis of bipolar disorder (BD) in youth. SMD and BP-NOS are distinct phenotypes that differ in clinical presentation and longitudinal course. The purpose of this review is…

Mathematical Learning Disabilities in Special Populations: Phenotypic Variation and Cross-Disorder Comparisons

ERIC Educational Resources Information Center

Dennis, Maureen; Berch, Daniel B.; Mazzocco, Michele M. M.

2009-01-01

What is mathematical learning disability (MLD)? The reviews in this special issue adopt different approaches to defining the construct of MLD. Collectively, they demonstrate the current status of efforts to establish a consensus definition and the challenges faced in this endeavor. In this commentary, we reflect upon the proposed pathways to…

POLG1 mutations and stroke like episodes: a distinct clinical entity rather than an atypical MELAS syndrome

PubMed Central

2013-01-01

Background POLG1 mutations have been associated with MELAS-like phenotypes. However given several clinical differences it is unknown whether POLG1 mutations are possible causes of MELAS or give raise to a distinct clinical and genetic entity, named POLG1-associated encephalopathy. Case presentation We describe a 74 years old man carrying POLG1 mutations presenting with strokes, myopathy and ragged red fibers with some atypical aspects for MELAS such as late onset, lack of cerebral calcification and presence of frontal and occipital MRI lesions better consistent with the POLG associated-encephalopathy spectrum. Conclusion The lack of available data hampers a definite diagnosis in our patient as well as makes it difficult to compare MELAS, which is a clearly defined clinical syndrome, with POLG1-associated encephalopathy, which is so far a purely molecularly defined syndrome with a quite heterogeneous clinical picture. However, the present report contributes to expand the phenotypic spectrum of POLG1 mutations underlining the importance of searching POLG1 mutations in patients with mitochondrial signs and MELAS like phenotypes but negative for common mtDNA mutations. PMID:23324391

Vertically transmitted fecal IgA levels distinguish extra-chromosomal phenotypic variation

PubMed Central

Wallace, Meghan A.; D, Carey-Ann; Burnham; Virgin, Herbert W.; Stappenbeck, Thaddeus S.

2014-01-01

Summary The proliferation of genetically modified mouse models has exposed phenotypic variation between investigators and institutions that has been challenging to control1-5. In many cases, the microbiota is the presumed culprit of the variation. Current solutions to account for phenotypic variability include littermate and maternal controls or defined microbial consortia in gnotobiotic mice6,7. In conventionally raised mice, the microbiome is transmitted from the dam2,8,9. Here we show that microbially–driven dichotomous fecal IgA levels in WT mice within the same facility mimic the effects of chromosomal mutations. We observed in multiple facilities that vertically-transmissible bacteria in IgA-Low mice dominantly lowered fecal IgA levels in IgA-High mice after cohousing or fecal transplantation. In response to injury, IgA-Low mice showed increased damage that was transferable by fecal transplantation and driven by fecal IgA differences. We found that bacteria from IgA-Low mice degraded the secretory component (SC) of SIgA as well as IgA itself. These data indicate that phenotypic comparisons between mice must take into account the non-chromosomal hereditary variation between different breeders. We propose fecal IgA as one marker of microbial variability and conclude that cohousing and/or fecal transplantation enables analysis of progeny from different dams. PMID:25686606

Mapping the functional landscape of frequent phenylalanine hydroxylase (PAH) genotypes promotes personalised medicine in phenylketonuria.

PubMed

Danecka, Marta K; Woidy, Mathias; Zschocke, Johannes; Feillet, François; Muntau, Ania C; Gersting, Søren W

2015-03-01

In phenylketonuria, genetic heterogeneity, frequent compound heterozygosity, and the lack of functional data for phenylalanine hydroxylase genotypes hamper reliable phenotype prediction and individualised treatment. A literature search revealed 690 different phenylalanine hydroxylase genotypes in 3066 phenylketonuria patients from Europe and the Middle East. We determined phenylalanine hydroxylase function of 30 frequent homozygous and compound heterozygous genotypes covering 55% of the study population, generated activity landscapes, and assessed the phenylalanine hydroxylase working range in the metabolic (phenylalanine) and therapeutic (tetrahydrobiopterin) space. Shared patterns in genotype-specific functional landscapes were linked to biochemical and pharmacological phenotypes, where (1) residual activity below 3.5% was associated with classical phenylketonuria unresponsive to pharmacological treatment; (2) lack of defined peak activity induced loss of response to tetrahydrobiopterin; (3) a higher cofactor need was linked to inconsistent clinical phenotypes and low rates of tetrahydrobiopterin response; and (4) residual activity above 5%, a defined peak of activity, and a normal cofactor need were associated with pharmacologically treatable mild phenotypes. In addition, we provide a web application for retrieving country-specific information on genotypes and genotype-specific phenylalanine hydroxylase function that warrants continuous extension, updates, and research on demand. The combination of genotype-specific functional analyses with biochemical, clinical, and therapeutic data of individual patients may serve as a powerful tool to enable phenotype prediction and to establish personalised medicine strategies for dietary regimens and pharmacological treatment in phenylketonuria. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Evaluation and integration of disparate classification systems for clefts of the lip

PubMed Central

Wang, Kathie H.; Heike, Carrie L.; Clarkson, Melissa D.; Mejino, Jose L. V.; Brinkley, James F.; Tse, Raymond W.; Birgfeld, Craig B.; Fitzsimons, David A.; Cox, Timothy C.

2014-01-01

Orofacial clefting is a common birth defect with wide phenotypic variability. Many systems have been developed to classify cleft patterns to facilitate diagnosis, management, surgical treatment, and research. In this review, we examine the rationale for different existing classification schemes and determine their inter-relationships, as well as strengths and deficiencies for subclassification of clefts of the lip. The various systems differ in how they describe and define attributes of cleft lip (CL) phenotypes. Application and analysis of the CL classifications reveal discrepancies that may result in errors when comparing studies that use different systems. These inconsistencies in terminology, variable levels of subclassification, and ambiguity in some descriptions may confound analyses and impede further research aimed at understanding the genetics and etiology of clefts, development of effective treatment options for patients, as well as cross-institutional comparisons of outcome measures. Identification and reconciliation of discrepancies among existing systems is the first step toward creating a common standard to allow for a more explicit interpretation that will ultimately lead to a better understanding of the causes and manifestations of phenotypic variations in clefting. PMID:24860508

Molecular basis of the Duffy blood group system

PubMed Central

Höher, Gabriela; Fiegenbaum, Marilu; Almeida, Silvana

2018-01-01

ACKR1, located on chromosome 1q23.2, is the gene that encodes a glycoprotein expressing the Duffy blood group antigens. This gene is transcribed in two mRNA variants yielding two isoforms, encoding proteins with 338 and 336 amino acids. This review provides a general overview of the Duffy blood group to characterise and elucidate the genetic basis of this system. The Fya and Fyb antigens are encoded by co-dominant FY*A (FY*01) and FY*B (FY*02) alleles, which differ by c.125G>A (rs12075), defining the Fy(a+b−), Fy(a−b+) and Fy(a+b+) phenotypes. The Fy(a−b−) phenotype that occurs in Africans provides an explanation for the apparent absence of Plasmodium vivax in this region: this phenotype arises from homozygosity for the FY*B allele carrying a point mutation c.1-67T>C (rs2814778), which prevents Fyb antigen expression only in red blood cells. The same mutation has also been found on the FY*A allele, but it is very rare. The Fy(a−b−) phenotype in Europeans and Asians arises from mutations in the coding region of the FY*A or FY*B allele, preventing Duffy antigen expression on any cell in the body and thus are true Duffy null phenotypes. According to the International Society for Blood Transfusion, ten alleles are associated with the null expression of the Fy antigens. Furthermore, different allelic forms of FY*B modify Fyb antigen expression, which may result in very weak or equivocal serology results. The mostly common found variants, c.265C>T (rs34599082) and c.298G>A (rs13962) -previously defined in combination only with the FY*B allele - have already been observed in the FY*A allele. Thus, six alleles have been recognised and associated with weak expression of the Fy antigens. Considering the importance of the Duffy blood group system in clinical medicine, additional studies via molecular biology approaches must be performed to resolve and clarify the discrepant results that are present in the erythrocyte phenotyping. PMID:28151395

Molecular basis of the Duffy blood group system.

PubMed

Höher, Gabriela; Fiegenbaum, Marilu; Almeida, Silvana

2018-01-01

ACKR1, located on chromosome 1q23.2, is the gene that encodes a glycoprotein expressing the Duffy blood group antigens. This gene is transcribed in two mRNA variants yielding two isoforms, encoding proteins with 338 and 336 amino acids. This review provides a general overview of the Duffy blood group to characterise and elucidate the genetic basis of this system. The Fy a and Fy b antigens are encoded by co-dominant FY*A (FY*01) and FY*B (FY*02) alleles, which differ by c.125G>A (rs12075), defining the Fy(a+b-), Fy(a-b+) and Fy(a+b+) phenotypes. The Fy(a-b-) phenotype that occurs in Africans provides an explanation for the apparent absence of Plasmodium vivax in this region: this phenotype arises from homozygosity for the FY*B allele carrying a point mutation c.1-67T>C (rs2814778), which prevents Fy b antigen expression only in red blood cells. The same mutation has also been found on the FY*A allele, but it is very rare. The Fy(a-b-) phenotype in Europeans and Asians arises from mutations in the coding region of the FY*A or FY*B allele, preventing Duffy antigen expression on any cell in the body and thus are true Duffy null phenotypes. According to the International Society for Blood Transfusion, ten alleles are associated with the null expression of the Fy antigens. Furthermore, different allelic forms of FY*B modify Fy b antigen expression, which may result in very weak or equivocal serology results. The mostly common found variants, c.265C>T (rs34599082) and c.298G>A (rs13962) -previously defined in combination only with the FY*B allele - have already been observed in the FY*A allele. Thus, six alleles have been recognised and associated with weak expression of the Fy antigens. Considering the importance of the Duffy blood group system in clinical medicine, additional studies via molecular biology approaches must be performed to resolve and clarify the discrepant results that are present in the erythrocyte phenotyping.

Molecular cytogenetics characterization of seven small supernumerary marker chromosomes derived from chromosome 19: Genotype-phenotype correlation and review of the literature.

PubMed

Recalcati, Maria Paola; Bonati, Maria Teresa; Beltrami, Nicola; Cardarelli, Laura; Catusi, Ilaria; Costa, Asia; Garzo, Maria; Mammi, Isabella; Mattina, Teresa; Nalesso, Elisa; Nardone, Anna Maria; Postorivo, Diana; Sajeva, Anna; Varricchio, Aminta; Verri, Annapia; Villa, Nicoletta; Larizza, Lidia; Giardino, Daniela

2018-03-01

Only a few subjects carrying supernumerary marker chromosomes derived from 19 chromosome (sSMC(19)) have been described to date and for a small portion of them the genic content has been defined at the molecular level. We present seven new different sSMCs(19) identified in eight individuals, seven of whom unrelated. The presence of the sSMC is associated with a clinical phenotype in five subjects, while the other three carriers, two of whom related, are normal. All sSMCs(19) have been characterized by means of conventional and molecular cytogenetics. We compare the sSMCs(19) carriers with a clinical phenotype to already described patients with gains (sSMCs or microduplications) of overlapping genomic regions with the aim to deepen the pathogenicity of the encountered imbalances and to assess the role of the involved genes on the phenotype. The present work supports the correlation between the gain of some chromosome 19 critical regions and specific phenotypes. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Cytokeratin characterization of human prostatic carcinoma and its derived cell lines.

PubMed

Nagle, R B; Ahmann, F R; McDaniel, K M; Paquin, M L; Clark, V A; Celniker, A

1987-01-01

Two murine monoclonal anti-cytokeratin antibodies with defined specificity were shown to distinguish between basal cells and luminal cells in human prostate tissue. Forty-one biopsies or transurethral resection specimens were characterized using these two antibodies. In cases of benign prostatic hyperplasia, focal loss of the basal cell layer was noted in areas of glandular proliferation. Ten cases of adenocarcinoma of the prostate, varying in Gleason's histological grade from 2 to 4, were also studied. In each case the carcinoma was shown to represent the luminal cell phenotype with no evidence of involvement of the basal cell phenotype. An analysis of three established metastatic prostatic carcinoma cell lines (DU-145, PC-3, and LNCaP) using two-dimensional electrophoresis showed that the cytokeratin complement of each cell line was slightly different but retained the phenotype of the luminal cell. It was concluded that during both hyperplasia and neoplastic transformation of the prostate, the luminal cell phenotype is primarily involved and that the basal cell phenotype does not appear to contribute to either intraluminal proliferation or invasive cell populations.

Defining the clinical course of multiple sclerosis

PubMed Central

Reingold, Stephen C.; Cohen, Jeffrey A.; Cutter, Gary R.; Sørensen, Per Soelberg; Thompson, Alan J.; Wolinsky, Jerry S.; Balcer, Laura J.; Banwell, Brenda; Barkhof, Frederik; Bebo, Bruce; Calabresi, Peter A.; Clanet, Michel; Comi, Giancarlo; Fox, Robert J.; Freedman, Mark S.; Goodman, Andrew D.; Inglese, Matilde; Kappos, Ludwig; Kieseier, Bernd C.; Lincoln, John A.; Lubetzki, Catherine; Miller, Aaron E.; Montalban, Xavier; O'Connor, Paul W.; Petkau, John; Pozzilli, Carlo; Rudick, Richard A.; Sormani, Maria Pia; Stüve, Olaf; Waubant, Emmanuelle; Polman, Chris H.

2014-01-01

Accurate clinical course descriptions (phenotypes) of multiple sclerosis (MS) are important for communication, prognostication, design and recruitment of clinical trials, and treatment decision-making. Standardized descriptions published in 1996 based on a survey of international MS experts provided purely clinical phenotypes based on data and consensus at that time, but imaging and biological correlates were lacking. Increased understanding of MS and its pathology, coupled with general concern that the original descriptors may not adequately reflect more recently identified clinical aspects of the disease, prompted a re-examination of MS disease phenotypes by the International Advisory Committee on Clinical Trials of MS. While imaging and biological markers that might provide objective criteria for separating clinical phenotypes are lacking, we propose refined descriptors that include consideration of disease activity (based on clinical relapse rate and imaging findings) and disease progression. Strategies for future research to better define phenotypes are also outlined. PMID:24871874

Conceptual Challenges of the Systemic Approach in Understanding Cell Differentiation.

PubMed

Paldi, Andras

2018-01-01

The cells of a multicellular organism are derived from a single zygote and genetically identical. Yet, they are phenotypically very different. This difference is the result of a process commonly called cell differentiation. How the phenotypic diversity emerges during ontogenesis or regeneration is a central and intensely studied but still unresolved issue in biology. Cell biology is facing conceptual challenges that are frequently confused with methodological difficulties. How to define a cell type? What stability or change means in the context of cell differentiation and how to deal with the ubiquitous molecular variations seen in the living cells? What are the driving forces of the change? We propose to reframe the problem of cell differentiation in a systemic way by incorporating different theoretical approaches. The new conceptual framework is able to capture the insights made at different levels of cellular organization and considered previously as contradictory. It also provides a formal strategy for further experimental studies.

Connectome-Wide Phenotypical and Genotypical Associations in Focal Dystonia

PubMed Central

Fuertinger, Stefan

2017-01-01

Isolated focal dystonia is a debilitating movement disorder of unknown pathophysiology. Early studies in focal dystonias have pointed to segregated changes in brain activity and connectivity. Only recently has the notion that dystonia pathophysiology may lie in abnormalities of large-scale brain networks appeared in the literature. Here, we outline a novel concept of functional connectome-wide alterations that are linked to dystonia phenotype and genotype. Using a neural community detection strategy and graph theoretical analysis of functional MRI data in human patients with the laryngeal form of dystonia (LD) and healthy controls (both males and females), we identified an abnormally widespread hub formation in LD, which particularly affected the primary sensorimotor and parietal cortices and thalamus. Left thalamic regions formed a delineated functional community that highlighted differences in network topology between LD patients with and without family history of dystonia. Conversely, marked differences in the topological organization of parietal regions were found between phenotypically different forms of LD. The interface between sporadic genotype and adductor phenotype of LD yielded four functional communities that were primarily governed by intramodular hub regions. Conversely, the interface between familial genotype and abductor phenotype was associated with numerous long-range hub nodes and an abnormal integration of left thalamus and basal ganglia. Our findings provide the first comprehensive atlas of functional topology across different phenotypes and genotypes of focal dystonia. As such, this study constitutes an important step toward defining dystonia as a large-scale network disorder, understanding its causative pathophysiology, and identifying disorder-specific markers. SIGNIFICANCE STATEMENT The architecture of the functional connectome in focal dystonia was analyzed in a large population of patients with laryngeal dystonia. Breaking with the empirical concept of dystonia as a basal ganglia disorder, we discovered large-scale alterations of neural communities that are significantly influenced by the disorder's clinical phenotype and genotype. PMID:28674168

A rolling phenotype in Crohn's disease.

PubMed

Irwin, James; Ferguson, Emma; Simms, Lisa A; Hanigan, Katherine; Carbonnel, Franck; Radford-Smith, Graham

2017-01-01

The Montreal classification of disease behaviour in Crohn's disease describes progression of disease towards a stricturing and penetrating phenotype. In the present paper, we propose an alternative representation of the long-term course of Crohn's disease complications, the rolling phenotype. As is commonly observed in clinical practice, this definition allows progression to a more severe phenotype (stricturing, penetrating) but also, regression to a less severe behaviour (inflammatory, or remission) over time. All patients diagnosed with Crohn's Disease between 01/01/1994 and 01/03/2008, managed at a single centre and observed for a minimum of 5 years, had development and resolution of all complications recorded. A rolling phenotype was defined at each time point based on all observed complications in the three years prior to the time point. Phenotype was defined as B1, B2, B3, or B23 (penetrating and stenotic). The progression over time of the rolling phenotype was compared to that of the cumulative Montreal phenotype. 305 patients were observed a median of 10.0 (Intraquartile range 7.3-13.7) years. Longitudinal progression of rolling phenotype demonstrated a consistent proportion of patients with B1 (70%), B2 (20%), B3 (5%) and B23 (5%) phenotypes. These proportions were observed regardless of initial phenotype. In contrast, the cumulative Montreal phenotype progressed towards a more severe phenotype with time (B1 (39%), B2 (26%), B3(35%) at 10 years). A rolling phenotype provides an alternative view of the longitudinal burden of intra-abdominal complications in Crohn's disease. From this viewpoint, 70% of patients have durable freedom from complication over time (>3 years).

Characterization of skin abnormalities in a mouse model of osteogenesis imperfecta using high resolution magnetic resonance imaging and Fourier transform infrared imaging spectroscopy.

PubMed

Canuto, H C; Fishbein, K W; Huang, A; Doty, S B; Herbert, R A; Peckham, J; Pleshko, N; Spencer, R G

2012-01-01

Evaluation of the skin phenotype in osteogenesis imperfecta (OI) typically involves biochemical measurements, such as histologic or biochemical assessment of the collagen produced from biopsy-derived dermal fibroblasts. As an alternative, the current study utilized non-invasive magnetic resonance imaging (MRI) microscopy and optical spectroscopy to define biophysical characteristics of skin in an animal model of OI. MRI of skin harvested from control, homozygous oim/oim and heterozygous oim/+ mice demonstrated several differences in anatomic and biophysical properties. Fourier transform infrared imaging spectroscopy (FT-IRIS) was used to interpret observed MRI signal characteristics in terms of chemical composition. Differences between wild-type and OI mouse skin included the appearance of a collagen-depleted lower dermal layer containing prominent hair follicles in the oim/oim mice, accounting for 55% of skin thickness in these. The MRI magnetization transfer rate was lower by 50% in this layer as compared to the upper dermis, consistent with lower collagen content. The MRI transverse relaxation time, T2, was greater by 30% in the dermis of the oim/oim mice compared to controls, consistent with a more highly hydrated collagen network. Similarly, an FT-IRIS-defined measure of collagen integrity was 30% lower in the oim/oim mice. We conclude that characterization of phenotypic differences between the skin of OI and wild-type mice by MRI and FT-IRIS is feasible, and that these techniques provide powerful complementary approaches for the analysis of the skin phenotype in animal models of disease. Copyright © 2011 John Wiley & Sons, Ltd.

Characterization and classification of zebrafish brain morphology mutants

PubMed Central

Lowery, Laura Anne; De Rienzo, Gianluca; Gutzman, Jennifer H.; Sive, Hazel

2010-01-01

The mechanisms by which the vertebrate brain achieves its three-dimensional structure are clearly complex, requiring the functions of many genes. Using the zebrafish as a model, we have begun to define genes required for brain morphogenesis, including brain ventricle formation, by studying 16 mutants previously identified as having embryonic brain morphology defects. We report the phenotypic characterization of these mutants at several time-points, using brain ventricle dye injection, imaging, and immunohistochemistry with neuronal markers. Most of these mutants display early phenotypes, affecting initial brain shaping, while others show later phenotypes, affecting brain ventricle expansion. In the early phenotype group, we further define four phenotypic classes and corresponding functions required for brain morphogenesis. Although we did not use known genotypes for this classification, basing it solely on phenotypes, many mutants with defects in functionally related genes clustered in a single class. In particular, class 1 mutants show midline separation defects, corresponding to epithelial junction defects; class 2 mutants show reduced brain ventricle size; class 3 mutants show midbrain-hindbrain abnormalities, corresponding to basement membrane defects; and class 4 mutants show absence of ventricle lumen inflation, corresponding to defective ion pumping. Later brain ventricle expansion requires the extracellular matrix, cardiovascular circulation, and transcription/splicing-dependent events. We suggest that these mutants define processes likely to be used during brain morphogenesis throughout the vertebrates. PMID:19051268

Social-Cognition and the Broad Autism Phenotype: Identifying Genetically Meaningful Phenotypes

ERIC Educational Resources Information Center

Losh, Molly; Piven, Joseph

2007-01-01

Background: Strong evidence from twin and family studies suggests that the genetic liability to autism may be expressed through personality and language characteristics qualitatively similar, but more subtly expressed than those defining the full syndrome. This study examined behavioral features of this "broad autism phenotype" (BAP) in relation…

Behavioural Phenotypes and Special Educational Needs: Is Aetiology Important in the Classroom?

ERIC Educational Resources Information Center

Reilly, C.

2012-01-01

Background: A number of genetic conditions with associated intellectual disability and/or special educational needs have increasingly well-defined behavioural phenotypes. Thus, the concept of "behavioural phenotype" and aetiology of intellectual disability may be important with regard to school-based interventions. Method: The evidence for…

The Broad Autism Phenotype Questionnaire

ERIC Educational Resources Information Center

Hurley, Robert S. E.; Losh, Molly; Parlier, Morgan; Reznick, J. Steven; Piven, Joseph

2007-01-01

The broad autism phenotype (BAP) is a set of personality and language characteristics that reflect the phenotypic expression of the genetic liability to autism, in non-autistic relatives of autistic individuals. These characteristics are milder but qualitatively similar to the defining features of autism. A new instrument designed to measure the…

Centronuclear myopathies: genotype-phenotype correlation and frequency of defined genetic forms in an Italian cohort.

PubMed

Fattori, Fabiana; Maggi, Lorenzo; Bruno, Claudio; Cassandrini, Denise; Codemo, Valentina; Catteruccia, Michela; Tasca, Giorgio; Berardinelli, Angela; Magri, Francesca; Pane, Marika; Rubegni, Anna; Santoro, Lucio; Ruggiero, Lucia; Fiorini, Patrizio; Pini, Antonella; Mongini, Tiziana; Messina, Sonia; Brisca, Giacomo; Colombo, Irene; Astrea, Guja; Fiorillo, Chiara; Bragato, Cinzia; Moroni, Isabella; Pegoraro, Elena; D'Apice, Maria Rosaria; Alfei, Enrico; Mora, Marina; Morandi, Lucia; Donati, Alice; Evilä, Anni; Vihola, Anna; Udd, Bjarne; Bernansconi, Pia; Mercuri, Eugenio; Santorelli, Filippo Maria; Bertini, Enrico; D'Amico, Adele

2015-07-01

Centronuclear myopathies (CNMs) are a group of clinically and genetically heterogeneous muscle disorders. To date, mutation in 7 different genes has been reported to cause CNMs but 30 % of cases still remain genetically undefined. Genetic investigations are often expensive and time consuming. Clinical and morphological clues are needed to facilitate genetic tests and to choose the best approach for genetic screening. We aimed to describe genotype-phenotype correlation in an Italian cohort of patients affected by CNMs, to define the relative frequencies of its defined genetic forms and to draw a diagnostic algorithm to address genetic investigations. We recruited patients with CNMs from all the Italian tertiary neuromuscular centers following clinical and histological criteria. All selected patients were screened for the four 'canonical' genes related to CNMs: MTM1, DNM2, RYR1 and BIN1. Pathogenetic mutations were found in 38 of the 54 screened patients (70 %), mostly in patients with congenital onset (25 of 30 patients, 83 %): 15 in MTM1, 6 in DNM2, 3 in RYR1 and one in TTN. Among the 13 patients with a childhood-adolescence onset, mutations were found in 6 patients (46 %), all in DNM2. In the group of the 11 patients with adult onset, mutations were identified in 7 patients (63 %), again in DNM2, confirming that variants in this gene are relatively more common in late-onset phenotypes. The present study provides the relative molecular frequency of centronuclear myopathy and of its genetically defined forms in Italy and also proposes a diagnostic algorithm to be used in clinical practice to address genetic investigations.

MOLECULAR AND MORPHOLOGICAL CHANGES IN ZEBRAFISH FOLLOWING TRANSIENT ETHANOL EXPOSURE DURING DEFINED DEVELOPMENTAL STAGES

PubMed Central

Zhang, Chengjin; Frazier, Jared M.; Chen, Hao; Liu, Yao; Lee, Ju-Ahng; Cole, Gregory J.

2014-01-01

Alcohol is a teratogen that has diverse effects on brain and craniofacial development, leading to a constellation of developmental disorders referred to as fetal alcohol spectrum disorder (FASD). The molecular basis of ethanol insult remains poorly understood, as does the relationship between molecular and behavioral changes as a consequence of prenatal ethanol exposure. Zebrafish embryos were exposed to a range of ethanol concentrations (0.5–5.0%) during defined developmental stages, and examined for morphological phenotypes characteristic of FASD. Embryos were also analyzed by in situ hybridization for changes in expression of defined cell markers for neural cell types that are sonic hedgehog-dependent. We show that transient binge-like ethanol exposures during defined developmental stages, such as early gastrulation and early neurulation, result in a range of phenotypes and changes in expression of Shh-dependent genes. The severity of fetal alcohol syndrome (FAS) morphological phenotypes, such as microphthalmia, depends on the embryonic stage and concentration of alcohol exposure, as does diminution of retinal Pax6a or forebrain and hindbrain GAD1 gene expression. We also show that changes in eye and brain morphology correlate with changes in Pax6a and GAD1 gene expression. Our results therefore show that transient binge-like ethanol exposures in zebrafish embryos produce the stereotypical morphological phenotypes of FAS, with the severity of phenotypes depending on the developmental stage and alcohol concentration of exposure. PMID:24929233

Defining the Borders of Dose Addition: Mixture Effects of 2,3,7,8-Tetrachlorodibenzo-p-dioxin and Dibutyl phthalate on Male Rat Reproductive Tract Development

EPA Science Inventory

In utero exposure to either dibutyl phthalate (DBP) or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) disrupts male rat reproductive tract differentiation. However, they act via different modes of toxicity and induce distinct postnatal phenotypes. DBP exposure decreases anogenital di...

The Nutritional Phenotype in the Age of Metabolomics

PubMed Central

Zeisel, S. H.; Freake, H. C.; Bauman, D. E.; Bier, D. M.; Burrin, D. G.; German, J. B.; Klein, S.; Marquis, G. S.; Milner, J. A.; Pelto, G. H.; Rasmussen, K. M.

2008-01-01

The concept of the nutritional phenotype is proposed as a defined and integrated set of genetic, proteomic, metabolomic, functional, and behavioral factors that, when measured, form the basis for assessment of human nutritional status. The nutritional phenotype integrates the effects of diet on disease/wellness and is the quantitative indication of the paths by which genes and environment exert their effects on health. Advances in technology and in fundamental biological knowledge make it possible to define and measure the nutritional phenotype accurately in a cross section of individuals with various states of health and disease. This growing base of data and knowledge could serve as a resource for all scientific disciplines involved in human health. Nutritional sciences should be a prime mover in making key decisions that include: what environmental inputs (in addition to diet) are needed; what genes/proteins/metabolites should be measured; what end-point phenotypes should be included; and what informatics tools are available to ask nutritionally relevant questions. Nutrition should be the major discipline establishing how the elements of the nutritional phenotype vary as a function of diet. Nutritional sciences should also be instrumental in linking the elements that are responsive to diet with the functional outcomes in organisms that derive from them. As the first step in this initiative, a prioritized list of genomic, proteomic, and metabolomic as well as functional and behavioral measures that defines a practically useful subset of the nutritional phenotype for use in clinical and epidemiological investigations must be developed. From this list, analytic platforms must then be identified that are capable of delivering highly quantitative data on these endpoints. This conceptualization of a nutritional phenotype provides a concrete form and substance to the recognized future of nutritional sciences as a field addressing diet, integrated metabolism, and health. PMID:15987837

A refined characterisation of the NeoHepatocyte phenotype necessitates a reappraisal of the transdifferentiation hypothesis.

PubMed

Riquelme, Paloma; Wundt, Judith; Hutchinson, James A; Brulport, Marc; Jun, Yu; Sotnikova, Anna; Girreser, Ulrich; Braun, Felix; Gövert, Felix; Soria, Bernat; Nüssler, Andreas; Clement, Bernd; Hengstler, Jan G; Fändrich, Fred

2009-03-01

Under certain culture conditions human peripheral blood monocytes may be induced to express phenotypic markers of non-haematopoietic lineages, including hepatocyte-defining traits. One such example, the NeoHepatocyte, was previously shown to express a broad panel of hepatocyte-like marker antigens and metabolic activities, both in vitro and following engraftment in the liver of immunodeficient mice. In this report, a refined description of NeoHepatocytes, with regard to their expression of xenobiotic-metabolising enzymes, morphology, hepatocyte marker expression and cell surface phenotype, is presented in comparison with human macrophages in defined states of activation. Contrary to prior assertions, it would seem more likely that NeoHepatocytes express particular hepatocyte-defining genes during a normal programme of macrophage differentiation rather than undergoing a process of transdifferentiation to become hepatocyte-like cells.

Proteomics to assess the role of phenotypic plasticity in aquatic organisms exposed to pollution and global warming.

PubMed

Silvestre, Frédéric; Gillardin, Virginie; Dorts, Jennifer

2012-11-01

Nowadays, the unprecedented rates of anthropogenic changes in ecosystems suggest that organisms have to migrate to new distributional ranges or to adapt commensurately quickly to new conditions to avoid becoming extinct. Pollution and global warming are two of the most important threats aquatic organisms will have to face in the near future. If genetic changes in a population in response to natural selection are extensively studied, the role of acclimation through phenotypic plasticity (the property of a given genotype to produce different phenotypes in response to particular environmental conditions) in a species to deal with new environmental conditions remains largely unknown. Proteomics is the extensive study of the protein complement of a genome. It is dynamic and depends on the specific tissue, developmental stage, and environmental conditions. As the final product of gene expression, it is subjected to several regulatory steps from gene transcription to the functional protein. Consequently, there is a discrepancy between the abundance of mRNA and the abundance of the corresponding protein. Moreover, proteomics is closer to physiology and gives a more functional knowledge of the regulation of gene expression than does transcriptomics. The study of protein-expression profiles, however, gives a better portrayal of the cellular phenotype and is considered as a key link between the genotype and the organismal phenotype. Under new environmental conditions, we can observe a shift of the protein-expression pattern defining a new cellular phenotype that can possibly improve the fitness of the organism. It is now necessary to define a proteomic norm of reaction for organisms acclimating to environmental stressors. Its link to fitness will give new insights into how organisms can evolve in a changing environment. The proteomic literature bearing on chronic exposure to pollutants and on acclimation to heat stress in aquatic organisms, as well as potential application of proteomics in evolutionary issues, are outlined. While the transcriptome responses are commonly investigated, proteomics approaches now need to be intensified, with the new perspective of integrating the cellular phenotype with the organismal phenotype and with the mechanisms of the regulation of gene expression, such as epigenetics.

Informatics and machine learning to define the phenotype.

PubMed

Basile, Anna Okula; Ritchie, Marylyn DeRiggi

2018-03-01

For the past decade, the focus of complex disease research has been the genotype. From technological advancements to the development of analysis methods, great progress has been made. However, advances in our definition of the phenotype have remained stagnant. Phenotype characterization has recently emerged as an exciting area of informatics and machine learning. The copious amounts of diverse biomedical data that have been collected may be leveraged with data-driven approaches to elucidate trait-related features and patterns. Areas covered: In this review, the authors discuss the phenotype in traditional genetic associations and the challenges this has imposed.Approaches for phenotype refinement that can aid in more accurate characterization of traits are also discussed. Further, the authors highlight promising machine learning approaches for establishing a phenotype and the challenges of electronic health record (EHR)-derived data. Expert commentary: The authors hypothesize that through unsupervised machine learning, data-driven approaches can be used to define phenotypes rather than relying on expert clinician knowledge. Through the use of machine learning and an unbiased set of features extracted from clinical repositories, researchers will have the potential to further understand complex traits and identify patient subgroups. This knowledge may lead to more preventative and precise clinical care.

Host Genetics and Environment Drive Divergent Responses of Two Resource Sharing Gall-Formers on Norway Spruce: A Common Garden Analysis.

PubMed

Axelsson, E Petter; Iason, Glenn R; Julkunen-Tiitto, Riitta; Whitham, Thomas G

2015-01-01

A central issue in the field of community genetics is the expectation that trait variation among genotypes play a defining role in structuring associated species and in forming community phenotypes. Quantifying the existence of such community phenotypes in two common garden environments also has important consequences for our understanding of gene-by-environment interactions at the community level. The existence of community phenotypes has not been evaluated in the crowns of boreal forest trees. In this study we address the influence of tree genetics on needle chemistry and genetic x environment interactions on two gall-inducing adelgid aphids (Adelges spp. and Sacchiphantes spp.) that share the same elongating bud/shoot niche. We examine the hypothesis that the canopies of different genotypes of Norway spruce (Picea abies L.) support different community phenotypes. Three patterns emerged. First, the two gallers show clear differences in their response to host genetics and environment. Whereas genetics significantly affected the abundance of Adelges spp. galls, Sacchiphantes spp. was predominately affected by the environment suggesting that the genetic influence is stronger in Adelges spp. Second, the among family variation in genetically controlled resistance was large, i.e. fullsib families differed as much as 10 fold in susceptibility towards Adelges spp. (0.57 to 6.2 galls/branch). Also, the distribution of chemical profiles was continuous, showing both overlap as well as examples of significant differences among fullsib families. Third, despite the predicted effects of host chemistry on galls, principal component analyses using 31 different phenolic substances showed only limited association with galls and a similarity test showed that trees with similar phenolic chemical characteristics, did not host more similar communities of gallers. Nonetheless, the large genetic variation in trait expression and clear differences in how community members respond to host genetics supports our hypothesis that the canopies of Norway spruce differ in their community phenotypes.

Fine phenotyping of pod and seed traits in Arachis germplasm accessions using digital image analysis

USDA-ARS?s Scientific Manuscript database

Reliable and objective phenotyping of peanut pod and seed traits is important for cultivar selection and genetic mapping of yield components. To develop useful and efficient methods to quantitatively define peanut pod and seed traits, a group of peanut germplasm with high levels of phenotypic varia...

Association Between the Hypertriglyceridemic Waist Phenotype, Prediabetes, and Diabetes Mellitus Among Adults in Puerto Rico.

PubMed

Díaz-Santana, Mary Vanellys; Suárez Pérez, Erick L; Ortiz Martínez, Ana P; Guzmán Serrano, Manuel; Pérez Cardona, Cynthia M

2016-02-01

This study assessed the association of the hypertriglyceridemic waist (HTGW) phenotype with prediabetes and diabetes (DM) in a group of Hispanics. Analysis of a cross-sectional study of 858 adults residing in Puerto Rico that collected data on blood pressure, biochemical, and anthropometric measurements was performed. HTGW phenotype was defined as elevated triglycerides and elevated waist circumference. Prediabetes was defined as a fasting glucose of 100-125 mg/dL and DM as a fasting glucose ≥126 mg/dL or prior diagnosis. Prevalence of HTGW, prediabetes, and DM was 27.9, 38.0, and 21.6 %, respectively. Subjects with the HTGW phenotype had higher adjusted odds of prediabetes (POR 5.55; 95 % CI 3.38-9.13) and DM (POR 7.28; 95 % CI 3.63-14.63) compared to those without the phenotype. The association for prediabetes was stronger for women than among men. HTGW phenotype was strongly associated with prediabetes and DM, reinforcing the need to further assess its performance as a screening tool to identify at-risk individuals for cardiometabolic conditions.

Humanized medium (h7H) allows long-term primary follicular thyroid cultures from human normal thyroid, benign neoplasm, and cancer.

PubMed

Bravo, Susana B; Garcia-Rendueles, Maria E R; Garcia-Rendueles, Angela R; Rodrigues, Joana S; Perez-Romero, Sihara; Garcia-Lavandeira, Montserrat; Suarez-Fariña, Maria; Barreiro, Francisco; Czarnocka, Barbara; Senra, Ana; Lareu, Maria V; Rodriguez-Garcia, Javier; Cameselle-Teijeiro, Jose; Alvarez, Clara V

2013-06-01

Mechanisms of thyroid physiology and cancer are principally studied in follicular cell lines. However, human thyroid cancer lines were found to be heavily contaminated by other sources, and only one supposedly normal-thyroid cell line, immortalized with SV40 antigen, is available. In primary culture, human follicular cultures lose their phenotype after passage. We hypothesized that the loss of the thyroid phenotype could be related to culture conditions in which human cells are grown in medium optimized for rodent culture, including hormones with marked differences in its affinity for the relevant rodent/human receptor. The objective of the study was to define conditions that allow the proliferation of primary human follicular thyrocytes for many passages without losing phenotype. Concentrations of hormones, transferrin, iodine, oligoelements, antioxidants, metabolites, and ethanol were adjusted within normal homeostatic human serum ranges. Single cultures were identified by short tandem repeats. Human-rodent interspecies contamination was assessed. We defined an humanized 7 homeostatic additives medium enabling growth of human thyroid cultures for more than 20 passages maintaining thyrocyte phenotype. Thyrocytes proliferated and were grouped as follicle-like structures; expressed Na+/I- symporter, pendrin, cytokeratins, thyroglobulin, and thyroperoxidase showed iodine-uptake and secreted thyroglobulin and free T3. Using these conditions, we generated a bank of thyroid tumors in culture from normal thyroids, Grave's hyperplasias, benign neoplasms (goiter, adenomas), and carcinomas. Using appropriate culture conditions is essential for phenotype maintenance in human thyrocytes. The bank of thyroid tumors in culture generated under humanized humanized 7 homeostatic additives culture conditions will provide a much-needed tool to compare similarly growing cells from normal vs pathological origins and thus to elucidate the molecular basis of thyroid disease.

Association of the hypertriglyceridemic waist phenotype and type 2 diabetes mellitus among adults in China.

PubMed

Ren, Yongcheng; Zhang, Ming; Zhao, Jingzhi; Wang, Chongjian; Luo, Xinping; Zhang, Jiatong; Zhu, Tian; Li, Xi; Yin, Lei; Pang, Chao; Feng, Tianping; Wang, Bingyuan; Zhang, Lu; Li, Linlin; Yang, Xiangyu; Zhang, Hongyan; Hu, Dongsheng

2016-09-01

To clarify the association of the hypertriglyceridemic waist phenotype and type 2 diabetes mellitus among adults in China. In the present case-control study, we included 1,685 patients with type 2 diabetes mellitus and 7,141 normal glucose-tolerant controls from the Henan Province of China in 2011. Elevated waist circumference (GW) was defined as ≥90 cm for men and ≥80 cm for women. Hypertriglyceridemia (HT) was defined as >1.7 m mol/L triglycerides (TG) level. The association of hypertriglyceridemic waist phenotype and type 2 diabetes mellitus was investigated by sex, body mass index, physical activity, and family history of diabetes. Cases and controls differed in age, waist circumference (WC), weight, TG level, fasting glucose, body mass index, smoking status, diabetic family history, physical activity and hypertriglyceridemic waist phenotype (P < 0.05), but not alcohol drinking (P = 0.63). In the overall sample, as compared with the phenotype of normal TG level and normal WC (NTNW), normal TG level/enlarged WC (NTGW), elevated TG level/normal WC (HTNW) and elevated TG level/enlarged WC (HTGW) were associated with type 2 diabetes mellitus (odds ratio 4.14, 2.42 and 6.23, respectively). Only HTGW was consistently associated with risk of type 2 diabetes mellitus, with or without adjustment. The strongest relationship between HTGW and type 2 diabetes mellitus was for subjects with body mass index <24.0 kg/m(2) (odds ratio 6.54, 95% confidence interval 4.22-10.14) after adjustment for cofounding variables. HTGW was stably and significantly associated with risk of type 2 diabetes mellitus in adult Chinese. © 2016 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.

Characterizing discrete subsets of polycystic ovary syndrome as defined by the Rotterdam criteria: the impact of weight on phenotype and metabolic features.

PubMed

Welt, C K; Gudmundsson, J A; Arason, G; Adams, J; Palsdottir, H; Gudlaugsdottir, G; Ingadottir, G; Crowley, W F

2006-12-01

The Rotterdam criteria for polycystic ovary syndrome (PCOS) defines discrete subgroups whose phenotypes are not yet clear. The phenotypic characteristics of women in the PCOS subgroups defined by the Rotterdam criteria were compared. The study was observational. Subjects were studied in an outpatient setting in Boston and Reykjavik. Four subgroups of subjects with PCOS defined by 1) irregular menses (IM), hyperandrogenism (HA), and polycystic ovary morphology (PCOM, n = 298); 2) IM/HA (n = 7); 3) HA/PCOM (n = 77); and 4) IM/PCOM (n = 36) and a group of controls (n = 64), aged 18-45 yr, were examined. Subjects underwent a physical exam; fasting blood samples for androgens, gonadotropins, and metabolic parameters; and a transvaginal ultrasound. The phenotype was compared between groups. Ninety-seven percent of women with IM/HA had PCOM. Therefore, the groups with and without PCOM were combined. The Ferriman-Gallwey score and androgen levels were highest in the hyperandrogenic groups (IM/HA and HA/PCOM), whereas ovarian volume was higher in all PCOS subgroups compared with controls, as expected based on the definitions of the PCOS subgroups. Body mass index and insulin levels were highest in the IM/HA subgroup. Subjects with PCOS defined by IM/HA are the most severely affected women on the basis of androgen levels, ovarian volumes, and insulin levels. Their higher body mass index partially accounts for the increased insulin levels, suggesting that weight gain exacerbates the symptoms of PCOS.

Using iterative cluster merging with improved gap statistics to perform online phenotype discovery in the context of high-throughput RNAi screens

PubMed Central

Yin, Zheng; Zhou, Xiaobo; Bakal, Chris; Li, Fuhai; Sun, Youxian; Perrimon, Norbert; Wong, Stephen TC

2008-01-01

Background The recent emergence of high-throughput automated image acquisition technologies has forever changed how cell biologists collect and analyze data. Historically, the interpretation of cellular phenotypes in different experimental conditions has been dependent upon the expert opinions of well-trained biologists. Such qualitative analysis is particularly effective in detecting subtle, but important, deviations in phenotypes. However, while the rapid and continuing development of automated microscope-based technologies now facilitates the acquisition of trillions of cells in thousands of diverse experimental conditions, such as in the context of RNA interference (RNAi) or small-molecule screens, the massive size of these datasets precludes human analysis. Thus, the development of automated methods which aim to identify novel and biological relevant phenotypes online is one of the major challenges in high-throughput image-based screening. Ideally, phenotype discovery methods should be designed to utilize prior/existing information and tackle three challenging tasks, i.e. restoring pre-defined biological meaningful phenotypes, differentiating novel phenotypes from known ones and clarifying novel phenotypes from each other. Arbitrarily extracted information causes biased analysis, while combining the complete existing datasets with each new image is intractable in high-throughput screens. Results Here we present the design and implementation of a novel and robust online phenotype discovery method with broad applicability that can be used in diverse experimental contexts, especially high-throughput RNAi screens. This method features phenotype modelling and iterative cluster merging using improved gap statistics. A Gaussian Mixture Model (GMM) is employed to estimate the distribution of each existing phenotype, and then used as reference distribution in gap statistics. This method is broadly applicable to a number of different types of image-based datasets derived from a wide spectrum of experimental conditions and is suitable to adaptively process new images which are continuously added to existing datasets. Validations were carried out on different dataset, including published RNAi screening using Drosophila embryos [Additional files 1, 2], dataset for cell cycle phase identification using HeLa cells [Additional files 1, 3, 4] and synthetic dataset using polygons, our methods tackled three aforementioned tasks effectively with an accuracy range of 85%–90%. When our method is implemented in the context of a Drosophila genome-scale RNAi image-based screening of cultured cells aimed to identifying the contribution of individual genes towards the regulation of cell-shape, it efficiently discovers meaningful new phenotypes and provides novel biological insight. We also propose a two-step procedure to modify the novelty detection method based on one-class SVM, so that it can be used to online phenotype discovery. In different conditions, we compared the SVM based method with our method using various datasets and our methods consistently outperformed SVM based method in at least two of three tasks by 2% to 5%. These results demonstrate that our methods can be used to better identify novel phenotypes in image-based datasets from a wide range of conditions and organisms. Conclusion We demonstrate that our method can detect various novel phenotypes effectively in complex datasets. Experiment results also validate that our method performs consistently under different order of image input, variation of starting conditions including the number and composition of existing phenotypes, and dataset from different screens. In our findings, the proposed method is suitable for online phenotype discovery in diverse high-throughput image-based genetic and chemical screens. PMID:18534020

Decomposing phenotype descriptions for the human skeletal phenome.

PubMed

Groza, Tudor; Hunter, Jane; Zankl, Andreas

2013-01-01

Over the course of the last few years there has been a significant amount of research performed on ontology-based formalization of phenotype descriptions. The intrinsic value and knowledge captured within such descriptions can only be expressed by taking advantage of their inner structure that implicitly combines qualities and anatomical entities. We present a meta-model (the Phenotype Fragment Ontology) and a processing pipeline that enable together the automatic decomposition and conceptualization of phenotype descriptions for the human skeletal phenome. We use this approach to showcase the usefulness of the generic concept of phenotype decomposition by performing an experimental study on all skeletal phenotype concepts defined in the Human Phenotype Ontology.

Triarchic conceptualization of psychopathy: developmental origins of disinhibition, boldness, and meanness.

PubMed

Patrick, Christopher J; Fowles, Don C; Krueger, Robert F

2009-01-01

The clinical concept of psychopathy ("psychopathic personality") is generally considered to entail persistent behavioral deviancy in the company of emotional-interpersonal detachment. However, longstanding debates continue regarding the appropriate scope and boundaries of the concept. Here, we review alternative historic descriptions of the disorder together with empirical findings for the best-established assessment instruments in use with adolescents and youth as a basis for formulating an integrative, triarchic model of psychopathy. The essence of the triarchic model is that psychopathy encompasses three distinct phenotypic constructs: disinhibition, which reflects a general propensity toward problems of impulse control; boldness, which is defined as the nexus of social dominance, emotional resiliency, and venturesomeness; and meanness, which is defined as aggressive resource seeking without regard for others ("dysaffliated agency"). These differing phenotypic components are considered in terms of relevant etiologic and developmental pathways. The triarchic conceptualization provides a basis for reconciling and accommodating alternative descriptive accounts of psychopathy, and a framework for coordinating research on neurobiological and developmental processes contributing to varying manifestations of the disorder.

shinyGISPA: A web application for characterizing phenotype by gene sets using multiple omics data combinations.

PubMed

Dwivedi, Bhakti; Kowalski, Jeanne

2018-01-01

While many methods exist for integrating multi-omics data or defining gene sets, there is no one single tool that defines gene sets based on merging of multiple omics data sets. We present shinyGISPA, an open-source application with a user-friendly web-based interface to define genes according to their similarity in several molecular changes that are driving a disease phenotype. This tool was developed to help facilitate the usability of a previously published method, Gene Integrated Set Profile Analysis (GISPA), among researchers with limited computer-programming skills. The GISPA method allows the identification of multiple gene sets that may play a role in the characterization, clinical application, or functional relevance of a disease phenotype. The tool provides an automated workflow that is highly scalable and adaptable to applications that go beyond genomic data merging analysis. It is available at http://shinygispa.winship.emory.edu/shinyGISPA/.

shinyGISPA: A web application for characterizing phenotype by gene sets using multiple omics data combinations

PubMed Central

Dwivedi, Bhakti

2018-01-01

While many methods exist for integrating multi-omics data or defining gene sets, there is no one single tool that defines gene sets based on merging of multiple omics data sets. We present shinyGISPA, an open-source application with a user-friendly web-based interface to define genes according to their similarity in several molecular changes that are driving a disease phenotype. This tool was developed to help facilitate the usability of a previously published method, Gene Integrated Set Profile Analysis (GISPA), among researchers with limited computer-programming skills. The GISPA method allows the identification of multiple gene sets that may play a role in the characterization, clinical application, or functional relevance of a disease phenotype. The tool provides an automated workflow that is highly scalable and adaptable to applications that go beyond genomic data merging analysis. It is available at http://shinygispa.winship.emory.edu/shinyGISPA/. PMID:29415010

Clinical phenotypes and the biological parameters of Congolese patients suffering from sickle cell anemia: A first report from Central Africa.

PubMed

Mikobi, Tite M; Lukusa Tshilobo, Prosper; Aloni, Michel N; Akilimali, Pierre Z; Mvumbi-Lelo, Georges; Mbuyi-Muamba, Jean Marie

2017-11-01

The influence of phenotype on the clinical course and laboratory features of sickle cell anemia (SCA) is rarely described in sub-Saharan Africa. A cross-sectional study was conducted in Kinshasa. A clinical phenotype score was built up. The following definitions were applied: asymptomatic clinical phenotype (ACP; score≤5), moderate clinical phenotype (MCP; score between 6 and 15), and severe clinical phenotype (SCP; score≥16). ANOVA test were used to compare differences among categorical variables. We have studied 140 patients. The mean body mass index (BMI) value of three groups was lower (<25 kg/m 2 ) than the limit defining overweight. BMI of the subjects with ACP was significantly higher than those of other phenotypes (P<.05). Sickle cell patients with ACP have a high mean steady-state hemoglobin concentration compared to those with MCP and SCP (P<.001). A significant elevated baseline leukocyte count is associated with SCP (P<.001). Fetal Hemoglobin (HbF) was significantly higher in ACP. Significant elevation of alpha 1 and alpha 2 globulins in SCP were observed. In our study, fetal hemoglobin has an influence on the clinical severity and the biological parameters of SCA. The study provides data concerning the sickle cell anemia clinical and biological variability in our midst. © 2017 Wiley Periodicals, Inc.

Contrasting phenotypic plasticity in the photoprotective strategies of the invasive species Carpobrotus edulis and the coexisting native species Crithmum maritimum.

PubMed

Fenollosa, Erola; Munné-Bosch, Sergi; Pintó-Marijuan, Marta

2017-06-01

Photoprotective strategies vary greatly within the plant kingdom and reflect a plant's physiological status and capacity to cope with environment variations. The plasticity and intensity of these responses may determine plant success. Invasive species are reported to show increased vigor to displace native species. Describing the mechanisms that confer such vigor is essential to understanding the success of invasive species. We performed an experiment whereby two species were monitored: Carpobrotus edulis, an aggressive invasive species in the Mediterranean basin, and Crithmum maritimum, a coexisting native species in the Cap de Creus Natural Park (NE Spain). We analyzed their photoprotective responses to seasonal environmental dynamics by comparing the capacity of the invader to respond to the local environmental stresses throughout the year. Our study analyses ecophysiological markers and photoprotective strategies to gain an insight into the success of invaders. We found that both species showed completely different but effective photoprotective strategies: in summer, C. edulis took special advantage of the xanthophyll cycle, whereas the success of C. maritimum in summer stemmed from morphological changes and alterations on β-carotene content. Winter also presented differences between the species, as the native showed reduced F v /F m ratios. Our experimental design allowed us to introduce a new approach to compare phenotypic plasticity: the integrated phenotypic plasticity index (PP int ), defined as the maximum Euclidian distance between phenotypes, using a combination of different variables to describe them. This index revealed significantly greater phenotypic plasticity in the invasive species compared to the native species. © 2017 Scandinavian Plant Physiology Society.

Root Ideotype Influences Nitrogen Transport and Assimilation in Maize

PubMed Central

Dechorgnat, Julie; Francis, Karen L.; Dhugga, Kanwarpal S.; Rafalski, J. A.; Tyerman, Stephen D.; Kaiser, Brent N.

2018-01-01

Maize (Zea mays, L.) yield is strongly influenced by external nitrogen inputs and their availability in the soil solution. Overuse of nitrogen-fertilizers can have detrimental ecological consequences through increased nitrogen pollution of water and the release of the potent greenhouse gas, nitrous oxide. To improve yield and overall nitrogen use efficiency (NUE), a deeper understanding of nitrogen uptake and utilization is required. This study examines the performance of two contrasting maize inbred lines, B73 and F44. F44 was selected in Florida on predominantly sandy acidic soils subject to nitrate leaching while B73 was selected in Iowa on rich mollisol soils. Transcriptional, enzymatic and nitrogen transport analytical tools were used to identify differences in their N absorption and utilization capabilities. Our results show that B73 and F44 differ significantly in their genetic, enzymatic, and biochemical root nitrogen transport and assimilatory pathways. The phenotypes show a strong genetic relationship linked to nitrogen form, where B73 showed a greater capacity for ammonium transport and assimilation whereas F44 preferred nitrate. The contrasting phenotypes are typified by differences in root system architecture (RSA) developed in the presence of both nitrate and ammonium. F44 crown roots were longer, had a higher surface area and volume with a greater lateral root number and density than B73. In contrast, B73 roots (primary, seminal, and crown) were more abundant but lacked the defining features of the F44 crown roots. An F1 hybrid between B73 and F44 mirrored the B73 nitrogen specificity and root architecture phenotypes, indicating complete dominance of the B73 inbred. This study highlights the important link between RSA and nitrogen management and why both variables need to be tested together when defining NUE improvements in any selection program. PMID:29740466

Estimating summary statistics for electronic health record laboratory data for use in high-throughput phenotyping algorithms

PubMed Central

Elhadad, N.; Claassen, J.; Perotte, R.; Goldstein, A.; Hripcsak, G.

2018-01-01

We study the question of how to represent or summarize raw laboratory data taken from an electronic health record (EHR) using parametric model selection to reduce or cope with biases induced through clinical care. It has been previously demonstrated that the health care process (Hripcsak and Albers, 2012, 2013), as defined by measurement context (Hripcsak and Albers, 2013; Albers et al., 2012) and measurement patterns (Albers and Hripcsak, 2010, 2012), can influence how EHR data are distributed statistically (Kohane and Weber, 2013; Pivovarov et al., 2014). We construct an algorithm, PopKLD, which is based on information criterion model selection (Burnham and Anderson, 2002; Claeskens and Hjort, 2008), is intended to reduce and cope with health care process biases and to produce an intuitively understandable continuous summary. The PopKLD algorithm can be automated and is designed to be applicable in high-throughput settings; for example, the output of the PopKLD algorithm can be used as input for phenotyping algorithms. Moreover, we develop the PopKLD-CAT algorithm that transforms the continuous PopKLD summary into a categorical summary useful for applications that require categorical data such as topic modeling. We evaluate our methodology in two ways. First, we apply the method to laboratory data collected in two different health care contexts, primary versus intensive care. We show that the PopKLD preserves known physiologic features in the data that are lost when summarizing the data using more common laboratory data summaries such as mean and standard deviation. Second, for three disease-laboratory measurement pairs, we perform a phenotyping task: we use the PopKLD and PopKLD-CAT algorithms to define high and low values of the laboratory variable that are used for defining a disease state. We then compare the relationship between the PopKLD-CAT summary disease predictions and the same predictions using empirically estimated mean and standard deviation to a gold standard generated by clinical review of patient records. We find that the PopKLD laboratory data summary is substantially better at predicting disease state. The PopKLD or PopKLD-CAT algorithms are not meant to be used as phenotyping algorithms, but we use the phenotyping task to show what information can be gained when using a more informative laboratory data summary. In the process of evaluation our method we show that the different clinical contexts and laboratory measurements necessitate different statistical summaries. Similarly, leveraging the principle of maximum entropy we argue that while some laboratory data only have sufficient information to estimate a mean and standard deviation, other laboratory data captured in an EHR contain substantially more information than can be captured in higher-parameter models. PMID:29369797

Estimating summary statistics for electronic health record laboratory data for use in high-throughput phenotyping algorithms.

PubMed

Albers, D J; Elhadad, N; Claassen, J; Perotte, R; Goldstein, A; Hripcsak, G

2018-02-01

We study the question of how to represent or summarize raw laboratory data taken from an electronic health record (EHR) using parametric model selection to reduce or cope with biases induced through clinical care. It has been previously demonstrated that the health care process (Hripcsak and Albers, 2012, 2013), as defined by measurement context (Hripcsak and Albers, 2013; Albers et al., 2012) and measurement patterns (Albers and Hripcsak, 2010, 2012), can influence how EHR data are distributed statistically (Kohane and Weber, 2013; Pivovarov et al., 2014). We construct an algorithm, PopKLD, which is based on information criterion model selection (Burnham and Anderson, 2002; Claeskens and Hjort, 2008), is intended to reduce and cope with health care process biases and to produce an intuitively understandable continuous summary. The PopKLD algorithm can be automated and is designed to be applicable in high-throughput settings; for example, the output of the PopKLD algorithm can be used as input for phenotyping algorithms. Moreover, we develop the PopKLD-CAT algorithm that transforms the continuous PopKLD summary into a categorical summary useful for applications that require categorical data such as topic modeling. We evaluate our methodology in two ways. First, we apply the method to laboratory data collected in two different health care contexts, primary versus intensive care. We show that the PopKLD preserves known physiologic features in the data that are lost when summarizing the data using more common laboratory data summaries such as mean and standard deviation. Second, for three disease-laboratory measurement pairs, we perform a phenotyping task: we use the PopKLD and PopKLD-CAT algorithms to define high and low values of the laboratory variable that are used for defining a disease state. We then compare the relationship between the PopKLD-CAT summary disease predictions and the same predictions using empirically estimated mean and standard deviation to a gold standard generated by clinical review of patient records. We find that the PopKLD laboratory data summary is substantially better at predicting disease state. The PopKLD or PopKLD-CAT algorithms are not meant to be used as phenotyping algorithms, but we use the phenotyping task to show what information can be gained when using a more informative laboratory data summary. In the process of evaluation our method we show that the different clinical contexts and laboratory measurements necessitate different statistical summaries. Similarly, leveraging the principle of maximum entropy we argue that while some laboratory data only have sufficient information to estimate a mean and standard deviation, other laboratory data captured in an EHR contain substantially more information than can be captured in higher-parameter models. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Phenotypic similarities and differences in patients with a p.Met112Ile mutation in SOX10.

PubMed

Pingault, Veronique; Pierre-Louis, Laurence; Chaoui, Asma; Verloes, Alain; Sarrazin, Elisabeth; Brandberg, Goran; Bondurand, Nadege; Uldall, Peter; Manouvrier-Hanu, Sylvie

2014-09-01

Waardenburg syndrome (WS) is characterized by an association of pigmentation abnormalities and sensorineural hearing loss. Four types, defined on clinical grounds, have been delineated, but this phenotypic classification correlates imperfectly with known molecular anomalies. SOX10 mutations have been found in patients with type II and type IV WS (i.e., with Hirschsprung disease), more complex syndromes, and partial forms of the disease. The phenotype induced by SOX10 mutations is highly variable and, except for the neurological forms of the disease, no genotype-phenotype correlation has been characterized to date. There is no mutation hotspot in SOX10 and most cases are sporadic, making it particularly difficult to correlate the phenotypic and genetic variability. This study reports on three independent families with SOX10 mutations predicted to result in the same missense mutation at the protein level (p.Met112Ile), offering a rare opportunity to improve our understanding of the mechanisms underlying phenotypic variability. The pigmentation defects of these patients are very similar, and the neurological symptoms showed a somewhat similar evolution over time, indicating a potential partial genotype-phenotype correlation. However, variability in gastrointestinal symptoms suggests that other genetic factors contribute to the expression of these phenotypes. No correlation between the rs2435357 polymorphism of RET and the expression of Hirschsprung disease was found. In addition, one of the patients has esophageal achalasia, which has rarely been described in WS. © 2014 Wiley Periodicals, Inc.

Phenotypic similarities and differences in patients with a p.Met112Ile mutation in SOX10

PubMed Central

Pingault, Veronique; Pierre-Louis, Laurence; Chaoui, Asma; Verloes, Alain; Sarrazin, Elisabeth; Brandberg, Goran; Bondurand, Nadege; Uldall, Peter; Manouvrier-Hanu, Sylvie

2014-01-01

Waardenburg syndrome (WS) is characterized by an association of pigmentation abnormalities and sensorineural hearing loss. Four types, defined on clinical grounds, have been delineated, but this phenotypic classification correlates imperfectly with known molecular anomalies. SOX10 mutations have been found in patients with type II and type IV WS (i.e., with Hirschsprung disease), more complex syndromes, and partial forms of the disease. The phenotype induced by SOX10 mutations is highly variable and, except for the neurological forms of the disease, no genotype-phenotype correlation has been characterized to date. There is no mutation hotspot in SOX10 and most cases are sporadic, making it particularly difficult to correlate the phenotypic and genetic variability. This study reports on three independent families with SOX10 mutations predicted to result in the same missense mutation at the protein level (p.Met112Ile), offering a rare opportunity to improve our understanding of the mechanisms underlying phenotypic variability. The pigmentation defects of these patients are very similar, and the neurological symptoms showed a somewhat similar evolution over time, indicating a potential partial genotype-phenotype correlation. However, variability in gastrointestinal symptoms suggests that other genetic factors contribute to the expression of these phenotypes. No correlation between the rs2435357 polymorphism of RET and the expression of Hirschsprung disease was found. In addition, one of the patients has esophageal achalasia, which has rarely been described in WS. PMID:24845202

Querying phenotype-genotype relationships on patient datasets using semantic web technology: the example of Cerebrotendinous xanthomatosis.

PubMed

Taboada, María; Martínez, Diego; Pilo, Belén; Jiménez-Escrig, Adriano; Robinson, Peter N; Sobrido, María J

2012-07-31

Semantic Web technology can considerably catalyze translational genetics and genomics research in medicine, where the interchange of information between basic research and clinical levels becomes crucial. This exchange involves mapping abstract phenotype descriptions from research resources, such as knowledge databases and catalogs, to unstructured datasets produced through experimental methods and clinical practice. This is especially true for the construction of mutation databases. This paper presents a way of harmonizing abstract phenotype descriptions with patient data from clinical practice, and querying this dataset about relationships between phenotypes and genetic variants, at different levels of abstraction. Due to the current availability of ontological and terminological resources that have already reached some consensus in biomedicine, a reuse-based ontology engineering approach was followed. The proposed approach uses the Ontology Web Language (OWL) to represent the phenotype ontology and the patient model, the Semantic Web Rule Language (SWRL) to bridge the gap between phenotype descriptions and clinical data, and the Semantic Query Web Rule Language (SQWRL) to query relevant phenotype-genotype bidirectional relationships. The work tests the use of semantic web technology in the biomedical research domain named cerebrotendinous xanthomatosis (CTX), using a real dataset and ontologies. A framework to query relevant phenotype-genotype bidirectional relationships is provided. Phenotype descriptions and patient data were harmonized by defining 28 Horn-like rules in terms of the OWL concepts. In total, 24 patterns of SWQRL queries were designed following the initial list of competency questions. As the approach is based on OWL, the semantic of the framework adapts the standard logical model of an open world assumption. This work demonstrates how semantic web technologies can be used to support flexible representation and computational inference mechanisms required to query patient datasets at different levels of abstraction. The open world assumption is especially good for describing only partially known phenotype-genotype relationships, in a way that is easily extensible. In future, this type of approach could offer researchers a valuable resource to infer new data from patient data for statistical analysis in translational research. In conclusion, phenotype description formalization and mapping to clinical data are two key elements for interchanging knowledge between basic and clinical research.

Gene Expression Signatures Characterized by Longitudinal Stability and Interindividual Variability Delineate Baseline Phenotypic Groups with Distinct Responses to Immune Stimulation.

PubMed

Scheid, Adam D; Van Keulen, Virginia P; Felts, Sara J; Neier, Steven C; Middha, Sumit; Nair, Asha A; Techentin, Robert W; Gilbert, Barry K; Jen, Jin; Neuhauser, Claudia; Zhang, Yuji; Pease, Larry R

2018-03-01

Human immunity exhibits remarkable heterogeneity among individuals, which engenders variable responses to immune perturbations in human populations. Population studies reveal that, in addition to interindividual heterogeneity, systemic immune signatures display longitudinal stability within individuals, and these signatures may reliably dictate how given individuals respond to immune perturbations. We hypothesize that analyzing relationships among these signatures at the population level may uncover baseline immune phenotypes that correspond with response outcomes to immune stimuli. To test this, we quantified global gene expression in peripheral blood CD4 + cells from healthy individuals at baseline and following CD3/CD28 stimulation at two time points 1 mo apart. Systemic CD4 + cell baseline and poststimulation molecular immune response signatures (MIRS) were defined by identifying genes expressed at levels that were stable between time points within individuals and differential among individuals in each state. Iterative differential gene expression analyses between all possible phenotypic groupings of at least three individuals using the baseline and stimulated MIRS gene sets revealed shared baseline and response phenotypic groupings, indicating the baseline MIRS contained determinants of immune responsiveness. Furthermore, significant numbers of shared phenotype-defining sets of determinants were identified in baseline data across independent healthy cohorts. Combining the cohorts and repeating the analyses resulted in identification of over 6000 baseline immune phenotypic groups, implying that the MIRS concept may be useful in many immune perturbation contexts. These findings demonstrate that patterns in complex gene expression variability can be used to define immune phenotypes and discover determinants of immune responsiveness. Copyright © 2018 by The American Association of Immunologists, Inc.

Influence of mom and dad: quantitative genetic models for maternal effects and genomic imprinting.

PubMed

Santure, Anna W; Spencer, Hamish G

2006-08-01

The expression of an imprinted gene is dependent on the sex of the parent it was inherited from, and as a result reciprocal heterozygotes may display different phenotypes. In contrast, maternal genetic terms arise when the phenotype of an offspring is influenced by the phenotype of its mother beyond the direct inheritance of alleles. Both maternal effects and imprinting may contribute to resemblance between offspring of the same mother. We demonstrate that two standard quantitative genetic models for deriving breeding values, population variances and covariances between relatives, are not equivalent when maternal genetic effects and imprinting are acting. Maternal and imprinting effects introduce both sex-dependent and generation-dependent effects that result in differences in the way additive and dominance effects are defined for the two approaches. We use a simple example to demonstrate that both imprinting and maternal genetic effects add extra terms to covariances between relatives and that model misspecification may over- or underestimate true covariances or lead to extremely variable parameter estimation. Thus, an understanding of various forms of parental effects is essential in correctly estimating quantitative genetic variance components.

3D mapping of airway wall thickening in asthma with MSCT: a level set approach

NASA Astrophysics Data System (ADS)

Fetita, Catalin; Brillet, Pierre-Yves; Hartley, Ruth; Grenier, Philippe A.; Brightling, Christopher

2014-03-01

Assessing the airway wall thickness in multi slice computed tomography (MSCT) as image marker for airway disease phenotyping such asthma and COPD is a current trend and challenge for the scientific community working in lung imaging. This paper addresses the same problem from a different point of view: considering the expected wall thickness-to-lumen-radius ratio for a normal subject as known and constant throughout the whole airway tree, the aim is to build up a 3D map of airway wall regions of larger thickness and to define an overall score able to highlight a pathological status. In this respect, the local dimension (caliber) of the previously segmented airway lumen is obtained on each point by exploiting the granulometry morphological operator. A level set function is defined based on this caliber information and on the expected wall thickness ratio, which allows obtaining a good estimate of the airway wall throughout all segmented lumen generations. Next, the vascular (or mediastinal dense tissue) contact regions are automatically detected and excluded from analysis. For the remaining airway wall border points, the real wall thickness is estimated based on the tissue density analysis in the airway radial direction; thick wall points are highlighted on a 3D representation of the airways and several quantification scores are defined. The proposed approach is fully automatic and was evaluated (proof of concept) on a patient selection coming from different databases including mild, severe asthmatics and normal cases. This preliminary evaluation confirms the discriminative power of the proposed approach regarding different phenotypes and is currently extending to larger cohorts.

The Lewis A phenotype is a restriction factor for Rotateq and Rotarix vaccine-take in Nicaraguan children.

PubMed

Bucardo, Filemón; Nordgren, Johan; Reyes, Yaoska; Gonzalez, Fredman; Sharma, Sumit; Svensson, Lennart

2018-01-24

Histo-blood group antigens (HBGAs) and the Lewis and secretor antigens are associated with susceptibility to rotavirus infection in a genotype-dependent manner. Nicaraguan children were prospectively enrolled in two cohorts vaccinated with either RotaTeq RV5 (n = 68) or Rotarix RV1 (n = 168). Lewis and secretor antigens were determined by saliva phenotyping and genotyping. Seroconversion was defined as a 4-fold increase in plasma IgA antibody titer 1 month after administration of the first dose of the vaccine. Regardless of the vaccine administered, significantly fewer of the children with Lewis A phenotype (0/14) seroconverted after receiving the first vaccine dose compared to 26% (45/175) of those with the Lewis B phenotype and 32% (15/47) of the Lewis negative individuals (P < 0.01). Furthermore, following administration of the RV1 vaccine, secretor-positive ABO blood group B children seroconverted to a significantly lesser extent (5%) compared to secretor-positive children with ABO blood groups A (26%) and O (27%) (P < 0.05). Other factors such as pre-vaccination titers, sex, breastfeeding, and calprotectin levels did not influence vaccine-take. Differences in HBGA expression appear to be a contributing factor in the discrepancy in vaccine-take and thus, in vaccine efficacy in different ethnic populations.

Divergent and convergent evolution in metastases suggest treatment strategies based on specific metastatic sites

PubMed Central

Cunningham, Jessica J.; Brown, Joel S.; Vincent, Thomas L.

2015-01-01

Background and objective: Systemic therapy for metastatic cancer is currently determined exclusively by the site of tumor origin. Yet, there is increasing evidence that the molecular characteristics of metastases significantly differ from the primary tumor. We define the evolutionary dynamics of metastases that govern this molecular divergence and examine their potential contribution to variations in response to targeted therapies. Methodology: Darwinian interactions of transformed cells with the tissue microenvironments at primary and metastatic sites are analyzed using evolutionary game theory. Computational models simulate responses to targeted therapies in different organs within the same patient. Results: Tumor cells, although maximally fit at their primary site, typically have lower fitness on the adaptive landscapes offered by the metastatic sites due to organ-specific variations in mesenchymal properties and signaling pathways. Clinically evident metastases usually exhibit time-dependent divergence from the phenotypic mean of the primary population as the tumor cells evolve and adapt to their new circumstances. In contrast, tumors from different primary sites evolving on identical metastatic adaptive landscapes exhibit phenotypic convergence. Thus, metastases in the liver from different primary tumors and even in different hosts will evolve toward similar adaptive phenotypes. The combination of evolutionary divergence from the primary cancer phenotype and convergence towards similar adaptive strategies in the same tissue cause significant variations in treatment responses particularly for highly targeted therapies. Conclusion and implications: The results suggest that optimal therapies for disseminated cancer must take into account the site(s) of metastatic growth as well as the primary organ. PMID:25794501

Influence of in vivo growth on human glioma cell line gene expression: Convergent profiles under orthotopic conditions

PubMed Central

Camphausen, Kevin; Purow, Benjamin; Sproull, Mary; Scott, Tamalee; Ozawa, Tomoko; Deen, Dennis F.; Tofilon, Philip J.

2005-01-01

Defining the molecules that regulate tumor cell survival is an essential prerequisite for the development of targeted approaches to cancer treatment. Whereas many studies aimed at identifying such targets use human tumor cells grown in vitro or as s.c. xenografts, it is unclear whether such experimental models replicate the phenotype of the in situ tumor cell. To begin addressing this issue, we have used microarray analysis to define the gene expression profile of two human glioma cell lines (U251 and U87) when grown in vitro and in vivo as s.c. or as intracerebral (i.c.) xenografts. For each cell line, the gene expression profile generated from tissue culture was significantly different from that generated from the s.c. tumor, which was significantly different from those grown i.c. The disparity between the i.c gene expression profiles and those generated from s.c. xenografts suggests that whereas an in vivo growth environment modulates gene expression, orthotopic growth conditions induce a different set of modifications. In this study the U251 and U87 gene expression profiles generated under the three growth conditions were also compared. As expected, the profiles of the two glioma cell lines were significantly different when grown as monolayer cultures. However, the glioma cell lines had similar gene expression profiles when grown i.c. These results suggest that tumor cell gene expression, and thus phenotype, as defined in vitro is affected not only by in vivo growth but also by orthotopic growth, which may have implications regarding the identification of relevant targets for cancer therapy. PMID:15928080

Generation of diverse neuronal subtypes in cloned populations of stem-like cells

PubMed Central

Varga, Balázs V; Hádinger, Nóra; Gócza, Elen; Dulberg, Vered; Demeter, Kornél; Madarász, Emília; Herberth, Balázs

2008-01-01

Background The central nervous tissue contains diverse subtypes of neurons with characteristic morphological and physiological features and different neurotransmitter phenotypes. The generation of neurons with defined neurotransmitter phenotypes seems to be governed by factors differently expressed along the anterior-posterior and dorsal-ventral body axes. The mechanisms of the cell-type determination, however, are poorly understood. Selected neuronal phenotypes had been generated from embryonic stem (ES) cells, but similar results were not obtained on more restricted neural stem cells, presumably due to the lack of homogeneous neural stem cell populations as a starting material. Results In the presented work, the establishment of different neurotransmitter phenotypes was investigated in the course of in vitro induced neural differentiation of a one-cell derived neuroectodermal cell line, in conjunction with the activation of various region-specific genes. For comparison, similar studies were carried out on the R1 embryonic stem (ES) and P19 multipotent embryonic carcinoma (EC) cells. In response to a short treatment with all-trans retinoic acid, all cell lines gave rise to neurons and astrocytes. Non-induced neural stem cells and self-renewing cells persisting in differentiated cultures, expressed "stemness genes" along with early embryonic anterior-dorsal positional genes, but did not express the investigated CNS region-specific genes. In differentiating stem-like cell populations, on the other hand, different region-specific genes, those expressed in non-overlapping regions along the body axes were activated. The potential for diverse regional specifications was induced in parallel with the initiation of neural tissue-type differentiation. In accordance with the wide regional specification potential, neurons with different neurotransmitter phenotypes developed. Mechanisms inherent to one-cell derived neural stem cell populations were sufficient to establish glutamatergic and GABAergic neuronal phenotypes but failed to manifest cathecolaminergic neurons. Conclusion The data indicate that genes involved in positional determination are activated along with pro-neuronal genes in conditions excluding any outside influences. Interactions among progenies of one cell derived neural stem cells are sufficient for the activation of diverse region specific genes and initiate different routes of neuronal specification. PMID:18808670

The role of IDH1 mutated tumour cells in secondary glioblastomas: an evolutionary game theoretical view

NASA Astrophysics Data System (ADS)

Basanta, David; Scott, Jacob G.; Rockne, Russ; Swanson, Kristin R.; Anderson, Alexander R. A.

2011-02-01

Recent advances in clinical medicine have elucidated two significantly different subtypes of glioblastoma which carry very different prognoses, both defined by mutations in isocitrate dehydrogenase-1 (IDH-1). The mechanistic consequences of this mutation have not yet been fully clarified, with conflicting opinions existing in the literature; however, IDH-1 mutation may be used as a surrogate marker to distinguish between primary and secondary glioblastoma multiforme (sGBM) from malignant progression of a lower grade glioma. We develop a mathematical model of IDH-1 mutated secondary glioblastoma using evolutionary game theory to investigate the interactions between four different phenotypic populations within the tumor: autonomous growth, invasive, glycolytic, and the hybrid invasive/glycolytic cells. Our model recapitulates glioblastoma behavior well and is able to reproduce two recent experimental findings, as well as make novel predictions concerning the rate of invasive growth as a function of vascularity, and fluctuations in the proportions of phenotypic populations that a glioblastoma will experience under different microenvironmental constraints.

Clinicopathological characteristics of triple negative breast cancer at a tertiary care hospital in India.

PubMed

Dogra, Atika; Doval, Dinesh Chandra; Sardana, Manjula; Chedi, Subhash Kumar; Mehta, Anurag

2014-01-01

Triple-negative breast cancer (TNBC), characterized by the lack of expression of estrogen receptor, progesterone receptor and human epidermal growth factor receptor-2, is typically associated with a poor prognosis. The majority of TNBCs show the expression of basal markers on gene expression profiling and most authors accept TNBC as basal-like (BL) breast cancer. However, a smaller fraction lacks a BL phenotype despite being TNBC. The literature is silent on non-basal-like (NBL) type of TNBC. The present study was aimed at defining behavioral differences between BL and NBL phenotypes. i) Identify the TNBCs and categorize them into BL and NBL breast cancer. ii) Examine the behavioral differences between two subtypes. iii) Observe the pattern of treatment failure among TNBCs. All TNBC cases during January 2009-December 2010 were retrieved. The subjects fitting the inclusion criteria of study were differentiated into BL and NBL phenotypes using surrogate immunohistochemistry with three basal markers 34βE12, c-Kit and EGFR as per the algorithm defined by Nielsen et al. The detailed data of subjects were collated from clinical records. The comparison of clinicopathological features between two subgroups was done using statistical analyses. The pattern of treatment failure along with its association with prognostic factors was assessed. TNBC constituted 18% of breast cancer cases considered in the study. The BL and NBL subtypes accounted for 81% and 19% respectively of the TNBC group. No statistically significant association was seen between prognostic parameters and two phenotypes. Among patients with treatment failure, 19% were with BL and 15% were with NBL phenotype. The mean disease free survival (DFS) in groups BL and NBL was 30.0 and 37.9 months respectively, while mean overall survival (OS) was 31.93 and 38.5 months respectively. Treatment failure was significantly associated with stage (p=.023) among prognostic factors. Disease stage at presentation is an important prognostic factor influencing the treatment failure and survival among TNBCs. Increasing tumor size is related to lymph node positivity. BL tumors have a more aggressive clinical course than that of NBL as shown by shorter DFS and OS, despite having no statistically significant difference between prognostic parameters. New therapeutic alternatives should be explored for patients with this subtype of breast cancer.

Hepatic Oval Cells Have the Side Population Phenotype Defined by Expression of ATP-Binding Cassette Transporter ABCG2/BCRP1

PubMed Central

Shimano, Koichi; Satake, Makoto; Okaya, Atsuhito; Kitanaka, Junichi; Kitanaka, Nobue; Takemura, Motohiko; Sakagami, Masafumi; Terada, Nobuyuki; Tsujimura, Tohru

2003-01-01

Organ-specific stem cells can be identified by the side population (SP) phenotype, which is defined by the property to effectively exclude the Hoechst 33342 dye. The ATP-binding cassette transporter ABCG2/BCRP1 mediates the SP phenotype. Because hepatic oval cells possess several characteristics of stem cells, we examined whether they have the SP phenotype using the 2-acetylaminofluorene/partial hepatectomy (PH) model. Fluorescence-activated cell sorting analysis showed that a population of non-parenchymal cells containing oval cells, prepared on day 7 after PH, carried a significant number of SP cells, whereas that of non-parenchymal cells without oval cells, prepared on day 0 after PH, did not. Northern blot analysis using total liver RNA obtained on various days after PH showed that the expression of ABCG2/BCRP1 mRNA increased after PH, reaching the highest level on day 7, and then gradually decreased. This pattern of changes in the ABCG2/BCRP1 mRNA level was well correlated to that in the number of oval cells. Furthermore, in situ hybridization revealed that oval cells were the sites of expression of ABCG2/BCRP1 mRNA. These results indicate that oval cells have the SP phenotype defined by expression of ABCG2/BCRP1, suggesting that oval cells may represent stem cells in the liver. PMID:12819005

Association between the hypertriglyceridemic waist phenotype, prediabetes and diabetes mellitus among adults in Puerto Rico

PubMed Central

Díaz-Santana, MV; Suárez, E; Ortiz, AP; Guzmán, M; Pérez, CM

2014-01-01

Background This study assessed the association of the hypertriglyceridemic waist (HTGW) phenotype with prediabetes and diabetes (DM) in a group of Hispanics. Methods Analysis of a cross-sectional study of 858 adults residing in Puerto Rico that collected data on blood pressure, biochemical, and anthropometric measurements was performed. HTGW phenotype was defined as elevated triglycerides and elevated waist circumference. Prediabetes was defined as a fasting glucose of 100–125 mg/dL and DM as a fasting glucose ≥126 mg/dL or prior diagnosis. Results Prevalence of HTGW, prediabetes and DM was 27.9%, 38.0% and 21.6%, respectively. Subjects with the HTGW phenotype had higher adjusted odds of prediabetes (POR=5.55; 95% CI=3.38–9.13) and DM (POR=7.28; 95% CI=3.63–14.63) compared to those without the phenotype. The association for prediabetes was stronger for women than among men. Discussion HTGW phenotype was strongly associated with prediabetes and DM, reinforcing the need to further assess its performance as a screening tool to identify at-risk individuals for cardiometabolic conditions. PMID:24519258

Evolving Digital Ecological Networks

PubMed Central

Wagner, Aaron P.; Ofria, Charles

2013-01-01

“It is hard to realize that the living world as we know it is just one among many possibilities” [1]. Evolving digital ecological networks are webs of interacting, self-replicating, and evolving computer programs (i.e., digital organisms) that experience the same major ecological interactions as biological organisms (e.g., competition, predation, parasitism, and mutualism). Despite being computational, these programs evolve quickly in an open-ended way, and starting from only one or two ancestral organisms, the formation of ecological networks can be observed in real-time by tracking interactions between the constantly evolving organism phenotypes. These phenotypes may be defined by combinations of logical computations (hereafter tasks) that digital organisms perform and by expressed behaviors that have evolved. The types and outcomes of interactions between phenotypes are determined by task overlap for logic-defined phenotypes and by responses to encounters in the case of behavioral phenotypes. Biologists use these evolving networks to study active and fundamental topics within evolutionary ecology (e.g., the extent to which the architecture of multispecies networks shape coevolutionary outcomes, and the processes involved). PMID:23533370

Quantitative genetics of human morphology and obesity-related phenotypes in nuclear families from the Greater Bilbao (Spain): comparison with other populations.

PubMed

Jelenkovic, Aline; Poveda, Alaitz; Rebato, Esther

2011-07-01

It is well established that variation of soft-tissue traits is less influenced by the genetic component than skeletal traits. However, it is still unclear whether heritabilities (h(2)) of obesity-related phenotypes present a common pattern across populations. To estimate familial resemblance and heritability of body size, shape and composition phenotypes and to compare these results with those from other populations. The subject group consisted of 533 nuclear families living in Greater Bilbao and included 1702 individuals aged 2-61 years. Familial correlations and h(2) were estimated for 29 anthropometric phenotypes (19 simple measures, three derived factors, four obesity indices and the three Heath-Carter somatotype components) using MAN and SOLAR programmes. All phenotypes were influenced by additive genetic factors with narrow sense heritabilities ranging from 0.28-0.69. In general, skeletal traits exhibited the highest h(2), whereas phenotypes defining the amount of adipose tissue, particularly central fat, were less determined by genetic factors. Familial correlations and heritability estimates of body morphology and composition from the Greater Bilbao sample were within the range observed in other studies. The lower heritability detected for central fat has also been found in some other populations, but further investigations in different populations using the same anthropometric traits and estimation methods are needed in order to obtain more robust conclusions.

Unique and shared functions of nuclear lamina LEM domain proteins in Drosophila.

PubMed

Barton, Lacy J; Wilmington, Shameika R; Martin, Melinda J; Skopec, Hannah M; Lovander, Kaylee E; Pinto, Belinda S; Geyer, Pamela K

2014-06-01

The nuclear lamina is an extensive protein network that contributes to nuclear structure and function. LEM domain (LAP2, emerin, MAN1 domain, LEM-D) proteins are components of the nuclear lamina, identified by a shared ∼45-amino-acid motif that binds Barrier-to-autointegration factor (BAF), a chromatin-interacting protein. Drosophila melanogaster has three nuclear lamina LEM-D proteins, named Otefin (Ote), Bocksbeutel (Bocks), and dMAN1. Although these LEM-D proteins are globally expressed, loss of either Ote or dMAN1 causes tissue-specific defects in adult flies that differ from each other. The reason for such distinct tissue-restricted defects is unknown. Here, we generated null alleles of bocks, finding that loss of Bocks causes no overt adult phenotypes. Next, we defined phenotypes associated with lem-d double mutants. Although the absence of individual LEM-D proteins does not affect viability, loss of any two proteins causes lethality. Mutant phenotypes displayed by lem-d double mutants differ from baf mutants, suggesting that BAF function is retained in animals with a single nuclear lamina LEM-D protein. Interestingly, lem-d double mutants displayed distinct developmental and cellular mutant phenotypes, suggesting that Drosophila LEM-D proteins have developmental functions that are differentially shared with other LEM-D family members. This conclusion is supported by studies showing that ectopically produced LEM-D proteins have distinct capacities to rescue the tissue-specific phenotypes found in single lem-d mutants. Our findings predict that cell-specific mutant phenotypes caused by loss of LEM-D proteins reflect both the constellation of LEM-D proteins within the nuclear lamina and the capacity of functional compensation of the remaining LEM-D proteins. Copyright © 2014 by the Genetics Society of America.

Unique and Shared Functions of Nuclear Lamina LEM Domain Proteins in Drosophila

PubMed Central

Barton, Lacy J.; Wilmington, Shameika R.; Martin, Melinda J.; Skopec, Hannah M.; Lovander, Kaylee E.; Pinto, Belinda S.; Geyer, Pamela K.

2014-01-01

The nuclear lamina is an extensive protein network that contributes to nuclear structure and function. LEM domain (LAP2, emerin, MAN1 domain, LEM-D) proteins are components of the nuclear lamina, identified by a shared ∼45-amino-acid motif that binds Barrier-to-autointegration factor (BAF), a chromatin-interacting protein. Drosophila melanogaster has three nuclear lamina LEM-D proteins, named Otefin (Ote), Bocksbeutel (Bocks), and dMAN1. Although these LEM-D proteins are globally expressed, loss of either Ote or dMAN1 causes tissue-specific defects in adult flies that differ from each other. The reason for such distinct tissue-restricted defects is unknown. Here, we generated null alleles of bocks, finding that loss of Bocks causes no overt adult phenotypes. Next, we defined phenotypes associated with lem-d double mutants. Although the absence of individual LEM-D proteins does not affect viability, loss of any two proteins causes lethality. Mutant phenotypes displayed by lem-d double mutants differ from baf mutants, suggesting that BAF function is retained in animals with a single nuclear lamina LEM-D protein. Interestingly, lem-d double mutants displayed distinct developmental and cellular mutant phenotypes, suggesting that Drosophila LEM-D proteins have developmental functions that are differentially shared with other LEM-D family members. This conclusion is supported by studies showing that ectopically produced LEM-D proteins have distinct capacities to rescue the tissue-specific phenotypes found in single lem-d mutants. Our findings predict that cell-specific mutant phenotypes caused by loss of LEM-D proteins reflect both the constellation of LEM-D proteins within the nuclear lamina and the capacity of functional compensation of the remaining LEM-D proteins. PMID:24700158

A phenotype of early infancy predicts reactivity of the amygdala in male adults.

PubMed

Schwartz, C E; Kunwar, P S; Greve, D N; Kagan, J; Snidman, N C; Bloch, R B

2012-10-01

One of the central questions that has occupied those disciplines concerned with human development is the nature of continuities and discontinuities from birth to maturity. The amygdala has a central role in the processing of novelty and emotion in the brain. Although there is considerable variability among individuals in the reactivity of the amygdala to novel and emotional stimuli, the origin of these individual differences is not well understood. Four-month old infants called high reactive (HR) demonstrate a distinctive pattern of vigorous motor activity and crying to specific unfamiliar visual, auditory and olfactory stimuli in the laboratory. Low-reactive infants show the complementary pattern. Here, we demonstrate that the HR infant phenotype predicts greater amygdalar reactivity to novel faces almost two decades later in adults. A prediction of individual differences in brain function at maturity can be made on the basis of a single behavioral assessment made in the laboratory at 4 months of age. This is the earliest known human behavioral phenotype that predicts individual differences in patterns of neural activity at maturity. These temperamental differences rooted in infancy may be relevant to understanding individual differences in vulnerability and resilience to clinical psychiatric disorder. Males who were HR infants showed particularly high levels of reactivity to novel faces in the amygdala that distinguished them as adults from all other sex/temperament subgroups, suggesting that their amygdala is particularly prone to engagement by unfamiliar faces. These findings underline the importance of taking gender into account when studying the developmental neurobiology of human temperament and anxiety disorders. The genetic study of behavioral and biologic intermediate phenotypes (or 'endophenotypes') indexing anxiety-proneness offers an important alternative to examining phenotypes based on clinically defined disorder. As the HR phenotype is characterized by specific patterns of reactivity to elemental visual, olfactory and auditory stimuli, well before complex social behaviors such as shyness or fearful interaction with strangers can be observed, it may be closer to underlying neurobiological mechanisms than behavioral profiles observed later in life. This possibility, together with the fact that environmental factors have less time to impact the 4-month phenotype, suggests that this temperamental profile may be a fruitful target for high-risk genetic studies.

Genetic modifiers of Duchenne and facioscapulohumeral muscular dystrophies.

PubMed

Hightower, Rylie M; Alexander, Matthew S

2018-01-01

Muscular dystrophy is defined as the progressive wasting of skeletal muscles that is caused by inherited or spontaneous genetic mutations. Next-generation sequencing has greatly improved the accuracy and speed of diagnosis for different types of muscular dystrophy. Advancements in depth of coverage, convenience, and overall reduced cost have led to the identification of genetic modifiers that are responsible for phenotypic variability in affected patients. These genetic modifiers have been postulated to explain key differences in disease phenotypes, including age of loss of ambulation, steroid responsiveness, and the presence or absence of cardiac defects in patients with the same form of muscular dystrophy. This review highlights recent findings on genetic modifiers of Duchenne and facioscapulohumeral muscular dystrophies based on animal and clinical studies. These genetic modifiers hold great promise to be developed into novel therapeutic targets for the treatment of muscular dystrophies. Muscle Nerve 57: 6-15, 2018. © 2017 Wiley Periodicals, Inc.

Genetic Modifiers of Duchenne and Facioscapulohumeral Muscular Dystrophies

PubMed Central

Hightower, Rylie M.; Alexander, Matthew S.

2017-01-01

Muscular dystrophy is defined as the progressive wasting of skeletal muscles that is caused by inherited or spontaneous genetic mutations. Next-generation sequencing (NGS) has greatly improved the accuracy and speed of diagnosis for different types of muscular dystrophy. Advancements in depth of coverage, convenience, and overall reduced cost, have led to the identification of genetic modifiers that are responsible for phenotypic variability in affected patients. These genetic modifiers have been postulated to explain key differences in disease phenotypes including age of loss of ambulation, steroid-responsiveness, and the presence or absence of cardiac defects in patients with the same form of muscular dystrophy. Here we review and highlight recent findings on genetic modifiers of Duchenne and Facioscapulohumeral muscular dystrophies based on animal and clinical studies. These genetic modifiers hold great promise to be developed into novel therapeutic targets for the treatment of muscular dystrophies. PMID:28877560

Phenotype variability of infantile-onset multisystem neurologic, endocrine, and pancreatic disease IMNEPD.

PubMed

Picker-Minh, Sylvie; Mignot, Cyril; Doummar, Diane; Hashem, Mais; Faqeih, Eissa; Josset, Patrice; Dubern, Béatrice; Alkuraya, Fowzan S; Kraemer, Nadine; Kaindl, Angela M

2016-04-29

Infantile-onset multisystem neurologic, endocrine, and pancreatic disease (IMNEPD) has been recently linked to biallelic mutation of the peptidyl-tRNA hydrolase 2 gene PTRH2. Two index patients with IMNEPD in the original report had multiple neurological symptoms such as postnatal microcephaly, intellectual disability, developmental delay, sensorineural deafness, cerebellar atrophy, ataxia, and peripheral neuropathy. In addition, distal muscle weakness and abnormalities of thyroid, pancreas, and liver were found. Here, we report five further IMNEPD patients with a different homozygous PTRH2 mutation, broaden the phenotypic spectrum of the disease and differentiate common symptoms and interindividual variability in IMNEPD associated with a unique mutation. We thereby hope to better define IMNEPD and promote recognition and diagnosis of this novel disease entity.

Peripheral blood antigen presenting cell responses in otitis-prone and non-otitis-prone infants.

PubMed

Surendran, Naveen; Nicolosi, Ted; Kaur, Ravinder; Pichichero, Michael E

2016-01-01

Stringently defined otitis-prone (sOP) children represent a new classification of the otitis-prone condition. Previous studies showed dysfunction in Ab, B-cell memory and T-cell memory responses. We sought to determine whether there are defects in numbers, phenotype and/or function of professional APC in the peripheral blood of sOP infants. APC phenotypic counts, MHC II expression and intracellular cytokine levels were determined in response to TLR7/8 (R848) stimulation by flow cytometry. Innate immune mRNA expression was measured using RT-PCR and cytokines were measured using Luminex technology. Significant (P < 0.05) increases in the phenotypic counts of monocytes and conventional dendritic cells but not plasmacytoid DCs were observed in sOP compared with non-otitis-prone (NOP) age-matched infants. No significant differences in APC activation or function were observed. Expression of various TLRs, intracellular signaling molecules and downstream cytokines was also not found to be significantly different between sOP and NOP infants. Higher numbers of APCs in sOP infants suggest the possibility of a persistent mucosal inflammatory status. Transcriptional and cytokine profiles of PBMCs among sOP infants suggest their systemic innate responses are not different compared to NOP infants. © The Author(s) 2015.

Gastritis: the histology report.

PubMed

Rugge, Massimo; Pennelli, Gianmaria; Pilozzi, Emanuela; Fassan, Matteo; Ingravallo, Giuseppe; Russo, Valentina M; Di Mario, Francesco

2011-03-01

Gastritis is defined as inflammation of the gastric mucosa. In histological terms, it is distinguishable into two main categories, i.e. non-atrophic and atrophic. In the gastric mucosa, atrophy is defined as the loss of appropriate glands. There are several etiological types of gastritis, their different etiology being related to different clinical manifestations and pathological features. Atrophic gastritis (resulting mainly from long-standing Helicobacter pylori infection) is a major risk factor for the onset of (intestinal type) gastric cancer. The extent and site of the atrophic changes correlate significantly with the cancer risk. The current format for histology reporting in cases of gastritis fails to establish an immediate link between gastritis phenotype and risk of malignancy. Building on current knowledge of the biology of gastritis, an international group of pathologists [Operative Link for Gastritis Assessment (OLGA)] has proposed a system for reporting gastritis in terms of its stage (the OLGA Staging System): this system places the histological phenotypes of gastritis on a scale of progressively increasing gastric cancer risk, from the lowest (Stage 0) to the highest (Stage IV). The aim of this tutorial is to provide unequivocal information on how to standardize histology reports on gastritis in diagnostic practice. Copyright © 2011 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd.. All rights reserved.

Phenotypic and molecular characterizations of Yersinia pestis isolates from Kazakhstan and adjacent regions.

PubMed

Lowell, Jennifer L; Zhansarina, Aigul; Yockey, Brook; Meka-Mechenko, Tatyana; Stybayeva, Gulnaz; Atshabar, Bakyt; Nekrassova, Larissa; Tashmetov, Rinat; Kenghebaeva, Kuralai; Chu, May C; Kosoy, Michael; Antolin, Michael F; Gage, Kenneth L

2007-01-01

Recent interest in characterizing infectious agents associated with bioterrorism has resulted in the development of effective pathogen genotyping systems, but this information is rarely combined with phenotypic data. Yersinia pestis, the aetiological agent of plague, has been well defined genotypically on local and worldwide scales using multi-locus variable number tandem repeat analysis (MLVA), with emphasis on evolutionary patterns using old isolate collections from countries where Y. pestis has existed the longest. Worldwide MLVA studies are largely based on isolates that have been in long-term laboratory culture and storage, or on field material from parts of the world where Y. pestis has potentially circulated in nature for thousands of years. Diversity in these isolates suggests that they may no longer represent the wild-type organism phenotypically, including the possibility of altered pathogenicity. This study focused on the phenotypic and genotypic properties of 48 Y. pestis isolates collected from 10 plague foci in and bordering Kazakhstan. Phenotypic characterization was based on diagnostic tests typically performed in reference laboratories working with Y. pestis. MLVA was used to define the genotypic relationships between the central-Asian isolates and a group of North American isolates, and to examine Kazakh Y. pestis diversity according to predefined plague foci and on an intermediate geographical scale. Phenotypic properties revealed that a large portion of this collection lacks one or more plasmids necessary to complete the blocked flea/mammal transmission cycle, has lost Congo red binding capabilities (Pgm-), or both. MLVA analysis classified isolates into previously identified biovars, and in some cases groups of isolates collected within the same plague focus formed a clade. Overall, MLVA did not distinguish unique phylogeographical groups of Y. pestis isolates as defined by plague foci and indicated higher genetic diversity among older biovars.

Surprisal analysis of genome-wide transcript profiling identifies differentially expressed genes and pathways associated with four growth conditions in the microalga Chlamydomonas.

PubMed

Bogaert, Kenny A; Manoharan-Basil, Sheeba S; Perez, Emilie; Levine, Raphael D; Remacle, Francoise; Remacle, Claire

2018-01-01

The usual cultivation mode of the green microalga Chlamydomonas is liquid medium and light. However, the microalga can also be grown on agar plates and in darkness. Our aim is to analyze and compare gene expression of cells cultivated in these different conditions. For that purpose, RNA-seq data are obtained from Chlamydomonas samples of two different labs grown in four environmental conditions (agar@light, agar@dark, liquid@light, liquid@dark). The RNA seq data are analyzed by surprisal analysis, which allows the simultaneous meta-analysis of all the samples. First we identify a balance state, which defines a state where the expression levels are similar in all the samples irrespectively of their growth conditions, or lab origin. In addition our analysis identifies additional constraints needed to quantify the deviation with respect to the balance state. The first constraint differentiates the agar samples versus the liquid ones; the second constraint the dark samples versus the light ones. The two constraints are almost of equal importance. Pathways involved in stress responses are found in the agar phenotype while the liquid phenotype comprises ATP and NADH production pathways. Remodeling of membrane is suggested in the dark phenotype while photosynthetic pathways characterize the light phenotype. The same trends are also present when performing purely statistical analysis such as K-means clustering and differentially expressed genes.

Integration of Network Biology and Imaging to Study Cancer Phenotypes and Responses.

PubMed

Tian, Ye; Wang, Sean S; Zhang, Zhen; Rodriguez, Olga C; Petricoin, Emanuel; Shih, Ie-Ming; Chan, Daniel; Avantaggiati, Maria; Yu, Guoqiang; Ye, Shaozhen; Clarke, Robert; Wang, Chao; Zhang, Bai; Wang, Yue; Albanese, Chris

2014-01-01

Ever growing "omics" data and continuously accumulated biological knowledge provide an unprecedented opportunity to identify molecular biomarkers and their interactions that are responsible for cancer phenotypes that can be accurately defined by clinical measurements such as in vivo imaging. Since signaling or regulatory networks are dynamic and context-specific, systematic efforts to characterize such structural alterations must effectively distinguish significant network rewiring from random background fluctuations. Here we introduced a novel integration of network biology and imaging to study cancer phenotypes and responses to treatments at the molecular systems level. Specifically, Differential Dependence Network (DDN) analysis was used to detect statistically significant topological rewiring in molecular networks between two phenotypic conditions, and in vivo Magnetic Resonance Imaging (MRI) was used to more accurately define phenotypic sample groups for such differential analysis. We applied DDN to analyze two distinct phenotypic groups of breast cancer and study how genomic instability affects the molecular network topologies in high-grade ovarian cancer. Further, FDA-approved arsenic trioxide (ATO) and the ND2-SmoA1 mouse model of Medulloblastoma (MB) were used to extend our analyses of combined MRI and Reverse Phase Protein Microarray (RPMA) data to assess tumor responses to ATO and to uncover the complexity of therapeutic molecular biology.

Assessing spatial and temporal variability of phytoplankton communities' composition in the Iroise Sea ecosystem (Brittany, France): A 3D modeling approach. Part 2: Linking summer mesoscale distribution of phenotypic diversity to hydrodynamism

NASA Astrophysics Data System (ADS)

Cadier, Mathilde; Sourisseau, Marc; Gorgues, Thomas; Edwards, Christopher A.; Memery, Laurent

2017-05-01

Tidal front ecosystems are especially dynamic environments usually characterized by high phytoplankton biomass and high primary production. However, the description of functional microbial diversity occurring in these regions remains only partially documented. In this article, we use a numerical model, simulating a large number of phytoplankton phenotypes to explore the three-dimensional spatial patterns of phytoplankton abundance and diversity in the Iroise Sea (western Brittany). Our results suggest that, in boreal summer, a seasonally marked tidal front shapes the phytoplankton species richness. A diversity maximum is found in the surface mixed layer located slightly west of the tidal front (i.e., not strictly co-localized with high biomass concentrations) which separates tidally mixed from stratified waters. Differences in phenotypic composition between sub-regions with distinct hydrodynamic regimes (defined by vertical mixing, nutrients gradients and light penetration) are discussed. Local growth and/or physical transport of phytoplankton phenotypes are shown to explain our simulated diversity distribution. We find that a large fraction (64%) of phenotypes present during the considered period of September are ubiquitous, found in the frontal area and on both sides of the front (i.e., over the full simulated domain). The frontal area does not exhibit significant differences between its community composition and that of either the well-mixed region or an offshore Deep Chlorophyll Maximum (DCM). Only three phenotypes (out of 77) specifically grow locally and are found at substantial concentration only in the surface diversity maximum. Thus, this diversity maximum is composed of a combination of ubiquitous phenotypes with specific picoplankton deriving from offshore, stratified waters (including specific phenotypes from both the surface and the DCM) and imported through physical transport, completed by a few local phenotypes. These results are discussed in light of the three-dimensional general circulation at frontal interfaces. Processes identified by this study are likely to be common in tidal front environments and may be generalized to other shallow, tidally mixed environments worldwide.

Querying phenotype-genotype relationships on patient datasets using semantic web technology: the example of cerebrotendinous xanthomatosis

PubMed Central

2012-01-01

Background Semantic Web technology can considerably catalyze translational genetics and genomics research in medicine, where the interchange of information between basic research and clinical levels becomes crucial. This exchange involves mapping abstract phenotype descriptions from research resources, such as knowledge databases and catalogs, to unstructured datasets produced through experimental methods and clinical practice. This is especially true for the construction of mutation databases. This paper presents a way of harmonizing abstract phenotype descriptions with patient data from clinical practice, and querying this dataset about relationships between phenotypes and genetic variants, at different levels of abstraction. Methods Due to the current availability of ontological and terminological resources that have already reached some consensus in biomedicine, a reuse-based ontology engineering approach was followed. The proposed approach uses the Ontology Web Language (OWL) to represent the phenotype ontology and the patient model, the Semantic Web Rule Language (SWRL) to bridge the gap between phenotype descriptions and clinical data, and the Semantic Query Web Rule Language (SQWRL) to query relevant phenotype-genotype bidirectional relationships. The work tests the use of semantic web technology in the biomedical research domain named cerebrotendinous xanthomatosis (CTX), using a real dataset and ontologies. Results A framework to query relevant phenotype-genotype bidirectional relationships is provided. Phenotype descriptions and patient data were harmonized by defining 28 Horn-like rules in terms of the OWL concepts. In total, 24 patterns of SWQRL queries were designed following the initial list of competency questions. As the approach is based on OWL, the semantic of the framework adapts the standard logical model of an open world assumption. Conclusions This work demonstrates how semantic web technologies can be used to support flexible representation and computational inference mechanisms required to query patient datasets at different levels of abstraction. The open world assumption is especially good for describing only partially known phenotype-genotype relationships, in a way that is easily extensible. In future, this type of approach could offer researchers a valuable resource to infer new data from patient data for statistical analysis in translational research. In conclusion, phenotype description formalization and mapping to clinical data are two key elements for interchanging knowledge between basic and clinical research. PMID:22849591

The Role of 16S rRNA Gene Sequencing in Identification of Microorganisms Misidentified by Conventional Methods

PubMed Central

Petti, C. A.; Polage, C. R.; Schreckenberger, P.

2005-01-01

Traditional methods for microbial identification require the recognition of differences in morphology, growth, enzymatic activity, and metabolism to define genera and species. Full and partial 16S rRNA gene sequencing methods have emerged as useful tools for identifying phenotypically aberrant microorganisms. We report on three bacterial blood isolates from three different College of American Pathologists-certified laboratories that were referred to ARUP Laboratories for definitive identification. Because phenotypic identification suggested unusual organisms not typically associated with the submitted clinical diagnosis, consultation with the Medical Director was sought and further testing was performed including partial 16S rRNA gene sequencing. All three patients had endocarditis, and conventional methods identified isolates from patients A, B, and C as a Facklamia sp., Eubacterium tenue, and a Bifidobacterium sp. 16S rRNA gene sequencing identified the isolates as Enterococcus faecalis, Cardiobacterium valvarum, and Streptococcus mutans, respectively. We conclude that the initial identifications of these three isolates were erroneous, may have misled clinicians, and potentially impacted patient care. 16S rRNA gene sequencing is a more objective identification tool, unaffected by phenotypic variation or technologist bias, and has the potential to reduce laboratory errors. PMID:16333109

The Relation between Diverse Phenotypes of PCOS with Clinical Manifestations, Anthropometric Indices and Metabolic Characteristics.

PubMed

Shahrami, Seyedeh Hajar; Abbasi Ranjbar, Zahra; Milani, Forozan; Kezem-Nejad, Ehsan; Hassanzadeh Rad, Afagh; Dalil Heirat, Seyedeh Fatemeh

2016-02-01

Critical issue regarding to variation of findings based on different phenotypes led investigators to define whether they are distinct features or overlapping ones. Therefore, we aimed to investigate the association between diverse phenotypes of PCOS (Poly Cystic Ovary Syndrome) with clinical manifestations, anthropometric indices, and metabolic characteristics. This was a descriptive cross-sectional study conducted in 15-39 years old women with PCOS referred to infertility clinics in the north part of Iran, Rasht during 2010-2011. Data were gathered through an interview by a form consisted of demographic characteristics, laboratory findings, ovarian volume and anthropometric indices. A total of 214 patients consisted of 161 PCOS (cases) and 53 normal women (controls) participated in this study. The most prevalent phenotype in PCOS population was IM/PCO/HA (54%), followed by IM/HA (28%) and IM/PCO (13%). PCO/HA was present only in 6 PCOS patients (5%). PCOS patients were significantly younger than controls (P=0.07). Results showed that increased ovarian volume were higher in PCOS group in comparison with controls and IM/PCO/HA, and IM/PCO had respectively the largest ovarian volumes. Also, a significant relation was observed based on Cholesterol, 17OHP, LH, TG, 2hpp, and LH/FSH between patients with PCOS and control groups. There were significant differences in demographic, anthropometric, hormonal and ultrasound findings between PCOS and controls. Therefore, it seems that classification of the characteristics of each phenotype could offer an appropriate guide for screening risks of PCOS and may facilitate performing most favorable treatment for these complications.

High-Density Genetic Mapping Identifies New Susceptibility Variants in Sarcoidosis Phenotypes and Shows Genomic-driven Phenotypic Differences

PubMed Central

Ronninger, Marcus; Shchetynsky, Klementy; Franke, Andre; Nöthen, Markus M.; Müller-Quernheim, Joachim; Schreiber, Stefan; Adrianto, Indra; Karakaya, Bekir; van Moorsel, Coline H. M.; Navratilova, Zdenka; Kolek, Vitezslav; Rybicki, Benjamin A.; Iannuzzi, Michael C.; Petrek, Martin; Grutters, Jan C.; Montgomery, Courtney; Fischer, Annegret; Eklund, Anders; Padyukov, Leonid; Grunewald, Johan

2016-01-01

Rationale: Sarcoidosis is a multisystem disease of unknown cause. Löfgren’s syndrome (LS) is a characteristic subgroup of sarcoidosis that is associated with a good prognosis in sarcoidosis. However, little is known about its genetic architecture or its broader phenotype, non-LS sarcoidosis. Objectives: To address the genetic architecture of sarcoidosis phenotypes, LS and non-LS. Methods: An association study in a white Swedish cohort of 384 LS, 664 non-LS, and 2,086 control subjects, totaling 3,134 subjects using a fine-mapping genotyping platform was conducted. Replication was performed in four independent cohorts, three of white European descent (Germany, n = 4,975; the Netherlands, n = 613; and Czech Republic, n = 521), and one of black African descent (United States, n = 1,657), totaling 7,766 subjects. Measurements and Main Results: A total of 727 LS-associated variants expanding throughout the extended major histocompatibility complex (MHC) region and 68 non-LS–associated variants located in the MHC class II region were identified and confirmed. A shared overlap between LS and non-LS defined by 17 variants located in the MHC class II region was found. Outside the MHC region, two LS-associated loci, in ADCY3 and between CSMD1 and MCPH1, were observed and replicated. Conclusions: Comprehensive and integrative analyses of genetics, transcription, and pathway modeling on LS and non-LS indicates that these sarcoidosis phenotypes have different genetic susceptibility, genomic distributions, and cellular activities, suggesting distinct molecular mechanisms in pathways related to immune response with a common region. PMID:26651848

Induced responses to competition and herbivory: natural selection on multi-trait phenotypic plasticity.

PubMed

Boege, Karina

2010-09-01

Herbivory and competition are two of the most common biotic stressors for plants. When occurring simultaneously, responses to one interaction can constrain the induction of responses to the other interaction due to resource limitation and other interactive effects. Thus, to maximize fitness when interacting with competitors and herbivores, plants are likely to express particular combinations of plastic responses. This study reports the interactive effects of herbivory and competition on responses induced in Tithonia tubaeformis plants and describes how natural selection acts on particular plastic responses and on their different combinations. Competition induced a stem elongation response, expressed through an increase in height and mean internode length, together with a decrease in basal diameter. Interestingly, realized resistance increased in both competition and herbivory treatments, suggesting a plastic response in both constitutive and induced resistance traits. Particular combinations of plastic responses defined three plant phenotypes: vigorous, elongated, and resistant plants. The ecological context in which plants grew modified the traits and the particular combinations of plastic responses that were favored by selection. Vigorous plants were favored by selection in all environments, except when they were damaged by herbivores in the absence of neighbors. The combination of responses defining an elongated plant phenotype was favored by selection in crowded conditions. Resistance was negatively selected in the absence of competition and herbivory but favored in the presence of both interactions. In addition, contextual analyses detected that population structure in heterogeneous environments can also influence the outcomes of selection. These findings suggest that natural selection can act on particular combinations of plastic responses, which may allow plants to adjust their phenotypes to those that promote greater fitness under particular ecological conditions.

Integrated Behavioral Z-Scoring Increases the Sensitivity and Reliability of Behavioral Phenotyping in mice: Relevance to Emotionality and Sex

PubMed Central

Guilloux, Jean-Philippe; Seney, Marianne; Edgar, Nicole; Sibille, Etienne

2011-01-01

Defining anxiety- and depressive-like states in mice (“emotionality”) is best characterized by the use of complementary tests, leading sometimes to puzzling discrepancies and lack of correlation between similar paradigms. To address this issue, we hypothesized that integrating measures along the same behavioral dimensions in different tests would reduce the intrinsic variability of single tests and provide a robust characterization of the underlying “emotionality” of individual mouse, similarly as mood and related syndromes are defined in humans through various related symptoms over time. We describe the use of simple mathematical and integrative tools to help phenotype animals across related behavioral tests (syndrome diagnosis) and experiments (meta-analysis). We applied z-normalization across complementary measures of emotionality in different behavioral tests after unpredictable chronic mild stress (UCMS) or prolonged corticosterone exposure - two approaches to induce anxious-/depressive-like states in mice. Combining z-normalized test values, lowered the variance of emotionality measurement, enhanced the reliability of behavioral phenotyping, and increased analytical opportunities. Comparing integrated emotionality scores across studies revealed a robust sexual dimorphism in the vulnerability to develop high emotionality, manifested as higher UCMS-induced emotionality z-scores, but lower corticosterone-induced scores in females compared to males. Interestingly, the distribution of individual z-scores revealed a pattern of increased baseline emotionality in female mice, reminiscent of what is observed in humans. Together, we show that the z-scoring method yields robust measures of emotionality across complementary tests for individual mice and experimental groups, hence facilitating the comparison across studies and refining the translational applicability of these models. PMID:21277897

Integrated behavioral z-scoring increases the sensitivity and reliability of behavioral phenotyping in mice: relevance to emotionality and sex.

PubMed

Guilloux, Jean-Philippe; Seney, Marianne; Edgar, Nicole; Sibille, Etienne

2011-04-15

Defining anxiety- and depressive-like states in mice (emotionality) is best characterized by the use of complementary tests, leading sometimes to puzzling discrepancies and lack of correlation between similar paradigms. To address this issue, we hypothesized that integrating measures along the same behavioral dimensions in different tests would reduce the intrinsic variability of single tests and provide a robust characterization of the underlying "emotionality" of individual mouse, similarly as mood and related syndromes are defined in humans through various related symptoms over time. We describe the use of simple mathematical and integrative tools to help phenotype animals across related behavioral tests (syndrome diagnosis) and experiments (meta-analysis). We applied z-normalization across complementary measures of emotionality in different behavioral tests after unpredictable chronic mild stress (UCMS) or prolonged corticosterone exposure - two approaches to induce anxious-/depressive-like states in mice. Combining z-normalized test values, lowered the variance of emotionality measurement, enhanced the reliability of behavioral phenotyping, and increased analytical opportunities. Comparing integrated emotionality scores across studies revealed a robust sexual dimorphism in the vulnerability to develop high emotionality, manifested as higher UCMS-induced emotionality z-scores, but lower corticosterone-induced scores in females compared to males. Interestingly, the distribution of individual z-scores revealed a pattern of increased baseline emotionality in female mice, reminiscent of what is observed in humans. Together, we show that the z-scoring method yields robust measures of emotionality across complementary tests for individual mice and experimental groups, hence facilitating the comparison across studies and refining the translational applicability of these models. Copyright © 2011 Elsevier B.V. All rights reserved.

Morphometrics within dog breeds are highly reproducible and dispute Rensch’s rule

PubMed Central

Sutter, Nathan B.; Mosher, Dana S.; Gray, Melissa M.

2009-01-01

Using 27 body measurements, we have identified 13 breed-defining metrics for 109 of 159 domestic dog breeds, most of which are recognized by the American Kennel Club (AKC). The data set included 1,155 dogs at least 1 year old (average 5.4 years), and for 53 breed populations, complete measurement data were collected from at least three males and three females. We demonstrate, first, that AKC breed standards are rigorously adhered to for most domestic breeds with little variation observed within breeds. Second, Rensch’s rule, which describes a scaling among taxa such that sexual dimorphism is greater among larger species if males are the larger sex, with less pronounced differences in male versus female body size in smaller species, is not maintained in domestic dog breeds because the proportional size difference between males and females of small and large breeds is essentially the same. Finally, principal components (PCs) analysis describes both the overall body size (PC1) and the shape (length versus width) of the skeleton (PC2). That the integrity of the data set is sufficiently rich to discern PCs has strong implications for mapping studies, suggesting that individual measurements may not be needed for genetic studies of morphologic traits, particularly in the case of breed-defining traits that are typically under strong selection. Rather, phenotypes derived from data sets such as these, collected at a fraction of the effort and cost, may be used to direct whole-genome association studies aimed at understanding the genetic basis of fixed morphologic phenotypes defining distinct dog breeds. PMID:19020935

The Structure of The Extended Psychosis Phenotype in Early Adolescence—A Cross-sample Replication

PubMed Central

Wigman, Johanna T. W.; Vollebergh, Wilma A. M.; Raaijmakers, Quinten A. W.; Iedema, Jurjen; van Dorsselaer, Saskia; Ormel, Johan; Verhulst, Frank C.; van Os, Jim

2011-01-01

The extended psychosis phenotype, or the expression of nonclinical positive psychotic experiences, is already prevalent in adolescence and has a dose-response risk relationship with later psychotic disorder. In 2 large adolescent general population samples (n = 5422 and n = 2230), prevalence and structure of the extended psychosis phenotype was investigated. Positive psychotic experiences, broadly defined, were reported by the majority of adolescents. Exploratory analysis with Structural Equation Modelling (Exploratory Factor Analysis followed by Confirmatory Factor Analysis [CFA]) in sample 1 suggested that psychotic experiences were best represented by 5 underlying dimensions; CFA in sample 2 provided a replication of this model. Dimensions were labeled Hallucinations, Delusions, Paranoia, Grandiosity, and Paranormal beliefs. Prevalences differed strongly, Hallucinations having the lowest and Paranoia having the highest rates. Girls reported more experiences on all dimensions, except Grandiosity, and from age 12 to 16 years rates increased. Hallucinations, Delusions, and Paranoia, but not Grandiosity and Paranormal beliefs, were associated with distress and general measures of psychopathology. Thus, only some of the dimensions of the extended psychosis phenotype in young people may represent a continuum with more severe psychopathology and predict later psychiatric disorder. PMID:20044595

Mapping Second Chromosome Mutations to Defined Genomic Regions in Drosophila melanogaster

PubMed Central

Kahsai, Lily; Cook, Kevin R.

2017-01-01

Hundreds of Drosophila melanogaster stocks are currently maintained at the Bloomington Drosophila Stock Center with mutations that have not been associated with sequence-defined genes. They have been preserved because they have interesting loss-of-function phenotypes. The experimental value of these mutations would be increased by tying them to specific genomic intervals so that geneticists can more easily associate them with annotated genes. Here, we report the mapping of 85 second chromosome complementation groups in the Bloomington collection to specific, small clusters of contiguous genes or individual genes in the sequenced genome. This information should prove valuable to Drosophila geneticists interested in processes associated with particular phenotypes and those searching for mutations affecting specific sequence-defined genes. PMID:29066472

High-throughput discovery of novel developmental phenotypes.

PubMed

Dickinson, Mary E; Flenniken, Ann M; Ji, Xiao; Teboul, Lydia; Wong, Michael D; White, Jacqueline K; Meehan, Terrence F; Weninger, Wolfgang J; Westerberg, Henrik; Adissu, Hibret; Baker, Candice N; Bower, Lynette; Brown, James M; Caddle, L Brianna; Chiani, Francesco; Clary, Dave; Cleak, James; Daly, Mark J; Denegre, James M; Doe, Brendan; Dolan, Mary E; Edie, Sarah M; Fuchs, Helmut; Gailus-Durner, Valerie; Galli, Antonella; Gambadoro, Alessia; Gallegos, Juan; Guo, Shiying; Horner, Neil R; Hsu, Chih-Wei; Johnson, Sara J; Kalaga, Sowmya; Keith, Lance C; Lanoue, Louise; Lawson, Thomas N; Lek, Monkol; Mark, Manuel; Marschall, Susan; Mason, Jeremy; McElwee, Melissa L; Newbigging, Susan; Nutter, Lauryl M J; Peterson, Kevin A; Ramirez-Solis, Ramiro; Rowland, Douglas J; Ryder, Edward; Samocha, Kaitlin E; Seavitt, John R; Selloum, Mohammed; Szoke-Kovacs, Zsombor; Tamura, Masaru; Trainor, Amanda G; Tudose, Ilinca; Wakana, Shigeharu; Warren, Jonathan; Wendling, Olivia; West, David B; Wong, Leeyean; Yoshiki, Atsushi; MacArthur, Daniel G; Tocchini-Valentini, Glauco P; Gao, Xiang; Flicek, Paul; Bradley, Allan; Skarnes, William C; Justice, Monica J; Parkinson, Helen E; Moore, Mark; Wells, Sara; Braun, Robert E; Svenson, Karen L; de Angelis, Martin Hrabe; Herault, Yann; Mohun, Tim; Mallon, Ann-Marie; Henkelman, R Mark; Brown, Steve D M; Adams, David J; Lloyd, K C Kent; McKerlie, Colin; Beaudet, Arthur L; Bućan, Maja; Murray, Stephen A

2016-09-22

Approximately one-third of all mammalian genes are essential for life. Phenotypes resulting from knockouts of these genes in mice have provided tremendous insight into gene function and congenital disorders. As part of the International Mouse Phenotyping Consortium effort to generate and phenotypically characterize 5,000 knockout mouse lines, here we identify 410 lethal genes during the production of the first 1,751 unique gene knockouts. Using a standardized phenotyping platform that incorporates high-resolution 3D imaging, we identify phenotypes at multiple time points for previously uncharacterized genes and additional phenotypes for genes with previously reported mutant phenotypes. Unexpectedly, our analysis reveals that incomplete penetrance and variable expressivity are common even on a defined genetic background. In addition, we show that human disease genes are enriched for essential genes, thus providing a dataset that facilitates the prioritization and validation of mutations identified in clinical sequencing efforts.

High-throughput discovery of novel developmental phenotypes

PubMed Central

Dickinson, Mary E.; Flenniken, Ann M.; Ji, Xiao; Teboul, Lydia; Wong, Michael D.; White, Jacqueline K.; Meehan, Terrence F.; Weninger, Wolfgang J.; Westerberg, Henrik; Adissu, Hibret; Baker, Candice N.; Bower, Lynette; Brown, James M.; Caddle, L. Brianna; Chiani, Francesco; Clary, Dave; Cleak, James; Daly, Mark J.; Denegre, James M.; Doe, Brendan; Dolan, Mary E.; Edie, Sarah M.; Fuchs, Helmut; Gailus-Durner, Valerie; Galli, Antonella; Gambadoro, Alessia; Gallegos, Juan; Guo, Shiying; Horner, Neil R.; Hsu, Chih-wei; Johnson, Sara J.; Kalaga, Sowmya; Keith, Lance C.; Lanoue, Louise; Lawson, Thomas N.; Lek, Monkol; Mark, Manuel; Marschall, Susan; Mason, Jeremy; McElwee, Melissa L.; Newbigging, Susan; Nutter, Lauryl M.J.; Peterson, Kevin A.; Ramirez-Solis, Ramiro; Rowland, Douglas J.; Ryder, Edward; Samocha, Kaitlin E.; Seavitt, John R.; Selloum, Mohammed; Szoke-Kovacs, Zsombor; Tamura, Masaru; Trainor, Amanda G; Tudose, Ilinca; Wakana, Shigeharu; Warren, Jonathan; Wendling, Olivia; West, David B.; Wong, Leeyean; Yoshiki, Atsushi; MacArthur, Daniel G.; Tocchini-Valentini, Glauco P.; Gao, Xiang; Flicek, Paul; Bradley, Allan; Skarnes, William C.; Justice, Monica J.; Parkinson, Helen E.; Moore, Mark; Wells, Sara; Braun, Robert E.; Svenson, Karen L.; de Angelis, Martin Hrabe; Herault, Yann; Mohun, Tim; Mallon, Ann-Marie; Henkelman, R. Mark; Brown, Steve D.M.; Adams, David J.; Lloyd, K.C. Kent; McKerlie, Colin; Beaudet, Arthur L.; Bucan, Maja; Murray, Stephen A.

2016-01-01

Approximately one third of all mammalian genes are essential for life. Phenotypes resulting from mouse knockouts of these genes have provided tremendous insight into gene function and congenital disorders. As part of the International Mouse Phenotyping Consortium effort to generate and phenotypically characterize 5000 knockout mouse lines, we have identified 410 lethal genes during the production of the first 1751 unique gene knockouts. Using a standardised phenotyping platform that incorporates high-resolution 3D imaging, we identified novel phenotypes at multiple time points for previously uncharacterized genes and additional phenotypes for genes with previously reported mutant phenotypes. Unexpectedly, our analysis reveals that incomplete penetrance and variable expressivity are common even on a defined genetic background. In addition, we show that human disease genes are enriched for essential genes identified in our screen, thus providing a novel dataset that facilitates prioritization and validation of mutations identified in clinical sequencing efforts. PMID:27626380

Loss of the Mechanotransducer Zyxin Promotes a Synthetic Phenotype of Vascular Smooth Muscle Cells

PubMed Central

Ghosh, Subhajit; Kollar, Branislav; Nahar, Taslima; Suresh Babu, Sahana; Wojtowicz, Agnieszka; Sticht, Carsten; Gretz, Norbert; Wagner, Andreas H; Korff, Thomas; Hecker, Markus

2015-01-01

Background Exposure of vascular smooth muscle cells (VSMCs) to excessive cyclic stretch such as in hypertension causes a shift in their phenotype. The focal adhesion protein zyxin can transduce such biomechanical stimuli to the nucleus of both endothelial cells and VSMCs, albeit with different thresholds and kinetics. However, there is no distinct vascular phenotype in young zyxin-deficient mice, possibly due to functional redundancy among other gene products belonging to the zyxin family. Analyzing zyxin function in VSMCs at the cellular level might thus offer a better mechanistic insight. We aimed to characterize zyxin-dependent changes in gene expression in VSMCs exposed to biomechanical stretch and define the functional role of zyxin in controlling the resultant VSMC phenotype. Methods and Results DNA microarray analysis was used to identify genes and pathways that were zyxin regulated in static and stretched human umbilical artery–derived and mouse aortic VSMCs. Zyxin-null VSMCs showed a remarkable shift to a growth-promoting, less apoptotic, promigratory and poorly contractile phenotype with ≈90% of the stretch-responsive genes being zyxin dependent. Interestingly, zyxin-null cells already seemed primed for such a synthetic phenotype, with mechanical stretch further accentuating it. This could be accounted for by higher RhoA activity and myocardin-related transcription factor-A mainly localized to the nucleus of zyxin-null VSMCs, and a condensed and localized accumulation of F-actin upon stretch. Conclusions At the cellular level, zyxin is a key regulator of stretch-induced gene expression. Loss of zyxin drives VSMCs toward a synthetic phenotype, a process further consolidated by exaggerated stretch. PMID:26071033

Joubert syndrome: A model for untangling recessive disorders with extreme genetic heterogeneity

PubMed Central

R, Bachmann-Gagescu; JC, Dempsey; IG, Phelps; BJ, O’Roak; DM, Knutzen; TC, Rue; GE, Ishak; CR, Isabella; N, Gorden; J, Adkins; EA, Boyle; N, de Lacy; D, O’Day; A, Alswaid; AR, Devi; L, Lingappa; C, Lourenço; L, Martorell; À, Garcia-Cazorla; H, Ozyürek; G, Haliloğlu; B, Tuysuz; M, Topçu; P, Chance; MA, Parisi; I, Glass; J, Shendure; D, Doherty

2016-01-01

Background Joubert syndrome (JS) is a recessive neurodevelopmental disorder characterized by hypotonia, ataxia, cognitive impairment, abnormal eye movements, respiratory control disturbances, and a distinctive mid-hindbrain malformation. JS demonstrates substantial phenotypic variability and genetic heterogeneity. This study provides a comprehensive view of the current genetic basis, phenotypic range and gene-phenotype associations in JS. Methods We sequenced 27 JS-associated genes in 440 affected individuals (375 families) from a cohort of 532 individuals (440 families) with JS, using molecular inversion probe-based targeted capture and next generation sequencing. Variant pathogenicity was defined using the Combined Annotation Dependent Depletion (CADD) algorithm with an optimized score cut-off. Results We identified presumed causal variants in 62% of pedigrees, including the first B9D2 mutations associated with JS. 253 different mutations in 23 genes highlight the extreme genetic heterogeneity of JS. Phenotypic analysis revealed that only 34% of individuals have a “pure JS” phenotype. Retinal disease is present in 30% of individuals, renal disease in 25%, coloboma in 17%, polydactyly in 15%, liver fibrosis in 14% and encephalocele in 8%. Loss of CEP290 function is associated with retinal dystrophy, while loss of TMEM67 function is associated with liver fibrosis and coloboma, but we observe no clear-cut distinction between JS-subtypes. Conclusion This work illustrates how combining advanced sequencing techniques with phenotypic data addresses extreme genetic heterogeneity to provide diagnostic and carrier testing, guide medical monitoring for progressive complications, facilitate interpretation of genome-wide sequencing results in individuals with a variety of phenotypes, and enable gene-specific treatments in the future. PMID:26092869

Iterative sorting reveals CD133+ and CD133- melanoma cells as phenotypically distinct populations.

PubMed

Grasso, Carole; Anaka, Matthew; Hofmann, Oliver; Sompallae, Ramakrishna; Broadley, Kate; Hide, Winston; Berridge, Michael V; Cebon, Jonathan; Behren, Andreas; McConnell, Melanie J

2016-09-09

The heterogeneity and tumourigenicity of metastatic melanoma is attributed to a cancer stem cell model, with CD133 considered to be a cancer stem cell marker in melanoma as well as other tumours, but its role has remained controversial. We iteratively sorted CD133+ and CD133- cells from 3 metastatic melanoma cell lines, and observed tumourigenicity and phenotypic characteristics over 7 generations of serial xeno-transplantation in NOD/SCID mice. We demonstrate that iterative sorting is required to make highly pure populations of CD133+ and CD133- cells from metastatic melanoma, and that these two populations have distinct characteristics not related to the cancer stem cell phenotype. In vitro, gene set enrichment analysis indicated CD133+ cells were related to a proliferative phenotype, whereas CD133- cells were of an invasive phenotype. However, in vivo, serial transplantation of CD133+ and CD133- tumours over 7 generations showed that both populations were equally able to initiate and propagate tumours. Despite this, both populations remained phenotypically distinct, with CD133- cells only able to express CD133 in vivo and not in vitro. Loss of CD133 from the surface of a CD133+ cell was observed in vitro and in vivo, however CD133- cells derived from CD133+ retained the CD133+ phenotype, even in the presence of signals from the tumour microenvironment. We show for the first time the necessity of iterative sorting to isolate pure marker-positive and marker-negative populations for comparative studies, and present evidence that despite CD133+ and CD133- cells being equally tumourigenic, they display distinct phenotypic differences, suggesting CD133 may define a distinct lineage in melanoma.

Differential factors associated with challenge-proven food allergy phenotypes in a population cohort of infants: a latent class analysis.

PubMed

Peters, R L; Allen, K J; Dharmage, S C; Lodge, C J; Koplin, J J; Ponsonby, A-L; Wake, M; Lowe, A J; Tang, M L K; Matheson, M C; Gurrin, L C

2015-05-01

Food allergy, eczema and wheeze are early manifestations of allergic disease and commonly co-occur in infancy although their interrelationship is not well understood. Data from population studies are essential to determine whether there are differential drivers of multi-allergy phenotypes. We aimed to define phenotypes and risk factors of allergic disease using latent class analysis (LCA). The HealthNuts study is a prospective, population-based cohort of 5276 12-month-old infants in Melbourne, Australia. LCA was performed using the following baseline data collected at age 12 months: food sensitization (skin prick test ≥ 2 mm) and allergy (oral food challenge) to egg, peanut and sesame; early (< 4 months) and late-onset eczema; and wheeze in the first year of life. Risk factors were modelled using multinomial logistic regression. Five distinct phenotypes were identified: no allergic disease (70%), non-food-sensitized eczema (16%), single egg allergy (9%), multiple food allergies (predominantly peanut) (3%) and multiple food allergies (predominantly egg) (2%). Compared to the baseline group of no allergic disease, shared risk factors for all allergic phenotypes were parents born overseas (particularly Asia), delayed introduction of egg, male gender (except for single egg allergy) and family history of allergic disease, whilst exposure to pet dogs was protective for all phenotypes. Other factors including filaggrin mutations, vitamin D and the presence of older siblings differed by phenotype. Multiple outcomes in infancy can be used to determine five distinct allergy phenotypes at the population level, which have both shared and separate risk factors suggesting differential mechanisms of disease. © 2014 John Wiley & Sons Ltd.

Phenotypic factors influencing the variation in response of circulating cholesterol level to personalised dietary advice in the Food4Me study.

PubMed

Kirwan, Laura; Walsh, Marianne C; Celis-Morales, Carlos; Marsaux, Cyril F M; Livingstone, Katherine M; Navas-Carretero, Santiago; Fallaize, Rosalind; O'Donovan, Clare B; Woolhead, Clara; Forster, Hannah; Kolossa, Silvia; Daniel, Hannelore; Moschonis, George; Manios, Yannis; Surwillo, Agnieszka; Godlewska, Magdalena; Traczyk, Iwona; Drevon, Christian A; Gibney, Mike J; Lovegrove, Julie A; Martinez, J Alfredo; Saris, Wim H M; Mathers, John C; Gibney, Eileen R; Brennan, Lorraine

2016-12-01

Individual response to dietary interventions can be highly variable. The phenotypic characteristics of those who will respond positively to personalised dietary advice are largely unknown. The objective of this study was to compare the phenotypic profiles of differential responders to personalised dietary intervention, with a focus on total circulating cholesterol. Subjects from the Food4Me multi-centre study were classified as responders or non-responders to dietary advice on the basis of the change in cholesterol level from baseline to month 6, with lower and upper quartiles defined as responder and non-responder groups, respectively. There were no significant differences between demographic and anthropometric profiles of the groups. Furthermore, with the exception of alcohol, there was no significant difference in reported dietary intake, at baseline. However, there were marked differences in baseline fatty acid profiles. The responder group had significantly higher levels of stearic acid (18 : 0, P=0·034) and lower levels of palmitic acid (16 : 0, P=0·009). Total MUFA (P=0·016) and total PUFA (P=0·008) also differed between the groups. In a step-wise logistic regression model, age, baseline total cholesterol, glucose, five fatty acids and alcohol intakes were selected as factors that successfully discriminated responders from non-responders, with sensitivity of 82 % and specificity of 83 %. The successful delivery of personalised dietary advice may depend on our ability to identify phenotypes that are responsive. The results demonstrate the potential use of metabolic profiles in identifying response to an intervention and could play an important role in the development of precision nutrition.

Association of FTO rs9939609 SNP with Obesity and Obesity- Associated Phenotypes in a North Indian Population

PubMed Central

Prakash, Jai; Mittal, Balraj; Srivastava, Apurva; Awasthi, Shally; Srivastava, Neena

2016-01-01

Objectives Obesity is a common disorder that has a significant impact on morbidity and mortality. Twin and adoption studies support the genetic influence on variation of obesity, and the estimates of the heritability of body mass index (BMI) is significantly high (30 to 70%). Variants in the fat mass and obesity-associated (FTO) gene have been associated with obesity and obesity-related phenotypes in different populations. The aim of this study was to examine the association of FTO rs9939609 with obesity and related phenotypes in North Indian subjects.   Methods Gene variants were investigated for association with obesity in 309 obese and 333 non-obese patients. Genotyping of the FTO rs9939609 single nucleotide polymorphism (SNP) was analyzed using Restriction Fragment Length Polymorphism Analysis of PCR-Amplified Fragments. We also measured participants fasting glucose and insulin levels, lipid profile, percentage body fat, fat mass and fat free mass.   Results Waist to hip ratio, systolic blood pressure, diastolic blood pressure, percentage body fat, fat mass, insulin concentration, and homeostasis model assessment index (HOMA-Index) showed a significant difference between the study groups. Significant associations were found for FTO rs9939609 SNP with obesity and obesity-related phenotypes. The significant associations were observed between the rs9939609 SNP and blood pressure, fat mass, insulin, and HOMA-index under a different model.   Conclusion This study presents significant association between FTO rs9939609 and obesity defined by BMI and also established the strong association with several measures of obesity in North Indian population. PMID:27168919

The Human Phenotype Ontology in 2017

PubMed Central

Köhler, Sebastian; Vasilevsky, Nicole A.; Engelstad, Mark; Foster, Erin; McMurry, Julie; Aymé, Ségolène; Baynam, Gareth; Bello, Susan M.; Boerkoel, Cornelius F.; Boycott, Kym M.; Brudno, Michael; Buske, Orion J.; Chinnery, Patrick F.; Cipriani, Valentina; Connell, Laureen E.; Dawkins, Hugh J.S.; DeMare, Laura E.; Devereau, Andrew D.; de Vries, Bert B.A.; Firth, Helen V.; Freson, Kathleen; Greene, Daniel; Hamosh, Ada; Helbig, Ingo; Hum, Courtney; Jähn, Johanna A.; James, Roger; Krause, Roland; F. Laulederkind, Stanley J.; Lochmüller, Hanns; Lyon, Gholson J.; Ogishima, Soichi; Olry, Annie; Ouwehand, Willem H.; Pontikos, Nikolas; Rath, Ana; Schaefer, Franz; Scott, Richard H.; Segal, Michael; Sergouniotis, Panagiotis I.; Sever, Richard; Smith, Cynthia L.; Straub, Volker; Thompson, Rachel; Turner, Catherine; Turro, Ernest; Veltman, Marijcke W.M.; Vulliamy, Tom; Yu, Jing; von Ziegenweidt, Julie; Zankl, Andreas; Züchner, Stephan; Zemojtel, Tomasz; Jacobsen, Julius O.B.; Groza, Tudor; Smedley, Damian; Mungall, Christopher J.; Haendel, Melissa; Robinson, Peter N.

2017-01-01

Deep phenotyping has been defined as the precise and comprehensive analysis of phenotypic abnormalities in which the individual components of the phenotype are observed and described. The three components of the Human Phenotype Ontology (HPO; www.human-phenotype-ontology.org) project are the phenotype vocabulary, disease-phenotype annotations and the algorithms that operate on these. These components are being used for computational deep phenotyping and precision medicine as well as integration of clinical data into translational research. The HPO is being increasingly adopted as a standard for phenotypic abnormalities by diverse groups such as international rare disease organizations, registries, clinical labs, biomedical resources, and clinical software tools and will thereby contribute toward nascent efforts at global data exchange for identifying disease etiologies. This update article reviews the progress of the HPO project since the debut Nucleic Acids Research database article in 2014, including specific areas of expansion such as common (complex) disease, new algorithms for phenotype driven genomic discovery and diagnostics, integration of cross-species mapping efforts with the Mammalian Phenotype Ontology, an improved quality control pipeline, and the addition of patient-friendly terminology. PMID:27899602

The Human Phenotype Ontology in 2017

DOE PAGES

Köhler, Sebastian; Vasilevsky, Nicole A.; Engelstad, Mark; ...

2016-11-24

Deep phenotyping has been defined as the precise and comprehensive analysis of phenotypic abnormalities in which the individual components of the phenotype are observed and described. The three components of the Human PhenotypeOntology (HPO; www.human-phenotype-ontology.org) project are the phenotype vocabulary, disease-phenotype annotations and the algorithms that operate on these. These components are being used for computational deep phenotyping and precision medicine as well as integration of clinical data into translational research. The HPO is being increasingly adopted as a standard for phenotypic abnormalities by diverse groups such as international rare disease organizations, registries, clinical labs, biomedical resources, and clinical softwaremore » tools and will thereby contribute toward nascent efforts at global data exchange for identifying disease etiologies. This update article reviews the progress of the HPO project since the debut Nucleic Acids Research database article in 2014, including specific areas of expansion such as common (complex) disease, new algorithms for phenotype driven genomic discovery and diagnostics, integration of cross-species mapping efforts with the Mammalian Phenotype Ontology, an improved quality control pipeline, and the addition of patient-friendly terminology.« less

The triticeae toolbox: combining phenotype and genotype data to advance small-grains breeding

USDA-ARS?s Scientific Manuscript database

The Triticeae Toolbox (http://triticeaetoolbox.org; T3) is the database schema enabling plant breeders and researchers to combine, visualize, and interrogate the wealth of phenotype and genotype data generated by the Triticeae Coordinated Agricultural Project (TCAP). T3 enables users to define speci...

Behavioural Phenotypes in Disability Research: Historical Perspectives

ERIC Educational Resources Information Center

Goodey, C. F.

2006-01-01

Western medicine has a long history of accounting for behaviour by reducing the body to ultimate explanatory entities. In pre-modern medicine these were invisible "animal spirits" circulating the body. In modern medicine, they are "genes". Both raise questions. The psychological phenotype is defined by human consensus, varying according to time…

DOE Office of Scientific and Technical Information (OSTI.GOV)

Köhler, Sebastian; Vasilevsky, Nicole A.; Engelstad, Mark

Deep phenotyping has been defined as the precise and comprehensive analysis of phenotypic abnormalities in which the individual components of the phenotype are observed and described. The three components of the Human PhenotypeOntology (HPO; www.human-phenotype-ontology.org) project are the phenotype vocabulary, disease-phenotype annotations and the algorithms that operate on these. These components are being used for computational deep phenotyping and precision medicine as well as integration of clinical data into translational research. The HPO is being increasingly adopted as a standard for phenotypic abnormalities by diverse groups such as international rare disease organizations, registries, clinical labs, biomedical resources, and clinical softwaremore » tools and will thereby contribute toward nascent efforts at global data exchange for identifying disease etiologies. This update article reviews the progress of the HPO project since the debut Nucleic Acids Research database article in 2014, including specific areas of expansion such as common (complex) disease, new algorithms for phenotype driven genomic discovery and diagnostics, integration of cross-species mapping efforts with the Mammalian Phenotype Ontology, an improved quality control pipeline, and the addition of patient-friendly terminology.« less

The chronic bronchitis phenotype in subjects with and without COPD: the PLATINO study.

PubMed

de Oca, Maria Montes; Halbert, Ronald J; Lopez, Maria Victorina; Perez-Padilla, Rogelio; Tálamo, Carlos; Moreno, Dolores; Muiño, Adrianna; Jardim, José Roberto B; Valdivia, Gonzalo; Pertuzé, Julio; Menezes, Ana Maria B

2012-07-01

Little information exists regarding the epidemiology of the chronic bronchitis phenotype in unselected chronic obstructive pulmonary disease (COPD) populations. We examined the prevalence of the chronic bronchitis phenotype in COPD and non-COPD subjects from the PLATINO study, and investigated how it is associated with important outcomes. Post-bronchodilator forced expiratory volume in 1 s/forced vital capacity <0.70 was used to define COPD. Chronic bronchitis was defined as phlegm on most days, at least 3 months per year for ≥ 2 yrs. We also analysed another definition: cough and phlegm on most days, at least 3 months per year for ≥ 2 yrs. Spirometry was performed in 5,314 subjects (759 with and 4,554 without COPD). The proportion of subjects with and without COPD with chronic bronchitis defined as phlegm on most days, at least 3 months per year for ≥ 2 yrs was 14.4 and 6.2%, respectively. Using the other definition the prevalence was lower: 7.4% with and 2.5% without COPD. Among subjects with COPD, those with chronic bronchitis had worse lung function and general health status, and had more respiratory symptoms, physical activity limitation and exacerbations. Our study helps to understand the prevalence of the chronic bronchitis phenotype in an unselected COPD population at a particular time-point and suggests that chronic bronchitis in COPD is possibly associated with worse outcomes.

Heritability of specific language impairment depends on diagnostic criteria.

PubMed

Bishop, D V M; Hayiou-Thomas, M E

2008-04-01

Heritability estimates for specific language impairment (SLI) have been inconsistent. Four twin studies reported heritability of 0.5 or more, but a recent report from the Twins Early Development Study found negligible genetic influence in 4-year-olds. We considered whether the method of ascertainment influenced results and found substantially higher heritability if SLI was defined in terms of referral to speech and language pathology services than if defined by language test scores. Further analysis showed that presence of speech difficulties played a major role in determining whether a child had contact with services. Childhood language disorders that are identified by population screening are likely to have a different phenotype and different etiology from clinically referred cases. Genetic studies are more likely to find high heritability if they focus on cases who have speech difficulties and who have been referred for intervention.

The intrauterine environment affects learning ability of Tokai high avoider rat offspring derived using cryopreservation and embryo transfer-mediated reproduction.

PubMed

Endo, Hitoshi; Eto, Tomoo; Yoshii, Fumihito; Owada, Satoshi; Watanabe, Tetsu; Tatemichi, Masayuki; Kimura, Minoru

2017-07-22

Embryo transfer (ET) to recipient female animals is a useful technique in biological and experimental animal studies. While cryopreservation of two-cell stage rat embryos and ET to recipient rats are currently well-defined, it is unknown whether these artificial reproductive techniques and maternal factors affect offspring phenotype, particularly higher brain functions. Therefore, we assessed the effects of cryopreservation, ET, and maternal care on learning behaviour of the offspring, using Tokai high avoider (THA) rats that have a high learning ability phenotype. We found that the high learning ability of THA rat offspring was not replicated following ET to surrogate Wistar rats with a low-avoidance phenotype. Additionally, the characteristic phenotype of offspring obtained through mating of ET-derived rats was similar to that of THA rats. A postnatal cross-fostering investigation with the offspring of Wistar and THA rats showed that maternal behaviour, including postnatal care and lactation traits, did not differ between the dams of low-avoidance Wistar rats and THA rats; therefore, learning behaviour was retained in both Wistar and THA rat offspring. We conclude that the offspring phenotype, although unchanged, has an imperceptible effect on the learning ability of ET-derived THA rats through the intrauterine environment of the recipient. Copyright © 2017 Elsevier Inc. All rights reserved.

Association of Arrhythmia-Related Genetic Variants With Phenotypes Documented in Electronic Medical Records.

PubMed

Van Driest, Sara L; Wells, Quinn S; Stallings, Sarah; Bush, William S; Gordon, Adam; Nickerson, Deborah A; Kim, Jerry H; Crosslin, David R; Jarvik, Gail P; Carrell, David S; Ralston, James D; Larson, Eric B; Bielinski, Suzette J; Olson, Janet E; Ye, Zi; Kullo, Iftikhar J; Abul-Husn, Noura S; Scott, Stuart A; Bottinger, Erwin; Almoguera, Berta; Connolly, John; Chiavacci, Rosetta; Hakonarson, Hakon; Rasmussen-Torvik, Laura J; Pan, Vivian; Persell, Stephen D; Smith, Maureen; Chisholm, Rex L; Kitchner, Terrie E; He, Max M; Brilliant, Murray H; Wallace, John R; Doheny, Kimberly F; Shoemaker, M Benjamin; Li, Rongling; Manolio, Teri A; Callis, Thomas E; Macaya, Daniela; Williams, Marc S; Carey, David; Kapplinger, Jamie D; Ackerman, Michael J; Ritchie, Marylyn D; Denny, Joshua C; Roden, Dan M

2016-01-05

Large-scale DNA sequencing identifies incidental rare variants in established Mendelian disease genes, but the frequency of related clinical phenotypes in unselected patient populations is not well established. Phenotype data from electronic medical records (EMRs) may provide a resource to assess the clinical relevance of rare variants. To determine the clinical phenotypes from EMRs for individuals with variants designated as pathogenic by expert review in arrhythmia susceptibility genes. This prospective cohort study included 2022 individuals recruited for nonantiarrhythmic drug exposure phenotypes from October 5, 2012, to September 30, 2013, for the Electronic Medical Records and Genomics Network Pharmacogenomics project from 7 US academic medical centers. Variants in SCN5A and KCNH2, disease genes for long QT and Brugada syndromes, were assessed for potential pathogenicity by 3 laboratories with ion channel expertise and by comparison with the ClinVar database. Relevant phenotypes were determined from EMRs, with data available from 2002 (or earlier for some sites) through September 10, 2014. One or more variants designated as pathogenic in SCN5A or KCNH2. Arrhythmia or electrocardiographic (ECG) phenotypes defined by International Classification of Diseases, Ninth Revision (ICD-9) codes, ECG data, and manual EMR review. Among 2022 study participants (median age, 61 years [interquartile range, 56-65 years]; 1118 [55%] female; 1491 [74%] white), a total of 122 rare (minor allele frequency <0.5%) nonsynonymous and splice-site variants in 2 arrhythmia susceptibility genes were identified in 223 individuals (11% of the study cohort). Forty-two variants in 63 participants were designated potentially pathogenic by at least 1 laboratory or ClinVar, with low concordance across laboratories (Cohen κ = 0.26). An ICD-9 code for arrhythmia was found in 11 of 63 (17%) variant carriers vs 264 of 1959 (13%) of those without variants (difference, +4%; 95% CI, -5% to +13%; P = .35). In the 1270 (63%) with ECGs, corrected QT intervals were not different in variant carriers vs those without (median, 429 vs 439 milliseconds; difference, -10 milliseconds; 95% CI, -16 to +3 milliseconds; P = .17). After manual review, 22 of 63 participants (35%) with designated variants had any ECG or arrhythmia phenotype, and only 2 had corrected QT interval longer than 500 milliseconds. Among laboratories experienced in genetic testing for cardiac arrhythmia disorders, there was low concordance in designating SCN5A and KCNH2 variants as pathogenic. In an unselected population, the putatively pathogenic genetic variants were not associated with an abnormal phenotype. These findings raise questions about the implications of notifying patients of incidental genetic findings.

Genetic predisposition to obesity affects behavioural traits including food reward and anxiety-like behaviour in rats.

PubMed

Vogel, Heike; Kraemer, Maria; Rabasa, Cristina; Askevik, Kaisa; Adan, Roger A H; Dickson, Suzanne L

2017-06-15

Here we sought to define behavioural traits linked to anxiety, reward, and exploration in different strains of rats commonly used in obesity research. We hypothesized that genetic variance may contribute not only to their metabolic phenotype (that is well documented) but also to the expression of these behavioural traits. Rat strains that differ in their susceptibility to develop an obese phenotype (Sprague-Dawley, Obese Prone, Obese Resistant, and Zucker rats) were exposed to a number of behavioural tests starting at the age of 8 weeks. We found a similar phenotype in the obesity susceptible models, Obese Prone and Zucker rats, with a lower locomotor activity, exploratory activity, and higher level of anxiety-like behaviour in comparison to the leaner Obese Resistant strain. We did not find evidence that rat strains with a genetic predisposition to obesity differed in their ability to experience reward from chocolate (in a condition place preference task). However, Zucker rats show higher motivated behaviour for sucrose compared to Obese Resistant rats when the effort required to obtain palatable food is relatively low. Together our data demonstrate that rat strains that differ in their genetic predisposition to develop obesity also differ in their performance in behavioural tests linked to anxiety, exploration, and reward and that these differences are independent of body weight. We conclude that genetic variations which determine body weight and the aforementioned behaviours co-exist but that future studies are required to identify whether (and which) common genes are involved. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Metabolic profiles of placenta in preeclampsia using HR-MAS MRS metabolomics.

PubMed

Austdal, Marie; Thomsen, Liv Cecilie Vestrheim; Tangerås, Line Haugstad; Skei, Bente; Mathew, Seema; Bjørge, Line; Austgulen, Rigmor; Bathen, Tone Frost; Iversen, Ann-Charlotte

2015-12-01

Preeclampsia is a heterogeneous gestational disease characterized by maternal hypertension and proteinuria, affecting 2-7% of pregnancies. The disorder is initiated by insufficient placental development, but studies characterizing the placental disease components are lacking. Our aim was to phenotype the preeclamptic placenta using high-resolution magic angle spinning nuclear magnetic resonance spectroscopy (HR-MAS MRS). Placental samples collected after delivery from women with preeclampsia (n = 19) and normotensive pregnancies (n = 15) were analyzed for metabolic biomarkers including amino acids, osmolytes, and components of the energy and phospholipid metabolism. The metabolic biomarkers were correlated to clinical characteristics and inflammatory biomarkers in the maternal sera. Principal component analysis showed inherent differences in placental metabolic profiles between preeclamptic and normotensive pregnancies. Significant differences in metabolic profiles were found between placentas from severe and non-severe preeclampsia, but not between preeclamptic pregnancies with fetal growth restricted versus normal weight neonates. The placental metabolites correlated with the placental stress marker sFlt-1 and triglycerides in maternal serum, suggesting variation in placental stress signaling between different placental phenotypes. HR-MAS MRS is a sensitive method for defining the placental disease component of preeclampsia, identifying several altered metabolic pathways. Placental HR-MAS MRS analysis may improve insight into processes affected in the preeclamptic placenta, and represents a novel long-required tool for a sensitive placental phenotyping of this heterogeneous disease. Copyright © 2015 Elsevier Ltd. All rights reserved.

A Cladistic Analysis of Phenotypic Associations with Haplotypes Inferred from Restriction Endonuclease Mapping. IV. Nested Analyses with Cladogram Uncertainty and Recombination

PubMed Central

Templeton, A. R.; Sing, C. F.

1993-01-01

We previously developed an analytical strategy based on cladistic theory to identify subsets of haplotypes that are associated with significant phenotypic deviations. Our initial approach was limited to segments of DNA in which little recombination occurs. In such cases, a cladogram can be constructed from the restriction site data to estimate the evolutionary steps that interrelate the observed haplotypes to one another. The cladogram is then used to define a nested statistical design for identifying mutational steps associated with significant phenotypic deviations. The central assumption behind this strategy is that a mutation responsible for a particular phenotypic effect is embedded within the evolutionary history that is represented by the cladogram. The power of this approach depends on the accuracy of the cladogram in portraying the evolutionary history of the DNA region. This accuracy can be diminished both by recombination and by uncertainty in the estimated cladogram topology. In a previous paper, we presented an algorithm for estimating the set of likely cladograms and recombination events. In this paper we present an algorithm for defining a nested statistical design under cladogram uncertainty and recombination. Given the nested design, phenotypic associations can be examined using either a nested analysis of variance (for haploids or homozygous strains) or permutation testing (for outcrossed, diploid gene regions). In this paper we also extend this analytical strategy to include categorical phenotypes in addition to quantitative phenotypes. Some worked examples are presented using Drosophila data sets. These examples illustrate that having some recombination may actually enhance the biological inferences that may derived from a cladistic analysis. In particular, recombination can be used to assign a physical localization to a given subregion for mutations responsible for significant phenotypic effects. PMID:8100789

Codominant expression of genes coding for different sets of inducible salivary polypeptides associated with parotid hypertrophy in two inbred mouse strains.

PubMed

López-Solís, Remigio O; Kemmerling, Ulrike

2005-05-01

Experimental mouse parotid hypertrophy has been associated with the expression of a number of isoproterenol-induced salivary proline-rich polypeptides (IISPs). Mouse salivary proline-rich proteins (PRPs) have been mapped both to chromosomes 6 and 8. Recently, mice of two inbred strains (A/Snell and A. Swiss) have been found to differ drastically in the IISPs. In this study, mice of both strains were used for cross-breeding experiments addressed to define the pattern of inheritance of the IISP phenotype and to establish whether the IISPs are coded on a single or on several chromosomes. The IISP phenotype of individual mice was assessed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) of whole saliva collected after three daily stimulations by isoproterenol. Parental A/Snell and A. Swiss mice were homogeneous for distinctive strain-associated IISP-patterns. First filial generation (F1) mice obtained from the cross of A/Snell with A. Swiss mice expressed with no exception both the A/Snell and A. Swiss IISPs (coexpression). In the second filial generation (F2) both parental IISP phenotypes reappeared together with a majority of mice expressing the F1-hybrid phenotype (1:2:1 ratio). Backcrosses of F1 x A/Snell and F1 x A. Swiss produced offsprings displaying the F1 and the corresponding parental phenotypes with a 1:1 ratio. No recombinants were observed among F2 mice or among mice resulting from backcrosses. Thus, genes coding for the IISPs that are expressed differentially in both mouse strains are located on the same chromosome, probably at the same locus (alleles) or at quite closely linked loci (nonalleles). 2005 Wiley-Liss, Inc

Adult-Onset Asthma Becomes the Dominant Phenotype among Women by Age 40 Years. The Longitudinal CARDIA Study

PubMed Central

Qualls, Clifford; Schuyler, Mark; Arynchyn, Alexander; Alvarado, Jesse H.; Smith, Lewis J.; Jacobs, David R.

2013-01-01

Rationale: Although asthma is usually considered to originate in childhood, adult-onset disease is being increasingly reported. Objectives: To contrast the proportion and natural history of adult-onset versus pediatric-onset asthma in a community-based cohort. We hypothesized that asthma in women is predominantly of adult onset rather than of pediatric onset. Methods: This study used data from the Coronary Artery Risk Development in Young Adults (CARDIA) cohort in the United States over a 25-year period. Adult- and pediatric-onset asthma phenotypes were studied, as defined by age at onset of 18 years or older. Subjects with asthma were categorized by sex, obesity, atopy, smoking, and race by mean age/examination year, using a three-way analysis of covariance model. Natural history of disease was examined using probabilities derived from a Markov chain model. Measurements and Main Results: Asthma of adult onset became the dominant (i.e., exceeded 50%) phenotype in women by age 40 years. The age by which adult-onset asthma became the dominant phenotype was further lowered for obese, nonatopic, ever-smoking, or white women. The prevalence trend with increasing time for adult-onset disease was greater among subjects with nonatopic than atopic asthma among both sexes. Furthermore, adult-onset asthma had remarkable sex-related differences in risk factors. In both sexes, the quiescent state for adult-onset asthma was less frequent and also “less stable” over time than for pediatric-onset asthma. Conclusions: Using a large national cohort, this study challenges the dictum that most asthma in adults originates in childhood. Studies of the differences between pediatric- and adult-onset asthma may provide greater insight into the phenotypic heterogeneity of asthma. PMID:23802814

Genomic and phenotypic characterization of myxoma virus from Great Britain reveals multiple evolutionary pathways distinct from those in Australia

PubMed Central

Kerr, Peter J.; Cattadori, Isabella M.; Fitch, Adam; Geber, Adam; Liu, June; Sim, Derek G.; Boag, Brian; Ghedin, Elodie

2017-01-01

The co-evolution of myxoma virus (MYXV) and the European rabbit occurred independently in Australia and Europe from different progenitor viruses. Although this is the canonical study of the evolution of virulence, whether the genomic and phenotypic outcomes of MYXV evolution in Europe mirror those observed in Australia is unknown. We addressed this question using viruses isolated in the United Kingdom early in the MYXV epizootic (1954–1955) and between 2008–2013. The later UK viruses fell into three distinct lineages indicative of a long period of separation and independent evolution. Although rates of evolutionary change were almost identical to those previously described for MYXV in Australia and strongly clock-like, genome evolution in the UK and Australia showed little convergence. The phenotypes of eight UK viruses from three lineages were characterized in laboratory rabbits and compared to the progenitor (release) Lausanne strain. Inferred virulence ranged from highly virulent (grade 1) to highly attenuated (grade 5). Two broad disease types were seen: cutaneous nodular myxomatosis characterized by multiple raised secondary cutaneous lesions, or an amyxomatous phenotype with few or no secondary lesions. A novel clinical outcome was acute death with pulmonary oedema and haemorrhage, often associated with bacteria in many tissues but an absence of inflammatory cells. Notably, reading frame disruptions in genes defined as essential for virulence in the progenitor Lausanne strain were compatible with the acquisition of high virulence. Combined, these data support a model of ongoing host-pathogen co-evolution in which multiple genetic pathways can produce successful outcomes in the field that involve both different virulence grades and disease phenotypes, with alterations in tissue tropism and disease mechanisms. PMID:28253375

Genomic and phenotypic characterization of myxoma virus from Great Britain reveals multiple evolutionary pathways distinct from those in Australia.

PubMed

Kerr, Peter J; Cattadori, Isabella M; Rogers, Matthew B; Fitch, Adam; Geber, Adam; Liu, June; Sim, Derek G; Boag, Brian; Eden, John-Sebastian; Ghedin, Elodie; Read, Andrew F; Holmes, Edward C

2017-03-01

The co-evolution of myxoma virus (MYXV) and the European rabbit occurred independently in Australia and Europe from different progenitor viruses. Although this is the canonical study of the evolution of virulence, whether the genomic and phenotypic outcomes of MYXV evolution in Europe mirror those observed in Australia is unknown. We addressed this question using viruses isolated in the United Kingdom early in the MYXV epizootic (1954-1955) and between 2008-2013. The later UK viruses fell into three distinct lineages indicative of a long period of separation and independent evolution. Although rates of evolutionary change were almost identical to those previously described for MYXV in Australia and strongly clock-like, genome evolution in the UK and Australia showed little convergence. The phenotypes of eight UK viruses from three lineages were characterized in laboratory rabbits and compared to the progenitor (release) Lausanne strain. Inferred virulence ranged from highly virulent (grade 1) to highly attenuated (grade 5). Two broad disease types were seen: cutaneous nodular myxomatosis characterized by multiple raised secondary cutaneous lesions, or an amyxomatous phenotype with few or no secondary lesions. A novel clinical outcome was acute death with pulmonary oedema and haemorrhage, often associated with bacteria in many tissues but an absence of inflammatory cells. Notably, reading frame disruptions in genes defined as essential for virulence in the progenitor Lausanne strain were compatible with the acquisition of high virulence. Combined, these data support a model of ongoing host-pathogen co-evolution in which multiple genetic pathways can produce successful outcomes in the field that involve both different virulence grades and disease phenotypes, with alterations in tissue tropism and disease mechanisms.

Growth platform-dependent and -independent phenotypic and metabolic responses of Arabidopsis and its halophytic relative, Eutrema salsugineum, to salt stress.

PubMed

Kazachkova, Yana; Batushansky, Albert; Cisneros, Aroldo; Tel-Zur, Noemi; Fait, Aaron; Barak, Simon

2013-07-01

Comparative studies of the stress-tolerant Arabidopsis (Arabidopsis thaliana) halophytic relative, Eutrema salsugineum, have proven a fruitful approach to understanding natural stress tolerance. Here, we performed comparative phenotyping of Arabidopsis and E. salsugineum vegetative development under control and salt-stress conditions, and then compared the metabolic responses of the two species on different growth platforms in a defined leaf developmental stage. Our results reveal both growth platform-dependent and -independent phenotypes and metabolic responses. Leaf emergence was affected in a similar way in both species grown in vitro but the effects observed in Arabidopsis occurred at higher salt concentrations in E. salsugineum. No differences in leaf emergence were observed on soil. A new effect of a salt-mediated reduction in E. salsugineum leaf area was unmasked. On soil, leaf area reduction in E. salsugineum was mainly due to a fall in cell number, whereas both cell number and cell size contributed to the decrease in Arabidopsis leaf area. Common growth platform-independent leaf metabolic signatures such as high raffinose and malate, and low fumarate contents that could reflect core stress tolerance mechanisms, as well as growth platform-dependent metabolic responses were identified. In particular, the in vitro growth platform led to repression of accumulation of many metabolites including sugars, sugar phosphates, and amino acids in E. salsugineum compared with the soil system where these same metabolites accumulated to higher levels in E. salsugineum than in Arabidopsis. The observation that E. salsugineum maintains salt tolerance despite growth platform-specific phenotypes and metabolic responses suggests a considerable degree of phenotypic and metabolic adaptive plasticity in this extremophile.

[Behavioural phenotypes in Prader-Willi syndrome].

PubMed

Rosell-Raga, L

2003-02-01

The behavioural phenotype of Prader-Willi syndrome (PWS) is defined by a neurological profile and a characteristic pattern of behavioural disorders which include cognitive deficits, learning difficulties and behavioural problems, which increase with age, both in number and gravity. We review the behavioural phenotype of the cases of PWS in the Valencian Community, together with their peculiar behaviours, and analyse how these generate family and social problems. The description of a peculiar behaviour opens up new horizons when understanding and treating PWS, both from a pharmacological and neuropsychological perspective.

Diurnal fluctuation in the number of hypocretin/orexin and histamine producing: Implication for understanding and treating neuronal loss

PubMed Central

McGregor, Ronald; Shan, Ling; Wu, Ming-Fung

2017-01-01

The loss of specific neuronal phenotypes, as determined by immunohistochemistry, has become a powerful tool for identifying the nature and cause of neurological diseases. Here we show that the number of neurons identified and quantified using this method misses a substantial percentage of extant neurons in a phenotype specific manner. In mice, 24% more hypocretin/orexin (Hcrt) neurons are seen in the night compared to the day, and an additional 17% are seen after inhibiting microtubule polymerization with colchicine. We see no such difference between the number of MCH (melanin concentrating hormone) neurons in dark, light or colchicine conditions, despite MCH and Hcrt both being hypothalamic peptide transmitters. Although the size of Hcrt neurons did not differ between light and dark, the size of MCH neurons was increased by 15% in the light phase. The number of neurons containing histidine decarboxylase (HDC), the histamine synthesizing enzyme, was 34% greater in the dark than in the light, but, like Hcrt, cell size did not differ. We did not find a significant difference in the number or the size of neurons expressing choline acetyltransferase (ChAT), the acetylcholine synthesizing enzyme, in the horizontal diagonal band (HBD) during the dark and light conditions. As expected, colchicine treatment did not increase the number of these neurons. Understanding the function and dynamics of transmitter production within “non-visible” phenotypically defined cells has fundamental implications for our understanding of brain plasticity. PMID:28570646

A Nested Case-Control Study of Metabolically Defined Body Size Phenotypes and Risk of Colorectal Cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC).

PubMed

Murphy, Neil; Cross, Amanda J; Abubakar, Mustapha; Jenab, Mazda; Aleksandrova, Krasimira; Boutron-Ruault, Marie-Christine; Dossus, Laure; Racine, Antoine; Kühn, Tilman; Katzke, Verena A; Tjønneland, Anne; Petersen, Kristina E N; Overvad, Kim; Quirós, J Ramón; Jakszyn, Paula; Molina-Montes, Esther; Dorronsoro, Miren; Huerta, José-María; Barricarte, Aurelio; Khaw, Kay-Tee; Wareham, Nick; Travis, Ruth C; Trichopoulou, Antonia; Lagiou, Pagona; Trichopoulos, Dimitrios; Masala, Giovanna; Krogh, Vittorio; Tumino, Rosario; Vineis, Paolo; Panico, Salvatore; Bueno-de-Mesquita, H Bas; Siersema, Peter D; Peeters, Petra H; Ohlsson, Bodil; Ericson, Ulrika; Palmqvist, Richard; Nyström, Hanna; Weiderpass, Elisabete; Skeie, Guri; Freisling, Heinz; Kong, So Yeon; Tsilidis, Kostas; Muller, David C; Riboli, Elio; Gunter, Marc J

2016-04-01

Obesity is positively associated with colorectal cancer. Recently, body size subtypes categorised by the prevalence of hyperinsulinaemia have been defined, and metabolically healthy overweight/obese individuals (without hyperinsulinaemia) have been suggested to be at lower risk of cardiovascular disease than their metabolically unhealthy (hyperinsulinaemic) overweight/obese counterparts. Whether similarly variable relationships exist for metabolically defined body size phenotypes and colorectal cancer risk is unknown. The association of metabolically defined body size phenotypes with colorectal cancer was investigated in a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Metabolic health/body size phenotypes were defined according to hyperinsulinaemia status using serum concentrations of C-peptide, a marker of insulin secretion. A total of 737 incident colorectal cancer cases and 737 matched controls were divided into tertiles based on the distribution of C-peptide concentration amongst the control population, and participants were classified as metabolically healthy if below the first tertile of C-peptide and metabolically unhealthy if above the first tertile. These metabolic health definitions were then combined with body mass index (BMI) measurements to create four metabolic health/body size phenotype categories: (1) metabolically healthy/normal weight (BMI < 25 kg/m2), (2) metabolically healthy/overweight (BMI ≥ 25 kg/m2), (3) metabolically unhealthy/normal weight (BMI < 25 kg/m2), and (4) metabolically unhealthy/overweight (BMI ≥ 25 kg/m2). Additionally, in separate models, waist circumference measurements (using the International Diabetes Federation cut-points [≥80 cm for women and ≥94 cm for men]) were used (instead of BMI) to create the four metabolic health/body size phenotype categories. Statistical tests used in the analysis were all two-sided, and a p-value of <0.05 was considered statistically significant. In multivariable-adjusted conditional logistic regression models with BMI used to define adiposity, compared with metabolically healthy/normal weight individuals, we observed a higher colorectal cancer risk among metabolically unhealthy/normal weight (odds ratio [OR] = 1.59, 95% CI 1.10-2.28) and metabolically unhealthy/overweight (OR = 1.40, 95% CI 1.01-1.94) participants, but not among metabolically healthy/overweight individuals (OR = 0.96, 95% CI 0.65-1.42). Among the overweight individuals, lower colorectal cancer risk was observed for metabolically healthy/overweight individuals compared with metabolically unhealthy/overweight individuals (OR = 0.69, 95% CI 0.49-0.96). These associations were generally consistent when waist circumference was used as the measure of adiposity. To our knowledge, there is no universally accepted clinical definition for using C-peptide level as an indication of hyperinsulinaemia. Therefore, a possible limitation of our analysis was that the classification of individuals as being hyperinsulinaemic-based on their C-peptide level-was arbitrary. However, when we used quartiles or the median of C-peptide, instead of tertiles, as the cut-point of hyperinsulinaemia, a similar pattern of associations was observed. These results support the idea that individuals with the metabolically healthy/overweight phenotype (with normal insulin levels) are at lower colorectal cancer risk than those with hyperinsulinaemia. The combination of anthropometric measures with metabolic parameters, such as C-peptide, may be useful for defining strata of the population at greater risk of colorectal cancer.

Genotyping in 46 patients with tentative diagnosis of Treacher Collins syndrome revealed unexpected phenotypic variation.

PubMed

Teber, Ozge Altug; Gillessen-Kaesbach, Gabriele; Fischer, Sven; Böhringer, Stefan; Albrecht, Beate; Albert, Angelika; Arslan-Kirchner, Mine; Haan, Eric; Hagedorn-Greiwe, Monika; Hammans, Christof; Henn, Wolfram; Hinkel, Georg Klaus; König, Rainer; Kunstmann, Erdmute; Kunze, Jürgen; Neumann, Luitgard M; Prott, Eva-Christina; Rauch, Anita; Rott, Hans-Dieter; Seidel, Heide; Spranger, Stephanie; Sprengel, Martin; Zoll, Barbara; Lohmann, Dietmar R; Wieczorek, Dagmar

2004-11-01

To define the range of phenotypic expression in Treacher Collins syndrome (TCS; Franceschetti-Klein syndrome), we performed mutation analysis in the TCOF1 gene in 46 patients with tentative diagnosis of TCS and evaluated the clinical data, including a scoring system. A total of 27 coding exons of TCOF1 and adjacent splice junctions were analysed by direct sequencing. In 36 patients with a clinically unequivocal diagnosis of TCS, we detected 28 pathogenic mutations, including 25 novel alterations. No mutation was identified in the remaining eight patients with unequivocal diagnosis of TCS and 10 further patients, in whom the referring diagnosis of TCS was clinically doubtful. There is no overt genotype-phenotype correlation except that conductive deafness is significantly less frequent in patients with mutations in the 3' part of the open reading frame. Inter- and intrafamilial variation is wide. Some mutation carriers, parents of typically affected patients, are so mildly affected that the diagnosis might be overlooked clinically. This suggests that modifying factors are important for phenotypic expression. Based on these findings, minimal diagnostic criteria were defined: downward slanting palpebral fissures and hypoplasia of the zygomatic arch. The difficulties in genetic counselling, especially diagnosis of family members with a mild phenotype, are described.

The vaginal microbiome: New information about genital tract flora using molecular based techniques

PubMed Central

Lamont, Ronald F.; Sobel, Jack D.; Akins, Robert A.; Hassan, Sonia S.; Chaiworapongsa, Tinnakorn; Kusanovic, Juan Pedro; Romero, Roberto

2011-01-01

Vaginal microbiome studies provide information which may change the way we define vaginal flora. Normal flora appears dominated by one or two species of Lactobacillus. Significant numbers of healthy women lack appreciable numbers of vaginal lactobacilli. Bacterial vaginosis (BV) is not a single entity, but different bacterial communities or profiles of greater microbial diversity than is evident from cultivation-dependent studies. BV should be considered a syndrome of variable composition which results in different symptoms, phenotypical outcomes, and responses to different antibiotic regimens. This information may help to elucidate the link between BV and infection-related adverse outcomes of pregnancy. PMID:21251190

Quantitative Analysis of Adventitious Root Growth Phenotypes in Carnation Stem Cuttings

PubMed Central

Birlanga, Virginia; Villanova, Joan; Cano, Antonio; Cano, Emilio A.; Acosta, Manuel; Pérez-Pérez, José Manuel

2015-01-01

Carnation is one of the most important species on the worldwide market of cut flowers. Commercial carnation cultivars are vegetatively propagated from terminal stem cuttings that undergo a rooting and acclimation process. For some of the new cultivars that are being developed by ornamental breeders, poor adventitious root (AR) formation limits its commercial scaling-up, due to a significant increase in the production costs. We have initiated a genetical-genomics approach to determine the molecular basis of the differences found between carnation cultivars during adventitious rooting. The detailed characterization of AR formation in several carnation cultivars differing in their rooting losses has been performed (i) during commercial production at a breeders’ rooting station and (ii) on a defined media in a controlled environment. Our study reveals the phenotypic signatures that distinguishes the bad-rooting cultivars and provides the appropriate set-up for the molecular identification of the genes involved in AR development in this species. PMID:26230608

The holist tradition in twentieth century genetics. Wilhelm Johannsen's genotype concept.

PubMed

Roll-Hansen, Nils

2014-06-01

The terms 'genotype', 'phenotype' and 'gene' originally had a different meaning from that in the Modern Synthesis. These terms were coined in the first decade of the twentieth century by the Danish plant physiologist Wilhelm Johannsen. His bean selection experiment and his theoretical analysis of the difference between genotype and phenotype were important inputs to the formation of genetics as a well-defined special discipline. This paper shows how Johannsen's holistic genotype theory provided a platform for criticism of narrowly genocentric versions of the chromosome theory of heredity that came to dominate genetics in the middle decades of the twentieth century. Johannsen came to recognize the epoch-making importance of the work done by the Drosophila group, but he continued to insist on the incompleteness of the chromosome theory. Genes of the kind that they mapped on the chromosomes could only give a partial explanation of biological heredity and evolution. © 2014 The Author. The Journal of Physiology © 2014 The Physiological Society.

Sarcopenic obesity and overall mortality: Results from the application of novel models of body composition phenotypes to the National Health and Nutrition Examination Survey 1999-2004.

PubMed

Van Aller, Carla; Lara, Jose; Stephan, Blossom C M; Donini, Lorenzo Maria; Heymsfield, Steven; Katzmarzyk, Peter T; Wells, Jonathan C K; Prado, Carla M; Siervo, Mario

2018-02-15

There is no consensus on the definition of sarcopenic obesity (SO), resulting in inconsistent associations of SO with mortality risk. We aim to evaluate association of dual energy x-ray absorptiometry (DXA) SO models with mortality risk in a US adult population (≥50 years). The study population consisted of 3577 participants aged 50 years and older from the 1999-2004 National Health and Nutrition and Examination Survey with mortality follow-up data through December 31, 2011. Difference in survival time in people with and without SO defined by three body composition DXA models (Model 1: body composition phenotype model; Model 2: Truncal Fat Mass (TrFM)/Appendicular Skeletal Muscle Mass (ASM) ratio model; Model 3: Fat Mass (FM)/Fat Free Mass (FFM) ratio). The differences between the models were assessed by the acceleration failure time model, and expressed as time ratios (TR). Participants age 50-70 years with SO had a significantly decreased survival time, according to the body composition phenotype model (TR: 0.92; 95% CI: 0.87-0.97), and TrFM/ASM ratio model (TR: 0.88; 95% CI: 0.81-0.95). The FM/FFM ratio model did not detect significant differences in survival time. Participants with SO aged 70 years and older did not have a significantly decreased survival time, according to all three models. A SO phenotype increases mortality risk in people of age 50-70 years, but not in people aged 70 years and older. The application of the body composition phenotype and the TrFM/ASM ratio models may represent useful diagnostic approaches to improve the prediction of disease and mortality risk. Copyright © 2018 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Global Gene Expression Differences in Joints of Mice with Divergent Post Traumatic Osteoarthritis Phenotypes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kibui, J.

Osteoarthritis (OA) is a debilitating joint disease characterized by cartilage degradation which prompts pain, stiffness and swelling. Contributing factors include age, genetics, obesity, injury and overuse of joints. OA is defined by an acute phase and a chronic phase whereby inflammation and degeneration of articular cartilage and other tissues is followed by joint pain and limited mobility. Patients remain asymptomatic until substantial joint damage has occurred and therefore rely on long term surgical joint replacement and pain management as their sole treatment options. For this reason, there is an increasing need to identify early stage osteoarthritis biomarkers. Our study aimedmore » to identify and characterize gene expression variances in 3 different mouse strains (STR/ort, C57BL/6 and MRL/MpJ) with different susceptibility to post traumatic osteoarthritis (PTOA). Through RNA sequence analysis of whole knee joint RNA, we identified differentially expressed genes associated with the initial stages of PTOA in relation to mice with divergent phenotypes. These results will help elucidate potential mechanisms responsible for PTOA outcomes.« less

Change in the manifestations of asthma and asthma-related traits in childhood: a latent transition analysis.

PubMed

Garden, Frances L; Simpson, Judy M; Mellis, Craig M; Marks, Guy B

2016-02-01

It is known that asthma is a heterogeneous entity whose manifestations vary with age. Our objective was to examine changes in the manifestation of asthma and asthma-related traits in childhood by defining empirically derived childhood asthma phenotypes and examining their transitions over time.To define the phenotypes we used data on respiratory symptoms, healthcare utilisation, medications, spirometry, airway hyperresponsiveness (AHR), exhaled nitric oxide concentration and atopy from a birth cohort recruited on the basis of having a first-degree relative with asthma. Data were acquired at ages 1.5-11.5 years and analysed using latent transition analysis.In a study population of 370 participants, we classified subjects into four phenotypes: 1) nonatopic, few symptoms (prevalence range from 1.5 to 5 years: 52-60%), 2) atopic, few symptoms (3-21%), 3) nonatopic, asthma and rhinitis symptoms (13-35%), and 4) atopic, asthma and rhinitis symptoms (2-14%) in early childhood; and 1) nonatopic, no respiratory disease (prevalence range from 8 to 11.5 years: 41-46%), 2) atopic, no respiratory disease (23-33%), 3) nonatopic, asthma symptoms, no AHR or airway inflammation (8-12%) and 4) atopic asthma (19%) in mid-childhood. Transitioning between phenotypes was common in early childhood, but less common in later childhood.This analysis represents the first attempt to incorporate longitudinal patterns of several manifestations of asthma into a single model to simultaneously define phenotypes and examine their transitions over time. It provides quantitative support for the view that asthma is a heterogeneous entity, and that some children with wheeze and other respiratory symptoms in early life progress to asthma in mid-childhood, while others become asymptomatic. Copyright ©ERS 2016.

Capturing the essence of a metabolic network: a flux balance analysis approach.

PubMed

Murabito, Ettore; Simeonidis, Evangelos; Smallbone, Kieran; Swinton, Jonathan

2009-10-07

As genome-scale metabolic reconstructions emerge, tools to manage their size and complexity will be increasingly important. Flux balance analysis (FBA) is a constraint-based approach widely used to study the metabolic capabilities of cellular or subcellular systems. FBA problems are highly underdetermined and many different phenotypes can satisfy any set of constraints through which the metabolic system is represented. Two of the main concerns in FBA are exploring the space of solutions for a given metabolic network and finding a specific phenotype which is representative for a given task such as maximal growth rate. Here, we introduce a recursive algorithm suitable for overcoming both of these concerns. The method proposed is able to find the alternate optimal patterns of active reactions of an FBA problem and identify the minimal subnetwork able to perform a specific task as optimally as the whole. Our method represents an alternative to and an extension of other approaches conceived for exploring the space of solutions of an FBA problem. It may also be particularly helpful in defining a scaffold of reactions upon which to build up a dynamic model, when the important pathways of the system have not yet been well-defined.

Influenza virus sequence feature variant type analysis: evidence of a role for NS1 in influenza virus host range restriction.

PubMed

Noronha, Jyothi M; Liu, Mengya; Squires, R Burke; Pickett, Brett E; Hale, Benjamin G; Air, Gillian M; Galloway, Summer E; Takimoto, Toru; Schmolke, Mirco; Hunt, Victoria; Klem, Edward; García-Sastre, Adolfo; McGee, Monnie; Scheuermann, Richard H

2012-05-01

Genetic drift of influenza virus genomic sequences occurs through the combined effects of sequence alterations introduced by a low-fidelity polymerase and the varying selective pressures experienced as the virus migrates through different host environments. While traditional phylogenetic analysis is useful in tracking the evolutionary heritage of these viruses, the specific genetic determinants that dictate important phenotypic characteristics are often difficult to discern within the complex genetic background arising through evolution. Here we describe a novel influenza virus sequence feature variant type (Flu-SFVT) approach, made available through the public Influenza Research Database resource (www.fludb.org), in which variant types (VTs) identified in defined influenza virus protein sequence features (SFs) are used for genotype-phenotype association studies. Since SFs have been defined for all influenza virus proteins based on known structural, functional, and immune epitope recognition properties, the Flu-SFVT approach allows the rapid identification of the molecular genetic determinants of important influenza virus characteristics and their connection to underlying biological functions. We demonstrate the use of the SFVT approach to obtain statistical evidence for effects of NS1 protein sequence variations in dictating influenza virus host range restriction.

Comparative Phenotypical and Molecular Analyses of Arabidopsis Grown under Fluorescent and LED Light

PubMed Central

Seiler, Franka; Soll, Jürgen; Bölter, Bettina

2017-01-01

Comparative analyses of phenotypic and molecular traits of Arabidopsis thaliana grown under standardised conditions is still a challenge using climatic devices supplied with common light sources. These are in most cases fluorescent lights, which have several disadvantages such as heat production at higher light intensities, an invariable spectral output, and relatively rapid “ageing”. This results in non-desired variations of growth conditions and lowers the comparability of data acquired over extended time periods. In this study, we investigated the growth behaviour of Arabidopsis Col0 under different light conditions, applying fluorescent compared to LED lamps, and we conducted physiological as well as gene expression analyses. By changing the spectral composition and/or light intensity of LEDs we can clearly influence the growth behaviour of Arabidopsis and thereby study phenotypic attributes under very specific light conditions that are stable and reproducible, which is not necessarily given for fluorescent lamps. By using LED lights, we can also roughly mimic the sun light emission spectrum, enabling us to study plant growth in a more natural-like light set-up. We observed distinct growth behaviour under the different light regimes which was reflected by physiological properties of the plants. In conclusion, LEDs provide variable emission spectra for studying plant growth under defined, stable light conditions. PMID:28608805

Non-Compact Cardiomyopathy or Ventricular Non-Compact Syndrome?

PubMed Central

2014-01-01

Ventricular myocardial non-compaction has been recognized and defined as a genetic cardiomyopathy by American Heart Association since 2006. The argument on the nomenclature and pathogenesis of this kind of ventricular myocardial non-compaction characterized by regional ventricular wall thickening and deep trabecular recesses often complicated with chronic heart failure, arrhythmia and thromboembolism and usually overlap the genetics and phenotypes of other kind of genetic or mixed cardiomyopathy still exist. The proper classification and correct nomenclature of the non-compact ventricles will contribute to the precisely and completely understanding of etiology and its related patho-physiological mechanism for a better risk stratification and more personalized therapy of the disease individually. All of the genetic heterogeneity and phenotypical overlap and the variety in histopathological, electromechanical and clinical presentation indicates that some of the cardiomyopathies might just be the different consequence of myocardial development variations related to gene mutation and phenotype of one or group genes induced by the interacted and disturbed process of gene modulation at different links of gene function expression and some other etiologies. This review aims to establish a new concept of "ventricular non-compaction syndrome" based on the demonstration of the current findings of etiology, epidemiology, histopathology and echocardiography related to the disorder of ventricular myocardial compaction and myocardial electromechanical function development. PMID:25580189

Limitations of Climatic Data for Inferring Species Boundaries: Insights from Speckled Rattlesnakes

PubMed Central

Flores-Villela, Oscar; Fujita, Matthew K.

2015-01-01

Phenotypes, DNA, and measures of ecological differences are widely used in species delimitation. Although rarely defined in such studies, ecological divergence is almost always approximated using multivariate climatic data associated with sets of specimens (i.e., the “climatic niche”); the justification for this approach is that species-specific climatic envelopes act as surrogates for physiological tolerances. Using identical statistical procedures, we evaluated the usefulness and validity of the climate-as-proxy assumption by comparing performance of genetic (nDNA SNPs and mitochondrial DNA), phenotypic, and climatic data for objective species delimitation in the speckled rattlesnake (Crotalus mitchellii) complex. Ordination and clustering patterns were largely congruent among intrinsic (heritable) traits (nDNA, mtDNA, phenotype), and discordance is explained by biological processes (e.g., ontogeny, hybridization). In contrast, climatic data did not produce biologically meaningful clusters that were congruent with any intrinsic dataset, but rather corresponded to regional differences in atmospheric circulation and climate, indicating an absence of inherent taxonomic signal in these data. Surrogating climate for physiological tolerances adds artificial weight to evidence of species boundaries, as these data are irrelevant for that purpose. Based on the evidence from congruent clustering of intrinsic datasets, we recommend that three subspecies of C. mitchellii be recognized as species: C. angelensis, C. mitchellii, and C. Pyrrhus. PMID:26107178

Limitations of climatic data for inferring species boundaries: insights from speckled rattlesnakes.

PubMed

Meik, Jesse M; Streicher, Jeffrey W; Lawing, A Michelle; Flores-Villela, Oscar; Fujita, Matthew K

2015-01-01

Phenotypes, DNA, and measures of ecological differences are widely used in species delimitation. Although rarely defined in such studies, ecological divergence is almost always approximated using multivariate climatic data associated with sets of specimens (i.e., the "climatic niche"); the justification for this approach is that species-specific climatic envelopes act as surrogates for physiological tolerances. Using identical statistical procedures, we evaluated the usefulness and validity of the climate-as-proxy assumption by comparing performance of genetic (nDNA SNPs and mitochondrial DNA), phenotypic, and climatic data for objective species delimitation in the speckled rattlesnake (Crotalus mitchellii) complex. Ordination and clustering patterns were largely congruent among intrinsic (heritable) traits (nDNA, mtDNA, phenotype), and discordance is explained by biological processes (e.g., ontogeny, hybridization). In contrast, climatic data did not produce biologically meaningful clusters that were congruent with any intrinsic dataset, but rather corresponded to regional differences in atmospheric circulation and climate, indicating an absence of inherent taxonomic signal in these data. Surrogating climate for physiological tolerances adds artificial weight to evidence of species boundaries, as these data are irrelevant for that purpose. Based on the evidence from congruent clustering of intrinsic datasets, we recommend that three subspecies of C. mitchellii be recognized as species: C. angelensis, C. mitchellii, and C. Pyrrhus.

Combining high-throughput phenotyping and genome-wide association studies to reveal natural genetic variation in rice

PubMed Central

Yang, Wanneng; Guo, Zilong; Huang, Chenglong; Duan, Lingfeng; Chen, Guoxing; Jiang, Ni; Fang, Wei; Feng, Hui; Xie, Weibo; Lian, Xingming; Wang, Gongwei; Luo, Qingming; Zhang, Qifa; Liu, Qian; Xiong, Lizhong

2014-01-01

Even as the study of plant genomics rapidly develops through the use of high-throughput sequencing techniques, traditional plant phenotyping lags far behind. Here we develop a high-throughput rice phenotyping facility (HRPF) to monitor 13 traditional agronomic traits and 2 newly defined traits during the rice growth period. Using genome-wide association studies (GWAS) of the 15 traits, we identify 141 associated loci, 25 of which contain known genes such as the Green Revolution semi-dwarf gene, SD1. Based on a performance evaluation of the HRPF and GWAS results, we demonstrate that high-throughput phenotyping has the potential to replace traditional phenotyping techniques and can provide valuable gene identification information. The combination of the multifunctional phenotyping tools HRPF and GWAS provides deep insights into the genetic architecture of important traits. PMID:25295980

Arylamine N-acetyltransferase (NAT2) mutations and their allelic linkage in unrelated caucasian individuals: Correlation with phenotypic activity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cascorbi, I.; Drakoulis, N.; Brockmoeller, J.

1995-09-01

The polymorphic arylamine N-acetyltransferase (NAT2; EC2.3.1.5) is supposed to be a susceptibility factor for several drug side effects and certain malignancies. A group of 844 unrelated German subjects was genotyped for their acetylation type, and 563 of them were also phenotyped. Seven mutations of the NAT2 gene were evaluated by allele-specific PCR (mutation 341C to T) and PCR-RFLP for mutations at nt positions 191, 282, 481, 590, 803, and 857. From the mutation pattern eight different alleles, including the wild type coding for rapid acetylation and seven alleles coding for slow phenotype, were determined. Four hundred ninety-seven subjects had amore » genotype of slow acetylation (58.9%; 95% confidence limits 55.5%-62.2%). Phenotypic acetylation capacity was expressed as the ratio of 5-acetylamino-6-formylamino-3-methyluracil and 1-methylxanthine in urine after caffeine intake. Some 6.7% of the cases deviated in genotype and phenotype, but sequencing DNA of these probands revealed no new mutations. Furthermore, linkage pattern of the mutations was always confirmed, as tested in 533 subjects. In vivo acetylation capacity of homozygous wild-type subjects (NAT2{sup *}4/{sup *}4) was significantly higher than in heterozygous genotypes (P = .001). All mutant alleles showed low in vivo acetylation capacities, including the previously not-yet-defined alleles {sup *}5A, {sup *}5C, and {sup *}13. Moreover, distinct slow genotypes differed significantly among each other, as reflected in lower acetylation capacity of {sup *}6A, {sup *}7B, and {sup *}13 alleles than the group of {sup *}5 alleles. The study demonstrated differential phenotypic activity of various NAT2 genes and gives a solid basis for clinical and molecular-epidemiological investigations. 34 refs., 4 figs., 7 tabs.« less

Arterial stiffness is increased in asymptomatic nondiabetic postmenopausal women with a polycystic ovary syndrome phenotype.

PubMed

Armeni, Eleni; Stamatelopoulos, Kimon; Rizos, Demetrios; Georgiopoulos, George; Kazani, Maria; Kazani, Aikaterini; Kolyviras, Athanasios; Stellos, Konstantinos; Panoulis, Konstantinos; Alexandrou, Andreas; Creatsa, Maria; Papamichael, Christos; Lambrinoudaki, Irene

2013-10-01

The metabolic dysfunction accompanying the polycystic ovary syndrome (PCOS) may increase the risk of hypertension and cardiovascular disease (CVD). Although menopause per se may be an additional risk factor of CVD, the association between PCOS in postmenopausal women and cardiovascular risk has not been adequately investigated. We aimed to evaluate the effect of PCOS on markers of subclinical atherosclerosis in nondiabetic postmenopausal women. This cross-sectional study included 286 postmenopausal women with intact ovaries. PCOS phenotype was defined if three of the following were present: insulin resistance, current hyperandrogenism or history of clinical androgen excess, history of infertility, central obesity and history of irregular menses. Traditional CVD risk factors, as well as indices of arterial structure (intima-media thickness, atheromatous plaques presence) and function [flow-mediated dilation, pulse wave velocity (PWV), augmentation index] were compared between women with a PCOS phenotype and the rest of the sample, who served as controls. Women with the PCOS phenotype (N=43) had higher SBP and triglycerides and lower high-density lipoprotein (HDL)-cholesterol than controls. Mean values of PWV differed significantly between PCOS cases and controls (9.46±1.74 vs. 8.60±1.51 m/s, P=0.001, univariate). Multivariate regression analysis showed that the PCOS phenotype, age and SBP were the only independent predictors of PWV. Arterial stiffness is increased in asymptomatic, nondiabetic women with a putative PCOS phenotype, independently of age, BMI or blood pressure. This might present one mechanism through which PCOS increases the risk of CVD and hypertension later in life.

Implementation of genomic recursions in single-step genomic best linear unbiased predictor for US Holsteins with a large number of genotyped animals.

PubMed

Masuda, Y; Misztal, I; Tsuruta, S; Legarra, A; Aguilar, I; Lourenco, D A L; Fragomeni, B O; Lawlor, T J

2016-03-01

The objectives of this study were to develop and evaluate an efficient implementation in the computation of the inverse of genomic relationship matrix with the recursion algorithm, called the algorithm for proven and young (APY), in single-step genomic BLUP. We validated genomic predictions for young bulls with more than 500,000 genotyped animals in final score for US Holsteins. Phenotypic data included 11,626,576 final scores on 7,093,380 US Holstein cows, and genotypes were available for 569,404 animals. Daughter deviations for young bulls with no classified daughters in 2009, but at least 30 classified daughters in 2014 were computed using all the phenotypic data. Genomic predictions for the same bulls were calculated with single-step genomic BLUP using phenotypes up to 2009. We calculated the inverse of the genomic relationship matrix GAPY(-1) based on a direct inversion of genomic relationship matrix on a small subset of genotyped animals (core animals) and extended that information to noncore animals by recursion. We tested several sets of core animals including 9,406 bulls with at least 1 classified daughter, 9,406 bulls and 1,052 classified dams of bulls, 9,406 bulls and 7,422 classified cows, and random samples of 5,000 to 30,000 animals. Validation reliability was assessed by the coefficient of determination from regression of daughter deviation on genomic predictions for the predicted young bulls. The reliabilities were 0.39 with 5,000 randomly chosen core animals, 0.45 with the 9,406 bulls, and 7,422 cows as core animals, and 0.44 with the remaining sets. With phenotypes truncated in 2009 and the preconditioned conjugate gradient to solve mixed model equations, the number of rounds to convergence for core animals defined by bulls was 1,343; defined by bulls and cows, 2,066; and defined by 10,000 random animals, at most 1,629. With complete phenotype data, the number of rounds decreased to 858, 1,299, and at most 1,092, respectively. Setting up GAPY(-1) for 569,404 genotyped animals with 10,000 core animals took 1.3h and 57 GB of memory. The validation reliability with APY reaches a plateau when the number of core animals is at least 10,000. Predictions with APY have little differences in reliability among definitions of core animals. Single-step genomic BLUP with APY is applicable to millions of genotyped animals. Copyright © 2016 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Sexual reproduction, sporophyte development and molecular variation in the model moss Physcomitrella patens: introducing the ecotype Reute.

PubMed

Hiss, Manuel; Meyberg, Rabea; Westermann, Jens; Haas, Fabian B; Schneider, Lucas; Schallenberg-Rüdinger, Mareike; Ullrich, Kristian K; Rensing, Stefan A

2017-05-01

Rich ecotype collections are used for several plant models to unravel the molecular causes of phenotypic differences, and to investigate the effects of environmental adaption and acclimation. For the model moss Physcomitrella patens collections of accessions are available, and have been used for phylogenetic and taxonomic studies, for example, but few have been investigated further for phenotypic differences. Here, we focus on the Reute accession and provide expression profiling and comparative developmental data for several stages of sporophyte development, as well as information on genetic variation via genomic sequencing. We analysed cross-technology and cross-laboratory data to define a confident set of 15 mature sporophyte-specific genes. We find that the standard laboratory strain Gransden produces fewer sporophytes than Reute or Villersexel, although gametangia develop with the same time course and do not show evident morphological differences. Reute exhibits less genetic variation relative to Gransden than Villersexel, yet we found variation between Gransden and Reute in the expression profiles of several genes, as well as variation hot spots and genes that appear to evolve under positive Darwinian selection. We analyzed expression differences between the ecotypes for selected candidate genes in the GRAS transcription factor family, the chalcone synthase family and in genes involved in cell wall modification that are potentially related to phenotypic differences. We confirm that Reute is a P. patens ecotype, and suggest its use for reverse-genetics studies that involve progression through the life cycle and multiple generations. © 2017 The Authors The Plant Journal © 2017 John Wiley & Sons Ltd.

Novel quantitative pigmentation phenotyping enhances genetic association, epistasis, and prediction of human eye colour.

PubMed

Wollstein, Andreas; Walsh, Susan; Liu, Fan; Chakravarthy, Usha; Rahu, Mati; Seland, Johan H; Soubrane, Gisèle; Tomazzoli, Laura; Topouzis, Fotis; Vingerling, Johannes R; Vioque, Jesus; Böhringer, Stefan; Fletcher, Astrid E; Kayser, Manfred

2017-02-27

Success of genetic association and the prediction of phenotypic traits from DNA are known to depend on the accuracy of phenotype characterization, amongst other parameters. To overcome limitations in the characterization of human iris pigmentation, we introduce a fully automated approach that specifies the areal proportions proposed to represent differing pigmentation types, such as pheomelanin, eumelanin, and non-pigmented areas within the iris. We demonstrate the utility of this approach using high-resolution digital eye imagery and genotype data from 12 selected SNPs from over 3000 European samples of seven populations that are part of the EUREYE study. In comparison to previous quantification approaches, (1) we achieved an overall improvement in eye colour phenotyping, which provides a better separation of manually defined eye colour categories. (2) Single nucleotide polymorphisms (SNPs) known to be involved in human eye colour variation showed stronger associations with our approach. (3) We found new and confirmed previously noted SNP-SNP interactions. (4) We increased SNP-based prediction accuracy of quantitative eye colour. Our findings exemplify that precise quantification using the perceived biological basis of pigmentation leads to enhanced genetic association and prediction of eye colour. We expect our approach to deliver new pigmentation genes when applied to genome-wide association testing.

[Behavioral phenotypes: cognitive and emotional explanation].

PubMed

Pérez-Alvarez, F; Timoneda-Gallart, C

We present a series of Behavioural phenotypes treated with neurocognitive and neuroemotional procedure. A sample of 26 cases were selected according to qualitative methodology from neuropediatric patients. The method was based on using the PASS theory of intelligence to approach the cognitive problem and the theory of masquerade behaviour as self-defence to solve the emotional problem. Both theories have neurological bases. DN:CAS battery was utilized for assessment of cognitive processes. On the other hand, analysis of cases was carried out doing data analysis with video recorder device. All cases were considered responder cases although in different degree. The responder was defined as the patient which reached better intellectual achievement with respect to cognitive function and which gave up, at least partially, masquerade Behaviour with respect to emotional function. The Behaviour of the Behavioural phenotypes has neurological rationale. The PASS theory and the planning, in particular, supported by prefrontal cortex justifies consistently some behaviours. The masquerade Behaviour theory is explained by the fear emotional response mechanism which means emotion is a cerebral processing with neurological rationale. The Behavioural phenotypes are Behaviours and every Behaviour can be explained by neurological reasons both cognitive and emotional reasons. So, they can be treated by a cognitive and emotional procedure understood in the light of the neurology.

Novel quantitative pigmentation phenotyping enhances genetic association, epistasis, and prediction of human eye colour

PubMed Central

Wollstein, Andreas; Walsh, Susan; Liu, Fan; Chakravarthy, Usha; Rahu, Mati; Seland, Johan H.; Soubrane, Gisèle; Tomazzoli, Laura; Topouzis, Fotis; Vingerling, Johannes R.; Vioque, Jesus; Böhringer, Stefan; Fletcher, Astrid E.; Kayser, Manfred

2017-01-01

Success of genetic association and the prediction of phenotypic traits from DNA are known to depend on the accuracy of phenotype characterization, amongst other parameters. To overcome limitations in the characterization of human iris pigmentation, we introduce a fully automated approach that specifies the areal proportions proposed to represent differing pigmentation types, such as pheomelanin, eumelanin, and non-pigmented areas within the iris. We demonstrate the utility of this approach using high-resolution digital eye imagery and genotype data from 12 selected SNPs from over 3000 European samples of seven populations that are part of the EUREYE study. In comparison to previous quantification approaches, (1) we achieved an overall improvement in eye colour phenotyping, which provides a better separation of manually defined eye colour categories. (2) Single nucleotide polymorphisms (SNPs) known to be involved in human eye colour variation showed stronger associations with our approach. (3) We found new and confirmed previously noted SNP-SNP interactions. (4) We increased SNP-based prediction accuracy of quantitative eye colour. Our findings exemplify that precise quantification using the perceived biological basis of pigmentation leads to enhanced genetic association and prediction of eye colour. We expect our approach to deliver new pigmentation genes when applied to genome-wide association testing. PMID:28240252

A Newborn with Panhypopituitarism and Seizures.

PubMed

Kale, Trupti; Patil, Rachit; Pandit, Ramesh

2017-01-01

Interstitial deletions on the short arm of chromosome 20 are uncommon, and therefore the clinical phenotype is poorly defined. Very few cases have been reported in the literature so far. In this report, we describe a 4-month-old female with a heterozygous deletion at 20p11.21p12.1 with panhypopituitarism and cardiac, gastrointestinal, and genitourinary anomalies along with dysmorphic facial features. We compared and discussed similar cases with overlapping deletions in 20p11 region. We wish to report this rare occurrence as this may better define the phenotypes of the 20p interstitial deletion with certain dysmorphic features, multiorgan involvement, and related clinical characteristics in this patient population.

Defining a genetic ideotype for crop improvement.

PubMed

Trethowan, Richard M

2014-01-01

While plant breeders traditionally base selection on phenotype, the development of genetic ideotypes can help focus the selection process. This chapter provides a road map for the establishment of a refined genetic ideotype. The first step is an accurate definition of the target environment including the underlying constraints, their probability of occurrence, and impact on phenotype. Once the environmental constraints are established, the wealth of information on plant physiological responses to stresses, known gene information, and knowledge of genotype ×environment and gene × environment interaction help refine the target ideotype and form a basis for cross prediction.Once a genetic ideotype is defined the challenge remains to build the ideotype in a plant breeding program. A number of strategies including marker-assisted recurrent selection and genomic selection can be used that also provide valuable information for the optimization of genetic ideotype. However, the informatics required to underpin the realization of the genetic ideotype then becomes crucial. The reduced cost of genotyping and the need to combine pedigree, phenotypic, and genetic data in a structured way for analysis and interpretation often become the rate-limiting steps, thus reducing genetic gain. Systems for managing these data and an example of ideotype construction for a defined environment type are discussed.

The Molecular Basis of Dominance

PubMed Central

Kacser, Henrik; Burns, James A.

1981-01-01

The best known genes of microbes, mice and men are those that specify enzymes. Wild type, mutant and heterozygote for variants of such genes differ in the catalytic activity at the step in the enzyme network specified by the gene in question. The effect on the respective phenotypes of such changes in catalytic activity, however, is not defined by the enzyme change as estimated by in vitro determination of the activities obtained from the extracts of the three types. In vivo enzymes do not act in isolation, but are kinetically linked to other enzymes via their substrates and products. These interactions modify the effect of enzyme variation on the phenotype, depending on the nature and quantity of the other enzymes present. An output of such a system, say a flux, is therefore a systemic property, and its response to variation at one locus must be measured in the whole system. This response is best described by the sensitivity coefficient, Z, which is defined by the fractional change in flux over the fractional change in enzyme activity.(see PDF)Its magnitude determines the extent to which a particular enzyme "controls" a particular flux or phenotype and, implicitly, determines the values that the three phenotypes will have. There are as many sensitivity coefficients for a given flux as there are enzymes in the system. It can be shown that the sum of all such coefficients equals unity.(see PDF)Since n, the number of enzymes, is large, this summation property results in the individual coefficients being small. The effect of making a large change in enzyme activity therefore usually results in only a negligible change in flux. A reduction to 50% activity in the heterozygote, a common feature for many mutants, is therefore not expected to be detectable in the phenotype. The mutant would therefore be described as "recessive". The widespread occurrence of recessive mutants is thus seen to be the inevitable consequence of the kinetic structure of enzyme networks. The ad hoc hypothesis of "modifiers" selected to maximize the fitness of the heterozygote, as proposed by Fisher, is therefore unnecessary. It is based on the false general expectation of an intermediate phenotype in the heterozygote. Wright's analysis, substantially sound in its approach, proposed selection of a "safety factor" in enzyme activity. The derivation of the summation property explains why such safety factors are automatically present in almost all enzymes without selection. PMID:7297851

Comparison of Phenotypic and Functional Characteristics Between Canine Non-B, Non-T Natural Killer Lymphocytes and CD3+CD5dimCD21- Cytotoxic Large Granular Lymphocytes.

PubMed

Lee, Soo-Hyeon; Shin, Dong-Jun; Kim, Yoseop; Kim, Cheol-Jung; Lee, Je-Jung; Yoon, Mee Sun; Uong, Tung Nguyen Thanh; Yu, Dohyeon; Jung, Ji-Youn; Cho, Duck; Jung, Bock-Gie; Kim, Sang-Ki; Suh, Guk-Hyun

2018-01-01

Natural killer (NK) cells play a pivotal role in the immune response against infections and malignant transformation, and adopted transfer of NK cells is thought to be a promising therapeutic approach for cancer patients. Previous reports describing the phenotypic features of canine NK cells have produced inconsistent results. Canine NK cells are still defined as non-B and non-T (CD3 - CD21 - ) large granular lymphocytes. However, a few reports have demonstrated that canine NK cells share the phenotypic characteristics of T lymphocytes, and that CD3 + CD5 dim CD21 - lymphocytes are putative canine NK cells. Based on our previous reports, we hypothesized that phenotypic modulation could occur between these two populations during activation. In this study, we investigated the phenotypic and functional differences between CD3 + CD5 dim CD21 - (cytotoxic large granular lymphocytes) and CD3 - CD5 - CD21 - NK lymphocytes before and after culture of peripheral blood mononuclear cells isolated from normal dogs. The results of this study show that CD3 + CD5 dim CD21 - lymphocytes can be differentiated into non-B, non-T NK (CD3 - CD5 - CD21 - TCRαβ - TCRγδ - GranzymeB + ) lymphocytes through phenotypic modulation in response to cytokine stimulation. In vitro studies of purified CD3 + CD5 dim CD21 - cells showed that CD3 - CD5 - CD21 - cells are derived from CD3 + CD5 dim CD21 - cells through phenotypic modulation. CD3 + CD5 dim CD21 - cells share more NK cell functional characteristics compared with CD3 - CD5 - CD21 - cells, including the expression of T-box transcription factors (Eomes, T-bet), the production of granzyme B and interferon-γ, and the expression of NK cell-related molecular receptors such as NKG2D and NKp30. In conclusion, the results of this study suggest that CD3 + CD5 dim CD21 - and CD3 - CD5 - CD21 - cells both contain a subset of putative NK cells, and the difference between the two populations may be due to the degree of maturation.

Escherichia coli mastitis strains: In vitro phenotypes and severity of infection in vivo.

PubMed

Roussel, Perrine; Porcherie, Adeline; Répérant-Ferter, Maryline; Cunha, Patricia; Gitton, Christophe; Rainard, Pascal; Germon, Pierre

2017-01-01

Mastitis remains a major infection of dairy cows and an important issue for dairy farmers and the dairy industry, in particular infections due to Escherichia coli strains. So far, properties specific to E. coli causing mastitis remain ill defined. In an attempt to better understand the properties required for E. coli to trigger mastitis, we used a range of in vitro assays to phenotypically characterize four E. coli strains, including the prototypical E. coli mastitis strain P4, possessing different relative abilities to cause mastitis in a mouse model. Our results indicate that a certain level of serum resistance might be required for colonization of the mammary gland. Resistance to neutrophil killing is also likely to contribute to a slower clearance of bacteria and higher chances to colonize the udder. In addition, we show that the four different strains do induce a pro-inflammatory response by mammary epithelial cells but with different intensities. Interestingly, the prototypical mastitis strain P4 actually induces the less intense response while it is responsible for the most severe infections in vivo. Altogether, our results suggest that different strategies can be used by E. coli strains to colonize the mammary gland and cause mastitis.

Low level of polyandry constrains phenotypic plasticity of male body size in mites.

PubMed

Schausberger, Peter; Walzer, Andreas; Murata, Yasumasa; Osakabe, Masahiro

2017-01-01

Polyandry, i.e. females mating with multiple males, is more common than previously anticipated and potentially provides both direct and indirect fitness benefits to females. The level of polyandry (defined by the lifetime number of male mates of a female) is an important determinant of the occurrence and intensity of sexual selection acting on male phenotypes. While the forces of sexual selection acting on phenotypic male traits such as body size are relatively well understood, sexual selection acting on phenotypic plasticity of these traits is unexplored. We tackled this issue by scrutinizing the link between polyandry and phenotypic plasticity of male body size in two sympatric plant-inhabiting predatory mite species, Phytoseiulus persimilis and Neoseiulus californicus. These two species are similar in life history, ecological niche requirements, mating behavior, polygyny and female body size plasticity but strikingly differ in the level of both polyandry and phenotypic plasticity of male body size (both lower in P. persimilis). We hypothesized that deviations from standard body size, i.e. the size achieved under favorable conditions, incur higher costs for males in the less polyandrous P. persimilis. To test our hypotheses, we conducted two experiments on (i) the effects of male body size on spermatophore transfer in singly mating females and (ii) the effects of mate sequence (switching the order of standard-sized and small males) on mating behavior and paternity success in doubly mating females. In P. persimilis but not N. californicus, small males transferred fewer but larger spermatophores to the females; in both species, females re-mated more likely with standard-sized following small than small following standard-sized males; in P. persimilis, first standard-sized males sired a higher proportion of offspring produced after re-mating by the female than first small males, whereas in N. californicus the paternity success of small and standard-sized males was independent of the mating sequence. Based on our results and pertinent previous studies, which showed that females of P. persimilis, but not N. californicus, prefer mating with standard-sized over small males and allow them fertilizing more eggs, the lack of interspecific difference in female body size plasticity, and the absence of any clue pointing at a role of natural selection, we suggest that the interspecific difference in male body size plasticity is sexually selected. Our study provides an indication of sexual selection constraining plasticity of male phenotypes, suggesting that the level of polyandry may be an important co-determinant of the level of phenotypic plasticity of male body size.

Low level of polyandry constrains phenotypic plasticity of male body size in mites

PubMed Central

Walzer, Andreas; Murata, Yasumasa; Osakabe, Masahiro

2017-01-01

Polyandry, i.e. females mating with multiple males, is more common than previously anticipated and potentially provides both direct and indirect fitness benefits to females. The level of polyandry (defined by the lifetime number of male mates of a female) is an important determinant of the occurrence and intensity of sexual selection acting on male phenotypes. While the forces of sexual selection acting on phenotypic male traits such as body size are relatively well understood, sexual selection acting on phenotypic plasticity of these traits is unexplored. We tackled this issue by scrutinizing the link between polyandry and phenotypic plasticity of male body size in two sympatric plant-inhabiting predatory mite species, Phytoseiulus persimilis and Neoseiulus californicus. These two species are similar in life history, ecological niche requirements, mating behavior, polygyny and female body size plasticity but strikingly differ in the level of both polyandry and phenotypic plasticity of male body size (both lower in P. persimilis). We hypothesized that deviations from standard body size, i.e. the size achieved under favorable conditions, incur higher costs for males in the less polyandrous P. persimilis. To test our hypotheses, we conducted two experiments on (i) the effects of male body size on spermatophore transfer in singly mating females and (ii) the effects of mate sequence (switching the order of standard-sized and small males) on mating behavior and paternity success in doubly mating females. In P. persimilis but not N. californicus, small males transferred fewer but larger spermatophores to the females; in both species, females re-mated more likely with standard-sized following small than small following standard-sized males; in P. persimilis, first standard-sized males sired a higher proportion of offspring produced after re-mating by the female than first small males, whereas in N. californicus the paternity success of small and standard-sized males was independent of the mating sequence. Based on our results and pertinent previous studies, which showed that females of P. persimilis, but not N. californicus, prefer mating with standard-sized over small males and allow them fertilizing more eggs, the lack of interspecific difference in female body size plasticity, and the absence of any clue pointing at a role of natural selection, we suggest that the interspecific difference in male body size plasticity is sexually selected. Our study provides an indication of sexual selection constraining plasticity of male phenotypes, suggesting that the level of polyandry may be an important co-determinant of the level of phenotypic plasticity of male body size. PMID:29190832

Primer in Genetics and Genomics, Article 5-Further Defining the Concepts of Genotype and Phenotype and Exploring Genotype-Phenotype Associations.

PubMed

Wright, Fay; Fessele, Kristen

2017-10-01

As nurses begin to incorporate genetic and genomic sciences into clinical practice, education, and research, it is essential that they have a working knowledge of the terms foundational to the science. The first article in this primer series provided brief definitions of the basic terms (e.g., genetics and genomics) and introduced the concept of phenotype during the discussion of Mendelian inheritance. These terms, however, are inconsistently used in publications and conversations, and the linkage between genotype and phenotype requires clarification. The goal of this fifth article in the series is to elucidate these terms, provide an overview of the research methods used to determine genotype-phenotype associations, and discuss their significance to nursing through examples from the current nursing literature.

Design of synthetic bacterial communities for predictable plant phenotypes

PubMed Central

Herrera Paredes, Sur; Gao, Tianxiang; Law, Theresa F.; Finkel, Omri M.; Mucyn, Tatiana; Teixeira, Paulo José Pereira Lima; Salas González, Isaí; Feltcher, Meghan E.; Powers, Matthew J.; Shank, Elizabeth A.; Jones, Corbin D.; Jojic, Vladimir; Dangl, Jeffery L.; Castrillo, Gabriel

2018-01-01

Specific members of complex microbiota can influence host phenotypes, depending on both the abiotic environment and the presence of other microorganisms. Therefore, it is challenging to define bacterial combinations that have predictable host phenotypic outputs. We demonstrate that plant–bacterium binary-association assays inform the design of small synthetic communities with predictable phenotypes in the host. Specifically, we constructed synthetic communities that modified phosphate accumulation in the shoot and induced phosphate starvation–responsive genes in a predictable fashion. We found that bacterial colonization of the plant is not a predictor of the plant phenotypes we analyzed. Finally, we demonstrated that characterizing a subset of all possible bacterial synthetic communities is sufficient to predict the outcome of untested bacterial consortia. Our results demonstrate that it is possible to infer causal relationships between microbiota membership and host phenotypes and to use these inferences to rationally design novel communities. PMID:29462153

Keeping track of worm trackers.

PubMed

Husson, Steven J; Costa, Wagner Steuer; Schmitt, Cornelia; Gottschalk, Alexander

2013-02-22

C. elegans is used extensively as a model system in the neurosciences due to its well defined nervous system. However, the seeming simplicity of this nervous system in anatomical structure and neuronal connectivity, at least compared to higher animals, underlies a rich diversity of behaviors. The usefulness of the worm in genome-wide mutagenesis or RNAi screens, where thousands of strains are assessed for phenotype, emphasizes the need for computational methods for automated parameterization of generated behaviors. In addition, behaviors can be modulated upon external cues like temperature, O(subscript)2(/subscript) and CO(subscript)2(/subscript) concentrations, mechanosensory and chemosensory inputs. Different machine vision tools have been developed to aid researchers in their efforts to inventory and characterize defined behavioral "outputs". Here we aim at providing an overview of different worm-tracking packages or video analysis tools designed to quantify different aspects of locomotion such as the occurrence of directional changes (turns, omega bends), curvature of the sinusoidal shape (amplitude, body bend angles) and velocity (speed, backward or forward movement).

Structural Basis of Cerebellar Microcircuits in the Rat

PubMed Central

Cerminara, Nadia L.; Aoki, Hanako; Loft, Michaela; Apps, Richard

2013-01-01

The topography of the cerebellar cortex is described by at least three different maps, with the basic units of each map termed “microzones,” “patches,” and “bands.” These are defined, respectively, by different patterns of climbing fiber input, mossy fiber input, and Purkinje cell (PC) phenotype. Based on embryological development, the “one-map” hypothesis proposes that the basic units of each map align in the adult animal and the aim of the present study was to test this possibility. In barbiturate anesthetized adult rats, nanoinjections of bidirectional tracer (Retrobeads and biotinylated dextran amine) were made into somatotopically identified regions within the hindlimb C1 zone in copula pyramidis. Injection sites were mapped relative to PC bands defined by the molecular marker zebrin II and were correlated with the pattern of retrograde cell labeling within the inferior olive and in the basilar pontine nuclei to determine connectivity of microzones and patches, respectively, and also with the distributions of biotinylated dextran amine-labeled PC terminals in the cerebellar nuclei. Zebrin bands were found to be related to both climbing fiber and mossy fiber inputs and also to cortical representation of different parts of the ipsilateral hindpaw, indicating a precise spatial organization within cerebellar microcircuitry. This precise connectivity extends to PC terminal fields in the cerebellar nuclei and olivonuclear projections. These findings strongly support the one-map hypothesis and suggest that, at the microcircuit level of resolution, the cerebellar cortex has a common plan of spatial organization for major inputs, outputs, and PC phenotype. PMID:24133249

Assessing the complex architecture of polygenic traits in diverged yeast populations.

PubMed

Cubillos, Francisco A; Billi, Eleonora; Zörgö, Enikö; Parts, Leopold; Fargier, Patrick; Omholt, Stig; Blomberg, Anders; Warringer, Jonas; Louis, Edward J; Liti, Gianni

2011-04-01

Phenotypic variation arising from populations adapting to different niches has a complex underlying genetic architecture. A major challenge in modern biology is to identify the causative variants driving phenotypic variation. Recently, the baker's yeast, Saccharomyces cerevisiae has emerged as a powerful model for dissecting complex traits. However, past studies using a laboratory strain were unable to reveal the complete architecture of polygenic traits. Here, we present a linkage study using 576 recombinant strains obtained from crosses of isolates representative of the major lineages. The meiotic recombinational landscape appears largely conserved between populations; however, strain-specific hotspots were also detected. Quantitative measurements of growth in 23 distinct ecologically relevant environments show that our recombinant population recapitulates most of the standing phenotypic variation described in the species. Linkage analysis detected an average of 6.3 distinct QTLs for each condition tested in all crosses, explaining on average 39% of the phenotypic variation. The QTLs detected are not constrained to a small number of loci, and the majority are specific to a single cross-combination and to a specific environment. Moreover, crosses between strains of similar phenotypes generate greater variation in the offspring, suggesting the presence of many antagonistic alleles and epistatic interactions. We found that subtelomeric regions play a key role in defining individual quantitative variation, emphasizing the importance of the adaptive nature of these regions in natural populations. This set of recombinant strains is a powerful tool for investigating the complex architecture of polygenic traits. © 2011 Blackwell Publishing Ltd.

PheProb: probabilistic phenotyping using diagnosis codes to improve power for genetic association studies.

PubMed

Sinnott, Jennifer A; Cai, Fiona; Yu, Sheng; Hejblum, Boris P; Hong, Chuan; Kohane, Isaac S; Liao, Katherine P

2018-05-17

Standard approaches for large scale phenotypic screens using electronic health record (EHR) data apply thresholds, such as ≥2 diagnosis codes, to define subjects as having a phenotype. However, the variation in the accuracy of diagnosis codes can impair the power of such screens. Our objective was to develop and evaluate an approach which converts diagnosis codes into a probability of a phenotype (PheProb). We hypothesized that this alternate approach for defining phenotypes would improve power for genetic association studies. The PheProb approach employs unsupervised clustering to separate patients into 2 groups based on diagnosis codes. Subjects are assigned a probability of having the phenotype based on the number of diagnosis codes. This approach was developed using simulated EHR data and tested in a real world EHR cohort. In the latter, we tested the association between low density lipoprotein cholesterol (LDL-C) genetic risk alleles known for association with hyperlipidemia and hyperlipidemia codes (ICD-9 272.x). PheProb and thresholding approaches were compared. Among n = 1462 subjects in the real world EHR cohort, the threshold-based p-values for association between the genetic risk score (GRS) and hyperlipidemia were 0.126 (≥1 code), 0.123 (≥2 codes), and 0.142 (≥3 codes). The PheProb approach produced the expected significant association between the GRS and hyperlipidemia: p = .001. PheProb improves statistical power for association studies relative to standard thresholding approaches by leveraging information about the phenotype in the billing code counts. The PheProb approach has direct applications where efficient approaches are required, such as in Phenome-Wide Association Studies.

Latent class analysis reveals clinically relevant atopy phenotypes in 2 birth cohorts.

PubMed

Hose, Alexander J; Depner, Martin; Illi, Sabina; Lau, Susanne; Keil, Thomas; Wahn, Ulrich; Fuchs, Oliver; Pfefferle, Petra Ina; Schmaußer-Hechfellner, Elisabeth; Genuneit, Jon; Lauener, Roger; Karvonen, Anne M; Roduit, Caroline; Dalphin, Jean-Charles; Riedler, Josef; Pekkanen, Juha; von Mutius, Erika; Ege, Markus J

2017-06-01

Phenotypes of childhood-onset asthma are characterized by distinct trajectories and functional features. For atopy, definition of phenotypes during childhood is less clear. We sought to define phenotypes of atopic sensitization over the first 6 years of life using a latent class analysis (LCA) integrating 3 dimensions of atopy: allergen specificity, time course, and levels of specific IgE (sIgE). Phenotypes were defined by means of LCA in 680 children of the Multizentrische Allergiestudie (MAS) and 766 children of the Protection against allergy: Study in Rural Environments (PASTURE) birth cohorts and compared with classical nondisjunctive definitions of seasonal, perennial, and food sensitization with respect to atopic diseases and lung function. Cytokine levels were measured in the PASTURE cohort. The LCA classified predominantly by type and multiplicity of sensitization (food vs inhalant), allergen combinations, and sIgE levels. Latent classes were related to atopic disease manifestations with higher sensitivity and specificity than the classical definitions. LCA detected consistently in both cohorts a distinct group of children with severe atopy characterized by high seasonal sIgE levels and a strong propensity for asthma; hay fever; eczema; and impaired lung function, also in children without an established asthma diagnosis. Severe atopy was associated with an increased IL-5/IFN-γ ratio. A path analysis among sensitized children revealed that among all features of severe atopy, only excessive sIgE production early in life affected asthma risk. LCA revealed a set of benign, symptomatic, and severe atopy phenotypes. The severe phenotype emerged as a latent condition with signs of a dysbalanced immune response. It determined high asthma risk through excessive sIgE production and directly affected impaired lung function. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

The phenotypic manifestations of rare genic CNVs in autism spectrum disorder

PubMed Central

Merikangas, A K; Segurado, R; Heron, E A; Anney, R J L; Paterson, A D; Cook, E H; Pinto, D; Scherer, S W; Szatmari, P; Gill, M; Corvin, A P; Gallagher, L

2015-01-01

Significant evidence exists for the association between copy number variants (CNVs) and Autism Spectrum Disorder (ASD); however, most of this work has focused solely on the diagnosis of ASD. There is limited understanding of the impact of CNVs on the ‘sub-phenotypes' of ASD. The objective of this paper is to evaluate associations between CNVs in differentially brain expressed (DBE) genes or genes previously implicated in ASD/intellectual disability (ASD/ID) and specific sub-phenotypes of ASD. The sample consisted of 1590 cases of European ancestry from the Autism Genome Project (AGP) with a diagnosis of an ASD and at least one rare CNV impacting any gene and a core set of phenotypic measures, including symptom severity, language impairments, seizures, gait disturbances, intelligence quotient (IQ) and adaptive function, as well as paternal and maternal age. Classification analyses using a non-parametric recursive partitioning method (random forests) were employed to define sets of phenotypic characteristics that best classify the CNV-defined groups. There was substantial variation in the classification accuracy of the two sets of genes. The best variables for classification were verbal IQ for the ASD/ID genes, paternal age at birth for the DBE genes and adaptive function for de novo CNVs. CNVs in the ASD/ID list were primarily associated with communication and language domains, whereas CNVs in DBE genes were related to broader manifestations of adaptive function. To our knowledge, this is the first study to examine the associations between sub-phenotypes and CNVs genome-wide in ASD. This work highlights the importance of examining the diverse sub-phenotypic manifestations of CNVs in ASD, including the specific features, comorbid conditions and clinical correlates of ASD that comprise underlying characteristics of the disorder. PMID:25421404

The phenotypic manifestations of rare genic CNVs in autism spectrum disorder.

PubMed

Merikangas, A K; Segurado, R; Heron, E A; Anney, R J L; Paterson, A D; Cook, E H; Pinto, D; Scherer, S W; Szatmari, P; Gill, M; Corvin, A P; Gallagher, L

2015-11-01

Significant evidence exists for the association between copy number variants (CNVs) and Autism Spectrum Disorder (ASD); however, most of this work has focused solely on the diagnosis of ASD. There is limited understanding of the impact of CNVs on the 'sub-phenotypes' of ASD. The objective of this paper is to evaluate associations between CNVs in differentially brain expressed (DBE) genes or genes previously implicated in ASD/intellectual disability (ASD/ID) and specific sub-phenotypes of ASD. The sample consisted of 1590 cases of European ancestry from the Autism Genome Project (AGP) with a diagnosis of an ASD and at least one rare CNV impacting any gene and a core set of phenotypic measures, including symptom severity, language impairments, seizures, gait disturbances, intelligence quotient (IQ) and adaptive function, as well as paternal and maternal age. Classification analyses using a non-parametric recursive partitioning method (random forests) were employed to define sets of phenotypic characteristics that best classify the CNV-defined groups. There was substantial variation in the classification accuracy of the two sets of genes. The best variables for classification were verbal IQ for the ASD/ID genes, paternal age at birth for the DBE genes and adaptive function for de novo CNVs. CNVs in the ASD/ID list were primarily associated with communication and language domains, whereas CNVs in DBE genes were related to broader manifestations of adaptive function. To our knowledge, this is the first study to examine the associations between sub-phenotypes and CNVs genome-wide in ASD. This work highlights the importance of examining the diverse sub-phenotypic manifestations of CNVs in ASD, including the specific features, comorbid conditions and clinical correlates of ASD that comprise underlying characteristics of the disorder.

The group of epidermal nevus syndromes Part I. Well defined phenotypes.

PubMed

Happle, Rudolf

2010-07-01

The epidermal nevus syndromes represent a group of distinct disorders that can be distinguished by the type of associated epidermal nevus and by the criterion of presence or absence of heritability. Well defined syndromes characterized by organoid epidermal nevi include Schimmelpenning syndrome, phacomatosis pigmentokeratotica, nevus comedonicus syndrome, angora hair nevus syndrome, and Becker nevus syndrome. The molecular basis of these disorders has so far not been identified. By contrast, the group of syndromes characterized by keratinocytic nevi comprises three phenotypes with a known molecular etiology in the form of CHILD (congenital hemidysplasia with ichthyosiform nevus and limb defects) syndrome, type 2 segmental Cowden disease, and fibroblast growth factor receptor 3 epidermal nevus syndrome (García-Hafner-Happle syndrome), whereas Proteus syndrome is still of unknown origin. From this overview, it is clear that a specific type of these disorders cannot be classified by the name "epidermal nevus syndrome" nor by the terms "organoid nevus syndrome" or "keratinocytic nevus syndrome." After completing this learning activity, participants should be able to distinguish nine different epidermal nevus syndromes by their characteristic features, understand the practical significance of avoiding terms like "epidermal nevus syndrome" or "keratinocytic nevus syndrome" to define any specific entity within this group of disorders, and differentiate between nonhereditary traits and those bearing a genetic risk because of either Mendelian or non-Mendelian inheritance. Copyright (c) 2010 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.

Screening NK-, B- and T-cell phenotype and function in patients suffering from Chronic Fatigue Syndrome.

PubMed

Curriu, Marta; Carrillo, Jorge; Massanella, Marta; Rigau, Josepa; Alegre, José; Puig, Jordi; Garcia-Quintana, Ana M; Castro-Marrero, Jesus; Negredo, Eugènia; Clotet, Bonaventura; Cabrera, Cecilia; Blanco, Julià

2013-03-20

Chronic Fatigue Syndrome (CFS) is a debilitating neuro-immune disorder of unknown etiology diagnosed by an array of clinical manifestations. Although several immunological abnormalities have been described in CFS, their heterogeneity has limited diagnostic applicability. Immunological features of CFS were screened in 22 CFS diagnosed individuals fulfilling Fukuda criteria and 30 control healthy individuals. Peripheral blood T, B and NK cell function and phenotype were analyzed by flow cytometry in both groups. CFS diagnosed individuals showed similar absolute numbers of T, B and NK cells, with minor differences in the percentage of CD4+ and CD8+ T cells. B cells showed similar subset frequencies and proliferative responses between groups. Conversely, significant differences were observed in T cell subsets. CFS individuals showed increased levels of T regulatory cells (CD25+/FOXP3+) CD4 T cells, and lower proliferative responses in vitro and in vivo. Moreover, CD8 T cells from the CFS group showed significantly lower activation and frequency of effector memory cells. No clear signs of T-cell immunosenescence were observed. NK cells from CFS individuals displayed higher expression of NKp46 and CD69 but lower expression of CD25 in all NK subsets defined. Overall, T cell and NK cell features clearly clustered CFS individuals. Our findings suggest that alterations in T-cell phenotype and proliferative response along with the specific signature of NK cell phenotype may be useful to identify CFS individuals. The striking down modulation of T cell mediated immunity may help to understand intercurrent viral infections in CFS.

Screening NK-, B- and T-cell phenotype and function in patients suffering from Chronic Fatigue Syndrome

PubMed Central

2013-01-01

Background Chronic Fatigue Syndrome (CFS) is a debilitating neuro-immune disorder of unknown etiology diagnosed by an array of clinical manifestations. Although several immunological abnormalities have been described in CFS, their heterogeneity has limited diagnostic applicability. Methods Immunological features of CFS were screened in 22 CFS diagnosed individuals fulfilling Fukuda criteria and 30 control healthy individuals. Peripheral blood T, B and NK cell function and phenotype were analyzed by flow cytometry in both groups. Results CFS diagnosed individuals showed similar absolute numbers of T, B and NK cells, with minor differences in the percentage of CD4+ and CD8+ T cells. B cells showed similar subset frequencies and proliferative responses between groups. Conversely, significant differences were observed in T cell subsets. CFS individuals showed increased levels of T regulatory cells (CD25+/FOXP3+) CD4 T cells, and lower proliferative responses in vitro and in vivo. Moreover, CD8 T cells from the CFS group showed significantly lower activation and frequency of effector memory cells. No clear signs of T-cell immunosenescence were observed. NK cells from CFS individuals displayed higher expression of NKp46 and CD69 but lower expression of CD25 in all NK subsets defined. Overall, T cell and NK cell features clearly clustered CFS individuals. Conclusions Our findings suggest that alterations in T-cell phenotype and proliferative response along with the specific signature of NK cell phenotype may be useful to identify CFS individuals. The striking down modulation of T cell mediated immunity may help to understand intercurrent viral infections in CFS. PMID:23514202

Cranial suture biology of the Aleutian Island inhabitants.

PubMed

Cray, James; Mooney, Mark P; Siegel, Michael I

2011-04-01

Research on cranial suture biology suggests there is biological and taxonomic information to be garnered from the heritable pattern of suture synostosis. Suture synostosis along with brain growth patterns, diet, and biomechanical forces influence phenotypic variability in cranial vault morphology. This study was designed to determine the pattern of ectocranial suture synostosis in skeletal populations from the Aleutian Islands. We address the hypothesis that ectocranial suture synostosis pattern will differ according to cranial vault shape. Ales Hrdlicka identified two phenotypes in remains excavated from the Aleutian Island. The Paleo-Aleutians, exhibiting a dolichocranic phenotype with little prognathism linked to artifacts distinguished from later inhabitants, Aleutians, who exhibited a brachycranic phenotype with a greater amount of prognathism. A total of 212 crania representing Paleo-Aleuts and Aleutian as defined by Hrdlicka were investigated for suture synostosis pattern following standard methodologies. Comparisons were performed using Guttmann analyses. Results revealed similar suture fusion patterns for the Paleo-Aleut and Aleutian, a strong anterior to posterior pattern of suture fusion for the lateral-anterior suture sites, and a pattern of early termination at the sagittal suture sites for the vault. These patterns were found to differ from that reported in the literature. Because these two populations with distinct cranial shapes exhibit similar patterns of suture synostosis it appears pattern is independent of cranial shape in these populations of Homo sapiens. These findings suggest that suture fusion patterns may be population dependent and that a standardized methodology, using suture fusion to determine age-at-death, may not be applicable to all populations. Copyright © 2011 Wiley-Liss, Inc.

CHALLENGES IN PHENOTYPE DEFINITION IN THE WHOLE-GENOME ERA: MULTIVARIATE MODELS OF MEMORY AND INTELLIGENCE

PubMed Central

SABB, F. W.; BURGGREN, A. C.; HIGIER, R. G.; FOX, J.; HE, J.; PARKER, D. S.; POLDRACK, R. A.; CHU, W.; CANNON, T. D.; FREIMER, N. B.; BILDER, R. M.

2009-01-01

Refining phenotypes for the study of neuropsychiatric disorders is of paramount importance in neuroscience. Poor phenotype definition provides the greatest obstacle for making progress in disorders like schizophrenia, bipolar disorder, Attention Deficit/Hyperactivity Disorder (ADHD), and autism. Using freely available informatics tools developed by the Consortium for Neuropsychiatric Phenomics (CNP), we provide a framework for defining and refining latent constructs used in neuroscience research and then apply this strategy to review known genetic contributions to memory and intelligence in healthy individuals. This approach can help us begin to build multi-level phenotype models that express the interactions between constructs necessary to understand complex neuropsychiatric diseases. PMID:19450667

Phenotypic models of evolution and development: geometry as destiny.

PubMed

François, Paul; Siggia, Eric D

2012-12-01

Quantitative models of development that consider all relevant genes typically are difficult to fit to embryonic data alone and have many redundant parameters. Computational evolution supplies models of phenotype with relatively few variables and parameters that allows the patterning dynamics to be reduced to a geometrical picture for how the state of a cell moves. The clock and wavefront model, that defines the phenotype of somitogenesis, can be represented as a sequence of two discrete dynamical transitions (bifurcations). The expression-time to space map for Hox genes and the posterior dominance rule are phenotypes that naturally follow from computational evolution without considering the genetics of Hox regulation. Copyright © 2012 Elsevier Ltd. All rights reserved.

Beyond BMI: Conceptual Issues Related to Overweight and Obese Patients

PubMed Central

Müller, Manfred James; Braun, Wiebke; Enderle, Janna; Bosy-Westphal, Anja

2016-01-01

BMI is widely used as a measure of weight status and disease risks; it defines overweight and obesity based on statistical criteria. BMI is a score; neither is it biologically sound nor does it reflect a suitable phenotype worthwhile to study. Because of its limited value, BMI cannot provide profound insight into obesity biology and its co-morbidity. Alternative assessments of weight status include detailed phenotyping by body composition analysis (BCA). However, predicting disease risks, fat mass, and fat-free mass as assessed by validated techniques (i.e., densitometry, dual energy X ray absorptiometry, and bioelectrical impedance analysis) does not exceed the value of BMI. Going beyond BMI and descriptive BCA, the concept of functional body composition (FBC) integrates body components into regulatory systems. FBC refers to the masses of body components, organs, and tissues as well as to their inter-relationships within the context of endocrine, metabolic and immune functions. FBC can be used to define specific phenotypes of obesity, e.g. the sarcopenic-obese patient. Well-characterized obesity phenotypes are a precondition for targeted research (e.g., on the genomics of obesity) and patient-centered care (e.g., adequate treatment of individual obese phenotypes such as the sarcopenic-obese patient). FBC contributes to a future definition of overweight and obesity based on physiological criteria rather than on body weight alone. PMID:27286962

Lower core body temperature and greater body fat are components of a human thrifty phenotype.

PubMed

Reinhardt, M; Schlögl, M; Bonfiglio, S; Votruba, S B; Krakoff, J; Thearle, M S

2016-05-01

In small studies, a thrifty human phenotype, defined by a greater 24-hour energy expenditure (EE) decrease with fasting, is associated with less weight loss during caloric restriction. In rodents, models of diet-induced obesity often have a phenotype including a reduced EE and decreased core body temperature. We assessed whether a thrifty human phenotype associates with differences in core body temperature or body composition. Data for this cross-sectional analysis were obtained from 77 individuals participating in one of two normal physiology studies while housed on our clinical research unit. Twenty-four-hour EE using a whole-room indirect calorimeter and 24-h core body temperature were measured during 24 h each of fasting and 200% overfeeding with a diet consisting of 50% carbohydrates, 20% protein and 30% fat. Body composition was measured by dual X-ray absorptiometry. To account for the effects of body size on EE, changes in EE were expressed as a percentage change from 24-hour EE (%EE) during energy balance. A greater %EE decrease with fasting correlated with a smaller %EE increase with overfeeding (r=0.27, P=0.02). The %EE decrease with fasting was associated with both fat mass and abdominal fat mass, even after accounting for covariates (β=-0.16 (95% CI: -0.26, -0.06) %EE per kg fat mass, P=0.003; β=-0.0004 (-0.0007, -0.00004) %EE kg(-1) abdominal fat mass, P=0.03). In men, a greater %EE decrease in response to fasting was associated with a lower 24- h core body temperature, even after adjusting for covariates (β=1.43 (0.72, 2.15) %EE per 0.1 °C, P=0.0003). Thrifty individuals, as defined by a larger EE decrease with fasting, were more likely to have greater overall and abdominal adiposity as well as lower core body temperature consistent with a more efficient metabolism.

(Epi)genotype–phenotype correlations in Beckwith–Wiedemann syndrome

PubMed Central

Mussa, Alessandro; Russo, Silvia; De Crescenzo, Agostina; Freschi, Andrea; Calzari, Luciano; Maitz, Silvia; Macchiaiolo, Marina; Molinatto, Cristina; Baldassarre, Giuseppina; Mariani, Milena; Tarani, Luigi; Bedeschi, Maria Francesca; Milani, Donatella; Melis, Daniela; Bartuli, Andrea; Cubellis, Maria Vittoria; Selicorni, Angelo; Cirillo Silengo, Margherita; Larizza, Lidia; Riccio, Andrea; Ferrero, Giovanni Battista

2016-01-01

Beckwith–Wiedemann syndrome (BWS) is characterized by cancer predisposition, overgrowth and highly variable association of macroglossia, abdominal wall defects, nephrourological anomalies, nevus flammeus, ear malformations, hypoglycemia, hemihyperplasia, and organomegaly. BWS molecular defects, causing alteration of expression or activity of the genes regulated by two imprinting centres (IC) in the 11p15 chromosomal region, are also heterogeneous. In this paper we define (epi)genotype–phenotype correlations in molecularly confirmed BWS patients. The characteristics of 318 BWS patients with proven molecular defect were compared among the main four molecular subclasses: IC2 loss of methylation (IC2-LoM, n=190), IC1 gain of methylation (IC1-GoM, n=31), chromosome 11p15 paternal uniparental disomy (UPD, n=87), and cyclin-dependent kinase inhibitor 1C gene (CDKN1C) variants (n=10). A characteristic growth pattern was found in each group; neonatal macrosomia was almost constant in IC1-GoM, postnatal overgrowth in IC2-LoM, and hemihyperplasia more common in UPD (P<0.001). Exomphalos was more common in IC2/CDKN1C patients (P<0.001). Renal defects were typical of UPD/IC1 patients, uretheral malformations of IC1-GoM cases (P<0.001). Ear anomalies and nevus flammeus were associated with IC2/CDKN1C genotype (P<0.001). Macroglossia was less common among UPD patients (P<0.001). Wilms' tumor was associated with IC1-GoM or UPD and never observed in IC2-LoM patients (P<0.001). Hepatoblastoma occurred only in UPD cases. Cancer risk was lower in IC2/CDKN1C, intermediate in UPD, and very high in IC1 cases (P=0.009). In conclusion, (epi)genotype–phenotype correlations define four different phenotypic BWS profiles with some degree of clinical overlap. These observations impact clinical care allowing to move toward (epi) genotype-based follow-up and cancer screening. PMID:25898929

Identification of a prospective early motor progression cluster of Parkinson's disease: Data from the PPMI study.

PubMed

Vavougios, George D; Doskas, Triantafyllos; Kormas, Constantinos; Krogfelt, Karen A; Zarogiannis, Sotirios G; Stefanis, Leonidas

2018-04-15

The aim of our study is to phenotype PD motor progression, and to detect whether serum, cerebrospinal fluid (CSF), neuroimaging biomarkers and neuropsychological measures characterize PD motor progression phenotypes. We defined motor progression as a difference of at least one point in the Hoehn & Yahr (H&Y) scale between the baseline (Visit 0, V0), 12 months (Visit 04, V04) and 36 months (Visit 08, V08) milestones of the Progression Markers Initiative (PPMI) study. H&Y progression events were recorded at each milestone in order to be used as cluster analysis variables, in order to produce progression phenotypes. Subsequently, cross-cluster comparisons prior to and following (pairwise) propensity score matching were performed in order to assess phenotype - defining characteristics. Four progression clusters where identified: SPPD: Secondarily Progressive PD, H&Y progression between V04 and V08; EPPD: Early Progressive PD. H&Y progression between V0 and V04; NPPD: Non Progressive PD, no H&Y progression; MIPD: Minimally Improving PD, i.e. Minimal H&Y improvement H&Y progression between V04 and V08;. Independent Samples Mann Whitney U tests determined CSF aSyn (p = 0.006, adj p-value = 0.036. I) and Semantic Animal fluency T-score (SFT, p = 0.003, adjusted p-value = 0.016.) as statistically significant cross-cluster characteristics. Following Propensity Score Matching, SFT, Hopkins Verbal Learning Test (Retention/Recall), Serum IGF1, CSF aSyn, DaT-SPECT binding ratios (SBRs) and the Benton Judgement of Line Orientation Test (BJLOT) were determined as statistically significant predictors of cluster differentiation (p < 0.05). SFT, Serum IGF1, CSF aSyn and DaT-SPECT-derived, basal ganglia Striatal Binding Ratios warrant further investigation as possible motor progression biomarkers. Copyright © 2018 Elsevier B.V. All rights reserved.

“Gestaltomics”: Systems Biology Schemes for the Study of Neuropsychiatric Diseases

PubMed Central

Gutierrez Najera, Nora A.; Resendis-Antonio, Osbaldo; Nicolini, Humberto

2017-01-01

The integration of different sources of biological information about what defines a behavioral phenotype is difficult to unify in an entity that reflects the arithmetic sum of its individual parts. In this sense, the challenge of Systems Biology for understanding the “psychiatric phenotype” is to provide an improved vision of the shape of the phenotype as it is visualized by “Gestalt” psychology, whose fundamental axiom is that the observed phenotype (behavior or mental disorder) will be the result of the integrative composition of every part. Therefore, we propose the term “Gestaltomics” as a term from Systems Biology to integrate data coming from different sources of information (such as the genome, transcriptome, proteome, epigenome, metabolome, phenome, and microbiome). In addition to this biological complexity, the mind is integrated through multiple brain functions that receive and process complex information through channels and perception networks (i.e., sight, ear, smell, memory, and attention) that in turn are programmed by genes and influenced by environmental processes (epigenetic). Today, the approach of medical research in human diseases is to isolate one disease for study; however, the presence of an additional disease (co-morbidity) or more than one disease (multimorbidity) adds complexity to the study of these conditions. This review will present the challenge of integrating psychiatric disorders at different levels of information (Gestaltomics). The implications of increasing the level of complexity, for example, studying the co-morbidity with another disease such as cancer, will also be discussed. PMID:28536537

Developmental loss of effect of a Chromosome 15 QTL on alcohol acceptance.

PubMed

McClearn, G E; Tarantino, L M; Hofer, S M; Jones, B; Plomin, R

1998-12-01

Human alcohol abuse and alcoholism have clear developmental features, suggesting the possibility of changes over time in heritability and in quantitative genetic architecture, and raising prospects of identifying individual genes or quantitative trait loci (QTLs) that display different influence on alcohol-related phenotypes at different ages. The identification of specific loci showing such age-related changes will open up opportunities of focused association studies and of genotype manipulation by various mating procedures. Most animal model research in alcohol assesses the phenotypes of the animals at an early age; developmental studies are rare. Here we report on a QTL on Chromosome (Chr) 15 of the mouse that has been shown in several populations, including BXD recombinant inbred strains, an F2, and genotypically selected lines, to affect a measure of alcohol consumption. In the present study, we measured alcohol acceptance in the genotypically selected animals and in an F4 sample at about 100 days and again at about 300 days of age. In both groups, and in both sexes, significant differences were observed at 100 days between animals that were homozygous for the "increasing" haplotype defining the QTL region and those homozygous for the "decreasing" haplotype. At 300 days of age, the effect is absent in females and has diminished or disappeared in males. The results provide a further confirmation of the Chr 15 QTL in young mice, offer a new perspective on the development of alcohol-related phenotypes, and have strong implications for research design.

Distinct mutations in yeast TAF(II)25 differentially affect the composition of TFIID and SAGA complexes as well as global gene expression patterns.

PubMed

Kirschner, Doris B; vom Baur, Elmar; Thibault, Christelle; Sanders, Steven L; Gangloff, Yann-Gaël; Davidson, Irwin; Weil, P Anthony; Tora, Làszlò

2002-05-01

The RNA polymerase II transcription factor TFIID, composed of the TATA-binding protein (TBP) and TBP-associated factors (TAF(II)s), nucleates preinitiation complex formation at protein-coding gene promoters. SAGA, a second TAF(II)-containing multiprotein complex, is involved in transcription regulation in Saccharomyces cerevisiae. One of the essential protein components common to SAGA and TFIID is yTAF(II)25. We define a minimal evolutionarily conserved 91-amino-acid region of TAF(II)25 containing a histone fold domain that is necessary and sufficient for growth in vivo. Different temperature-sensitive mutations of yTAF(II)25 or chimeras with the human homologue TAF(II)30 arrested cell growth at either the G(1) or G(2)/M cell cycle phase and displayed distinct phenotypic changes and gene expression patterns. Immunoprecipitation studies revealed that TAF(II)25 mutation-dependent gene expression and phenotypic changes correlated at least partially with the integrity of SAGA and TFIID. Genome-wide expression analysis revealed that the five TAF(II)25 temperature-sensitive mutant alleles individually affect the expression of between 18 and 33% of genes, whereas taken together they affect 64% of all class II genes. Thus, different yTAF(II)25 mutations induce distinct phenotypes and affect the regulation of different subsets of genes, demonstrating that no individual TAF(II) mutant allele reflects the full range of its normal functions.

PVAT and Its Relation to Brown, Beige, and White Adipose Tissue in Development and Function

PubMed Central

Hildebrand, Staffan; Stümer, Jasmin; Pfeifer, Alexander

2018-01-01

Adipose tissue is commonly categorized into three types with distinct functions, phenotypes, and anatomical localizations. White adipose tissue (WAT) is the major energy store; the largest depots of WAT are found in subcutaneous or intravisceral sites. Brown adipose tissue (BAT) is responsible for energy dissipation during cold-exposure (i.e., non-shivering thermogenesis) and is primarily located in the interscapular region. Beige or brite (brown-in-white) adipose tissue can be found interspersed in WAT and can attain a brown-like phenotype. These three types of tissues also have endocrine functions and play major roles in whole body metabolism especially in obesity and its co-morbidities, such as cardiovascular disease. Over the last years, perivascular adipose tissue (PVAT) has emerged as an adipose organ with endocrine and paracrine functions. Pro and anti-inflammatory agents released by PVAT affect vascular health, and are implicated in the inflammatory aspects of atherosclerosis. PVAT shares several of the defining characteristics of brown adipose tissue, including its cellular morphology and expression of thermogenic genes characteristic for brown adipocytes. However, PVATs from different vessels are phenotypically different, and significant developmental differences exist between PVAT and other adipose tissues. Whether PVAT represents classical BAT, beige adipose tissue, or WAT with changing characteristics, is unclear. In this review, we summarize the current knowledge on how PVAT relates to other types of adipose tissue, both in terms of functionality, developmental origins, and its role in obesity-related cardiovascular disease and inflammation. PMID:29467675

Phenotypic screening in cancer drug discovery - past, present and future.

PubMed

Moffat, John G; Rudolph, Joachim; Bailey, David

2014-08-01

There has been a resurgence of interest in the use of phenotypic screens in drug discovery as an alternative to target-focused approaches. Given that oncology is currently the most active therapeutic area, and also one in which target-focused approaches have been particularly prominent in the past two decades, we investigated the contribution of phenotypic assays to oncology drug discovery by analysing the origins of all new small-molecule cancer drugs approved by the US Food and Drug Administration (FDA) over the past 15 years and those currently in clinical development. Although the majority of these drugs originated from target-based discovery, we identified a significant number whose discovery depended on phenotypic screening approaches. We postulate that the contribution of phenotypic screening to cancer drug discovery has been hampered by a reliance on 'classical' nonspecific drug effects such as cytotoxicity and mitotic arrest, exacerbated by a paucity of mechanistically defined cellular models for therapeutically translatable cancer phenotypes. However, technical and biological advances that enable such mechanistically informed phenotypic models have the potential to empower phenotypic drug discovery in oncology.

The PCOS Patients differ in Lipid Profile According to their Phenotypes.

PubMed

Spałkowska, Magdalena; Mrozińska, Sandra; Gałuszka-Bednarczyk, Anna; Gosztyła, Katarzyna; Przywara, Agnieszka; Guzik, Justyna; Janeczko, Marek; Milewicz, Tomasz; Wojas-Pelc, Anna

2018-01-31

Polycystic ovary syndrome (PCOS) affects 4-18% of women of reproductive age. The number of reports exploring the lipid profiles among PCOS patients and number of studied patients are limited. The aim of our study was to assess the lipid profile separately in lean and non-lean women with polycystic ovary syndrome divided according to hyperandrogenemia, defined as free androgen index (FAI)≥5. The second aim was to compare the lipid profiles among lean and non-lean PCOS patients with respect to hyperandrogenemia and regularity of menstruation cycles. We evaluated 232 patients from Department of Endocrinological Gynecology, Jagiellonian University Medical College in Krakow diagnosed with PCOS. The population consisted of 166 lean and 66 non-lean women. We observed higher levels of total cholesterol, high-density lipoprotein cholesterol (HDL-C) in lean patients with FAI<5 than in lean patients with FAI≥5. There were no differences in lipid profile between non-lean patients with FAI≥5 and non-lean patients with FAI<5. Among lean patients higher total cholesterol levels were observed in those with irregular menstruation cycles and FAI<5 than in patients with FAI≥5 and regular cycles. There were no differences in lipid profiles between four phenotypes among non-lean PCOS patients. The results of our study showed differences in lipid profile between lean PCOS patients according to their phenotype based on androgens' level. This effect was abandoned by fat tissue mass in non-lean ones. Further studies should be conducted to explore these associations. © Georg Thieme Verlag KG Stuttgart · New York.

Genetic utility of broadly defined bipolar schizoaffective disorder as a diagnostic concept

PubMed Central

Hamshere, M. L.; Green, E. K.; Jones, I. R.; Jones, L.; Moskvina, V.; Kirov, G.; Grozeva, D.; Nikolov, I.; Vukcevic, D.; Caesar, S.; Gordon-Smith, K.; Fraser, C.; Russell, E.; Breen, G.; St Clair, D.; Collier, D. A.; Young, A. H.; Ferrier, I. N.; Farmer, A.; McGuffin, P.; Holmans, P. A.; Owen, M. J.; O’Donovan, M. C.; Craddock, N.

2009-01-01

Background Psychiatric phenotypes are currently defined according to sets of descriptive criteria. Although many of these phenotypes are heritable, it would be useful to know whether any of the various diagnostic categories in current use identify cases that are particularly helpful for biological–genetic research. Aims To use genome-wide genetic association data to explore the relative genetic utility of seven different descriptive operational diagnostic categories relevant to bipolar illness within a large UK case–control bipolar disorder sample. Method We analysed our previously published Wellcome Trust Case Control Consortium (WTCCC) bipolar disorder genome-wide association data-set, comprising 1868 individuals with bipolar disorder and 2938 controls genotyped for 276 122 single nucleotide polymorphisms (SNPs) that met stringent criteria for genotype quality. For each SNP we performed a test of association (bipolar disorder group v. control group) and used the number of associated independent SNPs statistically significant at P<0.00001 as a metric for the overall genetic signal in the sample. We next compared this metric with that obtained using each of seven diagnostic subsets of the group with bipolar disorder: Research Diagnostic Criteria (RDC): bipolar I disorder; manic disorder; bipolar II disorder; schizoaffective disorder, bipolar type; DSM–IV: bipolar I disorder; bipolar II disorder; schizoaffective disorder, bipolar type. Results The RDC schizoaffective disorder, bipolar type (v. controls) stood out from the other diagnostic subsets as having a significant excess of independent association signals (P<0.003) compared with that expected in samples of the same size selected randomly from the total bipolar disorder group data-set. The strongest association in this subset of participants with bipolar disorder was at rs4818065 (P = 2.42×10–7). Biological systems implicated included gamma amniobutyric acid (GABA)A receptors. Genes having at least one associated polymorphism at P<10–4 included B3GALTS, A2BP1, GABRB1, AUTS2, BSN, PTPRG, GIRK2 and CDH12. Conclusions Our findings show that individuals with broadly defined bipolar schizoaffective features have either a particularly strong genetic contribution or that, as a group, are genetically more homogeneous than the other phenotypes tested. The results point to the importance of using diagnostic approaches that recognise this group of individuals. Our approach can be applied to similar data-sets for other psychiatric and non-psychiatric phenotypes. PMID:19567891

The association of incident hypertension with metabolic health and obesity status: definition of metabolic health does not matter.

PubMed

Kang, Yu Mi; Jung, Chang Hee; Jang, Jung Eun; Hwang, Jenie Yoonoo; Kim, Eun Hee; Park, Joong-Yeol; Kim, Hong-Kyu; Lee, Woo Je

2016-08-01

Metabolically healthy obese (MHO) phenotype refers to obese individuals with a favourable metabolic profile. Its prognostic value remains controversial and may partly depend on differences in how the phenotype is defined. We aimed to investigate whether the MHO phenotype is associated with future development of incident hypertension in a Korean population according to various definitions of metabolic health. The study population comprised 31 033 Koreans without hypertension. Participants were stratified into metabolically healthy nonobese (MHNO), metabolically unhealthy nonobese (MUNO), metabolically healthy obese (MHO) and metabolically unhealthy obese (MUO) by body mass index (cut-off value, 25·0 kg/m(2) ) and metabolic health state, using four different definitions: Adult Treatment Panel (ATP)-III, Wildman, Karelis and the homoeostasis model assessment (HOMA) criteria. Over the median follow-up period of 35·0 months (range, 4·5-81·4 months), 4589 of the 31 033 individuals (14·8%) developed incident hypertension. Compared with the MHNO group, the MHO group showed increased association with incident hypertension with multivariate-adjusted odds ratios of 1·56 (95% confidence interval [CI], 1·41-1·72), 1·58 (95% CI 1·42-1·75), 1·52 (95% CI 1·35-1·71) and 1·46 (95% CI 1·33-1·61), when defined by ATP-III, Wildman, Karelis and HOMA criteria, respectively. MUO individuals showed the highest association with the incident hypertension (adjusted odds ratios up to 2·00). MHO subjects showed an approximately 1·5-fold higher association with incident hypertension than their nonobese counterpart regardless of the definition of metabolic health used. Thus, considering both metabolic health and obesity is important for the assessment of potential cardiovascular outcomes. © 2016 John Wiley & Sons Ltd.

Global Analysis of the Fungal Microbiome in Cystic Fibrosis Patients Reveals Loss of Function of the Transcriptional Repressor Nrg1 as a Mechanism of Pathogen Adaptation

PubMed Central

Kim, Sang Hu; Clark, Shawn T.; Surendra, Anuradha; Copeland, Julia K.; Wang, Pauline W.; Ammar, Ron; Collins, Cathy; Tullis, D. Elizabeth; Nislow, Corey; Hwang, David M.; Guttman, David S.; Cowen, Leah E.

2015-01-01

The microbiome shapes diverse facets of human biology and disease, with the importance of fungi only beginning to be appreciated. Microbial communities infiltrate diverse anatomical sites as with the respiratory tract of healthy humans and those with diseases such as cystic fibrosis, where chronic colonization and infection lead to clinical decline. Although fungi are frequently recovered from cystic fibrosis patient sputum samples and have been associated with deterioration of lung function, understanding of species and population dynamics remains in its infancy. Here, we coupled high-throughput sequencing of the ribosomal RNA internal transcribed spacer 1 (ITS1) with phenotypic and genotypic analyses of fungi from 89 sputum samples from 28 cystic fibrosis patients. Fungal communities defined by sequencing were concordant with those defined by culture-based analyses of 1,603 isolates from the same samples. Different patients harbored distinct fungal communities. There were detectable trends, however, including colonization with Candida and Aspergillus species, which was not perturbed by clinical exacerbation or treatment. We identified considerable inter- and intra-species phenotypic variation in traits important for host adaptation, including antifungal drug resistance and morphogenesis. While variation in drug resistance was largely between species, striking variation in morphogenesis emerged within Candida species. Filamentation was uncoupled from inducing cues in 28 Candida isolates recovered from six patients. The filamentous isolates were resistant to the filamentation-repressive effects of Pseudomonas aeruginosa, implicating inter-kingdom interactions as the selective force. Genome sequencing revealed that all but one of the filamentous isolates harbored mutations in the transcriptional repressor NRG1; such mutations were necessary and sufficient for the filamentous phenotype. Six independent nrg1 mutations arose in Candida isolates from different patients, providing a poignant example of parallel evolution. Together, this combined clinical-genomic approach provides a high-resolution portrait of the fungal microbiome of cystic fibrosis patient lungs and identifies a genetic basis of pathogen adaptation. PMID:26588216

Global Analysis of the Fungal Microbiome in Cystic Fibrosis Patients Reveals Loss of Function of the Transcriptional Repressor Nrg1 as a Mechanism of Pathogen Adaptation.

PubMed

Kim, Sang Hu; Clark, Shawn T; Surendra, Anuradha; Copeland, Julia K; Wang, Pauline W; Ammar, Ron; Collins, Cathy; Tullis, D Elizabeth; Nislow, Corey; Hwang, David M; Guttman, David S; Cowen, Leah E

2015-11-01

The microbiome shapes diverse facets of human biology and disease, with the importance of fungi only beginning to be appreciated. Microbial communities infiltrate diverse anatomical sites as with the respiratory tract of healthy humans and those with diseases such as cystic fibrosis, where chronic colonization and infection lead to clinical decline. Although fungi are frequently recovered from cystic fibrosis patient sputum samples and have been associated with deterioration of lung function, understanding of species and population dynamics remains in its infancy. Here, we coupled high-throughput sequencing of the ribosomal RNA internal transcribed spacer 1 (ITS1) with phenotypic and genotypic analyses of fungi from 89 sputum samples from 28 cystic fibrosis patients. Fungal communities defined by sequencing were concordant with those defined by culture-based analyses of 1,603 isolates from the same samples. Different patients harbored distinct fungal communities. There were detectable trends, however, including colonization with Candida and Aspergillus species, which was not perturbed by clinical exacerbation or treatment. We identified considerable inter- and intra-species phenotypic variation in traits important for host adaptation, including antifungal drug resistance and morphogenesis. While variation in drug resistance was largely between species, striking variation in morphogenesis emerged within Candida species. Filamentation was uncoupled from inducing cues in 28 Candida isolates recovered from six patients. The filamentous isolates were resistant to the filamentation-repressive effects of Pseudomonas aeruginosa, implicating inter-kingdom interactions as the selective force. Genome sequencing revealed that all but one of the filamentous isolates harbored mutations in the transcriptional repressor NRG1; such mutations were necessary and sufficient for the filamentous phenotype. Six independent nrg1 mutations arose in Candida isolates from different patients, providing a poignant example of parallel evolution. Together, this combined clinical-genomic approach provides a high-resolution portrait of the fungal microbiome of cystic fibrosis patient lungs and identifies a genetic basis of pathogen adaptation.

Phenotypic differentiation of the Red Sea gastropods in response to the environmental deterioration: Geometric morphometric approach

NASA Astrophysics Data System (ADS)

Abdelhady, Ahmed Awad

2016-03-01

The negative impacts of degradation in the coastal zone of the Red Sea are becoming well known in upper portions of the trophic web (e.g., humans and fish), but are less well known among the benthic primary consumers. In addition, the degree to which heavy metals are entering the trophic web can be better-quantified using macrobenthos. Two-gastropod genera encompassing Echinolittorina subnodosa and Planaxis sulcatus from three different localities on the Egyptian coast of the Red Sea were examined in order to deduce the impact of environmental deterioration on the morphology of shells. The examined sites include clean pristine, slightly polluted, and markedly polluted rocky shores. Phosphate/lead industry is the main source of pollution in this zone. Because landmarks on the rugose Echinolittorina are difficult to define and to ensure finer resolution of the analyses, a newly 'grid-based' landmarks was implemented. Both Canonical Variate Analysis (CVA) and Thin Plate Spline (TPS) were particularly capable to capture and terrace the minor morphological variations accurately. Two phenotypes portioned among the environmentally different populations were recognized and interpreted as ecotypes with many intermediate forms. The first ecotype has a higher spire and smaller aperture and dominating the pristine site North of Marsa Alam, whereas the second ecotype has a globular shell shape with big aperture and dominating the markedly polluted site. The intermediate forms dominating the slightly polluted site. The shape differences are interpreted as an adaptive differentiation to different metal concentrations. As the morphological variation between the two-ecotypes of both taxa is still minors, and both ecotypes occur together with many intermediate forms, the phenotypic divergence stage has not yet accomplished. The gradational shape change among the investigated populations was positively correlated with index of Pollution (IP). As the human activities were the main driver of the phenotypic changes, hence anthropogenic impact may shift the evolution and/or the extinction rates.

A Newborn with Panhypopituitarism and Seizures

PubMed Central

Patil, Rachit; Pandit, Ramesh

2017-01-01

Interstitial deletions on the short arm of chromosome 20 are uncommon, and therefore the clinical phenotype is poorly defined. Very few cases have been reported in the literature so far. In this report, we describe a 4-month-old female with a heterozygous deletion at 20p11.21p12.1 with panhypopituitarism and cardiac, gastrointestinal, and genitourinary anomalies along with dysmorphic facial features. We compared and discussed similar cases with overlapping deletions in 20p11 region. We wish to report this rare occurrence as this may better define the phenotypes of the 20p interstitial deletion with certain dysmorphic features, multiorgan involvement, and related clinical characteristics in this patient population. PMID:28255477

Genotype-phenotype associations in obesity dependent on definition of the obesity phenotype.

PubMed

Kring, Sofia Inez Iqbal; Larsen, Lesli Hingstrup; Holst, Claus; Toubro, Søren; Hansen, Torben; Astrup, Arne; Pedersen, Oluf; Sørensen, Thorkild I A

2008-01-01

In previous studies of associations of variants in the genes UCP2, UCP3, PPARG2, CART, GRL, MC4R, MKKS, SHP, GHRL, and MCHR1 with obesity, we have used a case-control approach with cases defined by a threshold for BMI. In the present study, we assess the association of seven abdominal, peripheral, and overall obesity phenotypes, which were analyzed quantitatively, and thirteen candidate gene polymorphisms in these ten genes in the same cohort. Obese Caucasian men (n = 234, BMI >or= 31.0 kg/m(2)) and a randomly sampled non-obese group (n = 323), originally identified at the draft board examinations, were re-examined at median ages of 47.0 or 49.0 years by anthropometry and DEXA scanning. Obesity phenotypes included BMI, fat body mass index, waist circumference, waist for given BMI, intra-abdominal adipose tissue, hip circumference and lower body fat mass (%). Using logistic regression models, we estimated the odds for defined genotypes (dominant or recessive genetic transmission) in relation to z-scores of the phenotypes. The minor (rare) allele for SHP 512G>C (rs6659176) was associated with increased hip circumference. The minor allele for UCP2 Ins45bp was associated with increased BMI, increased abdominal obesity, and increased hip circumference. The minor allele for UCP2 -866G>A (rs6593669) was associated with borderline increased fat body mass index. The minor allele for MCHR1 100213G>A (rs133072) was associated with reduced abdominal obesity. None of the other genotype-phenotype combinations showed appreciable associations. If replicated in independent studies with focus on the specific phenotypes, our explorative studies suggest significant associations between some candidate gene polymorphisms and distinct obesity phenotypes, predicting beneficial and detrimental effects, depending on compartments for body fat accumulation. Copyright 2008 S. Karger AG, Basel.

Integrative DNA methylation and gene expression analysis to assess the universality of the CpG island methylator phenotype.

PubMed

Moarii, Matahi; Reyal, Fabien; Vert, Jean-Philippe

2015-10-13

The CpG island methylator phenotype (CIMP) was first characterized in colorectal cancer but since has been extensively studied in several other tumor types such as breast, bladder, lung, and gastric. CIMP is of clinical importance as it has been reported to be associated with prognosis or response to treatment. However, the identification of a universal molecular basis to define CIMP across tumors has remained elusive. We perform a genome-wide methylation analysis of over 2000 tumor samples from 5 cancer sites to assess the existence of a CIMP with common molecular basis across cancers. We then show that the CIMP phenotype is associated with specific gene expression variations. However, we do not find a common genetic signature in all tissues associated with CIMP. Our results suggest the existence of a universal epigenetic and transcriptomic signature that defines the CIMP across several tumor types but does not indicate the existence of a common genetic signature of CIMP.

Morphometricity as a measure of the neuroanatomical signature of a trait.

PubMed

Sabuncu, Mert R; Ge, Tian; Holmes, Avram J; Smoller, Jordan W; Buckner, Randy L; Fischl, Bruce

2016-09-27

Complex physiological and behavioral traits, including neurological and psychiatric disorders, often associate with distributed anatomical variation. This paper introduces a global metric, called morphometricity, as a measure of the anatomical signature of different traits. Morphometricity is defined as the proportion of phenotypic variation that can be explained by macroscopic brain morphology. We estimate morphometricity via a linear mixed-effects model that uses an anatomical similarity matrix computed based on measurements derived from structural brain MRI scans. We examined over 3,800 unique MRI scans from nine large-scale studies to estimate the morphometricity of a range of phenotypes, including clinical diagnoses such as Alzheimer's disease, and nonclinical traits such as measures of cognition. Our results demonstrate that morphometricity can provide novel insights about the neuroanatomical correlates of a diverse set of traits, revealing associations that might not be detectable through traditional statistical techniques.

Mathematical Learning Disabilities in Special Populations: Phenotypic Variation and Cross-Disorder Comparisons

PubMed Central

Dennis, Maureen; Berch, Daniel B.; Mazzocco, Michèle M.M.

2011-01-01

What is mathematical learning disability (MLD)? The reviews in this special issue adopt different approaches to defining the construct of MLD. Collectively, they demonstrate the current status of efforts to establish a consensus definition and the challenges faced in this endeavor. In this commentary, we reflect upon the proposed pathways to mathematical learning difficulties and disabilities presented across the reviews. Specifically we consider how each of the reviews contributes to identifying the MLD phenotype by specifying the range of assets and deficits in mathematics, identifying sources of individual variation, and characterizing the natural progression of MLD over the life course. We show how principled comparisons across disorders address issues about the cognitive and behavioral co-morbidities of MLD, and whether commonalities in brain dysmorphology are associated with common mathematics performance profiles. We project the status of MLD research ten years hence with respect to theoretical gains, advances in methodology, and principled intervention studies. PMID:19213019

Harvesting of novel polyhydroxyalkanaote (PHA) synthase encoding genes from a soil metagenome library using phenotypic screening.

PubMed

Schallmey, Marcus; Ly, Anh; Wang, Chunxia; Meglei, Gabriela; Voget, Sonja; Streit, Wolfgang R; Driscoll, Brian T; Charles, Trevor C

2011-08-01

We previously reported the construction of metagenomic libraries in the IncP cosmid vector pRK7813, enabling heterologous expression of these broad-host-range libraries in multiple bacterial hosts. Expressing these libraries in Sinorhizobium meliloti, we have successfully complemented associated phenotypes of polyhydroxyalkanoate synthesis mutants. DNA sequence analysis of three clones indicates that the complementing genes are homologous to, but substantially different from, known polyhydroxyalkanaote synthase-encoding genes. Thus we have demonstrated the ability to isolate diverse genes for polyhydroxyalkanaote synthesis by functional complementation of defined mutants. Such genes might be of use in the engineering of more efficient systems for the industrial production of bioplastics. The use of functional complementation will also provide a vehicle to probe the genetics of polyhydroxyalkanaote metabolism and its relation to carbon availability in complex microbial assemblages. 2011 Federation of European Microbiological Societies. Published by Blackwell Publishing Ltd. All rights reserved.

Bacterial mycophagy: definition and diagnosis of a unique bacterial-fungal interaction.

PubMed

Leveau, Johan H J; Preston, Gail M

2008-01-01

This review analyses the phenomenon of bacterial mycophagy, which we define as a set of phenotypic behaviours that enable bacteria to obtain nutrients from living fungi and thus allow the conversion of fungal into bacterial biomass. We recognize three types of bacterial strategies to derive nutrition from fungi: necrotrophy, extracellular biotrophy and endocellular biotrophy. Each is characterized by a set of uniquely sequential and differently overlapping interactions with the fungal target. We offer a detailed analysis of the nature of these interactions, as well as a comprehensive overview of methodologies for assessing and quantifying their individual contributions to the mycophagy phenotype. Furthermore, we discuss future prospects for the study and exploitation of bacterial mycophagy, including the need for appropriate tools to detect bacterial mycophagy in situ in order to be able to understand, predict and possibly manipulate the way in which mycophagous bacteria affect fungal activity, turnover, and community structure in soils and other ecosystems.

Genetic influences on schizophrenia and subcortical brain volumes: large-scale proof-of-concept and roadmap for future studies

PubMed Central

Anttila, Verneri; Hibar, Derrek P; van Hulzen, Kimm J E; Arias-Vasquez, Alejandro; Smoller, Jordan W; Nichols, Thomas E; Neale, Michael C; McIntosh, Andrew M; Lee, Phil; McMahon, Francis J; Meyer-Lindenberg, Andreas; Mattheisen, Manuel; Andreassen, Ole A; Gruber, Oliver; Sachdev, Perminder S; Roiz-Santiañez, Roberto; Saykin, Andrew J; Ehrlich, Stefan; Mather, Karen A; Turner, Jessica A; Schwarz, Emanuel; Thalamuthu, Anbupalam; Shugart, Yin Yao; Ho, Yvonne YW; Martin, Nicholas G; Wright, Margaret J

2016-01-01

Schizophrenia is a devastating psychiatric illness with high heritability. Brain structure and function differ, on average, between schizophrenia cases and healthy individuals. As common genetic associations are emerging for both schizophrenia and brain imaging phenotypes, we can now use genome-wide data to investigate genetic overlap. Here we integrated results from common variant studies of schizophrenia (33,636 cases, 43,008 controls) and volumes of several (mainly subcortical) brain structures (11,840 subjects). We did not find evidence of genetic overlap between schizophrenia risk and subcortical volume measures either at the level of common variant genetic architecture or for single genetic markers. The current study provides proof-of-concept (albeit based on a limited set of structural brain measures), and defines a roadmap for future studies investigating the genetic covariance between structural/functional brain phenotypes and risk for psychiatric disorders. PMID:26854805

Morphometricity as a measure of the neuroanatomical signature of a trait

PubMed Central

Sabuncu, Mert R.; Ge, Tian; Holmes, Avram J.; Smoller, Jordan W.; Buckner, Randy L.; Fischl, Bruce

2016-01-01

Complex physiological and behavioral traits, including neurological and psychiatric disorders, often associate with distributed anatomical variation. This paper introduces a global metric, called morphometricity, as a measure of the anatomical signature of different traits. Morphometricity is defined as the proportion of phenotypic variation that can be explained by macroscopic brain morphology. We estimate morphometricity via a linear mixed-effects model that uses an anatomical similarity matrix computed based on measurements derived from structural brain MRI scans. We examined over 3,800 unique MRI scans from nine large-scale studies to estimate the morphometricity of a range of phenotypes, including clinical diagnoses such as Alzheimer’s disease, and nonclinical traits such as measures of cognition. Our results demonstrate that morphometricity can provide novel insights about the neuroanatomical correlates of a diverse set of traits, revealing associations that might not be detectable through traditional statistical techniques. PMID:27613854

The Sponge Hologenome

PubMed Central

Thomas, Torsten

2016-01-01

ABSTRACT A paradigm shift has recently transformed the field of biological science; molecular advances have revealed how fundamentally important microorganisms are to many aspects of a host’s phenotype and evolution. In the process, an era of “holobiont” research has emerged to investigate the intricate network of interactions between a host and its symbiotic microbial consortia. Marine sponges are early-diverging metazoa known for hosting dense, specific, and often highly diverse microbial communities. Here we synthesize current thoughts about the environmental and evolutionary forces that influence the diversity, specificity, and distribution of microbial symbionts within the sponge holobiont, explore the physiological pathways that contribute to holobiont function, and describe the molecular mechanisms that underpin the establishment and maintenance of these symbiotic partnerships. The collective genomes of the sponge holobiont form the sponge hologenome, and we highlight how the forces that define a sponge’s phenotype in fact act on the genomic interplay between the different components of the holobiont. PMID:27103626

Genetic influences on schizophrenia and subcortical brain volumes: large-scale proof of concept.

PubMed

Franke, Barbara; Stein, Jason L; Ripke, Stephan; Anttila, Verneri; Hibar, Derrek P; van Hulzen, Kimm J E; Arias-Vasquez, Alejandro; Smoller, Jordan W; Nichols, Thomas E; Neale, Michael C; McIntosh, Andrew M; Lee, Phil; McMahon, Francis J; Meyer-Lindenberg, Andreas; Mattheisen, Manuel; Andreassen, Ole A; Gruber, Oliver; Sachdev, Perminder S; Roiz-Santiañez, Roberto; Saykin, Andrew J; Ehrlich, Stefan; Mather, Karen A; Turner, Jessica A; Schwarz, Emanuel; Thalamuthu, Anbupalam; Shugart, Yin Yao; Ho, Yvonne Yw; Martin, Nicholas G; Wright, Margaret J; O'Donovan, Michael C; Thompson, Paul M; Neale, Benjamin M; Medland, Sarah E; Sullivan, Patrick F

2016-03-01

Schizophrenia is a devastating psychiatric illness with high heritability. Brain structure and function differ, on average, between people with schizophrenia and healthy individuals. As common genetic associations are emerging for both schizophrenia and brain imaging phenotypes, we can now use genome-wide data to investigate genetic overlap. Here we integrated results from common variant studies of schizophrenia (33,636 cases, 43,008 controls) and volumes of several (mainly subcortical) brain structures (11,840 subjects). We did not find evidence of genetic overlap between schizophrenia risk and subcortical volume measures either at the level of common variant genetic architecture or for single genetic markers. These results provide a proof of concept (albeit based on a limited set of structural brain measures) and define a roadmap for future studies investigating the genetic covariance between structural or functional brain phenotypes and risk for psychiatric disorders.

Modeling thrombin generation: plasma composition based approach.

PubMed

Brummel-Ziedins, Kathleen E; Everse, Stephen J; Mann, Kenneth G; Orfeo, Thomas

2014-01-01

Thrombin has multiple functions in blood coagulation and its regulation is central to maintaining the balance between hemorrhage and thrombosis. Empirical and computational methods that capture thrombin generation can provide advancements to current clinical screening of the hemostatic balance at the level of the individual. In any individual, procoagulant and anticoagulant factor levels together act to generate a unique coagulation phenotype (net balance) that is reflective of the sum of its developmental, environmental, genetic, nutritional and pharmacological influences. Defining such thrombin phenotypes may provide a means to track disease progression pre-crisis. In this review we briefly describe thrombin function, methods for assessing thrombin dynamics as a phenotypic marker, computationally derived thrombin phenotypes versus determined clinical phenotypes, the boundaries of normal range thrombin generation using plasma composition based approaches and the feasibility of these approaches for predicting risk.

Intermediate phenotypes and biomarkers of treatment outcome in major depressive disorder

PubMed Central

Leuchter, Andrew F.; Hunter, Aimee M.; Krantz, David E.; Cook, Ian A.

2014-01-01

Major depressive disorder (MDD) is a pleomorphic illness originating from gene x environment interactions. Patients with differing symptom phenotypes receive the same diagnosis and similar treatment recommendations without regard to genomics, brain structure or function, or other physiologic or psychosocial factors. Using this present approach, only one third of patients enter remission with the first medication prescribed, and patients may take longer than 1 year to enter remission with repeated trials. Research to improve treatment effectiveness recently has focused on identification of intermediate phenotypes (IPs) that could parse the heterogeneous population of patients with MDD into subgroups with more homogeneous responses to treatment. Such IPs could be used to develop biomarkers that could be applied clinically to match patients with the treatment that would be most likely to lead to remission. Putative biomarkers include genetic polymorphisms, RNA and protein expression (transcriptome and proteome), neurotransmitter levels (metabolome), additional measures of signaling cascades, oscillatory synchrony, neuronal circuits and neural pathways (connectome), along with other possible physiologic measures. All of these measures represent components of a continuum that extends from proximity to the genome to proximity to the clinical phenotype of depression, and there are many levels along this continuum at which useful IPs may be defined. Because of the highly integrative nature of brain systems and the complex neurobiology of depression, the most useful biomarkers are likely to be those with intermediate proximity both to the genome and the clinical phenotype of MDD. Translation of findings across the spectrum from genotype to phenotype promises to better characterize the complex disruptions in signaling and neuroplasticity that accompany MDD, and ultimately to lead to greater understanding of the causes of depressive illness. PMID:25733956

Genetic associations with viral respiratory illnesses and asthma control in children

PubMed Central

Loisel, Dagan A; Du, Gaixin; Ahluwalia, Tarunveer Singh; Tisler, Christopher J.; Evans, Michael D.; Myers, Rachel A.; Gangnon, Ronald E.; Kreiner-Møller, Eskil; Bønnelykke, Klaus; Bisgaard, Hans; Jackson, Daniel J.; Lemanske, Robert F.; Nicolae, Dan L.; Gern, James E.; Ober, Carole

2015-01-01

Background Viral respiratory infections can cause acute wheezing illnesses in children and exacerbations of asthma. Objective We sought to identify variation in genes with known antiviral and pro-inflammatory functions to identify specific associations with more severe viral respiratory illnesses and the risk of virus-induced exacerbations during the peak fall season. Methods The associations between genetic variation at 326 SNPs in 63 candidate genes and 10 phenotypes related to viral respiratory infection and asthma control were examined in 226 children enrolled in the RhinoGen study. Replication of asthma control phenotypes was performed in 2,128 children in the Copenhagen Prospective Study on Asthma in Childhood (COPSAC). Significant associations in RhinoGen were further validated using virus-induced wheezing illness and asthma phenotypes in an independent sample of 122 children enrolled in the Childhood Origins of Asthma birth cohort study (COAST). Results A significant excess of P values smaller than 0.05 was observed in the analysis of the 10 RhinoGen phenotypes. Polymorphisms in 12 genes were significantly associated with variation in the four phenotypes showing a significant enrichment of small P values. Six of those genes (STAT4, JAK2, MX1, VDR, DDX58, and EIF2AK2) also showed significant associations with asthma exacerbations in the COPSAC study or with asthma or virus-induced wheezing phenotypes in the COAST study. Conclusions We identified genetic factors contributing to individual differences in childhood viral respiratory illnesses and virus-induced exacerbations of asthma. Defining mechanisms of these associations may provide insight into the pathogenesis of viral respiratory infections and virus-induced exacerbations of asthma. PMID:26399222

The physical phenotype of frailty for risk stratification of older medical inpatients.

PubMed

Forti, P; Maioli, F; Zagni, E; Lucassenn, T; Montanari, L; Maltoni, B; Luca Pirazzoli, G; Bianchi, G; Zoli, M

2014-12-01

To determine the usefulness of physical phenotype of frailty, cognitive impairment, and serum albumin for risk stratification of elderly medical impatients. Prospective, observational cohort study. A general internal medicine unit of a university hospital in Italy. Inpatients with an average age of 80.8 ± 7.5 yr (N = 470). Frailty was defined using the Study of Osteoporotic Fractures Index, a parsimonious version of the physical phenotype (two of the following markers: weight loss, inability to rise five times from a chair, and exhaustion). Two frailty markers from non-physical dimensions were also evaluated: cognitive impairment (Mini-Cog score < 3) and low serum albumin on ward admission (< 3,5 gr/dl). Logistic regression adjusted for preadmission and admission-related confounders was used to investigate whether the physical phenotype of frailty and the two non-physical markers were associated with ward length of stay and unfavorable discharge (death plus any other ward discharge disposition different from direct return home). Areas Under the receiver operating characteristic Curve (AUCs) and Likelihood Ratios (LRs) were used for evaluation of discriminatory ability and clinical usefulness of significant predictors. The physical phenotype of frailty was associated with both study outcomes (p < 0.010) but the association was mainly mediated by chair standing ability. Non-physical markers were associated only with unfavourable discharge (p < 0.001). All of these predictors, either alone or in combination, had poor discriminatory ability (AUCs < 0.70) and poor clinical usefulness (+LRs near 1) for the study outcomes. The physical phenotype of frailty appears of limited clinical use for risk stratification of older medical inpatients. Combination with markers from non-physical dimensions does not improve its prognostic abilities.

Effect of Apoptotic Cell Recognition on Macrophage Polarization and Mycobacterial Persistence

PubMed Central

de Oliveira Fulco, Tatiana; Andrade, Priscila Ribeiro; de Mattos Barbosa, Mayara Garcia; Pinto, Thiago Gomes Toledo; Ferreira, Paula Fernandez; Ferreira, Helen; da Costa Nery, José Augusto; Real, Suzana Côrte; Borges, Valéria Matos; Moraes, Milton Ozório; Sarno, Euzenir Nunes; Sampaio, Elizabeth Pereira

2014-01-01

Intracellular Mycobacterium leprae infection modifies host macrophage programming, creating a protective niche for bacterial survival. The milieu regulating cellular apoptosis in the tissue plays an important role in defining susceptible and/or resistant phenotypes. A higher density of apoptotic cells has been demonstrated in paucibacillary leprosy lesions than in multibacillary ones. However, the effect of apoptotic cell removal on M. leprae-stimulated cells has yet to be fully elucidated. In this study, we investigated whether apoptotic cell removal (efferocytosis) induces different phenotypes in proinflammatory (Mϕ1) and anti-inflammatory (Mϕ2) macrophages in the presence of M. leprae. We stimulated Mϕ1 and Mϕ2 cells with M. leprae in the presence or absence of apoptotic cells and subsequently evaluated the M. leprae uptake, cell phenotype, and cytokine pattern in the supernatants. In the presence of M. leprae and apoptotic cells, Mϕ1 macrophages changed their phenotype to resemble the Mϕ2 phenotype, displaying increased CD163 and SRA-I expression as well as higher phagocytic capacity. Efferocytosis increased M. leprae survival in Mϕ1 cells, accompanied by reduced interleukin-15 (IL-15) and IL-6 levels and increased transforming growth factor beta (TGF-β) and IL-10 secretion. Mϕ1 cells primed with M. leprae in the presence of apoptotic cells induced the secretion of Th2 cytokines IL-4 and IL-13 in autologous T cells compared with cultures stimulated with M. leprae or apoptotic cells alone. Efferocytosis did not alter the Mϕ2 cell phenotype or cytokine secretion profile, except for TGF-β. Based on these data, we suggest that, in paucibacillary leprosy patients, efferocytosis contributes to mycobacterial persistence by increasing the Mϕ2 population and sustaining the infection. PMID:25024361

Volatile organic compounds as non-invasive markers for plant phenotyping.

PubMed

Niederbacher, B; Winkler, J B; Schnitzler, J P

2015-09-01

Plants emit a great variety of volatile organic compounds (VOCs) that can actively participate in plant growth and protection against biotic and abiotic stresses. VOC emissions are strongly dependent on environmental conditions; the greatest ambiguity is whether or not the predicted change in climate will influence and modify plant-pest interactions that are mediated by VOCs. The constitutive and induced emission patterns between plant genotypes, species, and taxa are highly variable and can be used as pheno(chemo)typic markers to distinguish between different origins and provenances. In recent years significant progress has been made in molecular and genetic plant breeding. However, there is actually a lack of knowledge in functionally linking genotypes and phenotypes, particularly in analyses of plant-environment interactions. Plant phenotyping, the assessment of complex plant traits such as growth, development, tolerance, resistance, etc., has become a major bottleneck, and quantitative information on genotype-environment relationships is the key to addressing major future challenges. With increasing demand to support and accelerate progress in breeding for novel traits, the plant research community faces the need to measure accurately increasingly large numbers of plants and plant traits. In this review article, we focus on the promising outlook of VOC phenotyping as a fast and non-invasive measure of phenotypic dynamics. The basic principle is to define plant phenotypes according to their disease resistance and stress tolerance, which in turn will help in improving the performance and yield of economically relevant plants. © The Author 2015. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Phenotype detection in morphological mutant mice using deformation features.

PubMed

Roy, Sharmili; Liang, Xi; Kitamoto, Asanobu; Tamura, Masaru; Shiroishi, Toshihiko; Brown, Michael S

2013-01-01

Large-scale global efforts are underway to knockout each of the approximately 25,000 mouse genes and interpret their roles in shaping the mammalian embryo. Given the tremendous amount of data generated by imaging mutated prenatal mice, high-throughput image analysis systems are inevitable to characterize mammalian development and diseases. Current state-of-the-art computational systems offer only differential volumetric analysis of pre-defined anatomical structures between various gene-knockout mice strains. For subtle anatomical phenotypes, embryo phenotyping still relies on the laborious histological techniques that are clearly unsuitable in such big data environment. This paper presents a system that automatically detects known phenotypes and assists in discovering novel phenotypes in muCT images of mutant mice. Deformation features obtained from non-linear registration of mutant embryo to a normal consensus average image are extracted and analyzed to compute phenotypic and candidate phenotypic areas. The presented system is evaluated using C57BL/10 embryo images. All cases of ventricular septum defect and polydactyly, well-known to be present in this strain, are successfully detected. The system predicts potential phenotypic areas in the liver that are under active histological evaluation for possible phenotype of this mouse line.

Increased association of coronary artery calcification in apparently healthy Korean adults with hypertriglyceridemic waist phenotype: The Kangbuk Samsung Health Study.

PubMed

Moon, Byung Sub; Park, Hye-Jeong; Lee, Min-Kyung; Jeon, Won Seon; Park, Se Eun; Park, Cheol-Young; Lee, Won-Yong; Oh, Ki-Won; Park, Sung-Woo; Rhee, Eun-Jung

2015-09-01

Hypertriglyceridemic waist phenotype is a simple screening parameter to identify people at increased risk for cardiovascular disease. We evaluated whether hypertriglyceridemic waist (HTGW) phenotype increases the risk for coronary artery calcification (CAC) in apparently healthy Korean adults. A total of 32,186 participants (mean age 41.3, 80.2% men) in a health screening program, in whom the coronary artery calcium score (CACS) was measured, were analyzed. Subjects were divided into four groups: 1) normal waist circumference (WC)-normal triglyceride (TG) (NWNT), 2) normal WC-high TG (NWHT), 3) enlarged WC-normal TG (EWNT), and 4) enlarged WC-high TG (EWHT). Enlarged WC was defined as WC ≥ 90 cm for men and ≥ 85 cm for women; high serum TG was defined as TG ≥ 150 mg/dL. The presence of CAC was defined by CACS >0, and CACS was analyzed in a logarithmized form of CACS plus 1 {ln(CACS+1)}. A total of 14.9% of the participants had CAC. The EWHT group showed the highest mean value for ln(CACS+1) among the four groups. The EWHT group showed the highest odds ratio for CAC, with NWHT group the second, and with EWNT group the third compared with the NWNT group after adjusting for confounding variables (1.579, 1.302, and 1.266 vs. NWNT). The EWHT group showed the highest association for CAC, suggesting this HTGW phenotype as a useful marker for the detection of subjects with high cardiometabolic risk in healthy Korean adults. Copyright © 2015. Published by Elsevier Ireland Ltd.

Redox Abnormalities as a Vulnerability Phenotype for Autism and Related Alterations in CNS Development

DTIC Science & Technology

2011-10-01

ming during pre- and post-natal neurodevelopment . Previously, we reported that many children with autism have abnormal plasma levels of metabolites...dysregulation in autism . 1. Introduction Autism is a behaviorally defined neurodevelopmental disor- der that usually presents in early childhood and is charac...Phenotype for Autism and Related Alterations in CNS Development PRINCIPAL INVESTIGATOR: Sandra Jill James, Ph.D

Challenging the present definition of "normal" vitamin D levels obtained by a single blood test. Can we develop a formula to predict vitamin D levels in the 4 seasons from a single season's measure?

PubMed

Tandeter, Howard

2014-08-01

Publications on the health effects of vitamin D (25(OH) D) had almost triplicate in the last 10years, not only for its known "calcemic effects" (calcium, phosphor, PTH), but for the more recent findings on its "non-calcemic effects" (all-cause and cardiovascular mortality, and relation with certain types of cancer). Part of these publications deal with the definition of what is a "normal" circulating level of 25(OH) D that may distinguish between health and disease. The literature also deals with seasonal variations of vitamin D, showing levels that rise in summer and fall in winter and with DBP phenotypes and geographical location that affect seasonality of 25(OH) D measurements. Despite the knowledge of the existence of these phenomena many studies on vitamin D fail to acknowledge the time of the year the blood sample was extracted. Thus, when we compare results from different studies without defining the season that the samples were drawn, we compare incomparable figures. Furthermore, it is quite absurd to define "normal levels" as a static measure (over or under a certain value) using a single blood test when the value measured is known to change with seasons. Knowing that people have different vitamin D levels in different seasons of the year, we should ask ourselves which of these measurements should be used to define a "real" or "normal" level? Is it the lower one? Is there a "mean measure" that should be used for this matter? If yes, how do we obtain it? Do we have to make 4 seasonal measurements in each patient? Alternatively, might there be a possibility of developing a formula to help us obtain the mean from a single season's measure or one season's prediction from another season's measurement? And knowing that DBP phenotypes and geographical location affect seasonality of 25(OH) D measurements; shouldn't we include this in the equation? In this article I will discuss the hypothetical existence of an Individual Mean Annual vitamin D level that I will call the "IMAD level" and a recovery formula "RF" that may be used to calculate this mean having one single measure (in any of the 4 seasons) and to predict any season's value from another season's measurement. IMAD levels should be obtained in the two main DBP phenotypes, taking into account the geographical location of the test. Copyright © 2014 Elsevier Ltd. All rights reserved.

Chronobiology differs between men and women with cluster headache, clinical phenotype does not.

PubMed

Lund, Nunu; Barloese, Mads; Petersen, Anja; Haddock, Bryan; Jensen, Rigmor

2017-03-14

To describe differences between the sexes in the phenotype of cluster headache (CH) in a large, well-characterized clinical CH population. Patients from the Danish CH survey aged 18-65 years, diagnosed with CH according to International Classification of Headache Disorders, second edition, completed questionnaires and structured interviews. A total of 351 patients with CH participated, with a male:female ratio of 2:1. The diurnal variation of attacks showed moments of peak prominence in men's attack cycle to be advanced by 1 hour compared to women's, despite no difference in self-reported bedtime or chronotype ( p = 0.31). The onset of CH decreased with increasing age for both sexes. Diagnostic delay was numerically longer for men vs women (6.56 vs 5.50 years, p = 0.21); however, more women had previously been misdiagnosed (61.1% vs 45.5%, p < 0.01) and received the correct diagnosis at a tertiary headache center (38.8% vs 20.9%, p < 0.001). Only minor sex differences in clinical characteristics were found but chronic CH was more prevalent in women compared to men (44.0% vs 31.9%, p < 0.05). Despite a similar clinical phenotype, diurnal attack cycle is advanced by 1 hour in men with CH compared to women. Rhythmicity is a defining characteristic of CH and these findings suggest differences in the hypothalamus' influence on attack occurrence between the sexes. In addition, women were more often misdiagnosed and diagnosis in the primary or secondary sector more often failed. Furthermore, women had chronic CH more frequently than men. A long diagnostic delay and frequent misdiagnosis emphasize the need for increased awareness of CH in both sexes. © 2017 American Academy of Neurology.

Update on oral-facial-digital syndromes (OFDS).

PubMed

Franco, Brunella; Thauvin-Robinet, Christel

2016-01-01

Oral-facial-digital syndromes (OFDS) represent a heterogeneous group of rare developmental disorders affecting the mouth, the face and the digits. Additional signs may involve brain, kidneys and other organs thus better defining the different clinical subtypes. With the exception of OFD types I and VIII, which are X-linked, the majority of OFDS is transmitted as an autosomal recessive syndrome. A number of genes have already found to be mutated in OFDS and most of the encoded proteins are predicted or proven to be involved in primary cilia/basal body function. Preliminary data indicate a physical interaction among some of those proteins and future studies will clarify whether all OFDS proteins are part of a network functionally connected to cilia. Mutations in some of the genes can also lead to other types of ciliopathies with partially overlapping phenotypes, such as Joubert syndrome (JS) and Meckel syndrome (MKS), supporting the concept that cilia-related diseases might be a continuous spectrum of the same phenotype with different degrees of severity. To date, seven of the described OFDS still await a molecular definition and two unclassified forms need further clinical and molecular validation. Next-generation sequencing (NGS) approaches are expected to shed light on how many OFDS geneticists should consider while evaluating oral-facial-digital cases. Functional studies will establish whether the non-ciliary functions of the transcripts mutated in OFDS might contribute to any of the phenotypic abnormalities observed in OFDS.

Disease severity in familial cases of IBD.

PubMed

Andreu, M; Márquez, L; Domènech, E; Gisbert, J P; García, V; Marín-Jiménez, I; Peñalva, M; Gomollón, F; Calvet, X; Merino, O; Garcia-Planella, E; Vázquez-Romero, N; Esteve, M; Nos, P; Gutiérrez, A; Vera, I; Cabriada, J L; Martín, M D; Cañas-Ventura, A; Panés, J

2014-03-01

Phenotypic traits of familial IBD relative to sporadic cases are controversial, probably related to limited statistical power of published evidence. To know if there are phenotype differences between familial and sporadic IBD, evaluating the prospective Spanish registry (ENEIDA) with 11,983 cases. 5783 patients (48.3%) had ulcerative colitis (UC) and 6200 (51.7%) Crohn's disease (CD). Cases with one or more 1st, 2nd or 3rd degree relatives affected by UC/CD were defined as familial case. In UC and CD, familial cases compared with sporadic cases had an earlier disease onset (UC: 33 years [IQR 25-44] vs 37 years [IQR 27-49]; p<0.0001); (CD: 27 years [IQR 21-35] vs 29 years [IQR 22-40]; p<0.0001), higher prevalence of extraintestinal immune-related manifestations (EIMs) (UC: 17.2% vs 14%; p=0.04); (CD: 30.1% vs 23.6%; p<0.0001). Familial CD had higher percentage of ileocolic location (42.7% vs 51.8%; p=0.0001), penetrating behavior (21% vs 17.6%; p=0.01) and perianal disease (32% vs 27.1%; p=0.003). Differences are not influenced by degree of consanguinity. When a sufficiently powered cohort is evaluated, familial aggregation in IBD is associated to an earlier disease onset, more EIMs and more severe phenotype in CD. This feature should be taken into account at establishing predictors of disease course. © 2013.

Using Y-Chromosomal Haplogroups in Genetic Association Studies and Suggested Implications.

PubMed

Erzurumluoglu, A Mesut; Baird, Denis; Richardson, Tom G; Timpson, Nicholas J; Rodriguez, Santiago

2018-01-22

Y-chromosomal (Y-DNA) haplogroups are more widely used in population genetics than in genetic epidemiology, although associations between Y-DNA haplogroups and several traits, including cardiometabolic traits, have been reported. In apparently homogeneous populations defined by principal component analyses, there is still Y-DNA haplogroup variation which will result from population history. Therefore, hidden stratification and/or differential phenotypic effects by Y-DNA haplogroups could exist. To test this, we hypothesised that stratifying individuals according to their Y-DNA haplogroups before testing for associations between autosomal single nucleotide polymorphisms (SNPs) and phenotypes will yield difference in association. For proof of concept, we derived Y-DNA haplogroups from 6537 males from two epidemiological cohorts, Avon Longitudinal Study of Parents and Children (ALSPAC) ( n = 5080; 816 Y-DNA SNPs) and the 1958 Birth Cohort ( n = 1457; 1849 Y-DNA SNPs), and studied the robust associations between 32 SNPs and body mass index (BMI), including SNPs in or near Fat Mass and Obesity-associated protein ( FTO ) which yield the strongest effects. Overall, no association was replicated in both cohorts when Y-DNA haplogroups were considered and this suggests that, for BMI at least, there is little evidence of differences in phenotype or SNP association by Y-DNA structure. Further studies using other traits, phenome-wide association studies (PheWAS), other haplogroups and/or autosomal SNPs are required to test the generalisability and utility of this approach.

Pheno- and genotyping of Brucella abortus biovar 5 isolated from a water buffalo (Bubalus bubalis) fetus: First case reported in the Americas.

PubMed

Martínez, Diana; Thompson, Carolina; Draghi, Graciela; Canavesio, Vilma; Jacobo, Roberto; Zimmer, Patricia; Elena, Sebastián; Nicola, Ana M; de Echaide, Susana Torioni

2014-09-17

An isolate of Brucella spp. from an aborted water buffalo (Bubalus bubalis) fetus was characterized based on its pheno- and genotype. The phenotype was defined by carbon dioxide requirement, hydrogen sulfide production, sensitivity to thionin and basic fuchsin and agglutination with Brucella A and M monospecific antisera. The genotype was based on the amplification of the following genes: bcsp31, omp2ab, and eri and the species-specific localization of the insertion sequence IS711 in the Brucella chromosome via B. abortus-B. melitensis-B. ovis-B. suis (AMOS)-PCR. Unexpectedly, the isolate showed a phenotype different from B. abortus bv 1, the most prevalent strain in cattle in Argentina, and from vaccine strain 19, currently used in bovines and water buffaloes. Genotyping supported the phenotypic results, as the analysis of the omp2ab gene sequence showed an identical pattern to either B. abortus bv 5 or B. melitensis. Finally, the AMOS PCR generated a 1700-bp fragment from the isolate, different than those amplified from B. abortus bv 1 (498bp) and B. melitensis (731bp), confirming the presence of B. abortus bv 5. The OIE/FAO Reference Laboratory for Brucellosis confirmed this typing. This is the first report of B. abortus bv 5 from a water buffalo in the Americas. Copyright © 2014 Elsevier B.V. All rights reserved.

Controversy in clinical endocrinology: diagnosis of polycystic ovarian syndrome: the Rotterdam criteria are premature.

PubMed

Azziz, Ricardo

2006-03-01

Polycystic ovary syndrome (PCOS) is defined most commonly according to the proceedings of an expert conference sponsored by the National Institutes of Health (NIH) in April 1990, which noted the disorder as having 1) hyperandrogenism and/or hyperandrogenemia, 2) oligoovulation, and 3) exclusion of known disorders. Alternatively, another expert conference held in Rotterdam in May 2003 defined PCOS, after the exclusion of related disorders, by two of the following three features: 1) oligo- or anovulation, 2) clinical and/or biochemical signs of hyperandrogenism, or 3) polycystic ovaries. In essence, the Rotterdam 2003 expanded the NIH 1990 definition creating two new phenotypes: 1) ovulatory women with polycystic ovaries and hyperandrogenism, and 2) oligoanovulatory women with polycystic ovaries, but without hyperandrogenism. The objective of this study was to ascertain the validity of using the Rotterdam 2003 criteria rather than the NIH 1991 criteria for the diagnosis of PCOS. Interventions included the use of the Rotterdam 2003 criteria for diagnosing PCOS and, in particular, the proposal to define two new phenotypes as PCOS. POSITIONS: Available data suggest that hyperandrogenic ovulatory women with polycystic ovaries tend to have mild insulin resistance and mild evidence of ovarian dysfunction, although significantly less than women with anovulatory PCOS. However, whether these women will have an increased risk of infertility or metabolic complications, such as type 2 diabetes, remains to be determined. Alternatively, the risk of insulin resistance and long-term metabolic risks of oligoovulatory women with polycystic ovaries is even less well characterized and may be nonexistent. Because of the paucity of data on the two new phenotypes and their long-term implications and the potential negative impact on research, clinical practice, and patient insurability, the adoption of the Rotterdam 2003 criteria for defining PCOS should be considered premature. However, because polycystic ovaries are a frequent feature of PCOS, a modification of the NIH 1990 criteria is proposed. Additional research characterizing the phenotypes and associated morbidities of PCOS is urgently required.

Genomes by design

PubMed Central

Haimovich, Adrian D.; Muir, Paul; Isaacs, Farren J.

2016-01-01

Next-generation DNA sequencing has revealed the complete genome sequences of numerous organisms, establishing a fundamental and growing understanding of genetic variation and phenotypic diversity. Engineering at the gene, network and whole-genome scale aims to introduce targeted genetic changes both to explore emergent phenotypes and to introduce new functionalities. Expansion of these approaches into massively parallel platforms establishes the ability to generate targeted genome modifications, elucidating causal links between genotype and phenotype, as well as the ability to design and reprogramme organisms. In this Review, we explore techniques and applications in genome engineering, outlining key advances and defining challenges. PMID:26260262

Tolerance and Exhaustion: Defining Mechanisms of T cell Dysfunction

PubMed Central

Schietinger, Andrea; Greenberg, Philip D.

2013-01-01

CD8 T cell activation and differentiation is tightly controlled, and dependent on the context in which naïve T cells encounter antigen, can either result in functional memory or T cell dysfunction, including exhaustion, tolerance, anergy, or senescence. With the identification of phenotypic and functional traits shared in different settings of T cell dysfunction, distinctions between such dysfunctional `states' have become blurred. Here, we discuss distinct states of CD8 T cell dysfunction, with emphasis on (i) T cell tolerance to self-antigens (self-tolerance), (ii) T cell exhaustion during chronic infections, and (iii) tumor-induced T cell dysfunction. We highlight recent findings on cellular and molecular characteristics defining these states, cell-intrinsic regulatory mechanisms that induce and maintain them, and strategies that can lead to their reversal. PMID:24210163

Autoantibodies Associated With Connective Tissue Diseases: What Meaning for Clinicians?

PubMed Central

Didier, Kevin; Bolko, Loïs; Giusti, Delphine; Toquet, Segolene; Robbins, Ailsa; Antonicelli, Frank; Servettaz, Amelie

2018-01-01

Connective tissue diseases (CTDs) such as systemic lupus erythematosus, systemic sclerosis, myositis, Sjögren’s syndrome, and rheumatoid arthritis are systemic diseases which are often associated with a challenge in diagnosis. Autoantibodies (AAbs) can be detected in these diseases and help clinicians in their diagnosis. Actually, pathophysiology of these diseases is associated with the presence of antinuclear antibodies. In the last decades, many new antibodies were discovered, but their implication in pathogenesis of CTDs remains unclear. Furthermore, the classification of these AAbs is nowadays misused, as their targets can be localized outside of the nuclear compartment. Interestingly, in most cases, each antibody is associated with a specific phenotype in CTDs and therefore help in better defining either the disease subtypes or diseases activity and outcome. Because of recent progresses in their detection and in the comprehension of their pathogenesis implication in CTD-associated antibodies, clinicians should pay attention to the presence of these different AAbs to improve patient’s management. In this review, we propose to focus on the different phenotypes and features associated with each autoantibody used in clinical practice in those CTDs. PMID:29632529

Adult pituitary stem cells: from pituitary plasticity to adenoma development.

PubMed

Florio, Tullio

2011-01-01

The pituitary needs high plasticity of the hormone-producing cell compartment to generate the continuously changing hormonal signals that govern the key physiological processes it is involved in, as well as homeostatic cell turnover. However, the underlying mechanisms are still poorly understood. It was proposed that adult stem cells direct the generation of newborn cells with a hormonal phenotype according to the physiological requirements. However, only in recent years adult pituitary stem cells have begun to be phenotypically characterized in several studies that identified multiple stem/progenitor cell candidates. Also considering the incompletely defined features of this cell subpopulation, some discrepancies among the different reports are clearly apparent and long-term self-renewal remains to be unequivocally demonstrated. Here, all the recently published evidence is analyzed, trying, when possible, to reconcile the results of the different studies. Finally, with the perspective of shedding light on pituitary tumorigenesis and the development of potentially new pharmacological approaches directed against these cells, very recent evidence on the presence of putative cancer stem cells in human pituitary adenomas is discussed. Copyright © 2011 S. Karger AG, Basel.

The role of regulatory B cells in digestive system diseases.

PubMed

Zhou, Zhenyu; Gong, Lei; Wang, Xiaoyun; Hu, Zhen; Wu, Gaojue; Tang, Xuejun; Peng, Xiaobin; Tang, Shuan; Meng, Miao; Feng, Hui

2017-04-01

The past decade has provided striking insights into a newly identified subset of B cells known as regulatory B cells (Bregs). In addition to producing antibody, Bregs also regulate diseases via cytokine production and antigen presentation. This subset of B cells has protective and potentially therapeutic effects. However, the particularity of Bregs has caused some difficulties in conducting research on their roles. Notably, human B10 cells, which are Bregs that produce interleukin 10, share phenotypic characteristics with other previously defined B cell subsets, and currently, there is no known surface phenotype that is unique to B10 cells. An online search was performed in the PubMed and Web of Science databases for articles published providing evidences on the role of regulatory B cells in digestive system diseases. Abundant evidence has demonstrated that Bregs play a regulatory role in inflammatory, autoimmune, and tumor diseases, and regulatory B cells play different roles in different diseases, but future work needs to determine the mechanisms by which Bregs are activated and how these cells affect their target cells.

Types of pediatric diabetes mellitus defined by anti-islet autoimmunity and random C-peptide at diagnosis

USDA-ARS?s Scientific Manuscript database

The objective of this study was to test the hypothesis that anti-islet autoantibody expression and random serum C-peptide obtained at diagnosis define phenotypes of pediatric diabetes with distinct clinical features. We analyzed 607 children aged <19 yr consecutively diagnosed with diabetes after ex...

Evaluation of Semantic Web Technologies for Storing Computable Definitions of Electronic Health Records Phenotyping Algorithms.

PubMed

Papež, Václav; Denaxas, Spiros; Hemingway, Harry

2017-01-01

Electronic Health Records are electronic data generated during or as a byproduct of routine patient care. Structured, semi-structured and unstructured EHR offer researchers unprecedented phenotypic breadth and depth and have the potential to accelerate the development of precision medicine approaches at scale. A main EHR use-case is defining phenotyping algorithms that identify disease status, onset and severity. Phenotyping algorithms utilize diagnoses, prescriptions, laboratory tests, symptoms and other elements in order to identify patients with or without a specific trait. No common standardized, structured, computable format exists for storing phenotyping algorithms. The majority of algorithms are stored as human-readable descriptive text documents making their translation to code challenging due to their inherent complexity and hinders their sharing and re-use across the community. In this paper, we evaluate the two key Semantic Web Technologies, the Web Ontology Language and the Resource Description Framework, for enabling computable representations of EHR-driven phenotyping algorithms.

Behavioural phenotypes predict disease susceptibility and infectiousness

PubMed Central

Araujo, Alessandra; Kirschman, Lucas

2016-01-01

Behavioural phenotypes may provide a means for identifying individuals that disproportionally contribute to disease spread and epizootic outbreaks. For example, bolder phenotypes may experience greater exposure and susceptibility to pathogenic infection because of distinct interactions with conspecifics and their environment. We tested the value of behavioural phenotypes in larval amphibians for predicting ranavirus transmission in experimental trials. We found that behavioural phenotypes characterized by latency-to-food and swimming profiles were predictive of disease susceptibility and infectiousness defined as the capacity of an infected host to transmit an infection by contacts. While viral shedding rates were positively associated with transmission, we also found an inverse relationship between contacts and infections. Together these results suggest intrinsic traits that influence behaviour and the quantity of pathogens shed during conspecific interactions may be an important contributor to ranavirus transmission. These results suggest that behavioural phenotypes provide a means to identify individuals more likely to spread disease and thus give insights into disease outbreaks that threaten wildlife and humans. PMID:27555652

Behavioural phenotypes predict disease susceptibility and infectiousness.

PubMed

Araujo, Alessandra; Kirschman, Lucas; Warne, Robin W

2016-08-01

Behavioural phenotypes may provide a means for identifying individuals that disproportionally contribute to disease spread and epizootic outbreaks. For example, bolder phenotypes may experience greater exposure and susceptibility to pathogenic infection because of distinct interactions with conspecifics and their environment. We tested the value of behavioural phenotypes in larval amphibians for predicting ranavirus transmission in experimental trials. We found that behavioural phenotypes characterized by latency-to-food and swimming profiles were predictive of disease susceptibility and infectiousness defined as the capacity of an infected host to transmit an infection by contacts. While viral shedding rates were positively associated with transmission, we also found an inverse relationship between contacts and infections. Together these results suggest intrinsic traits that influence behaviour and the quantity of pathogens shed during conspecific interactions may be an important contributor to ranavirus transmission. These results suggest that behavioural phenotypes provide a means to identify individuals more likely to spread disease and thus give insights into disease outbreaks that threaten wildlife and humans. © 2016 The Author(s).

Alterations in muscle mass and contractile phenotype in response to unloading models: role of transcriptional/pretranslational mechanisms

PubMed Central

Baldwin, Kenneth M.; Haddad, Fadia; Pandorf, Clay E.; Roy, Roland R.; Edgerton, V. Reggie

2013-01-01

Skeletal muscle is the largest organ system in mammalian organisms providing postural control and movement patterns of varying intensity. Through evolution, skeletal muscle fibers have evolved into three phenotype clusters defined as a motor unit which consists of all muscle fibers innervated by a single motoneuron linking varying numbers of fibers of similar phenotype. This fundamental organization of the motor unit reflects the fact that there is a remarkable interdependence of gene regulation between the motoneurons and the muscle mainly via activity-dependent mechanisms. These fiber types can be classified via the primary type of myosin heavy chain (MHC) gene expressed in the motor unit. Four MHC gene encoded proteins have been identified in striated muscle: slow type I MHC and three fast MHC types, IIa, IIx, and IIb. These MHCs dictate the intrinsic contraction speed of the myofiber with the type I generating the slowest and IIb the fastest contractile speed. Over the last ~35 years, a large body of knowledge suggests that altered loading state cause both fiber atrophy/wasting and a slow to fast shift in the contractile phenotype in the target muscle(s). Hence, this review will examine findings from three different animal models of unloading: (1) space flight (SF), i.e., microgravity; (2) hindlimb suspension (HS), a procedure that chronically eliminates weight bearing of the lower limbs; and (3) spinal cord isolation (SI), a surgical procedure that eliminates neural activation of the motoneurons and associated muscles while maintaining neurotrophic motoneuron-muscle connectivity. The collective findings demonstrate: (1) all three models show a similar pattern of fiber atrophy with differences mainly in the magnitude and kinetics of alteration; (2) transcriptional/pretranslational processes play a major role in both the atrophy process and phenotype shifts; and (3) signaling pathways impacting these alterations appear to be similar in each of the models investigated. PMID:24130531

Shift from slow- to fast-water habitats accelerates lineage and phenotype evolution in a clade of Neotropical suckermouth catfishes (Loricariidae: Hypoptopomatinae).

PubMed

Roxo, Fábio F; Lujan, Nathan K; Tagliacollo, Victor A; Waltz, Brandon T; Silva, Gabriel S C; Oliveira, Claudio; Albert, James S

2017-01-01

Identifying habitat characteristics that accelerate organismal evolution is essential to understanding both the origins of life on Earth and the ecosystem properties that are most critical to maintaining life into the future. Searching for these characteristics on a large scale has only recently become possible via advances in phylogenetic reconstruction, time-calibration, and comparative analyses. In this study, we combine these tools with habitat and phenotype data for 105 species in a clade of Neotropical suckermouth catfishes commonly known as cascudinhos. Our goal was to determine whether riverine mesohabitats defined by different flow rates (i.e., pools vs. rapids) and substrates (plants vs. rocks) have affected rates of cascudinho cladogenesis and morphological diversification. In contrast to predictions based on general theory related to life in fast-flowing, rocky riverine habitats, Neoplecostomini lineages associated with these habitats exhibited increased body size, head shape diversity, and lineage and phenotype diversification rates. These findings are consistent with a growing understanding of river rapids as incubators of biological diversification and specialization. They also highlight the urgent need to conserve rapids habitats throughout the major rivers of the world.

Molecular deconstruction, detection, and computational prediction of microenvironment-modulated cellular responses to cancer therapeutics

PubMed Central

LaBarge, Mark A; Parvin, Bahram; Lorens, James B

2014-01-01

The field of bioengineering has pioneered the application of new precision fabrication technologies to model the different geometric, physical or molecular components of tissue microenvironments on solid-state substrata. Tissue engineering approaches building on these advances are used to assemble multicellular mimetic-tissues where cells reside within defined spatial contexts. The functional responses of cells in fabricated microenvironments has revealed a rich interplay between the genome and extracellular effectors in determining cellular phenotypes, and in a number of cases has revealed the dominance of microenvironment over genotype. Precision bioengineered substrata are limited to a few aspects, whereas cell/tissue-derived microenvironments have many undefined components. Thus introducing a computational module may serve to integrate these types of platforms to create reasonable models of drug responses in human tissues. This review discusses how combinatorial microenvironment microarrays and other biomimetic microenvironments have revealed emergent properties of cells in particular microenvironmental contexts, the platforms that can measure phenotypic changes within those contexts, and the computational tools that can unify the microenvironment-imposed functional phenotypes with underlying constellations of proteins and genes. Ultimately we propose that a merger of these technologies will enable more accurate pre-clinical drug discovery. PMID:24582543

A unified anatomy ontology of the vertebrate skeletal system.

PubMed

Dahdul, Wasila M; Balhoff, James P; Blackburn, David C; Diehl, Alexander D; Haendel, Melissa A; Hall, Brian K; Lapp, Hilmar; Lundberg, John G; Mungall, Christopher J; Ringwald, Martin; Segerdell, Erik; Van Slyke, Ceri E; Vickaryous, Matthew K; Westerfield, Monte; Mabee, Paula M

2012-01-01

The skeleton is of fundamental importance in research in comparative vertebrate morphology, paleontology, biomechanics, developmental biology, and systematics. Motivated by research questions that require computational access to and comparative reasoning across the diverse skeletal phenotypes of vertebrates, we developed a module of anatomical concepts for the skeletal system, the Vertebrate Skeletal Anatomy Ontology (VSAO), to accommodate and unify the existing skeletal terminologies for the species-specific (mouse, the frog Xenopus, zebrafish) and multispecies (teleost, amphibian) vertebrate anatomy ontologies. Previous differences between these terminologies prevented even simple queries across databases pertaining to vertebrate morphology. This module of upper-level and specific skeletal terms currently includes 223 defined terms and 179 synonyms that integrate skeletal cells, tissues, biological processes, organs (skeletal elements such as bones and cartilages), and subdivisions of the skeletal system. The VSAO is designed to integrate with other ontologies, including the Common Anatomy Reference Ontology (CARO), Gene Ontology (GO), Uberon, and Cell Ontology (CL), and it is freely available to the community to be updated with additional terms required for research. Its structure accommodates anatomical variation among vertebrate species in development, structure, and composition. Annotation of diverse vertebrate phenotypes with this ontology will enable novel inquiries across the full spectrum of phenotypic diversity.

Characteristics of Fluency and Speech in Two Families With High Incidences of Stuttering.

PubMed

Stager, Sheila V; Freeman, Frances J; Braun, Allen

2015-10-01

This study presents data from 2 families with high incidence of stuttering, comparing methods of phenotype assignment and exploring the presence of other fluency disorders and corresponding speech characteristics. Three methods for assigning phenotype of stuttering were used: self-identification, family identification, and expert identification. Agreement on which individuals were assigned by each of these methods was studied. Multiple measures of fluency and speech production were obtained. Self-reports and descriptions of blocking rather than self-identification as a person who stutters demonstrated the best agreement with expert identification of stuttering. Family identification showed poor agreement with both expert and self-identification of stuttering. Using binary categories of fluent or stuttering, 90% of individuals in 1 family were classified by expert consensus. Only 70% of the other family could be similarly categorized. Experts required 2 other categories, cluttering and other fluency disorders, to fully characterize dysfluency within this family. These 2 families also demonstrated differences in speech production. Some families with high incidence of stuttering may also have high incidence of other fluency disorders and other speech-production difficulties. This finding may have ramifications for genetic studies, including criteria for defining phenotype and collapsing data across multiple families.

Revisiting Type 2-high and Type 2-low airway inflammation in asthma: current knowledge and therapeutic implications.

PubMed

Robinson, D; Humbert, M; Buhl, R; Cruz, A A; Inoue, H; Korom, S; Hanania, N A; Nair, P

2017-02-01

Asthma is a complex respiratory disorder characterized by marked heterogeneity in individual patient disease triggers and response to therapy. Several asthma phenotypes have now been identified, each defined by a unique interaction between genetic and environmental factors, including inflammatory, clinical and trigger-related phenotypes. Endotypes further describe the functional or pathophysiologic mechanisms underlying the patient's disease. type 2-driven asthma is an emerging nomenclature for a common subtype of asthma and is characterized by the release of signature cytokines IL-4, IL-5 and IL-13 from cells of both the innate and adaptive immune systems. A number of well-recognized biomarkers have been linked to mechanisms involved in type 2 airway inflammation, including fractional exhaled nitric oxide, serum IgE, periostin, and blood and sputum eosinophils. These type 2 cytokines are targets for pharmaceutical intervention, and a number of therapeutic options are under clinical investigation for the management of patients with uncontrolled severe asthma. Anticipating and understanding the heterogeneity of asthma and subsequent improved characterization of different phenotypes and endotypes must guide the selection of treatment to meet individual patients' needs. © 2017 The Authors. Clinical & Experimental Allergy Published by John Wiley & Sons Ltd.

A Unified Anatomy Ontology of the Vertebrate Skeletal System

PubMed Central

Dahdul, Wasila M.; Balhoff, James P.; Blackburn, David C.; Diehl, Alexander D.; Haendel, Melissa A.; Hall, Brian K.; Lapp, Hilmar; Lundberg, John G.; Mungall, Christopher J.; Ringwald, Martin; Segerdell, Erik; Van Slyke, Ceri E.; Vickaryous, Matthew K.; Westerfield, Monte; Mabee, Paula M.

2012-01-01

The skeleton is of fundamental importance in research in comparative vertebrate morphology, paleontology, biomechanics, developmental biology, and systematics. Motivated by research questions that require computational access to and comparative reasoning across the diverse skeletal phenotypes of vertebrates, we developed a module of anatomical concepts for the skeletal system, the Vertebrate Skeletal Anatomy Ontology (VSAO), to accommodate and unify the existing skeletal terminologies for the species-specific (mouse, the frog Xenopus, zebrafish) and multispecies (teleost, amphibian) vertebrate anatomy ontologies. Previous differences between these terminologies prevented even simple queries across databases pertaining to vertebrate morphology. This module of upper-level and specific skeletal terms currently includes 223 defined terms and 179 synonyms that integrate skeletal cells, tissues, biological processes, organs (skeletal elements such as bones and cartilages), and subdivisions of the skeletal system. The VSAO is designed to integrate with other ontologies, including the Common Anatomy Reference Ontology (CARO), Gene Ontology (GO), Uberon, and Cell Ontology (CL), and it is freely available to the community to be updated with additional terms required for research. Its structure accommodates anatomical variation among vertebrate species in development, structure, and composition. Annotation of diverse vertebrate phenotypes with this ontology will enable novel inquiries across the full spectrum of phenotypic diversity. PMID:23251424

[Laboratory diagnosis of lipid imbalance].

PubMed

Siemianowicz, K

1996-01-01

Accurate diagnosis of hyperlipidaemia is necessary for the effective treatment. Measurements in serum or plasma obtained after an overnight fast of over 16 hours should include total cholesterol, triglycerides and HDL-cholesterol concentrations; LDL-cholesterol can be calculated using the Friedelwald's formula. Lipoprotein electrophoresis is used to define different phenotypes of hyperlipoproteinaemia according to the Fredrickson's classification. More sophisticated tests include apolipoprotein analysis, determination of Lp(a) concentration, activities of enzymes involved in lipid metabolism and genetic studies. Secondary causes of hyperlipidaemia, including liver, kidney, endocrine disorders should be excluded using the laboratory methods.

Loss of IL-15 receptor α alters the endurance, fatigability, and metabolic characteristics of mouse fast skeletal muscles

PubMed Central

Pistilli, Emidio E.; Bogdanovich, Sasha; Garton, Fleur; Yang, Nan; Gulbin, Jason P.; Conner, Jennifer D.; Anderson, Barbara G.; Quinn, LeBris S.; North, Kathryn; Ahima, Rexford S.; Khurana, Tejvir S.

2011-01-01

IL-15 receptor α (IL-15Rα) is a component of the heterotrimeric plasma membrane receptor for the pleiotropic cytokine IL-15. However, IL-15Rα is not merely an IL-15 receptor subunit, as mice lacking either IL-15 or IL-15Rα have unique phenotypes. IL-15 and IL-15Rα have been implicated in muscle phenotypes, but a role in muscle physiology has not been defined. Here, we have shown that loss of IL-15Rα induces a functional oxidative shift in fast muscles, substantially increasing fatigue resistance and exercise capacity. IL-15Rα–knockout (IL-15Rα–KO) mice ran greater distances and had greater ambulatory activity than controls. Fast muscles displayed fatigue resistance and a slower contractile phenotype. The molecular signature of these muscles included altered markers of mitochondrial biogenesis and calcium homeostasis. Morphologically, fast muscles had a greater number of muscle fibers, smaller fiber areas, and a greater ratio of nuclei to fiber area. The alterations of physiological properties and increased resistance to fatigue in fast muscles are consistent with a shift toward a slower, more oxidative phenotype. Consistent with a conserved functional role in humans, a genetic association was found between a SNP in the IL15RA gene and endurance in athletes stratified by sport. Therefore, we propose that IL-15Rα has a role in defining the phenotype of fast skeletal muscles in vivo. PMID:21765213

The digital revolution in phenotyping

PubMed Central

Oellrich, Anika; Collier, Nigel; Groza, Tudor; Rebholz-Schuhmann, Dietrich; Shah, Nigam; Bodenreider, Olivier; Boland, Mary Regina; Georgiev, Ivo; Liu, Hongfang; Livingston, Kevin; Luna, Augustin; Mallon, Ann-Marie; Manda, Prashanti; Robinson, Peter N.; Rustici, Gabriella; Simon, Michelle; Wang, Liqin; Winnenburg, Rainer; Dumontier, Michel

2016-01-01

Phenotypes have gained increased notoriety in the clinical and biological domain owing to their application in numerous areas such as the discovery of disease genes and drug targets, phylogenetics and pharmacogenomics. Phenotypes, defined as observable characteristics of organisms, can be seen as one of the bridges that lead to a translation of experimental findings into clinical applications and thereby support ‘bench to bedside’ efforts. However, to build this translational bridge, a common and universal understanding of phenotypes is required that goes beyond domain-specific definitions. To achieve this ambitious goal, a digital revolution is ongoing that enables the encoding of data in computer-readable formats and the data storage in specialized repositories, ready for integration, enabling translational research. While phenome research is an ongoing endeavor, the true potential hidden in the currently available data still needs to be unlocked, offering exciting opportunities for the forthcoming years. Here, we provide insights into the state-of-the-art in digital phenotyping, by means of representing, acquiring and analyzing phenotype data. In addition, we provide visions of this field for future research work that could enable better applications of phenotype data. PMID:26420780

DNA methylation analysis of phenotype specific stratified Indian population.

PubMed

Rotti, Harish; Mallya, Sandeep; Kabekkodu, Shama Prasada; Chakrabarty, Sanjiban; Bhale, Sameer; Bharadwaj, Ramachandra; Bhat, Balakrishna K; Dedge, Amrish P; Dhumal, Vikram Ram; Gangadharan, G G; Gopinath, Puthiya M; Govindaraj, Periyasamy; Joshi, Kalpana S; Kondaiah, Paturu; Nair, Sreekumaran; Nair, S N Venugopalan; Nayak, Jayakrishna; Prasanna, B V; Shintre, Pooja; Sule, Mayura; Thangaraj, Kumarasamy; Patwardhan, Bhushan; Valiathan, Marthanda Varma Sankaran; Satyamoorthy, Kapaettu

2015-05-08

DNA methylation and its perturbations are an established attribute to a wide spectrum of phenotypic variations and disease conditions. Indian traditional system practices personalized medicine through indigenous concept of distinctly descriptive physiological, psychological and anatomical features known as prakriti. Here we attempted to establish DNA methylation differences in these three prakriti phenotypes. Following structured and objective measurement of 3416 subjects, whole blood DNA of 147 healthy male individuals belonging to defined prakriti (Vata, Pitta and Kapha) between the age group of 20-30years were subjected to methylated DNA immunoprecipitation (MeDIP) and microarray analysis. After data analysis, prakriti specific signatures were validated through bisulfite DNA sequencing. Differentially methylated regions in CpG islands and shores were significantly enriched in promoters/UTRs and gene body regions. Phenotypes characterized by higher metabolism (Pitta prakriti) in individuals showed distinct promoter (34) and gene body methylation (204), followed by Vata prakriti which correlates to motion showed DNA methylation in 52 promoters and 139 CpG islands and finally individuals with structural attributes (Kapha prakriti) with 23 and 19 promoters and CpG islands respectively. Bisulfite DNA sequencing of prakriti specific multiple CpG sites in promoters and 5'-UTR such as; LHX1 (Vata prakriti), SOX11 (Pitta prakriti) and CDH22 (Kapha prakriti) were validated. Kapha prakriti specific CDH22 5'-UTR CpG methylation was also found to be associated with higher body mass index (BMI). Differential DNA methylation signatures in three distinct prakriti phenotypes demonstrate the epigenetic basis of Indian traditional human classification which may have relevance to personalized medicine.

Phenotypes Associated with SHOX Deficiency.

PubMed

Ross, J L; Scott, C; Marttila, P; Kowal, K; Nass, A; Papenhausen, P; Abboudi, J; Osterman, L; Kushner, H; Carter, P; Ezaki, M; Elder, F; Wei, F; Chen, H; Zinn, A R

2001-12-01

Leri-Weill dyschondrosteosis (LWD) (MIM 127300) is a dominantly inherited skeletal dysplasia characterized phenotypically by Madelung wrist deformity, mesomelia, and short stature. LWD can now be defined genetically by haploinsufficiency of the SHOX (short stature homeobox-containing) gene. We have studied 21 LWD families (43 affected LWD subjects, including 32 females and 11 males, ages 3-56 yr) with confirmed SHOX abnormalities. We investigated the relationship between SHOX mutations, height deficit, and Madelung deformity to determine the contribution of SHOX haploinsufficiency to the LWD and Turner syndrome (TS) phenotypes. Also, we examined the effects of age, gender, and female puberty (estrogen) on the LWD phenotype. SHOX deletions were present in affected individuals from 17 families (81%), and point mutations were detected in 4 families (19%). In the LWD subjects, height deficits ranged from -4.6 to +0.6 SD (mean +/- SD = -2.2 +/- 1.0). There were no statistically significant effects of age, gender, pubertal status, or parental origin of SHOX mutations on height z-score. The height deficit in LWD is approximately two thirds that of TS. Madelung deformity was present in 74% of LWD children and adults and was more frequent and severe in females than males. The prevalence of the Madelung deformity was higher in the LWD vs. a TS population. The prevalence of increased carrying angle, high arched palate, and scoliosis was similar in the two populations. In conclusion, SHOX deletions or mutations accounted for all of our LWD cases. SHOX haploinsufficiency accounts for most, but not all, of the TS height deficit. The LWD phenotype shows some gender- and age-related differences.

The intriguing metabolically healthy but obese phenotype: cardiovascular prognosis and role of fitness.

PubMed

Ortega, Francisco B; Lee, Duck-Chul; Katzmarzyk, Peter T; Ruiz, Jonatan R; Sui, Xuemei; Church, Timothy S; Blair, Steven N

2013-02-01

Current knowledge on the prognosis of metabolically healthy but obese phenotype is limited due to the exclusive use of the body mass index to define obesity and the lack of information on cardiorespiratory fitness. We aimed to test the following hypotheses: (i) metabolically healthy but obese individuals have a higher fitness level than their metabolically abnormal and obese peers; (ii) after accounting for fitness, metabolically healthy but obese phenotype is a benign condition, in terms of cardiovascular disease and mortality. Fitness was assessed by a maximal exercise test on a treadmill and body fat per cent (BF%) by hydrostatic weighing or skinfolds (obesity = BF% ≥ 25 or ≥ 30%, men or women, respectively) in 43 265 adults (24.3% women). Metabolically healthy was considered if meeting 0 or 1 of the criteria for metabolic syndrome. Metabolically healthy but obese participants (46% of the obese subsample) had a better fitness than metabolically abnormal obese participants (P < 0.001). When adjusting for fitness and other confounders, metabolically healthy but obese individuals had lower risk (30-50%, estimated by hazard ratios) of all-cause mortality, non-fatal and fatal cardiovascular disease, and cancer mortality than their metabolically unhealthy obese peers; while no significant differences were observed between metabolically healthy but obese and metabolically healthy normal-fat participants. (i) Higher fitness should be considered a characteristic of metabolically healthy but obese phenotype. (ii) Once fitness is accounted for, the metabolically healthy but obese phenotype is a benign condition, with a better prognosis for mortality and morbidity than metabolically abnormal obese individuals.

The intriguing metabolically healthy but obese phenotype: cardiovascular prognosis and role of fitness

PubMed Central

Ortega, Francisco B.; Lee, Duck-chul; Katzmarzyk, Peter T.; Ruiz, Jonatan R.; Sui, Xuemei; Church, Timothy S.; Blair, Steven N.

2013-01-01

Aims Current knowledge on the prognosis of metabolically healthy but obese phenotype is limited due to the exclusive use of the body mass index to define obesity and the lack of information on cardiorespiratory fitness. We aimed to test the following hypotheses: (i) metabolically healthy but obese individuals have a higher fitness level than their metabolically abnormal and obese peers; (ii) after accounting for fitness, metabolically healthy but obese phenotype is a benign condition, in terms of cardiovascular disease and mortality. Methods and results Fitness was assessed by a maximal exercise test on a treadmill and body fat per cent (BF%) by hydrostatic weighing or skinfolds (obesity = BF% ≥25 or ≥30%, men or women, respectively) in 43 265 adults (24.3% women). Metabolically healthy was considered if meeting 0 or 1 of the criteria for metabolic syndrome. Metabolically healthy but obese participants (46% of the obese subsample) had a better fitness than metabolically abnormal obese participants (P < 0.001). When adjusting for fitness and other confounders, metabolically healthy but obese individuals had lower risk (30–50%, estimated by hazard ratios) of all-cause mortality, non-fatal and fatal cardiovascular disease, and cancer mortality than their metabolically unhealthy obese peers; while no significant differences were observed between metabolically healthy but obese and metabolically healthy normal-fat participants. Conclusions (i) Higher fitness should be considered a characteristic of metabolically healthy but obese phenotype. (ii) Once fitness is accounted for, the metabolically healthy but obese phenotype is a benign condition, with a better prognosis for mortality and morbidity than metabolically abnormal obese individuals. PMID:22947612

A homozygous PMS2 founder mutation with an attenuated constitutional mismatch repair deficiency phenotype.

PubMed

Li, Lili; Hamel, Nancy; Baker, Kristi; McGuffin, Michael J; Couillard, Martin; Gologan, Adrian; Marcus, Victoria A; Chodirker, Bernard; Chudley, Albert; Stefanovici, Camelia; Durandy, Anne; Hegele, Robert A; Feng, Bing-Jian; Goldgar, David E; Zhu, Jun; De Rosa, Marina; Gruber, Stephen B; Wimmer, Katharina; Young, Barbara; Chong, George; Tischkowitz, Marc D; Foulkes, William D

2015-05-01

Inherited mutations in DNA mismatch repair genes predispose to different cancer syndromes depending on whether they are mono-allelic or bi-allelic. This supports a causal relationship between expression level in the germline and phenotype variation. As a model to study this relationship, our study aimed to define the pathogenic characteristics of a recurrent homozygous coding variant in PMS2 displaying an attenuated phenotype identified by clinical genetic testing in seven Inuit families from Northern Quebec. Pathogenic characteristics of the PMS2 mutation NM_000535.5:c.2002A>G were studied using genotype-phenotype correlation, single-molecule expression detection and single genome microsatellite instability analysis. This PMS2 mutation generates a de novo splice site that competes with the authentic site. In homozygotes, expression of the full-length protein is reduced to a level barely detectable by conventional diagnostics. Median age at primary cancer diagnosis is 22 years among 13 NM_000535.5:c.2002A>G homozygotes, versus 8 years in individuals carrying bi-allelic truncating mutations. Residual expression of full-length PMS2 transcript was detected in normal tissues from homozygotes with cancers in their 20s. Our genotype-phenotype study of c.2002A>G illustrates that an extremely low level of PMS2 expression likely delays cancer onset, a feature that could be exploited in cancer preventive intervention. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Developmental Coordination Disorder in a Patient with Mental Disability and a Mild Phenotype Carrying Terminal 6q26-qter Deletion

PubMed Central

De Cinque, Marianna; Palumbo, Orazio; Mazzucco, Ermelinda; Simone, Antonella; Palumbo, Pietro; Ciavatta, Renata; Maria, Giuliana; Ferese, Rosangela; Gambardella, Stefano; Angiolillo, Antonella; Carella, Massimo; Garofalo, Silvio

2017-01-01

Terminal deletion of chromosome 6q is a rare chromosomal abnormality associated with variable phenotype spectrum. Although intellectual disability, facial dysmorphism, seizures and brain abnormalities are typical features of this syndrome, genotype–phenotype correlation needs to be better understood. We report the case of a 6-year-old Caucasian boy with a clinical diagnosis of intellectual disability, delayed language development and dyspraxia who carries an approximately 8 Mb de novo heterozygous microdeletion in the 6q26-q27 locus identified by karyotype and defined by high-resolution SNP-array analysis. This patient has no significant structural brain or other organ malformation, and he shows a very mild phenotype compared to similar 6q26-qter deletion. The patient phenotype also suggests that a dyspraxia susceptibility gene is located among the deleted genes. PMID:29270193

Chm-1 gene-modified bone marrow mesenchymal stem cells maintain the chondrogenic phenotype of tissue-engineered cartilage.

PubMed

Chen, Zhuoyue; Wei, Jing; Zhu, Jun; Liu, Wei; Cui, Jihong; Li, Hongmin; Chen, Fulin

2016-05-05

Marrow mesenchymal stem cells (MSCs) can differentiate into specific phenotypes, including chondrocytes, and have been widely used for cartilage tissue engineering. However, cartilage grafts from MSCs exhibit phenotypic alternations after implantation, including matrix calcification and vascular ingrowth. We compared chondromodulin-1 (Chm-1) expression between chondrocytes and MSCs. We found that chondrocytes expressed a high level of Chm-1. We then adenovirally transduced MSCs with Chm-1 and applied modified cells to engineer cartilage in vivo. A gross inspection and histological observation indicated that the chondrogenic phenotype of the tissue-engineered cartilage graft was well maintained, and the stable expression of Chm-1 was detected by immunohistological staining in the cartilage graft derived from the Chm-1 gene-modified MSCs. Our findings defined an essential role for Chm-1 in maintaining chondrogenic phenotype and demonstrated that Chm-1 gene-modified MSCs may be used in cartilage tissue engineering.

Translation of Genotype to Phenotype by a Hierarchy of Cell Subsystems.

PubMed

Yu, Michael Ku; Kramer, Michael; Dutkowski, Janusz; Srivas, Rohith; Licon, Katherine; Kreisberg, Jason; Ng, Cherie T; Krogan, Nevan; Sharan, Roded; Ideker, Trey

2016-02-24

Accurately translating genotype to phenotype requires accounting for the functional impact of genetic variation at many biological scales. Here we present a strategy for genotype-phenotype reasoning based on existing knowledge of cellular subsystems. These subsystems and their hierarchical organization are defined by the Gene Ontology or a complementary ontology inferred directly from previously published datasets. Guided by the ontology's hierarchical structure, we organize genotype data into an "ontotype," that is, a hierarchy of perturbations representing the effects of genetic variation at multiple cellular scales. The ontotype is then interpreted using logical rules generated by machine learning to predict phenotype. This approach substantially outperforms previous, non-hierarchical methods for translating yeast genotype to cell growth phenotype, and it accurately predicts the growth outcomes of two new screens of 2,503 double gene knockouts impacting DNA repair or nuclear lumen. Ontotypes also generalize to larger knockout combinations, setting the stage for interpreting the complex genetics of disease.

From genotype to phenotype: genetics and medical practice in the new millennium.

PubMed Central

Weatherall, D

1999-01-01

The completion of the human genome project will provide a vast amount of information about human genetic diversity. One of the major challenges for the medical sciences will be to relate genotype to phenotype. Over recent years considerable progress has been made in relating the molecular pathology of monogenic diseases to the associated clinical phenotypes. Studies of the inherited disorders of haemoglobin, notably the thalassaemias, have shown how even in these, the simplest of monogenic diseases, there is remarkable complexity with respect to their phenotypic expression. Although studies of other monogenic diseases are less far advanced, it is clear that the same level of complexity will exist. This information provides some indication of the difficulties that will be met when trying to define the genes that are involved in common multigenic disorders and, in particular, in trying to relate disease phenotypes to the complex interactions between many genes and multiple environmental factors. PMID:10670020

Pancreatic Autoantibodies Against CUZD1 and GP2 Are Associated with Distinct Clinical Phenotypes of Crohn's Disease.

PubMed

Michaels, Maike Anna; Jendrek, Sebastian Torben; Korf, Tobias; Nitzsche, Thomas; Teegen, Bianca; Komorowski, Lars; Derer, Stefanie; Schröder, Torsten; Baer, Florian; Lehnert, Henrik; Büning, Jürgen; Fellerman, Klaus; Sina, Christian

2015-12-01

Inflammatory bowel disease (IBD) is characterized by a broad spectrum of clinical phenotypes with different outcomes. In the last decades, several IBD-associated autoantibodies have been identified and investigated for their diagnostic relevance. Autoantibodies against the pancreatic glycoproteins (PAB) CUB and zona pellucida-like domains-containing protein 1 (CUZD1), and glycoprotein 2 (GP2) have been demonstrated to possess high specificity for the diagnosis of IBD. Although several studies have shown significant interrelations of anti-GP2 positivity with disease phenotype, associations of clinical phenotypes with anti-CUZD1 are still unknown. The aim was to identify the association of clinical phenotypes with anti-CUZD1 and anti-GP2 in a well-defined German IBD cohort. Patients with IBD (224 patients with Crohn's disease and 136 patients with ulcerative colitis), who were tested for anti-GP2 and anti-CUZD1 immunoglobulin G and immunoglobulin A by indirect immunofluorescence on transfected cells between 2005 and 2013, were included. Serotype and specified phenotypic data were collected in retrospect and statistically analyzed. Both anti-GP2 (P < 0.001) and anti-CUZD1 (P < 0.001) were significantly more prevalent in patients with Crohn's disease than in ulcerative colitis. PAB positivity was associated with ileocolonic disease (P = 0.002), perianal disease (P = 0.011), immunosuppressive treatment (P = 0.036), and ASCA positivity (P = 0.036). Anti-CUZD1 positivity was associated with ileocolonic (P = 0.016) and perianal disease (P = 0.002), whereas anti-GP2 positivity was positively associated with stricturing behavior (P = 0.016). We found distinct clinical phenotypes to be associated with PAB positivity. Therefore, determination of PABs and their subgroup analysis might identify patients with complicated disease behavior. However, the clinical relevance of our findings should be further evaluated in prospective cohorts.

Craniofacial and Dental Development in Costello Syndrome

PubMed Central

Goodwin, Alice F.; Oberoi, Snehlata; Landan, Maya; Charles, Cyril; Massie, Jessica C.; Fairley, Cecilia; Rauen, Katherine A.; Klein, Ophir D.

2014-01-01

Costello syndrome (CS) is a RASopathy characterized by a wide range of cardiac, musculoskeletal, dermatological, and developmental abnormalities. The RASopathies are defined as a group of syndromes caused by activated Ras/mitogen-activated protein kinase (MAPK) signaling. Specifically, CS is caused by activating mutations in HRAS. Although receptor tyrosine kinase (RTK) signaling, which is upstream of Ras/MAPK, is known to play a critical role in craniofacial and dental development, the craniofacial and dental features of CS have not been systematically defined in a large group of individuals. In order to address this gap in our understanding and fully characterize the CS phenotype, we evaluated the craniofacial and dental phenotype in a large cohort (n=41) of CS individuals. We confirmed that the craniofacial features common in CS include macrocephaly, bitemporal narrowing, convex facial profile, full cheeks, and large mouth. Additionally, CS patients have a characteristic dental phenotype that includes malocclusion with anterior open bite and posterior crossbite, enamel hypo-mineralization, delayed tooth development and eruption, gingival hyperplasia, thickening of the alveolar ridge, and high palate. Comparison of the craniofacial and dental phenotype in CS with other RASopathies, such as cardio-facio-cutaneous syndrome (CFC), provides insight into the complexities of Ras/MAPK signaling in human craniofacial and dental development. PMID:24668879

The impact of ex vivo clinical grade activation protocols on human T-cell phenotype and function for the generation of genetically modified cells for adoptive cell transfer therapy.

PubMed

Tumeh, Paul C; Koya, Richard C; Chodon, Thinle; Graham, Nicholas A; Graeber, Thomas G; Comin-Anduix, Begoña; Ribas, Antoni

2010-10-01

Optimized conditions for the ex vivo activation, genetic manipulation, and expansion of human lymphocytes for adoptive cell therapy may lead to protocols that maximize their in vivo function. We analyzed the effects of 4 clinical grade activation and expansion protocols over 3 weeks on cell proliferative rate, immunophenotype, cell metabolism, and transduction efficiency of human peripheral blood mononuclear cells (PBMCs). Peak lentiviral transduction efficiency was early (days 2 to 4), at a time when cells showed a larger size, maximal uptake of metabolic substrates, and the highest level of proximal T-cell receptor signaling engagement. Anti-CD2/3/28 activation beads induced greater proliferation rate and skewed PBMCs early on to a CD4 phenotype when compared with the cells cultured in OKT3. Multicolor surface phenotyping demonstrated that changes in T-cell surface markers that define T-cell functional phenotypes were dependent on the time spent in culture as opposed to the particular activation protocol. In conclusion, ex vivo activation of human PBMCs for adoptive cell therapy demonstrate defined immunophenotypic and functional signatures over time, with cells early on showing larger sizes, higher transduction efficiency, maximal metabolic activity, and zeta-chain-associated protein-70 activation.

Craniofacial and dental development in Costello syndrome.

PubMed

Goodwin, Alice F; Oberoi, Snehlata; Landan, Maya; Charles, Cyril; Massie, Jessica C; Fairley, Cecilia; Rauen, Katherine A; Klein, Ophir D

2014-06-01

Costello syndrome (CS) is a RASopathy characterized by a wide range of cardiac, musculoskeletal, dermatological, and developmental abnormalities. The RASopathies are defined as a group of syndromes caused by activated Ras/mitogen-activated protein kinase (MAPK) signaling. Specifically, CS is caused by activating mutations in HRAS. Although receptor tyrosine kinase (RTK) signaling, which is upstream of Ras/MAPK, is known to play a critical role in craniofacial and dental development, the craniofacial and dental features of CS have not been systematically defined in a large group of individuals. In order to address this gap in our understanding and fully characterize the CS phenotype, we evaluated the craniofacial and dental phenotype in a large cohort (n = 41) of CS individuals. We confirmed that the craniofacial features common in CS include macrocephaly, bitemporal narrowing, convex facial profile, full cheeks, and large mouth. Additionally, CS patients have a characteristic dental phenotype that includes malocclusion with anterior open bite and posterior crossbite, enamel hypo-mineralization, delayed tooth development and eruption, gingival hyperplasia, thickening of the alveolar ridge, and high palate. Comparison of the craniofacial and dental phenotype in CS with other RASopathies, such as cardio-facio-cutaneous syndrome (CFC), provides insight into the complexities of Ras/MAPK signaling in human craniofacial and dental development. © 2014 Wiley Periodicals, Inc.

The impact of ex vivo clinical grade activation protocols on human T cell phenotype and function for the generation of genetically modified cells for adoptive cell transfer therapy

PubMed Central

Tumeh, Paul C.; Koya, Richard C.; Chodon, Thinle; Graham, Nicholas A.; Graeber, Thomas G.; Comin-Anduix, Begoña; Ribas, Antoni

2011-01-01

Optimized conditions for the ex vivo activation, genetic manipulation, and expansion of human lymphocytes for adoptive cell therapy (ACT) may lead to protocols that maximize their in vivo function. We analyzed the effects of four clinical grade activation and expansion protocols over three weeks on cell proliferative rate, immunophenotype, cell metabolism, and transduction efficiency of human peripheral blood mononuclear cells (PBMCs). Peak lentiviral transduction efficiency was early (days 2 to 4), at a time when cells demonstrated a larger size, maximal uptake of metabolic substrates, and the highest level of proximal TCR signaling engagement. Anti-CD2/3/28 activation beads induced greater proliferation rate and skewed PBMCs early on to a CD4 phenotype when compared to the cells cultured in OKT3. Multicolor surface phenotyping demonstrated that changes in T cell surface markers that define T cell functional phenotypes were dependent on the time spent in culture as opposed to the particular activation protocol. In conclusion, ex vivo activation of human PBMCs for ACT demonstrate defined immunophenotypic and functional signatures over time, with cells early on showing larger sizes, higher transduction efficiency, maximal metabolic activity and ZAP-70 activation. PMID:20842061

Critical thoughts on current rodent models for evaluating potential treatments of alcohol addiction and withdrawal

PubMed Central

Ripley, Tamzin L; Stephens, David N

2011-01-01

Despite years of neurobiological research that have helped to identify potential therapeutic targets, we do not have a reliable pharmacological treatment for alcoholism. There are a range of possible explanations for this failure, including arguments that alcoholism is a spectrum disorder and that different population subtypes may respond to different treatments. This view is supported by categorisations such as early- and late-onset alcoholism, whilst multifactorial genetic factors may also alter responsivity to pharmacological agents. Furthermore, experience of alcohol withdrawal may play a role in future drinking in a way that may distinguish alcoholism from other forms of addiction. Additionally, our neurobiological models, based largely upon results from rodent studies, may not mimic specific aspects of the human condition and may reflect different underlying phenomena and biological processes from the clinical pattern. As a result, potential treatments may be targeting inappropriate aspects of alcohol-related behaviours. Instead, we suggest a more profitable approach is (a) to identify well-defined intermediate behavioural phenotypes in human experimental models that reflect defined aspects of the human clinical disorder and (b) to develop animal models that are homologous with those phenotypes in terms of psychological processes and underlying neurobiological mechanisms. This review describes an array of animal models currently used in the addiction field and what they tell us about alcoholism. We will then examine how established pharmacological agents have been developed using only a limited number of these models, before describing some alternative novel approaches to achieving homology between animal and human experimental measures. LINKED ARTICLES This article is part of a themed issue on Translational Neuropharmacology. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.164.issue-4 PMID:21470204

Analysis of adenovirus-induced immunity to infection with Listeria monocytogenes: Fading protection coincides with declining CD8 T cell numbers and phenotypic changes.

PubMed

Jahn, Marie Louise; Steffensen, Maria Abildgaard; Christensen, Jan Pravsgaard; Thomsen, Allan Randrup

2018-05-11

Defining correlates of T cell mediated protection is important in order to accelerate the development of efficient T cell based vaccines conferring long-term immunity. Extensive studies have provided important insight regarding the characteristics and functional properties of the effector and memory CD8 T cells induced by viral vector based vaccines. However, long-term protection has been difficult to achieve with T cell inducing vaccines, and the determinants underlying this loss in protection over time are still not fully defined. In this study we analyzed different parameters of the CD8 T cell response as a function of time after vaccination with a human serotype 5 adenovector expressing the glycoprotein (GP) of LCMV tethered to the MHC class II-associated invariant chain. Using this vector we have previously found that CD8 T cells mediate protection from challenge with GP-expressing Listeria monocytogenes at 60 days post vaccination, but only little protection after further 60 days, and we now confirm this observation. A comparison of vaccine-primed CD8 T cells early and late after vaccination revealed a minor decline in the overall numbers of antigen specific memory CD8 T cells during this interval. More importantly, we also observed phenotypic changes over time with a distinct decline in the frequency and number of KLRG1 + CD8 T cells, and, notably, adoptive transfer studies confirmed that memory CD8 T cells expressing KLRG1 are central to protection from systemic L. monocytogenes infection. Together these findings imply that multiple factors including changes in memory T cell numbers and phenotypic composition over time influence the longevity of CD8 T-cell mediated protection. Copyright © 2018 Elsevier Ltd. All rights reserved.

Clinical spectrum of Castleman disease–associated neuropathy

PubMed Central

Naddaf, Elie; Dispenzieri, Angela; Mandrekar, Jay

2016-01-01

Objective: To define the peripheral neuropathy phenotypes associated with Castleman disease. Methods: We conducted a retrospective chart review for patients with biopsy-proven Castleman disease evaluated between January 2003 and December 2014. Patients with associated peripheral neuropathy were identified and divided into 2 groups: those with Castleman disease without POEMS syndrome (CD-PN) and those with Castleman disease with POEMS syndrome (CD-POEMS). We used a cohort of patients with POEMS as controls. Clinical, electrodiagnostic, and laboratory characteristics were collected and compared among patient subgroups. Results: There were 7 patients with CD-PN, 20 with CD-POEMS, and 122 with POEMS. Patients with CD-PN had the mildest neuropathy characterized by predominant sensory symptoms with no pain and mild distal sensory deficits (median Neuropathy Impairment Score of 7 points). Although both patients with CD-POEMS and patients with POEMS had a severe sensory and motor neuropathy, patients with CD-POEMS were less affected (median Neuropathy Impairment Score of 33 and 66 points, respectively). The degree of severity was also reflected on electrodiagnostic testing in which patients with CD-PN demonstrated a mild degree of axonal loss, followed by patients with CD-POEMS and then those with POEMS. Demyelinating features, defined by European Federation of Neurologic Societies/Peripheral Nerve Society criteria, were present in 43% of the CD-PN, 78% of the CD-POEMS, and 86% of the POEMS group. Conclusion: There is a spectrum of demyelinating peripheral neuropathies associated with Castleman disease. CD-PN is sensory predominant and is the mildest phenotype, whereas CD-POEMS is a more severe sensory and motor neuropathy. Compared to the POEMS cohort, those with CD-POEMS neuropathy have a similar but less severe phenotype. Whether these patients respond differently to treatment deserves further study. PMID:27807187

Clinical spectrum of Castleman disease-associated neuropathy.

PubMed

Naddaf, Elie; Dispenzieri, Angela; Mandrekar, Jay; Mauermann, Michelle L

2016-12-06

To define the peripheral neuropathy phenotypes associated with Castleman disease. We conducted a retrospective chart review for patients with biopsy-proven Castleman disease evaluated between January 2003 and December 2014. Patients with associated peripheral neuropathy were identified and divided into 2 groups: those with Castleman disease without POEMS syndrome (CD-PN) and those with Castleman disease with POEMS syndrome (CD-POEMS). We used a cohort of patients with POEMS as controls. Clinical, electrodiagnostic, and laboratory characteristics were collected and compared among patient subgroups. There were 7 patients with CD-PN, 20 with CD-POEMS, and 122 with POEMS. Patients with CD-PN had the mildest neuropathy characterized by predominant sensory symptoms with no pain and mild distal sensory deficits (median Neuropathy Impairment Score of 7 points). Although both patients with CD-POEMS and patients with POEMS had a severe sensory and motor neuropathy, patients with CD-POEMS were less affected (median Neuropathy Impairment Score of 33 and 66 points, respectively). The degree of severity was also reflected on electrodiagnostic testing in which patients with CD-PN demonstrated a mild degree of axonal loss, followed by patients with CD-POEMS and then those with POEMS. Demyelinating features, defined by European Federation of Neurologic Societies/Peripheral Nerve Society criteria, were present in 43% of the CD-PN, 78% of the CD-POEMS, and 86% of the POEMS group. There is a spectrum of demyelinating peripheral neuropathies associated with Castleman disease. CD-PN is sensory predominant and is the mildest phenotype, whereas CD-POEMS is a more severe sensory and motor neuropathy. Compared to the POEMS cohort, those with CD-POEMS neuropathy have a similar but less severe phenotype. Whether these patients respond differently to treatment deserves further study. © 2016 American Academy of Neurology.

Common variant rs356182 near SNCA defines a Parkinson's disease endophenotype.

PubMed

Cooper, Christine A; Jain, Nimansha; Gallagher, Michael D; Weintraub, Daniel; Xie, Sharon X; Berlyand, Yosef; Espay, Alberto J; Quinn, Joseph; Edwards, Karen L; Montine, Thomas; Van Deerlin, Vivianna M; Trojanowski, John; Zabetian, Cyrus P; Chen-Plotkin, Alice S

2017-01-01

Parkinson's disease (PD) presents clinically with several motor subtypes that exhibit variable treatment response and prognosis. Here, we investigated genetic variants for their potential association with PD motor phenotype and progression. We screened 10 SNPs, previously associated with PD risk, for association with tremor-dominant (TD) versus postural-instability gait disorder (PIGD) motor subtypes. SNPs that correlated with the TD/PIGD ratio in a discovery cohort of 251 PD patients were then evaluated in a multi-site replication cohort of 559 PD patients. SNPs associated with motor phenotype in both cross-sectional cohorts were next evaluated for association with (1) rates of motor progression in a longitudinal subgroup of 230 PD patients and (2) brain alpha-synuclein ( SNCA ) expression in the GTEx (Genotype-Tissue Expression project) consortium database. Genotype at rs356182, near SNCA , correlated with the TD/PIGD ratio in both the discovery (Bonferroni-corrected P = 0.04) and replication cohorts ( P = 0.02). The rs356182 GG genotype was associated with a more tremor-predominant phenotype and predicted a slower rate of motor progression (1-point difference in annual rate of UPDRS-III motor score change, P = 0.01). The rs356182 genotype was associated with SNCA expression in the cerebellum ( P = 0.005). Our study demonstrates that the GG genotype at rs356182 provides molecular definition for a clinically important endophenotype associated with (1) more tremor-predominant motor phenomenology, (2) slower rates of motor progression, and (3) decreased brain expression of SNCA . Such molecularly defined endophenotyping in PD may benefit both clinical trial design and tailoring of clinical care as we enter the era of precision medicine.

Panton-valentine leukocidin-positive and toxic shock syndrome toxin 1-positive methicillin-resistant Staphylococcus aureus: a French multicenter prospective study in 2008.

PubMed

Robert, Jérôme; Tristan, Anne; Cavalié, Laurent; Decousser, Jean-Winoc; Bes, Michèle; Etienne, Jerome; Laurent, Frédéric

2011-04-01

The epidemiology of community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) differs from country to country. We assess the features of the ST80 European clone, which is the most prevalent PVL-positive CA-MRSA clone in Europe, and the TSST-1 ST5 clone that was recently described in France. In 2008, all MRSA strains susceptible to fluoroquinolones and gentamicin and resistant to fusidic acid that were isolated in 104 French laboratories were characterized using agr alleles, spa typing, and the staphylococcal cassette chromosome mec element and PCR profiling of 21 toxin genes. Three phenotypes were defined: (i) kanamycin resistant, associated with the ST80 clone; (ii) kanamycin and tobramycin resistant, associated with the ST5 clone; and (iii) aminoglycoside susceptible, which was less frequently associated with the ST5 clone. Among the 7,253 MRSA strains isolated, 91 (1.3%) were ST80 CA-MRSA (89 phenotype 1) and 190 (2.6%) were ST5 CA-MRSA (146 phenotype 2, 42 phenotype 3). Compared to the latter, ST80 CA-MRSAs were more likely to be community acquired (80% versus 46%) and found in young patients (median age, 26.0 years versus 49.5 years) with deep cutaneous infections (48% versus 6%). They were less likely to be tetracycline susceptible (22% versus 85%) and to be isolated from respiratory infections (6% versus 27%). The TSST-1 ST5 clone has rapidly emerged in France and has become even more prevalent than the ST80 European clone, whose prevalence has remained stable. The epidemiological and clinical patterns of the two clones differ drastically. Given the low prevalence of both among all staphylococcal infections, no modification of antibiotic recommendations is required yet.

A mesenchymal-like phenotype and expression of CD44 predict lack of apoptotic response to sorafenib in liver tumor cells.

PubMed

Fernando, Joan; Malfettone, Andrea; Cepeda, Edgar B; Vilarrasa-Blasi, Roser; Bertran, Esther; Raimondi, Giulia; Fabra, Àngels; Alvarez-Barrientos, Alberto; Fernández-Salguero, Pedro; Fernández-Rodríguez, Conrado M; Giannelli, Gianluigi; Sancho, Patricia; Fabregat, Isabel

2015-02-15

The multikinase inhibitor sorafenib is the only effective drug in advanced cases of hepatocellular carcinoma (HCC). However, response differs among patients and effectiveness only implies a delay. We have recently described that sorafenib sensitizes HCC cells to apoptosis. In this work, we have explored the response to this drug of six different liver tumor cell lines to define a phenotypic signature that may predict lack of response in HCC patients. Results have indicated that liver tumor cells that show a mesenchymal-like phenotype, resistance to the suppressor effects of transforming growth factor beta (TGF-β) and high expression of the stem cell marker CD44 were refractory to sorafenib-induced cell death in in vitro studies, which correlated with lack of response to sorafenib in nude mice xenograft models of human HCC. In contrast, epithelial-like cells expressing the stem-related proteins EpCAM or CD133 were sensitive to sorafenib-induced apoptosis both in vitro and in vivo. A cross-talk between the TGF-β pathway and the acquisition of a mesenchymal-like phenotype with up-regulation of CD44 expression was found in the HCC cell lines. Targeted CD44 knock-down in the mesenchymal-like cells indicated that CD44 plays an active role in protecting HCC cells from sorafenib-induced apoptosis. However, CD44 effect requires a TGF-β-induced mesenchymal background, since the only overexpression of CD44 in epithelial-like HCC cells is not sufficient to impair sorafenib-induced cell death. In conclusion, a mesenchymal profile and expression of CD44, linked to activation of the TGF-β pathway, may predict lack of response to sorafenib in HCC patients. © 2014 UICC.

Dynamic species classification of microorganisms across time, abiotic and biotic environments—A sliding window approach

PubMed Central

Griffiths, Jason I.; Fronhofer, Emanuel A.; Garnier, Aurélie; Seymour, Mathew; Altermatt, Florian; Petchey, Owen L.

2017-01-01

The development of video-based monitoring methods allows for rapid, dynamic and accurate monitoring of individuals or communities, compared to slower traditional methods, with far reaching ecological and evolutionary applications. Large amounts of data are generated using video-based methods, which can be effectively processed using machine learning (ML) algorithms into meaningful ecological information. ML uses user defined classes (e.g. species), derived from a subset (i.e. training data) of video-observed quantitative features (e.g. phenotypic variation), to infer classes in subsequent observations. However, phenotypic variation often changes due to environmental conditions, which may lead to poor classification, if environmentally induced variation in phenotypes is not accounted for. Here we describe a framework for classifying species under changing environmental conditions based on the random forest classification. A sliding window approach was developed that restricts temporal and environmentally conditions to improve the classification. We tested our approach by applying the classification framework to experimental data. The experiment used a set of six ciliate species to monitor changes in community structure and behavior over hundreds of generations, in dozens of species combinations and across a temperature gradient. Differences in biotic and abiotic conditions caused simplistic classification approaches to be unsuccessful. In contrast, the sliding window approach allowed classification to be highly successful, as phenotypic differences driven by environmental change, could be captured by the classifier. Importantly, classification using the random forest algorithm showed comparable success when validated against traditional, slower, manual identification. Our framework allows for reliable classification in dynamic environments, and may help to improve strategies for long-term monitoring of species in changing environments. Our classification pipeline can be applied in fields assessing species community dynamics, such as eco-toxicology, ecology and evolutionary ecology. PMID:28472193

Impact of human immunodeficiency virus type 1 reverse transcriptase inhibitor drug resistance mutation interactions on phenotypic susceptibility.

PubMed

Trivedi, Vinod; Von Lindern, Jana; Montes-Walters, Miguel; Rojo, Daniel R; Shell, Elisabeth J; Parkin, Neil; O'Brien, William A; Ferguson, Monique R

2008-10-01

The role specific reverse transcriptase (RT) drug resistance mutations play in influencing phenotypic susceptibility to RT inhibitors in virus strains with complex resistance interaction patterns was assessed using recombinant viruses that consisted of RT-PCR-amplified pol fragments derived from plasma HIV-1 RNA from two treatment-experienced patients. Specific modifications of key RT amino acids were performed by site-directed mutagenesis. A panel of viruses with defined genotypic resistance mutations was assessed for phenotypic drug resistance. Introduction of M184V into several different clones expressing various RT resistance mutations uniformly decreased susceptibility to abacavir, lamivudine, and didanosine, and increased susceptibility to zidovudine, stavudine, and tenofovir; replication capacity was decreased. The L74V mutation had similar but slightly different effects, contributing to decreased susceptibility to abacavir, lamivudine, and didanosine and increased susceptibility to zidovudine and tenofovir, but in contrast to M184V, L74V contributed to decreased susceptibility to stavudine. In virus strains with the nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations K101E and G190S, the L74V mutation increased replication capacity, consistent with published observations, but replication capacity was decreased in strains without NNRTI resistance mutations. K101E and G190S together tend to decrease susceptibility to all nucleoside RT inhibitors, but the K103N mutation had little effect on nucleoside RT inhibitor susceptibility. Mutational interactions can have a substantial impact on drug resistance phenotype and replication capacity, and this has been exploited in clinical practice with the development of fixed-dose combination pills. However, we are the first to report these mutational interactions using molecularly cloned recombinant strains derived from viruses that occur naturally in HIV-infected individuals.

Impact of Human Immunodeficiency Virus Type 1 Reverse Transcriptase Inhibitor Drug Resistance Mutation Interactions on Phenotypic Susceptibility

PubMed Central

Trivedi, Vinod; Von Lindern, Jana; Montes-Walters, Miguel; Rojo, Daniel R.; Shell, Elisabeth J.; Parkin, Neil; O'Brien, William A.

2008-01-01

Abstract The role specific reverse transcriptase (RT) drug resistance mutations play in influencing phenotypic susceptibility to RT inhibitors in virus strains with complex resistance interaction patterns was assessed using recombinant viruses that consisted of RT-PCR-amplified pol fragments derived from plasma HIV-1 RNA from two treatment-experienced patients. Specific modifications of key RT amino acids were performed by site-directed mutagenesis. A panel of viruses with defined genotypic resistance mutations was assessed for phenotypic drug resistance. Introduction of M184V into several different clones expressing various RT resistance mutations uniformly decreased susceptibility to abacavir, lamivudine, and didanosine, and increased susceptibility to zidovudine, stavudine, and tenofovir; replication capacity was decreased. The L74V mutation had similar but slightly different effects, contributing to decreased susceptibility to abacavir, lamivudine, and didanosine and increased susceptibility to zidovudine and tenofovir, but in contrast to M184V, L74V contributed to decreased susceptibility to stavudine. In virus strains with the nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations K101E and G190S, the L74V mutation increased replication capacity, consistent with published observations, but replication capacity was decreased in strains without NNRTI resistance mutations. K101E and G190S together tend to decrease susceptibility to all nucleoside RT inhibitors, but the K103N mutation had little effect on nucleoside RT inhibitor susceptibility. Mutational interactions can have a substantial impact on drug resistance phenotype and replication capacity, and this has been exploited in clinical practice with the development of fixed-dose combination pills. However, we are the first to report these mutational interactions using molecularly cloned recombinant strains derived from viruses that occur naturally in HIV-infected individuals. PMID:18844463

Indirect genetic effect model using feeding behaviour traits to define the degree of interaction between mates: an implementation in pigs growth rate.

PubMed

Ragab, M; Piles, M; Quintanilla, R; Sánchez, J P

2018-06-06

An alternative implementation of the animal model including indirect genetic effect (IGE) is presented considering pair-mate-specific interaction degrees to improve the performance of the model. Data consisted of average daily gain (ADG) records from 663 pigs kept in groups of 10 to 14 mates during the fattening period. Three types of models were used to fit ADG data: (i) animal model (AM); (ii) AM with classical IGE (AM-IGE); and (iii) AM fitting IGE with a specific degree of interaction between each pair of mates (AM-IGEi). Several feeding behavior phenotypes were used to define the pair-mate-specific degree of interaction in AM-IGEi: feeding rate (g/min), feeding frequency (min/day), the time between consecutive visits to the feeder (min/day), occupation time (min/day) and an index considering all these variables. All models included systematic effects batch, initial age (covariate), final age (covariate), number of pigs per pen (covariate), plus the random effect of the pen. Estimated posterior mean (posterior SD) of heritability was 0.47 (0.15) using AM. Including social genetic effects in the model, total heritable variance expressed as a proportion of total phenotypic variance (T 2) was 0.54 (0.29) using AM-IGE, whereas it ranged from 0.51 to 0.55 (0.12 to 0.14) with AM-IGEi, depending on the behavior trait used to define social interactions. These results confirm the contribution of IGEs to the total heritable variation of ADG. Moreover, important differences between models were observed in EBV rankings. The percentage of coincidence of top 10% animals between AM and AM-IGEi ranged from 0.44 to 0.89 and from 0.41to 0.68 between AM-IGE and AM-IGEi. Based on the goodness of fit and predictive ability, social models are preferred for the genetic evaluation of ADG. Among models including IGEs, when the pair-specific degree of interaction was defined using feeding behavior phenotypes we obtained an increase in the accuracy of genetic parameters estimates, the better goodness of fit and higher predictive ability. We conclude that feeding behavior variables can be used to measure the interaction between pen mates and to improve the performance of models including IGEs.

Recurrent mutations in the CDKL5 gene: genotype-phenotype relationships.

PubMed

Bahi-Buisson, Nadia; Villeneuve, Nathalie; Caietta, Emilie; Jacquette, Aurélia; Maurey, Helene; Matthijs, Gert; Van Esch, Hilde; Delahaye, Andrée; Moncla, Anne; Milh, Mathieu; Zufferey, Flore; Diebold, Bertrand; Bienvenu, Thierry

2012-07-01

Mutations in the cyclin-dependent kinase-like 5 gene (CDKL5) have been described in epileptic encephalopathies in females with infantile spasms with features that overlap with Rett syndrome. With more than 80 reported patients, the phenotype of CDKL5-related encephalopathy is well-defined. The main features consist of seizures starting before 6 months of age, severe intellectual disability with absent speech and hand stereotypies and deceleration of head growth, which resembles Rett syndrome. However, some clinical discrepancies suggested the influence of genetics and/or environmental factors. No genotype-phenotype correlation has been defined and thus there is a need to examine individual mutations. In this study, we analyzed eight recurrent CDKL5 mutations to test whether the clinical phenotype of patients with the same mutation is similar and whether patients with specific CDKL5 mutations have a milder phenotype than those with other CDKL5 mutations. Patients bearing missense mutations in the ATP binding site such as the p.Ala40Val mutation typically walked unaided, had normocephaly, better hand use ability, and less frequent refractory epilepsy when compared to girls with other CDKL5 mutations. In contrast, patients with mutations in the kinase domain (such as p.Arg59X, p.Arg134X, p.Arg178Trp/Pro/Gln, or c.145 + 2T > C) and frameshift mutations in the C-terminal region (such as c.2635_2636delCT) had a more severe phenotype with infantile spasms, refractory epileptic encephalopathy, absolute microcephaly, and inability to walk. It is important for clinicians to have this information when such patients are diagnosed. Copyright © 2012 Wiley Periodicals, Inc.

Optimizing experimental procedures for quantitative evaluation of crop plant performance in high throughput phenotyping systems

PubMed Central

Junker, Astrid; Muraya, Moses M.; Weigelt-Fischer, Kathleen; Arana-Ceballos, Fernando; Klukas, Christian; Melchinger, Albrecht E.; Meyer, Rhonda C.; Riewe, David; Altmann, Thomas

2015-01-01

Detailed and standardized protocols for plant cultivation in environmentally controlled conditions are an essential prerequisite to conduct reproducible experiments with precisely defined treatments. Setting up appropriate and well defined experimental procedures is thus crucial for the generation of solid evidence and indispensable for successful plant research. Non-invasive and high throughput (HT) phenotyping technologies offer the opportunity to monitor and quantify performance dynamics of several hundreds of plants at a time. Compared to small scale plant cultivations, HT systems have much higher demands, from a conceptual and a logistic point of view, on experimental design, as well as the actual plant cultivation conditions, and the image analysis and statistical methods for data evaluation. Furthermore, cultivation conditions need to be designed that elicit plant performance characteristics corresponding to those under natural conditions. This manuscript describes critical steps in the optimization of procedures for HT plant phenotyping systems. Starting with the model plant Arabidopsis, HT-compatible methods were tested, and optimized with regard to growth substrate, soil coverage, watering regime, experimental design (considering environmental inhomogeneities) in automated plant cultivation and imaging systems. As revealed by metabolite profiling, plant movement did not affect the plants' physiological status. Based on these results, procedures for maize HT cultivation and monitoring were established. Variation of maize vegetative growth in the HT phenotyping system did match well with that observed in the field. The presented results outline important issues to be considered in the design of HT phenotyping experiments for model and crop plants. It thereby provides guidelines for the setup of HT experimental procedures, which are required for the generation of reliable and reproducible data of phenotypic variation for a broad range of applications. PMID:25653655

Morphology captures diet and locomotor types in rodents.

PubMed

Verde Arregoitia, Luis D; Fisher, Diana O; Schweizer, Manuel

2017-01-01

To understand the functional meaning of morphological features, we need to relate what we know about morphology and ecology in a meaningful, quantitative framework. Closely related species usually share more phenotypic features than distant ones, but close relatives do not necessarily have the same ecologies. Rodents are the most diverse group of living mammals, with impressive ecomorphological diversification. We used museum collections and ecological literature to gather data on morphology, diet and locomotion for 208 species of rodents from different bioregions to investigate how morphological similarity and phylogenetic relatedness are associated with ecology. After considering differences in body size and shared evolutionary history, we find that unrelated species with similar ecologies can be characterized by a well-defined suite of morphological features. Our results validate the hypothesized ecological relevance of the chosen traits. These cranial, dental and external (e.g. ears) characters predicted diet and locomotion and showed consistent differences among species with different feeding and substrate use strategies. We conclude that when ecological characters do not show strong phylogenetic patterns, we cannot simply assume that close relatives are ecologically similar. Museum specimens are valuable records of species' phenotypes and with the characters proposed here, morphology can reflect functional similarity, an important component of community ecology and macroevolution.

Identification of chronic rhinosinusitis phenotypes using cluster analysis.

PubMed

Soler, Zachary M; Hyer, J Madison; Ramakrishnan, Viswanathan; Smith, Timothy L; Mace, Jess; Rudmik, Luke; Schlosser, Rodney J

2015-05-01

Current clinical classifications of chronic rhinosinusitis (CRS) have been largely defined based upon preconceived notions of factors thought to be important, such as polyp or eosinophil status. Unfortunately, these classification systems have little correlation with symptom severity or treatment outcomes. Unsupervised clustering can be used to identify phenotypic subgroups of CRS patients, describe clinical differences in these clusters and define simple algorithms for classification. A multi-institutional, prospective study of 382 patients with CRS who had failed initial medical therapy completed the Sino-Nasal Outcome Test (SNOT-22), Rhinosinusitis Disability Index (RSDI), Medical Outcomes Study Short Form-12 (SF-12), Pittsburgh Sleep Quality Index (PSQI), and Patient Health Questionnaire (PHQ-2). Objective measures of CRS severity included Brief Smell Identification Test (B-SIT), CT, and endoscopy scoring. All variables were reduced and unsupervised hierarchical clustering was performed. After clusters were defined, variations in medication usage were analyzed. Discriminant analysis was performed to develop a simplified, clinically useful algorithm for clustering. Clustering was largely determined by age, severity of patient reported outcome measures, depression, and fibromyalgia. CT and endoscopy varied somewhat among clusters. Traditional clinical measures, including polyp/atopic status, prior surgery, B-SIT and asthma, did not vary among clusters. A simplified algorithm based upon productivity loss, SNOT-22 score, and age predicted clustering with 89% accuracy. Medication usage among clusters did vary significantly. A simplified algorithm based upon hierarchical clustering is able to classify CRS patients and predict medication usage. Further studies are warranted to determine if such clustering predicts treatment outcomes. © 2015 ARS-AAOA, LLC.

Extensive Diversity of Prion Strains Is Defined by Differential Chaperone Interactions and Distinct Amyloidogenic Regions

PubMed Central

Stein, Kevin C.; True, Heather L.

2014-01-01

Amyloidogenic proteins associated with a variety of unrelated diseases are typically capable of forming several distinct self-templating conformers. In prion diseases, these different structures, called prion strains (or variants), confer dramatic variation in disease pathology and transmission. Aggregate stability has been found to be a key determinant of the diverse pathological consequences of different prion strains. Yet, it remains largely unclear what other factors might account for the widespread phenotypic variation seen with aggregation-prone proteins. Here, we examined a set of yeast prion variants of the [RNQ+] prion that differ in their ability to induce the formation of another yeast prion called [PSI+]. Remarkably, we found that the [RNQ+] variants require different, non-contiguous regions of the Rnq1 protein for both prion propagation and [PSI+] induction. This included regions outside of the canonical prion-forming domain of Rnq1. Remarkably, such differences did not result in variation in aggregate stability. Our analysis also revealed a striking difference in the ability of these [RNQ+] variants to interact with the chaperone Sis1. Thus, our work shows that the differential influence of various amyloidogenic regions and interactions with host cofactors are critical determinants of the phenotypic consequences of distinct aggregate structures. This helps reveal the complex interdependent factors that influence how a particular amyloid structure may dictate disease pathology and progression. PMID:24811344

Host-associated differences in morphometric traits of parasitic larvae Hirsutiella zachvatkini (Actinotrichida: Trombiculidae).

PubMed

Moniuszko, Hanna; Zaleśny, Grzegorz; Mąkol, Joanna

2015-09-01

Examination of host-associated variation in the chigger mite Hirsutiella zachvatkini (Schluger) revealed morphological differences among larvae infesting sympatric hosts: Apodemus agrarius, Apodemus flavicollis and Myodes glareolus. The analysis included 61 variables of larvae obtained from their gnathosoma, idiosoma and legs (measurements and counts). Statistically significant differences were observed for metric characters of the legs as opposed to the scutum. In view of the conspecificity of the mites, supported by comparison of COI gene products obtained from larvae and laboratory-reared deutonymphs, the observed variation is attributed to phenotypic plasticity. The knowledge of larval morphology, including intraspecific variation of metric characters, supported by molecular and host range data, places H. zachvatkini among the most comprehensively defined members of Trombiculidae.

Whole genome expression and biochemical correlates of extreme constitutional types defined in Ayurveda.

PubMed

Prasher, Bhavana; Negi, Sapna; Aggarwal, Shilpi; Mandal, Amit K; Sethi, Tav P; Deshmukh, Shailaja R; Purohit, Sudha G; Sengupta, Shantanu; Khanna, Sangeeta; Mohammad, Farhan; Garg, Gaurav; Brahmachari, Samir K; Mukerji, Mitali

2008-09-09

Ayurveda is an ancient system of personalized medicine documented and practiced in India since 1500 B.C. According to this system an individual's basic constitution to a large extent determines predisposition and prognosis to diseases as well as therapy and life-style regime. Ayurveda describes seven broad constitution types (Prakritis) each with a varying degree of predisposition to different diseases. Amongst these, three most contrasting types, Vata, Pitta, Kapha, are the most vulnerable to diseases. In the realm of modern predictive medicine, efforts are being directed towards capturing disease phenotypes with greater precision for successful identification of markers for prospective disease conditions. In this study, we explore whether the different constitution types as described in Ayurveda has molecular correlates. Normal individuals of the three most contrasting constitutional types were identified following phenotyping criteria described in Ayurveda in Indian population of Indo-European origin. The peripheral blood samples of these individuals were analysed for genome wide expression levels, biochemical and hematological parameters. Gene Ontology (GO) and pathway based analysis was carried out on differentially expressed genes to explore if there were significant enrichments of functional categories among Prakriti types. Individuals from the three most contrasting constitutional types exhibit striking differences with respect to biochemical and hematological parameters and at genome wide expression levels. Biochemical profiles like liver function tests, lipid profiles, and hematological parameters like haemoglobin exhibited differences between Prakriti types. Functional categories of genes showing differential expression among Prakriti types were significantly enriched in core biological processes like transport, regulation of cyclin dependent protein kinase activity, immune response and regulation of blood coagulation. A significant enrichment of housekeeping, disease related and hub genes were observed in these extreme constitution types. Ayurveda based method of phenotypic classification of extreme constitutional types allows us to uncover genes that may contribute to system level differences in normal individuals which could lead to differential disease predisposition. This is a first attempt towards unraveling the clinical phenotyping principle of a traditional system of medicine in terms of modern biology. An integration of Ayurveda with genomics holds potential and promise for future predictive medicine.

Whole genome expression and biochemical correlates of extreme constitutional types defined in Ayurveda

PubMed Central

Prasher, Bhavana; Negi, Sapna; Aggarwal, Shilpi; Mandal, Amit K; Sethi, Tav P; Deshmukh, Shailaja R; Purohit, Sudha G; Sengupta, Shantanu; Khanna, Sangeeta; Mohammad, Farhan; Garg, Gaurav; Brahmachari, Samir K; Mukerji, Mitali

2008-01-01

Background Ayurveda is an ancient system of personalized medicine documented and practiced in India since 1500 B.C. According to this system an individual's basic constitution to a large extent determines predisposition and prognosis to diseases as well as therapy and life-style regime. Ayurveda describes seven broad constitution types (Prakritis) each with a varying degree of predisposition to different diseases. Amongst these, three most contrasting types, Vata, Pitta, Kapha, are the most vulnerable to diseases. In the realm of modern predictive medicine, efforts are being directed towards capturing disease phenotypes with greater precision for successful identification of markers for prospective disease conditions. In this study, we explore whether the different constitution types as described in Ayurveda has molecular correlates. Methods Normal individuals of the three most contrasting constitutional types were identified following phenotyping criteria described in Ayurveda in Indian population of Indo-European origin. The peripheral blood samples of these individuals were analysed for genome wide expression levels, biochemical and hematological parameters. Gene Ontology (GO) and pathway based analysis was carried out on differentially expressed genes to explore if there were significant enrichments of functional categories among Prakriti types. Results Individuals from the three most contrasting constitutional types exhibit striking differences with respect to biochemical and hematological parameters and at genome wide expression levels. Biochemical profiles like liver function tests, lipid profiles, and hematological parameters like haemoglobin exhibited differences between Prakriti types. Functional categories of genes showing differential expression among Prakriti types were significantly enriched in core biological processes like transport, regulation of cyclin dependent protein kinase activity, immune response and regulation of blood coagulation. A significant enrichment of housekeeping, disease related and hub genes were observed in these extreme constitution types. Conclusion Ayurveda based method of phenotypic classification of extreme constitutional types allows us to uncover genes that may contribute to system level differences in normal individuals which could lead to differential disease predisposition. This is a first attempt towards unraveling the clinical phenotyping principle of a traditional system of medicine in terms of modern biology. An integration of Ayurveda with genomics holds potential and promise for future predictive medicine. PMID:18782426

Genotype–phenotype characteristics and baseline natural history of heritable neuropathies caused by mutations in the MPZ gene

PubMed Central

Feely, Shawna; Scherer, Steven S.; Herrmann, David N.; Burns, Joshua; Muntoni, Francesco; Li, Jun; Siskind, Carly E.; Day, John W.; Laura, Matilde; Sumner, Charlotte J.; Lloyd, Thomas E.; Ramchandren, Sindhu; Shy, Rosemary R.; Grider, Tiffany; Bacon, Chelsea; Finkel, Richard S.; Yum, Sabrina W.; Moroni, Isabella; Piscosquito, Giuseppe; Pareyson, Davide; Reilly, Mary M.; Shy, Michael E.

2015-01-01

We aimed to characterize genotype–phenotype correlations and establish baseline clinical data for peripheral neuropathies caused by mutations in the myelin protein zero (MPZ) gene. MPZ mutations are the second leading cause of Charcot–Marie–Tooth disease type 1. Recent research makes clinical trials for patients with MPZ mutations a realistic possibility. However, the clinical severity varies with different mutations and natural history data on progression is sparse. We present cross-sectional data to begin to define the phenotypic spectrum and clinical baseline of patients with these mutations. A cohort of patients with MPZ gene mutations was identified in 13 centres of the Inherited Neuropathies Consortium - Rare Disease Clinical Research Consortium (INC-RDCRC) between 2009 and 2012 and at Wayne State University between 1996 and 2009. Patient phenotypes were quantified by the Charcot–Marie–Tooth disease neuropathy score version 1 or 2 and the Charcot–Marie–Tooth disease paediatric scale outcome instruments. Genetic testing was performed in all patients and/or in first- or second-degree relatives to document mutation in MPZ gene indicating diagnosis of Charcot–Marie–Tooth disease type 1B. There were 103 patients from 71 families with 47 different MPZ mutations with a mean age of 40 years (range 3–84 years). Patients and mutations were separated into infantile, childhood and adult-onset groups. The infantile onset group had higher Charcot–Marie–Tooth disease neuropathy score version 1 or 2 and slower nerve conductions than the other groups, and severity increased with age. Twenty-three patients had no family history of Charcot–Marie–Tooth disease. Sixty-one patients wore foot/ankle orthoses, 19 required walking assistance or support, and 10 required wheelchairs. There was hearing loss in 21 and scoliosis in 17. Forty-two patients did not begin walking until after 15 months of age. Half of the infantile onset patients then required ambulation aids or wheelchairs for ambulation. Our results demonstrate that virtually all MPZ mutations are associated with specific phenotypes. Early onset (infantile and childhood) phenotypes likely represent developmentally impaired myelination, whereas the adult-onset phenotype reflects axonal degeneration without antecedent demyelination. Data from this cohort of patients will provide the baseline data necessary for clinical trials of patients with Charcot–Marie–Tooth disease caused by MPZ gene mutations. PMID:26310628

Yeast Phenomics: An Experimental Approach for Modeling Gene Interaction Networks that Buffer Disease

PubMed Central

Hartman, John L.; Stisher, Chandler; Outlaw, Darryl A.; Guo, Jingyu; Shah, Najaf A.; Tian, Dehua; Santos, Sean M.; Rodgers, John W.; White, Richard A.

2015-01-01

The genome project increased appreciation of genetic complexity underlying disease phenotypes: many genes contribute each phenotype and each gene contributes multiple phenotypes. The aspiration of predicting common disease in individuals has evolved from seeking primary loci to marginal risk assignments based on many genes. Genetic interaction, defined as contributions to a phenotype that are dependent upon particular digenic allele combinations, could improve prediction of phenotype from complex genotype, but it is difficult to study in human populations. High throughput, systematic analysis of S. cerevisiae gene knockouts or knockdowns in the context of disease-relevant phenotypic perturbations provides a tractable experimental approach to derive gene interaction networks, in order to deduce by cross-species gene homology how phenotype is buffered against disease-risk genotypes. Yeast gene interaction network analysis to date has revealed biology more complex than previously imagined. This has motivated the development of more powerful yeast cell array phenotyping methods to globally model the role of gene interaction networks in modulating phenotypes (which we call yeast phenomic analysis). The article illustrates yeast phenomic technology, which is applied here to quantify gene X media interaction at higher resolution and supports use of a human-like media for future applications of yeast phenomics for modeling human disease. PMID:25668739

Experimental evidence for nutrition regulated stress resistance in Drosophila ananassae.

PubMed

Sisodia, Seema; Singh, Bashisth N

2012-01-01

The amount and quality of nutrients consumed by organisms have a strong impact on stress resistance, life-history traits and reproduction. The balance between energy acquisition and expenditure is crucial to the survival and reproductive success of animals. The ability of organisms to adjust their development, physiology or behavior in response to environmental conditions, called phenotypic plasticity, is a defining property of life. One of the most familiar and important examples of phenotypic plasticity is the response of stress tolerance and reproduction to changes in developmental nutrition. Larval nutrition may affect a range of different life-history traits as well as responses to environmental stress in adult. Here we investigate the effect of larval nutrition on desiccation, starvation, chill-coma recovery, heat resistance as well as egg to adult viability, egg production and ovariole number in Drosophila ananassae. We raised larvae on either protein rich diet or carbohydrate rich diet. We found that flies consuming protein rich diet have higher desiccation and heat shock resistance whereas flies developed on carbohydrate rich diet have higher starvation and cold resistance. Egg production was higher in females developed on protein rich diet and we also found trade-off between egg production and Egg to adult viability of the flies. Viability was higher in carbohydrate rich diet. However, sex specific viability was found in different nutritional regimes. Higher Egg production might be due to higher ovariole number in females of protein rich diet. Thus, Drosophila ananassae adapts different stress tolerance and life-history strategies according to the quality of the available diet, which are correlated with phenotypic adjustment at anatomical and physiological levels.

DNA fragmentation and nuclear phenotype in tendons exposed to low-intensity infrared laser

NASA Astrophysics Data System (ADS)

de Paoli, Flavia; Ramos Cerqueira, Larissa; Martins Ramos, Mayara; Campos, Vera M.; Ferreira-Machado, Samara C.; Geller, Mauro; de Souza da Fonseca, Adenilson

2015-03-01

Clinical protocols are recommended in device guidelines outlined for treating many diseases on empirical basis. However, effects of low-intensity infrared lasers at fluences used in clinical protocols on DNA are controversial. Excitation of endogenous chromophores in tissues and free radicals generation could be described as a consequence of laser used. DNA lesions induced by free radicals cause changes in DNA structure, chromatin organization, ploidy degrees and cell death. In this work, we investigated whether low-intensity infrared laser therapy could alter the fibroblasts nuclei characteristics and induce DNA fragmentation. Tendons of Wistar rats were exposed to low-intensity infrared laser (830 nm), at different fluences (1, 5 and 10 J/cm2), in continuous wave (power output of 10mW, power density of 79.6 mW/cm2). Different frequencies were analyzed for the higher fluence (10 J/cm2), at pulsed emission mode (2.5, 250 and 2500 Hz), with the laser source at surface of skin. Geometric, densitometric and textural parameters obtained for Feulgen-stained nuclei by image analysis were used to define nuclear phenotypes. Significant differences were observed on the nuclear phenotype of tendons after exposure to laser, as well as, high cell death percentages was observed for all fluences and frequencies analyzed here, exception 1 J/cm2 fluence. Our results indicate that low-intensity infrared laser can alter geometric, densitometric and textural parameters in tendon fibroblasts nuclei. Laser can also induce DNA fragmentation, chromatin lost and consequently cell death, using fluences, frequencies and emission modes took out from clinical protocols.

Diversity of Antimicrobial Resistance Phenotypes in Salmonella Isolated from Commercial Poultry Farms.

PubMed

Liljebjelke, Karen A; Hofacre, Charles L; White, David G; Ayers, Sherry; Lee, Margie D; Maurer, John J

2017-01-01

Salmonella remains the leading cause of foodborne illness in the United States, and the dissemination of drug-resistant Salmonellae through the food chain has important implications for treatment failure of salmonellosis. We investigated the ecology of Salmonella in integrated broiler production in order to understand the flow of antibiotic susceptible and resistant strains within this system. Data were analyzed from a retrospective study focused on antimicrobial resistant Salmonella recovered from commercial broiler chicken farms conducted during the initial years of the US FDA's foray into retail meat surveillance by the National Antimicrobial Resistance Monitoring System (NARMS). Sixty-three percentage of Salmonella were pan-susceptible to a panel of 19 antimicrobials used by the NARMS program. Twenty-five antimicrobial resistance phenotypes were observed in Salmonella isolated from two broiler chicken farms. However, Salmonella displaying resistance to streptomycin, alone, and in combination with other antibiotics was the most prevalent (36.3%) antimicrobial resistance phenotype observed. Resistance to streptomycin and sulfadimethoxine appeared to be linked to the transposon, Tn 21 . Combinations of resistance against streptomycin, gentamicin, sulfadimethoxine, trimethoprim, and tetracycline were observed for a variety of Salmonella enterica serovars and genetic types as defined by pulsed-field gel electrophoresis. There were within and between farm differences in the antibiotic susceptibilities of Salmonella and some of these differences were linked to specific serovars. However, farm differences were not linked to antibiotic usage. Analysis of the temporal and spatial distribution of the endemic Salmonella serovars on these farms suggests that preventing vertical transmission of antibiotic-resistant Salmonella would reduce carcass contamination with antibiotic-resistant Salmonella and subsequently human risk exposure.

Genomic features separating ten strains of Neorhizobium galegae with different symbiotic phenotypes.

PubMed

Österman, Janina; Mousavi, Seyed Abdollah; Koskinen, Patrik; Paulin, Lars; Lindström, Kristina

2015-05-02

The symbiotic phenotype of Neorhizobium galegae, with strains specifically fixing nitrogen with either Galega orientalis or G. officinalis, has made it a target in research on determinants of host specificity in nitrogen fixation. The genomic differences between representative strains of the two symbiovars are, however, relatively small. This introduced a need for a dataset representing a larger bacterial population in order to make better conclusions on characteristics typical for a subset of the species. In this study, we produced draft genomes of eight strains of N. galegae having different symbiotic phenotypes, both with regard to host specificity and nitrogen fixation efficiency. These genomes were analysed together with the previously published complete genomes of N. galegae strains HAMBI 540T and HAMBI 1141. The results showed that the presence of an additional rpoN sigma factor gene in the symbiosis gene region is a characteristic specific to symbiovar orientalis, required for nitrogen fixation. Also the nifQ gene was shown to be crucial for functional symbiosis in both symbiovars. Genome-wide analyses identified additional genes characteristic of strains of the same symbiovar and of strains having similar plant growth promoting properties on Galega orientalis. Many of these genes are involved in transcriptional regulation or in metabolic functions. The results of this study confirm that the only symbiosis-related gene that is present in one symbiovar of N. galegae but not in the other is an rpoN gene. The specific function of this gene remains to be determined, however. New genes that were identified as specific for strains of one symbiovar may be involved in determining host specificity, while others are defined as potential determinant genes for differences in efficiency of nitrogen fixation.

Association of T and NK Cell Phenotype With the Diagnosis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS).

PubMed

Rivas, Jose Luis; Palencia, Teresa; Fernández, Guerau; García, Milagros

2018-01-01

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a pathological condition characterized by incapacitating fatigue and a combination of neurologic, immunologic, and endocrine symptoms. At present its diagnosis is based exclusively on clinical criteria. Several studies have described altered immunologic profiles; therefore, we proposed to further examine the more significant differences, particularly T and NK cell subpopulations that could be conditioned by viral infections, to discern their utility in improving the diagnosis and characterization of the patients. The study included 76 patients that fulfilled the revised Canadian Consensus Criteria (CCC 2010) for ME/CFS and 73 healthy controls, matched for age and gender. Immunophenotyping of different T cell and natural killer cell subpopulations in peripheral blood was determined by flow cytometry. ME/CFS patients showed significantly lower values of T regulatory cells (CD4 + CD25 ++(high) FOXP3 + ) and higher NKT-like cells (CD3 + CD16 +/- CD56 + ) than the healthy individuals. Regarding NK phenotypes, NKG2C was significantly lower and NKCD69 and NKCD56 bright were significantly higher in the patients group. A classification model was generated using the more relevant cell phenotype differences (NKG2C and T regulatory cells) that was able to classify the individuals as ME/CFS patients or healthy in a 70% of cases. The observed differences in some of the subpopulations of T and NK cells between patients and healthy controls could define a distinct immunological profile that can help in the diagnostic process of ME/CFS patients, contribute to the recognition of the disease and to the search of more specific treatments. However, more studies are needed to corroborate these findings and to contribute to establish a consensus in diagnosis.

Association of T and NK Cell Phenotype With the Diagnosis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

PubMed Central

Rivas, Jose Luis; Palencia, Teresa; Fernández, Guerau; García, Milagros

2018-01-01

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a pathological condition characterized by incapacitating fatigue and a combination of neurologic, immunologic, and endocrine symptoms. At present its diagnosis is based exclusively on clinical criteria. Several studies have described altered immunologic profiles; therefore, we proposed to further examine the more significant differences, particularly T and NK cell subpopulations that could be conditioned by viral infections, to discern their utility in improving the diagnosis and characterization of the patients. The study included 76 patients that fulfilled the revised Canadian Consensus Criteria (CCC 2010) for ME/CFS and 73 healthy controls, matched for age and gender. Immunophenotyping of different T cell and natural killer cell subpopulations in peripheral blood was determined by flow cytometry. ME/CFS patients showed significantly lower values of T regulatory cells (CD4+CD25++(high)FOXP3+) and higher NKT-like cells (CD3+CD16+/−CD56+) than the healthy individuals. Regarding NK phenotypes, NKG2C was significantly lower and NKCD69 and NKCD56 bright were significantly higher in the patients group. A classification model was generated using the more relevant cell phenotype differences (NKG2C and T regulatory cells) that was able to classify the individuals as ME/CFS patients or healthy in a 70% of cases. The observed differences in some of the subpopulations of T and NK cells between patients and healthy controls could define a distinct immunological profile that can help in the diagnostic process of ME/CFS patients, contribute to the recognition of the disease and to the search of more specific treatments. However, more studies are needed to corroborate these findings and to contribute to establish a consensus in diagnosis. PMID:29867995

CD133+ cell content correlates with tumour growth in melanomas from skin with chronic sun-induced damage.

PubMed

González-Herrero, I; Romero-Camarero, I; Cañueto, J; Cardeñoso-Álvarez, E; Fernández-López, E; Pérez-Losada, J; Sánchez-García, I; Román-Curto, C

2013-10-01

Melanoma is responsible for almost 80% of the deaths attributed to skin cancer. Stem cells, defined by CD133 expression, have been implicated in melanoma tumour growth, but their specific role is still uncertain. We hypothesized that the phenotypic heterogeneity of human cutaneous melanomas is related to their content of CD133+ cells. We compared the percentages of CD133+ cells in 29 tumours from four classic types of melanoma: lentigo maligna melanoma (LMM), superficial spreading melanoma, nodular melanoma and acral lentiginous melanoma (ALM). Also, we compared the percentages of CD133+ cells in melanomas with different degrees of exposure to ultraviolet radiation: 16 melanomas from skin with chronic sun-induced damage and 13 melanomas from skin without such damage. We found a statistically significant increase of CD133+ cells in three different contexts: in melanomas arising on skin with signs of chronic sun-induced damage vs. nonexposed skin, in melanomas in situ vs. invasive melanomas, and in LMM vs. ALM. The proportions of CD133+ cells did not differ among samples of normal skin with different degrees of sun exposure. A distinct subpopulation of CD133+CXCR4+ cancer stem cells (CSCs) was identified and shown to be related to the invasive phenotype of the tumours. Here, we provide evidence showing, for the first time, that an increase in the CD133+ cell content is associated both with melanomas arising on skin with signs of chronic sun-induced damage and in melanomas in situ with better prognosis. Moreover, our study further confirms the existence of a subpopulation of CD133+CXCR4+ CSCs in cutaneous melanomas with invasive phenotype and poor prognosis. © 2013 British Association of Dermatologists.

Virulence, immunopathology and transmissibility of selected strains of Mycobacterium tuberculosis in a murine model

PubMed Central

Marquina-Castillo, Brenda; García-García, Lourdes; Ponce-de-León, Alfredo; Jimenez-Corona, Maria-Eugenia; Bobadilla-del Valle, Miriam; Cano-Arellano, Bulmaro; Canizales-Quintero, Sergio; Martinez-Gamboa, Areli; Kato-Maeda, Midori; Robertson, Brian; Young, Douglas; Small, Peter; Schoolnik, Gary; Sifuentes-Osornio, Jose; Hernandez-Pando, Rogelio

2009-01-01

After encounter with Mycobacterium tuberculosis, a series of non-uniform immune responses are triggered that define the course of the infection. Eight M. tuberculosis strains were selected from a prospective population-based study of pulmonary tuberculosis patients (1995–2003) based on relevant clinical/epidemiological patterns and tested in a well-characterized BALB/c mouse model of progressive pulmonary tuberculosis. In addition, a new mouse model of transmissibility consisting of prolonged cohousing (up to 60 days) of infected and naïve animals was tested. Four phenotypes were defined based on strain virulence (mouse survival, lung bacillary load and tissue damage), immunology response (cytokine expression determined by real-time polymerase chain reaction) and transmissibility (lung bacillary loads and cutaneous delayed-type hypersensitivity in naïve animals).We identified four clearly defined strain phenotypes: (1) hypervirulent strain with non-protective immune response and highly transmissible; (2) virulent strain, associated with high expression of proinflammatory cytokines (tumour necrosis factor and interferon) and very low anti-inflammatory cytokine expression (interleukins 4 and 10), which induced accelerated death by immunopathology; (3) strain inducing efficient protective immunity with lower virulence, and (4) strain demonstrating strong and early macrophage activation (innate immunity) with delayed participation of acquired immunity (interferon expression). We were able to correlate virulent and transmissible phenotypes in the mouse model and markers of community transmission such as tuberculin reactivity among contacts, rapid progression to disease and cluster status. However, we were not able to find correlation with the other two phenotypes. Our new transmission model supported the hypothesis that among these strains increased virulence was linked to increased transmission. PMID:19191912

Localization of canine brachycephaly using an across breed mapping approach.

PubMed

Bannasch, Danika; Young, Amy; Myers, Jeffrey; Truvé, Katarina; Dickinson, Peter; Gregg, Jeffrey; Davis, Ryan; Bongcam-Rudloff, Eric; Webster, Matthew T; Lindblad-Toh, Kerstin; Pedersen, Niels

2010-03-10

The domestic dog, Canis familiaris, exhibits profound phenotypic diversity and is an ideal model organism for the genetic dissection of simple and complex traits. However, some of the most interesting phenotypes are fixed in particular breeds and are therefore less tractable to genetic analysis using classical segregation-based mapping approaches. We implemented an across breed mapping approach using a moderately dense SNP array, a low number of animals and breeds carefully selected for the phenotypes of interest to identify genetic variants responsible for breed-defining characteristics. Using a modest number of affected (10-30) and control (20-60) samples from multiple breeds, the correct chromosomal assignment was identified in a proof of concept experiment using three previously defined loci; hyperuricosuria, white spotting and chondrodysplasia. Genome-wide association was performed in a similar manner for one of the most striking morphological traits in dogs: brachycephalic head type. Although candidate gene approaches based on comparable phenotypes in mice and humans have been utilized for this trait, the causative gene has remained elusive using this method. Samples from nine affected breeds and thirteen control breeds identified strong genome-wide associations for brachycephalic head type on Cfa 1. Two independent datasets identified the same genomic region. Levels of relative heterozygosity in the associated region indicate that it has been subjected to a selective sweep, consistent with it being a breed defining morphological characteristic. Genotyping additional dogs in the region confirmed the association. To date, the genetic structure of dog breeds has primarily been exploited for genome wide association for segregating traits. These results demonstrate that non-segregating traits under strong selection are equally tractable to genetic analysis using small sample numbers.

Evolution and ecology meet molecular genetics: adaptive phenotypic plasticity in two isolated Negev desert populations of Acacia raddiana at either end of a rainfall gradient

PubMed Central

Ward, David; Shrestha, Madan K.; Golan-Goldhirsh, Avi

2012-01-01

Background and Aims The ecological, evolutionary and genetic bases of population differentiation in a variable environment are often related to the selection pressures that plants experience. We compared differences in several growth- and defence-related traits in two isolated populations of Acacia raddiana trees from sites at either end of an extreme environmental gradient in the Negev desert. Methods We used random amplified polymorphic DNA (RAPD) to determine the molecular differences between populations. We grew plants under two levels of water, three levels of nutrients and three levels of herbivory to test for phenotypic plasticity and adaptive phenotypic plasticity. Key Results The RAPD analyses showed that these populations are highly genetically differentiated. Phenotypic plasticity in various morphological traits in A. raddiana was related to patterns of population genetic differentiation between the two study sites. Although we did not test for maternal effects in these long-lived trees, significant genotype × environment (G × E) interactions in some of these traits indicated that such plasticity may be adaptive. Conclusions The main selection pressure in this desert environment, perhaps unsurprisingly, is water. Increased water availability resulted in greater growth in the southern population, which normally receives far less rain than the northern population. Even under the conditions that we defined as low water and/or nutrients, the performance of the seedlings from the southern population was significantly better, perhaps reflecting selection for these traits. Consistent with previous studies of this genus, there was no evidence of trade-offs between physical and chemical defences and plant growth parameters in this study. Rather, there appeared to be positive correlations between plant size and defence parameters. The great variation in several traits in both populations may result in a diverse potential for responding to selection pressures in different environments. PMID:22039007

Phenotypic and functional consequences of different isolation protocols on skin mononuclear phagocytes.

PubMed

Botting, Rachel A; Bertram, Kirstie M; Baharlou, Heeva; Sandgren, Kerrie J; Fletcher, James; Rhodes, Jake W; Rana, Hafsa; Plasto, Toby M; Wang, Xin Maggie; Lim, Jake J K; Barnouti, Laith; Kohout, Mark P; Papadopoulos, Tim; Merten, Steve; Olbourne, Norman; Cunningham, Anthony L; Haniffa, Muzlifah; Harman, Andrew N

2017-06-01

Mononuclear phagocytes are present in skin and mucosa and represent one of the first lines of defense against invading pathogens, which they detect via an array of pathogen-binding receptors expressed on their surface. However, their extraction from tissue is difficult, and the isolation technique used has functional consequences on the cells obtained. Here, we compare mononuclear phagocytes isolated from human skin using either enzymatic digestion or spontaneous migration. Cells isolated via enzymatic digestion are in an immature state, and all subsets are easily defined. However, cells isolated by spontaneous migration are in a mature state, and CD141 cross-presenting DCs (cDC1) are more difficult to define. Different pathogen-binding receptors are susceptible to cleavage by blends of collagenase, demonstrating that great care must be taken in choosing the correct enzyme blend to digest tissue if carrying out pathogen-interaction assays. Finally, we have optimized mononuclear phagocyte culture conditions to enhance their survival after liberation from the tissue. © The Author(s).

Phenotypic and functional consequences of different isolation protocols on skin mononuclear phagocytes

PubMed Central

Botting, Rachel A.; Bertram, Kirstie M.; Baharlou, Heeva; Sandgren, Kerrie J.; Fletcher, James; Rhodes, Jake W.; Rana, Hafsa; Plasto, Toby M.; Wang, Xin Maggie; Lim, Jake J. K.; Barnouti, Laith; Kohout, Mark P.; Papadopoulos, Tim; Merten, Steve; Olbourne, Norman; Cunningham, Anthony L.; Haniffa, Muzlifah; Harman, Andrew N.

2017-01-01

Mononuclear phagocytes are present in skin and mucosa and represent one of the first lines of defense against invading pathogens, which they detect via an array of pathogen-binding receptors expressed on their surface. However, their extraction from tissue is difficult, and the isolation technique used has functional consequences on the cells obtained. Here, we compare mononuclear phagocytes isolated from human skin using either enzymatic digestion or spontaneous migration. Cells isolated via enzymatic digestion are in an immature state, and all subsets are easily defined. However, cells isolated by spontaneous migration are in a mature state, and CD141 cross-presenting DCs (cDC1) are more difficult to define. Different pathogen-binding receptors are susceptible to cleavage by blends of collagenase, demonstrating that great care must be taken in choosing the correct enzyme blend to digest tissue if carrying out pathogen-interaction assays. Finally, we have optimized mononuclear phagocyte culture conditions to enhance their survival after liberation from the tissue. PMID:28270408

CYP2D6 activity and the risk of recurrence of Plasmodium vivax malaria in the Brazilian Amazon: a prospective cohort study.

PubMed

Brasil, Larissa W; Rodrigues-Soares, Fernanda; Santoro, Ana B; Almeida, Anne C G; Kühn, Andrea; Ramasawmy, Rajendranath; Lacerda, Marcus V G; Monteiro, Wuelton M; Suarez-Kurtz, Guilherme

2018-02-01

CYP2D6 pathway mediates the activation of primaquine into active metabolite(s) in hepatocytes. CYP2D6 is highly polymorphic, encoding CYP2D6 isoforms with normal, reduced, null or increased activity. It is hypothesized that Plasmodium vivax malaria patients with defective CYP2D6 function would be at increased risk for primaquine failure to prevent recurrence. The aim of this study was to investigate the association of CYP2D6 polymorphisms and inferred CYP2D6 phenotypes with malaria recurrence in patients from the Western Brazilian Amazon, following chloroquine/primaquine combined therapy. The prospective cohort consisted of P. vivax malaria patients who were followed for 6 months after completion of the chloroquine/primaquine therapy. Recurrence was defined as one or more malaria episodes, 28-180 days after the initial episode. Genotyping for nine CYP2D6 SNPs and copy number variation was performed using TaqMan assays in a Fast 7500 Real-Time System. CYP2D6 star alleles (haplotypes), diplotypes and CYP2D6 phenotypes were inferred, and the activity score system was used to define the functionality of the CYP2D6 diplotypes. CYP2D6 activity scores (AS) were dichotomized at ≤ 1 (gPM, gIM and gNM-S phenotypes) and ≥ 1.5 (gNM-F and gUM phenotypes). Genotyping was successfully performed in 190 patients (44 with recurrence and 146 without recurrences). Recurrence incidence was higher in individuals presenting reduced activity CYP2D6 phenotypes (adjusted relative risk = 1.89, 95% CI 1.01-3.70; p = 0.049). Attributable risk and population attributable fraction were 11.5 and 9.9%, respectively. The time elapsed from the first P. vivax malaria episode until the recurrence did not differ between patients with AS of ≤ 1 versus ≥ 1.5 (p = 0.917). The results suggest that CYP2D6 polymorphisms are associated with increased risk of recurrence of vivax malaria, following chloroquine-primaquine combined therapy. This association is interpreted as the result of reduced conversion of primaquine into its active metabolites in patients with reduced CYP2D6 enzymatic activity.

Clinical characteristics and outcomes of prosthetic joint infection caused by small colony variant staphylococci.

PubMed

Tande, Aaron J; Osmon, Douglas R; Greenwood-Quaintance, Kerryl E; Mabry, Tad M; Hanssen, Arlen D; Patel, Robin

2014-09-30

Small colony variants (SCVs) are naturally occurring subpopulations of bacteria. The clinical characteristics and treatment outcomes of patients with prosthetic joint infection (PJI) caused by staphylococcal SCVs are unknown. This study was a retrospective series of 113 patients with staphylococcal PJI, with prospective testing of archived sonicate fluid samples. SCVs were defined using two-investigator review. Treatment failure was defined as (i) subsequent revision surgery for any reason, (ii) PJI after the index surgery, (iii) prosthesis nonreimplantation due to ongoing infection, or (iv) amputation of the affected limb. There were 38 subjects (34%) with SCVs and 75 (66%) with only normal-phenotype (NP) bacteria. Subjects with SCVs were more likely to have been on chronic antimicrobials prior to surgery (P = 0.048), have had prior surgery for PJI (P = 0.03), have had a longer duration of symptoms (P = 0.0003), and have had a longer time since joint implantation (P = 0.007), compared to those with only NP bacteria. Over a median follow-up of 30.6 months, 9 subjects (24%) with SCVs and 23 (32%) with only NP bacteria experienced treatment failure (P = 0.51). Subjects infected with Staphylococcus aureus were more likely to fail than were those infected with Staphylococcus epidermidis (hazard ratio [HR], 4.03; 95% confidence interval [CI], 1.80 to 9.04). While frequently identified in subjects with PJI and associated with several potential predisposing factors, SCVs were not associated with excess treatment failure compared to NP infections in this study, where they were primarily managed with two-stage arthroplasty exchange. Bacteria with the small colony variant (SCV) phenotype are described in small case series as causing persistent or relapsing infection, but there are insufficient data to suggest that they should be managed differently than infection with normal-phenotype bacteria. In an effort to investigate the clinical importance of this phenotype, we determined whether SCVs were present in biofilms dislodged from the surfaces of arthroplasties of patients with staphylococcal prosthetic joint infection and assessed the clinical outcomes associated with detection of SCVs. We found that prosthetic joint infection caused by SCV staphylococci was associated with a longer duration of symptoms and more prior treatment for infection but not with an increased rate of treatment failure, compared to infection caused by normal-phenotype staphylococci. Copyright © 2014 Tande et al.

Phenotype analysis of congenital and neurodevelopmental disorders in the next generation sequencing era.

PubMed

Carey, John C

2017-09-01

The designation, phenotype, was proposed as a term by Wilhelm Johannsen in 1909. The word is derived from the Greek, phano (showing) and typo (type), phanotypos. Phenotype has become a widely recognized term, even outside of the genetics community, in recent years with the ongoing identification of human disease genes. The term has been defined as the observable constitution of an organism, but sometimes refers to a condition when a person has a particular clinical presentation. Analysis of phenotype is a timely theme because advances in the understanding of the genetic basis of human disease and the emergence of next generation sequencing have spurred a renewed interest in phenotype and the proposal to establish a "Human Phenome Project." This article summarizes the principles of phenotype analysis that are important in medical genetics and describes approaches to comprehensive phenotype analysis in the investigation of patients with human disorders. I discuss the various elements related to disease phenotypes and highlight neurofibromatosis type 1 and the Elements of Morphology Project as illustrations of the principles. In recent years, the notion of "deep phenotyping" has emerged. Currently there are now a number of proposed strategies and resources to approach this concept. Not since the 1960s and 1970s has there been such an exciting time in the history of medicine surrounding the analysis of phenotype in genetic disorders. © 2017 Wiley Periodicals, Inc.

Neuroanatomic alterations and social and communication deficits in monozygotic twins discordant for autism disorder.

PubMed

Mitchell, Shanti R; Reiss, Allan L; Tatusko, Danielle H; Ikuta, Ichiro; Kazmerski, Dana B; Botti, Jo-Anna C; Burnette, Courtney P; Kates, Wendy R

2009-08-01

Investigating neuroanatomic differences in monozygotic twins who are discordant for autism can help unravel the relative contributions of genetics and environment to this pervasive developmental disorder. The authors used magnetic resonance imaging (MRI) to investigate several brain regions of interest in monozygotic twins who varied in degree of phenotypic discordance for narrowly defined autism. The subjects were 14 pairs of monozygotic twins between the ages of 5 and 14 years old and 14 singleton age- and gender-matched typically developing comparison subjects. The monozygotic twin group was a cohort of children with narrowly defined autistic deficits and their co-twins who presented with varying levels of autistic deficits. High-resolution MRIs were acquired and volumetric/area measurements obtained for the frontal lobe, amygdala, and hippocampus and subregions of the prefrontal cortex, corpus callosum, and cerebellar vermis. No neurovolumetric/area differences were found between twin pairs. Relative to typically developing comparison subjects, dorsolateral prefrontal cortex volumes and anterior areas of the corpus callosum were significantly altered in autistic twins, and volumes of the posterior vermis were altered in both autistic twins and co-twins. Intraclass correlation analysis of brain volumes between children with autism and their co-twins indicated that the degree of within-pair neuroanatomic concordance varied with brain region. In the group of subjects with narrowly defined autism only, dorsolateral prefrontal cortex, amygdala, and posterior vermis volumes were significantly associated with the severity of autism based on scores from the Autism Diagnostic Observation Schedule-Generic. These findings support previous research demonstrating alterations in the prefrontal cortex, corpus callosum, and posterior vermis in children with autism and further suggest that alterations are associated with the severity of the autism phenotype. Continued research involving twins who are concordant and discordant for autism is essential to disentangle the genetic and environmental contributions to autism.

Phenotype variations affect genetic association studies of degenerative disc disease: conclusions of analysis of genetic association of 58 single nucleotide polymorphisms with highly specific phenotypes for disc degeneration in 332 subjects.

PubMed

Rajasekaran, S; Kanna, Rishi Mugesh; Senthil, Natesan; Raveendran, Muthuraja; Cheung, Kenneth M C; Chan, Danny; Subramaniam, Sakthikanal; Shetty, Ajoy Prasad

2013-10-01

Although the influence of genetics on the process of disc degeneration is well recognized, in recently published studies, there is a wide variation in the race and selection criteria for such study populations. More importantly, the radiographic features of disc degeneration that are selected to represent the disc degeneration phenotype are variable in these studies. The study presented here evaluates the association between single nucleotide polymorphisms (SNPs) of candidate genes and three distinct radiographic features that can be defined as the degenerative disc disease (DDD) phenotype. The study objectives were to examine the allelic diversity of 58 SNPs related to 35 candidate genes related to lumbar DDD, to evaluate the association in a hitherto unevaluated ethnic Indian population that represents more than one-sixth of the world population, and to analyze how genetic associations can vary in the same study subjects with the choice of phenotype. A cross-sectional, case-control study of an ethnic Indian population was carried out. Fifty-eight SNPs in 35 potential candidate genes were evaluated in 342 subjects and the associations were analyzed against three highly specific markers for DDD, namely disc degeneration by Pfirrmann grading, end-plate damage evaluated by total end-plate damage score, and annular tears evaluated by disc herniations and hyperintense zones. Genotyping of cases and controls was performed on a genome-wide SNP array to identify potential associated disease loci. The results from the genome-wide SNP array were then used to facilitate SNP selection and genotype validation was conducted using Sequenom-based genotyping. Eleven of the 58 SNPs provided evidence of association with one of the phenotypes. For annular tears, rs1042631 SNP of AGC1 and rs467691 SNP of ADAMTS5 were highly significantly associated (p<.01) and SNPs in NGFB, IL1B, IL18RAP, and MMP10 were also significantly associated (p<.05). The rs4076018 SNP of NGFB was highly significant (p<.01) and rs2292657 SNP of GLI1 was significantly (p<.05) correlated to disc degeneration. For end-plate damage, the rs2252070 SNP of MMP 13 showed a significant association (p<.05). Previously associated genes such as COL 9, SKT, CHST 3, CILP, IGFR, SOXp, BMP, MMP 2-12, ADH2, IL1RN, and COX2 were not significantly associated and new associations (NGFB and GLI1) were identified. The validity of all the associations was found to be phenotype dependent. For the first time, genetic associations with DDD have been performed in an Indian population. Apart from identifying new associations, the highlight of the study was that in the same study population with DDD, SNP associations completely changed when different radiographic features were used to define the DDD phenotype. Our study results therefore indicate that standardization of the phenotypes chosen to study the genetics of disc degeneration is essential and should be strongly considered before planning genetic association studies. Copyright © 2013 Elsevier Inc. All rights reserved.

Lactobacilli Activate Human Dendritic Cells that Skew T Cells Toward T Helper 1 Polarization

DTIC Science & Technology

2005-01-06

Species Modulate the Phenotype and Function of MDCs. Previous studies have shown that Lactobacillus plantarum and Lactobacillus rhamnosus can induce...cell immune responses at both systemic and mucosal sites. Many Lactobacillus species are normal members of the human gut microflora and most are regarded...several well defined strains, representing three species of Lactobacillus on human myeloid DCs (MDCs) and found that they modulated the phenotype and

Disentangling the heterogeneity of autism spectrum disorder through genetic findings

PubMed Central

Jeste, Shafali S.; Geschwind, Daniel H.

2014-01-01

Autism spectrum disorder (ASD) represents a heterogeneous group of disorders, which presents a substantial challenge to diagnosis and treatment. Over the past decade, considerable progress has been made in the identification of genetic risk factors for ASD that define specific mechanisms and pathways underlying the associated behavioural deficits. In this Review, we discuss how some of the latest advances in the genetics of ASD have facilitated parsing of the phenotypic heterogeneity of this disorder. We argue that only through such advances will we begin to define endophenotypes that can benefit from targeted, hypothesis-driven treatments. We review the latest technologies used to identify and characterize the genetics underlying ASD and then consider three themes—single-gene disorders, the gender bias in ASD, and the genetics of neurological comorbidities—that highlight ways in which we can use genetics to define the many phenotypes within the autism spectrum. We also present current clinical guidelines for genetic testing in ASD and their implications for prognosis and treatment. PMID:24468882

By their genes ye shall know them: genomic signatures of predatory bacteria

PubMed Central

Pasternak, Zohar; Pietrokovski, Shmuel; Rotem, Or; Gophna, Uri; Lurie-Weinberger, Mor N; Jurkevitch, Edouard

2013-01-01

Predatory bacteria are taxonomically disparate, exhibit diverse predatory strategies and are widely distributed in varied environments. To date, their predatory phenotypes cannot be discerned in genome sequence data thereby limiting our understanding of bacterial predation, and of its impact in nature. Here, we define the ‘predatome,' that is, sets of protein families that reflect the phenotypes of predatory bacteria. The proteomes of all sequenced 11 predatory bacteria, including two de novo sequenced genomes, and 19 non-predatory bacteria from across the phylogenetic and ecological landscapes were compared. Protein families discriminating between the two groups were identified and quantified, demonstrating that differences in the proteomes of predatory and non-predatory bacteria are large and significant. This analysis allows predictions to be made, as we show by confirming from genome data an over-looked bacterial predator. The predatome exhibits deficiencies in riboflavin and amino acids biosynthesis, suggesting that predators obtain them from their prey. In contrast, these genomes are highly enriched in adhesins, proteases and particular metabolic proteins, used for binding to, processing and consuming prey, respectively. Strikingly, predators and non-predators differ in isoprenoid biosynthesis: predators use the mevalonate pathway, whereas non-predators, like almost all bacteria, use the DOXP pathway. By defining predatory signatures in bacterial genomes, the predatory potential they encode can be uncovered, filling an essential gap for measuring bacterial predation in nature. Moreover, we suggest that full-genome proteomic comparisons are applicable to other ecological interactions between microbes, and provide a convenient and rational tool for the functional classification of bacteria. PMID:23190728

A Hierarchical Causal Taxonomy of Psychopathology across the Life Span

PubMed Central

Lahey, Benjamin B.; Krueger, Robert F.; Rathouz, Paul J.; Waldman, Irwin D.; Zald, David H.

2016-01-01

We propose a taxonomy of psychopathology based on patterns of shared causal influences identified in a review of multivariate behavior genetic studies that distinguish genetic and environmental influences that are either common to multiple dimensions of psychopathology or unique to each dimension. At the phenotypic level, first-order dimensions are defined by correlations among symptoms; correlations among first-order dimensions similarly define higher-order domains (e.g., internalizing or externalizing psychopathology). We hypothesize that the robust phenotypic correlations among first-order dimensions reflect a hierarchy of increasingly specific etiologic influences. Some nonspecific etiologic factors increase risk for all first-order dimensions of psychopathology to varying degrees through a general factor of psychopathology. Other nonspecific etiologic factors increase risk only for all first-order dimensions within a more specific higher-order domain. Furthermore, each first-order dimension has its own unique causal influences. Genetic and environmental influences common to family members tend to be nonspecific, whereas environmental influences unique to each individual are more dimension-specific. We posit that these causal influences on psychopathology are moderated by sex and developmental processes. This causal taxonomy also provides a novel framework for understanding the heterogeneity of each first-order dimension: Different persons exhibiting similar symptoms may be influenced by different combinations of etiologic influences from each of the three levels of the etiologic hierarchy. Furthermore, we relate the proposed causal taxonomy to transdimensional psychobiological processes, which also impact the heterogeneity of each psychopathology dimension. This causal taxonomy implies the need for changes in strategies for studying the etiology, psychobiology, prevention, and treatment of psychopathology. PMID:28004947

USP22 regulates oncogenic signaling pathways to drive lethal cancer progression.

PubMed

Schrecengost, Randy S; Dean, Jeffry L; Goodwin, Jonathan F; Schiewer, Matthew J; Urban, Mark W; Stanek, Timothy J; Sussman, Robyn T; Hicks, Jessica L; Birbe, Ruth C; Draganova-Tacheva, Rossitza A; Visakorpi, Tapio; DeMarzo, Angelo M; McMahon, Steven B; Knudsen, Karen E

2014-01-01

Increasing evidence links deregulation of the ubiquitin-specific proteases 22 (USP22) deubitiquitylase to cancer development and progression in a select group of tumor types, but its specificity and underlying mechanisms of action are not well defined. Here we show that USP22 is a critical promoter of lethal tumor phenotypes that acts by modulating nuclear receptor and oncogenic signaling. In multiple xenograft models of human cancer, modeling of tumor-associated USP22 deregulation demonstrated that USP22 controls androgen receptor accumulation and signaling, and that it enhances expression of critical target genes coregulated by androgen receptor and MYC. USP22 not only reprogrammed androgen receptor function, but was sufficient to induce the transition to therapeutic resistance. Notably, in vivo depletion experiments revealed that USP22 is critical to maintain phenotypes associated with end-stage disease. This was a significant finding given clinical evidence that USP22 is highly deregulated in tumors, which have achieved therapeutic resistance. Taken together, our findings define USP22 as a critical effector of tumor progression, which drives lethal phenotypes, rationalizing this enzyme as an appealing therapeutic target to treat advanced disease.

An ontology approach to comparative phenomics in plants

USDA-ARS?s Scientific Manuscript database

Plant phenotypes (observable characteristics) are described using many different formats and specialized vocabularies or "ontologies". Similar phenotypes in different species may be given different names. These differences in terms complicate phenotype comparisons across species. This research descr...

Genetic influences on alcohol-related hangover.

PubMed

Slutske, Wendy S; Piasecki, Thomas M; Nathanson, Lisa; Statham, Dixie J; Martin, Nicholas G

2014-12-01

To quantify the relative contributions of genetic and environmental factors to alcohol hangover. Biometric models were used to partition the variance in hangover phenotypes. A community-based sample of Australian twins. Members of the Australian Twin Registry, Cohort II who reported consuming alcohol in the past year when surveyed in 2004-07 (n = 4496). Telephone interviews assessed participants' frequency of drinking to intoxication and frequency of hangover the day after drinking. Analyses examined three phenotypes: hangover frequency, hangover susceptibility (i.e. residual variance in hangover frequency after accounting for intoxication frequency) and hangover resistance (a dichotomous variable defined as having been intoxicated at least once in the past year with no reported hangovers). Genetic factors accounted for 45% [95% confidence interval (CI) = 37-53%] and 40% (95% CI = 33-48%) of the variation in hangover frequency in men and women, respectively. Most of the genetic variation in hangover frequency overlapped with genetic contributions to intoxication frequency. Genetic influences accounted for 24% (95% CI = 14-35%) and 16% (95% CI = 8-25%) of the residual hangover susceptibility variance in men and women, respectively. Forty-three per cent (95% CI = 22-63%) of the variation in hangover resistance was explained by genetic influences, with no evidence for significant sex differences. There was no evidence for shared environmental influences for any of the hangover phenotypes. Individual differences in the propensity to experience a hangover and of being resistant to hangover at a given level of alcohol use are genetically influenced. © 2014 Society for the Study of Addiction.

Humans display a reduced set of consistent behavioral phenotypes in dyadic games.

PubMed

Poncela-Casasnovas, Julia; Gutiérrez-Roig, Mario; Gracia-Lázaro, Carlos; Vicens, Julian; Gómez-Gardeñes, Jesús; Perelló, Josep; Moreno, Yamir; Duch, Jordi; Sánchez, Angel

2016-08-01

Socially relevant situations that involve strategic interactions are widespread among animals and humans alike. To study these situations, theoretical and experimental research has adopted a game theoretical perspective, generating valuable insights about human behavior. However, most of the results reported so far have been obtained from a population perspective and considered one specific conflicting situation at a time. This makes it difficult to extract conclusions about the consistency of individuals' behavior when facing different situations and to define a comprehensive classification of the strategies underlying the observed behaviors. We present the results of a lab-in-the-field experiment in which subjects face four different dyadic games, with the aim of establishing general behavioral rules dictating individuals' actions. By analyzing our data with an unsupervised clustering algorithm, we find that all the subjects conform, with a large degree of consistency, to a limited number of behavioral phenotypes (envious, optimist, pessimist, and trustful), with only a small fraction of undefined subjects. We also discuss the possible connections to existing interpretations based on a priori theoretical approaches. Our findings provide a relevant contribution to the experimental and theoretical efforts toward the identification of basic behavioral phenotypes in a wider set of contexts without aprioristic assumptions regarding the rules or strategies behind actions. From this perspective, our work contributes to a fact-based approach to the study of human behavior in strategic situations, which could be applied to simulating societies, policy-making scenario building, and even a variety of business applications.

Different demographic, genetic, and longitudinal traits in language versus memory Alzheimer's subgroups.

PubMed

Mez, Jesse; Cosentino, Stephanie; Brickman, Adam M; Huey, Edward D; Mayeux, Richard

2013-01-01

The study's objective was to compare demographics, APOE genotypes, and rate of rise over time in functional impairment in neuropsychologically defined language, typical, and memory subgroups of clinical Alzheimer's disease (AD). 1,368 participants from the National Alzheimer's Coordinating Center database with a diagnosis of probable AD (CDR 0.5-1.0) were included. A language subgroup (n = 229) was defined as having language performance >1 SD worse than memory performance. A memory subgroup (n = 213) was defined as having memory performance >1 SD worse than language performance. A typical subgroup (n = 926) was defined as having a difference in language and memory performance of <1 SD. Compared with the memory subgroup, the language subgroup was 3.7 years older and more frequently self-identified as African American (OR = 3.69). Under a dominant genetic model, the language subgroup had smaller odds of carrying at least one APOEε4 allele relative to the memory subgroup. While this difference was present for all ages, it was more striking at a younger age (OR = 0.19 for youngest tertile; OR = 0.52 for oldest tertile). Compared with the memory subgroup, the language subgroup rose 35% faster on the Functional Assessment Questionnaire and 44% faster on CDR sum of boxes over time. Among a subset of participants who underwent autopsy (n = 98), the language, memory, and typical subgroups were equally likely to have an AD pathologic diagnosis, suggesting that variation in non-AD pathologies across subtypes did not lead to the observed differences. The study demonstrates that a language subgroup of AD has different demographics, genetic profile, and disease course in addition to cognitive phenotype.

Phenotypic spectrum associated with mutations of the mitochondrial polymerase gamma gene.

PubMed

Horvath, Rita; Hudson, Gavin; Ferrari, Gianfrancesco; Fütterer, Nancy; Ahola, Sofia; Lamantea, Eleonora; Prokisch, Holger; Lochmüller, Hanns; McFarland, Robert; Ramesh, V; Klopstock, Thomas; Freisinger, Peter; Salvi, Fabrizio; Mayr, Johannes A; Santer, Rene; Tesarova, Marketa; Zeman, Jiri; Udd, Bjarne; Taylor, Robert W; Turnbull, Douglass; Hanna, Michael; Fialho, Doreen; Suomalainen, Anu; Zeviani, Massimo; Chinnery, Patrick F

2006-07-01

Mutations in the gene coding for the catalytic subunit of the mitochondrial DNA (mtDNA) polymerase gamma (POLG1) have recently been described in patients with diverse clinical presentations, revealing a complex relationship between genotype and phenotype in patients and their families. POLG1 was sequenced in patients from different European diagnostic and research centres to define the phenotypic spectrum and advance understanding of the recurrence risks. Mutations were identified in 38 cases, with the majority being sporadic compound heterozygotes. Eighty-nine DNA sequence changes were identified, including 2 predicted to alter a splice site, 1 predicted to cause a premature stop codon and 13 predicted to cause novel amino acid substitutions. The majority of children had a mutation in the linker region, often 1399G-->A (A467T), and a mutation affecting the polymerase domain. Others had mutations throughout the gene, and 11 had 3 or more substitutions. The clinical presentation ranged from the neonatal period to late adult life, with an overlapping phenotypic spectrum from severe encephalopathy and liver failure to late-onset external ophthalmoplegia, ataxia, myopathy and isolated muscle pain or epilepsy. There was a strong gender bias in children, with evidence of an environmental interaction with sodium valproate. POLG1 mutations cause an overlapping clinical spectrum of disease with both dominant and recessive modes of inheritance. 1399G-->A (A467T) is common in children, but complete POLG1 sequencing is required to identify multiple mutations that can have complex implications for genetic counselling.

Epigenetics of human asthma and allergy: promises to keep.

PubMed

Devries, Avery; Vercelli, Donata

2013-09-01

The interest in asthma epigenetics is high because epigenetic mechanisms likely contribute to the environmental origins of the disease and its phenotypic variability. This review presents the main findings of asthma epigenetics and the challenges that still delay progress. We examined the current literature on asthma epigenetics (31 reviews and 25 original data publications). We focused on DNA methylation studies in populations. Both genome-wide and candidate gene studies have explored DNA methylation in allergic disease. Genome-wide studies ask whether and which regions of the genome are differentially methylated in relation to the phenotype of interest. Identification of such regions provides clues about the identity of the genes, pathways and networks underpinning a phenotype and connects these networks to the phenotype through epigenetic mechanisms. Candidate gene studies examine DNA methylation in genes chosen because of their known or hypothesized role in immunity, responses to environmental stimuli or disease pathogenesis. Most existing studies in asthma and allergy focused on candidate genes involved in the response to environmental pollutants. Asthma epigenetics is still in its infancy. The paucity of primary literature originates from methodological and analytical challenges of genome-wide studies, the difficulties in interpreting small differences in DNA methylation, and the need to develop robust bioinformatic tools for pathway, network and system analyses of epigenetic data. Once these challenges have been overcome, epigenetic studies will likely provide important insights about the inception and pathogenesis of allergic disease and will help define disease endotypes.

Prioritization of candidate disease genes by topological similarity between disease and protein diffusion profiles.

PubMed

Zhu, Jie; Qin, Yufang; Liu, Taigang; Wang, Jun; Zheng, Xiaoqi

2013-01-01

Identification of gene-phenotype relationships is a fundamental challenge in human health clinic. Based on the observation that genes causing the same or similar phenotypes tend to correlate with each other in the protein-protein interaction network, a lot of network-based approaches were proposed based on different underlying models. A recent comparative study showed that diffusion-based methods achieve the state-of-the-art predictive performance. In this paper, a new diffusion-based method was proposed to prioritize candidate disease genes. Diffusion profile of a disease was defined as the stationary distribution of candidate genes given a random walk with restart where similarities between phenotypes are incorporated. Then, candidate disease genes are prioritized by comparing their diffusion profiles with that of the disease. Finally, the effectiveness of our method was demonstrated through the leave-one-out cross-validation against control genes from artificial linkage intervals and randomly chosen genes. Comparative study showed that our method achieves improved performance compared to some classical diffusion-based methods. To further illustrate our method, we used our algorithm to predict new causing genes of 16 multifactorial diseases including Prostate cancer and Alzheimer's disease, and the top predictions were in good consistent with literature reports. Our study indicates that integration of multiple information sources, especially the phenotype similarity profile data, and introduction of global similarity measure between disease and gene diffusion profiles are helpful for prioritizing candidate disease genes. Programs and data are available upon request.

FABP4 is a leading candidate gene associated with residual feed intake in growing Holstein calves.

PubMed

Cohen-Zinder, Miri; Asher, Aviv; Lipkin, Ehud; Feingersch, Roi; Agmon, Rotem; Karasik, David; Brosh, Arieh; Shabtay, Ariel

2016-05-01

Ecological and economic concerns drive the need to improve feed utilization by domestic animals. Residual feed intake (RFI) is one of the most acceptable measures for feed efficiency (FE). However, phenotyping RFI-related traits is complex and expensive and requires special equipment. Advances in marker technology allow the development of various DNA-based selection tools. To assimilate these technologies for the benefit of RFI-based selection, reliable phenotypic measures are prerequisite. In the current study, we identified single nucleotide polymorphisms (SNPs) associated with RFI phenotypic consistency across different ages and diets (named RFI 1-3), using DNA samples of high or low RFI ranked Holstein calves. Using targeted sequencing of chromosomal regions associated with FE- and RFI-related traits, we identified 48 top SNPs significantly associated with at least one of three defined RFIs. Eleven of these SNPs were harbored by the fatty acid binding protein 4 (FABP4). While 10 significant SNPs found in FABP4 were common for RFI 1 and RFI 3, one SNP (FABP4_5; A

Heterogeneous vancomycin-intermediate susceptibility phenotype in bloodstream methicillin-resistant Staphylococcus aureus isolates from an international cohort of patients with infective endocarditis: prevalence, genotype, and clinical significance.

PubMed

Bae, In-Gyu; Federspiel, Jerome J; Miró, José M; Woods, Christopher W; Park, Lawrence; Rybak, Michael J; Rude, Thomas H; Bradley, Suzanne; Bukovski, Suzana; de la Maria, Cristina Garcia; Kanj, Souha S; Korman, Tony M; Marco, Francesc; Murdoch, David R; Plesiat, Patrick; Rodriguez-Creixems, Marta; Reinbott, Porl; Steed, Lisa; Tattevin, Pierre; Tripodi, Marie-Françoise; Newton, Karly L; Corey, G Ralph; Fowler, Vance G

2009-11-01

The significance of heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA) is unknown. Using a multinational collection of isolates from methicillin-resistant S. aureus (MRSA) infective endocarditis (IE), we characterized patients with IE with and without hVISA, and we genotyped the infecting strains. MRSA bloodstream isolates from 65 patients with definite IE from 8 countries underwent polymerase chain reaction (PCR) for 31 virulence genes, pulsed-field gel electrophoresis, and multilocus sequence typing. hVISA was defined using population analysis profiling. Nineteen (29.2%) of 65 MRSA IE isolates exhibited the hVISA phenotype by population analysis profiling. Isolates from Oceania and Europe were more likely to exhibit the hVISA phenotype than isolates from the United States (77.8% and 35.0% vs 13.9%; P < .001). The prevalence of hVISA was higher among isolates with a vancomycin minimum inhibitory concentration of 2 mg/L (P = .026). hVISA-infected patients were more likely to have persistent bacteremia (68.4% vs 37.0%; P = .029) and heart failure (47.4% vs 19.6%; P = .033). Mortality did not differ between hVISA- and non-hVISA-infected patients (42.1% vs 34.8%, P = .586). hVISA and non-hVISA isolates were genotypically similar. In these analyses, the hVISA phenotype occurred in more than one-quarter of MRSA IE isolates, was associated with certain IE complications, and varied in frequency by geographic region.

Using Perceptual Signatures to Define and Dissociate Condition-Specific Neural Etiology: Autism and Fragile X Syndrome as Model Conditions

ERIC Educational Resources Information Center

Bertone, Armando; Hanck, Julie; Kogan, Cary; Chaudhuri, Avi; Cornish, Kim

2010-01-01

The functional link between genetic alteration and behavioral end-state is rarely straightforward and never linear. Cases where neurodevlopmental conditions defined by a distinct genetic etiology share behavioral phenotypes are exemplary, as is the case for autism and Fragile X Syndrome (FXS). In this paper and its companion paper, we propose a…

The Human Phenotype Ontology project: linking molecular biology and disease through phenotype data

PubMed Central

Köhler, Sebastian; Doelken, Sandra C.; Mungall, Christopher J.; Bauer, Sebastian; Firth, Helen V.; Bailleul-Forestier, Isabelle; Black, Graeme C. M.; Brown, Danielle L.; Brudno, Michael; Campbell, Jennifer; FitzPatrick, David R.; Eppig, Janan T.; Jackson, Andrew P.; Freson, Kathleen; Girdea, Marta; Helbig, Ingo; Hurst, Jane A.; Jähn, Johanna; Jackson, Laird G.; Kelly, Anne M.; Ledbetter, David H.; Mansour, Sahar; Martin, Christa L.; Moss, Celia; Mumford, Andrew; Ouwehand, Willem H.; Park, Soo-Mi; Riggs, Erin Rooney; Scott, Richard H.; Sisodiya, Sanjay; Vooren, Steven Van; Wapner, Ronald J.; Wilkie, Andrew O. M.; Wright, Caroline F.; Vulto-van Silfhout, Anneke T.; de Leeuw, Nicole; de Vries, Bert B. A.; Washingthon, Nicole L.; Smith, Cynthia L.; Westerfield, Monte; Schofield, Paul; Ruef, Barbara J.; Gkoutos, Georgios V.; Haendel, Melissa; Smedley, Damian; Lewis, Suzanna E.; Robinson, Peter N.

2014-01-01

The Human Phenotype Ontology (HPO) project, available at http://www.human-phenotype-ontology.org, provides a structured, comprehensive and well-defined set of 10,088 classes (terms) describing human phenotypic abnormalities and 13,326 subclass relations between the HPO classes. In addition we have developed logical definitions for 46% of all HPO classes using terms from ontologies for anatomy, cell types, function, embryology, pathology and other domains. This allows interoperability with several resources, especially those containing phenotype information on model organisms such as mouse and zebrafish. Here we describe the updated HPO database, which provides annotations of 7,278 human hereditary syndromes listed in OMIM, Orphanet and DECIPHER to classes of the HPO. Various meta-attributes such as frequency, references and negations are associated with each annotation. Several large-scale projects worldwide utilize the HPO for describing phenotype information in their datasets. We have therefore generated equivalence mappings to other phenotype vocabularies such as LDDB, Orphanet, MedDRA, UMLS and phenoDB, allowing integration of existing datasets and interoperability with multiple biomedical resources. We have created various ways to access the HPO database content using flat files, a MySQL database, and Web-based tools. All data and documentation on the HPO project can be found online. PMID:24217912

Recruited brain tumor-derived mesenchymal stem cells contribute to brain tumor progression.

PubMed

Behnan, Jinan; Isakson, Pauline; Joel, Mrinal; Cilio, Corrado; Langmoen, Iver A; Vik-Mo, Einar O; Badn, Wiaam

2014-05-01

The identity of the cells that contribute to brain tumor structure and progression remains unclear. Mesenchymal stem cells (MSCs) have recently been isolated from normal mouse brain. Here, we report the infiltration of MSC-like cells into the GL261 murine glioma model. These brain tumor-derived mesenchymal stem cells (BT-MSCs) are defined with the phenotype (Lin-Sca-1+CD9+CD44+CD166+/-) and have multipotent differentiation capacity. We show that the infiltration of BT-MSCs correlates to tumor progression; furthermore, BT-MSCs increased the proliferation rate of GL261 cells in vitro. For the first time, we report that the majority of GL261 cells expressed mesenchymal phenotype under both adherent and sphere culture conditions in vitro and that the non-MSC population is nontumorigenic in vivo. Although the GL261 cell line expressed mesenchymal phenotype markers in vitro, most BT-MSCs are recruited cells from host origin in both wild-type GL261 inoculated into green fluorescent protein (GFP)-transgenic mice and GL261-GFP cells inoculated into wild-type mice. We show the expression of chemokine receptors CXCR4 and CXCR6 on different recruited cell populations. In vivo, the GL261 cells change marker profile and acquire a phenotype that is more similar to cells growing in sphere culture conditions. Finally, we identify a BT-MSC population in human glioblastoma that is CD44+CD9+CD166+ both in freshly isolated and culture-expanded cells. Our data indicate that cells with MSC-like phenotype infiltrate into the tumor stroma and play an important role in tumor cell growth in vitro and in vivo. Thus, we suggest that targeting BT-MSCs could be a possible strategy for treating glioblastoma patients. © 2013 AlphaMed Press.

Mitochondrial DNA haplogroup D4a is a marker for extreme longevity in Japan.

PubMed

Bilal, Erhan; Rabadan, Raul; Alexe, Gabriela; Fuku, Noriyuki; Ueno, Hitomi; Nishigaki, Yutaka; Fujita, Yasunori; Ito, Masafumi; Arai, Yasumichi; Hirose, Nobuyoshi; Ruckenstein, Andrei; Bhanot, Gyan; Tanaka, Masashi

2008-06-11

We report results from the analysis of complete mitochondrial DNA (mtDNA) sequences from 112 Japanese semi-supercentenarians (aged above 105 years) combined with previously published data from 96 patients in each of three non-disease phenotypes: centenarians (99-105 years of age), healthy non-obese males, obese young males and four disease phenotypes, diabetics with and without angiopathy, and Alzheimer's and Parkinson's disease patients. We analyze the correlation between mitochondrial polymorphisms and the longevity phenotype using two different methods. We first use an exhaustive algorithm to identify all maximal patterns of polymorphisms shared by at least five individuals and define a significance score for enrichment of the patterns in each phenotype relative to healthy normals. Our study confirms the correlations observed in a previous study showing enrichment of a hierarchy of haplogroups in the D clade for longevity. For the extreme longevity phenotype we see a single statistically significant signal: a progressive enrichment of certain "beneficial" patterns in centenarians and semi-supercentenarians in the D4a haplogroup. We then use Principal Component Spectral Analysis of the SNP-SNP Covariance Matrix to compare the measured eigenvalues to a Null distribution of eigenvalues on Gaussian datasets to determine whether the correlations in the data (due to longevity) arises from some property of the mutations themselves or whether they are due to population structure. The conclusion is that the correlations are entirely due to population structure (phylogenetic tree). We find no signal for a functional mtDNA SNP correlated with longevity. The fact that the correlations are from the population structure suggests that hitch-hiking on autosomal events is a possible explanation for the observed correlations.

Mitochondrial DNA Haplogroup D4a Is a Marker for Extreme Longevity in Japan

PubMed Central

Bilal, Erhan; Rabadan, Raul; Alexe, Gabriela; Fuku, Noriyuki; Ueno, Hitomi; Nishigaki, Yutaka; Fujita, Yasunori; Ito, Masafumi; Arai, Yasumichi; Hirose, Nobuyoshi; Ruckenstein, Andrei; Bhanot, Gyan; Tanaka, Masashi

2008-01-01

We report results from the analysis of complete mitochondrial DNA (mtDNA) sequences from 112 Japanese semi-supercentenarians (aged above 105 years) combined with previously published data from 96 patients in each of three non-disease phenotypes: centenarians (99–105 years of age), healthy non-obese males, obese young males and four disease phenotypes, diabetics with and without angiopathy, and Alzheimer's and Parkinson's disease patients. We analyze the correlation between mitochondrial polymorphisms and the longevity phenotype using two different methods. We first use an exhaustive algorithm to identify all maximal patterns of polymorphisms shared by at least five individuals and define a significance score for enrichment of the patterns in each phenotype relative to healthy normals. Our study confirms the correlations observed in a previous study showing enrichment of a hierarchy of haplogroups in the D clade for longevity. For the extreme longevity phenotype we see a single statistically significant signal: a progressive enrichment of certain “beneficial” patterns in centenarians and semi-supercentenarians in the D4a haplogroup. We then use Principal Component Spectral Analysis of the SNP-SNP Covariance Matrix to compare the measured eigenvalues to a Null distribution of eigenvalues on Gaussian datasets to determine whether the correlations in the data (due to longevity) arises from some property of the mutations themselves or whether they are due to population structure. The conclusion is that the correlations are entirely due to population structure (phylogenetic tree). We find no signal for a functional mtDNA SNP correlated with longevity. The fact that the correlations are from the population structure suggests that hitch-hiking on autosomal events is a possible explanation for the observed correlations. PMID:18545700

DNA hypomethylation at ALOX12 is associated with persistent wheezing in childhood.

PubMed

Morales, Eva; Bustamante, Mariona; Vilahur, Nadia; Escaramis, Georgia; Montfort, Magda; de Cid, Rafael; Garcia-Esteban, Raquel; Torrent, Maties; Estivill, Xavier; Grimalt, Joan O; Sunyer, Jordi

2012-05-01

Epigenetic changes may play a role in the occurrence of asthma-related phenotypes. To identify epigenetic marks in terms of DNA methylation of asthma-related phenotypes in childhood, and to assess the effect of prenatal exposures and genetic variation on these epigenetic marks. Data came from two cohorts embedded in the Infancia y Medio Ambiente (INMA) PROJECT: Menorca (n = 122) and Sabadell (n = 236). Wheezing phenotypes were defined at age 4-6 years. Cytosine-guanine (CpG) dinucleotide site DNA methylation differences associated with wheezing phenotypes were screened in children of the Menorca study using the Illumina GoldenGate Panel I. Findings were validated and replicated using pyrosequencing. Information on maternal smoking and folate supplement use was obtained through questionnaires. Dichlorodiphenyldichloroethylene was measured in cord blood or maternal serum. Genotypes were extracted from genome-wide data. Screening identified lower DNA methylation at a CpG site in the arachidonate 12-lipoxygenase (ALOX12) gene in children having persistent wheezing compared with those never wheezed (P = 0.003). DNA hypomethylation at ALOX12 loci was associated with higher risk of persistent wheezing in the Menorca study (odds ratio per 1% methylation decrease, 1.13; 95% confidence interval, 0.99-1.29; P = 0.077) and in the Sabadell study (odds ratio, 1.16; 95% confidence interval, 1.03-1.37; P = 0.017). Higher levels of prenatal dichlorodiphenyldichloroethylene were associated with DNA hypomethylation of ALOX12 in the Menorca study (P = 0.033), but not in the Sabadell study (P = 0.377). ALOX12 DNA methylation was strongly determined by underlying genetic polymorphisms. DNA methylation of ALOX12 may be an epigenetic biomarker for the risk of asthma-related phenotypes.

Heterozygous Ambra1 Deficiency in Mice: A Genetic Trait with Autism-Like Behavior Restricted to the Female Gender

PubMed Central

Dere, Ekrem; Dahm, Liane; Lu, Derek; Hammerschmidt, Kurt; Ju, Anes; Tantra, Martesa; Kästner, Anne; Chowdhury, Kamal; Ehrenreich, Hannelore

2014-01-01

Autism-spectrum disorders (ASD) are heterogeneous, highly heritable neurodevelopmental conditions affecting around 0.5% of the population across cultures, with a male/female ratio of approximately 4:1. Phenotypically, ASD are characterized by social interaction and communication deficits, restricted interests, repetitive behaviors, and reduced cognitive flexibility. Identified causes converge at the level of the synapse, ranging from mutation of synaptic genes to quantitative alterations in synaptic protein expression, e.g., through compromised transcriptional or translational control. We wondered whether reduced turnover and degradation of synapses, due to deregulated autophagy, would lead to similar phenotypical consequences. Ambra1, strongly expressed in cortex, hippocampus, and striatum, is a positive regulator of Beclin1, a principal player in autophagosome formation. While homozygosity of the Ambra1 null mutation causes embryonic lethality, heterozygous mice with reduced Ambra1 expression are viable, reproduce normally, and lack any immediately obvious phenotype. Surprisingly, comprehensive behavioral characterization of these mice revealed an autism-like phenotype in Ambra1+/− females only, including compromised communication and social interactions, a tendency of enhanced stereotypies/repetitive behaviors, and impaired cognitive flexibility. Reduced ultrasound communication was found in adults as well as pups, which achieved otherwise normal neurodevelopmental milestones. These features were all absent in male Ambra1+/− mice. As a first hint explaining this gender difference, we found a much stronger reduction of Ambra1 protein in the cortex of Ambra1+/− females compared to males. To conclude, Ambra1 deficiency can induce an autism-like phenotype. The restriction to the female gender of autism-generation by a defined genetic trait is unique thus far and warrants further investigation. PMID:24904333

Heterozygous ambra1 deficiency in mice: a genetic trait with autism-like behavior restricted to the female gender.

PubMed

Dere, Ekrem; Dahm, Liane; Lu, Derek; Hammerschmidt, Kurt; Ju, Anes; Tantra, Martesa; Kästner, Anne; Chowdhury, Kamal; Ehrenreich, Hannelore

2014-01-01

Autism-spectrum disorders (ASD) are heterogeneous, highly heritable neurodevelopmental conditions affecting around 0.5% of the population across cultures, with a male/female ratio of approximately 4:1. Phenotypically, ASD are characterized by social interaction and communication deficits, restricted interests, repetitive behaviors, and reduced cognitive flexibility. Identified causes converge at the level of the synapse, ranging from mutation of synaptic genes to quantitative alterations in synaptic protein expression, e.g., through compromised transcriptional or translational control. We wondered whether reduced turnover and degradation of synapses, due to deregulated autophagy, would lead to similar phenotypical consequences. Ambra1, strongly expressed in cortex, hippocampus, and striatum, is a positive regulator of Beclin1, a principal player in autophagosome formation. While homozygosity of the Ambra1 null mutation causes embryonic lethality, heterozygous mice with reduced Ambra1 expression are viable, reproduce normally, and lack any immediately obvious phenotype. Surprisingly, comprehensive behavioral characterization of these mice revealed an autism-like phenotype in Ambra1 (+/-) females only, including compromised communication and social interactions, a tendency of enhanced stereotypies/repetitive behaviors, and impaired cognitive flexibility. Reduced ultrasound communication was found in adults as well as pups, which achieved otherwise normal neurodevelopmental milestones. These features were all absent in male Ambra1 (+/-) mice. As a first hint explaining this gender difference, we found a much stronger reduction of Ambra1 protein in the cortex of Ambra1 (+/-) females compared to males. To conclude, Ambra1 deficiency can induce an autism-like phenotype. The restriction to the female gender of autism-generation by a defined genetic trait is unique thus far and warrants further investigation.

Altered cytoskeletal organization characterized lethal but not surviving Brtl+/− mice: insight on phenotypic variability in osteogenesis imperfecta

PubMed Central

Bianchi, Laura; Gagliardi, Assunta; Maruelli, Silvia; Besio, Roberta; Landi, Claudia; Gioia, Roberta; Kozloff, Kenneth M.; Khoury, Basma M.; Coucke, Paul J.; Symoens, Sofie; Marini, Joan C.; Rossi, Antonio; Bini, Luca; Forlino, Antonella

2015-01-01

Osteogenesis imperfecta (OI) is a heritable bone disease with dominant and recessive transmission. It is characterized by a wide spectrum of clinical outcomes ranging from very mild to lethal in the perinatal period. The intra- and inter-familiar OI phenotypic variability in the presence of an identical molecular defect is still puzzling to the research field. We used the OI murine model Brtl+/− to investigate the molecular basis of OI phenotypic variability. Brtl+/− resembles classical dominant OI and shows either a moderately severe or a lethal outcome associated with the same Gly349Cys substitution in the α1 chain of type I collagen. A systems biology approach was used. We took advantage of proteomic pathway analysis to functionally link proteins differentially expressed in bone and skin of Brtl+/− mice with different outcomes to define possible phenotype modulators. The skin/bone and bone/skin hybrid networks highlighted three focal proteins: vimentin, stathmin and cofilin-1, belonging to or involved in cytoskeletal organization. Abnormal cytoskeleton was indeed demonstrated by immunohistochemistry to occur only in tissues from Brtl+/− lethal mice. The aberrant cytoskeleton affected osteoblast proliferation, collagen deposition, integrin and TGF-β signaling with impairment of bone structural properties. Finally, aberrant cytoskeletal assembly was detected in fibroblasts obtained from lethal, but not from non-lethal, OI patients carrying an identical glycine substitution. Our data demonstrated that compromised cytoskeletal assembly impaired both cell signaling and cellular trafficking in mutant lethal mice, altering bone properties. These results point to the cytoskeleton as a phenotypic modulator and potential novel target for OI treatment. PMID:26264579

Extracellular Vesicle (EV) Array: microarray capturing of exosomes and other extracellular vesicles for multiplexed phenotyping.

PubMed

Jørgensen, Malene; Bæk, Rikke; Pedersen, Shona; Søndergaard, Evo K L; Kristensen, Søren R; Varming, Kim

2013-01-01

Exosomes are one of the several types of cell-derived vesicles with a diameter of 30-100 nm. These extracellular vesicles are recognized as potential markers of human diseases such as cancer. However, their use in diagnostic tests requires an objective and high-throughput method to define their phenotype and determine their concentration in biological fluids. To identify circulating as well as cell culture-derived vesicles, the current standard is immunoblotting or a flow cytometrical analysis for specific proteins, both of which requires large amounts of purified vesicles. Based on the technology of protein microarray, we hereby present a highly sensitive Extracellular Vesicle (EV) Array capable of detecting and phenotyping exosomes and other extracellular vesicles from unpurified starting material in a high-throughput manner. To only detect the exosomes captured on the EV Array, a cocktail of antibodies against the tetraspanins CD9, CD63 and CD81 was used. These antibodies were selected to ensure that all exosomes captured are detected, and concomitantly excluding the detection of other types of microvesicles. The limit of detection (LOD) was determined on exosomes derived from the colon cancer cell line LS180. It clarified that supernatant from only approximately 10(4) cells was needed to obtain signals or that only 2.5×10(4) exosomes were required for each microarray spot (~1 nL). Phenotyping was performed on plasma (1-10 µL) from 7 healthy donors, which were applied to the EV Array with a panel of antibodies against 21 different cellular surface antigens and cancer antigens. For each donor, there was considerable heterogeneity in the expression levels of individual markers. The protein profiles of the exosomes (defined as positive for CD9, CD63 and CD81) revealed that only the expression level of CD9 and CD81 was approximately equal in the 7 donors. This implies questioning the use of CD63 as a standard exosomal marker since the expression level of this tetraspanin was considerably lower.

Imaging Phenotype of Occupational Endotoxin-Related Lung Function Decline.

PubMed

Lai, Peggy S; Hang, Jing-Qing; Zhang, Feng-Ying; Sun, J; Zheng, Bu-Yong; Su, Li; Washko, George R; Christiani, David C

2016-09-01

Although occupational exposures contribute to a significant proportion of obstructive lung disease, the phenotype of obstructive lung disease associated with work-related organic dust exposure independent of smoking remains poorly defined. We identified the relative contributions of smoking and occupational endotoxin exposure to parenchymal and airway remodeling as defined by quantitative computed tomography (CT). The Shanghai Textile Worker Study is a longitudinal study of endotoxin-exposed cotton workers and endotoxin-unexposed silk workers that was initiated in 1981. Spirometry, occupational endotoxin exposure, and smoking habits were assessed at 5-year intervals. High-resolution computed tomography (CT) was performed in 464 retired workers in 2011, along with quantitative lung densitometric and airway analysis. Significant differences in all CT measures were noted across exposure groups. Occupational endotoxin exposure was associated with a decrease (-1.3%) in percent emphysema (LAAI-950), a 3.3-Hounsfield unit increase in 15th percentile density, an 18.1-g increase in lung mass, and a 2.3% increase in wall area percent. Current but not former smoking was associated with a similar CT phenotype. Changes in LAAI-950 were highly correlated with 15th percentile density (correlation -1.0). Lung mass was the only measure associated with forced expiratory volume in 1 sec (FEV1) decline, with each 10-g increase in lung mass associated with an additional loss (-6.1 mL) of FEV1 (p = 0.001) between 1981 and 2011. There are many similarities between the effects of occupational endotoxin exposure and those of tobacco smoke exposure on lung parenchyma and airway remodeling. The effects of occupational endotoxin exposure appear to persist even after the cessation of exposure. LAAI-950 may not be a reliable indicator of emphysema in subjects without spirometric impairment. Lung mass is a CT-based biomarker of accelerated lung function decline. Lai PS, Hang J, Zhang F, Sun J, Zheng BY, Su L, Washko GR, Christiani DC. 2016. Imaging phenotype of occupational endotoxin-related lung function decline. Environ Health Perspect 124:1436-1442; http://dx.doi.org/10.1289/EHP195.

Correlation of RNA secondary structure and attenuation of Sabin vaccine strains of poliovirus in tissue culture.

PubMed

Macadam, A J; Ferguson, G; Burlison, J; Stone, D; Skuce, R; Almond, J W; Minor, P D

1992-08-01

Part of the 5' noncoding regions of all three Sabin vaccine strains of poliovirus contains determinants of attenuation that are shown here to influence the ability of these strains to grow at elevated temperatures in BGM cells. The predicted RNA secondary structure of this region (nt 464-542 in P3/Sabin) suggests that both phenotypes are due to perturbation of base-paired stems. Ts phenotypes of site-directed mutants with defined changes in this region correlated well with predicted secondary structure stabilities. Reversal of base-pair orientation had little effect whereas stem disruption led to marked increases in temperature sensitivity. Phenotypic revertants of such viruses displayed mutations on either side of the stem. Mutations destabilizing stems led to intermediate phenotypes. These results provided evidence for the biological significance of the predicted RNA secondary structure.

Morphological and niche divergence of pinyon pines.

PubMed

Ortiz-Medrano, Alejandra; Scantlebury, Daniel Patrick; Vázquez-Lobo, Alejandra; Mastretta-Yanes, Alicia; Piñero, Daniel

2016-05-01

The environmental variables that define a species ecological niche should be associated with the evolutionary patterns present in the adaptations that resulted from living in these conditions. Thus, when comparing across species, we can expect to find an association between phylogenetically independent phenotypic characters and ecological niche evolution. Few studies have evaluated how organismal phenotypes might mirror patterns of niche evolution if these phenotypes reflect adaptations. Doing so could contribute on the understanding of the origin and maintenance of phenotypic diversity observed in nature. Here, we show the pattern of niche evolution of the pinyon pine lineage (Pinus subsection Cembroides); then, we suggest morphological adaptations possibly related to niche divergence, and finally, we test for correlation between ecological niche and morphology. We demonstrate that niche divergence is the general pattern within the clade and that it is positively correlated with adaptation.

Defining the phenotype of young healthy nucleus pulposus cells: recommendations of the Spine Research Interest Group at the 2014 annual ORS meeting.

PubMed

Risbud, Makarand V; Schoepflin, Zachary R; Mwale, Fackson; Kandel, Rita A; Grad, Sibylle; Iatridis, James C; Sakai, Daisuke; Hoyland, Judith A

2015-03-01

Low back pain is a major physical and socioeconomic problem. Degeneration of the intervertebral disc and especially that of nucleus pulposus (NP) has been linked to low back pain. In spite of much research focusing on the NP, consensus among the research community is lacking in defining the NP cell phenotype. A consensus agreement will allow easier distinguishing of NP cells from annulus fibrosus (AF) cells and endplate chondrocytes, a better gauge of therapeutic success, and a better guidance of tissue-engineering-based regenerative strategies that attempt to replace lost NP tissue. Most importantly, a clear definition will further the understanding of physiology and function of NP cells, ultimately driving development of novel cell-based therapeutic modalities. The Spine Research Interest Group at the 2014 Annual ORS Meeting in New Orleans convened with the task of compiling a working definition of the NP cell phenotype with hope that a consensus statement will propel disc research forward into the future. Based on evaluation of recent studies describing characteristic NP markers and their physiologic relevance, we make the recommendation of the following healthy NP phenotypic markers: stabilized expression of HIF-1α, GLUT-1, aggrecan/collagen II ratio >20, Shh, Brachyury, KRT18/19, CA12, and CD24. © 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

A Generic Data Harmonization Process for Cross-linked Research and Network Interaction. Construction and Application for the Lung Cancer Phenotype Database of the German Center for Lung Research.

PubMed

Firnkorn, D; Ganzinger, M; Muley, T; Thomas, M; Knaup, P

2015-01-01

Joint data analysis is a key requirement in medical research networks. Data are available in heterogeneous formats at each network partner and their harmonization is often rather complex. The objective of our paper is to provide a generic approach for the harmonization process in research networks. We applied the process when harmonizing data from three sites for the Lung Cancer Phenotype Database within the German Center for Lung Research. We developed a spreadsheet-based solution as tool to support the harmonization process for lung cancer data and a data integration procedure based on Talend Open Studio. The harmonization process consists of eight steps describing a systematic approach for defining and reviewing source data elements and standardizing common data elements. The steps for defining common data elements and harmonizing them with local data definitions are repeated until consensus is reached. Application of this process for building the phenotype database led to a common basic data set on lung cancer with 285 structured parameters. The Lung Cancer Phenotype Database was realized as an i2b2 research data warehouse. Data harmonization is a challenging task requiring informatics skills as well as domain knowledge. Our approach facilitates data harmonization by providing guidance through a uniform process that can be applied in a wide range of projects.

Beyond mean allelic effects: A locus at the major color gene MC1R associates also with differing levels of phenotypic and genetic (co)variance for coloration in barn owls.

PubMed

San-Jose, Luis M; Ducret, Valérie; Ducrest, Anne-Lyse; Simon, Céline; Roulin, Alexandre

2017-10-01

The mean phenotypic effects of a discovered variant help to predict major aspects of the evolution and inheritance of a phenotype. However, differences in the phenotypic variance associated to distinct genotypes are often overlooked despite being suggestive of processes that largely influence phenotypic evolution, such as interactions between the genotypes with the environment or the genetic background. We present empirical evidence for a mutation at the melanocortin-1-receptor gene, a major vertebrate coloration gene, affecting phenotypic variance in the barn owl, Tyto alba. The white MC1R allele, which associates with whiter plumage coloration, also associates with a pronounced phenotypic and additive genetic variance for distinct color traits. Contrarily, the rufous allele, associated with a rufous coloration, relates to a lower phenotypic and additive genetic variance, suggesting that this allele may be epistatic over other color loci. Variance differences between genotypes entailed differences in the strength of phenotypic and genetic associations between color traits, suggesting that differences in variance also alter the level of integration between traits. This study highlights that addressing variance differences of genotypes in wild populations provides interesting new insights into the evolutionary mechanisms and the genetic architecture underlying the phenotype. © 2017 The Author(s). Evolution © 2017 The Society for the Study of Evolution.

Whole-Exome Sequencing in Two Extreme Phenotypes of Response to VEGF-Targeted Therapies in Patients With Metastatic Clear Cell Renal Cell Carcinoma.

PubMed

Fay, Andre P; de Velasco, Guillermo; Ho, Thai H; Van Allen, Eliezer M; Murray, Bradley; Albiges, Laurence; Signoretti, Sabina; Hakimi, A Ari; Stanton, Melissa L; Bellmunt, Joaquim; McDermott, David F; Atkins, Michael B; Garraway, Levi A; Kwiatkowski, David J; Choueiri, Toni K

2016-07-01

Advances in next-generation sequencing have provided a unique opportunity to understand the biology of disease and mechanisms of sensitivity or resistance to specific agents. Renal cell carcinoma (RCC) is a heterogeneous disease and highly variable clinical responses have been observed with vascular endothelial growth factor (VEGF)-targeted therapy (VEGF-TT). We hypothesized that whole-exome sequencing analysis might identify genotypes associated with extreme response or resistance to VEGF-TT in metastatic (mRCC). Patients with mRCC who had received first-line sunitinib or pazopanib and were in 2 extreme phenotypes of response were identified. Extreme responders (ERs) were defined as those with partial response or complete response for 3 or more years (n=13) and primary refractory patients (PRPs) were defined as those with progressive disease within the first 3 months of therapy (n=14). International Metastatic RCC Database Consortium prognostic scores were not significantly different between the groups (P=.67). Considering the genes known to be mutated in RCC at significant frequency, PBRM1 mutations were identified in 7 ERs (54%) versus 1 PRP (7%) (P=.01). In addition, mutations in TP53 (n=4) were found only in PRPs (P=.09). Our data suggest that mutations in some genes in RCC may impact response to VEGF-TT. Copyright © 2016 by the National Comprehensive Cancer Network.

Late-onset Bartter syndrome type II.

PubMed

Gollasch, Benjamin; Anistan, Yoland-Marie; Canaan-Kühl, Sima; Gollasch, Maik

2017-10-01

Mutations in the ROMK1 potassium channel gene ( KCNJ1 ) cause antenatal/neonatal Bartter syndrome type II (aBS II), a renal disorder that begins in utero , accounting for the polyhydramnios and premature delivery that is typical in affected infants, who develop massive renal salt wasting, hypokalaemic metabolic alkalosis, secondary hyperreninaemic hyperaldosteronism, hypercalciuria and nephrocalcinosis. This BS type is believed to represent a disorder of the infancy, but not in adulthood. We herein describe a female patient with a remarkably late-onset and mild clinical manifestation of BS II with compound heterozygous KCNJ1 missense mutations, consisting of a novel c.197T > A (p.I66N) and a previously reported c.875G > A (p.R292Q) KCNJ1 mutation. We implemented and evaluated the performance of two different bioinformatics-based approaches of targeted massively parallel sequencing [next generation sequencing (NGS)] in defining the molecular diagnosis. Our results demonstrate that aBS II may be suspected in patients with a late-onset phenotype. Our experimental approach of NGS-based mutation screening combined with Sanger sequencing proved to be a reliable molecular approach for defining the clinical diagnosis in our patient, and results in important differential diagnostic and therapeutic implications for patients with BS. Our results could have a significant impact on the diagnosis and methodological approaches of genetic testing in other patients with clinical unclassified phenotypes of nephrocalcinosis and congenital renal electrolyte abnormalities.

Chemical rescue of cleft palate and midline defects in conditional GSK-3beta mice.

PubMed

Liu, Karen J; Arron, Joseph R; Stankunas, Kryn; Crabtree, Gerald R; Longaker, Michael T

2007-03-01

Glycogen synthase kinase-3beta (GSK-3beta) has integral roles in a variety of biological processes, including development, diabetes, and the progression of Alzheimer's disease. As such, a thorough understanding of GSK-3beta function will have a broad impact on human biology and therapeutics. Because GSK-3beta interacts with many different pathways, its specific developmental roles remain unclear. We have discovered a genetic requirement for GSK-3beta in midline development. Homozygous null mice display cleft palate, incomplete fusion of the ribs at the midline and bifid sternum as well as delayed sternal ossification. Using a chemically regulated allele of GSK-3beta (ref. 6), we have defined requirements for GSK-3beta activity during discrete temporal windows in palatogenesis and skeletogenesis. The rapamycin-dependent allele of GSK-3beta produces GSK-3beta fused to a tag, FRB* (FKBP/rapamycin binding), resulting in a rapidly destabilized chimaeric protein. In the absence of drug, GSK-3beta(FRB)*(/FRB)* mutants appear phenotypically identical to GSK-3beta-/- mutants. In the presence of drug, GSK-3betaFRB* is rapidly stabilized, restoring protein levels and activity. Using this system, mutant phenotypes were rescued by restoring endogenous GSK-3beta activity during two distinct periods in gestation. This technology provides a powerful tool for defining windows of protein function during development.

Delineating HIV-associated neurocognitive disorders using transgenic models: the neuropathogenic actions of Vpr.

PubMed

Power, Christopher; Hui, Elizabeth; Vivithanaporn, Pornpun; Acharjee, Shaona; Polyak, Maria

2012-06-01

HIV-associated neurocognitive disorders (HAND) represent a constellation of neurological disabilities defined by neuropsychological impairments, neurobehavioral abnormalities and motor deficits. To gain insights into the mechanisms underlying the development of these disabilities, several transgenic models have been developed over the past two decades, which have provided important information regarding the cellular and molecular factors contributing to the neuropathogenesis of HAND. Herein, we concentrate on the neuropathogenic effects of HIV-1 Vpr expressed under the control of c-fms, resulting transgene expression in myeloid cells in both the central and peripheral nervous systems. Vpr's actions, possibly through its impact on cell cycle machinery, in brain culminate in neuronal and astrocyte injury and death through apoptosis involving activation of caspases-3, -6 and -9 depending on the individual target cell type. Indeed, these outcomes are also induced by soluble Vpr implying Vpr's effects stem from direct interaction with target cells. Remarkably, in vivo transgenic Vpr expression induces a neurodegenerative phenotype defined by neurobehavioral deficits and neuronal loss in the absence of frank inflammation. Implantation of another viral protein, hepatitis C virus (HCV) core, into Vpr transgenic animals' brains stimulated neuroinflammation and amplified the neurodegenerative disease phenotype, thereby recapitulating HCV's putative neuropathogenic actions. The availability of different transgenic models to study HIV neuropathogenesis represents exciting and innovative approaches to understanding disease mechanisms and perhaps developing new therapeutic strategies in the future.

Associations of circulating plasma microRNAs with age, body mass index and sex in a population-based study.

PubMed

Ameling, Sabine; Kacprowski, Tim; Chilukoti, Ravi Kumar; Malsch, Carolin; Liebscher, Volkmar; Suhre, Karsten; Pietzner, Maik; Friedrich, Nele; Homuth, Georg; Hammer, Elke; Völker, Uwe

2015-10-14

Non-cellular blood circulating microRNAs (plasma miRNAs) represent a promising source for the development of prognostic and diagnostic tools owing to their minimally invasive sampling, high stability, and simple quantification by standard techniques such as RT-qPCR. So far, the majority of association studies involving plasma miRNAs were disease-specific case-control analyses. In contrast, in the present study, plasma miRNAs were analysed in a sample of 372 individuals from a population-based cohort study, the Study of Health in Pomerania (SHIP). Quantification of miRNA levels was performed by RT-qPCR using the Exiqon Serum/Plasma Focus microRNA PCR Panel V3.M covering 179 different miRNAs. Of these, 155 were included in our analyses after quality-control. Associations between plasma miRNAs and the phenotypes age, body mass index (BMI), and sex were assessed via a two-step linear regression approach per miRNA. The first step regressed out the technical parameters and the second step determined the remaining associations between the respective plasma miRNA and the phenotypes of interest. After regressing out technical parameters and adjusting for the respective other two phenotypes, 7, 15, and 35 plasma miRNAs were significantly (q < 0.05) associated with age, BMI, and sex, respectively. Additional adjustment for the blood cell parameters identified 12 and 19 miRNAs to be significantly associated with age and BMI, respectively. Most of the BMI-associated miRNAs likely originate from liver. Sex-associated differences in miRNA levels were largely determined by differences in blood cell parameters. Thus, only 7 as compared to originally 35 sex-associated miRNAs displayed sex-specific differences after adjustment for blood cell parameters. These findings emphasize that circulating miRNAs are strongly impacted by age, BMI, and sex. Hence, these parameters should be considered as covariates in association studies based on plasma miRNA levels. The established experimental and computational workflow can now be used in future screening studies to determine associations of plasma miRNAs with defined disease phenotypes.

Characterization of the CPAP-treated patient population in Catalonia

PubMed Central

Gavaldá, Ricard; Teixidó, Ivan; Woehrle, Holger; Rué, Montserrat; Solsona, Francesc; Escarrabill, Joan; Colls, Cristina; García-Altés, Anna; de Batlle, Jordi; Sánchez de-la-Torre, Manuel

2017-01-01

There are different phenotypes of obstructive sleep apnoea (OSA), many of which have not been characterised. Identification of these different phenotypes is important in defining prognosis and guiding the therapeutic strategy. The aim of this study was to characterise the entire population of continuous positive airway pressure (CPAP)-treated patients in Catalonia and identify specific patient profiles using cluster analysis. A total of 72,217 CPAP-treated patients who contacted the Catalan Health System (CatSalut) during the years 2012 and 2013 were included. Six clusters were identified, classified as “Neoplastic patients” (Cluster 1, 10.4%), “Metabolic syndrome patients” (Cluster 2, 27.7%), “Asthmatic patients” (Cluster 3, 5.8%), “Musculoskeletal and joint disorder patients” (Cluster 4, 10.3%), “Patients with few comorbidities” (Cluster 5, 35.6%) and “Oldest and cardiac disease patients” (Cluster 6, 10.2%). Healthcare facility use and mortality were highest in patients from Cluster 1 and 6. Conversely, patients in Clusters 2 and 4 had low morbidity, mortality and healthcare resource use. Our findings highlight the heterogeneity of CPAP-treated patients, and suggest that OSA is associated with a different prognosis in the clusters identified. These results suggest the need for a comprehensive and individualised approach to CPAP treatment of OSA. PMID:28934303

Phenotypic presentation of chronic cough in children

PubMed Central

2017-01-01

Chronic cough in children is increasingly defined as a cough that lasts more than four weeks. It is recognized as a different entity than cough in adults. As a result, the diagnostic approach and management of chronic cough in children are no longer extrapolated from adult guidelines. These differences are attributed to the various characteristics of the respiratory tract, immunological system and nervous system in children. Specific paediatric guidelines and algorithms for chronic cough are now widely applied. Post-infectious cough, asthma, bronchiectasis, malacia and protracted bacterial bronchitis (PBB) appear to be the major causes of cough in young children. By adolescence, the causes of cough are more likely to be similar to those in adults, namely, gastroesophageal reflux, asthma, and upper airway syndrome. In a primary setting, it is essential to investigate the underlying disease entity that initiates and sustains chronic cough. The use of cough management protocols or algorithms improves clinical outcomes and should differ depending on the associated characteristics of the cough and the child’s clinical history. Performing a thorough history and physical examination is crucial to starting an individualised approach. A correct interpretation of the phenotypic presentation can be translated into guidance for workup. This approach will be helpful for adequate management without the risk of inappropriate investigations or inadequate treatment. PMID:28523136

UFO: an Arabidopsis gene involved in both floral meristem and floral organ development.

PubMed

Levin, J Z; Meyerowitz, E M

1995-05-01

We describe the role of the UNUSUAL FLORAL ORGANS (UFO) gene in Arabidopsis floral development based on a genetic and molecular characterization of the phenotypes of nine ufo alleles. UFO is required for the proper identity of the floral meristem and acts in three different aspects of the process that distinguishes flowers from shoots. UFO is involved in establishing the whorled pattern of floral organs, controlling the determinacy of the floral meristem, and activating the APETALA3 and PISTILLATA genes required for petal and stamen identity. In many respects, UFO acts in a manner similar to LEAFY, but the ufo mutant phenotype also suggests an additional role for UFO in defining boundaries within the floral primordia or controlling cell proliferation during floral organ growth. Finally, genetic interactions that prevent flower formation and lead to the generation of filamentous structures implicate UFO as a member of a new, large, and diverse class of genes in Arabidopsis necessary for flower formation.

Multi-Scale Molecular Deconstruction of the Serotonin Neuron System.

PubMed

Okaty, Benjamin W; Freret, Morgan E; Rood, Benjamin D; Brust, Rachael D; Hennessy, Morgan L; deBairos, Danielle; Kim, Jun Chul; Cook, Melloni N; Dymecki, Susan M

2015-11-18

Serotonergic (5HT) neurons modulate diverse behaviors and physiology and are implicated in distinct clinical disorders. Corresponding diversity in 5HT neuronal phenotypes is becoming apparent and is likely rooted in molecular differences, yet a comprehensive approach characterizing molecular variation across the 5HT system is lacking, as is concomitant linkage to cellular phenotypes. Here we combine intersectional fate mapping, neuron sorting, and genome-wide RNA-seq to deconstruct the mouse 5HT system at multiple levels of granularity-from anatomy, to genetic sublineages, to single neurons. Our unbiased analyses reveal principles underlying system organization, 5HT neuron subtypes, constellations of differentially expressed genes distinguishing subtypes, and predictions of subtype-specific functions. Using electrophysiology, subtype-specific neuron silencing, and conditional gene knockout, we show that these molecularly defined 5HT neuron subtypes are functionally distinct. Collectively, this resource classifies molecular diversity across the 5HT system and discovers sertonergic subtypes, markers, organizing principles, and subtype-specific functions with potential disease relevance. Copyright © 2015 Elsevier Inc. All rights reserved.

Phenotypic Antimicrobial Susceptibility Testing with Deep Learning Video Microscopy.

PubMed

Yu, Hui; Jing, Wenwen; Iriya, Rafael; Yang, Yunze; Syal, Karan; Mo, Manni; Grys, Thomas E; Haydel, Shelley E; Wang, Shaopeng; Tao, Nongjian

2018-05-15

Timely determination of antimicrobial susceptibility for a bacterial infection enables precision prescription, shortens treatment time, and helps minimize the spread of antibiotic resistant infections. Current antimicrobial susceptibility testing (AST) methods often take several days and thus impede these clinical and health benefits. Here, we present an AST method by imaging freely moving bacterial cells in urine in real time and analyzing the videos with a deep learning algorithm. The deep learning algorithm determines if an antibiotic inhibits a bacterial cell by learning multiple phenotypic features of the cell without the need for defining and quantifying each feature. We apply the method to urinary tract infection, a common infection that affects millions of people, to determine the minimum inhibitory concentration of pathogens from both bacteria spiked urine and clinical infected urine samples for different antibiotics within 30 min and validate the results with the gold standard broth macrodilution method. The deep learning video microscopy-based AST holds great potential to contribute to the solution of increasing drug-resistant infections.

Protein model discrimination using mutational sensitivity derived from deep sequencing.

PubMed

Adkar, Bharat V; Tripathi, Arti; Sahoo, Anusmita; Bajaj, Kanika; Goswami, Devrishi; Chakrabarti, Purbani; Swarnkar, Mohit K; Gokhale, Rajesh S; Varadarajan, Raghavan

2012-02-08

A major bottleneck in protein structure prediction is the selection of correct models from a pool of decoys. Relative activities of ∼1,200 individual single-site mutants in a saturation library of the bacterial toxin CcdB were estimated by determining their relative populations using deep sequencing. This phenotypic information was used to define an empirical score for each residue (RankScore), which correlated with the residue depth, and identify active-site residues. Using these correlations, ∼98% of correct models of CcdB (RMSD ≤ 4Å) were identified from a large set of decoys. The model-discrimination methodology was further validated on eleven different monomeric proteins using simulated RankScore values. The methodology is also a rapid, accurate way to obtain relative activities of each mutant in a large pool and derive sequence-structure-function relationships without protein isolation or characterization. It can be applied to any system in which mutational effects can be monitored by a phenotypic readout. Copyright © 2012 Elsevier Ltd. All rights reserved.

Velo-cardio-facial syndrome: Frequency and textent of 22q11 deletions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lindsay, E.A.; Goldberg, R.; Jurecic, V.

Velo-cardio-facial (VCFS) or Shprintzen syndrome is associated with deletions in a region of chromosome 22q11.2 also deleted in DiGeorge anomaly and some forms of congenital heart disease. Due to the variability of phenotype, the evaluation of the incidence of deletions has been hampered by uncertainty of diagnosis. In this study, 54 patients were diagnosed with VCFS by a single group of clinicians using homogeneous clinical criteria independent of the deletion status. Cell lines of these patients were established and the deletion status evaluated for three loci within the commonly deleted region at 22q11.2 using fluorescence in situ hybridization (FISH). Inmore » 81% of the patients all three loci were hemizygous. In one patient we observed a smaller interstitial deletion than that defined by the three loci. The phenotype of this patient was not different from that observed in patients with larger deletions. 22 refs., 2 figs., 1 tab.« less

Multi-Scale Molecular Deconstruction of the Serotonin Neuron System

PubMed Central

Okaty, Benjamin W.; Freret, Morgan E.; Rood, Benjamin D.; Brust, Rachael D.; Hennessy, Morgan L.; deBairos, Danielle; Kim, Jun Chul; Cook, Melloni N.; Dymecki, Susan M.

2016-01-01

Summary Serotonergic (5HT) neurons modulate diverse behaviors and physiology and are implicated in distinct clinical disorders. Corresponding diversity in 5HT neuronal phenotypes is becoming apparent and is likely rooted in molecular differences, yet a comprehensive approach characterizing molecular variation across the 5HT system is lacking, as is concomitant linkage to cellular phenotypes. Here we combine intersectional fate mapping, neuron sorting, and genome-wide RNA-Seq to deconstruct the mouse 5HT system at multiple levels of granularity—from anatomy, to genetic sublineages, to single neurons. Our unbiased analyses reveal: principles underlying system organization, novel 5HT neuron subtypes, constellations of differentially expressed genes distinguishing subtypes, and predictions of subtype-specific functions. Using electrophysiology, subtype-specific neuron silencing, and conditional gene knockout, we show that these molecularly defined 5HT neuron subtypes are functionally distinct. Collectively, this resource classifies molecular diversity across the 5HT system and discovers new subtypes, markers, organizing principles, and subtype-specific functions with potential disease relevance. PMID:26549332

Atorvastatin calcium inhibits phenotypic modulation of PDGF-BB-induced VSMCs via down-regulation the Akt signaling pathway.

PubMed

Chen, Shuang; Liu, Baoqin; Kong, Dehui; Li, Si; Li, Chao; Wang, Huaqin; Sun, Yingxian

2015-01-01

Plasticity of vascular smooth muscle cells (VSMCs) plays a central role in the onset and progression of proliferative vascular diseases. In adult tissue, VSMCs exist in a physiological contractile-quiescent phenotype, which is defined by lack of the ability of proliferation and migration, while high expression of contractile marker proteins. After injury to the vessel, VSMC shifts from a contractile phenotype to a pathological synthetic phenotype, associated with increased proliferation, migration and matrix secretion. It has been demonstrated that PDGF-BB is a critical mediator of VSMCs phenotypic switch. Atorvastatin calcium, a selective inhibitor of 3-hydroxy-3-methyl-glutaryl l coenzyme A (HMG-CoA) reductase, exhibits various protective effects against VSMCs. In this study, we investigated the effects of atorvastatin calcium on phenotype modulation of PDGF-BB-induced VSMCs and the related intracellular signal transduction pathways. Treatment of VSMCs with atorvastatin calcium showed dose-dependent inhibition of PDGF-BB-induced proliferation. Atorvastatin calcium co-treatment inhibited the phenotype modulation and cytoskeleton rearrangements and improved the expression of contractile phenotype marker proteins such as α-SM actin, SM22α and calponin in comparison with PDGF-BB alone stimulated VSMCs. Although Akt phosphorylation was strongly elicited by PDGF-BB, Akt activation was attenuated when PDGF-BB was co-administrated with atorvastatin calcium. In conclusion, atorvastatin calcium inhibits phenotype modulation of PDGF-BB-induced VSMCs and activation of the Akt signaling pathway, indicating that Akt might play a vital role in the modulation of phenotype.

Cognitive Phenotypes and the Evolution of Animal Decisions.

PubMed

Mendelson, Tamra C; Fitzpatrick, Courtney L; Hauber, Mark E; Pence, Charles H; Rodríguez, Rafael L; Safran, Rebecca J; Stern, Caitlin A; Stevens, Jeffrey R

2016-11-01

Despite the clear fitness consequences of animal decisions, the science of animal decision making in evolutionary biology is underdeveloped compared with decision science in human psychology. Specifically, the field lacks a conceptual framework that defines and describes the relevant components of a decision, leading to imprecise language and concepts. The 'judgment and decision-making' (JDM) framework in human psychology is a powerful tool for framing and understanding human decisions, and we apply it here to components of animal decisions, which we refer to as 'cognitive phenotypes'. We distinguish multiple cognitive phenotypes in the context of a JDM framework and highlight empirical approaches to characterize them as evolvable traits. Copyright © 2016 Elsevier Ltd. All rights reserved.

Partial epilepsy and 47,XXX karyotype: report of four cases.

PubMed

Roubertie, Agathe; Humbertclaude, Véronique; Leydet, Julie; Lefort, Geneviève; Echenne, Bernard

2006-07-01

Epilepsy is a common finding in chromosomal imbalances, but only a few chromosome abnormalities have a characteristic electro-clinical pattern. Trisomy X is one of the most common sex chromosome abnormalities in females, and is associated with considerable phenotypic variability. This report describes four 47,XXX females with mental deficiency and epilepsy. Although a specific electro-clinical pattern could not be defined, the epileptic phenotypes of these patients share many features; we suggest that the association 47,XXX/epilepsy/mental retardation may not be coincidental. This report also enlarges the clinical spectrum of the 47,XXX phenotype. Moreover, these observations highlight the critical role of chromosome X in epilepsy and mental retardation.

A comprehensive global genotype-phenotype database for rare diseases.

PubMed

Trujillano, Daniel; Oprea, Gabriela-Elena; Schmitz, Yvonne; Bertoli-Avella, Aida M; Abou Jamra, Rami; Rolfs, Arndt

2017-01-01

The ability to discover genetic variants in a patient runs far ahead of the ability to interpret them. Databases with accurate descriptions of the causal relationship between the variants and the phenotype are valuable since these are critical tools in clinical genetic diagnostics. Here, we introduce a comprehensive and global genotype-phenotype database focusing on rare diseases. This database (CentoMD ® ) is a browser-based tool that enables access to a comprehensive, independently curated system utilizing stringent high-quality criteria and a quickly growing repository of genetic and human phenotype ontology (HPO)-based clinical information. Its main goals are to aid the evaluation of genetic variants, to enhance the validity of the genetic analytical workflow, to increase the quality of genetic diagnoses, and to improve evaluation of treatment options for patients with hereditary diseases. The database software correlates clinical information from consented patients and probands of different geographical backgrounds with a large dataset of genetic variants and, when available, biomarker information. An automated follow-up tool is incorporated that informs all users whenever a variant classification has changed. These unique features fully embedded in a CLIA/CAP-accredited quality management system allow appropriate data quality and enhanced patient safety. More than 100,000 genetically screened individuals are documented in the database, resulting in more than 470 million variant detections. Approximately, 57% of the clinically relevant and uncertain variants in the database are novel. Notably, 3% of the genetic variants identified and previously reported in the literature as being associated with a particular rare disease were reclassified, based on internal evidence, as clinically irrelevant. The database offers a comprehensive summary of the clinical validity and causality of detected gene variants with their associated phenotypes, and is a valuable tool for identifying new disease genes through the correlation of novel genetic variants with specific, well-defined phenotypes.

Spare capacity and phenotypic flexibility in the digestive system of a migratory bird: defining the limits of animal design

PubMed Central

McWilliams, Scott R.; Karasov, William H.

2014-01-01

Flexible phenotypes enable animals to live in environments that change over space and time, and knowing the limits to and the required time scale for this flexibility provides insights into constraints on energy and nutrient intake, diet diversity and niche width. We quantified the level of immediate and ultimate spare capacity, and thus the extent of phenotypic flexibility, in the digestive system of a migratory bird in response to increased energy demand, and identified the digestive constraints responsible for the limits on sustained energy intake. Immediate spare capacity decreased from approximately 50% for birds acclimated to relatively benign temperatures to less than 20% as birds approached their maximum sustainable energy intake. Ultimate spare capacity enabled an increase in feeding rate of approximately 126% as measured in birds acclimated for weeks at −29°C compared with +21°C. Increased gut size and not tissue-specific differences in nutrient uptake or changes in digestive efficiency or retention time were primarily responsible for this increase in capacity with energy demand, and this change required more than 1–2 days. Thus, the pace of change in digestive organ size may often constrain energy intake and, for birds, retard the pace of their migration. PMID:24718764

Spare capacity and phenotypic flexibility in the digestive system of a migratory bird: defining the limits of animal design.

PubMed

McWilliams, Scott R; Karasov, William H

2014-05-22

Flexible phenotypes enable animals to live in environments that change over space and time, and knowing the limits to and the required time scale for this flexibility provides insights into constraints on energy and nutrient intake, diet diversity and niche width. We quantified the level of immediate and ultimate spare capacity, and thus the extent of phenotypic flexibility, in the digestive system of a migratory bird in response to increased energy demand, and identified the digestive constraints responsible for the limits on sustained energy intake. Immediate spare capacity decreased from approximately 50% for birds acclimated to relatively benign temperatures to less than 20% as birds approached their maximum sustainable energy intake. Ultimate spare capacity enabled an increase in feeding rate of approximately 126% as measured in birds acclimated for weeks at -29°C compared with +21°C. Increased gut size and not tissue-specific differences in nutrient uptake or changes in digestive efficiency or retention time were primarily responsible for this increase in capacity with energy demand, and this change required more than 1-2 days. Thus, the pace of change in digestive organ size may often constrain energy intake and, for birds, retard the pace of their migration.

Improving the phenotype predictions of a yeast genome-scale metabolic model by incorporating enzymatic constraints

DOE PAGES

Sánchez, Benjamín J.; Zhang, Cheng; Nilsson, Avlant; ...

2017-03-08

Genome-scale metabolic models (GEMs) are widely used to calculate metabolic phenotypes. They rely on defining a set of constraints, the most common of which is that the production of metabolites and/or growth are limited by the carbon source uptake rate. However, enzyme abundances and kinetics, which act as limitations on metabolic fluxes, are not taken into account. Here, we present GECKO, a method that enhances a GEM to account for enzymes as part of reactions, thereby ensuring that each metabolic flux does not exceed its maximum capacity, equal to the product of the enzyme's abundance and turnover number. We appliedmore » GECKO to a Saccharomyces cerevisiae GEM and demonstrated that the new model could correctly describe phenotypes that the previous model could not, particularly under high enzymatic pressure conditions, such as yeast growing on different carbon sources in excess, coping with stress, or overexpressing a specific pathway. GECKO also allows to directly integrate quantitative proteomics data; by doing so, we significantly reduced flux variability of the model, in over 60% of metabolic reactions. Additionally, the model gives insight into the distribution of enzyme usage between and within metabolic pathways. The developed method and model are expected to increase the use of model-based design in metabolic engineering.« less

ADHD latent class clusters: DSM-IV subtypes and comorbidity

PubMed Central

Elia, Josephine; Arcos-Burgos, Mauricio; Bolton, Kelly L.; Ambrosini, Paul J.; Berrettini, Wade; Muenke, Maximilian

2014-01-01

ADHD (Attention Deficit Hyperactivity Disorder) has a complex, heterogeneous phenotype only partially captured by Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria. In this report, latent class analyses (LCA) are used to identify ADHD phenotypes using K-SADS-IVR (Schedule for Affective Disorders & Schizophrenia for School Age Children-IV-Revised) symptoms and symptom severity data from a clinical sample of 500 ADHD subjects, ages 6–18, participating in an ADHD genetic study. Results show that LCA identified six separate ADHD clusters, some corresponding to specific DSM-IV subtypes while others included several subtypes. DSM-IV comorbid anxiety and mood disorders were generally similar across all clusters, and subjects without comorbidity did not aggregate within any one cluster. Age and gender composition also varied. These results support findings from population-based LCA studies. The six clusters provide additional homogenous groups that can be used to define ADHD phenotypes in genetic association studies. The limited age ranges aggregating in the different clusters may prove to be a particular advantage in genetic studies where candidate gene expression may vary during developmental phases. DSM-IV comorbid mood and anxiety disorders also do not appear to increase cluster heterogeneity; however, longitudinal studies that cover period of risk are needed to support this finding. PMID:19900717

A high-content platform to characterise human induced pluripotent stem cell lines.

PubMed

Leha, Andreas; Moens, Nathalie; Meleckyte, Ruta; Culley, Oliver J; Gervasio, Mia K; Kerz, Maximilian; Reimer, Andreas; Cain, Stuart A; Streeter, Ian; Folarin, Amos; Stegle, Oliver; Kielty, Cay M; Durbin, Richard; Watt, Fiona M; Danovi, Davide

2016-03-01

Induced pluripotent stem cells (iPSCs) provide invaluable opportunities for future cell therapies as well as for studying human development, modelling diseases and discovering therapeutics. In order to realise the potential of iPSCs, it is crucial to comprehensively characterise cells generated from large cohorts of healthy and diseased individuals. The human iPSC initiative (HipSci) is assessing a large panel of cell lines to define cell phenotypes, dissect inter- and intra-line and donor variability and identify its key determinant components. Here we report the establishment of a high-content platform for phenotypic analysis of human iPSC lines. In the described assay, cells are dissociated and seeded as single cells onto 96-well plates coated with fibronectin at three different concentrations. This method allows assessment of cell number, proliferation, morphology and intercellular adhesion. Altogether, our strategy delivers robust quantification of phenotypic diversity within complex cell populations facilitating future identification of the genetic, biological and technical determinants of variance. Approaches such as the one described can be used to benchmark iPSCs from multiple donors and create novel platforms that can readily be tailored for disease modelling and drug discovery. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Improving the phenotype predictions of a yeast genome-scale metabolic model by incorporating enzymatic constraints

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sánchez, Benjamín J.; Zhang, Cheng; Nilsson, Avlant

Genome-scale metabolic models (GEMs) are widely used to calculate metabolic phenotypes. They rely on defining a set of constraints, the most common of which is that the production of metabolites and/or growth are limited by the carbon source uptake rate. However, enzyme abundances and kinetics, which act as limitations on metabolic fluxes, are not taken into account. Here, we present GECKO, a method that enhances a GEM to account for enzymes as part of reactions, thereby ensuring that each metabolic flux does not exceed its maximum capacity, equal to the product of the enzyme's abundance and turnover number. We appliedmore » GECKO to a Saccharomyces cerevisiae GEM and demonstrated that the new model could correctly describe phenotypes that the previous model could not, particularly under high enzymatic pressure conditions, such as yeast growing on different carbon sources in excess, coping with stress, or overexpressing a specific pathway. GECKO also allows to directly integrate quantitative proteomics data; by doing so, we significantly reduced flux variability of the model, in over 60% of metabolic reactions. Additionally, the model gives insight into the distribution of enzyme usage between and within metabolic pathways. The developed method and model are expected to increase the use of model-based design in metabolic engineering.« less

Is junk DNA bunk? A critique of ENCODE.

PubMed

Doolittle, W Ford

2013-04-02

Do data from the Encyclopedia Of DNA Elements (ENCODE) project render the notion of junk DNA obsolete? Here, I review older arguments for junk grounded in the C-value paradox and propose a thought experiment to challenge ENCODE's ontology. Specifically, what would we expect for the number of functional elements (as ENCODE defines them) in genomes much larger than our own genome? If the number were to stay more or less constant, it would seem sensible to consider the rest of the DNA of larger genomes to be junk or, at least, assign it a different sort of role (structural rather than informational). If, however, the number of functional elements were to rise significantly with C-value then, (i) organisms with genomes larger than our genome are more complex phenotypically than we are, (ii) ENCODE's definition of functional element identifies many sites that would not be considered functional or phenotype-determining by standard uses in biology, or (iii) the same phenotypic functions are often determined in a more diffuse fashion in larger-genomed organisms. Good cases can be made for propositions ii and iii. A larger theoretical framework, embracing informational and structural roles for DNA, neutral as well as adaptive causes of complexity, and selection as a multilevel phenomenon, is needed.

Aggregates, Crystals, Gels, and Amyloids: Intracellular and Extracellular Phenotypes at the Crossroads of Immunoglobulin Physicochemical Property and Cell Physiology

PubMed Central

2013-01-01

Recombinant immunoglobulins comprise an important class of human therapeutics. Although specific immunoglobulins can be purposefully raised against desired antigen targets by various methods, identifying an immunoglobulin clone that simultaneously possesses potent therapeutic activities and desirable manufacturing-related attributes often turns out to be challenging. The variable domains of individual immunoglobulins primarily define the unique antigen specificities and binding affinities inherent to each clone. The primary sequence of the variable domains also specifies the unique physicochemical properties that modulate various aspects of individual immunoglobulin life cycle, starting from the biosynthetic steps in the endoplasmic reticulum, secretory pathway trafficking, secretion, and the fate in the extracellular space and in the endosome-lysosome system. Because of the diverse repertoire of immunoglobulin physicochemical properties, some immunoglobulin clones' intrinsic properties may manifest as intriguing cellular phenotypes, unusual solution behaviors, and serious pathologic outcomes that are of scientific and clinical importance. To gain renewed insights into identifying manufacturable therapeutic antibodies, this paper catalogs important intracellular and extracellular phenotypes induced by various subsets of immunoglobulin clones occupying different niches of diverse physicochemical repertoire space. Both intrinsic and extrinsic factors that make certain immunoglobulin clones desirable or undesirable for large-scale manufacturing and therapeutic use are summarized. PMID:23533417

Plant Phenotyping through the Eyes of Complex Systems: Theoretical Considerations

NASA Astrophysics Data System (ADS)

Kim, J.

2017-12-01

Plant phenotyping is an emerging transdisciplinary research which necessitates not only the communication and collaboration of scientists from different disciplines but also the paradigm shift to a holistic approach. Complex system is defined as a system having a large number of interacting parts (or particles, agents), whose interactions give rise to non-trivial properties like self-organization and emergence. Plant ecosystems are complex systems which are continually morphing dynamical systems, i.e. self-organizing hierarchical open systems. Such systems are composed of many subunits/subsystems with nonlinear interactions and feedback. The throughput such as the flow of energy, matter and information is the key control parameter in complex systems. Information theoretic approaches can be used to understand and identify such interactions, structures and dynamics through reductions in uncertainty (i.e. entropy). The theoretical considerations based on network and thermodynamic thinking and exemplary analyses (e.g. dynamic process network, spectral entropy) of the throughput time series will be presented. These can be used as a framework to develop more discipline-specific fundamental approaches to provide tools for the transferability of traits between measurement scales in plant phenotyping. Acknowledgment: This work was funded by the Weather Information Service Engine Program of the Korea Meteorological Administration under Grant KMIPA-2012-0001.

Molecular deconstruction, detection, and computational prediction of microenvironment-modulated cellular responses to cancer therapeutics.

PubMed

Labarge, Mark A; Parvin, Bahram; Lorens, James B

2014-04-01

The field of bioengineering has pioneered the application of new precision fabrication technologies to model the different geometric, physical or molecular components of tissue microenvironments on solid-state substrata. Tissue engineering approaches building on these advances are used to assemble multicellular mimetic-tissues where cells reside within defined spatial contexts. The functional responses of cells in fabricated microenvironments have revealed a rich interplay between the genome and extracellular effectors in determining cellular phenotypes and in a number of cases have revealed the dominance of microenvironment over genotype. Precision bioengineered substrata are limited to a few aspects, whereas cell/tissue-derived microenvironments have many undefined components. Thus, introducing a computational module may serve to integrate these types of platforms to create reasonable models of drug responses in human tissues. This review discusses how combinatorial microenvironment microarrays and other biomimetic microenvironments have revealed emergent properties of cells in particular microenvironmental contexts, the platforms that can measure phenotypic changes within those contexts, and the computational tools that can unify the microenvironment-imposed functional phenotypes with underlying constellations of proteins and genes. Ultimately we propose that a merger of these technologies will enable more accurate pre-clinical drug discovery. Copyright © 2014 Elsevier B.V. All rights reserved.

Is junk DNA bunk? A critique of ENCODE

PubMed Central

Doolittle, W. Ford

2013-01-01

Do data from the Encyclopedia Of DNA Elements (ENCODE) project render the notion of junk DNA obsolete? Here, I review older arguments for junk grounded in the C-value paradox and propose a thought experiment to challenge ENCODE’s ontology. Specifically, what would we expect for the number of functional elements (as ENCODE defines them) in genomes much larger than our own genome? If the number were to stay more or less constant, it would seem sensible to consider the rest of the DNA of larger genomes to be junk or, at least, assign it a different sort of role (structural rather than informational). If, however, the number of functional elements were to rise significantly with C-value then, (i) organisms with genomes larger than our genome are more complex phenotypically than we are, (ii) ENCODE’s definition of functional element identifies many sites that would not be considered functional or phenotype-determining by standard uses in biology, or (iii) the same phenotypic functions are often determined in a more diffuse fashion in larger-genomed organisms. Good cases can be made for propositions ii and iii. A larger theoretical framework, embracing informational and structural roles for DNA, neutral as well as adaptive causes of complexity, and selection as a multilevel phenomenon, is needed. PMID:23479647

Characteristics of Fluency and Speech in Two Families With High Incidences of Stuttering

PubMed Central

Freeman, Frances J.; Braun, Allen

2015-01-01

Purpose This study presents data from 2 families with high incidence of stuttering, comparing methods of phenotype assignment and exploring the presence of other fluency disorders and corresponding speech characteristics. Method Three methods for assigning phenotype of stuttering were used: self-identification, family identification, and expert identification. Agreement on which individuals were assigned by each of these methods was studied. Multiple measures of fluency and speech production were obtained. Results Self-reports and descriptions of blocking rather than self-identification as a person who stutters demonstrated the best agreement with expert identification of stuttering. Family identification showed poor agreement with both expert and self-identification of stuttering. Using binary categories of fluent or stuttering, 90% of individuals in 1 family were classified by expert consensus. Only 70% of the other family could be similarly categorized. Experts required 2 other categories, cluttering and other fluency disorders, to fully characterize dysfluency within this family. These 2 families also demonstrated differences in speech production. Conclusion Some families with high incidence of stuttering may also have high incidence of other fluency disorders and other speech-production difficulties. This finding may have ramifications for genetic studies, including criteria for defining phenotype and collapsing data across multiple families. PMID:26126023

Audiological findings in Usher syndrome types IIa and II (non-IIa).

PubMed

Sadeghi, Mehdi; Cohn, Edward S; Kelly, William J; Kimberling, William J; Tranebjoerg, Lisbeth; Möller, Claes

2004-03-01

The aim was to define the natural history of hearing loss in Usher syndrome type IIa compared to non-IIa. People with Usher syndrome type II show moderate-to-severe hearing loss, normal balance and retinitis pigmentosa. Several genes cause Usher syndrome type II. Our subjects formed two genetic groups: (1) subjects with Usher syndrome type IIa with a mutation and/or linkage to the Usher IIa gene; (2) subjects with the Usher II phenotype with no mutation and/or linkage to the Usher IIa gene. Four hundred and two audiograms of 80 Usher IIa subjects were compared with 435 audiograms of 87 non-IIa subjects. Serial audiograms with intervals of > or = 5 years were examined for progression in 109 individuals Those with Usher syndrome type IIa had significantly worse hearing thresholds than those with non-IIa Usher syndrome after the second decade. The hearing loss in Usher syndrome type IIa was found to be more progressive, and the progression started earlier than in non-IIa Usher syndrome. This suggests an auditory phenotype for Usher syndrome type IIa that is different from that of other types of Usher syndrome II. Thus, this is to our knowledge one of the first studies showing a genotype-phenotype auditory correlation.

[Language and reality: the origin of man].

PubMed

Maturana, H

1989-07-01

The author proposes: 1. That a lineage of living systems is constituted by the reproductive conservation of a manner of living under the form of an ontogenic phenotype. 2. That language is a manner of living in recurrent consensual coordinations of consensual coordinations of actions. 3. That the human manner of living entails among other things, a braiding of languaging and emotioning that we call conversation. 4. That human beings arise in the history of bipedal primates with the origin of language, and the constitution of a lineage defined by the conservation of an ontogenic phenotype that includes conversations as part of it. 5. That the magnitude of the involvement of the brain and anatomy of the larynx and face in speech as our main manner of languaging indicate that language cannot have arisen later than two to three millions year ago. 6. That rationally pertains to the operational coherences of languaging and that different rational domains are constituted by different basic notions that are accepted a priori. That is, on preference. 7. That responsibility and freedom are a function of our awareness of the participation of our emotions (preferences) in the constitution of the rational domains in which we operate.

MAPA distinguishes genotype-specific variability of highly similar regulatory protein isoforms in potato tuber.

PubMed

Hoehenwarter, Wolfgang; Larhlimi, Abdelhalim; Hummel, Jan; Egelhofer, Volker; Selbig, Joachim; van Dongen, Joost T; Wienkoop, Stefanie; Weckwerth, Wolfram

2011-07-01

Mass Accuracy Precursor Alignment is a fast and flexible method for comparative proteome analysis that allows the comparison of unprecedented numbers of shotgun proteomics analyses on a personal computer in a matter of hours. We compared 183 LC-MS analyses and more than 2 million MS/MS spectra and could define and separate the proteomic phenotypes of field grown tubers of 12 tetraploid cultivars of the crop plant Solanum tuberosum. Protein isoforms of patatin as well as other major gene families such as lipoxygenase and cysteine protease inhibitor that regulate tuber development were found to be the primary source of variability between the cultivars. This suggests that differentially expressed protein isoforms modulate genotype specific tuber development and the plant phenotype. We properly assigned the measured abundance of tryptic peptides to different protein isoforms that share extensive stretches of primary structure and thus inferred their abundance. Peptides unique to different protein isoforms were used to classify the remaining peptides assigned to the entire subset of isoforms based on a common abundance profile using multivariate statistical procedures. We identified nearly 4000 proteins which we used for quantitative functional annotation making this the most extensive study of the tuber proteome to date.

Chemical Fluxes in Cellular Steady States Measured by Fluorescence Correlation Spectroscopy

NASA Astrophysics Data System (ADS)

Qian, Hong; Elson, Elliot L.

Genetically, identical cells adopt phenotypes that have different structures, functions, and metabolic properties. In multi-cellular organisms, for example, tissue-specific phenotypes distinguish muscle cells, liver cells, fibroblasts, and blood cells that differ in biochemical functions, geometric forms, and interactions with extracellular environments. Tissue-specific cells usually have different metabolic functions such as synthesis of distinct spectra of secreted proteins, e.g., by liver or pancreatic cells, or of structural proteins, e.g., muscle vs. epithelial cells. But more importantly, a phenotype should include a dynamic aspect: different phenotypes can have distinctly different dynamic functions such as contraction of muscle cells and locomotion of leukocytes. The phenotypes of differentiated tissue cells are typically stable, but they can respond to changes in external conditions, e.g., as in the hypertrophy of muscle cells in response to extra load [1] or the phenotypic shift of fibroblasts to myofibroblasts as part of the wound healing response [2]. Cells pass through sequences of phenotypes during development and also undergo malignant phenotypic transformations as occur in cancer and heart disease.

The myositis autoantibody phenotypes of the juvenile idiopathic inflammatory myopathies.

PubMed

Rider, Lisa G; Shah, Mona; Mamyrova, Gulnara; Huber, Adam M; Rice, Madeline Murguia; Targoff, Ira N; Miller, Frederick W

2013-07-01

The juvenile idiopathic inflammatory myopathies (JIIM) are systemic autoimmune diseases characterized by skeletal muscle weakness, characteristic rashes, and other systemic features. In follow-up to our study defining the major clinical subgroup phenotypes of JIIM, we compared demographics, clinical features, laboratory measures, and outcomes among myositis-specific autoantibody (MSA) subgroups, as well as with published data on adult idiopathic inflammatory myopathy patients enrolled in a separate natural history study. In the present study, of 430 patients enrolled in a nationwide registry study who had serum tested for myositis autoantibodies, 374 had either a single specific MSA (n = 253) or no identified MSA (n = 121) and were the subject of the present report. Following univariate analysis, we used random forest classification and exact logistic regression modeling to compare autoantibody subgroups. Anti-p155/140 autoantibodies were the most frequent subgroup, present in 32% of patients with juvenile dermatomyositis (JDM) or overlap myositis with JDM, followed by anti-MJ autoantibodies, which were seen in 20% of JIIM patients, primarily in JDM. Other MSAs, including anti-synthetase, anti-signal recognition particle (SRP), and anti-Mi-2, were present in only 10% of JIIM patients. Features that characterized the anti-p155/140 autoantibody subgroup included Gottron papules, malar rash, "shawl-sign" rash, photosensitivity, cuticular overgrowth, lowest creatine kinase (CK) levels, and a predominantly chronic illness course. The features that differed for patients with anti-MJ antibodies included muscle cramps, dysphonia, intermediate CK levels, a high frequency of hospitalization, and a monocyclic disease course. Patients with anti-synthetase antibodies had higher frequencies of interstitial lung disease, arthralgia, and "mechanic's hands," and had an older age at diagnosis. The anti-SRP group, which had exclusively juvenile polymyositis, was characterized by high frequencies of black race, severe onset, distal weakness, falling episodes, Raynaud phenomenon, cardiac involvement, high CK levels, chronic disease course, frequent hospitalization, and wheelchair use. Characteristic features of the anti-Mi-2 subgroup included Hispanic ethnicity, classic dermatomyositis and malar rashes, high CK levels, and very low mortality. Finally, the most common features of patients without any currently defined MSA or myositis-associated autoantibodies included linear extensor erythema, arthralgia, and a monocyclic disease course. Several demographic and clinical features were shared between juvenile and adult idiopathic inflammatory myopathy subgroups, but with several important differences. We conclude that juvenile myositis is a heterogeneous group of illnesses with distinct autoantibody phenotypes defined by varying clinical and demographic characteristics, laboratory features, and outcomes.

The Myositis Autoantibody Phenotypes of the Juvenile Idiopathic Inflammatory Myopathies

PubMed Central

Shah, Mona; Mamyrova, Gulnara; Huber, Adam M.; Rice, Madeline Murguia; Targoff, Ira N.; Miller, Frederick W.

2013-01-01

Abstract The juvenile idiopathic inflammatory myopathies (JIIM) are systemic autoimmune diseases characterized by skeletal muscle weakness, characteristic rashes, and other systemic features. In follow-up to our study defining the major clinical subgroup phenotypes of JIIM, we compared demographics, clinical features, laboratory measures, and outcomes among myositis-specific autoantibody (MSA) subgroups, as well as with published data on adult idiopathic inflammatory myopathy patients enrolled in a separate natural history study. In the present study, of 430 patients enrolled in a nationwide registry study who had serum tested for myositis autoantibodies, 374 had either a single specific MSA (n = 253) or no identified MSA (n = 121) and were the subject of the present report. Following univariate analysis, we used random forest classification and exact logistic regression modeling to compare autoantibody subgroups. Anti-p155/140 autoantibodies were the most frequent subgroup, present in 32% of patients with juvenile dermatomyositis (JDM) or overlap myositis with JDM, followed by anti-MJ autoantibodies, which were seen in 20% of JIIM patients, primarily in JDM. Other MSAs, including anti-synthetase, anti-signal recognition particle (SRP), and anti-Mi-2, were present in only 10% of JIIM patients. Features that characterized the anti-p155/140 autoantibody subgroup included Gottron papules, malar rash, “shawl-sign” rash, photosensitivity, cuticular overgrowth, lowest creatine kinase (CK) levels, and a predominantly chronic illness course. The features that differed for patients with anti-MJ antibodies included muscle cramps, dysphonia, intermediate CK levels, a high frequency of hospitalization, and a monocyclic disease course. Patients with anti-synthetase antibodies had higher frequencies of interstitial lung disease, arthralgia, and “mechanic’s hands,” and had an older age at diagnosis. The anti-SRP group, which had exclusively juvenile polymyositis, was characterized by high frequencies of black race, severe onset, distal weakness, falling episodes, Raynaud phenomenon, cardiac involvement, high CK levels, chronic disease course, frequent hospitalization, and wheelchair use. Characteristic features of the anti-Mi-2 subgroup included Hispanic ethnicity, classic dermatomyositis and malar rashes, high CK levels, and very low mortality. Finally, the most common features of patients without any currently defined MSA or myositis-associated autoantibodies included linear extensor erythema, arthralgia, and a monocyclic disease course. Several demographic and clinical features were shared between juvenile and adult idiopathic inflammatory myopathy subgroups, but with several important differences. We conclude that juvenile myositis is a heterogeneous group of illnesses with distinct autoantibody phenotypes defined by varying clinical and demographic characteristics, laboratory features, and outcomes. PMID:23877355

The differential view of genotype–phenotype relationships

PubMed Central

Orgogozo, Virginie; Morizot, Baptiste; Martin, Arnaud

2015-01-01

An integrative view of diversity and singularity in the living world requires a better understanding of the intricate link between genotypes and phenotypes. Here we re-emphasize the old standpoint that the genotype–phenotype (GP) relationship is best viewed as a connection between two differences, one at the genetic level and one at the phenotypic level. As of today, predominant thinking in biology research is that multiple genes interact with multiple environmental variables (such as abiotic factors, culture, or symbionts) to produce the phenotype. Often, the problem of linking genotypes and phenotypes is framed in terms of genotype and phenotype maps, and such graphical representations implicitly bring us away from the differential view of GP relationships. Here we show that the differential view of GP relationships is a useful explanatory framework in the context of pervasive pleiotropy, epistasis, and environmental effects. In such cases, it is relevant to view GP relationships as differences embedded into differences. Thinking in terms of differences clarifies the comparison between environmental and genetic effects on phenotypes and helps to further understand the connection between genotypes and phenotypes. PMID:26042146

Risk of breast cancer with CXCR4-using HIV defined by V3 loop sequencing.

PubMed

Goedert, James J; Swenson, Luke C; Napolitano, Laura A; Haddad, Mojgan; Anastos, Kathryn; Minkoff, Howard; Young, Mary; Levine, Alexandra; Adeyemi, Oluwatoyin; Seaberg, Eric C; Aouizerat, Bradley; Rabkin, Charles S; Harrigan, P Richard; Hessol, Nancy A

2015-01-01

Evaluate the risk of female breast cancer associated with HIV-CXCR4 (X4) tropism as determined by various genotypic measures. A breast cancer case-control study, with pairwise comparisons of tropism determination methods, was conducted. From the Women's Interagency HIV Study repository, one stored plasma specimen was selected from 25 HIV-infected cases near the breast cancer diagnosis date and 75 HIV-infected control women matched for age and calendar date. HIV-gp120 V3 sequences were derived by Sanger population sequencing (PS) and 454-pyro deep sequencing (DS). Sequencing-based HIV-X4 tropism was defined using the geno2pheno algorithm, with both high-stringency DS [false-positive rate (3.5) and 2% X4 cutoff], and lower stringency DS (false-positive rate, 5.75 and 15% X4 cutoff). Concordance of tropism results by PS, DS, and previously performed phenotyping was assessed with kappa (κ) statistics. Case-control comparisons used exact P values and conditional logistic regression. In 74 women (19 cases, 55 controls) with complete results, prevalence of HIV-X4 by PS was 5% in cases vs 29% in controls (P = 0.06; odds ratio, 0.14; confidence interval: 0.003 to 1.03). Smaller case-control prevalence differences were found with high-stringency DS (21% vs 36%, P = 0.32), lower stringency DS (16% vs 35%, P = 0.18), and phenotyping (11% vs 31%, P = 0.10). HIV-X4 tropism concordance was best between PS and lower stringency DS (93%, κ = 0.83). Other pairwise concordances were 82%-92% (κ = 0.56-0.81). Concordance was similar among cases and controls. HIV-X4 defined by population sequencing (PS) had good agreement with lower stringency DS and was significantly associated with lower odds of breast cancer.

Biologic treatment eligibility for real-world patients with severe asthma: The IDEAL study.

PubMed

Albers, Frank C; Müllerová, Hana; Gunsoy, Necdet B; Shin, Ji-Yeon; Nelsen, Linda M; Bradford, Eric S; Cockle, Sarah M; Suruki, Robert Y

2018-02-01

Severe asthma comprises several distinct phenotypes. Consequently, patients with severe asthma can be eligible for more than one biologic treatment targeting Th2 inflammation, such as anti-interleukin (IL)-5 and anti-immunoglobulin (Ig) E. The objective of this study was to describe treatment eligibility and overlap in treatment eligibility for mepolizumab (anti-IL-5), omalizumab (anti-IgE) and reslizumab (anti-IL-5) in patients with severe asthma, who were recruited from clinical practice. This cross-sectional, single-visit, observational study in six countries enrolled patients with severe asthma (defined by American Thoracic Society/European Respiratory Society guidelines). Assessable patients were analysed as a total cohort and a sub-cohort, who were not currently receiving omalizumab. Treatment eligibility was defined according to the local prescribing information or protocol-defined inclusion/exclusion criteria. Patients currently receiving omalizumab were automatically categorised as omalizumab-eligible. The total cohort comprised 670 patients who met the analysis criteria, of whom 20% were eligible for mepolizumab, 31-41% were eligible for omalizumab (depending on eligibility criteria used), and 5% were eligible for reslizumab. In patients not currently receiving omalizumab (n = 502), proportions eligible for each biologic were similar (mepolizumab: 20%, reslizumab 6%) or lower (omalizumab 7-21%) than those for the total cohort. Overlap in treatment eligibility varied; in mepolizumab-eligible patients not currently receiving omalizumab (n = 101), 27-37% were omalizumab-eligible and 18% were reslizumab-eligible. Treatment eligibility for mepolizumab and omalizumab was higher than that for reslizumab. Although there was some overlap in treatment eligibility, the patient groups eligible for treatment with anti-IL-5 or anti-IgE therapies were often distinct, emphasising the different phenotypes and endotypes in severe asthma.

Diversity of Antimicrobial Resistance Phenotypes in Salmonella Isolated from Commercial Poultry Farms

PubMed Central

Liljebjelke, Karen A.; Hofacre, Charles L.; White, David G.; Ayers, Sherry; Lee, Margie D.; Maurer, John J.

2017-01-01

Salmonella remains the leading cause of foodborne illness in the United States, and the dissemination of drug-resistant Salmonellae through the food chain has important implications for treatment failure of salmonellosis. We investigated the ecology of Salmonella in integrated broiler production in order to understand the flow of antibiotic susceptible and resistant strains within this system. Data were analyzed from a retrospective study focused on antimicrobial resistant Salmonella recovered from commercial broiler chicken farms conducted during the initial years of the US FDA’s foray into retail meat surveillance by the National Antimicrobial Resistance Monitoring System (NARMS). Sixty-three percentage of Salmonella were pan-susceptible to a panel of 19 antimicrobials used by the NARMS program. Twenty-five antimicrobial resistance phenotypes were observed in Salmonella isolated from two broiler chicken farms. However, Salmonella displaying resistance to streptomycin, alone, and in combination with other antibiotics was the most prevalent (36.3%) antimicrobial resistance phenotype observed. Resistance to streptomycin and sulfadimethoxine appeared to be linked to the transposon, Tn21. Combinations of resistance against streptomycin, gentamicin, sulfadimethoxine, trimethoprim, and tetracycline were observed for a variety of Salmonella enterica serovars and genetic types as defined by pulsed-field gel electrophoresis. There were within and between farm differences in the antibiotic susceptibilities of Salmonella and some of these differences were linked to specific serovars. However, farm differences were not linked to antibiotic usage. Analysis of the temporal and spatial distribution of the endemic Salmonella serovars on these farms suggests that preventing vertical transmission of antibiotic-resistant Salmonella would reduce carcass contamination with antibiotic-resistant Salmonella and subsequently human risk exposure. PMID:28691011

Understanding the addiction cycle: a complex biology with distinct contributions of genotype vs. sex at each stage.

PubMed

Wilhelm, C J; Hashimoto, J G; Roberts, M L; Sonmez, M K; Wiren, K M

2014-10-24

Ethanol abuse can lead to addiction, brain damage and premature death. The cycle of alcohol addiction has been described as a composite consisting of three stages: intoxication, withdrawal and craving/abstinence. There is evidence for contributions of both genotype and sex to alcoholism, but an understanding of the biological underpinnings is limited. Utilizing both sexes of genetic animal models with highly divergent alcohol withdrawal severity, Withdrawal Seizure-Resistant (WSR) and Withdrawal Seizure-Prone (WSP) mice, the distinct contributions of genotype/phenotype and of sex during addiction stages on neuroadaptation were characterized. Transcriptional profiling was performed to identify expression changes as a consequence of chronic intoxication in the medial prefrontal cortex. Significant expression differences were identified on a single platform and tracked over a behaviorally relevant time course that covered each stage of alcohol addiction; i.e., after chronic intoxication, during peak withdrawal, and after a defined period of abstinence. Females were more sensitive to ethanol with higher fold expression differences. Bioinformatics showed a strong effect of sex on the data structure of expression profiles during chronic intoxication and at peak withdrawal irrespective of genetic background. However, during abstinence, differences were observed instead between the lines/phenotypes irrespective of sex. Confirmation of identified pathways showed distinct inflammatory signaling following intoxication at peak withdrawal, with a pro-inflammatory phenotype in females but overall suppression of immune signaling in males. Combined, these results suggest that each stage of the addiction cycle is influenced differentially by sex vs. genetic background and support the development of stage- and sex-specific therapies for alcohol withdrawal and the maintenance of sobriety. Published by Elsevier Ltd.

Cytomegalovirus-Specific CD8+ T-Cells With Different T-Cell Receptor Affinities Segregate T-Cell Phenotypes and Correlate With Chronic Graft-Versus-Host Disease in Patients Post-Hematopoietic Stem Cell Transplantation

PubMed Central

Poiret, Thomas; Axelsson-Robertson, Rebecca; Remberger, Mats; Luo, Xiao-Hua; Rao, Martin; Nagchowdhury, Anurupa; Von Landenberg, Anna; Ernberg, Ingemar; Ringden, Olle; Maeurer, Markus

2018-01-01

Virus-specific T-cell responses are crucial to control cytomegalovirus (CMV) infections/reactivation in immunocompromised individuals. Adoptive cellular therapy with CMV-specific T-cells has become a viable treatment option. High-affinity anti-viral cellular immune responses are associated with improved long-term immune protection against CMV infection. To date, the characterization of high-affinity T-cell responses against CMV has not been achieved in blood from patients after allogeneic hematopoietic stem cell transplantation (HSCT). Therefore, the purpose of this study was to describe and analyze the phenotype and clinical impact of different CMV-specific CD8+ cytotoxic T-lymphocytes (CMV-CTL) classes based on their T-cell receptor (TCR) affinity. T-cells isolated from 23 patients during the first year following HSCT were tested for the expression of memory markers, programmed cell death 1 (PD-1), as well as TCR affinity, using three different HLA-A*02:01 CMVNLVPMVATV-Pp65 tetramers (wild-type, a245v and q226a mutants). High-affinity CMV-CTL defined by q226a tetramer binding, exhibited a higher frequency in CD8+ T-cells in the first month post-HSCT and exhibited an effector memory phenotype associated with strong PD-1 expression as compared to the medium- and low-affinity CMV-CTLs. High-affinity CMV-CTL was found at higher proportion in patients with chronic graft-versus-host disease (p < 0.001). This study provides a first insight into the detailed TCR affinities of CMV-CTL. This may be useful in order to improve current immunotherapy protocols using isolation of viral-specific T-cell populations based on their TCR affinity. PMID:29692783

Characterization of bacterial coliform occurrences in different zones of a drinking water distribution system.

PubMed

Blanch, A R; Galofré, B; Lucena, F; Terradillos, A; Vilanova, X; Ribas, F

2007-03-01

To compare the bacterial coliforms detected from occurrences in three zones of a water distribution system supplied by two separate water sources. Conventional and standardized protocols for identifying enterobacterial populations were applied. Additional tests to confirm isolates were included. Analyses of diversity and population similarity were performed using the Phene Plate System, a miniaturized biochemical phenotyping method. Isolates were identified by the API 20E system in tandem with biochemical phenotyping. A total of 16 576 samples were taken from the water distribution system, with 1416 isolates analysed. A low number of coliform occurrences were observed (2%). Escherichia coli was not detected in either water origin or in Zone 2 samples; however, in Zones 1 and 3 a low number of cases of E. coli were recorded. The percentages of E. coli depended on the identification criteria. Eight biochemical profiles for coliform populations were defined according to the results of the confirmative tests. There was a high diversity among these populations in the three zones studied, although no significant variations in their composition (associated with occurrences in the different zones) were observed. Klebsiella oxytoca was the most commonly detected species irrespective of zone, although seven other enterobacterial genera were also found. Analysis of the enzymatic activity of beta-glucuronidase or application of the criteria established in the norm ISO 9308-1, in tandem with thermotolerance was needed to evaluate the occurrence of E. coli in the distribution systems. Detected occurrences of bacterial coliforms could be associated with re-growth patterns for specific sampling points in the distribution system. Seasonal differences, independent of the studied zones, were observed. Biochemical phenotyping of bacterial coliforms was shown to be a useful method on the characterization of occurrences in water distribution systems.

Demystifying animal 'personality' (or not): why individual variation matters to experimental biologists.

PubMed

Roche, Dominique G; Careau, Vincent; Binning, Sandra A

2016-12-15

Animal 'personality', defined as repeatable inter-individual differences in behaviour, is a concept in biology that faces intense controversy. Critics argue that the field is riddled with terminological and methodological inconsistencies and lacks a sound theoretical framework. Nevertheless, experimental biologists are increasingly studying individual differences in physiology and relating these to differences in behaviour, which can lead to fascinating insights. We encourage this trend, and in this Commentary we highlight some of the benefits of estimating variation in (and covariation among) phenotypic traits at the inter- and intra-individual levels. We focus on behaviour while drawing parallels with physiological and performance-related traits. First, we outline some of the confusion surrounding the terminology used to describe repeatable inter-individual differences in behaviour. Second, we argue that acknowledging individual behavioural differences can help researchers avoid sampling and experimental bias, increase explanatory power and, ultimately, understand how selection acts on physiological traits. Third, we summarize the latest methods to collect, analyse and present data on individual trait variation. We note that, while measuring the repeatability of phenotypic traits is informative in its own right, it is only the first step towards understanding how natural selection and genetic architecture shape intra-specific variation in complex, labile traits. Thus, understanding how and why behavioural traits evolve requires linking repeatable inter-individual behavioural differences with core aspects of physiology (e.g. neurophysiology, endocrinology, energy metabolism) and evolutionary biology (e.g. selection gradients, heritability). © 2016. Published by The Company of Biologists Ltd.

Using measures of single-cell physiology and physiological state to understand organismic aging.

PubMed

Mendenhall, Alexander; Driscoll, Monica; Brent, Roger

2016-02-01

Genetically identical organisms in homogeneous environments have different lifespans and healthspans. These differences are often attributed to stochastic events, such as mutations and 'epimutations', changes in DNA methylation and chromatin that change gene function and expression. But work in the last 10 years has revealed differences in lifespan- and health-related phenotypes that are not caused by lasting changes in DNA or identified by modifications to DNA or chromatin. This work has demonstrated persistent differences in single-cell and whole-organism physiological states operationally defined by values of reporter gene signals in living cells. While some single-cell states, for example, responses to oxygen deprivation, were defined previously, others, such as a generally heightened ability to make proteins, were, revealed by direct experiment only recently, and are not well understood. Here, we review technical progress that promises to greatly increase the number of these measurable single-cell physiological variables and measureable states. We discuss concepts that facilitate use of single-cell measurements to provide insight into physiological states and state transitions. We assert that researchers will use this information to relate cell level physiological readouts to whole-organism outcomes, to stratify aging populations into groups based on different physiologies, to define biomarkers predictive of outcomes, and to shed light on the molecular processes that bring about different individual physiologies. For these reasons, quantitative study of single-cell physiological variables and state transitions should provide a valuable complement to genetic and molecular explanations of how organisms age. © 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

Analysis on endocrine and metabolic features of different phenotypes of polycystic ovary syndrome patients.

PubMed

Li, Feng; Yao, Li; Wu, Hong; Cao, Shihong

2016-09-01

To discuss the manifestations of endocrine and metabolism for polycystic ovary syndrome patients with different phenotype. This study selected 226 cases of Rotterdam Standard diagnosed polycystic ovary syndrome patients in People's Hospital of Zhengzhou from October 2013 to February 2015. The control group was the 100 cases of non hyperandrogen menstrual women as the control group. Polycystic ovary syndrome included 4 phenotype: /or anovulatio (O) combined with hyperandrogenism (H) and polycystic ovary morphology (P), phenotype of O and P, phenotype of H and P, and phenotype of O and P. All patients were detected for the clinical endocrine and metabolism related parameters. The phenotype of O and P occupied 55.8%, it had significant difference on the comparison between control group and the luteinizing hormone (LH) and luteinizing hormone/follicle stimulating hormone (LH/FSH) of phenotype of O, H and P, phenotype of O and H and phenotype of O and P; the testosterone (T) of phenotype of O,H and P and phenotype of O and H was apparently higher than phenotype of O and P and control group; The total cholesterol (TC) and triglyceride (TG) in phenotype of O, H and P was greatly higher than phenotype of O and P and control group. The phenotype of O and P was the most common phenotype in PCOS patients. It was same for the clinical endocrine and metabolism of two classic characteristics in PCOS. Compared to other PCOS phenotype, the metabolism in phenotype of O and P was lower. The phenotype classification of PCOS patients could better guide clinical individualized treatment in patients with PCOS.

Heritabilities and genetic correlations in the same traits across different strata of herds created according to continuous genomic, genetic, and phenotypic descriptors.

PubMed

Yin, Tong; König, Sven

2018-03-01

The most common approach in dairy cattle to prove genotype by environment interactions is a multiple-trait model application, and considering the same traits in different environments as different traits. We enhanced such concepts by defining continuous phenotypic, genetic, and genomic herd descriptors, and applying random regression sire models. Traits of interest were test-day traits for milk yield, fat percentage, protein percentage, and somatic cell score, considering 267,393 records from 32,707 first-lactation Holstein cows. Cows were born in the years 2010 to 2013, and kept in 52 large-scale herds from 2 federal states of north-east Germany. The average number of genotyped cows per herd (45,613 single nucleotide polymorphism markers per cow) was 133.5 (range: 45 to 415 genotyped cows). Genomic herd descriptors were (1) the level of linkage disequilibrium (r 2 ) within specific chromosome segments, and (2) the average allele frequency for single nucleotide polymorphisms in close distance to a functional mutation. Genetic herd descriptors were the (1) intra-herd inbreeding coefficient, and (2) the percentage of daughters from foreign sires. Phenotypic herd descriptors were (1) herd size, and (2) the herd mean for nonreturn rate. Most correlations among herd descriptors were close to 0, indicating independence of genomic, genetic, and phenotypic characteristics. Heritabilities for milk yield increased with increasing intra-herd linkage disequilibrium, inbreeding, and herd size. Genetic correlations in same traits between adjacent levels of herd descriptors were close to 1, but declined for descriptor levels in greater distance. Genetic correlation declines were more obvious for somatic cell score, compared with test-day traits with larger heritabilities (fat percentage and protein percentage). Also, for milk yield, alterations of herd descriptor levels had an obvious effect on heritabilities and genetic correlations. By trend, multiple trait model results (based on created discrete herd classes) confirmed the random regression estimates. Identified alterations of breeding values in dependency of herd descriptors suggest utilization of specific sires for specific herd structures, offering new possibilities to improve sire selection strategies. Regarding genomic selection designs and genetic gain transfer into commercial herds, cow herds for the utilization in cow training sets should reflect the genomic, genetic, and phenotypic pattern of the broad population. Copyright © 2018 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

CXCR6, a newly defined biomarker of tissue-specific stem cell asymmetric self-renewal, identifies more aggressive human melanoma cancer stem cells.

PubMed

Taghizadeh, Rouzbeh; Noh, Minsoo; Huh, Yang Hoon; Ciusani, Emilio; Sigalotti, Luca; Maio, Michele; Arosio, Beatrice; Nicotra, Maria R; Natali, PierGiorgio; Sherley, James L; La Porta, Caterina A M

2010-12-22

A fundamental problem in cancer research is identifying the cell type that is capable of sustaining neoplastic growth and its origin from normal tissue cells. Recent investigations of a variety of tumor types have shown that phenotypically identifiable and isolable subfractions of cells possess the tumor-forming ability. In the present paper, using two lineage-related human melanoma cell lines, primary melanoma line IGR39 and its metastatic derivative line IGR37, two main observations are reported. The first one is the first phenotypic evidence to support the origin of melanoma cancer stem cells (CSCs) from mutated tissue-specific stem cells; and the second one is the identification of a more aggressive subpopulation of CSCs in melanoma that are CXCR6+. We defined CXCR6 as a new biomarker for tissue-specific stem cell asymmetric self-renewal. Thus, the relationship between melanoma formation and ABCG2 and CXCR6 expression was investigated. Consistent with their non-metastatic character, unsorted IGR39 cells formed significantly smaller tumors than unsorted IGR37 cells. In addition, ABCG2+ cells produced tumors that had a 2-fold greater mass than tumors produced by unsorted cells or ABCG2- cells. CXCR6+ cells produced more aggressive tumors. CXCR6 identifies a more discrete subpopulation of cultured human melanoma cells with a more aggressive MCSC phenotype than cells selected on the basis of the ABCG2+ phenotype alone. The association of a more aggressive tumor phenotype with asymmetric self-renewal phenotype reveals a previously unrecognized aspect of tumor cell physiology. Namely, the retention of some tissue-specific stem cell attributes, like the ability to asymmetrically self-renew, impacts the natural history of human tumor development. Knowledge of this new aspect of tumor development and progression may provide new targets for cancer prevention and treatment.

Increased entropy of signal transduction in the cancer metastasis phenotype.

PubMed

Teschendorff, Andrew E; Severini, Simone

2010-07-30

The statistical study of biological networks has led to important novel biological insights, such as the presence of hubs and hierarchical modularity. There is also a growing interest in studying the statistical properties of networks in the context of cancer genomics. However, relatively little is known as to what network features differ between the cancer and normal cell physiologies, or between different cancer cell phenotypes. Based on the observation that frequent genomic alterations underlie a more aggressive cancer phenotype, we asked if such an effect could be detectable as an increase in the randomness of local gene expression patterns. Using a breast cancer gene expression data set and a model network of protein interactions we derive constrained weighted networks defined by a stochastic information flux matrix reflecting expression correlations between interacting proteins. Based on this stochastic matrix we propose and compute an entropy measure that quantifies the degree of randomness in the local pattern of information flux around single genes. By comparing the local entropies in the non-metastatic versus metastatic breast cancer networks, we here show that breast cancers that metastasize are characterised by a small yet significant increase in the degree of randomness of local expression patterns. We validate this result in three additional breast cancer expression data sets and demonstrate that local entropy better characterises the metastatic phenotype than other non-entropy based measures. We show that increases in entropy can be used to identify genes and signalling pathways implicated in breast cancer metastasis and provide examples of de-novo discoveries of gene modules with known roles in apoptosis, immune-mediated tumour suppression, cell-cycle and tumour invasion. Importantly, we also identify a novel gene module within the insulin growth factor signalling pathway, alteration of which may predispose the tumour to metastasize. These results demonstrate that a metastatic cancer phenotype is characterised by an increase in the randomness of the local information flux patterns. Measures of local randomness in integrated protein interaction mRNA expression networks may therefore be useful for identifying genes and signalling pathways disrupted in one phenotype relative to another. Further exploration of the statistical properties of such integrated cancer expression and protein interaction networks will be a fruitful endeavour.

Juxtaposition of chemical and mutation-induced developmental defects in zebrafish reveal a copper-chelating activity for kalihinol F.

PubMed

Sandoval, Imelda T; Manos, Elizabeth J; Van Wagoner, Ryan M; Delacruz, Richard Glenn C; Edes, Kornelia; Winge, Dennis R; Ireland, Chris M; Jones, David A

2013-06-20

A major hurdle in using complex systems for drug screening is the difficulty of defining the mechanistic targets of small molecules. The zebrafish provides an excellent model system for juxtaposing developmental phenotypes with mechanism discovery using organism genetics. We carried out a phenotype-based screen of uncharacterized small molecules in zebrafish that produced a variety of chemically induced phenotypes with potential genetic parallels. Specifically, kalihinol F caused an undulated notochord, defects in pigment formation, hematopoiesis, and neural development. These phenotypes were strikingly similar to the zebrafish mutant, calamity, an established model of copper deficiency. Further studies into the mechanism of action of kalihinol F revealed a copper-chelating activity. Our data support this mechanism of action for kalihinol F and the utility of zebrafish as an effective system for identifying therapeutic and target pathways. Copyright © 2013 Elsevier Ltd. All rights reserved.

Main characteristics of metabolically obese normal weight and metabolically healthy obese phenotypes.

PubMed

Teixeira, Tatiana F S; Alves, Raquel D M; Moreira, Ana Paula B; Peluzio, Maria do Carmo G

2015-03-01

In this review, the influence of fat depots on insulin resistance and the main characteristics of metabolically obese normal-weight and metabolically healthy obese phenotypes are discussed. Medline/PubMed and Science Direct were searched for articles related to the terms metabolically healthy obesity, metabolically obese normal weight, adipose tissue, and insulin resistance. Normal weight and obesity might be heterogeneous in regard to their effects. Fat distribution and lower insulin sensitivity are the main factors defining phenotypes within the same body mass index. Although these terms are interesting, controversies about them remain. Future studies exploring these phenotypes will help elucidate the roles of adiposity and/or insulin resistance in the development of metabolic alterations. © The Author(s) 2015. Published by Oxford University Press on behalf of the International Life Sciences Institute. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Mouse Genome Informatics (MGI) Is the International Resource for Information on the Laboratory Mouse.

PubMed

Law, MeiYee; Shaw, David R

2018-01-01

Mouse Genome Informatics (MGI, http://www.informatics.jax.org/ ) web resources provide free access to meticulously curated information about the laboratory mouse. MGI's primary goal is to help researchers investigate the genetic foundations of human diseases by translating information from mouse phenotypes and disease models studies to human systems. MGI provides comprehensive phenotypes for over 50,000 mutant alleles in mice and provides experimental model descriptions for over 1500 human diseases. Curated data from scientific publications are integrated with those from high-throughput phenotyping and gene expression centers. Data are standardized using defined, hierarchical vocabularies such as the Mammalian Phenotype (MP) Ontology, Mouse Developmental Anatomy and the Gene Ontologies (GO). This chapter introduces you to Gene and Allele Detail pages and provides step-by-step instructions for simple searches and those that take advantage of the breadth of MGI data integration.

Principles of dynamical modularity in biological regulatory networks

PubMed Central

Deritei, Dávid; Aird, William C.; Ercsey-Ravasz, Mária; Regan, Erzsébet Ravasz

2016-01-01

Intractable diseases such as cancer are associated with breakdown in multiple individual functions, which conspire to create unhealthy phenotype-combinations. An important challenge is to decipher how these functions are coordinated in health and disease. We approach this by drawing on dynamical systems theory. We posit that distinct phenotype-combinations are generated by interactions among robust regulatory switches, each in control of a discrete set of phenotypic outcomes. First, we demonstrate the advantage of characterizing multi-switch regulatory systems in terms of their constituent switches by building a multiswitch cell cycle model which points to novel, testable interactions critical for early G2/M commitment to division. Second, we define quantitative measures of dynamical modularity, namely that global cell states are discrete combinations of switch-level phenotypes. Finally, we formulate three general principles that govern the way coupled switches coordinate their function. PMID:26979940

[Strategies to identify supernumerary chromosomal markers in constitutional cytogenetics].

PubMed

Douet-Guilbert, N; Basinko, A; Le Bris, M-J; Herry, A; Morel, F; De Braekeleer, M

2008-09-01

Supernumerary marker chromosomes (SMCs) are defined as extrastructurally abnormal chromosomes which origin and composition cannot be determined by conventional cytogenetics. SMCs are an heterogeneous group of abnormalities concerning all chromosomes with variable structure and size and are associated with phenotypic heterogeneity. The characterisation of SMCs is of utmost importance for genetic counselling. Different molecular techniques are used to identify chromosomal material present in markers such as 24-colour FISH (MFISH, SKY), centromere specific multicolour FISH (cenMFISH) and derivatives (acroMFISH, subcenMFISH), comparative genomic hybridisation (CGH), arrayCGH, and targeted FISH techniques (banding techniques, whole chromosome painting...). Based on the morphology of SMC with conventional cytogenetic and clinical data, we tried to set up different molecular strategies with all available techniques.

Depdc5 knockdown causes mTOR-dependent motor hyperactivity in zebrafish.

PubMed

de Calbiac, Hortense; Dabacan, Adriana; Marsan, Elise; Tostivint, Hervé; Devienne, Gabrielle; Ishida, Saeko; Leguern, Eric; Baulac, Stéphanie; Muresan, Raul C; Kabashi, Edor; Ciura, Sorana

2018-05-01

DEPDC5 was identified as a major genetic cause of focal epilepsy with deleterious mutations found in a wide range of inherited forms of focal epilepsy, associated with malformation of cortical development in certain cases. Identification of frameshift, truncation, and deletion mutations implicates haploinsufficiency of DEPDC5 in the etiology of focal epilepsy. DEPDC5 is a component of the GATOR1 complex, acting as a negative regulator of mTOR signaling. Zebrafish represents a vertebrate model suitable for genetic analysis and drug screening in epilepsy-related disorders. In this study, we defined the expression of depdc5 during development and established an epilepsy model with reduced Depdc5 expression. Here we report a zebrafish model of Depdc5 loss-of-function that displays a measurable behavioral phenotype, including hyperkinesia, circular swimming, and increased neuronal activity. These phenotypic features persisted throughout embryonic development and were significantly reduced upon treatment with the mTORC1 inhibitor, rapamycin, as well as overexpression of human WT DEPDC5 transcript. No phenotypic rescue was obtained upon expression of epilepsy-associated DEPDC5 mutations (p.Arg487* and p.Arg485Gln), indicating that these mutations cause a loss of function of the protein. This study demonstrates that Depdc5 knockdown leads to early-onset phenotypic features related to motor and neuronal hyperactivity. Restoration of phenotypic features by WT but not epilepsy-associated Depdc5 mutants, as well as by mTORC1 inhibition confirm the role of Depdc5 in the mTORC1-dependent molecular cascades, defining this pathway as a potential therapeutic target for DEPDC5 -inherited forms of focal epilepsy.

Effects of different extracts of curcumin on TPC1 papillary thyroid cancer cell line.

PubMed

Perna, Angelica; De Luca, Antonio; Adelfi, Laura; Pasquale, Tammaro; Varriale, Bruno; Esposito, Teresa

2018-02-15

The thyroid gland is one of the largest endocrine glands in the body. The vast majority of TCs (> 90%) originate from follicular cells and are defined as differentiated thyroid cancers (DTC) and the two histological subtypes are the papillary TC with its variants and the follicular TC. Curcumin possesses a wide variety of biological functions, and thanks to its properties, it has gained considerable attention due to its profound medicinal values (Prasad, Gupta, Tyagi, and Aggarwal, Biotechnol Adv 32:1053-1064, 2014). We have undertaken the present work in order to define the possible role of curcumin in modulating the genetic expression of cell markers and to understand the effectiveness of this nutraceutical in modulating the regression of cancer phenotype. As a template we used the TPC-1 cells treated with the different extracts of turmeric, and examined the levels of expression of different markers (proliferative, inflammatory, antioxidant, apoptotic). Treatment with the three different curcumin extracts displays anti-inflammatory, antioxidant properties and it is able to influence cell cycle with slightly different effects upon the extracts. Furthermore curcumin is able to influence cell metabolic activity vitality. In conclusion curcumin has the potential to be developed as a safe therapeutic but further studies are needed to verify its antitumor ability in vivo.

Identification and individualized prediction of clinical phenotypes in bipolar disorders using neurocognitive data, neuroimaging scans and machine learning.

PubMed

Wu, Mon-Ju; Mwangi, Benson; Bauer, Isabelle E; Passos, Ives C; Sanches, Marsal; Zunta-Soares, Giovana B; Meyer, Thomas D; Hasan, Khader M; Soares, Jair C

2017-01-15

Diagnosis, clinical management and research of psychiatric disorders remain subjective - largely guided by historically developed categories which may not effectively capture underlying pathophysiological mechanisms of dysfunction. Here, we report a novel approach of identifying and validating distinct and biologically meaningful clinical phenotypes of bipolar disorders using both unsupervised and supervised machine learning techniques. First, neurocognitive data were analyzed using an unsupervised machine learning approach and two distinct clinical phenotypes identified namely; phenotype I and phenotype II. Second, diffusion weighted imaging scans were pre-processed using the tract-based spatial statistics (TBSS) method and 'skeletonized' white matter fractional anisotropy (FA) and mean diffusivity (MD) maps extracted. The 'skeletonized' white matter FA and MD maps were entered into the Elastic Net machine learning algorithm to distinguish individual subjects' phenotypic labels (e.g. phenotype I vs. phenotype II). This calculation was performed to ascertain whether the identified clinical phenotypes were biologically distinct. Original neurocognitive measurements distinguished individual subjects' phenotypic labels with 94% accuracy (sensitivity=92%, specificity=97%). TBSS derived FA and MD measurements predicted individual subjects' phenotypic labels with 76% and 65% accuracy respectively. In addition, individual subjects belonging to phenotypes I and II were distinguished from healthy controls with 57% and 92% accuracy respectively. Neurocognitive task variables identified as most relevant in distinguishing phenotypic labels included; Affective Go/No-Go (AGN), Cambridge Gambling Task (CGT) coupled with inferior fronto-occipital fasciculus and callosal white matter pathways. These results suggest that there may exist two biologically distinct clinical phenotypes in bipolar disorders which can be identified from healthy controls with high accuracy and at an individual subject level. We suggest a strong clinical utility of the proposed approach in defining and validating biologically meaningful and less heterogeneous clinical sub-phenotypes of major psychiatric disorders. Copyright © 2016 Elsevier Inc. All rights reserved.

Phenotypic and Causal Structure of Conduct Disorder in the Broader Context of Prevalent Forms of Psychopathology

PubMed Central

Lahey, Benjamin B.; Waldman, Irwin D.

2011-01-01

Background A better understanding of the nature and etiology of conduct disorder (CD) can inform nosology and vice-versa. We posit that any prevalent form of psychopathology, including CD, can be best understood if it is studied in the context of other correlated forms of child and adolescent psychopathology using formal models to guide inquiry. Methods Review of both cross-sectional and longitudinal studies of the place of CD in the phenotypic and causal structure of prevalent psychopathology, with an emphasis on similarities and differences between CD and oppositional defiant disorder (ODD). Papers were located using Web of Science by topic searches with no restriction on year of publication. Results Although some important nosologic questions remain unanswered, the dimensional phenotype of CD is well defined. CD differs from other disorders in its correlates, associated impairment, and course. Nonetheless, it is robustly correlated with many other prevalent dimensions of psychopathology both concurrently and predictively, including both other “externalizing” disorders and some “internalizing” disorders. Based on emerging evidence, we hypothesize that these concurrent and predictive correlations result primarily from widespread genetic pleiotropy, with some genetic factors nonspecifically influencing risk for multiple correlated dimensions of psychopathology. In contrast, environmental influences mostly act to differentiate dimensions of psychopathology from one another both concurrently and over time. CD and ODD share half of their genetic influences, but their genetic etiologies are distinct in other ways. Unlike most other dimensions of psychopathology, half of the genetic influences on CD appear to be unique to CD. In contrast, ODD broadly shares nearly all of its genetic influences with other disorders and has little unique genetic variance. Conclusions CD is a relatively distinct syndrome at both phenotypic and etiologic levels, but much is revealed by studying CD in the context of its causal and phenotypic associations with other disorders over time. Advancing and refining formal causal models that specify the common and unique causes and biological mechanisms underlying each correlated dimension of psychopathology should facilitate research on the fundamental nature and nosology of CD. PMID:22211395

PROKR2 and PROK2 mutations cause isolated congenital anosmia without gonadotropic deficiency.

PubMed

Moya-Plana, Antoine; Villanueva, Carine; Laccourreye, Ollivier; Bonfils, Pierre; de Roux, Nicolas

2013-01-01

Isolated congenital anosmia (ICA) is a rare phenotype defined as absent recall of any olfactory sensations since birth and the absence of any disease known to cause anosmia. Although most cases of ICA are sporadic, reports of familial cases suggest a genetic cause. ICA due to olfactory bulb agenesis and associated to hypogonadotropic hypogonadism defines Kallmann syndrome (KS), in which several gene defects have been described. In KS families, the phenotype may be restricted to ICA. We therefore hypothesized that mutations in KS genes cause ICA in patients, even in the absence of family history of reproduction disorders. In 25 patients with ICA and olfactory bulb agenesis, a detailed phenotype analysis was conducted and the coding sequences of KAL1, FGFR1, FGF8, PROKR2, and PROK2 were sequenced. Three PROKR2 mutations previously described in KS and one new PROK2 mutation were found. Investigation of the families showed incomplete penetrance of these mutations. This study is the first to report genetic causes of ICA and indicates that KS genes must be screened in patients with ICA. It also confirms the considerable complexity of GNRH neuron development in humans.

A hierarchical causal taxonomy of psychopathology across the life span.

PubMed

Lahey, Benjamin B; Krueger, Robert F; Rathouz, Paul J; Waldman, Irwin D; Zald, David H

2017-02-01

We propose a taxonomy of psychopathology based on patterns of shared causal influences identified in a review of multivariate behavior genetic studies that distinguish genetic and environmental influences that are either common to multiple dimensions of psychopathology or unique to each dimension. At the phenotypic level, first-order dimensions are defined by correlations among symptoms; correlations among first-order dimensions similarly define higher-order domains (e.g., internalizing or externalizing psychopathology). We hypothesize that the robust phenotypic correlations among first-order dimensions reflect a hierarchy of increasingly specific etiologic influences . Some nonspecific etiologic factors increase risk for all first-order dimensions of psychopathology to varying degrees through a general factor of psychopathology. Other nonspecific etiologic factors increase risk only for all first-order dimensions within a more specific higher-order domain. Furthermore, each first-order dimension has its own unique causal influences. Genetic and environmental influences common to family members tend to be nonspecific, whereas environmental influences unique to each individual are more dimension-specific. We posit that these causal influences on psychopathology are moderated by sex and developmental processes. This causal taxonomy also provides a novel framework for understanding the heterogeneity of each first-order dimension: Different persons exhibiting similar symptoms may be influenced by different combinations of etiologic influences from each of the 3 levels of the etiologic hierarchy. Furthermore, we relate the proposed causal taxonomy to transdimensional psychobiological processes, which also impact the heterogeneity of each psychopathology dimension. This causal taxonomy implies the need for changes in strategies for studying the etiology, psychobiology, prevention, and treatment of psychopathology. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

A pyrosequencing assay for the quantitative methylation analysis of the PCDHB gene cluster, the major factor in neuroblastoma methylator phenotype.

PubMed

Banelli, Barbara; Brigati, Claudio; Di Vinci, Angela; Casciano, Ida; Forlani, Alessandra; Borzì, Luana; Allemanni, Giorgio; Romani, Massimo

2012-03-01

Epigenetic alterations are hallmarks of cancer and powerful biomarkers, whose clinical utilization is made difficult by the absence of standardization and of common methods of data interpretation. The coordinate methylation of many loci in cancer is defined as 'CpG island methylator phenotype' (CIMP) and identifies clinically distinct groups of patients. In neuroblastoma (NB), CIMP is defined by a methylation signature, which includes different loci, but its predictive power on outcome is entirely recapitulated by the PCDHB cluster only. We have developed a robust and cost-effective pyrosequencing-based assay that could facilitate the clinical application of CIMP in NB. This assay permits the unbiased simultaneous amplification and sequencing of 17 out of 19 genes of the PCDHB cluster for quantitative methylation analysis, taking into account all the sequence variations. As some of these variations were at CpG doublets, we bypassed the data interpretation conducted by the methylation analysis software to assign the corrected methylation value at these sites. The final result of the assay is the mean methylation level of 17 gene fragments in the protocadherin B cluster (PCDHB) cluster. We have utilized this assay to compare the methylation levels of the PCDHB cluster between high-risk and very low-risk NB patients, confirming the predictive value of CIMP. Our results demonstrate that the pyrosequencing-based assay herein described is a powerful instrument for the analysis of this gene cluster that may simplify the data comparison between different laboratories and, in perspective, could facilitate its clinical application. Furthermore, our results demonstrate that, in principle, pyrosequencing can be efficiently utilized for the methylation analysis of gene clusters with high internal homologies.

Identifying Novel Phenotypes of Vulnerability and Resistance to Activity-Based Anorexia in Adolescent Female Rats

PubMed Central

Barbarich-Marsteller, Nicole C.; Underwood, Mark D.; Foltin, Richard W.; Myers, Michael M.; Walsh, B. Timothy; Barrett, Jeffrey S.; Marsteller, Douglas A.

2018-01-01

Objective Activity-based anorexia is a translational rodent model that results in severe weight loss, hyperactivity, and voluntary self-starvation. The goal of our investigation was to identify vulnerable and resistant phenotypes of activity-based anorexia in adolescent female rats. Method Sprague-Dawley rats were maintained under conditions of restricted access to food (N = 64; or unlimited access, N = 16) until experimental exit, predefined as a target weight loss of 30–35% or meeting predefined criteria for animal health. Nonlinear mixed effects statistical modeling was used to describe wheel running behavior, time to event analysis was used to assess experimental exit, and a regressive partitioning algorithm was used to classify phenotypes. Results Objective criteria were identified for distinguishing novel phenotypes of activity-based anorexia, including a vulnerable phenotype that conferred maximal hyperactivity, minimal food intake, and the shortest time to experimental exit, and a resistant phenotype that conferred minimal activity and the longest time to experimental exit. Discussion The identification of objective criteria for defining vulnerable and resistant phenotypes of activity-based anorexia in adolescent female rats provides an important framework for studying the neural mechanisms that promote vulnerability to or protection against the development of self-starvation and hyperactivity during adolescence. Ultimately, future studies using these novel phenotypes may provide important translational insights into the mechanisms that promote these maladaptive behaviors characteristic of anorexia nervosa. PMID:23853140

Identifying novel phenotypes of vulnerability and resistance to activity-based anorexia in adolescent female rats.

PubMed

Barbarich-Marsteller, Nicole C; Underwood, Mark D; Foltin, Richard W; Myers, Michael M; Walsh, B Timothy; Barrett, Jeffrey S; Marsteller, Douglas A

2013-11-01

Activity-based anorexia is a translational rodent model that results in severe weight loss, hyperactivity, and voluntary self-starvation. The goal of our investigation was to identify vulnerable and resistant phenotypes of activity-based anorexia in adolescent female rats. Sprague-Dawley rats were maintained under conditions of restricted access to food (N = 64; or unlimited access, N = 16) until experimental exit, predefined as a target weight loss of 30-35% or meeting predefined criteria for animal health. Nonlinear mixed effects statistical modeling was used to describe wheel running behavior, time to event analysis was used to assess experimental exit, and a regressive partitioning algorithm was used to classify phenotypes. Objective criteria were identified for distinguishing novel phenotypes of activity-based anorexia, including a vulnerable phenotype that conferred maximal hyperactivity, minimal food intake, and the shortest time to experimental exit, and a resistant phenotype that conferred minimal activity and the longest time to experimental exit. The identification of objective criteria for defining vulnerable and resistant phenotypes of activity-based anorexia in adolescent female rats provides an important framework for studying the neural mechanisms that promote vulnerability to or protection against the development of self-starvation and hyperactivity during adolescence. Ultimately, future studies using these novel phenotypes may provide important translational insights into the mechanisms that promote these maladaptive behaviors characteristic of anorexia nervosa. Copyright © 2013 Wiley Periodicals, Inc.

Metabolic phenotype and risk of colorectal cancer in normal-weight postmenopausal women

PubMed Central

Liang, Xiaoyun; Margolis, Karen L.; Hendryx, Michael; Rohan, Thomas; Groessl, Erik J.; Thomson, Cynthia A.; Kroenke, Candyce H.; Simon, Michael; Lane, Dorothy; Stefanick, Marcia; Luo, Juhua

2016-01-01

Background The prevalence of metabolically unhealthy phenotype in normal-weight adults is 30%, and few studies have explored the association between metabolic phenotype and colorectal cancer incidence in normal-weight individuals. Our aim was to compare the risk of colorectal cancer in normal-weight postmenopausal women who were characterized by either the metabolically healthy phenotype or the metabolically unhealthy phenotype. Methods A large prospective cohort, the Women’s Health Initiative (WHI), was used. The analytical sample included 5,068 postmenopausal women with BMI 18.5–<25 kg/m2. Metabolic phenotype was defined using the Adult Treatment Panel-III (ATP-III) definition, excluding waist circumference; therefore, women with one or none of the four components (elevated triglycerides, low HDL-C, elevated blood pressure, and elevated fasting glucose) were classified as metabolically healthy. Multivariable Cox proportional hazards regression was used to estimate adjusted hazard ratios for the association between metabolic phenotype and risk of colorectal cancer. Results Among normal-weight women, those who were metabolically unhealthy had higher risks of colorectal cancer (HR: 1.49, 95% CI: 1.02–2.18) compared to those who were metabolically healthy. Conclusions A metabolically unhealthy phenotype was associated with higher risk of colorectal cancer among normal-weight women. Impact Normal-weight women should still be evaluated for metabolic health and appropriate steps taken to reduce their risk of colorectal cancer. PMID:28148595

3D Laser Triangulation for Plant Phenotyping in Challenging Environments

PubMed Central

Kjaer, Katrine Heinsvig; Ottosen, Carl-Otto

2015-01-01

To increase the understanding of how the plant phenotype is formed by genotype and environmental interactions, simple and robust high-throughput plant phenotyping methods should be developed and considered. This would not only broaden the application range of phenotyping in the plant research community, but also increase the ability for researchers to study plants in their natural environments. By studying plants in their natural environment in high temporal resolution, more knowledge on how multiple stresses interact in defining the plant phenotype could lead to a better understanding of the interaction between plant responses and epigenetic regulation. In the present paper, we evaluate a commercial 3D NIR-laser scanner (PlantEye, Phenospex B.V., Herleen, The Netherlands) to track daily changes in plant growth with high precision in challenging environments. Firstly, we demonstrate that the NIR laser beam of the scanner does not affect plant photosynthetic performance. Secondly, we demonstrate that it is possible to estimate phenotypic variation amongst the growth pattern of ten genotypes of Brassica napus L. (rapeseed), using a simple linear correlation between scanned parameters and destructive growth measurements. Our results demonstrate the high potential of 3D laser triangulation for simple measurements of phenotypic variation in challenging environments and in a high temporal resolution. PMID:26066990

Chronic Obstructive Pulmonary Disease: official diagnosis and treatment guidelines of the Czech Pneumological and Phthisiological Society; a novel phenotypic approach to COPD with patient-oriented care.

PubMed

Koblizek, Vladimir; Chlumsky, Jan; Zindr, Vladimir; Neumannova, Katerina; Zatloukal, Jakub; Zak, Jaroslav; Sedlak, Vratislav; Kocianova, Jana; Zatloukal, Jaromir; Hejduk, Karel; Pracharova, Sarka

2013-06-01

COPD is a global concern. Currently, several sets of guidelines, statements and strategies to managing COPD exist around the world. The Czech Pneumological and Phthisiological Society (CPPS) has commissioned an Expert group to draft recommended guidelines for the management of stable COPD. Subsequent revisions were further discussed at the National Consensus Conference (NCC). Reviewers' comments contributed to the establishment of the document's final version. The hallmark of the novel approach to COPD is the integrated evaluation of the patient's lung functions, symptoms, exacerbations and identifications of clinical phenotype(s). The CPPS defines 6 clinically relevant phenotypes: frequent exacerbator, COPD-asthma overlap, COPD-bronchiectasis overlap, emphysematic phenotype, bronchitic phenotype and pulmonary cachexia phenotype. Treatment recommendations can be divided into four steps. 1(st) step = Risk exposure elimination: reduction of smoking and environmental tobacco smoke (ETS), decrease of home and occupational exposure risks. 2(nd) step = Standard treatment: inhaled bronchodilators, regular physical activity, pulmonary rehabilitation, education, inhalation training, comorbidity treatment, vaccination. 3(rd) step = Phenotype-specific therapy: PDE4i, ICS+LABA, LVRS, BVR, AAT augmentation, physiotherapy, mucolytic, ABT. 4(th) step = Care for respiratory insufficiency and terminal COPD: LTOT, lung transplantation, high intensity-NIV and palliative care. Optimal treatment of COPD patients requires an individualised, multidisciplinary approach to the patient's symptoms, clinical phenotypes, needs and wishes. The new Czech COPD guideline reflects and covers these requirements.

Environmental drivers defining linkages among life-history traits: mechanistic insights from a semiterrestrial amphipod subjected to macroscale gradients.

PubMed

Gómez, Julio; Barboza, Francisco R; Defeo, Omar

2013-10-01

Determining the existence of interconnected responses among life-history traits and identifying underlying environmental drivers are recognized as key goals for understanding the basis of phenotypic variability. We studied potentially interconnected responses among senescence, fecundity, embryos size, weight of brooding females, size at maturity and sex ratio in a semiterrestrial amphipod affected by macroscale gradients in beach morphodynamics and salinity. To this end, multiple modelling processes based on generalized additive mixed models were used to deal with the spatio-temporal structure of the data obtained at 10 beaches during 22 months. Salinity was the only nexus among life-history traits, suggesting that this physiological stressor influences the energy balance of organisms. Different salinity scenarios determined shifts in the weight of brooding females and size at maturity, having consequences in the number and size of embryos which in turn affected sex determination and sex ratio at the population level. Our work highlights the importance of analysing field data to find the variables and potential mechanisms that define concerted responses among traits, therefore defining life-history strategies.

Novel clustering of items from the Autism Diagnostic Interview-Revised to define phenotypes within autism spectrum disorders

PubMed Central

Hu, Valerie W.; Steinberg, Mara E.

2009-01-01

Heterogeneity in phenotypic presentation of ASD has been cited as one explanation for the difficulty in pinpointing specific genes involved in autism. Recent studies have attempted to reduce the “noise” in genetic and other biological data by reducing the phenotypic heterogeneity of the sample population. The current study employs multiple clustering algorithms on 123 item scores from the Autism Diagnostic Interview-Revised (ADI-R) diagnostic instrument of nearly 2000 autistic individuals to identify subgroups of autistic probands with clinically relevant behavioral phenotypes in order to isolate more homogeneous groups of subjects for gene expression analyses. Our combined cluster analyses suggest optimal division of the autistic probands into 4 phenotypic clusters based on similarity of symptom severity across the 123 selected item scores. One cluster is characterized by severe language deficits, while another exhibits milder symptoms across the domains. A third group possesses a higher frequency of savant skills while the fourth group exhibited intermediate severity across all domains. Grouping autistic individuals by multivariate cluster analysis of ADI-R scores reveals meaningful phenotypes of subgroups within the autistic spectrum which we show, in a related (accompanying) study, to be associated with distinct gene expression profiles. PMID:19455643

Molecular Mechanisms Modulating the Phenotype of Macrophages and Microglia

PubMed Central

Amici, Stephanie A.; Dong, Joycelyn; Guerau-de-Arellano, Mireia

2017-01-01

Macrophages and microglia play crucial roles during central nervous system development, homeostasis and acute events such as infection or injury. The diverse functions of tissue macrophages and microglia are mirrored by equally diverse phenotypes. A model of inflammatory/M1 versus a resolution phase/M2 macrophages has been widely used. However, the complexity of macrophage function can only be achieved by the existence of varied, plastic and tridimensional macrophage phenotypes. Understanding how tissue macrophages integrate environmental signals via molecular programs to define pathogen/injury inflammatory responses provides an opportunity to better understand the multilayered nature of macrophages, as well as target and modulate cellular programs to control excessive inflammation. This is particularly important in MS and other neuroinflammatory diseases, where chronic inflammatory macrophage and microglial responses may contribute to pathology. Here, we perform a comprehensive review of our current understanding of how molecular pathways modulate tissue macrophage phenotype, covering both classic pathways and the emerging role of microRNAs, receptor-tyrosine kinases and metabolism in macrophage phenotype. In addition, we discuss pathway parallels in microglia, novel markers helpful in the identification of peripheral macrophages versus microglia and markers linked to their phenotype. PMID:29176977

Molecular Characteristics of Erythromycin-Resistant Streptococcus pyogenes Strains Isolated from Children Patients in Tunis, Tunisia.

PubMed

Ksia, Sonia; Smaoui, Hanen; Hraoui, Manel; Bouafsoun, Aida; Boutiba-Ben Boubaker, Ihem; Kechrid, Amel

2017-07-01

The aims of our study were to characterize phenotypically and genotypically erythromycin-resistant Streptococcus pyogenes or group A streptococci (ERGAS) isolates, to evaluate macrolide resistance and to analyze the association between emm types and virulence factors. Included in this study were all ERGAS strains isolated from 2000 to 2013 at the Children's hospital of Tunis. Antimicrobial susceptibility was performed according to the CA-SFM guidelines. Macrolide resistance genes were revealed by polymerase chain reaction (PCR) method. Virulence factor genes (pyrogenic exotoxin genes and superantigen gene) were detected by PCR, and the emm types were defined by the sequencing of the variable 5' end of the emm gene. Among the 289 GAS isolates collected, 15 (5.2%) were resistant to erythromycin; 7 of the strains were assigned to the cMLS B phenotype (46.6%); 5 harbored ermB gene alone (33.3%); and 2 strains coharbored ermB and mefA (13.3%). The remaining (53.4%) were assigned to the M phenotype and harbored the mefA gene. The frequency of detection of each toxin gene among ERGAS was 13.4% for speA (2 strains), 53.4% for speC (8 strains), and 13.4% for ssa (2 strains). Emm types 1, 58, 11, and 78 were the most frequent among ERGAS strains. The distribution of the cMLS B and M phenotypes changed over the period of investigation with a decrement of cMLS B phenotype and ermB gene that predominated between 2000 and 2006 and an increase of M phenotype and mefA gene between 2007 and 2013, but this difference was nonstatistically significant because of the low number of resistant strains. Emm types 1, 58, and 4 were only present among strains assigned to the M phenotype. However strains assigned to the cMLS B phenotype were associated to emm11, emm22, emm28, emm78, or emm76. There was diversity in emm distribution in ERGAS between the two study periods. There was diversity in emm distribution among ERGAS particularly in 2000-2006. Indeed, from 2000 to 2006, the 6 ERGAS belonged to 5 different emm types (22, 28, 76, 11, and 4), while between 2007 and 2013, seven among the nine ERGAS belonged to only 2 emm types 58 and 1. The speA gene was present only among emm1 isolates, and the ssa gene was associated with emm4 and emm78 types. All emm78, emm28, and emm11 strains harbored speC gene. Our study revealed a low frequency of ERGAS and few emm types were associated with these strains.

Atorvastatin Calcium Inhibits Phenotypic Modulation of PDGF-BB-Induced VSMCs via Down-Regulation the Akt Signaling Pathway

PubMed Central

Chen, Shuang; Liu, Baoqin; Kong, Dehui; Li, Si; Li, Chao; Wang, Huaqin; Sun, Yingxian

2015-01-01

Plasticity of vascular smooth muscle cells (VSMCs) plays a central role in the onset and progression of proliferative vascular diseases. In adult tissue, VSMCs exist in a physiological contractile-quiescent phenotype, which is defined by lack of the ability of proliferation and migration, while high expression of contractile marker proteins. After injury to the vessel, VSMC shifts from a contractile phenotype to a pathological synthetic phenotype, associated with increased proliferation, migration and matrix secretion. It has been demonstrated that PDGF-BB is a critical mediator of VSMCs phenotypic switch. Atorvastatin calcium, a selective inhibitor of 3-hydroxy-3-methyl-glutaryl l coenzyme A (HMG-CoA) reductase, exhibits various protective effects against VSMCs. In this study, we investigated the effects of atorvastatin calcium on phenotype modulation of PDGF-BB-induced VSMCs and the related intracellular signal transduction pathways. Treatment of VSMCs with atorvastatin calcium showed dose-dependent inhibition of PDGF-BB-induced proliferation. Atorvastatin calcium co-treatment inhibited the phenotype modulation and cytoskeleton rearrangements and improved the expression of contractile phenotype marker proteins such as α-SM actin, SM22α and calponin in comparison with PDGF-BB alone stimulated VSMCs. Although Akt phosphorylation was strongly elicited by PDGF-BB, Akt activation was attenuated when PDGF-BB was co-administrated with atorvastatin calcium. In conclusion, atorvastatin calcium inhibits phenotype modulation of PDGF-BB-induced VSMCs and activation of the Akt signaling pathway, indicating that Akt might play a vital role in the modulation of phenotype. PMID:25874930

Impact of body mass index and metabolic phenotypes on coronary artery disease according to glucose tolerance status.

PubMed

Fujihara, K; Matsubayashi, Y; Yamamoto, M; Osawa, T; Ishizawa, M; Kaneko, M; Matsunaga, S; Kato, K; Seida, H; Yamanaka, N; Kodama, S; Sone, H

2017-12-01

This study aimed to examine the impact of obesity, as defined by body mass index (BMI), and a metabolically unhealthy phenotype on the development of coronary artery disease (CAD) according to glucose tolerance status. This population-based retrospective cohort study included 123,746 Japanese men aged 18-72years (normal glucose tolerance: 72,047; prediabetes: 39,633; diabetes: 12,066). Obesity was defined as a BMI≥25kg/m 2 . Metabolically unhealthy individuals were defined as those with one or more of the following conditions: hypertension, hypertriglyceridaemia and/or low HDL cholesterol. A Cox proportional hazards regression model identified variables related to CAD incidence. The prevalences of obese subjects with normal glucose tolerance, prediabetes and diabetes were 21%, 34% and 53%, whereas those for metabolically unhealthy people were 43%, 60% and 79%, respectively. Multivariate analysis showed that a metabolically unhealthy phenotype increases hazard ratios (HRs) for CAD compared with a metabolically healthy phenotype, regardless of glucose tolerance status (normal glucose tolerance: 1.98, 95% CI: 1.32-2.95; prediabetes: 2.91, 95% CI: 1.85-4.55; diabetes: 1.90, 95% CI: 1.18-3.06). HRs for CAD among metabolically unhealthy non-obese diabetes patients and obese diabetes patients with a metabolically unhealthy status were 6.14 (95% CI: 3.94-9.56) and 7.86 (95% CI: 5.21-11.9), respectively, compared with non-obese subjects with normal glucose tolerance and without a metabolically unhealthy status. A metabolically unhealthy state can associate with CAD independently of obesity across all glucose tolerance stages. Clinicians may need to consider those with at least one or more conditions indicating a metabolically unhealthy state as being at high risk for CAD regardless of glucose tolerance status. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

The broader autism phenotype in infancy: when does it emerge?

PubMed

Ozonoff, Sally; Young, Gregory S; Belding, Ashleigh; Hill, Monique; Hill, Alesha; Hutman, Ted; Johnson, Scott; Miller, Meghan; Rogers, Sally J; Schwichtenberg, A J; Steinfeld, Marybeth; Iosif, Ana-Maria

2014-04-01

This study had 3 goals, which were to examine the following: the frequency of atypical development, consistent with the broader autism phenotype, in high-risk infant siblings of children with autism spectrum disorder (ASD); the age at which atypical development is first evident; and which developmental domains are affected. A prospective longitudinal design was used to compare 294 high-risk infants and 116 low-risk infants. Participants were tested at 6, 12, 18, 24, and 36 months of age. At the final visit, outcome was classified as ASD, Typical Development (TD), or Non-TD (defined as elevated Autism Diagnostic Observation Schedule [ADOS] score, low Mullen Scale scores, or both). Of the high-risk group, 28% were classified as Non-TD at 36 months of age. Growth curve models demonstrated that the Non-TD group could not be distinguished from the other groups at 6 months of age, but differed significantly from the Low-Risk TD group by 12 months on multiple measures. The Non-TD group demonstrated atypical development in cognitive, motor, language, and social domains, with differences particularly prominent in the social-communication domain. These results demonstrate that features of atypical development, consistent with the broader autism phenotype, are detectable by the first birthday and affect development in multiple domains. This highlights the necessity for close developmental surveillance of infant siblings of children with ASD, along with implementation of appropriate interventions as needed. Copyright © 2014 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.

JBASE: Joint Bayesian Analysis of Subphenotypes and Epistasis.

PubMed

Colak, Recep; Kim, TaeHyung; Kazan, Hilal; Oh, Yoomi; Cruz, Miguel; Valladares-Salgado, Adan; Peralta, Jesus; Escobedo, Jorge; Parra, Esteban J; Kim, Philip M; Goldenberg, Anna

2016-01-15

Rapid advances in genotyping and genome-wide association studies have enabled the discovery of many new genotype-phenotype associations at the resolution of individual markers. However, these associations explain only a small proportion of theoretically estimated heritability of most diseases. In this work, we propose an integrative mixture model called JBASE: joint Bayesian analysis of subphenotypes and epistasis. JBASE explores two major reasons of missing heritability: interactions between genetic variants, a phenomenon known as epistasis and phenotypic heterogeneity, addressed via subphenotyping. Our extensive simulations in a wide range of scenarios repeatedly demonstrate that JBASE can identify true underlying subphenotypes, including their associated variants and their interactions, with high precision. In the presence of phenotypic heterogeneity, JBASE has higher Power and lower Type 1 Error than five state-of-the-art approaches. We applied our method to a sample of individuals from Mexico with Type 2 diabetes and discovered two novel epistatic modules, including two loci each, that define two subphenotypes characterized by differences in body mass index and waist-to-hip ratio. We successfully replicated these subphenotypes and epistatic modules in an independent dataset from Mexico genotyped with a different platform. JBASE is implemented in C++, supported on Linux and is available at http://www.cs.toronto.edu/∼goldenberg/JBASE/jbase.tar.gz. The genotype data underlying this study are available upon approval by the ethics review board of the Medical Centre Siglo XXI. Please contact Dr Miguel Cruz at mcruzl@yahoo.com for assistance with the application. anna.goldenberg@utoronto.ca Supplementary data are available at Bioinformatics online. © The Author 2015. Published by Oxford University Press.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bunge, S.; Steglich, C.; Kleijer, W.J.

Mucopolysaccharidosis type I (MPS I) is caused by alpha-L-iduronidase (IDUA) deficiency. Clinical severity ranges from mild (Scheie) and intermediate (Hurler/Scheie) to severe (Hurler) forms. We investigated 70 patients with various MPS I phenotypes for mutations of the IDUA gene. 28 different mutations on 93% of mutant alleles, defining 90% of the genotypes were characterized. The two common missense mutations Q70X and W402X were found on, respectively, 31% and 28% of mutant alleles. However, Q70X is much more frequent in Scandinavia (64%) than in other European countries (16%). L218P (4.3%) and A327P (6.4%) were also identified in several patients, while allmore » other mutations were found on only one or two alleles each. Of the 11 novel mutations identified in this study, G51D, L218P, D315Y, A327P, R489P, E404X, and R621X were associated with severe phenotypes. Eleven different small deletions and insertions were detected (134del12, 964delC, 1132del6, 1782del11, 1995del11, {Delta}D444/445, 252insC, 396insAC, 682insAC, 974ins12, and 1277ins9), most of them causing severe MPS I. Two novel Hurler/Scheie (M504T and W626R) and two novel Scheie point mutations (R89W and R383H) were also identified. Characterization of the primary genetic defect and establishing genotype/phenotype correlation is important for prognostic predictions, evaluation of therapeutic success, and prenatal diagnosis.« less

Customized Molecular Phenotyping by Quantitative Gene Expression and Pattern Recognition Analysis

PubMed Central

Akilesh, Shreeram; Shaffer, Daniel J.; Roopenian, Derry

2003-01-01

Description of the molecular phenotypes of pathobiological processes in vivo is a pressing need in genomic biology. We have implemented a high-throughput real-time PCR strategy to establish quantitative expression profiles of a customized set of target genes. It enables rapid, reproducible data acquisition from limited quantities of RNA, permitting serial sampling of mouse blood during disease progression. We developed an easy to use statistical algorithm—Global Pattern Recognition—to readily identify genes whose expression has changed significantly from healthy baseline profiles. This approach provides unique molecular signatures for rheumatoid arthritis, systemic lupus erythematosus, and graft versus host disease, and can also be applied to defining the molecular phenotype of a variety of other normal and pathological processes. PMID:12840047

Ion Channel Genes and Epilepsy: Functional Alteration, Pathogenic Potential, and Mechanism of Epilepsy.

PubMed

Wei, Feng; Yan, Li-Min; Su, Tao; He, Na; Lin, Zhi-Jian; Wang, Jie; Shi, Yi-Wu; Yi, Yong-Hong; Liao, Wei-Ping

2017-08-01

Ion channels are crucial in the generation and modulation of excitability in the nervous system and have been implicated in human epilepsy. Forty-one epilepsy-associated ion channel genes and their mutations are systematically reviewed. In this paper, we analyzed the genotypes, functional alterations (funotypes), and phenotypes of these mutations. Eleven genes featured loss-of-function mutations and six had gain-of-function mutations. Nine genes displayed diversified funotypes, among which a distinct funotype-phenotype correlation was found in SCN1A. These data suggest that the funotype is an essential consideration in evaluating the pathogenicity of mutations and a distinct funotype or funotype-phenotype correlation helps to define the pathogenic potential of a gene.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Harwood, Caroline S

The goal of this project is to identify gene networks that are critical for efficient biohydrogen production by leveraging variation in gene content and gene expression in independently isolated Rhodopseudomonas palustris strains. Coexpression methods were applied to large data sets that we have collected to define probabilistic causal gene networks. To our knowledge this a first systems level approach that takes advantage of strain-to strain variability to computationally define networks critical for a particular bacterial phenotypic trait.

Resistant and Refractory Hypertension: Antihypertensive Treatment Resistance vs Treatment Failure

PubMed Central

Siddiqui, Mohammed; Dudenbostel, Tanja; Calhoun, David A.

2017-01-01

Resistant or difficult to treat hypertension is defined as high blood pressure that remains uncontrolled with 3 or more different antihypertensive medications, including a diuretic. Recent definitions also include controlled blood pressure with use of 4 or more medications as also being resistant to treatment. Recently, refractory hypertension, an extreme phenotype of antihypertensive treatment failure has been defined as hypertension uncontrolled with use of 5 or more antihypertensive agents, including a long-acting thiazide diuretic and a mineralocorticoid receptor antagonist. Patients with resistant vs refractory hypertension share similar characteristics and comorbidities, including obesity, African American race, female sex, diabetes, coronary heart disease, chronic kidney disease, and obstructive sleep apnea. Patients with refractory vs resistant hypertension tend to be younger and are more likely to have been diagnosed with congestive heart failure. Refractory hypertension might also differ from resistant hypertension in terms of underlying cause. Preliminary evidence suggests that refractory hypertension is more likely to be neurogenic in etiology (ie, heightened sympathetic tone), vs a volume-dependent hypertension that is more characteristic of resistant hypertension in general. PMID:26514749

Neurophysiology versus clinical genetics in Rett syndrome: A multicenter study.

PubMed

Halbach, Nicky; Smeets, Eric E; Julu, Peter; Witt-Engerström, Ingegerd; Pini, Giorgio; Bigoni, Stefania; Hansen, Stig; Apartopoulos, Flora; Delamont, Robert; van Roozendaal, Kees; Scusa, Maria F; Borelli, Paolo; Candel, Math; Curfs, Leopold

2016-09-01

Many studies have attempted to establish the genotype-phenotype correlation in Rett syndrome (RTT). Cardiorespiratory measurements provide robust objective data, to correlate with each of the different clinical phenotypes. It has important implications for the management and treatment of this syndrome. The aim of this study was to correlate the genotype with the quantitative cardiorespiratory data obtained by neurophysiological measurement combined with a clinical severity score. This international multicenter study was conducted in four European countries from 1999 to 2012. The study cohort consisted of a group of 132 well-defined RTT females aged between 2 and 43 years with extended clinical, molecular, and neurophysiological assessments. Diagnosis of RTT was based on the consensus criteria for RTT and molecular confirmation. Genotype-phenotype analyses of clinical features and cardiorespiratory data were performed after grouping mutations by the same type and localization or having the same putative biological effect on the MeCP2 protein, and subsequently on eight single recurrent mutations. A less severe phenotype was seen in females with CTS, p.R133C, and p.R294X mutations. Autonomic disturbances were present in all females, and not restricted to nor influenced by one specific group or any single recurrent mutation. The objective information from non-invasive neurophysiological evaluation of the disturbed central autonomic control is of great importance in helping to organize the lifelong care for females with RTT. Further research is needed to provide insights into the pathogenesis of autonomic dysfunction, and to develop evidence-based management in RTT. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Defining the Relationship Between Phenotypic and Genotypic Resistance Profiles of Multidrug-Resistant Enterobacterial Clinical Isolates.

PubMed

Galal, Lamis; Abdel Aziz, Neveen A; Hassan, Walaa M

2018-05-11

Fluoroquinolones and aminoglycosides offer effective therapy for extended-spectrum beta-lactamase (ESBL)-producing enterobacterial infections, but their usefulness is threatened by increasing resistant strains. This study was conducted to demonstrate the phenotypic outcomes of the coexistence of genetic determinants mediating resistance to extended-spectrum cephalosporins and quinolones in enterobacterial isolates collected from patients with health-care-associated infections in Egypt. ESBL phenotype was determined using double-disk synergy test (DDST). The PCR technique was used to detect the presence of the genes mediating quinolone resistance (qnr and aac(6')-Ib-cr) and coexistence with ESBL genes. We also examined the association between the genetic makeup of the isolates and their resistance profiles including effect on MIC results. Phenotypically ESBLs were detected in 60-82% of the enterobacterial isolates. ESBL, qnr and aac(6')-Ib-cr genes were detected with the following percentages in Citrobacter isolates (69%, 69%, and 43%, respectively), E.coli isolates (65%, 70%, and 45%, respectively), Enterobacter isolates (56%, 67%, and 33%, respectively), and finally Klebsiella isolates (42%, 66%, and 25%, respectively). The coexistence of these multiresistant genetic elements significantly increased the MIC values of the tested antibiotics from different classes. We suggest using blaTEM, blaCTX-M-15, qnr, and aac(6')-Ib-cr genes for better and faster prediction of suitable antibiotic therapy with effective doses against ESBL-producing isolates harboring plasmid-mediated quinolone resistance (PMQR) determinants. Amikacin, meropenem, gentamicin, and imipenem seem to be better choices of treatment for such life-threatening infections, because of their remaining highest activity.

Social Communication and Theory of Mind in Boys with Autism and Fragile X Syndrome

PubMed Central

Losh, Molly; Martin, Gary E.; Klusek, Jessica; Hogan-Brown, Abigail L.; Sideris, John

2012-01-01

Impairments in the social use of language, or pragmatics, constitute a core characteristic of autism. Problems with pragmatic language have also been documented in fragile X syndrome (FXS), a monogenic condition that is the most common known genetic cause of autism. Evidence suggests that social cognitive ability, or theory of mind, may also be impaired in both conditions, and in autism, may importantly relate to pragmatic language ability. Given the substantial overlap observed in autism and FXS, this study aimed to better define those social-communicative phenotypes that overlap in these two conditions by comparing pragmatic language ability and theory of mind in children with idiopathic autism and children with FXS, with and without autism, as well as children with Down syndrome and typically developing controls. We further examined correlations between these cognitive-behavioral phenotypes and molecular genetic variation related to the Fragile X Mental Retardation-1 gene (FMR1) in the FXS group. Results indicated that children with idiopathic autism and those with FXS and autism performed comparably on direct-assessment measures of pragmatic language and theory of mind, whereas those with FXS only did not differ from controls. Theory of mind was related to pragmatic language ability in all groups. Pragmatic language and theory of mind also correlated with genetic variation at the FMR1 locus (Cytosine-Guanine-Guanine repeats and percent methylation). These results point toward substantial overlap in the social and language phenotypes in autism and FXS and suggest a molecular genetic basis to these phenotypic profiles. PMID:22934085

Social communication and theory of mind in boys with autism and fragile x syndrome.

PubMed

Losh, Molly; Martin, Gary E; Klusek, Jessica; Hogan-Brown, Abigail L; Sideris, John

2012-01-01

Impairments in the social use of language, or pragmatics, constitute a core characteristic of autism. Problems with pragmatic language have also been documented in fragile X syndrome (FXS), a monogenic condition that is the most common known genetic cause of autism. Evidence suggests that social cognitive ability, or theory of mind, may also be impaired in both conditions, and in autism, may importantly relate to pragmatic language ability. Given the substantial overlap observed in autism and FXS, this study aimed to better define those social-communicative phenotypes that overlap in these two conditions by comparing pragmatic language ability and theory of mind in children with idiopathic autism and children with FXS, with and without autism, as well as children with Down syndrome and typically developing controls. We further examined correlations between these cognitive-behavioral phenotypes and molecular genetic variation related to the Fragile X Mental Retardation-1 gene (FMR1) in the FXS group. Results indicated that children with idiopathic autism and those with FXS and autism performed comparably on direct-assessment measures of pragmatic language and theory of mind, whereas those with FXS only did not differ from controls. Theory of mind was related to pragmatic language ability in all groups. Pragmatic language and theory of mind also correlated with genetic variation at the FMR1 locus (Cytosine-Guanine-Guanine repeats and percent methylation). These results point toward substantial overlap in the social and language phenotypes in autism and FXS and suggest a molecular genetic basis to these phenotypic profiles.

Deciphering the Function of New Gonococcal Vaccine Antigens Using Phenotypic Microarrays

PubMed Central

Baarda, Benjamin I.; Emerson, Sarah; Proteau, Philip J.

2017-01-01

ABSTRACT The function and extracellular location of cell envelope proteins make them attractive candidates for developing vaccines against bacterial diseases, including challenging drug-resistant pathogens, such as Neisseria gonorrhoeae. A proteomics-driven reverse vaccinology approach has delivered multiple gonorrhea vaccine candidates; however, the biological functions of many of them remain to be elucidated. Herein, the functions of six gonorrhea vaccine candidates—NGO2121, NGO1985, NGO2054, NGO2111, NGO1205, and NGO1344—in cell envelope homeostasis were probed using phenotype microarrays under 1,056 conditions and a ΔbamE mutant (Δngo1780) as a reference of perturbed outer membrane integrity. Optimal growth conditions for an N. gonorrhoeae phenotype microarray assay in defined liquid medium were developed, which can be useful in other applications, including rapid and thorough antimicrobial susceptibility assessment. Our studies revealed 91 conditions having uniquely positive or negative effects on one of the examined mutants. A cluster analysis of 37 and 57 commonly beneficial and detrimental compounds, respectively, revealed three separate phenotype groups: NGO2121 and NGO1985; NGO1344 and BamE; and the trio of NGO1205, NGO2111, and NGO2054, with the last protein forming an independent branch of this cluster. Similar phenotypes were associated with loss of these vaccine candidates in the highly antibiotic-resistant WHO X strain. Based on their extensive sensitivity phenomes, NGO1985 and NGO2121 appear to be the most promising vaccine candidates. This study establishes the principle that phenotype microarrays can be successfully applied to a fastidious bacterial organism, such as N. gonorrhoeae. IMPORTANCE Innovative approaches are required to develop vaccines against prevalent and neglected sexually transmitted infections, such as gonorrhea. Herein, we have utilized phenotype microarrays in the first such investigation into Neisseria gonorrhoeae to probe the function of proteome-derived vaccine candidates in cell envelope homeostasis. Information gained from this screening can feed the vaccine candidate decision tree by providing insights into the roles these proteins play in membrane permeability, integrity, and overall N. gonorrhoeae physiology. The optimized screening protocol can be applied in investigations into the function of other hypothetical proteins of N. gonorrhoeae discovered in the expanding number of whole-genome sequences, in addition to revealing phenotypic differences between clinical and laboratory strains. PMID:28630127

Clustering high-dimensional mixed data to uncover sub-phenotypes: joint analysis of phenotypic and genotypic data.

PubMed

McParland, D; Phillips, C M; Brennan, L; Roche, H M; Gormley, I C

2017-12-10

The LIPGENE-SU.VI.MAX study, like many others, recorded high-dimensional continuous phenotypic data and categorical genotypic data. LIPGENE-SU.VI.MAX focuses on the need to account for both phenotypic and genetic factors when studying the metabolic syndrome (MetS), a complex disorder that can lead to higher risk of type 2 diabetes and cardiovascular disease. Interest lies in clustering the LIPGENE-SU.VI.MAX participants into homogeneous groups or sub-phenotypes, by jointly considering their phenotypic and genotypic data, and in determining which variables are discriminatory. A novel latent variable model that elegantly accommodates high dimensional, mixed data is developed to cluster LIPGENE-SU.VI.MAX participants using a Bayesian finite mixture model. A computationally efficient variable selection algorithm is incorporated, estimation is via a Gibbs sampling algorithm and an approximate BIC-MCMC criterion is developed to select the optimal model. Two clusters or sub-phenotypes ('healthy' and 'at risk') are uncovered. A small subset of variables is deemed discriminatory, which notably includes phenotypic and genotypic variables, highlighting the need to jointly consider both factors. Further, 7 years after the LIPGENE-SU.VI.MAX data were collected, participants underwent further analysis to diagnose presence or absence of the MetS. The two uncovered sub-phenotypes strongly correspond to the 7-year follow-up disease classification, highlighting the role of phenotypic and genotypic factors in the MetS and emphasising the potential utility of the clustering approach in early screening. Additionally, the ability of the proposed approach to define the uncertainty in sub-phenotype membership at the participant level is synonymous with the concepts of precision medicine and nutrition. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

Systemic Lupus Erythematosus: Definitions, Contexts, Conflicts, Enigmas

PubMed Central

Rekvig, Ole Petter

2018-01-01

Systemic lupus erythematosus (SLE) is an inadequately defined syndrome. Etiology and pathogenesis remain largely unknown. SLE is on the other hand a seminal syndrome that has challenged immunologists, biologists, genetics, and clinicians to solve its nature. The syndrome is characterized by multiple, etiologically unlinked manifestations. Unexpectedly, they seem to occur in different stochastically linked clusters, although single gene defects may promote a smaller spectrum of symptoms/criteria typical for SLE. There is no known inner coherence of parameters (criteria) making up the disease. These parameters are, nevertheless, implemented in The American College of Rheumatology (ACR) and The Systemic Lupus Collaborating Clinics (SLICC) criteria to classify SLE. Still, SLE is an abstraction since the ACR or SLICC criteria allow us to define hundreds of different clinical SLE phenotypes. This is a major point of the present discussion and uses “The anti-dsDNA antibody” as an example related to the problematic search for biomarkers for SLE. The following discussion will show how problematic this is: the disease is defined through non-coherent classification criteria, its complexity is recognized and accepted, its pathogenesis is plural and poorly understood. Therapy is focused on dominant symptoms or organ manifestations, and not on the syndrome itself. From basic scientific evidences, we can add substantial amount of data that are not sufficiently considered in clinical medicine, which may change the paradigms linked to what “The Anti-DNA antibody” is—and is not—in context of the imperfectly defined syndrome SLE. PMID:29545801

Cuticular hydrocarbon phenotypes do not indicate cryptic species in fungus-growing termites (Isoptera: Macrotermitinae).

PubMed

Marten, Andreas; Kaib, Manfred; Brandl, Roland

2009-05-01

In several termite species, distinct differences in the composition of cuticular hydrocarbons among colonies correspond to high genetic divergence of mitochondrial DNA sequences. These observations suggest that hydrocarbon phenotypes represent cryptic species. Different cuticular hydrocarbon phenotypes also are found among colonies of fungus-growing termites of the genus Macrotermes. To determine if these hydrocarbon differences in Macrotermes also indicate cryptic species, we sequenced the mitochondrial CO I gene from species in West and East Africa. Among individuals of a supposed species but belonging to different cuticular hydrocarbon phenotypes, the genetic distances are much smaller than distances between species. Unlike what has been observed in other termites, Macrotermes hydrocarbon phenotypes do not represent cryptic species. Our findings suggest fundamental differences in the evolution and/or function of cuticular hydrocarbons among different termite lineages.

A systems biology approach to defining regulatory mechanisms for cartilage and tendon cell phenotypes.

PubMed

Mueller, A J; Tew, S R; Vasieva, O; Clegg, P D; Canty-Laird, E G

2016-09-27

Phenotypic plasticity of adult somatic cells has provided emerging avenues for the development of regenerative therapeutics. In musculoskeletal biology the mechanistic regulatory networks of genes governing the phenotypic plasticity of cartilage and tendon cells has not been considered systematically. Additionally, a lack of strategies to effectively reproduce in vitro functional models of cartilage and tendon is retarding progress in this field. De- and redifferentiation represent phenotypic transitions that may contribute to loss of function in ageing musculoskeletal tissues. Applying a systems biology network analysis approach to global gene expression profiles derived from common in vitro culture systems (monolayer and three-dimensional cultures) this study demonstrates common regulatory mechanisms governing de- and redifferentiation transitions in cartilage and tendon cells. Furthermore, evidence of convergence of gene expression profiles during monolayer expansion of cartilage and tendon cells, and the expression of key developmental markers, challenges the physiological relevance of this culture system. The study also suggests that oxidative stress and PI3K signalling pathways are key modulators of in vitro phenotypes for cells of musculoskeletal origin.

Androgen receptor expression in breast cancer in relation to molecular phenotype: results from the Nurses' Health Study.

PubMed

Collins, Laura C; Cole, Kimberly S; Marotti, Jonathan D; Hu, Rong; Schnitt, Stuart J; Tamimi, Rulla M

2011-07-01

Previous studies have demonstrated that androgen receptor is expressed in many breast cancers, but its expression in relation to the various breast cancer subtypes as defined by molecular profiling has not been studied in detail. We constructed tissue microarrays from 3093 breast cancers that developed in women enrolled in the Nurses' Health Study. Tissue microarray sections were immunostained for estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), cytokeratin 5/6, epidermal growth factor receptor (EGFR) and androgen receptor (ER). Immunostain results were used to categorize each cancer as luminal A or B, HER2 and basal like. The relationships between androgen receptor expression and molecular subtype were analyzed. Overall, 77% of the invasive breast carcinomas were androgen receptor positive. Among 2171 invasive cancers, 64% were luminal A, 15% luminal B, 6% HER2 and 11% basal like. The frequency of androgen receptor expression varied significantly across the molecular phenotypes (P<0.0001). In particular, androgen receptor expression was commonly observed in luminal A (91%) and B (68%) cancers, but was less frequently seen in HER2 cancers (59%). Despite being defined by the absence of ER and PR expression and being considered hormonally unresponsive, 32% of basal-like cancers expressed androgen receptor. Among 246 cases of ductal carcinoma in situ, 86% were androgen receptor positive, but the frequency of androgen receptor expression differed significantly across the molecular phenotypes (P=0.001), and high nuclear grade lesions were less likely to be androgen receptor positive compared with lower-grade lesions. Androgen receptor expression is most commonly seen in luminal A and B invasive breast cancers. However, expression of androgen receptor is also seen in approximately one-third of basal-like cancers, providing further evidence that basal-like cancers represent a heterogeneous group. Our findings raise the possibility that targeting the androgen receptor pathway may represent a novel therapeutic approach to the management of patients with basal-like cancers.

Identification of two new mutations in the GPR98 and the PDE6B genes segregating in a Tunisian family.

PubMed

Hmani-Aifa, Mounira; Benzina, Zeineb; Zulfiqar, Fareeha; Dhouib, Houria; Shahzadi, Amber; Ghorbel, Abdelmonem; Rebaï, Ahmed; Söderkvist, Peter; Riazuddin, Sheikh; Kimberling, William J; Ayadi, Hammadi

2009-04-01

Autosomal recessive retinitis pigmentosa (ARRP) is a genetically heterogeneous disorder. ARRP could be associated with extraocular manifestations that define specific syndromes such as Usher syndrome (USH) characterized by retinal degeneration and congenital hearing loss (HL). The USH type II (USH2) associates RP and mild-to-moderate HL with preserved vestibular function. At least three genes USH2A, the very large G-protein-coupled receptor, GPR98, and DFNB31 are responsible for USH2 syndrome. Here, we report on the segregation of non-syndromic ARRP and USH2 syndrome in a consanguineous Tunisian family, which was previously used to define USH2B locus. With regard to the co-occurrence of these two different pathologies, clinical and genetic reanalysis of the extended family showed (i) phenotypic heterogeneity within USH2 patients and (ii) excluded linkage to USH2B locus. Indeed, linkage analysis disclosed the cosegregation of the USH2 phenotype with the USH2C locus markers, D5S428 and D5S618, whereas the ARRP perfectly segregates with PDE6B flanking markers D4S3360 and D4S2930. Molecular analysis revealed two new missense mutations, p.Y6044C and p.W807R, occurring in GPR98 and PDE6B genes, respectively. In conclusion, our results show that the USH2B locus at chromosome 3p23-24.2 does not exist, and we therefore withdraw this locus designation. The combination of molecular findings for GPR98 and PDE6B genes enable us to explain the phenotypic heterogeneity and particularly the severe ocular affection first observed in one USH2 patient. This report presents an illustration of how consanguinity could increase familial clustering of multiple hereditary diseases within the same family.

Rationale and Design of the Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis Study. Alpha-1 Protocol.

PubMed

Strange, Charlie; Senior, Robert M; Sciurba, Frank; O'Neal, Scott; Morris, Alison; Wisniewski, Stephen R; Bowler, Russell; Hochheiser, Harry S; Becich, Michael J; Zhang, Yingze; Leader, Joseph K; Methé, Barbara A; Kaminski, Naftali; Sandhaus, Robert A

2015-10-01

Severe deficiency of alpha-1 antitrypsin has a highly variable clinical presentation. The Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis α1 Study is a prospective, multicenter, cross-sectional study of adults older than age 35 years with PiZZ or PiMZ alpha-1 antitrypsin genotypes. It is designed to better understand if microbial factors influence this heterogeneity. Clinical symptoms, pulmonary function testing, computed chest tomography, exercise capacity, and bronchoalveolar lavage (BAL) will be used to define chronic obstructive pulmonary disease (COPD) phenotypes that can be studied with an integrated systems biology approach that includes plasma proteomics; mouth, BAL, and stool microbiome and virome analysis; and blood microRNA and blood mononuclear cell RNA and DNA profiling. We will rely on global genome, transcriptome, proteome, and metabolome datasets. Matched cohorts of PiZZ participants on or off alpha-1 antitrypsin augmentation therapy, PiMZ participants not on augmentation therapy, and control participants from the Subpopulations and Intermediate Outcome Measures in COPD Study who match on FEV1 and age will be compared. In the primary analysis, we will determine if the PiZZ individuals on augmentation therapy have a difference in lower respiratory tract microbes identified compared with matched PiZZ individuals who are not on augmentation therapy. By characterizing the microbiome in alpha-1 antitrypsin deficiency (AATD), we hope to define new phenotypes of COPD that explain some of the diversity of clinical presentations. As a unique genetic cause of COPD, AATD may inform typical COPD pathogenesis, and better understanding of it may illuminate the complex interplay between environment and genetics. Although the biologic approaches are hypothesis generating, the results may lead to development of novel biomarkers, better understanding of COPD phenotypes, and development of novel diagnostic and therapeutic trials in AATD and COPD. Clinical trial registered with www.clinicaltrials.gov (NCT01832220).

Rationale and Design of the Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis Study. Alpha-1 Protocol

PubMed Central

Senior, Robert M.; Sciurba, Frank; O’Neal, Scott; Morris, Alison; Wisniewski, Stephen R.; Bowler, Russell; Hochheiser, Harry S.; Becich, Michael J.; Zhang, Yingze; Leader, Joseph K.; Methé, Barbara A.; Kaminski, Naftali; Sandhaus, Robert A.

2015-01-01

Severe deficiency of alpha-1 antitrypsin has a highly variable clinical presentation. The Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis α1 Study is a prospective, multicenter, cross-sectional study of adults older than age 35 years with PiZZ or PiMZ alpha-1 antitrypsin genotypes. It is designed to better understand if microbial factors influence this heterogeneity. Clinical symptoms, pulmonary function testing, computed chest tomography, exercise capacity, and bronchoalveolar lavage (BAL) will be used to define chronic obstructive pulmonary disease (COPD) phenotypes that can be studied with an integrated systems biology approach that includes plasma proteomics; mouth, BAL, and stool microbiome and virome analysis; and blood microRNA and blood mononuclear cell RNA and DNA profiling. We will rely on global genome, transcriptome, proteome, and metabolome datasets. Matched cohorts of PiZZ participants on or off alpha-1 antitrypsin augmentation therapy, PiMZ participants not on augmentation therapy, and control participants from the Subpopulations and Intermediate Outcome Measures in COPD Study who match on FEV1 and age will be compared. In the primary analysis, we will determine if the PiZZ individuals on augmentation therapy have a difference in lower respiratory tract microbes identified compared with matched PiZZ individuals who are not on augmentation therapy. By characterizing the microbiome in alpha-1 antitrypsin deficiency (AATD), we hope to define new phenotypes of COPD that explain some of the diversity of clinical presentations. As a unique genetic cause of COPD, AATD may inform typical COPD pathogenesis, and better understanding of it may illuminate the complex interplay between environment and genetics. Although the biologic approaches are hypothesis generating, the results may lead to development of novel biomarkers, better understanding of COPD phenotypes, and development of novel diagnostic and therapeutic trials in AATD and COPD. Clinical trial registered with www.clinicaltrials.gov (NCT01832220) PMID:26153726

Characterizing the pathotype of neonatal meningitis causing Escherichia coli (NMEC).

PubMed

Wijetunge, D S S; Gongati, S; DebRoy, C; Kim, K S; Couraud, P O; Romero, I A; Weksler, B; Kariyawasam, S

2015-10-14

Neonatal meningitis-causing Escherichia coli (NMEC) is the predominant Gram-negative bacterial pathogen associated with meningitis in newborn infants. High levels of heterogeneity and diversity have been observed in the repertoire of virulence traits and other characteristics among strains of NMEC making it difficult to define the NMEC pathotype. The objective of the present study was to identify genotypic and phenotypic characteristics of NMEC that can be used to distinguish them from commensal E. coli. A total of 53 isolates of NMEC obtained from neonates with meningitis and 48 isolates of fecal E. coli obtained from healthy individuals (HFEC) were comparatively evaluated using five phenotypic (serotyping, serum bactericidal assay, biofilm assay, antimicorbial susceptibility testing, and in vitro cell invasion assay) and three genotypic (phylogrouping, virulence genotyping, and pulsed-field gel electrophoresis) methods. A majority (67.92%) of NMEC belonged to B2 phylogenetic group whereas 59% of HFEC belonged to groups A and D. Serotyping revealed that the most common O and H types present in NMEC tested were O1 (15%), O8 (11.3%), O18 (13.2%), and H7 (25.3%). In contrast, none of the HFEC tested belonged to O1 or O18 serogroups. The most common serogroup identified in HFEC was O8 (6.25%). The virulence genotyping reflected that more than 70% of NMEC carried kpsII, K1, neuC, iucC, sitA, and vat genes with only less than 27% of HFEC possessing these genes. All NMEC and 79% of HFEC tested were able to invade human cerebral microvascular endothelial cells. No statistically significant difference was observed in the serum resistance phenotype between NMEC and HFEC. The NMEC strains demonstrated a greater ability to form biofilms in Luria Bertani broth medium than did HFEC (79.2% vs 39.9%). The results of our study demonstrated that virulence genotyping and phylogrouping may assist in defining the potential NMEC pathotype.

Tumor morphology and phenotypic evolution driven by selective pressure from the microenvironment.

PubMed

Anderson, Alexander R A; Weaver, Alissa M; Cummings, Peter T; Quaranta, Vito

2006-12-01

Emergence of invasive behavior in cancer is life-threatening, yet ill-defined due to its multifactorial nature. We present a multiscale mathematical model of cancer invasion, which considers cellular and microenvironmental factors simultaneously and interactively. Unexpectedly, the model simulations predict that harsh tumor microenvironment conditions (e.g., hypoxia, heterogenous extracellular matrix) exert a dramatic selective force on the tumor, which grows as an invasive mass with fingering margins, dominated by a few clones with aggressive traits. In contrast, mild microenvironment conditions (e.g., normoxia, homogeneous matrix) allow clones with similar aggressive traits to coexist with less aggressive phenotypes in a heterogeneous tumor mass with smooth, noninvasive margins. Thus, the genetic make-up of a cancer cell may realize its invasive potential through a clonal evolution process driven by definable microenvironmental selective forces. Our mathematical model provides a theoretical/experimental framework to quantitatively characterize this selective pressure for invasion and test ways to eliminate it.

Michelin tire baby syndrome: a review of the literature and a proposal for diagnostic criteria with adoption of the name circumferential skin folds syndrome.

PubMed

Rothman, Ilene L

2014-01-01

The term Michelin tire baby (MTB), named for the cartoon mascot of the Michelin Tire Company, has been used to describe babies with multiple symmetric circumferential rings of folded skin. In those reported with this phenotype who had skin biopsies, pathology has shown nevus lipomatosis, smooth muscle hamartoma, degenerative collagen, and scarring. Others did not undergo biopsy or had normal skin. Many individuals with the MTB phenotype have had a variety of other congenital anomalies. I review the literature on MTB and the history of the designation Michelin tire baby Syndrome (MTBS). Because the term MTBS has been poorly defined or not defined at all, I propose strict criteria for diagnosis. In doing so, it is recommended that the syndrome be renamed to avoid further confusion. © 2014 Wiley Periodicals, Inc.

ABO, Secretor and Lewis histo-blood group systems influence the digestive form of Chagas disease.

PubMed

Bernardo, Cássia Rubia; Camargo, Ana Vitória Silveira; Ronchi, Luís Sérgio; de Oliveira, Amanda Priscila; de Campos Júnior, Eumildo; Borim, Aldenis Albaneze; Brandão de Mattos, Cinara Cássia; Bestetti, Reinaldo Bulgarelli; de Mattos, Luiz Carlos

2016-11-01

Chagas disease, caused by Trypanosoma cruzi, can affect the heart, esophagus and colon. The reasons that some patients develop different clinical forms or remain asymptomatic are unclear. It is believed that tissue immunogenetic markers influence the tropism of T. cruzi for different organs. ABO, Secretor and Lewis histo-blood group systems express a variety of tissue carbohydrate antigens that influence the susceptibility or resistance to diseases. This study aimed to examine the association of ABO, secretor and Lewis histo-blood systems with the clinical forms of Chagas disease. We enrolled 339 consecutive adult patients with chronic Chagas disease regardless of gender (cardiomyopathy: n=154; megaesophagus: n=119; megacolon: n=66). The control group was composed by 488 healthy blood donors. IgG anti-T. cruzi antibodies were detected by ELISA. ABO and Lewis phenotypes were defined by standard hemagglutination tests. Secretor (FUT2) and Lewis (FUT3) genotypes, determined by Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), were used to infer the correct histo-blood group antigens expressed in the gastrointestinal tract. The proportions between groups were compared using the χ2 test with Yates correction and Fisher's exact test and the Odds Ratio (OR) and 95% Confidence Interval (95% CI) were calculated. An alpha error of 5% was considered significant with p-values <0.05 being corrected for multiple comparisons (pc). No statistically significant differences were found for the ABO (X 2 : 2.635; p-value=0.451), Secretor (X 2 : 0.056; p-value=0.812) or Lewis (X 2 : 2.092; p-value=0.351) histo-blood group phenotypes between patients and controls. However, B plus AB Secretor phenotypes were prevalent in pooled data from megaesophagus and megacolon patients (OR: 5.381; 95% CI: 1.230-23.529; p-value=0.011; pc=0.022) in comparison to A plus O Secretor phenotypes. The tissue antigen variability resulting from the combined action of ABO and Secretor histo-blood systems is associated with the digestive forms of Chagas disease. Copyright © 2016 Elsevier B.V. All rights reserved.

Effects of Age and Disease Severity on Systemic Corticosteroid Responses in Asthma.

PubMed

Phipatanakul, Wanda; Mauger, David T; Sorkness, Ronald L; Gaffin, Jonathan M; Holguin, Fernando; Woodruff, Prescott G; Ly, Ngoc P; Bacharier, Leonard B; Bhakta, Nirav R; Moore, Wendy C; Bleecker, Eugene R; Hastie, Annette T; Meyers, Deborah A; Castro, Mario; Fahy, John V; Fitzpatrick, Anne M; Gaston, Benjamin M; Jarjour, Nizar N; Levy, Bruce D; Peters, Stephen P; Teague, W Gerald; Fajt, Merritt; Wenzel, Sally E; Erzurum, Serpil C; Israel, Elliot

2017-06-01

Phenotypic distinctions between severe asthma (SA) and nonsevere asthma (NONSA) may be confounded by differential adherence or incorrect use of corticosteroids. To determine if there are persistent phenotypic distinctions between SA (as defined by 2014 American Thoracic Society/European Respiratory Society guidelines) and NONSA after intramuscular triamcinolone acetonide (TA), and to identify predictors of a corticosteroid response in these populations. A total of 526 adults age 18 years and older (315 SA) and 188 children age 6 to less than 18 years (107 SA) in the NHLBI Severe Asthma Research Program III were characterized before and 3 weeks after TA. The primary outcome for corticosteroid response was defined as greater than or equal to 10-point improvement in percent predicted FEV 1 . Adult asthma groups exhibited a small but significant mean FEV 1 % predicted improvement after TA (SA group mean difference, 3.4%; 95% confidence interval, 2.2-4.7%; P = 0.001), whereas children did not. Adult SA continued to manifest lower FEV 1 and worse asthma control as compared with NONSA after TA. In children, after TA only prebronchodilator FEV 1 distinguished SA from NONSA. A total of 21% of adults with SA and 20% of children with SA achieved greater than or equal to 10% improvement after TA. Baseline bronchodilator response and fractional exhaled nitric oxide had good sensitivity and specificity for predicting response in all groups except children with NONSA. One in five patients with SA exhibit greater than or equal to 10% improvement in FEV 1 with parenteral corticosteroid. Those likely to respond had greater bronchodilator responsiveness and fractional exhaled nitric oxide levels. In adults, differences in airflow obstruction and symptoms between SA and NONSA persist after parenteral corticosteroids, suggesting a component of corticosteroid nonresponsive pathobiology in adults with SA that may differ in children. Clinical trial registered with www.clinicaltrials.gov (NCT 01606826).

A Molecular Perspective on Systematics, Taxonomy and Classification Amazonian Discus Fishes of the Genus Symphysodon

PubMed Central

Amado, Manuella Villar; Farias, Izeni P.; Hrbek, Tomas

2011-01-01

With the goal of contributing to the taxonomy and systematics of the Neotropical cichlid fishes of the genus Symphysodon, we analyzed 336 individuals from 24 localities throughout the entire distributional range of the genus. We analyzed variation at 13 nuclear microsatellite markers, and subjected the data to Bayesian analysis of genetic structure. The results indicate that Symphysodon is composed of four genetic groups: group PURPLE—phenotype Heckel and abacaxi; group GREEN—phenotype green; group RED—phenotype blue and brown; and group PINK—populations of Xingú and Cametá. Although the phenotypes blue and brown are predominantly biological group RED, they also have substantial contributions from other biological groups, and the patterns of admixture of the two phenotypes are different. The two phenotypes are further characterized by distinct and divergent mtDNA haplotype groups, and show differences in mean habitat use measured as pH and conductivity. Differences in mean habitat use is also observed between most other biological groups. We therefore conclude that Symphysodon comprises five evolutionary significant units: Symphysodon discus (Heckel and abacaxi phenotypes), S. aequifasciatus (brown phenotype), S. tarzoo (green phenotype), Symphysodon sp. 1 (blue phenotype) and Symphysodon sp. 2 (Xingú group). PMID:21811676

The Impact of "Possible Patients" on Phenotyping Algorithms: Electronic Phenotype Algorithms Can Only Be Reproduced by Sharing Detailed Annotation Criteria.

PubMed

Kagawa, Rina; Kawazoe, Yoshimasa; Shinohara, Emiko; Imai, Takeshi; Ohe, Kazuhiko

2017-01-01

Phenotyping is an automated technique for identifying patients diagnosed with a particular disease based on electronic health records (EHRs). To evaluate phenotyping algorithms, which should be reproducible, the annotation of EHRs as a gold standard is critical. However, we have found that the different types of EHRs cannot be definitively annotated into CASEs or CONTROLs. The influence of such "possible patients" on phenotyping algorithms is unknown. To assess these issues, for four chronic diseases, we annotated EHRs by using information not directly referring to the diseases and developed two types of phenotyping algorithms for each disease. We confirmed that each disease included different types of possible patients. The performance of phenotyping algorithms differed depending on whether possible patients were considered as CASEs, and this was independent of the type of algorithms. Our results indicate that researchers must share annotation criteria for classifying the possible patients to reproduce phenotyping algorithms.

From Genes to Environment: Using integrative genomics to build a “systems level” understanding of autism spectrum disorders

PubMed Central

Hu, Valerie W.

2012-01-01

Autism spectrum disorders (ASD) are pervasive neurodevelopmental disorders that affect an estimated 1 in 110 individuals. Although there is a strong genetic component associated with these disorders, this review focuses on the multi-factorial nature of ASD and how different genome-wide (genomic) approaches contribute to our understanding of autism. Emphasis is placed on the need to study defined ASD phenotypes as well as to integrate large-scale ‘omics’ data in order to develop a “systems level” perspective of ASD which, in turn, is necessary to allow predictions regarding responses to specific perturbations and interventions. PMID:22497667

A statistical dynamics approach to the study of human health data: Resolving population scale diurnal variation in laboratory data

NASA Astrophysics Data System (ADS)

Albers, D. J.; Hripcsak, George

2010-02-01

Statistical physics and information theory is applied to the clinical chemistry measurements present in a patient database containing 2.5 million patients' data over a 20-year period. Despite the seemingly naive approach of aggregating all patients over all times (with respect to particular clinical chemistry measurements), both a diurnal signal in the decay of the time-delayed mutual information and the presence of two sub-populations with differing health are detected. This provides a proof in principle that the highly fragmented data in electronic health records has potential for being useful in defining disease and human phenotypes.

A Polyphasic and Taxogenomic Evaluation Uncovers Arcobacter cryaerophilus as a Species Complex That Embraces Four Genomovars

PubMed Central

Pérez-Cataluña, Alba; Collado, Luis; Salgado, Oscar; Lefiñanco, Violeta; Figueras, María J.

2018-01-01

The species Arcobacter cryaerophilus is found in many food products of animal origin and is the dominating species in wastewater. In addition, it is associated with cases of farm animal and human infectious diseases,. The species embraces two subgroups i.e., 1A (LMG 24291T = LMG 9904T) and 1B (LMG 10829) that can be differentiated by their 16S rRNA-RFLP pattern. However, some authors, on the basis of the shared intermediate levels of DNA-DNA hybridization, have suggested abandoning the subgroup classification. This contradiction indicates that the taxonomy of this species is not yet resolved. The objective of the present study was to perform a taxonomic evaluation of the diversity of A. cryaerophilus. Genomic information was used along with a Multilocus Phylogenetic Analysis (MLPA) and phenotypic characterization on a group of 52 temporally and geographically dispersed strains, coming from different types of samples and hosts from nine countries. The MLPA analysis showed that those strains formed four clusters (I–IV). Values of Average Nucleotide Identity (ANI) and in silico DNA-DNA Hybridization (isDDH) obtained between 13 genomes representing strains of the four clusters were below the proposed cut-offs of 96 and 70%, respectively, confirming that each of the clusters represented a different genomic species. However, none of the evaluated phenotypic tests enabled their unequivocal differentiation into species. Therefore, the genomic delimited clusters should be considered genomovars of the species A. cryaerophilus. These genomovars could have different clinical importance, since only the cluster I included strains isolated from human specimens. The discovery of at least one stable distinctive phenotypic character would be needed to define each cluster or genomovar as a different species. Until then, we propose naming them “A. cryaerophilus gv. pseudocryaerophilus” (Cluster I = LMG 10229T), “A. cryaerophilus gv. crypticus” (Cluster II = LMG 9065T), “A. cryaerophilus gv. cryaerophilus” (Cluster III = LMG 24291T) and “A. cryaerophilus gv. occultus” (Cluster IV = LMG 29976T).

Careflow Mining Techniques to Explore Type 2 Diabetes Evolution.

PubMed

Dagliati, Arianna; Tibollo, Valentina; Cogni, Giulia; Chiovato, Luca; Bellazzi, Riccardo; Sacchi, Lucia

2018-03-01

In this work we describe the application of a careflow mining algorithm to detect the most frequent patterns of care in a type 2 diabetes patients cohort. The applied method enriches the detected patterns with clinical data to define temporal phenotypes across the studied population. Novel phenotypes are discovered from heterogeneous data of 424 Italian patients, and compared in terms of metabolic control and complications. Results show that careflow mining can help to summarize the complex evolution of the disease into meaningful patterns, which are also significant from a clinical point of view.

Odd MECP2-mutated Rett variant-long-term follow-up profile to age 25.

PubMed

Hagberg, Bengt; Erlandsson, Anna; Kyllerman, Mårten; Larsson, Gunillla

2003-01-01

A 25-year-old MECP2-mutated female with odd developmental and dyspraxic/ataxic features, followed up through two decades, is reported. She does not fit either the classical Rett syndrome or the criteria required for any Rett variant phenotypes so far described. Nevertheless, she belongs clinically to the latter group. This case deserves attention in order, among other things, to provide important clues to better understand the puzzling battery of neuroimpairments and behavioural abnormalities met in classical Rett phenotypes and Rett variants defined thus far.

Ethnicity-Dependent and -Independent Heterogeneity in Healthy Normal Breast Hierarchy Impacts Tumor Characterization

PubMed Central

Nakshatri, Harikrishna; Anjanappa, Manjushree; Bhat-Nakshatri, Poornima

2015-01-01

Recent reports of widespread genetic variation affecting regulation of gene expression raise the possibility of significant inter-individual differences in stem-progenitor-mature cell hierarchy in adult organs. This has not been explored because of paucity of methods to quantitatively assess subpopulation of normal epithelial cells on individual basis. We report the remarkable inter-individual differences in differentiation capabilities as documented by phenotypic heterogeneity in stem-progenitor-mature cell hierarchy of the normal breast. Ethnicity and genetic predisposition are partly responsible for this heterogeneity, evidenced by the finding that CD44+/CD24- and PROCR+/EpCAM- multi-potent stem cells were elevated significantly in African American women compared with Caucasians. ALDEFLUOR+ luminal stem/progenitor cells were lower in BRCA1-mutation carriers compared with cells from healthy donors (p = 0.0014). Moreover, tumor and adjoining-normal breast cells of the same patients showed distinct CD49f+/EpCAM+ progenitor, CD271+/EpCAM- basal, and ALDEFLUOR+ cell profiles. These inter-individual differences in the rate of differentiation in the normal breast may contribute to a substantial proportion of transcriptome, epigenome, and signaling pathway alterations and consequently has the potential to spuriously magnify the extent of documented tumor-specific gene expression. Therefore, comparative analysis of phenotypically defined subpopulations of normal and tumor cells on an individual basis may be required to identify cancer-specific aberrations. PMID:26311223

Ethnicity-Dependent and -Independent Heterogeneity in Healthy Normal Breast Hierarchy Impacts Tumor Characterization.

PubMed

Nakshatri, Harikrishna; Anjanappa, Manjushree; Bhat-Nakshatri, Poornima

2015-08-27

Recent reports of widespread genetic variation affecting regulation of gene expression raise the possibility of significant inter-individual differences in stem-progenitor-mature cell hierarchy in adult organs. This has not been explored because of paucity of methods to quantitatively assess subpopulation of normal epithelial cells on individual basis. We report the remarkable inter-individual differences in differentiation capabilities as documented by phenotypic heterogeneity in stem-progenitor-mature cell hierarchy of the normal breast. Ethnicity and genetic predisposition are partly responsible for this heterogeneity, evidenced by the finding that CD44+/CD24- and PROCR+/EpCAM- multi-potent stem cells were elevated significantly in African American women compared with Caucasians. ALDEFLUOR+ luminal stem/progenitor cells were lower in BRCA1-mutation carriers compared with cells from healthy donors (p = 0.0014). Moreover, tumor and adjoining-normal breast cells of the same patients showed distinct CD49f+/EpCAM+ progenitor, CD271+/EpCAM- basal, and ALDEFLUOR+ cell profiles. These inter-individual differences in the rate of differentiation in the normal breast may contribute to a substantial proportion of transcriptome, epigenome, and signaling pathway alterations and consequently has the potential to spuriously magnify the extent of documented tumor-specific gene expression. Therefore, comparative analysis of phenotypically defined subpopulations of normal and tumor cells on an individual basis may be required to identify cancer-specific aberrations.

"Metabolically healthy" obesity: Prevalence, clinical features and association with myocardial ischaemia.

PubMed

De Lorenzo, Andrea; Glerian, Leticia; Amaral, Ana Carolina; Reis, Thiago B; Lima, Ronaldo S L

To evaluate the prevalence of the "metabolically healthy" (MH) or "metabolically unhealthy" (MU) obesity phenotypes and their association with cardiorespiratory fitness and inducible myocardial ischaemia. Individuals without known coronary artery disease undergoing myocardial perfusion single-photon emission computed tomography (MPS) were studied. Those without dyslipidemia, hypertension, or diabetes were considered MH, and when ≥1 of these was present, MU status was considered present. Summed stress and difference perfusion scores (SSS and SDS, respectively) were calculated; a SDS >1 defined ischaemic MPS. MH patients were 35.0% of the nonobese population and 23.5% of the obese (p<0.001). The prevalence of ischaemia was not significantly different between MH patients with obesity or MH patients without obesity (10.9% vs 9.1%, p=0.3), except for patients with body mass index ≥40kg/m 2 (21.9%). MH obese patients were less frequently able to exercise and had lower exercise capacity than the nonobese patients. The prevalence of myocardial ischaemia was not significantly different between MH obese or nonobese individuals, supporting the concept of the "metabolically healthy obesity". However, there are other factors involved, such as the ability to exercise, that influence the risk of myocardial ischaemia, limiting the "safety" of that obesity phenotype. Copyright © 2016 Asia Oceania Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.

Metabolically healthy obese individuals present similar chronic inflammation level but less insulin-resistance than obese individuals with metabolic syndrome

PubMed Central

Penas Steinhardt, Alberto; López, Ariel Pablo; González, Claudio Daniel; Vilariño, Jorge; Frechtel, Gustavo Daniel; Cerrone, Gloria Edith

2017-01-01

The Metabolic Syndrome (MetS) is a cluster of cardiometabolic risk factors, usually accompanied by the presence of insulin resistance (IR) and a systemic subclinical inflammation state. Metabolically healthy obese (MHO) individuals seem to be protected against cardiometabolic complications. The aim of this work was to characterize phenotypically the low-grade inflammation and the IR in MHO individuals in comparison to obese individuals with MetS and control non obese. We studied two different populations: 940 individuals from the general population of Buenos Aires and 518 individuals from the general population of Venado Tuerto; grouped in three groups: metabolically healthy non-obese individuals (MHNO), MHO and obese individuals with MetS (MSO). Inflammation was measured by the levels of hs-CRP (high-sensitivity C reactive protein), and we found that MHO presented an increase in inflammation when compared with MHNO (Buenos Aires: p<0.001; Venado Tuerto: p<0.001), but they did not differ from MSO. To evaluate IR we analyzed the HOMA (Homoeostatic Model Assessment) values, and we found differences between MHO and MSO (Buenos Aires: p<0.001; Venado Tuerto: p<0.001), but not between MHNO and MHO. In conclusion, MHO group would be defined as a subgroup of obese individuals with an intermediate phenotype between MHNO and MSO individuals considering HOMA, hs-CRP and central obesity. PMID:29284058

Heterogeneous phenotypes of insulin resistance and its implications for defining metabolic syndrome in Asian Indian adolescents.

PubMed

Vikram, Naval K; Misra, Anoop; Pandey, Ravindra M; Luthra, Kalpana; Wasir, Jasjeet S; Dhingra, Vibha

2006-05-01

To assess the phenotypic correlations of insulin resistance with obesity and its relationship with the metabolic syndrome in Asian Indian adolescents. We analyzed clinical, anthropometric (body mass index [BMI], waist circumference [WC]) and laboratory (fasting blood glucose [FBG], lipids and fasting serum insulin) data from 793 subjects (401 males and 392 females) aged 14-19 years randomly selected from Epidemiological Study of Adolescents and Young (ESAY) adults (n=1447). The percentile cut-offs for 14-19 years age from ESAY cohort were used for defining abnormal values of variables. We devised three sets of definitions of metabolic syndrome by including BMI and fasting insulin levels with other defining variables. Nearly 28.9% of adolescents had fasting hyperinsulinemia despite normal values of BMI, WC, FBG, lipids, and blood pressure. Remarkably, NCEP criteria with appropriate percentile cut-off points for Asian Indian adolescents identified metabolic syndrome in only six (0.8%) subjects. Inclusion of both BMI and WC in the definition resulted in increase in the prevalence of metabolic syndrome to 4.3%. With inclusion of hyperinsulinemia, the prevalence of metabolic syndrome increased to 4.2% (from 0.8%) in the modified NCEP definition, 5.2% (from 0.9%) when BMI was substituted for WC, and 10.2 (from 4.3%) when both BMI and WC were included. Our data show marked heterogeneity of phenotypes of insulin resistance and poor value of NCEP definition to identify metabolic syndrome. We propose that BMI and fasting insulin should be evaluated in candidate definitions of metabolic syndrome in Asian Indian adolescents.

“Dynamic Range” of Inferred Phenotypic HIV Drug Resistance Values in Clinical Practice

PubMed Central

Swenson, Luke C.; Pollock, Graham; Wynhoven, Brian; Mo, Theresa; Dong, Winnie; Hogg, Robert S.; Montaner, Julio S. G.; Harrigan, P. Richard

2011-01-01

Background ‘Virtual’ or inferred phenotypes (vPhenotypes) are commonly used to assess resistance to antiretroviral agents in patients failing therapy. In this study, we provide a clinical context for understanding vPhenotype values. Methods All HIV-infected persons enrolled in the British Columbia Drug Treatment Program with a baseline plasma viral load (pVL) and follow-up genotypic resistance and pVL results were included up to October 29, 2008 (N = 5,277). Change from baseline pVL was determined as a function of Virco vPhenotype, and the “dynamic range” (defined here by the 10th and 90th percentiles for fold-change in IC50 amongst all patients) was estimated from the distribution of vPhenotye fold-changes across the cohort. Results The distribution of vPhenotypes from a large cohort of HIV patients who have failed therapy are presented for all available antiretroviral agents. A maximum change in IC50 of at least 13-fold was observed for all drugs. The dideoxy drugs, tenofovir and most PIs exhibited small “dynamic ranges” with values of <4-fold change observed in >99% of samples. In contrast, zidovudine, lamivudine, emtricitabine and the non-nucleoside reverse transcriptase inihibitors (excluding etravirine) had large dynamic ranges. Conclusion We describe the populational distribution of vPhenotypes such that vPhenotype results can be interpreted relative to other patients in a drug-specific manner. PMID:21390218

A novel healthy blood pressure phenotype in the Long Life Family Study.

PubMed

Marron, Megan M; Singh, Jatinder; Boudreau, Robert M; Christensen, Kaare; Cosentino, Stephanie; Feitosa, Mary F; Minster, Ryan L; Perls, Thomas; Schupf, Nicole; Sebastiani, Paola; Ukraintseva, Svetlana; Wojczynski, Mary K; Newman, Anne B

2018-01-01

Hypertension tends to run in families and has both genetic and environmental determinants. We assessed the hypothesis that a novel healthy blood pressure (BP) phenotype is also familial and sought to identify its associated factors. We developed a healthy BP phenotype in the Long Life Family Study, a cohort of two-generation families selected for longevity. Participants from the offspring generation (n = 2211, ages 32-88) were classified as having healthy BP if their age-adjusted and sex-adjusted SBP z-score was between -1.5 and -0.5. Offspring on antihypertensive medications were classified as not having healthy BP. Families with at least two offspring (n = 419 families) were defined as meeting the healthy BP phenotype if at least two and at least 50% of their offspring had healthy BP. Among 2211 offspring, 476 (21.5%) met the healthy BP phenotype. When examining the 419 families, only 44 (10.5%) families met the criteria for the healthy BP phenotype. Both offspring and probands from families with healthy BP performed better on neuropsychological tests that place demands on complex attention and executive function when compared with offspring and probands from remaining families. Among families with the healthy BP phenotype compared with families without, a higher proportion of offspring met the American Heart Association definition of ideal cardiovascular health (10.8 versus 3.8%, respectively; driven by BP, smoking status, and BMI components). In this cohort of familial longevity, few families had a novel healthy BP phenotype in multiple members. Families with this healthy BP phenotype may represent a specific pathway to familial longevity.

Are "functionally related polymorphisms" of renin-angiotensin-aldosterone system gene polymorphisms associated with hypertension?

PubMed

Hahntow, Ines N; Mairuhu, Gideon; van Valkengoed, Irene Gm; Koopmans, Richard P; Michel, Martin C

2010-06-02

Genotype-phenotype association studies are typically based upon polymorphisms or haplotypes comprised of multiple polymorphisms within a single gene. It has been proposed that combinations of polymorphisms in distinct genes, which functionally impact the same phenotype, may have stronger phenotype associations than those within a single gene. We have tested this hypothesis using genes encoding components of the renin-angiotensin-aldosterone system and the high blood pressure phenotype. Our analysis is based on 1379 participants of the cross-sectional SUNSET study randomly selected from the population register of Amsterdam. Each subject was genotyped for the angiotensinogen M235T, the angiotensin-converting enzyme insertion/deletion and the angiotensin II type 1 receptor A1166C polymorphism. The phenotype high blood pressure was defined either as a categorical variable comparing hypertension versus normotension as in most previous studies or as a continuous variable using systolic, diastolic and mean blood pressure in a multiple regression analysis with gender, ethnicity, age, body-mass-index and antihypertensive medication as covariates. Genotype-phenotype relationships were explored for each polymorphism in isolation and for double and triple polymorphism combinations. At the single polymorphism level, only the A allele of the angiotensin II type 1 receptor was associated with a high blood pressure phenotype. Using combinations of polymorphisms of two or all three genes did not yield stronger/more consistent associations. We conclude that combinations of physiologically related polymorphisms of multiple genes, at least with regard to the renin-angiotensin-aldosterone system and the hypertensive phenotype, do not necessarily offer additional benefit in analyzing genotype/phenotype associations.

Delving deeper into technological innovations to understand differences in rice quality.

PubMed

Calingacion, Mariafe; Fang, Lu; Quiatchon-Baeza, Lenie; Mumm, Roland; Riedel, Arthur; Hall, Robert D; Fitzgerald, Melissa

2015-12-01

Increasing demand for better quality rice varieties, which are also more suited to growth under sub-optimal cultivation conditions, is driving innovation in rice research. Here we have used a multi-disciplinary approach, involving SNP-based genotyping together with phenotyping based on yield analysis, metabolomic analysis of grain volatiles, and sensory panel analysis to determine differences between two contrasting rice varieties, Apo and IR64. Plants were grown under standard and drought-induced conditions. Results revealed important differences between the volatile profiles of the two rice varieties and we relate these differences to those perceived by the sensory panel. Apo, which is the more drought tolerant variety, was less affected by the drought condition concerning both sensory profile and yield; IR64, which has higher quality but is drought sensitive, showed greater differences in these characteristics in response to the two growth conditions. Metabolomics analyses using GCxGC-MS, followed by multivariate statistical analyses of the data, revealed a number of discriminatory compounds between the varieties, but also effects of the difference in cultivation conditions. Results indicate the complexity of rice volatile profile, even of non-aromatic varieties, and how metabolomics can be used to help link changes in aroma profile with the sensory phenotype. Our outcomes also suggest valuable multi-disciplinary approaches which can be used to help define the aroma profile in rice, and its underlying genetic background, in order to support breeders in the generation of improved rice varieties combining high yield with high quality, and tolerance of both these traits to climate change.

Taxonomy and phenotypic relationships of the Anastrepha fraterculus complex in the Mesoamerican and Pacific Neotropical dominions (Diptera, Tephritidae)

PubMed Central

Hernández-Ortiz, Vicente; Canal, Nelson A.; Salas, Juan O. Tigrero; Ruíz-Hurtado, Freddy M.; Dzul-Cauich, José F.

2015-01-01

Abstract Previous morphometric studies based on linear measurements of female structures of the aculeus, mesonotum, and wing revealed the existence of seven morphotypes within the Anastrepha fraterculus cryptic species complex along the Neotropical Region. The current research followed linear and geometric morphometric approaches in 40 population samples of the nominal species Anastrepha fraterculus (Wiedemann) spread throughout the Meso-American and Pacific Neotropical dominions (including Mexico, Central America, Venezuela, Colombia, Ecuador, and Peru). The goals were to explore the phenotypic relationships of the morphotypes in these biogeographical areas; evaluate the reliability of procedures used for delimitation of morphotypes; and describe their current distribution. Findings determined that morphotypes previously recognized via the linear morphometrics were also supported by geometric morphometrics of the wing shape. In addition, we found an eighth morphotype inhabiting the highlands of Ecuador and Peru. Morphotypes are related into three natural phenotypic groups nominated as Mesoamerican-Caribbean lineage, Andean lineage, and Brazilian lineage. The hypothesis that lineages are not directly related to each other is discussed, supported by their large morphological divergence and endemicity in these three well-defined biogeographic areas. In addition, this hypothesis of the non-monophyly of the Anastrepha fraterculus complex is also supported by evidence from other authors based on molecular studies and the strong reproductive isolation between morphs from different lineages. PMID:26798256

MLL2 mutation detection in 86 patients with Kabuki syndrome: a genotype-phenotype study.

PubMed

Makrythanasis, P; van Bon, B W; Steehouwer, M; Rodríguez-Santiago, B; Simpson, M; Dias, P; Anderlid, B M; Arts, P; Bhat, M; Augello, B; Biamino, E; Bongers, E M H F; Del Campo, M; Cordeiro, I; Cueto-González, A M; Cuscó, I; Deshpande, C; Frysira, E; Izatt, L; Flores, R; Galán, E; Gener, B; Gilissen, C; Granneman, S M; Hoyer, J; Yntema, H G; Kets, C M; Koolen, D A; Marcelis, C l; Medeira, A; Micale, L; Mohammed, S; de Munnik, S A; Nordgren, A; Psoni, S; Reardon, W; Revencu, N; Roscioli, T; Ruiterkamp-Versteeg, M; Santos, H G; Schoumans, J; Schuurs-Hoeijmakers, J H M; Silengo, M C; Toledo, L; Vendrell, T; van der Burgt, I; van Lier, B; Zweier, C; Reymond, A; Trembath, R C; Perez-Jurado, L; Dupont, J; de Vries, B B A; Brunner, H G; Veltman, J A; Merla, G; Antonarakis, S E; Hoischen, A

2013-12-01

Recently, pathogenic variants in the MLL2 gene were identified as the most common cause of Kabuki (Niikawa-Kuroki) syndrome (MIM#147920). To further elucidate the genotype-phenotype correlation, we studied a large cohort of 86 clinically defined patients with Kabuki syndrome (KS) for mutations in MLL2. All patients were assessed using a standardized phenotype list and all were scored using a newly developed clinical score list for KS (MLL2-Kabuki score 0-10). Sequencing of the full coding region and intron-exon boundaries of MLL2 identified a total of 45 likely pathogenic mutations (52%): 31 nonsense, 10 missense and four splice-site mutations, 34 of which were novel. In five additional patients, novel, i.e. non-dbSNP132 variants of clinically unknown relevance, were identified. Patients with likely pathogenic nonsense or missense MLL2 mutations were usually more severely affected (median 'MLL2-Kabuki score' of 6) as compared to the patients without MLL2 mutations (median 'MLL2-Kabuki score' of 5), a significant difference (p < 0.0014). Several typical facial features such as large dysplastic ears, arched eyebrows with sparse lateral third, blue sclerae, a flat nasal tip with a broad nasal root, and a thin upper and a full lower lip were observed more often in mutation positive patients. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Mucosal BCG Vaccination Induces Protective Lung-Resident Memory T Cell Populations against Tuberculosis

PubMed Central

Perdomo, Carolina; Zedler, Ulrike; Kühl, Anja A.; Lozza, Laura; Saikali, Philippe; Sander, Leif E.; Vogelzang, Alexis; Kupz, Andreas

2016-01-01

ABSTRACT Mycobacterium bovis Bacille Calmette-Guérin (BCG) is the only licensed vaccine against tuberculosis (TB), yet its moderate efficacy against pulmonary TB calls for improved vaccination strategies. Mucosal BCG vaccination generates superior protection against TB in animal models; however, the mechanisms of protection remain elusive. Tissue-resident memory T (TRM) cells have been implicated in protective immune responses against viral infections, but the role of TRM cells following mycobacterial infection is unknown. Using a mouse model of TB, we compared protection and lung cellular infiltrates of parenteral and mucosal BCG vaccination. Adoptive transfer and gene expression analyses of lung airway cells were performed to determine the protective capacities and phenotypes of different memory T cell subsets. In comparison to subcutaneous vaccination, intratracheal and intranasal BCG vaccination generated T effector memory and TRM cells in the lung, as defined by surface marker phenotype. Adoptive mucosal transfer of these airway-resident memory T cells into naive mice mediated protection against TB. Whereas airway-resident memory CD4+ T cells displayed a mixture of effector and regulatory phenotype, airway-resident memory CD8+ T cells displayed prototypical TRM features. Our data demonstrate a key role for mucosal vaccination-induced airway-resident T cells in the host defense against pulmonary TB. These results have direct implications for the design of refined vaccination strategies. PMID:27879332

Phenotypic and Functional Heterogeneity of Bovine Blood Monocytes

PubMed Central

Hussen, Jamal; Düvel, Anna; Sandra, Olivier; Smith, David; Sheldon, Iain Martin; Zieger, Peter; Schuberth, Hans-Joachim

2013-01-01

Murine and human peripheral blood monocytes are heterogeneous in size, granularity, nuclear morphology, phenotype and function. Whether and how bovine blood monocytes follow this pattern was analyzed in this study. Flow cytometrically, classical monocytes (cM) CD14+ CD16−, intermediate monocytes (intM) CD14+ CD16+ and nonclassical monocytes (ncM) CD14+ CD16+ were identified, with cM being the predominant subset (89%). cM showed a significant lower expression of CD172a, intM expressed the highest level of MHC class II molecules, and ncM were low positive for CD163. Compared to cM and intM, ncM showed a significantly reduced phagocytosis capacity, a significantly reduced generation of reactive oxygen species, and reduced mRNA expression of CXCL8, CXCL1 and IL-1β after LPS stimulation. Based on IL-1β secretion after LPS/ATP stimulation, the inflammasome could be activated in cM and intM, but not in ncM. IFNγ increased the expression of CD16 selectively on cM and induced a shift from cM into intM in vitro. In summary, bovine CD172a-positive mononuclear cells define three monocyte subsets with distinct phenotypic and functional differences. Bovine cM and intM share homologies with their human counterparts, whereas bovine ncM are not inflammatory monocytes. PMID:23967219

Craniofacial morphometric analysis of individuals with X-linked hypohidrotic ectodermal dysplasia.

PubMed

Goodwin, Alice F; Larson, Jacinda R; Jones, Kyle B; Liberton, Denise K; Landan, Maya; Wang, Zhifeng; Boekelheide, Anne; Langham, Margaret; Mushegyan, Vagan; Oberoi, Snehlata; Brao, Rosalie; Wen, Timothy; Johnson, Ramsey; Huttner, Kenneth; Grange, Dorothy K; Spritz, Richard A; Hallgrímsson, Benedikt; Jheon, Andrew H; Klein, Ophir D

2014-09-01

Hypohidrotic ectodermal dysplasia (HED) is the most prevalent type of ectodermal dysplasia (ED). ED is an umbrella term for a group of syndromes characterized by missing or malformed ectodermal structures, including skin, hair, sweat glands, and teeth. The X-linked recessive (XL), autosomal recessive (AR), and autosomal dominant (AD) types of HED are caused by mutations in the genes encoding ectodysplasin (EDA1), EDA receptor (EDAR), or EDAR-associated death domain (EDARADD). Patients with HED have a distinctive facial appearance, yet a quantitative analysis of the HED craniofacial phenotype using advanced three-dimensional (3D) technologies has not been reported. In this study, we characterized craniofacial morphology in subjects with X-linked hypohidrotic ectodermal dysplasia (XLHED) by use of 3D imaging and geometric morphometrics (GM), a technique that uses defined landmarks to quantify size and shape in complex craniofacial morphologies. We found that the XLHED craniofacial phenotype differed significantly from controls. Patients had a smaller and shorter face with a proportionally longer chin and midface, prominent midfacial hypoplasia, a more protrusive chin and mandible, a narrower and more pointed nose, shorter philtrum, a narrower mouth, and a fuller and more rounded lower lip. Our findings refine the phenotype of XLHED and may be useful both for clinical diagnosis of XLHED and to extend understanding of the role of EDA in craniofacial development.

Hyperfunctional Voice Disorder in Children With Attention Deficit Hyperactivity Disorder (ADHD). A Phenotypic Characteristic?

PubMed

Barona-Lleo, Luz; Fernandez, Secundino

2016-01-01

The purpose of this study was to detect specific vocal aerodynamic patterns in attention deficit hyperactivity disorder (ADHD) patients and to define a possible new phenotypic feature of this disorder that must be diagnosed and treated. This is a prospective study. Seventy-nine children aged 5-13 years were recruited: 44 children with ADHD diagnosis and 35 children, as a control group, matched according to age and gender. All children were evaluated in the voice laboratory. Each subject repeated sustained vowels, syllables, words, and sentences several times. Intraoral pressure, transglottal airflow, microphone, and electroglottograph results were recorded and analyzed. Children affected by ADHD, with adequate tolerance, were evaluated endoscopically and by the speech therapist. The aerodynamic analysis shows that the subglottal pressure is higher and transglottal airflow is lower in ADHD children compared with the children of the control group. Those differences are statistically significant. The endoscopic physical examination showed vocal nodules in 25 children (78.125%) and hyperfunctional vocal behavior in all ADHD children studied. We proposed that every child with ADHD disorder must be evaluated from a laryngeal point of view (otolaryngologist and speech therapist) as an important part of the diagnosis and global treatment. It could be considered as a new phenotypic characteristic of this disorder. Copyright © 2016 The Voice Foundation. Published by Elsevier Inc. All rights reserved.

Whorled hairless nevus of the scalp, linear hyperpigmentation, and telangiectatic nevi of the lower limbs: a novel variant of the "phacomatosis complex".

PubMed

Castori, Marco; Scarciolla, Oronzo; Morlino, Silvia; Manente, Liborio; Biscaglia, Assunta; Fragasso, Alberto; Grammatico, Paola

2012-02-01

The term "phacomatosis" refers to a growing number of sporadic genetic skin disorders characterized by the combination of two or more different nevi and possibly resulting from non-allelic twin spotting. While phacomatosis pigmentovascularis (PPV) and pigmentokeratotica represent the most common patterns, some patients do not fit with either condition and are temporarily classified as unique phenotypes. We report on an 8-year-old boy with striking right hemihypoplasia, resulting in limb asymmetry and fixed dislocation of right hip. Skin on the affected side showed three distinct nevi: (i) A whorled, hairless nevus of the scalp in close proximity with (ii) epidermal hyperpigmentation following lines of Blaschko on the neck and right upper limb, and (iii) multiple telangiectatic nevi of the right lower limb and hemiscrotum. Didymosis atricho-melanotica was proposed for the combination of adjacent patchy congenital alopecia and linear hyperpigmentation, while phacomatosis atricho-pigmento-vascularis appears to define the entire cutaneous phenotype, thus implying the involvement of three neighboring loci influencing the development of distinct constituents of the skin. Given the striking asymmetry of the observed phenotype, the effect of mosaicism (either genomic or functional) for a mutation in a single gene with pleiotropic action and influenced by the lateralization pattern of early development cannot be excluded. Copyright © 2012 Wiley Periodicals, Inc.

Pollinator-mediated selection on floral morphology: evidence for transgressive evolution in a derived hybrid lineage.

PubMed

Anton, K A; Ward, J R; Cruzan, M B

2013-03-01

Hybridization between closely related lineages is a mechanism that might promote substantive changes in phenotypic traits of descendants, resulting in transgressive evolution. Interbreeding between divergent but morphologically similar lineages can produce exceptional phenotypes, but the potential for transgressive variation to facilitate long-term trait changes in derived hybrid lineages has received little attention. We compare pollinator-mediated selection on transgressive floral traits in both early-generation and derived hybrid lineages of the Piriqueta cistoides ssp. caroliniana complex. The bowl-shaped flowers of morphotypes in this complex have similar gross morphologies and attract a common suite of small insect pollinators. However, they are defined by significant differences in characters that generate pollinator interest and visitation, including floral area and petal separation. In common garden experiments, patterns of pollen deposition in early-generation recombinant hybrids indicate that Piriqueta's pollinators favour flowers with greater area and reduced petal separation. Changes in floral morphology in derived hybrid lineages are consistent with predictions from selection gradients, but the magnitude of change is limited relative to the range of transgressive variation. These results suggest that hybridization provides variation for evolution of divergent floral traits. However, the potential for extreme transgressive variants to contribute to phenotypic shifts may be limited due to reduced heritability, evolutionary constraints or fitness trade-offs. © 2013 The Authors. Journal of Evolutionary Biology © 2013 European Society For Evolutionary Biology.

Disruptive de novo mutations of DYRK1A lead to a syndromic form of autism and ID.

PubMed

van Bon, B W M; Coe, B P; Bernier, R; Green, C; Gerdts, J; Witherspoon, K; Kleefstra, T; Willemsen, M H; Kumar, R; Bosco, P; Fichera, M; Li, D; Amaral, D; Cristofoli, F; Peeters, H; Haan, E; Romano, C; Mefford, H C; Scheffer, I; Gecz, J; de Vries, B B A; Eichler, E E

2016-01-01

Dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1 A (DYRK1A) maps to the Down syndrome critical region; copy number increase of this gene is thought to have a major role in the neurocognitive deficits associated with Trisomy 21. Truncation of DYRK1A in patients with developmental delay (DD) and autism spectrum disorder (ASD) suggests a different pathology associated with loss-of-function mutations. To understand the phenotypic spectrum associated with DYRK1A mutations, we resequenced the gene in 7162 ASD/DD patients (2446 previously reported) and 2169 unaffected siblings and performed a detailed phenotypic assessment on nine patients. Comparison of our data and published cases with 8696 controls identified a significant enrichment of DYRK1A truncating mutations (P=0.00851) and an excess of de novo mutations (P=2.53 × 10(-10)) among ASD/intellectual disability (ID) patients. Phenotypic comparison of all novel (n=5) and recontacted (n=3) cases with previous case reports, including larger CNV and translocation events (n=7), identified a syndromal disorder among the 15 patients. It was characterized by ID, ASD, microcephaly, intrauterine growth retardation, febrile seizures in infancy, impaired speech, stereotypic behavior, hypertonia and a specific facial gestalt. We conclude that mutations in DYRK1A define a syndromic form of ASD and ID with neurodevelopmental defects consistent with murine and Drosophila knockout models.

Interspecific competition alters natural selection on shade avoidance phenotypes in Impatiens capensis.

PubMed

McGoey, Brechann V; Stinchcombe, John R

2009-08-01

Shade avoidance syndrome is a known adaptive response for Impatiens capensis growing in dense intraspecific competition. However, I. capensis also grow with dominant interspecific competitors in marshes. Here, we compare the I. capensis shade-avoidance phenotypes produced in the absence and presence of heterospecific competitors, as well as selection on those traits. Two treatments were established in a marsh; in one treatment all heterospecifics were removed, while in the other, all competitors remained. We compared morphological traits, light parameters, seed output and, using phenotypic selection analysis, examined directional and nonlinear selection operating in the different competitive treatments. Average phenotypes, light parameters and seed production all varied depending on competitive treatment. Phenotypic selection analyses revealed different directional, disruptive, stabilizing and correlational selection. The disparities seen in both phenotypes and selection between the treatments related to the important differences in elongation timing depending on the presence of heterospecifics, although environmental covariances between traits and fitness could also contribute. Phenotypes produced by I. capensis depend on their competitive environment, and differing selection on shade-avoidance traits between competitive environments could indirectly select for increased plasticity given gene flow between populations in different competitive contexts.