What is metabolic syndrome, and why are children getting it?

PubMed Central

Weiss, Ram; Bremer, Andrew A; Lustig, Robert H

2013-01-01

Metabolic syndrome comprises a cluster of cardiovascular risk factors (hypertension, altered glucose metabolism, dyslipidemia, and abdominal obesity) that occur in obese children. However, metabolic syndrome can also occur in lean individuals, suggesting that obesity is a marker for the syndrome, not a cause. Metabolic syndrome is difficult to define, due to its nonuniform classification and reliance on hard cutoffs in the evaluation of disorders with non-Gaussian distributions. Defining the syndrome is even more difficult in children, owing to racial and pubertal differences and lack of cardiovascular events. Lipid partitioning among specific fat depots is associated with insulin resistance, which can lead to mitochondrial overload and dysfunctional subcellular energy use and drive the various elements of metabolic syndrome. Multiple environmental factors, in particular a typical Western diet, drive mitochondrial overload, while other changes in Western society, such as stress and sleep deprivation, increase insulin resistance and the propensity for food intake. These culminate in an adverse biochemical phenotype, including development of altered glucose metabolism and early atherogenesis during childhood and early adulthood. PMID:23356701

Human spleen and red blood cells

NASA Astrophysics Data System (ADS)

Pivkin, Igor; Peng, Zhangli; Karniadakis, George; Buffet, Pierre; Dao, Ming

2016-11-01

Spleen plays multiple roles in the human body. Among them is removal of old and altered red blood cells (RBCs), which is done by filtering cells through the endothelial slits, small micron-sized openings. There is currently no experimental technique available that allows us to observe RBC passage through the slits. It was previously noticed that people without a spleen have less deformable red blood cells, indicating that the spleen may play a role in defining the size and shape of red blood cells. We used detailed RBC model implemented within the Dissipative Particle Dynamics (DPD) simulation framework to study the filter function of the spleen. Our results demonstrate that spleen indeed plays major role in defining the size and shape of the healthy human red blood cells.

A versatile modular vector system for rapid combinatorial mammalian genetics.

PubMed

Albers, Joachim; Danzer, Claudia; Rechsteiner, Markus; Lehmann, Holger; Brandt, Laura P; Hejhal, Tomas; Catalano, Antonella; Busenhart, Philipp; Gonçalves, Ana Filipa; Brandt, Simone; Bode, Peter K; Bode-Lesniewska, Beata; Wild, Peter J; Frew, Ian J

2015-04-01

Here, we describe the multiple lentiviral expression (MuLE) system that allows multiple genetic alterations to be introduced simultaneously into mammalian cells. We created a toolbox of MuLE vectors that constitute a flexible, modular system for the rapid engineering of complex polycistronic lentiviruses, allowing combinatorial gene overexpression, gene knockdown, Cre-mediated gene deletion, or CRISPR/Cas9-mediated (where CRISPR indicates clustered regularly interspaced short palindromic repeats) gene mutation, together with expression of fluorescent or enzymatic reporters for cellular assays and animal imaging. Examples of tumor engineering were used to illustrate the speed and versatility of performing combinatorial genetics using the MuLE system. By transducing cultured primary mouse cells with single MuLE lentiviruses, we engineered tumors containing up to 5 different genetic alterations, identified genetic dependencies of molecularly defined tumors, conducted genetic interaction screens, and induced the simultaneous CRISPR/Cas9-mediated knockout of 3 tumor-suppressor genes. Intramuscular injection of MuLE viruses expressing oncogenic H-RasG12V together with combinations of knockdowns of the tumor suppressors cyclin-dependent kinase inhibitor 2A (Cdkn2a), transformation-related protein 53 (Trp53), and phosphatase and tensin homolog (Pten) allowed the generation of 3 murine sarcoma models, demonstrating that genetically defined autochthonous tumors can be rapidly generated and quantitatively monitored via direct injection of polycistronic MuLE lentiviruses into mouse tissues. Together, our results demonstrate that the MuLE system provides genetic power for the systematic investigation of the molecular mechanisms that underlie human diseases.

Cell biology of sarcomeric protein engineering: disease modeling and therapeutic potential.

PubMed

Thompson, Brian R; Metzger, Joseph M

2014-09-01

The cardiac sarcomere is the functional unit for myocyte contraction. Ordered arrays of sarcomeric proteins, held in stoichiometric balance with each other, respond to calcium to coordinate contraction and relaxation of the heart. Altered sarcomeric structure-function underlies the primary basis of disease in multiple acquired and inherited heart disease states. Hypertrophic and restrictive cardiomyopathies are caused by inherited mutations in sarcomeric genes and result in altered contractility. Ischemia-mediated acidosis directly alters sarcomere function resulting in decreased contractility. In this review, we highlight the use of acute genetic engineering of adult cardiac myocytes through stoichiometric replacement of sarcomeric proteins in these disease states with particular focus on cardiac troponin I. Stoichiometric replacement of disease causing mutations has been instrumental in defining the molecular mechanisms of hypertrophic and restrictive cardiomyopathy in a cellular context. In addition, taking advantage of stoichiometric replacement through gene therapy is discussed, highlighting the ischemia-resistant histidine-button, A164H cTnI. Stoichiometric replacement of sarcomeric proteins offers a potential gene therapy avenue to replace mutant proteins, alter sarcomeric responses to pathophysiologic insults, or neutralize altered sarcomeric function in disease. © 2014 Wiley Periodicals, Inc.

Companion diagnostics for the targeted therapy of gastric cancer.

PubMed

Yoo, Changhoon; Park, Young Soo

2015-10-21

Gastric cancer is the fourth most common type of cancer and represents a major cause of cancer-related deaths worldwide. With recent biomedical advances in our understanding of the molecular characteristics of gastric cancer, many genetic alterations have been identified as potential targets for its treatment. Multiple novel agents are currently under development as the demand for active agents that improve the survival of gastric cancer patients constantly increases. Based on lessons from previous trials of targeted agents, it is now widely accepted that the establishment of an optimal diagnostic test to select molecularly defined patients is of equal importance to the development of active agents against targetable genetic alterations. Herein, we highlight the current status and future perspectives of companion diagnostics in the treatment of gastric cancer.

Prognostic Classification Factors Associated With Development of Multiple Autoantibodies, Dysglycemia, and Type 1 Diabetes-A Recursive Partitioning Analysis.

PubMed

Xu, Ping; Krischer, Jeffrey P

2016-06-01

To define prognostic classification factors associated with the progression from single to multiple autoantibodies, multiple autoantibodies to dysglycemia, and dysglycemia to type 1 diabetes onset in relatives of individuals with type 1 diabetes. Three distinct cohorts of subjects from the Type 1 Diabetes TrialNet Pathway to Prevention Study were investigated separately. A recursive partitioning analysis (RPA) was used to determine the risk classes. Clinical characteristics, including genotype, antibody titers, and metabolic markers were analyzed. Age and GAD65 autoantibody (GAD65Ab) titers defined three risk classes for progression from single to multiple autoantibodies. The 5-year risk was 11% for those subjects >16 years of age with low GAD65Ab titers, 29% for those ≤16 years of age with low GAD65Ab titers, and 45% for those subjects with high GAD65Ab titers regardless of age. Progression to dysglycemia was associated with islet antigen 2 Ab titers, and 2-h glucose and fasting C-peptide levels. The 5-year risk is 28%, 39%, and 51% for respective risk classes defined by the three predictors. Progression to type 1 diabetes was associated with the number of positive autoantibodies, peak C-peptide level, HbA1c level, and age. Four risk classes defined by RPA had a 5-year risk of 9%, 33%, 62%, and 80%, respectively. The use of RPA offered a new classification approach that could predict the timing of transitions from one preclinical stage to the next in the development of type 1 diabetes. Using these RPA classes, new prevention techniques can be tailored based on the individual prognostic risk characteristics at different preclinical stages. © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

[Anatomy and pathogenesis of diverticular disease].

PubMed

Wedel, T; Böttner, M

2014-04-01

Although diverticular disease is one of the most frequent gastrointestinal disorders the pathogenesis is not yet sufficiently clarified. The aim is to define the anatomy and pathogenesis of diverticular disease considering the risk factors and description of structural and functional alterations of the bowel wall. This article gives an appraisal of the literature, presentation and evaluation of classical etiological factors, analysis and discussion of novel pathogenetic concepts. Colonic diverticulosis is defined as an acquired out-pouching of multiple and initially asymptomatic pseudodiverticula through muscular gaps in the colon wall. Diverticular disease is characterized by diverticular bleeding and/or inflammatory processes (diverticulitis) with corresponding complications (e.g. abscess formation, fistula, covered and open perforation, peritonitis and stenosis). Risk factors for diverticular disease include increasing age, genetic predisposition, congenital connective tissue diseases, low fiber diet, high meat consumption and pronounced overweight. Alterations of connective tissue cause a weakening of preformed exit sites of diverticula and rigidity of the bowel wall with reduced flexibility. It is assumed that intestinal innervation disorders and structural alterations of the musculature induce abnormal contractile patterns with increased intraluminal pressure, thereby promoting the development of diverticula. Moreover, an increased release of pain-mediating neurotransmitters is considered to be responsible for persistent pain in chronic diverticular disease. According to the present data the pathogenesis of diverticular disease cannot be attributed to a single factor but should be considered as a multifactorial event.

Identification of candidate genes involved in neuroblastoma progression by combining genomic and expression microarrays with survival data.

PubMed

Łastowska, M; Viprey, V; Santibanez-Koref, M; Wappler, I; Peters, H; Cullinane, C; Roberts, P; Hall, A G; Tweddle, D A; Pearson, A D J; Lewis, I; Burchill, S A; Jackson, M S

2007-11-22

Identifying genes, whose expression is consistently altered by chromosomal gains or losses, is an important step in defining genes of biological relevance in a wide variety of tumour types. However, additional criteria are needed to discriminate further among the large number of candidate genes identified. This is particularly true for neuroblastoma, where multiple genomic copy number changes of proven prognostic value exist. We have used Affymetrix microarrays and a combination of fluorescent in situ hybridization and single nucleotide polymorphism (SNP) microarrays to establish expression profiles and delineate copy number alterations in 30 primary neuroblastomas. Correlation of microarray data with patient survival and analysis of expression within rodent neuroblastoma cell lines were then used to define further genes likely to be involved in the disease process. Using this approach, we identify >1000 genes within eight recurrent genomic alterations (loss of 1p, 3p, 4p, 10q and 11q, 2p gain, 17q gain, and the MYCN amplicon) whose expression is consistently altered by copy number change. Of these, 84 correlate with patient survival, with the minimal regions of 17q gain and 4p loss being enriched significantly for such genes. These include genes involved in RNA and DNA metabolism, and apoptosis. Orthologues of all but one of these genes on 17q are overexpressed in rodent neuroblastoma cell lines. A significant excess of SNPs whose copy number correlates with survival is also observed on proximal 4p in stage 4 tumours, and we find that deletion of 4p is associated with improved outcome in an extended cohort of tumours. These results define the major impact of genomic copy number alterations upon transcription within neuroblastoma, and highlight genes on distal 17q and proximal 4p for downstream analyses. They also suggest that integration of discriminators, such as survival and comparative gene expression, with microarray data may be useful in the identification of critical genes within regions of loss or gain in many human cancers.

Pathway Profiling and Rational Trial Design for Studies in Advanced Stage Cervical Carcinoma: A Review and a Perspective

PubMed Central

Scholl, Susy M. E.; Kenter, Gemma; Kurzeder, Christian; Beuzeboc, Philippe

2011-01-01

Multiple genetic abnormalities will have occurred in advanced cervical cancer and multiple targeting is likely to be needed to control tumor growth. To date, dominant therapeutic targets under scrutiny for cervical cancer treatment have been EGFR pathway and angiogenesis inhibition as well as anti-HPV vaccines. The potentially most effective targets to be blocked may be downstream from the membrane receptor or at the level of the nucleus. Alterations of the pathways involved in DNA repair and in checkpoint activations, as well as the specific site of HPV genome integration, appear worth assessing. For genetic mutational analysis, complete exon sequencing may become the norm in the future but at this stage frequent mutations (that matter) can be verified by PCR analysis. A precise documentation of relevant alterations of a large spectrum of protein biomarkers can be carried out by reverse phase protein array (RPPA) or by multiplex analysis. Clinical decision-making on the drug(s) of choice as a function of the biological alteration will need input from bio-informatics platforms as well as novel statistical designs. Endpoints are yet to be defined such as the loss (or reappearance) of a predictive biomarker. Single or dual targeting needs to be explored first in relevant preclinical animal and in xenograft models prior to clinical deployment. PMID:22091418

Altered structural connectivity of pain-related brain network in burning mouth syndrome-investigation by graph analysis of probabilistic tractography.

PubMed

Wada, Akihiko; Shizukuishi, Takashi; Kikuta, Junko; Yamada, Haruyasu; Watanabe, Yusuke; Imamura, Yoshiki; Shinozaki, Takahiro; Dezawa, Ko; Haradome, Hiroki; Abe, Osamu

2017-05-01

Burning mouth syndrome (BMS) is a chronic intraoral pain syndrome featuring idiopathic oral pain and burning discomfort despite clinically normal oral mucosa. The etiology of chronic pain syndrome is unclear, but preliminary neuroimaging research has suggested the alteration of volume, metabolism, blood flow, and diffusion at multiple brain regions. According to the neuromatrix theory of Melzack, pain sense is generated in the brain by the network of multiple pain-related brain regions. Therefore, the alteration of pain-related network is also assumed as an etiology of chronic pain. In this study, we investigated the brain network of BMS brain by using probabilistic tractography and graph analysis. Fourteen BMS patients and 14 age-matched healthy controls underwent 1.5T MRI. Structural connectivity was calculated in 83 anatomically defined regions with probabilistic tractography of 60-axis diffusion tensor imaging and 3D T1-weighted imaging. Graph theory network analysis was used to evaluate the brain network at local and global connectivity. In BMS brain, a significant difference of local brain connectivity was recognized at the bilateral rostral anterior cingulate cortex, right medial orbitofrontal cortex, and left pars orbitalis which belong to the medial pain system; however, no significant difference was recognized at the lateral system including the somatic sensory cortex. A strengthened connection of the anterior cingulate cortex and medial prefrontal cortex with the basal ganglia, thalamus, and brain stem was revealed. Structural brain network analysis revealed the alteration of the medial system of the pain-related brain network in chronic pain syndrome.

Pharmacomicrobiomics: the impact of human microbiome variations on systems pharmacology and personalized therapeutics.

PubMed

ElRakaiby, Marwa; Dutilh, Bas E; Rizkallah, Mariam R; Boleij, Annemarie; Cole, Jason N; Aziz, Ramy K

2014-07-01

The Human Microbiome Project (HMP) is a global initiative undertaken to identify and characterize the collection of human-associated microorganisms at multiple anatomic sites (skin, mouth, nose, colon, vagina), and to determine how intra-individual and inter-individual alterations in the microbiome influence human health, immunity, and different disease states. In this review article, we summarize the key findings and applications of the HMP that may impact pharmacology and personalized therapeutics. We propose a microbiome cloud model, reflecting the temporal and spatial uncertainty of defining an individual's microbiome composition, with examples of how intra-individual variations (such as age and mode of delivery) shape the microbiome structure. Additionally, we discuss how this microbiome cloud concept explains the difficulty to define a core human microbiome and to classify individuals according to their biome types. Detailed examples are presented on microbiome changes related to colorectal cancer, antibiotic administration, and pharmacomicrobiomics, or drug-microbiome interactions, highlighting how an improved understanding of the human microbiome, and alterations thereof, may lead to the development of novel therapeutic agents, the modification of antibiotic policies and implementation, and improved health outcomes. Finally, the prospects of a collaborative computational microbiome research initiative in Africa are discussed.

Pharmacomicrobiomics: The Impact of Human Microbiome Variations on Systems Pharmacology and Personalized Therapeutics

PubMed Central

ElRakaiby, Marwa; Dutilh, Bas E.; Rizkallah, Mariam R.; Boleij, Annemarie; Cole, Jason N.

2014-01-01

Abstract The Human Microbiome Project (HMP) is a global initiative undertaken to identify and characterize the collection of human-associated microorganisms at multiple anatomic sites (skin, mouth, nose, colon, vagina), and to determine how intra-individual and inter-individual alterations in the microbiome influence human health, immunity, and different disease states. In this review article, we summarize the key findings and applications of the HMP that may impact pharmacology and personalized therapeutics. We propose a microbiome cloud model, reflecting the temporal and spatial uncertainty of defining an individual's microbiome composition, with examples of how intra-individual variations (such as age and mode of delivery) shape the microbiome structure. Additionally, we discuss how this microbiome cloud concept explains the difficulty to define a core human microbiome and to classify individuals according to their biome types. Detailed examples are presented on microbiome changes related to colorectal cancer, antibiotic administration, and pharmacomicrobiomics, or drug–microbiome interactions, highlighting how an improved understanding of the human microbiome, and alterations thereof, may lead to the development of novel therapeutic agents, the modification of antibiotic policies and implementation, and improved health outcomes. Finally, the prospects of a collaborative computational microbiome research initiative in Africa are discussed. PMID:24785449

How I treat smoldering multiple myeloma

PubMed Central

Landgren, Ola

2014-01-01

Smoldering myeloma is a heterogeneous clinical entity where a subset of patients has an indolent course of disease that mimics monoclonal gammopathy of undermined significance, whereas others have a more aggressive course that has been described as “early myeloma.” It is defined as either serum M-protein ≥3 g/L or ≥10% monoclonal plasma cells in the bone marrow. There are currently no molecular factors to differentiate risks of progression for these patients. Current recommendations of therapy continue to be patient observation or patient enrollment in clinical trials. However, new definitions of active multiple myeloma recently agreed upon by the International Myeloma Working Group may alter the timing of therapy. On the basis of emerging data of therapy in these patients, it seems reasonable to believe that future recommendations for therapy of patients with smoldering myeloma will become an increasingly important topic. In this article, we review the current knowledge of this disease and risk factors associated with progression. We also examine biological insights and alterations that occur in the tumor clone and the surrounding bone marrow niche. Finally, we review clinical trials that have been performed in these patients and provide recommendations for follow-up of patients with this unique disease entity. PMID:25298034

D’Andrea’s disease (angiomegaly): a currently well-defined nosological entitys.

PubMed

Taurone, S; Spoletini, M; Di Matteo, F M; Mele, R; Tromba, L; Grippaudo, F R; Minni, A; Artico, M

2017-01-01

In 1997 D’Andrea et al. described a new nosological entity the characteristics of which consisted of lengthening, dilation and tortuosity of blood vessels, arteries or veins, less prominent, but also less circumscribed than an aneurysm. This condition does not necessarily imply specific aneurysm formation although aneurysms at multiple sites are a frequent observation. The term used by authors for angiomegaly of the venous system was venomegaly and the analogous condition of the arterial system was termed arteriomegaly. Although tortuosity and dilation of arteries and veins have been widely reported, suggesting a systemic disorder which affects the structural integrity of all vessels, most papers dealing with this intriguing condition did not describe any alterations in the components of vessel walls. In the present paper, the authors describe a well-defined condition, D’Andrea’s Disease (or DD, in this article), analyzing its salient morphological and clinical features and clarifying this pathological condition as a distinct and now well-defined nosological entity.

Characterizing complex structural variation in germline and somatic genomes

PubMed Central

Quinlan, Aaron R.; Hall, Ira M.

2011-01-01

Genome structural variation (SV) is a major source of genetic diversity in mammals and a hallmark of cancer. While SV is typically defined by its canonical forms – duplication, deletion, insertion, inversion and translocation – recent breakpoint mapping studies have revealed a surprising number of “complex” variants that evade simple classification. Complex SVs are defined by clustered breakpoints that arose through a single mutation but cannot be explained by one simple end-joining or recombination event. Some complex variants exhibit profoundly complicated rearrangements between distinct loci from multiple chromosomes, while others involve more subtle alterations at a single locus. These diverse and unpredictable features present a challenge for SV mapping experiments. Here, we review current knowledge of complex SV in mammals, and outline techniques for identifying and characterizing complex variants using next-generation DNA sequencing. PMID:22094265

Defining And Employing Reference Conditions For Ecological Restoration Of The Lower Missouri River, USA

NASA Astrophysics Data System (ADS)

Jacobson, R. B.; Elliott, C. M.; Reuter, J. M.

2008-12-01

Ecological reference conditions are especially challenging for large, intensively managed rivers like the Lower Missouri. Historical information provides broad understanding of how the river has changed, but translating historical information into quantitative reference conditions remains a challenge. Historical information is less available for biological and chemical conditions than for physical conditions. For physical conditions, much of the early historical condition is documented in date-specific measurements or maps, and it is difficult to determine how representative these conditions are for a river system that was characterized historically by large floods and high channel migration rates. As an alternative to a historically defined least- disturbed condition, spatial variation within the Missouri River basin provides potential for defining a best- attainable reference condition. A possibility for the best-attainable condition for channel morphology is an unchannelized segment downstream of the lowermost dam (rkm 1298 - 1203). This segment retains multiple channels and abundant sandbars although it has a highly altered flow regime and a greatly diminished sediment supply. Conversely, downstream river segments have more natural flow regimes, but have been narrowed and simplified for navigation and bank stability. We use two computational tools to compensate for the lack of ideal reference conditions. The first is a hydrologic model that synthesizes natural and altered flow regimes based on 100 years of daily inputs to the river (daily routing model, DRM, US Army Corps of Engineers, 1998); the second tool is hydrodynamic modeling of habitat availability. The flow-regime and hydrodynamic outputs are integrated to define habitat-duration curves as the basis for reference conditions (least-disturbed flow regime and least-disturbed channel morphology). Lacking robust biological response models, we use mean residence time of water and a habitat diversity index as generic ecosystem indicators.

iGC-an integrated analysis package of gene expression and copy number alteration.

PubMed

Lai, Yi-Pin; Wang, Liang-Bo; Wang, Wei-An; Lai, Liang-Chuan; Tsai, Mong-Hsun; Lu, Tzu-Pin; Chuang, Eric Y

2017-01-14

With the advancement in high-throughput technologies, researchers can simultaneously investigate gene expression and copy number alteration (CNA) data from individual patients at a lower cost. Traditional analysis methods analyze each type of data individually and integrate their results using Venn diagrams. Challenges arise, however, when the results are irreproducible and inconsistent across multiple platforms. To address these issues, one possible approach is to concurrently analyze both gene expression profiling and CNAs in the same individual. We have developed an open-source R/Bioconductor package (iGC). Multiple input formats are supported and users can define their own criteria for identifying differentially expressed genes driven by CNAs. The analysis of two real microarray datasets demonstrated that the CNA-driven genes identified by the iGC package showed significantly higher Pearson correlation coefficients with their gene expression levels and copy numbers than those genes located in a genomic region with CNA. Compared with the Venn diagram approach, the iGC package showed better performance. The iGC package is effective and useful for identifying CNA-driven genes. By simultaneously considering both comparative genomic and transcriptomic data, it can provide better understanding of biological and medical questions. The iGC package's source code and manual are freely available at https://www.bioconductor.org/packages/release/bioc/html/iGC.html .

Murine genetically engineered and human xenograft models of chronic lymphocytic leukemia.

PubMed

Chen, Shih-Shih; Chiorazzi, Nicholas

2014-07-01

Chronic lymphocytic leukemia (CLL) is a genetically complex disease, with multiple factors having an impact on onset, progression, and response to therapy. Genetic differences/abnormalities have been found in hematopoietic stem cells from patients, as well as in B lymphocytes of individuals with monoclonal B-cell lymphocytosis who may develop the disease. Furthermore, after the onset of CLL, additional genetic alterations occur over time, often causing disease worsening and altering patient outcomes. Therefore, being able to genetically engineer mouse models that mimic CLL or at least certain aspects of the disease will help us understand disease mechanisms and improve treatments. This notwithstanding, because neither the genetic aberrations responsible for leukemogenesis and progression nor the promoting factors that support these are likely identical in character or influences for all patients, genetically engineered mouse models will only completely mimic CLL when all of these factors are precisely defined. In addition, multiple genetically engineered models may be required because of the heterogeneity in susceptibility genes among patients that can have an effect on genetic and environmental characteristics influencing disease development and outcome. For these reasons, we review the major murine genetically engineered and human xenograft models in use at the present time, aiming to report the advantages and disadvantages of each. Copyright © 2014 Elsevier Inc. All rights reserved.

Using photoshop filters to create anatomic line-art medical images.

PubMed

Kirsch, Jacobo; Geller, Brian S

2006-08-01

There are multiple ways to obtain anatomic drawings suitable for publication or presentations. This article demonstrates how to use Photoshop to alter digital radiologic images to create line-art illustrations in a quick and easy way. We present two simple to use methods; however, not every image can adequately be transformed and personal preferences and specific changes need to be applied to each image to obtain the desired result. There are multiple ways to obtain anatomic drawings suitable for publication or to prepare presentations. Medical illustrators have always played a major role in the radiology and medical education process. Whether used to teach a complex surgical or radiologic procedure, to define typical or atypical patterns of the spread of disease, or to illustrate normal or aberrant anatomy, medical illustration significantly affects learning (). However, if you are not an accomplished illustrator, the alternatives can be expensive (contacting a professional medical illustrator or buying an already existing stock of digital images) or simply not necessarily applicable to what you are trying to communicate. The purpose of this article is to demonstrate how using Photoshop (Adobe Systems, San Jose, CA) to alter digital radiologic images we can create line-art illustrations in a quick, inexpensive, and easy way in preparation for electronic presentations and publication.

Current Progress in Therapeutic Gene Editing for Monogenic Diseases

PubMed Central

Prakash, Versha; Moore, Marc; Yáñez-Muñoz, Rafael J

2016-01-01

Programmable nucleases allow defined alterations in the genome with ease-of-use, efficiency, and specificity. Their availability has led to accurate and widespread genome engineering, with multiple applications in basic research, biotechnology, and therapy. With regard to human gene therapy, nuclease-based gene editing has facilitated development of a broad range of therapeutic strategies based on both nonhomologous end joining and homology-dependent repair. This review discusses current progress in nuclease-based therapeutic applications for a subset of inherited monogenic diseases including cystic fibrosis, Duchenne muscular dystrophy, diseases of the bone marrow, and hemophilia and highlights associated challenges and future prospects. PMID:26765770

Alterity: Learning Polyvalent Selves, Resisting Disabling Notions of the Self

ERIC Educational Resources Information Center

Walker, Wayland

2011-01-01

This article queries how one type of human difference--alterity, the experience of multiple distinct consciousnesses, or "alters," by one person--is pathologized in American culture. This experience is inscribed as a mental illness, labeled now as dissociative identity disorder (DID) and formerly known as multiple personality disorder (MPD). In…

Brain network alterations in the inflammatory soup animal model of migraine.

PubMed

Becerra, Lino; Bishop, James; Barmettler, Gabi; Kainz, Vanessa; Burstein, Rami; Borsook, David

2017-04-01

Advances in our understanding of the human pain experience have shifted much of the focus of pain research from the periphery to the brain. Current hypotheses suggest that the progression of migraine depends on abnormal functioning of neurons in multiple brain regions. Accordingly, we sought to capture functional brain changes induced by the application of an inflammatory cocktail known as inflammatory soup (IS), to the dura mater across multiple brain networks. Specifically, we aimed to determine whether IS alters additional neural networks indirectly related to the primary nociceptive pathways via the spinal cord to the thalamus and cortex. IS comprises an acidic combination of bradykinin, serotonin, histamine and prostaglandin PGE2 and was introduced to basic pain research as a tool to activate and sensitize peripheral nociceptors when studying pathological pain conditions associated with allodynia and hyperalgesia. Using this model of intracranial pain, we found that dural application of IS in awake, fully conscious, rats enhanced thalamic, hypothalamic, hippocampal and somatosensory cortex responses to mechanical stimulation of the face (compared to sham synthetic interstitial fluid administration). Furthermore, resting state MRI data revealed altered functional connectivity in a number of networks previously identified in clinical chronic pain populations. These included the default mode, sensorimotor, interoceptive (Salience) and autonomic networks. The findings suggest that activation and sensitization of meningeal nociceptors by IS can enhance the extent to which the brain processes nociceptive signaling, define new level of modulation of affective and cognitive responses to pain; set new tone for hypothalamic regulation of autonomic outflow to the cranium; and change cerebellar functions. Copyright © 2017. Published by Elsevier B.V.

Brain network alterations in the inflammatory soup animal model of migraine

PubMed Central

Becerra, Lino; Bishop, James; Barmettler, Gabi; Kainz, Vanessa; Burstein, Rami; Borsook, David

2017-01-01

Advances in our understanding of the human pain experience have shifted much of the focus of pain research from the periphery to the brain. Current hypotheses suggest that the progression of migraine depends on abnormal functioning of neurons in multiple brain regions. Accordingly, we sought to capture functional brain changes induced by the application of an inflammatory cocktail known as inflammatory soup (IS), to the dura mater across multiple brain networks. Specifically, we aimed to determine whether IS alters additional neural networks indirectly related to the primary nociceptive pathways via the spinal cord to the thalamus and cortex. IS comprises an acidic combination of bradykinin, serotonin, histamine and prostaglandin PGE2 and was introduced to basic pain research as a tool to activate and sensitize peripheral nociceptors when studying pathological pain conditions associated with allodynia and hyperalgesia. Using this model of intracranial pain, we found that dural application of IS in awake, fully conscious, rats enhanced thalamic, hypothalamic, hippocampal and somatosensory cortex responses to mechanical stimulation of the face (compared to sham synthetic interstitial fluid administration). Furthermore, resting state MRI data revealed altered functional connectivity in a number of networks previously identified in clinical chronic pain populations. These included the default mode, sensorimotor, interoceptive (Salience) and autonomic networks. The findings suggest that activation and sensitization of meningeal nociceptors by IS can enhance the extent to which the brain processes nociceptive signaling, define new level of modulation of affective and cognitive responses to pain; set new tone for hypothalamic regulation of autonomic outflow to the cranium; and change cerebellar functions. PMID:28167076

IG/MYC rearrangements are the main cytogenetic alteration in plasmablastic lymphomas.

PubMed

Valera, Alexandra; Balagué, Olga; Colomo, Luis; Martínez, Antonio; Delabie, Jan; Taddesse-Heath, Lekidelu; Jaffe, Elaine S; Campo, Elías

2010-11-01

Plasmablastic lymphoma (PBL) is an aggressive lymphoma characterized by a terminally differentiated B-cell phenotype that usually occurs in the immunocompromised or elderly patients. Although the clinical and pathologic characteristics of these tumors have been defined, the genetic alterations involved in their pathogenesis are not well known. In this study, we have investigated the chromosomal alterations of MYC, BCL2, BCL6, MALT1, PAX5, and IGH loci using fluorescence in situ hybridization in 42 PBL and 3 extracavitary primary effusion lymphomas. MYC rearrangements were identified in 20 of 41 (49%) PBL and the immunoglobulin (IG) genes were the partners in most tumors. MYC rearrangements were more common in Epstein-Barr virus (EBV)-positive (14 of 19, 74%) than EBV-negative (9 of 21, 43%) tumors (P<0.05). No rearrangements of BCL2, BCL6, MALT1, or PAX5 were detected in any PBL but gains of these loci were observed in 31% to 41% of the cases examined. Twelve of the 40 PBL in which 3 or more loci could be investigated had multiple simultaneous gains in 3 or more loci. No differences in the survival of the patients according to MYC were observed but the 4 patients with the longest survival (>50 mo) had no or low number of gains (<3). No rearrangements of any of these loci were seen in the primary effusion lymphomas. In conclusion, PBL are genetically characterized by frequent IG/MYC translocations and gains in multiple chromosomal loci. The oncogenic activation of MYC in these lymphomas may be an important pathogenetic element associated with EBV infection.

Meta-analysis of global metabolomics and proteomics data to link alterations with phenotype

DOE PAGES

Patti, Gary J.; Tautenhahn, Ralf; Fonslow, Bryan R.; ...

2011-01-01

Global metabolomics has emerged as a powerful tool to interrogate cellular biochemistry at the systems level by tracking alterations in the levels of small molecules. One approach to define cellular dynamics with respect to this dysregulation of small molecules has been to consider metabolic flux as a function of time. While flux measurements have proven effective for model organisms, acquiring multiple time points at appropriate temporal intervals for many sample types (e.g., clinical specimens) is challenging. As an alternative, meta-analysis provides another strategy for delineating metabolic cause and effect perturbations. That is, the combination of untargeted metabolomic data from multiplemore » pairwise comparisons enables the association of specific changes in small molecules with unique phenotypic alterations. We recently developed metabolomic software called metaXCMS to automate these types of higher order comparisons. Here we discuss the potential of metaXCMS for analyzing proteomic datasets and highlight the biological value of combining meta-results from both metabolomic and proteomic analyses. The combined meta-analysis has the potential to facilitate efforts in functional genomics and the identification of metabolic disruptions related to disease pathogenesis.« less

Explicit versus implicit social cognition testing in autism spectrum disorder.

PubMed

Callenmark, Björn; Kjellin, Lars; Rönnqvist, Louise; Bölte, Sven

2014-08-01

Although autism spectrum disorder is defined by reciprocal social-communication impairments, several studies have found no evidence for altered social cognition test performance. This study examined explicit (i.e. prompted) and implicit (i.e. spontaneous) variants of social cognition testing in autism spectrum disorder. A sample of 19 adolescents with autism spectrum disorder and 19 carefully matched typically developing controls completed the Dewey Story Test. 'Explicit' (multiple-choice answering format) and 'implicit' (free interview) measures of social cognition were obtained. Autism spectrum disorder participants did not differ from controls regarding explicit social cognition performance. However, the autism spectrum disorder group performed more poorly than controls on implicit social cognition performance in terms of spontaneous perspective taking and social awareness. Findings suggest that social cognition alterations in autism spectrum disorder are primarily implicit in nature and that an apparent absence of social cognition difficulties on certain tests using rather explicit testing formats does not necessarily mean social cognition typicality in autism spectrum disorder. © The Author(s) 2013.

Germline Mutations and Polymorphisms in the Origins of Cancers in Women

PubMed Central

Hirshfield, Kim M.; Rebbeck, Timothy R.; Levine, Arnold J.

2010-01-01

Several female malignancies including breast, ovarian, and endometrial cancers can be characterized based on known somatic and germline mutations. Initiation and propagation of tumors reflect underlying genomic alterations such as mutations, polymorphisms, and copy number variations found in genes of multiple cellular pathways. The contributions of any single genetic variation or mutation in a population depend on its frequency and penetrance as well as tissue-specific functionality. Genome wide association studies, fluorescence in situ hybridization, comparative genomic hybridization, and candidate gene studies have enumerated genetic contributors to cancers in women. These include p53, BRCA1, BRCA2, STK11, PTEN, CHEK2, ATM, BRIP1, PALB2, FGFR2, TGFB1, MDM2, MDM4 as well as several other chromosomal loci. Based on the heterogeneity within a specific tumor type, a combination of genomic alterations defines the cancer subtype, biologic behavior, and in some cases, response to therapeutics. Consideration of tumor heterogeneity is therefore important in the critical analysis of gene associations in cancer. PMID:20111735

Migraine: Multiple Processes, Complex Pathophysiology

PubMed Central

Noseda, Rodrigo; Borsook, David

2015-01-01

Migraine is a common, multifactorial, disabling, recurrent, hereditary neurovascular headache disorder. It usually strikes sufferers a few times per year in childhood and then progresses to a few times per week in adulthood, particularly in females. Attacks often begin with warning signs (prodromes) and aura (transient focal neurological symptoms) whose origin is thought to involve the hypothalamus, brainstem, and cortex. Once the headache develops, it typically throbs, intensifies with an increase in intracranial pressure, and presents itself in association with nausea, vomiting, and abnormal sensitivity to light, noise, and smell. It can also be accompanied by abnormal skin sensitivity (allodynia) and muscle tenderness. Collectively, the symptoms that accompany migraine from the prodromal stage through the headache phase suggest that multiple neuronal systems function abnormally. As a consequence of the disease itself or its genetic underpinnings, the migraine brain is altered structurally and functionally. These molecular, anatomical, and functional abnormalities provide a neuronal substrate for an extreme sensitivity to fluctuations in homeostasis, a decreased ability to adapt, and the recurrence of headache. Advances in understanding the genetic predisposition to migraine, and the discovery of multiple susceptible gene variants (many of which encode proteins that participate in the regulation of glutamate neurotransmission and proper formation of synaptic plasticity) define the most compelling hypothesis for the generalized neuronal hyperexcitability and the anatomical alterations seen in the migraine brain. Regarding the headache pain itself, attempts to understand its unique qualities point to activation of the trigeminovascular pathway as a prerequisite for explaining why the pain is restricted to the head, often affecting the periorbital area and the eye, and intensifies when intracranial pressure increases. PMID:25926442

The mTOR signalling cascade: paving new roads to cure neurological disease.

PubMed

Crino, Peter B

2016-07-01

Defining the multiple roles of the mechanistic (formerly 'mammalian') target of rapamycin (mTOR) signalling pathway in neurological diseases has been an exciting and rapidly evolving story of bench-to-bedside translational research that has spanned gene mutation discovery, functional experimental validation of mutations, pharmacological pathway manipulation, and clinical trials. Alterations in the dual contributions of mTOR - regulation of cell growth and proliferation, as well as autophagy and cell death - have been found in developmental brain malformations, epilepsy, autism and intellectual disability, hypoxic-ischaemic and traumatic brain injuries, brain tumours, and neurodegenerative disorders. mTOR integrates a variety of cues, such as growth factor levels, oxygen levels, and nutrient and energy availability, to regulate protein synthesis and cell growth. In line with the positioning of mTOR as a pivotal cell signalling node, altered mTOR activation has been associated with a group of phenotypically diverse neurological disorders. To understand how altered mTOR signalling leads to such divergent phenotypes, we need insight into the differential effects of enhanced or diminished mTOR activation, the developmental context of these changes, and the cell type affected by altered signalling. A particularly exciting feature of the tale of mTOR discovery is that pharmacological mTOR inhibitors have shown clinical benefits in some neurological disorders, such as tuberous sclerosis complex, and are being considered for clinical trials in epilepsy, autism, dementia, traumatic brain injury, and stroke.

Glucocorticoid action in human corneal epithelial cells establishes roles for corticosteroids in wound healing and barrier function of the eye.

PubMed

Kadmiel, Mahita; Janoshazi, Agnes; Xu, Xiaojiang; Cidlowski, John A

2016-11-01

Glucocorticoids play diverse roles in almost all physiological systems of the body, including both anti-inflammatory and immunosuppressive roles. Synthetic glucocorticoids are one of the most widely prescribed drugs and are used in the treatment of conditions such as autoimmune diseases, allergies, ocular disorders and certain types of cancers. In the interest of investigating glucocorticoid actions in the cornea of the eye, we established that multiple cell types in mouse corneas express functional glucocorticoid receptor (GR) with corneal epithelial cells having robust expression. To define glucocorticoid actions in a cell type-specific manner, we employed immortalized human corneal epithelial (HCE) cell line to define the glucocorticoid transcriptome and elucidated its functions in corneal epithelial cells. Over 4000 genes were significantly regulated within 6 h of dexamethasone treatment, and genes associated with cell movement, cytoskeletal remodeling and permeability were highly regulated. Real-time in vitro wound healing assays revealed that glucocorticoids delay wound healing by attenuating cell migration. These functional alterations were associated with cytoskeletal remodeling at the wounded edge of a scratch-wounded monolayer. However, glucocorticoid treatment improved the organization of tight-junction proteins and enhanced the epithelial barrier function. Our results demonstrate that glucocorticoids profoundly alter corneal epithelial gene expression and many of these changes likely impact both wound healing and epithelial cell barrier function. Published by Elsevier Ltd.

Integrative, multimodal analysis of glioblastoma using TCGA molecular data, pathology images, and clinical outcomes.

PubMed

Kong, Jun; Cooper, Lee A D; Wang, Fusheng; Gutman, David A; Gao, Jingjing; Chisolm, Candace; Sharma, Ashish; Pan, Tony; Van Meir, Erwin G; Kurc, Tahsin M; Moreno, Carlos S; Saltz, Joel H; Brat, Daniel J

2011-12-01

Multimodal, multiscale data synthesis is becoming increasingly critical for successful translational biomedical research. In this letter, we present a large-scale investigative initiative on glioblastoma, a high-grade brain tumor, with complementary data types using in silico approaches. We integrate and analyze data from The Cancer Genome Atlas Project on glioblastoma that includes novel nuclear phenotypic data derived from microscopic slides, genotypic signatures described by transcriptional class and genetic alterations, and clinical outcomes defined by response to therapy and patient survival. Our preliminary results demonstrate numerous clinically and biologically significant correlations across multiple data types, revealing the power of in silico multimodal data integration for cancer research.

Dynamic Skin Patterns in Cephalopods

PubMed Central

How, Martin J.; Norman, Mark D.; Finn, Julian; Chung, Wen-Sung; Marshall, N. Justin

2017-01-01

Cephalopods are unrivaled in the natural world in their ability to alter their visual appearance. These mollusks have evolved a complex system of dermal units under neural, hormonal, and muscular control to produce an astonishing variety of body patterns. With parallels to the pixels on a television screen, cephalopod chromatophores can be coordinated to produce dramatic, dynamic, and rhythmic displays, defined collectively here as “dynamic patterns.” This study examines the nature, context, and potential functions of dynamic patterns across diverse cephalopod taxa. Examples are presented for 21 species, including 11 previously unreported in the scientific literature. These range from simple flashing or flickering patterns, to highly complex passing wave patterns involving multiple skin fields. PMID:28674500

Intraosseous schwannoma in schwannomatosis.

PubMed

Kashima, T G; Gibbons, M R J P; Whitwell, D; Gibbons, C L M H; Bradley, K M; Ostlere, S J; Athanasou, N A

2013-12-01

This study investigates the clinical, radiological, and pathological features of two cases of intraosseous schwannoma that arose in patients with multiple soft tissue schwannomas. In both cases, the patients were adult females and the tibial bone was affected. Vestibular schwannomas were not identified, indicating that these were not cases of neurofibromatosis 2 (NF2). Radiographs showed a well-defined lytic lesion in the proximal tibia; in one case, this was associated with a pathological fracture. Histologically, both cases showed typical features of benign schwannoma. Molecular analysis of one of the excised tumors showed different alterations in the NF2 gene in keeping with a diagnosis of schwannomatosis. Our findings show for the first time that intraosseous schwannomas can occur in schwannomatosis.

Vertebrate Development in Space: Gravity Is a Drag (and Has Been for Eons and Eons)

NASA Technical Reports Server (NTRS)

Keefe, J. R.

1985-01-01

Brief sketches of developmental biology studies during spaceflight presented are intended to be complete in scope and to provide the reader with an overview of the present status of such studies. Means of evaluating both the direct role of gravity on all processes of mammalian reproduction and development as well as defining the means of assessing indirect transplacemental aspects are considered. The potential present in the development of a spaceflight system/program specifically designed to provide chronic exposure of a representative variety of mammalian species with periodic sampling for multiple generations to fully assess the potential impact of an altered gravitational vector on general mammalian development is also considered.

The Plasmodium falciparum transcriptome in severe malaria reveals altered expression of genes involved in important processes including surface antigen–encoding var genes

PubMed Central

Tonkin-Hill, Gerry Q.; Trianty, Leily; Noviyanti, Rintis; Nguyen, Hanh H. T.; Sebayang, Boni F.; Lampah, Daniel A.; Marfurt, Jutta; Cobbold, Simon A.; Rambhatla, Janavi S.; McConville, Malcolm J.; Rogerson, Stephen J.; Brown, Graham V.; Day, Karen P.; Price, Ric N.; Anstey, Nicholas M.

2018-01-01

Within the human host, the malaria parasite Plasmodium falciparum is exposed to multiple selection pressures. The host environment changes dramatically in severe malaria, but the extent to which the parasite responds to—or is selected by—this environment remains unclear. From previous studies, the parasites that cause severe malaria appear to increase expression of a restricted but poorly defined subset of the PfEMP1 variant, surface antigens. PfEMP1s are major targets of protective immunity. Here, we used RNA sequencing (RNAseq) to analyse gene expression in 44 parasite isolates that caused severe and uncomplicated malaria in Papuan patients. The transcriptomes of 19 parasite isolates associated with severe malaria indicated that these parasites had decreased glycolysis without activation of compensatory pathways; altered chromatin structure and probably transcriptional regulation through decreased histone methylation; reduced surface expression of PfEMP1; and down-regulated expression of multiple chaperone proteins. Our RNAseq also identified novel associations between disease severity and PfEMP1 transcripts, domains, and smaller sequence segments and also confirmed all previously reported associations between expressed PfEMP1 sequences and severe disease. These findings will inform efforts to identify vaccine targets for severe malaria and also indicate how parasites adapt to—or are selected by—the host environment in severe malaria. PMID:29529020

Distinct genetic profiles in colorectal tumors with or without the CpG island methylator phenotype

PubMed Central

Toyota, Minoru; Ohe-Toyota, Mutsumi; Ahuja, Nita; Issa, Jean-Pierre J.

2000-01-01

Colorectal cancers (CRCs) are characterized by multiple genetic (mutations) and epigenetic (CpG island methylation) alterations, but it is not known whether these evolve independently through stochastic processes. We have recently described a novel pathway termed CpG island methylator phenotype (CIMP) in CRC, which is characterized by the simultaneous methylation of multiple CpG islands, including several known genes, such as p16, hMLH1, and THBS1. We have now studied mutations in K-RAS, p53, DPC4, and TGFβRII in a panel of colorectal tumors with or without CIMP. We find that CIMP defines two groups of tumors with significantly different genetic lesions: frequent K-RAS mutations were found in CIMP+ CRCs (28/41, 68%) compared with CIMP− cases (14/47, 30%, P = 0.0005). By contrast, p53 mutations were found in 24% (10/41) of CIMP+ CRCs vs. 60% (30/46) of CIMP− cases (P = 0.002). Both of these differences were independent of microsatellite instability. These interactions between CIMP, K-RAS mutations, and p53 mutations were preserved in colorectal adenomas, suggesting that they occur early in carcinogenesis. The distinct combinations of epigenetic and genetic alterations in each group suggest that activation of oncogenes and inactivation of tumor suppressor genes is related to the underlying mechanism of generating molecular diversity in cancer, rather than simply accumulate stochastically during cancer development. PMID:10639144

APC conditional knock-out mouse is a model of infantile spasms with elevated neuronal β-catenin levels, neonatal spasms, and chronic seizures

PubMed Central

Pirone, Antonella; Alexander, Jon; Lau, Lauren A.; Hampton, David; Zayachkivsky, Andrew; Yee, Amy; Yee, Audrey; Jacob, Michele H.; Dulla, Chris G.

2016-01-01

Infantile spasms (IS) are a catastrophic childhood epilepsy syndrome characterized by flexion-extension spasms during infancy that progress to chronic seizures and cognitive deficits in later life. The molecular causes of IS are poorly defined. Genetic screens of individuals with IS have identified multiple risk genes, several of which are predicted to alter β-catenin pathways. However, evidence linking malfunction of β-catenin pathways and IS is lacking. Here, we show that conditional deletion in mice of the adenomatous polyposis coli gene (APC cKO), the major negative regulator of β-catenin, leads to excessive β-catenin levels and multiple salient features of human IS. Compared with wild-type littermates, neonatal APC cKO mice exhibit flexion-extension motor spasms and abnormal high-amplitude electroencephalographic discharges. Additionally, the frequency of excitatory postsynaptic currents is increased in layer V pyramidal cells, the major output neurons of the cerebral cortex. At adult ages, APC cKOs display spontaneous electroclinical seizures. These data provide the first evidence that malfunctions of APC/β-catenin pathways cause pathophysiological changes consistent with IS. Our findings demonstrate that the APC cKO is a new genetic model of IS, provide novel insights into molecular and functional alterations that can lead to IS, and suggest novel targets for therapeutic intervention. PMID:27852007

Enhanced peripheral visual processing in congenitally deaf humans is supported by multiple brain regions, including primary auditory cortex.

PubMed

Scott, Gregory D; Karns, Christina M; Dow, Mark W; Stevens, Courtney; Neville, Helen J

2014-01-01

Brain reorganization associated with altered sensory experience clarifies the critical role of neuroplasticity in development. An example is enhanced peripheral visual processing associated with congenital deafness, but the neural systems supporting this have not been fully characterized. A gap in our understanding of deafness-enhanced peripheral vision is the contribution of primary auditory cortex. Previous studies of auditory cortex that use anatomical normalization across participants were limited by inter-subject variability of Heschl's gyrus. In addition to reorganized auditory cortex (cross-modal plasticity), a second gap in our understanding is the contribution of altered modality-specific cortices (visual intramodal plasticity in this case), as well as supramodal and multisensory cortices, especially when target detection is required across contrasts. Here we address these gaps by comparing fMRI signal change for peripheral vs. perifoveal visual stimulation (11-15° vs. 2-7°) in congenitally deaf and hearing participants in a blocked experimental design with two analytical approaches: a Heschl's gyrus region of interest analysis and a whole brain analysis. Our results using individually-defined primary auditory cortex (Heschl's gyrus) indicate that fMRI signal change for more peripheral stimuli was greater than perifoveal in deaf but not in hearing participants. Whole-brain analyses revealed differences between deaf and hearing participants for peripheral vs. perifoveal visual processing in extrastriate visual cortex including primary auditory cortex, MT+/V5, superior-temporal auditory, and multisensory and/or supramodal regions, such as posterior parietal cortex (PPC), frontal eye fields, anterior cingulate, and supplementary eye fields. Overall, these data demonstrate the contribution of neuroplasticity in multiple systems including primary auditory cortex, supramodal, and multisensory regions, to altered visual processing in congenitally deaf adults.

Detecting molecular forms of antithrombin by LC-MRM-MS: defining the measurands.

PubMed

Ruhaak, L Renee; Romijn, Fred P H T M; Smit, Nico P M; van der Laarse, Arnoud; Pieterse, Mervin M; de Maat, Moniek P M; Haas, Fred J L M; Kluft, Cornelis; Amiral, Jean; Meijer, Piet; Cobbaert, Christa M

2018-05-01

Antithrombin (AT) is a critical regulator of coagulation, and its overall activity is typically measured using functional tests. A large number of molecular forms of AT have been identified and each individual carries multiple molecular proteoforms representing variable activities. Conventional functional tests are completely blind for these proteoforms. A method that ensures properly defined measurands for AT is therefore needed. We here assess whether mass spectrometry technology, in particular multiple reaction monitoring (MRM), is suitable for the quantification of AT and the qualitative detection of its molecular proteoforms. Plasma proteins were denatured, reduced and alkylated prior to enzymatic digestion. MRM transitions were developed towards tryptic peptides and glycopeptides using AT purified from human plasma. For each peptide, three transitions were measured, and stable isotope-labeled peptides were used for quantitation. Completeness of digestion was assessed using digestion time curves. MRM transitions were developed for 19 tryptic peptides and 4 glycopeptides. Two peptides, FDTISEK and FATTFYQHLADSK, were used for quantitation, and using a calibration curve of isolated AT in 40 g/L human serum albumin, CVs below 3.5% were obtained for FDTISEK, whereas CVs below 8% were obtained for FATTFYQHLADSK. Of the 26 important AT mutations, 20 can be identified using this method, while altered glycosylation profiles can also be detected. We here show the feasibility of the liquid chromatography multiple reaction monitoring mass spectrometry (LC-MRM-MS) technique for the quantitation of AT and the qualitative analysis of most of its molecular proteoforms. Knowing the measurands will enable standardization of AT tests by providing in-depth information on the molecular proteoforms of AT.

Formation of albitite-hosted uranium within IOCG systems: the Southern Breccia, Great Bear magmatic zone, Northwest Territories, Canada

NASA Astrophysics Data System (ADS)

Montreuil, Jean-François; Corriveau, Louise; Potter, Eric G.

2015-03-01

Uranium and polymetallic U mineralization hosted within brecciated albitites occurs one kilometer south of the magnetite-rich Au-Co-Bi-Cu NICO deposit in the southern Great Bear magmatic zone (GBMZ), Canada. Concentrations up to 1 wt% U are distributed throughout a 3 by 0.5 km albitization corridor defined as the Southern Breccia zone. Two distinct U mineralization events are observed. Primary uraninite precipitated with or without pyrite-chalcopyrite ± molybdenite within magnetite-ilmenite-biotite-K-feldspar-altered breccias during high-temperature potassic-iron alteration. Subsequently, pitchblende precipitated in earthy hematite-specular hematite-chlorite veins associated with a low-temperature iron-magnesium alteration. The uraninite-bearing mineralization postdates sodic (albite) and more localized high-temperature potassic-iron (biotite-magnetite ± K-feldspar) alteration yet predates potassic (K-feldspar), boron (tourmaline) and potassic-iron-magnesium (hematite ± K-feldspar ± chlorite) alteration. The Southern Breccia zone shares attributes of the Valhalla (Australia) and Lagoa Real (Brazil) albitite-hosted U deposits but contains greater iron oxide contents and lower contents of riebeckite and carbonates. Potassium, Ni, and Th are also enriched whereas Zr and Sr are depleted with respect to the aforementioned albitite-hosted U deposits. Field relationships, geochemical signatures and available U-Pb dates on pre-, syn- and post-mineralization intrusions place the development of the Southern Breccia and the NICO deposit as part of a single iron oxide alkali-altered (IOAA) system. In addition, this case example illustrates that albitite-hosted U deposits can form in albitization zones that predate base and precious metal ore zones in a single IOAA system and become traps for U and multiple metals once the tectonic regime favors fluid mixing and oxidation-reduction reactions.

Evolution of synthetic signaling scaffolds by recombination of modular protein domains.

PubMed

Lai, Andicus; Sato, Paloma M; Peisajovich, Sergio G

2015-06-19

Signaling scaffolds are proteins that interact via modular domains with multiple partners, regulating signaling networks in space and time and providing an ideal platform from which to alter signaling functions. However, to better exploit scaffolds for signaling engineering, it is necessary to understand the full extent of their modularity. We used a directed evolution approach to identify, from a large library of randomly shuffled protein interaction domains, variants capable of rescuing the signaling defect of a yeast strain in which Ste5, the scaffold in the mating pathway, had been deleted. After a single round of selection, we identified multiple synthetic scaffold variants with diverse domain architectures, able to mediate mating pathway activation in a pheromone-dependent manner. The facility with which this signaling network accommodates changes in scaffold architecture suggests that the mating signaling complex does not possess a single, precisely defined geometry into which the scaffold has to fit. These relaxed geometric constraints may facilitate the evolution of signaling networks, as well as their engineering for applications in synthetic biology.

Resilience to Meet the Challenge of Addiction

PubMed Central

Alim, Tanja N.; Lawson, William B.; Feder, Adriana; Iacoviello, Brian M.; Saxena, Shireen; Bailey, Christopher R.; Greene, Allison M.; Neumeister, Alexander

2012-01-01

Acute and chronic stress–related mechanisms play an important role in the development of addiction and its chronic, relapsing nature. Multisystem adaptations in brain, body, behavioral, and social function may contribute to a dysregulated physiological state that is maintained beyond the homeostatic range. In addition, chronic abuse of substances leads to an altered set point across multiple systems. Resilience can be defined as the absence of psychopathology despite exposure to high stress and reflects a person’s ability to cope successfully in the face of adversity, demonstrating adaptive psychological and physiological stress responses. The study of resilience can be approached by examining interindividual stress responsibility at multiple phenotypic levels, ranging from psychological differences in the way people cope with stress to differences in neurochemical or neural circuitry function. The ultimate goal of such research is the development of strategies and interventions to enhance resilience and coping in the face of stress and prevent the onset of addiction problems or relapse. PMID:23584116

Epigenetic changes in neurology: DNA methylation in multiple sclerosis.

PubMed

Iridoy Zulet, M; Pulido Fontes, L; Ayuso Blanco, T; Lacruz Bescos, F; Mendioroz Iriarte, M

2017-09-01

Epigenetics is defined as the study of the mechanisms that regulate gene expression without altering the underlying DNA sequence. The best known is DNA methylation. Multiple Sclerosis (MS) is a disease with no entirely known etiology, in which it is stated that the involvement of environmental factors on people with a genetic predisposition, may be key to the development of the disease. It is at this intersection between genetic predisposition and environmental factors where DNA methylation may play a pathogenic role. A literature review of the effects of environmental risk factors for the development of MS can have on the different epigenetic mechanisms as well as the implication that such changes have on the development of the disease. Knowledge of epigenetic modifications involved in the pathogenesis of MS, opens a new avenue of research for identification of potential biomarkers, as well as finding new therapeutic targets. Copyright © 2015 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

Integrated Patient-Derived Models Delineate Individualized Therapeutic Vulnerabilities of Pancreatic Cancer.

PubMed

Witkiewicz, Agnieszka K; Balaji, Uthra; Eslinger, Cody; McMillan, Elizabeth; Conway, William; Posner, Bruce; Mills, Gordon B; O'Reilly, Eileen M; Knudsen, Erik S

2016-08-16

Pancreatic ductal adenocarcinoma (PDAC) harbors the worst prognosis of any common solid tumor, and multiple failed clinical trials indicate therapeutic recalcitrance. Here, we use exome sequencing of patient tumors and find multiple conserved genetic alterations. However, the majority of tumors exhibit no clearly defined therapeutic target. High-throughput drug screens using patient-derived cell lines found rare examples of sensitivity to monotherapy, with most models requiring combination therapy. Using PDX models, we confirmed the effectiveness and selectivity of the identified treatment responses. Out of more than 500 single and combination drug regimens tested, no single treatment was effective for the majority of PDAC tumors, and each case had unique sensitivity profiles that could not be predicted using genetic analyses. These data indicate a shortcoming of reliance on genetic analysis to predict efficacy of currently available agents against PDAC and suggest that sensitivity profiling of patient-derived models could inform personalized therapy design for PDAC. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

Mediator-regulated transcription through the +1 nucleosome.

PubMed

Nock, Adam; Ascano, Janice M; Barrero, Maria J; Malik, Sohail

2012-12-28

Many genes are regulated at the level of a Pol II that is recruited to a nucleosome-free region upstream of the +1 nucleosome. How the Mediator coactivator complex, which functions at multiple steps, affects transcription through the promoter proximal region, including this nucleosome, remains largely unaddressed. We have established a fully defined in vitro assay system to delineate mechanisms for Pol II transit across the +1 nucleosome. Our results reveal cooperative functions of multiple cofactors, particularly of Mediator and elongation factor SII, in transcribing into this nucleosome. This is achieved, in part, through an unusual activity of SII that alters the intrinsic catalytic properties of promoter-proximal Pol II and, in concert with the Mediator, leads to enhancement in transcription of nucleosomal DNA. Our data provide additional mechanistic bases for Mediator function after recruitment of Pol II and, potentially, for regulation of genes controlled via nucleosome-mediated promoter-proximal pausing. Copyright © 2012 Elsevier Inc. All rights reserved.

integIRTy: a method to identify genes altered in cancer by accounting for multiple mechanisms of regulation using item response theory.

PubMed

Tong, Pan; Coombes, Kevin R

2012-11-15

Identifying genes altered in cancer plays a crucial role in both understanding the mechanism of carcinogenesis and developing novel therapeutics. It is known that there are various mechanisms of regulation that can lead to gene dysfunction, including copy number change, methylation, abnormal expression, mutation and so on. Nowadays, all these types of alterations can be simultaneously interrogated by different types of assays. Although many methods have been proposed to identify altered genes from a single assay, there is no method that can deal with multiple assays accounting for different alteration types systematically. In this article, we propose a novel method, integration using item response theory (integIRTy), to identify altered genes by using item response theory that allows integrated analysis of multiple high-throughput assays. When applied to a single assay, the proposed method is more robust and reliable than conventional methods such as Student's t-test or the Wilcoxon rank-sum test. When used to integrate multiple assays, integIRTy can identify novel-altered genes that cannot be found by looking at individual assay separately. We applied integIRTy to three public cancer datasets (ovarian carcinoma, breast cancer, glioblastoma) for cross-assay type integration which all show encouraging results. The R package integIRTy is available at the web site http://bioinformatics.mdanderson.org/main/OOMPA:Overview. kcoombes@mdanderson.org. Supplementary data are available at Bioinformatics online.

Morphologic Basis for Developing Diverticular Disease, Diverticulitis, and Diverticular Bleeding.

PubMed

Wedel, Thilo; Barrenschee, Martina; Lange, Christina; Cossais, François; Böttner, Martina

2015-04-01

Diverticula of the colon are pseudodiverticula defined by multiple outpouchings of the mucosal and submucosal layers penetrating through weak spots of the muscle coat along intramural blood vessels. A complete prolapse consists of a diverticular opening, a narrowed neck, and a thinned diverticular dome underneath the serosal covering. The susceptibility of diverticula to inflammation is explained by local ischemia, translocation of pathogens due to retained stool, stercoral trauma by fecaliths, and microperforations. Local inflammation may lead to phlegmonous diverticulitis, paracolic/mesocolic abscess, bowel perforation, peritonitis, fistula formation, and stenotic strictures. Diverticular bleeding is due to an asymmetric rupture of distended vasa recta at the diverticular dome and not primarily linked to inflammation. Structural and functional changes of the bowel wall in diverticular disease comprise: i) Altered amount, composition, and metabolism of connective tissue; ii) Enteric myopathy with muscular thickening, deranged architecture, and altered myofilament composition; iii) Enteric neuropathy with hypoganglionosis, neurotransmitter imbalance, deficiency of neurotrophic factors and nerve fiber remodeling; and iv) Disturbed intestinal motility both in vivo (increased intraluminal pressure, motility index, high-amplitude propagated contractions) and in vitro (altered spontaneous and pharmacologically triggered contractility). Besides established etiologic factors, recent studies suggest that novel pathophysiologic concepts should be considered in the pathogenesis of diverticular disease.

Morphologic Basis for Developing Diverticular Disease, Diverticulitis, and Diverticular Bleeding

PubMed Central

Wedel, Thilo; Barrenschee, Martina; Lange, Christina; Cossais, François; Böttner, Martina

2015-01-01

Diverticula of the colon are pseudodiverticula defined by multiple outpouchings of the mucosal and submucosal layers penetrating through weak spots of the muscle coat along intramural blood vessels. A complete prolapse consists of a diverticular opening, a narrowed neck, and a thinned diverticular dome underneath the serosal covering. The susceptibility of diverticula to inflammation is explained by local ischemia, translocation of pathogens due to retained stool, stercoral trauma by fecaliths, and microperforations. Local inflammation may lead to phlegmonous diverticulitis, paracolic/mesocolic abscess, bowel perforation, peritonitis, fistula formation, and stenotic strictures. Diverticular bleeding is due to an asymmetric rupture of distended vasa recta at the diverticular dome and not primarily linked to inflammation. Structural and functional changes of the bowel wall in diverticular disease comprise: i) Altered amount, composition, and metabolism of connective tissue; ii) Enteric myopathy with muscular thickening, deranged architecture, and altered myofilament composition; iii) Enteric neuropathy with hypoganglionosis, neurotransmitter imbalance, deficiency of neurotrophic factors and nerve fiber remodeling; and iv) Disturbed intestinal motility both in vivo (increased intraluminal pressure, motility index, high-amplitude propagated contractions) and in vitro (altered spontaneous and pharmacologically triggered contractility). Besides established etiologic factors, recent studies suggest that novel pathophysiologic concepts should be considered in the pathogenesis of diverticular disease. PMID:26989376

Prostate cancer molecular profiling: the Achilles heel for the implementation of precision medicine.

PubMed

Oliveira-Barros, Eliane Gouvêa; Nicolau-Neto, Pedro; Da Costa, Nathalia Meireles; Pinto, Luís Felipe Ribeiro; Palumbo, Antonio; Nasciutti, Luiz Eurico

2017-11-01

Cancer has been mainly treated by traditional therapeutic approaches which do not consider the human genetic diversity and present limitations, probably as a consequence of a poor knowledge of both patient's genetic background and tumor biology. Due to genome project conclusion and large-scale gene analyses emergence, the therapeutic management of several prevalent and aggressive tumors has dramatically improved and represents the closest examples of a precision medicine intervention in this field. Nonetheless, prostate cancer (PCa) remains as a challenge to personalized medicine implementation, probably due to its notorious heterogeneous molecular profile. Cancer treatment personalized approaches rely on the premise that a well-defined panorama of tumor molecular alterations can help selecting new and specific therapeutic targets for its treatment and potentially discriminate tumors which behave differentially. Lately, molecular and genetic studies have been investigating PCa basis, revealing multiple recurrent genomic alterations that include mutations, DNA copy-number variations, rearrangements, and gene fusions, among others. In addition to the increment on PCa molecular biology knowledge, mapping the molecular alterations pattern of this neoplasia, especially the differences existent between tumors displaying distinct behaviors, could represent a great improvement concerning the identification of new targets, personalized medicine, and patients' management and prognosis. © 2017 International Federation for Cell Biology.

Identification of five novel modifier loci of ApcMin harbored in the BXH14 recombinant inbred strain

PubMed Central

Siracusa, Linda D.

2012-01-01

Every year thousands of people in the USA are diagnosed with small intestine and colorectal cancers (CRC). Although environmental factors affect disease etiology, uncovering underlying genetic factors is imperative for risk assessment and developing preventative therapies. Familial adenomatous polyposis is a heritable genetic disorder in which individuals carry germ-line mutations in the adenomatous polyposis coli (APC) gene that predisposes them to CRC. The Apc Min mouse model carries a point mutation in the Apc gene and develops polyps along the intestinal tract. Inbred strain background influences polyp phenotypes in Apc Min mice. Several Modifier of Min (Mom) loci that alter tumor phenotypes associated with the Apc Min mutation have been identified to date. We screened BXH recombinant inbred (RI) strains by crossing BXH RI females with C57BL/6J (B6) Apc Min males and quantitating tumor phenotypes in backcross progeny. We found that the BXH14 RI strain harbors five modifier loci that decrease polyp multiplicity. Furthermore, we show that resistance is determined by varying combinations of these modifier loci. Gene interaction network analysis shows that there are multiple networks with proven gene–gene interactions, which contain genes from all five modifier loci. We discuss the implications of this result for studies that define susceptibility loci, namely that multiple networks may be acting concurrently to alter tumor phenotypes. Thus, the significance of this work resides not only with the modifier loci we identified but also with the combinations of loci needed to get maximal protection against polyposis and the impact of this finding on human disease studies. Abbreviations:APCadenomatous polyposis coliGWASgenome-wide association studiesQTLquantitative trait lociSNPsingle-nucleotide polymorphism. PMID:22637734

Identifying multiple coral reef regimes and their drivers across the Hawaiian archipelago

PubMed Central

Jouffray, Jean-Baptiste; Nyström, Magnus; Norström, Albert V.; Williams, Ivor D.; Wedding, Lisa M.; Kittinger, John N.; Williams, Gareth J.

2015-01-01

Loss of coral reef resilience can lead to dramatic changes in benthic structure, often called regime shifts, which significantly alter ecosystem processes and functioning. In the face of global change and increasing direct human impacts, there is an urgent need to anticipate and prevent undesirable regime shifts and, conversely, to reverse shifts in already degraded reef systems. Such challenges require a better understanding of the human and natural drivers that support or undermine different reef regimes. The Hawaiian archipelago extends across a wide gradient of natural and anthropogenic conditions and provides us a unique opportunity to investigate the relationships between multiple reef regimes, their dynamics and potential drivers. We applied a combination of exploratory ordination methods and inferential statistics to one of the most comprehensive coral reef datasets available in order to detect, visualize and define potential multiple ecosystem regimes. This study demonstrates the existence of three distinct reef regimes dominated by hard corals, turf algae or macroalgae. Results from boosted regression trees show nonlinear patterns among predictors that help to explain the occurrence of these regimes, and highlight herbivore biomass as the key driver in addition to effluent, latitude and depth.

Hydrothermal alteration of felsic volcanic rocks at the Helen Siderite Deposit, Wawa, Ontario

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

Morton, R.L.; Nebel, M.L.

1984-09-01

Felsic lavas and pyroclastic rocks, underlying the Archean Helen iron-formation, have been variably altered by hydrothermal solutions which, when discharged onto the sea floor, formed the Helen siderite deposit. Within the footwall volcanic sequence five chemically and mineralogically distinct alteration types have been defined: least altered, sericite, chlorite chloritoid, and ankerite. Based on mineralogy and chemistry of the altered rocks and on the geometry of the alteration zones, an alteration model is proposed.

Cerebral fat embolism syndrome after long bone fracture due to gunshot injury.

PubMed

Duran, Latif; Kayhan, Servet; Kati, Celal; Akdemir, Hizir Ufuk; Balci, Kemal; Yavuz, Yucel

2014-03-01

Cerebral fat embolism syndrome is a lethal complication of long-bone fractures and clinically manifasted with respiratory distress, altered mental status, and petechial rash. We presented a 20-year-old male admitted with gun-shot wounds to his left leg. Twenty-four hours after the event, he had generalized tonic clonic seizures, decorticate posture and a Glascow Coma Scale of seven with localization of painful stimuli. Subsequent magnetic resonance imaging of the brain showed a star-field pattern defining multiple lesions of restricted diffusion. On a 4-week follow-up, he had returned to normal neurological function. Despite the severity of the neurological condition upon initial presentation, the case cerebral fat embolism illustrates that, cerebral dysfunction associated with cerebral fat embolism illustrates reversible.

Nuclear envelope alterations generate an aging-like epigenetic pattern in mice deficient in Zmpste24 metalloprotease.

PubMed

Osorio, Fernando G; Varela, Ignacio; Lara, Ester; Puente, Xose S; Espada, Jesús; Santoro, Raffaella; Freije, José M P; Fraga, Mario F; López-Otín, Carlos

2010-12-01

Mutations in the nuclear envelope protein lamin A or in its processing protease ZMPSTE24 cause human accelerated aging syndromes, including Hutchinson-Gilford progeria syndrome. Similarly, Zmpste24-deficient mice accumulate unprocessed prelamin A and develop multiple progeroid symptoms, thus representing a valuable animal model for the study of these syndromes. Zmpste24-deficient mice also show marked transcriptional alterations associated with chromatin disorganization, but the molecular links between both processes are unknown. We report herein that Zmpste24-deficient mice show a hypermethylation of rDNA that reduces the transcription of ribosomal genes, being this reduction reversible upon treatment with DNA methyltransferase inhibitors. This alteration has been previously described during physiological aging in rodents, suggesting its potential role in the development of the progeroid phenotypes. We also show that Zmpste24-deficient mice present global hypoacetylation of histones H2B and H4. By using a combination of RNA sequencing and chromatin immunoprecipitation assays, we demonstrate that these histone modifications are associated with changes in the expression of several genes involved in the control of cell proliferation and metabolic processes, which may contribute to the plethora of progeroid symptoms exhibited by Zmpste24-deficient mice. The identification of these altered genes may help to clarify the molecular mechanisms underlying aging and progeroid syndromes as well as to define new targets for the treatment of these dramatic diseases. © 2010 The Authors. Aging Cell © 2010 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.

Interactome disassembly during apoptosis occurs independent of caspase cleavage.

PubMed

Scott, Nichollas E; Rogers, Lindsay D; Prudova, Anna; Brown, Nat F; Fortelny, Nikolaus; Overall, Christopher M; Foster, Leonard J

2017-01-12

Protein-protein interaction networks (interactomes) define the functionality of all biological systems. In apoptosis, proteolysis by caspases is thought to initiate disassembly of protein complexes and cell death. Here we used a quantitative proteomics approach, protein correlation profiling (PCP), to explore changes in cytoplasmic and mitochondrial interactomes in response to apoptosis initiation as a function of caspase activity. We measured the response to initiation of Fas-mediated apoptosis in 17,991 interactions among 2,779 proteins, comprising the largest dynamic interactome to date. The majority of interactions were unaffected early in apoptosis, but multiple complexes containing known caspase targets were disassembled. Nonetheless, proteome-wide analysis of proteolytic processing by terminal amine isotopic labeling of substrates (TAILS) revealed little correlation between proteolytic and interactome changes. Our findings show that, in apoptosis, significant interactome alterations occur before and independently of caspase activity. Thus, apoptosis initiation includes a tight program of interactome rearrangement, leading to disassembly of relatively few, select complexes. These early interactome alterations occur independently of cleavage of these protein by caspases. © 2017 The Authors. Published under the terms of the CC BY 4.0 license.

Compounding Effects of Agricultural Land Use and Water Use in Free-Flowing Rivers: Confounding Issues for Environmental Flows

NASA Astrophysics Data System (ADS)

Hardie, Scott A.; Bobbi, Chris J.

2018-03-01

Defining the ecological impacts of water extraction from free-flowing river systems in altered landscapes is challenging as multiple stressors (e.g., flow regime alteration, increased sedimentation) may have simultaneous effects and attributing causality is problematic. This multiple-stressor context has been acknowledged in environmental flows science, but is often neglected when it comes to examining flow-ecology relationships, and setting and implementing environmental flows. We examined the impacts of land and water use on rivers in the upper Ringarooma River catchment in Tasmania (south-east Australia), which contains intensively irrigated agriculture, to support implementation of a water management plan. Temporal and spatial and trends in river condition were assessed using benthic macroinvertebrates as bioindicators. Relationships between macroinvertebrate community structure and environmental variables were examined using univariate and multivariate analyses, focusing on the impacts of agricultural land use and water use. Structural changes in macroinvertebrate communities in rivers in the catchment indicated temporal and spatial declines in the ecological condition of some stretches of river associated with agricultural land and water use. Moreover, water extraction appeared to exacerbate impairment associated with agricultural land use (e.g., reduced macroinvertebrate density, more flow-avoiding taxa). The findings of our catchment-specific bioassessments will underpin decision-making during the implementation of the Ringarooma water management plan, and highlight the need to consider compounding impacts of land and water use in environmental flows and water planning in agricultural landscapes.

Compounding Effects of Agricultural Land Use and Water Use in Free-Flowing Rivers: Confounding Issues for Environmental Flows.

PubMed

Hardie, Scott A; Bobbi, Chris J

2018-03-01

Defining the ecological impacts of water extraction from free-flowing river systems in altered landscapes is challenging as multiple stressors (e.g., flow regime alteration, increased sedimentation) may have simultaneous effects and attributing causality is problematic. This multiple-stressor context has been acknowledged in environmental flows science, but is often neglected when it comes to examining flow-ecology relationships, and setting and implementing environmental flows. We examined the impacts of land and water use on rivers in the upper Ringarooma River catchment in Tasmania (south-east Australia), which contains intensively irrigated agriculture, to support implementation of a water management plan. Temporal and spatial and trends in river condition were assessed using benthic macroinvertebrates as bioindicators. Relationships between macroinvertebrate community structure and environmental variables were examined using univariate and multivariate analyses, focusing on the impacts of agricultural land use and water use. Structural changes in macroinvertebrate communities in rivers in the catchment indicated temporal and spatial declines in the ecological condition of some stretches of river associated with agricultural land and water use. Moreover, water extraction appeared to exacerbate impairment associated with agricultural land use (e.g., reduced macroinvertebrate density, more flow-avoiding taxa). The findings of our catchment-specific bioassessments will underpin decision-making during the implementation of the Ringarooma water management plan, and highlight the need to consider compounding impacts of land and water use in environmental flows and water planning in agricultural landscapes.

Hormone-induced protection against mammary tumorigenesis is conserved in multiple rat strains and identifies a core gene expression signature induced by pregnancy.

PubMed

Blakely, Collin M; Stoddard, Alexander J; Belka, George K; Dugan, Katherine D; Notarfrancesco, Kathleen L; Moody, Susan E; D'Cruz, Celina M; Chodosh, Lewis A

2006-06-15

Women who have their first child early in life have a substantially lower lifetime risk of breast cancer. The mechanism for this is unknown. Similar to humans, rats exhibit parity-induced protection against mammary tumorigenesis. To explore the basis for this phenomenon, we identified persistent pregnancy-induced changes in mammary gene expression that are tightly associated with protection against tumorigenesis in multiple inbred rat strains. Four inbred rat strains that exhibit marked differences in their intrinsic susceptibilities to carcinogen-induced mammary tumorigenesis were each shown to display significant protection against methylnitrosourea-induced mammary tumorigenesis following treatment with pregnancy levels of estradiol and progesterone. Microarray expression profiling of parous and nulliparous mammary tissue from these four strains yielded a common 70-gene signature. Examination of the genes constituting this signature implicated alterations in transforming growth factor-beta signaling, the extracellular matrix, amphiregulin expression, and the growth hormone/insulin-like growth factor I axis in pregnancy-induced alterations in breast cancer risk. Notably, related molecular changes have been associated with decreased mammographic density, which itself is strongly associated with decreased breast cancer risk. Our findings show that hormone-induced protection against mammary tumorigenesis is widely conserved among divergent rat strains and define a gene expression signature that is tightly correlated with reduced mammary tumor susceptibility as a consequence of a normal developmental event. Given the conservation of this signature, these pathways may contribute to pregnancy-induced protection against breast cancer.

Multiplicity in Early Stellar Evolution

NASA Astrophysics Data System (ADS)

Reipurth, B.; Clarke, C. J.; Boss, A. P.; Goodwin, S. P.; Rodríguez, L. F.; Stassun, K. G.; Tokovinin, A.; Zinnecker, H.

Observations from optical to centimeter wavelengths have demonstrated that multiple systems of two or more bodies is the norm at all stellar evolutionary stages. Multiple systems are widely agreed to result from the collapse and fragmentation of cloud cores, despite the inhibiting influence of magnetic fields. Surveys of class 0 protostars with millimeter interferometers have revealed a very high multiplicity frequency of about 2/3, even though there are observational difficulties in resolving close protobinaries, thus supporting the possibility that all stars could be born in multiple systems. Near-infrared adaptive optics observations of class I protostars show a lower binary frequency relative to the class 0 phase, a declining trend that continues through the class II/III stages to the field population. This loss of companions is a natural consequence of dynamical interplay in small multiple systems, leading to ejection of members. We discuss observational consequences of this dynamical evolution, and its influence on circumstellar disks, and we review the evolution of circumbinary disks and their role in defining binary mass ratios. Special attention is paid to eclipsing PMS binaries, which allow for observational tests of evolutionary models of early stellar evolution. Many stars are born in clusters and small groups, and we discuss how interactions in dense stellar environments can significantly alter the distribution of binary separations through dissolution of wider binaries. The binaries and multiples we find in the field are the survivors of these internal and external destructive processes, and we provide a detailed overview of the multiplicity statistics of the field, which form a boundary condition for all models of binary evolution. Finally, we discuss various formation mechanisms for massive binaries, and the properties of massive trapezia.

Defining Success in Adult Basic Education Settings: Multiple Stakeholders, Multiple Perspectives

ERIC Educational Resources Information Center

Tighe, Elizabeth L.; Barnes, Adrienne E.; Connor, Carol M.; Steadman, Sharilyn C.

2013-01-01

This study employed quantitative and qualitative research approaches to investigate what constitutes success in adult basic education (ABE) programs from the perspectives of multiple educational stakeholders: the state funding agency, the teachers, and the students. Success was defined in multiple ways. In the quantitative section of the study, we…

Stratovolcano stability assessment methods and results from Citlaltepetl, Mexico

USGS Publications Warehouse

Zimbelman, D.R.; Watters, R.J.; Firth, I.R.; Breit, G.N.; Carrasco-Nunez, Gerardo

2004-01-01

Citlaltépetl volcano is the easternmost stratovolcano in the Trans-Mexican Volcanic Belt. Situated within 110 km of Veracruz, it has experienced two major collapse events and, subsequent to its last collapse, rebuilt a massive, symmetrical summit cone. To enhance hazard mitigation efforts we assess the stability of Citlaltépetl's summit cone, the area thought most likely to fail during a potential massive collapse event. Through geologic mapping, alteration mineralogy, geotechnical studies, and stability modeling we provide important constraints on the likelihood, location, and size of a potential collapse event. The volcano's summit cone is young, highly fractured, and hydrothermally altered. Fractures are most abundant within 5–20-m wide zones defined by multiple parallel to subparallel fractures. Alteration is most pervasive within the fracture systems and includes acid sulfate, advanced argillic, argillic, and silicification ranks. Fractured and altered rocks both have significantly reduced rock strengths, representing likely bounding surfaces for future collapse events. The fracture systems and altered rock masses occur non-uniformly, as an orthogonal set with N–S and E–W trends. Because these surfaces occur non-uniformly, hazards associated with collapse are unevenly distributed about the volcano. Depending on uncertainties in bounding surfaces, but constrained by detailed field studies, potential failure volumes are estimated to range between 0.04–0.5 km3. Stability modeling was used to assess potential edifice failure events. Modeled failure of the outer portion of the cone initially occurs as an "intact block" bounded by steeply dipping joints and outwardly dipping flow contacts. As collapse progresses, more of the inner cone fails and the outer "intact" block transforms into a collection of smaller blocks. Eventually, a steep face develops in the uppermost and central portion of the cone. This modeled failure morphology mimics collapse amphitheaters

Presence of multiple sites containing polar material in spherical Escherichia coli cells that lack MreB.

PubMed

Nilsen, Trine; Yan, Arthur W; Gale, Gregory; Goldberg, Marcia B

2005-09-01

In rod-shaped bacteria, certain proteins are specifically localized to the cell poles. The nature of the positional information that leads to the proper localization of these proteins is unclear. In a screen for factors required for the localization of the Shigella sp. actin assembly protein IcsA to the bacterial pole, a mutant carrying a transposon insertion in mreB displayed altered targeting of IcsA. The phenotype of cells containing a transposon insertion in mreB was indistinguishable from that of cells containing a nonpolar mutation in mreB or that of wild-type cells treated with the MreB inhibitor A22. In cells lacking MreB, a green fluorescent protein (GFP) fusion to a cytoplasmic derivative of IcsA localized to multiple sites. Secreted full-length native IcsA was present in multiple faint patches on the surfaces of these cells in a pattern similar to that seen for the cytoplasmic IcsA-GFP fusion. EpsM, the polar Vibrio cholerae inner membrane protein, also localized to multiple sites in mreB cells and colocalized with IcsA, indicating that localization to multiple sites is not unique to IcsA. Our results are consistent with the requirement, either direct or indirect, for MreB in the restriction of certain polar material to defined sites within the cell and, in the absence of MreB, with the formation of ectopic sites containing polar material.

Exploring metabolic pathway disruption in the subchronic phencyclidine model of schizophrenia with the Generalized Singular Value Decomposition

PubMed Central

2011-01-01

Background The quantification of experimentally-induced alterations in biological pathways remains a major challenge in systems biology. One example of this is the quantitative characterization of alterations in defined, established metabolic pathways from complex metabolomic data. At present, the disruption of a given metabolic pathway is inferred from metabolomic data by observing an alteration in the level of one or more individual metabolites present within that pathway. Not only is this approach open to subjectivity, as metabolites participate in multiple pathways, but it also ignores useful information available through the pairwise correlations between metabolites. This extra information may be incorporated using a higher-level approach that looks for alterations between a pair of correlation networks. In this way experimentally-induced alterations in metabolic pathways can be quantitatively defined by characterizing group differences in metabolite clustering. Taking this approach increases the objectivity of interpreting alterations in metabolic pathways from metabolomic data. Results We present and justify a new technique for comparing pairs of networks--in our case these networks are based on the same set of nodes and there are two distinct types of weighted edges. The algorithm is based on the Generalized Singular Value Decomposition (GSVD), which may be regarded as an extension of Principle Components Analysis to the case of two data sets. We show how the GSVD can be interpreted as a technique for reordering the two networks in order to reveal clusters that are exclusive to only one. Here we apply this algorithm to a new set of metabolomic data from the prefrontal cortex (PFC) of a translational model relevant to schizophrenia, rats treated subchronically with the N-methyl-D-Aspartic acid (NMDA) receptor antagonist phencyclidine (PCP). This provides us with a means to quantify which predefined metabolic pathways (Kyoto Encyclopedia of Genes and Genomes (KEGG) metabolite pathway database) were altered in the PFC of PCP-treated rats. Several significant changes were discovered, notably: 1) neuroactive ligands active at glutamate and GABA receptors are disrupted in the PFC of PCP-treated animals, 2) glutamate dysfunction in these animals was not limited to compromised glutamatergic neurotransmission but also involves the disruption of metabolic pathways linked to glutamate; and 3) a specific series of purine reactions Xanthine ← Hypoxyanthine ↔ Inosine ← IMP → adenylosuccinate is also disrupted in the PFC of PCP-treated animals. Conclusions Network reordering via the GSVD provides a means to discover statistically validated differences in clustering between a pair of networks. In practice this analytical approach, when applied to metabolomic data, allows us to quantify the alterations in metabolic pathways between two experimental groups. With this new computational technique we identified metabolic pathway alterations that are consistent with known results. Furthermore, we discovered disruption in a novel series of purine reactions that may contribute to the PFC dysfunction and cognitive deficits seen in schizophrenia. PMID:21575198

Defining ecological and economical hydropoweroperations: a framework for managing dam releasesto meet multiple conflicting objectives

USGS Publications Warehouse

Irwin, Elise R.

2014-01-01

Hydroelectric dams are a flexible source of power, provide flood control, and contribute to the economic growth of local communities through real-estate and recreation. Yet the impoundment of rivers can alter and fragment miles of critical riverine habitat needed for other competing needs such as downstream consumptive water use, fish and wildlife population viability, or other forms of recreation. Multiple conflicting interests can compromise progressive management especially with recognized uncertainties related to whether management actions will fulfill the objectives of policy makers, resource managers and/or facility owners. Decision analytic tools were used in a stakeholder-driven process to develop and implement a template for evaluation and prediction of the effects of water resource management of multiple-use systems under the context provided by R.L. Harris Dam on the Tallapoosa River, Alabama, USA. The approach provided a transparent and structured framework for decision-making and incorporated both existing and new data to meet multiple management objectives. Success of the template has been evaluated by the stakeholder governing body in an adaptive resource management framework since 2005 and is ongoing. Consequences of management of discharge at the dam were evaluated annually relative to stakeholder satisfaction to allow for adjustment of both management scenarios and objectives. This template can be applied to attempt to resolve conflict inherent in many dam-regulated systems where management decisions impact diverse values of stakeholders.

Biomathematical modeling of pulsatile hormone secretion: a historical perspective.

PubMed

Evans, William S; Farhy, Leon S; Johnson, Michael L

2009-01-01

Shortly after the recognition of the profound physiological significance of the pulsatile nature of hormone secretion, computer-based modeling techniques were introduced for the identification and characterization of such pulses. Whereas these earlier approaches defined perturbations in hormone concentration-time series, deconvolution procedures were subsequently employed to separate such pulses into their secretion event and clearance components. Stochastic differential equation modeling was also used to define basal and pulsatile hormone secretion. To assess the regulation of individual components within a hormone network, a method that quantitated approximate entropy within hormone concentration-times series was described. To define relationships within coupled hormone systems, methods including cross-correlation and cross-approximate entropy were utilized. To address some of the inherent limitations of these methods, modeling techniques with which to appraise the strength of feedback signaling between and among hormone-secreting components of a network have been developed. Techniques such as dynamic modeling have been utilized to reconstruct dose-response interactions between hormones within coupled systems. A logical extension of these advances will require the development of mathematical methods with which to approximate endocrine networks exhibiting multiple feedback interactions and subsequently reconstruct their parameters based on experimental data for the purpose of testing regulatory hypotheses and estimating alterations in hormone release control mechanisms.

Excited Delirium Syndrome (ExDS): defining based on a review of the literature.

PubMed

Vilke, Gary M; DeBard, Mark L; Chan, Theodore C; Ho, Jeffrey D; Dawes, Donald M; Hall, Christine; Curtis, Michael D; Costello, Melissa Wysong; Mash, Deborah C; Coffman, Stewart R; McMullen, Mary Jo; Metzger, Jeffery C; Roberts, James R; Sztajnkrcer, Matthew D; Henderson, Sean O; Adler, Jason; Czarnecki, Fabrice; Heck, Joseph; Bozeman, William P

2012-11-01

Patients present to police, Emergency Medical Services, and the emergency department with aggressive behavior, altered sensorium, and a host of other signs that may include hyperthermia, "superhuman" strength, diaphoresis, and lack of willingness to yield to overwhelming force. A certain percentage of these individuals will go on to expire from a sudden cardiac arrest and death, despite optimal therapy. Traditionally, the forensic community would often classify these as "Excited Delirium" deaths. This article will review selected examples of the literature on this topic to determine if it is definable as a discrete medical entity, has a recognizable history, epidemiology, clinical presentation, pathophysiology, and treatment recommendations. Excited delirium syndrome is characterized by delirium, agitation, acidosis, and hyperadrenergic autonomic dysfunction, typically in the setting of acute-on-chronic drug abuse or serious mental illness or a combination of both. Based upon available evidence, it is the consensus of an American College of Emergency Physicians Task Force that Excited Delirium Syndrome is a real syndrome with uncertain, likely multiple, etiologies. Copyright © 2012 Elsevier Inc. All rights reserved.

Update on pigment dispersion syndrome and pigmentary glaucoma.

PubMed

Okafor, Kingsley; Vinod, Kateki; Gedde, Steven J

2017-03-01

The present article reviews the clinical features and pathogenesis of pigment dispersion syndrome and pigmentary glaucoma and provides an update regarding their diagnosis and management. Newer imaging modalities including ultrasound biomicroscopy and anterior segment optical coherence tomography facilitate visualization of the iris concavity characteristic of eyes with pigment dispersion syndrome and pigmentary glaucoma. Patients with pigmentary glaucoma may be distinguished from those with other glaucoma types by the presence of typical symptoms, personality type, and patterns of diurnal intraocular pressure fluctuation. Although laser iridotomy has been shown to alter iris anatomy in pigmentary glaucoma, it is not proven to slow visual field progression. Multiple trials have validated the safety and efficacy of filtering surgery in treating pigmentary glaucoma, with fewer studies published on the role of micro-invasive glaucoma surgery. Literature from the review period has further defined the unique clinical characteristics of pigment dispersion syndrome and pigmentary glaucoma. Laser surgery has a limited role in the management of these entities, whereas trabeculectomy remains an acceptable first-line surgical treatment. Further studies are needed to define the potential application of the newer micro-invasive glaucoma procedures in pigmentary glaucoma.

Systems-wide RNAi analysis of CASP8AP2/FLASH shows transcriptional deregulation of the replication-dependent histone genes and extensive effects on the transcriptome of colorectal cancer cells

PubMed Central

2012-01-01

Background Colorectal carcinomas (CRC) carry massive genetic and transcriptional alterations that influence multiple cellular pathways. The study of proteins whose loss-of-function (LOF) alters the growth of CRC cells can be used to further understand the cellular processes cancer cells depend upon for survival. Results A small-scale RNAi screen of ~400 genes conducted in SW480 CRC cells identified several candidate genes as required for the viability of CRC cells, most prominently CASP8AP2/FLASH. To understand the function of this gene in maintaining the viability of CRC cells in an unbiased manner, we generated gene specific expression profiles following RNAi. Silencing of CASP8AP2/FLASH resulted in altered expression of over 2500 genes enriched for genes associated with cellular growth and proliferation. Loss of CASP8AP2/FLASH function was significantly associated with altered transcription of the genes encoding the replication-dependent histone proteins as a result of the expression of the non-canonical polyA variants of these transcripts. Silencing of CASP8AP2/FLASH also mediated enrichment of changes in the expression of targets of the NFκB and MYC transcription factors. These findings were confirmed by whole transcriptome analysis of CASP8AP2/FLASH silenced cells at multiple time points. Finally, we identified and validated that CASP8AP2/FLASH LOF increases the expression of neurofilament heavy polypeptide (NEFH), a protein recently linked to regulation of the AKT1/ß-catenin pathway. Conclusions We have used unbiased RNAi based approaches to identify and characterize the function of CASP8AP2/FLASH, a protein not previously reported as required for cell survival. This study further defines the role CASP8AP2/FLASH plays in the regulating expression of the replication-dependent histones and shows that its LOF results in broad and reproducible effects on the transcriptome of colorectal cancer cells including the induction of expression of the recently described tumor suppressor gene NEFH. PMID:22216762

Systems-wide RNAi analysis of CASP8AP2/FLASH shows transcriptional deregulation of the replication-dependent histone genes and extensive effects on the transcriptome of colorectal cancer cells.

PubMed

Hummon, Amanda B; Pitt, Jason J; Camps, Jordi; Emons, Georg; Skube, Susan B; Huppi, Konrad; Jones, Tamara L; Beissbarth, Tim; Kramer, Frank; Grade, Marian; Difilippantonio, Michael J; Ried, Thomas; Caplen, Natasha J

2012-01-04

Colorectal carcinomas (CRC) carry massive genetic and transcriptional alterations that influence multiple cellular pathways. The study of proteins whose loss-of-function (LOF) alters the growth of CRC cells can be used to further understand the cellular processes cancer cells depend upon for survival. A small-scale RNAi screen of ~400 genes conducted in SW480 CRC cells identified several candidate genes as required for the viability of CRC cells, most prominently CASP8AP2/FLASH. To understand the function of this gene in maintaining the viability of CRC cells in an unbiased manner, we generated gene specific expression profiles following RNAi. Silencing of CASP8AP2/FLASH resulted in altered expression of over 2500 genes enriched for genes associated with cellular growth and proliferation. Loss of CASP8AP2/FLASH function was significantly associated with altered transcription of the genes encoding the replication-dependent histone proteins as a result of the expression of the non-canonical polyA variants of these transcripts. Silencing of CASP8AP2/FLASH also mediated enrichment of changes in the expression of targets of the NFκB and MYC transcription factors. These findings were confirmed by whole transcriptome analysis of CASP8AP2/FLASH silenced cells at multiple time points. Finally, we identified and validated that CASP8AP2/FLASH LOF increases the expression of neurofilament heavy polypeptide (NEFH), a protein recently linked to regulation of the AKT1/ß-catenin pathway. We have used unbiased RNAi based approaches to identify and characterize the function of CASP8AP2/FLASH, a protein not previously reported as required for cell survival. This study further defines the role CASP8AP2/FLASH plays in the regulating expression of the replication-dependent histones and shows that its LOF results in broad and reproducible effects on the transcriptome of colorectal cancer cells including the induction of expression of the recently described tumor suppressor gene NEFH.

Cerebral fat embolism syndrome after long bone fracture due to gunshot injury

PubMed Central

Duran, Latif; Kayhan, Servet; Kati, Celal; Akdemir, Hizir Ufuk; Balci, Kemal; Yavuz, Yucel

2014-01-01

Cerebral fat embolism syndrome is a lethal complication of long-bone fractures and clinically manifasted with respiratory distress, altered mental status, and petechial rash. We presented a 20-year-old male admitted with gun-shot wounds to his left leg. Twenty-four hours after the event, he had generalized tonic clonic seizures, decorticate posture and a Glascow Coma Scale of seven with localization of painful stimuli. Subsequent magnetic resonance imaging of the brain showed a star-field pattern defining multiple lesions of restricted diffusion. On a 4-week follow-up, he had returned to normal neurological function. Despite the severity of the neurological condition upon initial presentation, the case cerebral fat embolism illustrates that, cerebral dysfunction associated with cerebral fat embolism illustrates reversible. PMID:24701067

Pushing precipitation to the extremes in distributed experiments: Recommendations for simulating wet and dry years

USGS Publications Warehouse

Knapp, Alan K.; Avolio, Meghan L.; Beier, Claus; Carroll, Charles J.W.; Collins, Scott L.; Dukes, Jeffrey S.; Fraser, Lauchlan H.; Griffin-Nolan, Robert J.; Hoover, David L.; Jentsch, Anke; Loik, Michael E.; Phillips, Richard P.; Post, Alison K.; Sala, Osvaldo E.; Slette, Ingrid J.; Yahdjian, Laura; Smith, Melinda D.

2017-01-01

Intensification of the global hydrological cycle, ranging from larger individual precipitation events to more extreme multiyear droughts, has the potential to cause widespread alterations in ecosystem structure and function. With evidence that the incidence of extreme precipitation years (defined statistically from historical precipitation records) is increasing, there is a clear need to identify ecosystems that are most vulnerable to these changes and understand why some ecosystems are more sensitive to extremes than others. To date, opportunistic studies of naturally occurring extreme precipitation years, combined with results from a relatively small number of experiments, have provided limited mechanistic understanding of differences in ecosystem sensitivity, suggesting that new approaches are needed. Coordinated distributed experiments (CDEs) arrayed across multiple ecosystem types and focused on water can enhance our understanding of differential ecosystem sensitivity to precipitation extremes, but there are many design challenges to overcome (e.g., cost, comparability, standardization). Here, we evaluate contemporary experimental approaches for manipulating precipitation under field conditions to inform the design of ‘Drought-Net’, a relatively low-cost CDE that simulates extreme precipitation years. A common method for imposing both dry and wet years is to alter each ambient precipitation event. We endorse this approach for imposing extreme precipitation years because it simultaneously alters other precipitation characteristics (i.e., event size) consistent with natural precipitation patterns. However, we do not advocate applying identical treatment levels at all sites – a common approach to standardization in CDEs. This is because precipitation variability varies >fivefold globally resulting in a wide range of ecosystem-specific thresholds for defining extreme precipitation years. For CDEs focused on precipitation extremes, treatments should be based on each site's past climatic characteristics. This approach, though not often used by ecologists, allows ecological responses to be directly compared across disparate ecosystems and climates, facilitating process-level understanding of ecosystem sensitivity to precipitation extremes.

Pushing precipitation to the extremes in distributed experiments: recommendations for simulating wet and dry years.

PubMed

Knapp, Alan K; Avolio, Meghan L; Beier, Claus; Carroll, Charles J W; Collins, Scott L; Dukes, Jeffrey S; Fraser, Lauchlan H; Griffin-Nolan, Robert J; Hoover, David L; Jentsch, Anke; Loik, Michael E; Phillips, Richard P; Post, Alison K; Sala, Osvaldo E; Slette, Ingrid J; Yahdjian, Laura; Smith, Melinda D

2017-05-01

Intensification of the global hydrological cycle, ranging from larger individual precipitation events to more extreme multiyear droughts, has the potential to cause widespread alterations in ecosystem structure and function. With evidence that the incidence of extreme precipitation years (defined statistically from historical precipitation records) is increasing, there is a clear need to identify ecosystems that are most vulnerable to these changes and understand why some ecosystems are more sensitive to extremes than others. To date, opportunistic studies of naturally occurring extreme precipitation years, combined with results from a relatively small number of experiments, have provided limited mechanistic understanding of differences in ecosystem sensitivity, suggesting that new approaches are needed. Coordinated distributed experiments (CDEs) arrayed across multiple ecosystem types and focused on water can enhance our understanding of differential ecosystem sensitivity to precipitation extremes, but there are many design challenges to overcome (e.g., cost, comparability, standardization). Here, we evaluate contemporary experimental approaches for manipulating precipitation under field conditions to inform the design of 'Drought-Net', a relatively low-cost CDE that simulates extreme precipitation years. A common method for imposing both dry and wet years is to alter each ambient precipitation event. We endorse this approach for imposing extreme precipitation years because it simultaneously alters other precipitation characteristics (i.e., event size) consistent with natural precipitation patterns. However, we do not advocate applying identical treatment levels at all sites - a common approach to standardization in CDEs. This is because precipitation variability varies >fivefold globally resulting in a wide range of ecosystem-specific thresholds for defining extreme precipitation years. For CDEs focused on precipitation extremes, treatments should be based on each site's past climatic characteristics. This approach, though not often used by ecologists, allows ecological responses to be directly compared across disparate ecosystems and climates, facilitating process-level understanding of ecosystem sensitivity to precipitation extremes. © 2016 John Wiley & Sons Ltd.

Dynamic transcriptional signature and cell fate analysis reveals plasticity of individual neural plate border cells

PubMed Central

Roellig, Daniela; Tan-Cabugao, Johanna; Esaian, Sevan; Bronner, Marianne E

2017-01-01

The ‘neural plate border’ of vertebrate embryos contains precursors of neural crest and placode cells, both defining vertebrate characteristics. How these lineages segregate from neural and epidermal fates has been a matter of debate. We address this by performing a fine-scale quantitative temporal analysis of transcription factor expression in the neural plate border of chick embryos. The results reveal significant overlap of transcription factors characteristic of multiple lineages in individual border cells from gastrula through neurula stages. Cell fate analysis using a Sox2 (neural) enhancer reveals that cells that are initially Sox2+ cells can contribute not only to neural tube but also to neural crest and epidermis. Moreover, modulating levels of Sox2 or Pax7 alters the apportionment of neural tube versus neural crest fates. Our results resolve a long-standing question and suggest that many individual border cells maintain ability to contribute to multiple ectodermal lineages until or beyond neural tube closure. DOI: http://dx.doi.org/10.7554/eLife.21620.001 PMID:28355135

Characterizing patients with multiple chromosomal aberrations detected by FISH in chronic lymphocytic leukemia.

PubMed

González-Gascón Y Marín, Isabel; Hernández-Sanchez, María; Rodríguez-Vicente, Ana Eugenia; Puiggros, Anna; Collado, Rosa; Luño, Elisa; González, Teresa; Ruiz-Xivillé, Neus; Ortega, Margarita; Gimeno, Eva; Muñoz, Carolina; Infante, Maria Stefania; Delgado, Julio; Vargas, María Teresa; González, Marcos; Bosch, Francesc; Espinet, Blanca; Hernández-Rivas, Jesús María; Hernández, José Ángel

2018-03-01

We analyzed the features of chronic lymphocytic leukemia (CLL) with multiple abnormalities (MA) detected by FISH. A local database including 2095 CLL cases was used and 323 with MA (15.4%) were selected. MA was defined by the presence of two or more alterations (deletions of 13q14 (13q-), 11q22 (11q-), 17p13 (17p-) or trisomy 12 (+12)). The combination of 13q- with 11q- and 13q- with 17p-, accounted for 58.2% of the series, in contrast to 11q- with 17p- (3.7%). Patients carrying MA since diagnosis presented a short time to first therapy(TTFT) (27 months) and overall survival (OS) (76 months). The combinations including 17p- had a shorter OS (58 months) than the ones without 17p- (not reached, p = .002). Patients with a complex-FISH were the ones with worse OS (34 months). MA imply poor prognosis when they emerge at diagnosis, probably due to the high incidence of bad prognosis markers, which may be a reflection of a more complex karyotype.

Malignant Transformation and Stromal Invasion from Normal or Hyperplastic Tissues: True or False?

PubMed Central

Man, Yan-gao; Grinkemeyer, Michael; Izadjoo, Mina; Stojadinovic, Alexander

2011-01-01

Carcinogenesis is believed to be a multi-step process, progressing sequentially from normal to hyperplastic, to in situ, and to invasive stages. A number of studies, however, have detected malignancy-associated alterations in normal or hyperplastic tissues. As the molecular profile and clinical features of these tissues have not been defined, the authors invited several well-recognized pathologist, oncologists, biologist, surgeons, and molecular biologist to offer their opinion on: (1) whether these tissues belong to a previously unrevealed malignant entity or focal alterations with no significant consequence? (2) whether these alterations are linked to early onset of cancer or cancer of unknown primary site, and (3) how to further define these lesions? PMID:21811519

The Altered Schaedler Flora: Continued Applications of a Defined Murine Microbial Community

PubMed Central

Wymore Brand, Meghan; Wannemuehler, Michael J.; Phillips, Gregory J.; Proctor, Alexandra; Overstreet, Anne-Marie; Jergens, Albert E.; Orcutt, Roger P.; Fox, James G.

2015-01-01

The gastrointestinal (GI) microbiota forms a mutualistic relationship with the host through complex and dynamic interactions. Because of the complexity and interindividual variation of the GI microbiota, investigating how members of the microbiota interact with each other, as well as with the host, is daunting. The altered Schaedler flora (ASF) is a model community of eight microorganisms that was developed by R.P. Orcutt and has been in use since the late 1970s. The eight microorganisms composing the ASF were all derived from mice, can be cultured in vitro, and are stably passed through multiple generations (at least 15 years or more by the authors) in gnotobiotic mice continually bred in isolator facilities. With the limitations associated with conventional, mono- or biassociated, and germfree mice, use of mice colonized with a consortium of known bacteria that naturally inhabit the murine gut offers a powerful system to investigate mechanisms governing host–microbiota relationships, and how members of the GI microbiota interact with one another. The ASF community offers significant advantages to study homeostatic as well as disease-related interactions by taking advantage of a well-defined, limited community of microorganisms. For example, quantification and spatial distribution of individual members, microbial genetic manipulation, genomic-scale analysis, and identification of microorganism-specific host immune responses are all achievable using the ASF model. This review compiles highlights associated with the 37-year history of the ASF, including descriptions of its continued use in biomedical research to elucidate the complexities of host-microbiome interactions in health and disease. PMID:26323627

Radiation efficiency of earthquake sources at different hierarchical levels

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

Kocharyan, G. G., E-mail: gevorgkidg@mail.ru; Moscow Institute of Physics and Technology

Such factors as earthquake size and its mechanism define common trends in alteration of radiation efficiency. The macroscopic parameter that controls the efficiency of a seismic source is stiffness of fault or fracture. The regularities of this parameter alteration with scale define several hierarchical levels, within which earthquake characteristics obey different laws. Small variations of physical and mechanical properties of the fault principal slip zone can lead to dramatic differences both in the amplitude of released stress and in the amount of radiated energy.

A comparison between the pathophysiology of multiple sclerosis and normal pressure hydrocephalus: is pulse wave encephalopathy a component of MS?

PubMed

Bateman, Grant A; Lechner-Scott, Jeannette; Lea, Rodney A

2016-09-22

It has been suggested there is a chronic neurodegenerative disorder, underlying the pathophysiology of multiple sclerosis (MS), which is distinct from the more obvious immune-mediated attack on the white matter. Limited data exists indicating there is an alteration in pulse wave propagation within the craniospinal cavity in MS, similar to the findings in normal pressure hydrocephalus (NPH). It is hypothesized MS may harbor pulse wave encephalopathy. The purpose of this study is to compare blood flow and pulse wave measurements in MS patients with a cohort of NPH patients and control subjects, to test this hypothesis. Twenty patients with MS underwent magnetic resonance (MR) flow quantification techniques. Mean blood flow and stroke volume were measured in the arterial inflow and venous out flow from the sagittal (SSS) and straight sinus (ST). The arteriovenous delay (AVD) was defined. The results were compared with both age-matched controls and NPH patients. In MS there was a 35 % reduction in arteriovenous delay and a 5 % reduction in the percentage of the arterial inflow returning via the sagittal sinus compared to age matched controls. There was an alteration in pulse wave propagation, with a 26 % increase in arterial stroke volume but 30 % reduction in SSS and ST stroke volume. The AVD and blood flow changes were in the same direction to those of NPH patients. There are blood flow and pulsation propagation changes in MS patients which are similar to those of NPH patients. The findings would be consistent with an underlying pulse wave encephalopathy component in MS.

Detection of Mutant Huntingtin Aggregation Conformers and Modulation of SDS-Soluble Fibrillar Oligomers by Small Molecules

PubMed Central

Sontag, Emily Mitchell; Lotz, Gregor P.; Yang, Guocheng; Sontag, Christopher J.; Cummings, Brian J.; Glabe, Charles G.; Muchowski, Paul J.; Thompson, Leslie Michels

2012-01-01

The Huntington’s disease (HD) mutation leads to a complex process of Huntingtin (Htt) aggregation into multimeric species that eventually form visible inclusions in cytoplasm, nuclei and neuronal processes. One hypothesis is that smaller, soluble forms of amyloid proteins confer toxic effects and contribute to early cell dysfunction. However, analysis of mutant Htt aggregation intermediates to identify conformers that may represent toxic forms of the protein and represent potential drug targets remains difficult. We performed a detailed analysis of aggregation conformers in multiple in vitro, cell and ex vivo models of HD. Conformation-specific antibodies were used to identify and characterize aggregation species, allowing assessment of multiple conformers present during the aggregation process. Using a series of assays together with these antibodies, several forms could be identified. Fibrillar oligomers, defined as having a β-sheet rich conformation, are observed in vitro using recombinant protein and in protein extracts from cells in culture or mouse brain and shown to be globular, soluble and non-sedimentable structures. Compounds previously described to modulate visible inclusion body formation and reduce toxicity in HD models were also tested and consistently found to alter the formation of fibrillar oligomers. Interestingly, these compounds did not alter the rate of visible inclusion formation, indicating that fibrillar oligomers are not necessarily the rate limiting step of inclusion body formation. Taken together, we provide insights into the structure and formation of mutant Htt fibrillar oligomers that are modulated by small molecules with protective potential in HD models. PMID:24086178

Thyroid disrupting chemicals: Mechanisms and mixtures

EPA Science Inventory

Environmental contaminants are known to act as thyroid disrupting chemicals (TDCs). Broadly defined, TDCs are xenobiotics that alter the structure or function of the thyroid gland, alter regulatory enzymes associated with thyroid hormone (TH) homeostasis, or change circulating o...

Iceland as a Model for Chemical Alteration on Mars

NASA Technical Reports Server (NTRS)

Bishop, Janice L.; Schiffman, P.; Murad, E.; Southard, R.; DeVincenzi, Donald L. (Technical Monitor)

2001-01-01

Subglacial volcanic activity on Iceland has led to the formation of a variety of silicate and iron oxide-rich alteration products that may serve as a model for chemical alteration on Mars. Multiple palagonitic tuffs, altered pillow lavas, hydrothermal springs and alteration at glacial run-off streams were observed during a recent field trip in Iceland. Formation of alteration products and ferrihydrite in similar environments on Mars may have contributed to the ferric oxide-rich surface material there. The spectral and chemical properties of Icelandic alteration products and ferrihydrites are presented here.

Diagnosis and classification of hematologic malignancies on the basis of genetics

PubMed Central

2017-01-01

Genomic analysis has greatly influenced the diagnosis and clinical management of patients affected by diverse forms of hematologic malignancies. Here, we review how genetic alterations define subclasses of patients with acute leukemias, myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPNs), non-Hodgkin lymphomas, and classical Hodgkin lymphoma. These include new subtypes of acute myeloid leukemia defined by mutations in RUNX1 or BCR-ABL1 translocations as well as a constellation of somatic structural DNA alterations in acute lymphoblastic leukemia. Among patients with MDS, detection of mutations in SF3B1 define a subgroup of patients with the ring sideroblast form of MDS and a favorable prognosis. For patients with MPNs, detection of the BCR-ABL1 fusion delineates chronic myeloid leukemia from classic BCR-ABL1− MPNs, which are largely defined by mutations in JAK2, CALR, or MPL. In the B-cell lymphomas, detection of characteristic rearrangements involving MYC in Burkitt lymphoma, BCL2 in follicular lymphoma, and MYC/BCL2/BCL6 in high-grade B-cell lymphomas are essential for diagnosis. In T-cell lymphomas, anaplastic large-cell lymphoma is defined by mutually exclusive rearrangements of ALK, DUSP22/IRF4, and TP63. Genetic alterations affecting TP53 and the mutational status of the immunoglobulin heavy-chain variable region are important in clinical management of chronic lymphocytic leukemia. Additionally, detection of BRAFV600E mutations is helpful in the diagnosis of classical hairy cell leukemia and a number of histiocytic neoplasms. Numerous additional examples provided here demonstrate how clinical evaluation of genomic alterations have refined classification of myeloid neoplasms and major forms of lymphomas arising from B, T, or natural killer cells. PMID:28600336

Quantifying patterns of change in marine ecosystem response to multiple pressures.

PubMed

Large, Scott I; Fay, Gavin; Friedland, Kevin D; Link, Jason S

2015-01-01

The ability to understand and ultimately predict ecosystem response to multiple pressures is paramount to successfully implement ecosystem-based management. Thresholds shifts and nonlinear patterns in ecosystem responses can be used to determine reference points that identify levels of a pressure that may drastically alter ecosystem status, which can inform management action. However, quantifying ecosystem reference points has proven elusive due in large part to the multi-dimensional nature of both ecosystem pressures and ecosystem responses. We used ecological indicators, synthetic measures of ecosystem status and functioning, to enumerate important ecosystem attributes and to reduce the complexity of the Northeast Shelf Large Marine Ecosystem (NES LME). Random forests were used to quantify the importance of four environmental and four anthropogenic pressure variables to the value of ecological indicators, and to quantify shifts in aggregate ecological indicator response along pressure gradients. Anthropogenic pressure variables were critical defining features and were able to predict an average of 8-13% (up to 25-66% for individual ecological indicators) of the variation in ecological indicator values, whereas environmental pressures were able to predict an average of 1-5 % (up to 9-26% for individual ecological indicators) of ecological indicator variation. Each pressure variable predicted a different suite of ecological indicator's variation and the shapes of ecological indicator responses along pressure gradients were generally nonlinear. Threshold shifts in ecosystem response to exploitation, the most important pressure variable, occurred when commercial landings were 20 and 60% of total surveyed biomass. Although present, threshold shifts in ecosystem response to environmental pressures were much less important, which suggests that anthropogenic pressures have significantly altered the ecosystem structure and functioning of the NES LME. Gradient response curves provide ecologically informed transformations of pressure variables to explain patterns of ecosystem structure and functioning. By concurrently identifying thresholds for a suite of ecological indicator responses to multiple pressures, we demonstrate that ecosystem reference points can be evaluated and used to support ecosystem-based management.

The role of follow-up ultrasound and clinical parameters after abdominal MDCT in patients with multiple trauma.

PubMed

Geyer, Lucas L; Körner, M; Linsenmaier, U; Wirth, S; Reiser, M F; Meindl, T

2014-05-01

Beside its value during the initial trauma work-up (focused assessment with sonography for trauma), ultrasound (US) is recommended for early follow-up examinations of the abdomen in multiple injured patients. However, multidetector CT (MDCT) has proven to reliably diagnose traumatic lesions of abdominal organs, to depict their extent, and to assess their clinical relevance. To evaluate the diagnostic impact of follow-up US studies after MDCT of the abdomen and to identify possible clinical parameters indicating the need of a follow-up US. During a 30-month period, patients with suspected multiple trauma were allocated. Patients with admission to the ICU, an initial abdominal MDCT scan, and an US follow-up examination after 6 and 24 h were included. Two patient cohorts were defined: patients with normal abdominal MDCT (group 1), patients with trauma-related pathologic abdominal MDCT (group 2). In all patients, parameters indicating alteration of vital functions or hemorrhage within the first 24 h were obtained by reviewing the medical charts. Forty-four of 193 patients were included: 24 were categorized in group 1 (mean age, 41.1 years; range, 21-90 years), 20 in group 2 (mean age, 36.6 years; range, 16-71 years). In group 1, US did not provide new information compared to emergency MDCT. In group 2, there were no contradictory 6- and 24-h follow-up US findings. In patients with positive MDCT findings and alterations of clinical parameters, US did not detect progression of a previously diagnosed pathology or any late manifestation of such a lesion. In none of the patients with negative abdominal MDCT and pathological clinical parameters US indicated an abdominal injury. Routine US follow-up does not yield additional information after abdominal trauma. In patients with MDCT-proven organ lesions, follow-up MDCT should be considered if indicated by abnormal clinical and/or laboratory findings.

An ecological perspective on U.S. industrial poultry production: the role of anthropogenic ecosystems on the emergence of drug-resistant bacteria from agricultural environments.

PubMed

Davis, Meghan F; Price, Lance B; Liu, Cindy Meng-Hsin; Silbergeld, Ellen K

2011-06-01

The industrialization of food animal production, specifically the widespread use of antimicrobials, not only increased pressure on microbial populations, but also changed the ecosystems in which antimicrobials and bacteria interact. In this review, we argue that industrial food animal production (IFAP) is appropriately defined as an anthropogenic ecosystem. This paper uses an ecosystem perspective to frame an examination of these changes in the context of U.S. broiler chicken production. This perspective emphasizes multiple modes by which IFAP has altered microbiomes and also suggests a means of generating hypotheses for understanding and predicting the ecological impacts of IFAP in terms of the resistome and the flow of resistance within and between microbiomes. Copyright © 2011 Elsevier Ltd. All rights reserved.

Radiation-induced genomic instability and its implications for radiation carcinogenesis

NASA Technical Reports Server (NTRS)

Huang, Lei; Snyder, Andrew R.; Morgan, William F.

2003-01-01

Radiation-induced genomic instability is characterized by an increased rate of genetic alterations including cytogenetic rearrangements, mutations, gene amplifications, transformation and cell death in the progeny of irradiated cells multiple generations after the initial insult. Chromosomal rearrangements are the best-characterized end point of radiation-induced genomic instability, and many of the rearrangements described are similar to those found in human cancers. Chromosome breakage syndromes are defined by chromosome instability, and individuals with these diseases are cancer prone. Consequently, chromosomal instability as a phenotype may underlie some fraction of those changes leading to cancer. Here we attempt to relate current knowledge regarding radiation-induced chromosome instability with the emerging molecular information on the chromosome breakage syndromes. The goal is to understand how genetic and epigenetic factors might influence the onset of chromosome instability and the role of chromosomal instability in carcinogenesis.

Mini-review: perspective of the microbiome in the pathogenesis of urothelial carcinoma

PubMed Central

Xu, Weisheng; Yang, Liying; Lee, Peng; Huang, William C; Nossa, Carlos; Ma, Yingfei; Deng, Fang-Ming; Zhou, Ming; Melamed, Jonathan; Pei, Zhiheng

2014-01-01

The microbiome is a new center of attention for studies on the pathogenesis of human disease by focusing on the alterations of all microorganisms living in a particular site or system of human body, referred as microbiota. Evidence suggests that microbiota could contribute to the pathogenesis of a number of chronic diseases, including cancers, both locally and remotely. Multiple mechanisms have been proposed and/or proven for the microbiota’s role in tumorigenesis, such as via induction of chronic inflammation, genotoxicity, bacterium-mediated cell proliferation, and activation of procarcinogens. Emerging data suggest that indigenous microbiota in the urinary tract may play an important role in the tumorigenesis of urothelial carcinoma, similar to other tumors. Future studies are needed to adequately define the microbiota composition and correlate its change with urothelial carcinoma. PMID:25126590

Alteration textures in terrestrial volcanic glass and the associated bacterial community.

PubMed

Cockell, C S; Olsson-Francis, K; Herrera, A; Meunier, A

2009-01-01

Alteration textures were examined in subglacial (hyaloclastite) deposits at Valafell, Southern Iceland. Pitted and 'elongate' alteration features are observed in the glass similar to granular and tubular features reported previously in deep-ocean basaltic glasses, but elongate features generally did not have a length to width ratio greater than five. Elongate features were found in only 7% of surfaces. Crystalline basalt clasts, which are incorporated into the hyaloclastite, did not display elongate structures. Pitted alteration features were poorly defined in crystalline basalt, comprising only 4% of the surface compared to 47% in the case of basaltic glass. Examination of silica-rich glass (obsidian) and rhyolite similarly showed poorly defined pitted textures that comprised less than 15% of the surface and no elongate features were observed. These data highlight the differences in alteration textures between terrestrial basaltic glass and previously studied deep-ocean and subsurface basaltic glass, and the important role of mineralogy in controlling the type and abundance of alteration features. The hyaloclastite contains a diverse and abundant bacterial population, as determined by 16S rDNA analysis, which could be involved in weathering the glass. Despite the presence of phototrophs, we show that they were not involved in the production of most alteration textures in the basaltic glass materials we examined.

THYROID HORMONE DISRUPTION: FROM KINETICS TO DYNAMICS.

EPA Science Inventory

A wide range of chemicals with diverse structures act as thyroid disrupting chemicals (TDCs). Broadly defined, TDCs are chemicals that alter the structure or function of the thyroid gland, alter regulatory enzymes associated with thyroid hormones (THs), or change circulating or t...

Diffuse large B-cell lymphoma patient-derived xenograft models capture the molecular and biological heterogeneity of the disease.

PubMed

Chapuy, Bjoern; Cheng, Hongwei; Watahiki, Akira; Ducar, Matthew D; Tan, Yuxiang; Chen, Linfeng; Roemer, Margaretha G M; Ouyang, Jing; Christie, Amanda L; Zhang, Liye; Gusenleitner, Daniel; Abo, Ryan P; Farinha, Pedro; von Bonin, Frederike; Thorner, Aaron R; Sun, Heather H; Gascoyne, Randy D; Pinkus, Geraldine S; van Hummelen, Paul; Wulf, Gerald G; Aster, Jon C; Weinstock, David M; Monti, Stefano; Rodig, Scott J; Wang, Yuzhuo; Shipp, Margaret A

2016-05-05

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease defined by transcriptional classifications, specific signaling and survival pathways, and multiple low-frequency genetic alterations. Preclinical model systems that capture the genetic and functional heterogeneity of DLBCL are urgently needed. Here, we generated and characterized a panel of large B-cell lymphoma (LBCL) patient-derived xenograft (PDX) models, including 8 that reflect the immunophenotypic, transcriptional, genetic, and functional heterogeneity of primary DLBCL and 1 that is a plasmablastic lymphoma. All LBCL PDX models were subjected to whole-transcriptome sequencing to classify cell of origin and consensus clustering classification (CCC) subtypes. Mutations and chromosomal rearrangements were evaluated by whole-exome sequencing with an extended bait set. Six of the 8 DLBCL models were activated B-cell (ABC)-type tumors that exhibited ABC-associated mutations such as MYD88, CD79B, CARD11, and PIM1. The remaining 2 DLBCL models were germinal B-cell type, with characteristic alterations of GNA13, CREBBP, and EZH2, and chromosomal translocations involving IgH and either BCL2 or MYC Only 25% of the DLBCL PDX models harbored inactivating TP53 mutations, whereas 75% exhibited copy number alterations of TP53 or its upstream modifier, CDKN2A, consistent with the reported incidence and type of p53 pathway alterations in primary DLBCL. By CCC criteria, 6 of 8 DLBCL PDX models were B-cell receptor (BCR)-type tumors that exhibited selective surface immunoglobulin expression and sensitivity to entospletinib, a recently developed spleen tyrosine kinase inhibitor. In summary, we have established and characterized faithful PDX models of DLBCL and demonstrated their usefulness in functional analyses of proximal BCR pathway inhibition. © 2016 by The American Society of Hematology.

Quantitative Proteomic Profiling of Prostate Cancer Reveals a Role for miR-128 in Prostate Cancer*

PubMed Central

Khan, Amjad P.; Poisson, Laila M.; Bhat, Vadiraja B.; Fermin, Damian; Zhao, Rong; Kalyana-Sundaram, Shanker; Michailidis, George; Nesvizhskii, Alexey I.; Omenn, Gilbert S.; Chinnaiyan, Arul M.; Sreekumar, Arun

2010-01-01

Multiple, complex molecular events characterize cancer development and progression. Deciphering the molecular networks that distinguish organ-confined disease from metastatic disease may lead to the identification of biomarkers of cancer invasion and disease aggressiveness. Although alterations in gene expression have been extensively quantified during neoplastic progression, complementary analyses of proteomic changes have been limited. Here we interrogate the proteomic alterations in a cohort of 15 prostate-derived tissues that included five each from adjacent benign prostate, clinically localized prostate cancer, and metastatic disease from distant sites. The experimental strategy couples isobaric tags for relative and absolute quantitation with multidimensional liquid phase peptide fractionation followed by tandem mass spectrometry. Over 1000 proteins were quantified across the specimens and delineated into clinically localized and metastatic prostate cancer-specific signatures. Included in these class-specific profiles were both proteins that were known to be dysregulated during prostate cancer progression and new ones defined by this study. Enrichment analysis of the prostate cancer-specific proteomic signature, to gain insight into the functional consequences of these alterations, revealed involvement of miR-128-a/b regulation during prostate cancer progression. This finding was validated using real time PCR analysis for microRNA transcript levels in an independent set of 15 clinical specimens. miR-128 levels were elevated in benign prostate epithelial cell lines compared with invasive prostate cancer cells. Knockdown of miR-128 induced invasion in benign prostate epithelial cells, whereas its overexpression attenuated invasion in prostate cancer cells. Taken together, our profiles of the proteomic alterations of prostate cancer progression revealed miR-128 as a potentially important negative regulator of prostate cancer cell invasion. PMID:19955085

Examination of Physiological Function and Biochemical Disorders in a Rat Model of Prolonged Asphyxia-Induced Cardiac Arrest followed by Cardio Pulmonary Bypass Resuscitation

PubMed Central

Kim, Junhwan; Yin, Tai; Yin, Ming; Zhang, Wei; Shinozaki, Koichiro; Selak, Mary A.; Pappan, Kirk L.; Lampe, Joshua W.; Becker, Lance B.

2014-01-01

Background Cardiac arrest induces whole body ischemia, which causes damage to multiple organs particularly the heart and the brain. There is clinical and preclinical evidence that neurological injury is responsible for high mortality and morbidity of patients even after successful cardiopulmonary resuscitation. A better understanding of the metabolic alterations in the brain during ischemia will enable the development of better targeted resuscitation protocols that repair the ischemic damage and minimize the additional damage caused by reperfusion. Method A validated whole body model of rodent arrest followed by resuscitation was utilized; animals were randomized into three groups: control, 30 minute asphyxial arrest, or 30 minutes asphyxial arrest followed by 60 min cardiopulmonary bypass (CPB) resuscitation. Blood gases and hemodynamics were monitored during the procedures. An untargeted metabolic survey of heart and brain tissues following cardiac arrest and after CPB resuscitation was conducted to better define the alterations associated with each condition. Results After 30 min cardiac arrest and 60 min CPB, the rats exhibited no observable brain function and weakened heart function in a physiological assessment. Heart and brain tissues harvested following 30 min ischemia had significant changes in the concentration of metabolites in lipid and carbohydrate metabolism. In addition, the brain had increased lysophospholipid content. CPB resuscitation significantly normalized metabolite concentrations in the heart tissue, but not in the brain tissue. Conclusion The observation that metabolic alterations are seen primarily during cardiac arrest suggests that the events of ischemia are the major cause of neurological damage in our rat model of asphyxia-CPB resuscitation. Impaired glycolysis and increased lysophospholipids observed only in the brain suggest that altered energy metabolism and phospholipid degradation may be a central mechanism in unresuscitatable brain damage. PMID:25383962

Examination of physiological function and biochemical disorders in a rat model of prolonged asphyxia-induced cardiac arrest followed by cardio pulmonary bypass resuscitation.

PubMed

Kim, Junhwan; Yin, Tai; Yin, Ming; Zhang, Wei; Shinozaki, Koichiro; Selak, Mary A; Pappan, Kirk L; Lampe, Joshua W; Becker, Lance B

2014-01-01

Cardiac arrest induces whole body ischemia, which causes damage to multiple organs particularly the heart and the brain. There is clinical and preclinical evidence that neurological injury is responsible for high mortality and morbidity of patients even after successful cardiopulmonary resuscitation. A better understanding of the metabolic alterations in the brain during ischemia will enable the development of better targeted resuscitation protocols that repair the ischemic damage and minimize the additional damage caused by reperfusion. A validated whole body model of rodent arrest followed by resuscitation was utilized; animals were randomized into three groups: control, 30 minute asphyxial arrest, or 30 minutes asphyxial arrest followed by 60 min cardiopulmonary bypass (CPB) resuscitation. Blood gases and hemodynamics were monitored during the procedures. An untargeted metabolic survey of heart and brain tissues following cardiac arrest and after CPB resuscitation was conducted to better define the alterations associated with each condition. After 30 min cardiac arrest and 60 min CPB, the rats exhibited no observable brain function and weakened heart function in a physiological assessment. Heart and brain tissues harvested following 30 min ischemia had significant changes in the concentration of metabolites in lipid and carbohydrate metabolism. In addition, the brain had increased lysophospholipid content. CPB resuscitation significantly normalized metabolite concentrations in the heart tissue, but not in the brain tissue. The observation that metabolic alterations are seen primarily during cardiac arrest suggests that the events of ischemia are the major cause of neurological damage in our rat model of asphyxia-CPB resuscitation. Impaired glycolysis and increased lysophospholipids observed only in the brain suggest that altered energy metabolism and phospholipid degradation may be a central mechanism in unresuscitatable brain damage.

Mitochondrial Targeted Coenzyme Q, Superoxide, and Fuel Selectivity in Endothelial Cells

PubMed Central

Fink, Brian D.; O'Malley, Yunxia; Dake, Brian L.; Ross, Nicolette C.; Prisinzano, Thomas E.; Sivitz, William I.

2009-01-01

Background Previously, we reported that the “antioxidant” compound “mitoQ” (mitochondrial-targeted ubiquinol/ubiquinone) actually increased superoxide production by bovine aortic endothelial (BAE) cell mitochondria incubated with complex I but not complex II substrates. Methods and Results To further define the site of action of the targeted coenzyme Q compound, we extended these studies to include different substrate and inhibitor conditions. In addition, we assessed the effects of mitoquinone on mitochondrial respiration, measured respiration and mitochondrial membrane potential in intact cells, and tested the intriguing hypothesis that mitoquinone might impart fuel selectivity in intact BAE cells. In mitochondria respiring on differing concentrations of complex I substrates, mitoquinone and rotenone had interactive effects on ROS consistent with redox cycling at multiple sites within complex I. Mitoquinone increased respiration in isolated mitochondria respiring on complex I but not complex II substrates. Mitoquinone also increased oxygen consumption by intact BAE cells. Moreover, when added to intact cells at 50 to 1000 nM, mitoquinone increased glucose oxidation and reduced fat oxidation, at doses that did not alter membrane potential or induce cell toxicity. Although high dose mitoquinone reduced mitochondrial membrane potential, the positively charged mitochondrial-targeted cation, decyltriphenylphosphonium (mitoquinone without the coenzyme Q moiety), decreased membrane potential more than mitoquinone, but did not alter fuel selectivity. Therefore, non-specific effects of the positive charge were not responsible and the quinone moiety is required for altered nutrient selectivity. Conclusions In summary, the interactive effects of mitoquinone and rotenone are consistent with redox cycling at more than one site within complex I. In addition, mitoquinone has substrate dependent effects on mitochondrial respiration, increases repiration by intact cells, and alters fuel selectivity favoring glucose over fatty acid oxidation at the intact cell level. PMID:19158951

Mitochondrial targeted coenzyme Q, superoxide, and fuel selectivity in endothelial cells.

PubMed

Fink, Brian D; O'Malley, Yunxia; Dake, Brian L; Ross, Nicolette C; Prisinzano, Thomas E; Sivitz, William I

2009-01-01

Previously, we reported that the "antioxidant" compound "mitoQ" (mitochondrial-targeted ubiquinol/ubiquinone) actually increased superoxide production by bovine aortic endothelial (BAE) cell mitochondria incubated with complex I but not complex II substrates. To further define the site of action of the targeted coenzyme Q compound, we extended these studies to include different substrate and inhibitor conditions. In addition, we assessed the effects of mitoquinone on mitochondrial respiration, measured respiration and mitochondrial membrane potential in intact cells, and tested the intriguing hypothesis that mitoquinone might impart fuel selectivity in intact BAE cells. In mitochondria respiring on differing concentrations of complex I substrates, mitoquinone and rotenone had interactive effects on ROS consistent with redox cycling at multiple sites within complex I. Mitoquinone increased respiration in isolated mitochondria respiring on complex I but not complex II substrates. Mitoquinone also increased oxygen consumption by intact BAE cells. Moreover, when added to intact cells at 50 to 1000 nM, mitoquinone increased glucose oxidation and reduced fat oxidation, at doses that did not alter membrane potential or induce cell toxicity. Although high dose mitoquinone reduced mitochondrial membrane potential, the positively charged mitochondrial-targeted cation, decyltriphenylphosphonium (mitoquinone without the coenzyme Q moiety), decreased membrane potential more than mitoquinone, but did not alter fuel selectivity. Therefore, non-specific effects of the positive charge were not responsible and the quinone moiety is required for altered nutrient selectivity. In summary, the interactive effects of mitoquinone and rotenone are consistent with redox cycling at more than one site within complex I. In addition, mitoquinone has substrate dependent effects on mitochondrial respiration, increases repiration by intact cells, and alters fuel selectivity favoring glucose over fatty acid oxidation at the intact cell level.

Genomic markers for decision making: what is preventing us from using markers?

PubMed

Coyle, Vicky M; Johnston, Patrick G

2010-02-01

The advent of novel genomic technologies that enable the evaluation of genomic alterations on a genome-wide scale has significantly altered the field of genomic marker research in solid tumors. Researchers have moved away from the traditional model of identifying a particular genomic alteration and evaluating the association between this finding and a clinical outcome measure to a new approach involving the identification and measurement of multiple genomic markers simultaneously within clinical studies. This in turn has presented additional challenges in considering the use of genomic markers in oncology, such as clinical study design, reproducibility and interpretation and reporting of results. This Review will explore these challenges, focusing on microarray-based gene-expression profiling, and highlights some common failings in study design that have impacted on the use of putative genomic markers in the clinic. Despite these rapid technological advances there is still a paucity of genomic markers in routine clinical use at present. A rational and focused approach to the evaluation and validation of genomic markers is needed, whereby analytically validated markers are investigated in clinical studies that are adequately powered and have pre-defined patient populations and study endpoints. Furthermore, novel adaptive clinical trial designs, incorporating putative genomic markers into prospective clinical trials, will enable the evaluation of these markers in a rigorous and timely fashion. Such approaches have the potential to facilitate the implementation of such markers into routine clinical practice and consequently enable the rational and tailored use of cancer therapies for individual patients.

Altered gene regulation and synaptic morphology in Drosophila learning and memory mutants

PubMed Central

Guan, Zhuo; Buhl, Lauren K.; Quinn, William G.; Littleton, J. Troy

2011-01-01

Genetic studies in Drosophila have revealed two separable long-term memory pathways defined as anesthesia-resistant memory (ARM) and long-lasting long-term memory (LLTM). ARM is disrupted in radish (rsh) mutants, whereas LLTM requires CREB-dependent protein synthesis. Although the downstream effectors of ARM and LLTM are distinct, pathways leading to these forms of memory may share the cAMP cascade critical for associative learning. Dunce, which encodes a cAMP-specific phosphodiesterase, and rutabaga, which encodes an adenylyl cyclase, both disrupt short-term memory. Amnesiac encodes a pituitary adenylyl cyclase-activating peptide homolog and is required for middle-term memory. Here, we demonstrate that the Radish protein localizes to the cytoplasm and nucleus and is a PKA phosphorylation target in vitro. To characterize how these plasticity pathways may manifest at the synaptic level, we assayed synaptic connectivity and performed an expression analysis to detect altered transcriptional networks in rutabaga, dunce, amnesiac, and radish mutants. All four mutants disrupt specific aspects of synaptic connectivity at larval neuromuscular junctions (NMJs). Genome-wide DNA microarray analysis revealed ∼375 transcripts that are altered in these mutants, suggesting defects in multiple neuronal signaling pathways. In particular, the transcriptional target Lapsyn, which encodes a leucine-rich repeat cell adhesion protein, localizes to synapses and regulates synaptic growth. This analysis provides insights into the Radish-dependent ARM pathway and novel transcriptional targets that may contribute to memory processing in Drosophila. PMID:21422168

Multiple biomarkers in molecular oncology. I. Molecular diagnostics applications in cervical cancer detection.

PubMed

Malinowski, Douglas P

2007-03-01

The screening for cervical carcinoma and its malignant precursors (cervical neoplasia) currently employs morphology-based detection methods (Papanicolaou [Pap] smear) in addition to the detection of high-risk human papillomavirus. The combination of the Pap smear with human papillomavirus testing has achieved significant improvements in sensitivity for the detection of cervical disease. Diagnosis of cervical neoplasia is dependent upon histology assessment of cervical biopsy specimens. Attempts to improve the specificity of cervical disease screening have focused on the investigation of molecular biomarkers for adjunctive use in combination with the Pap smear. Active research into the genomic and proteomic alterations that occur during human papillomavirus-induced neoplastic transformation have begun to characterize some of the basic mechanisms inherent to the disease process of cervical cancer development. This research continues to demonstrate the complexity of multiple genomic and proteomic alterations that accumulate during the tumorigenesis process. Despite this diversity, basic patterns of uncontrolled signal transduction, cell cycle deregulation, activation of DNA replication and altered extracellular matrix interactions are beginning to emerge as common features inherent to cervical cancer development. Some of these gene or protein expression alterations have been investigated as potential biomarkers for screening and diagnostics applications. The contribution of multiple gene alterations in the development of cervical cancer suggests that the application of multiple biomarker panels has the potential to develop clinically useful molecular diagnostics. In this review, the application of biomarkers for the improvement of sensitivity and specificity of the detection of cervical neoplasia within cytology specimens will be discussed.

Software Defined Radios - Architectures, Systems and Functions

NASA Technical Reports Server (NTRS)

Sims, Herb

2017-01-01

Software Defined Radio (SDR) technology has been proven in the commercial sector since the early 90's. Today's rapid advancement in mobile telephone reliability and power management capabilities exemplifies the effectiveness of the SDR technology for the modern communications market. SDR technology offers potential to revolutionize satellite transponder technology by increasing science data through-put capability by at least an order of magnitude. While the SDR is adaptive in nature and is "One-size-fits-all" by design, conventional transponders are built to a specific platform and must be redesigned for every new bus. The SDR uses a minimum amount of analog/Radio Frequency (RF) components to up/down-convert the RF signal to/from a digital format. Once analog data is digitized, all processing is performed using hardware logic. Typical SDR processes include; filtering, modulation, up/down converting and demodulation. These innovations have reduced the cost of transceivers, a decrease in power requirements and a commensurate reduction in volume. An additional pay-off is the increased flexibility of the SDR: allowing the same hardware to implement multiple transponder types by altering hardware logic -no change of analog hardware is required -all of which can be ultimately accomplished in orbit.

Plant responses, climate pivot points, and trade-offs in water-limited ecosystems

NASA Astrophysics Data System (ADS)

Munson, S. M.; Bunting, E.

2017-12-01

Ecosystem transitions and thresholds are conceptually well-defined and have become a framework to address vegetation response to climate change and land-use intensification, yet there are few approaches to define the environmental conditions which can lead to them. We demonstrate a novel climate pivot point approach using long-term monitoring data from a broad network of permanent plots, satellite imagery, and experimental treatments across the southwestern U.S. The climate pivot point identifies conditions that lead to decreased plant performance and serves as an early warning sign of increased vulnerability of crossing a threshold into an altered ecosystem state. Plant responses and climate pivot points aligned with the lifespan and structural characteristics of species, were modified by soil and landscape attributes of a site, and had non-linear dynamics in some cases. Species with strong increases in abundance when water was available were most susceptible to losses during water shortages, reinforcing plant energetic and physiological tradeoffs. Future research to uncover the heterogeneity of plant responses and climate pivot points at multiple scales can lead to greater understanding of shifts in ecosystem productivity and vulnerability to climate change.

Process signatures in glatiramer acetate synthesis: structural and functional relationships.

PubMed

Campos-García, Víctor R; Herrera-Fernández, Daniel; Espinosa-de la Garza, Carlos E; González, German; Vallejo-Castillo, Luis; Avila, Sandra; Muñoz-García, Leslie; Medina-Rivero, Emilio; Pérez, Néstor O; Gracia-Mora, Isabel; Pérez-Tapia, Sonia Mayra; Salazar-Ceballos, Rodolfo; Pavón, Lenin; Flores-Ortiz, Luis F

2017-09-21

Glatiramer Acetate (GA) is an immunomodulatory medicine approved for the treatment of multiple sclerosis, whose mechanisms of action are yet to be fully elucidated. GA is comprised of a complex mixture of polypeptides with different amino acid sequences and structures. The lack of sensible information about physicochemical characteristics of GA has contributed to its comprehensiveness complexity. Consequently, an unambiguous determination of distinctive attributes that define GA is of highest relevance towards dissecting its identity. Herein we conducted a study of characteristic GA heterogeneities throughout its manufacturing process (process signatures), revealing a strong impact of critical process parameters (CPPs) on the reactivity of amino acid precursors; reaction initiation and polymerization velocities; and peptide solubility, susceptibility to hydrolysis, and size-exclusion properties. Further, distinctive GA heterogeneities were correlated to defined immunological and toxicological profiles, revealing that GA possesses a unique repertoire of active constituents (epitopes) responsible of its immunological responses, whose modification lead to altered profiles. This novel approach established CPPs influence on intact GA peptide mixture, whose physicochemical identity cannot longer rely on reduced properties (based on complete or partial GA degradation), providing advanced knowledge on GA structural and functional relationships to ensure a consistent manufacturing of safe and effective products.

Jumping translocations of 1q12 in multiple myeloma: a novel mechanism for deletion of 17p in cytogenetically defined high-risk disease.

PubMed

Sawyer, Jeffrey R; Tian, Erming; Heuck, Christoph J; Epstein, Joshua; Johann, Donald J; Swanson, Charles M; Lukacs, Janet L; Johnson, Marian; Binz, Regina; Boast, Angela; Sammartino, Gael; Usmani, Saad; Zangari, Maurizio; Waheed, Sarah; van Rhee, Frits; Barlogie, Bart

2014-04-17

Multiple myeloma (MM) is a B-cell malignancy driven in part by increasing copy number alterations (CNAs) during disease progression. Prognostically significant CNAs accumulate during clonal evolution and include gains of 1q21 and deletions of 17p, among others. Unfortunately, the mechanisms underlying the accumulation of CNAs and resulting subclonal heterogeneity in high-risk MM are poorly understood. To investigate the impact of jumping translocations of 1q12 (JT1q12) on receptor chromosomes (RCs) and subsequent clonal evolution, we analyzed specimens from 86 patients selected for unbalanced 1q12 aberrations by G-banding. Utilizing spectral karyotyping and locus-specific fluorescence in situ hybridization, we identified 10 patients with unexpected focal amplifications of an RC that subsequently translocated as part of a sequential JT1q12 to one or more additional RCs. Four patients exhibited amplification and translocation of 8q24 (MYC), 3 showed amplification of 16q11, and 1 each displayed amplification of 18q21.3 (BCL2), 18q23, or 4p16 (FGFR3). Unexpectedly, in 6 of 14 patients with the combination of the t(4;14) and deletion of 17p, we identified the loss of 17p as resulting from a JT1q12. Here, we provide evidence that the JT1q12 is a mechanism for the simultaneous gain of 1q21 and deletion of 17p in cytogenetically defined high-risk disease.

THYROID DISRUPTING CHEMICALS: CHALLENGES IN ASSESSING NEUROTOXIC RISK FROM ENVIRONMENTAL MIXTURES.

EPA Science Inventory

Environmental contaminants are known to act as thyroid disrupting chemicals (TDCs). Broadly defined, TDCs are xenobiotics that alter the structure or function of the thyroid gland, alter regulatory enzymes associated with thyroid hormone (TH) homeostasis, or change circulating o...

Oxygen isotope constraints on the alteration temperatures of CM chondrites

NASA Astrophysics Data System (ADS)

Verdier-Paoletti, Maximilien J.; Marrocchi, Yves; Avice, Guillaume; Roskosz, Mathieu; Gurenko, Andrey; Gounelle, Matthieu

2017-01-01

We report a systematic oxygen isotopic survey of Ca-carbonates in nine different CM chondrites characterized by different degrees of alteration, from the least altered known to date (Paris, 2.7-2.8) to the most altered (ALH 88045, CM1). Our data define a continuous trend that crosses the Terrestrial Fractionation Line (TFL), with a general relationship that is indistinguishable within errors from the trend defined by both matrix phyllosilicates and bulk O-isotopic compositions of CM chondrites. This bulk-matrix-carbonate (BMC) trend does not correspond to a mass-dependent fractionation (i.e., slope 0.52) as it would be expected during fluid circulation along a temperature gradient. It is instead a direct proxy of the degree of O-isotopic equilibration between 17,18O-rich fluids and 16O-rich anhydrous minerals. Our O-isotopic survey revealed that, for a given CM, no carbonate is in O-isotopic equilibrium with its respective surrounding matrix. This precludes direct calculation of the temperature of carbonate precipitation. However, the O-isotopic compositions of alteration water in different CMs (inferred from isotopic mass-balance calculation and direct measurements) define another trend (CMW for CM Water), parallel to BMC but with a different intercept. The distance between the BMC and CMW trends is directly related to the temperature of CM alteration and corresponds to average carbonates and serpentine formation temperatures of 110 °C and 75 °C, respectively. However, carbonate O-isotopic variations around the BMC trend indicate that they formed at various temperatures ranging between 50 and 300 °C, with 50% of the carbonates studied here showing precipitation temperature higher than 100 °C. The average Δ17O and the average carbonate precipitation temperature per chondrite are correlated, revealing that all CMs underwent similar maximum temperature peaks, but that altered CMs experienced protracted carbonate precipitation event(s) at lower temperatures than the least altered CMs. Our data suggest that the Δ17O value of Ca-carbonates could be a reliable proxy of the degree of alteration experienced by CM chondrites.

The Altered Schaedler Flora: Continued Applications of a Defined Murine Microbial Community.

PubMed

Wymore Brand, Meghan; Wannemuehler, Michael J; Phillips, Gregory J; Proctor, Alexandra; Overstreet, Anne-Marie; Jergens, Albert E; Orcutt, Roger P; Fox, James G

2015-01-01

The gastrointestinal (GI) microbiota forms a mutualistic relationship with the host through complex and dynamic interactions. Because of the complexity and interindividual variation of the GI microbiota, investigating how members of the microbiota interact with each other, as well as with the host, is daunting. The altered Schaedler flora (ASF) is a model community of eight microorganisms that was developed by R.P. Orcutt and has been in use since the late 1970s. The eight microorganisms composing the ASF were all derived from mice, can be cultured in vitro, and are stably passed through multiple generations (at least 15 years or more by the authors) in gnotobiotic mice continually bred in isolator facilities. With the limitations associated with conventional, mono- or biassociated, and germfree mice, use of mice colonized with a consortium of known bacteria that naturally inhabit the murine gut offers a powerful system to investigate mechanisms governing host-microbiota relationships, and how members of the GI microbiota interact with one another. The ASF community offers significant advantages to study homeostatic as well as disease-related interactions by taking advantage of a well-defined, limited community of microorganisms. For example, quantification and spatial distribution of individual members, microbial genetic manipulation, genomic-scale analysis, and identification of microorganism-specific host immune responses are all achievable using the ASF model. This review compiles highlights associated with the 37-year history of the ASF, including descriptions of its continued use in biomedical research to elucidate the complexities of host-microbiome interactions in health and disease. © The Author 2015. Published by Oxford University Press on behalf of the Institute for Laboratory Animal Research. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Control of microtubule trajectory within an electric field by altering surface charge density

PubMed Central

Isozaki, Naoto; Ando, Suguru; Nakahara, Tasuku; Shintaku, Hirofumi; Kotera, Hidetoshi; Meyhöfer, Edgar; Yokokawa, Ryuji

2015-01-01

One of challenges for using microtubules (MTs) driven by kinesin motors in microfluidic environments is to control their direction of movement. Although applying physical biases to rectify MTs is prevalent, it has not been established as a design methodology in conjunction with microfluidic devices. In the future, the methodology is expected to achieve functional motor-driven nanosystems. Here, we propose a method to guide kinesin-propelled MTs in multiple directions under an electric field by designing a charged surface of MT minus ends labeled with dsDNA via a streptavidin-biotin interaction. MTs labeled with 20-bp or 50-bp dsDNA molecules showed significantly different trajectories according to the DNA length, which were in good agreement with values predicted from electrophoretic mobilities measured for their minus ends. Since the effective charge of labeled DNA molecules was equal to that of freely dispersed DNA molecules in a buffer solution, MT trajectory could be estimated by selecting labeling molecules with known charges. Moreover, the estimated trajectory enables to define geometrical sizes of a microfluidic device. This rational molecular design and prediction methodology allows MTs to be guided in multiple directions, demonstrating the feasibility of using molecular sorters driven by motor proteins. PMID:25567007

Control of microtubule trajectory within an electric field by altering surface charge density.

PubMed

Isozaki, Naoto; Ando, Suguru; Nakahara, Tasuku; Shintaku, Hirofumi; Kotera, Hidetoshi; Meyhöfer, Edgar; Yokokawa, Ryuji

2015-01-08

One of challenges for using microtubules (MTs) driven by kinesin motors in microfluidic environments is to control their direction of movement. Although applying physical biases to rectify MTs is prevalent, it has not been established as a design methodology in conjunction with microfluidic devices. In the future, the methodology is expected to achieve functional motor-driven nanosystems. Here, we propose a method to guide kinesin-propelled MTs in multiple directions under an electric field by designing a charged surface of MT minus ends labeled with dsDNA via a streptavidin-biotin interaction. MTs labeled with 20-bp or 50-bp dsDNA molecules showed significantly different trajectories according to the DNA length, which were in good agreement with values predicted from electrophoretic mobilities measured for their minus ends. Since the effective charge of labeled DNA molecules was equal to that of freely dispersed DNA molecules in a buffer solution, MT trajectory could be estimated by selecting labeling molecules with known charges. Moreover, the estimated trajectory enables to define geometrical sizes of a microfluidic device. This rational molecular design and prediction methodology allows MTs to be guided in multiple directions, demonstrating the feasibility of using molecular sorters driven by motor proteins.

NMR-based Metabolomics Analysis of Liver from C57BL/6 Mouse Exposed to Ionizing Radiation

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

Xiao, Xiongjie; Hu, Mary; Zhang, Xu

The health effects of exposing to ionizing radiation are attracting great interest in the space exploration community and patients considering radiotherapy. However, the impact to metabolism after exposure to high dose radiation has not yet been clearly defined in livers. In the present study, 1H nuclear magnetic resonance (NMR) based metabolomics combined with multivariate data analysis are applied to study the changes of metabolism in the liver of C57BL/6 mouse after whole body exposure to either gamma (3.0 and 7.8 Gy) or proton (3.0 Gy) radiation. Principal component analysis (PCA) and orthogonal projection to latent structures analysis (OPLS) are employedmore » for classification and identification of potential biomarkers associated with gamma and proton irradiation. The results show that the radiation exposed groups can be well separated from the control group. At the same radiation dosage, the group exposed to proton radiation is well separated from the group exposed to gamma radiation, indicating different radiation sources induce different alterations based on metabolic profiling. Common to both gamma and proton radiation at the high radiation doses studied in this work, compared with the control groups the concentrations of choline, O-phosphocholine and trimethylamine N-oxide are decreased statistically, while those of glutamine, glutathione, malate, creatinine, phosphate, betaine and 4-hydroxyphenylacetate are statistically and significantly elevated after exposure to radiation. Since these altered metabolites are associated with multiple biological pathways, the changes suggest that the exposure to radiation induce abnormality in multiple biological pathways. In particular, metabolites such as 4-hydroxyphenylacetate, betaine, glutamine, choline and trimethylamine N-oxide may be good candidates of pre-diagnose biomarkers for ionizing radiation in liver.« less

Atypical anticipatory postural adjustments during gait initiation among individuals with sub-acute stroke.

PubMed

Rajachandrakumar, Roshanth; Fraser, Julia E; Schinkel-Ivy, Alison; Inness, Elizabeth L; Biasin, Lou; Brunton, Karen; McIlroy, William E; Mansfield, Avril

2017-02-01

Anticipatory postural adjustments, executed prior to gait initiation, help preserve lateral stability when stepping. Atypical patterns of anticipatory activity prior to gait initiation may occur in individuals with unilateral impairment (e.g., stroke). This study aimed to determine the prevalence, correlates, and consequences of atypical anticipatory postural adjustment patterns prior to gait initiation in a sub-acute stroke population. Forty independently-ambulatory individuals with sub-acute stroke stood on two force plates and initiated gait at a self-selected speed. Medio-lateral centre of pressure displacement was calculated and used to define anticipatory postural adjustments (shift in medio-lateral centre of pressure >10mm from baseline). Stroke severity, motor recovery, and functional balance and mobility status were also obtained. Three patterns were identified: single (typical), absent (atypical), and multiple (atypical) anticipatory postural adjustments. Thirty-five percent of trials had atypical anticipatory postural adjustments (absent and multiple). Frequency of absent anticipatory postural adjustments was negatively correlated with walking speed. Multiple anticipatory postural adjustments were more prevalent when leading with the non-paretic than the paretic limb. Trials with multiple anticipatory postural adjustments had longer duration of anticipatory postural adjustment and time to foot-off, and shorter unloading time than trials with single anticipatory postural adjustments. A high prevalence of atypical anticipatory control prior to gait initiation was found in individuals with stroke. Temporal differences were identified with multiple anticipatory postural adjustments, indicating altered gait initiation. These findings provide insight into postural control during gait initiation in individuals with sub-acute stroke, and may inform interventions to improve ambulation in this population. Copyright © 2016 Elsevier B.V. All rights reserved.

Structural basis for the antifolding activity of a molecular chaperone

NASA Astrophysics Data System (ADS)

Huang, Chengdong; Rossi, Paolo; Saio, Tomohide; Kalodimos, Charalampos G.

2016-09-01

Molecular chaperones act on non-native proteins in the cell to prevent their aggregation, premature folding or misfolding. Different chaperones often exert distinct effects, such as acceleration or delay of folding, on client proteins via mechanisms that are poorly understood. Here we report the solution structure of SecB, a chaperone that exhibits strong antifolding activity, in complex with alkaline phosphatase and maltose-binding protein captured in their unfolded states. SecB uses long hydrophobic grooves that run around its disk-like shape to recognize and bind to multiple hydrophobic segments across the length of non-native proteins. The multivalent binding mode results in proteins wrapping around SecB. This unique complex architecture alters the kinetics of protein binding to SecB and confers strong antifolding activity on the chaperone. The data show how the different architectures of chaperones result in distinct binding modes with non-native proteins that ultimately define the activity of the chaperone.

Transformative environmental governance

USGS Publications Warehouse

Chaffin, Brian C.; Garmestani, Ahjond S.; Gunderson, Lance H.; Harm Benson, Melinda; Angeler, David G.; Arnold, Craig Anthony (Tony); Cosens, Barbara; Kundis Craig, Robin; Ruhl, J.B.; Allen, Craig R.

2016-01-01

Transformative governance is an approach to environmental governance that has the capacity to respond to, manage, and trigger regime shifts in coupled social-ecological systems (SESs) at multiple scales. The goal of transformative governance is to actively shift degraded SESs to alternative, more desirable, or more functional regimes by altering the structures and processes that define the system. Transformative governance is rooted in ecological theories to explain cross-scale dynamics in complex systems, as well as social theories of change, innovation, and technological transformation. Similar to adaptive governance, transformative governance involves a broad set of governance components, but requires additional capacity to foster new social-ecological regimes including increased risk tolerance, significant systemic investment, and restructured economies and power relations. Transformative governance has the potential to actively respond to regime shifts triggered by climate change, and thus future research should focus on identifying system drivers and leading indicators associated with social-ecological thresholds.

Thermoneutral housing exacerbates non-alcoholic fatty liver disease in mice and allows for sex-independent disease modeling

PubMed Central

Giles, Daniel A; Moreno-Fernandez, Maria E; Stankiewicz, Traci E; Graspeuntner, Simon; Cappelletti, Monica; Wu, David; Mukherjee, Rajib; Chan, Calvin C; Lawson, Matthew J; Klarquist, Jared; Sünderhauf, Annika; Softic, Samir; Kahn, C Ronald; Stemmer, Kerstin; Iwakura, Yoichiro; Aronow, Bruce J; Karns, Rebekah; Steinbrecher, Kris A; Karp, Christopher L; Sheridan, Rachel; Shanmukhappa, Shiva K; Reynaud, Damien; Haslam, David B; Sina, Christian; Rupp, Jan; Hogan, Simon P; Divanovic, Senad

2017-01-01

Non-alcoholic fatty liver disease (NAFLD), a common prelude to cirrhosis and hepatocellular carcinoma, is the most common chronic liver disease worldwide. Defining the molecular mechanisms underlying the pathogenesis of NAFLD has been hampered by a lack of animal models that closely recapitulate the severe end of the human disease spectrum, including bridging hepatic fibrosis. Here, we demonstrate that a novel experimental model employing thermoneutral housing, as opposed to standard housing, resulted in lower stress-driven production of corticosterone, augmented mouse proinflammatory immune responses and markedly exacerbated high fat diet (HFD)-induced NAFLD pathogenesis. Disease exacerbation at thermoneutrality was conserved across multiple mouse strains and was associated with augmented intestinal permeability, an altered microbiome and activation of inflammatory pathways associated with human disease. Depletion of Gram-negative microbiota, hematopoietic cell deletion of Toll-like receptor 4 (TLR4) and inactivation of the interleukin-17 (IL-17) axis resulted in altered immune responsiveness and protection from thermoneutral housing-driven NAFLD amplification. Finally, female mice, typically resistant to HFD-induced obesity and NAFLD, develop full-blown disease at thermoneutrality. Thus, thermoneutral housing provides a sex-independent model of exacerbated NAFLD in mice and represents a novel approach for interrogation of the cellular and molecular mechanisms underlying disease pathogenesis. PMID:28604704

BIG: a calossin-like protein required for polar auxin transport in Arabidopsis

PubMed Central

Gil, Pedro; Dewey, Elizabeth; Friml, Jiri; Zhao, Yunde; Snowden, Kimberley C.; Putterill, Jo; Palme, Klaus; Estelle, Mark; Chory, Joanne

2001-01-01

Polar auxin transport is crucial for the regulation of auxin action and required for some light-regulated responses during plant development. We have found that two mutants of Arabidopsis—doc1, which displays altered expression of light-regulated genes, and tir3, known for its reduced auxin transport—have similar defects and define mutations in a single gene that we have renamed BIG. BIG is very similar to the Drosophila gene Calossin/Pushover, a member of a gene family also present in Caenorhabditis elegans and human genomes. The protein encoded by BIG is extraordinary in size, 560 kD, and contains several putative Zn-finger domains. Expression-profiling experiments indicate that altered expression of multiple light-regulated genes in doc1 mutants can be suppressed by elevated levels of auxin caused by overexpression of an auxin biosynthetic gene, suggesting that normal auxin distribution is required to maintain low-level expression of these genes in the dark. Double mutants of tir3 with the auxin mutants pin1, pid, and axr1 display severe defects in auxin-dependent growth of the inflorescence. Chemical inhibitors of auxin transport change the intracellular localization of the auxin efflux carrier PIN1 in doc1/tir3 mutants, supporting the idea that BIG is required for normal auxin efflux. PMID:11485992

The Biochemistry of Bereavement: Possible Basis for Chemotherapy?

ERIC Educational Resources Information Center

Fredrick, Jerome F.

1982-01-01

Reviews the physiological effect of acute grief and explores the increased susceptibility to infectious disease agents in terms of the altered biochemistry of the bereaved individual. Until basic reactions of grief are defined and the altered biochemistry established, psychological methods appear to offer the best therapy. (Author/JAC)

[Effect of pharmacologic treatment of the nutritional status of neurologic patients].

PubMed

Piñeiro Corrales, Guadalupe; Vázquez López, Cristina; Álvarez Payero, Miriam

2014-01-01

Clinical manifestations accompanying neurological diseases are diverse and affect multiple organs. Nutritional status of patients with certain neurological diseases such as stroke, Alzheimer's disease, Parkinson's disease, Epilepsy and Multiple Sclerosis can be altered because of symptoms associated with disease course, including certain micronutrient deficiency (folic acid, zinc, vitamin B6 and B12, vitamin D, vitamin E and vitamin C), changes in energy expenditure, intake decreased, gastrointestinal disorders and dysfunction of the bone mass. Also, we have to take in account other factors as: advanced age, multiple co morbidities, polypharmacy, the use of herbal products, social habits, diet and pharmacological treatments effect. An assessment of the factors related to neurological treatment that cause alterations in metabolic and nutritional status was performed: side effects of anti-Parkinson drugs, antiepileptic drugs, and multiple sclerosis drugs; drug-nutrient interactions; and nutrient-drug interactions.

Nitrogen retention in salt marsh systems across nutrient-enrichment, elevation, and precipitation regimes: a multiple stressor experiment

EPA Science Inventory

In the Northeastern U.S., multiple anthropogenic stressors, including changing nutrient loads, accelerated sea-level rise, and altered climactic patterns are co-occurring, and are likely to influence salt marsh nitrogen (N) dynamics. We conducted a multiple stressor mesocosm expe...

Transgenerational Effects of Di (2-Ethylhexyl) Phthalate in the Male CRL:CD(SD) Rat: Added Value of Assessing Multiple Offspring per Litter

PubMed Central

Gray, Leon Earl; Barlow, Norman J.; Howdeshell, Kembra L.; Ostby, Joseph S.; Furr, Johnathan R.; Gray, Clark L.

2009-01-01

In the rat, some phthalates alter sexual differentiation at relatively low dosage levels by altering fetal Leydig cell development and hormone synthesis, thereby inducing abnormalities of the testis, gubernacular ligaments, epididymis, and other androgen-dependent tissues. In order to define the dose-response relationship between di(2-ethylhexyl) phthalate (DEHP) and the Phthalate Syndrome of reproductive alterations in F1 male rats, Sprague-Dawley (SD) rat dams were dosed by gavage from gestational day 8 to day 17 of lactation with 0, 11, 33, 100, or 300 mg/kg/day DEHP (71–93 males per dose from 12 to 14 litters per dose). Some of the male offspring continued to be exposed to DEHP via gavage from 18 days of age to necropsy at 63–65 days of age (PUB cohort; 16–20/dose). Remaining males were not exposed after postnatal day 17 (in utero-lactational [IUL] cohort) and were necropsied after reaching full maturity. Anogenital distance, sperm counts and reproductive organ weights were reduced in F1 males in the 300 mg/kg/day group and they displayed retained nipples. In the IUL cohort, seminal vesicle weight also was reduced at 100 mg/kg/day. In contrast, serum testosterone and estradiol levels were unaffected in either the PUB or IUL cohorts at necropsy. A significant percentage of F1 males displayed one or more Phthalate Syndrome lesions at 11 mg/kg/day DEHP and above. We were able to detect effects in the lower dose groups only because we examined all the males in each litter rather than only one male per litter. Power calculations demonstrate how using multiple males versus one male/litter enhances the detection of the effects of DEHP. The results at 11 mg/kg/day confirm those reported from a National Toxicology Program multigenerational study which reported no observed adverse effect levels-lowest observed adverse effect levels of 5 and 10 mg/kg/day DEHP, respectively, via the diet. PMID:19482887

Improving Mixed Variable Optimization of Computational and Model Parameters Using Multiple Surrogate Functions

DTIC Science & Technology

2008-03-01

multiplicative corrections as well as space mapping transformations for models defined over a lower dimensional space. A corrected surrogate model for the...correction functions used in [72]. If the low fidelity model g(x̃) is defined over a lower dimensional space then a space mapping transformation is...required. As defined in [21, 72], space mapping is a method of mapping between models of different dimensionality or fidelity. Let P denote the space

Mechanical Influences on Morphogenesis of the Knee Joint Revealed through Morphological, Molecular and Computational Analysis of Immobilised Embryos

PubMed Central

Roddy, Karen A.; Prendergast, Patrick J.; Murphy, Paula

2011-01-01

Very little is known about the regulation of morphogenesis in synovial joints. Mechanical forces generated from muscle contractions are required for normal development of several aspects of normal skeletogenesis. Here we show that biophysical stimuli generated by muscle contractions impact multiple events during chick knee joint morphogenesis influencing differential growth of the skeletal rudiment epiphyses and patterning of the emerging tissues in the joint interzone. Immobilisation of chick embryos was achieved through treatment with the neuromuscular blocking agent Decamethonium Bromide. The effects on development of the knee joint were examined using a combination of computational modelling to predict alterations in biophysical stimuli, detailed morphometric analysis of 3D digital representations, cell proliferation assays and in situ hybridisation to examine the expression of a selected panel of genes known to regulate joint development. This work revealed the precise changes to shape, particularly in the distal femur, that occur in an altered mechanical environment, corresponding to predicted changes in the spatial and dynamic patterns of mechanical stimuli and region specific changes in cell proliferation rates. In addition, we show altered patterning of the emerging tissues of the joint interzone with the loss of clearly defined and organised cell territories revealed by loss of characteristic interzone gene expression and abnormal expression of cartilage markers. This work shows that local dynamic patterns of biophysical stimuli generated from muscle contractions in the embryo act as a source of positional information guiding patterning and morphogenesis of the developing knee joint. PMID:21386908

Sequential addition of short DNA oligos in DNA-polymerase-based synthesis reactions

DOEpatents

Gardner, Shea N [San Leandro, CA; Mariella, Jr., Raymond P.; Christian, Allen T [Tracy, CA; Young, Jennifer A [Berkeley, CA; Clague, David S [Livermore, CA

2011-01-18

A method of fabricating a DNA molecule of user-defined sequence. The method comprises the steps of preselecting a multiplicity of DNA sequence segments that will comprise the DNA molecule of user-defined sequence, separating the DNA sequence segments temporally, and combining the multiplicity of DNA sequence segments with at least one polymerase enzyme wherein the multiplicity of DNA sequence segments join to produce the DNA molecule of user-defined sequence. Sequence segments may be of length n, where n is an even or odd integer. In one embodiment the length of desired hybridizing overlap is specified by the user and the sequences and the protocol for combining them are guided by computational (bioinformatics) predictions. In one embodiment sequence segments are combined from multiple reading frames to span the same region of a sequence, so that multiple desired hybridizations may occur with different overlap lengths. In one embodiment starting sequence fragments are of different lengths, n, n+1, n+2, etc.

[Significance of revision of the occupational illness legislation for evaluating intervertebral disk damage].

PubMed

Weber, M; Morgenthaler, M

1997-01-01

Are there any radiological criterions which are able to indicate the profession related disease No. 2108? The medical documents and x-rays of the whole spine of 390 back pain patients who applied for a profession related disease of the spine were evaluated. Those patients who fulfilled the professional claims for acknowledgement of the profession related disease were compared to those who didn't fulfill these conditions. Concerning the segmental alterations of the cervical and the lumbal spine specific allocation frequencies were found. The dominance of L3/4 in the comparison group was conspicuous. Looking at the allocation frequencies of the cervical and lumbal disc alterations in view of affection heaviness it was obvious, that the predominating slight alterations mainly were located in the central parts of the cervical and the lumbal spine whereas bad alterations mainly were found in the lower parts. Regarding this matter test and comparison groups behaved the same way. Looking at the allocation frequencies concerning single respectively multiple alterations it was found that in the comparison group single respectively bisegmentale alterations could be recognized even in duplicate than in the test group in which the multiple alterations were dominant. The comparison of the cervical and the lumbal spine regarding chondrotic? spondylotic, slight and bad alterations in all mentioned features the next deeper located segment was affected particularly in the test group. Therefore a distal shift of the chondrotic alterations could be recognized. In case of the spondylotic affections it was the other way round: a cranial shift was conspicuous. After doing heavy labour for years only a few isolated multiple affections of the lumbal spine are found. On the strength of this fact the proof of exclusively in the lumbal spine located alterations doesn't allow the acknowledgement of a profession related disease. However, a distal shift of osteochondrotic alterations respectively a cranial shift of spondylotic affections in the lumbal spine is suspicous for being job-related. L3/4 takes a very special place in the differential diagnosis of profession related disease of the spine. In the test group this part of the lumbal spine showed bad alterations much more frequent. The affection of L3/4 pleads against a considerable participation of mechanical influences and therefore against a profession related disease. Singular or bisegmental disc affections are out of question for being a profession related disease because these alterations are seen much more frequent in the comparison than in the test group.

[Folate, vitamin B12 and human health].

PubMed

Brito, Alex; Hertrampf, Eva; Olivares, Manuel; Gaitán, Diego; Sánchez, Hugo; Allen, Lindsay H; Uauy, Ricardo

2012-11-01

During the past decade the role of folate and vitamin B12 in human nutrition have been under constant re-examination. Basic knowledge on the metabolism and interactions between these essential nutrients has expanded and multiple complexities have been unraveled. These micronutrients have shared functions and intertwined metabolic pathways that define the size of the "methyl donor" pool utilized in multiple metabolic pathways; these include DNA methylation and synthesis of nucleic acids. In Chile, folate deficiency is virtually nonexistent, while vitamin B12 deficiency affects approximately 8.5-51% depending on the cut-off value used to define deficiency. Folate is found naturally mainly in vegetables or added as folic acid to staple foods. Vitamin B12 in its natural form is present only in foods of animal origin, which is why deficit is more common among strict vegetarians and populations with a low intake of animal foods. Poor folate status in vulnerable women of childbearing age increases the risk of neural tube birth defects, so the critical time for the contribution of folic acid is several months before conception since neural tube closure occurs during the first weeks of life. The absorption of vitamin B12 from food is lower in older adults, who are considered to have higher risk of gastric mucosa atrophy, altered production of intrinsic factor and acid secretion. Deficiency of these vitamins is associated with hematological disorders. Vitamin B12 deficiency can also induce clinical and sub-clinical neurological and of other disorders. The purpose of this review is to provide an update on recent advances in the basic and applied knowledge of these vitamins relative to human health.

Prediction of outcome in newly diagnosed myeloma: a meta-analysis of the molecular profiles of 1905 trial patients

PubMed Central

Shah, V; Sherborne, A L; Walker, B A; Johnson, D C; Boyle, E M; Ellis, S; Begum, D B; Proszek, P Z; Jones, J R; Pawlyn, C; Savola, S; Jenner, M W; Drayson, M T; Owen, R G; Houlston, R S; Cairns, D A; Gregory, W M; Cook, G; Davies, F E; Jackson, G H; Morgan, G J; Kaiser, M F

2018-01-01

Robust establishment of survival in multiple myeloma (MM) and its relationship to recurrent genetic aberrations is required as outcomes are variable despite apparent similar staging. We assayed copy number alterations (CNA) and translocations in 1036 patients from the NCRI Myeloma XI trial and linked these to overall survival (OS) and progression-free survival. Through a meta-anlysis of these data with data from MRC Myeloma IX trial, totalling 1905 newly diagnosed MM patients (NDMM), we confirm the association of t(4;14), t(14;16), t(14;20), del(17p) and gain(1q21) with poor prognosis with hazard ratios (HRs) for OS of 1.60 (P=4.77 × 10−7), 1.74 (P=0.0005), 1.90 (P=0.0089), 2.10 (P=8.86 × 10−14) and 1.68 (P=2.18 × 10−14), respectively. Patients with ‘double-hit’ defined by co-occurrence of at least two adverse lesions have an especially poor prognosis with HRs for OS of 2.67 (P=8.13 × 10−27) for all patients and 3.19 (P=1.23 × 10−18) for intensively treated patients. Using comprehensive CNA and translocation profiling in Myeloma XI we also demonstrate a strong association between t(4;14) and BIRC2/BIRC3 deletion (P=8.7 × 10−15), including homozygous deletion. Finally, we define distinct sub-groups of hyperdiploid MM, with either gain(1q21) and CCND2 overexpression (P<0.0001) or gain(11q25) and CCND1 overexpression (P<0.0001). Profiling multiple genetic lesions can identify MM patients likely to relapse early allowing stratification of treatment. PMID:28584253

Single-cell systems level analysis of human Toll-Like-Receptor activation defines a chemokine signature in Systemic Lupus Erythematosus

PubMed Central

O'Gorman, William E.; Hsieh, Elena W.Y.; Savig, Erica S.; Gherardini, Pier Federico; Hernandez, Joseph D.; Hansmann, Leo; Balboni, Imelda M.; Utz, Paul J.; Bendall, Sean C.; Fantl, Wendy J.; Lewis, David B.; Nolan, Garry P.; Davis, Mark M.

2015-01-01

Background Activation of Toll-Like Receptors (TLRs) induces inflammatory responses involved in immunity to pathogens and autoimmune pathogenesis, such as in Systemic Lupus Erythematosus (SLE). Although TLRs are differentially expressed across the immune system, a comprehensive analysis of how multiple immune cell subsets respond in a system-wide manner has previously not been described. Objective To characterize TLR activation across multiple immune cell subsets and individuals, with the goal of establishing a reference framework against which to compare pathological processes. Methods Peripheral whole blood samples were stimulated with TLR ligands, and analyzed by mass cytometry simultaneously for surface marker expression, activation states of intracellular signaling proteins, and cytokine production. We developed a novel data visualization tool to provide an integrated view of TLR signaling networks with single-cell resolution. We studied seventeen healthy volunteer donors and eight newly diagnosed untreated SLE patients. Results Our data revealed the diversity of TLR-induced responses within cell types, with TLR ligand specificity. Subsets of NK and T cells selectively induced NF-κB in response to TLR2 ligands. CD14hi monocytes exhibited the most polyfunctional cytokine expression patterns, with over 80 distinct cytokine combinations. Monocytic TLR-induced cytokine patterns were shared amongst a group of healthy donors, with minimal intra- and inter- individual variability. Furthermore, autoimmune disease altered baseline cytokine production, as newly diagnosed untreated SLE patients shared a distinct monocytic chemokine signature, despite clinical heterogeneity. Conclusion Mass cytometry analysis defined a systems-level reference framework for human TLR activation, which can be applied to study perturbations in inflammatory disease, such as SLE. PMID:26037552

Traits, properties, and performance: how woody plants combine hydraulic and mechanical functions in a cell, tissue, or whole plant.

PubMed

Lachenbruch, Barbara; McCulloh, Katherine A

2014-12-01

This review presents a framework for evaluating how cells, tissues, organs, and whole plants perform both hydraulic and mechanical functions. The morphological alterations that affect dual functionality are varied: individual cells can have altered morphology; tissues can have altered partitioning to functions or altered cell alignment; and organs and whole plants can differ in their allocation to different tissues, or in the geometric distribution of the tissues they have. A hierarchical model emphasizes that morphological traits influence the hydraulic or mechanical properties; the properties, combined with the plant unit's environment, then influence the performance of that plant unit. As a special case, we discuss the mechanisms by which the proxy property wood density has strong correlations to performance but without direct causality. Traits and properties influence multiple aspects of performance, and there can be mutual compensations such that similar performance occurs. This compensation emphasizes that natural selection acts on, and a plant's viability is determined by, its performance, rather than its contributing traits and properties. Continued research on the relationships among traits, and on their effects on multiple aspects of performance, will help us better predict, manage, and select plant material for success under multiple stresses in the future. © 2014 The Authors. New Phytologist © 2014 New Phytologist Trust.

Decomposing Oncogenic Transcriptional Signatures to Generate Maps of Divergent Cellular States* | Office of Cancer Genomics

Cancer.gov

The systematic sequencing of the cancer genome has led to the identification of numerous genetic alterations in cancer. However, a deeper understanding of the functional consequences of these alterations is necessary to guide appropriate therapeutic strategies. Here, we describe Onco-GPS (OncoGenic Positioning System), a data-driven analysis framework to organize individual tumor samples with shared oncogenic alterations onto a reference map defined by their underlying cellular states.

Acting: An Altered State of Consciousness.

ERIC Educational Resources Information Center

Scheiffele, Eberhard

2001-01-01

Uses notions from the field Psychology of Consciousness, including an explanation of how psychologists define and investigate Altered States of Consciousness (ASCs). Argues that actors routinely enter an ASC. Establishes acting as a way to enter an ASC and discusses why theater artists, educators, and advocates need to be aware of both the dangers…

Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets

DOE PAGES

Schulze, Kornelius; Imbeaud, Sandrine; Letouzé, Eric; ...

2015-03-30

Our genomic analyses promise to improve tumor characterization to optimize personalized treatment for patients with hepatocellular carcinoma (HCC). Exome sequencing analysis of 243 liver tumors identified mutational signatures associated with specific risk factors, mainly combined alcohol and tobacco consumption and exposure to aflatoxin B1. We identified 161 putative driver genes associated with 11 recurrently altered pathways. Associations of mutations defined 3 groups of genes related to risk factors and centered on CTNNB1 (alcohol), TP53 (hepatitis B virus, HBV) and AXIN1. These analyses according to tumor stage progression identified TERT promoter mutation as an early event, whereasFGF3, FGF4, FGF19 or CCND1more » amplification and TP53 and CDKN2A alterations appeared at more advanced stages in aggressive tumors. In 28% of the tumors, we identified genetic alterations potentially targetable by US Food and Drug Administration (FDA)–approved drugs. Finally, we identified risk factor–specific mutational signatures and defined the extensive landscape of altered genes and pathways in HCC, which will be useful to design clinical trials for targeted therapy.« less

Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets

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

Schulze, Kornelius; Imbeaud, Sandrine; Letouzé, Eric

Our genomic analyses promise to improve tumor characterization to optimize personalized treatment for patients with hepatocellular carcinoma (HCC). Exome sequencing analysis of 243 liver tumors identified mutational signatures associated with specific risk factors, mainly combined alcohol and tobacco consumption and exposure to aflatoxin B1. We identified 161 putative driver genes associated with 11 recurrently altered pathways. Associations of mutations defined 3 groups of genes related to risk factors and centered on CTNNB1 (alcohol), TP53 (hepatitis B virus, HBV) and AXIN1. These analyses according to tumor stage progression identified TERT promoter mutation as an early event, whereasFGF3, FGF4, FGF19 or CCND1more » amplification and TP53 and CDKN2A alterations appeared at more advanced stages in aggressive tumors. In 28% of the tumors, we identified genetic alterations potentially targetable by US Food and Drug Administration (FDA)–approved drugs. Finally, we identified risk factor–specific mutational signatures and defined the extensive landscape of altered genes and pathways in HCC, which will be useful to design clinical trials for targeted therapy.« less

Elemental Abundance Distributions in Basalt Clays and Meteorites: Is It a Biosignature?

NASA Technical Reports Server (NTRS)

Fisk, M. R.; Storrie-Lombardi, M. C.; Joseph, J.

2005-01-01

Volcanic glass altered by microorganisms exhibits distinctive textures differing significantly from abiotic alteration [1-4]. We have previously presented morphological evidence of bioweathering in sub-oceanic basalt glass [5] and olivine [6], and noted similar alterations in Nakhla [7]. We have also introduced an autonomous Bayesian probabilistic classification methodology to identify biotic and abiotic alteration in sub-oceanic basalts using elemental abundance data [8]. We now present data from multiple sub-oceanic sites addressing the more general question of utilizing elemental abundance distribution in clays as a valid biosignature for the exploration of putative clay alteration products in meteorites.

Radiation damage-controlled localization of alteration haloes in albite: implications for alteration types and patterns vis-à-vis mineralization and element mobilization

NASA Astrophysics Data System (ADS)

Pal, D. C.; Chaudhuri, T.

2016-12-01

Uraninite, besides occurring in other modes, occurs as inclusions in albite in feldspathic schist in the Bagjata uranium deposits, Singhbhum shear zone, India. The feldspathic schist, considered the product of Na-metasomatism, witnessed multiple hydrothermal events, the signatures of which are preserved in the alteration halo in albite surrounding uraninite. Here we report radiation damage-controlled localization of alteration halo in albite and its various geological implications. Microscopic observation and SRIM/TRIM simulations reveal that the dimension of the alteration halo is dependent collectively on the zone of maximum cumulative α dose that albite was subjected to and by the extent of dissolution of uraninite during alteration. In well-preserved alteration haloes, from uraninite to the unaltered part of albite, the alteration minerals are systematically distributed in different zones; zone-1: K-feldspar; zone-2: chlorite; zone-3: LREE-phase/pyrite/U-Y-silicate. Based on textures of alteration minerals in the alteration microdomain, we propose a generalized Na+➔K+➔H+ alteration sequence, which is in agreement with the regional-scale alteration pattern. Integrating distribution of ore and alteration minerals in the alteration zone and their geochemistry, we further propose multiple events of U, REE, and sulfide mineralization/mobilization in the Bagjata deposit. The alteration process also involved interaction of the hydrothermal fluid with uraninite inclusions resulting in resorption of uraninite, redistribution of elements, including U and Pb, and resetting of isotopic clock. Thus, our study demonstrates that alteration halo is a miniature scale-model of the regional hydrothermal alteration types and patterns vis-à-vis mineralization/mobilization. This study further demonstrates that albite is vulnerable to radiation damage and damage-controlled fluid-assisted alteration, which may redistribute metals, including actinides, from radioactive minerals included in albite. This has important implications in geochronology. Such a study can also provide important clues to the chemical behavior of granite, in which albite is a common constituent, in a physico-chemical ambience analogous to a site of deep borehole disposal of radioactive waste.

Dendritic Spine Pathology in Schizophrenia

PubMed Central

Glausier, Jill R.; Lewis, David A.

2012-01-01

Schizophrenia is a neurodevelopmental disorder whose clinical features include impairments in perception, cognition and motivation. These impairments reflect alterations in neuronal circuitry within and across multiple brain regions that are due, at least in part, to deficits in dendritic spines, the site of most excitatory synaptic connections. Dendritic spine alterations have been identified in multiple brain regions in schizophrenia, but are best characterized in layer 3 of the neocortex, where pyramidal cell spine density is lower. These spine deficits appear to arise during development, and thus are likely the result of disturbances in the molecular mechanisms that underlie spine formation, pruning, and/or maintenance. Each of these mechanisms may provide insight into novel therapeutic targets for preventing or repairing the alterations in neural circuitry that mediate the debilitating symptoms of schizophrenia. PMID:22546337

Quercetin does not alter the oral bioavailability of Atorvastatin in rats.

PubMed

Koritala, Rekha; Challa, Siva Reddy; Ragam, Satheesh Kumar; Geddam, Lal Babu; Venkatesh Reddy Challa, Venkatesh Reddy; Devi, Renuka; Sattenapalli, Srinu; Babu, Narendra

2015-09-01

The study was undertaken to evaluate the effect of Quercetin on the pharmacokinetics of Atorvastatin Calcium. In-vivo Pharmacokinetic studies were performed on rats in a single dose study and multiple dose study. Rats were treated with Quercetin (10 mg/kg) and Atorvastatin Calcium (20 mg/kg) orally and blood samples were collected at (0) pretreatment and 0.5, 1, 1.5, 2, 2.5, 3, 4, 8, 12, 24 hours post treatment. Plasma concentrations of Atorvastatin were estimated by HPLC method. Quercetin treatment did not significantly alter the pharmacokinetic parameters of atorvastatin like AUC(0-24), AUC(0-α) , T(max), C(max) and T(½) in both single dose and multiple dose studies of Atorvastatin Calcium. Quercetin does not alter the oral bioavailability of Atorvastatin Calcium in rats.

Meeting the challenge of interacting threats in freshwater ecosystems: A call to scientists and managers

USGS Publications Warehouse

Craig, Laura S.; Olden, Julian D.; Arthington, Angela; Entrekin, Sally; Hawkins, Charles P.; Kelly, John J.; Kennedy, Theodore A.; Maitland, Bryan M.; Rosi, Emma J.; Roy, Allison; Strayer, David L.; Tank, Jennifer L.; West, Amie O.; Wooten, Matthew S.

2017-01-01

Human activities create threats that have consequences for freshwater ecosystems and, in most watersheds, observed ecological responses are the result of complex interactions among multiple threats and their associated ecological alterations. Here we discuss the value of considering multiple threats in research and management, offer suggestions for filling knowledge gaps, and provide guidance for addressing the urgent management challenges posed by multiple threats in freshwater ecosystems. There is a growing literature assessing responses to multiple alterations, and we build off this background to identify three areas that require greater attention: linking observed alterations to threats, understanding when and where threats overlap, and choosing metrics that best quantify the effects of multiple threats. Advancing science in these areas will help us understand existing ecosystem conditions and predict future risk from multiple threats. Because addressing the complex issues and novel ecosystems that arise from the interaction of multiple threats in freshwater ecosystems represents a significant management challenge, and the risks of management failure include loss of biodiversity, ecological goods, and ecosystem services, we also identify actions that could improve decision-making and management outcomes. These actions include drawing insights from management of individual threats, using threat attributes (e.g., causes and spatio-temporal dynamics) to identify suitable management approaches, testing management strategies that are likely to be successful despite uncertainties about the nature of interactions among threats, avoiding unintended consequences, and maximizing conservation benefits. We also acknowledge the broadly applicable challenges of decision-making within a socio-political and economic framework, and suggest that multidisciplinary teams will be needed to innovate solutions to meet the current and future challenge of interacting threats in freshwater ecosystems. 

Generating clock signals for a cycle accurate, cycle reproducible FPGA based hardware accelerator

DOEpatents

Asaad, Sameth W.; Kapur, Mohit

2016-01-05

A method, system and computer program product are disclosed for generating clock signals for a cycle accurate FPGA based hardware accelerator used to simulate operations of a device-under-test (DUT). In one embodiment, the DUT includes multiple device clocks generating multiple device clock signals at multiple frequencies and at a defined frequency ratio; and the FPG hardware accelerator includes multiple accelerator clocks generating multiple accelerator clock signals to operate the FPGA hardware accelerator to simulate the operations of the DUT. In one embodiment, operations of the DUT are mapped to the FPGA hardware accelerator, and the accelerator clock signals are generated at multiple frequencies and at the defined frequency ratio of the frequencies of the multiple device clocks, to maintain cycle accuracy between the DUT and the FPGA hardware accelerator. In an embodiment, the FPGA hardware accelerator may be used to control the frequencies of the multiple device clocks.

Preliminary report on the use of LANDSAT-1 (ERTS-1) reflectance data in locating alteration zones associated with uranium mineralization near Cameron, Arizona

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

Spirakis, C.S.; Condit, C.D.

1975-01-01

LANDSAT-1 (ERTS-1) multispectral reflectance data were used to enhance the detection of alteration around uranium deposits near Cameron, Ariz. The technique involved stretching and ratioing computer-enhanced data from which electronic noise and atmospheric haze had been removed. Using present techniques, the work proves that LANDSAT-1 data are useful in detecting alteration around uranium deposits, but the method may still be improved. Bluish-gray mudstone in the target area could not be differentiated from the altered zones on the ratioed images. Further experiments involving combinations of ratioed and nonratioed data will be required to uniquely define the altered zones.

Constitutively active transforming growth factor β receptor 1 in the mouse ovary promotes tumorigenesis

PubMed Central

Gao, Yang; Vincent, David F.; Davis, Anna Jane; Sansom, Owen J.; Bartholin, Laurent; Li, Qinglei

2016-01-01

Despite the well-established tumor suppressive role of TGFβ proteins, depletion of key TGFβ signaling components in the mouse ovary does not induce a growth advantage. To define the role of TGFβ signaling in ovarian tumorigenesis, we created a mouse model expressing a constitutively active TGFβ receptor 1 (TGFBR1) in ovarian somatic cells using conditional gain-of-function approach. Remarkably, these mice developed ovarian sex cord-stromal tumors with complete penetrance, leading to reproductive failure and mortality. The tumors expressed multiple granulosa cell markers and caused elevated serum inhibin and estradiol levels, reminiscent of granulosa cell tumors. Consistent with the tumorigenic effect, overactivation of TGFBR1 altered tumor microenvironment by promoting angiogenesis and enhanced ovarian cell proliferation, accompanied by impaired cell differentiation and dysregulated expression of critical genes in ovarian function. By further exploiting complementary genetic models, we substantiated our finding that constitutively active TGFBR1 is a potent oncogenic switch in mouse granulosa cells. In summary, overactivation of TGFBR1 drives gonadal tumor development. The TGFBR1 constitutively active mouse model phenocopies a number of morphological, hormonal, and molecular features of human granulosa cell tumors and are potentially valuable for preclinical testing of targeted therapies to treat granulosa cell tumors, a class of poorly defined ovarian malignancies. PMID:27344183

Excessive Heat Events and National Security: Building Resilience based on Early Warning Systems

NASA Astrophysics Data System (ADS)

Vintzileos, A.

2017-12-01

Excessive heat events (EHE) affect security of Nations in multiple direct and indirect ways. EHE are the top cause for morbidity/mortality associated to any atmospheric extremes. Higher energy consumption used for cooling can lead to black-outs and social disorder. EHE affect the food supply chain reducing crop yield and increasing the probability of food contamination during delivery and storage. Distribution of goods during EHE can be severely disrupted due to mechanical failure of transportation equipment. EHE during athletic events e.g., marathons, may result to a high number of casualties. Finally, EHE may also affect military planning by e.g. reducing hours of exercise and by altering combat gear. Early warning systems for EHE allow for building resilience. In this paper we first define EHE as at least two consecutive heat days; a heat day is defined as a day with a maximum heat index with probability of occurrence that exceeds a certain threshold. We then use retrospective forecasts performed with a multitude of operational models and show that it is feasible to forecast EHE at forecast lead of week-2 and week-3 over the contiguous United States. We finally introduce an improved definition of EHE based on an intensity index and investigate forecast skill of the predictive system in the tropics and subtropics.

Extracellular environment modulates the formation and propagation of particular amyloid structures

PubMed Central

Westergard, Laura; True, Heather L.

2016-01-01

Summary Amyloidogenic proteins, including prions, assemble into multiple forms of structurally distinct fibres. The [PSI+] prion, endogenous to the yeast Saccharomyces cerevisiae, is a dominantly inherited, epigenetic modifier of phenotypes. [PSI+] formation relies on the coexistence of another prion, [RNQ+]. Here, in order to better define the role of amyloid diversity on cellular phenotypes, we investigated how physiological and environmental changes impact the generation and propagation of diverse protein conformations from a single polypeptide. Utilizing the yeast model system, we defined extracellular factors that influence the formation of a spectrum of alternative self-propagating amyloid structures of the Sup35 protein, called [PSI+] variants. Strikingly, exposure to specific stressful environments dramatically altered the variants of [PSI+] that formed de novo. Additionally, we found that stress also influenced the association between the [PSI+] and [RNQ+] prions in a way that it superceded their typical relationship. Furthermore, changing the growth environment modified both the biochemical properties and [PSI+]-inducing capabilities of the [RNQ+] template. These data suggest that the cellular environment contributes to both the generation and the selective propagation of specific amyloid structures, providing insight into a key feature that impacts phenotypic diversity in yeast and the cross-species transmission barriers characteristic of prion diseases. PMID:24628771

The proinflammatory cytokine interleukin-18 alters multiple signaling pathways to inhibit natural killer cell death

USGS Publications Warehouse

Hodge, D.L.; Subleski, J.J.; Reynolds, D.A.; Buschman, M.D.; Schill, W.B.; Burkett, M.W.; Malyguine, A.M.; Young, H.A.

2006-01-01

The proinflammatory cytokine, interleukin-18 (IL-18), is a natural killer (NK) cell activator that induces NK cell cytotoxicity and interferon-?? (IFN-??) expression. In this report, we define a novel role for IL-18 as an NK cell protective agent. Specifically, IL-18 prevents NK cell death initiated by different and distinct stress mechanisms. IL-18 reduces NK cell self-destruction during NK-targeted cell killing, and in the presence of staurosporin, a potent apoptotic inducer, IL-18 reduces caspase-3 activity. The critical regulatory step in this process is downstream of the mitochondrion and involves reduced cleavage and activation of caspase-9 and caspase-3. The ability of IL-18 to regulate cell survival is not limited to a caspase death pathway in that IL-18 augments tumor necrosis factor (TNF) signaling, resulting in increased and prolonged mRNA expression of c-apoptosis inhibitor 2 (cIAP2), a prosurvival factor and caspase-3 inhibitor, and TNF receptor-associated factor 1 (TRAF1), a prosurvival protein. The cumulative effects of IL-18 define a novel role for this cytokine as a molecular survival switch that functions to both decrease cell death through inhibition of the mitochondrial apoptotic pathway and enhance TNF induction of prosurvival factors. ?? Mary Ann Liebert, Inc.

Alterations in taste perception due to recreational drug use are due to smoking a substance rather than ingesting it.

PubMed

Dovey, Terence M; Boyland, Emma J; Trayner, Penelope; Miller, Jo; Rarmoul-Bouhadjar, Amin; Cole, Jon; Halford, Jason C G

2016-12-01

Two studies explored the differences in tastant (salt, sour, bitter, sweet and spicy) concentration preference between recreational drug users and abstainers. In study 1, 250 opportunistically recruited abstainers, cannabis only users and multiple-drug users completed psychometric questionnaires and a concentration preference tastant test. In study 2, 76 participants purposefully recruited abstainers, daily tobacco users, recreational cannabis users and daily cannabis users completed the same protocol as study 1. Study 1 demonstrated that both multiple drug users and cannabis users had a higher preference for salt and sour tastants than abstainers. Study 2 showed that daily cannabis and tobacco users had a higher preference for sweet and spicy tastants than recreational cannabis users and abstainers. As predicted, recreational drug users scored higher on both sensation-seeking and impulsivity compared to abstainers. Participants who habitually smoke tobacco or cannabis daily have different concentration preference for specific tastants. The aim of the current study was to provide an explanation for the inconsistency in published results on taste preferences in recreational drug users. The data offered in this paper indicate that variation in recruitment strategy, definition of 'drug users', and mode of drug delivery, as well as multiple drug use, may explain the preference for stronger tastants in habitual drug users. Future research exploring the psychobiological underpinnings of the impact of drug use on food preferences should carefully define recreational drug user groups. Copyright © 2016 Elsevier Ltd. All rights reserved.

Evaluation of Spatial Pattern of Altered Flow Regimes on a River Network Using a Distributed Hydrological Model

PubMed Central

Ryo, Masahiro; Iwasaki, Yuichi; Yoshimura, Chihiro; Saavedra V., Oliver C.

2015-01-01

Alteration of the spatial variability of natural flow regimes has been less studied than that of the temporal variability, despite its ecological importance for river ecosystems. Here, we aimed to quantify the spatial patterns of flow regime alterations along a river network in the Sagami River, Japan, by estimating river discharge under natural and altered flow conditions. We used a distributed hydrological model, which simulates hydrological processes spatiotemporally, to estimate 20-year daily river discharge along the river network. Then, 33 hydrologic indices (i.e., Indicators of Hydrologic Alteration) were calculated from the simulated discharge to estimate the spatial patterns of their alterations. Some hydrologic indices were relatively well estimated such as the magnitude and timing of maximum flows, monthly median flows, and the frequency of low and high flow pulses. The accuracy was evaluated with correlation analysis (r > 0.4) and the Kolmogorov–Smirnov test (α = 0.05) by comparing these indices calculated from both observed and simulated discharge. The spatial patterns of the flow regime alterations varied depending on the hydrologic indices. For example, both the median flow in August and the frequency of high flow pulses were reduced by the maximum of approximately 70%, but these strongest alterations were detected at different locations (i.e., on the mainstream and the tributary, respectively). These results are likely caused by different operational purposes of multiple water control facilities. The results imply that the evaluation only at discharge gauges is insufficient to capture the alteration of the flow regime. Our findings clearly emphasize the importance of evaluating the spatial pattern of flow regime alteration on a river network where its discharge is affected by multiple water control facilities. PMID:26207997

Mapping the Margins in Higher Education: On the Promise of Intersectionality Frameworks in Research and Discourse

ERIC Educational Resources Information Center

Museus, Samuel D.; Griffin, Kimberly A.

2011-01-01

"Intersectionality" can be defined as the "relationships among multiple social dimensions and modalities of social relations and subject formations." In simpler terms, it can be defined as the processes through which multiple social identities converge and ultimately shape individual and group experiences. In this article, the authors discuss the…

Multiple methods integration for structural mechanics analysis and design

NASA Technical Reports Server (NTRS)

Housner, J. M.; Aminpour, M. A.

1991-01-01

A new research area of multiple methods integration is proposed for joining diverse methods of structural mechanics analysis which interact with one another. Three categories of multiple methods are defined: those in which a physical interface are well defined; those in which a physical interface is not well-defined, but selected; and those in which the interface is a mathematical transformation. Two fundamental integration procedures are presented that can be extended to integrate various methods (e.g., finite elements, Rayleigh Ritz, Galerkin, and integral methods) with one another. Since the finite element method will likely be the major method to be integrated, its enhanced robustness under element distortion is also examined and a new robust shell element is demonstrated.

Translating Music Intelligibly: Musical Paraphrase in the Long 20th Century

ERIC Educational Resources Information Center

Orosz, Jeremy White

2013-01-01

This dissertation is a study of the practice of musical paraphrase in the long 20th century. Musical paraphrase is defined as the adaptation, alteration, or embellishment of musical material, often borrowed from another source. My project is built around a single guiding question: If a composer borrows music from another source and alters it for…

Microglia in the developing brain: a potential target with lifetime effects

PubMed Central

Harry, G. Jean; Kraft, Andrew D.

2012-01-01

Microglia are a heterogeneous group of monocyte-derived cells serving multiple roles within the brain, many of which are associated with immune and macrophage like properties. These cells are known to serve a critical role during brain injury and to maintain homeostasis; yet, their defined roles during development have yet to be elucidated. Microglial actions appear to influence events associated with neuronal proliferation and differentiation during development, as well as, contribute to processes associated with the removal of dying neurons or cellular debris and management of synaptic connections. These long-lived cells display changes during injury and with aging that are critical to the maintenance of the neuronal environment over the lifespan of the organism. These processes may be altered by changes in the colonization of the brain or by inflammatory events during development. This review addresses the role of microglia during brain development, both structurally and functionally, as well as the inherent vulnerability of the developing nervous system. A framework is presented considering microglia as a critical nervous system-specific cell that can influence multiple aspects of brain development (e.g., vascularization, synaptogenesis, and myelination) and have a long term impact on the functional vulnerability of the nervous system to a subsequent insult, whether environmental, physical, age-related, or disease-related. PMID:22322212

FabH Mutations Confer Resistance to FabF-Directed Antibiotics in Staphylococcus aureus

PubMed Central

Parsons, Joshua B.; Yao, Jiangwei; Frank, Matthew W.

2014-01-01

Delineating the mechanisms for genetically acquired antibiotic resistance is a robust approach to target validation and anticipates the evolution of clinical drug resistance. This study defines a spectrum of mutations in fabH that render Staphylococcus aureus resistant to multiple natural products known to inhibit the elongation condensing enzyme (FabF) of bacterial type II fatty acid synthesis. Twenty independently isolated clones resistant to platensimycin, platencin, or thiolactomycin were isolated. All mutants selected against one antibiotic were cross-resistant to the other two antibiotics. Mutations were not detected in fabF, but the resistant strains harbored missense mutations in fabH. The altered amino acids clustered in and around the FabH active-site tunnel. The mutant FabH proteins were catalytically compromised based on the low activities of the purified enzymes, a fatty acid-dependent growth phenotype, and elevated expression of the fabHF operon in the mutant strains. Independent manipulation of fabF and fabH expression levels showed that the FabH/FabF activity ratio was a major determinant of antibiotic sensitivity. Missense mutations that reduce FabH activity are sufficient to confer resistance to multiple antibiotics that bind to the FabF acyl-enzyme intermediate in S. aureus. PMID:25403676

Inflammasomes link vascular disease with neuroinflammation and brain disorders

PubMed Central

Lénárt, Nikolett; Brough, David

2016-01-01

The role of inflammation in neurological disorders is increasingly recognised. Inflammatory processes are associated with the aetiology and clinical progression of migraine, psychiatric conditions, epilepsy, cerebrovascular diseases, dementia and neurodegeneration, such as seen in Alzheimer’s or Parkinson’s disease. Both central and systemic inflammatory actions have been linked with the development of brain diseases, suggesting that complex neuro-immune interactions could contribute to pathological changes in the brain across multiple temporal and spatial scales. However, the mechanisms through which inflammation impacts on neurological disease are improperly defined. To develop effective therapeutic approaches, it is imperative to understand how detrimental inflammatory processes could be blocked selectively, or controlled for prolonged periods, without compromising essential immune defence mechanisms. Increasing evidence indicates that common risk factors for brain disorders, such as atherosclerosis, diabetes, hypertension, obesity or infection involve the activation of NLRP3, NLRP1, NLRC4 or AIM2 inflammasomes, which are also associated with various neurological diseases. This review focuses on the mechanisms whereby inflammasomes, which integrate diverse inflammatory signals in response to pathogen-driven stimuli, tissue injury or metabolic alterations in multiple cell types and different organs of the body, could functionally link vascular- and neurological diseases and hence represent a promising therapeutic target. PMID:27486046

Pathophysiology of anorexia in the cancer cachexia syndrome

PubMed Central

Ezeoke, Chukwuemeka Charles; Morley, John E

2015-01-01

Anorexia is commonly present in persons with cancer and a major component of cancer cachexia. There are multiple causes of anorexia in cancer. Peripherally, these can be due to (i) substances released from or by the tumour, e.g. pro-inflammatory cytokines, lactate, and parathormone-related peptide; (ii) tumours causing dysphagia or altering gut function; (iii) tumours altering nutrients, e.g. zinc deficiency; (iv) tumours causing hypoxia; (v) increased peripheral tryptophan leading to increased central serotonin; or (vi) alterations of release of peripheral hormones that alter feeding, e.g. peptide tyrosine tyrosine and ghrelin. Central effects include depression and pain, decreasing the desire to eat. Within the central nervous system, tumours create multiple alterations in neurotransmitters, neuropeptides, and prostaglandins that modulate feeding. Many of these neurotransmitters appear to produce their anorectic effects through the adenosine monophosphate kinase/methylmalonyl coenzyme A/fatty acid system in the hypothalamus. Dynamin is a guanosine triphosphatase that is responsible for internalization of melanocortin 4 receptors and prostaglandin receptors. Dynamin is up-regulated in a mouse model of cancer anorexia. A number of drugs, e.g. megestrol acetate, cannabinoids, and ghrelin agonists, have been shown to have some ability to be orexigenic in cancer patients. PMID:26675762

Pathophysiology of anorexia in the cancer cachexia syndrome.

PubMed

Ezeoke, Chukwuemeka Charles; Morley, John E

2015-12-01

Anorexia is commonly present in persons with cancer and a major component of cancer cachexia. There are multiple causes of anorexia in cancer. Peripherally, these can be due to (i) substances released from or by the tumour, e.g. pro-inflammatory cytokines, lactate, and parathormone-related peptide; (ii) tumours causing dysphagia or altering gut function; (iii) tumours altering nutrients, e.g. zinc deficiency; (iv) tumours causing hypoxia; (v) increased peripheral tryptophan leading to increased central serotonin; or (vi) alterations of release of peripheral hormones that alter feeding, e.g. peptide tyrosine tyrosine and ghrelin. Central effects include depression and pain, decreasing the desire to eat. Within the central nervous system, tumours create multiple alterations in neurotransmitters, neuropeptides, and prostaglandins that modulate feeding. Many of these neurotransmitters appear to produce their anorectic effects through the adenosine monophosphate kinase/methylmalonyl coenzyme A/fatty acid system in the hypothalamus. Dynamin is a guanosine triphosphatase that is responsible for internalization of melanocortin 4 receptors and prostaglandin receptors. Dynamin is up-regulated in a mouse model of cancer anorexia. A number of drugs, e.g. megestrol acetate, cannabinoids, and ghrelin agonists, have been shown to have some ability to be orexigenic in cancer patients.

26 CFR 1.804-3 - Gross investment income of a life insurance company.

Code of Federal Regulations, 2010 CFR

2010-04-01

... insurance company. (a) Gross investment income defined. For purposes of part I, subchapter L, chapter 1 of the Code, section 804(b) defines the term gross investment income of a life insurance company as the... which the life insurance company may derive interest, rents, or royalties. (v) The alteration or...

Words Come in Families.

ERIC Educational Resources Information Center

Horowitz, Edward

This vocabulary enrichment book presents over 100 word roots of the English language. Each root is defined and its origin discussed. Words which derive from the roots are also defined and used in sentences which illustrate their meaning and usage. Over a thousand words are included in all, deriving from such roots as: allos, alter, ambul, arch,…

Defining Success in Adult Basic Education Settings: Multiple Stakeholders, Multiple Perspectives

PubMed Central

Tighe, Elizabeth L.; Barnes, Adrienne E.; Connor, Carol M.; Steadman, Sharilyn C.

2015-01-01

This study employed quantitative and qualitative research approaches to investigate what constitutes “success” in Adult Basic Education (ABE) programs from the perspectives of multiple educational stakeholders: the state funding agency, the teachers, and the students. Success was defined in multiple ways. In the quantitative section of the study, we computed classroom value-added scores (used as a metric of the state’s definition of success) to identify more and less effective ABE classrooms in two Florida counties. In the qualitative section of the study, we observed and conducted interviews with teachers and students in the selected classrooms to investigate how these stakeholders defined success in ABE. Iterative consideration of the qualitative data revealed three principal markers of success: (a) instructional strategies and teacher-student interactions; (b) views on standardized testing; and (c) student motivational factors. In general, classrooms with higher value-added scores were characterized by multiple instructional approaches, positive and collaborative teacher-student interactions, and students engaging in goal setting and citing motivational factors such as family and personal fulfillment. The implications for ABE programs are discussed. PMID:26279590

Hypothalamic digoxin, hemispheric chemical dominance, and oncogenesis: evidence from multiple myeloma.

PubMed

Kurup, Ravi Kumar; Kurup, Paramesware Achutha

2003-12-01

This study assessed the changes in the isoprenoid pathway and its metabolites digoxin, dolichol, and ubiquinone in multiple myeloma. The isoprenoid pathway and digoxin status were also studied for comparison in individuals of differing hemispheric dominance to find out the rote of cerebral dominance in the genesis of multiple myeloma and neoplasms. The following parameters were assessed: isoprenoid pathway metabolites, tyrosine and tryptophan catabolites, glycoconjugate metabolism, RBC membrane composition, and free radical metabolism--in multiple myeloma, as well as in individuals of differing hemispheric dominance. There was elevation in plasma HMG CoA reductase activity, serum digoxin, and dolichol, and a reduction in RBC membrane Na(+)-K+ ATPase activity, serum ubiquinone, and magnesium levels. Serum tryptophan, serotonin, nicotine, strychnine, and quinolinic acid were elevated, while tyrosine, dopamine, noradrenaline, and morphine were decreased. The total serum glycosaminoglycans and glycosaminoglycan fractions, the activity of GAG degrading enzymes and glycohydrolases, carbohydrate residues of glycoproteins, and serum glycolipids were elevated. The RBC membrane glycosaminoglycans, hexose, and fucose residues of glycoproteins, cholesterol, and phospholipids were reduced. The activity of all free-radical scavenging enzymes, concentration of glutathione, iron binding capacity, and ceruloplasmin decreased significantly, while the concentration of lipid peroxidation products and nitric oxide increased. Hyperdigoxinemia-related altered intracellular Ca++/Mg++ ratios mediated oncogene activation, dolichol-induced altered glycoconjugate metabolism, and ubiquinone deficiency-related mitochondrial dysfunction can contribute to the pathogenesis of multiple myeloma. The biochemical patterns obtained in multiple myeloma are similar to those obtained in left-handed/right hemispheric chemically dominant individuals by the dichotic listening test. But all the patients with multiple myeloma were right-handed/left hemispheric dominant by the dichotic listening test. Hemispheric chemical dominance has no correlation with handedness or the dichotic listening test. Multiple myeloma occurs in right hemispheric chemically dominant individuals and is a reflection of altered brain function.

Beyond a good story: from Hawthorne Effect to reactivity in health professions education research.

PubMed

Paradis, Elise; Sutkin, Gary

2017-01-01

Observational research is increasingly being used in health professions education (HPE) research, yet it is often criticised for being prone to observer effects (also known as the Hawthorne Effect), defined as a research participant's altered behaviour in response to being observed. This article explores this concern. First, this article briefly reviews the initial Hawthorne studies and the original formulation of the Hawthorne Effect, before turning to contemporary studies of the Hawthorne Effect in HPE and beyond. Second, using data from two observational studies (in the operating theatre and in the intensive care unit), this article investigates the Hawthorne Effect in HPE. Evidence of a Hawthorne Effect is scant, and amounts to little more than a good story. This is surprising given the foundational nature of the Hawthorne Studies in the social sciences and the prevalence of our concern with observer effects in HPE research. Moreover, the multiple and inconsistent uses of the Hawthorne Effect have left researchers without a coherent and helpful understanding of research participants' responses to observation. The authors' HPE research illustrates the complexity of observer effects in HPE, suggests that significant alteration of behaviour is unlikely in many research contexts, and shows how sustained contact with participants over time improves the quality of data collection. This article thus concludes with three recommendations: that researchers, editors and reviewers in the HPE community use the phrase 'participant reactivity' when considering the participant, observer and research question triad; that researchers invest in interpersonal relationships at their study site to mitigate the effects of altered behaviour; and that researchers use theory to make sense of participants' altered behaviour and use it as a window into the social world. The term 'participant reactivity' better reflects current scientific understandings of the research process and highlights the cognitive work required of participants to alter their behaviour when observed. Perhaps the most important lesson to be learned from the original Hawthorne experiments is the power of a good story (Levitt & List, 2011). © 2016 John Wiley & Sons Ltd and The Association for the Study of Medical Education.

Alterations of papilla dimensions after orthodontic closure of the maxillary midline diastema: a retrospective longitudinal study.

PubMed

Jeong, Jin-Seok; Lee, Seung-Youp; Chang, Moontaek

2016-06-01

The aim of this study was to evaluate alterations of papilla dimensions after orthodontic closure of the diastema between maxillary central incisors. Sixty patients who had a visible diastema between maxillary central incisors that had been closed by orthodontic approximation were selected for this study. Various papilla dimensions were assessed on clinical photographs and study models before the orthodontic treatment and at the follow-up examination after closure of the diastema. Influences of the variables assessed before orthodontic treatment on the alterations of papilla height (PH) and papilla base thickness (PBT) were evaluated by univariate regression analysis. To analyze potential influences of the 3-dimensional papilla dimensions before orthodontic treatment on the alterations of PH and PBT, a multiple regression model was formulated including the 3-dimensional papilla dimensions as predictor variables. On average, PH decreased by 0.80 mm and PBT increased after orthodontic closure of the diastema (P<0.01). Univariate regression analysis revealed that the PH (P=0.002) and PBT (P=0.047) before orthodontic treatment influenced the alteration of PH. With respect to the alteration of PBT, the diastema width (P=0.045) and PBT (P=0.000) were found to be influential factors. PBT before the orthodontic treatment significantly influenced the alteration of PBT in the multiple regression model. PH decreased but PBT increased after orthodontic closure of the diastema. The papilla dimensions before orthodontic treatment influenced the alterations of PH and PBT after closure of the diastema. The PBT increased more when the diastema width before the orthodontic treatment was larger.

Altered dopamine ontogeny in the developmentally vitamin D deficient rat and its relevance to schizophrenia.

PubMed

Kesby, James P; Cui, Xiaoying; Burne, Thomas H J; Eyles, Darryl W

2013-01-01

Schizophrenia is a heterogeneous group of disorders with unknown etiology. Although abnormalities in multiple neurotransmitter systems have been linked to schizophrenia, alterations in dopamine (DA) neurotransmission remain central to the treatment of this disorder. Given that schizophrenia is considered a neurodevelopmental disorder we have hypothesized that abnormal DA signaling in the adult patient may result from altered DA signaling during fetal brain development. Environmental and genetic risk factors can be modeled in rodents to allow for the investigation of early neurodevelopmental pathogenesis that may lead to clues into the etiology of schizophrenia. To address this we created an animal model of one such risk factor, developmental vitamin D (DVD) deficiency. DVD-deficient adult rats display an altered behavioral profile in response to DA releasing and blocking agents that are reminiscent of that seen in schizophrenia patients. Furthermore, developmental studies revealed that DVD deficiency also altered cell proliferation, apoptosis, and neurotransmission across the embryonic brain. In particular, DVD deficiency reduces the expression of crucial dopaminergic specification factors and alters DA metabolism in the developing brain. We speculate such alterations in fetal brain development may change the trajectory of DA neuron ontogeny to induce the behavioral abnormalities observed in adult offspring. The widespread evidence that both dopaminergic and structural changes are present in people who develop schizophrenia prior to onset also suggest that early alterations in development are central to the disease. Taken together, early alterations in DA ontogeny may represent a core feature in the pathology of schizophrenia. Such a mechanism could bring together evidence from multiple risk factors and genetic vulnerabilities to form a convergent pathway in disease pathophysiology.

Hypochlorite modification of sphingomyelin generates chlorinated lipid species that induce apoptosis and proteome alterations in dopaminergic PC12 neurons in vitro

PubMed Central

Nusshold, Christoph; Kollroser, Manfred; Köfeler, Harald; Rechberger, Gerald; Reicher, Helga; Üllen, Andreas; Bernhart, Eva; Waltl, Sabine; Kratzer, Ingrid; Hermetter, Albin; Hackl, Hubert; Trajanoski, Zlatko; Hrzenjak, Andelko; Malle, Ernst; Sattler, Wolfgang

2014-01-01

Recent observations link myeloperoxidase (MPO) activation to neurodegeneration. In multiple sclerosis MPO is present in areas of active demyelination where the potent oxidant hypochlorous acid (HOCl), formed by MPO from H2O2 and chloride ions, could oxidatively damage myelin-associated lipids. The purpose of this study was (i) to characterize reaction products of sphingomyelin (SM) formed in response to modification by HOCl, (ii) to define the impact of exogenously added SM and HOCl-modified SM (HOCl-SM) on viability parameters of a neuronal cell line (PC12), and (iii) to study alterations in the PC12 cell proteome in response to SM and HOCl-SM. MALDI-TOF-MS analyses revealed that HOCl, added as reagent or generated enzymatically, transforms SM into chlorinated species. On the cellular level HOCl-SM but not SM induced the formation of reactive oxygen species. HOCl-SM induced severely impaired cell viability, dissipation of the mitochondrial membrane potential, and activation of caspase-3 and DNA damage. Proteome analyses identified differential expression of specific subsets of proteins in response to SM and HOCl-SM. Our results demonstrate that HOCl modification of SM results in the generation of chlorinated lipid species with potent neurotoxic properties. Given the emerging connections between the MPO–H2O2–chloride axis and neurodegeneration, this chlorinating pathway might be implicated in neuropathogenesis. PMID:20226853

New insights on hereditary erythrocyte membrane defects.

PubMed

Andolfo, Immacolata; Russo, Roberta; Gambale, Antonella; Iolascon, Achille

2016-11-01

After the first proposed model of the red blood cell membrane skeleton 36 years ago, several additional proteins have been discovered during the intervening years, and their relationship with the pathogenesis of the related disorders have been somewhat defined. The knowledge of erythrocyte membrane structure is important because it represents the model for spectrin-based membrane skeletons in all cells and because defects in its structure underlie multiple hemolytic anemias. This review summarizes the main features of erythrocyte membrane disorders, dividing them into structural and altered permeability defects, focusing particularly on the most recent advances. New proteins involved in alterations of the red blood cell membrane permeability were recently described. The mechanoreceptor PIEZO1 is the largest ion channel identified to date, the fundamental regulator of erythrocyte volume homeostasis. Missense, gain-of-function mutations in the PIEZO1 gene have been identified in several families as causative of dehydrated hereditary stomatocytosis or xerocytosis. Similarly, the KCNN4 gene, codifying the so called Gardos channel, has been recently identified as a second causative gene of hereditary xerocytosis. Finally, ABCB6 missense mutations were identified in different pedigrees of familial pseudohyperkalemia. New genomic technologies have improved the quality and reduced the time of diagnosis of these diseases. Moreover, they are essential for the identification of the new causative genes. However, many questions remain to solve, and are currently objects of intensive studies. Copyright© Ferrata Storti Foundation.

New insights on hereditary erythrocyte membrane defects

PubMed Central

Andolfo, Immacolata; Russo, Roberta; Gambale, Antonella; Iolascon, Achille

2016-01-01

After the first proposed model of the red blood cell membrane skeleton 36 years ago, several additional proteins have been discovered during the intervening years, and their relationship with the pathogenesis of the related disorders have been somewhat defined. The knowledge of erythrocyte membrane structure is important because it represents the model for spectrin-based membrane skeletons in all cells and because defects in its structure underlie multiple hemolytic anemias. This review summarizes the main features of erythrocyte membrane disorders, dividing them into structural and altered permeability defects, focusing particularly on the most recent advances. New proteins involved in alterations of the red blood cell membrane permeability were recently described. The mechanoreceptor PIEZO1 is the largest ion channel identified to date, the fundamental regulator of erythrocyte volume homeostasis. Missense, gain-of-function mutations in the PIEZO1 gene have been identified in several families as causative of dehydrated hereditary stomatocytosis or xerocytosis. Similarly, the KCNN4 gene, codifying the so called Gardos channel, has been recently identified as a second causative gene of hereditary xerocytosis. Finally, ABCB6 missense mutations were identified in different pedigrees of familial pseudohyperkalemia. New genomic technologies have improved the quality and reduced the time of diagnosis of these diseases. Moreover, they are essential for the identification of the new causative genes. However, many questions remain to solve, and are currently objects of intensive studies. PMID:27756835

Targeted next generation sequencing of parotid gland cancer uncovers genetic heterogeneity.

PubMed

Grünewald, Inga; Vollbrecht, Claudia; Meinrath, Jeannine; Meyer, Moritz F; Heukamp, Lukas C; Drebber, Uta; Quaas, Alexander; Beutner, Dirk; Hüttenbrink, Karl-Bernd; Wardelmann, Eva; Hartmann, Wolfgang; Büttner, Reinhard; Odenthal, Margarete; Stenner, Markus

2015-07-20

Salivary gland cancer represents a heterogeneous group of malignant tumors. Due to their low incidence and the existence of multiple morphologically defined subtypes, these tumors are still poorly understood with regard to their molecular pathogenesis and therapeutically relevant genetic alterations.Performing a systematic and comprehensive study covering 13 subtypes of salivary gland cancer, next generation sequencing was done on 84 tissue samples of parotid gland cancer using multiplex PCR for enrichment of cancer related gene loci covering hotspots of 46 cancer genes.Mutations were identified in 22 different genes. The most frequent alterations affected TP53, followed by RAS genes, PIK3CA, SMAD4 and members of the ERB family. HRAS mutations accounted for more than 90% of RAS mutations, occurring especially in epithelial-myoepithelial carcinomas and salivary duct carcinomas. Additional mutations in PIK3CA also affected particularly epithelial-myoepithelial carcinomas and salivary duct carcinomas, occurring simultaneously with HRAS mutations in almost all cases, pointing to an unknown and therapeutically relevant molecular constellation. Interestingly, 14% of tumors revealed mutations in surface growth factor receptor genes including ALK, HER2, ERBB4, FGFR, cMET and RET, which might prove to be targetable by new therapeutic agents. 6% of tumors revealed mutations in SMAD4.In summary, our data provide novel insight into the fundamental molecular heterogeneity of salivary gland cancer, relevant in terms of tumor classification and the establishment of targeted therapeutic concepts.

The head and neck cancer cell oncogenome: a platform for the development of precision molecular therapies

PubMed Central

Martin, Daniel; Abba, Martin C.; Molinolo, Alfredo A.; Vitale-Cross, Lynn; Wang, Zhiyong; Zaida, Moraima; Delic, Naomi C.; Samuels, Yardena; Lyons, J. Guy; Gutkind, J. Silvio

2014-01-01

The recent elucidation of the genomic landscape of head and neck squamous cell carcinoma (HNSCC) has provided a unique opportunity to develop selective cancer treatment options. These efforts will require the establishment of relevant HNSCC models for preclinical testing. Here, we performed full exome and transcriptome sequencing of a large panel of HNSCC-derived cells from different anatomical locations and human papillomavirus (HPV) infection status. These cells exhibit typical mutations in TP53, FAT1, CDK2NA, CASP8, and NOTCH1, and copy number variations (CNVs) and mutations in PIK3CA, HRAS, and PTEN that reflect the widespread activation of the PI3K-mTOR pathway. SMAD4 alterations were observed that may explain the decreased tumor suppressive effect of TGF-β in HNSCC. Surprisingly, we identified HPV+ HNSCC cells harboring TP53 mutations, and documented aberrant TP53 expression in a subset of HPV+ HNSCC cases. This analysis also revealed that most HNSCC cells harbor multiple mutations and CNVs in epigenetic modifiers (e.g., EP300, CREBP, MLL1, MLL2, MLL3, KDM6A, and KDM6B) that may contribute to HNSCC initiation and progression. These genetically-defined experimental HNSCC cellular systems, together with the identification of novel actionable molecular targets, may now facilitate the pre-clinical evaluation of emerging therapeutic agents in tumors exhibiting each precise genomic alteration. PMID:25275298

Effects of flooding of the River Paraná on the temporal activity of Anopheles (Nyssorhynchus) darlingi Root (Diptera: Culicidae), at the border state of Mato Grosso do Sul and São Paulo, Brazil.

PubMed

Gomes, Almério de Castro; Paula, Marcia Bicudo de; Natal, Delsio; Gotlieb, Sabina Léa Davidson; Mucci, Luis Filipe

2010-01-01

Study of the temporal activity of malaria vectors during the implantation of a hydroelectric power station on the River Paraná, intended to generate electrical energy. The river separates the States of São Paulo and Mato Grosso do Sul, in Brazil. The objective was to verify whether alterations occurred in the wealth and diversity indices of Anopheles, following two successive floods, extended to the temporal activity and nycthemeral rhythm followed over a five year period. Mosquito capture was performed monthly using the Human Attraction Technique and Shannon Traps. The first, executed for 24h, provided the nycthemeral rhythm and the second, lasting 15 h, permitted the tracking of Anopheles during the two floods. The bimodal pattern of Anopheles darlingi defined before these floods was modified throughout the environment interventions. The same effect had repercussions on the populations of An albitarsis s.l., An triannulatus and An galvaoi. Activity prior to twilight was less affected by the environment alterations. The dam construction provoked changes in Anopheles temporal activity patterns, permitting classification of the area as an ecologically steady and unstable situation. Differences observed in Anopheles behavior due to the capture methods revealed the influence of solo and multiple attractiveness inside the populations studied.

Feedforward and Feedback Motor Control Abnormalities Implicate Cerebellar Dysfunctions in Autism Spectrum Disorder

PubMed Central

Mohanty, Suman; Greene, Rachel K.; Cook, Edwin H.; Vaillancourt, David E.; Sweeney, John A.

2015-01-01

Sensorimotor abnormalities are common in autism spectrum disorder (ASD) and among the earliest manifestations of the disorder. They have been studied far less than the social-communication and cognitive deficits that define ASD, but a mechanistic understanding of sensorimotor abnormalities in ASD may provide key insights into the neural underpinnings of the disorder. In this human study, we examined rapid, precision grip force contractions to determine whether feedforward mechanisms supporting initial motor output before sensory feedback can be processed are disrupted in ASD. Sustained force contractions also were examined to determine whether reactive adjustments to ongoing motor behavior based on visual feedback are altered. Sustained force was studied across multiple force levels and visual gains to assess motor and visuomotor mechanisms, respectively. Primary force contractions of individuals with ASD showed greater peak rate of force increases and large transient overshoots. Individuals with ASD also showed increased sustained force variability that scaled with force level and was more severe when visual gain was highly amplified or highly degraded. When sustaining a constant force level, their reactive adjustments were more periodic than controls, and they showed increased reliance on slower feedback mechanisms. Feedforward and feedback mechanism alterations each were associated with more severe social-communication impairments in ASD. These findings implicate anterior cerebellar circuits involved in feedforward motor control and posterior cerebellar circuits involved in transforming visual feedback into precise motor adjustments in ASD. PMID:25653359

Standing Genetic Variation in Contingency Loci Drives the Rapid Adaptation of Campylobacter jejuni to a Novel Host

PubMed Central

Jerome, John P.; Bell, Julia A.; Plovanich-Jones, Anne E.; Barrick, Jeffrey E.; Brown, C. Titus; Mansfield, Linda S.

2011-01-01

The genome of the food-borne pathogen Campylobacter jejuni contains multiple highly mutable sites, or contingency loci. It has been suggested that standing variation at these loci is a mechanism for rapid adaptation to a novel environment, but this phenomenon has not been shown experimentally. In previous work we showed that the virulence of C. jejuni NCTC11168 increased after serial passage through a C57BL/6 IL-10-/- mouse model of campylobacteriosis. Here we sought to determine the genetic basis of this adaptation during passage. Re-sequencing of the 1.64Mb genome to 200-500X coverage allowed us to define variation in 23 contingency loci to an unprecedented depth both before and after in vivo adaptation. Mutations in the mouse-adapted C. jejuni were largely restricted to the homopolymeric tracts of thirteen contingency loci. These changes cause significant alterations in open reading frames of genes in surface structure biosynthesis loci and in genes with only putative functions. Several loci with open reading frame changes also had altered transcript abundance. The increase in specific phases of contingency loci during in vivo passage of C. jejuni, coupled with the observed virulence increase and the lack of other types of genetic changes, is the first experimental evidence that these variable regions play a significant role in C. jejuni adaptation and virulence in a novel host. PMID:21283682

Potassium Channels in Epilepsy

PubMed Central

Köhling, Rüdiger; Wolfart, Jakob

2016-01-01

This review attempts to give a concise and up-to-date overview on the role of potassium channels in epilepsies. Their role can be defined from a genetic perspective, focusing on variants and de novo mutations identified in genetic studies or animal models with targeted, specific mutations in genes coding for a member of the large potassium channel family. In these genetic studies, a demonstrated functional link to hyperexcitability often remains elusive. However, their role can also be defined from a functional perspective, based on dynamic, aggravating, or adaptive transcriptional and posttranslational alterations. In these cases, it often remains elusive whether the alteration is causal or merely incidental. With ∼80 potassium channel types, of which ∼10% are known to be associated with epilepsies (in humans) or a seizure phenotype (in animals), if genetically mutated, a comprehensive review is a challenging endeavor. This goal may seem all the more ambitious once the data on posttranslational alterations, found both in human tissue from epilepsy patients and in chronic or acute animal models, are included. We therefore summarize the literature, and expand only on key findings, particularly regarding functional alterations found in patient brain tissue and chronic animal models. PMID:27141079

Two Novel Point Mutations in Clinical Staphylococcus aureus Reduce Linezolid Susceptibility and Switch on the Stringent Response to Promote Persistent Infection

PubMed Central

Gao, Wei; Chua, Kyra; Davies, John K.; Newton, Hayley J.; Seemann, Torsten; Harrison, Paul F.; Holmes, Natasha E.; Rhee, Hyun-Woo; Hong, Jong-In; Hartland, Elizabeth L.; Stinear, Timothy P.; Howden, Benjamin P.

2010-01-01

Staphylococcus aureus frequently invades the human bloodstream, leading to life threatening bacteremia and often secondary foci of infection. Failure of antibiotic therapy to eradicate infection is frequently described; in some cases associated with altered S. aureus antimicrobial resistance or the small colony variant (SCV) phenotype. Newer antimicrobials, such as linezolid, remain the last available therapy for some patients with multi-resistant S. aureus infections. Using comparative and functional genomics we investigated the molecular determinants of resistance and SCV formation in sequential S. aureus isolates from a patient who had a persistent and recurrent S. aureus infection, after failed therapy with multiple antimicrobials, including linezolid. Two point mutations in key staphylococcal genes dramatically affected clinical behaviour of the bacterium, altering virulence and antimicrobial resistance. Most strikingly, a single nucleotide substitution in relA (SACOL1689) reduced RelA hydrolase activity and caused accumulation of the intracellular signalling molecule guanosine 3′, 5′-bis(diphosphate) (ppGpp) and permanent activation of the stringent response, which has not previously been reported in S. aureus. Using the clinical isolate and a defined mutant with an identical relA mutation, we demonstrate for the first time the impact of an active stringent response in S. aureus, which was associated with reduced growth, and attenuated virulence in the Galleria mellonella model. In addition, a mutation in rlmN (SACOL1230), encoding a ribosomal methyltransferase that methylates 23S rRNA at position A2503, caused a reduction in linezolid susceptibility. These results reinforce the exquisite adaptability of S. aureus and show how subtle molecular changes cause major alterations in bacterial behaviour, as well as highlighting potential weaknesses of current antibiotic treatment regimens. PMID:20548948

Low-frequency connectivity is associated with mild traumatic brain injury.

PubMed

Dunkley, B T; Da Costa, L; Bethune, A; Jetly, R; Pang, E W; Taylor, M J; Doesburg, S M

2015-01-01

Mild traumatic brain injury (mTBI) occurs from a closed-head impact. Often referred to as concussion, about 20% of cases complain of secondary psychological sequelae, such as disorders of attention and memory. Known as post-concussive symptoms (PCS), these problems can severely disrupt the patient's quality of life. Changes in local spectral power, particularly low-frequency amplitude increases and/or peak alpha slowing have been reported in mTBI, but large-scale connectivity metrics based on inter-regional amplitude correlations relevant for integration and segregation in functional brain networks, and their association with disorders in cognition and behaviour, remain relatively unexplored. Here, we used non-invasive neuroimaging with magnetoencephalography to examine functional connectivity in a resting-state protocol in a group with mTBI (n = 20), and a control group (n = 21). We observed a trend for atypical slow-wave power changes in subcortical, temporal and parietal regions in mTBI, as well as significant long-range increases in amplitude envelope correlations among deep-source, temporal, and frontal regions in the delta, theta, and alpha bands. Subsequently, we conducted an exploratory analysis of patterns of connectivity most associated with variability in secondary symptoms of mTBI, including inattention, anxiety, and depression. Differential patterns of altered resting state neurophysiological network connectivity were found across frequency bands. This indicated that multiple network and frequency specific alterations in large scale brain connectivity may contribute to overlapping cognitive sequelae in mTBI. In conclusion, we show that local spectral power content can be supplemented with measures of correlations in amplitude to define general networks that are atypical in mTBI, and suggest that certain cognitive difficulties are mediated by disturbances in a variety of alterations in network interactions which are differentially expressed across canonical neurophysiological frequency ranges.

Resistance to pentamidine is mediated by AdeAB, regulated by AdeRS, and influenced by growth conditions in Acinetobacter baumannii ATCC 17978.

PubMed

Adams, Felise G; Stroeher, Uwe H; Hassan, Karl A; Marri, Shashikanth; Brown, Melissa H

2018-01-01

In recent years, effective treatment of infections caused by Acinetobacter baumannii has become challenging due to the ability of the bacterium to acquire or up-regulate antimicrobial resistance determinants. Two component signal transduction systems are known to regulate expression of virulence factors including multidrug efflux pumps. Here, we investigated the role of the AdeRS two component signal transduction system in regulating the AdeAB efflux system, determined whether AdeA and/or AdeB can individually confer antimicrobial resistance, and explored the interplay between pentamidine resistance and growth conditions in A. baumannii ATCC 17978. Results identified that deletion of adeRS affected resistance towards chlorhexidine and 4',6-diamidino-2-phenylindole dihydrochloride, two previously defined AdeABC substrates, and also identified an 8-fold decrease in resistance to pentamidine. Examination of ΔadeA, ΔadeB and ΔadeAB cells augmented results seen for ΔadeRS and identified a set of dicationic AdeAB substrates. RNA-sequencing of ΔadeRS revealed transcription of 290 genes were ≥2-fold altered compared to the wildtype. Pentamidine shock significantly increased adeA expression in the wildtype, but decreased it in ΔadeRS, implying that AdeRS activates adeAB transcription in ATCC 17978. Investigation under multiple growth conditions, including the use of Biolog phenotypic microarrays, revealed resistance to pentamidine in ATCC 17978 and mutants could be altered by bioavailability of iron or utilization of different carbon sources. In conclusion, the results of this study provide evidence that AdeAB in ATCC 17978 can confer intrinsic resistance to a subset of dicationic compounds and in particular, resistance to pentamidine can be significantly altered depending on the growth conditions.

Prognostic relevance of aberrant DNA methylation in g1 and g2 pancreatic neuroendocrine tumors.

PubMed

Stefanoli, Michele; La Rosa, Stefano; Sahnane, Nora; Romualdi, Chiara; Pastorino, Roberta; Marando, Alessandro; Capella, Carlo; Sessa, Fausto; Furlan, Daniela

2014-01-01

The occurrence and clinical relevance of DNA hypermethylation and global hypomethylation in pancreatic neuroendocrine tumours (PanNETs) are still unknown. We evaluated the frequency of both epigenetic alterations in PanNETs to assess the relationship between methylation profiles and chromosomal instability, tumour phenotypes and prognosis. In a well-characterized series of 56 sporadic G1 and G2 PanNETs, methylation-sensitive multiple ligation-dependent probe amplification was performed to assess hypermethylayion of 33 genes and copy number alterations (CNAs) of 53 chromosomal regions. Long interspersed nucleotide element-1 (LINE-1) hypomethylation was quantified by pyrosequencing. Unsupervised hierarchical clustering allowed to identify a subset of 22 PanNETs (39%) exhibiting high frequency of gene-specific methylation and low CNA percentages. This tumour cluster was significantly associated with stage IV (p = 0.04) and with poor prognosis in univariable analysis (p = 0.004). LINE-1 methylation levels in PanNETs were significantly lower than in normal samples (p < 0.01) and were approximately normally distributed. 12 tumours (21%) were highly hypomethylated, showing variable levels of CNA. Interestingly, only 5 PanNETs (9%) were observed to show simultaneously LINE-1 hypomethylation and high frequency of gene-specific methylation. LINE-1 hypomethylation was strongly correlated with advanced stage (p = 0.002) and with poor prognosis (p < 0.0001). In the multivariable analysis, low LINE-1 methylation status and methylation clusters were the only independent significant predictors of outcome (p = 0.034 and p = 0.029, respectively). The combination of global DNA hypomethylation and gene hypermethylation analyses may be useful to define distinct subsets of PanNETs. Both alterations are common in PanNETs and could be directly correlated with tumour progression. © 2014 S. Karger AG, Basel.

Sequential addition of short DNA oligos in DNA-polymerase-based synthesis reactions

DOEpatents

Gardner, Shea N; Mariella, Jr., Raymond P; Christian, Allen T; Young, Jennifer A; Clague, David S

2013-06-25

A method of preselecting a multiplicity of DNA sequence segments that will comprise the DNA molecule of user-defined sequence, separating the DNA sequence segments temporally, and combining the multiplicity of DNA sequence segments with at least one polymerase enzyme wherein the multiplicity of DNA sequence segments join to produce the DNA molecule of user-defined sequence. Sequence segments may be of length n, where n is an odd integer. In one embodiment the length of desired hybridizing overlap is specified by the user and the sequences and the protocol for combining them are guided by computational (bioinformatics) predictions. In one embodiment sequence segments are combined from multiple reading frames to span the same region of a sequence, so that multiple desired hybridizations may occur with different overlap lengths.

Mammalian Polyamine Metabolism and Function

PubMed Central

Pegg, Anthony E.

2009-01-01

Summary Polyamines are ubiquitous small basic molecules that play multiple essential roles in mammalian physiology. Their cellular content is highly regulated and there is convincing evidence that altered metabolism is involvement in many disease states. Drugs altering polyamine levels may therefore have a variety of important targets. This review will summarize the current state of understanding of polyamine metabolism and function, the regulation of polyamine content, and heritable pathological conditions that may be derived from altered polyamine metabolism. PMID:19603518

Al-Mg Isotopic Constraints on Alteration of Allende Ca-Al-rich Inclusions

NASA Astrophysics Data System (ADS)

Fagan, T. J.; Guan, Y.; MacPherson, G. J.

2006-03-01

Multiple stages of alteration of Allende CAIs are implied from SIMS analyses of Al-Mg isotopes in secondary minerals from one B2 and one FTA CAI. 26Mg-excesses are absent from most B2 analyses, but present in one B2 grossular and most FTA analyses.

Macroinvertebrate colonization dynamics on artificial substrates along an algal resource gradient

Treesearch

A. Braccia; S.L. Eggert; N. King

2014-01-01

Riparian canopy removal and land use may introduce multiple stressors that can alter food and habitat for stream organisms, but the influence of these alterations on macroinvertebrate colonization dynamics is less well known. A field study involving the simultaneous placement and removal of artificial substrates was performed to examine how macroinvertebrate...

Stand-level Allometry in Pinus taeda as Affected by Irrigation and Fertilization

Treesearch

J.S. King; T.J. Albaugh; H.L. Allen; L.W. Kress

1999-01-01

Changing environmental conditions have the potential to alter allometric relationships between plant parts, possibly leading to ecosystem-level feedbacks. We quantified allometric shifts in field-grown loblolly pine (Pinus taeda L.) in response to altered resource availability based on data from multiple harvests to correct for size-related changes...

The development and validation of EpiComet-Chip, a modified high-throughput comet assay for the assessment of DNA methylation status.

PubMed

Townsend, Todd A; Parrish, Marcus C; Engelward, Bevin P; Manjanatha, Mugimane G

2017-08-01

DNA damage and alterations in global DNA methylation status are associated with multiple human diseases and are frequently correlated with clinically relevant information. Therefore, assessing DNA damage and epigenetic modifications, including DNA methylation, is critical for predicting human exposure risk of pharmacological and biological agents. We previously developed a higher-throughput platform for the single cell gel electrophoresis (comet) assay, CometChip, to assess DNA damage and genotoxic potential. Here, we utilized the methylation-dependent endonuclease, McrBC, to develop a modified alkaline comet assay, "EpiComet," which allows single platform evaluation of genotoxicity and global DNA methylation [5-methylcytosine (5-mC)] status of single-cell populations under user-defined conditions. Further, we leveraged the CometChip platform to create an EpiComet-Chip system capable of performing quantification across simultaneous exposure protocols to enable unprecedented speed and simplicity. This system detected global methylation alterations in response to exposures which included chemotherapeutic and environmental agents. Using EpiComet-Chip on 63 matched samples, we correctly identified single-sample hypermethylation (≥1.5-fold) at 87% (20/23), hypomethylation (≥1.25-fold) at 100% (9/9), with a 4% (2/54) false-negative rate (FNR), and 10% (4/40) false-positive rate (FPR). Using a more stringent threshold to define hypermethylation (≥1.75-fold) allowed us to correctly identify 94% of hypermethylation (17/18), but increased our FPR to 16% (7/45). The successful application of this novel technology will aid hazard identification and risk characterization of FDA-regulated products, while providing utility for investigating epigenetic modes of action of agents in target organs, as the assay is amenable to cultured cells or nucleated cells from any tissue. Environ. Mol. Mutagen. 58:508-521, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Mutants of Arabidopsis thaliana with decreased amplitude in their phototropic response

NASA Technical Reports Server (NTRS)

Khurana, J. P.; Ren, Z.; Steinitz, B.; Parks, B.; Best, T. R.; Poff, K. L.

1989-01-01

Two mutants of Arabidopsis thaliana have been identified with decreased phototropism to 450-nanometer light. Fluence-response relationships for these strains (ZR8 and ZR19) to single and multiple flashes of light show thresholds, curve shapes, and fluence for maximum curvature in first positive' phototropism which are the same as those of the wild type. Similarly, there is no alteration from the wild type in the kinetics of curvature or in the optimum dark period separating sequential flashes in a multiple flash regimen. In addition, in both strains, gravitropism is decreased compared to the wild type by an amount which is comparable to the decrease in phototropism. Based on reciprocal backcrosses, it appears that the alteration is due to a recessive nuclear mutation. It is suggested that ZR8 and ZR19 represent alterations in some step analogous to an amplifier, downstream of the photoreceptor pigment, and common to both phototropism and gravitropism.

Targeting Plasmodium PI(4)K to eliminate malaria.

PubMed

McNamara, Case W; Lee, Marcus Cs; Lim, Chek Shik; Lim, Siau Hoi; Roland, Jason; Simon, Oliver; Yeung, Bryan Ks; Chatterjee, Arnab K; McCormack, Susan L; Manary, Micah J; Zeeman, Anne-Marie; Dechering, Koen J; Kumar, Tr Santha; Henrich, Philipp P; Gagaring, Kerstin; Ibanez, Maureen; Kato, Nobutaka; Kuhen, Kelli L; Fischli, Christoph; Nagle, Advait; Rottmann, Matthias; Plouffe, David M; Bursulaya, Badry; Meister, Stephan; Rameh, Lucia; Trappe, Joerg; Haasen, Dorothea; Timmerman, Martijn; Sauerwein, Robert W; Suwanarusk, Rossarin; Russell, Bruce; Renia, Laurent; Nosten, Francois; Tully, David C; Kocken, Clemens Hm; Glynne, Richard J; Bodenreider, Christophe; Fidock, David A; Diagana, Thierry T; Winzeler, Elizabeth A

2013-12-12

Achieving the goal of malaria elimination will depend on targeting Plasmodium pathways essential across all life stages. Here we identify a lipid kinase, phosphatidylinositol-4-OH kinase (PI(4)K), as the target of imidazopyrazines, a new antimalarial compound class that inhibits the intracellular development of multiple Plasmodium species at each stage of infection in the vertebrate host. Imidazopyrazines demonstrate potent preventive, therapeutic, and transmission-blocking activity in rodent malaria models, are active against blood-stage field isolates of the major human pathogens P. falciparum and P. vivax, and inhibit liver-stage hypnozoites in the simian parasite P. cynomolgi. We show that imidazopyrazines exert their effect through inhibitory interaction with the ATP-binding pocket of PI(4)K, altering the intracellular distribution of phosphatidylinositol-4-phosphate. Collectively, our data define PI(4)K as a key Plasmodium vulnerability, opening up new avenues of target-based discovery to identify drugs with an ideal activity profile for the prevention, treatment and elimination of malaria.

Single Molecule Analysis of Serotonin Transporter Regulation Using Antagonist-Conjugated Quantum Dots Reveals Restricted, p38 MAPK-Dependent Mobilization Underlying Uptake Activation

PubMed Central

Chang, Jerry C.; Tomlinson, Ian D.; Warnement, Michael R.; Ustione, Alessandro; Carneiro, Ana M. D.; Piston, David W.; Blakely, Randy D.; Rosenthal, Sandra J.

2012-01-01

The presynaptic serotonin (5-HT) transporter (SERT) is targeted by widely prescribed antidepressant medications. Altered SERT expression or regulation has been implicated in multiple neuropsychiatric disorders, including anxiety, depression and autism. Here, we implement a generalizable strategy that exploits antagonist-conjugated quantum dots (Qdots) to monitor, for the first time, single SERT proteins on the surface of serotonergic cells. We document two pools of SERT proteins defined by lateral mobility, one that exhibits relatively free diffusion, and a second, localized to cholesterol and GM1 ganglioside-enriched microdomains, that displays restricted mobility. Receptor-linked signalling pathways that enhance SERT activity mobilize transporters that, nonetheless, remain confined to membrane microdomains. Mobilization of transporters arise from a p38 MAPK-dependent untethering of the SERT C-terminus from the juxtamembrane actin cytoskeleton. Our studies establish the utility of ligand-conjugated Qdots for analysis of the behaviour of single membrane proteins and reveal a physical basis for signaling-mediated SERT regulation. PMID:22745492

Oceanographic and biological effects of shoaling of the oxygen minimum zone.

PubMed

Gilly, William F; Beman, J Michael; Litvin, Steven Y; Robison, Bruce H

2013-01-01

Long-term declines in oxygen concentrations are evident throughout much of the ocean interior and are particularly acute in midwater oxygen minimum zones (OMZs). These regions are defined by extremely low oxygen concentrations (<20-45 μmol kg(-1)), cover wide expanses of the ocean, and are associated with productive oceanic and coastal regions. OMZs have expanded over the past 50 years, and this expansion is predicted to continue as the climate warms worldwide. Shoaling of the upper boundaries of the OMZs accompanies OMZ expansion, and decreased oxygen at shallower depths can affect all marine organisms through multiple direct and indirect mechanisms. Effects include altered microbial processes that produce and consume key nutrients and gases, changes in predator-prey dynamics, and shifts in the abundance and accessibility of commercially fished species. Although many species will be negatively affected by these effects, others may expand their range or exploit new niches. OMZ shoaling is thus likely to have major and far-reaching consequences.

Prelamin A causes progeria through cell-extrinsic mechanisms and prevents cancer invasion

PubMed Central

de la Rosa, Jorge; Freije, José M. P.; Cabanillas, Rubén; Osorio, Fernando G.; Fraga, Mario F.; Fernández-García, M. Soledad; Rad, Roland; Fanjul, Víctor; Ugalde, Alejandro P.; Liang, Qi; Prosser, Haydn M.; Bradley, Allan; Cadiñanos, Juan; López-Otín, Carlos

2013-01-01

Defining the relationship between ageing and cancer is a crucial but challenging task. Mice deficient in Zmpste24, a metalloproteinase mutated in human progeria and involved in nuclear prelamin A maturation, recapitulate multiple features of ageing. However, their short lifespan and serious cell-intrinsic and cell-extrinsic alterations restrict the application and interpretation of carcinogenesis protocols. Here we present Zmpste24 mosaic mice that lack these limitations. Zmpste24 mosaic mice develop normally and keep similar proportions of Zmpste24-deficient (prelamin A accumulating) and Zmpste24-proficient (mature lamin A containing) cells throughout life, revealing that cell-extrinsic mechanisms are preeminent for progeria development. Moreover, prelamin A accumulation does not impair tumour initiation and growth, but it decreases the incidence of infiltrating oral carcinomas. Accordingly, silencing of ZMPSTE24 reduces human cancer cell invasiveness. Our results support the potential of cell-based and systemic therapies for progeria and highlight ZMPSTE24 as a new anticancer target. PMID:23917225

Targeting Plasmodium PI(4)K to eliminate malaria

NASA Astrophysics Data System (ADS)

McNamara, Case W.; Lee, Marcus C. S.; Lim, Chek Shik; Lim, Siau Hoi; Roland, Jason; Nagle, Advait; Simon, Oliver; Yeung, Bryan K. S.; Chatterjee, Arnab K.; McCormack, Susan L.; Manary, Micah J.; Zeeman, Anne-Marie; Dechering, Koen J.; Kumar, T. R. Santha; Henrich, Philipp P.; Gagaring, Kerstin; Ibanez, Maureen; Kato, Nobutaka; Kuhen, Kelli L.; Fischli, Christoph; Rottmann, Matthias; Plouffe, David M.; Bursulaya, Badry; Meister, Stephan; Rameh, Lucia; Trappe, Joerg; Haasen, Dorothea; Timmerman, Martijn; Sauerwein, Robert W.; Suwanarusk, Rossarin; Russell, Bruce; Renia, Laurent; Nosten, Francois; Tully, David C.; Kocken, Clemens H. M.; Glynne, Richard J.; Bodenreider, Christophe; Fidock, David A.; Diagana, Thierry T.; Winzeler, Elizabeth A.

2013-12-01

Achieving the goal of malaria elimination will depend on targeting Plasmodium pathways essential across all life stages. Here we identify a lipid kinase, phosphatidylinositol-4-OH kinase (PI(4)K), as the target of imidazopyrazines, a new antimalarial compound class that inhibits the intracellular development of multiple Plasmodium species at each stage of infection in the vertebrate host. Imidazopyrazines demonstrate potent preventive, therapeutic, and transmission-blocking activity in rodent malaria models, are active against blood-stage field isolates of the major human pathogens P. falciparum and P. vivax, and inhibit liver-stage hypnozoites in the simian parasite P. cynomolgi. We show that imidazopyrazines exert their effect through inhibitory interaction with the ATP-binding pocket of PI(4)K, altering the intracellular distribution of phosphatidylinositol-4-phosphate. Collectively, our data define PI(4)K as a key Plasmodium vulnerability, opening up new avenues of target-based discovery to identify drugs with an ideal activity profile for the prevention, treatment and elimination of malaria.

Inhibition-Based Biomarkers for Autism Spectrum Disorder.

PubMed

Levin, April R; Nelson, Charles A

2015-07-01

Autism spectrum disorder (ASD) is a behaviorally defined and heterogeneous disorder. Biomarkers for ASD offer the opportunity to improve prediction, diagnosis, stratification by severity and subtype, monitoring over time and in response to interventions, and overall understanding of the underlying biology of this disorder. A variety of potential biomarkers, from the level of genes and proteins to network-level interactions, is currently being examined. Many of these biomarkers relate to inhibition, which is of particular interest because in many cases ASD is thought to be a disorder of imbalance between excitation and inhibition. Abnormalities in inhibition at the cellular level lead to emergent properties in networks of neurons. These properties take into account a more complete genetic and cellular background than findings at the level of individual genes or cells, and are able to be measured in live humans, offering additional potential as diagnostic biomarkers and predictors of behaviors. In this review we provide examples of how altered inhibition may inform the search for ASD biomarkers at multiple levels, from genes to cells to networks.

Patterns of fMRI activity dissociate overlapping functional brain areas that respond to biological motion.

PubMed

Peelen, Marius V; Wiggett, Alison J; Downing, Paul E

2006-03-16

Accurate perception of the actions and intentions of other people is essential for successful interactions in a social environment. Several cortical areas that support this process respond selectively in fMRI to static and dynamic displays of human bodies and faces. Here we apply pattern-analysis techniques to arrive at a new understanding of the neural response to biological motion. Functionally defined body-, face-, and motion-selective visual areas all responded significantly to "point-light" human motion. Strikingly, however, only body selectivity was correlated, on a voxel-by-voxel basis, with biological motion selectivity. We conclude that (1) biological motion, through the process of structure-from-motion, engages areas involved in the analysis of the static human form; (2) body-selective regions in posterior fusiform gyrus and posterior inferior temporal sulcus overlap with, but are distinct from, face- and motion-selective regions; (3) the interpretation of region-of-interest findings may be substantially altered when multiple patterns of selectivity are considered.

A directed matched filtering algorithm (DMF) for discriminating hydrothermal alteration zones using the ASTER remote sensing data

NASA Astrophysics Data System (ADS)

Fereydooni, H.; Mojeddifar, S.

2017-09-01

This study introduced a different procedure to implement matched filtering algorithm (MF) on the ASTER images to obtain the distribution map of alteration minerals in the northwestern part of the Kerman Cenozoic Magmatic Arc (KCMA). This region contains many areas with porphyry copper mineralization such as Meiduk, Abdar, Kader, Godekolvari, Iju, Serenu, Chahfiroozeh and Parkam. Also argillization, sericitization and propylitization are the most common types of hydrothermal alteration in the area. Matched filtering results were provided for alteration minerals with a matched filtering score, called MF image. To identify the pixels which contain only one material (endmember), an appropriate threshold value should be used to the MF image. The chosen threshold classifies a MF image into background and target pixels. This article argues that the current thresholding process (the choice of a threshold) shows misclassification for MF image. To address the issue, this paper introduced the directed matched filtering (DMF) algorithm in which a spectral signature-based filter (SSF) was used instead of the thresholding process. SSF is a user-defined rule package which contains numeral descriptions about the spectral reflectance of alteration minerals. On the other hand, the spectral bands are defined by an upper and lower limit in SSF filter for each alteration minerals. SSF was developed for chlorite, kaolinite, alunite, and muscovite minerals to map alteration zones. The validation proved that, at first: selecting a contiguous range of MF values could not identify desirable results, second: unexpectedly, considerable frequency of pure pixels was observed in the MF scores less than threshold value. Also, the comparison between DMF results and field studies showed an accuracy of 88.51%.

Epigenetics Mechanisms in Alzheimer’s disease

PubMed Central

Mastroeni, Diego; Grover, Andrew; Delvaux, Elaine; Whiteside, Charisse; Coleman, Paul D.; Rogers, Joseph

2011-01-01

Epigenetic modifications help orchestrate sweeping developmental, aging, and disease-causing changes in phenotype by altering transcriptional activity in multiple genes spanning multiple biologic pathways. Although previous epigenetic research has focused primarily on dividing cells, particularly in cancer, recent studies have shown rapid, dynamic, and persistent epigenetic modifications in neurons that have significant neuroendocrine, neurophysiologic, and neurodegenerative consequences. Here, we provide a review of the major mechanisms for epigenetic modification and how they are reportedly altered in aging and Alzheimer’s disease (AD). Because of their reach across the genome, epigenetic mechanisms may provide a unique integrative framework for the pathologic diversity and complexity of AD. PMID:21482442

Developmental vitamin D deficiency alters multiple neurotransmitter systems in the neonatal rat brain.

PubMed

Kesby, James P; Turner, Karly M; Alexander, Suzanne; Eyles, Darryl W; McGrath, John J; Burne, Thomas H J

2017-11-01

Epidemiological evidence suggests that developmental vitamin D (DVD) deficiency is a risk factor for neuropsychiatric disorders, such as schizophrenia. DVD deficiency in rats is associated with altered brain structure and adult behaviours indicating alterations in dopamine and glutamate signalling. Developmental alterations in dopamine neurotransmission have also been observed in DVD-deficient rats but a comprehensive assessment of brain neurochemistry has not been undertaken. Thus, the current study determined the regional concentrations of dopamine, noradrenaline, serotonin, glutamine, glutamate and γ-aminobutyric acid (GABA), and associated metabolites, in DVD-deficient neonates. Sprague-Dawley rats were fed a vitamin D deficient diet or control diet six weeks prior to mating until birth and housed under UVB-free lighting conditions. Neurotransmitter concentration was assessed by high-performance liquid chromatography on post-mortem neonatal brain tissue. Ubiquitous reductions in the levels of glutamine (12-24%) were observed in DVD-deficient neonates compared with control neonates. Similarly, in multiple brain regions DVD-deficient neonates had increased levels of noradrenaline and serine compared with control neonates. In contrast, increased levels of dopamine and decreased levels of serotonin in DVD-deficient neonates were limited to striatal subregions compared with controls. Our results confirm that DVD deficiency leads to changes in multiple neurotransmitter systems in the neonate brain. Importantly, this regionally-based assessment in DVD-deficient neonates identified both widespread neurotransmitter changes (glutamine/noradrenaline) and regionally selective neurotransmitter changes (dopamine/serotonin). Thus, vitamin D may have both general and local actions depending on the neurotransmitter system being investigated. Taken together, these data suggest that DVD deficiency alters neurotransmitter systems relevant to schizophrenia in the developing rat brain. Copyright © 2017 ISDN. All rights reserved.

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

Response to Hostage Taking for Medium and Small Size Law Enforcement Agencies

DTIC Science & Technology

1992-01-01

Negotiator: Police officer specially trained in persuading a suspect to surrender to police and release hostages unharmed. Hypnosis : An altered state of...states (such as hypnosis and transcendental meditation) experience increased sensory perception. 26 James Frank, Persuasion and Healing (Baltimore...direct stimuli. 35 HYPNOSIS The notion of suggestibility is often linked with the hypnotic state. Hypnosis is defined as an altered state of

Impaired insulin signaling pathways affect ovarian steroidogenesis in cows with COD.

PubMed

Gareis, N C; Huber, E; Hein, G J; Rodríguez, F M; Salvetti, N R; Angeli, E; Ortega, H H; Rey, F

2018-05-01

Cystic ovarian disease (COD) represents an important cause of infertility in dairy cattle and is associated with multiple physiological disorders. Steroidogenesis, which is necessary to ensure normal ovarian functions, involves multiple enzymatic pathways coordinated by insulin and other proteins. We have previously shown that cows with COD have an altered insulin response. Therefore, in the present study, we evaluated further alterations in intermediates downstream of the PI3K pathway and pathways mediated by ERK as critical signals for the expression of steroidogenic enzymes in the ovaries of control cows and cows with spontaneous COD. To this end, we evaluated the gene and protein expression of pan-AKT, mTOR, ERK1/2, and steroidogenic enzymes by real-time PCR and immunohistochemistry. Steroid hormone concentrations were assessed at systemic and intrafollicular level. Results showed altered expression of intermediate molecules of the insulin signaling pathway, whose action might modify the synthetic pathway of steroidogenic hormones. Similarly, the expression of steroidogenic enzymes and the concentration of progesterone in serum and follicular fluid were altered. These alterations support the hypothesis that systemic factors contribute to the development and/or maintenance of COD, and that metabolic hormones within follicles such as insulin exert determinant effects on ovarian functionality in cows with COD. Copyright © 2018 Elsevier B.V. All rights reserved.

Changes in skeletal muscle gene expression consequent to altered weight bearing

NASA Technical Reports Server (NTRS)

Booth, F. W.; Kirby, C. R.

1992-01-01

Skeletal muscle is a dynamic organ that adapts to alterations in weight bearing. This brief review examines changes in muscle gene expression resulting from the removal of weight bearing by hindlimb suspension and from increased weight bearing due to eccentric exercise. Acute (less than or equal to 2 days) non-weight bearing of adult rat soleus muscle alters only the translational control of muscle gene expression, while chronic (greater than or equal to 7 days) removal of weight bearing appears to influence pretranslational, translational, and posttranslational mechanisms of control. Acute and chronic eccentric exercise are associated with alterations of translational and posttranslational control, while chronic eccentric training also alters the pretranslational control of muscle gene expression. Thus alterations in weight bearing influence multiple sites of gene regulation.

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.

Neonatal Pain-Related Stress Predicts Cortical Thickness at Age 7 Years in Children Born Very Preterm

PubMed Central

Ranger, Manon; Chau, Cecil M. Y.; Garg, Amanmeet; Woodward, Todd S.; Beg, Mirza Faisal; Bjornson, Bruce; Poskitt, Kenneth; Fitzpatrick, Kevin; Synnes, Anne R.; Miller, Steven P.; Grunau, Ruth E.

2013-01-01

Background Altered brain development is evident in children born very preterm (24–32 weeks gestational age), including reduction in gray and white matter volumes, and thinner cortex, from infancy to adolescence compared to term-born peers. However, many questions remain regarding the etiology. Infants born very preterm are exposed to repeated procedural pain-related stress during a period of very rapid brain development. In this vulnerable population, we have previously found that neonatal pain-related stress is associated with atypical brain development from birth to term-equivalent age. Our present aim was to evaluate whether neonatal pain-related stress (adjusted for clinical confounders of prematurity) is associated with altered cortical thickness in very preterm children at school age. Methods 42 right-handed children born very preterm (24–32 weeks gestational age) followed longitudinally from birth underwent 3-D T1 MRI neuroimaging at mean age 7.9 yrs. Children with severe brain injury and major motor/sensory/cognitive impairment were excluded. Regional cortical thickness was calculated using custom developed software utilizing FreeSurfer segmentation data. The association between neonatal pain-related stress (defined as the number of skin-breaking procedures) accounting for clinical confounders (gestational age, illness severity, infection, mechanical ventilation, surgeries, and morphine exposure), was examined in relation to cortical thickness using constrained principal component analysis followed by generalized linear modeling. Results After correcting for multiple comparisons and adjusting for neonatal clinical factors, greater neonatal pain-related stress was associated with significantly thinner cortex in 21/66 cerebral regions (p-values ranged from 0.00001 to 0.014), predominately in the frontal and parietal lobes. Conclusions In very preterm children without major sensory, motor or cognitive impairments, neonatal pain-related stress appears to be associated with thinner cortex in multiple regions at school age, independent of other neonatal risk factors. PMID:24204657

Alterations of papilla dimensions after orthodontic closure of the maxillary midline diastema: a retrospective longitudinal study

PubMed Central

2016-01-01

Purpose The aim of this study was to evaluate alterations of papilla dimensions after orthodontic closure of the diastema between maxillary central incisors. Methods Sixty patients who had a visible diastema between maxillary central incisors that had been closed by orthodontic approximation were selected for this study. Various papilla dimensions were assessed on clinical photographs and study models before the orthodontic treatment and at the follow-up examination after closure of the diastema. Influences of the variables assessed before orthodontic treatment on the alterations of papilla height (PH) and papilla base thickness (PBT) were evaluated by univariate regression analysis. To analyze potential influences of the 3-dimensional papilla dimensions before orthodontic treatment on the alterations of PH and PBT, a multiple regression model was formulated including the 3-dimensional papilla dimensions as predictor variables. Results On average, PH decreased by 0.80 mm and PBT increased after orthodontic closure of the diastema (P<0.01). Univariate regression analysis revealed that the PH (P=0.002) and PBT (P=0.047) before orthodontic treatment influenced the alteration of PH. With respect to the alteration of PBT, the diastema width (P=0.045) and PBT (P=0.000) were found to be influential factors. PBT before the orthodontic treatment significantly influenced the alteration of PBT in the multiple regression model. Conclusions PH decreased but PBT increased after orthodontic closure of the diastema. The papilla dimensions before orthodontic treatment influenced the alterations of PH and PBT after closure of the diastema. The PBT increased more when the diastema width before the orthodontic treatment was larger. PMID:27382507

Molecular genetic anatomy of inter- and intraserotype variation in the human bacterial pathogen group A Streptococcus.

PubMed

Beres, Stephen B; Richter, Ellen W; Nagiec, Michal J; Sumby, Paul; Porcella, Stephen F; DeLeo, Frank R; Musser, James M

2006-05-02

In recent years we have studied the relationship between strain genotypes and patient phenotypes in group A Streptococcus (GAS), a model human bacterial pathogen that causes extensive morbidity and mortality worldwide. We have concentrated our efforts on serotype M3 organisms because these strains are common causes of pharyngeal and invasive infections, produce unusually severe invasive infections, and can exhibit epidemic behavior. Our studies have been hindered by the lack of genome-scale phylogenies of multiple GAS strains and whole-genome sequences of multiple serotype M3 strains recovered from individuals with defined clinical phenotypes. To remove some of these impediments, we sequenced to closure the genome of four additional GAS strains and conducted comparative genomic resequencing of 12 contemporary serotype M3 strains representing distinct genotypes and phenotypes. Serotype M3 strains are a single phylogenetic lineage. Strains from asymptomatic throat carriers were significantly less virulent for mice than sterile-site isolates and evolved to a less virulent phenotype by multiple genetic pathways. Strain persistence or extinction between epidemics was strongly associated with presence or absence, respectively, of the prophage encoding streptococcal pyrogenic exotoxin A. A serotype M3 clone significantly underrepresented among necrotizing fasciitis cases has a unique frameshift mutation that truncates MtsR, a transcriptional regulator controlling expression of genes encoding iron-acquisition proteins. Expression microarray analysis of this clone confirmed significant alteration in expression of genes encoding iron metabolism proteins. Our analysis provided unprecedented detail about the molecular anatomy of bacterial strain genotype-patient phenotype relationships.

Early clinical observations on the use of imatinib mesylate in FOP: A report of seven cases.

PubMed

Kaplan, Frederick S; Andolina, Jeffrey R; Adamson, Peter C; Teachey, David T; Finklestein, Jerry Z; Ebb, David H; Whitehead, Benjamin; Jacobs, Benjamin; Siegel, David M; Keen, Richard; Hsiao, Edward; Pignolo, Robert J

2018-04-01

Fibrodysplasia ossificans progressiva (FOP) is an ultrarare genetic disorder of progressive, disabling heterotopic ossification (HO) for which there is presently no definitive treatment. Research studies have identified multiple potential targets for therapy in FOP, and novel drug candidates are being developed for testing in clinical trials. A complementary approach seeks to identify approved drugs that could be re-purposed for off-label use against defined targets in FOP. One such drug is imatinib mesylate, a tyrosine kinase inhibitor originally developed for use in patients with chronic myeloid leukemia (CML). Imatinib has the desirable effect of attacking multiple targets involved in the early hypoxic and inflammatory stages of FOP flare-ups, including HIF1-α, PDGFRα, c-KIT, and multiple MAP kinases. Based on compelling biologic rationale, strong preclinical data, and a favorable safety profile, imatinib has been prescribed on an off-label basis in a non-trial setting in seven children with continuous FOP flare-ups, predominantly in the axial regions, and which were not responsive to standard-of-care regimens. Anecdotal reports in these seven isolated cases document that the medication was well-tolerated with a ubiquitous reported decrease in the intensity of flare-ups in the six children who took the medication. These early clinical observations support the implementation of clinical trials in children with uncontrolled FOP flare-ups to determine if imatinib may ameliorate symptoms or alter the natural history of this debilitating and life-threatening disease. Copyright © 2017 Elsevier Inc. All rights reserved.

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…

Heterocyclic Salt Synthesis and Rational Properties Tailoring (PREPRINT)

DTIC Science & Technology

2009-06-23

performance behavior can be tailored in a controlled manner, defines the objective of a pertinent synthesis effort. Achieving this objective by...the structure of the anion. To illustrate this premise, four general synthesis methods to synthesize heterocyclic salts, including several new binary...manner, defines the objective of a pertinent synthesis effort. Achieving this objective by introducing structural alterations in a neutral covalent

Drought and increased CO2 alter floral visual and olfactory traits with context-dependent effects on pollinator visitation

Treesearch

William R. Glenny; Justin B. Runyon; Laura A. Burkle

2018-01-01

Climate change can alter species interactions essential for maintaining biodiversity and ecosystem function, such as pollination. Understanding the interactive effects of multiple abiotic conditions on floral traits and pollinator visitation are important to anticipate the implications of climate change on pollinator services. Floral visual and olfactory traits were...

Invasions by two non-native insects alter regional forest species composition and successional trajectories

Treesearch

Randall S. Morin; Andrew M. Liebhold

2015-01-01

While invasions of individual non-native phytophagous insect species are known to affect growth and mortality of host trees, little is known about how multiple invasions combine to alter forest dynamics over large regions. In this study we integrate geographical data describing historical invasion spread of the hemlock woolly adelgid, Adelges tsugae...

Wasatch and Uinta Mountains Ecoregion: Chapter 9 in Status and trends of land change in the Western United States--1973 to 2000

USGS Publications Warehouse

Brooks, Mark S.

2012-01-01

The Wasatch and Uinta Mountains Ecoregion covers approximately 44,176 km2 (17, 057 mi2) (fig. 1) (Omernik, 1987; U.S. Environmental Protection Agency, 1997). With the exception of a small part of the ecoregion extending into southern Wyoming and southern Idaho, the vast majority of the ecoregion is located along the eastern mountain ranges of Utah. The ecoregion is situated between the Wyoming Basin and Colorado Plateaus Ecoregions to the east and south and the Central Basin and Range Ecoregion to the west; in addition, the Middle Rockies, Snake River Basin, and Northern Basin and Range Ecoregions are nearby to the north. Considered the western front of the Rocky Mountains, the two major mountain ranges that define the Wasatch and Uinta Mountains Ecoregion include the north-south-trending Wasatch Range and east-west- trending Uinta Mountains. Both mountain ranges have been altered by multiple mountain building and burial cycles since the Precambrian era 2.6 billion years ago, and they have been shaped by glacial processes as early as 1.6 million years ago. The terrain is defined by sharp ridgelines, glacial lakes, and narrow canyons, with elevations ranging from 1,829 m in the lower canyons to 4,123 m at Kings Peak, the highest point in Utah (Milligan, 2010).

Heart rate variability is differentially altered in multiple sclerosis: implications for acute, worsening and progressive disability.

PubMed

Studer, Valeria; Rocchi, Camilla; Motta, Caterina; Lauretti, Benedetta; Perugini, Jacopo; Brambilla, Laura; Pareja-Gutierrez, Lorena; Camera, Giorgia; Barbieri, Francesca Romana; Marfia, Girolama A; Centonze, Diego; Rossi, Silvia

2017-01-01

Sympathovagal imbalance has been associated with poor prognosis in chronic diseases, but there is conflicting evidence in multiple sclerosis. The objective of this study was to investigate the autonomic nervous system dysfunction correlation with inflammation and progression in multiple sclerosis. Heart rate variability was analysed in 120 multiple sclerosis patients and 60 healthy controls during supine rest and head-up tilt test; the normalised units of low frequency and high frequency power were considered to assess sympathetic and vagal components, respectively. Correlation analyses with clinical and radiological markers of disease activity and progression were performed. Sympathetic dysfunction was closely related to the progression of disability in multiple sclerosis: progressive patients showed altered heart rate variability with respect to healthy controls and relapsing-remitting patients, with higher rest low frequency power and lacking the expected low frequency power increase during the head-up tilt test. In relapsing-remitting patients, disease activity, even subclinical, was associated with lower rest low frequency power, whereas stable relapsing-remitting patients did not differ from healthy controls. Less sympathetic reactivity and higher low frequency power at rest were associated with incomplete recovery from relapse. Autonomic balance appears to be intimately linked with both the inflammatory activity of multiple sclerosis, which is featured by an overall hypoactivity of the sympathetic nervous system, and its compensatory plastic processes, which appear inefficient in case of worsening and progressive multiple sclerosis.

Systematic review and meta-analysis of single-balloon enteroscopy-assisted ERCP in patients with surgically altered GI anatomy.

PubMed

Inamdar, Sumant; Slattery, Eoin; Sejpal, Divyesh V; Miller, Larry S; Pleskow, Douglas K; Berzin, Tyler M; Trindade, Arvind J

2015-07-01

Surgically altered pancreaticobiliary anatomy increases the difficulty of performing ERCP. Single-balloon enteroscopy (SBE) is a relatively new technique that can be used for ERCP in patients with surgically altered anatomy. To evaluate the therapeutic and diagnostic success of SBE-ERCP among patients with surgically altered anatomy. Systematic review and meta-analysis of studies involving SBE-ERCP in patients with Roux-en-Y gastric bypass, hepaticojejunostomy, or Whipple procedure. Enteroscopy success was defined as success in reaching the papilla and/or biliary anastomosis by using SBE. Diagnostic success was defined as obtaining a cholangiogram. Procedural success was defined as the ability to provide successful intervention, if appropriate. A random-effects model was used. A total of 461 patients underwent SBE-ERCP from 15 trials. The pooled enteroscopy, diagnostic, and procedural success rates were 80.9% (95% confidence interval [CI], 75.3%-86.4%), 69.4% (95% CI, 61.0%-77.9%), and 61.7% (95% CI, 52.9%-70.5%), respectively. There was statistical large heterogeneity for enteroscopy, diagnostic, and therapeutic success (P < .001 for all). Adverse events occurred in 6.5% (95% CI, 4.7%-9.1%) of patients. There was no evidence of publication bias in this meta-analysis. Our findings and interpretations are limited by the quantity and heterogeneity of the studies included in the analysis. SBE-ERCP has high diagnostic and procedural success rates in this challenging patient population. It should be considered a first-line intervention when biliary access is required after Roux-en-Y gastric bypass, hepaticojejunostomy, or Whipple procedure. Copyright © 2015 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.

Beta/Gamma Oscillations and Event-Related Potentials Indicate Aberrant Multisensory Processing in Schizophrenia

PubMed Central

Balz, Johanna; Roa Romero, Yadira; Keil, Julian; Krebber, Martin; Niedeggen, Michael; Gallinat, Jürgen; Senkowski, Daniel

2016-01-01

Recent behavioral and neuroimaging studies have suggested multisensory processing deficits in patients with schizophrenia (SCZ). Thus far, the neural mechanisms underlying these deficits are not well understood. Previous studies with unisensory stimulation have shown altered neural oscillations in SCZ. As such, altered oscillations could contribute to aberrant multisensory processing in this patient group. To test this assumption, we conducted an electroencephalography (EEG) study in 15 SCZ and 15 control participants in whom we examined neural oscillations and event-related potentials (ERPs) in the sound-induced flash illusion (SIFI). In the SIFI multiple auditory stimuli that are presented alongside a single visual stimulus can induce the illusory percept of multiple visual stimuli. In SCZ and control participants we compared ERPs and neural oscillations between trials that induced an illusion and trials that did not induce an illusion. On the behavioral level, SCZ (55.7%) and control participants (55.4%) did not significantly differ in illusion rates. The analysis of ERPs revealed diminished amplitudes and altered multisensory processing in SCZ compared to controls around 135 ms after stimulus onset. Moreover, the analysis of neural oscillations revealed altered 25–35 Hz power after 100 to 150 ms over occipital scalp for SCZ compared to controls. Our findings extend previous observations of aberrant neural oscillations in unisensory perception paradigms. They suggest that altered ERPs and altered occipital beta/gamma band power reflect aberrant multisensory processing in SCZ. PMID:27999553

A Technical Approach to Expedited Processing of NTPR Radiation Dose Assessments

DTIC Science & Technology

2011-10-01

Pharynx ET Region+ Surrogate Oral Cavity and Pharynx (140-149) None PNLGL Pineal Gland Brain Surrogate Other Endocrine Glands (194) PITTGL PITTGL...including brain); endocrine glands other than thyroid; other and ill-defined sites; lymphoma and multiple myeloma Risk depends on age at exposure...endocrine glands 14 45 Cancers of other and ill-defined sites 16 50 Lymphoma and multiple myeloma 22 61 Leukemia, excluding CLL 1.9 (5 years) 41

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

Time Average Holography Study of Human Tympanic Membrane with Altered Middle Ear Ossicular Chain

NASA Astrophysics Data System (ADS)

Cheng, Jeffrey T.; Ravicz, Michael E.; Rosowski, John J.; Hulli, Nesim; Hernandez-Montes, Maria S.; Furlong, Cosme

2009-02-01

Computer-assisted time average holographic interferometry was used to study the vibration of the human tympanic membrane (TM) in cadaveric temporal bones before and after alterations of the ossicular chain. Simultaneous laser Doppler vibrometer measurements of stapes velocity were performed to estimate the conductive hearing loss caused by ossicular alterations. The quantified TM motion described from holographic images was correlated with stapes velocity to define relations between TM motion and stapes velocity in various ossicular disorders. The results suggest that motions of the TM are relatively uncoupled from stapes motion at frequencies above 1000 Hz.

White matter microstructural alterations in clinically isolated syndrome and multiple sclerosis.

PubMed

Huang, Jing; Liu, Yaou; Zhao, Tengda; Shu, Ni; Duan, Yunyun; Ren, Zhuoqiong; Sun, Zheng; Liu, Zheng; Chen, Hai; Dong, Huiqing; Li, Kuncheng

2018-07-01

This study aims to determine whether and how diffusion alteration occurs in the earliest stage of multiple sclerosis (MS) and the differences in diffusion metrics between CIS and MS by using the tract-based spatial statistics (TBSS) method based on diffusion tensor imaging (DTI). Thirty-six CIS patients (mean age ± SD: 34.0 years ± 12.6), 36 relapsing-remitting multiple sclerosis (RRMS) patients (mean age ± SD: 35.0 years ± 9.4) and 36 age- and gender-matched normal controls (NCs) were included in this study. Voxel-wise analyses were performed with TBSS using multiple diffusion metrics, including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (λ 1 ) and radial diffusivity (λ 23 ). In the CIS patients, TBSS analyses revealed diffusion alterations in a few white matter (WM) regions including the anterior thalamic radiation, corticospinal tract, inferior fronto-occipital fasciculus, superior longitudinal fasciculus, body and splenium of the corpus callosum, internal capsule, external capsule, and cerebral peduncle. MS patients showed more widespread diffusion changes (decreased FA, increased λ 1 , λ 23 and MD) than CIS. Exploratory analyses also revealed the possible associations between WM diffusion metrics and clinical variables (Expanded Disability Status Scale and disease duration) in the patients. This study provided imaging evidence for DTI abnormalities in CIS and MS and suggested that DTI can improve our knowledge of the path physiology of CIS and MS and clinical progression. Copyright © 2018 Elsevier Ltd. All rights reserved.

Protein function prediction--the power of multiplicity.

PubMed

Rentzsch, Robert; Orengo, Christine A

2009-04-01

Advances in experimental and computational methods have quietly ushered in a new era in protein function annotation. This 'age of multiplicity' is marked by the notion that only the use of multiple tools, multiple evidence and considering the multiple aspects of function can give us the broad picture that 21st century biology will need to link and alter micro- and macroscopic phenotypes. It might also help us to undo past mistakes by removing errors from our databases and prevent us from producing more. On the downside, multiplicity is often confusing. We therefore systematically review methods and resources for automated protein function prediction, looking at individual (biochemical) and contextual (network) functions, respectively.

Directed alteration of Saccharomyces cerevisiae mitochondrial DNA by biolistic transformation and homologous recombination.

PubMed

Bonnefoy, Nathalie; Fox, Thomas D

2007-01-01

Saccharomyces cerevisiae is currently the only species in which genetic transformation of mitochondria can be used to generate a wide variety of defined alterations in mitochondrial deoxyribonucleic acid (mtDNA). DNA sequences can be delivered into yeast mitochondria by microprojectile bombardment (biolistic transformation) and subsequently incorporated into mtDNA by the highly active homologous recombination machinery present in the organelle. Although transformation frequencies are relatively low, the availability of strong mitochondrial selectable markers for the yeast system, both natural and synthetic, makes the isolation of transformants routine. The strategies and procedures reviewed here allow the researcher to insert defined mutations into endogenous mitochondrial genes and to insert new genes into mtDNA. These methods provide powerful in vivo tools for the study of mitochondrial biology.

The effects of short-term hypergravity on Caenorhabditis elegans

NASA Astrophysics Data System (ADS)

Saldanha, Jenifer N.; Pandey, Santosh; Powell-Coffman, Jo Anne

2016-08-01

As we seek to recognize the opportunities of advanced aerospace technologies and spaceflight, it is increasingly important to understand the impacts of hypergravity, defined as gravitational forces greater than those present on the earth's surface. The nematode Caenorhabditis elegans has been established as a powerful model to study the effects of altered gravity regimens and has displayed remarkable resilience to space travel. In this study, we investigate the effects of short-term and defined hypergravity exposure on C. elegans motility, brood size, pharyngeal pumping rates, and lifespan. The results from this study advance our understanding of the effects of shorter durations of exposure to increased gravitational forces on C. elegans, and also contribute to the growing body of literature on the impacts of altered gravity regimens on earth's life forms.

DsbA Plays a Critical and Multifaceted Role in the Production of Secreted Virulence Factors by the Phytopathogen Erwinia carotovora subsp. atroseptica*S⃞

PubMed Central

Coulthurst, Sarah J.; Lilley, Kathryn S.; Hedley, Peter E.; Liu, Hui; Toth, Ian K.; Salmond, George P. C.

2008-01-01

Erwinia carotovora subsp. atroseptica is an enterobacterial phytopathogen causing economically significant soft rot disease. Pathogenesis is mediated by multiple secreted virulence factors, many of which are secreted by the type II (Out) secretion system. DsbA catalyzes the introduction of disulfide bonds into periplasmic and secreted proteins. In this study, the extracellular proteome (secretome) of wild type E. carotovora subsp. atroseptica SCRI1043, and dsbA and out mutants, was analyzed by spectral counting mass spectrometry. This revealed that dsbA inactivation had a huge impact on the secretome and identified diverse DsbA- and Out-dependent secreted proteins, representing known, predicted, and novel candidate virulence factors. Further characterization of the dsbA mutant showed that secreted enzyme activities, motility, production of the quorumsensing signal, and virulence were absent or substantially reduced. The impact of DsbA on secreted virulence factor production was mediated at multiple levels, including impacting on the Out secretion system and the virulence gene regulatory network. Transcriptome analyses revealed that the abundance of a broad, but defined, set of transcripts, including many virulence factors, was altered in the dsbA mutant, identifying a new virulence regulon responsive to extracytoplasmic conditions. In conclusion, DsbA plays a crucial, multifaceted role in the pathogenesis of E. carotovora subsp. atroseptica. PMID:18562317

Forward-backward multiplicity correlations in sNN=200 GeV Au+Au collisions

NASA Astrophysics Data System (ADS)

Back, B. B.; Baker, M. D.; Ballintijn, M.; Barton, D. S.; Betts, R. R.; Bickley, A. A.; Bindel, R.; Budzanowski, A.; Busza, W.; Carroll, A.; Chai, Z.; Decowski, M. P.; García, E.; Gburek, T.; George, N.; Gulbrandsen, K.; Gushue, S.; Halliwell, C.; Hamblen, J.; Hauer, M.; Heintzelman, G. A.; Henderson, C.; Hofman, D. J.; Hollis, R. S.; Hołyński, R.; Holzman, B.; Iordanova, A.; Johnson, E.; Kane, J. L.; Katzy, J.; Khan, N.; Kucewicz, W.; Kulinich, P.; Kuo, C. M.; Lin, W. T.; Manly, S.; McLeod, D.; Mignerey, A. C.; Noucier, R.; Olszewski, A.; Pak, R.; Park, I. C.; Pernegger, H.; Reed, C.; Remsberg, L. P.; Reuter, M.; Roland, C.; Roland, G.; Rosenberg, L.; Sagerer, J.; Sarin, P.; Sawicki, P.; Seals, H.; Sedykh, I.; Skulski, W.; Smith, C. E.; Stankiewicz, M. A.; Steinberg, P.; Stephans, G. S. F.; Sukhanov, A.; Tang, J.-L.; Tonjes, M. B.; Trzupek, A.; Vale, C.; Nieuwenhuizen, G. J. Van; Vaurynovich, S. S.; Verdier, R.; Veres, G. I.; Wenger, E.; Wolfs, F. L. H.; Wosiek, B.; Woźniak, K.; Wuosmaa, A. H.; Wysłouch, B.

2006-07-01

Forward-backward correlations of charged-particle multiplicities in symmetric bins in pseudorapidity are studied to gain insight into the underlying correlation structure of particle production in Au+Au collisions. The PHOBOS detector is used to measure integrated multiplicities in bins centered at η, defined within |η|<3, and covering intervals Δη. The variance σC2 of a suitably defined forward-backward asymmetry variable C is calculated as a function of η,Δη, and centrality. It is found to be sensitive to short-range correlations, and the concept of “clustering” is used to interpret comparisons to phenomenological models.

The influence of pregnancy on systemic immunity.

PubMed

Pazos, Michael; Sperling, Rhoda S; Moran, Thomas M; Kraus, Thomas A

2012-12-01

Adaptations in maternal systemic immunity are presumed to be responsible for observed alterations in disease susceptibility and severity as pregnancy progresses. Epidemiological evidence as well as animal studies have shown that influenza infections are more severe during the second and third trimesters of pregnancy, resulting in greater morbidity and mortality, although the reason for this is still unclear. Our laboratory has taken advantage of 20 years of experience studying the murine immune response to respiratory viruses to address questions of altered immunity during pregnancy. With clinical studies and unique animal model systems, we are working to define the mechanisms responsible for altered immune responses to influenza infection during pregnancy and what roles hormones such as estrogen or progesterone play in these alterations.

Decomposing Oncogenic Transcriptional Signatures to Generate Maps of Divergent Cellular States.

PubMed

Kim, Jong Wook; Abudayyeh, Omar O; Yeerna, Huwate; Yeang, Chen-Hsiang; Stewart, Michelle; Jenkins, Russell W; Kitajima, Shunsuke; Konieczkowski, David J; Medetgul-Ernar, Kate; Cavazos, Taylor; Mah, Clarence; Ting, Stephanie; Van Allen, Eliezer M; Cohen, Ofir; Mcdermott, John; Damato, Emily; Aguirre, Andrew J; Liang, Jonathan; Liberzon, Arthur; Alexe, Gabriella; Doench, John; Ghandi, Mahmoud; Vazquez, Francisca; Weir, Barbara A; Tsherniak, Aviad; Subramanian, Aravind; Meneses-Cime, Karina; Park, Jason; Clemons, Paul; Garraway, Levi A; Thomas, David; Boehm, Jesse S; Barbie, David A; Hahn, William C; Mesirov, Jill P; Tamayo, Pablo

2017-08-23

The systematic sequencing of the cancer genome has led to the identification of numerous genetic alterations in cancer. However, a deeper understanding of the functional consequences of these alterations is necessary to guide appropriate therapeutic strategies. Here, we describe Onco-GPS (OncoGenic Positioning System), a data-driven analysis framework to organize individual tumor samples with shared oncogenic alterations onto a reference map defined by their underlying cellular states. We applied the methodology to the RAS pathway and identified nine distinct components that reflect transcriptional activities downstream of RAS and defined several functional states associated with patterns of transcriptional component activation that associates with genomic hallmarks and response to genetic and pharmacological perturbations. These results show that the Onco-GPS is an effective approach to explore the complex landscape of oncogenic cellular states across cancers, and an analytic framework to summarize knowledge, establish relationships, and generate more effective disease models for research or as part of individualized precision medicine paradigms. Copyright © 2017 Elsevier Inc. All rights reserved.

Casimir meets Poisson: improved quark/gluon discrimination with counting observables

DOE PAGES

Frye, Christopher; Larkoski, Andrew J.; Thaler, Jesse; ...

2017-09-19

Charged track multiplicity is among the most powerful observables for discriminating quark- from gluon-initiated jets. Despite its utility, it is not infrared and collinear (IRC) safe, so perturbative calculations are limited to studying the energy evolution of multiplicity moments. While IRC-safe observables, like jet mass, are perturbatively calculable, their distributions often exhibit Casimir scaling, such that their quark/gluon discrimination power is limited by the ratio of quark to gluon color factors. In this paper, we introduce new IRC-safe counting observables whose discrimination performance exceeds that of jet mass and approaches that of track multiplicity. The key observation is that trackmore » multiplicity is approximately Poisson distributed, with more suppressed tails than the Sudakov peak structure from jet mass. By using an iterated version of the soft drop jet grooming algorithm, we can define a “soft drop multiplicity” which is Poisson distributed at leading-logarithmic accuracy. In addition, we calculate the next-to-leading-logarithmic corrections to this Poisson structure. If we allow the soft drop groomer to proceed to the end of the jet branching history, we can define a collinear-unsafe (but still infrared-safe) counting observable. Exploiting the universality of the collinear limit, we define generalized fragmentation functions to study the perturbative energy evolution of collinear-unsafe multiplicity.« less

Casimir meets Poisson: improved quark/gluon discrimination with counting observables

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

Frye, Christopher; Larkoski, Andrew J.; Thaler, Jesse

Charged track multiplicity is among the most powerful observables for discriminating quark- from gluon-initiated jets. Despite its utility, it is not infrared and collinear (IRC) safe, so perturbative calculations are limited to studying the energy evolution of multiplicity moments. While IRC-safe observables, like jet mass, are perturbatively calculable, their distributions often exhibit Casimir scaling, such that their quark/gluon discrimination power is limited by the ratio of quark to gluon color factors. In this paper, we introduce new IRC-safe counting observables whose discrimination performance exceeds that of jet mass and approaches that of track multiplicity. The key observation is that trackmore » multiplicity is approximately Poisson distributed, with more suppressed tails than the Sudakov peak structure from jet mass. By using an iterated version of the soft drop jet grooming algorithm, we can define a “soft drop multiplicity” which is Poisson distributed at leading-logarithmic accuracy. In addition, we calculate the next-to-leading-logarithmic corrections to this Poisson structure. If we allow the soft drop groomer to proceed to the end of the jet branching history, we can define a collinear-unsafe (but still infrared-safe) counting observable. Exploiting the universality of the collinear limit, we define generalized fragmentation functions to study the perturbative energy evolution of collinear-unsafe multiplicity.« less

Rhomboid Enhancer Activity Defines a Subset of Drosophila Neural Precursors Required for Proper Feeding, Growth and Viability

PubMed Central

Gresser, Amy L.; Gutzwiller, Lisa M.; Gauck, Mackenzie K.; Hartenstein, Volker; Cook, Tiffany A.; Gebelein, Brian

2015-01-01

Organismal growth regulation requires the interaction of multiple metabolic, hormonal and neuronal pathways. While the molecular basis for many of these are well characterized, less is known about the developmental origins of growth regulatory structures and the mechanisms governing control of feeding and satiety. For these reasons, new tools and approaches are needed to link the specification and maturation of discrete cell populations with their subsequent regulatory roles. In this study, we characterize a rhomboid enhancer element that selectively labels four Drosophila embryonic neural precursors. These precursors give rise to the hypopharyngeal sensory organ of the peripheral nervous system and a subset of neurons in the deutocerebral region of the embryonic central nervous system. Post embryogenesis, the rhomboid enhancer is active in a subset of cells within the larval pharyngeal epithelium. Enhancer-targeted toxin expression alters the morphology of the sense organ and results in impaired larval growth, developmental delay, defective anterior spiracle eversion and lethality. Limiting the duration of toxin expression reveals differences in the critical periods for these effects. Embryonic expression causes developmental defects and partially penetrant pre-pupal lethality. Survivors of embryonic expression, however, ultimately become viable adults. In contrast, post-embryonic toxin expression results in fully penetrant lethality. To better define the larval growth defect, we used a variety of assays to demonstrate that toxin-targeted larvae are capable of locating, ingesting and clearing food and they exhibit normal food search behaviors. Strikingly, however, following food exposure these larvae show a rapid decrease in consumption suggesting a satiety-like phenomenon that correlates with the period of impaired larval growth. Together, these data suggest a critical role for these enhancer-defined lineages in regulating feeding, growth and viability. PMID:26252385

Multiple primary tumors of the upper aerodigestive tract: is there a role for constitutional mutations in the p53 gene?

PubMed

Gallo, O; Sardi, I; Pepe, G; Franchi, A; Attanasio, M; Giusti, B; Bocciolini, C; Abbate, R

1999-07-19

Head-and-neck cancer (HNC) patients have a high risk of developing second primary tumors of the upper aerodigestive tract, the main cause of death. Although the roles of tobacco and diet in multiple head-and-neck carcinogenesis have been thoroughly investigated, little is known about individual genetic susceptibility factors involved in this process. Genomic instability, reflecting the propensity and the susceptibility of the genome to acquire multiple alterations, could be considered a driving force behind multiple carcinogenesis. Mutation of the p53 tumor-suppressor gene has been proposed to play an important role in this process. Therefore, we evaluated the incidence of inherited p53 germ-line alteration(s) in a population of 24 consecutive HNC patients and their first-degree relatives affected by multiple malignancies as well as the occurrence of p53 somatic acquired mutation(s) in 16 cancers, including first and second primaries from 5 HNCs of the same group. Mutations in exons 4-11 of the p53 gene were investigated using SSCP-PCR analysis and DNA sequencing. Analysis was extended to the peripheral blood and cancer biopsies available from first-degree relatives of cancer-prone families with p53 germ-line mutations. p53 germ-line mutations were identified in the peripheral blood and corresponding cancers of 3 HNC patients who had multiple malignancies. The only missense mutation detected was mapped in exon 6; it is a GTG to GAG substitution with an amino acid change from Val to Glu at codon 197. The remaining 2 p53 germ-line mutations were single-nucleotide substitutions without amino acid change in exon 6 (codon 213, CGA to CGG) and in exon 8 (codon 295, CCT to CCC), respectively. These mutations were found in HNC patients with a family history of cancer. Abnormal expression of wild-type p53 protein in normal and pathological tissues from patients with the same sense single-nucleotide substitutions was detected by immuno-histochemistry.

Aesthetic breast shape preferences among plastic surgeons.

PubMed

Broer, Peter Niclas; Juran, Sabrina; Walker, Marc E; Ng, Reuben; Weichman, Katie; Tanna, Neil; Liu, Yuen-Jong; Shah, Ajul; Patel, Anup; Persing, John A; Thomson, James Grant

2015-06-01

There has been little discussion in the plastic surgery literature regarding breast shape preferences among plastic surgeons, despite strong evidence that such aesthetic preferences are influenced by multiple factors. Much effort has been focused on delineating the objective criteria by which an "attractive" breast might be defined. This study aimed at providing a better understanding of the presence and significance of differences in personal aesthetic perception, and how these relate to a plastic surgeon's demographic, ethnic, and cultural background, as well as practice type (academic vs private). An interactive online survey was designed. Modifiable ranges of upper pole fullness and areola size were achieved via digital alteration, enabling participants to interactively change the shape of a model's breasts. The questionnaire was translated into multiple languages and sent to plastic surgeons worldwide. Demographic data were also collected. Analysis of variance was used to elucidate plastic surgeon's breast shape preferences in respect to sex and age, geographic and ethnic background, as well as practice type. The authors gathered 614 responses from 29 different countries. Significant differences regarding preferences for upper pole fullness, areola size in the natural breast, and areola size in the augmented breast were identified across surgeons from the different countries. Further, significant relationships regarding breast shape preferences were distilled between the age and sex of the surgeon, as well as the practice type. No differences were found in respect to the surgeons' self-reported ethnic background. Country of residence, age, and practice type significantly impact breast shape preferences of plastic surgeons. These findings have implications for both patients seeking and surgeons performing cosmetic and reconstructive breast surgery. In an increasingly global environment, cultural differences and international variability must be considered when defining and publishing new techniques and aesthetic outcomes. When both the plastic surgeon and the patient are able to adequately and effectively communicate their preferences regarding the shape and relations of the breast, they will be more successful at achieving satisfying results.

The Influence of Multiple Host Contacts on the Acquisition and Transmission of Dengue-2 Virus

DTIC Science & Technology

1993-01-01

5500 Stanoard Form 298 (Rev 2-89) PIs~~ bv AtI %t .34-| II Best Available Copy ABSTRACT Title of Dissertation: THE INFLUENCE OF MULTIPLE HOST CONTACTS...ABSTRACT Title of the Dissertaton: THE INFLUENCE OF MULTIPLE HOST CONTACTS ON THE ACQUISITION AND TRANSMISSION OF DENGUE-2 VIRUS BY A=DISAEX2 . John L...virus does not alter the feeding behavior of An. n•ngy~i. THE INFLUENCE OF MULTIPLE HOST CONTACTS ON THE ACQUISITION AND TRANSMISSION OF DENGUE-2 VIRUS BY

Components of the anorexia-cachexia syndrome: gastrointestinal symptom correlates of cancer anorexia.

PubMed

Yavuzsen, Tugba; Walsh, Declan; Davis, Mellar P; Kirkova, Jordanka; Jin, Tao; LeGrand, Susan; Lagman, Ruth; Bicanovsky, Lesley; Estfan, Bassam; Cheema, Bushra; Haddad, Abdo

2009-12-01

Cancer-related anorexia is traditionally considered part of a complex but ill-defined anorexia-cachexia syndrome in which anorexia is intimately associated with other gastrointestinal (GI) symptoms and weight loss. We surveyed cancer patients with anorexia to learn more about the relationship between anorexia and these symptoms. A 22-item GI questionnaire assessed the severity of anorexia and the prevalence of concurrent GI symptoms, including taste changes, food aversions, altered sense of smell, and diurnal food intake changes. The relationship between anorexia severity and anticancer therapy and prior menstrual or pregnancy-related appetite changes was also assessed. Ninety-five of 101 patients with anorexia surveyed had complete data. Seventy-eight percent of them had moderate or severe anorexia. Abnormal diurnal appetite variation, taste changes, and food aversions were present in over 50% of all those with anorexia. Judged by the numerical rating scale, the worse the anorexia, the more prevalent were early satiety, constipation, vomiting, and food aversions. Those with more severe anorexia had greater weight loss, and worse performance status. Anorexia severity did not correlate with that during prior menses/pregnancy or antitumor therapy. Evaluation of multiple other GI symptoms is important in understanding the total experience of cancer anorexia. Early satiety, taste changes, food aversions, and altered sense of smell are important accompanying GI symptoms. Most validated anorexia tools do not assess these commonly associated GI symptoms. Future research should develop a comprehensive anorexia symptom questionnaire.

Clinical Pharmacokinetics in Kidney Disease: Fundamental Principles.

PubMed

Lea-Henry, Tom N; Carland, Jane E; Stocker, Sophie L; Sevastos, Jacob; Roberts, Darren M

2018-06-22

Kidney disease is an increasingly common comorbidity that alters the pharmacokinetics of many drugs. Prescribing to patients with kidney disease requires knowledge about the drug, the extent of the patient's altered physiology, and pharmacokinetic principles that influence the design of dosing regimens. There are multiple physiologic effects of impaired kidney function, and the extent to which they occur in an individual at any given time can be difficult to define. Although some guidelines are available for dosing in kidney disease, they may be on the basis of limited data or not widely applicable, and therefore, an understanding of pharmacokinetic principles and how to apply them is important to the practicing clinician. Whether kidney disease is acute or chronic, drug clearance decreases, and the volume of distribution may remain the same or increase. Although in CKD, these changes progress relatively slowly, they are dynamic in AKI, and recovery is possible depending on the etiology and treatments. This, and the use of kidney replacement therapies further complicate attempts to quantify drug clearance at the time of prescribing and dosing in AKI. The required change in the dosing regimen can be estimated or even quantitated in certain instances through the application of pharmacokinetic principles to guide rational drug dosing. This offers an opportunity to provide personalized medical care and minimizes adverse drug events from either under- or overdosing. We discuss the principles of pharmacokinetics that are fundamental for the design of an appropriate dosing regimen in this review. Copyright © 2018 by the American Society of Nephrology.

Profiling global kinome signatures of the radioresistant MCF-7/C6 breast cancer cells using MRM-based targeted proteomics.

PubMed

Guo, Lei; Xiao, Yongsheng; Fan, Ming; Li, Jian Jian; Wang, Yinsheng

2015-01-02

Ionizing radiation is widely used in cancer therapy; however, cancer cells often develop radioresistance, which compromises the efficacy of cancer radiation therapy. Quantitative assessment of the alteration of the entire kinome in radioresistant cancer cells relative to their radiosensitive counterparts may provide important knowledge to define the mechanism(s) underlying tumor adaptive radioresistance and uncover novel target(s) for effective prevention and treatment of tumor radioresistance. By employing a scheduled multiple-reaction monitoring analysis in conjunction with isotope-coded ATP affinity probes, we assessed the global kinome of radioresistant MCF-7/C6 cells and their parental MCF-7 human breast cancer cells. We rigorously quantified 120 kinases, of which (1)/3 exhibited significant differences in expression levels or ATP binding affinities. Several kinases involved in cell cycle progression and DNA damage response were found to be overexpressed or hyperactivated, including checkpoint kinase 1 (CHK1), cyclin-dependent kinases 1 and 2 (CDK1 and CDK2), and the catalytic subunit of DNA-dependent protein kinase. The elevated expression of CHK1, CDK1, and CDK2 in MCF-7/C6 cells was further validated by Western blot analysis. Thus, the altered kinome profile of radioresistant MCF-7/C6 cells suggests the involvement of kinases on cell cycle progression and DNA repair in tumor adaptive radioresistance. The unique kinome profiling results also afforded potential effective targets for resensitizing radioresistant cancer cells and counteracting deleterious effects of ionizing radiation exposure.

Mixture modeling of multi-component data sets with application to ion-probe zircon ages

NASA Astrophysics Data System (ADS)

Sambridge, M. S.; Compston, W.

1994-12-01

A method is presented for detecting multiple components in a population of analytical observations for zircon and other ages. The procedure uses an approach known as mixture modeling, in order to estimate the most likely ages, proportions and number of distinct components in a given data set. Particular attention is paid to estimating errors in the estimated ages and proportions. At each stage of the procedure several alternative numerical approaches are suggested, each having their own advantages in terms of efficency and accuracy. The methodology is tested on synthetic data sets simulating two or more mixed populations of zircon ages. In this case true ages and proportions of each population are known and compare well with the results of the new procedure. Two examples are presented of its use with sets of SHRIMP U-238 - Pb-206 zircon ages from Palaeozoic rocks. A published data set for altered zircons from bentonite at Meishucun, South China, previously treated as a single-component population after screening for gross alteration effects, can be resolved into two components by the new procedure and their ages, proportions and standard errors estimated. The older component, at 530 +/- 5 Ma (2 sigma), is our best current estimate for the age of the bentonite. Mixture modeling of a data set for unaltered zircons from a tonalite elsewhere defines the magmatic U-238 - Pb-206 age at high precision (2 sigma +/- 1.5 Ma), but one-quarter of the 41 analyses detect hidden and significantly older cores.

Geologic and geochemical study of tin-bearing rhyolites in the Broken Ridge area, southern Wah Wah Mountains, Utah

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

Duttweiler, K.A.; Griffitts, W.R.

This study was undertaken to document the geologic, petrologic, and geochemical relationships of the tin-bearing rhyolitic lava flows and domes of the 12-m.y.-old Steamboat Mountain Formation of Thompson and Perry in the area of Broken Ridge. Early phases of volcanic activity produced a crystal-rich, topaz-bearing rhyolite flow followed by eruption of a crystal-poor rhyolite from many local centers. These geochemical characteristics are typical of other topaz-bearing rhyolites in the western United States and suggest that such rhyolites formed as highly differentiated magmas. The 23-m.y.-old Bible Spring fault zone was reactivated after emplacement of the rhyolite flows that resulted in amore » series of high-angle normal faults. Multiple hydrothermal events resulted in widespread alteration along the faults and concentration of Be, F, Sn, Nb, Mo, Cu, Zn, W, and Ba. Alteration types include silicification, argillization, and alunitization. Crystalline cassiterite and wood tin are widespread and locally abundant in heavy-mineral-concentrate samples from the Broken Ridge area. The only visible cassiterite in the rocks occurs with specular hematite in veins within the silicified topaz-bearing rhyolite, immediately adjacent to a vent breccia. Trace element anomalies of Sn, Mo, Nb, and Be in rock samples well-define the vein area. The combined geologic, geochemical, and structural data suggest that an intrusive may be at depth directly beneath Broken Ridge.« less

Tissue-specific regulation of sirtuin and nicotinamide adenine dinucleotide biosynthetic pathways identified in C57Bl/6 mice in response to high-fat feeding.

PubMed

Drew, Janice E; Farquharson, Andrew J; Horgan, Graham W; Williams, Lynda M

2016-11-01

The sirtuin (SIRT)/nicotinamide adenine dinucleotide (NAD) system is implicated in development of type 2 diabetes (T2D) and diet-induced obesity, a major risk factor for T2D. Mechanistic links have not yet been defined. SIRT/NAD system gene expression and NAD/NADH levels were measured in liver, white adipose tissue (WAT) and skeletal muscle from mice fed either a low-fat diet or high-fat diet (HFD) for 3 days up to 16 weeks. An in-house custom-designed multiplex gene expression assay assessed all 7 mouse SIRTs (SIRT1-7) and 16 enzymes involved in conversion of tryptophan, niacin, nicotinamide riboside and metabolic precursors to NAD. Significantly altered transcription was correlated with body weight, fat mass, plasma lipids and hormones. Regulation of the SIRT/NAD system was associated with early (SIRT4, SIRT7, NAPRT1 and NMNAT2) and late phases (NMNAT3, NMRK2, ABCA1 and CD38) of glucose intolerance. TDO2 and NNMT were identified as markers of HFD consumption. Altered regulation of the SIRT/NAD system in response to HFD was prominent in liver compared with WAT or muscle. Multiple components of the SIRTs and NAD biosynthetic enzymes network respond to consumption of dietary fat. Novel molecular targets identified above could direct strategies for dietary/therapeutic interventions to limit metabolic dysfunction and development of T2D. Copyright © 2016 Elsevier Inc. All rights reserved.

Feedforward and feedback motor control abnormalities implicate cerebellar dysfunctions in autism spectrum disorder.

PubMed

Mosconi, Matthew W; Mohanty, Suman; Greene, Rachel K; Cook, Edwin H; Vaillancourt, David E; Sweeney, John A

2015-02-04

Sensorimotor abnormalities are common in autism spectrum disorder (ASD) and among the earliest manifestations of the disorder. They have been studied far less than the social-communication and cognitive deficits that define ASD, but a mechanistic understanding of sensorimotor abnormalities in ASD may provide key insights into the neural underpinnings of the disorder. In this human study, we examined rapid, precision grip force contractions to determine whether feedforward mechanisms supporting initial motor output before sensory feedback can be processed are disrupted in ASD. Sustained force contractions also were examined to determine whether reactive adjustments to ongoing motor behavior based on visual feedback are altered. Sustained force was studied across multiple force levels and visual gains to assess motor and visuomotor mechanisms, respectively. Primary force contractions of individuals with ASD showed greater peak rate of force increases and large transient overshoots. Individuals with ASD also showed increased sustained force variability that scaled with force level and was more severe when visual gain was highly amplified or highly degraded. When sustaining a constant force level, their reactive adjustments were more periodic than controls, and they showed increased reliance on slower feedback mechanisms. Feedforward and feedback mechanism alterations each were associated with more severe social-communication impairments in ASD. These findings implicate anterior cerebellar circuits involved in feedforward motor control and posterior cerebellar circuits involved in transforming visual feedback into precise motor adjustments in ASD. Copyright © 2015 the authors 0270-6474/15/352015-11$15.00/0.

Activation of antioxidant pathways in ras-mediated oncogenic transformation of human surface ovarian epithelial cells revealed by functional proteomics and mass spectrometry.

PubMed

Young, Travis W; Mei, Fang C; Yang, Gong; Thompson-Lanza, Jennifer A; Liu, Jinsong; Cheng, Xiaodong

2004-07-01

Cellular transformation is a complex process involving genetic alterations associated with multiple signaling pathways. Development of a transformation model using defined genetic elements has provided an opportunity to elucidate the role of oncogenes and tumor suppressor genes in the initiation and development of ovarian cancer. To study the cellular and molecular mechanisms of Ras-mediated oncogenic transformation of ovarian epithelial cells, we used a proteomic approach involving two-dimensional electrophoresis and mass spectrometry to profile two ovarian epithelial cell lines, one immortalized with SV40 T/t antigens and the human catalytic subunit of telomerase and the other transformed with an additional oncogenic ras(V12) allele. Of approximately 2200 observed protein spots, we have identified >30 protein targets that showed significant changes between the immortalized and transformed cell lines using peptide mass fingerprinting. Among these identified targets, one most notable group of proteins altered significantly consists of enzymes involved in cellular redox balance. Detailed analysis of these protein targets suggests that activation of Ras-signaling pathways increases the threshold of reactive oxidative species (ROS) tolerance by up-regulating the overall antioxidant capacity of cells, especially in mitochondria. This enhanced antioxidant capacity protects the transformed cells from high levels of ROS associated with the uncontrolled growth potential of tumor cells. It is conceivable that an enhanced antioxidation capability may constitute a common mechanism for tumor cells to evade apoptosis induced by oxidative stresses at high ROS levels.

Multiple stages of aqueous alteration along fractures in mudstone and sandstone strata in Gale Crater, Mars

NASA Astrophysics Data System (ADS)

Yen, A. S.; Ming, D. W.; Vaniman, D. T.; Gellert, R.; Blake, D. F.; Morris, R. V.; Morrison, S. M.; Bristow, T. F.; Chipera, S. J.; Edgett, K. S.; Treiman, A. H.; Clark, B. C.; Downs, R. T.; Farmer, J. D.; Grotzinger, J. P.; Rampe, E. B.; Schmidt, M. E.; Sutter, B.; Thompson, L. M.; MSL Science Team

2017-08-01

The Mars rover Curiosity in Gale crater conducted the first-ever direct chemical and mineralogical comparisons of samples that have clear parent (unaltered) and daughter (altered) relationships. The mineralogy and chemistry of samples within and adjacent to alteration halos in a sandstone formation were established by the Chemistry and Mineralogy (CheMin) X-ray diffraction (XRD) instrument and the Alpha Particle X-ray Spectrometer (APXS), respectively. The Stimson formation sandstones unconformably overlie the Murray mudstone formation and represent the youngest stratigraphic unit explored by Curiosity to date. Aqueous alteration of the parent sandstone resulted in a loss of half of the original crystalline mineral phases and a three-fold increase in X-ray amorphous material. Aqueous fluids extensively leached Mg, Al, Mn, Fe, Ni, Zn and other elements from the parent material, decreased the pyroxene to feldspar ratio by a factor of two, introduced Ca and mixed-cation sulfates, and both passively and actively enriched the silica content. Leaching of Mg, Al, Mn, Fe, Ni and Zn and enrichment of Si and S are also observed in alteration halos in the underlying mudstone. These observations are consistent with infiltration of subsurface fluids, initially acidic and then alkaline, propagating along fractures crosscutting the Stimson sandstone and Murray mudstone. The geochemistry and mineralogy suggest a complicated diagenetic history with multiple stages of aqueous alteration under a variety of environmental conditions (e.g. both low and moderate pH). The formation of these alteration halos post-dates lithification of the sandstones and mudstones and represents one of the youngest hydrogeologic events presently known to have occurred in Gale crater.

Mutants of Arabidopsis thaliana with decreased amplitude in their phototropic response

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

Khurana, J.P.; Ren, Zhangling; Steinitz, B.

1989-10-01

Two mutants of Arabidopsis thaliana have been identified with decreased phototropism to 450-nanometer light. Fluence-response relationships for these strains (ZR8 and ZR19) to single and multiple flashes of light show thresholds, curve shapes, and fluence for maximum curvature in first positive phototropism which are the same as those of the wild type. Similarly, there is no alteration from the wild type in the kinetics of curvature or in the optimum dark period separating sequential flashes in a multiple flash regimen. In addition, in both strains, gravitropism is decreased compared to the wild type by an amount which is comparable tomore » the decrease in phototropism. Based on reciprocal backcrosses, it appears that the alteration is due to a recessive nuclear mutation. It is suggested that ZR8 and ZR19 represent alterations in some step analogous to an amplifier, downstream of the photoreceptor pigment, and common to both phototropism and gravitropism.« less

ITS system specification

DOT National Transportation Integrated Search

1997-01-21

The objective of the Polaris Project is to define an Intelligent Transportation Systems (ITS) architecture for the state of Minnesota. An architecture is a framework that defines how multiple ITS Components interrelate and contribute to the overall I...

ITS component specification

DOT National Transportation Integrated Search

1997-01-20

The objective of the Polaris Project is to define an Intelligent Transportation Systems (ITS) architecture for the state of Minnesota. An architecture is a framework that defines how multiple ITS Components interrelate and contribute to the overall I...

Evidence Report: Risk of Crew Adverse Health Event Due to Altered Immune Response

NASA Technical Reports Server (NTRS)

Crucian, Brian; Sams, Clarence F.

2013-01-01

The Risk of Crew Adverse Health Event Due to Altered Immune Response is identified by the National Aeronautics and Space Administration (NASA) Human Research Program (HRP) as a recognized risk to human health and performance in space. The HRP Program Requirements Document (PRD) defines these risks. This Evidence Report provides a summary of the evidence that has been used to identify and characterize this risk. It is known that human immune function is altered in- and post-flight, but it is unclear at present if such alterations lead to increased susceptibility to disease. Reactivation of latent viruses has been documented in crewmembers, although this reactivation has not been directly correlated with immune changes or with observed diseases. As described in this report, further research is required to better characterize the relationships between altered immune response and susceptibility to disease during and after spaceflight. This is particularly important for future deep-space exploration missions.

Detection of alteration associated with a porphyry copper deposit in southern Arizona

NASA Technical Reports Server (NTRS)

Abrams, M. J.; Siegal, B. S.

1977-01-01

Computer processing of Landsat MSS data was performed using contrast stretching and band-to-band ratioing. A false color ratio composite picture showed color anomalies which coincided with known areas of alteration on and about Red Mountain. A helicopter survey of the study area was undertaken using a portable field reflectance spectrometer. One hundred fifty-six spectra were obtained in the 0.4 to 2.5 micrometer wavelength region. The spectra were digitized, and contour maps for 24 wavelength intervals were produced; no spectral anomalies were evident for the known altered areas. A contour map produced from the 1.6 and 2.2 micrometer ratio generally delineated the alteration areas. The 1.3, 1.6, and 2.2 micrometer wavelength data were canonically transformed using a transformation empirically derived from discriminant function analysis of altered and unaltered materials for the Goldfield, Nevada region, and a contour map was produced for the first canonical variable. The known areas of alteration were clearly defined on the contour map.

Numerical Function Generators Using LUT Cascades

DTIC Science & Technology

2007-06-01

either algebraically (for example, sinðxÞ) or as a table of input/ output values. The user defines the numerical function by using the syntax of Scilab ...defined function in Scilab or specify it directly. Note that, by changing the parser of our system, any format can be used for the design entry. First...Methods for Multiple-Valued Input Address Generators,” Proc. 36th IEEE Int’l Symp. Multiple-Valued Logic (ISMVL ’06), May 2006. [29] Scilab 3.0, INRIA-ENPC

SLC12A7 alters adrenocortical carcinoma cell adhesion properties to promote an aggressive invasive behavior.

PubMed

Brown, Taylor C; Murtha, Timothy D; Rubinstein, Jill C; Korah, Reju; Carling, Tobias

2018-06-08

Altered expression of Solute Carrier Family 12 Member 7 (SLC12A7) is implicated to promote malignant behavior in multiple cancer types through an incompletely understood mechanism. Recent studies have shown recurrent gene amplifications and overexpression of SLC12A7 in adrenocortical carcinoma (ACC). The potential mechanistic effect(s) of SLC12A7 amplifications in portending an aggressive behavior in ACC has not been previously studied and is investigated here using two established ACC cell lines, SW-13 and NCI-H295R. SW-13 cells, which express negligible amounts of SLC12A7, were enforced to express SLC12A7 constitutively, while RNAi gene silencing was performed in NCI-H295R cells, which have robust endogenous expression of SLC12A7. In vitro studies tested the outcomes of experimental alterations in SLC12A7 expression on malignant characteristics, including cell viability, growth, colony formation potential, motility, invasive capacity, adhesion and detachment kinetics, and cell membrane organization. Further, potential alterations in transcription regulation downstream to induced SLC12A7 overexpression was explored using targeted transcription factor expression arrays. Enforced SLC12A7 overexpression in SW-13 cells robustly promoted motility and invasive characteristics (p < 0.05) without significantly altering cell viability, growth, or colony formation potential. SLC12A7 overexpression also significantly increased rates of cellular attachment and detachment turnover (p < 0.05), potentially propelled by increased filopodia formation and/or Ezrin interaction. In contrast, RNAi gene silencing of SLC12A7 stymied cell attachment strength as well as migration and invasion capacity in NCI-H295R cells. Transcription factor expression analysis identified multiple signally pathways potentially affected by SLC12A7 overexpression, including osmotic stress, bone morphogenetic protein, and Hippo signaling pathways. Amplification of SLC12A7 observed in ACCs is shown here, in vitro, to exacerbate the malignant behavior of ACC cells by promoting invasive capacities, possibly mediated by alterations in multiple signaling pathways, including the osmotic stress pathway.

Instrumentation for Non-Invasive Assessment of Cardiovascular Regulation

NASA Technical Reports Server (NTRS)

Cohen, Richard J.

1999-01-01

It is critically important to be able to assess alterations in cardiovascular regulation during and after space flight. We propose to develop an instrument for the non-invasive assessment of such alterations that can be used on the ground and potentially during space flight. This instrumentation would be used by the Cardiovascular Alterations Team at multiple sites for the study of the effects of space flight on the cardiovascular system and the evaluation of countermeasures. In particular, the Cardiovascular Alterations Team will use this instrumentation in conjunction with ground-based human bed-rest studies and during application of acute stresses e.g., tilt, lower body negative pressure, and exercise. In future studies, the Cardiovascular Alterations Team anticipates using this instrumentation to study astronauts before and after space flight and ultimately, during space flight. The instrumentation may also be used by the Bone Demineralization/Calcium Metabolism Team, the Neurovestibular Team and the Human Performance Factors, Sleep and Chronobiology Team to measure changes in autonomic nervous function. The instrumentation will be based on a powerful new technology - cardiovascular system identification (CSI) - which has been developed in our laboratory. CSI provides a non-invasive approach for the study of alterations in cardiovascular regulation. This approach involves the analysis of second-to-second fluctuations in physiologic signals such as heart rate and non-invasively measured arterial blood pressure in order to characterize quantitatively the physiologic mechanisms responsible for the couplings between these signals. Through the characterization of multiple physiologic mechanisms, CSI provides a closed-loop model of the cardiovascular regulatory state in an individual subject.

Amphibian egg cytoplasm response to altered g-forces and gravity orientation

NASA Technical Reports Server (NTRS)

Neff, A. W.; Smith, R. C.; Malacinski, G. M.

1986-01-01

Elucidation of dorsal/ventral polarity and primary embryonic axis development in amphibian embryos requires an understanding of cytoplasmic rearrangements in fertile eggs at the biophysical, physiological, and biochemical levels. Evidence is presented that amphibian egg cytoplasmic components are compartmentalized. The effects of altered orientation to the gravitational vector (i.e., egg inversion) and alterations in gravity force ranging from hypergravity (centrifugation) to simulated microgravity (i.e., horizontal clinostat rotation) on cytoplasmic compartment rearrangements are reviewed. The behavior of yolk compartments as well as a newly defined (with monoclonal antibody) nonyolk cytoplasmic compartment, in inverted eggs and in eggs rotated on horizontal clinostats at their buoyant density, is discussed.

Meeting the Needs of Clients with Dissociative Identity Disorder: Considerations for Psychotherapy

ERIC Educational Resources Information Center

Ringrose, Jo L.

2011-01-01

Psychotherapy for clients with Dissociative Identity Disorder (DID) is different to therapy with most clients because these clients are multiple, comprising one or more host, and one or more alter personalities. The necessary components to be addressed in order that clients can live successfully either as a multiple or as an integrated person are…

A Multiple Choice Version of the Sentence Completion Method

ERIC Educational Resources Information Center

Shouval, Ron; And Others

1975-01-01

It was concluded that a multiple choice form corresponding to a sentence completion measure, test clearly defined personality areas (such as autonomy) could be a reasonable alternative for many purposes. (Author/DEP)

Glucose uptake heterogeneity of the leg muscles is similar between patients with multiple sclerosis and healthy controls during walking.

PubMed

Kindred, John H; Ketelhut, Nathaniel B; Rudroff, Thorsten

2015-02-01

Difficulties in ambulation are one of the main problems reported by patients with multiple sclerosis. A previous study by our research group showed increased recruitment of muscle groups during walking, but the influence of skeletal muscle properties, such as muscle fiber activity, has not been fully elucidated. The purpose of this investigation was to use the novel method of calculating glucose uptake heterogeneity in the leg muscles of patients with multiple sclerosis and compare these results to healthy controls. Eight patients with multiple sclerosis (4 men) and 8 healthy controls (4 men) performed 15 min of treadmill walking at a comfortable self-selected speed following muscle strength tests. Participants were injected with ≈ 8 mCi of [(18)F]-fluorodeoxyglucose during walking after which positron emission tomography/computed tomography imaging was performed. No differences in muscle strength were detected between multiple sclerosis and control groups (P>0.27). Within the multiple sclerosis, group differences in muscle volume existed between the stronger and weaker legs in the vastus lateralis, semitendinosus, and semimembranosus (P<0.03). Glucose uptake heterogeneity between the groups was not different for any muscle group or individual muscle of the legs (P>0.16, P≥0.05). Patients with multiple sclerosis and healthy controls showed similar muscle fiber activity during walking. Interpretations of these results, with respect to our previous study, suggest that walking difficulties in patients with multiple sclerosis may be more associated with altered central nervous system motor patterns rather than alterations in skeletal muscle properties. Published by Elsevier Ltd.

A Preliminary Heat Flow Model for Cooling a Batholith near Ica, Peru

NASA Astrophysics Data System (ADS)

Gonzalez, L. U.; Clausen, B. L.; Molano, J. C.; Martinez, A. M.; Poma, O.

2014-12-01

This research models the cooling of a suite in the Linga Super-unit located at the north end of the Arequipa segment in the Cretaceous Peruvian Coastal Batholith. The monzogabbro to granite Linga suite is approximately 50 km long and 15 km wide, with an estimated vertical extent of about 5 km originally intruded to a depth of 3 km. The emplacement was in andesitic volcanics on the west and the Pampahuasi diorite Super-unit on the east and has incorporated earlier gabbroic bodies. The Linga suite is thought to be the result of a sequence of three pulses: an elongate unit to the west then two elliptical units to the northeast and southeast. The data for modeling comes from field observations on internal and external contacts, some well-defined magma chamber walls and roof, pendant and stoped blocks, magma chamber zoning, the nature and distribution of enclaves and xenoliths, magmatic fabric, evidences of magma mingling, rock porosity, mineralogical associations in metamorphic aureoles, extensive mineralization and brecciated conduits, and the types of hydrothermal alteration varying with distance from contacts. More than forty hand samples, thin sections, and geochemical analyses were used to estimate water content, magma and country rock temperature, liquid density, and viscosity. Further data will come from: zircon U-Pb ages for country rock and magma batch timeframes, fluid inclusions for magma pressure and temperature, and δ18O data for source of hydrothermal fluids. Simple heat conduction calculations using MATLAB and HEAT 3D for a single tabular intrusion estimated a cooling time to solidus of about 300 k.y. More complex modeling includes magma convection and multiple intrusions. Extensive veining and pervasive alteration suggested the use of HYDROTHERM to model possible additional heat flow effects from hydrothermal fluids. Extensive propylitic and significant potassic alteration were observed and, with TerraSpec infrared spectroscopy to identify mineralogical content of altered outcrops, fluid flux and temperatures were estimated. Rough calculations for cooling times are made using the modeling of Hayba and Ingebritsen (1997).

THE MOLECULAR PATHOLOGY OF MELANOMA: AN INTEGRATED TAXONOMY OF MELANOCYTIC NEOPLASIA

PubMed Central

Bastian, Boris C.

2016-01-01

Melanomas are comprised of multiple biologically distinct categories, which differ in cell of origin, age of onset, clinical and histologic presentation, pattern of metastasis, ethnic distribution, causative role of UV radiation, predisposing germ line alterations, mutational processes, and patterns of somatic mutations. Neoplasms are initiated by gain of function mutations in one of several primary oncogenes, typically leading to benign melanocytic nevi with characteristic histologic features. The progression of nevi is restrained by multiple tumor suppressive mechanisms. Secondary genetic alterations override these barriers and promote intermediate or overtly malignant tumors along distinct progression trajectories. The current knowledge about pathogenesis, clinical, histological and genetic features of primary melanocytic neoplasms is reviewed and integrated into a taxonomic framework. PMID:24460190

Acute monocytic leukemia and multiple abnormalities in a child with duplication of 1q detected by GTG-banding and SKY.

PubMed

Scrideli, Carlos A; Baruffi, Marcelo R; Squire, Jeremy A; Ramos, Ester S; Karaskova, Jana; Heck, Benjamin; Tone, Luiz G

2005-12-01

Patients with 1q duplication have demonstrated a wide range of multiple congenital abnormalities. Alterations involving this chromosomal region have being described in hematopoietic malignancies and a series of candidate genes that may be associated with neoplasias have been mapped in this region. We describe a case of partial trisomy 1q "syndrome" and acute monocytic leukemia. Cytogenetic study of the bone marrow cells by GTG-banding and spectral karyotyping (SKY) showed dup(1)(q23q44) in all cells analyzed. The dismorphological features with the dup(1q) suggest a constitutional chromosome alteration and the first, in our knowledge, association of a trisomy 1q "syndrome" with AML.

Altered receptor trafficking in Huntingtin Interacting Protein 1-transformed cells.

PubMed

Rao, Dinesh S; Bradley, Sarah V; Kumar, Priti D; Hyun, Teresa S; Saint-Dic, Djenann; Oravecz-Wilson, Katherine; Kleer, Celina G; Ross, Theodora S

2003-05-01

The clathrin-associated protein, Huntingtin Interacting Protein 1 (HIP1), is overexpressed in multiple human epithelial tumors. Here, we report that HIP1 is a novel oncoprotein that transforms cells. HIP1-transformed cells, in contrast to RasV12-transformed cells, have dysregulation of multiple receptors involved in clathrin trafficking. Examples include upregulation of the epidermal growth factor receptor (EGFR) and the transferrin receptor. Furthermore, accumulation of transferrin and EGF in the HIP1-transformed cells was increased, and breast tumors that had EGFR expressed also had HIP1 upregulated. Thus, HIP1 overexpression promotes tumor formation and is associated with a general alteration in receptor trafficking. HIP1 is the first endocytic protein to be directly implicated in tumor formation.

Free water determines diffusion alterations and clinical status in cerebral small vessel disease.

PubMed

Duering, Marco; Finsterwalder, Sofia; Baykara, Ebru; Tuladhar, Anil Man; Gesierich, Benno; Konieczny, Marek J; Malik, Rainer; Franzmeier, Nicolai; Ewers, Michael; Jouvent, Eric; Biessels, Geert Jan; Schmidt, Reinhold; de Leeuw, Frank-Erik; Pasternak, Ofer; Dichgans, Martin

2018-06-01

Diffusion tensor imaging detects early tissue alterations in Alzheimer's disease and cerebral small vessel disease (SVD). However, the origin of diffusion alterations in SVD is largely unknown. To gain further insight, we applied free water (FW) imaging to patients with genetically defined SVD (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy [CADASIL], n = 57), sporadic SVD (n = 444), and healthy controls (n = 28). We modeled freely diffusing water in the extracellular space (FW) and measures reflecting fiber structure (tissue compartment). We tested associations between these measures and clinical status (processing speed and disability). Diffusion alterations in SVD were mostly driven by increased FW and less by tissue compartment alterations. Among imaging markers, FW showed the strongest association with clinical status (R 2 up to 34%, P < .0001). Findings were consistent across patients with CADASIL and sporadic SVD. Diffusion alterations and clinical status in SVD are largely determined by extracellular fluid increase rather than alterations of white matter fiber organization. Copyright © 2018 the Alzheimer's Association. All rights reserved.

Characteristics of hydrothermal alteration mineralogy and geochemistry of igneous rocks from the epithermal Co-O mine and district, Eastern Mindanao (Philippines)

NASA Astrophysics Data System (ADS)

Sonntag, Iris; Hagemann, Steffen

2010-05-01

Detailed petrographic as well as hyperspectral analyses using PIMA (Portable Infrared Mineral Analyser) and geochemical (major, trace and rare earth elements) studies were conducted on samples of the epithermal, low sulfidation Co-O mine (47,869 ounces gold produced in 2009 with an average grade of 13.3 g/t gold) and district in Eastern Mindanao (Philippines). The aims of the study were to unravel the petrogenetic origin of the various volcanic (host rocks) and intrusive rocks (potential fluid driver) as well as their relationship and influence on the hydrothermal alteration zoning and fluid chemistry. The auriferous veins at the Co-O mine were formed during two hydrothermal stages associated with the district wide D1 and D2 deformation events. Gold in stage 1 quartz veins is in equilibrium with galena and sphalerite, whereas in stage 2 it is associated with pyrite. Auriferous quartz veins of stage 1 reflect temperatures below 250° C or strong variations in pH and fO2 at higher temperatures, due to potential involvement of acidic gas or meteoric water. Cathodoluminescense studies revealed strong zonation of quartz associated with Au, presumably related to changes in the Al content, which is influenced by the pH. Plumose textures indicate times of rapid deposition, whereas saccharoidal quartz grains are related to potential calcite replacement. The geology of the Co-O mine and district is dominated by Miocene volcanic rocks (basic to intermediate flows and pyroclastics units), which are partly covered by Pliocene volcanic rocks and late Oligocene to Miocene limestones. The Miocene units are intruded by diorite (presumably Miocene in age). The epithermal mineralization event may be related to diorite intrusions. The geochemistry of all igneous rocks in the district is defined by a sub-alkaline affinity and is low to medium K in composition. Most units are related to a Miocene subduction zone with westward subduction, whereas the younger Pliocene rocks are related to the currently active east dipping subduction zone. At the Co-O mine the proximal hydrothermal alteration zone is defined by phyllic to argillic alteration displayed in sericitized to carbonated feldspar, quartz and chloritized amphiboles surrounded by a distal alteration halo displaying propylitic alteration. The alteration geochemistry of these hydrothermal altered rocks is defined by an increase in K2O and Na2O and decrease in Al2O3. However, adularia usually associated with hydrothermal alteration in low epithermal Au quartz veins, has so far not been described, which points to a K-poor magma system. PIMA hydrothermal alteration studies indicate the dominant presence of smectite rather than white mica, which supports the involvement of a K-poor hydrothermal fluid. The epithermal Co-O mine and district displays low to medium potassic magma series and a hydrothermal alteration mineralogy that is K-poor. However, the Co-O mine hosts significant amounts of epithermal gold mineralization. The recognition of poor K melts and hydrothermal alteration mineralogy associated with distinct low-sulfidation epithermal gold mineralization has important implication for exploration in the Co-O district and, potentially, also in other areas in the Philippines and worldwide.

Oncogenic Signaling Pathways in The Cancer Genome Atlas.

PubMed

Sanchez-Vega, Francisco; Mina, Marco; Armenia, Joshua; Chatila, Walid K; Luna, Augustin; La, Konnor C; Dimitriadoy, Sofia; Liu, David L; Kantheti, Havish S; Saghafinia, Sadegh; Chakravarty, Debyani; Daian, Foysal; Gao, Qingsong; Bailey, Matthew H; Liang, Wen-Wei; Foltz, Steven M; Shmulevich, Ilya; Ding, Li; Heins, Zachary; Ochoa, Angelica; Gross, Benjamin; Gao, Jianjiong; Zhang, Hongxin; Kundra, Ritika; Kandoth, Cyriac; Bahceci, Istemi; Dervishi, Leonard; Dogrusoz, Ugur; Zhou, Wanding; Shen, Hui; Laird, Peter W; Way, Gregory P; Greene, Casey S; Liang, Han; Xiao, Yonghong; Wang, Chen; Iavarone, Antonio; Berger, Alice H; Bivona, Trever G; Lazar, Alexander J; Hammer, Gary D; Giordano, Thomas; Kwong, Lawrence N; McArthur, Grant; Huang, Chenfei; Tward, Aaron D; Frederick, Mitchell J; McCormick, Frank; Meyerson, Matthew; Van Allen, Eliezer M; Cherniack, Andrew D; Ciriello, Giovanni; Sander, Chris; Schultz, Nikolaus

2018-04-05

Genetic alterations in signaling pathways that control cell-cycle progression, apoptosis, and cell growth are common hallmarks of cancer, but the extent, mechanisms, and co-occurrence of alterations in these pathways differ between individual tumors and tumor types. Using mutations, copy-number changes, mRNA expression, gene fusions and DNA methylation in 9,125 tumors profiled by The Cancer Genome Atlas (TCGA), we analyzed the mechanisms and patterns of somatic alterations in ten canonical pathways: cell cycle, Hippo, Myc, Notch, Nrf2, PI-3-Kinase/Akt, RTK-RAS, TGFβ signaling, p53 and β-catenin/Wnt. We charted the detailed landscape of pathway alterations in 33 cancer types, stratified into 64 subtypes, and identified patterns of co-occurrence and mutual exclusivity. Eighty-nine percent of tumors had at least one driver alteration in these pathways, and 57% percent of tumors had at least one alteration potentially targetable by currently available drugs. Thirty percent of tumors had multiple targetable alterations, indicating opportunities for combination therapy. Copyright © 2018. Published by Elsevier Inc.

The relative effects on math performance of single- versus multiple-ratio schedules: a case study1

PubMed Central

Lovitt, Tom C.; Esveldt, Karen A.

1970-01-01

This series of four experiments sought to assess the comparative effects of multiple- versus single-ratio schedules on a pupil's responding to mathematics materials. Experiment I, which alternated between single- and multiple-ratio contingencies, revealed that during the latter phase the subject responded at a higher rate. Similar findings were revealed by Exp. II. The third experiment, which manipulated frequency of reinforcement rather than multiple ratios, revealed that the alteration had a minimal effect on the subject's response rate. A final experiment, conducted to assess further the effects of multiple ratios, provided data similar to those of Exp. I and II. PMID:16795267

Predictors of vision impairment in Multiple Sclerosis.

PubMed

Sanchez-Dalmau, Bernardo; Martinez-Lapiscina, Elena H; Pulido-Valdeolivas, Irene; Zubizarreta, Irati; Llufriu, Sara; Blanco, Yolanda; Sola-Valls, Nuria; Sepulveda, Maria; Guerrero, Ana; Alba, Salut; Andorra, Magi; Camos, Anna; Sanchez-Vela, Laura; Alfonso, Veronica; Saiz, Albert; Villoslada, Pablo

2018-01-01

Visual impairment significantly alters the quality of life of people with Multiple Sclerosis (MS). The objective of this study was to identify predictors (independent variables) of visual outcomes, and to define their relationship with neurological disability and retinal atrophy when assessed by optical coherence tomography (OCT). We performed a cross-sectional analysis of 119 consecutive patients with MS, assessing vision using high contrast visual acuity (LogMar), 2.5% and 1.25% low contrast visual acuity (Sloan charts), and color vision (Hardy-Rand-Rittler plates). Quality of vision is a patient reported outcome based on an individual's unique perception of his or her vision and was assessed with the Visual Functioning Questionnaire-25 (VFQ-25) with the 10 neuro-ophthalmologic items. MS disability was assessed using the expanded disability status scale (EDSS), the MS functional composite (MSFC) and the brief repetitive battery-neuropsychology (BRB-N). Retinal atrophy was assessed using spectral domain OCT, measuring the thickness of the peripapillar retinal nerve fiber layer (pRNFL) and the volume of the ganglion cell plus inner plexiform layer (GCIPL). The vision of patients with MS was impaired, particularly in eyes with prior optic neuritis. Retinal atrophy (pRNFL and GCIPL) was closely associated with impaired low contrast vision and color vision, whereas the volume of the GCIPL showed a trend (p = 0.092) to be associated with quality of vision. Multiple regression analysis revealed that EDSS was an explanatory variable for high contrast vision after stepwise analysis, GCIPL volume for low contrast vision, and GCIPL volume and EDSS for color vision. The explanatory variables for quality of vision were high contrast vision and color vision. In summary, quality of vision in MS depends on the impairment of high contrast visual acuity and color vision due to the disease.

Role of tumour necrosis factor (TNF)-α and TNFRSF1A R92Q mutation in the pathogenesis of TNF receptor-associated periodic syndrome and multiple sclerosis

PubMed Central

Caminero, A; Comabella, M; Montalban, X

2011-01-01

It has long been known that tumour necrosis factor (TNF)/TNFRSF1A signalling is involved in the pathophysiology of multiple sclerosis (MS). Different genetic and clinical findings over the last few years have generated renewed interest in this relationship. This paper provides an update on these recent findings. Genome-wide association studies have identified the R92Q mutation in the TNFRSF1A gene as a genetic risk factor for MS (odds ratio 1·6). This allele, which is also common in the general population and in other inflammatory conditions, therefore only implies a modest risk for MS and provides yet another piece of the puzzle that defines the multiple genetic risk factors for this disease. TNFRSF1A mutations have been associated with an autoinflammatory disease known as TNF receptor-associated periodic syndrome (TRAPS). Clinical observations have identified a group of MS patients carrying the R92Q mutation who have additional TRAPS symptoms. Hypothetically, the co-existence of MS and TRAPS or a co-morbidity relationship between the two could be mediated by this mutation. The TNFRSF1A R92Q mutation behaves as a genetic risk factor for MS and other inflammatory diseases, including TRAPS. Nevertheless, this mutation does not appear to be a severity marker of the disease, neither modifying the clinical progression of MS nor its therapeutic response. An alteration in TNF/TNFRS1A signalling may increase proinflammatory signals; the final clinical phenotype may possibly be determined by other genetic or environmental modifying factors that have not yet been identified. PMID:22059991

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.

Experimental Models of Maternal Obesity and Neuroendocrine Programming of Metabolic Disorders in Offspring.

PubMed

Reynolds, Clare M; Segovia, Stephanie A; Vickers, Mark H

2017-01-01

Evidence from epidemiological, clinical, and experimental studies have clearly shown that disease risk in later life is increased following a poor early life environment, a process preferentially termed developmental programming. In particular, this work clearly highlights the importance of the nutritional environment during early development with alterations in maternal nutrition, including both under- and overnutrition, increasing the risk for a range of cardiometabolic and neurobehavioral disorders in adult offspring characterized by both adipokine resistance and obesity. Although the mechanistic basis for such developmental programming is not yet fully defined, a common feature derived from experimental animal models is that of alterations in the wiring of the neuroendocrine pathways that control energy balance and appetite regulation during early stages of developmental plasticity. The adipokine leptin has also received significant attention with clear experimental evidence that normal regulation of leptin levels during the early life period is critical for the normal development of tissues and related signaling pathways that are involved in metabolic and cardiovascular homeostasis. There is also increasing evidence that alterations in the epigenome and other underlying mechanisms including an altered gut-brain axis may contribute to lasting cardiometabolic dysfunction in offspring. Ongoing studies that further define the mechanisms between these associations will allow for identification of early risk markers and implementation of strategies around interventions that will have obvious beneficial implications in breaking a programmed transgenerational cycle of metabolic disorders.

Identification of hydrated silicate minerals on Mars using MRO-CRISM: Geologic context near Nili Fossae and implications for aqueous alteration

USGS Publications Warehouse

Ehlmann, B.L.; Mustard, J.F.; Swayze, G.A.; Clark, R.N.; Bishop, J.L.; Poulet, F.; Des Marais, D.J.; Roach, L.H.; Milliken, R.E.; Wray, J.J.; Barnouin-Jha, O.; Murchie, S.L.

2009-01-01

The Noachian terrain west of the Isidis basin hosts a diverse collection of alteration minerals in rocks comprising varied geomorphic units within a 100,000 km2 region in and near the Nili Fossae. Prior investigations in this region by the Observatoire pour l'Min??ralogie, l'Eau, les Glaces, et l'Activit?? (OMEGA) instrument on Mars Express revealed large exposures of both mafic minerals and iron magnesium phyllosilicates in stratigraphic context. Expanding on the discoveries of OMEGA, the Compact Reconnaissance Imaging Spectrometer for Mars (CRISM) aboard the Mars Reconnaissance Orbiter (MRO) has found more spatially widespread and mineralogically diverse alteration minerals than previously realized, which represent multiple aqueous environments. Using CRISM near-infrared spectral data, we detail the basis for identification of iron and magnesium smectites (including both nontronite and more Mg-rich varieties), chlorite, prehnite, serpentine, kaolinite, potassium mica (illite or muscovite), hydrated (opaline) silica, the sodium zeolite analcime, and magnesium carbonate. The detection of serpentine and analcime on Mars is reported here for the first time. We detail the geomorphic context of these minerals using data from high-resolution imagers onboard MRO in conjunction with CRISM. We find that the distribution of alteration minerals is not homogeneous; rather, they occur in provinces with distinctive assemblages of alteration minerals. Key findings are (1) a distinctive stratigraphy, in and around the Nili Fossae, of kaolinite and magnesium carbonate in bedrock units always overlying Fe/Mg smectites and (2) evidence for mineral phases and assemblages indicative of low-grade metamorphic or hydrothermal aqueous alteration in cratered terrains. The alteration minerals around the Nili Fossae are more typical of those resulting from neutral to alkaline conditions rather than acidic conditions, which appear to have dominated much of Mars. Moreover, the mineralogic diversity and geologic context of alteration minerals found in the region around the Nili Fossae indicates several episodes of aqueous activity in multiple distinct environments. Copyright 2009 by the American Geophysical Union.

The use of positrons to survey alteration layers on synthetic nuclear waste glasses

NASA Astrophysics Data System (ADS)

Reiser, Joelle T.; Parruzot, Benjamin; Weber, Marc H.; Ryan, Joseph V.; McCloy, John S.; Wall, Nathalie A.

2017-07-01

In order to safeguard society and the environment, understanding radioactive waste glass alteration mechanisms in interactions with solutions and near-field materials, such as Fe, is essential to nuclear waste repository performance assessments. Alteration products are formed at the surface of glasses after reaction with solution. In this study, glass altered in the presence of Fe0 in aqueous solution formed two alteration layers: one embedded with Fe closer to the surface and one without Fe found deeper in the sample. Both layers were found to be thinner than the alteration layer found in glass altered in aqueous solution only. For the first time, Doppler Broadening Positron Annihilation Spectroscopy (DB-PAS) is used to non-destructively characterize the pore structures of glass altered in the presence of Fe0. Advantages and disadvantages of DB-PAS compared to other techniques used to analyze pore structures for altered glass samples are discussed. Ultimately, DB-PAS has shown to be an excellent choice for pore structure characterization for glasses with multiple alteration layers. Monte Carlo modeling predicted positron trajectories through the layers, and helped explain DB-PAS data, which showed that the deeper alteration layer without Fe had a similar composition and pore structure to layers on glass altered in water only.

The use of positrons to survey alteration layers on synthetic nuclear waste glasses

DOE PAGES

Reiser, Joelle T.; Parruzot, Benjamin; Weber, Marc H.; ...

2017-07-01

Here, in order to safeguard society and the environment, understanding radioactive waste glass alteration mechanisms in interactions with solutions and near-field materials, such as Fe, is essential to nuclear waste repository performance assessments. Alteration products are formed at the surface of glasses after reaction with solution. In this study, glass altered in the presence of Fe 0 in aqueous solution formed two alteration layers: one embedded with Fe closer to the surface and one without Fe found deeper in the sample. Both layers were found to be thinner than the alteration layer found in glass altered in aqueous solution only.more » For the first time, Doppler Broadening Positron Annihilation Spectroscopy (DB-PAS) is used to non-destructively characterize the pore structures of glass altered in the presence of Fe 0. Advantages and disadvantages of DB-PAS compared to other techniques used to analyze pore structures for altered glass samples are discussed. Ultimately, DB-PAS has shown to be an excellent choice for pore structure characterization for glasses with multiple alteration layers. Monte Carlo modeling predicted positron trajectories through the layers, and helped explain DB-PAS data, which showed that the deeper alteration layer without Fe had a similar composition and pore structure to layers on glass altered in water only.« less

The use of positrons to survey alteration layers on synthetic nuclear waste glasses

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

Reiser, Joelle T.; Parruzot, Benjamin; Weber, Marc H.

Here, in order to safeguard society and the environment, understanding radioactive waste glass alteration mechanisms in interactions with solutions and near-field materials, such as Fe, is essential to nuclear waste repository performance assessments. Alteration products are formed at the surface of glasses after reaction with solution. In this study, glass altered in the presence of Fe 0 in aqueous solution formed two alteration layers: one embedded with Fe closer to the surface and one without Fe found deeper in the sample. Both layers were found to be thinner than the alteration layer found in glass altered in aqueous solution only.more » For the first time, Doppler Broadening Positron Annihilation Spectroscopy (DB-PAS) is used to non-destructively characterize the pore structures of glass altered in the presence of Fe 0. Advantages and disadvantages of DB-PAS compared to other techniques used to analyze pore structures for altered glass samples are discussed. Ultimately, DB-PAS has shown to be an excellent choice for pore structure characterization for glasses with multiple alteration layers. Monte Carlo modeling predicted positron trajectories through the layers, and helped explain DB-PAS data, which showed that the deeper alteration layer without Fe had a similar composition and pore structure to layers on glass altered in water only.« less

Defining biophysical reference conditions for dynamics river systems: an Alaskan example

NASA Astrophysics Data System (ADS)

Pess, G. R.

2008-12-01

Defining reference conditions for dynamic river ecosystems is difficult for two reasons. First long-term, persistent anthropogenic influences such as land development, harvest of biological resources, and invasive species have resulted in degraded, reduced, and simplified ecological communities and associated habitats. Second, river systems that have not been altered through human disturbance rarely have a long-term dataset on ecological conditions. However there are exceptions which can help us define the dynamic nature of river ecosystems. One large-scale exception is the Wood River system in Bristol Bay, Alaska, where habitat and salmon populations have not been altered by anthropogenic influences such as land development, hatchery production, and invasive species. In addition, the one major anthropogenic disturbance, salmon (Oncorhynchus spp.) harvest, has been quantified and regulated since its inception. First, we examined the variation in watershed and stream habitat characteristics across the Wood River system. We then compared these stream habitat characteristics with data that was collected in the 1950s. Lastly, we examined the correlation between pink (Oncorhynchus gorbuscha), chum (O. keta), and Chinook (O. tshawytscha), and sockeye salmon (O. nerka), and habitat characteristics in the Wood River system using four decades of data on salmon. We found that specific habitat attributes such as stream channel wetted width, depth, cover type, and the proportion of spawnable area were similar to data collected in the 1950s. Greater stream habitat variation occurred among streams than over time. Salmon occurrence and abundance, however was more temporal and spatially variable. The occurrence of pink and chum salmon increased from the 1970's to the present in the Wood River system, while sockeye abundance has fluctuated with changes in ocean conditions. Pink, Chinook and chum salmon ranged from non-existent to episodic to abundantly perennial, while sockeye dominated all streams in the Wood River system. One main trend was the frequency of occurrence and abundance of pink, Chinook, and chum salmon increased with watershed drainage area and stream depth and, to a lesser extent, decreased with sockeye salmon density. Conversely, sockeye salmon densities decreased with watershed drainage area and stream depth. Wood river habitat was temporally stable and spatially variable, thus identifying the suite of stream channel types that occur and identifying reference states for each is critical to capture reference conditions. Wood River biological reference states need to be established over a longer time frame than physical attributes because of the large-scale temporal variability that is forced by climatic conditions and larger scale spatially- explicit trends. Thus biological reference states for the Wood River system need to be defined with multiple streams, similar to developing reference states for different stream channel types, in order to capture the range of biological variability.

B cell biology: implications for treatment of systemic lupus erythematosus.

PubMed

Anolik, J H

2013-04-01

B cells are critical players in the orchestration of properly regulated immune responses, normally providing protective immunity without autoimmunity. Balance in the B cell compartment is achieved through the finely regulated participation of multiple B cell populations with different antibody-dependent and independent functions. Both types of functions allow B cells to modulate other components of the innate and adaptive immune system. Autoantibody-independent B cell functions include antigen presentation, T cell activation and polarization, and dendritic cell modulation. Several of these functions are mediated by the ability of B cells to produce immunoregulatory cytokines and chemokines and by their critical contribution to lymphoid tissue development and organization including the development of ectopic tertiary lymphoid tissue. Additionally, the functional versatility of B cells enables them to play either protective or pathogenic roles in autoimmunity. In turn, B cell dysfunction has been critically implicated in the pathophysiology of systemic lupus erythematosus (SLE), a complex disease characterized by the production of autoantibodies and heterogeneous clinical involvement. Thus, the breakdown of B cell tolerance is a defining and early event in the disease process and may occur by multiple pathways, including alterations in factors that affect B cell activation thresholds, B cell longevity, and apoptotic cell processing. Once tolerance is broken, autoantibodies contribute to autoimmunity by multiple mechanisms including immune-complex mediated Type III hypersensitivity reactions, type II antibody-dependent cytotoxicity, and by instructing innate immune cells to produce pathogenic cytokines including IFNα, TNF and IL-1. The complexity of B cell functions has been highlighted by the variable success of B cell-targeted therapies in multiple autoimmune diseases, including those conventionally viewed as T cell-mediated conditions. Given the widespread utilization of B cell depletion therapy in autoimmune diseases and the need for new therapeutic approaches in SLE, a better understanding of human B cell subsets and the balance of pathogenic and regulatory functions is of the essence.

Alternative Splicing of sept9a and sept9b in Zebrafish Produces Multiple mRNA Transcripts Expressed Throughout Development

PubMed Central

Hannibal, Mark C.; Kimelman, David

2010-01-01

Background Septins are involved in a number of cellular processes including cytokinesis and organization of the cytoskeleton. Alterations in human septin-9 (SEPT9) levels have been linked to multiple cancers, whereas mutations in SEPT9 cause the episodic neuropathy, hereditary neuralgic amyotrophy (HNA). Despite its important function in human health, the in vivo role of SEPT9 is unknown. Methodology/Principal Findings Here we utilize zebrafish to study the role of SEPT9 in early development. We show that zebrafish possess two genes, sept9a and sept9b that, like humans, express multiple transcripts. Knockdown or overexpression of sept9a transcripts results in specific developmental alterations including circulation defects and aberrant epidermal development. Conclusions/Significance Our work demonstrates that sept9 plays an important role in zebrafish development, and establishes zebrafish as a valuable model organism for the study of SEPT9. PMID:20502708

Material mechanical characterization method for multiple strains and strain rates

DOEpatents

Erdmand, III, Donald L.; Kunc, Vlastimil; Simunovic, Srdjan; Wang, Yanli

2016-01-19

A specimen for measuring a material under multiple strains and strain rates. The specimen including a body having first and second ends and a gage region disposed between the first and second ends, wherein the body has a central, longitudinal axis passing through the first and second ends. The gage region includes a first gage section and a second gage section, wherein the first gage section defines a first cross-sectional area that is defined by a first plane that extends through the first gage section and is perpendicular to the central, longitudinal axis. The second gage section defines a second cross-sectional area that is defined by a second plane that extends through the second gage section and is perpendicular to the central, longitudinal axis and wherein the first cross-sectional area is different in size than the second cross-sectional area.

A defined medium for Leishmania culture allows definition of essential amino acids.

PubMed

Nayak, Archana; Akpunarlieva, Snezhana; Barrett, Michael; Burchmore, Richard

2018-02-01

Axenic culture of Leishmania is generally performed in rich, serum-supplemented media which sustain robust growth over multiple passages. The use of such undefined media, however, obscures proteomic analyses and confounds the study of metabolism. We have established a simple, defined culture medium that supports the sustained growth of promastigotes over multiple passages and which yields parasites that have similar infectivity to macrophages to parasites grown in a conventional semi-defined medium. We have exploited this medium to investigate the amino acid requirements of promastigotes in culture and have found that phenylalanine, tryptophan, arginine, leucine, lysine and valine are essential for viability in culture. Most of the 20 proteogenic amino acids promote growth of Leishmania promastigotes, with the exception of alanine, asparagine, and glycine. This defined medium will be useful for further studies of promastigote substrate requirements, and will facilitate future proteomic and metabolomic analyses. Copyright © 2018 Elsevier Inc. All rights reserved.

Small Area Indices of Multiple Deprivation in South Africa

ERIC Educational Resources Information Center

Noble, Michael; Barnes, Helen; Wright, Gemma; Roberts, Benjamin

2010-01-01

This paper presents the Provincial Indices of Multiple Deprivation that were constructed by the authors at ward level using 2001 Census data for each of South Africa's nine provinces. The principles adopted in conceptualising the indices are described and multiple deprivation is defined as a weighted combination of discrete dimensions of…

Beyond Tracking: Multiple Pathways to College, Career, and Civic Participation

ERIC Educational Resources Information Center

Oakes, Jeannie, Ed.; Saunders, Marisa, Ed.

2008-01-01

"Beyond Tracking" responds to the a sobering assessment of American high schools by delineating and promoting an innovative and well-defined notion of multiple pathways. The book's authors clearly distinguish their use of the term "multiple pathways" from any updated version of the tracking system that marked so many American high schools during…

Rapid evolution of introduced tree pathogens via episodic selection and horizontal gene transfer

Treesearch

Clive Brasier

2012-01-01

Routine selection is simply defined as “the ecological constraints experienced by an endemic organism that favor a relatively stable but fluctuating population structure over time.” Its antithesis is episodic selection, defined as “any sudden ecological disturbance likely to lead to a significant alteration in a species’ population structure” (Brasier 1986, 1995). In...

The role of Epstein–Barr virus in epithelial malignancies

PubMed Central

Tsao, Sai-Wah; Tsang, Chi Man; To, Ka-Fai; Lo, Kwok-Wai

2015-01-01

The close association of Epstein–Barr virus (EBV) infection with non-keratinizing nasopharyngeal carcinomas and a subset of gastric carcinomas suggests that EBV infection is a crucial event in these cancers. The difficulties encountered in infecting and transforming primary epithelial cells in experimental systems suggest that the role of EBV in epithelial malignancies is complex and multifactorial in nature. Genetic alterations in the premalignant epithelium may support the establishment of latent EBV infection, which is believed to be an initiation event. Oncogenic properties have been reported in multiple EBV latent genes. The BamH1 A rightwards transcripts (BARTs) and the BART-encoded microRNAs (miR-BARTs) are highly expressed in EBV-associated epithelial malignancies and may induce malignant transformation. However, enhanced proliferation may not be the crucial function of EBV infection in epithelial malignancies, at least in the early stages of cancer development. EBV-encoded gene products may confer anti-apoptotic properties and promote the survival of infected premalignant epithelial cells harbouring genetic alterations. Multiple EBV-encoded microRNAs have been reported to have immune evasion functions. Genetic alterations in host cells, as well as inflammatory stroma, could modulate the expression of EBV genes and alter the growth properties of infected premalignant epithelial cells, encouraging their selection during carcinogenesis. PMID:25251730

Reduced cognitive function, increased blood-brain-barrier transport and inflammatory responses, and altered brain metabolites in LDLr -/-and C57BL/6 mice fed a western diet

PubMed Central

Lee, Linda L.; Puchowicz, Michelle; Golub, Mari S.; Befroy, Douglas E.; Wilson, Dennis W.; Anderson, Steven; Cline, Gary; Bini, Jason; Borkowski, Kamil; Knotts, Trina A.; Rutledge, John C.

2018-01-01

Recent work suggests that diet affects brain metabolism thereby impacting cognitive function. Our objective was to determine if a western diet altered brain metabolism, increased blood-brain barrier (BBB) transport and inflammation, and induced cognitive impairment in C57BL/6 (WT) mice and low-density lipoprotein receptor null (LDLr -/-) mice, a model of hyperlipidemia and cognitive decline. We show that a western diet and LDLr -/- moderately influence cognitive processes as assessed by Y-maze and radial arm water maze. Also, western diet significantly increased BBB transport, as well as microvessel factor VIII in LDLr -/- and microglia IBA1 staining in WT, both indicators of activation and neuroinflammation. Interestingly, LDLr -/- mice had a significant increase in 18F- fluorodeoxyglucose uptake irrespective of diet and brain 1H-magnetic resonance spectroscopy showed increased lactate and lipid moieties. Metabolic assessments of whole mouse brain by GC/MS and LC/MS/MS showed that a western diet altered brain TCA cycle and β-oxidation intermediates, levels of amino acids, and complex lipid levels and elevated proinflammatory lipid mediators. Our study reveals that the western diet has multiple impacts on brain metabolism, physiology, and altered cognitive function that likely manifest via multiple cellular pathways. PMID:29444171

Early pathological alterations of lower lumbar cords detected by ultrahigh-field MRI in a mouse multiple sclerosis model.

PubMed

Mori, Yuki; Murakami, Masaaki; Arima, Yasunobu; Zhu, Dasong; Terayama, Yasuo; Komai, Yutaka; Nakatsuji, Yuji; Kamimura, Daisuke; Yoshioka, Yoshichika

2014-02-01

Magnetic resonance imaging (MRI) is widely employed for the diagnosis of multiple sclerosis (MS). However, sometimes, the lesions found by MRI do not correlate with the neurological impairments observed in MS patients. We recently showed autoreactive T cells accumulate in the fifth lumbar cord (L5) to pass the blood-brain barrier and cause inflammation in the central nervous system of experimental autoimmune encephalomyelitis (EAE) mice, an MS model. We here investigated this early event using ultrahigh-field MRI. T2-weighted image signals, which conform to the water content, increased in L4 and L5 during the development of EAE. At the same time, the sizes of L4 and L5 changed. Moreover, angiographic images of MRI showed branch positions of the blood vessels in the lower lumbar cords were significantly altered. Interestingly, EAE mice showed occluded and thickened vessels, particularly during the peak phase, followed by reperfusion in the remission phase. Additionally, demyelination regions of some MS patients had increased lactic acid content, suggesting the presence of ischemic events. These results suggest that inflammation-mediated alterations in the lower lumbar cord change the homeostasis of the spinal cord and demonstrate that ultrahigh-field MRI enables the detection of previously invisible pathological alterations in EAE.

Interactive effects of climate change and biodiversity loss on ecosystem functioning.

PubMed

Pires, Aliny P F; Srivastava, Diane S; Marino, Nicholas A C; MacDonald, A Andrew M; Figueiredo-Barros, Marcos Paulo; Farjalla, Vinicius F

2018-05-01

Climate change and biodiversity loss are expected to simultaneously affect ecosystems, however research on how each driver mediates the effect of the other has been limited in scope. The multiple stressor framework emphasizes non-additive effects, but biodiversity may also buffer the effects of climate change, and climate change may alter which mechanisms underlie biodiversity-function relationships. Here, we performed an experiment using tank bromeliad ecosystems to test the various ways that rainfall changes and litter diversity may jointly determine ecological processes. Litter diversity and rainfall changes interactively affected multiple functions, but how depends on the process measured. High litter diversity buffered the effects of altered rainfall on detritivore communities, evidence of insurance against impacts of climate change. Altered rainfall affected the mechanisms by which litter diversity influenced decomposition, reducing the importance of complementary attributes of species (complementarity effects), and resulting in an increasing dependence on the maintenance of specific species (dominance effects). Finally, altered rainfall conditions prevented litter diversity from fueling methanogenesis, because such changes in rainfall reduced microbial activity by 58%. Together, these results demonstrate that the effects of climate change and biodiversity loss on ecosystems cannot be understood in isolation and interactions between these stressors can be multifaceted. © 2018 by the Ecological Society of America.

Pharmacotherapeutics directed at deficiencies associated with cocaine dependence: Focus on dopamine, norepinephrine and glutamate

PubMed Central

Haile, Colin N.; Mahoney, James J.; Newton, Thomas F.; De La Garza, Richard

2012-01-01

Much effort has been devoted to research focused on pharmacotherapies for cocaine dependence yet there are no FDA-approved medications for this brain disease. Preclinical models have been essential to defining the central and peripheral effects produced by cocaine. Recent evidence suggests that cocaine exerts its reinforcing effects by acting on multiple neurotransmitter systems within mesocorticolimibic circuitry. Imaging studies in cocaine-dependent individuals have identified deficiencies in dopaminergic signaling primarily localized to corticolimbic areas. In addition to dysregulated striatal dopamine, norepinephrine and glutamate are also altered in cocaine dependence. In this review, we present these brain abnormalities as therapeutic targets for the treatment of cocaine dependence. We then survey promising medications that exert their therapeutic effects by presumably ameliorating these brain deficiencies. Correcting neurochemical deficits in cocaine-dependent individuals improves memory and impulse control, and reduces drug craving that may decrease cocaine use. We hypothesize that using medications aimed at reversing known neurochemical imbalances is likely to be more productive than current approaches. This view is also consistent with treatment paradigms used in neuropsychiatry and general medicine. PMID:22327234

Rivers, runoff, and reefs

USGS Publications Warehouse

McLaughlin, C.J.; Smith, C.A.; Buddemeier, R.W.; Bartley, J.D.; Maxwell, B.A.

2003-01-01

The role of terrigenous sediment in controlling the occurrence of coral reef ecosystems is qualitatively understood and has been studied at local scales, but has not been systematically evaluated on a global-to-regional scale. Current concerns about degradation of reef environments and alteration of the hydrologic and sediment cycles place the issue at a focal point of multiple environmental concerns. We use a geospatial clustering of a coastal zone database of river and local runoff identified with 0.5?? grid cells to identify areas of high potential runoff effects, and combine this with a database of reported coral reef locations. Coastal cells with high runoff values are much less likely to contain reefs than low runoff cells and GIS buffer analysis demonstrates that this inhibition extends to offshore ocean cells as well. This analysis does not uniquely define the effects of sediment, since salinity, nutrients, and contaminants are potentially confounding variables also associated with runoff. However, sediment effects are likely to be a major factor and a basis is provided for extending the study to higher resolution with more specific variables. ?? 2003 Elsevier B.V. All rights reserved.

Implications of the Hierarchical Structure of Psychopathology for Psychiatric Neuroimaging.

PubMed

Zald, David H; Lahey, Benjamin B

2017-05-01

Research into the neurobiological substrates of psychopathology has been impeded by heterogeneity within diagnostic categories, comorbidity among mental disorders, and the presence of symptoms that transcend diagnostic categories. Solutions to these issues increasingly focus neurobiological research on isolated or narrow groupings of symptoms or functional constructs rather than categorical diagnoses. Here we argue for a more integrative approach that also incorporates the broad hierarchical structure of psychopathological symptoms and their etiological mechanisms. This approach places clinical neuroscience research in the context of a hierarchy of empirically defined factors of symptoms such as internalizing disorders, externalizing disorders, and the general factor of psychopathology. Application of this hierarchical approach has the potential to reveal neural substrates that nonspecifically contribute to multiple forms of psychopathology and their comorbidity, and in doing so, facilitate the study of mechanisms that are specific to single dimensions and subsets of symptoms. Neurobiological research on the hierarchy of dimensions of psychopathology is only just beginning to emerge, but has the potential to radically alter our understanding of the neurobiology of abnormal behavior.

On the Relationship between Cosmic Ray Exposure Ages and Petrography of CM Chondrites

NASA Technical Reports Server (NTRS)

Takenouchi, A.; Zolensky, M. E.; Nishiizumi, K.; Caffee, M.; Velbel, M. A.; Ross, K.; Zolensky, A.; Lee, L.; Imae, N.; Yamaguchi, A.;

Apolipoprotein A5: A newly identified gene impacting plasmatriglyceride levels in humans and mice

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

Pennacchio, Len A.; Rubin, Edward M.

2002-09-15

Apolipoprotein A5 (APOA5) is a newly described member of theapolipoprotein gene family whose initial discovery arose from comparativesequence analysis of the mammalian APOA1/C3/A4 gene cluster. Functionalstudies in mice indicated that alteration in the level of APOA5significantly impacted plasma triglyceride concentrations. Miceover-expressing human APOA5 displayed significantly reducedtriglycerides, while mice lacking apoA5 had a large increase in thislipid parameter. Studies in humans have also suggested an important rolefor APOA5 in determining plasma triglyceride concentrations. In theseexperiments, polymorphisms in the human gene were found to define severalcommon haplotypes that were associated with significant changes intriglyceride concentrations in multiple populations. Several separateclinical studies havemore » provided consistent and strong support for theeffect with 24 percent of Caucasians, 35 percent of African-Americans and53 percent of Hispanics carrying APOA5 haplotypes associated withincreased plasma triglyceride levels. In summary, APOA5 represents anewly discovered gene involved in triglyceride metabolism in both humansand mice whose mechanism of action remains to be deciphered.« less

Hierarchical organization in the temporal structure of infant-direct speech and song.

PubMed

Falk, Simone; Kello, Christopher T

2017-06-01

Caregivers alter the temporal structure of their utterances when talking and singing to infants compared with adult communication. The present study tested whether temporal variability in infant-directed registers serves to emphasize the hierarchical temporal structure of speech. Fifteen German-speaking mothers sang a play song and told a story to their 6-months-old infants, or to an adult. Recordings were analyzed using a recently developed method that determines the degree of nested clustering of temporal events in speech. Events were defined as peaks in the amplitude envelope, and clusters of various sizes related to periods of acoustic speech energy at varying timescales. Infant-directed speech and song clearly showed greater event clustering compared with adult-directed registers, at multiple timescales of hundreds of milliseconds to tens of seconds. We discuss the relation of this newly discovered acoustic property to temporal variability in linguistic units and its potential implications for parent-infant communication and infants learning the hierarchical structures of speech and language. Copyright © 2017 Elsevier B.V. All rights reserved.

On a collision course: competition and dispersal differences create no-analogue communities and cause extinctions during climate change

PubMed Central

Urban, Mark C.; Tewksbury, Josh J.; Sheldon, Kimberly S.

2012-01-01

Most climate change predictions omit species interactions and interspecific variation in dispersal. Here, we develop a model of multiple competing species along a warming climatic gradient that includes temperature-dependent competition, differences in niche breadth and interspecific differences in dispersal ability. Competition and dispersal differences decreased diversity and produced so-called ‘no-analogue’ communities, defined as a novel combination of species that does not currently co-occur. Climate change altered community richness the most when species had narrow niches, when mean community-wide dispersal rates were low and when species differed in dispersal abilities. With high interspecific dispersal variance, the best dispersers tracked climate change, out-competed slower dispersers and caused their extinction. Overall, competition slowed the advance of colonists into newly suitable habitats, creating lags in climate tracking. We predict that climate change will most threaten communities of species that have narrow niches (e.g. tropics), vary in dispersal (most communities) and compete strongly. Current forecasts probably underestimate climate change impacts on biodiversity by neglecting competition and dispersal differences. PMID:22217718

Open label study to assess the safety of VM202 in subjects with amyotrophic lateral sclerosis.

PubMed

Sufit, Robert L; Ajroud-Driss, Senda; Casey, Patricia; Kessler, John A

2017-05-01

To assess safety and define efficacy measures of hepatocyte growth factor (HGF) DNA plasmid, VM202, administered by intramuscular injections in patients with amyotrophic lateral sclerosis (ALS). Eighteen participants were treated with VM202 administered in divided doses by injections alternating between the upper and lower limbs on d 0, 7, 14, and 21. Subjects were followed for nine months to evaluate possible adverse events. Functional outcome was assessed using the ALS Functional Rating Scale-Revised (ALSFRS-R) as well as by serially measuring muscle strength, muscle circumference, and forced vital capacity. Seventeen of 18 participants completed the study. All participants tolerated 64 mg of VM202 well with no serious adverse events (SAE) related to the drug. Twelve participants reported 26 mild or moderate injection site reactions. Three participants experienced five SAEs unrelated to VM202. One subject died from respiratory insufficiency secondary to ALS progression. Multiple intramuscular injection of VM202 into the limbs appears safe in ALS subjects. Future trials with retreatment after three months will determine whether VM202 treatment alters the long-term course of ALS.

Better conditions for mammalian in vitro splicing provided by acetate and glutamate as potassium counterions

PubMed Central

Reichert, Vienna; Moore, Melissa J.

2000-01-01

We demonstrate here that replacing potassium chloride (KCl) with potassium acetate (KAc) or potassium glutamate (KGlu) routinely enhances the yield of RNA intermediates and products obtained from in vitro splicing reactions performed in HeLa cell nuclear extract. This effect was reproducibly observed with multiple splicing substrates. The enhanced yields are at least partially due to stabilization of splicing precursors and products in the KAc and KGlu reactions. This stabilization relative to KCl reactions was greatest with KGlu and was observed over an extended potassium concentration range. The RNA stability differences could not be attributed to heavy metal contamination of the KCl, since ultrapure preparations of this salt yielded similar results. After testing various methods for altering the salts, we found that substitution of KAc or KGlu for KCl and MgAc2 for MgCl2 in splicing reactions is the simplest and most effective. Since the conditions defined here more closely mimic in vivo ionic concentrations, they may permit the study of more weakly spliced substrates, as well as facilitate more detailed analyses of spliceosome structure and function. PMID:10606638

Attenuated BMP1 Function Compromises Osteogenesis, Leading to Bone Fragility in Humans and Zebrafish

PubMed Central

Asharani, P.V.; Keupp, Katharina; Semler, Oliver; Wang, Wenshen; Li, Yun; Thiele, Holger; Yigit, Gökhan; Pohl, Esther; Becker, Jutta; Frommolt, Peter; Sonntag, Carmen; Altmüller, Janine; Zimmermann, Katharina; Greenspan, Daniel S.; Akarsu, Nurten A.; Netzer, Christian; Schönau, Eckhard; Wirth, Radu; Hammerschmidt, Matthias; Nürnberg, Peter; Wollnik, Bernd; Carney, Thomas J.

2012-01-01

Bone morphogenetic protein 1 (BMP1) is an astacin metalloprotease with important cellular functions and diverse substrates, including extracellular-matrix proteins and antagonists of some TGFβ superfamily members. Combining whole-exome sequencing and filtering for homozygous stretches of identified variants, we found a homozygous causative BMP1 mutation, c.34G>C, in a consanguineous family affected by increased bone mineral density and multiple recurrent fractures. The mutation is located within the BMP1 signal peptide and leads to impaired secretion and an alteration in posttranslational modification. We also characterize a zebrafish bone mutant harboring lesions in bmp1a, demonstrating conservation of BMP1 function in osteogenesis across species. Genetic, biochemical, and histological analyses of this mutant and a comparison to a second, similar locus reveal that Bmp1a is critically required for mature-collagen generation, downstream of osteoblast maturation, in bone. We thus define the molecular and cellular bases of BMP1-dependent osteogenesis and show the importance of this protein for bone formation and stability. PMID:22482805

The complex and specific pMHC interactions with diverse HIV-1 TCR clonotypes reveal a structural basis for alterations in CTL function

NASA Astrophysics Data System (ADS)

Xia, Zhen; Chen, Huabiao; Kang, Seung-Gu; Huynh, Tien; Fang, Justin W.; Lamothe, Pedro A.; Walker, Bruce D.; Zhou, Ruhong

2014-02-01

Immune control of viral infections is modulated by diverse T cell receptor (TCR) clonotypes engaging peptide-MHC class I complexes on infected cells, but the relationship between TCR structure and antiviral function is unclear. Here we apply in silico molecular modeling with in vivo mutagenesis studies to investigate TCR-pMHC interactions from multiple CTL clonotypes specific for a well-defined HIV-1 epitope. Our molecular dynamics simulations of viral peptide-HLA-TCR complexes, based on two independent co-crystal structure templates, reveal that effective and ineffective clonotypes bind to the terminal portions of the peptide-MHC through similar salt bridges, but their hydrophobic side-chain packings can be very different, which accounts for the major part of the differences among these clonotypes. Non-specific hydrogen bonding to viral peptide also accommodates greater epitope variants. Furthermore, free energy perturbation calculations for point mutations on the viral peptide KK10 show excellent agreement with in vivo mutagenesis assays, with new predictions confirmed by additional experiments. These findings indicate a direct structural basis for heterogeneous CTL antiviral function.

Neonatal Restriction of Tactile Inputs Leads to Long-Lasting Impairments of Cross-Modal Processing

PubMed Central

Röder, Brigitte; Hanganu-Opatz, Ileana L.

2015-01-01

Optimal behavior relies on the combination of inputs from multiple senses through complex interactions within neocortical networks. The ontogeny of this multisensory interplay is still unknown. Here, we identify critical factors that control the development of visual-tactile processing by combining in vivo electrophysiology with anatomical/functional assessment of cortico-cortical communication and behavioral investigation of pigmented rats. We demonstrate that the transient reduction of unimodal (tactile) inputs during a short period of neonatal development prior to the first cross-modal experience affects feed-forward subcortico-cortical interactions by attenuating the cross-modal enhancement of evoked responses in the adult primary somatosensory cortex. Moreover, the neonatal manipulation alters cortico-cortical interactions by decreasing the cross-modal synchrony and directionality in line with the sparsification of direct projections between primary somatosensory and visual cortices. At the behavioral level, these functional and structural deficits resulted in lower cross-modal matching abilities. Thus, neonatal unimodal experience during defined developmental stages is necessary for setting up the neuronal networks of multisensory processing. PMID:26600123

Substance use in young adults with schizophrenic disorders.

PubMed

Test, M A; Wallisch, L S; Allness, D J; Ripp, K

1989-01-01

Use of nonprescribed mood altering substances is pervasive and problematic in young adults with serious mental illnesses in community care. Fifty-eight percent of young adult clients with clearly defined schizophrenia or schizophrenia-related disorders participating in a long-term community treatment study were rated by staff or themselves as using alcohol, cannabis, or other street drugs several times a week or more. We interviewed in depth a random sample of these "significant users" to obtain their perspective on their frequencies, patterns, histories, contributing factors to, and effects of substance use and their related treatment experiences. Results revealed these clients' substance use to be of long duration and deeply entrenched, with current use often involving multiple substances including both street drugs and substances of "everyday life" (e.g., caffeine, nicotine). Clients reported compelling reasons for use including anxiety reduction, relief of boredom, and a means for social contact. Staff and clients clearly view substance use quite differently, with the latter focusing at least as much on consequences of symptom relief as symptom exacerbation. Treatment implications are discussed.

Implications of the Hierarchical Structure of Psychopathology for Psychiatric Neuroimaging

PubMed Central

Zald, David H.; Lahey, Benjamin B.

2017-01-01

Research into the neurobiological substrates of psychopathology has been impeded by heterogeneity within diagnostic categories, comorbidity among mental disorders, and the presence of symptoms that transcend diagnostic categories. Solutions to these issues increasingly focus neurobiological research on isolated or narrow groupings of symptoms or functional constructs rather than categorical diagnoses. Here we argue for a more integrative approach that also incorporates the broad hierarchical structure of psychopathological symptoms and their etiological mechanisms. This approach places clinical neuroscience research in the context of a hierarchy of empirically defined factors of symptoms such as internalizing disorders, externalizing disorders, and the general factor of psychopathology. Application of this hierarchical approach has the potential to reveal neural substrates that nonspecifically contribute to multiple forms of psychopathology and their comorbidity, and in doing so, facilitate the study of mechanisms that are specific to single dimensions and subsets of symptoms. Neurobiological research on the hierarchy of dimensions of psychopathology is only just beginning to emerge, but has the potential to radically alter our understanding of the neurobiology of abnormal behavior. PMID:28713866

Geochemistry of the New Caledonia Serpentinites: Evidences for Multiple Serpentinization Events at Various Depths

NASA Astrophysics Data System (ADS)

Ulrich, M.; Munoz, M.; Boulvais, P.; Cathelineau, M.; Guillot, S.; Picard, C.; Putlitz, B.

2016-12-01

Studies of serpentine minerals around the world have shown that different varieties can coexist depending on external conditions such as temperature, pressure and chemical exchanges. Identifying serpentine variety can thus provide significant constraints on the geodynamic environment at the time of formation. In the New Caledonia (NC) ophiolite, serpentinization is ubiquitous (>50%). The base of the ophiolite is made of a thick serpentinite sole that recorded multiple serpentinization events. This study aims at deciphering the nature and the origin of fluids involved in serpentinization processes from the characterization of primary minerals and serpentine geochemistry, including: in situ major and trace elements and stable oxygen and hydrogen isotopes. Our results show that lizardite is the main mineral species ( 80% of the serpentine). In the serpentinite sole, lizardite is crosscut by multiple serpentine veins ordered as follow: lizardite 1→lizardite 2→antigorite→chrysotile→polygonal serpentine. From the trace elements analysis, we demonstrate that the transition from primary minerals to lizardite 1 occurs almost isochemically. However, serpentine composition in the sole strongly differs from lizardite 1 and show a great enrichment in fluid-mobile elements and an increase of Fe3+/FeT ratio. Stable isotopes show that serpentines display a wide range in δ18O (1.9-14‰) and a narrow range in δD (88-106‰). These results were then modeled based on Monte-Carlo simulations. Fluids in equilibrium with NC serpentines define a linear trend that extends from the meteoric water line to an area defined between 3‰ and 8‰ in δ18O and -80‰ and -60‰ in δD. These compositions are consistent with fluids derived from the dehydration of the altered oceanic crust during the subduction in the South Loyalty Basin at temperatures between 250°C and 400°C. No evidence of sedimentary contribution was observed, suggesting that the serpentinization of the NC ophiolite was complete within few million years after the initiation of the subduction. Low δ18O values indicate that the latest generation of serpentine may derive from the circulation of meteoric fluids at low temperature (<150°C), suggesting that the latest steps of serpentinization started from the beginning of the ophiolite obduction.

Isomalto-oligosaccharides, a prebiotic, functionally augment green tea effects against high fat diet-induced metabolic alterations via preventing gut dysbacteriosis in mice.

PubMed

Singh, Dhirendra Pratap; Singh, Jagdeep; Boparai, Ravneet Kaur; Zhu, JianHua; Mantri, Shrikant; Khare, Pragyanshu; Khardori, Romesh; Kondepudi, Kanthi Kiran; Chopra, Kanwaljit; Bishnoi, Mahendra

2017-09-01

High fat diet (HFD)-induced alterations in gut microbiota and resultant 'leaky gut' phenomenon promotes metabolic endotoxemia, ectopic fat deposition, and low-grade systemic inflammation. Here we evaluated the effects of a combination of green tea extract (GTE) with isomalto-oligosaccharide (IMOs) on HFD-induced alterations in mice. Male Swiss albino mice were fed with HFD (58% fat kcal) for 12 weeks. Systemic adiposity, gut derangement parameters and V3-V4 region based 16S rRNA metagenomic sequencing, ectopic fat deposition, liver metabolome analysis, systemic and tissue inflammation, and energy homeostasis markers along with gene expression analysis in multiple tissues were done in mice supplemented with GTE, IMOs or their combination. The combination of GTE and IMOs effectively prevented HFD-induced adiposity and lipid accumulation in liver and muscle while normalizing fasting blood glucose, insulin, glucagon, and leptin levels. Co-administration of GTE with IMOs effectively modulated liver metabolome associated with lipid metabolism. It also prevented leaky gut phenotype and HFD-induced increase in circulating lipopolysaccharides and pro-inflammatory cytokines (e.g. resistin, TNF-α, and IL-1β) and reduction in anti-inflammatory cytokines (e.g. adiponectin and IL-6). Gene expression analysis across multiple tissues further supported these functional outcomes. Most importantly, this combination improved beneficial gut microbiota (Lactobacillus sp., Bifidobacteria, Akkermansia muciniphila, Roseburia spp.) abundances, restored Firmicutes/Bacteriodetes and improved Prevotella/Bacteroides proportions. In particular, a combination of these two agents has shown improved beneficial effects on multiple parameters studied. Data presented herein suggests that strategically chosen food components might be highly effective in the prevention of HFD-induced alterations and may further be developed as functional foods. Copyright © 2017 Elsevier Ltd. All rights reserved.

Deciphering the associations between gene expression and copy number alteration using a sparse double Laplacian shrinkage approach

PubMed Central

Shi, Xingjie; Zhao, Qing; Huang, Jian; Xie, Yang; Ma, Shuangge

2015-01-01

Motivation: Both gene expression levels (GEs) and copy number alterations (CNAs) have important biological implications. GEs are partly regulated by CNAs, and much effort has been devoted to understanding their relations. The regulation analysis is challenging with one gene expression possibly regulated by multiple CNAs and one CNA potentially regulating the expressions of multiple genes. The correlations among GEs and among CNAs make the analysis even more complicated. The existing methods have limitations and cannot comprehensively describe the regulation. Results: A sparse double Laplacian shrinkage method is developed. It jointly models the effects of multiple CNAs on multiple GEs. Penalization is adopted to achieve sparsity and identify the regulation relationships. Network adjacency is computed to describe the interconnections among GEs and among CNAs. Two Laplacian shrinkage penalties are imposed to accommodate the network adjacency measures. Simulation shows that the proposed method outperforms the competing alternatives with more accurate marker identification. The Cancer Genome Atlas data are analysed to further demonstrate advantages of the proposed method. Availability and implementation: R code is available at http://works.bepress.com/shuangge/49/ Contact: shuangge.ma@yale.edu Supplementary information: Supplementary data are available at Bioinformatics online. PMID:26342102

Extensive vascular remodeling in the spinal cord of pre-symptomatic experimental autoimmune encephalomyelitis mice; increased vessel expression of fibronectin and the α5β1 integrin

PubMed Central

Boroujerdi, Amin; Welser-Alves, Jennifer V.; Milner, Richard

2013-01-01

Alterations in vascular structure and function are a central component of demyelinating disease. In addition to blood-brain barrier (BBB) breakdown, which occurs early in the course of disease, recent studies have described angiogenic remodeling, both in multiple sclerosis tissue and in the mouse demyelinating model, experimental autoimmune encephalomyelitis (EAE). As the precise timing of vascular remodeling in demyelinating disease has yet to be fully defined, the purpose of the current study was to define the time-course of these events in the MOG35-55 EAE model. Quantification of endothelial cell proliferation and vessel density revealed that a large part of angiogenic remodeling in cervical spinal cord white matter occurs during the pre-symptomatic phase of EAE. At the height of vascular remodeling, blood vessels in the cervical spinal cord showed strong transient upregulation of fibronectin and the α5β1 integrin. In vitro experiments revealed that α5 integrin inhibition reduced brain endothelial cell proliferation under inflammatory conditions. Interestingly, loss of vascular integrity was evident in all vessels during the first 4–7 days post-immunization, but after 14 days, was localized predominantly to venules. Taken together, our data demonstrate that extensive vascular remodeling occurs during the pre-symptomatic phase of EAE and point to a potential role for the fibronectin-α5β1 integrin interaction in promoting vascular remodeling during demyelinating disease. PMID:24056042

Exercise training and immune crosstalk in breast cancer microenvironment: exploring the paradigms of exercise-induced immune modulation and exercise-induced myokines.

PubMed

Goh, Jorming; Niksirat, Negin; Campbell, Kristin L

2014-01-01

Observational research suggests that exercise may reduce the risk of breast cancer and improve survival. One proposed mechanism for the protective effect of aerobic exercise related to cancer risk and outcomes, but has not been examined definitively, is the immune response to aerobic exercise. Two prevailing paradigms are proposed. The first considers the host immune response as modifiable by aerobic exercise training. This exercise-modulated immune-tumor crosstalk in the mammary microenvironment may alter the balance between tumor initiation and progression versus tumor suppression. The second paradigm considers the beneficial role of exercise-induced, skeletal muscle-derived cytokines, termed "myokines". These myokines exert endocrine-like effects on multiple organs, including the mammary glands. In this systematic review, we i) define the role of macrophages and T-cells in breast cancer initiation and progression; ii) address the two paradigms that support exercise-induced immunomodulation; iii) systematically assessed the literature for exercise intervention that assessed biomarkers relevant to both paradigms in human intervention trials of aerobic exercise training, in healthy women and women with breast cancer; iv) incorporated pre-clinical animal studies and non-RCTs for background discussion of putative mechanisms, through which aerobic exercise training modulates the immunological crosstalk, or the myokine-tumor interaction in the tumor microenvironment; and v) speculated on the potential biomarkers and mechanisms that define an exercise-induced, anti-tumor "signature", with a view toward developing relevant biomarkers for future aerobic exercise intervention trials.

Extensive vascular remodeling in the spinal cord of pre-symptomatic experimental autoimmune encephalomyelitis mice; increased vessel expression of fibronectin and the α5β1 integrin.

PubMed

Boroujerdi, Amin; Welser-Alves, Jennifer V; Milner, Richard

2013-12-01

Alterations in vascular structure and function are a central component of demyelinating disease. In addition to blood-brain barrier (BBB) breakdown, which occurs early in the course of disease, recent studies have described angiogenic remodeling, both in multiple sclerosis tissue and in the mouse demyelinating model, experimental autoimmune encephalomyelitis (EAE). As the precise timing of vascular remodeling in demyelinating disease has yet to be fully defined, the purpose of the current study was to define the time-course of these events in the MOG35-55 EAE model. Quantification of endothelial cell proliferation and vessel density revealed that a large part of angiogenic remodeling in cervical spinal cord white matter occurs during the pre-symptomatic phase of EAE. At the height of vascular remodeling, blood vessels in the cervical spinal cord showed strong transient upregulation of fibronectin and the α5β1 integrin. In vitro experiments revealed that α5 integrin inhibition reduced brain endothelial cell proliferation under inflammatory conditions. Interestingly, loss of vascular integrity was evident in all vessels during the first 4-7days post-immunization, but after 14days, was localized predominantly to venules. Taken together, our data demonstrate that extensive vascular remodeling occurs during the pre-symptomatic phase of EAE and point to a potential role for the fibronectin-α5β1 integrin interaction in promoting vascular remodeling during demyelinating disease. © 2013.

Cisplatin Resistance: A Cellular Self-Defense Mechanism Resulting from Multiple Epigenetic and Genetic Changes

PubMed Central

Shen, Ding-Wu; Pouliot, Lynn M.; Hall, Matthew D.

2012-01-01

Cisplatin is one of the most effective broad-spectrum anticancer drugs. Its effectiveness seems to be due to the unique properties of cisplatin, which enters cells via multiple pathways and forms multiple different DNA-platinum adducts while initiating a cellular self-defense system by activating or silencing a variety of different genes, resulting in dramatic epigenetic and/or genetic alternations. As a result, the development of cisplatin resistance in human cancer cells in vivo and in vitro by necessity stems from bewilderingly complex genetic and epigenetic changes in gene expression and alterations in protein localization. Extensive published evidence has demonstrated that pleiotropic alterations are frequently detected during development of resistance to this toxic metal compound. Changes occur in almost every mechanism supporting cell survival, including cell growth-promoting pathways, apoptosis, developmental pathways, DNA damage repair, and endocytosis. In general, dozens of genes are affected in cisplatin-resistant cells, including pathways involved in copper metabolism as well as transcription pathways that alter the cytoskeleton, change cell surface presentation of proteins, and regulate epithelial-to-mesenchymal transition. Decreased accumulation is one of the most common features resulting in cisplatin resistance. This seems to be a consequence of numerous epigenetic and genetic changes leading to the loss of cell-surface binding sites and/or transporters for cisplatin, and decreased fluid phase endocytosis. PMID:22659329

Cisplatin resistance: a cellular self-defense mechanism resulting from multiple epigenetic and genetic changes.

PubMed

Shen, Ding-Wu; Pouliot, Lynn M; Hall, Matthew D; Gottesman, Michael M

2012-07-01

Cisplatin is one of the most effective broad-spectrum anticancer drugs. Its effectiveness seems to be due to the unique properties of cisplatin, which enters cells via multiple pathways and forms multiple different DNA-platinum adducts while initiating a cellular self-defense system by activating or silencing a variety of different genes, resulting in dramatic epigenetic and/or genetic alternations. As a result, the development of cisplatin resistance in human cancer cells in vivo and in vitro by necessity stems from bewilderingly complex genetic and epigenetic changes in gene expression and alterations in protein localization. Extensive published evidence has demonstrated that pleiotropic alterations are frequently detected during development of resistance to this toxic metal compound. Changes occur in almost every mechanism supporting cell survival, including cell growth-promoting pathways, apoptosis, developmental pathways, DNA damage repair, and endocytosis. In general, dozens of genes are affected in cisplatin-resistant cells, including pathways involved in copper metabolism as well as transcription pathways that alter the cytoskeleton, change cell surface presentation of proteins, and regulate epithelial-to-mesenchymal transition. Decreased accumulation is one of the most common features resulting in cisplatin resistance. This seems to be a consequence of numerous epigenetic and genetic changes leading to the loss of cell-surface binding sites and/or transporters for cisplatin, and decreased fluid phase endocytosis.

Cerebral arterial bolus arrival time is prolonged in multiple sclerosis and associated with disability

PubMed Central

Paling, David; Thade Petersen, Esben; Tozer, Daniel J; Altmann, Daniel R; Wheeler-Kingshott, Claudia AM; Kapoor, Raju; Miller, David H; Golay, Xavier

2014-01-01

Alterations in the overall cerebral hemodynamics have been reported in multiple sclerosis (MS); however, their cause and significance is unknown. While potential venous causes have been examined, arterial causes have not. In this study, a multiple delay time arterial spin labeling magnetic resonance imaging sequence at 3T was used to quantify the arterial hemodynamic parameter bolus arrival time (BAT) and cerebral blood flow (CBF) in normal-appearing white matter (NAWM) and deep gray matter in 33 controls and 35 patients with relapsing–remitting MS. Bolus arrival time was prolonged in MS in NAWM (1.0±0.2 versus 0.9±0.2 seconds, P=0.031) and deep gray matter (0.90±0.18 versus 0.80±0.14 seconds, P=0.001) and CBF was increased in NAWM (14±4 versus 10±2 mL/100 g/min, P=0.001). Prolonged BAT in NAWM (P=0.042) and deep gray matter (P=0.01) were associated with higher expanded disability status score. This study demonstrates alteration in cerebral arterial hemodynamics in MS. One possible cause may be widespread inflammation. Bolus arrival time was longer in patients with greater disability independent of atrophy and T2 lesion load, suggesting alterations in cerebral arterial hemodynamics may be a marker of clinically relevant pathology. PMID:24045400

Association of urinary metal profiles with altered glucose levels and diabetes risk: a population-based study in China.

PubMed

Feng, Wei; Cui, Xiuqing; Liu, Bing; Liu, Chuanyao; Xiao, Yang; Lu, Wei; Guo, Huan; He, Meian; Zhang, Xiaomin; Yuan, Jing; Chen, Weihong; Wu, Tangchun

2015-01-01

Elevated heavy metals and fasting plasma glucose (FPG) levels were both associated with increased risk of cardiovascular diseases. However, studies on the associations of heavy metals and essential elements with altered FPG and diabetes risk were limited or conflicting. The objective of this study was to evaluate the potential associations of heavy metals and essential trace elements with FPG and diabetes risk among general Chinese population. We conducted a cross-sectional study to investigate the associations of urinary concentrations of 23 metals with FPG, impaired fasting glucose (IFG) and diabetes among 2242 community-based Chinese adults in Wuhan. We used the false discovery rate (FDR) method to correct for multiple hypothesis tests. After adjusting for potential confounders, urinary aluminum, titanium, cobalt, nickel, copper, zinc, selenium, rubidium, strontium, molybdenum, cadmium, antimony, barium, tungsten and lead were associated with altered FPG, IFG or diabetes risk (all P< 0.05); arsenic was only dose-dependently related to diabetes (P< 0.05). After additional adjustment for multiple testing, titanium, copper, zinc, selenium, rubidium, tungsten and lead were still significantly associated with one or more outcomes (all FDR-adjusted P< 0.05). Our results suggest that multiple metals in urine are associated with FPG, IFG or diabetes risk. Because the cross-sectional design precludes inferences about causality, further prospective studies are warranted to validate our findings.

ITS system specification. Appendix A, architectural trade-off analysis

DOT National Transportation Integrated Search

1997-01-01

The objective of the Polaris Project is to define an Intelligent Transportation Systems (ITS) architecture for the state of Minnesota. An architecture is a framework that defines how multiple ITS Components interrelate and contribute to the overall I...

ITS system specification. Appendix D, physical architecture component interfaces

DOT National Transportation Integrated Search

1997-01-01

The objective of the Polaris Project is to define an Intelligent Transportation Systems (ITS) architecture for the state of Minnesota. An architecture is a framework that defines how multiple ITS Components interrelate and contribute to the overall I...

Pancreatic and Duodenal Homeobox Protein 1 (Pdx-1) Maintains Endoplasmic Reticulum Calcium Levels through Transcriptional Regulation of Sarco-endoplasmic Reticulum Calcium ATPase 2b (SERCA2b) in the Islet β Cell*

PubMed Central

Johnson, Justin S.; Kono, Tatsuyoshi; Tong, Xin; Yamamoto, Wataru R.; Zarain-Herzberg, Angel; Merrins, Matthew J.; Satin, Leslie S.; Gilon, Patrick; Evans-Molina, Carmella

2014-01-01

Although the pancreatic duodenal homeobox 1 (Pdx-1) transcription factor is known to play an indispensable role in β cell development and secretory function, recent data also implicate Pdx-1 in the maintenance of endoplasmic reticulum (ER) health. The sarco-endoplasmic reticulum Ca2+ ATPase 2b (SERCA2b) pump maintains a steep Ca2+ gradient between the cytosol and ER lumen. In models of diabetes, our data demonstrated loss of β cell Pdx-1 that occurs in parallel with altered SERCA2b expression, whereas in silico analysis of the SERCA2b promoter revealed multiple putative Pdx-1 binding sites. We hypothesized that Pdx-1 loss under inflammatory and diabetic conditions leads to decreased SERCA2b levels and activity with concomitant alterations in ER health. To test this, siRNA-mediated knockdown of Pdx-1 was performed in INS-1 cells. The results revealed reduced SERCA2b expression and decreased ER Ca2+, which was measured using fluorescence lifetime imaging microscopy. Cotransfection of human Pdx-1 with a reporter fused to the human SERCA2 promoter increased luciferase activity 3- to 4-fold relative to an empty vector control, and direct binding of Pdx-1 to the proximal SERCA2 promoter was confirmed by chromatin immunoprecipitation. To determine whether restoration of SERCA2b could rescue ER stress induced by Pdx-1 loss, Pdx1+/− mice were fed a high-fat diet. Isolated islets demonstrated an increased spliced-to-total Xbp1 ratio, whereas SERCA2b overexpression reduced the Xbp1 ratio to that of wild-type controls. Together, these results identify SERCA2b as a novel transcriptional target of Pdx-1 and define a role for altered ER Ca2+ regulation in Pdx-1-deficient states. PMID:25271154

Systematic review with meta-analysis: risk factors for non-alcoholic fatty liver disease suggest a shared altered metabolic and cardiovascular profile between lean and obese patients.

PubMed

Sookoian, S; Pirola, C J

2017-07-01

The pathogenesis of non-alcoholic fatty liver disease (NAFLD) is closely associated with the co-occurrence of multiple pathological conditions characterising the metabolic syndrome (MetS), obesity in particular. However, NAFLD also develops in lean subjects, whose risk factors remain poorly defined. We performed a meta-analysis of 15 studies, along with the data pertaining to our own population (n=336 patients). Data from lean (n=1966) and obese (n=5938) patients with NAFLD were analysed; lean (n=9946) and obese (n=6027) subjects without NAFLD served as controls. Relative to the lean non-NAFLD controls, lean patients with NAFLD were older (3.79±0.72 years, P=1.36×10 -6 ) and exhibited the entire spectrum of the MetS risk factors. Specifically, they had a significant (P=10 -10 ) increase in plasma glucose levels (6.44±1.12 mg/dL) and HOMA-IR (0.52±0.094-unit increment), blood lipids (triglycerides: 48.37±3.6, P=10 -10 and total cholesterol: 7.04±3.8, mg/dL, P=4.2×10 -7 ), systolic (5.64±0.7) and diastolic (3.37±0.9) blood pressure (mm Hg), P=10 -10 , and waist circumference (5.88±0.4 cm, P=10 -10 ); values denote difference in means±SE. Nevertheless, the overall alterations in the obese group were much more severe when compared to lean subjects, regardless of the presence of NAFLD. Meta-regression suggested that NAFLD is a modifier of the level of blood lipids. Lean and obese patients with NAFLD share a common altered metabolic and cardiovascular profile. The former, while having normal body weight, showed excess of abdominal adipose tissue as well as other MetS features. © 2017 John Wiley & Sons Ltd.

Glucose hypermetabolism in the thalamus of patients with drug-induced blepharospasm.

PubMed

Suzuki, Y; Kiyosawa, M; Wakakura, M; Mochizuki, M; Ishiwata, K; Oda, K; Ishii, K

2014-03-28

We examined the difference in cerebral function alterations between drug-induced blepharospasm patients and essential blepharospasm (EB) patients by using positron emission tomography with (18)F-fluorodeoxyglucose. Cerebral glucose metabolism was examined in 21 patients with drug-induced blepharospasm (5 men and 16 women; mean age, 53.1 [range, 29-78] years), 21 essential EB patients (5 men and 16 women; mean age, 53.0 [range, 33-72] years) and 24 healthy subjects (6 men and 18 women; mean age, 57.9 [range, 22-78] years) with long-term history of benzodiazepines use (drug healthy subjects). Drug-induced blepharospasm patients developed symptoms while taking benzodiazepines or thienodiazepines. Sixty-three normal volunteers (15 men and 48 women; mean age, 53.6 [range, 20-70] years) were examined as controls. Differences between the patient groups and control group were examined by statistical parametric mapping. Additionally, we defined regions of interests on both sides of the thalamus, caudate nucleus, anterior putamen, posterior putamen and primary somatosensory area. The differences between groups were tested using two-sample t-tests with Bonferroni correction for multiple comparisons. Cerebral glucose hypermetabolism on both side of the thalamus was detected in drug-induced blepharospasm, EB patients and drug healthy subjects by statistical parametric mapping. In the analysis of regions of interest, glucose metabolism in both sides of the thalamus in the drug-induced blepharospasm group was significantly lower than that in the EB group. Moreover, we observed glucose hypermetabolism in the anterior and posterior putamen bilaterally in EB group but not in drug-induced blepharospasm group and drug healthy subjects. Long-term regimens of benzodiazepines or thienodiazepines may cause down-regulation of benzodiazepine receptors in the brain. We suggest that the functional brain alteration in drug-induced blepharospasm patients is similar to that in EB patients, and that alteration of the GABAergic system might be related to the pathology of both blepharospasm types. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

Clinical and radiological features of invasive Klebsiella pneumoniae liver abscess syndrome.

PubMed

Shin, Sung Ui; Park, Chang Min; Lee, Youkyung; Kim, Eui-Chong; Kim, Soo Jin; Goo, Jin Mo

2013-06-01

Recently, a striking new clinical manifestation of Klebsiella pneumoniae (KP) infection referred to as invasive KP liver abscess syndrome (IKPLAS), defined by liver abscess with contemporaneous metastatic KP infections at other body sites has been documented. Until now, however, there have been relatively few reports regarding its radiologic features. To describe the clinical and radiological features of IKPLAS patients, and to compare them with those with KP liver abscess without metastatic infections to ascertain possible predictors of IKPLAS. From January 2008 to May 2010, 35 patients (26 men and 9 women; mean age, 59.4 years) with both liver abscess and metastatic KP infections were diagnosed with IKPLAS. Their clinical and radiological features were retrospectively evaluated and compared with those of 25 contemporaneous non-metastatic patients to investigate predictive factors for metastatic infections. The rate of intensive care unit admissions and overall mortality was 34.3% and 17.1% in IKPLAS patients, and was significantly higher than those of the non-metastatic group (8% and 0%, respectively). As for metastatic infections, the lung was the most common site and multiple nodules or masses (n = 9) were the most common manifestations. Univariate analysis revealed that liver abscess ≤5.8 cm, bilobar involvement of abscess and altered mentality were significantly related with IKPLAS. At multivariate analysis, liver abscess ≤5.8 cm was proven to be a significant independent predictor of IKPLAS (OR, 3.6; P = 0.038). In addition, altered mentality was present solely in IKPLAS (25.7% vs. 0%) although its P value (P = 0.052) did not reach a statistical significance at multivariate analysis. IKPLAS has significantly worse prognosis than non-metastatic KP abscess patients. In patients with KP liver abscess, liver abscess ≤5.8 cm can be used as an independent predictor of IKPLAS and altered mentality as a very specific feature in diagnosing IKPLAS. © 2013 The Foundation Acta Radiologica.

Impact of magnetic resonance imaging on preoperative planning for breast cancer surgery.

PubMed

Law, Y; Cheung, Polly S Y; Lau, Silvia; Lo, Gladys G

2013-08-01

To review the impact of preoperative breast magnetic resonance imaging on the management of planned surgery, and the appropriateness of any resulting alterations. Retrospective review. A private hospital in Hong Kong. PATIENTS; For the 147 consecutive biopsy-proven breast cancer patients who underwent preoperative magnetic resonance imaging to determine tumour extent undergoing operation by a single surgeon between 1 January 2006 and 31 December 2009, the impact of magnetic resonance imaging findings was reviewed in terms of management alterations and their appropriateness. The most common indication for breast magnetic resonance imaging was the presence of multiple indeterminate shadows on ultrasound scans (53%), followed by ill-defined border of the main tumour on ultrasound scans (19%). In 66% (97 out of 147) of the patients, the extent of the operation was upgraded. Upgrading entailed: lumpectomy to wider lumpectomy (23 out of 97), lumpectomy to mastectomy (47 out of 97), lumpectomy to bilateral lumpectomy (15 out of 97), and other (12 out of 97). Mostly, these management changes were because magnetic resonance imaging showed more extensive disease (n=29), additional cancer foci (n=39), or contralateral disease (n=24). In five instances, upgrading was due to patient preference. In 34% (50 out of 147) of the patients, there was no change in the planned operation. Regarding 97 of the patients having altered management, in 12 the changes were considered inappropriately extensive (due to false-positive magnetic resonance imaging findings). In terms of magnetic resonance imaging detection of more extensive, multifocal, multicentric, or contralateral disease, the false-positive rate was 13% and false-negative rate 7%. Corresponding rates for sensitivity and specificity were 95% and 81%, using the final pathology as the gold standard. Preoperative magnetic resonance imaging had a clinically significant and mostly correct impact on management plans. Magnetic resonance imaging should be included as part of the preoperative investigation in patients planned for breast-conserving surgery, in whom there are doubts about the extent of the tumours based on conventional assessment.

Marine benthic ecological functioning over decreasing taxonomic richness

NASA Astrophysics Data System (ADS)

Törnroos, Anna; Bonsdorff, Erik; Bremner, Julie; Blomqvist, Mats; Josefson, Alf B.; Garcia, Clement; Warzocha, Jan

2015-04-01

Alterations to ecosystem function due to reductions in species richness are predicted to increase as humans continue to affect the marine environment, especially in coastal areas, which serve as the interface between land and sea. The potential functional consequences due to reductions in species diversity have attracted considerable attention recently but little is known about the consequence of such loss in natural communities. We examined how the potential for function is affected by natural reductions in taxon richness using empirical (non-simulated) coastal marine benthic macrofaunal data from the Skagerrak-Baltic Sea region (N. Europe), where taxon richness decreases 25-fold, from 151 to 6 taxa. To estimate functional changes we defined multiple traits (10 traits and 51 categories) on which trait category richness, functional diversity (FD) and number of taxa per trait category were calculated. Our results show that decrease in taxon richness leads to an overall reduction in function but functional richness remains comparatively high even at the lowest level of taxon richness. Although the taxonomic reduction was sharp, up to 96% of total taxon richness, we identified both potential thresholds in functioning and subtler changes where function was maintained along the gradient. The functional changes were not only caused by reductions in taxa per trait category, some categories were maintained or even increased. Primarily, the reduction in species richness altered trait categories related to feeding, living and movement and thus potentially could have an effect on various ecosystem processes. This highlights the importance of recognising ecosystem multifunctionality, especially at low taxonomic richness. We also found that in this system rare species (singletons) did not stand for the functional complexities and changes. Our findings were consistent with theoretical and experimental predictions and suggest that a large proportion of the information about alterations of function is found in measures such as functional diversity and number of taxa per trait category.

A Paleomagnetic and Diagenetic Study of the Woodford Shale, Oklahoma, U.S.A.: The Timing of Hydrothermal Alteration

NASA Astrophysics Data System (ADS)

Roberts, J.; Elmore, R. D.

2017-12-01

An oriented Woodford Shale core from the Ardmore Basin near the Ouachita thrust zone (Core B) was sampled to identify diagenetic events and interpret their origin, and to test if a magnetization was present that can be used to date the altering event(s). The shale is extensively altered, exhibiting a complex paragenesis with multiple fractures and brecciated intervals. Multiple hydrothermal minerals, including biotite, magnesite, norsethite, witherite, gorceixite, potassium feldspar, sphalerite, chalcopyrite, and saddle dolomite, are present in and around fractures and in the matrix. Vitrinite and bitumen reflectance measurements indicate VRo values of 1.82% ( 230°C). Two other Woodford Shale cores (A and C) from the Anadarko Basin also contain hydrothermal minerals. Vitrinite and bitumen reflectance data reveal trends between thermal maturity and the level of hydrothermal alteration, with Core A (0.80% VRo ( 125°C) displaying the lowest alteration, and Core C ( 1.5% VRo ( 210°C) displaying intermediate alteration compared to core B. Paleomagnetic analysis of Core B reveals the presence of a characteristic remanent magnetization (ChRM) with south-southeasterly declinations and shallow inclinations that is unblocked by 450°C and is interpreted to reside in magnetite. This ChRM is interpreted to be either a chemical remanent magnetization (CRM) or a thermochemical remanent magnetization (TCRM) acquired during the Late Permian based on the pole position. The presence of specimens with the CRM/TCRM in altered rock and high thermal maturities suggests that this CRM/TCRM originated from alteration by hydrothermal fluids. These results suggest that the Woodford Shale evolved into an open diagenetic system. In addition to causing heightened thermal maturities, these hydrothermal fluids both increased porosity through dissolution and decreased porosity through precipitation of minerals. The Late Permian timing agrees with the dating of hydrothermal alteration found within the Ouachita and Arbuckle Mountains in other studies. The timing for these events is postcollisional, and the most consistent model for the origin of the hydrothermal minerals is fluid flow as a result of faulting that accessed reservoir(s) of warm fluids.

Alterations of parenchymal microstructure, neuronal connectivity and cerebrovascular resistance at adolescence following mild to moderate traumatic brain injury in early development.

PubMed

Parent, Maxime; Li, Ying; Santhakumar, Vijayalakshmi; Hyder, Fahmeed; Sanganahalli, Basavaraju G; Kannurpatti, Sridhar

2018-06-01

TBI is a leading cause of morbidity in children. To investigate outcome of early developmental TBI during adolescence, a rat model of fluid percussion injury was developed, where previous work reported deficits in sensorimotor behavior and cortical blood flow at adolescence. 1 Based on the non-localized outcome, we hypothesized that multiple neurophysiological components of brain function, namely neuronal connectivity, synapse/axonal microstructural integrity and neurovascular function are altered and magnetic resonance imaging (MRI) methods could be used to determine regional alterations. Adolescent outcomes of developmental TBI were studied 2-months after injury, using functional MRI (fMRI) and Diffusion Tensor Imaging (DTI). fMRI based resting state functional connectivity (RSFC), representing neural connectivity, was significantly altered between sham and TBI. RSFC strength decreased in the cortex, hippocampus and thalamus accompanied by decrease in the spatial extent of their corresponding RSFC networks and inter-hemispheric asymmetry. Cerebrovascular reactivity to arterial CO2 changes diminished after TBI across both hemispheres, with a more pronounced decrease in the ipsilateral hippocampus, thalamus and motor cortex. DTI measures of fractional anisotropy (FA) and apparent diffusion coefficient (ADC), reporting on axonal and microstructural integrity of the brain, indicated similar inter-hemispheric asymmetry, with highest change in the ipsilateral hippocampus and regions adjoining the ipsilateral thalamus, hypothalamus and amygdala. TBI-induced corpus callosal microstructural alterations indicated measurable changes in inter-hemispheric structural connectivity. Hippocampus, thalamus and select cortical regions were most consistently affected in multiple imaging markers. The multi-modal MRI results demonstrate cortical and subcortical alterations in neural connectivity, cerebrovascular resistance and parenchymal microstructure in the adolescent brain, indicating the highly diffuse and persistent nature of the lateral fluid percussion TBI early in development.

HIV skews the lineage-defining transcriptional profile of Mycobacterium tuberculosis-specific CD4+ T cells

PubMed Central

Riou, Catherine; Strickland, Natalie; Soares, Andreia P.; Corleis, Bjorn; Kwon, Douglas; Wherry, E. John; Wilkinson, Robert J.; Burgers, Wendy A.

2016-01-01

HIV-infected persons are at greater risk of developing tuberculosis (TB) even before profound CD4 loss occurs, suggesting that HIV alters CD4+T cell functions capable of containing bacterial replication. An effective immune response to Mycobacterium tuberculosis likely relies on the development of a balanced CD4 response, where distinct CD4+T helper subsets act in synergy to control the infection. To define the diversity of Mtb-specific CD4+Th subsets and determine whether HIV infection impacts such responses, the expression of lineage-defining transcription factors T-bet, Gata3, RORγt and Foxp3 was measured in Mtb-specific CD4+T cells in HIV-uninfected (n=20) and HIV-infected individuals (n=20) with latent TB infection. Our results show that upon 5 day restimulation in vitro, Mtb-specific CD4+T cells from healthy individuals have the ability to exhibit a broad spectrum of T helper subsets, defined by specific patterns of transcription factor co-expression. These transcription factor profiles were skewed in HIV-infected individuals where the proportion of T-bethighFoxp3+ Mtb-specific CD4+T cells was significantly decreased (p=0.002) compared to HIV-uninfected individuals, a change that correlated inversely with HIV viral load (p=0.0007) and plasma TNF-α (p=0.027). Our data demonstrate an important balance in T helper subset diversity defined by lineage-defining transcription factor co-expression profiles that is disrupted by HIV infection and suggest a role for HIV in impairing TB immunity by altering the equilibrium of Mtb-specific CD4+T helper subsets. PMID:26927799

Passive band-gap reconfiguration born from bifurcation asymmetry.

PubMed

Bernard, Brian P; Mann, Brian P

2013-11-01

Current periodic structures are constrained to have fixed energy transmission behavior unless active control or component replacement is used to alter their wave propagation characteristics. The introduction of nonlinearity to generate multiple stable equilibria is an alternative strategy for realizing distinct energy propagation behaviors. We investigate the creation of a reconfigurable band-gap system by implementing passive switching between multiple stable states of equilibrium, to alter the level of energy attenuation in response to environmental stimuli. The ability to avoid potentially catastrophic loads is demonstrated by tailoring the bandpass and band-gap regions to coalesce for two stable equilibria and varying an external load parameter to trigger a bifurcation. The proposed phenomenon could be utilized in remote or autonomous applications where component modifications and active control are impractical.

The Multiple-Car Method. Exploring Its Use in Driver and Traffic Safety Education. Second Edition.

ERIC Educational Resources Information Center

American Driver and Traffic Safety Education Association, Washington, DC.

Primarily written for school administrators and driver education teachers, this publication presents information on planning and implementing the multiple car method of driver instruction. An introductory section presents a definition of the multiple car method and its history of development. It is defined as an off-street paved area incorporating…

The Multiple Worlds of Ghanaian-Born Immigrant Students and Academic Success

ERIC Educational Resources Information Center

Kumi-Yeboah, Alex

2018-01-01

Background/Context: The multiple worlds model is defined as the ability of students to connect, manage, and negotiate to cross the borders of their two worlds to successfully transition through different everyday worlds of school, family, and peers. Prior research has linked multiple worlds such as school, teacher, family, and peers to the…

Excited delirium syndrome (ExDS): treatment options and considerations.

PubMed

Vilke, Gary M; Bozeman, William P; Dawes, Donald M; Demers, Gerard; Wilson, Michael P

2012-04-01

The term Excited Delirium Syndrome (ExDS) has traditionally been used in the forensic literature to describe findings in a subgroup of patients with delirium who suffered lethal consequences from their untreated severe agitation.(1-5) Excited delirium syndrome, also known as agitated delirium, is generally defined as altered mental status and combativeness or aggressiveness. Although the exact signs and symptoms are difficult to define precisely, clinical findings often include many of the following: tolerance to significant pain, rapid breathing, sweating, severe agitation, elevated temperature, delirium, non-compliance or poor awareness to direction from police or medical personnel, lack of fatiguing, unusual or superhuman strength, and inappropriate clothing for the current environment. It has become increasingly recognized that individuals displaying ExDS are at high risk for sudden death, and ExDS therefore represents a true medical emergency. Recently the American College of Emergency Physicians (ACEP) published the findings of a white paper on the topic of ExDS to better find consensus on the issues of definition, diagnosis, and treatment.(6) In so doing, ACEP joined the National Association of Medical Examiners (NAME) in recognizing ExDS as a medical condition. For both paramedics and physicians, the difficulty in diagnosing the underlying cause of ExDS in an individual patient is that the presenting clinical signs and symptoms of ExDS can be produced by a wide variety of clinical disease processes. For example, agitation, combativeness, and altered mental status can be produced by hypoglycemia, thyroid storm, certain kinds of seizures, and these conditions can be difficult to distinguish from those produced by cocaine or methamphetamine intoxication.(7) Prehospital personnel are generally not expected to differentiate between the multiple possible causes of the patient's presentation, but rather simply to recognize that the patient has a medical emergency and initiate appropriate stabilizing treatment. ExDS patients will generally require transfer to an emergency department (ED) for further management, evaluation, and definitive care. In this paper, we present a typical ExDS case and then review existing literature for current treatment options. Copyright © 2011 Elsevier Ltd and Faculty of Forensic and Legal Medicine. All rights reserved.

An observational model for biomechanical assessment of sprint kayaking technique.

PubMed

McDonnell, Lisa K; Hume, Patria A; Nolte, Volker

2012-11-01

Sprint kayaking stroke phase descriptions for biomechanical analysis of technique vary among kayaking literature, with inconsistencies not conducive for the advancement of biomechanics applied service or research. We aimed to provide a consistent basis for the categorisation and analysis of sprint kayak technique by proposing a clear observational model. Electronic databases were searched using key words kayak, sprint, technique, and biomechanics, with 20 sources reviewed. Nine phase-defining positions were identified within the kayak literature and were divided into three distinct types based on how positions were defined: water-contact-defined positions, paddle-shaft-defined positions, and body-defined positions. Videos of elite paddlers from multiple camera views were reviewed to determine the visibility of positions used to define phases. The water-contact-defined positions of catch, immersion, extraction, and release were visible from multiple camera views, therefore were suitable for practical use by coaches and researchers. Using these positions, phases and sub-phases were created for a new observational model. We recommend that kayaking data should be reported using single strokes and described using two phases: water and aerial. For more detailed analysis without disrupting the basic two-phase model, a four-sub-phase model consisting of entry, pull, exit, and aerial sub-phases should be used.

Intestinal microbiota in primary sclerosing cholangitis.

PubMed

Hov, Johannes R; Kummen, Martin

2017-03-01

Alterations of the gut-liver axis have been linked to the pathogenesis of primary sclerosing cholangitis (PSC) since the disease was first described. The purpose of this review is to discuss multiple recent studies on the intestinal microbiota in human PSC and experimental models of this disease. Data are available from eight cross-sectional studies of human PSC, which include a variable number of patients (n = 11-85), material (mucosal or fecal), and microbiota profiling methodology. Despite the heterogeneity of the studies, a pattern of differences is observed that could represent a theme or signature of the PSC gut microbiota, characterized by low diversity and with alterations in multiple bacterial taxa. In experimental models of PSC, re-derivation of animals into germ-free facilities may either aggravate or attenuate the disease, depending on host genetics and putative disease mechanisms (e.g., fibrotic or immune-driven processes, respectively). The present data provide a strong rationale to explore the functional consequences of the observed gut microbial alterations and their influence on the pathogenesis in PSC. Studies of gut microbiota as biomarker and treatment target may potentially also lead to early translation into clinical practice.

Actin filaments-A target for redox regulation.

PubMed

Wilson, Carlos; Terman, Jonathan R; González-Billault, Christian; Ahmed, Giasuddin

2016-10-01

Actin and its ability to polymerize into dynamic filaments is critical for the form and function of cells throughout the body. While multiple proteins have been characterized as affecting actin dynamics through noncovalent means, actin and its protein regulators are also susceptible to covalent modifications of their amino acid residues. In this regard, oxidation-reduction (Redox) intermediates have emerged as key modulators of the actin cytoskeleton with multiple different effects on cellular form and function. Here, we review work implicating Redox intermediates in post-translationally altering actin and discuss what is known regarding how these alterations affect the properties of actin. We also focus on two of the best characterized enzymatic sources of these Redox intermediates-the NADPH oxidase NOX and the flavoprotein monooxygenase MICAL-and detail how they have both been identified as altering actin, but share little similarity and employ different means to regulate actin dynamics. Finally, we discuss the role of these enzymes and redox signaling in regulating the actin cytoskeleton in vivo and highlight their importance for neuronal form and function in health and disease. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Actin filaments – a target for redox regulation

PubMed Central

Wilson, Carlos; Terman, Jonathan R.; González-Billault, Christian; Ahmed, Giasuddin

2016-01-01

Actin and its ability to polymerize into dynamic filaments is critical for the form and function of cells throughout the body. While multiple proteins have been characterized as affecting actin dynamics through non-covalent means, actin and its protein regulators are also susceptible to covalent modifications of their amino acid residues. In this regard, oxidation-reduction (Redox) intermediates have emerged as key modulators of the actin cytoskeleton with multiple different effects on cellular form and function. Here, we review work implicating Redox intermediates in post-translationally altering actin and discuss what is known regarding how these alterations affect the properties of actin. We also focus on two of the best characterized enzymatic sources of these Redox intermediates – the NADPH oxidase NOX and the flavoprotein monooxygenase MICAL – and detail how they have both been identified as altering actin, but share little similarity and employ different means to regulate actin dynamics. Finally, we discuss the role of these enzymes and redox signaling in regulating the actin cytoskeleton in vivo and highlight their importance for neuronal form and function in health and disease. PMID:27309342

Multiple sclerosis-related white matter microstructural change alters the BOLD hemodynamic response.

PubMed

Hubbard, Nicholas A; Turner, Monroe; Hutchison, Joanna L; Ouyang, Austin; Strain, Jeremy; Oasay, Larry; Sundaram, Saranya; Davis, Scott; Remington, Gina; Brigante, Ryan; Huang, Hao; Hart, John; Frohman, Teresa; Frohman, Elliot; Biswal, Bharat B; Rypma, Bart

2016-11-01

Multiple sclerosis (MS) results in inflammatory damage to white matter microstructure. Prior research using blood-oxygen-level dependent (BOLD) imaging indicates MS-related alterations to brain function. What is currently unknown is the extent to which white matter microstructural damage influences BOLD signal in MS. Here we assessed changes in parameters of the BOLD hemodynamic response function (HRF) in patients with relapsing-remitting MS compared to healthy controls. We also used diffusion tensor imaging to assess whether MS-related changes to the BOLD-HRF were affected by changes in white matter microstructural integrity. Our results showed MS-related reductions in BOLD-HRF peak amplitude. These MS-related amplitude decreases were influenced by individual differences in white matter microstructural integrity. Other MS-related factors including altered reaction time, limited spatial extent of BOLD activity, elevated lesion burden, or lesion proximity to regions of interest were not mediators of group differences in BOLD-HRF amplitude. Results are discussed in terms of functional hyperemic mechanisms and implications for analysis of BOLD signal differences. © The Author(s) 2015.

Specific role of impaired glucose metabolism and diabetes mellitus in endothelial progenitor cell characteristics and function.

PubMed

Yiu, Kai-Hang; Tse, Hung-Fat

2014-06-01

The disease burden of diabetes mellitus (DM) and its associated cardiovascular complications represent a growing and major global health problem. Recent studies suggest that circulating exogenous endothelial progenitor cells (EPCs) play an important role in endothelial repair and neovascularization at sites of injury or ischemia. Both experimental and clinical studies have demonstrated that hyperglycemia related to DM can induce alterations to EPCs. The reduction and dysfunction of EPCs related to DM correlate with the occurrence and severity of microvascular and macrovascular complications, suggesting a close mechanistic link between EPC dysfunction and impaired vascular function/repair in DM. These alterations to EPCs, likely mediated by multiple pathophysiological mechanisms, including inflammation, oxidative stress, and alterations in Akt and the nitric oxide pathway, affect EPCs at multiple stages: differentiation and mobilization in the bone marrow, trafficking and survival in the circulation, and homing and neovascularization. Several different therapeutic approaches have consequently been proposed to reverse the reduction and dysfunction of EPCs in DM and may represent a novel therapeutic approach to prevent and treat DM-related cardiovascular complications. © 2014 American Heart Association, Inc.

ITS system specification. Appendix B, requirements by service/function/subfunction

DOT National Transportation Integrated Search

1997-01-01

The objective of the Polaris Project is to define an Intelligent Transportation Systems (ITS) architecture for the state of Minnesota. An architecture is a framework that defines how multiple ITS Components interrelate and contribute to the overall I...

Oxygen isotope evidence for hydrothermal alteration within a Quaternary stratovolcano, Lassen Volcanic National Park, California

NASA Astrophysics Data System (ADS)

Rose, Timothy P.; Criss, Robert E.; Mughannam, Andrew J.; Clynne, Michael A.

1994-11-01

Brokeoff volcano, a Quaternary stratocone located in the Lassen volcanic center in northern California, has been deeply eroded, exposing a 10-sq km meteoric hydrothermal alteration zone at the core of the volcano. Portions of the former volcanic edifice are sufficiently well preserved that an unusual opportunity exists wherein the alteration pattern can be correlated with the position of the volcanic cone. The delta(O-18) analyses of more than 100 whole rock samples, consisting primarily of andesitic lavas, vary from +9.8 to +0.6 per mil. The highest delta(O-18) values occur in bleached, solfatarically altered rocks that have interacted with low-pH, fumarolic hot springs associated with the present-day hydrothermal system. Low delta(O-18) values are found in propylitically altered rocks that underwent isotopic exchange with meteoric hydrothermal fluids at elevated temperatures, mostly during the stratovolcanic stage (650-400 ka) of the hydrothermal system, but probably continuing today at depth. Electron microprobe analyses of secondary layer silicate minerals in strongly propylitized samples (delta(O-18) is less than +5.0) revealed the presence of discrete chlorite, suggesting that temperatures up to 200 to 250 C were attained in the shallow levels of the system. Two zones of pervasive meteoric hydrothermal alteration, defined by concentric O-18 contours that are probably interconnected at depth, are located within the original topographic edifice of the volcano. The most intensely altered rocks within these equant zones of alteration define NNW trends that coincide with stream valleys and with regional structural patterns. A comparison of the characteristics of the O-18-depleted zone at Brokeoff with those of more deeply eroded volcanic centers, such as the Comstock Lode mining district (Criss and Champion, 1991), permits the construction of composite O-18 cross sections through a hypothetical intact stratovolcano. At both Brokeoff and Comstock, hydrothermal fluids were strongly focused into plumelike zones of intense O-18 depletion. At Comstock, these low-O-18 plumes are associated with faults. Although major fault displacements are not observed at Brokeoff, the topographic and alteration patterns are consistent with the presence of a linear array of faults that acted as conduits for fluid flow up into the shallow levels of the volcano.

Cystathionine beta-synthase deficiency alters hepatic phospholipid and choline metabolism: Post-translational repression of phosphatidylethanolamine N-methyltransferase is a consequence rather than a cause of liver injury in homocystinuria.

PubMed

Jacobs, René L; Jiang, Hua; Kennelly, John P; Orlicky, David J; Allen, Robert H; Stabler, Sally P; Maclean, Kenneth N

2017-04-01

Classical homocystinuria (HCU) due to inactivating mutation of cystathionine β-synthase (CBS) is a poorly understood life-threatening inborn error of sulfur metabolism. A previously described cbs-/- mouse model exhibits a semi-lethal phenotype due to neonatal liver failure. The transgenic HO mouse model of HCU exhibits only mild liver injury and recapitulates multiple aspects of the disease as it occurs in humans. Disruption of the methionine cycle in HCU has the potential to impact multiple aspect of phospholipid (PL) metabolism by disruption of both the Kennedy pathway and phosphatidylethanolamine N-methyltransferase (PEMT) mediated synthesis of phosphatidylcholine (PC). Comparative metabolomic analysis of HO mouse liver revealed decreased levels of choline, and choline phosphate indicating disruption of the Kennedy pathway. Alterations in the relative levels of multiple species of PL included significant increases in PL degradation products consistent with enhanced membrane PL turnover. A significant decrease in PC containing 20:4n6 which primarily formed by the methylation of phosphatidylethanolamine to PC was consistent with decreased flux through PEMT. Hepatic expression of PEMT in both the cbs-/- and HO models is post-translationally repressed with decreased levels of PEMT protein and activity that inversely-correlates with the scale of liver injury. Failure to induce further repression of PEMT in HO mice by increased homocysteine, methionine and S-adenosylhomocysteine or depletion of glutathione combined with examination of multiple homocysteine-independent models of liver injury indicated that repression of PEMT in HCU is a consequence rather than a cause of liver injury. Collectively, our data show significant alteration of a broad range of hepatic PL and choline metabolism in HCU with the potential to contribute to multiple aspects of pathogenesis in this disease. Copyright © 2017 Elsevier Inc. All rights reserved.

Chronic Pain: Content Validation of Nursing Diagnosis in Slovakia and the Czech Republic.

PubMed

Zeleníková, Renáta; Maniaková, Lenka

2015-10-01

The main purpose of the study was to validate the defining characteristics and related factors of the nursing diagnosis "chronic pain" in Slovakia and the Czech Republic. This is a descriptive study. The validation process involved was based on Fehring's Diagnostic Content Validity Model. Three defining characteristics (reports pain, altered ability to continue previous activities, and depression) were classified as major by Slovak nurses, and one defining characteristic (reports pain) was classified as major by Czech nurses. The results of the study provide guidance in devising strategies of pain assessment and can aid in the formulation of accurate nursing diagnoses. The defining characteristic "reports pain" is important for arriving at the nursing diagnosis "chronic pain." © 2014 NANDA International, Inc.

General Anesthesia and Altered States of Arousal: A Systems Neuroscience Analysis

PubMed Central

Brown, Emery N.; Purdon, Patrick L.; Van Dort, Christa J.

2011-01-01

Placing a patient in a state of general anesthesia is crucial for safely and humanely performing most surgical and many nonsurgical procedures. How anesthetic drugs create the state of general anesthesia is considered a major mystery of modern medicine. Unconsciousness, induced by altered arousal and/or cognition, is perhaps the most fascinating behavioral state of general anesthesia. We perform a systems neuroscience analysis of the altered arousal states induced by five classes of intravenous anesthetics by relating their behavioral and physiological features to the molecular targets and neural circuits at which these drugs are purported to act. The altered states of arousal are sedation-unconsciousness, sedation-analgesia, dissociative anesthesia, pharmaco-logic non-REM sleep, and neuroleptic anesthesia. Each altered arousal state results from the anesthetic drugs acting at multiple targets in the central nervous system. Our analysis shows that general anesthesia is less mysterious than currently believed. PMID:21513454

Integrated Multiregional Analysis Proposing a New Model of Colorectal Cancer Evolution.

PubMed

Uchi, Ryutaro; Takahashi, Yusuke; Niida, Atsushi; Shimamura, Teppei; Hirata, Hidenari; Sugimachi, Keishi; Sawada, Genta; Iwaya, Takeshi; Kurashige, Junji; Shinden, Yoshiaki; Iguchi, Tomohiro; Eguchi, Hidetoshi; Chiba, Kenichi; Shiraishi, Yuichi; Nagae, Genta; Yoshida, Kenichi; Nagata, Yasunobu; Haeno, Hiroshi; Yamamoto, Hirofumi; Ishii, Hideshi; Doki, Yuichiro; Iinuma, Hisae; Sasaki, Shin; Nagayama, Satoshi; Yamada, Kazutaka; Yachida, Shinichi; Kato, Mamoru; Shibata, Tatsuhiro; Oki, Eiji; Saeki, Hiroshi; Shirabe, Ken; Oda, Yoshinao; Maehara, Yoshihiko; Komune, Shizuo; Mori, Masaki; Suzuki, Yutaka; Yamamoto, Ken; Aburatani, Hiroyuki; Ogawa, Seishi; Miyano, Satoru; Mimori, Koshi

2016-02-01

Understanding intratumor heterogeneity is clinically important because it could cause therapeutic failure by fostering evolutionary adaptation. To this end, we profiled the genome and epigenome in multiple regions within each of nine colorectal tumors. Extensive intertumor heterogeneity is observed, from which we inferred the evolutionary history of the tumors. First, clonally shared alterations appeared, in which C>T transitions at CpG site and CpG island hypermethylation were relatively enriched. Correlation between mutation counts and patients' ages suggests that the early-acquired alterations resulted from aging. In the late phase, a parental clone was branched into numerous subclones. Known driver alterations were observed frequently in the early-acquired alterations, but rarely in the late-acquired alterations. Consistently, our computational simulation of the branching evolution suggests that extensive intratumor heterogeneity could be generated by neutral evolution. Collectively, we propose a new model of colorectal cancer evolution, which is useful for understanding and confronting this heterogeneous disease.

Contextual cuing contributes to the independent modification of multiple internal models for vocal control

PubMed Central

Keough, Dwayne

2011-01-01

Research on the control of visually guided limb movements indicates that the brain learns and continuously updates an internal model that maps the relationship between motor commands and sensory feedback. A growing body of work suggests that an internal model that relates motor commands to sensory feedback also supports vocal control. There is evidence from arm-reaching studies that shows that when provided with a contextual cue, the motor system can acquire multiple internal models, which allows an animal to adapt to different perturbations in diverse contexts. In this study we show that trained singers can rapidly acquire multiple internal models regarding voice fundamental frequency (F0). These models accommodate different perturbations to ongoing auditory feedback. Participants heard three musical notes and reproduced each one in succession. The musical targets could serve as a contextual cue to indicate which direction (up or down) feedback would be altered on each trial; however, participants were not explicitly instructed to use this strategy. When participants were gradually exposed to altered feedback adaptation was observed immediately following vocal onset. Aftereffects were target specific and did not influence vocal productions on subsequent trials. When target notes were no longer a contextual cue, adaptation occurred during altered feedback trials and evidence for trial-by-trial adaptation was found. These findings indicate that the brain is exceptionally sensitive to the deviations between auditory feedback and the predicted consequence of a motor command during vocalization. Moreover, these results indicate that, with contextual cues, the vocal control system may maintain multiple internal models that are capable of independent modification during different tasks or environments. PMID:21346208

Microstructural White Matter Alterations in the Corpus Callosum of Girls With Conduct Disorder.

PubMed

Menks, Willeke Martine; Furger, Reto; Lenz, Claudia; Fehlbaum, Lynn Valérie; Stadler, Christina; Raschle, Nora Maria

2017-03-01

Diffusion tensor imaging (DTI) studies in adolescent conduct disorder (CD) have demonstrated white matter alterations of tracts connecting functionally distinct fronto-limbic regions, but only in boys or mixed-gender samples. So far, no study has investigated white matter integrity in girls with CD on a whole-brain level. Therefore, our aim was to investigate white matter alterations in adolescent girls with CD. We collected high-resolution DTI data from 24 girls with CD and 20 typically developing control girls using a 3T magnetic resonance imaging system. Fractional anisotropy (FA) and mean diffusivity (MD) were analyzed for whole-brain as well as a priori-defined regions of interest, while controlling for age and intelligence, using a voxel-based analysis and an age-appropriate customized template. Whole-brain findings revealed white matter alterations (i.e., increased FA) in girls with CD bilaterally within the body of the corpus callosum, expanding toward the right cingulum and left corona radiata. The FA and MD results in a priori-defined regions of interest were more widespread and included changes in the cingulum, corona radiata, fornix, and uncinate fasciculus. These results were not driven by age, intelligence, or attention-deficit/hyperactivity disorder comorbidity. This report provides the first evidence of white matter alterations in female adolescents with CD as indicated through white matter reductions in callosal tracts. This finding enhances current knowledge about the neuropathological basis of female CD. An increased understanding of gender-specific neuronal characteristics in CD may influence diagnosis, early detection, and successful intervention strategies. Copyright © 2017 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.

Altered Cytochrome c Display Precedes Apoptotic Cell Death in Drosophila

PubMed Central

Varkey, Johnson; Chen, Po; Jemmerson, Ronald; Abrams, John M.

1999-01-01

Drosophila affords a genetically well-defined system to study apoptosis in vivo. It offers a powerful extension to in vitro models that have implicated a requirement for cytochrome c in caspase activation and apoptosis. We found that an overt alteration in cytochrome c anticipates programmed cell death (PCD) in Drosophila tissues, occurring at a time that considerably precedes other known indicators of apoptosis. The altered configuration is manifested by display of an otherwise hidden epitope and occurs without release of the protein into the cytosol. Conditional expression of the Drosophila death activators, reaper or grim, provoked apoptogenic cytochrome c display and, surprisingly, caspase activity was necessary and sufficient to induce this alteration. In cell-free studies, cytosolic caspase activation was triggered by mitochondria from apoptotic cells but identical preparations from healthy cells were inactive. Our observations provide compelling validation of an early role for altered cytochrome c in PCD and suggest propagation of apoptotic physiology through reciprocal, feed-forward amplification involving cytochrome c and caspases. PMID:10037791

MECHANISMS IN ENDOCRINOLOGY: Aging and anti-aging: a Combo-Endocrinology overview.

PubMed

Diamanti-Kandarakis, Evanthia; Dattilo, Maurizio; Macut, Djuro; Duntas, Leonidas; Gonos, Efstathios S; Goulis, Dimitrios G; Gantenbein, Christina Kanaka; Kapetanou, Marianna; Koukkou, Eftychia; Lambrinoudaki, Irene; Michalaki, Marina; Eftekhari-Nader, Shahla; Pasquali, Renato; Peppa, Melpomeni; Tzanela, Marinella; Vassilatou, Evangeline; Vryonidou, Andromachi

2017-06-01

Aging and its underlying pathophysiological background has always attracted the attention of the scientific society. Defined as the gradual, time-dependent, heterogeneous decline of physiological functions, aging is orchestrated by a plethora of molecular mechanisms, which vividly interact to alter body homeostasis. The ability of an organism to adjust to these alterations, in conjunction with the dynamic effect of various environmental stimuli across lifespan, promotes longevity, frailty or disease. Endocrine function undergoes major changes during aging, as well. Specifically, alterations in hormonal networks and concomitant hormonal deficits/excess, augmented by poor sensitivity of tissues to their action, take place. As hypothalamic-pituitary unit is the central regulator of crucial body functions, these alterations can be translated in significant clinical sequelae that can impair the quality of life and promote frailty and disease. Delineating the hormonal signaling alterations that occur across lifespan and exploring possible remedial interventions could possibly help us improve the quality of life of the elderly and promote longevity. © 2017 European Society of Endocrinology.

Intron Definition Is Required for Excision of the Minute Virus of Mice Small Intron and Definition of the Upstream Exon

PubMed Central

Haut, Donald D.; Pintel, D. J.

1998-01-01

Alternative splicing of pre-mRNAs plays a critical role in maximizing the coding capacity of the small parvovirus genome. The small-intron region of minute virus of mice (MVM) pre-mRNAs undergoes an unusual pattern of overlapping alternative splicing—using two donors (D1 and D2) and two acceptors (A1 and A2) within a region of 120 nucleotides—that determines the steady-state ratios of the various viral mRNAs. In this report, we show that the determinants that govern excision of the small intron are complex and are also required for efficient definition of the upstream exon. For the MVM small intron in its natural context, the two donors appear to compete for the splicing machinery: the position of D1 favors its usage, while the primary sequence of D2 must be more like the consensus sequence than is D1 to be used efficiently. We have genetically defined the branch points that are used for generation of the major and minor spliced forms and show that recognition of components of the small-intron acceptors is likely to be the dominant determinant in alternative small-intron excision. We have also identified a G-rich intronic enhancer sequence within the small intron that is essential for splicing of the minor form (D2 to A2) but not the major form (D1 to A1) of MVM mRNAs and is required for efficient definition of the upstream NS2-specific exon. In its natural context, the small intron appears to be excised by a mechanism consistent with intron definition. When the MVM small intron is expanded, various parameters of its excision are altered, indicating that critical cis-acting signals are context dependent. Relative use of the donors and acceptors is altered, and the upstream NS2-specific exon is no longer efficiently defined. The fact that definition of the upstream NS2-specific exon can be achieved by the MVM small intron in its natural context, but not when it is expanded, suggests that the multiple determinants that govern definition and excision of the small intron are required, in concert, for upstream exon definition. Our data are consistent with a model in which alternative splicing of the MVM P4-generated pre-mRNAs is governed by a hybrid of intron- and exon-defining mechanisms. PMID:9499034

slc7a6os gene plays a critical role in defined areas of the developing CNS in zebrafish.

PubMed

Benini, Anna; Cignarella, Francesca; Calvarini, Laura; Mantovanelli, Silvia; Giacopuzzi, Edoardo; Zizioli, Daniela; Borsani, Giuseppe

2015-01-01

The aim of this study is to shed light on the functional role of slc7a6os, a gene highly conserved in vertebrates. The Danio rerio slc7a6os gene encodes a protein of 326 amino acids with 46% identity to human SLC7A6OS and 14% to Saccharomyces cerevisiae polypeptide Iwr1. Yeast Iwr1 specifically binds RNA pol II, interacts with the basal transcription machinery and regulates the transcription of specific genes. In this study we investigated for the first time the biological role of SLC7A6OS in vertebrates. Zebrafish slc7a6os is a maternal gene that is expressed throughout development, with a prevalent localization in the developing central nervous system (CNS). The gene is also expressed, although at different levels, in various tissues of the adult fish. To determine the functional role of slc7a6os during zebrafish development, we knocked-down the gene by injecting a splice-blocking morpholino. At 24 hpf morphants show morphological defects in the CNS, particularly the interface between hindbrain and midbrain is not well-defined. At 28 hpf the morpholino injected embryos present an altered somite morphology and appear partially or completely immotile. At this stage the midbrain, hindbrain and cerebellum are compromised and not well defined compared with control embryos. The observed alterations persist at later developmental stages. Consistently, the expression pattern of two markers specifically expressed in the developing CNS, pax2a and neurod, is significantly altered in morphants. The co-injection of embryos with synthetic slc7a6os mRNA, rescues the morphant phenotype and restores the wild type expression pattern of pax2a and neurod. Our data suggest that slc7a6os might play a critical role in defined areas of the developing CNS in vertebrates, probably by regulating the expression of key genes.

slc7a6os Gene Plays a Critical Role in Defined Areas of the Developing CNS in Zebrafish

PubMed Central

Benini, Anna; Cignarella, Francesca; Calvarini, Laura; Mantovanelli, Silvia; Giacopuzzi, Edoardo; Zizioli, Daniela; Borsani, Giuseppe

2015-01-01

The aim of this study is to shed light on the functional role of slc7a6os, a gene highly conserved in vertebrates. The Danio rerio slc7a6os gene encodes a protein of 326 amino acids with 46% identity to human SLC7A6OS and 14% to Saccharomyces cerevisiae polypeptide Iwr1. Yeast Iwr1 specifically binds RNA pol II, interacts with the basal transcription machinery and regulates the transcription of specific genes. In this study we investigated for the first time the biological role of SLC7A6OS in vertebrates. Zebrafish slc7a6os is a maternal gene that is expressed throughout development, with a prevalent localization in the developing central nervous system (CNS). The gene is also expressed, although at different levels, in various tissues of the adult fish. To determine the functional role of slc7a6os during zebrafish development, we knocked-down the gene by injecting a splice-blocking morpholino. At 24 hpf morphants show morphological defects in the CNS, particularly the interface between hindbrain and midbrain is not well-defined. At 28 hpf the morpholino injected embryos present an altered somite morphology and appear partially or completely immotile. At this stage the midbrain, hindbrain and cerebellum are compromised and not well defined compared with control embryos. The observed alterations persist at later developmental stages. Consistently, the expression pattern of two markers specifically expressed in the developing CNS, pax2a and neurod, is significantly altered in morphants. The co-injection of embryos with synthetic slc7a6os mRNA, rescues the morphant phenotype and restores the wild type expression pattern of pax2a and neurod. Our data suggest that slc7a6os might play a critical role in defined areas of the developing CNS in vertebrates, probably by regulating the expression of key genes. PMID:25803583

The Emergence of Precision Urologic Oncology: A Collaborative Review on Biomarker-driven Therapeutics.

PubMed

Barbieri, Christopher E; Chinnaiyan, Arul M; Lerner, Seth P; Swanton, Charles; Rubin, Mark A

2017-02-01

Biomarker-driven cancer therapy, also referred to as precision oncology, has received increasing attention for its promise of improving patient outcomes by defining subsets of patients more likely to respond to various therapies. In this collaborative review article, we examine recent literature regarding biomarker-driven therapeutics in urologic oncology, to better define the state of the field, explore the current evidence supporting utility of this approach, and gauge potential for the future. We reviewed relevant literature, with a particular focus on recent studies about targeted therapy, predictors of response, and biomarker development. The recent advances in molecular profiling have led to a rapid expansion of potential biomarkers and predictive information for patients with urologic malignancies. Across disease states, distinct molecular subtypes of cancers have been identified, with the potential to inform choices of management strategy. Biomarkers predicting response to standard therapies (such as platinum-based chemotherapy) are emerging. In several malignancies (particularly renal cell carcinoma and castration-resistant prostate cancer), targeted therapy against commonly altered signaling pathways has emerged as standard of care. Finally, targeted therapy against alterations present in rare patients (less than 2%) across diseases has the potential to drastically alter patterns of care and choices of therapeutic options. Precision medicine has the highest potential to impact the care of patients. Prospective studies in the setting of clinical trials and standard of care therapy will help define reliable predictive biomarkers and new therapeutic targets leading to real improvement in patient outcomes. Precision oncology uses molecular information (DNA and RNA) from the individual and the tumor to match the right patient with the right treatment. Tremendous strides have been made in defining the molecular underpinnings of urologic malignancies and understanding how these predict response to treatment-this represents the future of urologic oncology. Copyright © 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.

The Emergence of Precision Urologic Oncology: A Collaborative Review on Biomarker-driven Therapeutics

PubMed Central

Barbieri, Christopher E.; Chinnaiyan, Arul M.; Lerner, Seth P.; Swanton, Charles; Rubin, Mark A.

2016-01-01

Context Biomarker-driven cancer therapy, also referred to as precision oncology, has received increasing attention for its promise of improving patient outcomes by defining subsets of patients more likely to respond to various therapies. Objective In this collaborative review article, we examine recent literature regarding biomarker-driven therapeutics in urologic oncology, to better define the state of the field, explore the current evidence supporting utility of this approach, and gauge potential for the future. Evidence acquisition We reviewed relevant literature, with a particular focus on recent studies about targeted therapy, predictors of response, and biomarker development. Evidence synthesis The recent advances in molecular profiling have led to a rapid expansion of potential biomarkers and predictive information for patients with urologic malignancies. Across disease states, distinct molecular subtypes of cancers have been identified, with the potential to inform choices of management strategy. Biomarkers predicting response to standard therapies (such as platinum-based chemotherapy) are emerging. In several malignancies (particularly renal cell carcinoma and castration-resistant prostate cancer), targeted therapy against commonly altered signaling pathways has emerged as standard of care. Finally, targeted therapy against alterations present in rare patients (less than 2%) across diseases has the potential to drastically alter patterns of care and choices of therapeutic options. Conclusions Precision medicine has the highest potential to impact the care of patients. Prospective studies in the setting of clinical trials and standard of care therapy will help define reliable predictive biomarkers and new therapeutic targets leading to real improvement in patient outcomes. Patient summary Precision oncology uses molecular information (DNA and RNA) from the individual and the tumor to match the right patient with the right treatment. Tremendous strides have been made in defining the molecular underpinnings of urologic malignancies and understanding how these predict response to treatment—this represents the future of urologic oncology. PMID:27567210

Criteria for the use of regression analysis for remote sensing of sediment and pollutants

NASA Technical Reports Server (NTRS)

Whitlock, C. H.; Kuo, C. Y.; Lecroy, S. R.

1982-01-01

An examination of limitations, requirements, and precision of the linear multiple-regression technique for quantification of marine environmental parameters is conducted. Both environmental and optical physics conditions have been defined for which an exact solution to the signal response equations is of the same form as the multiple regression equation. Various statistical parameters are examined to define a criteria for selection of an unbiased fit when upwelled radiance values contain error and are correlated with each other. Field experimental data are examined to define data smoothing requirements in order to satisfy the criteria of Daniel and Wood (1971). Recommendations are made concerning improved selection of ground-truth locations to maximize variance and to minimize physical errors associated with the remote sensing experiment.

ITS system specification. Appendix C, data flows by function for ITS services

DOT National Transportation Integrated Search

1997-01-01

The objective of the Polaris Project is to define an Intelligent Transportation Systems (ITS) architecture for the state of Minnesota. An architecture is a framework that defines how multiple ITS Components interrelate and contribute to the overall I...

Individual lifetime pollen and nectar foraging preferences in bumble bees

NASA Astrophysics Data System (ADS)

Hagbery, Jessica; Nieh, James C.

2012-10-01

Foraging specialization plays an important role in the ability of social insects to efficiently allocate labor. However, relatively little is known about the degree to which individual bumble bees specialize on collecting nectar or pollen, when such preferences manifest, and if individuals can alter their foraging preferences in response to changes in the colony workforce. Using Bombus impatiens, we monitored all foraging visits made by every bee in multiple colonies and showed that individual foragers exhibit consistent lifetime foraging preferences. Based upon the distribution of foraging preferences, we defined three forager types (pollen specialists, nectar specialists, and generalists). In unmanipulated colonies, 16-36 % of individuals specialized (≥90 % of visits) on nectar or pollen only. On its first day of foraging, an individual's foraging choices (nectar only, pollen only, or nectar and pollen) significantly predicted its lifetime foraging preferences. Foragers that only collected pollen on their first day of foraging made 1.61- to 1.67-fold more lifetime pollen foraging visits (as a proportion of total trips) than foragers that only collected nectar on their first foraging day. Foragers were significantly larger than bees that stayed only in the nest. We also determined the effect of removing pollen specialists at early (brood present) or later (brood absent) stages in colony life. These results suggest that generalists can alter their foraging preferences in response to the loss of a small subset of foragers. Thus, bumble bees exhibit individual lifetime foraging preferences that are established early in life, but generalists may be able to adapt to colony needs.

A high-resolution transcriptome map of cell cycle reveals novel connections between periodic genes and cancer

PubMed Central

Dominguez, Daniel; Tsai, Yi-Hsuan; Gomez, Nicholas; Jha, Deepak Kumar; Davis, Ian; Wang, Zefeng

2016-01-01

Progression through the cell cycle is largely dependent on waves of periodic gene expression, and the regulatory networks for these transcriptome dynamics have emerged as critical points of vulnerability in various aspects of tumor biology. Through RNA-sequencing of human cells during two continuous cell cycles (>2.3 billion paired reads), we identified over 1 000 mRNAs, non-coding RNAs and pseudogenes with periodic expression. Periodic transcripts are enriched in functions related to DNA metabolism, mitosis, and DNA damage response, indicating these genes likely represent putative cell cycle regulators. Using our set of periodic genes, we developed a new approach termed “mitotic trait” that can classify primary tumors and normal tissues by their transcriptome similarity to different cell cycle stages. By analyzing >4 000 tumor samples in The Cancer Genome Atlas (TCGA) and other expression data sets, we found that mitotic trait significantly correlates with genetic alterations, tumor subtype and, notably, patient survival. We further defined a core set of 67 genes with robust periodic expression in multiple cell types. Proteins encoded by these genes function as major hubs of protein-protein interaction and are mostly required for cell cycle progression. The core genes also have unique chromatin features including increased levels of CTCF/RAD21 binding and H3K36me3. Loss of these features in uterine and kidney cancers is associated with altered expression of the core 67 genes. Our study suggests new chromatin-associated mechanisms for periodic gene regulation and offers a predictor of cancer patient outcomes. PMID:27364684

Canonical discrimination of the effect of a new broiler production facility on soil chemical profiles as related to current management practices.

PubMed

Sheffield, Cynthia L; Crippen, Tawni L; Byrd, J Allen; Beier, Ross C; Yeater, Kathleen

2015-01-01

The effect dirt-floored broiler houses have on the underlying native soil, and the potential for contamination of the ground water by leaching under the foundation, is an understudied area. This study examines alterations in fifteen quantitative soil parameters (Ca, Cu, electrical conductivity, Fe, K, Mg, Mn, Na, NO3, organic matter, P, pH, S, soil moisture and Zn) in the underlayment of a newly constructed dirt-floored broiler house over the first two years of production (Native through Flock 11). The experiment was conducted near NW Robertson County, Texas, where the native soil is a fine, smectitic thermic Udertic Paleustalfs and the slopes range from zero to three percent. Multiple samples were collected from under each of three water and three feed lines the length of the house, in a longitudinal study during February 2008 through August 2010. To better define the relationship between the soil parameters and sampling times, a canonical discriminant analysis approach was used. The soil profiles assembled into five distinctive clusters corresponding to time and management practices. Results of this work revealed that the majority of parameters increased over time. The management practices of partial and total house clean-outs markedly altered soil profiles the house underlayment, thus reducing the risk of infiltration into the ground water near the farm. This is important as most broiler farms consist of several houses within a small area, so the cumulative ecological impact could be substantial if not properly managed.

Deletion of IFT80 Impairs Epiphyseal and Articular Cartilage Formation Due to Disruption of Chondrocyte Differentiation

PubMed Central

Yuan, Xue; Yang, Shuying

2015-01-01

Intraflagellar transport proteins (IFT) play important roles in cilia formation and organ development. Partial loss of IFT80 function leads Jeune asphyxiating thoracic dystrophy (JATD) or short-rib polydactyly (SRP) syndrome type III, displaying narrow thoracic cavity and multiple cartilage anomalies. However, it is unknown how IFT80 regulates cartilage formation. To define the role and mechanism of IFT80 in chondrocyte function and cartilage formation, we generated a Col2α1; IFT80f/f mouse model by crossing IFT80f/f mice with inducible Col2α1-CreER mice, and deleted IFT80 in chondrocyte lineage by injection of tamoxifen into the mice in embryonic or postnatal stage. Loss of IFT80 in the embryonic stage resulted in short limbs at birth. Histological studies showed that IFT80-deficient mice have shortened cartilage with marked changes in cellular morphology and organization in the resting, proliferative, pre-hypertrophic, and hypertrophic zones. Moreover, deletion of IFT80 in the postnatal stage led to mouse stunted growth with shortened growth plate but thickened articular cartilage. Defects of ciliogenesis were found in the cartilage of IFT80-deficient mice and primary IFT80-deficient chondrocytes. Further study showed that chondrogenic differentiation was significantly inhibited in IFT80-deficient mice due to reduced hedgehog (Hh) signaling and increased Wnt signaling activities. These findings demonstrate that loss of IFT80 blocks chondrocyte differentiation by disruption of ciliogenesis and alteration of Hh and Wnt signaling transduction, which in turn alters epiphyseal and articular cartilage formation. PMID:26098911

Canonical Discrimination of the Effect of a New Broiler Production Facility on Soil Chemical Profiles as Related to Current Management Practices

PubMed Central

Sheffield, Cynthia L.; Crippen, Tawni L.; Byrd, J. Allen; Beier, Ross C.; Yeater, Kathleen

2015-01-01

The effect dirt-floored broiler houses have on the underlying native soil, and the potential for contamination of the ground water by leaching under the foundation, is an understudied area. This study examines alterations in fifteen quantitative soil parameters (Ca, Cu, electrical conductivity, Fe, K, Mg, Mn, Na, NO3, organic matter, P, pH, S, soil moisture and Zn) in the underlayment of a newly constructed dirt-floored broiler house over the first two years of production (Native through Flock 11). The experiment was conducted near NW Robertson County, Texas, where the native soil is a fine, smectitic thermic Udertic Paleustalfs and the slopes range from zero to three percent. Multiple samples were collected from under each of three water and three feed lines the length of the house, in a longitudinal study during February 2008 through August 2010. To better define the relationship between the soil parameters and sampling times, a canonical discriminant analysis approach was used. The soil profiles assembled into five distinctive clusters corresponding to time and management practices. Results of this work revealed that the majority of parameters increased over time. The management practices of partial and total house clean-outs markedly altered soil profiles the house underlayment, thus reducing the risk of infiltration into the ground water near the farm. This is important as most broiler farms consist of several houses within a small area, so the cumulative ecological impact could be substantial if not properly managed. PMID:26029909

Metabolic pathway profiling of mitochondrial respiratory chain mutants in C. elegans

PubMed Central

MJ, Falk; Z, Zhang; Rosenjack; Nissim; E, Daikhin; Nissim; MM, Sedensky; M, Yudkoff; PG, Morgan

2008-01-01

C. elegans affords a model of primary mitochondrial dysfunction that provides insight into cellular adaptations which accompany mutations in nuclear gene that encode mitochondrial proteins. To this end, we characterized genome-wide expression profiles of C. elegans strains with mutations in nuclear-encoded subunits of respiratory chain complexes. Our goal was to detect concordant changes among clusters of genes that comprise defined metabolic pathways. Results indicate that respiratory chain mutants significantly upregulate a variety of basic cellular metabolic pathways involved in carbohydrate, amino acid, and fatty acid metabolism, as well as cellular defense pathways such as the metabolism of P450 and glutathione. To further confirm and extend expression analysis findings, quantitation of whole worm free amino acid levels was performed in C. elegans mitochondrial mutants for subunits of complexes I, II, and III. Significant differences were seen for 13 of 16 amino acid levels in complex I mutants compared with controls, as well as overarching similarities among profiles of complex I, II, and III mutants compared with controls. The specific pattern of amino acid alterations observed provides novel evidence to suggest that an increase in glutamate-linked transamination reactions caused by the failure of NAD+ dependent oxidation of ketoacids occurs in primary mitochondrial respiratory chain mutants. Recognition of consistent alterations among patterns of nuclear gene expression for multiple biochemical pathways and in quantitative amino acid profiles in a translational genetic model of mitochondrial dysfunction allows insight into the complex pathogenesis underlying primary mitochondrial disease. Such knowledge may enable the development of a metabolomic profiling diagnostic tool applicable to human mitochondrial disease. PMID:18178500

Symmetry of initial cell divisions among primitive hematopoietic progenitors is independent of ontogenic age and regulatory molecules.

PubMed

Huang, S; Law, P; Francis, K; Palsson, B O; Ho, A D

1999-10-15

We have developed a time-lapse camera system to follow the replication history and the fate of hematopoietic stem cells (HSC) at a single-cell level. Combined with single-cell culture, we correlated the early replication behavior with colony development after 14 days. The membrane dye PKH26 was used to monitor cell division. In addition to multiple, synchronous, and symmetric divisions, single-sorted CD34(+)/CD38(-) cells derived from fetal liver (FLV) also gave rise to a daughter cell that remained quiescent for up to 8 days, whereas the other daughter cell proliferated exponentially. Upon separation and replating as single cells onto medium containing a cytokine cocktail, 60.6% +/- 9.8% of the initially quiescent cells (PKH26 bright) gave rise again to colonies and 15.8% +/- 7.8% to blast colonies that could be replated. We have then determined the effects of various regulatory molecules on symmetry of initial cell divisions. After single-cell sorting, the CD34(+)/CD38(-) cells derived from FLV were exposed to flt3-ligand, thrombopoietin, stem cell factor (SCF), or medium containing a cytokine cocktail (with SCF, interleukin-3, interleukin-6, granulocyte-macrophage colony-stimulating factor, and erythropoietin). Whereas mitotic rate, colony efficiency, and asymmetric divisions could be altered using various regulatory molecules, the asymmetric division index, defined as the number of asymmetric divisions versus the number of dividing cells, was not altered significantly. This observation suggests that, although lineage commitment and cell proliferation can be skewed by extrinsic signaling, symmetry of early divisions is probably under the control of intrinsic factors.

Hyperspectral image analysis for the determination of alteration minerals in geothermal fields: Çürüksu (Denizli) Graben, Turkey

NASA Astrophysics Data System (ADS)

Uygur, Merve; Karaman, Muhittin; Kumral, Mustafa

2016-04-01

Çürüksu (Denizli) Graben hosts various geothermal fields such as Kızıldere, Yenice, Gerali, Karahayıt, and Tekkehamam. Neotectonic activities, which are caused by extensional tectonism, and deep circulation in sub-volcanic intrusions are heat sources of hydrothermal solutions. The temperature of hydrothermal solutions is between 53 and 260 degree Celsius. Phyllic, argillic, silicic, and carbonatization alterations and various hydrothermal minerals have been identified in various research studies of these areas. Surfaced hydrothermal alteration minerals are one set of potential indicators of geothermal resources. Developing the exploration tools to define the surface indicators of geothermal fields can assist in the recognition of geothermal resources. Thermal and hyperspectral imaging and analysis can be used for defining the surface indicators of geothermal fields. This study tests the hypothesis that hyperspectral image analysis based on EO-1 Hyperion images can be used for the delineation and definition of surfaced hydrothermal alteration in geothermal fields. Hyperspectral image analyses were applied to images covering the geothermal fields whose alteration characteristic are known. To reduce data dimensionality and identify spectral endmembers, Kruse's multi-step process was applied to atmospherically and geometrically-corrected hyperspectral images. Minimum Noise Fraction was used to reduce the spectral dimensions and isolate noise in the images. Extreme pixels were identified from high order MNF bands using the Pixel Purity Index. n-Dimensional Visualization was utilized for unique pixel identification. Spectral similarities between pixel spectral signatures and known endmember spectrum (USGS Spectral Library) were compared with Spectral Angle Mapper Classification. EO-1 Hyperion hyperspectral images and hyperspectral analysis are sensitive to hydrothermal alteration minerals, as their diagnostic spectral signatures span the visible and shortwave infrared seen in geothermal fields. Hyperspectral analysis results indicated that kaolinite, smectite, illite, montmorillonite, and sepiolite minerals were distributed in a wide area, which covered the hot spring outlet. Rectorite, lizardite, richterite, dumortierite, nontronite, erionite, and clinoptilolite were observed occasionally.

MULTIPLE EPISODES OF IGNEOUS ACTIVITY, MINERALIZATION, AND ALTERATION IN THE WESTERN TUSHAR MOUNTAINS, UTAH.

USGS Publications Warehouse

Cunningham, Charles G.; Steven, Thomas A.; Campbell, David L.; Naeser, Charles W.; Pitkin, James A.; Duval, Joseph S.

1984-01-01

The report outlines the complex history of igneous activity and associated alteration and mineralization in the western Tushar Mountains, Utah and pointss out implciations for minerals exploration. The area has been subjected to recurrent episodes of igneous intrusion, hydrothermal alteration, and mineralization, and the mineral-resource potential of the different mineralized areas is directly related to local geologic history. The mineral commodities to be expected vary from one hydrothermal system to another, and from one depth to another within any given system. Uranium and molybdenum seem likely to have the greatest economic potential, although significant concentrations of gold may also exist.

Conditional Selection of Genomic Alterations Dictates Cancer Evolution and Oncogenic Dependencies.

PubMed

Mina, Marco; Raynaud, Franck; Tavernari, Daniele; Battistello, Elena; Sungalee, Stephanie; Saghafinia, Sadegh; Laessle, Titouan; Sanchez-Vega, Francisco; Schultz, Nikolaus; Oricchio, Elisa; Ciriello, Giovanni

2017-08-14

Cancer evolves through the emergence and selection of molecular alterations. Cancer genome profiling has revealed that specific events are more or less likely to be co-selected, suggesting that the selection of one event depends on the others. However, the nature of these evolutionary dependencies and their impact remain unclear. Here, we designed SELECT, an algorithmic approach to systematically identify evolutionary dependencies from alteration patterns. By analyzing 6,456 genomes from multiple tumor types, we constructed a map of oncogenic dependencies associated with cellular pathways, transcriptional readouts, and therapeutic response. Finally, modeling of cancer evolution shows that alteration dependencies emerge only under conditional selection. These results provide a framework for the design of strategies to predict cancer progression and therapeutic response. Copyright © 2017 Elsevier Inc. All rights reserved.

Can Concentration - Discharge Relationships Diagnose Material Source During Extreme Events?

NASA Astrophysics Data System (ADS)

Karwan, D. L.; Godsey, S.; Rose, L.

2017-12-01

Floods can carry >90% of the basin material exported in a given year as well as alter flow pathways and material sources. In turn, sediment and solute fluxes can increase flood damages and negatively impact water quality and integrate physical and chemical weathering of landscapes and channels. Concentration-discharge (C-Q) relationships are used to both describe export patterns as well as compute them. Metrics for describing C-Q patterns and inferring their controls are vulnerable to infrequent sampling that affects how C-Q relationships are interpolated and interpreted. C-Q relationships are typically evaluated from multiple samples, but because hydrological extremes are rare, data are often unavailable for extreme events. Because solute and sediment C-Q relationships likely respond to changes in hydrologic extremes in different ways, there is a pressing need to define their behavior under extreme conditions, including how to properly sample to capture these patterns. In the absence of such knowledge, improving load estimates in extreme floods will likely remain difficult. Here we explore the use of C-Q relationships to determine when an event alters a watershed system such that it enters a new material source/transport regime. We focus on watersheds with sediment and discharge time series include low-frequency and/or extreme events. For example, we compare solute and sediment patterns in White Clay Creek in southeastern Pennsylvania across a range of flows inclusive of multiple hurricanes for which we have ample ancillary hydrochemical data. TSS is consistently mobilized during high flow events, even during extreme floods associated with hurricanes, and sediment fingerprinting indicates different sediment sources, including in-channel remobilization and landscape erosion, are active at different times. In other words, TSS mobilization in C-Q space is not sensitive to the source of material being mobilized. Unlike sediments, weathering solutes in this watershed tend to exhibit a relatively chemostatic C-Q pattern, except during the runoff-dominated Hurricane Irene, when they exhibit a diluting C-Q pattern. Finally, we summarize the vulnerability of these observations to shifts in sampling effort to highlight the utility and limitations of C-Q-derived export patterns.

On the multiple zeros of a real analytic function with applications to the averaging theory of differential equations

NASA Astrophysics Data System (ADS)

García, Isaac A.; Llibre, Jaume; Maza, Susanna

2018-06-01

In this work we consider real analytic functions , where , Ω is a bounded open subset of , is an interval containing the origin, are parameters, and ε is a small parameter. We study the branching of the zero-set of at multiple points when the parameter ε varies. We apply the obtained results to improve the classical averaging theory for computing T-periodic solutions of λ-families of analytic T-periodic ordinary differential equations defined on , using the displacement functions defined by these equations. We call the coefficients in the Taylor expansion of in powers of ε the averaged functions. The main contribution consists in analyzing the role that have the multiple zeros of the first non-zero averaged function. The outcome is that these multiple zeros can be of two different classes depending on whether the zeros belong or not to the analytic set defined by the real variety associated to the ideal generated by the averaged functions in the Noetheriang ring of all the real analytic functions at . We bound the maximum number of branches of isolated zeros that can bifurcate from each multiple zero z 0. Sometimes these bounds depend on the cardinalities of minimal bases of the former ideal. Several examples illustrate our results and they are compared with the classical theory, branching theory and also under the light of singularity theory of smooth maps. The examples range from polynomial vector fields to Abel differential equations and perturbed linear centers.

Defining Multiple Characteristic Raman Bands of α-Amino Acids as Biomarkers for Planetary Missions Using a Statistical Method

NASA Astrophysics Data System (ADS)

Rolfe, S. M.; Patel, M. R.; Gilmour, I.; Olsson-Francis, K.; Ringrose, T. J.

2016-06-01

Biomarker molecules, such as amino acids, are key to discovering whether life exists elsewhere in the Solar System. Raman spectroscopy, a technique capable of detecting biomarkers, will be on board future planetary missions including the ExoMars rover. Generally, the position of the strongest band in the spectra of amino acids is reported as the identifying band. However, for an unknown sample, it is desirable to define multiple characteristic bands for molecules to avoid any ambiguous identification. To date, there has been no definition of multiple characteristic bands for amino acids of interest to astrobiology. This study examined l-alanine, l-aspartic acid, l-cysteine, l-glutamine and glycine and defined several Raman bands per molecule for reference as characteristic identifiers. Per amino acid, 240 spectra were recorded and compared using established statistical tests including ANOVA. The number of characteristic bands defined were 10, 12, 12, 14 and 19 for l-alanine (strongest intensity band: 832 cm-1), l-aspartic acid (938 cm-1), l-cysteine (679 cm-1), l-glutamine (1090 cm-1) and glycine (875 cm-1), respectively. The intensity of bands differed by up to six times when several points on the crystal sample were rotated through 360 °; to reduce this effect when defining characteristic bands for other molecules, we find that spectra should be recorded at a statistically significant number of points per sample to remove the effect of sample rotation. It is crucial that sets of characteristic Raman bands are defined for biomarkers that are targets for future planetary missions to ensure a positive identification can be made.

Defining Multiple Characteristic Raman Bands of α-Amino Acids as Biomarkers for Planetary Missions Using a Statistical Method.

PubMed

Rolfe, S M; Patel, M R; Gilmour, I; Olsson-Francis, K; Ringrose, T J

2016-06-01

Biomarker molecules, such as amino acids, are key to discovering whether life exists elsewhere in the Solar System. Raman spectroscopy, a technique capable of detecting biomarkers, will be on board future planetary missions including the ExoMars rover. Generally, the position of the strongest band in the spectra of amino acids is reported as the identifying band. However, for an unknown sample, it is desirable to define multiple characteristic bands for molecules to avoid any ambiguous identification. To date, there has been no definition of multiple characteristic bands for amino acids of interest to astrobiology. This study examined L-alanine, L-aspartic acid, L-cysteine, L-glutamine and glycine and defined several Raman bands per molecule for reference as characteristic identifiers. Per amino acid, 240 spectra were recorded and compared using established statistical tests including ANOVA. The number of characteristic bands defined were 10, 12, 12, 14 and 19 for L-alanine (strongest intensity band: 832 cm(-1)), L-aspartic acid (938 cm(-1)), L-cysteine (679 cm(-1)), L-glutamine (1090 cm(-1)) and glycine (875 cm(-1)), respectively. The intensity of bands differed by up to six times when several points on the crystal sample were rotated through 360 °; to reduce this effect when defining characteristic bands for other molecules, we find that spectra should be recorded at a statistically significant number of points per sample to remove the effect of sample rotation. It is crucial that sets of characteristic Raman bands are defined for biomarkers that are targets for future planetary missions to ensure a positive identification can be made.

Sonographic findings of hepatobiliary fascioliasis accompanied by extrahepatic expansion and ectopic lesions.

PubMed

Teke, Memik; Önder, Hakan; Çiçek, Mutalip; Hamidi, Cihad; Göya, Cemil; Çetinçakmak, Mehmet Güli; Hattapoğlu, Salih; Ülger, Burak Veli

2014-12-01

The aim of the study was to describe the sonographic findings of hepatobiliary fascioliasis with extrahepatic expansion and ectopic lesions. The study included 45 patients with fascioliasis. All diagnoses were confirmed via serologic enzyme-linked immunosorbent assays. Sonographic findings in the hepatobiliary system, extrahepatic expansion, and ectopic lesions were defined. The most common hepatic lesions were subcapsular localized, small, confluent, multiple hypoechoic nodules with poorly defined borders. We also detected ectopic lesion in 5 patients (11.1%) and live parasites in the gallbladder and bile duct in 11 (24.4%). The large spectrum of entities in the differential diagnosis of hepatobiliary fascioliasis may lead to misdiagnosis and incorrect treatment. However, the diagnosis can be made when the characteristic sonographic features are seen, such as heterogeneity of the liver with multiple poorly defined hypoechoic-isoechoic lesions and multiple echogenic nonshadowing particles in the gallbladder or common bile ducts. Nonetheless, the differential diagnosis of fascioliasis versus other hepatic lesions may still be difficult. In these situations, pathologic confirmation should be performed to exclude the possibility of malignancy. © 2013 by the American Institute of Ultrasound in Medicine.

ANABOLIC STEROIDS ALTER THE PHYSIOLOGICAL ACTIVITY OF AGGRESSION CIRCUITS IN THE LATERAL ANTERIOR HYPOTHALAMUS

PubMed Central

Morrison, Thomas R.; Sikes, Robert W.; Melloni, Richard H.

2016-01-01

Syrian hamsters exposed to anabolic/androgenic steroids (AAS) during adolescence consistently show increased aggressive behavior across studies. Although the behavioral and anatomical profiles of AAS-induced alterations have been well characterized, there is a lack of data describing physiological changes that accompany these alterations. For instance, behavioral pharmacology and neuroanatomical studies show that AAS-induced changes in the vasopressin (AVP) neural system within the latero-anterior hypothalamus (LAH) interact with the serotonin (5HT) and dopamine (DA) systems to modulate aggression. To characterize the electrophysiological profile of the AAS aggression circuit, we recorded LAH neurons in adolescent male hamsters in vivo and microiontophoretically applied agonists and antagonists of aggressive behavior. The interspike interval (ISI) of neurons from AAS-treated animals correlated positively with aggressive behaviors, and adolescent AAS exposure altered parameters of activity in regular firing neurons while also changing the proportion of neuron types (i.e., bursting, regular, irregular). AAS treated animals had more responsive neurons that were excited by AVP application, while cells from control animals showed the opposite effect and were predominantly inhibited by AVP. Both DA D2 antagonists and 5HT increased the firing frequency of AVP responsive cells from AAS animals and dual application of AVP and D2 antagonists doubled the excitatory effect of AVP or D2 antagonist administration alone. These data suggest that multiple DA circuits in the LAH modulate AAS-induced aggressive responding. More broadly, these data show that multiple neurochemical interactions at the neurophysiological level are altered by adolescent AAS exposure. PMID:26691962

Cleavage/alteration of interleukin-8 by matrix metalloproteinase-9 in the female lower genital tract.

PubMed

Zariffard, M Reza; Anastos, Kathryn; French, Audrey L; Munyazesa, Elisaphane; Cohen, Mardge; Landay, Alan L; Spear, Gregory T

2015-01-01

Interleukin-8 (IL-8, CXCL8) plays important roles in immune responses at mucosal sites including in the lower genital tract. Since several types of bacteria produce proteases that cleave IL-8 and many types of bacteria can be present in lower genital tract microbiota, we assessed genital fluids for IL-8 cleavage/alteration. Genital fluids collected by lavage from 200 women (23 HIV-seronegative and 177 HIV-seropositive) were tested for IL-8 cleavage/alteration by ELISA. IL-8 cleaving/altering activity was observed in fluids from both HIV-positive (28%) and HIV-negative women (35%). There was no clear relationship between the activity and the types of bacteria present in the lower genital tract as determined by high-throughput sequencing of the 16S rRNA gene. Protease inhibitors specific for matrix metalloproteinases (MMPs) reduced the activity and a multiplex assay that detects both inactive and active MMPs showed the presence of multiple MMPs, including MMP-1, -3, -7, -8, -9, -10 and -12 in genital secretions from many of the women. The IL-8-cleaving/altering activity significantly correlated with active MMP-9 as well as with cleavage of a substrate that is acted on by several active MMPs. These studies show that multiple MMPs are present in the genital tract of women and strongly suggest that MMP-9 in genital secretions can cleave IL-8 at this mucosal site. These studies suggest that MMP-mediated cleavage of IL-8 can modulate inflammatory responses in the lower genital tract.

Reactive transport and mass balance modeling of the Stimson sedimentary formation and altered fracture zones constrain diagenetic conditions at Gale crater, Mars

NASA Astrophysics Data System (ADS)

Hausrath, E. M.; Ming, D. W.; Peretyazhko, T. S.; Rampe, E. B.

2018-06-01

On a planet as cold and dry as present-day Mars, evidence of multiple aqueous episodes offers an intriguing view into very different past environments. Fluvial, lacustrine, and eolian depositional environments are being investigated by the Mars Science Laboratory Curiosity in Gale crater, Mars. Geochemical and mineralogical observations of these sedimentary rocks suggest diagenetic processes affected the sediments. Here, we analyze diagenesis of the Stimson formation eolian parent material, which caused loss of olivine and formation of magnetite. Additional, later alteration in fracture zones resulted in preferential dissolution of pyroxene and precipitation of secondary amorphous silica and Ca sulfate. The ability to compare the unaltered parent material with the reacted material allows constraints to be placed on the characteristics of the altering solutions. In this work we use a combination of a mass balance approach calculating the fraction of a mobile element lost or gained, τ, with fundamental geochemical kinetics and thermodynamics in the reactive transport code CrunchFlow to examine the characteristics of multiple stages of aqueous alteration at Gale crater, Mars. Our model results indicate that early diagenesis of the Stimson sedimentary formation is consistent with leaching of an eolian deposit by a near-neutral solution, and that formation of the altered fracture zones is consistent with a very acidic, high sulfate solution containing Ca, P and Si. These results indicate a range of past aqueous conditions occurring at Gale crater, Mars, with important implications for past martian climate and environments.

Using Naturalistic Driving Performance Data to Develop an Empirically Defined Model of Distracted Driving

DOT National Transportation Integrated Search

2016-08-05

Driver distraction is defined as a diversion of attention away from the primary driving activity toward non-driving related tasks (Lee et al., 2008). Multiple resource theory (MRT) describes this diversion as a process of competition for attentional ...

Cloning: plants – micropropagation/tissue culture

USDA-ARS?s Scientific Manuscript database

Clonal micropropagation is the multiplication of the buds and shoots that occur in leaf axils on a defined nutrient medium in an aseptic in vitro environment. The resulting shoots are either subdivided for continued multiplication or rooted and acclimatized to the greenhouse or field. Micropropagati...

Alteration of Multiple Cell Membrane Functions in L-6 Myoblasts by T-2 Toxin: An Important Mechanism of Action.

DTIC Science & Technology

1986-06-04

menbrane functions. All are in a range that would in turn be expected to alter other cell functions. Intracellular LEH was reduced 10 min after T-2... Plasma amino F-id changes in guinea pigs injected with T-2 rnycotoxin. Fed. Proc. 42, 625. 20 1111" ll p J IIIý f%𔃻 11 IC IA 114 WEAVER, G.A., MW1•Z, H.J

Pregnancy-related pharmacokinetic changes.

PubMed

Tasnif, Y; Morado, J; Hebert, M F

2016-07-01

The pharmacokinetics of many drugs are altered by pregnancy. Drug distribution and protein binding are changed by pregnancy. While some drug metabolizing enzymes have an apparent increase in activity, others have an apparent decrease in activity. Not only is drug metabolism affected by pregnancy, but renal filtration is also increased. In addition, pregnancy alters the apparent activities of multiple drug transporters resulting in changes in the net renal secretion of drugs. © 2016 American Society for Clinical Pharmacology and Therapeutics.

High salt diet induces metabolic alterations in multiple biological processes of Dahl salt-sensitive rats.

PubMed

Wang, Yanjun; Liu, Xiangyang; Zhang, Chen; Wang, Zhengjun

2018-06-01

High salt induced renal disease is a condition resulting from the interactions of genetic and dietary factors causing multiple complications. To understand the metabolic alterations associated with renal disease, we comprehensively analyzed the metabonomic changes induced by high salt intake in Dahl salt-sensitive (SS) rats using GC-MS technology and biochemical analyses. Physiological features, serum chemistry, and histopathological data were obtained as complementary information. Our results showed that high salt (HS) intake for 16 weeks caused significant metabolic alterations in both the renal medulla and cortex involving a variety pathways involved in the metabolism of organic acids, amino acids, fatty acids, and purines. In addition, HS enhanced glycolysis (hexokinase, phosphofructokinase and pyruvate kinase) and amino acid metabolism and suppressed the TCA (citrate synthase and aconitase) cycle. Finally, HS intake caused up-regulation of the pentose phosphate pathway (glucose 6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase), the ratio of NADPH/NADP + , NADPH oxidase activity and ROS production, suggesting that increased oxidative stress was associated with an altered PPP pathway. The metabolic pathways identified may serve as potential targets for the treatment of renal damage. Our findings provide comprehensive biochemical details about the metabolic responses to a high salt diet, which may contribute to the understanding of renal disease and salt-induced hypertension in SS rats. Copyright © 2018. Published by Elsevier Inc.

MAPPING WATERSHED INTEGRITY FOR THE CONTERMINOUS UNITED STATES.

EPA Science Inventory

Watersheds provide a variety of ecosystem services valued by society. Production of these services is sensitive to watershed alteration by human activities. Flotemersch and others (2015), defined watershed integrity (WI) as the “capacity of a watershed to support and maint...

Mode of action from dose-response microarray data: case study using 10 environmental chemicals

EPA Science Inventory

Ligand-activated nuclear receptors regulate many biological processes through complex interactions with biological macromolecules. Certain xenobiotics alter nuclear receptor signaling through direct or indirect interactions. Defining the mode of action of such xenobiotics is di...

Virtual Reality: Real Promises and False Expectations.

ERIC Educational Resources Information Center

Homan, Willem J.

1994-01-01

Examines virtual reality (VR), and discusses the dilemma of defining VR, the limitations of the current technology, and the implications of VR for education. Highlights include a VR experience; human factors and the interface; and altered reality versus VR. (Author/AEF)

Mapping Watershed Integrity for the Conterminous United States

EPA Science Inventory

Watersheds provide a variety of ecosystem services valued by society. Production of these services is partially a function of the degree to which watersheds are altered by human activities. In a recent manuscript, Flotemersch and others (in preparation), defined watershed integr...

Dysregulation of NRXN1 by mutant MIR8485 leads to calcium overload in pre-synapses inducing neurodegeneration in Multiple sclerosis.

PubMed

Kattimani, Yogita; Veerappa, Avinash M

2018-04-09

To identify Damaging mutations in microRNAs (miRNAs) and 3' untranslated regions (UTRs) of target genes to establish Multiple sclerosis (MS) disease pathway. Female aged 16, with Relapsing Remitting Multiple sclerosis (RRMS) was reported with initial symptoms of blurred vision, severe immobility, upper and lower limb numbness and backache. Whole Exome Sequencing (WES) and disease pathway analysis was performed to identify mutations in miRNAs and UTRs. We identified Deleterious/Damaging multibase mutations in MIR8485 and NRXN1. miR-8485 was found carrying frameshift homozygous deletion of bases CA, while NRXN1 was found carrying nonframeshift homozygous substitution of bases CT to TC in exon 8 replacing Serine with Leucine. Mutations in miR-8485 and NRXN1 was found to alter calcium homeostasis and NRXN1/NLGN1 cell adhesion molecule binding affinities. The miR-8485 mutation leads to overexpression of NRXN1 altering pre-synaptic Ca 2+ homeostasis, inducing neurodegeneration. Copyright © 2018 Elsevier B.V. All rights reserved.

A Peptide Targeting Inflammatory CNS Lesions in the EAE Rat Model of Multiple Sclerosis.

PubMed

Boiziau, Claudine; Nikolski, Macha; Mordelet, Elodie; Aussudre, Justine; Vargas-Sanchez, Karina; Petry, Klaus G

2018-06-01

Multiple sclerosis is characterized by inflammatory lesions dispersed throughout the central nervous system (CNS) leading to severe neurological handicap. Demyelination, axonal damage, and blood brain barrier alterations are hallmarks of this pathology, whose precise processes are not fully understood. In the experimental autoimmune encephalomyelitis (EAE) rat model that mimics many features of human multiple sclerosis, the phage display strategy was applied to select peptide ligands targeting inflammatory sites in CNS. Due to the large diversity of sequences after phage display selection, a bioinformatics procedure called "PepTeam" designed to identify peptides mimicking naturally occurring proteins was used, with the goal to predict peptides that were not background noise. We identified a circular peptide CLSTASNSC called "Ph48" as an efficient binder of inflammatory regions of EAE CNS sections including small inflammatory lesions of both white and gray matter. Tested on human brain endothelial cells hCMEC/D3, Ph48 was able to bind efficiently when these cells were activated with IL1β to mimic inflammatory conditions. The peptide is therefore a candidate for further analyses of the molecular alterations in inflammatory lesions.

Organic light emitting device having multiple separate emissive layers

DOEpatents

Forrest, Stephen R [Ann Arbor, MI

2012-03-27

An organic light emitting device having multiple separate emissive layers is provided. Each emissive layer may define an exciton formation region, allowing exciton formation to occur across the entire emissive region. By aligning the energy levels of each emissive layer with the adjacent emissive layers, exciton formation in each layer may be improved. Devices incorporating multiple emissive layers with multiple exciton formation regions may exhibit improved performance, including internal quantum efficiencies of up to 100%.

The promise of epigenomic therapeutics in pancreatic cancer

PubMed Central

Lomberk, Gwen A; Iovanna, Juan; Urrutia, Raul

2016-01-01

Pancreatic ductal adenocarcinoma (PDAC) is often viewed to arise primarily by genetic alterations. However, today we know that many aspects of the cancer phenotype require a crosstalk among these genetic alterations with epigenetic changes. Indeed, aberrant gene expression patterns, driven by epigenetics are fixed by altered signaling from mutated oncogenes and tumor suppressors to define the PDAC phenotype. This conceptual framework may have significant mechanistic value and could offer novel possibilities for treating patients affected with PDAC. In fact, extensive investigations are leading to the development of small molecule drugs that reversibly modify the epigenome. These new ‘epigenetic therapeutics’ discussed herein are promising to fuel a new era of studies, by providing the medical community with new tools to treat this dismal disease. PMID:27337224

Effect of dietary protein restriction on renal ammonia metabolism

PubMed Central

Lee, Hyun-Wook; Osis, Gunars; Handlogten, Mary E.; Guo, Hui; Verlander, Jill W.

2015-01-01

Dietary protein restriction has multiple benefits in kidney disease. Because protein intake is a major determinant of endogenous acid production, it is important that net acid excretion change in parallel during protein restriction. Ammonia is the primary component of net acid excretion, and inappropriate ammonia excretion can lead to negative nitrogen balance. Accordingly, we examined ammonia excretion in response to protein restriction and then we determined the molecular mechanism of the changes observed. Wild-type C57Bl/6 mice fed a 20% protein diet and then changed to 6% protein developed an 85% reduction in ammonia excretion within 2 days, which persisted during a 10-day study. The expression of multiple proteins involved in renal ammonia metabolism was altered, including the ammonia-generating enzymes phosphate-dependent glutaminase (PDG) and phosphoenolpyruvate carboxykinase (PEPCK) and the ammonia-metabolizing enzyme glutamine synthetase. Rhbg, an ammonia transporter, increased in expression in the inner stripe of outer medullary collecting duct intercalated cell (OMCDis-IC). However, collecting duct-specific Rhbg deletion did not alter the response to protein restriction. Rhcg deletion did not alter ammonia excretion in response to dietary protein restriction. These results indicate 1) dietary protein restriction decreases renal ammonia excretion through coordinated regulation of multiple components of ammonia metabolism; 2) increased Rhbg expression in the OMCDis-IC may indicate a biological role in addition to ammonia transport; and 3) Rhcg expression is not necessary to decrease ammonia excretion during dietary protein restriction. PMID:25925252

Alteration of Multiple Leukocyte Gene Expression Networks is Linked with Magnetic Resonance Markers of Prognosis After Acute ST-Elevation Myocardial Infarction.

PubMed

Teren, A; Kirsten, H; Beutner, F; Scholz, M; Holdt, L M; Teupser, D; Gutberlet, M; Thiery, J; Schuler, G; Eitel, I

2017-02-03

Prognostic relevant pathways of leukocyte involvement in human myocardial ischemic-reperfusion injury are largely unknown. We enrolled 136 patients with ST-elevation myocardial infarction (STEMI) after primary angioplasty within 12 h after onset of symptoms. Following reperfusion, whole blood was collected within a median time interval of 20 h (interquartile range: 15-25 h) for genome-wide gene expression analysis. Subsequent CMR scans were performed using a standard protocol to determine infarct size (IS), area at risk (AAR), myocardial salvage index (MSI) and the extent of late microvascular obstruction (lateMO). We found 398 genes associated with lateMO and two genes with IS. Neither AAR, nor MSI showed significant correlations with gene expression. Genes correlating with lateMO were strongly related to several canonical pathways, including positive regulation of T-cell activation (p = 3.44 × 10 -5 ), and regulation of inflammatory response (p = 1.86 × 10 -3 ). Network analysis of multiple gene expression alterations associated with larger lateMO identified the following functional consequences: facilitated utilisation and decreased concentration of free fatty acid, repressed cell differentiation, enhanced phagocyte movement, increased cell death, vascular disease and compensatory vasculogenesis. In conclusion, the extent of lateMO after acute, reperfused STEMI correlated with altered activation of multiple genes related to fatty acid utilisation, lymphocyte differentiation, phagocyte mobilisation, cell survival, and vascular dysfunction.

Chemically defined medium and Caenorhabditis elegans

NASA Technical Reports Server (NTRS)

Szewczyk, Nathaniel J.; Kozak, Elena; Conley, Catharine A.

2003-01-01

BACKGROUND: C. elegans has been established as a powerful genetic system. Use of a chemically defined medium (C. elegans Maintenance Medium (CeMM)) now allows standardization and systematic manipulation of the nutrients that animals receive. Liquid cultivation allows automated culturing and experimentation and should be of use in large-scale growth and screening of animals. RESULTS: We find that CeMM is versatile and culturing is simple. CeMM can be used in a solid or liquid state, it can be stored unused for at least a year, unattended actively growing cultures may be maintained longer than with standard techniques, and standard C. elegans protocols work well with animals grown in defined medium. We also find that there are caveats to using defined medium. Animals in defined medium grow more slowly than on standard medium, appear to display adaptation to the defined medium, and display altered growth rates as they change the composition of the defined medium. CONCLUSIONS: As was suggested with the introduction of C. elegans as a potential genetic system, use of defined medium with C. elegans should prove a powerful tool.

Zero-inflated modeling of fish catch per unit area resulting from multiple gears: Application to channel catfish and shovelnose sturgeon in the Missouri River

USGS Publications Warehouse

Arab, A.; Wildhaber, M.L.; Wikle, C.K.; Gentry, C.N.

2008-01-01

Fisheries studies often employ multiple gears that result in large percentages of zero values. We considered a zero-inflated Poisson (ZIP) model with random effects to address these excessive zeros. By employing a Bayesian ZIP model that simultaneously incorporates data from multiple gears to analyze data from the Missouri River, we were able to compare gears and make more year, segment, and macrohabitat comparisons than did the original data analysis. For channel catfish Ictalurus punctatus, our results rank (highest to lowest) the mean catch per unit area (CPUA) for gears (beach seine, benthic trawl, electrofishing, and drifting trammel net); years (1998 and 1997); macrohabitats (tributary mouth, connected secondary channel, nonconnected secondary channel, and bend); and river segment zones (channelized, inter-reservoir, and least-altered). For shovelnose sturgeon Scaphirhynchus platorynchus, the mean CPUA was significantly higher for benthic trawls and drifting trammel nets; 1998 and 1997; tributary mouths, bends, and connected secondary channels; and some channelized or least-altered inter-reservoir segments. One important advantage of our approach is the ability to reliably infer patterns of relative abundance by means of multiple gears without using gear efficiencies. ?? Copyright by the American Fisheries Society 2008.

Selective dentate gyrus disruption causes memory impairment at the early stage of experimental multiple sclerosis.

PubMed

Planche, Vincent; Panatier, Aude; Hiba, Bassem; Ducourneau, Eva-Gunnel; Raffard, Gerard; Dubourdieu, Nadège; Maitre, Marlène; Lesté-Lasserre, Thierry; Brochet, Bruno; Dousset, Vincent; Desmedt, Aline; Oliet, Stéphane H; Tourdias, Thomas

2017-02-01

Memory impairment is an early and disabling manifestation of multiple sclerosis whose anatomical and biological substrates are still poorly understood. We thus investigated whether memory impairment encountered at the early stage of the disease could be explained by a differential vulnerability of particular hippocampal subfields. By using experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis, we identified that early memory impairment was associated with selective alteration of the dentate gyrus as pinpointed in vivo with diffusion-tensor-imaging (DTI). Neuromorphometric analyses and electrophysiological recordings confirmed dendritic degeneration, alteration in glutamatergic synaptic transmission and impaired long-term synaptic potentiation selectively in the dentate gyrus, but not in CA1, together with a more severe pattern of microglial activation in this subfield. Systemic injections of the microglial inhibitor minocycline prevented DTI, morphological, electrophysiological and behavioral impairments in EAE-mice. Furthermore, daily infusions of minocycline specifically within the dentate gyrus were sufficient to prevent memory impairment in EAE-mice while infusions of minocycline within CA1 were inefficient. We conclude that early memory impairment in EAE is due to a selective disruption of the dentate gyrus associated with microglia activation. These results open new pathophysiological, imaging, and therapeutic perspectives for memory impairment in multiple sclerosis. Copyright © 2016 Elsevier Inc. All rights reserved.

Effects of gravity reduction on phase equilibria. Part 1: Unary and binary isostructural solids

NASA Technical Reports Server (NTRS)

Larson, D. J., Jr.

1975-01-01

Analysis of the Skylab II M553 Experiment samples resulted in the hypothesis that the reduced gravity environment was altering the melting and solidification reactions. A theoretical study was conducted to define the conditions under which such alteration of phase relations is feasible, determine whether it is restricted to space processing, and, if so, ascertain which alloy systems or phase reactions are most likely to demonstrate such effects. Phase equilibria of unary and binary systems with a single solid phase (unary and isomorphous) were considered.

ALCHEMIST: Bringing Genomic Discovery and Targeted Therapies to Early-Stage Lung Cancer

PubMed Central

Gerber, DE; Oxnard, GR; Govindan, R

2016-01-01

The identification of druggable molecular alterations represents one of the greatest advances in cancer treatment. Such progress is particularly evident for lung cancer, which now has numerous molecularly defined subsets such as epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements. However, understanding of the significance of these genomic alterations is largely limited to incurable, metastatic lung cancer. ALCHEMIST (Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trial) is a National Cancer Institute–sponsored initiative to address these questions in earlier-stage disease. PMID:25677079

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas. | Office of Cancer Genomics

Cancer.gov

Although the MYC oncogene has been implicated in cancer, a systematic assessment of alterations of MYC, related transcription factors, and co-regulatory proteins, forming the proximal MYC network (PMN), across human cancers is lacking. Using computational approaches, we define genomic and proteomic features associated with MYC and the PMN across the 33 cancers of The Cancer Genome Atlas. Pan-cancer, 28% of all samples had at least one of the MYC paralogs amplified.

LANDSAT Study of Alteration Aureoles in Surface Rocks Overlying Petroleum Deposits. [Cement and Davenport oil fields, Oklahoma

NASA Technical Reports Server (NTRS)

Donovan, T. J. (Principal Investigator)

1975-01-01

The author has identified the following significant results. A series of low altitude underflight remote sensing experiments were flown at Cement and Davenport oil fields, Oklahoma. An experimental algorithm which employs a sinusoidal stretch of brightness values was developed and applied to a January 1973 scene (bands 4, 5, and 6) of Cement. The results, although not spectacular, are extremely encouraging and for the first time demonstrate that the alteration anomaly at Cement may be defined through enhanced LANDSAT images.

Motor control differs for increasing and releasing force

PubMed Central

Park, Seoung Hoon; Kwon, MinHyuk; Solis, Danielle; Lodha, Neha

2016-01-01

Control of the motor output depends on our ability to precisely increase and release force. However, the influence of aging on force increase and release remains unknown. The purpose of this study, therefore, was to determine whether force control differs while increasing and releasing force in young and older adults. Sixteen young adults (22.5 ± 4 yr, 8 females) and 16 older adults (75.7 ± 6.4 yr, 8 females) increased and released force at a constant rate (10% maximum voluntary contraction force/s) during an ankle dorsiflexion isometric task. We recorded the force output and multiple motor unit activity from the tibialis anterior (TA) muscle and quantified the following outcomes: 1) variability of force using the SD of force; 2) mean discharge rate and variability of discharge rate of multiple motor units; and 3) power spectrum of the multiple motor units from 0–4, 4–10, 10–35, and 35–60 Hz. Participants exhibited greater force variability while releasing force, independent of age (P < 0.001). Increased force variability during force release was associated with decreased modulation of multiple motor units from 35 to 60 Hz (R2 = 0.38). Modulation of multiple motor units from 35 to 60 Hz was further correlated to the change in mean discharge rate of multiple motor units (r = 0.66) and modulation from 0 to 4 Hz (r = −0.64). In conclusion, these findings suggest that force control is altered while releasing due to an altered modulation of the motor units. PMID:26961104

Risk Prediction Models for Other Cancers or Multiple Sites

Cancer.gov

Developing statistical models that estimate the probability of developing other multiple cancers over a defined period of time will help clinicians identify individuals at higher risk of specific cancers, allowing for earlier or more frequent screening and counseling of behavioral changes to decrease risk.

Multiple sensor fault diagnosis for dynamic processes.

PubMed

Li, Cheng-Chih; Jeng, Jyh-Cheng

2010-10-01

Modern industrial plants are usually large scaled and contain a great amount of sensors. Sensor fault diagnosis is crucial and necessary to process safety and optimal operation. This paper proposes a systematic approach to detect, isolate and identify multiple sensor faults for multivariate dynamic systems. The current work first defines deviation vectors for sensor observations, and further defines and derives the basic sensor fault matrix (BSFM), consisting of the normalized basic fault vectors, by several different methods. By projecting a process deviation vector to the space spanned by BSFM, this research uses a vector with the resulted weights on each direction for multiple sensor fault diagnosis. This study also proposes a novel monitoring index and derives corresponding sensor fault detectability. The study also utilizes that vector to isolate and identify multiple sensor faults, and discusses the isolatability and identifiability. Simulation examples and comparison with two conventional PCA-based contribution plots are presented to demonstrate the effectiveness of the proposed methodology. Copyright © 2010 ISA. Published by Elsevier Ltd. All rights reserved.

Hidden symmetries and equilibrium properties of multiplicative white-noise stochastic processes

NASA Astrophysics Data System (ADS)

González Arenas, Zochil; Barci, Daniel G.

2012-12-01

Multiplicative white-noise stochastic processes continue to attract attention in a wide area of scientific research. The variety of prescriptions available for defining them makes the development of general tools for their characterization difficult. In this work, we study equilibrium properties of Markovian multiplicative white-noise processes. For this, we define the time reversal transformation for such processes, taking into account that the asymptotic stationary probability distribution depends on the prescription. Representing the stochastic process in a functional Grassmann formalism, we avoid the necessity of fixing a particular prescription. In this framework, we analyze equilibrium properties and study hidden symmetries of the process. We show that, using a careful definition of the equilibrium distribution and taking into account the appropriate time reversal transformation, usual equilibrium properties are satisfied for any prescription. Finally, we present a detailed deduction of a covariant supersymmetric formulation of a multiplicative Markovian white-noise process and study some of the constraints that it imposes on correlation functions using Ward-Takahashi identities.

How and why multiple MCMs are loaded at origins of DNA replication.

PubMed

Das, Shankar P; Rhind, Nicholas

2016-07-01

Recent work suggests that DNA replication origins are regulated by the number of multiple mini-chromosome maintenance (MCM) complexes loaded. Origins are defined by the loading of MCM - the replicative helicase which initiates DNA replication and replication kinetics determined by origin's location and firing times. However, activation of MCM is heterogeneous; different origins firing at different times in different cells. Also, more MCMs are loaded in G1 than are used in S phase. These aspects of MCM biology are explained by the observation that multiple MCMs are loaded at origins. Having more MCMs at early origins makes them more likely to fire, effecting differences in origin efficiency that define replication timing. Nonetheless, multiple MCM loading raises new questions, such as how they are loaded, where these MCMs reside at origins, and how their presence affects replication timing. In this review, we address these questions and discuss future avenues of research. © 2016 WILEY Periodicals, Inc.

Multiple-pass high-pressure homogenization of milk for the development of pasteurization-like processing conditions.

PubMed

Ruiz-Espinosa, H; Amador-Espejo, G G; Barcenas-Pozos, M E; Angulo-Guerrero, J O; Garcia, H S; Welti-Chanes, J

2013-02-01

Multiple-pass ultrahigh pressure homogenization (UHPH) was used for reducing microbial population of both indigenous spoilage microflora in whole raw milk and a baroresistant pathogen (Staphylococcus aureus) inoculated in whole sterile milk to define pasteurization-like processing conditions. Response surface methodology was followed and multiple response optimization of UHPH operating pressure (OP) (100, 175, 250 MPa) and number of passes (N) (1-5) was conducted through overlaid contour plot analysis. Increasing OP and N had a significant effect (P < 0·05) on microbial reduction of both spoilage microflora and Staph. aureus in milk. Optimized UHPH processes (five 202-MPa passes; four 232-MPa passes) defined a region where a 5-log(10) reduction of total bacterial count of milk and a baroresistant pathogen are attainable, as a requisite parameter for establishing an alternative method of pasteurization. Multiple-pass UHPH optimized conditions might help in producing safe milk without the detrimental effects associated with thermal pasteurization. © 2012 The Society for Applied Microbiology.

The Immune System’s Role in Sepsis Progression, Resolution and Long-Term Outcome

PubMed Central

Delano, Matthew J.; Ward, Peter A.

2016-01-01

SUMMARY Sepsis occurs when an infection exceeds local tissue containment and induces a series of dysregulated physiologic responses that result in organ dysfunction. A subset of patients with sepsis progress to septic shock, defined by profound circulatory, cellular, and metabolic abnormalities, and associated with a greater mortality. Historically, sepsis-induced organ dysfunction and lethality were attributed to the complex interplay between the initial inflammatory and later anti-inflammatory responses. With advances in intensive care medicine and goal-directed interventions, early 30-day sepsis mortality has diminished, only to steadily escalate long after “recovery” from acute events. Since so many sepsis survivors succumb later to persistent, recurrent, nosocomial and secondary infections, many investigators have turned their attention to the long-term sepsis-induced alterations in cellular immune function. Sepsis clearly alters the innate and adaptive immune responses for sustained periods of time after clinical recovery, with immune suppression, chronic inflammation, and persistence of bacterial representing such alterations. Understanding that sepsis-associated immune cell defects correlate with long-term mortality, more investigations have centered on the potential for immune modulatory therapy to improve long term patient outcomes. These efforts are focused on more clearly defining and effectively reversing the persistent immune cell dysfunction associated with long-term sepsis mortality. PMID:27782333

White matter and schizophrenia: A meta-analysis of voxel-based morphometry and diffusion tensor imaging studies.

PubMed

Vitolo, Enrico; Tatu, Mona Karina; Pignolo, Claudia; Cauda, Franco; Costa, Tommaso; Ando', Agata; Zennaro, Alessandro

2017-12-30

Voxel-based morphometry (VBM) and diffusion tensor imaging (DTI) are the most implemented methodologies to detect alterations of both gray and white matter (WM). However, the role of WM in mental disorders is still not well defined. We aimed at clarifying the role of WM disruption in schizophrenia and at identifying the most frequently involved brain networks. A systematic literature search was conducted to identify VBM and DTI studies focusing on WM alterations in patients with schizophrenia compared to control subjects. We selected studies reporting the coordinates of WM reductions and we performed the anatomical likelihood estimation (ALE). Moreover, we labeled the WM bundles with an anatomical atlas and compared VBM and DTI ALE-scores of each significant WM tract. A total of 59 studies were eligible for the meta-analysis. WM alterations were reported in 31 and 34 foci with VBM and DTI methods, respectively. The most occurred WM bundles in both VBM and DTI studies and largely involved in schizophrenia were long projection fibers, callosal and commissural fibers, part of motor descending fibers, and fronto-temporal-limbic pathways. The meta-analysis showed a widespread WM disruption in schizophrenia involving specific cerebral circuits instead of well-defined regions. Copyright © 2017 Elsevier B.V. All rights reserved.

Cars & Censorship: How Advertising Pressure Can Corrupt a Free Press.

ERIC Educational Resources Information Center

Collins, Ronald K. L.

1992-01-01

Discusses "private censorship" as it relates to car dealers and television advertising. Defines "private censorship" as that which occurs when a broadcaster suppresses or alters a news story that affects commercial clients (advertisers). Makes recommendations for a freer press. (JOW)

Climate change, soil health, and ecosystem goods and services

USDA-ARS?s Scientific Manuscript database

Worldwide, climate change is predicted to alter precipitation regimes, annual temperatures, and occurrence of severe weather events. These changes have important implications for soil health-- defined as the capacity of a soil to contribute to ecosystem function and sustain producers and consumers--...

"Traveling Theory" and the Defining of New Rhetorics.

ERIC Educational Resources Information Center

Schilb, John

1992-01-01

Demonstrates how theory can alter as it "travels" from another region of inquiry into composition by examining Elaine Maimon's essay "Knowledge, Acknowledgment, and Writing across the Curriculum: Toward an Educated Community." Discusses how Maimon changes Stanley Fish's theory of "interpretive communities." (PRA)

Dynamic Microstructure Design Consortium

DTIC Science & Technology

2011-03-23

multiple realizations of polycrystalline microstructure. Cyclic microplasticity in favorably oriented martensite grains is the primary driver for the...can alter the residual stress distribution 13. The present work ex- plores how short-range microplastic deformation during cyclic loading promotes

Prognostic Classification Factors Associated With Development of Multiple Autoantibodies, Dysglycemia, and Type 1 Diabetes—A Recursive Partitioning Analysis

PubMed Central

Krischer, Jeffrey P.

2016-01-01

OBJECTIVE To define prognostic classification factors associated with the progression from single to multiple autoantibodies, multiple autoantibodies to dysglycemia, and dysglycemia to type 1 diabetes onset in relatives of individuals with type 1 diabetes. RESEARCH DESIGN AND METHODS Three distinct cohorts of subjects from the Type 1 Diabetes TrialNet Pathway to Prevention Study were investigated separately. A recursive partitioning analysis (RPA) was used to determine the risk classes. Clinical characteristics, including genotype, antibody titers, and metabolic markers were analyzed. RESULTS Age and GAD65 autoantibody (GAD65Ab) titers defined three risk classes for progression from single to multiple autoantibodies. The 5-year risk was 11% for those subjects >16 years of age with low GAD65Ab titers, 29% for those ≤16 years of age with low GAD65Ab titers, and 45% for those subjects with high GAD65Ab titers regardless of age. Progression to dysglycemia was associated with islet antigen 2 Ab titers, and 2-h glucose and fasting C-peptide levels. The 5-year risk is 28%, 39%, and 51% for respective risk classes defined by the three predictors. Progression to type 1 diabetes was associated with the number of positive autoantibodies, peak C-peptide level, HbA1c level, and age. Four risk classes defined by RPA had a 5-year risk of 9%, 33%, 62%, and 80%, respectively. CONCLUSIONS The use of RPA offered a new classification approach that could predict the timing of transitions from one preclinical stage to the next in the development of type 1 diabetes. Using these RPA classes, new prevention techniques can be tailored based on the individual prognostic risk characteristics at different preclinical stages. PMID:27208341

Hypoxia and Mucosal Inflammation

PubMed Central

Colgan, Sean P.; Campbell, Eric L.; Kominsky, Douglas J.

2016-01-01

Sites of inflammation are defined by significant changes in metabolic activity. Recent studies have suggested that O2 metabolism and hypoxia play a prominent role in inflammation so-called “inflammatory hypoxia,” which results from a combination of recruited inflammatory cells (e.g., neutrophils and monocytes), the local proliferation of multiple cell types, and the activation of multiple O2-consuming enzymes during inflammation. These shifts in energy supply and demand result in localized regions of hypoxia and have revealed the important function off the transcription factor HIF (hypoxia-inducible factor) in the regulation of key target genes that promote inflammatory resolution. Analysis of these pathways has provided multiple opportunities for understanding basic mechanisms of inflammation and has defined new targets for intervention. Here, we review recent work addressing tissue hypoxia and metabolic control of inflammation and immunity. PMID:27193451

Thermal Studies of Ammonium Cyanide Reactions: A Model for Thermal Alteration of Prebiotic Compounds in Meteorite Parent Bodies

NASA Technical Reports Server (NTRS)

Hammer, P. G.; Locke, D. R.; Burton, A. S.; Callahan, M. P.

2017-01-01

Organic compounds in carbonaceous chondrites were likely transformed by a variety of parent body processes including thermal and aqueous processing. Here, we analyzed ammonium cyanide reactions that were heated at different temperatures and times by multiple analytical techniques. The goal of this study is to better understand the effect of hydrothermal alteration on cyanide chemistry, which is believed to be responsible for the abiotic synthesis of purine nucleobases and their structural analogs detected in carbonaceous chondrites.

Participatory Pedagogy: A Compass for Transformative Learning?

ERIC Educational Resources Information Center

Simmons, Nicola; Barnard, Michelle; Fennema, Wendy

2011-01-01

In the Fall 2009 term, we participated as students and instructor in a graduate education course modeled after participatory pedagogy. Siemens (2008) defines this approach as "one that does not fully define all curricular needs in advance of interacting with learners...Multiple perspectives, opinions, and active creation on the part of…

Temporal Frequency Modulates Reaction Time Responses to First-Order and Second-Order Motion

ERIC Educational Resources Information Center

Hutchinson, Claire V.; Ledgeway, Tim

2010-01-01

This study investigated the effect of temporal frequency and modulation depth on reaction times for discriminating the direction of first-order (luminance-defined) and second-order (contrast-defined) motion, equated for visibility using equal multiples of direction-discrimination threshold. Results showed that reaction times were heavily…

Reduction of the Earth's magnetic field inhibits growth rates of model cancer cell lines.

PubMed

Martino, Carlos F; Portelli, Lucas; McCabe, Kevin; Hernandez, Mark; Barnes, Frank

2010-12-01

Small alterations in static magnetic fields have been shown to affect certain chemical reaction rates ex vivo. In this manuscript, we present data demonstrating that similar small changes in static magnetic fields between individual cell culture incubators results in significantly altered cell cycle rates for multiple cancer-derived cell lines. This change as assessed by cell number is not a result of apoptosis, necrosis, or cell cycle alterations. While the underlying mechanism is unclear, the implications for all cell culture experiments are clear; static magnetic field conditions within incubators must be considered and/or controlled just as one does for temperature, humidity, and carbon dioxide concentration. Copyright © 2010 Wiley-Liss, Inc.

Workshop on Spaceflight Alterations in Host-Microorganism Interactions

NASA Technical Reports Server (NTRS)

Ott, C. Mark

2010-01-01

On June 11, 2009, a workshop that included internal and external experts was convened to determine the risk of changes in microorganisms that could alter host-microorganism interactions during a mission. The evidence is based in part on multiple flight experiments which indicate altered virulence in Salmonella typhimurium when cultured in flight. The workshop participants were tasked to determine if adequate information was available to initiate changes in NASA's current approach to infectious disease risk assessment and medical operations. The consensus of the participants is that the current evidence was not adequate to provide direction for operational changes; however, the evidence is compelling and clearly indicates that changes to microorganisms were occurring during spaceflight and further research is required.

Margins Associated with Loss of Assured Safety for Systems with Multiple Time-Dependent Failure Modes.

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

Helton, Jon C.; Brooks, Dusty Marie; Sallaberry, Cedric Jean-Marie.

Representations for margins associated with loss of assured safety (LOAS) for weak link (WL)/strong link (SL) systems involving multiple time-dependent failure modes are developed. The following topics are described: (i) defining properties for WLs and SLs, (ii) background on cumulative distribution functions (CDFs) for link failure time, link property value at link failure, and time at which LOAS occurs, (iii) CDFs for failure time margins defined by (time at which SL system fails) – (time at which WL system fails), (iv) CDFs for SL system property values at LOAS, (v) CDFs for WL/SL property value margins defined by (property valuemore » at which SL system fails) – (property value at which WL system fails), and (vi) CDFs for SL property value margins defined by (property value of failing SL at time of SL system failure) – (property value of this SL at time of WL system failure). Included in this presentation is a demonstration of a verification strategy based on defining and approximating the indicated margin results with (i) procedures based on formal integral representations and associated quadrature approximations and (ii) procedures based on algorithms for sampling-based approximations.« less

Multiple Intelligences in the Schools.

ERIC Educational Resources Information Center

Quigley, Kathleen M.

Within the context of school improvement and school reform, it is important to examine Howard Gardner's theory of multiple intelligences (MI theory). His work has far-reaching implications for curriculum development and classroom implementation. Gardner believes that the culture defines intelligence too narrowly. He sought to broaden the scope of…

Untargeted Plasma Metabolomics Identifies Endogenous Metabolite with Drug-like Properties in Chronic Animal Model of Multiple Sclerosis*

PubMed Central

Poisson, Laila M.; Suhail, Hamid; Singh, Jaspreet; Datta, Indrani; Denic, Aleksandar; Labuzek, Krzysztof; Hoda, Md Nasrul; Shankar, Ashray; Kumar, Ashok; Cerghet, Mirela; Elias, Stanton; Mohney, Robert P.; Rodriguez, Moses; Rattan, Ramandeep; Mangalam, Ashutosh K.; Giri, Shailendra

2015-01-01

We performed untargeted metabolomics in plasma of B6 mice with experimental autoimmune encephalitis (EAE) at the chronic phase of the disease in search of an altered metabolic pathway(s). Of 324 metabolites measured, 100 metabolites that mapped to various pathways (mainly lipids) linked to mitochondrial function, inflammation, and membrane stability were observed to be significantly altered between EAE and control (p < 0.05, false discovery rate <0.10). Bioinformatics analysis revealed six metabolic pathways being impacted and altered in EAE, including α-linolenic acid and linoleic acid metabolism (PUFA). The metabolites of PUFAs, including ω-3 and ω-6 fatty acids, are commonly decreased in mouse models of multiple sclerosis (MS) and in patients with MS. Daily oral administration of resolvin D1, a downstream metabolite of ω-3, decreased disease progression by suppressing autoreactive T cells and inducing an M2 phenotype of monocytes/macrophages and resident brain microglial cells. This study provides a proof of principle for the application of metabolomics to identify an endogenous metabolite(s) possessing drug-like properties, which is assessed for therapy in preclinical mouse models of MS. PMID:26546682

Multiple toxic doses of methamphetamine alter neurotensin concentrations in various region of the rat brain

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

Hanson, G.R.; Merchant, K.; Gibb, J.W.

1986-03-05

The authors have previously reported that multiple high doses of methamphetamine (METH) alter neuronal monoamine metabolism and release. Recently, Hokfelt et al. showed that neurotensin, a tridecapeptide, has neurotransmitter properties which may be involved with DA neuronal activity. In the present study they investigated the possible effects of METH on the CNS neurotensin system. Five doses of METH (15 mg/kg) were administered every 6 h; control and treated rats were sacrificed 18 h after the last dose and concentrations of neurotensin-like immuno-reactivity (NTLI) were measured by radioimmunoassay. NTLI was elevated 200-300% in the nucleus accumbens, neostriatum, and substantia nigra; 30-40%more » increases in NTLI were measured in the hippocampus and hypothalamus. No change was observed in amygdala, A-10 or periaqueductal gray. In contrast to the above measured areas, the frontal lobe and olfactory bulb showed decreases of 25-35%. These findings demonstrate that METH treatment alters the activities of several CNS neurotensin systems, possibly due to the influence of this drug on DA pathways. The variability in the type and magnitude of these responses suggests that DA and neurotensin systems interact by more than one mechanism.« less

Chronic polyarthritis associated to Cercopithifilaria bainae infection in a dog.

PubMed

Gabrielli, Simona; Giannelli, Alessio; Brianti, Emanuele; Dantas-Torres, Filipe; Bufalini, Massimiliano; Fraulo, Maurizio; La Torre, Francesco; Ramos, Rafael A N; Cantacessi, Cinzia; Latrofa, Maria Stefania; Cancrini, Gabriella; Otranto, Domenico

2014-09-15

Despite the widespread distribution of Cercopithifilaria bainae among canine and tick populations worldwide, this filarioid is currently considered of 'minor importance' in veterinary medicine, particularly when compared to related filarioids, such as Dirofilaria immitis and Dirofilaria repens. To date, only a single case of dermatological alterations possibly associated to infection by C. bainae had been reported in a dog. In the present study, we describe the first case of systemic alterations associated to C. bainae infection in a dog suffering from diffused chronic polyarthritis. The animal had a previous history of reluctance to move and stiff gait and displayed multiple joint pain during manipulation of limbs. No biochemical, haematological and X-ray alterations were detected; microfilariae were observed in the synovial fluids collected from the joints. In spite of the morphological and molecular identification of these microfilariae as C. bainae, the dog did not respond to multiple microfilaricidal treatments with milbemicyn oxyme. The potential role of C. bainae in the pathogenesis of this clinical condition is discussed. Given the potential pathogenicity of this parasite, improved knowledge of this little known tick-borne nematode is warranted in order to assist the development of novel and effective treatment strategies. Copyright © 2014. Published by Elsevier B.V.

Study of adaptation to altered gravity through systems analysis of motor control.

PubMed

Fox, R A; Daunton, N G; Corcoran, M L

1998-01-01

Maintenance of posture and production of functional, coordinated movement demand integration of sensory feedback with spinal and supra-spinal circuitry to produce adaptive motor control in altered gravity (G). To investigate neuroplastic processes leading to optimal performance in altered G we have studied motor control in adult rats using a battery of motor function tests following chronic exposure to various treatments (hyper-G, hindlimb suspension, chemical distruction of hair cells, space flight). These treatments differentially affect muscle fibers, vestibular receptors, and behavioral compensations and, in consequence, differentially disrupt air righting, swimming, posture and gait. The time-course of recovery from these disruptions varies depending on the function tested and the duration and type of treatment. These studies, with others (e.g., D'Amelio et al. in this volume), indicate that adaptation to altered gravity involves alterations in multiple sensory-motor systems that change at different rates. We propose that the use of parallel studies under different altered G conditions will most efficiently lead to an understanding of the modifications in central (neural) and peripheral (sensory and neuromuscular) systems that underlie sensory-motor adaptation in active, intact individuals.

Study of adaptation to altered gravity through systems analysis of motor control

NASA Astrophysics Data System (ADS)

Fox, R. A.; Daunton, N. G.; Corcoran, M. L.

Maintenance of posture and production of functional, coordinated movement demand integration of sensory feedback with spinal and supra-spinal circuitry to produce adaptive motor control in altered gravity (G). To investigate neuroplastic processes leading to optimal performance in altered G we have studied motor control in adult rats using a battery of motor function tests following chronic exposure to various treatments (hyper-G, hindlimb suspension, chemical distruction of hair cells, space flight). These treatments differentially affect muscle fibers, vestibular receptors, and behavioral compensations and, in consequence, differentially disrupt air righting, swimming, posture and gait. The time-course of recovery from these disruptions varies depending on the function tested and the duration and type of treatment. These studies, with others (e.g., D'Amelio et al. in this volume), indicate that adaptation to altered gravity involves alterations in multiple sensory-motor systems that change at different rates. We propose that the use of parallel studies under different altered G conditions will most efficiently lead to an understanding of the modifications in central (neural) and peripheral (sensory and neuromuscular) systems that underlie sensory-motor adaptation in active, intact individuals.

Hyperspectral remote sensing applied to mineral exploration in southern Peru: A multiple data integration approach in the Chapi Chiara gold prospect

NASA Astrophysics Data System (ADS)

Carrino, Thais Andressa; Crósta, Alvaro Penteado; Toledo, Catarina Labouré Bemfica; Silva, Adalene Moreira

2018-02-01

Remote sensing is a strategic key tool for mineral exploration, due to its capacity of detecting hydrothermal alteration minerals or alteration mineral zones associated with different types of mineralization systems. A case study of an epithermal system located in southern Peru is presented, aimed at the characterization of mineral assemblies for discriminating potential high sulfidation epithermal targets, using hyperspectral imagery integrated with petrography, XRD and magnetic data. HyMap images were processed using the Mixture Tuned Matched Filtering (MTMF) technique for producing alteration map in the Chapi Chiara epithermal gold prospect. Extensive areas marked by advanced argillic alteration (alunite-kaolinite-dickite ± topaz) were mapped in detail, as well as limited argillic (illite-smectite) and propylitic (chlorite spectral domain) alteration. The magmatic-hydrothermal processes responsible for the formation of hypogene minerals were also related to the destruction of ferrimagnetic minerals (e.g., magnetite) of host rocks such as andesite, and the remobilization/formation of paramagnetic Fe-Ti oxides (e.g., rutile, anatase). The large alteration zones of advanced argillic alteration are controlled by structures related to a regional NW-SE trend, and also by local NE-SW and ENE-WSW ones.

Alteration mapping at Goldfield, Nevada, by cluster and discriminant analysis of LANDSAT digital data

NASA Technical Reports Server (NTRS)

Ballew, G.

1977-01-01

The ability of Landsat multispectral digital data to differentiate among 62 combinations of rock and alteration types at the Goldfield mining district of Western Nevada was investigated by using statistical techniques of cluster and discriminant analysis. Multivariate discriminant analysis was not effective in classifying each of the 62 groups, with classification results essentially the same whether data of four channels alone or combined with six ratios of channels were used. Bivariate plots of group means revealed a cluster of three groups including mill tailings, basalt and all other rock and alteration types. Automatic hierarchical clustering based on the fourth dimensional Mahalanobis distance between group means of 30 groups having five or more samples was performed. The results of the cluster analysis revealed hierarchies of mill tailings vs. natural materials, basalt vs. non-basalt, highly reflectant rocks vs. other rocks and exclusively unaltered rocks vs. predominantly altered rocks. The hierarchies were used to determine the order in which sets of multiple discriminant analyses were to be performed and the resulting discriminant functions were used to produce a map of geology and alteration which has an overall accuracy of 70 percent for discriminating exclusively altered rocks from predominantly altered rocks.

Floodplain geomorphic processes and environmental impacts of human alteration along coastal plain rivers, USA

USGS Publications Warehouse

Hupp, C.R.; Pierce, Aaron R.; Noe, G.B.

2009-01-01

Human alterations along stream channels and within catchments have affected fluvial geomorphic processes worldwide. Typically these alterations reduce the ecosystem services that functioning floodplains provide; in this paper we are concerned with the sediment and associated material trapping service. Similarly, these alterations may negatively impact the natural ecology of floodplains through reductions in suitable habitats, biodiversity, and nutrient cycling. Dams, stream channelization, and levee/canal construction are common human alterations along Coastal Plain fluvial systems. We use three case studies to illustrate these alterations and their impacts on floodplain geomorphic and ecological processes. They include: 1) dams along the lower Roanoke River, North Carolina, 2) stream channelization in west Tennessee, and 3) multiple impacts including canal and artificial levee construction in the central Atchafalaya Basin, Louisiana. Human alterations typically shift affected streams away from natural dynamic equilibrium where net sediment deposition is, approximately, in balance with net erosion. Identification and understanding of critical fluvial parameters (e.g., stream gradient, grain-size, and hydrography) and spatial and temporal sediment deposition/erosion process trajectories should facilitate management efforts to retain and/or regain important ecosystem services. ?? 2009, The Society of Wetland Scientists.

Directed deposition of inorganic oxide networks on patterned polymer templates

NASA Astrophysics Data System (ADS)

Ford, Thomas James Robert

Inspired by nature, we have successfully directed the deposition of inorganic oxide materials on polymer templates via a combination of top-down and bottom-up fabrication methods. We have functionally mimicked the hierarchical silica exoskeletons of diatoms, where specialized proteins chaperone the condensation of silicic acid into nanoscale silica networks confined by microscopic vesicle walls. We replaced the proteins with functionally analogous polyamines and vesicles with lithographically defined polymer templates. We grafted the polyamines either to the surface or throughout the template by changing the template chemistry and altering our grafting strategy. Exposure to an inorganic oxide precursor solution led to electrostatic aggregation at the polyamine chains, catalyzing hydrolysis and condensation to form long-range inorganic oxide nanoparticle networks. Grafted to epoxy surfaces, swelling effects and the hyperbranched brush morphology lead to the formation of nanofruit features that generated thin, conformal inorganic coatings. When the polyamines were grafted throughout hydrogel templates, we obtained composite networks that yielded faithful inorganic replicas of the original patterns. By varying the polyamine chain length and combustion parameters, we controlled the nanoparticle size, morphology, and crystalline phase. The polyamine morphology affected the resulting inorganic network in both fabrication schemes and we could control the depostion over multiple length scales. Because our methods were compatible with a variety of lithographic methods, we were able to generate inorganic replicas of 1D, 2D, and 3D polymer structures. These may be used for a wide range of applications, including sensing, catalysis, photonic, phononic, photovoltaic, and others that require well-defined inorganic structures.

Metabolic network failures in Alzheimer’s disease: A biochemical road map

PubMed Central

Toledo, Jon B.; Arnold, Matthias; Kastenmüuller, Gabi; Chang, Rui; Baillie, Rebecca A.; Han, Xianlin; Thambisetty, Madhav; Tenenbaum, Jessica D.; Suhre, Karsten; Thompson, J. Will; St. John-Williams, Lisa; MahmoudianDehkordi, Siamak; Rotroff, Daniel M.; Jack, John R.; Motsinger-Reif, Alison; Risacher, Shannon L.; Blach, Colette; Lucas, Joseph E.; Massaro, Tyler; Louie, Gregory; Zhu, Hongjie; Dallmann, Guido; Klavins, Kristaps; Koal, Therese; Kim, Sungeun; Nho, Kwangsik; Shen, Li; Casanova, Ramon; Varma, Sudhir; Legido-Quigley, Cristina; Moseley, M. Arthur; Zhu, Kuixi; Henrion, Marc Y. R.; van der Lee, Sven J.; Harms, Amy C.; Demirkan, Ayse; Hankemeier, Thomas; van Duijn, Cornelia M.; Trojanowski, John Q.; Shaw, Leslie M.; Saykin, Andrew J.; Weiner, Michael W.; Doraiswamy, P. Murali; Kaddurah-Daouk, Rima

2018-01-01

Introduction The Alzheimer’s Disease Research Summits of 2012 and 2015 incorporated experts from academia, industry, and nonprofit organizations to develop new research directions to transform our understanding of Alzheimer’s disease (AD) and propel the development of critically needed therapies. In response to their recommendations, big data at multiple levels are being generated and integrated to study network failures in disease. We used metabolomics as a global biochemical approach to identify peripheral metabolic changes in AD patients and correlate them to cerebrospinal fluid pathology markers, imaging features, and cognitive performance. Methods Fasting serum samples from the Alzheimer’s Disease Neuroimaging Initiative (199 control, 356 mild cognitive impairment, and 175 AD participants) were analyzed using the AbsoluteIDQ-p180 kit. Performance was validated in blinded replicates, and values were medication adjusted. Results Multivariable-adjusted analyses showed that sphingomyelins and ether-containing phosphatidylcholines were altered in preclinical biomarker-defined AD stages, whereas acylcarnitines and several amines, including the branched-chain amino acid valine and α-aminoadipic acid, changed in symptomatic stages. Several of the analytes showed consistent associations in the Rotterdam, Erasmus Rucphen Family, and Indiana Memory and Aging Studies. Partial correlation networks constructed for Aβ1–42, tau, imaging, and cognitive changes provided initial biochemical insights for disease-related processes. Coexpression networks interconnected key metabolic effectors of disease. Discussion Metabolomics identified key disease-related metabolic changes and disease-progression-related changes. Defining metabolic changes during AD disease trajectory and its relationship to clinical phenotypes provides a powerful roadmap for drug and biomarker discovery. PMID:28341160

Time delay spectrum conditioner

DOEpatents

Greiner, Norman R.

1980-01-01

A device for delaying specified frequencies of a multiple frequency laser beam. The device separates the multiple frequency beam into a series of spatially separated single frequency beams. The propagation distance of the single frequency beam is subsequently altered to provide the desired delay for each specific frequency. Focusing reflectors can be utilized to provide a simple but nonadjustable system or, flat reflectors with collimating and focusing optics can be utilized to provide an adjustable system.

Objective assessment of motor fatigue in multiple sclerosis using kinematic gait analysis: a pilot study

PubMed Central

2011-01-01

Background Fatigue is a frequent and serious symptom in patients with Multiple Sclerosis (MS). However, to date there are only few methods for the objective assessment of fatigue. The aim of this study was to develop a method for the objective assessment of motor fatigue using kinematic gait analysis based on treadmill walking and an infrared-guided system. Patients and methods Fourteen patients with clinically definite MS participated in this study. Fatigue was defined according to the Fatigue Scale for Motor and Cognition (FSMC). Patients underwent a physical exertion test involving walking at their pre-determined patient-specific preferred walking speed until they reached complete exhaustion. Gait was recorded using a video camera, a three line-scanning camera system with 11 infrared sensors. Step length, width and height, maximum circumduction with the right and left leg, maximum knee flexion angle of the right and left leg, and trunk sway were measured and compared using paired t-tests (α = 0.005). In addition, variability in these parameters during one-minute intervals was examined. The fatigue index was defined as the number of significant mean and SD changes from the beginning to the end of the exertion test relative to the total number of gait kinematic parameters. Results Clearly, for some patients the mean gait parameters were more affected than the variability of their movements while other patients had smaller differences in mean gait parameters with greater increases in variability. Finally, for other patients gait changes with physical exertion manifested both in changes in mean gait parameters and in altered variability. The variability and fatigue indices correlated significantly with the motoric but not with the cognitive dimension of the FSMC score (R = -0.602 and R = -0.592, respectively; P < 0.026). Conclusions Changes in gait patterns following a physical exertion test in patients with MS suffering from motor fatigue can be measured objectively. These changes in gait patterns can be described using the motor fatigue index and represent an objective measure to assess motor fatigue in MS patients. The results of this study have important implications for the assessments and treatment evaluations of fatigue in MS. PMID:22029427

Integrated Multiregional Analysis Proposing a New Model of Colorectal Cancer Evolution

PubMed Central

Niida, Atsushi; Shimamura, Teppei; Hirata, Hidenari; Sugimachi, Keishi; Sawada, Genta; Iwaya, Takeshi; Kurashige, Junji; Shinden, Yoshiaki; Iguchi, Tomohiro; Eguchi, Hidetoshi; Chiba, Kenichi; Shiraishi, Yuichi; Nagae, Genta; Yoshida, Kenichi; Nagata, Yasunobu; Haeno, Hiroshi; Yamamoto, Hirofumi; Ishii, Hideshi; Doki, Yuichiro; Iinuma, Hisae; Sasaki, Shin; Nagayama, Satoshi; Yamada, Kazutaka; Yachida, Shinichi; Kato, Mamoru; Shibata, Tatsuhiro; Oki, Eiji; Saeki, Hiroshi; Shirabe, Ken; Oda, Yoshinao; Maehara, Yoshihiko; Komune, Shizuo; Mori, Masaki; Suzuki, Yutaka; Yamamoto, Ken; Aburatani, Hiroyuki; Ogawa, Seishi; Miyano, Satoru; Mimori, Koshi

2016-01-01

Understanding intratumor heterogeneity is clinically important because it could cause therapeutic failure by fostering evolutionary adaptation. To this end, we profiled the genome and epigenome in multiple regions within each of nine colorectal tumors. Extensive intertumor heterogeneity is observed, from which we inferred the evolutionary history of the tumors. First, clonally shared alterations appeared, in which C>T transitions at CpG site and CpG island hypermethylation were relatively enriched. Correlation between mutation counts and patients’ ages suggests that the early-acquired alterations resulted from aging. In the late phase, a parental clone was branched into numerous subclones. Known driver alterations were observed frequently in the early-acquired alterations, but rarely in the late-acquired alterations. Consistently, our computational simulation of the branching evolution suggests that extensive intratumor heterogeneity could be generated by neutral evolution. Collectively, we propose a new model of colorectal cancer evolution, which is useful for understanding and confronting this heterogeneous disease. PMID:26890883

MOLECULAR ALTERATIONS IN GLIOBLASTOMA: POTENTIAL TARGETS FOR IMMUNOTHERAPY

PubMed Central

Haque, Azizul; Banik, Naren L.; Ray, Swapan K.

2015-01-01

Glioblastoma is the most common and deadly brain tumor, possibly arising from genetic and epigenetic alterations in normal astroglial cells. Multiple cytogenetic, chromosomal, and genetic alterations have been identified in glioblastoma, with distinct expression of antigens (Ags) and biomarkers that may alter therapeutic potential of this aggressive cancer. Current therapy consists of surgical resection, followed by radiation therapy and chemotherapy. In spite of these treatments, the prognosis for glioblastoma patients is poor. Although recent studies have focused on the development of novel immunotherapeutics against glioblastoma, little is known about glioblastoma specific immune responses. A better understanding of the molecular interactions among glioblastoma tumors, host immune cells, and the tumor microenvironment may give rise to novel integrated approaches for the simultaneous control of tumor escape pathways and the activation of antitumor immune responses. This review provides a detailed overview concerning genetic alterations in glioblastoma, their effects on Ag and biomarker expression and the future design of chemoimmunotherapeutics against glioblastoma. PMID:21199773

Software Defined Radios - Architectures, Systems and Functions

NASA Technical Reports Server (NTRS)

Sims, William H.

2017-01-01

Software Defined Radio is an industry term describing a method of utilizing a minimum amount of Radio Frequency (RF)/analog electronics before digitization takes place. Upon digitization all other functions are performed in software/firmware. There are as many different types of SDRs as there are data systems. Software Defined Radio (SDR) technology has been proven in the commercial sector since the early 90's. Today's rapid advancement in mobile telephone reliability and power management capabilities exemplifies the effectiveness of the SDR technology for the modern communications market. In contrast the foundations of transponder technology presently qualified for satellite applications were developed during the early space program of the 1960's. SDR technology offers potential to revolutionize satellite transponder technology by increasing science data through-put capability by at least an order of magnitude. While the SDR is adaptive in nature and is "One-size-fits-all" by design, conventional transponders are built to a specific platform and must be redesigned for every new bus. The SDR uses a minimum amount of analog/Radio Frequency components to up/down-convert the RF signal to/from a digital format. Once analog data is digitized, all processing is performed using hardware logic. Typical SDR processes include; filtering, modulation, up/down converting and demodulation. This presentation will show how the emerging SDR market has leveraged the existing commercial sector to provide a path to a radiation tolerant SDR transponder. These innovations will reduce the cost of transceivers, a decrease in power requirements and a commensurate reduction in volume. A second pay-off is the increased flexibility of the SDR by allowing the same hardware to implement multiple transponder types by altering hardware logic - no change of analog hardware is required - all of which can be ultimately accomplished in orbit. This in turn would provide high capability and low cost transponder to programs of all sizes.

Software Defined Radios - Architectures, Systems and Functions

NASA Technical Reports Server (NTRS)

Sims, Herb

2017-01-01

Software Defined Radio is an industry term describing a method of utilizing a minimum amount of Radio Frequency (RF)/analog electronics before digitization takes place. Upon digitization all other functions are performed in software/firmware. There are as many different types of SDRs as there are data systems. Software Defined Radio (SDR) technology has been proven in the commercial sector since the early 90's. Today's rapid advancement in mobile telephone reliability and power management capabilities exemplifies the effectiveness of the SDR technology for the modern communications market. In contrast the foundations of transponder technology presently qualified for satellite applications were developed during the early space program of the 1960's. SDR technology offers potential to revolutionize satellite transponder technology by increasing science data through-put capability by at least an order of magnitude. While the SDR is adaptive in nature and is "One-size-fits-all" by design, conventional transponders are built to a specific platform and must be redesigned for every new bus. The SDR uses a minimum amount of analog/Radio Frequency components to up/down-convert the RF signal to/from a digital format. Once analog data is digitized, all processing is performed using hardware logic. Typical SDR processes include; filtering, modulation, up/down converting and demodulation. This presentation will show how the emerging SDR market has leveraged the existing commercial sector to provide a path to a radiation tolerant SDR transponder. These innovations will reduce the cost of transceivers, a decrease in power requirements and a commensurate reduction in volume. A second pay-off is the increased flexibility of the SDR by allowing the same hardware to implement multiple transponder types by altering hardware logic - no change of analog hardware is required - all of which can be ultimately accomplished in orbit. This in turn would provide high capability and low cost transponder to programs of all sizes

Characterizing effects of hydropower plants on sub-daily flow regimes

NASA Astrophysics Data System (ADS)

Bejarano, María Dolores; Sordo-Ward, Álvaro; Alonso, Carlos; Nilsson, Christer

2017-07-01

A characterization of short-term changes in river flow is essential for understanding the ecological effects of hydropower plants, which operate by turning the turbines on or off to generate electricity following variations in the market demand (i.e., hydropeaking). The goal of our study was to develop an approach for characterizing the effects of hydropower plant operations on within-day flow regimes across multiple dams and rivers. For this aim we first defined ecologically meaningful metrics that provide a full representation of the flow regime at short time scales from free-flowing rivers and rivers exposed to hydropeaking. We then defined metrics that enable quantification of the deviation of the altered short-term flow regime variables from those of the unaltered state. The approach was successfully tested in two rivers in northern Sweden, one free-flowing and another regulated by cascades of hydropower plants, which were additionally classified based on their impact on short-term flows in sites of similar management. The largest differences between study sites corresponded to metrics describing sub-daily flow magnitudes such as amplitude (i.e., difference between the highest and the lowest hourly flows) and rates (i.e., rise and fall rates of hourly flows). They were closely followed by frequency-related metrics accounting for the numbers of within-day hourly flow patterns (i.e., rises, falls and periods of stability of hourly flows). In comparison, between-site differences for the duration-related metrics were smallest. In general, hydropeaking resulted in higher within-day flow amplitudes and rates and more but shorter periods of a similar hourly flow patterns per day. The impacted flow feature and the characteristics of the impact (i.e., intensity and whether the impact increases or decreases whatever is being described by the metric) varied with season. Our approach is useful for catchment management planning, defining environmental flow targets, prioritizing river restoration or dam reoperation efforts and contributing information for relicensing hydropower dams.

A broad investigation of the HBV-mediated changes to primary hepatocyte physiology reveals HBV significantly alters metabolic pathways.

PubMed

Lamontagne, R Jason; Casciano, Jessica C; Bouchard, Michael J

2018-06-01

As the leading risk factor for the development of liver cancer, chronic infection with hepatitis B virus (HBV) represents a significant global health concern. Although an effective HBV vaccine exists, at least 240 million people are chronically infected with HBV worldwide. Therapeutic options for the treatment of chronic HBV remain limited, and none achieve an absolute cure. To develop novel therapeutic targets, a better understanding of the complex network of virus-host interactions is needed. Because of the central metabolic role of the liver, we assessed the metabolic impact of HBV infection as a means to identify viral dependency factors and metabolic pathways that could serve as novel points of therapeutic intervention. Primary rat hepatocytes were infected with a control adenovirus, an adenovirus expressing a greater-than-unit-length copy of the HBV genome, or an adenovirus expressing the HBV X protein (HBx). A panel of 369 metabolites was analyzed for HBV- or HBx-induced changes 24 and 48 h post infection. Pathway analysis was used to identify key metabolic pathways altered in the presence of HBV or HBx expression, and these findings were further supported through integration of publically available gene expression data. We observed distinct changes to multiple metabolites in the context of HBV replication or HBx expression. Interestingly, a panel of 7 metabolites (maltotriose, maltose, myristate [14:0], arachidate [20:0], 3-hydroxybutyrate [BHBA], myo-inositol, and 2-palmitoylglycerol [16,0]) were altered by both HBV and HBx at both time points. In addition, incorporation of data from a transcriptome-based dataset allowed us to identify metabolic pathways, including long chain fatty acid metabolism, glycolysis, and glycogen metabolism, that were significantly altered by HBV and HBx. Because the liver is a central regulator of metabolic processes, it is important to understand how HBV replication and HBV protein expression affects the metabolic function of hepatocytes. Through analysis of a broad panel of metabolites we investigated this metabolic impact. The results of these studies have defined metabolic consequences of an HBV infection of hepatocytes and will help to lay the groundwork for novel research directions and, potentially, development of novel anti-HBV therapeutics. Copyright © 2018. Published by Elsevier Inc.

Serum Metabolomic Profiling in Acute Alcoholic Hepatitis Identifies Multiple Dysregulated Pathways

PubMed Central

Rachakonda, Vikrant; Gabbert, Charles; Raina, Amit; Bell, Lauren N.; Cooper, Sara; Malik, Shahid; Behari, Jaideep

2014-01-01

Background and Objectives While animal studies have implicated derangements of global energy homeostasis in the pathogenesis of acute alcoholic hepatitis (AAH), the relevance of these findings to the development of human AAH remains unclear. Using global, unbiased serum metabolomics analysis, we sought to characterize alterations in metabolic pathways associated with severe AAH and identify potential biomarkers for disease prognosis. Methods This prospective, case-control study design included 25 patients with severe AAH and 25 ambulatory patients with alcoholic cirrhosis. Serum samples were collected within 24 hours of the index clinical encounter. Global, unbiased metabolomics profiling was performed. Patients were followed for 180 days after enrollment to determine survival. Results Levels of 234 biochemicals were altered in subjects with severe AAH. Random-forest analysis, principal component analysis, and integrated hierarchical clustering methods demonstrated that metabolomics profiles separated the two cohorts with 100% accuracy. Severe AAH was associated with enhanced triglyceride lipolysis, impaired mitochondrial fatty acid beta oxidation, and upregulated omega oxidation. Low levels of multiple lysolipids and related metabolites suggested decreased plasma membrane remodeling in severe AAH. While most measured bile acids were increased in severe AAH, low deoxycholate and glycodeoxycholate levels indicated intestinal dysbiosis. Several changes in substrate utilization for energy homeostasis were identified in severe AAH, including increased glucose consumption by the pentose phosphate pathway, altered tricarboxylic acid (TCA) cycle activity, and enhanced peptide catabolism. Finally, altered levels of small molecules related to glutathione metabolism and antioxidant vitamin depletion were observed in patients with severe AAH. Univariable logistic regression revealed 15 metabolites associated with 180-day survival in severe AAH. Conclusion Severe AAH is characterized by a distinct metabolic phenotype spanning multiple pathways. Metabolomics profiling revealed a panel of biomarkers for disease prognosis, and future studies are planned to validate these findings in larger cohorts of patients with severe AAH. PMID:25461442

Altered proteomic polymorphisms in the caterpillar body and stroma of natural Cordyceps sinensis during maturation.

PubMed

Dong, Yun-Zi; Zhang, Li-Juan; Wu, Zi-Mei; Gao, Ling; Yao, Yi-Sang; Tan, Ning-Zhi; Wu, Jian-Yong; Ni, Luqun; Zhu, Jia-Shi

2014-01-01

To examine the maturational changes in proteomic polymorphisms resulting from differential expression by multiple intrinsic fungi in the caterpillar body and stroma of natural Cordyceps sinensis (Cs), an integrated micro-ecosystem. The surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) biochip technique was used to profile the altered protein compositions in the caterpillar body and stroma of Cs during its maturation. The MS chromatograms were analyzed using density-weighted algorithms to examine the similarities and cluster relationships among the proteomic polymorphisms of the Cs compartments and the mycelial products Hirsutella sinensis (Hs) and Paecilomyces hepiali (Ph). SELDI-TOF MS chromatograms displayed dynamic proteomic polymorphism alterations among samples from the different Cs compartments during maturation. More than 1,900 protein bands were analyzed using density-weighted ZUNIX similarity equations and clustering methods, revealing integral polymorphism similarities of 57.4% between the premature and mature stromata and 42.8% between the premature and mature caterpillar bodies. The across-compartment similarity was low, ranging from 10.0% to 18.4%. Consequently, each Cs compartment (i.e., the stroma and caterpillar body) formed a clustering clade, and the 2 clades formed a Cs cluster. The polymorphic similarities ranged from 0.51% to 1.04% between Hs and the Cs compartments and were 2.8- to 4.8-fold higher (1.92%-4.34%) between Ph and the Cs compartments. The Hs and Ph mycelial samples formed isolated clades outside of the Cs cluster. Proteomic polymorphisms in the caterpillar body and stroma of Cs change dynamically during maturation. The proteomic polymorphisms in Hs and Ph differ from those in Cs, suggesting the presence of multiple Cs-associated fungi and multiple Ophiocordyceps sinensis genotypes with altered differential protein expression in the Cs compartments during maturation. In conjunction with prior mycological and molecular observations, the findings from this proteomic study support the integrated micro-ecosystem hypothesis for natural Cs.

Altered Proteomic Polymorphisms in the Caterpillar Body and Stroma of Natural Cordyceps sinensis during Maturation

PubMed Central

Wu, Zi-Mei; Gao, Ling; Yao, Yi-Sang; Tan, Ning-Zhi; Wu, Jian-Yong; Ni, Luqun; Zhu, Jia-Shi

2014-01-01

Objective To examine the maturational changes in proteomic polymorphisms resulting from differential expression by multiple intrinsic fungi in the caterpillar body and stroma of natural Cordyceps sinensis (Cs), an integrated micro-ecosystem. Methods The surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) biochip technique was used to profile the altered protein compositions in the caterpillar body and stroma of Cs during its maturation. The MS chromatograms were analyzed using density-weighted algorithms to examine the similarities and cluster relationships among the proteomic polymorphisms of the Cs compartments and the mycelial products Hirsutella sinensis (Hs) and Paecilomyces hepiali (Ph). Results: SELDI-TOF MS chromatograms displayed dynamic proteomic polymorphism alterations among samples from the different Cs compartments during maturation. More than 1,900 protein bands were analyzed using density-weighted ZUNIX similarity equations and clustering methods, revealing integral polymorphism similarities of 57.4% between the premature and mature stromata and 42.8% between the premature and mature caterpillar bodies. The across-compartment similarity was low, ranging from 10.0% to 18.4%. Consequently, each Cs compartment (i.e., the stroma and caterpillar body) formed a clustering clade, and the 2 clades formed a Cs cluster. The polymorphic similarities ranged from 0.51% to 1.04% between Hs and the Cs compartments and were 2.8- to 4.8-fold higher (1.92%–4.34%) between Ph and the Cs compartments. The Hs and Ph mycelial samples formed isolated clades outside of the Cs cluster. Conclusion Proteomic polymorphisms in the caterpillar body and stroma of Cs change dynamically during maturation. The proteomic polymorphisms in Hs and Ph differ from those in Cs, suggesting the presence of multiple Cs-associated fungi and multiple Ophiocordyceps sinensis genotypes with altered differential protein expression in the Cs compartments during maturation. In conjunction with prior mycological and molecular observations, the findings from this proteomic study support the integrated micro-ecosystem hypothesis for natural Cs. PMID:25310818

Microarray expression profiling identifies genes with altered expression in HDL-deficient mice

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

Callow, Matthew J.; Dudoit, Sandrine; Gong, Elaine L.

2000-05-05

Based on the assumption that severe alterations in the expression of genes known to be involved in HDL metabolism may affect the expression of other genes we screened an array of over 5000 mouse expressed sequence tags (ESTs) for altered gene expression in the livers of two lines of mice with dramatic decreases in HDL plasma concentrations. Labeled cDNA from livers of apolipoprotein AI (apo AI) knockout mice, Scavenger Receptor BI (SR-BI) transgenic mice and control mice were co-hybridized to microarrays. Two-sample t-statistics were used to identify genes with altered expression levels in the knockout or transgenic mice compared withmore » the control mice. In the SR-BI group we found 9 array elements representing at least 5 genes to be significantly altered on the basis of an adjusted p value of less than 0.05. In the apo AI knockout group 8 array elements representing 4 genes were altered compared with the control group (p < 0.05). Several of the genes identified in the SR-BI transgenic suggest altered sterol metabolism and oxidative processes. These studies illustrate the use of multiple-testing methods for the identification of genes with altered expression in replicated microarray experiments of apo AI knockout and SR-BI transgenic mice.« less

Alteration mapping at Goldfield, Nevada, by cluster and discriminant analysis of Landsat digital data. [mapping of hydrothermally altered volcanic rocks

NASA Technical Reports Server (NTRS)

Ballew, G.

1977-01-01

The ability of Landsat multispectral digital data to differentiate among 62 combinations of rock and alteration types at the Goldfield mining district of Western Nevada was investigated by using statistical techniques of cluster and discriminant analysis. Multivariate discriminant analysis was not effective in classifying each of the 62 groups, with classification results essentially the same whether data of four channels alone or combined with six ratios of channels were used. Bivariate plots of group means revealed a cluster of three groups including mill tailings, basalt and all other rock and alteration types. Automatic hierarchical clustering based on the fourth dimensional Mahalanobis distance between group means of 30 groups having five or more samples was performed using Johnson's HICLUS program. The results of the cluster analysis revealed hierarchies of mill tailings vs. natural materials, basalt vs. non-basalt, highly reflectant rocks vs. other rocks and exclusively unaltered rocks vs. predominantly altered rocks. The hierarchies were used to determine the order in which sets of multiple discriminant analyses were to be performed and the resulting discriminant functions were used to produce a map of geology and alteration which has an overall accuracy of 70 percent for discriminating exclusively altered rocks from predominantly altered rocks.

A 2.5D Reactive Transport Model for Fracture Alteration Simulation

DOE PAGES

Deng, Hang; Molins, Sergi; Steefel, Carl; ...

2016-06-30

Understanding fracture alteration resulting from geochemical reactions is critical in predicting fluid migration in the subsurface and is relevant to multiple environmental challenges. Here in this paper, we present a novel 2.5D continuum reactive transport model that captures and predicts the spatial pattern of fracture aperture change and the development of an altered layer in the near-fracture region. The model considers permeability heterogeneity in the fracture plane and updates fracture apertures and flow fields based on local reactions. It tracks the reaction front of each mineral phase and calculates the thickness of the altered layer. Given this treatment, the modelmore » is able to account for the diffusion limitation on reaction rates associated with the altered layer. The model results are in good agreement with an experimental study in which a CO 2-acidified brine was injected into a fracture in the Duperow Dolomite, causing dissolution of calcite and dolomite that result in the formation of a preferential flow channel and an altered layer. Finally, with an effective diffusion coefficient consistent with the experimentally observed porosity of the altered layer, the model captures the progressive decrease in the dissolution rate of the fast-reacting mineral in the altered layer.« less

Brain gut microbiome interactions and functional bowel disorders

USDA-ARS?s Scientific Manuscript database

Alterations in the bidirectional interactions between the intestine and the nervous system have important roles in the pathogenesis of irritable bowel syndrome (IBS). A body of largely preclinical evidence suggests that the gut microbiota can modulate these interactions. A small and poorly defined r...

Role of the adverse outcome pathway framework in the validation of predictive biomarkers

EPA Science Inventory

Gene expression, enzyme activities, changes in endogenous metabolite or hormone titers, altered histology, etc. are widely used as biomarkers, but rarely, if ever, used for regulatory decision-making or to define management objectives. The disconnect between the measurements comm...

The epigenetic landscape of mammary gland development and functional differentiation

USDA-ARS?s Scientific Manuscript database

Most of the development and functional differentiation in the mammary gland occur after birth. Epigenetics is defined as the stable alterations in gene expression potential that arise during development and proliferation. Epigenetic changes are mediated at the biochemical level by the chromatin conf...

Cumulative effects of antiandrogenic chemical mixtures and their relevance to human health risk assessment

EPA Science Inventory

Toxicological studies of defined chemical mixtures assist human health risk assessment by establishing the manner by which chemicals interact with one another to induce an effect. This paper reviews how antiandrogenic chemical mixtures can alter reproductive tract development in ...

Engineering the gut microbiota to treat hyperammonemia.

PubMed

Shen, Ting-Chin David; Albenberg, Lindsey; Bittinger, Kyle; Chehoud, Christel; Chen, Ying-Yu; Judge, Colleen A; Chau, Lillian; Ni, Josephine; Sheng, Michael; Lin, Andrew; Wilkins, Benjamin J; Buza, Elizabeth L; Lewis, James D; Daikhin, Yevgeny; Nissim, Ilana; Yudkoff, Marc; Bushman, Frederic D; Wu, Gary D

2015-07-01

Increasing evidence indicates that the gut microbiota can be altered to ameliorate or prevent disease states, and engineering the gut microbiota to therapeutically modulate host metabolism is an emerging goal of microbiome research. In the intestine, bacterial urease converts host-derived urea to ammonia and carbon dioxide, contributing to hyperammonemia-associated neurotoxicity and encephalopathy in patients with liver disease. Here, we engineered murine gut microbiota to reduce urease activity. Animals were depleted of their preexisting gut microbiota and then inoculated with altered Schaedler flora (ASF), a defined consortium of 8 bacteria with minimal urease gene content. This protocol resulted in establishment of a persistent new community that promoted a long-term reduction in fecal urease activity and ammonia production. Moreover, in a murine model of hepatic injury, ASF transplantation was associated with decreased morbidity and mortality. These results provide proof of concept that inoculation of a prepared host with a defined gut microbiota can lead to durable metabolic changes with therapeutic utility.

Anaemia and iron deficiency in children with inflammatory bowel disease.

PubMed

Wiskin, Anthony E; Fleming, Ben J; Wootton, Stephen A; Beattie, R Mark

2012-07-01

Anaemia and iron deficiency are common in children with Inflammatory Bowel Disease (IBD) however it is not known if the prevalence of anaemia and iron deficiency alters following diagnosis. Laboratory results from diagnosis, and at follow up one and two years later were recorded retrospectively in children with IBD recruited from a tertiary centre. Anaemia was defined using WHO standards and iron deficiency defined using published guidelines. 46 children (16 girls) with Crohn's disease and 34 children (18 girls) with UC were studied. 75% of children with IBD were anaemic at diagnosis, 30% were anaemic at follow up two years later. 90% of children with Crohn's and 95% of children with Ulcerative Colitis (UC) were iron deficient at diagnosis. At follow up two years later 70% of children with Crohn's and 65% of children with UC were iron deficient. Persistent anaemia and iron deficiency are common in childhood IBD, prevalence alters with duration of time from diagnosis. Copyright © 2011. Published by Elsevier B.V.

Defining and diagnosing irritable bowel syndrome.

PubMed

Schuster, M M

2001-07-01

Approximately 20% of the general population has irritable bowel syndrome (IBS). Although the majority of these individuals do not consult a physician, IBS accounts for 25% of visits to a gastroenterologist and up to 12% of visits to a primary care physician. Consequently, the direct and indirect costs associated with IBS are estimated at $8 billion annually. IBS symptoms, with no apparent structural pathology, include altered bowel habits, abdominal pain/discomfort, and bloating. The Rome II criteria, a standardized guideline for the diagnosis of IBS, contains in its definition abdominal pain or discomfort associated with altered bowel habits. Bloating may often be present. Three patient subgroups are defined according to the predominant bowel symptom: constipation, diarrhea, or alternating constipation and diarrhea. Hematology, fecal occult blood test, flexible sigmoidoscopy, and lactose intolerance evaluations are recommended for all patients demonstrating symptoms of IBS. When indicated, tests are recommended to rule out bacterial or parasitic infections, pelvic floor muscle dyssynergia, colonic inertia, peptic ulcer, or inflammatory bowel disease.

Classification and Clustering Methods for Multiple Environmental Factors in Gene-Environment Interaction: Application to the Multi-Ethnic Study of Atherosclerosis.

PubMed

Ko, Yi-An; Mukherjee, Bhramar; Smith, Jennifer A; Kardia, Sharon L R; Allison, Matthew; Diez Roux, Ana V

2016-11-01

There has been an increased interest in identifying gene-environment interaction (G × E) in the context of multiple environmental exposures. Most G × E studies analyze one exposure at a time, but we are exposed to multiple exposures in reality. Efficient analysis strategies for complex G × E with multiple environmental factors in a single model are still lacking. Using the data from the Multiethnic Study of Atherosclerosis, we illustrate a two-step approach for modeling G × E with multiple environmental factors. First, we utilize common clustering and classification strategies (e.g., k-means, latent class analysis, classification and regression trees, Bayesian clustering using Dirichlet Process) to define subgroups corresponding to distinct environmental exposure profiles. Second, we illustrate the use of an additive main effects and multiplicative interaction model, instead of the conventional saturated interaction model using product terms of factors, to study G × E with the data-driven exposure subgroups defined in the first step. We demonstrate useful analytical approaches to translate multiple environmental exposures into one summary class. These tools not only allow researchers to consider several environmental exposures in G × E analysis but also provide some insight into how genes modify the effect of a comprehensive exposure profile instead of examining effect modification for each exposure in isolation.

Identification of Reference Genes in Human Myelomonocytic Cells for Gene Expression Studies in Altered Gravity

PubMed Central

Thiel, Cora S.; Hauschild, Swantje; Tauber, Svantje; Paulsen, Katrin; Raig, Christiane; Raem, Arnold; Biskup, Josefine; Gutewort, Annett; Hürlimann, Eva; Philpot, Claudia; Lier, Hartwin; Engelmann, Frank; Layer, Liliana E.

2015-01-01

Gene expression studies are indispensable for investigation and elucidation of molecular mechanisms. For the process of normalization, reference genes (“housekeeping genes”) are essential to verify gene expression analysis. Thus, it is assumed that these reference genes demonstrate similar expression levels over all experimental conditions. However, common recommendations about reference genes were established during 1 g conditions and therefore their applicability in studies with altered gravity has not been demonstrated yet. The microarray technology is frequently used to generate expression profiles under defined conditions and to determine the relative difference in expression levels between two or more different states. In our study, we searched for potential reference genes with stable expression during different gravitational conditions (microgravity, normogravity, and hypergravity) which are additionally not altered in different hardware systems. We were able to identify eight genes (ALB, B4GALT6, GAPDH, HMBS, YWHAZ, ABCA5, ABCA9, and ABCC1) which demonstrated no altered gene expression levels in all tested conditions and therefore represent good candidates for the standardization of gene expression studies in altered gravity. PMID:25654098

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas.

PubMed

Schaub, Franz X; Dhankani, Varsha; Berger, Ashton C; Trivedi, Mihir; Richardson, Anne B; Shaw, Reid; Zhao, Wei; Zhang, Xiaoyang; Ventura, Andrea; Liu, Yuexin; Ayer, Donald E; Hurlin, Peter J; Cherniack, Andrew D; Eisenman, Robert N; Bernard, Brady; Grandori, Carla

2018-03-28

Although the MYC oncogene has been implicated in cancer, a systematic assessment of alterations of MYC, related transcription factors, and co-regulatory proteins, forming the proximal MYC network (PMN), across human cancers is lacking. Using computational approaches, we define genomic and proteomic features associated with MYC and the PMN across the 33 cancers of The Cancer Genome Atlas. Pan-cancer, 28% of all samples had at least one of the MYC paralogs amplified. In contrast, the MYC antagonists MGA and MNT were the most frequently mutated or deleted members, proposing a role as tumor suppressors. MYC alterations were mutually exclusive with PIK3CA, PTEN, APC, or BRAF alterations, suggesting that MYC is a distinct oncogenic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such as immune response and growth factor signaling; chromatin, translation, and DNA replication/repair were conserved pan-cancer. This analysis reveals insights into MYC biology and is a reference for biomarkers and therapeutics for cancers with alterations of MYC or the PMN. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Brain Gut Microbiome Interactions and Functional Bowel Disorders

PubMed Central

Mayer, Emeran A.; Savidge, Tor; Shulman, Robert J.

2014-01-01

Alterations in the bidirectional interactions between the gut and the nervous system play an important role in IBS pathophysiology and symptom generation. A body of largely preclinical evidence suggests that the gut microbiota can modulate these interactions. Characterizations of alterations of gut microbiota in unselected IBS patients, and assessment of changes in subjective symptoms associated with manipulations of the gut microbiota with prebiotics, probiotics and antibiotics support a small, but poorly defined role of dybiosis in overall IBS symptoms. It remains to be determined if the observed abnormalities are a consequence of altered top down signaling from the brain to the gut and microbiota, if they are secondary to a primary perturbation of the microbiota, and if they play a role in the development of altered brain gut interactions early in life. Different mechanisms may play role in subsets of patients. Characterization of gut microbiome alterations in large cohorts of well phenotyped patients as well as evidence correlating gut metabolites with specific abnormalities in the gut brain axis are required to answer these questions. PMID:24583088

Identification of reference genes in human myelomonocytic cells for gene expression studies in altered gravity.

PubMed

Thiel, Cora S; Hauschild, Swantje; Tauber, Svantje; Paulsen, Katrin; Raig, Christiane; Raem, Arnold; Biskup, Josefine; Gutewort, Annett; Hürlimann, Eva; Unverdorben, Felix; Buttron, Isabell; Lauber, Beatrice; Philpot, Claudia; Lier, Hartwin; Engelmann, Frank; Layer, Liliana E; Ullrich, Oliver

2015-01-01

Gene expression studies are indispensable for investigation and elucidation of molecular mechanisms. For the process of normalization, reference genes ("housekeeping genes") are essential to verify gene expression analysis. Thus, it is assumed that these reference genes demonstrate similar expression levels over all experimental conditions. However, common recommendations about reference genes were established during 1 g conditions and therefore their applicability in studies with altered gravity has not been demonstrated yet. The microarray technology is frequently used to generate expression profiles under defined conditions and to determine the relative difference in expression levels between two or more different states. In our study, we searched for potential reference genes with stable expression during different gravitational conditions (microgravity, normogravity, and hypergravity) which are additionally not altered in different hardware systems. We were able to identify eight genes (ALB, B4GALT6, GAPDH, HMBS, YWHAZ, ABCA5, ABCA9, and ABCC1) which demonstrated no altered gene expression levels in all tested conditions and therefore represent good candidates for the standardization of gene expression studies in altered gravity.

Genome-wide network analysis of Wnt signaling in three pediatric cancers

NASA Astrophysics Data System (ADS)

Bao, Ju; Lee, Ho-Jin; Zheng, Jie J.

2013-10-01

Genomic structural alteration is common in pediatric cancers, and analysis of data generated by the Pediatric Cancer Genome Project reveals such tumor-related alterations in many Wnt signaling-associated genes. Most pediatric cancers are thought to arise within developing tissues that undergo substantial expansion during early organ formation, growth and maturation, and Wnt signaling plays an important role in this development. We examined three pediatric tumors--medullobastoma, early T-cell precursor acute lymphoblastic leukemia, and retinoblastoma--that show multiple genomic structural variations within Wnt signaling pathways. We mathematically modeled this pathway to investigate the effects of cancer-related structural variations on Wnt signaling. Surprisingly, we found that an outcome measure of canonical Wnt signaling was consistently similar in matched cancer cells and normal cells, even in the context of different cancers, different mutations, and different Wnt-related genes. Our results suggest that the cancer cells maintain a normal level of Wnt signaling by developing multiple mutations.

Dissociation in virtual reality: depersonalization and derealization

NASA Astrophysics Data System (ADS)

Garvey, Gregory P.

2010-01-01

This paper looks at virtual worlds such as Second Life7 (SL) as possible incubators of dissociation disorders as classified by the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition3 (also known as the DSM-IV). Depersonalization is where "a person feels that he or she has changed in some way or is somehow unreal." Derealization when "the same beliefs are held about one's surroundings." Dissociative Identity Disorder (DID), previously known as multiple personality disorder fits users of Second Life who adopt "in-world" avatars and in effect, enact multiple distinct identities or personalities (known as alter egos or alters). Select questions from the Structured Clinical Interview for Depersonalization (SCI-DER)8 will be discussed as they might apply to the user's experience in Second Life. Finally I would like to consider the hypothesis that rather than a pathological disorder, dissociation is a normal response to the "artificial reality" of Second Life.

EZH2 in Bladder Cancer, a Promising Therapeutic Target

PubMed Central

Martínez-Fernández, Mónica; Rubio, Carolina; Segovia, Cristina; López-Calderón, Fernando F.; Dueñas, Marta; Paramio, Jesús M.

2015-01-01

Bladder Cancer (BC) represents a current clinical and social challenge. The recent studies aimed to describe the genomic landscape of BC have underscored the relevance of epigenetic alterations in the pathogenesis of these tumors. Among the epigenetic alterations, histone modifications occupied a central role not only in cancer, but also in normal organism homeostasis and development. EZH2 (Enhancer of Zeste Homolog 2) belongs to the Polycomb repressive complex 2 as its catalytic subunit, which through the trimethylation of H3 (Histone 3) on K27 (Lysine 27), produces gene silencing. EZH2 is frequently overexpressed in multiple tumor types, including BC, and plays multiple roles besides the well-recognized histone mark generation. In this review, we summarize the present knowledge on the oncogenic roles of EZH2 and its potential use as a therapeutic target, with special emphasis on BC pathogenesis and management. PMID:26580594

The Array Representation and Primary Children's Understanding and Reasoning in Multiplication

ERIC Educational Resources Information Center

Barmby, Patrick; Harries, Tony; Higgins, Steve; Suggate, Jennifer

2009-01-01

We examine whether the array representation can support children's understanding and reasoning in multiplication. To begin, we define what we mean by understanding and reasoning. We adopt a "representational-reasoning" model of understanding, where understanding is seen as connections being made between mental representations of concepts, with…

The Multiplicative Zak Transform, Dimension Reduction, and Wavelet Analysis of LIDAR Data

DTIC Science & Technology

2010-01-01

systems is likely to fail. Auslander, Eichmann , Gertner, and Tolimieri defined a multiplicative Zak transform [1], mimicking the construction of the Gabor...L. Auslander, G. Eichmann , I. Gertner and R. Tolimieri, “Time-Frequency Analysis and Synthesis of Non-Stationary Signals,” Proc. Soc. Photo-Opt. In

Empowering Students through Organizational Empathy: Multiple Case Study Methodology

ERIC Educational Resources Information Center

Williams, Daniel

2017-01-01

This dissertation in practice employed a multiple case study design to better understand how two executive directors within a national network of arts and technology educational organizations defined, nurtured, and measured empathy with in their students. Empathy can connect diverse people and improve relationships, and it has been proven to…

Self-Rated Estimates of Multiple Intelligences Based on Approaches to Learning

ERIC Educational Resources Information Center

Bowles, Terry

2008-01-01

To date questionnaires that measure Multiple Intelligences (MIs) have typically not been systematically developed, have poor psychometric properties, and relatively low reliability. The aim of this research was to define the factor structure, and reliability of nine talents which are the behavioural outcomes of MIs, using items representing…

Hidden Item Variance in Multiple Mini-Interview Scores

ERIC Educational Resources Information Center

Zaidi, Nikki L.; Swoboda, Christopher M.; Kelcey, Benjamin M.; Manuel, R. Stephen

2017-01-01

The extant literature has largely ignored a potentially significant source of variance in multiple mini-interview (MMI) scores by "hiding" the variance attributable to the sample of attributes used on an evaluation form. This potential source of hidden variance can be defined as rating items, which typically comprise an MMI evaluation…

Developing an ecosystem diversity framework for landscape assessment

Treesearch

Robert D. Pfister; Michael D. Sweet

2000-01-01

Ecological diversity is being addressed in various research and management efforts, but a common foundation is not explicitly defined or displayed. A formal Ecosystem Diversity Framework (EDF) would improve landscape analysis and communication across multiple scales. The EDF represents a multiple-component vegetation classification system with inherent flexibility for...

"L"-Bivariate and "L"-Multivariate Association Coefficients. Research Report. ETS RR-08-40

ERIC Educational Resources Information Center

Kong, Nan; Lewis, Charles

2008-01-01

Given a system of multiple random variables, a new measure called the "L"-multivariate association coefficient is defined using (conditional) entropy. Unlike traditional correlation measures, the L-multivariate association coefficient measures the multiassociations or multirelations among the multiple variables in the given system; that…

Unmanned Multiple Exploratory Probe System (MEPS) for Mars observation. Volume 1: Trade analysis and design

NASA Technical Reports Server (NTRS)

Adams, Daniel E.; Crumbly, Christopher M.; Delp, Steve E.; Guidry, Michelle A.; Lisano, Michael E.; Packard, James D.; Striepe, Scott A.

1988-01-01

This report presents the unmanned Multiple Exploratory Probe Systems (MEPS), a space vehicle designed to observe the planet Mars in preparation for manned missions. The options considered for each major element are presented as a trade analysis, and the final vehicle design is defined.

Gleason Score 7 Prostate Cancers Emerge through Branched Evolution of Clonal Gleason Pattern 3 and 4.

PubMed

Sowalsky, Adam G; Kissick, Haydn T; Gerrin, Sean J; Schaefer, Rachel J; Xia, Zheng; Russo, Joshua W; Arredouani, M Simo; Bubley, Glenn J; Sanda, Martin G; Li, Wei; Ye, Huihui; Balk, Steven P

2017-07-15

Purpose: The molecular features that account for the distinct histology and aggressive biological behavior of Gleason pattern 4 (Gp4) versus Gp3 prostate cancer, and whether Gp3 tumors progress directly to Gp4, remain to be established. Experimental Design: Whole-exome sequencing and transcriptome profiling of laser capture-microdissected adjacent Gp3 and cribiform Gp4 were used to determine the relationship between these entities. Results: Sequencing confirmed that adjacent Gp3 and Gp4 were clonal based on multiple shared genomic alterations. However, large numbers of unique mutations in the Gp3 and Gp4 tumors showed that the Gp4 were not derived directly from the Gp3. Remarkably, the Gp3 tumors retain their indolent-appearing morphology despite acquisition of multiple genomic alterations, including tumor suppressor losses. Although there were no consistent genomic alterations that distinguished Gp3 from Gp4, pairwise transcriptome analyses identified increased c-Myc and decreased p53 activity in Gp4 versus adjacent clonal Gp3 foci. Conclusions: These findings establish that at least a subset of Gp3 and aggressive Gp4 tumors have a common origin, and support a branched evolution model wherein the Gp3 and Gp4 tumors emerge early from a common precursor and subsequently undergo substantial divergence. Genomic alterations detectable in the Gp3 may distinguish these tumors from truly indolent Gp3. Screening for a panel of these genomic alterations in men who have prostate biopsies showing only Gp3 (Gleason score 6, Gs6) may allow for more precise selection of men who can be safely managed by active surveillance versus those who may benefit from further intervention. Clin Cancer Res; 23(14); 3823-33. ©2017 AACR . ©2017 American Association for Cancer Research.

Multiple Head and Neck Tumors Frequently Originate from a Single Preneoplastic Lesion

PubMed Central

Tabor, Maarten P.; Brakenhoff, Ruud H.; Ruijter-Schippers, Henrique J.; van der Wal, Jacqueline E.; Snow, Gordon B.; Leemans, C. René; Braakhuis, Boudewijn J. M.

2002-01-01

The development of second primary tumors has a negative impact on the prognosis of head and neck squamous cell carcinoma. Previously, we detected genetically altered and tumor-related mucosal lesions in the resection margins in 25% of unselected head and neck squamous cell carcinoma patients (Tabor MP, Brakenhoff RH, van Houten VMM, Kummer JA, Snel MHJ, Snijders PJF, Snow GB, Leemans CR, Braakhuis BJM: Persistence of genetically altered fields in head and neck cancer patients: biological and clinical implications. Clin Cancer Res 2001, 7: 1523–1532). The aim of this study was to determine whether first and second primary tumors are clonally related and originate from a single genetically altered field. From 10 patients we analyzed the first tumor of the oral cavity or oropharynx, the >3-cm remote second primary tumor, and the mucosa from the tumor-free margins from both resection specimens. We compared TP53 mutations and loss of heterozygosity profiles using 19 microsatellite markers at chromosomes 3p, 9p, 13q, and 17p. In all patients, genetically altered mucosal lesions were detected in at least one resection margin from both first and second primary tumor. Evidence for a common clonal origin of the first tumor, second primary tumor, and the intervening mucosa was found for at least 6 of 10 patients. Our results indicate that a proportion of multiple primary tumors have developed within a single preneoplastic field. Based on different etiology and clinical consequences, we propose that independent second primary tumors should be distinguished from second field tumors, that arise from the same genetically altered field the first tumor has developed from. PMID:12213734

Identification and quantification of the basal and inducible Nrf2-dependent proteomes in mouse liver: Biochemical, pharmacological and toxicological implications

PubMed Central

Walsh, Joanne; Jenkins, Rosalind E.; Wong, Michael; Olayanju, Adedamola; Powell, Helen; Copple, Ian; O’Neill, Paul M.; Goldring, Christopher E.P.; Kitteringham, Neil R.; Park, B. Kevin

2014-01-01

The transcription factor Nrf2 is a master regulator of cellular defence: Nrf2 null mice (Nrf2(−/−)) are highly susceptible to chemically induced toxicities. We report a comparative iTRAQ-based study in Nrf2(−/−) mice treated with a potent inducer, methyl-2-cyano-3,12-dioxooleana-1,9(11)dien-28-oate (CDDO-me; bardoxolone -methyl), to define both the Nrf2-dependent basal and inducible hepatoproteomes. One thousand five hundred twenty-one proteins were fully quantified (FDR < 1%). One hundred sixty-one were significantly different (P < 0.05) between WT and Nrf2(−/−) mice, confirming extensive constitutive regulation by Nrf2. Treatment with CDDO-me (3 mg/kg; i.p.) resulted in significantly altered expression of 43 proteins at 24 h in WT animals. Six proteins were regulated at both basal and inducible levels exhibiting the largest dynamic range of Nrf2 regulation: cytochrome P4502A5 (CYP2A5; 17.2-fold), glutathione-S-transferase-Mu 3 (GSTM3; 6.4-fold), glutathione-S-transferase Mu 1 (GSTM1; 5.9-fold), ectonucleoside-triphosphate diphosphohydrolase (ENTPD5; 4.6-fold), UDP-glucose-6-dehydrogenase (UDPGDH; 4.1-fold) and epoxide hydrolase (EPHX1; 3.0-fold). These proteins, or their products, thus provide a potential source of biomarkers for Nrf2 activity. ENTPD5 is of interest due to its emerging role in AKT signalling and, to our knowledge, this protein has not been previously shown to be Nrf2-dependent. Only two proteins altered by CDDO-me in WT animals were similarly affected in Nrf2(−/−) mice, demonstrating the high degree of selectivity of CDDO-me for the Nrf2:Keap1 signalling pathway. Biological significance The Nrf2:Keap1 signalling pathway is attracting considerable interest as a therapeutic target for different disease conditions. For example, CDDO-me (bardoxolone methyl) was investigated in clinical trials for the treatment of acute kidney disease, and dimethyl fumarate, recently approved for reducing relapse rate in multiple sclerosis, is a potent Nrf2 inducer. Such compounds have been suggested to act through multiple mechanisms; therefore, it is important to define the selectivity of Nrf2 inducers to assess the potential for off-target effects that may lead to adverse drug reactions, and to provide biomarkers with which to assess therapeutic efficacy. Whilst there is considerable information on the global action of such inducers at the mRNA level, this is the first study to catalogue the hepatic protein expression profile following acute exposure to CDDO-me in mice. At a dose shown to evoke maximal Nrf2 induction in the liver, CDDO-me appeared highly selective for known Nrf2-regulated proteins. Using the transgenic Nrf2(−/−) mouse model, it could be shown that 97% of proteins induced in wild type mice were associated with a functioning Nrf2 signalling pathway. This analysis allowed us to identify a panel of proteins that were regulated both basally and following Nrf2 induction. Identification of these proteins, which display a large magnitude of variation in their expression, provides a rich source of potential biomarkers for Nrf2 activity for use in experimental animals, and which may be translatable to man to define individual susceptibility to chemical stress, including that associated with drugs, and also to monitor the pharmacological response to Nrf2 inducers. PMID:24859727

Identification and quantification of the basal and inducible Nrf2-dependent proteomes in mouse liver: biochemical, pharmacological and toxicological implications.

PubMed

Walsh, Joanne; Jenkins, Rosalind E; Wong, Michael; Olayanju, Adedamola; Powell, Helen; Copple, Ian; O'Neill, Paul M; Goldring, Christopher E P; Kitteringham, Neil R; Park, B Kevin

2014-08-28

The transcription factor Nrf2 is a master regulator of cellular defence: Nrf2 null mice (Nrf2((-/-))) are highly susceptible to chemically induced toxicities. We report a comparative iTRAQ-based study in Nrf2((-/-)) mice treated with a potent inducer, methyl-2-cyano-3,12-dioxooleana-1,9(11)dien-28-oate (CDDO-me; bardoxolone -methyl), to define both the Nrf2-dependent basal and inducible hepatoproteomes. One thousand five hundred twenty-one proteins were fully quantified (FDR <1%). One hundred sixty-one were significantly different (P<0.05) between WT and Nrf2((-/-)) mice, confirming extensive constitutive regulation by Nrf2. Treatment with CDDO-me (3mg/kg; i.p.) resulted in significantly altered expression of 43 proteins at 24h in WT animals. Six proteins were regulated at both basal and inducible levels exhibiting the largest dynamic range of Nrf2 regulation: cytochrome P4502A5 (CYP2A5; 17.2-fold), glutathione-S-transferase-Mu 3 (GSTM3; 6.4-fold), glutathione-S-transferase Mu 1 (GSTM1; 5.9-fold), ectonucleoside-triphosphate diphosphohydrolase (ENTPD5; 4.6-fold), UDP-glucose-6-dehydrogenase (UDPGDH; 4.1-fold) and epoxide hydrolase (EPHX1; 3.0-fold). These proteins, or their products, thus provide a potential source of biomarkers for Nrf2 activity. ENTPD5 is of interest due to its emerging role in AKT signalling and, to our knowledge, this protein has not been previously shown to be Nrf2-dependent. Only two proteins altered by CDDO-me in WT animals were similarly affected in Nrf2((-/-)) mice, demonstrating the high degree of selectivity of CDDO-me for the Nrf2:Keap1 signalling pathway. The Nrf2:Keap1 signalling pathway is attracting considerable interest as a therapeutic target for different disease conditions. For example, CDDO-me (bardoxolone methyl) was investigated in clinical trials for the treatment of acute kidney disease, and dimethyl fumarate, recently approved for reducing relapse rate in multiple sclerosis, is a potent Nrf2 inducer. Such compounds have been suggested to act through multiple mechanisms; therefore, it is important to define the selectivity of Nrf2 inducers to assess the potential for off-target effects that may lead to adverse drug reactions, and to provide biomarkers with which to assess therapeutic efficacy. Whilst there is considerable information on the global action of such inducers at the mRNA level, this is the first study to catalogue the hepatic protein expression profile following acute exposure to CDDO-me in mice. At a dose shown to evoke maximal Nrf2 induction in the liver, CDDO-me appeared highly selective for known Nrf2-regulated proteins. Using the transgenic Nrf2((-/-)) mouse model, it could be shown that 97% of proteins induced in wild type mice were associated with a functioning Nrf2 signalling pathway. This analysis allowed us to identify a panel of proteins that were regulated both basally and following Nrf2 induction. Identification of these proteins, which display a large magnitude of variation in their expression, provides a rich source of potential biomarkers for Nrf2 activity for use in experimental animals, and which may be translatable to man to define individual susceptibility to chemical stress, including that associated with drugs, and also to monitor the pharmacological response to Nrf2 inducers. Copyright © 2014. Published by Elsevier B.V.

DNA double-strand-break complexity levels and their possible contributions to the probability for error-prone processing and repair pathway choice.

PubMed

Schipler, Agnes; Iliakis, George

2013-09-01

Although the DNA double-strand break (DSB) is defined as a rupture in the double-stranded DNA molecule that can occur without chemical modification in any of the constituent building blocks, it is recognized that this form is restricted to enzyme-induced DSBs. DSBs generated by physical or chemical agents can include at the break site a spectrum of base alterations (lesions). The nature and number of such chemical alterations define the complexity of the DSB and are considered putative determinants for repair pathway choice and the probability that errors will occur during this processing. As the pathways engaged in DSB processing show distinct and frequently inherent propensities for errors, pathway choice also defines the error-levels cells opt to accept. Here, we present a classification of DSBs on the basis of increasing complexity and discuss how complexity may affect processing, as well as how it may cause lethal or carcinogenic processing errors. By critically analyzing the characteristics of DSB repair pathways, we suggest that all repair pathways can in principle remove lesions clustering at the DSB but are likely to fail when they encounter clusters of DSBs that cause a local form of chromothripsis. In the same framework, we also analyze the rational of DSB repair pathway choice.

Management of diffuse low-grade gliomas in adults - use of molecular diagnostics.

PubMed

Buckner, Jan; Giannini, Caterina; Eckel-Passow, Jeanette; Lachance, Daniel; Parney, Ian; Laack, Nadia; Jenkins, Robert

2017-06-01

Diffuse WHO grade II gliomas are histologically and genetically heterogeneous. The 2016 WHO classification redefines grade II gliomas with respect to morphological and molecular tumour alterations: grade II oligodendrogliomas are defined by the presence of whole-arm codeletion in chromosomal arms 1p/19q, whereas isocitrate dehydrogenase (IDH) mutations define subclasses of astrocytoma. Although histological grade remains useful, the prognoses of patients with glioma are more tightly associated with molecular alterations than with grade, and chromosomal and gene array technologies are becoming increasingly beneficial in understanding tumour genetic heterogeneity. The indolent nature of the disease often creates subtle neurological symptoms that can be overlooked or misunderstood, resulting in delayed diagnosis. Seizures often herald the diagnosis, especially in patients who have IDH mutations, which are associated with an increased production of 2-hydroxyglutarate. Treatment paradigms have shifted, owing to new diagnostic criteria and new clinical trial evidence. Patients benefit more from chemoradiation than radiation alone, especially those with tumour IDH1 Arg132His mutations; gross total resection of the tumour, including tumours with IDH mutations, is associated with prolonged survival. Initial observation remains appropriate in patients whose rate of disease growth is not yet completely defined; such patients could include those with completely resected disease and those with 1p/19q codeleted tumours.

Modal survey of the space shuttle solid rocket motor using multiple input methods

NASA Technical Reports Server (NTRS)

Brillhart, Ralph; Hunt, David L.; Jensen, Brent M.; Mason, Donald R.

1987-01-01

The ability to accurately characterize propellant in a finite element model is a concern of engineers tasked with studying the dynamic response of the Space Shuttle Solid Rocket Motor (SRM). THe uncertainties arising from propellant characterization through specimem testing led to the decision to perform a model survey and model correlation of a single segment of the Shuttle SRM. Multiple input methods were used to excite and define case/propellant modes of both an inert segment and, later, a live propellant segment. These tests were successful at defining highly damped, flexible modes, several pairs of which occured with frequency spacing of less than two percent.

Adaptations of Presynaptic Dopamine Terminals Induced by Psychostimulant Self-Administration

PubMed Central

2015-01-01

A great deal of research has focused on investigating neurobiological alterations induced by chronic psychostimulant use in an effort to describe, understand, and treat the pathology of psychostimulant addiction. It has been known for several decades that dopamine neurotransmission in the nucleus accumbens is integrally involved in the selection and execution of motivated and goal-directed behaviors, and that psychostimulants act on this system to exert many of their effects. As such, a large body of work has focused on defining the consequences of psychostimulant use on dopamine signaling in the striatum as it relates to addictive behaviors. Here, we review presynaptic dopamine terminal alterations observed following self-administration of cocaine and amphetamine, as well as possible mechanisms by which these alterations occur and their impact on the progression of addiction. PMID:25491345

Genetic and molecular alterations across medulloblastoma subgroups.

PubMed

Skowron, Patryk; Ramaswamy, Vijay; Taylor, Michael D

2015-10-01

Medulloblastoma is the most common malignant brain tumour diagnosed in children. Over the last few decades, advances in radiation and chemotherapy have significantly improved the odds of survival. Nevertheless, one third of all patients still succumb to their disease, and many long-term survivors are afflicted with neurocognitive sequelae. Large-scale multi-institutional efforts have provided insight into the transcriptional and genetic landscape of medulloblastoma. Four distinct subgroups of medulloblastoma have been identified, defined by distinct transcriptomes, genetics, demographics and outcomes. Integrated genomic profiling of each of these subgroups has revealed distinct genetic alterations, driving pathways and in some instances cells of origin. In this review, we highlight, in a subgroup-specific manner, our current knowledge of the genetic and molecular alterations in medulloblastoma and underscore the possible avenues for future therapeutic intervention.

Active suppression rather than ignorance: tolerance to abacavir-induced HLA-B*57:01 peptide repertoire alteration.

PubMed

Phillips, Elizabeth J; Mallal, Simon A

2018-05-21

The discovery of HLA-B*57:01-associated abacavir hypersensitivity is a translational success story that eliminated adverse reactions to abacavir through pretreatment screening and defined a mechanistic model of an altered peptide repertoire. In this issue of the JCI, Cardone et al. have developed an HLA-B*57:01-transgenic mouse model and demonstrated that CD4+ T cells play a key role in mediating tolerance to the dramatically altered endogenous peptide repertoire induced by abacavir and postulate a known mechanism by which CD4+ T cells suppress DC maturation. This report potentially explains why 45% of HLA-B*57:01 carriers tolerate abacavir and provides a framework for future studies of HLA-restricted, T cell-mediated drug tolerance and hypersensitivity.

Geophysical ore guides along the Colorado mineral belt

USGS Publications Warehouse

Case, James E.

1967-01-01

A 40-50-mgal gravity low trends northeast along the Colorado mineral belt between Monarch Pass and Breckenridge, Colorado. The low is probably caused by a silicic Tertiary batholith of lower density than adjacent Precambrian crystalline rocks. Many major mining districts associated with silicic Tertiary intrusives are near the axis of the low. Positive and negative aeromagnetic anomalies are present over the larger silicic Tertiary intrusive bodies. A good correlation exists between the magnetic lows and zones of altered, mineralized porphyry. Apparently, original magnetite in the silicic porphyries has been altered to relatively nonmagnetic pyrite or iron oxides. The regional gravity low aids in defining the limits of the mineral belt, and the magnetic lows over the porphyries indicate specific alteration zones and the possibility of associated mineral deposits.

Multiple Lower Extremity Mononeuropathies by Segmental Schwannomatosis: A Case Report

PubMed Central

Kwon, Na Yeon; Oh, Hyun-Mi

2015-01-01

Schwannoma is an encapsulated nerve sheath tumor that is distinct from neurofibromatosis. It is defined as the occurrence of multiple schwannomas without any bilateral vestibular schwannomas. A 46-year-old man with multiple schwannomas involving peripheral nerves of the ipsilateral lower extremity presented with neurologic symptoms. Electrodiagnostic studies revealed multiple mononeuropathies involving the left sciatic, common peroneal, tibial, femoral and superior gluteal nerves. Histologic findings confirmed the diagnosis of schwannoma. We reported this rare case of segmental schwannomatosis that presented with neurologic symptoms including motor weakness, which was confirmed as multiple mononeuropathies by electrodiagnostic studies. PMID:26605183

Multiple Lower Extremity Mononeuropathies by Segmental Schwannomatosis: A Case Report.

PubMed

Kwon, Na Yeon; Oh, Hyun-Mi; Ko, Young Jin

2015-10-01

Schwannoma is an encapsulated nerve sheath tumor that is distinct from neurofibromatosis. It is defined as the occurrence of multiple schwannomas without any bilateral vestibular schwannomas. A 46-year-old man with multiple schwannomas involving peripheral nerves of the ipsilateral lower extremity presented with neurologic symptoms. Electrodiagnostic studies revealed multiple mononeuropathies involving the left sciatic, common peroneal, tibial, femoral and superior gluteal nerves. Histologic findings confirmed the diagnosis of schwannoma. We reported this rare case of segmental schwannomatosis that presented with neurologic symptoms including motor weakness, which was confirmed as multiple mononeuropathies by electrodiagnostic studies.

Real-time optical multiple object recognition and tracking system and method

NASA Technical Reports Server (NTRS)

Chao, Tien-Hsin (Inventor); Liu, Hua Kuang (Inventor)

1987-01-01

The invention relates to an apparatus and associated methods for the optical recognition and tracking of multiple objects in real time. Multiple point spatial filters are employed that pre-define the objects to be recognized at run-time. The system takes the basic technology of a Vander Lugt filter and adds a hololens. The technique replaces time, space and cost-intensive digital techniques. In place of multiple objects, the system can also recognize multiple orientations of a single object. This later capability has potential for space applications where space and weight are at a premium.

System and method for optimal load and source scheduling in context aware homes

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

Shetty, Pradeep; Foslien Graber, Wendy; Mangsuli, Purnaprajna R.

A controller for controlling energy consumption in a home includes a constraints engine to define variables for multiple appliances in the home corresponding to various home modes and persona of an occupant of the home. A modeling engine models multiple paths of energy utilization of the multiple appliances to place the home into a desired state from a current context. An optimal scheduler receives the multiple paths of energy utilization and generates a schedule as a function of the multiple paths and a selected persona to place the home in a desired state.

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

Pelch, Katherine E.; Tokar, Erik J.; Merrick, B. Alex

Previous work shows altered methylation patterns in inorganic arsenic (iAs)- or cadmium (Cd)-transformed epithelial cells. Here, the methylation status near the transcriptional start site was assessed in the normal human prostate epithelial cell line (RWPE-1) that was malignantly transformed by 10 μM Cd for 11 weeks (CTPE) or 5 μM iAs for 29 weeks (CAsE-PE), at which time cells showed multiple markers of acquired cancer phenotype. Next generation sequencing of the transcriptome of CAsE-PE cells identified multiple dysregulated genes. Of the most highly dysregulated genes, five genes that can be relevant to the carcinogenic process (S100P, HYAL1, NTM, NES, ALDH1A1)more » were chosen for an in-depth analysis of the DNA methylation profile. DNA was isolated, bisulfite converted, and combined bisulfite restriction analysis was used to identify differentially methylated CpG sites, which was confirmed with bisulfite sequencing. Four of the five genes showed differential methylation in transformants relative to control cells that was inversely related to altered gene expression. Increased expression of HYAL1 (> 25-fold) and S100P (> 40-fold) in transformants was correlated with hypomethylation near the transcriptional start site. Decreased expression of NES (> 15-fold) and NTM (> 1000-fold) in transformants was correlated with hypermethylation near the transcriptional start site. ALDH1A1 expression was differentially expressed in transformed cells but was not differentially methylated relative to control. In conclusion, altered gene expression observed in Cd and iAs transformed cells may result from altered DNA methylation status. - Highlights: • Cd and iAs are known human carcinogens, yet neither appears directly mutagenic. • Prior data suggest epigenetic modification plays a role in Cd or iAs induced cancer. • Altered methylation of four misregulated genes was found in Cd or iAs transformants. • The resulting altered gene expression may be relevant to cellular transformation.« less

Software-defined networking control plane for seamless integration of multiple silicon photonic switches in Datacom networks.

PubMed

Shen, Yiwen; Hattink, Maarten H N; Samadi, Payman; Cheng, Qixiang; Hu, Ziyiz; Gazman, Alexander; Bergman, Keren

2018-04-16

Silicon photonics based switches offer an effective option for the delivery of dynamic bandwidth for future large-scale Datacom systems while maintaining scalable energy efficiency. The integration of a silicon photonics-based optical switching fabric within electronic Datacom architectures requires novel network topologies and arbitration strategies to effectively manage the active elements in the network. We present a scalable software-defined networking control plane to integrate silicon photonic based switches with conventional Ethernet or InfiniBand networks. Our software-defined control plane manages both electronic packet switches and multiple silicon photonic switches for simultaneous packet and circuit switching. We built an experimental Dragonfly network testbed with 16 electronic packet switches and 2 silicon photonic switches to evaluate our control plane. Observed latencies occupied by each step of the switching procedure demonstrate a total of 344 µs control plane latency for data-center and high performance computing platforms.

Aging Affects Dopaminergic Neural Mechanisms of Cognitive Flexibility.

PubMed

Berry, Anne S; Shah, Vyoma D; Baker, Suzanne L; Vogel, Jacob W; O'Neil, James P; Janabi, Mustafa; Schwimmer, Henry D; Marks, Shawn M; Jagust, William J

2016-12-14

Aging is accompanied by profound changes in the brain's dopamine system that affect cognitive function. Evidence of powerful individual differences in cognitive aging has sharpened focus on identifying biological factors underlying relative preservation versus vulnerability to decline. Dopamine represents a key target in these efforts. Alterations of dopamine receptors and dopamine synthesis are seen in aging, with receptors generally showing reduction and synthesis demonstrating increases. Using the PET tracer 6-[ 18 F]fluoro-l-m-tyrosine, we found strong support for upregulated striatal dopamine synthesis capacity in healthy older adult humans free of amyloid pathology, relative to young people. We next used fMRI to define the functional impact of elevated synthesis capacity on cognitive flexibility, a core component of executive function. We found clear evidence in young adults that low levels of synthesis capacity were suboptimal, associated with diminished cognitive flexibility and altered frontoparietal activation relative to young adults with highest synthesis values. Critically, these relationships between dopamine, performance, and activation were transformed in older adults with higher synthesis capacity. Variability in synthesis capacity was related to intrinsic frontoparietal functional connectivity across groups, suggesting that striatal dopamine synthesis influences the tuning of networks underlying cognitive flexibility. Together, these findings define striatal dopamine's association with cognitive flexibility and its neural underpinnings in young adults, and reveal the alteration in dopamine-related neural processes in aging. Few studies have combined measurement of brain dopamine with examination of the neural basis of cognition in youth and aging to delineate the underlying mechanisms of these associations. Combining in vivo PET imaging of dopamine synthesis capacity, fMRI, and a sensitive measure of cognitive flexibility, we reveal three core findings. First, we find evidence supporting older adults' capacity to upregulate dopamine synthesis. Second, we define relationships between dopamine, cognition, and frontoparietal activity in young adults indicating high levels of synthesis capacity are optimal. Third, we demonstrate alteration of these relationships in older adults, suggesting neurochemical modulation of cognitive flexibility changes with age. Copyright © 2016 the authors 0270-6474/16/3612559-11$15.00/0.

Case-control analysis in highway safety: Accounting for sites with multiple crashes.

PubMed

Gross, Frank

2013-12-01

There is an increased interest in the use of epidemiological methods in highway safety analysis. The case-control and cohort methods are commonly used in the epidemiological field to identify risk factors and quantify the risk or odds of disease given certain characteristics and factors related to an individual. This same concept can be applied to highway safety where the entity of interest is a roadway segment or intersection (rather than a person) and the risk factors of interest are the operational and geometric characteristics of a given roadway. One criticism of the use of these methods in highway safety is that they have not accounted for the difference between sites with single and multiple crashes. In the medical field, a disease either occurs or it does not; multiple occurrences are generally not an issue. In the highway safety field, it is necessary to evaluate the safety of a given site while accounting for multiple crashes. Otherwise, the analysis may underestimate the safety effects of a given factor. This paper explores the use of the case-control method in highway safety and two variations to account for sites with multiple crashes. Specifically, the paper presents two alternative methods for defining cases in a case-control study and compares the results in a case study. The first alternative defines a separate case for each crash in a given study period, thereby increasing the weight of the associated roadway characteristics in the analysis. The second alternative defines entire crash categories as cases (sites with one crash, sites with two crashes, etc.) and analyzes each group separately in comparison to sites with no crashes. The results are also compared to a "typical" case-control application, where the cases are simply defined as any entity that experiences at least one crash and controls are those entities without a crash in a given period. In a "typical" case-control design, the attributes associated with single-crash segments are weighted the same as the attributes of segments with multiple crashes. The results support the hypothesis that the "typical" case-control design may underestimate the safety effects of a given factor compared to methods that account for sites with multiple crashes. Compared to the first alternative case definition (where multiple crash segments represent multiple cases) the results from the "typical" case-control design are less pronounced (i.e., closer to unity). The second alternative (where case definitions are constructed for various crash categories and analyzed separately) provides further evidence that sites with single and multiple crashes should not be grouped together in a case-control analysis. This paper indicates a clear need to differentiate sites with single and multiple crashes in a case-control analysis. While the results suggest that sites with multiple crashes can be accounted for using a case-control design, further research is needed to determine the optimal method for addressing this issue. This paper provides a starting point for that research. Copyright © 2012 Elsevier Ltd. All rights reserved.

MODEST: a web-based design tool for oligonucleotide-mediated genome engineering and recombineering

PubMed Central

Bonde, Mads T.; Klausen, Michael S.; Anderson, Mads V.; Wallin, Annika I.N.; Wang, Harris H.; Sommer, Morten O.A.

2014-01-01

Recombineering and multiplex automated genome engineering (MAGE) offer the possibility to rapidly modify multiple genomic or plasmid sites at high efficiencies. This enables efficient creation of genetic variants including both single mutants with specifically targeted modifications as well as combinatorial cell libraries. Manual design of oligonucleotides for these approaches can be tedious, time-consuming, and may not be practical for larger projects targeting many genomic sites. At present, the change from a desired phenotype (e.g. altered expression of a specific protein) to a designed MAGE oligo, which confers the corresponding genetic change, is performed manually. To address these challenges, we have developed the MAGE Oligo Design Tool (MODEST). This web-based tool allows designing of MAGE oligos for (i) tuning translation rates by modifying the ribosomal binding site, (ii) generating translational gene knockouts and (iii) introducing other coding or non-coding mutations, including amino acid substitutions, insertions, deletions and point mutations. The tool automatically designs oligos based on desired genotypic or phenotypic changes defined by the user, which can be used for high efficiency recombineering and MAGE. MODEST is available for free and is open to all users at http://modest.biosustain.dtu.dk. PMID:24838561

Anatomy of a nonhost disease resistance response of pea to Fusarium solani: PR gene elicitation via DNase, chitosan and chromatin alterations

PubMed Central

Hadwiger, Lee A.

2015-01-01

Of the multiplicity of plant pathogens in nature, only a few are virulent on a given plant species. Conversely, plants develop a rapid “nonhost” resistance response to the majority of the pathogens. The anatomy of the nonhost resistance of pea endocarp tissue against a pathogen of bean, Fusarium solani f.sp. phaseoli (Fsph) and the susceptibility of pea to F. solani f sp. pisi (Fspi) has been described cytologically, biochemically and molecular-biologically. Cytological changes have been followed by electron microscope and stain differentiation under white and UV light. The induction of changes in transcription, protein synthesis, expression of pathogenesis-related (PR) genes, and increases in metabolic pathways culminating in low molecular weight, antifungal compounds are described biochemically. Molecular changes initiated by fungal signals to host organelles, primarily to chromatin within host nuclei, are identified according to source of the signal and the mechanisms utilized in activating defense genes. The functions of some PR genes are defined. A hypothesis based on this data is developed to explain both why fungal growth is suppressed in nonhost resistance and why growth can continue in a susceptible reaction. PMID:26124762

Functional dyspepsia

PubMed Central

Brun, Rita; Kuo, Braden

2010-01-01

Dyspepsia is a common term used for a heterogeneous group of abdominal symptoms. Functional dyspepsia (FD) is the focus of this review. The 2006 Rome III criteria defined FD and its subgroups, postprandial distress syndrome (PDS) and epigastric pain syndrome (EPS). FD is a very common condition with a high prevalence throughout the world, adversely affecting the quality of life of patients. The pathophysiology of FD has been under investigation during the past two decades. Multiple mechanisms such as abnormal gastric emptying, visceral hypersensitivity, impaired gastric accommodation, and central nervous system factors are likely involved. Several tests are available for the assessment of various physiologic functions possibly involved in the pathogenesis of FD, and some of these could be used in clinical practice, helping to understand the abnormalities underlining patients’ complaints. Currently, the possibilities of pharmacological therapy for FD are still limited, however, experience of using prokinetics, tricyclic antidepressants, selective serotonin-reuptake inhibitors (SSRIs), proton-pump inhibitors (PPIs), and several alternative techniques has been accumulated. The different combinations of alterations in physiologic gastrointestinal and central nervous system functions result in the very heterogeneous nature of FD so combined approaches to these patients could be beneficial in challenging cases. PMID:21180597

Environment, susceptibility windows, development and child health

PubMed Central

Wright, Robert O

2017-01-01

Purpose To illustrate the role of the exposome in child health while highlighting unique aspects of this research pertinent to children, such as the time dependency of environmental exposures on fetal programming, as well as the time dependent nature of child behavior, diet, and motor function, which alter the probability of exposure to different compounds. Future environmental health research will be more hypothesis generating but will also need to heed lessons learned from other “omic” sciences. The NIH Child Health Environmental Analysis Resource (CHEAR) is a major step towards providing the infrastructure needed to study the exposome and child health. Recent Findings Environmental exposures have overlapping mechanisms such as endocrine disruption and oxidative stress among others. The nature of the long term health impact of an exposure is dependent not only on dose, but also on the timing of exposure. Advances in exposure science, toxicology and biostatistics will create new opportunities to identify and better define windows of susceptibility to environmental exposures. Summary As exposure science matures, we will better understand the role of environment on health. Linking the exposome with genomics will unlock the root origins of multiple complex diseases. PMID:28107208

Rotation covariant image processing for biomedical applications.

PubMed

Skibbe, Henrik; Reisert, Marco

2013-01-01

With the advent of novel biomedical 3D image acquisition techniques, the efficient and reliable analysis of volumetric images has become more and more important. The amount of data is enormous and demands an automated processing. The applications are manifold, ranging from image enhancement, image reconstruction, and image description to object/feature detection and high-level contextual feature extraction. In most scenarios, it is expected that geometric transformations alter the output in a mathematically well-defined manner. In this paper we emphasis on 3D translations and rotations. Many algorithms rely on intensity or low-order tensorial-like descriptions to fulfill this demand. This paper proposes a general mathematical framework based on mathematical concepts and theories transferred from mathematical physics and harmonic analysis into the domain of image analysis and pattern recognition. Based on two basic operations, spherical tensor differentiation and spherical tensor multiplication, we show how to design a variety of 3D image processing methods in an efficient way. The framework has already been applied to several biomedical applications ranging from feature and object detection tasks to image enhancement and image restoration techniques. In this paper, the proposed methods are applied on a variety of different 3D data modalities stemming from medical and biological sciences.

The complex and specific pMHC interactions with diverse HIV-1 TCR clonotypes reveal a structural basis for alterations in CTL function

PubMed Central

Xia, Zhen; Chen, Huabiao; Kang, Seung-gu; Huynh, Tien; Fang, Justin W.; Lamothe, Pedro A.; Walker, Bruce D.; Zhou, Ruhong

2014-01-01

Immune control of viral infections is modulated by diverse T cell receptor (TCR) clonotypes engaging peptide-MHC class I complexes on infected cells, but the relationship between TCR structure and antiviral function is unclear. Here we apply in silico molecular modeling with in vivo mutagenesis studies to investigate TCR-pMHC interactions from multiple CTL clonotypes specific for a well-defined HIV-1 epitope. Our molecular dynamics simulations of viral peptide-HLA-TCR complexes, based on two independent co-crystal structure templates, reveal that effective and ineffective clonotypes bind to the terminal portions of the peptide-MHC through similar salt bridges, but their hydrophobic side-chain packings can be very different, which accounts for the major part of the differences among these clonotypes. Non-specific hydrogen bonding to viral peptide also accommodates greater epitope variants. Furthermore, free energy perturbation calculations for point mutations on the viral peptide KK10 show excellent agreement with in vivo mutagenesis assays, with new predictions confirmed by additional experiments. These findings indicate a direct structural basis for heterogeneous CTL antiviral function. PMID:24522437

Microfabricated systems and assays for studying the cytoskeletal organization, micromechanics, and motility patterns of cancerous cells

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

Huda, Sabil; Pilans, Didzis; Makurath, Monika

Cell motions are driven by coordinated actions of the intracellular cytoskeleton – actin, microtubules (MTs) and substrate/focal adhesions (FAs). This coordination is altered in metastatic cancer cells resulting in deregulated and increased cellular motility. Microfabrication tools, including photolithography, micromolding, microcontact printing, wet stamping and microfluidic devices have emerged as a powerful set of experimental tools with which to probe and define the differences in cytoskeleton organization/dynamics and cell motility patterns in non-metastatic and metastatic cancer cells. In this paper, we discuss four categories of microfabricated systems: (i) micropatterned substrates for studying of cell motility sub-processes (for example, MT targeting ofmore » FAs or cell polarization); (ii) systems for studying cell mechanical properties, (iii) systems for probing overall cell motility patterns within challenging geometric confines relevant to metastasis (for example, linear and ratchet geometries), and (iv) microfluidic devices that incorporate co-cultures of multiple cell types and chemical gradients to mimic in vivo intravasation/extravasation steps of metastasis. Finally, together, these systems allow for creating controlled microenvironments that not only mimic complex soft tissues, but are also compatible with live cell high-resolution imaging and quantitative analysis of single cell behavior.« less

Anatomy of a nonhost disease resistance response of pea to Fusarium solani: PR gene elicitation via DNase, chitosan and chromatin alterations.

PubMed

Hadwiger, Lee A

2015-01-01

Of the multiplicity of plant pathogens in nature, only a few are virulent on a given plant species. Conversely, plants develop a rapid "nonhost" resistance response to the majority of the pathogens. The anatomy of the nonhost resistance of pea endocarp tissue against a pathogen of bean, Fusarium solani f.sp. phaseoli (Fsph) and the susceptibility of pea to F. solani f sp. pisi (Fspi) has been described cytologically, biochemically and molecular-biologically. Cytological changes have been followed by electron microscope and stain differentiation under white and UV light. The induction of changes in transcription, protein synthesis, expression of pathogenesis-related (PR) genes, and increases in metabolic pathways culminating in low molecular weight, antifungal compounds are described biochemically. Molecular changes initiated by fungal signals to host organelles, primarily to chromatin within host nuclei, are identified according to source of the signal and the mechanisms utilized in activating defense genes. The functions of some PR genes are defined. A hypothesis based on this data is developed to explain both why fungal growth is suppressed in nonhost resistance and why growth can continue in a susceptible reaction.

Microfabricated systems and assays for studying the cytoskeletal organization, micromechanics, and motility patterns of cancerous cells

DOE PAGES

Huda, Sabil; Pilans, Didzis; Makurath, Monika; ...

2014-08-28

Cell motions are driven by coordinated actions of the intracellular cytoskeleton – actin, microtubules (MTs) and substrate/focal adhesions (FAs). This coordination is altered in metastatic cancer cells resulting in deregulated and increased cellular motility. Microfabrication tools, including photolithography, micromolding, microcontact printing, wet stamping and microfluidic devices have emerged as a powerful set of experimental tools with which to probe and define the differences in cytoskeleton organization/dynamics and cell motility patterns in non-metastatic and metastatic cancer cells. In this paper, we discuss four categories of microfabricated systems: (i) micropatterned substrates for studying of cell motility sub-processes (for example, MT targeting ofmore » FAs or cell polarization); (ii) systems for studying cell mechanical properties, (iii) systems for probing overall cell motility patterns within challenging geometric confines relevant to metastasis (for example, linear and ratchet geometries), and (iv) microfluidic devices that incorporate co-cultures of multiple cell types and chemical gradients to mimic in vivo intravasation/extravasation steps of metastasis. Finally, together, these systems allow for creating controlled microenvironments that not only mimic complex soft tissues, but are also compatible with live cell high-resolution imaging and quantitative analysis of single cell behavior.« less

Microplasma generator and methods therefor

DOEpatents

Hopwood, Jeffrey A

2015-04-14

A low-temperature, atmospheric-pressure microplasma generator comprises at least one strip of metal on a dielectric substrate. A first end of the strip is connected to a ground plane and the second end of the strip is adjacent to a grounded electrode, with a gap being defined between the second end of the strip and the grounded electrode. High frequency power is supplied to the strip. The frequency is selected so that the length of the strip is an odd integer multiple of 1/4 of the wavelength traveling on the strip. A microplasma forms in the gap between the second end of the strip and the grounded electrode due to electric fields in that region. A microplasma generator array comprises a plurality of strongly-coupled resonant strips in close proximity to one another. At least one of the strips has an input for high-frequency electrical power. The remaining strips resonate due to coupling from the at least one powered strip. The array can provide a continuous line or ring of plasma. The microplasma generator can be used to alter the surface of a substrate, such as by adding material (deposition), removal of material (etching), or modifying surface chemistry.

Establishment and Characterization of a Highly Tumourigenic and Cancer Stem Cell Enriched Pancreatic Cancer Cell Line as a Well Defined Model System

PubMed Central

Fredebohm, Johannes; Boettcher, Michael; Eisen, Christian; Gaida, Matthias M.; Heller, Anette; Keleg, Shereen; Tost, Jörg; Greulich-Bode, Karin M.; Hotz-Wagenblatt, Agnes; Lathrop, Mark; Giese, Nathalia A.; Hoheisel, Jörg D.

2012-01-01

Standard cancer cell lines do not model the intratumoural heterogeneity situation sufficiently. Clonal selection leads to a homogeneous population of cells by genetic drift. Heterogeneity of tumour cells, however, is particularly critical for therapeutically relevant studies, since it is a prerequisite for acquiring drug resistance and reoccurrence of tumours. Here, we report the isolation of a highly tumourigenic primary pancreatic cancer cell line, called JoPaca-1 and its detailed characterization at multiple levels. Implantation of as few as 100 JoPaca-1 cells into immunodeficient mice gave rise to tumours that were histologically very similar to the primary tumour. The high heterogeneity of JoPaca-1 was reflected by diverse cell morphology and a substantial number of chromosomal aberrations. Comparative whole-genome sequencing of JoPaca-1 and BxPC-3 revealed mutations in genes frequently altered in pancreatic cancer. Exceptionally high expression of cancer stem cell markers and a high clonogenic potential in vitro and in vivo was observed. All of these attributes make this cell line an extremely valuable model to study the biology of and pharmaceutical effects on pancreatic cancer. PMID:23152778

Queen pheromones

PubMed Central

2010-01-01

Group-living species produce signals that alter the behavior and even the physiology of their social partners. Social insects possess especially sophisticated chemical communication systems that govern every aspect of colony life, including the defining feature of eusociality: reproductive division of labor. Current evidence hints at the central importance of queen pheromones, but progress has been hindered by the fact that such pheromones have only been isolated in honeybees. In a pair of papers on the ant Lasius niger, we identified and investigated a queen pheromone regulating worker sterility. The cuticular hydrocarbon 3-methylhentriacontane (3-MeC31) is correlated with queen maturity and fecundity and workers are also more likely to execute surplus queens that have low amounts of this chemical. Experiments with synthetic 3-MeC31 found that it inhibits ovarian development in queenless workers and lowers worker aggression towards objects coated with it. Production of 3-MeC31 by queens was depressed by an experimental immune challenge, and the same chemical was abundant on queenlaid eggs, suggesting that the workers' responses to the queen are conditional on her health and fecundity. Together with other studies, these results indicate that queen pheromones are honest signals of quality that simultaneously regulate multiple social behaviors. PMID:21331238

Assembly of the mitochondrial membrane system: mutations in the pho2 locus of the mitochondrial genome of Saccharomyces cerevisiae.

PubMed

Coruzzi, G; Trembath, M K; Tzagoloff, A

1978-12-01

Two mutants of Saccharomyces cerevisiae which show a loss of mitochondrial rutamycin-sensitive ATPase activity are described. Although phenotypically similar to mutants of the mitochondrial locus pho1 [F. Foury and A. Tzagoloff (1976) Eur. J. Biochem. 68, 113-119], these mutants define a second ATPase locus on the mitochondrial DNA (designated pho2), which is genetically unlinked to pho1. Analysis of recombination in crosses involving multiple antibiotic resistance markers indicates that the locus is in the segment of the genome between ery1 and oli2, very close to oli1. In fact it is proposed that the oli1 and pho2 mutations are in the same gene. Supporting evidence for this proposal includes: 1. The analysis of marker retention in petite mutants shows that the oli1 and pho2 loci were either retained or lost together in all cases. 2. Recombination frequencies of 0.05% or less are observed in crosses between the oli1 and pho2 loci. 3. When rho+ revertants are isolated from the pho2 mutants they frequently are oligomycin resistant. 4. pho2 mutants have an altered subunit 9 of the ATPase complex.

FANNING OUT OF THE SOLAR f-MODE IN THE PRESENCE OF NON-UNIFORM MAGNETIC FIELDS?

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

Singh, Nishant K.; Brandenburg, Axel; Rheinhardt, Matthias, E-mail: nishant@nordita.org

2014-11-01

We show that in the presence of a magnetic field that is varying harmonically in space, the fundamental mode, or f-mode, in a stratified layer is altered in such a way that it fans out in the diagnostic kω diagram, with mode power also within the fan. In our simulations, the surface is defined by a temperature and density jump in a piecewise isothermal layer. Unlike our previous work (Singh et al. 2014), where a uniform magnetic field was considered, here we employ a non-uniform magnetic field together with hydromagnetic turbulence at length scales much smaller than those of themore » magnetic field. The expansion of the f-mode is stronger for fields confined to the layer below the surface. In some of those cases, the kω diagram also reveals a new class of low-frequency vertical stripes at multiples of twice the horizontal wavenumber of the background magnetic field. We argue that the study of the f-mode expansion might be a new and sensitive tool to determine subsurface magnetic fields with azimuthal or other horizontal periodicity.« less

Adaptation and visual salience

PubMed Central

McDermott, Kyle C.; Malkoc, Gokhan; Mulligan, Jeffrey B.; Webster, Michael A.

2011-01-01

We examined how the salience of color is affected by adaptation to different color distributions. Observers searched for a color target on a dense background of distractors varying along different directions in color space. Prior adaptation to the backgrounds enhanced search on the same background while adaptation to orthogonal background directions slowed detection. Advantages of adaptation were seen for both contrast adaptation (to different color axes) and chromatic adaptation (to different mean chromaticities). Control experiments, including analyses of eye movements during the search, suggest that these aftereffects are unlikely to reflect simple learning or changes in search strategies on familiar backgrounds, and instead result from how adaptation alters the relative salience of the target and background colors. Comparable effects were observed along different axes in the chromatic plane or for axes defined by different combinations of luminance and chromatic contrast, consistent with visual search and adaptation mediated by multiple color mechanisms. Similar effects also occurred for color distributions characteristic of natural environments with strongly selective color gamuts. Our results are consistent with the hypothesis that adaptation may play an important functional role in highlighting the salience of novel stimuli by discounting ambient properties of the visual environment. PMID:21106682

C-peptide and Central Nervous System Complications in Diabetes

PubMed Central

Li, Zhen-guo

2004-01-01

Substantial evidence collected from clinical data and experimental studies has indicated that CNS is not spared from diabetes complications. Impairments in CNS function are well documented in both type 1 and type 2 diabetic patients as well as in various animal models of diabetes, in terms of alterations in cognition, neuropsychology, neurobehavior, electrophysiology, structure, neurochemistry and apoptotic activities. These data suggest that primary diabetic encephalopathy exists as a definable diabetic complication. The mechanisms underlying this CNS complication are not clear. Experimental studies have suggested that neuronal apoptosis may play an important role in neuronal loss and impaired cognitive function. In diabetes multiple factors are responsible for neuronal apoptosis, such as a perturbed IGF system, hyperglycemia and the aging process itself. Recent data suggest that insulin/C-peptide deficiency may exert an eminent role. Administration of C-peptide partially corrects the perturbed IGF system in the brain and prevents neuronal apoptosis in hippocampus of type 1 diabetes. In neuroblastoma SH-SY5Y cells C-peptide provides a dose-dependent stimulation on cell proliferation and an anti-apoptotic effect as well. These studies provide a basis for administration of C-peptide as a potentially effective therapy for type 1 diabetes. PMID:15198373

The role of the NG2 proteoglycan in OPC and CNS network function.

PubMed

Sakry, Dominik; Trotter, Jacqueline

2016-05-01

In the normal mammalian CNS, the NG2 proteoglycan is expressed by oligodendrocyte precursor cells (OPC) but not by any other neural cell-type. NG2 is a type-1 membrane protein, exerting multiple roles in the CNS including intracellular signaling within the OPC, with effects on migration, cytoskeleton interaction and target gene regulation. It has been recently shown that the extracellular region of NG2, in addition to an adhesive function, acts as a soluble ECM component with the capacity to alter defined neuronal network properties. This region of NG2 is thus endowed with neuromodulatory properties. In order to generate biologically active fragments yielding these properties, the sequential cleavage of the NG2 protein by α- and γ-secretases occurs. The basal level of constitutive cleavage is stimulated by neuronal network activity. This processing leads to 4 major NG2 fragments which all have been associated with distinct biological functions. Here we summarize these functions, focusing on recent discoveries and their implications for the CNS. This article is part of a Special Issue entitled SI:NG2-glia(Invited only). Copyright © 2015 Elsevier B.V. All rights reserved.

Physiological and molecular characterization of genetic competence in Streptococcus sanguinis.

PubMed

Rodriguez, A M; Callahan, J E; Fawcett, P; Ge, X; Xu, P; Kitten, T

2011-04-01

Streptococcus sanguinis is a major component of the oral flora and an important cause of infective endocarditis. Although S. sanguinis is naturally competent, genome sequencing has suggested significant differences in the S. sanguinis competence system relative to those of other streptococci. An S. sanguinis mutant possessing an in-frame deletion in the comC gene, which encodes competence-stimulating peptide (CSP), was created. Addition of synthetic CSP induced competence in this strain. Gene expression in this strain was monitored by microarray analysis at multiple time-points from 2.5 to 30 min after CSP addition, and verified by quantitative reverse transcription-polymerase chain reaction. Over 200 genes were identified whose expression was altered at least two-fold in at least one time point, with the majority upregulated. The 'late' response was typical of that seen in previous studies. However, comparison of the 'early' response in S. sanguinis with that of other oral streptococci revealed unexpected differences with regard to the number of genes induced, the nature of those genes, and their putative upstream regulatory sequences. Streptococcus sanguinis possesses a comparatively limited early response, which may define a minimal streptococcal competence regulatory circuit. © 2011 John Wiley & Sons A/S.

Physiological and molecular characterization of genetic competence in Streptococcus sanguinis

PubMed Central

Rodriguez, Alejandro Miguel; Callahan, Jill E.; Fawcett, Paul; Ge, Xiuchun; Xu, Ping; Kitten, Todd

2011-01-01

SUMMARY Streptococcus sanguinis is a major component of the oral flora and an important cause of infective endocarditis. Although S. sanguinis is naturally competent, genome sequencing has suggested significant differences in the S. sanguinis competence system relative to those of other streptococci. An S. sanguinis mutant possessing an in-frame deletion in the comC gene, which encodes competence-stimulating peptide (CSP), was created. Addition of synthetic CSP induced competence in this strain. Gene expression in this strain was monitored by microarray analysis at multiple time points from 2.5 to 30 min after CSP addition, and verified by quantitative RT-PCR. Over 200 genes were identified whose expression was altered at least two-fold in at least one time point, with the majority upregulated. The “late” response was typical of that seen in previous studies. However, comparison of the “early” response in S. sanguinis with that of other oral streptococci revealed unexpected differences with regard to the number of genes induced, the nature of these genes, and their putative upstream regulatory sequences. S. sanguinis possesses a comparatively limited early response, which may define a minimal streptococcal competence regulatory circuit. PMID:21375701