Mutation of Neuron-Specific Chromatin Remodeling Subunit BAF53b: Rescue of Plasticity and Memory by Manipulating Actin Remodeling

ERIC Educational Resources Information Center

Ciernia, Annie Vogel; Kramár, Enikö A.; Matheos, Dina P.; Havekes, Robbert; Hemstedt, Thekla J.; Magnan, Christophe N.; Sakata, Keith; Tran, Ashley; Azzawi, Soraya; Lopez, Alberto; Dang, Richard; Wang, Weisheng; Trieu, Brian; Tong, Joyce; Barrett, Ruth M.; Post, Rebecca J.; Baldi, Pierre; Abel, Ted; Lynch, Gary; Wood, Marcelo A.

2017-01-01

Recent human exome-sequencing studies have implicated polymorphic Brg1-associated factor (BAF) complexes (mammalian SWI/SNF chromatin remodeling complexes) in several intellectual disabilities and cognitive disorders, including autism. However, it remains unclear how mutations in BAF complexes result in impaired cognitive function. Post-mitotic…

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

PubMed Central

Weatherall, D

1999-01-01

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

The Brain Prize 2014: complex human functions.

PubMed

Grigaityte, Kristina; Iacoboni, Marco

2014-11-01

Giacomo Rizzolatti, Stanislas Dehaene, and Trevor Robbins were recently awarded the 2014 Grete Lundbeck European Brain Research Prize for their 'pioneering research on higher brain mechanisms underpinning such complex human functions as literacy, numeracy, motivated behavior and social cognition, and for their effort to understand cognitive and behavioral disorders'. Why was their work highlighted? Is there anything that links together these seemingly disparate lines of research? Copyright © 2014 Elsevier Ltd. All rights reserved.

Natural Versus Synthetic Vitamin B Complexes in Human

ClinicalTrials.gov

2018-04-12

Healthy; Thiamine and Niacin Deficiency States; Pyridoxine Deficiency; Folic Acid Deficiency Anemia, Dietary; Vitamin B 12 Deficiency; Peroxidase; Defect; Polyphenols; Oxidative Stress; Homocystine; Metabolic Disorder

Cognitive Abilities on Transitive Inference Using a Novel Touchscreen Technology for Mice

PubMed Central

Silverman, J.L.; Gastrell, P.T.; Karras, M.N.; Solomon, M.; Crawley, J.N.

2015-01-01

Cognitive abilities are impaired in neurodevelopmental disorders, including autism spectrum disorder (ASD) and schizophrenia. Preclinical models with strong endophenotypes relevant to cognitive dysfunctions offer a valuable resource for therapeutic development. However, improved assays to test higher order cognition are needed. We employed touchscreen technology to design a complex transitive inference (TI) assay that requires cognitive flexibility and relational learning. C57BL/6J (B6) mice with good cognitive skills and BTBR T+tf/J (BTBR), a model of ASD with cognitive deficits, were evaluated in simple and complex touchscreen assays. Both B6 and BTBR acquired visual discrimination and reversal. BTBR displayed deficits on components of TI, when 4 stimuli pairs were interspersed, which required flexible integrated knowledge. BTBR displayed impairment on the A > E inference, analogous to the A > E deficit in ASD. B6 and BTBR mice both reached criterion on the B > D comparison, unlike the B > D impairment in schizophrenia. These results demonstrate that mice are capable of complex discriminations and higher order tasks using methods and equipment paralleling those used in humans. Our discovery that a mouse model of ASD displays a TI deficit similar to humans with ASD supports the use of the touchscreen technology for complex cognitive tasks in mouse models of neurodevelopmental disorders. PMID:24293564

The Big Role of Small RNAs in Anxiety and Stress-Related Disorders.

PubMed

Malan-Müller, S; Hemmings, S M J

2017-01-01

In the study of complex, heterogeneous disorders, such as anxiety and stress-related disorders, epigenetic factors provide an additional level of heritable complexity. MicroRNAs (miRNAs) are a class of small, noncoding RNAs that function as epigenetic modulators of gene expression by binding to target messenger RNAs (mRNAs) and subsequently blocking translation or accelerating their degradation. In light of their abundance in the central nervous system (CNS) and their involvement in synaptic plasticity and neuronal differentiation, miRNAs represent an exciting frontier to be explored in the etiology and treatment of anxiety and stress-related disorders. This chapter will present a thorough review of miRNAs, their functions, and mRNA targets in the CNS, focusing on their role in anxiety and stress-related disorders as described by studies performed in animals and human subjects. © 2017 Elsevier Inc. All rights reserved.

Eye-Tracking Study on Facial Emotion Recognition Tasks in Individuals with High-Functioning Autism Spectrum Disorders

ERIC Educational Resources Information Center

Tsang, Vicky

2018-01-01

The eye-tracking experiment was carried out to assess fixation duration and scan paths that individuals with and without high-functioning autism spectrum disorders employed when identifying simple and complex emotions. Participants viewed human photos of facial expressions and decided on the identification of emotion, the negative-positive emotion…

Probing conformational states of glutaryl-CoA dehydrogenase by fragment screening

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

Begley, Darren W.; Davies, Douglas R.; Hartley, Robert C.

Glutaric acidemia type 1 is an inherited metabolic disorder which can cause macrocephaly, muscular rigidity, spastic paralysis and other progressive movement disorders in humans. The defects in glutaryl-CoA dehydrogenase (GCDH) associated with this disease are thought to increase holoenzyme instability and reduce cofactor binding. Here, the first structural analysis of a GCDH enzyme in the absence of the cofactor flavin adenine dinucleotide (FAD) is reported. The apo structure of GCDH from Burkholderia pseudomallei reveals a loss of secondary structure and increased disorder in the FAD-binding pocket relative to the ternary complex of the highly homologous human GCDH. After conducting amore » fragment-based screen, four small molecules were identified which bind to GCDH from B. pseudomallei. Complex structures were determined for these fragments, which cause backbone and side-chain perturbations to key active-site residues. Structural insights from this investigation highlight differences from apo GCDH and the utility of small-molecular fragments as chemical probes for capturing alternative conformational states of preformed protein crystals.« less

Intersection of diverse neuronal genomes and neuropsychiatric disease: The Brain Somatic Mosaicism Network.

PubMed

McConnell, Michael J; Moran, John V; Abyzov, Alexej; Akbarian, Schahram; Bae, Taejeong; Cortes-Ciriano, Isidro; Erwin, Jennifer A; Fasching, Liana; Flasch, Diane A; Freed, Donald; Ganz, Javier; Jaffe, Andrew E; Kwan, Kenneth Y; Kwon, Minseok; Lodato, Michael A; Mills, Ryan E; Paquola, Apua C M; Rodin, Rachel E; Rosenbluh, Chaggai; Sestan, Nenad; Sherman, Maxwell A; Shin, Joo Heon; Song, Saera; Straub, Richard E; Thorpe, Jeremy; Weinberger, Daniel R; Urban, Alexander E; Zhou, Bo; Gage, Fred H; Lehner, Thomas; Senthil, Geetha; Walsh, Christopher A; Chess, Andrew; Courchesne, Eric; Gleeson, Joseph G; Kidd, Jeffrey M; Park, Peter J; Pevsner, Jonathan; Vaccarino, Flora M

2017-04-28

Neuropsychiatric disorders have a complex genetic architecture. Human genetic population-based studies have identified numerous heritable sequence and structural genomic variants associated with susceptibility to neuropsychiatric disease. However, these germline variants do not fully account for disease risk. During brain development, progenitor cells undergo billions of cell divisions to generate the ~80 billion neurons in the brain. The failure to accurately repair DNA damage arising during replication, transcription, and cellular metabolism amid this dramatic cellular expansion can lead to somatic mutations. Somatic mutations that alter subsets of neuronal transcriptomes and proteomes can, in turn, affect cell proliferation and survival and lead to neurodevelopmental disorders. The long life span of individual neurons and the direct relationship between neural circuits and behavior suggest that somatic mutations in small populations of neurons can significantly affect individual neurodevelopment. The Brain Somatic Mosaicism Network has been founded to study somatic mosaicism both in neurotypical human brains and in the context of complex neuropsychiatric disorders. Copyright © 2017, American Association for the Advancement of Science.

Multivalency regulates activity in an intrinsically disordered transcription factor

PubMed Central

Clark, Sarah; Myers, Janette B; King, Ashleigh; Fiala, Radovan; Novacek, Jiri; Pearce, Grant; Heierhorst, Jörg; Reichow, Steve L

2018-01-01

The transcription factor ASCIZ (ATMIN, ZNF822) has an unusually high number of recognition motifs for the product of its main target gene, the hub protein LC8 (DYNLL1). Using a combination of biophysical methods, structural analysis by NMR and electron microscopy, and cellular transcription assays, we developed a model that proposes a concerted role of intrinsic disorder and multiple LC8 binding events in regulating LC8 transcription. We demonstrate that the long intrinsically disordered C-terminal domain of ASCIZ binds LC8 to form a dynamic ensemble of complexes with a gradient of transcriptional activity that is inversely proportional to LC8 occupancy. The preference for low occupancy complexes at saturating LC8 concentrations with both human and Drosophila ASCIZ indicates that negative cooperativity is an important feature of ASCIZ-LC8 interactions. The prevalence of intrinsic disorder and multivalency among transcription factors suggests that formation of heterogeneous, dynamic complexes is a widespread mechanism for tuning transcriptional regulation. PMID:29714690

Context processing in adolescents with autism spectrum disorder: How complex could it be?

PubMed

Ben-Yosef, Dekel; Anaki, David; Golan, Ofer

2017-03-01

The ability of individuals with Autism Spectrum Disorder (ASD) to process context has long been debated: According to the Weak Central Coherence theory, ASD is characterized by poor global processing, and consequently-poor context processing. In contrast, the Social Cognition theory argues individuals with ASD will present difficulties only in social context processing. The complexity theory of autism suggests context processing in ASD will depend on task complexity. The current study examined this controversy through two priming tasks, one presenting human stimuli (facial expressions) and the other presenting non-human stimuli (animal faces). Both tasks presented visual targets, preceded by congruent, incongruent, or neutral auditory primes. Local and global processing were examined by presenting the visual targets in three spatial frequency conditions: High frequency, low frequency, and broadband. Tasks were administered to 16 adolescents with high functioning ASD and 16 matched typically developing adolescents. Reaction time and accuracy were measured for each task in each condition. Results indicated that individuals with ASD processed context for both human and non-human stimuli, except in one condition, in which human stimuli had to be processed globally (i.e., target presented in low frequency). The task demands presented in this condition, and the performance deficit shown in the ASD group as a result, could be understood in terms of cognitive overload. These findings provide support for the complexity theory of autism and extend it. Our results also demonstrate how associative priming could support intact context processing of human and non-human stimuli in individuals with ASD. Autism Res 2017, 10: 520-530. © 2016 International Society for Autism Research, Wiley Periodicals, Inc. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.

Human body may produce bacteria.

PubMed

Salerian, Alen J

2017-06-01

"Human body may produce bacteria" proposes that human body may produce bacteria and represent an independent source of infections contrary to the current paradigm of infectious disorders proposed by Louis Pasteur in 1880. The following observations are consistent with this hypothesis: A. Bidirectional transformations of both living and nonliving things have been commonly observed in nature. B. Complex multicellular organisms harbor the necessary properties to produce bacteria (water, nitrogen and oxygen). C. Physical laws suggest any previously observed phenomenon or action will occur again (life began on earth; a non living thing). D. Animal muscle cells may generate energy (fermentation). E. Sterilized food products (i.e. boiled eggs), may produce bacteria and fungus under special conditions and without any exposure to foreign living cells. "Human body may produce bacteria" may challenge the current medical paradigm that views human infectious disorders as the exclusive causative byproducts of invading foreign cells. It may also introduce new avenues to treat infectious disorders. Copyright © 2017 Elsevier Ltd. All rights reserved.

Convergent dysregulation of frontal cortical cognitive and reward systems in eating disorders.

PubMed

Stefano, George B; Ptáček, Radek; Kuželová, Hana; Mantione, Kirk J; Raboch, Jiří; Papezova, Hana; Kream, Richard M

2013-05-10

A substantive literature has drawn a compelling case for the functional involvement of mesolimbic/prefrontal cortical neural reward systems in normative control of eating and in the etiology and persistence of severe eating disorders that affect diverse human populations. Presently, we provide a short review that develops an equally compelling case for the importance of dysregulated frontal cortical cognitive neural networks acting in concert with regional reward systems in the regulation of complex eating behaviors and in the presentation of complex pathophysiological symptoms associated with major eating disorders. Our goal is to highlight working models of major eating disorders that incorporate complementary approaches to elucidate functionally interactive neural circuits defined by their regulatory neurochemical phenotypes. Importantly, we also review evidence-based linkages between widely studied psychiatric and neurodegenerative syndromes (e.g., autism spectrum disorders and Parkinson's disease) and co-morbid eating disorders to elucidate basic mechanisms involving dopaminergic transmission and its regulation by endogenously expressed morphine in these same cortical regions.

The Neuron-specific Chromatin Regulatory Subunit BAF53b is Necessary for Synaptic Plasticity and Memory

PubMed Central

Vogel-Ciernia, Annie; Matheos, Dina P.; Barrett, Ruth M.; Kramár, Enikö; Azzawi, Soraya; Chen, Yuncai; Magnan, Christophe N.; Zeller, Michael; Sylvain, Angelina; Haettig, Jakob; Jia, Yousheng; Tran, Anthony; Dang, Richard; Post, Rebecca J.; Chabrier, Meredith; Babayan, Alex; Wu, Jiang I.; Crabtree, Gerald R.; Baldi, Pierre; Baram, Tallie Z.; Lynch, Gary; Wood, Marcelo A.

2013-01-01

Recent exome sequencing studies have implicated polymorphic BAF complexes (mammalian SWI/SNF chromatin remodeling complexes) in several human intellectual disabilities and cognitive disorders. However, it is currently unknown how mutations in BAF complexes result in impaired cognitive function. Post mitotic neurons express a neuron specific assembly, nBAF, characterized by the neuron-specific subunit BAF53b. Mice harboring selective genetic manipulations of BAF53b have severe defects in longterm memory and long-lasting forms of hippocampal synaptic plasticity. We rescued memory impairments in BAF53b mutant mice by reintroducing BAF53b in the adult hippocampus, indicating a role for BAF53b beyond neuronal development. The defects in BAF53b mutant mice appear to derive from alterations in gene expression that produce abnormal postsynaptic components, such as spine structure and function, and ultimately lead to deficits in synaptic plasticity. Our studies provide new insight into the role of dominant mutations in subunits of BAF complexes in human intellectual and cognitive disorders. PMID:23525042

Complex biomarker discovery in neuroimaging data: Finding a needle in a haystack☆

PubMed Central

Atluri, Gowtham; Padmanabhan, Kanchana; Fang, Gang; Steinbach, Michael; Petrella, Jeffrey R.; Lim, Kelvin; MacDonald, Angus; Samatova, Nagiza F.; Doraiswamy, P. Murali; Kumar, Vipin

2013-01-01

Neuropsychiatric disorders such as schizophrenia, bipolar disorder and Alzheimer's disease are major public health problems. However, despite decades of research, we currently have no validated prognostic or diagnostic tests that can be applied at an individual patient level. Many neuropsychiatric diseases are due to a combination of alterations that occur in a human brain rather than the result of localized lesions. While there is hope that newer imaging technologies such as functional and anatomic connectivity MRI or molecular imaging may offer breakthroughs, the single biomarkers that are discovered using these datasets are limited by their inability to capture the heterogeneity and complexity of most multifactorial brain disorders. Recently, complex biomarkers have been explored to address this limitation using neuroimaging data. In this manuscript we consider the nature of complex biomarkers being investigated in the recent literature and present techniques to find such biomarkers that have been developed in related areas of data mining, statistics, machine learning and bioinformatics. PMID:24179856

Rethinking dependent personality disorder: comparing different human relatedness in cultural contexts.

PubMed

Chen, YuJu; Nettles, Margaret E; Chen, Shun-Wen

2009-11-01

We argue that the Diagnostic and Statistical Manual of Mental Disorders dependent personality disorder is a culturally related concept reflecting deeply rooted values, beliefs, and assumptions of American individualistic convictions about self and interpersonal relationship. This article integrates social psychology concepts into the exploration of psychopathology. Beginning with the construct of individualism and collectivism, we demonstrate the limitations of this commonly used framework. The indigenous Chinese concept of Confucianism and Chinese Relationalism is introduced to highlight that a well-differentiated self is not a universal premise of human beings, healthy existence. In East Asian Confucianism the manifestation of dependence and submission may be considered individuals' proper behavior and required for their social obligation, rather than a direct display of individuals' personality. Thus, the complexity of dependent personality disorder is beyond the neo-Kraepelinian approach assumed by the Diagnostic and Statistical Manual of Mental Disorders system.

Contribution of nonprimate animal models in understanding the etiology of schizophrenia

PubMed Central

Lazar, Noah L.; Neufeld, Richard W.J.; Cain, Donald P.

2011-01-01

Schizophrenia is a severe psychiatric disorder that is characterized by positive and negative symptoms and cognitive impairments. The etiology of the disorder is complex, and it is thought to follow a multifactorial threshold model of inheritance with genetic and neurodevelopmental contributions to risk. Human studies are particularly useful in capturing the richness of the phenotype, but they are often limited to the use of correlational approaches. By assessing behavioural abnormalities in both humans and rodents, nonprimate animal models of schizophrenia provide unique insight into the etiology and mechanisms of the disorder. This review discusses the phenomenology and etiology of schizophrenia and the contribution of current nonprimate animal models with an emphasis on how research with models of neurotransmitter dysregulation, environmental risk factors, neurodevelopmental disruption and genetic risk factors can complement the literature on schizophrenia in humans. PMID:21247514

Ethical and social implications of genetic testing for communication disorders.

PubMed

Arnos, Kathleen S

2008-01-01

Advances in genetics and genomics have quickly led to clinical applications to human health which have far-reaching consequences at the individual and societal levels. These new technologies have allowed a better understanding of the genetic factors involved in a wide range of disorders. During the past decade, incredible progress has been made in the identification of genes involved in the normal process of hearing. The resulting clinical applications have presented consumers with new information and choices. Many of the same gene identification techniques are increasingly being applied to the investigation of complex disorders of speech and language. In parallel with gene identification, studies of the legal, ethical and psychosocial impacts of the clinical application of these advances and their influence on specific behaviors of individuals with communication disorders are paramount, but often lag behind. These studies will help to ensure that new technologies are introduced into clinical practice in a responsible manner. As a result of this activity, the participant will be able to (1) explain the differences between Mendelian and complex forms of inheritance and why these differences complicate the ethical impact of genetic testing, (2) explain how publicly funded genome research through the Human Genome Project, the International HapMap Project and others have examined the ethical, legal and social implications of genome research, (3) list some of the ethical complexities of prenatal, newborn and predictive testing for various genetic disorders and (4) discuss the importance of evidence-based practice to the development of public policy for the introduction and clinical use of genetic tests.

Ethical and social implications of genetic testing for communication disorders

PubMed Central

Arnos, Kathleen S.

2013-01-01

Advances in genetics and genomics have quickly led to clinical applications to human health which have far-reaching consequences at the individual and societal levels. These new technologies have allowed a better understanding of the genetic factors involved in a wide range of disorders. During the past decade, incredible progress has been made in the identification of genes involved in the normal process of hearing. The resulting clinical applications have presented consumers with new information and choices. Many of the same gene identification techniques are increasingly being applied to the investigation of complex disorders of speech and language. In parallel with gene identification, studies of the legal, ethical and psychosocial impacts of the clinical application of these advances and their influence on specific behaviors of individuals with communication disorders are paramount, but often lag behind. These studies will help to ensure that new technologies are introduced into clinical practice in a responsible manner. Learning outcomes As a result of this activity, the participant will be able to (1) explain the differences between Mendelian and complex forms of inheritance and why these differences complicate the ethical impact of genetic testing, (2) explain how publicly funded genome research through the Human Genome Project, the International HapMap Project and others have examined the ethical, legal and social implications of genome research, (3) list some of the ethical complexities of prenatal, newborn and predictive testing for various genetic disorders and (4) discuss the importance of evidence-based practice to the development of public policy for the introduction and clinical use of genetic tests. PMID:18452941

Intergenerational Neuroimaging of Human Brain Circuitry

PubMed Central

Ho, Tiffany C.; Sanders, Stephan J.; Gotlib, Ian H.; Hoeft, Fumiko

2016-01-01

Neuroscientists are increasingly using advanced neuroimaging methods to elucidate the intergenerational transmission of human brain circuitry. This new line of work promises to shed insight into the ontogeny of complex behavioral traits, including psychiatric disorders, and possible mechanisms of transmission. Here, we highlight recent intergenerational neuroimaging studies and provide recommendations for future work. PMID:27623194

Primary Cortical Folding in the Human Newborn: An Early Marker of Later Functional Development

ERIC Educational Resources Information Center

Dubois, J.; Benders, M.; Borradori-Tolsa, C.; Cachia, A.; Lazeyras, F.; Leuchter, R. Ha-Vinh; Sizonenko, S. V.; Warfield, S. K.; Mangin, J. F.; Huppi, P. S.

2008-01-01

In the human brain, the morphology of cortical gyri and sulci is complex and variable among individuals, and it may reflect pathological functioning with specific abnormalities observed in certain developmental and neuropsychiatric disorders. Since cortical folding occurs early during brain development, these structural abnormalities might be…

Nuclear mRNA Surveillance Mechanisms: Function and Links to Human Disease.

PubMed

Singh, Pragyan; Saha, Upasana; Paira, Sunirmal; Das, Biswadip

2018-05-11

Production of export-competent mRNAs involves transcription and a series of dynamic processing and modification events of pre-messenger RNAs in the nucleus. Mutations in the genes encoding the transcription and mRNP processing machinery and the complexities involved in the biogenesis events lead to the formation of aberrant messages. These faulty transcripts are promptly eliminated by the nuclear RNA exosome and its cofactors to safeguard the cells and organisms from genetic catastrophe. Mutations in the components of the core nuclear exosome and its cofactors lead to the tissue-specific dysfunction of exosomal activities, which are linked to diverse human diseases and disorders. In this article, we examine the structure and function of both the yeast and human RNA exosome complex and its cofactors, discuss the nature of the various altered amino acid residues implicated in these diseases with the speculative mechanisms of the mutation-induced disorders and project the frontier and prospective avenues of the future research in this field. Copyright © 2018 Elsevier Ltd. All rights reserved.

A system utilizing radio frequency identification (RFID) technology to monitor individual rodent behavior in complex social settings.

PubMed

Howerton, Christopher L; Garner, Joseph P; Mench, Joy A

2012-07-30

Pre-clinical investigation of human CNS disorders relies heavily on mouse models. However these show low predictive validity for translational success to humans, partly due to the extensive use of rapid, high-throughput behavioral assays. Improved assays to monitor rodent behavior over longer time scales in a variety of contexts while still maintaining the efficiency of data collection associated with high-throughput assays are needed. We developed an apparatus that uses radio frequency identification device (RFID) technology to facilitate long-term automated monitoring of the behavior of mice in socially or structurally complex cage environments. Mice that were individually marked and implanted with transponders were placed in pairs in the apparatus, and their locations continuously tracked for 24 h. Video observation was used to validate the RFID readings. The apparatus and its associated software accurately tracked the locations of all mice, yielding information about each mouse's location over time, its diel activity patterns, and the amount of time it was in the same location as the other mouse in the pair. The information that can be efficiently collected in this apparatus has a variety of applications for pre-clinical research on human CNS disorders, for example major depressive disorder and autism spectrum disorder, in that it can be used to quantify validated endophenotypes or biomarkers of these disorders using rodent models. While the specific configuration of the apparatus described here was designed to answer particular experimental questions, it can be modified in various ways to accommodate different experimental designs. Copyright © 2012 Elsevier B.V. All rights reserved.

Comparative Genomic Analyses of the Human NPHP1 Locus Reveal Complex Genomic Architecture and Its Regional Evolution in Primates

PubMed Central

Yuan, Bo; Liu, Pengfei; Gupta, Aditya; Beck, Christine R.; Tejomurtula, Anusha; Campbell, Ian M.; Gambin, Tomasz; Simmons, Alexandra D.; Withers, Marjorie A.; Harris, R. Alan; Rogers, Jeffrey; Schwartz, David C.; Lupski, James R.

2015-01-01

Many loci in the human genome harbor complex genomic structures that can result in susceptibility to genomic rearrangements leading to various genomic disorders. Nephronophthisis 1 (NPHP1, MIM# 256100) is an autosomal recessive disorder that can be caused by defects of NPHP1; the gene maps within the human 2q13 region where low copy repeats (LCRs) are abundant. Loss of function of NPHP1 is responsible for approximately 85% of the NPHP1 cases—about 80% of such individuals carry a large recurrent homozygous NPHP1 deletion that occurs via nonallelic homologous recombination (NAHR) between two flanking directly oriented ~45 kb LCRs. Published data revealed a non-pathogenic inversion polymorphism involving the NPHP1 gene flanked by two inverted ~358 kb LCRs. Using optical mapping and array-comparative genomic hybridization, we identified three potential novel structural variant (SV) haplotypes at the NPHP1 locus that may protect a haploid genome from the NPHP1 deletion. Inter-species comparative genomic analyses among primate genomes revealed massive genomic changes during evolution. The aggregated data suggest that dynamic genomic rearrangements occurred historically within the NPHP1 locus and generated SV haplotypes observed in the human population today, which may confer differential susceptibility to genomic instability and the NPHP1 deletion within a personal genome. Our study documents diverse SV haplotypes at a complex LCR-laden human genomic region. Comparative analyses provide a model for how this complex region arose during primate evolution, and studies among humans suggest that intra-species polymorphism may potentially modulate an individual’s susceptibility to acquiring disease-associated alleles. PMID:26641089

Making the invisible visible.

PubMed

van Steensel, Maurice A M

2016-04-01

In this review, I will discuss how careful scrutiny of genetic skin disorders could help us to understand human biology. Like other organs, the skin and its appendages, such as hairs and teeth, experience fundamental biological processes ranging from lipid metabolism to vesicular transport and cellular migration. However, in contrast to other organ systems, they are accessible and can be studied with relative ease. By visually revealing the functional consequences of single gene defects, genetic skin diseases offer a unique opportunity to study human biology. Here, I will illustrate this concept by discussing how human genetic disorders of skin pigmentation reflect the mechanisms underlying this complex and vital process. Copyright © 2016 Elsevier Ltd. All rights reserved.

From neural development to cognition: unexpected roles for chromatin

PubMed Central

Ronan, Jehnna L.; Wu, Wei

2014-01-01

Recent genome-sequencing studies in human neurodevelopmental and psychiatric disorders have uncovered mutations in many chromatin regulators. These human genetic studies, along with studies in model organisms, are providing insight into chromatin regulatory mechanisms in neural development and how alterations to these mechanisms can cause cognitive deficits, such as intellectual disability. We discuss several implicated chromatin regulators, including BAF (also known as SWI/SNF) and CHD8 chromatin remodellers, HDAC4 and the Polycomb component EZH2. Interestingly, mutations in EZH2 and certain BAF complex components have roles in both neurodevelopmental disorders and cancer, and overlapping point mutations are suggesting functionally important residues and domains. We speculate on the contribution of these similar mutations to disparate disorders. PMID:23568486

Extreme disorder in an ultrahigh-affinity protein complex

NASA Astrophysics Data System (ADS)

Borgia, Alessandro; Borgia, Madeleine B.; Bugge, Katrine; Kissling, Vera M.; Heidarsson, Pétur O.; Fernandes, Catarina B.; Sottini, Andrea; Soranno, Andrea; Buholzer, Karin J.; Nettels, Daniel; Kragelund, Birthe B.; Best, Robert B.; Schuler, Benjamin

2018-03-01

Molecular communication in biology is mediated by protein interactions. According to the current paradigm, the specificity and affinity required for these interactions are encoded in the precise complementarity of binding interfaces. Even proteins that are disordered under physiological conditions or that contain large unstructured regions commonly interact with well-structured binding sites on other biomolecules. Here we demonstrate the existence of an unexpected interaction mechanism: the two intrinsically disordered human proteins histone H1 and its nuclear chaperone prothymosin-α associate in a complex with picomolar affinity, but fully retain their structural disorder, long-range flexibility and highly dynamic character. On the basis of closely integrated experiments and molecular simulations, we show that the interaction can be explained by the large opposite net charge of the two proteins, without requiring defined binding sites or interactions between specific individual residues. Proteome-wide sequence analysis suggests that this interaction mechanism may be abundant in eukaryotes.

SKIV2L Mutations Cause Syndromic Diarrhea, or Trichohepatoenteric Syndrome

PubMed Central

Fabre, Alexandre; Charroux, Bernard; Martinez-Vinson, Christine; Roquelaure, Bertrand; Odul, Egritas; Sayar, Ersin; Smith, Hilary; Colomb, Virginie; Andre, Nicolas; Hugot, Jean-Pierre; Goulet, Olivier; Lacoste, Caroline; Sarles, Jacques; Royet, Julien; Levy, Nicolas; Badens, Catherine

2012-01-01

Syndromic diarrhea (or trichohepatoenteric syndrome) is a rare congenital bowel disorder characterized by intractable diarrhea and woolly hair, and it has recently been associated with mutations in TTC37. Although databases report TTC37 as being the human ortholog of Ski3p, one of the yeast Ski-complex cofactors, this lead was not investigated in initial studies. The Ski complex is a multiprotein complex required for exosome-mediated RNA surveillance, including the regulation of normal mRNA and the decay of nonfunctional mRNA. Considering the fact that TTC37 is homologous to Ski3p, we explored a gene encoding another Ski-complex cofactor, SKIV2L, in six individuals presenting with typical syndromic diarrhea without variation in TTC37. We identified mutations in all six individuals. Our results show that mutations in genes encoding cofactors of the human Ski complex cause syndromic diarrhea, establishing a link between defects of the human exosome complex and a Mendelian disease. PMID:22444670

Current Applications of Chromatographic Methods in the Study of Human Body Fluids for Diagnosing Disorders.

PubMed

Jóźwik, Jagoda; Kałużna-Czaplińska, Joanna

2016-01-01

Currently, analysis of various human body fluids is one of the most essential and promising approaches to enable the discovery of biomarkers or pathophysiological mechanisms for disorders and diseases. Analysis of these fluids is challenging due to their complex composition and unique characteristics. Development of new analytical methods in this field has made it possible to analyze body fluids with higher selectivity, sensitivity, and precision. The composition and concentration of analytes in body fluids are most often determined by chromatography-based techniques. There is no doubt that proper use of knowledge that comes from a better understanding of the role of body fluids requires the cooperation of scientists of diverse specializations, including analytical chemists, biologists, and physicians. This article summarizes current knowledge about the application of different chromatographic methods in analyses of a wide range of compounds in human body fluids in order to diagnose certain diseases and disorders.

Structural Basis for Inactivation of the Human Pyruvate Dehydrogenase Complex by Phosphorylation: Role of Disordered Phosphorylation Loops

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

Kato, Masato; Wynn, R. Max; Chuang, Jacinta L.

2009-09-11

We report the crystal structures of the phosporylated pyruvate dehydrogenase (E1p) component of the human pyruvate dehydrogenase complex (PDC). The complete phosphorylation at Ser264-{alpha} (site 1) of a variant E1p protein was achieved using robust pyruvate dehydrogenase kinase 4 free of the PDC core. We show that unlike its unmodified counterpart, the presence of a phosphoryl group at Ser264-{alpha} prevents the cofactor thiamine diphosphate-induced ordering of the two loops carrying the three phosphorylation sites. The disordering of these phosphorylation loops is caused by a previously unrecognized steric clash between the phosphoryl group at site 1 and a nearby Ser266-{alpha}, whichmore » nullifies a hydrogen-bonding network essential for maintaining the loop conformations. The disordered phosphorylation loops impede the binding of lipoyl domains of the PDC core to E1p, negating the reductive acetylation step. This results in the disruption of the substrate channeling in the PDC, leading to the inactivation of this catalytic machine.« less

Regulating the chromatin landscape: structural and mechanistic perspectives.

PubMed

Bartholomew, Blaine

2014-01-01

A large family of chromatin remodelers that noncovalently modify chromatin is crucial in cell development and differentiation. They are often the targets of cancer, neurological disorders, and other human diseases. These complexes alter nucleosome positioning, higher-order chromatin structure, and nuclear organization. They also assemble chromatin, exchange out histone variants, and disassemble chromatin at defined locations. We review aspects of the structural organization of these complexes, the functional properties of their protein domains, and variation between complexes. We also address the mechanistic details of these complexes in mobilizing nucleosomes and altering chromatin structure. A better understanding of these issues will be vital for further analyses of subunits of these chromatin remodelers, which are being identified as targets in human diseases by NGS (next-generation sequencing).

Pharmacological NAD-Boosting Strategies Improve Mitochondrial Homeostasis in Human Complex I-Mutant Fibroblasts.

PubMed

Felici, Roberta; Lapucci, Andrea; Cavone, Leonardo; Pratesi, Sara; Berlinguer-Palmini, Rolando; Chiarugi, Alberto

2015-06-01

Mitochondrial disorders are devastating genetic diseases for which efficacious therapies are still an unmet need. Recent studies report that increased availability of intracellular NAD obtained by inhibition of the NAD-consuming enzyme poly(ADP-ribose) polymerase (PARP)-1 or supplementation with the NAD-precursor nicotinamide riboside (NR) ameliorates energetic derangement and symptoms in mouse models of mitochondrial disorders. Whether these pharmacological approaches also improve bioenergetics of human cells harboring mitochondrial defects is unknown. It is also unclear whether the same signaling cascade is prompted by PARP-1 inhibitors and NR supplementation to improve mitochondrial homeostasis. Here, we show that human fibroblasts mutant for the NADH dehydrogenase (ubiquinone) Fe-S protein 1 (NDUFS1) subunit of respiratory complex I have similar ATP, NAD, and mitochondrial content compared with control cells, but show reduced mitochondrial membrane potential. Interestingly, mutant cells also show increased transcript levels of mitochondrial DNA but not nuclear DNA respiratory complex subunits, suggesting activation of a compensatory response. At variance with prior work in mice, however, NR supplementation, but not PARP-1 inhibition, increased intracellular NAD content in NDUFS1 mutant human fibroblasts. Conversely, PARP-1 inhibitors, but not NR supplementation, increased transcription of mitochondrial transcription factor A and mitochondrial DNA-encoded respiratory complexes constitutively induced in mutant cells. Still, both NR and PARP-1 inhibitors restored mitochondrial membrane potential and increased organelle content as well as oxidative activity of NDUFS1-deficient fibroblasts. Overall, data provide the first evidence that in human cells harboring a mitochondrial respiratory defect exposure to NR or PARP-1, inhibitors activate different signaling pathways that are not invariantly prompted by NAD increases, but equally able to improve energetic derangement. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

The Stakeholder Model of voice research: Acknowledging barriers to human rights of all stakeholders in a communicative exchange.

PubMed

Madill, Catherine; Warhurst, Samantha; McCabe, Patricia

2018-02-01

The act of communication is a complex, transient and often abstract phenomenon that involves many stakeholders, each of whom has their own perspective: the speaker, the listener, the observer and the researcher. Current research practices in voice disorder are frequently framed through a single lens - that of the researcher/clinician or their participant/patient. This single lens approach risks overlooking significant barriers to the basic human right of freedom of expression for those with a voice disorder as it omits consideration of the impact of voice disorder on the listener, and consideration of the wider impact of the voice in the occupational context. Recent research in the area of voice has developed a multiple lens and subsequent Stakeholder Model that acknowledges the experience and reality of multiple stakeholders viewing the same phenomenon, the voice. This research paradigm is built on Article 19 of the Universal Declaration of Human Rights as it considers the realities of all stakeholders in forming a deeper understanding of the causality, impact and aspects of communication disorder. The Stakeholder Model will be presented as a suggestion for future investigations of communication disorders more widely.

Snakes, evolution, behavior systems, and autism spectrum disorder. Comment on: ;Implications of the idea of neurodiversity for understanding the origins of developmental disorders; by Nobuo Masataka

NASA Astrophysics Data System (ADS)

Burghardt, Gordon M.

2017-03-01

Nobuo Masataka [1] has provided a novel and ambitious approach to understanding variations in mental and neural functioning in humans by embedding them in the concept of neurodiversity. He is particularly interested in Autism Spectrum Disorder (ASD) and views it as on a continuum falling within normal human behavioral variation. If this is true and ASD has been maintained in a population by selection, then, he argues, ASD individuals may have had survival advantages during the EEA (environment of evolutionary adaptiveness), before the advent of large and complex societies. After this point, properly interpreting and responding to social and global cues gained importance at the expense of detailed feature based processing of nonsocial features of the environment.

The evolution of the search for novel genes in mammalian sex determination: from mice to men.

PubMed

Arboleda, Valerie A; Vilain, Eric

2011-01-01

Disorders of sex determination are a genetically heterogeneous group of rare disorders, presenting with sex-specific phenotypes and variable expressivity. Prior to the advent of the Human Genome Project, the identification of novel mammalian sex determination genes was hindered by the rarity of disorders of sex determination and small family sizes that made traditional linkage approaches difficult, if not impossible. This article reviews the revolutionary role of the Human Genome Project in the history of sex determination research and highlights the important role of inbred mouse models in elucidating the role of identified sex determination genes in mammalian sex determination. Next generation sequencing technologies has made it possible to sequence complete human genomes or exomes for the purpose of providing a genetic diagnosis to more patients with unexplained disorders of sex determination and identifying novel sex determination genes. However, beyond novel gene discovery, these tools have the power to inform us on more intricate and complex regulation-taking place within the heterogeneous cells that make up the testis and ovary. Copyright © 2011 Elsevier Inc. All rights reserved.

Physical biology of human brain development.

PubMed

Budday, Silvia; Steinmann, Paul; Kuhl, Ellen

2015-01-01

Neurodevelopment is a complex, dynamic process that involves a precisely orchestrated sequence of genetic, environmental, biochemical, and physical events. Developmental biology and genetics have shaped our understanding of the molecular and cellular mechanisms during neurodevelopment. Recent studies suggest that physical forces play a central role in translating these cellular mechanisms into the complex surface morphology of the human brain. However, the precise impact of neuronal differentiation, migration, and connection on the physical forces during cortical folding remains unknown. Here we review the cellular mechanisms of neurodevelopment with a view toward surface morphogenesis, pattern selection, and evolution of shape. We revisit cortical folding as the instability problem of constrained differential growth in a multi-layered system. To identify the contributing factors of differential growth, we map out the timeline of neurodevelopment in humans and highlight the cellular events associated with extreme radial and tangential expansion. We demonstrate how computational modeling of differential growth can bridge the scales-from phenomena on the cellular level toward form and function on the organ level-to make quantitative, personalized predictions. Physics-based models can quantify cortical stresses, identify critical folding conditions, rationalize pattern selection, and predict gyral wavelengths and gyrification indices. We illustrate that physical forces can explain cortical malformations as emergent properties of developmental disorders. Combining biology and physics holds promise to advance our understanding of human brain development and enable early diagnostics of cortical malformations with the ultimate goal to improve treatment of neurodevelopmental disorders including epilepsy, autism spectrum disorders, and schizophrenia.

Hyperphagia and Obesity in Prader⁻Willi Syndrome: PCSK1 Deficiency and Beyond?

PubMed

Ramos-Molina, Bruno; Molina-Vega, María; Fernández-García, José C; Creemers, John W

2018-06-07

Prader⁻Willi syndrome (PWS) is a complex genetic disorder that, besides cognitive impairments, is characterized by hyperphagia, obesity, hypogonadism, and growth impairment. Proprotein convertase subtilisin/kexin type 1 ( PCSK1 ) deficiency, a rare recessive congenital disorder, partially overlaps phenotypically with PWS, but both genetic disorders show clear dissimilarities as well. The recent observation that PCSK1 is downregulated in a model of human PWS suggests that overlapping pathways are affected. In this review we will not only discuss the mechanisms by which PWS and PCSK1 deficiency could lead to hyperphagia but also the therapeutic interventions to treat obesity in both genetic disorders.

Toward developmental models of psychiatric disorders in zebrafish

PubMed Central

Norton, William H. J.

2013-01-01

Psychiatric disorders are a diverse set of diseases that affect all aspects of mental function including social interaction, thinking, feeling, and mood. Although psychiatric disorders place a large economic burden on society, the drugs available to treat them are often palliative with variable efficacy and intolerable side-effects. The development of novel drugs has been hindered by a lack of knowledge about the etiology of these diseases. It is thus necessary to further investigate psychiatric disorders using a combination of human molecular genetics, gene-by-environment studies, in vitro pharmacological and biochemistry experiments, animal models, and investigation of the non-biological basis of these diseases, such as environmental effects. Many psychiatric disorders, including autism spectrum disorder, attention-deficit/hyperactivity disorder, mental retardation, and schizophrenia can be triggered by alterations to neural development. The zebrafish is a popular model for developmental biology that is increasingly used to study human disease. Recent work has extended this approach to examine psychiatric disorders as well. However, since psychiatric disorders affect complex mental functions that might be human specific, it is not possible to fully model them in fish. In this review, I will propose that the suitability of zebrafish for developmental studies, and the genetic tools available to manipulate them, provide a powerful model to study the roles of genes that are linked to psychiatric disorders during neural development. The relative speed and ease of conducting experiments in zebrafish can be used to address two areas of future research: the contribution of environmental factors to disease onset, and screening for novel therapeutic compounds. PMID:23637652

Understanding Neurodevelopmental Disorders: The Promise of Regulatory Variation in the 3'UTRome.

PubMed

Wanke, Kai A; Devanna, Paolo; Vernes, Sonja C

2018-04-01

Neurodevelopmental disorders have a strong genetic component, but despite widespread efforts, the specific genetic factors underlying these disorders remain undefined for a large proportion of affected individuals. Given the accessibility of exome sequencing, this problem has thus far been addressed from a protein-centric standpoint; however, protein-coding regions only make up ∼1% to 2% of the human genome. With the advent of whole genome sequencing we are in the midst of a paradigm shift as it is now possible to interrogate the entire sequence of the human genome (coding and noncoding) to fill in the missing heritability of complex disorders. These new technologies bring new challenges, as the number of noncoding variants identified per individual can be overwhelming, making it prudent to focus on noncoding regions of known function, for which the effects of variation can be predicted and directly tested to assess pathogenicity. The 3'UTRome is a region of the noncoding genome that perfectly fulfills these criteria and is of high interest when searching for pathogenic variation related to complex neurodevelopmental disorders. Herein, we review the regulatory roles of the 3'UTRome as binding sites for microRNAs or RNA binding proteins, or during alternative polyadenylation. We detail existing evidence that these regions contribute to neurodevelopmental disorders and outline strategies for identification and validation of novel putatively pathogenic variation in these regions. This evidence suggests that studying the 3'UTRome will lead to the identification of new risk factors, new candidate disease genes, and a better understanding of the molecular mechanisms contributing to neurodevelopmental disorders. Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Multilevel Analysis in Analyzing Speech Data

ERIC Educational Resources Information Center

Guddattu, Vasudeva; Krishna, Y.

2011-01-01

The speech produced by human vocal tract is a complex acoustic signal, with diverse applications in phonetics, speech synthesis, automatic speech recognition, speaker identification, communication aids, speech pathology, speech perception, machine translation, hearing research, rehabilitation and assessment of communication disorders and many…

Genetic aspects of autism spectrum disorders: insights from animal models

PubMed Central

Banerjee, Swati; Riordan, Maeveen; Bhat, Manzoor A.

2014-01-01

Autism spectrum disorders (ASDs) are a complex neurodevelopmental disorder that display a triad of core behavioral deficits including restricted interests, often accompanied by repetitive behavior, deficits in language and communication, and an inability to engage in reciprocal social interactions. ASD is among the most heritable disorders but is not a simple disorder with a singular pathology and has a rather complex etiology. It is interesting to note that perturbations in synaptic growth, development, and stability underlie a variety of neuropsychiatric disorders, including ASD, schizophrenia, epilepsy, and intellectual disability. Biological characterization of an increasing repertoire of synaptic mutants in various model organisms indicates synaptic dysfunction as causal in the pathophysiology of ASD. Our understanding of the genes and genetic pathways that contribute toward the formation, stabilization, and maintenance of functional synapses coupled with an in-depth phenotypic analysis of the cellular and behavioral characteristics is therefore essential to unraveling the pathogenesis of these disorders. In this review, we discuss the genetic aspects of ASD emphasizing on the well conserved set of genes and genetic pathways implicated in this disorder, many of which contribute to synapse assembly and maintenance across species. We also review how fundamental research using animal models is providing key insights into the various facets of human ASD. PMID:24605088

Drosophila and experimental neurology in the post-genomic era.

PubMed

Shulman, Joshua M

2015-12-01

For decades, the fruit fly, Drosophila melanogaster, has been among the premiere genetic model systems for probing fundamental neurobiology, including elucidation of mechanisms responsible for human neurologic disorders. Flies continue to offer virtually unparalleled versatility and speed for genetic manipulation, strong genomic conservation, and a nervous system that recapitulates a range of cellular and network properties relevant to human disease. I focus here on four critical challenges emerging from recent advances in our understanding of the genomic basis of human neurologic disorders where innovative experimental strategies are urgently needed: (1) pinpointing causal genes from associated genomic loci; (2) confirming the functional impact of allelic variants; (3) elucidating nervous system roles for novel or poorly studied genes; and (4) probing network interactions within implicated regulatory pathways. Drosophila genetic approaches are ideally suited to address each of these potential translational roadblocks, and will therefore contribute to mechanistic insights and potential breakthrough therapies for complex genetic disorders in the coming years. Strategic collaboration between neurologists, human geneticists, and the Drosophila research community holds great promise to accelerate progress in the post-genomic era. Copyright © 2015 Elsevier Inc. All rights reserved.

The role of research methodology in the rational use of technology in monitoring and preventing communication disorders.

PubMed

Chiari, Brasília M; Goulart, Bárbara N G

2009-09-01

Studies showing stronger scientific evidence related to speech, language and hearing pathology (SLP) have an impact on the prevention and rehabilitation of human communication and gained ground in SLP research agenda. In this paper we discuss some aspects and directions that should be considered for in-depth knowledge about speech, language and hearing needs in different population groups (age group, gender and other variables according to specific related disorders) for improved comprehensive care, successful efforts and effective use of financial and human resources. It is also discussed the decision making process for requesting complementary evaluations and tests, from routine to highly complex ones, that should be based on each test and/or procedure and their contribution to the diagnosis and therapeutic planning. In fact, it is crucial to have reliable parameters for planning, preventing and treating human communication and its related disorders. Epidemiology, biostatistics and social sciences can contribute with more specific information in human communication sciences and guide more specific studies on the international science and technology agenda, improving communication sciences involvement in the international health-related scientific scenario.

The role of sleep problems and circadian clock genes in attention-deficit hyperactivity disorder and mood disorders during childhood and adolescence: an update.

PubMed

Dueck, Alexander; Berger, Christoph; Wunsch, Katharina; Thome, Johannes; Cohrs, Stefan; Reis, Olaf; Haessler, Frank

2017-02-01

A more recent branch of research describes the importance of sleep problems in the development and treatment of mental disorders in children and adolescents, such as attention-deficit hyperactivity disorder (ADHD) and mood disorders (MD). Research about clock genes has continued since 2012 with a focus on metabolic processes within all parts of the mammalian body, but particularly within different cerebral regions. Research has focused on complex regulatory circuits involving clock genes themselves and their influence on circadian rhythms of diverse body functions. Current publications on basic research in human and animal models indicate directions for the treatment of mental disorders targeting circadian rhythms and mechanisms. The most significant lines of research are described in this paper.

The Role of Temperament in the Etiopathogenesis of Bipolar Spectrum Illness.

PubMed

Fountoulakis, Konstantinos N; Gonda, Xenia; Koufaki, Ioanna; Hyphantis, Thomas; Cloninger, C Robert

2016-01-01

Bipolar disorder constitutes a challenge for clinicians in everyday clinical practice. Our knowledge concerning this clinical entity is incomplete, and contemporary classification systems are unable to reflect the complexity of this disorder. The concept of temperament, which was first described in antiquity, provides a helpful framework for synthesizing our knowledge on how the human body works and what determines human behavior. Although the concept of temperament originally included philosophical and sociocultural approaches, the biomedical model is dominant today. It is possible that specific temperaments might constitute vulnerability factors, determine the clinical picture, or modify the course of illness. Temperaments might even act as a bridge between genes and clinical manifestations, thus giving rise to the concept of the bipolar spectrum, with major implications for mental health research and treatment. More specifically, it has been reported that the hyperthymic and the depressive temperaments are related to the more "classic" bipolar disorder, whereas cyclothymic, anxious, and irritable temperaments are related to more complex manifestations and might predict poor response to treatment, violent or suicidal behavior, and high comorbidity. Incorporating of the concept of temperament and the bipolar spectrum into the standard training of psychiatric residents might well result in an improvement of everyday clinical practice.

Endocannabinoid Signaling in Autism.

PubMed

Chakrabarti, Bhismadev; Persico, Antonio; Battista, Natalia; Maccarrone, Mauro

2015-10-01

Autism spectrum disorder (ASD) is a complex behavioral condition with onset during early childhood and a lifelong course in the vast majority of cases. To date, no behavioral, genetic, brain imaging, or electrophysiological test can specifically validate a clinical diagnosis of ASD. However, these medical procedures are often implemented in order to screen for syndromic forms of the disorder (i.e., autism comorbid with known medical conditions). In the last 25 years a good deal of information has been accumulated on the main components of the "endocannabinoid (eCB) system", a rather complex ensemble of lipid signals ("endocannabinoids"), their target receptors, purported transporters, and metabolic enzymes. It has been clearly documented that eCB signaling plays a key role in many human health and disease conditions of the central nervous system, thus opening the avenue to the therapeutic exploitation of eCB-oriented drugs for the treatment of psychiatric, neurodegenerative, and neuroinflammatory disorders. Here we present a modern view of the eCB system, and alterations of its main components in human patients and animal models relevant to ASD. This review will thus provide a critical perspective necessary to explore the potential exploitation of distinct elements of eCB system as targets of innovative therapeutics against ASD.

Refining psychiatric genetics: from ‘mouse psychiatry’ to understanding complex human disorders

PubMed Central

LaPorte, Justin L.; Ren-Patterson, Renee F.; Murphy, Dennis L.; Kalueff, Allan V.

2009-01-01

Investigating the pathogenesis of psychiatric disorders is a complicated and rigorous task for psychiatric geneticists, as the disorders often involve combinations of genetic, behavioral, personality, and environmental factors. To nurture further progress in this field, a new set of conceptual tools is needed in addition to the currently accepted approaches. Concepts that consider cross-species trait genetics and the interplay between the domains of disorders, as well as the full spectrum of potential symptoms and their place along the pathogenetic continuum, are particularly important to address these needs. Here, we outline recent concepts and approaches that can help refine the field and enable more precise dissection of the genetic mechanisms contributing to psychiatric disorders. PMID:18690099

Narcolepsy: Autoimmunity, Effector T Cell Activation Due to Infection, or T Cell Independent, Major Histocompatibility Complex Class II Induced Neuronal Loss?

ERIC Educational Resources Information Center

Fontana, Adriano; Gast, Heidemarie; Reith, Walter; Recher, Mike; Birchler, Thomas; Bassetti, Claudio L.

2010-01-01

Human narcolepsy with cataplexy is a neurological disorder, which develops due to a deficiency in hypocretin producing neurons in the hypothalamus. There is a strong association with human leucocyte antigens HLA-DR2 and HLA-DQB1*0602. The disease typically starts in adolescence. Recent developments in narcolepsy research support the hypothesis of…

Two-dimensional infrared spectroscopy reveals the complex behaviour of an amyloid fibril inhibitor

NASA Astrophysics Data System (ADS)

Middleton, Chris T.; Marek, Peter; Cao, Ping; Chiu, Chi-Cheng; Singh, Sadanand; Woys, Ann Marie; de Pablo, Juan J.; Raleigh, Daniel P.; Zanni, Martin T.

2012-05-01

Amyloid formation has been implicated in the pathology of over 20 human diseases, but the rational design of amyloid inhibitors is hampered by a lack of structural information about amyloid-inhibitor complexes. We use isotope labelling and two-dimensional infrared spectroscopy to obtain a residue-specific structure for the complex of human amylin (the peptide responsible for islet amyloid formation in type 2 diabetes) with a known inhibitor (rat amylin). Based on its sequence, rat amylin should block formation of the C-terminal β-sheet, but at 8 h after mixing, rat amylin blocks the N-terminal β-sheet instead. At 24 h after mixing, rat amylin blocks neither β-sheet and forms its own β-sheet, most probably on the outside of the human fibrils. This is striking, because rat amylin is natively disordered and not previously known to form amyloid β-sheets. The results show that even seemingly intuitive inhibitors may function by unforeseen and complex structural processes.

Call for participation in the neurogenetics consortium within the Human Variome Project.

PubMed

Haworth, Andrea; Bertram, Lars; Carrera, Paola; Elson, Joanna L; Braastad, Corey D; Cox, Diane W; Cruts, Marc; den Dunnen, Johann T; Farrer, Matthew J; Fink, John K; Hamed, Sherifa A; Houlden, Henry; Johnson, Dennis R; Nuytemans, Karen; Palau, Francesc; Rayan, Dipa L Raja; Robinson, Peter N; Salas, Antonio; Schüle, Birgitt; Sweeney, Mary G; Woods, Michael O; Amigo, Jorge; Cotton, Richard G H; Sobrido, Maria-Jesus

2011-08-01

The rate of DNA variation discovery has accelerated the need to collate, store and interpret the data in a standardised coherent way and is becoming a critical step in maximising the impact of discovery on the understanding and treatment of human disease. This particularly applies to the field of neurology as neurological function is impaired in many human disorders. Furthermore, the field of neurogenetics has been proven to show remarkably complex genotype-to-phenotype relationships. To facilitate the collection of DNA sequence variation pertaining to neurogenetic disorders, we have initiated the "Neurogenetics Consortium" under the umbrella of the Human Variome Project. The Consortium's founding group consisted of basic researchers, clinicians, informaticians and database creators. This report outlines the strategic aims established at the preliminary meetings of the Neurogenetics Consortium and calls for the involvement of the wider neurogenetic community in enabling the development of this important resource.

"The role of oxytocin in psychiatric disorders: A review of biological and therapeutic research findings"

PubMed Central

Cochran, David; Fallon, Daniel; Hill, Michael; Frazier, Jean A.

2014-01-01

Oxytocin is a peptide hormone integral in parturition, milk let-down, and maternal behaviors that has been demonstrated in animal studies to be important in the formation of pair bonds and in social behaviors. This hormone is increasingly recognized as an important regulator of human social behaviors, including social decision making, evaluating and responding to social stimuli, mediating social interactions, and forming social memories. In addition, oxytocin is intricately involved in a broad array of neuropsychiatric functions, and may be a common factor important in multiple psychiatric disorders such as autism, schizophrenia, mood and anxiety disorders. This review article examines the extant literature on the evidence for oxytocin dysfunction in a variety of psychiatric disorders and highlights the need for further research to understand the complex role of the oxytocin system in psychiatric disease to pave the way for developing new therapeutic modalities. Articles were selected that involved human participants with various psychiatric disorders, either comparing oxytocin biology to healthy controls or examining the effects of exogenous oxytocin administration. PMID:24651556

Mitochondrial Translation and Beyond: Processes Implicated in Combined Oxidative Phosphorylation Deficiencies

PubMed Central

Smits, Paulien; Smeitink, Jan; van den Heuvel, Lambert

2010-01-01

Mitochondrial disorders are a heterogeneous group of often multisystemic and early fatal diseases, which are amongst the most common inherited human diseases. These disorders are caused by defects in the oxidative phosphorylation (OXPHOS) system, which comprises five multisubunit enzyme complexes encoded by both the nuclear and the mitochondrial genomes. Due to the multitude of proteins and intricacy of the processes required for a properly functioning OXPHOS system, identifying the genetic defect that underlies an OXPHOS deficiency is not an easy task, especially in the case of combined OXPHOS defects. In the present communication we give an extensive overview of the proteins and processes (in)directly involved in mitochondrial translation and the biogenesis of the OXPHOS system and their roles in combined OXPHOS deficiencies. This knowledge is important for further research into the genetic causes, with the ultimate goal to effectively prevent and cure these complex and often devastating disorders. PMID:20396601

Genetics and Genomics of Single-Gene Cardiovascular Diseases: Common Hereditary Cardiomyopathies as Prototypes of Single-Gene Disorders

PubMed Central

Marian, Ali J.; van Rooij, Eva; Roberts, Robert

2016-01-01

This is the first of 2 review papers on genetics and genomics appearing as part of the series on “omics.” Genomics pertains to all components of an organism’s genes, whereas genetics involves analysis of a specific gene(s) in the context of heredity. The paper provides introductory comments, describes the basis of human genetic diversity, and addresses the phenotypic consequences of genetic variants. Rare variants with large effect sizes are responsible for single-gene disorders, whereas complex polygenic diseases are typically due to multiple genetic variants, each exerting a modest effect size. To illustrate the clinical implications of genetic variants with large effect sizes, 3 common forms of hereditary cardiomyopathies are discussed as prototypic examples of single-gene disorders, including their genetics, clinical manifestations, pathogenesis, and treatment. The genetic basis of complex traits is discussed in a separate paper. PMID:28007145

Topology and Oligomerization of Mono- and Oligomeric Proteins Regulate Their Half-Lives in the Cell.

PubMed

Mallik, Saurav; Kundu, Sudip

2018-06-05

To find additional structural constraints (besides disordered segments) that regulate protein half-life in the cell, we herein assess the influence of native topology of monomeric and sequestration of oligomeric proteins into multimeric complexes in yeast, human, and mouse. Native topology acts as a molecular marker of globular protein's mechanical resistance and consequently captures their half-life variations on genome scale. Sequestration into multimeric complexes elongates oligomeric protein half-life in the cell, presumably by burying ubiquitinoylation sites and disordered segments required for proteasomal recognition. The latter effect is stronger for proteins associated with multiple complexes and for those binding early during complex self-assembly, including proteins that oligomerize with large proportions of surface buried. After gene duplication, diversification of topology and sequestration into non-identical sets of complexes alter half-lives of paralogous proteins during the course of evolution. Thus, native topology and sequestration into multimeric complexes reflect designing principles of proteins to regulate their half-lives. Copyright © 2018 Elsevier Ltd. All rights reserved.

The determination factors of left-right asymmetry disorders- a short review.

PubMed

Catana, Andreea; Apostu, Adina Patricia

2017-01-01

Laterality defects in humans, situs inversus and heterotaxy, are rare disorders, with an incidence of 1:8000 to 1:10 000 in the general population, and a multifactorial etiology. It has been proved that 1.44/10 000 of all cardiac problems are associated with malformations of left-right asymmetry and heterotaxy accounts for 3% of all congenital heart defects. It is considered that defects of situs appear due to genetic and environmental factors. Also, there is evidence that the ciliopathies (defects of structure or function) are involved in development abnormalities. Over 100 genes have been reported to be involved in left-right patterning in model organisms, but only a few are likely to candidate for left-right asymmetry defects in humans. Left-right asymmetry disorders are genetically heterogeneous and have variable manifestations (from asymptomatic to serious clinical problems). The discovery of the right mechanism of left-right development will help explain the clinical complexity and may contribute to a therapy of these disorders.

Clinical Implications of Basic Science Discoveries: Immune Homeostasis and the Microbiome-Dietary and Therapeutic Modulation and Implications for Transplantation.

PubMed

Fishman, J A; Thomson, A W

2015-07-01

Links between the human microbiome and the innate and adaptive immune systems and their impact on autoimmune and inflammatory diseases are only beginning to be recognized. Characterization of the complex human microbial community is facilitated by culture-independent nucleic acid sequencing tools and bioinformatics systems. Specific organisms and microbial antigens are linked with initiation of innate immune responses that, depending on the context, may be associated with tolerogenic or effector immune responses. Further complexity is introduced by preclinical data that demonstrate the impacts of dietary manipulation on the prevention of genetically determined, systemic autoimmune disorders and on gastrointestinal microbiota. Investigation of interactions of complex microbial populations with the human immune system may provide new targets for clinical management in allotransplantation. © Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.

Principles and Practices of Neurodevelopmental Assessment in Children: Lessons Learned from the Centers for Children’s Environmental Health and Disease Prevention Research

PubMed Central

Dietrich, Kim N.; Eskenazi, Brenda; Schantz, Susan; Yolton, Kimberly; Rauh, Virginia A.; Johnson, Caroline B.; Alkon, Abbey; Canfield, Richard L.; Pessah, Isaac N.; Berman, Robert F.

2005-01-01

Principles and practices of pediatric neurotoxicology are reviewed here with the purpose of guiding the design and execution of the planned National Children’s Study. The developing human central nervous system is the target organ most vulnerable to environmental chemicals. An investigation of the effects of environmental exposures on child development is a complex endeavor that requires consideration of numerous critical factors pertinent to a study’s concept, design, and execution. These include the timing of neurodevelopmental assessment, matters of biologic plausibility, site, child and population factors, data quality assurance and control, the selection of appropriate domains and measures of neurobehavior, and data safety and monitoring. Here we summarize instruments for the assessment of the neonate, infant, and child that are being employed in the Centers for Children’s Environmental Health and Disease Prevention Research, sponsored by the National Institute of Environmental Health Sciences and the U.S. Environmental Protection Agency, discuss neural and neurobiologic measures of development, and consider the promises of gene–environment studies. The vulnerability of the human central nervous system to environmental chemicals has been well established, but the contribution these exposures may make to problems such as attention deficit disorder, conduct problems, pervasive developmental disorder, or autism spectrum disorder remain uncertain. Large-scale studies such as the National Children’s Study may provide some important clues. The human neurodevelopmental phenotype will be most clearly represented in models that include environmental chemical exposures, the social milieu, and complex human genetic characteristics that we are just beginning to understand. PMID:16203260

Significance of genome-wide association studies in molecular anthropology.

PubMed

Gupta, Vipin; Khadgawat, Rajesh; Sachdeva, Mohinder Pal

2009-12-01

The successful advent of a genome-wide approach in association studies raises the hopes of human geneticists for solving a genetic maze of complex traits especially the disorders. This approach, which is replete with the application of cutting-edge technology and supported by big science projects (like Human Genome Project; and even more importantly the International HapMap Project) and various important databases (SNP database, CNV database, etc.), has had unprecedented success in rapidly uncovering many of the genetic determinants of complex disorders. The magnitude of this approach in the genetics of classical anthropological variables like height, skin color, eye color, and other genome diversity projects has certainly expanded the horizons of molecular anthropology. Therefore, in this article we have proposed a genome-wide association approach in molecular anthropological studies by providing lessons from the exemplary study of the Wellcome Trust Case Control Consortium. We have also highlighted the importance and uniqueness of Indian population groups in facilitating the design and finding optimum solutions for other genome-wide association-related challenges.

Concise Review: Progress and Challenges in Using Human Stem Cells for Biological and Therapeutics Discovery: Neuropsychiatric Disorders.

PubMed

Panchision, David M

2016-03-01

In facing the daunting challenge of using human embryonic and induced pluripotent stem cells to study complex neural circuit disorders such as schizophrenia, mood and anxiety disorders, and autism spectrum disorders, a 2012 National Institute of Mental Health workshop produced a set of recommendations to advance basic research and engage industry in cell-based studies of neuropsychiatric disorders. This review describes progress in meeting these recommendations, including the development of novel tools, strides in recapitulating relevant cell and tissue types, insights into the genetic basis of these disorders that permit integration of risk-associated gene regulatory networks with cell/circuit phenotypes, and promising findings of patient-control differences using cell-based assays. However, numerous challenges are still being addressed, requiring further technological development, approaches to resolve disease heterogeneity, and collaborative structures for investigators of different disciplines. Additionally, since data obtained so far is on small sample sizes, replication in larger sample sets is needed. A number of individual success stories point to a path forward in developing assays to translate discovery science to therapeutics development. Published 2016. This article is a U.S. Government work and is in the public domain in the USA.

Genome-wide association studies for the identification of biomarkers in metabolic diseases.

PubMed

Pattin, Kristine A; Moore, Jason H

2010-01-01

The field of genetics as it relates to metabolic disorders such as obesity and type II diabetes is complicated, and along with the medical research community, great strides are being taken to begin to understand the biological and genetic underpinnings of these diseases, with the hope of improving therapeutic, diagnostic and preventive strategies. Although research on metabolic disorders has been continuing for decades, the completion of the Human Genome Project in 2003 and the International HapMap Project in 2005 gave rise to an abundance of research tools, such as genome-wide genotyping, which allow researchers to conduct genome-wide association studies (GWAS) for detecting genetic variants that confer increased or decreased susceptibility to such complex diseases. In this review, the complex nature of metabolic disorders is discussed, specifically obesity and type II diabetes, as well as the limitations of the GWAS as applied to these disorders. While acknowledging limitations of GWAS, it is hoped to provide an insight about how GWAS can be adapted and advantageous in the clinical setting, enhancing prevention, diagnosis and treatment of these diseases. To be able to use the GWAS in a clinical setting is a complex challenge, yet it is hoped that in the future this tool will ultimately allow the development of pharmaceutical options that are capable of targeting the cause of metabolic disorders, not just the symptoms themselves.

brain-coX: investigating and visualising gene co-expression in seven human brain transcriptomic datasets.

PubMed

Freytag, Saskia; Burgess, Rosemary; Oliver, Karen L; Bahlo, Melanie

2017-06-08

The pathogenesis of neurological and mental health disorders often involves multiple genes, complex interactions, as well as brain- and development-specific biological mechanisms. These characteristics make identification of disease genes for such disorders challenging, as conventional prioritisation tools are not specifically tailored to deal with the complexity of the human brain. Thus, we developed a novel web-application-brain-coX-that offers gene prioritisation with accompanying visualisations based on seven gene expression datasets in the post-mortem human brain, the largest such resource ever assembled. We tested whether our tool can correctly prioritise known genes from 37 brain-specific KEGG pathways and 17 psychiatric conditions. We achieved average sensitivity of nearly 50%, at the same time reaching a specificity of approximately 75%. We also compared brain-coX's performance to that of its main competitors, Endeavour and ToppGene, focusing on the ability to discover novel associations. Using a subset of the curated SFARI autism gene collection we show that brain-coX's prioritisations are most similar to SFARI's own curated gene classifications. brain-coX is the first prioritisation and visualisation web-tool targeted to the human brain and can be freely accessed via http://shiny.bioinf.wehi.edu.au/freytag.s/ .

Mapping of Human FOXP2 Enhancers Reveals Complex Regulation.

PubMed

Becker, Martin; Devanna, Paolo; Fisher, Simon E; Vernes, Sonja C

2018-01-01

Mutations of the FOXP2 gene cause a severe speech and language disorder, providing a molecular window into the neurobiology of language. Individuals with FOXP2 mutations have structural and functional alterations affecting brain circuits that overlap with sites of FOXP2 expression, including regions of the cortex, striatum, and cerebellum. FOXP2 displays complex patterns of expression in the brain, as well as in non-neuronal tissues, suggesting that sophisticated regulatory mechanisms control its spatio-temporal expression. However, to date, little is known about the regulation of FOXP2 or the genomic elements that control its expression. Using chromatin conformation capture (3C), we mapped the human FOXP2 locus to identify putative enhancer regions that engage in long-range interactions with the promoter of this gene. We demonstrate the ability of the identified enhancer regions to drive gene expression. We also show regulation of the FOXP2 promoter and enhancer regions by candidate regulators - FOXP family and TBR1 transcription factors. These data point to regulatory elements that may contribute to the temporal- or tissue-specific expression patterns of human FOXP2 . Understanding the upstream regulatory pathways controlling FOXP2 expression will bring new insight into the molecular networks contributing to human language and related disorders.

Mapping of Human FOXP2 Enhancers Reveals Complex Regulation

PubMed Central

Becker, Martin; Devanna, Paolo; Fisher, Simon E.; Vernes, Sonja C.

2018-01-01

Mutations of the FOXP2 gene cause a severe speech and language disorder, providing a molecular window into the neurobiology of language. Individuals with FOXP2 mutations have structural and functional alterations affecting brain circuits that overlap with sites of FOXP2 expression, including regions of the cortex, striatum, and cerebellum. FOXP2 displays complex patterns of expression in the brain, as well as in non-neuronal tissues, suggesting that sophisticated regulatory mechanisms control its spatio-temporal expression. However, to date, little is known about the regulation of FOXP2 or the genomic elements that control its expression. Using chromatin conformation capture (3C), we mapped the human FOXP2 locus to identify putative enhancer regions that engage in long-range interactions with the promoter of this gene. We demonstrate the ability of the identified enhancer regions to drive gene expression. We also show regulation of the FOXP2 promoter and enhancer regions by candidate regulators – FOXP family and TBR1 transcription factors. These data point to regulatory elements that may contribute to the temporal- or tissue-specific expression patterns of human FOXP2. Understanding the upstream regulatory pathways controlling FOXP2 expression will bring new insight into the molecular networks contributing to human language and related disorders. PMID:29515369

Genetic regulation of pituitary gland development in human and mouse.

PubMed

Kelberman, Daniel; Rizzoti, Karine; Lovell-Badge, Robin; Robinson, Iain C A F; Dattani, Mehul T

2009-12-01

Normal hypothalamopituitary development is closely related to that of the forebrain and is dependent upon a complex genetic cascade of transcription factors and signaling molecules that may be either intrinsic or extrinsic to the developing Rathke's pouch. These factors dictate organ commitment, cell differentiation, and cell proliferation within the anterior pituitary. Abnormalities in these processes are associated with congenital hypopituitarism, a spectrum of disorders that includes syndromic disorders such as septo-optic dysplasia, combined pituitary hormone deficiencies, and isolated hormone deficiencies, of which the commonest is GH deficiency. The highly variable clinical phenotypes can now in part be explained due to research performed over the last 20 yr, based mainly on naturally occurring and transgenic animal models. Mutations in genes encoding both signaling molecules and transcription factors have been implicated in the etiology of hypopituitarism, with or without other syndromic features, in mice and humans. To date, mutations in known genes account for a small proportion of cases of hypopituitarism in humans. However, these mutations have led to a greater understanding of the genetic interactions that lead to normal pituitary development. This review attempts to describe the complexity of pituitary development in the rodent, with particular emphasis on those factors that, when mutated, are associated with hypopituitarism in humans.

Chromosomal localization of three repair genes: The xeroderma pigmentosum group C gene and two human homologs of yeast RAD23

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

Spek, P.J. van der; Smit, E.M.E.; Beverloo, H.B.

1994-10-01

The nucleotide excision repair (NER) disorder xeroderma pigmentosum (XP) is characterized by sun (UV) sensitivity, predisposition to skin cancer, and extensive genetic heterogeneity. Recently, we reported the cloning and analysis of three human NER genes, XPC, HHR23A, and HHR23B. The previously cloned XPC gene is involved in the common XP complementation group C, which is defective in excision repair of nontranscribed sequences in the genome. The XPC protein was found to be complexed with the product of HHR23B, one of the two human homologs of the Saccharomyes cerevisiae NER gene RAD23. Here we present the chromosomal localization by in situmore » hybridization using haptenized probes of all three genes. The HHR23A gene was assigned to chromosome 19p13.2. Interestingly, the HHR23B and XPC genes, the product of which forms a tight complex, were found to colocalize on band 3p25.1. Pulsed-field gel electrophoresis revealed that the HHR23B and XPC genes possibly share a MluI restriction fragment of about 625 kb. Potential involvement of the HHR23 genes in human genetic disorders is discussed. 53 refs., 4 figs., 2 tabs.« less

Genetic Regulation of Pituitary Gland Development in Human and Mouse

PubMed Central

Kelberman, Daniel; Rizzoti, Karine; Lovell-Badge, Robin; Robinson, Iain C. A. F.; Dattani, Mehul T.

2009-01-01

Normal hypothalamopituitary development is closely related to that of the forebrain and is dependent upon a complex genetic cascade of transcription factors and signaling molecules that may be either intrinsic or extrinsic to the developing Rathke’s pouch. These factors dictate organ commitment, cell differentiation, and cell proliferation within the anterior pituitary. Abnormalities in these processes are associated with congenital hypopituitarism, a spectrum of disorders that includes syndromic disorders such as septo-optic dysplasia, combined pituitary hormone deficiencies, and isolated hormone deficiencies, of which the commonest is GH deficiency. The highly variable clinical phenotypes can now in part be explained due to research performed over the last 20 yr, based mainly on naturally occurring and transgenic animal models. Mutations in genes encoding both signaling molecules and transcription factors have been implicated in the etiology of hypopituitarism, with or without other syndromic features, in mice and humans. To date, mutations in known genes account for a small proportion of cases of hypopituitarism in humans. However, these mutations have led to a greater understanding of the genetic interactions that lead to normal pituitary development. This review attempts to describe the complexity of pituitary development in the rodent, with particular emphasis on those factors that, when mutated, are associated with hypopituitarism in humans. PMID:19837867

Obstetric nephrology: preeclampsia--the nephrologist's perspective.

PubMed

Umans, Jason G

2012-12-01

Preeclampsia, a common and potentially devastating multisystem disorder unique to human pregnancy, represents a novel form of secondary hypertension with complex renal and systemic effects. Recent translational and clinical research reveals key pathophysiologic contributions due to dysregulation of angiogenic factors and of angiotensin signaling. Despite these insights, there are still difficulties in the clinical definition of preeclampsia and in the diagnosis of women with this disorder. Although recent research suggests the potential for new preventive and treatment strategies, most have not yet been shown ready for clinical use.

SNAP-25 IN NEUROPSYCHIATRIC DISORDERS

PubMed Central

Corradini, Irene; Verderio, Claudia; Sala, Mariaelvina; Wilson, Michael C.; Matteoli, Michela

2009-01-01

SNAP-25 is plasma membrane protein which, together with syntaxin and the synaptic vesicle protein VAMP/synaptobrevin, forms the SNARE docking complex for regulated exocytosis. SNAP-25 also modulates different voltage-gated calcium channels, representing therefore a multifunctional protein that plays essential roles in neurotransmitter release at different steps. Recent genetic studies of human populations and of some mouse models implicate that alterations in SNAP-25 gene structure, expression and/or function may contribute directly to these distinct neuropsychiatric and neurological disorders. PMID:19161380

Carbohydrates and the human gut microbiota.

PubMed

Chassard, Christophe; Lacroix, Christophe

2013-07-01

Due to its scale and its important role in maintaining health, the gut microbiota can be considered as a 'new organ' inside the human body. Many complex carbohydrates are degraded and fermented by the human gut microbiota in the large intestine to both yield basic energy salvage and impact gut health through produced metabolites. This review will focus on the gut microbes and microbial mechanisms responsible for polysaccharides degradation and fermentation in the large intestine. Gut microbes and bacterial metabolites impact the host at many levels, including modulation of inflammation, and glucose and lipid metabolisms. A complex relationship occurs in the intestine between the human gut microbiota, diet and the host. Research on carbohydrates and gut microbiota composition and functionality is fast developing and will open opportunities for prevention and treatment of obesity, diabetes and other related metabolic disorders through manipulation of the gut ecosystem.

Mirror Me: Imitative Responses in Adults with Autism

ERIC Educational Resources Information Center

Schunke, Odette; Schöttle, Daniel; Vettorazzi, Eik; Brandt, Valerie; Kahl, Ursula; Bäumer, Tobias; Ganos, Christos; David, Nicole; Peiker, Ina; Engel, Andreas K; Brass, Marcel; Münchau, Alexander

2016-01-01

Dysfunctions of the human mirror neuron system have been postulated to underlie some deficits in autism spectrum disorders including poor imitative performance and impaired social skills. Using three reaction time experiments addressing mirror neuron system functions under simple and complex conditions, we examined 20 adult autism spectrum…

Recent Advances in the Genetics of Vocal Learning

PubMed Central

Condro, Michael C.; White, Stephanie A.

2015-01-01

Language is a complex communicative behavior unique to humans, and its genetic basis is poorly understood. Genes associated with human speech and language disorders provide some insights, originating with the FOXP2 transcription factor, a mutation in which is the source of an inherited form of developmental verbal dyspraxia. Subsequently, targets of FOXP2 regulation have been associated with speech and language disorders, along with other genes. Here, we review these recent findings that implicate genetic factors in human speech. Due to the exclusivity of language to humans, no single animal model is sufficient to study the complete behavioral effects of these genes. Fortunately, some animals possess subcomponents of language. One such subcomponent is vocal learning, which though rare in the animal kingdom, is shared with songbirds. We therefore discuss how songbird studies have contributed to the current understanding of genetic factors that impact human speech, and support the continued use of this animal model for such studies in the future. PMID:26052371

Convergent functional genomics of psychiatric disorders.

PubMed

Niculescu, Alexander B

2013-10-01

Genetic and gene expression studies, in humans and animal models of psychiatric and other medical disorders, are becoming increasingly integrated. Particularly for genomics, the convergence and integration of data across species, experimental modalities and technical platforms is providing a fit-to-disease way of extracting reproducible and biologically important signal, in contrast to the fit-to-cohort effect and limited reproducibility of human genetic analyses alone. With the advent of whole-genome sequencing and the realization that a major portion of the non-coding genome may contain regulatory variants, Convergent Functional Genomics (CFG) approaches are going to be essential to identify disease-relevant signal from the tremendous polymorphic variation present in the general population. Such work in psychiatry can provide an example of how to address other genetically complex disorders, and in turn will benefit by incorporating concepts from other areas, such as cancer, cardiovascular diseases, and diabetes. © 2013 Wiley Periodicals, Inc.

Immunologic Regulation in Pregnancy: From Mechanism to Therapeutic Strategy for Immunomodulation

PubMed Central

Chen, Shyi-Jou; Liu, Yung-Liang; Sytwu, Huey-Kang

2012-01-01

The immunologic interaction between the fetus and the mother is a paradoxical communication that is regulated by fetal antigen presentation and/or by recognition of and reaction to these antigens by the maternal immune system. There have been significant advances in understanding of abnormalities in the maternal-fetal immunologic relationship in the placental bed that can lead to pregnancy disorders. Moreover, immunologic recognition of pregnancy is vital for the maintenance of gestation, and inadequate recognition of fetal antigens may cause abortion. In this paper, we illustrate the complex immunologic aspects of human reproduction in terms of the role of human leukocyte antigen (HLA), immune cells, cytokines and chemokines, and the balance of immunity in pregnancy. In addition, we review the immunologic processes of human reproduction and the current immunologic therapeutic strategies for pathological disorders of pregnancy. PMID:22110530

Genetic architecture for human aggression: A study of gene-phenotype relationship in OMIM.

PubMed

Zhang-James, Yanli; Faraone, Stephen V

2016-07-01

Genetic studies of human aggression have mainly focused on known candidate genes and pathways regulating serotonin and dopamine signaling and hormonal functions. These studies have taught us much about the genetics of human aggression, but no genetic locus has yet achieved genome-significance. We here present a review based on a paradoxical hypothesis that studies of rare, functional genetic variations can lead to a better understanding of the molecular mechanisms underlying complex multifactorial disorders such as aggression. We examined all aggression phenotypes catalogued in Online Mendelian Inheritance in Man (OMIM), an Online Catalog of Human Genes and Genetic Disorders. We identified 95 human disorders that have documented aggressive symptoms in at least one individual with a well-defined genetic variant. Altogether, we retrieved 86 causal genes. Although most of these genes had not been implicated in human aggression by previous studies, the most significantly enriched canonical pathways had been previously implicated in aggression (e.g., serotonin and dopamine signaling). Our findings provide strong evidence to support the causal role of these pathways in the pathogenesis of aggression. In addition, the novel genes and pathways we identified suggest additional mechanisms underlying the origins of human aggression. Genome-wide association studies with very large samples will be needed to determine if common variants in these genes are risk factors for aggression. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.

Resting-State Functional Connectivity in the Human Connectome Project: Current Status and Relevance to Understanding Psychopathology.

PubMed

Barch, Deanna M

A key tenet of modern psychiatry is that psychiatric disorders arise from abnormalities in brain circuits that support human behavior. Our ability to examine hypotheses around circuit-level abnormalities in psychiatric disorders has been made possible by advances in human neuroimaging technologies. These advances have provided the basis for recent efforts to develop a more complex understanding of the function of brain circuits in health and of their relationship to behavior-providing, in turn, a foundation for our understanding of how disruptions in such circuits contribute to the development of psychiatric disorders. This review focuses on the use of resting-state functional connectivity MRI to assess brain circuits, on the advances generated by the Human Connectome Project, and on how these advances potentially contribute to understanding neural circuit dysfunction in psychopathology. The review gives particular attention to the methods developed by the Human Connectome Project that may be especially relevant to studies of psychopathology; it outlines some of the key findings about what constitutes a brain region; and it highlights new information about the nature and stability of brain circuits. Some of the Human Connectome Project's new findings particularly relevant to psychopathology-about neural circuits and their relationships to behavior-are also presented. The review ends by discussing the extension of Human Connectome Project methods across the lifespan and into manifest illness. Potential treatment implications are also considered.

The Neurobiological Basis for Social Affiliation in Autism Spectrum Disorder and Schizophrenia

PubMed Central

Crider, Amanda; Pillai, Anilkumar

2016-01-01

Social interaction and communication are complex behavioral paradigms involving many components. Many different neurotransmitters, hormones, sensory inputs, and brain regions are involved in the act of social engagement and verbal or nonverbal communication. Autism Spectrum Disorder (ASD) and schizophrenia are two neurodevelopmental disorders that have social and language deficits as hallmark symptoms, but show very different etiologies. The output of social dysfunction is common to both ASD and schizophrenia, but this likely arises from very different pathophysiological means. This review will attempt to compile and interpret human and animal studies showing the neurobiological basis for the development of social and language deficits in ASD and schizophrenia as well as a comparison of the two disorders. PMID:27695666

Glutamate and GABA in autism spectrum disorder-a translational magnetic resonance spectroscopy study in man and rodent models.

PubMed

Horder, Jamie; Petrinovic, Marija M; Mendez, Maria A; Bruns, Andreas; Takumi, Toru; Spooren, Will; Barker, Gareth J; Künnecke, Basil; Murphy, Declan G

2018-05-25

Autism spectrum disorder (ASD) is a pervasive neurodevelopmental syndrome with a high human and economic burden. The pathophysiology of ASD is largely unclear, thus hampering development of pharmacological treatments for the core symptoms of the disorder. Abnormalities in glutamate and GABA signaling have been hypothesized to underlie ASD symptoms, and may form a therapeutic target, but it is not known whether these abnormalities are recapitulated in humans with ASD, as well as in rodent models of the disorder. We used translational proton magnetic resonance spectroscopy ([1H]MRS) to compare glutamate and GABA levels in adult humans with ASD and in a panel of six diverse rodent ASD models, encompassing genetic and environmental etiologies. [1H]MRS was performed in the striatum and the medial prefrontal cortex, of the humans, mice, and rats in order to allow for direct cross-species comparisons in specific cortical and subcortical brain regions implicated in ASD. In humans with ASD, glutamate concentration was reduced in the striatum and this was correlated with the severity of social symptoms. GABA levels were not altered in either brain region. The reduction in striatal glutamate was recapitulated in mice prenatally exposed to valproate, and in mice and rats carrying Nlgn3 mutations, but not in rodent ASD models with other etiologies. Our findings suggest that glutamate/GABA abnormalities in the corticostriatal circuitry may be a key pathological mechanism in ASD; and may be linked to alterations in the neuroligin-neurexin signaling complex.

Serotonin: Modulator of a Drive to Withdraw

ERIC Educational Resources Information Center

Tops, Mattie; Russo, Sascha; Boksem, Maarten A. S.; Tucker, Don M.

2009-01-01

Serotonin is a fundamental neuromodulator in both vertebrate and invertebrate nervous systems, with a suspected role in many human mental disorders. Yet, because of the complexity of serotonergic function, researchers have been unable to agree on a general theory. One function suggested for serotonin systems is the avoidance of threat. We propose…

Complex Movement Disorders at Disease Onset in Childhood Narcolepsy with Cataplexy

ERIC Educational Resources Information Center

Plazzi, Giuseppe; Pizza, Fabio; Palaia, Vincenzo; Franceschini, Christian; Poli, Francesca; Moghadam, Keivan K.; Cortelli, Pietro; Nobili, Lino; Bruni, Oliviero; Dauvilliers, Yves; Lin, Ling; Edwards, Mark J.; Mignot, Emmanuel; Bhatia, Kailash P.

2011-01-01

Narcolepsy with cataplexy is characterized by daytime sleepiness, cataplexy (sudden loss of bilateral muscle tone triggered by emotions), sleep paralysis, hypnagogic hallucinations and disturbed nocturnal sleep. Narcolepsy with cataplexy is most often associated with human leucocyte antigen-DQB1*0602 and is caused by the loss of…

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

Chrencik, Jill E.; Orans, Jillian; Moore, Linda B.

The human nuclear xenobiotic receptor, pregnane X receptor (PXR), detects a variety of structurally distinct endogenous and xenobiotic compounds and controls expression of genes central to drug and cholesterol metabolism. The macrolide antibiotic rifampicin, a front-line treatment for tuberculosis, is an established PXR agonist and, at 823 Da, is one of the largest known ligands for the receptor. We present the 2.8 {angstrom} crystal structure of the ligand-binding domain of human PXR in complex with rifampicin. We also use structural and mutagenesis data to examine the origins of the directed promiscuity exhibited by the PXRs across species. Three structurally flexiblemore » loops adjacent to the ligand-binding pocket of PXR are disordered in this crystal structure, including the 200-210 region that is part of a sequence insert novel to the promiscuous PXRs relative to other members of the nuclear receptor superfamily. The 4-methyl-1-piperazinyl ring of rifampicin, which would lie adjacent to the disordered protein regions, is also disordered and not observed in the structure. Taken together, our results indicate that one wall of the PXR ligand-binding cavity can remain flexible even when the receptor is in complex with an activating ligand. These observations highlight the key role that structural flexibility plays in PXR's promiscuous response to xenobiotics.« less

Toward a Valid Animal Model of Bipolar Disorder: How the Research Domain Criteria Help Bridge the Clinical-Basic Science Divide.

PubMed

Cosgrove, Victoria E; Kelsoe, John R; Suppes, Trisha

2016-01-01

Bipolar disorder is a diagnostically heterogeneous disorder, although mania emerges as a distinct phenotype characterized by elevated mood and increased activity or energy. While bipolar disorder's cyclicity is difficult to represent in animals, models of mania have begun to decode its fundamental underlying neurobiology. When psychostimulants such as amphetamine or cocaine are administered to rodents, a resulting upsurge of motor activity is thought to share face and predictive validity with mania in humans. Studying black Swiss mice, which inherently exhibit proclivity for reward seeking and risk taking, also has yielded some insight. Further, translating the biology of bipolar disorder in humans into animal models has led to greater understanding of roles for candidate biological systems such as the GRIK2 and CLOCK genes, as well as the extracellular signal-related kinase pathway involved in the pathophysiology of the illness. The National Institute of Mental Health Research Domain Criteria initiative seeks to identify building blocks of complex illnesses like bipolar disorder in hopes of uncovering the neurobiology of each, as well as how each fits together to produce syndromes like bipolar disorder or why so many mental illnesses co-occur together. Research Domain Criteria-driven preclinical models of isolated behaviors and domains involved in mania and bipolar disorder will ultimately inform movement toward nosology supported by neurobiology. Copyright © 2016 Society of Biological Psychiatry. All rights reserved.

Suspected limbic encephalitis and seizure in cats associated with voltage-gated potassium channel (VGKC) complex antibody.

PubMed

Pakozdy, A; Halasz, P; Klang, A; Bauer, J; Leschnik, M; Tichy, A; Thalhammer, J G; Lang, B; Vincent, A

2013-01-01

Treatment-resistant complex partial seizures (CPS) with orofacial involvement recently were reported in cats in association with hippocampal pathology. The features had some similarity to those described in humans with limbic encephalitis and voltage-gated potassium channel (VGKC) complex antibody. The purpose of this pilot study was to evaluate cats with CPS and orofacial involvement for the presence of VGKC-complex antibody. Client-owned cats with acute orofacial CPS and control cats were investigated. Prospective study. Serum was collected from 14 cats in the acute stage of the disease and compared with 19 controls. VGKC-complex antibodies were determined by routine immunoprecipitation and by binding to leucine-rich glioma inactivated 1 (LGI1) and contactin-associated protein-like 2 (CASPR2), the 2 main targets of VGKC-complex antibodies in humans. Five of the 14 affected cats, but none of the 19 controls, had VGKC-complex antibody concentrations above the cut-off concentration (>100 pmol/L) based on control samples and similar to those found in humans. Antibodies in 4 cats were directed against LGI1, and none were directed against CASPR2. Follow-up sera were available for 5 cats in remission and all antibody concentrations were within the reference range. Our study suggests that an autoimmune limbic encephalitis exists in cats and that VGKC-complex/LGI1 antibodies may play a role in this disorder, as they are thought to in humans. Copyright © 2012 by the American College of Veterinary Internal Medicine.

Intelligence: shared genetic basis between Mendelian disorders and a polygenic trait.

PubMed

Franić, Sanja; Groen-Blokhuis, Maria M; Dolan, Conor V; Kattenberg, Mathijs V; Pool, René; Xiao, Xiangjun; Scheet, Paul A; Ehli, Erik A; Davies, Gareth E; van der Sluis, Sophie; Abdellaoui, Abdel; Hansell, Narelle K; Martin, Nicholas G; Hudziak, James J; van Beijsterveldt, Catherina E M; Swagerman, Suzanne C; Hulshoff Pol, Hilleke E; de Geus, Eco J C; Bartels, Meike; Ropers, H Hilger; Hottenga, Jouke-Jan; Boomsma, Dorret I

2015-10-01

Multiple inquiries into the genetic etiology of human traits indicated an overlap between genes underlying monogenic disorders (eg, skeletal growth defects) and those affecting continuous variability of related quantitative traits (eg, height). Extending the idea of a shared genetic basis between a Mendelian disorder and a classic polygenic trait, we performed an association study to examine the effect of 43 genes implicated in autosomal recessive cognitive disorders on intelligence in an unselected Dutch population (N=1316). Using both single-nucleotide polymorphism (SNP)- and gene-based association testing, we detected an association between intelligence and the genes of interest, with genes ELP2, TMEM135, PRMT10, and RGS7 showing the strongest associations. This is a demonstration of the relevance of genes implicated in monogenic disorders of intelligence to normal-range intelligence, and a corroboration of the utility of employing knowledge on monogenic disorders in identifying the genetic variability underlying complex traits.

Resilience concepts in psychiatry demonstrated with bipolar disorder.

PubMed

Angeler, David G; Allen, Craig R; Persson, Maj-Liz

2018-02-09

The term resilience describes stress-response patterns of subjects across scientific disciplines. In ecology, advances have been made to clearly distinguish resilience definitions based on underlying mechanistic assumptions. Engineering resilience (rebound) is used for describing the ability of subjects to recover from adverse conditions (disturbances), and is the rate of recovery. In contrast, the ecological resilience definition considers a systemic change: when complex systems (including humans) respond to disturbances by reorganizing into a new regime (stable state) where structural and functional aspects have fundamentally changed relative to the prior regime. In this context, resilience is an emergent property of complex systems. We argue that both resilience definitions and uses are appropriate in psychology and psychiatry, but although the differences are subtle, the implications and uses are profoundly different. We borrow from the field of ecology to discuss resilience concepts in the mental health sciences. In psychology and psychiatry, the prevailing view of resilience is adaptation to, coping with, and recovery (engineering resilience) from adverse social and environmental conditions. Ecological resilience may be useful for describing vulnerability, onset, and the irreversibility patterns of mental disorders. We discuss this in the context of bipolar disorder. Rebound, adaptation, and coping are processes that are subsumed within the broader systemic organization of humans, from which ecological resilience emanates. Discerning resilience concepts in psychology and psychiatry has potential for a mechanistically appropriate contextualization of mental disorders at large. This might contribute to a refinement of theory and contextualize clinical practice within the broader systemic functioning of mental illnesses.

Extensive domain motion and electron transfer in the human electron transferring flavoprotein.medium chain Acyl-CoA dehydrogenase complex.

PubMed

Toogood, Helen S; van Thiel, Adam; Basran, Jaswir; Sutcliffe, Mike J; Scrutton, Nigel S; Leys, David

2004-07-30

The crystal structure of the human electron transferring flavoprotein (ETF).medium chain acyl-CoA dehydrogenase (MCAD) complex reveals a dual mode of protein-protein interaction, imparting both specificity and promiscuity in the interaction of ETF with a range of structurally distinct primary dehydrogenases. ETF partitions the functions of partner binding and electron transfer between (i) the recognition loop, which acts as a static anchor at the ETF.MCAD interface, and (ii) the highly mobile redox active FAD domain. Together, these enable the FAD domain of ETF to sample a range of conformations, some compatible with fast interprotein electron transfer. Disorders in amino acid or fatty acid catabolism can be attributed to mutations at the protein-protein interface. Crucially, complex formation triggers mobility of the FAD domain, an induced disorder that contrasts with general models of protein-protein interaction by induced fit mechanisms. The subsequent interfacial motion in the MCAD.ETF complex is the basis for the interaction of ETF with structurally diverse protein partners. Solution studies using ETF and MCAD with mutations at the protein-protein interface support this dynamic model and indicate ionic interactions between MCAD Glu(212) and ETF Arg alpha(249) are likely to transiently stabilize productive conformations of the FAD domain leading to enhanced electron transfer rates between both partners.

Malleable machines in transcription regulation: the mediator complex.

PubMed

Tóth-Petróczy, Agnes; Oldfield, Christopher J; Simon, István; Takagi, Yuichiro; Dunker, A Keith; Uversky, Vladimir N; Fuxreiter, Monika

2008-12-01

The Mediator complex provides an interface between gene-specific regulatory proteins and the general transcription machinery including RNA polymerase II (RNAP II). The complex has a modular architecture (Head, Middle, and Tail) and cryoelectron microscopy analysis suggested that it undergoes dramatic conformational changes upon interactions with activators and RNAP II. These rearrangements have been proposed to play a role in the assembly of the preinitiation complex and also to contribute to the regulatory mechanism of Mediator. In analogy to many regulatory and transcriptional proteins, we reasoned that Mediator might also utilize intrinsically disordered regions (IDRs) to facilitate structural transitions and transmit transcriptional signals. Indeed, a high prevalence of IDRs was found in various subunits of Mediator from both Saccharomyces cerevisiae and Homo sapiens, especially in the Tail and the Middle modules. The level of disorder increases from yeast to man, although in both organisms it significantly exceeds that of multiprotein complexes of a similar size. IDRs can contribute to Mediator's function in three different ways: they can individually serve as target sites for multiple partners having distinctive structures; they can act as malleable linkers connecting globular domains that impart modular functionality on the complex; and they can also facilitate assembly and disassembly of complexes in response to regulatory signals. Short segments of IDRs, termed molecular recognition features (MoRFs) distinguished by a high protein-protein interaction propensity, were identified in 16 and 19 subunits of the yeast and human Mediator, respectively. In Saccharomyces cerevisiae, the functional roles of 11 MoRFs have been experimentally verified, and those in the Med8/Med18/Med20 and Med7/Med21 complexes were structurally confirmed. Although the Saccharomyces cerevisiae and Homo sapiens Mediator sequences are only weakly conserved, the arrangements of the disordered regions and their embedded interaction sites are quite similar in the two organisms. All of these data suggest an integral role for intrinsic disorder in Mediator's function.

Natural killer cell biology illuminated by primary immunodeficiency syndromes in humans.

PubMed

Voss, Matthias; Bryceson, Yenan T

2017-04-01

Natural killer (NK) cells are innate immune cytotoxic effector cells well known for their role in antiviral immunity and tumor immunosurveillance. In parts, this knowledge stems from rare inherited immunodeficiency disorders in humans that abrogate NK cell function leading to immune impairments, most notably associated with a high susceptibility to viral infections. Phenotypically, these disorders range from deficiencies selectively affecting NK cells to complex general immune defects that affect NK cells but also other immune cell subsets. Moreover, deficiencies may be associated with reduced NK cell numbers or rather impair specific NK cell effector functions. In recent years, genetic defects underlying the various NK cell deficiencies have been uncovered and have triggered investigative efforts to decipher the molecular mechanisms underlying these disorders. Here we review the associations between inherited human diseases and NK cell development as well as function, with a particular focus on defects in NK cell exocytosis and cytotoxicity. Furthermore we outline how reports of diverse genetic defects have shaped our understanding of NK cell biology. Copyright © 2015. Published by Elsevier Inc.

Benefits of agomelatine in behavioral, neurochemical and blood brain barrier alterations in prenatal valproic acid induced autism spectrum disorder.

PubMed

Kumar, Hariom; Sharma, B M; Sharma, Bhupesh

2015-12-01

Valproic acid administration during gestational period causes behavior and biochemical deficits similar to those observed in humans with autism spectrum disorder. Although worldwide prevalence of autism spectrum disorder has been increased continuously, therapeutic agents to ameliorate the social impairment are very limited. The present study has been structured to investigate the therapeutic potential of melatonin receptor agonist, agomelatine in prenatal valproic acid (Pre-VPA) induced autism spectrum disorder in animals. Pre-VPA has produced reduction in social interaction (three chamber social behavior apparatus), spontaneous alteration (Y-Maze), exploratory activity (Hole board test), intestinal motility, serotonin levels (prefrontal cortex and ileum) and prefrontal cortex mitochondrial complex activity (complex I, II, IV). Furthermore, Pre-VPA has increased locomotor activity (actophotometer), anxiety, brain oxidative stress (thiobarbituric acid reactive species, glutathione, and catalase), nitrosative stress (nitrite/nitrate), inflammation (brain and ileum myeloperoxidase activity), calcium levels and blood brain barrier leakage in animals. Treatment with agomelatine has significantly attenuated Pre-VPA induced reduction in social interaction, spontaneous alteration, exploratory activity intestinal motility, serotonin levels and prefrontal cortex mitochondrial complex activity. Furthermore, agomelatine also attenuated Pre-VPA induced increase in locomotion, anxiety, brain oxidative stress, nitrosative stress, inflammation, calcium levels and blood brain barrier leakage. It is concluded that, Pre-VPA has induced autism spectrum disorder, which was attenuated by agomelatine. Agomelatine has shown ameliorative effect on behavioral, neurochemical and blood brain barrier alteration in Pre-VPA exposed animals. Thus melatonin receptor agonists may provide beneficial therapeutic strategy for managing autism spectrum disorder. Copyright © 2015 Elsevier Ltd. All rights reserved.

Exploring the human seminal plasma proteome: an unexplored gold mine of biomarker for male infertility and male reproduction disorder.

PubMed

Gilany, Kambiz; Minai-Tehrani, Arash; Savadi-Shiraz, Elham; Rezadoost, Hassan; Lakpour, Niknam

2015-01-01

The human seminal fluid is a complex body fluid. It is not known how many proteins are expressed in the seminal plasma; however in analog with the blood it is possible up to 10,000 proteins are expressed in the seminal plasma. The human seminal fluid is a rich source of potential biomarkers for male infertility and reproduction disorder. In this review, the ongoing list of proteins identified from the human seminal fluid was collected. To date, 4188 redundant proteins of the seminal fluid are identified using different proteomics technology, including 2-DE, SDS-PAGE-LC-MS/MS, MudPIT. However, this was reduced to a database of 2168 non-redundant protein using UniProtKB/Swiss-Prot reviewed database. The core concept of proteome were analyzed including pI, MW, Amino Acids, Chromosome and PTM distribution in the human seminal plasma proteome. Additionally, the biological process, molecular function and KEGG pathway were investigated using DAVID software. Finally, the biomarker identified in different male reproductive system disorder was investigated using proteomics platforms so far. In this study, an attempt was made to update the human seminal plasma proteome database. Our finding showed that human seminal plasma studies used to date seem to have converged on a set of proteins that are repeatedly identified in many studies and that represent only a small fraction of the entire human seminal plasma proteome.

Systematic review of autosomal recessive ataxias and proposal for a classification.

PubMed

Beaudin, Marie; Klein, Christopher J; Rouleau, Guy A; Dupré, Nicolas

2017-01-01

The classification of autosomal recessive ataxias represents a significant challenge because of high genetic heterogeneity and complex phenotypes. We conducted a comprehensive systematic review of the literature to examine all recessive ataxias in order to propose a new classification and properly circumscribe this field as new technologies are emerging for comprehensive targeted gene testing. We searched Pubmed and Embase to identify original articles on recessive forms of ataxia in humans for which a causative gene had been identified. Reference lists and public databases, including OMIM and GeneReviews, were also reviewed. We evaluated the clinical descriptions to determine if ataxia was a core feature of the phenotype and assessed the available evidence on the genotype-phenotype association. Included disorders were classified as primary recessive ataxias, as other complex movement or multisystem disorders with prominent ataxia, or as disorders that may occasionally present with ataxia. After removal of duplicates, 2354 references were reviewed and assessed for inclusion. A total of 130 articles were completely reviewed and included in this qualitative analysis. The proposed new list of autosomal recessive ataxias includes 45 gene-defined disorders for which ataxia is a core presenting feature. We propose a clinical algorithm based on the associated symptoms. We present a new classification for autosomal recessive ataxias that brings awareness to their complex phenotypes while providing a unified categorization of this group of disorders. This review should assist in the development of a consensus nomenclature useful in both clinical and research applications.

On the Structural Plasticity of the Human Genome: Chromosomal Inversions Revisited

PubMed Central

Alves, Joao M; Lopes, Alexandra M; Chikhi, Lounès; Amorim, António

2012-01-01

With the aid of novel and powerful molecular biology techniques, recent years have witnessed a dramatic increase in the number of studies reporting the involvement of complex structural variants in several genomic disorders. In fact, with the discovery of Copy Number Variants (CNVs) and other forms of unbalanced structural variation, much attention has been directed to the detection and characterization of such rearrangements, as well as the identification of the mechanisms involved in their formation. However, it has long been appreciated that chromosomes can undergo other forms of structural changes - balanced rearrangements - that do not involve quantitative variation of genetic material. Indeed, a particular subtype of balanced rearrangement – inversions – was recently found to be far more common than had been predicted from traditional cytogenetics. Chromosomal inversions alter the orientation of a specific genomic sequence and, unless involving breaks in coding or regulatory regions (and, disregarding complex trans effects, in their close vicinity), appear to be phenotypically silent. Such a surprising finding, which is difficult to reconcile with the classical interpretation of inversions as a mechanism causing subfertility (and ultimately reproductive isolation), motivated a new series of theoretical and empirical studies dedicated to understand their role in human genome evolution and to explore their possible association to complex genetic disorders. With this review, we attempt to describe the latest methodological improvements to inversions detection at a genome wide level, while exploring some of the possible implications of inversion rearrangements on the evolution of the human genome. PMID:23730202

Decoding Mechanisms by which Silent Codon Changes Influence Protein Biogenesis and Function

PubMed Central

Bali, Vedrana; Bebok, Zsuzsanna

2015-01-01

Scope Synonymous codon usage has been a focus of investigation since the discovery of the genetic code and its redundancy. The occurrences of synonymous codons vary between species and within genes of the same genome, known as codon usage bias. Today, bioinformatics and experimental data allow us to compose a global view of the mechanisms by which the redundancy of the genetic code contributes to the complexity of biological systems from affecting survival in prokaryotes, to fine tuning the structure and function of proteins in higher eukaryotes. Studies analyzing the consequences of synonymous codon changes in different organisms have revealed that they impact nucleic acid stability, protein levels, structure and function without altering amino acid sequence. As such, synonymous mutations inevitably contribute to the pathogenesis of complex human diseases. Yet, fundamental questions remain unresolved regarding the impact of silent mutations in human disorders. In the present review we describe developments in this area concentrating on mechanisms by which synonymous mutations may affect protein function and human health. Purpose This synopsis illustrates the significance of synonymous mutations in disease pathogenesis. We review the different steps of gene expression affected by silent mutations, and assess the benefits and possible harmful effects of codon optimization applied in the development of therapeutic biologics. Physiological and medical relevance Understanding mechanisms by which synonymous mutations contribute to complex diseases such as cancer, neurodegeneration and genetic disorders, including the limitations of codon-optimized biologics, provides insight concerning interpretation of silent variants and future molecular therapies. PMID:25817479

Differential responses to lithium in hyperexcitable neurons from patients with bipolar disorder.

PubMed

Mertens, Jerome; Wang, Qiu-Wen; Kim, Yongsung; Yu, Diana X; Pham, Son; Yang, Bo; Zheng, Yi; Diffenderfer, Kenneth E; Zhang, Jian; Soltani, Sheila; Eames, Tameji; Schafer, Simon T; Boyer, Leah; Marchetto, Maria C; Nurnberger, John I; Calabrese, Joseph R; Ødegaard, Ketil J; McCarthy, Michael J; Zandi, Peter P; Alda, Martin; Alba, Martin; Nievergelt, Caroline M; Mi, Shuangli; Brennand, Kristen J; Kelsoe, John R; Gage, Fred H; Yao, Jun

2015-11-05

Bipolar disorder is a complex neuropsychiatric disorder that is characterized by intermittent episodes of mania and depression; without treatment, 15% of patients commit suicide. Hence, it has been ranked by the World Health Organization as a top disorder of morbidity and lost productivity. Previous neuropathological studies have revealed a series of alterations in the brains of patients with bipolar disorder or animal models, such as reduced glial cell number in the prefrontal cortex of patients, upregulated activities of the protein kinase A and C pathways and changes in neurotransmission. However, the roles and causation of these changes in bipolar disorder have been too complex to exactly determine the pathology of the disease. Furthermore, although some patients show remarkable improvement with lithium treatment for yet unknown reasons, others are refractory to lithium treatment. Therefore, developing an accurate and powerful biological model for bipolar disorder has been a challenge. The introduction of induced pluripotent stem-cell (iPSC) technology has provided a new approach. Here we have developed an iPSC model for human bipolar disorder and investigated the cellular phenotypes of hippocampal dentate gyrus-like neurons derived from iPSCs of patients with bipolar disorder. Guided by RNA sequencing expression profiling, we have detected mitochondrial abnormalities in young neurons from patients with bipolar disorder by using mitochondrial assays; in addition, using both patch-clamp recording and somatic Ca(2+) imaging, we have observed hyperactive action-potential firing. This hyperexcitability phenotype of young neurons in bipolar disorder was selectively reversed by lithium treatment only in neurons derived from patients who also responded to lithium treatment. Therefore, hyperexcitability is one early endophenotype of bipolar disorder, and our model of iPSCs in this disease might be useful in developing new therapies and drugs aimed at its clinical treatment.

[Projective identification in human relations].

PubMed

Göka, Erol; Yüksel, Fatih Volkan; Göral, F Sevinç

2006-01-01

Melanie Klein, one of the pioneers of Object Relations Theory, first defined "projective identification", which is regarded as one of the most efficacious psychoanalytic concepts after the discovery of the "unconscious". Examination of the literature on "projective identification" shows that there are various perspectives and theories suggesting different uses of this concept. Some clinicians argue that projective identification is a primitive defense mechanism observed in severe psychopathologies like psychotic disorder and borderline personality disorder, where the intra-psychic structure has been damaged severely. Others suggest it to be an indispensable part of the transference and counter-transference between the therapist and the patient during psychotherapy and it can be used as a treatment material in the therapy by a skillful therapist. The latter group expands the use of the concept through normal daily relationships by stating that projective identification is one type of communication and part of the main human relation mechanism operating in all close relationships. Therefore, they suggest that projective identification has benign forms experienced in human relations as well as malign forms seen in psychopathologies. Thus, discussions about the definition of the concept appear complex. In order to clarify and overcome the complexity of the concept, Melanie Klein's and other most important subsequent approaches are discussed in this review article. Thereby, the article aims to explain its important function in understanding the psychopathologies, psychotherapeutic relationships and different areas of normal human relations.

Brain/MINDS: brain-mapping project in Japan

PubMed Central

Okano, Hideyuki; Miyawaki, Atsushi; Kasai, Kiyoto

2015-01-01

There is an emerging interest in brain-mapping projects in countries across the world, including the USA, Europe, Australia and China. In 2014, Japan started a brain-mapping project called Brain Mapping by Integrated Neurotechnologies for Disease Studies (Brain/MINDS). Brain/MINDS aims to map the structure and function of neuronal circuits to ultimately understand the vast complexity of the human brain, and takes advantage of a unique non-human primate animal model, the common marmoset (Callithrix jacchus). In Brain/MINDS, the RIKEN Brain Science Institute acts as a central institute. The objectives of Brain/MINDS can be categorized into the following three major subject areas: (i) structure and functional mapping of a non-human primate brain (the marmoset brain); (ii) development of innovative neurotechnologies for brain mapping; and (iii) human brain mapping; and clinical research. Brain/MINDS researchers are highly motivated to identify the neuronal circuits responsible for the phenotype of neurological and psychiatric disorders, and to understand the development of these devastating disorders through the integration of these three subject areas. PMID:25823872

Contribution of Inhibitor of DNA Binding/Differentiation-3 and Endocrine Disrupting Chemicals to Pathophysiological Aspects of Chronic Disease

PubMed Central

2017-01-01

The overwhelming increase in the global incidence of obesity and its associated complications such as insulin resistance, atherosclerosis, pulmonary disease, and degenerative disorders including dementia constitutes a serious public health problem. The Inhibitor of DNA Binding/Differentiation-3 (ID3), a member of the ID family of transcriptional regulators, has been shown to play a role in adipogenesis and therefore ID3 may influence obesity and metabolic health in response to environmental factors. This review will highlight the current understanding of how ID3 may contribute to complex chronic diseases via metabolic perturbations. Based on the increasing number of reports that suggest chronic exposure to and accumulation of endocrine disrupting chemicals (EDCs) within the human body are associated with metabolic disorders, we will also consider the impact of these chemicals on ID3. Improved understanding of the ID3 pathways by which exposure to EDCs can potentiate complex chronic diseases in populations with metabolic disorders (obesity, metabolic syndrome, and glucose intolerance) will likely provide useful knowledge in the prevention and control of complex chronic diseases associated with exposure to environmental pollutants. PMID:28785583

Enhanced visual performance in obsessive compulsive personality disorder.

PubMed

Ansari, Zohreh; Fadardi, Javad Salehi

2016-12-01

Visual performance is considered as commanding modality in human perception. We tested whether Obsessive-compulsive personality disorder (OCPD) people do differently in visual performance tasks than people without OCPD. One hundred ten students of Ferdowsi University of Mashhad and non-student participants were tested by Structured Clinical Interview for DSM-IV Axis II Personality Disorders (SCID-II), among whom 18 (mean age = 29.55; SD = 5.26; 84% female) met the criteria for OCPD classification; controls were 20 persons (mean age = 27.85; SD = 5.26; female = 84%), who did not met the OCPD criteria. Both groups were tested on a modified Flicker task for two dimensions of visual performance (i.e., visual acuity: detecting the location of change, complexity, and size; and visual contrast sensitivity). The OCPD group had responded more accurately on pairs related to size, complexity, and contrast, but spent more time to detect a change on pairs related to complexity and contrast. The OCPD individuals seem to have more accurate visual performance than non-OCPD controls. The findings support the relationship between personality characteristics and visual performance within the framework of top-down processing model. © 2016 Scandinavian Psychological Associations and John Wiley & Sons Ltd.

Disruptive technology disorder: A past, present, and future neurologic syndrome.

PubMed

Weaver, Donald F

2017-07-25

Based upon an analysis of 6 major historical technological advances over the last 150 years, a new syndrome, disruptive technology disorder (DTD), is introduced. DTD describes the human health ailments that accompany the implementation of disruptive technologies. Elevator sickness, railway spine, and bicycle face are representative examples. Though the underlying causative disruptive technologies may differ, many neurologic symptoms (headache, dizziness, weakness) are common to multiple DTDs. Born of technology-driven societal change, DTDs manifest as a complex interplay between biological and psychological symptoms. © 2017 American Academy of Neurology.

The Spectrum Disorders: An Exploratory Study of Family, Social, Individual and Psychological Distress Dimensions.

ERIC Educational Resources Information Center

Zarski, John J.; And Others

Although there is literature on Acquired Immune Deficiency Syndrome (AIDS), empirical research on family, social, and individual factors that may influence the psychological distress experienced by AIDS, Aids-Related Complex (ARC), Human Immunodeficiency Virus positive (HIV+) and worried well individuals is limited. This study explored the…

Conserved TCP domain of Sas-4/CPAP is essential for pericentriolar material tethering during centrosome biogenesis

PubMed Central

Zheng, Xiangdong; Gooi, Li Ming; Wason, Arpit; Gabriel, Elke; Mehrjardi, Narges Zare; Yang, Qian; Zhang, Xingrun; Debec, Alain; Basiri, Marcus L.; Avidor-Reiss, Tomer; Pozniakovsky, Andrei; Poser, Ina; Šarić, Tomo; Hyman, Anthony A.; Li, Haitao; Gopalakrishnan, Jay

2014-01-01

Pericentriolar material (PCM) recruitment to centrioles forms a key step in centrosome biogenesis. Deregulation of this process leads to centrosome aberrations causing disorders, one of which is autosomal recessive primary microcephaly (MCPH), a neurodevelopmental disorder where brain size is reduced. During PCM recruitment, the conserved centrosomal protein Sas-4/CPAP/MCPH6, known to play a role in centriole formation, acts as a scaffold for cytoplasmic PCM complexes to bind and then tethers them to centrioles to form functional centrosomes. To understand Sas-4’s tethering role, we determined the crystal structure of its T complex protein 10 (TCP) domain displaying a solvent-exposed single-layer of β-sheets fold. This unique feature of the TCP domain suggests that it could provide an “extended surface-like” platform to tether the Sas-4–PCM scaffold to a centriole. Functional studies in Drosophila, human cells, and human induced pluripotent stem cell-derived neural progenitor cells were used to test this hypothesis, where point mutations within the 9–10th β-strands (β9–10 mutants including a MCPH-associated mutation) perturbed PCM tethering while allowing Sas-4/CPAP to scaffold cytoplasmic PCM complexes. Specifically, the Sas-4 β9–10 mutants displayed perturbed interactions with Ana2, a centrosome duplication factor, and Bld-10, a centriole microtubule-binding protein, suggesting a role for the β9–10 surface in mediating protein–protein interactions for efficient Sas-4–PCM scaffold centriole tethering. Hence, we provide possible insights into how centrosomal protein defects result in human MCPH and how Sas-4 proteins act as a vehicle to tether PCM complexes to centrioles independent of its well-known role in centriole duplication. PMID:24385583

[The communicating body--eating disorders and culture].

PubMed

Skårderud, Finn

2004-09-23

What is "culture" in eating disorders as culture-bound syndromes? The human body is a flesh-and-blood entity, but it also functions as a symbolic instrument. The body communicates about culture itself, about norms and boundaries. In this paper one central aspect in the phenomenology of eating disorders is emphasised: The subjective experience of lack of control and the sense of an overwhelming "chaos", both on the inner and outer level. On this basis rapid societal transitions are discussed as specific pathogenic factors. Sociocultural instability represents insecure conditions for construction of a healthy and stable identity. "The open body" is a relevant metaphor, with its dialectical relationship to the isolation and delimitation represented by eating disordered behaviour. With reference to history and geography the paper also discusses the pathoplasticity of eating disorders; how they change in time and space. Cultural analysis of eating disorders can contribute to a richer understanding of the complexity of the construction of meaning in these disorders, both across cultures and within our own cultural contexts.

Is Glycogen Synthase Kinase-3 a Central Modulator in Mood Regulation?

PubMed Central

Li, Xiaohua; Jope, Richard S

2010-01-01

Little is known regarding the mechanisms underlying the complex etiology of mood disorders, represented mainly by major depressive disorder and bipolar disorder. The 1996 discovery that lithium inhibits glycogen synthase kinase-3 (GSK3) raised the possibility that impaired inhibition of GSK3 is associated with mood disorders. This is now supported by evidence from animal biochemical, pharmacological, molecular, and behavioral studies and from human post-mortem brain, peripheral tissue, and genetic studies that are reviewed here. Mood disorders may result in part from impairments in mechanisms controlling the activity of GSK3 or GSK3-regulated functions, and disruptions of these regulating systems at different signaling sites may contribute to the heterogeneity of mood disorders. This substantial evidence supports the conclusion that bolstering the inhibitory control of GSK3 is an important component of the therapeutic actions of drugs used to treat mood disorders and that GSK3 is a valid target for developing new therapeutic interventions. PMID:20668436

Therapeutic opportunities of small interfering RNA.

PubMed

Goyal, Bhoomika R; Patel, Mayur M; Soni, Mithil K; Bhadada, Shraddha V

2009-08-01

Formation of small interfering RNA (siRNA) occurs in two steps involving binding of the RNA nucleases to a large double-stranded RNA (dsRNA) and its cleavage into fragments called siRNA. In the second step, these siRNAs join a multinuclease complex, which degrades the homologous single-stranded mRNAs. The delivery of siRNA involves viral- and non-viral-mediated delivery systems; the approaches for chemical modifications have also been developed. It has various therapeutic applications for disorders like cardiovascular diseases, central nervous system (CNS) disorders, cancer, human immunodeficiency virus (HIV), hepatic disorders, etc. The present review gives an overview of the applications of siRNA and their potential for treating many hitherto untreatable diseases.

Expression of the G72/G30 gene in transgenic mice induces behavioral changes

PubMed Central

Cheng, Lijun; Hattori, Eiji; Nakajima, Akira; Woehrle, Nancy S.; Opal, Mark D.; Zhang, Chunling; Grennan, Kay; Dulawa, Stephanie C.; Tang, Ya-Ping; Gershon, Elliot S.; Liu, Chunyu

2012-01-01

The G72/G30 gene complex is a candidate gene for schizophrenia and bipolar disorder. However, G72 and G30 mRNAs are expressed at very low levels in human brain, with only rare splicing forms observed. We report here G72/G30 expression profiles and behavioral changes in a G72/G30 transgenic mouse model. A human BAC clone containing the G72/G30 genomic region was used to establish the transgenic mouse model, on which gene expression studies, Western blot and behavioral tests were performed. Relative to their minimal expression in humans, G72 and G30 mRNAs were highly expressed in the transgenic mice, and had a more complex splicing pattern. The highest G72 transcript levels were found in testis, followed by cerebral cortex, with very low or undetectable levels in other tissues. No LG72 (the long putative isoform of G72) protein was detected in the transgenic mice. Whole-genome expression profiling identified 361 genes differentially-expressed in transgenic mice compared to wild-type, including genes previously implicated in neurological and psychological disorders. Relative to wild-type mice, the transgenic mice exhibited fewer stereotypic movements in the open field test, higher baseline startle responses in the course of the prepulse inhibition test, and lower hedonic responses in the sucrose preference test. The transcriptome profile changes and multiple mouse behavioral effects suggest that the G72 gene may play a role in modulating behaviors relevant to psychiatric disorders. PMID:23337943

A new mouse model to explore therapies for preeclampsia.

PubMed

Ahmed, Abdulwahab; Singh, Jameel; Khan, Ysodra; Seshan, Surya V; Girardi, Guillermina

2010-10-27

Pre-eclampsia, a pregnancy-specific multisystemic disorder is a leading cause of maternal and perinatal mortality and morbidity. This syndrome has been known to medical science since ancient times. However, despite considerable research, the cause/s of preeclampsia remain unclear, and there is no effective treatment. Development of an animal model that recapitulates this complex pregnancy-related disorder may help to expand our understanding and may hold great potential for the design and implementation of effective treatment. Here we show that the CBA/J x DBA/2 mouse model of recurrent miscarriage is also a model of immunologically-mediated preeclampsia (PE). DBA/J mated CBA/J females spontaneously develop many features of human PE (primigravidity, albuminuria, endotheliosis, increased sensitivity to angiotensin II and increased plasma leptin levels) that correlates with bad pregnancy outcomes. We previously reported that antagonism of vascular endothelial growth factor (VEGF) signaling by soluble VEGF receptor 1 (sFlt-1) is involved in placental and fetal injury in CBA/J x DBA/2 mice. Using this animal model that recapitulates many of the features of preeclampsia in women, we found that pravastatin restores angiogenic balance, ameliorates glomerular injury, diminishes hypersensitivity to angiotensin II and protects pregnancies. We described a new mouse model of PE, were the relevant key features of human preeclampsia develop spontaneously. The CBA/J x DBA/2 model, that recapitulates this complex disorder, helped us identify pravastatin as a candidate therapy to prevent preeclampsia and its related complications. We recognize that these studies were conducted in mice and that clinical trials are needed to confirm its application to humans.

Fatal autoimmunity in mice reconstituted with human hematopoietic stem cells encoding defective FOXP3

PubMed Central

Goettel, Jeremy A.; Biswas, Subhabrata; Lexmond, Willem S.; Yeste, Ada; Passerini, Laura; Patel, Bonny; Yang, Siyoung; Sun, Jiusong; Ouahed, Jodie; Shouval, Dror S.; McCann, Katelyn J.; Horwitz, Bruce H.; Mathis, Diane; Milford, Edgar L.; Notarangelo, Luigi D.; Roncarolo, Maria-Grazia; Fiebiger, Edda; Marasco, Wayne A.; Bacchetta, Rosa; Quintana, Francisco J.; Pai, Sung-Yun; Klein, Christoph; Muise, Aleixo M.

2015-01-01

Mice reconstituted with a human immune system provide a tractable in vivo model to assess human immune cell function. To date, reconstitution of murine strains with human hematopoietic stem cells (HSCs) from patients with monogenic immune disorders have not been reported. One obstacle precluding the development of immune-disease specific “humanized” mice is that optimal adaptive immune responses in current strains have required implantation of autologous human thymic tissue. To address this issue, we developed a mouse strain that lacks murine major histocompatibility complex class II (MHC II) and instead expresses human leukocyte antigen DR1 (HLA-DR1). These mice displayed improved adaptive immune responses when reconstituted with human HSCs including enhanced T-cell reconstitution, delayed-type hypersensitivity responses, and class-switch recombination. Following immune reconstitution of this novel strain with HSCs from a patient with immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, associated with aberrant FOXP3 function, mice developed a lethal inflammatory disorder with multiorgan involvement and autoantibody production mimicking the pathology seen in affected humans. This humanized mouse model permits in vivo evaluation of immune responses associated with genetically altered HSCs, including primary immunodeficiencies, and should facilitate the study of human immune pathobiology and the development of targeted therapeutics. PMID:25833964

Age-associated changes in rich-club organisation in autistic and neurotypical human brains

PubMed Central

Watanabe, Takamitsu; Rees, Geraint

2015-01-01

Macroscopic structural networks in the human brain have a rich-club architecture comprising both highly inter-connected central regions and sparsely connected peripheral regions. Recent studies show that disruption of this functionally efficient organisation is associated with several psychiatric disorders. However, despite increasing attention to this network property, whether age-associated changes in rich-club organisation occur during human adolescence remains unclear. Here, analysing a publicly shared diffusion tensor imaging dataset, we found that, during adolescence, brains of typically developing (TD) individuals showed increases in rich-club organisation and inferred network functionality, whereas individuals with autism spectrum disorders (ASD) did not. These differences between TD and ASD groups were statistically significant for both structural and functional properties. Moreover, this typical age-related changes in rich-club organisation were characterised by progressive involvement of the right anterior insula. In contrast, in ASD individuals, did not show typical increases in grey matter volume, and this relative anatomical immaturity was correlated with the severity of ASD social symptoms. These results provide evidence that rich-club architecture is one of the bases of functionally efficient brain networks underpinning complex cognitive functions in adult human brains. Furthermore, our findings suggest that immature rich-club organisation might be associated with some neurodevelopmental disorders. PMID:26537477

Neuropeptides and social behaviour: effects of oxytocin and vasopressin in humans.

PubMed

Heinrichs, Markus; Domes, Gregor

2008-01-01

The fundamental ability to form attachment is indispensable for human social relationships. Impairments in social behaviour are associated with decreased quality of life and psychopathological states. In non-human mammals, the neuropeptides oxytocin (OXT) and arginine vasopressin (AVP) are key mediators of complex social behaviours, including attachment, social recognition and aggression. In particular, OXT reduces behavioural and neuroendocrine responses to social stress and seems both to enable animals to overcome their natural avoidance of proximity and to inhibit defensive behaviour, thereby facilitating approach behaviour. AVP has primarily been implicated in male-typical social behaviours, including aggression and pair-bond formation, and mediates anxiogenic effects. Initial studies in humans suggest behavioural, neural, and endocrine effects of both neuropeptides, similar to those found in animal studies. This review focuses on advances made to date in the effort to understand the role of OXT and AVP in human social behaviour. First, the literature on OXT and AVP and their involvement in social stress and anxiety, social cognition, social approach, and aggression is reviewed. Second, we discuss clinical implications for mental disorders that are associated with social deficits (e.g. autism spectrum disorder, borderline personality disorder). Finally, a model of the interactions of anxiety and stress, social approach behaviour, and the oxytocinergic system is presented, which integrates the novel approach of a psychobiological therapy in psychopathological states.

Study of the relationship between tuberous sclerosis complex and autistic disorder.

PubMed

Wong, Virginia

2006-03-01

There has been increasing awareness that there are behavioral phenotypes in tuberous sclerosis complex with neuropsychiatric symptom complex such as autistic disorder and attention-deficit hyperactivity disorder (ADHD). However, the neurobiologic basis of autistic disorder in tuberous sclerosis complex is still unknown. We studied two cohorts of children followed up since 1986 until 2003, one cohort with tuberous sclerosis complex and another cohort with autistic disorder, to determine the incidence of autistic disorder in tuberous sclerosis complex and the incidence of tuberous sclerosis complex in autistic disorder respectively. We established a Tuberous Sclerosis Complex Registry in 1985 at the University of Hong Kong. In 2004, 44 index cases (the male to female ratio was 0.75:1) were registered. Three had a positive family history of tuberous sclerosis complex. Thus, the total number of tuberous sclerosis complex cases was 47. We adopted the diagnostic criteria of tuberous sclerosis complex for case ascertainment. The period prevalence rate of tuberous sclerosis complex for children and adolescents aged < 20 years is 3.5 per 10,000 (on Hong Kong island, excluding the eastern region with 125,100 aged < 20 years in 2003). Of 44 cases with tuberous sclerosis complex, 7 had autistic disorder. Thus, the incidence of autistic disorder in tuberous sclerosis complex is 16%. During the 17-year period (1986-2003), we collected a database of 753 children (668 boys and 84 girls; male to female ratio 8:1) with autistic disorder and pervasive developmental disorders. For all children with autistic disorder or pervasive developmental disorders, we routinely examined for any features of tuberous sclerosis complex by looking for neurocutaneous markers such as depigmented spots, which appear in 50% of children with tuberous sclerosis complex by the age of 2 years. For those with infantile spasm or epilepsy, the clinical features of tuberous sclerosis complex were monitored regularly during follow-up. Of these, seven had tuberous sclerosis complex. Thus, the incidence of tuberous sclerosis complex in autistic disorder is 0.9%. All of these children are mentally retarded, with moderate to severe grades in an intellectual assessment conducted by a clinical psychologist. Future studies should be directed toward looking at the various behavioral phenotypes in tuberous sclerosis complex and defining these with standardized criteria to look for any real association with the underlying genetic mutation of TSC1 or TSC2 gene or even the site of tubers in the brain.

Uncovering genes for cognitive (dys)function and predisposition for alcoholism spectrum disorders: A review of human brain oscillations as effective endophenotypes

PubMed Central

Rangaswamy, Madhavi; Porjesz, Bernice

2010-01-01

Brain oscillations provide a rich source of potentially useful endophenotypes (intermediate phenotypes) for psychiatric genetics, as they represent important correlates of human information processing and are associated with fundamental processes from perception to cognition. These oscillations are highly heritable, are modulated by genes controlling neurotransmitters in the brain, and provide links to associative and integrative brain functions. These endophenotypes represent traits that are less complex and more proximal to gene function than either diagnostic labels or traditional cognitive measures, providing a powerful strategy in searching for genes in psychiatric disorders. These intermediate phenotypes identify both affected and unaffected members of an affected family, including offspring at risk, providing a more direct connection with underlying biological vulnerability. Our group has utilized heritable neurophysiological features (i.e., brain oscillations) as endophenotypes, making it possible to identify susceptibility genes that may be difficult to detect with diagnosis alone. We have discussed our findings of significant linkage and association between brain oscillations and genes in GABAergic, cholinergic and glutamatergic systems (GABRA2, CHRM2, and GRM8). We have also shown that some oscillatory indices from both resting and active cognitive states have revealed a common subset of genetic foci that are shared with the diagnosis of alcoholism and related disorders. Implications of our findings have been discussed in the context of physiological and pharmacological studies on receptor function. These findings underscore the utility of quantitative neurophysiological endophenotypes in the study of the genetics of brain function and the genetic diathesis underlying complex psychiatric disorders. PMID:18634760

Uncovering genes for cognitive (dys)function and predisposition for alcoholism spectrum disorders: a review of human brain oscillations as effective endophenotypes.

PubMed

Rangaswamy, Madhavi; Porjesz, Bernice

2008-10-15

Brain oscillations provide a rich source of potentially useful endophenotypes (intermediate phenotypes) for psychiatric genetics, as they represent important correlates of human information processing and are associated with fundamental processes from perception to cognition. These oscillations are highly heritable, are modulated by genes controlling neurotransmitters in the brain, and provide links to associative and integrative brain functions. These endophenotypes represent traits that are less complex and more proximal to gene function than either diagnostic labels or traditional cognitive measures, providing a powerful strategy in searching for genes in psychiatric disorders. These intermediate phenotypes identify both affected and unaffected members of an affected family, including offspring at risk, providing a more direct connection with underlying biological vulnerability. Our group has utilized heritable neurophysiological features (i.e., brain oscillations) as endophenotypes, making it possible to identify susceptibility genes that may be difficult to detect with diagnosis alone. We have discussed our findings of significant linkage and association between brain oscillations and genes in GABAergic, cholinergic and glutamatergic systems (GABRA2, CHRM2, and GRM8). We have also shown that some oscillatory indices from both resting and active cognitive states have revealed a common subset of genetic foci that are shared with the diagnosis of alcoholism and related disorders. Implications of our findings have been discussed in the context of physiological and pharmacological studies on receptor function. These findings underscore the utility of quantitative neurophysiological endophenotypes in the study of the genetics of brain function and the genetic diathesis underlying complex psychiatric disorders.

Molecular medicine: a path towards a personalized medicine.

PubMed

Miranda, Debora Marques de; Mamede, Marcelo; Souza, Bruno Rezende de; Almeida Barros, Alexandre Guimarães de; Magno, Luiz Alexandre; Alvim-Soares, Antônio; Rosa, Daniela Valadão; Castro, Célio José de; Malloy-Diniz, Leandro; Gomez, Marcus Vinícius; Marco, Luiz Armando De; Correa, Humberto; Romano-Silva, Marco Aurélio

2012-03-01

Psychiatric disorders are among the most common human illnesses; still, the molecular and cellular mechanisms underlying their complex pathophysiology remain to be fully elucidated. Over the past 10 years, our group has been investigating the molecular abnormalities in major signaling pathways involved in psychiatric disorders. Recent evidences obtained by the Instituto Nacional de Ciência e Tecnologia de Medicina Molecular (National Institute of Science and Technology - Molecular Medicine, INCT-MM) and others using behavioral analysis of animal models provided valuable insights into the underlying molecular alterations responsible for many complex neuropsychiatric disorders, suggesting that "defects" in critical intracellular signaling pathways have an important role in regulating neurodevelopment, as well as in pathophysiology and treatment efficacy. Resources from the INCT have allowed us to start doing research in the field of molecular imaging. Molecular imaging is a research discipline that visualizes, characterizes, and quantifies the biologic processes taking place at cellular and molecular levels in humans and other living systems through the results of image within the reality of the physiological environment. In order to recognize targets, molecular imaging applies specific instruments (e.g., PET) that enable visualization and quantification in space and in real-time of signals from molecular imaging agents. The objective of molecular medicine is to individualize treatment and improve patient care. Thus, molecular imaging is an additional tool to achieve our ultimate goal.

Mutations in UNC80, Encoding Part of the UNC79-UNC80-NALCN Channel Complex, Cause Autosomal-Recessive Severe Infantile Encephalopathy.

PubMed

Shamseldin, Hanan E; Faqeih, Eissa; Alasmari, Ali; Zaki, Maha S; Gleeson, Joseph G; Alkuraya, Fowzan S

2016-01-07

Brain channelopathies represent a growing class of brain disorders that usually result in paroxysmal disorders, although their role in other neurological phenotypes, including the recently described NALCN-related infantile encephalopathy, is increasingly recognized. In three Saudi Arabian families and one Egyptian family all affected by a remarkably similar phenotype (infantile encephalopathy and largely normal brain MRI) to that of NALCN-related infantile encephalopathy, we identified a locus on 2q34 in which whole-exome sequencing revealed three, including two apparently loss-of-function, recessive mutations in UNC80. UNC80 encodes a large protein that is necessary for the stability and function of NALCN and for bridging NALCN to UNC79 to form a functional complex. Our results expand the clinical relevance of the UNC79-UNC80-NALCN channel complex. Copyright © 2016 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

NPAS1-ARNT and NPAS3-ARNT crystal structures implicate the bHLH-PAS family as multi-ligand binding transcription factors

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

Wu, Dalei; Su, Xiaoyu; Potluri, Nalini

Here, the neuronal PAS domain proteins NPAS1 and NPAS3 are members of the basic helix-loop-helix-PER-ARNT-SIM (bHLH-PAS) family, and their genetic deficiencies are linked to a variety of human psychiatric disorders including schizophrenia, autism spectrum disorders and bipolar disease. NPAS1 and NPAS3 must each heterodimerize with the aryl hydrocarbon receptor nuclear translocator (ARNT), to form functional transcription complexes capable of DNA binding and gene regulation. Here we examined the crystal structures of multi-domain NPAS1-ARNT and NPAS3-ARNT-DNA complexes, discovering each to contain four putative ligand-binding pockets. Through expanded architectural comparisons between these complexes and HIF-1α-ARNT, HIF-2α-ARNT and CLOCK-BMAL1, we show the widermore » mammalian bHLH-PAS family is capable of multi-ligand-binding and presents as an ideal class of transcription factors for direct targeting by small-molecule drugs.« less

NPAS1-ARNT and NPAS3-ARNT crystal structures implicate the bHLH-PAS family as multi-ligand binding transcription factors

DOE PAGES

Wu, Dalei; Su, Xiaoyu; Potluri, Nalini; ...

2016-10-26

Here, the neuronal PAS domain proteins NPAS1 and NPAS3 are members of the basic helix-loop-helix-PER-ARNT-SIM (bHLH-PAS) family, and their genetic deficiencies are linked to a variety of human psychiatric disorders including schizophrenia, autism spectrum disorders and bipolar disease. NPAS1 and NPAS3 must each heterodimerize with the aryl hydrocarbon receptor nuclear translocator (ARNT), to form functional transcription complexes capable of DNA binding and gene regulation. Here we examined the crystal structures of multi-domain NPAS1-ARNT and NPAS3-ARNT-DNA complexes, discovering each to contain four putative ligand-binding pockets. Through expanded architectural comparisons between these complexes and HIF-1α-ARNT, HIF-2α-ARNT and CLOCK-BMAL1, we show the widermore » mammalian bHLH-PAS family is capable of multi-ligand-binding and presents as an ideal class of transcription factors for direct targeting by small-molecule drugs.« less

Complex movement disorders at disease onset in childhood narcolepsy with cataplexy

PubMed Central

Pizza, Fabio; Palaia, Vincenzo; Franceschini, Christian; Poli, Francesca; Moghadam, Keivan K.; Cortelli, Pietro; Nobili, Lino; Bruni, Oliviero; Dauvilliers, Yves; Lin, Ling; Edwards, Mark J.; Mignot, Emmanuel; Bhatia, Kailash P.

2011-01-01

Narcolepsy with cataplexy is characterized by daytime sleepiness, cataplexy (sudden loss of bilateral muscle tone triggered by emotions), sleep paralysis, hypnagogic hallucinations and disturbed nocturnal sleep. Narcolepsy with cataplexy is most often associated with human leucocyte antigen-DQB1*0602 and is caused by the loss of hypocretin-producing neurons in the hypothalamus of likely autoimmune aetiology. Noting that children with narcolepsy often display complex abnormal motor behaviours close to disease onset that do not meet the classical definition of cataplexy, we systematically analysed motor features in 39 children with narcolepsy with cataplexy in comparison with 25 age- and sex-matched healthy controls. We found that patients with narcolepsy with cataplexy displayed a complex array of ‘negative’ (hypotonia) and ‘active’ (ranging from perioral movements to dyskinetic–dystonic movements or stereotypies) motor disturbances. ‘Active’ and ‘negative’ motor scores correlated positively with the presence of hypotonic features at neurological examination and negatively with disease duration, whereas ‘negative’ motor scores also correlated negatively with age at disease onset. These observations suggest that paediatric narcolepsy with cataplexy often co-occurs with a complex movement disorder at disease onset, a phenomenon that may vanish later in the course of the disease. Further studies are warranted to assess clinical course and whether the associated movement disorder is also caused by hypocretin deficiency or by additional neurochemical abnormalities. PMID:21930661

Medial Prefrontal Lesions in Mice Impair Sustained Attention but Spare Maintenance of Information in Working Memory

ERIC Educational Resources Information Center

Kahn, Julia B.; Ward, Ryan D.; Kahn, Lora W.; Rudy, Nicole M.; Kandel, Eric R.; Balsam, Peter D.; Simpson, Eleanor H.

2012-01-01

Working memory and attention are complex cognitive functions that are disrupted in several neuropsychiatric disorders. Mouse models of such human diseases are commonly subjected to maze-based tests that can neither distinguish between these cognitive functions nor isolate specific aspects of either function. Here, we have adapted a simple visual…

METAGENOMICS AND PERSONALIZED MEDICINE

PubMed Central

Virgin, Herbert W.; Todd, John A.

2015-01-01

The microbiome is a complex community of Bacteria, Archaea, Eukarya and viruses that infect humans and live in our tissues. It contributes the majority of genetic information to our metagenome, and consequently, to our resistance and susceptibility to diseases, especially common inflammatory diseases, such as type 1 diabetes, ulcerative colitis, and Crohn's disease. Here we discuss how host-gene-microbial interactions are major determinants for the development of these multifactorial chronic disorders and thus, for the relationship between genotype and phenotype. We also explore how genome-wide association studies (GWAS) on autoimmune and inflammatory diseases are uncovering mechanism-based sub-types for these disorders. Applying these emerging concepts will permit a more complete understanding of the etiologies of complex diseases and underpin the development of both next generation animal models and new therapeutic strategies for targeting personalized disease phenotypes. PMID:21962506

Comparison of visual sensitivity to human and object motion in autism spectrum disorder.

PubMed

Kaiser, Martha D; Delmolino, Lara; Tanaka, James W; Shiffrar, Maggie

2010-08-01

Successful social behavior requires the accurate detection of other people's movements. Consistent with this, typical observers demonstrate enhanced visual sensitivity to human movement relative to equally complex, nonhuman movement [e.g., Pinto & Shiffrar, 2009]. A psychophysical study investigated visual sensitivity to human motion relative to object motion in observers with autism spectrum disorder (ASD). Participants viewed point-light depictions of a moving person and, for comparison, a moving tractor and discriminated between coherent and scrambled versions of these stimuli in unmasked and masked displays. There were three groups of participants: young adults with ASD, typically developing young adults, and typically developing children. Across masking conditions, typical observers showed enhanced visual sensitivity to human movement while observers in the ASD group did not. Because the human body is an inherently social stimulus, this result is consistent with social brain theories [e.g., Pelphrey & Carter, 2008; Schultz, 2005] and suggests that the visual systems of individuals with ASD may not be tuned for the detection of socially relevant information such as the presence of another person. Reduced visual sensitivity to human movements could compromise important social behaviors including, for example, gesture comprehension.

Animal-assisted therapy with farm animals for persons with psychiatric disorders.

PubMed

Berget, Bente; Braastad, Bjarne O

2011-01-01

Animal-assisted therapy (AAT) with farm animals for humans with psychiatric disorders may reduce depression and state anxiety, and increase self-efficacy, in many participants. Social support by the farmer appears to be important. Positive effects are best documented for persons with affective disorders or clinical depression. Effects may sometimes take a long time to be detectable, but may occur earlier if the participants are encouraged to perform more complex working skills. Progress must however be individually adapted allowing for flexibility, also between days. Therapists involved with mental health show a pronounced belief in the effects of AAT with farm animals, variation being related to type of disorder, therapist's sex and his/her experience with AAT. Research is still scarce and further research is required to optimize and individually adapt the design of farm animal-assisted interventions.

Canonical TGF-β Signaling Negatively Regulates Neuronal Morphogenesis through TGIF/Smad Complex-Mediated CRMP2 Suppression.

PubMed

Nakashima, Hideyuki; Tsujimura, Keita; Irie, Koichiro; Ishizu, Masataka; Pan, Miao; Kameda, Tomonori; Nakashima, Kinichi

2018-05-16

Functional neuronal connectivity requires proper neuronal morphogenesis and its dysregulation causes neurodevelopmental diseases. Transforming growth factor-β (TGF-β) family cytokines play pivotal roles in development, but little is known about their contribution to morphological development of neurons. Here we show that the Smad-dependent canonical signaling of TGF-β family cytokines negatively regulates neuronal morphogenesis during brain development. Mechanistically, activated Smads form a complex with transcriptional repressor TG-interacting factor (TGIF), and downregulate the expression of a neuronal polarity regulator, collapsin response mediator protein 2. We also demonstrate that TGF-β family signaling inhibits neurite elongation of human induced pluripotent stem cell-derived neurons. Furthermore, the expression of TGF-β receptor 1, Smad4, or TGIF, which have mutations found in patients with neurodevelopmental disorders, disrupted neuronal morphogenesis in both mouse (male and female) and human (female) neurons. Together, these findings suggest that the regulation of neuronal morphogenesis by an evolutionarily conserved function of TGF-β signaling is involved in the pathogenesis of neurodevelopmental diseases. SIGNIFICANCE STATEMENT Canonical transforming growth factor-β (TGF-β) signaling plays a crucial role in multiple organ development, including brain, and mutations in components of the signaling pathway associated with several human developmental disorders. In this study, we found that Smads/TG-interacting factor-dependent canonical TGF-β signaling regulates neuronal morphogenesis through the suppression of collapsin response mediator protein-2 (CRMP2) expression during brain development, and that function of this signaling is evolutionarily conserved in the mammalian brain. Mutations in canonical TGF-β signaling factors identified in patients with neurodevelopmental disorders disrupt the morphological development of neurons. Thus, our results suggest that proper control of TGF-β/Smads/CRMP2 signaling pathways is critical for the precise execution of neuronal morphogenesis, whose impairment eventually results in neurodevelopmental disorders. Copyright © 2018 the authors 0270-6474/18/384791-20$15.00/0.

L-type Ca2+ channels in mood, cognition and addiction: integrating human and rodent studies with a focus on behavioural endophenotypes.

PubMed

Kabir, Z D; Lee, A S; Rajadhyaksha, A M

2016-10-15

Brain Ca v 1.2 and Ca v 1.3 L-type Ca 2+ channels play key physiological roles in various neuronal processes that contribute to brain function. Genetic studies have recently identified CACNA1C as a candidate risk gene for bipolar disorder (BD), schizophrenia (SCZ), major depressive disorder (MDD) and autism spectrum disorder (ASD), and CACNA1D for BD and ASD, suggesting a contribution of Ca v 1.2 and Ca v 1.3 Ca 2+ signalling to the pathophysiology of neuropsychiatric disorders. Once considered sole clinical entities, it is now clear that BD, SCZ, MDD and ASD share common phenotypic features, most likely due to overlapping neurocircuitry and common molecular mechanisms. A major future challenge lies in translating the human genetic findings to pathological mechanisms that are translatable back to the patient. One approach for tackling such a daunting scientific endeavour for complex behaviour-based neuropsychiatric disorders is to examine intermediate biological phenotypes in the context of endophenotypes within distinct behavioural domains. This will better allow us to integrate findings from genes to behaviour across species, and improve the chances of translating preclinical findings to clinical practice. © 2016 The Authors. The Journal of Physiology © 2016 The Physiological Society.

Quantification of nanoscale density fluctuations by electron microscopy: probing cellular alterations in early carcinogenesis

NASA Astrophysics Data System (ADS)

Pradhan, Prabhakar; Damania, Dhwanil; Joshi, Hrushikesh M.; Turzhitsky, Vladimir; Subramanian, Hariharan; Roy, Hemant K.; Taflove, Allen; Dravid, Vinayak P.; Backman, Vadim

2011-04-01

Most cancers are curable if they are diagnosed and treated at an early stage. Recent studies suggest that nanoarchitectural changes occur within cells during early carcinogenesis and that such changes precede microscopically evident tissue alterations. It follows that the ability to comprehensively interrogate cell nanoarchitecture (e.g., macromolecular complexes, DNA, RNA, proteins and lipid membranes) could be critical to the diagnosis of early carcinogenesis. We present a study of the nanoscale mass-density fluctuations of biological tissues by quantifying their degree of disorder at the nanoscale. Transmission electron microscopy images of human tissues are used to construct corresponding effective disordered optical lattices. The properties of nanoscale disorder are then studied by statistical analysis of the inverse participation ratio (IPR) of the spatially localized eigenfunctions of these optical lattices at the nanoscale. Our results show an increase in the disorder of human colonic epithelial cells in subjects harboring early stages of colon neoplasia. Furthermore, our findings strongly suggest that increased nanoscale disorder correlates with the degree of tumorigenicity. Therefore, the IPR technique provides a practicable tool for the detection of nanoarchitectural alterations in the earliest stages of carcinogenesis. Potential applications of the technique for early cancer screening and detection are also discussed. Originally submitted for the special focus issue on physical oncology.

Exploring the Validity of Proposed Transgenic Animal Models of Attention-Deficit Hyperactivity Disorder (ADHD).

PubMed

de la Peña, June Bryan; Dela Peña, Irene Joy; Custodio, Raly James; Botanas, Chrislean Jun; Kim, Hee Jin; Cheong, Jae Hoon

2018-05-01

Attention-deficit/hyperactivity disorder (ADHD) is a common, behavioral, and heterogeneous neurodevelopmental condition characterized by hyperactivity, impulsivity, and inattention. Symptoms of this disorder are managed by treatment with methylphenidate, amphetamine, and/or atomoxetine. The cause of ADHD is unknown, but substantial evidence indicates that this disorder has a significant genetic component. Transgenic animals have become an essential tool in uncovering the genetic factors underlying ADHD. Although they cannot accurately reflect the human condition, they can provide insights into the disorder that cannot be obtained from human studies due to various limitations. An ideal animal model of ADHD must have face (similarity in symptoms), predictive (similarity in response to treatment or medications), and construct (similarity in etiology or underlying pathophysiological mechanism) validity. As the exact etiology of ADHD remains unclear, the construct validity of animal models of ADHD would always be limited. The proposed transgenic animal models of ADHD have substantially increased and diversified over the years. In this paper, we compiled and explored the validity of proposed transgenic animal models of ADHD. Each of the reviewed transgenic animal models has strengths and limitations. Some fulfill most of the validity criteria of an animal model of ADHD and have been extensively used, while there are others that require further validation. Nevertheless, these transgenic animal models of ADHD have provided and will continue to provide valuable insights into the genetic underpinnings of this complex disorder.

Chronic complex dissociative disorders and borderline personality disorder: disorders of emotion dysregulation?

PubMed

Brand, Bethany L; Lanius, Ruth A

2014-01-01

Emotion dysregulation is a core feature of chronic complex dissociative disorders (DD), as it is for borderline personality disorder (BPD). Chronic complex DD include dissociative identity disorder (DID) and the most common form of dissociative disorder not otherwise specified (DDNOS, type 1), now known as Other Specified Dissociative Disorders (OSDD, type 1). BPD is a common comorbid disorder with DD, although preliminary research indicates the disorders have some distinguishing features as well as considerable overlap. This article focuses on the epidemiology, clinical presentation, psychological profile, treatment, and neurobiology of chronic complex DD with emphasis placed on the role of emotion dysregulation in each of these areas. Trauma experts conceptualize borderline symptoms as often being trauma based, as are chronic complex DD. We review the preliminary research that compares DD to BPD in the hopes that this will stimulate additional comparative research.

Mapping rare and common causal alleles for complex human diseases

PubMed Central

Raychaudhuri, Soumya

2011-01-01

Advances in genotyping and sequencing technologies have revolutionized the genetics of complex disease by locating rare and common variants that influence an individual’s risk for diseases, such as diabetes, cancers, and psychiatric disorders. However, to capitalize on this data for prevention and therapies requires the identification of causal alleles and a mechanistic understanding for how these variants contribute to the disease. After discussing the strategies currently used to map variants for complex diseases, this Primer explores how variants may be prioritized for follow-up functional studies and the challenges and approaches for assessing the contributions of rare and common variants to disease phenotypes. PMID:21962507

Genetics of human hydrocephalus

PubMed Central

Williams, Michael A.; Rigamonti, Daniele

2006-01-01

Human hydrocephalus is a common medical condition that is characterized by abnormalities in the flow or resorption of cerebrospinal fluid (CSF), resulting in ventricular dilatation. Human hydrocephalus can be classified into two clinical forms, congenital and acquired. Hydrocephalus is one of the complex and multifactorial neurological disorders. A growing body of evidence indicates that genetic factors play a major role in the pathogenesis of hydrocephalus. An understanding of the genetic components and mechanism of this complex disorder may offer us significant insights into the molecular etiology of impaired brain development and an accumulation of the cerebrospinal fluid in cerebral compartments during the pathogenesis of hydrocephalus. Genetic studies in animal models have started to open the way for understanding the underlying pathology of hydrocephalus. At least 43 mutants/loci linked to hereditary hydrocephalus have been identified in animal models and humans. Up to date, 9 genes associated with hydrocephalus have been identified in animal models. In contrast, only one such gene has been identified in humans. Most of known hydrocephalus gene products are the important cytokines, growth factors or related molecules in the cellular signal pathways during early brain development. The current molecular genetic evidence from animal models indicate that in the early development stage, impaired and abnormal brain development caused by abnormal cellular signaling and functioning, all these cellular and developmental events would eventually lead to the congenital hydrocephalus. Owing to our very primitive knowledge of the genetics and molecular pathogenesis of human hydrocephalus, it is difficult to evaluate whether data gained from animal models can be extrapolated to humans. Initiation of a large population genetics study in humans will certainly provide invaluable information about the molecular and cellular etiology and the developmental mechanisms of human hydrocephalus. This review summarizes the recent findings on this issue among human and animal models, especially with reference to the molecular genetics, pathological, physiological and cellular studies, and identifies future research directions. PMID:16773266

Identification and Characterization of FAM124B as a Novel Component of a CHD7 and CHD8 Containing Complex

PubMed Central

Batsukh, Tserendulam; Schulz, Yvonne; Wolf, Stephan; Rabe, Tamara I.; Oellerich, Thomas; Urlaub, Henning; Schaefer, Inga-Marie; Pauli, Silke

2012-01-01

Background Mutations in the chromodomain helicase DNA binding protein 7 gene (CHD7) lead to CHARGE syndrome, an autosomal dominant multiple malformation disorder. Proteins involved in chromatin remodeling typically act in multiprotein complexes. We previously demonstrated that a part of human CHD7 interacts with a part of human CHD8, another chromodomain helicase DNA binding protein presumably being involved in the pathogenesis of neurodevelopmental (NDD) and autism spectrum disorders (ASD). Because identification of novel CHD7 and CHD8 interacting partners will provide further insights into the pathogenesis of CHARGE syndrome and ASD/NDD, we searched for additional associated polypeptides using the method of stable isotope labeling by amino acids in cell culture (SILAC) in combination with mass spectrometry. Principle findings The hitherto uncharacterized FAM124B (Family with sequence similarity 124B) was identified as a potential interaction partner of both CHD7 and CHD8. We confirmed the result by co-immunoprecipitation studies and showed a direct binding to the CHD8 part by direct yeast two hybrid experiments. Furthermore, we characterized FAM124B as a mainly nuclear localized protein with a widespread expression in embryonic and adult mouse tissues. Conclusion Our results demonstrate that FAM124B is a potential interacting partner of a CHD7 and CHD8 containing complex. From the overlapping expression pattern between Chd7 and Fam124B at murine embryonic day E12.5 and the high expression of Fam124B in the developing mouse brain, we conclude that Fam124B is a novel protein possibly involved in the pathogenesis of CHARGE syndrome and neurodevelopmental disorders. PMID:23285124

A 3-Dimensional Atlas of Human Tongue Muscles

PubMed Central

SANDERS, IRA; MU, LIANCAI

2013-01-01

The human tongue is one of the most important yet least understood structures of the body. One reason for the relative lack of research on the human tongue is its complex anatomy. This is a real barrier to investigators as there are few anatomical resources in the literature that show this complex anatomy clearly. As a result, the diagnosis and treatment of tongue disorders lags behind that for other structures of the head and neck. This report intended to fill this gap by displaying the tongue’s anatomy in multiple ways. The primary material used in this study was serial axial images of the male and female human tongue from the Visible Human (VH) Project of the National Library of Medicine. In addition, thick serial coronal sections of three human tongues were rendered translucent. The VH axial images were computer reconstructed into serial coronal sections and each tongue muscle was outlined. These outlines were used to construct a 3-dimensional computer model of the tongue that allows each muscle to be seen in its in vivo anatomical position. The thick coronal sections supplement the 3-D model by showing details of the complex interweaving of tongue muscles throughout the tongue. The graphics are perhaps the clearest guide to date to aid clinical or basic science investigators in identifying each tongue muscle in any part of the human tongue. PMID:23650264

Complexity and multifractality of neuronal noise in mouse and human hippocampal epileptiform dynamics.

PubMed

Serletis, Demitre; Bardakjian, Berj L; Valiante, Taufik A; Carlen, Peter L

2012-10-01

Fractal methods offer an invaluable means of investigating turbulent nonlinearity in non-stationary biomedical recordings from the brain. Here, we investigate properties of complexity (i.e. the correlation dimension, maximum Lyapunov exponent, 1/f(γ) noise and approximate entropy) and multifractality in background neuronal noise-like activity underlying epileptiform transitions recorded at the intracellular and local network scales from two in vitro models: the whole-intact mouse hippocampus and lesional human hippocampal slices. Our results show evidence for reduced dynamical complexity and multifractal signal features following transition to the ictal epileptiform state. These findings suggest that pathological breakdown in multifractal complexity coincides with loss of signal variability or heterogeneity, consistent with an unhealthy ictal state that is far from the equilibrium of turbulent yet healthy fractal dynamics in the brain. Thus, it appears that background noise-like activity successfully captures complex and multifractal signal features that may, at least in part, be used to classify and identify brain state transitions in the healthy and epileptic brain, offering potential promise for therapeutic neuromodulatory strategies for afflicted patients suffering from epilepsy and other related neurological disorders.

Coenzyme Q biosynthesis in health and disease.

PubMed

Acosta, Manuel Jesús; Vazquez Fonseca, Luis; Desbats, Maria Andrea; Cerqua, Cristina; Zordan, Roberta; Trevisson, Eva; Salviati, Leonardo

2016-08-01

Coenzyme Q (CoQ, or ubiquinone) is a remarkable lipid that plays an essential role in mitochondria as an electron shuttle between complexes I and II of the respiratory chain, and complex III. It is also a cofactor of other dehydrogenases, a modulator of the permeability transition pore and an essential antioxidant. CoQ is synthesized in mitochondria by a set of at least 12 proteins that form a multiprotein complex. The exact composition of this complex is still unclear. Most of the genes involved in CoQ biosynthesis (COQ genes) have been studied in yeast and have mammalian orthologues. Some of them encode enzymes involved in the modification of the quinone ring of CoQ, but for others the precise function is unknown. Two genes appear to have a regulatory role: COQ8 (and its human counterparts ADCK3 and ADCK4) encodes a putative kinase, while PTC7 encodes a phosphatase required for the activation of Coq7. Mutations in human COQ genes cause primary CoQ(10) deficiency, a clinically heterogeneous mitochondrial disorder with onset from birth to the seventh decade, and with clinical manifestation ranging from fatal multisystem disorders, to isolated encephalopathy or nephropathy. The pathogenesis of CoQ(10) deficiency involves deficient ATP production and excessive ROS formation, but possibly other aspects of CoQ(10) function are implicated. CoQ(10) deficiency is unique among mitochondrial disorders since an effective treatment is available. Many patients respond to oral CoQ(10) supplementation. Nevertheless, treatment is still problematic because of the low bioavailability of the compound, and novel pharmacological approaches are currently being investigated. This article is part of a Special Issue entitled 'EBEC 2016: 19th European Bioenergetics Conference, Riva del Garda, Italy, July 2-6, 2016', edited by Prof. Paolo Bernardi. Copyright © 2016. Published by Elsevier B.V.

Comparative analyses of the neuron numbers and volumes of the amygdaloid complex in old and new world primates.

PubMed

Carlo, C N; Stefanacci, L; Semendeferi, K; Stevens, C F

2010-04-15

The amygdaloid complex (AC), a key component of the limbic system, is a brain region critical for the detection and interpretation of emotionally salient information. Therefore, changes in its structure and function are likely to provide correlates of mood and emotion disorders, diseases that afflict a large portion of the human population. Previous gross comparisons of the AC in control and diseased individuals have, however, mainly failed to discover these expected correlations with diseases. We have characterized AC nuclei in different nonhuman primate species to establish a baseline for more refined comparisons between the normal and the diseased amygdala. AC nuclei volume and neuron number in 19 subdivisions are reported from 13 Old and New World primate brains, spanning five primate species, and compared with corresponding data from humans. Analysis of the four largest AC nuclei revealed that volume and neuron number of one component, the central nucleus, has a negative allometric relationship with total amygdala volume and neuron number, which is in contrast with the isometric relationship found in the other AC nuclei (for both neuron number and volume). Neuron density decreases across all four nuclei according to a single power law with an exponent of about minus one-half. Because we have included quantitative comparisons with great apes and humans, our conclusions apply to human brains, and our scaling laws can potentially be used to study the anatomical correlates of the amygdala in disorders involving pathological emotion processing. (c) 2009 Wiley-Liss, Inc.

The role of intestinal microbiota in the pathogenesis of metabolic diseases.

PubMed

Węgielska, Iwona; Suliburska, Joanna

2016-01-01

The incidence of metabolic diseases is increasing rapidly all over the world. This situation has led researchers to attempt to explain the pathomechanisms of these disorders and to develop specific recommendations for the prevention and treatment of diseases such as obesity, type-2 diabetes, and atherosclerosis. Recent studies show clear evidence of the role of human intestinal microbiota in health and in predispositions to diseases. Gut microbiota affect a number of complex metabolic reactions, significantly altering the functioning of the human body. Numerous experiments have shown the key role played by the formation process of the intestinal ecosystem in the early stages of human life for programming its metabolic health. The following article is a compilation of the literature available on the formation of the complex intestinal ecosystem and its impact on the incidence of diseases such as obesity, type-2 diabetes, and atherosclerosis.

Human structural variation: mechanisms of chromosome rearrangements

PubMed Central

Weckselblatt, Brooke; Rudd, M. Katharine

2015-01-01

Chromosome structural variation (SV) is a normal part of variation in the human genome, but some classes of SV can cause neurodevelopmental disorders. Analysis of the DNA sequence at SV breakpoints can reveal mutational mechanisms and risk factors for chromosome rearrangement. Large-scale SV breakpoint studies have become possible recently owing to advances in next-generation sequencing (NGS) including whole-genome sequencing (WGS). These findings have shed light on complex forms of SV such as triplications, inverted duplications, insertional translocations, and chromothripsis. Sequence-level breakpoint data resolve SV structure and determine how genes are disrupted, fused, and/or misregulated by breakpoints. Recent improvements in breakpoint sequencing have also revealed non-allelic homologous recombination (NAHR) between paralogous long interspersed nuclear element (LINE) or human endogenous retrovirus (HERV) repeats as a cause of deletions, duplications, and translocations. This review covers the genomic organization of simple and complex constitutional SVs, as well as the molecular mechanisms of their formation. PMID:26209074

Biochemical Fractionation and Stable Isotope Dilution Liquid Chromatography-mass Spectrometry for Targeted and Microdomain-specific Protein Quantification in Human Postmortem Brain Tissue*

PubMed Central

MacDonald, Matthew L.; Ciccimaro, Eugene; Prakash, Amol; Banerjee, Anamika; Seeholzer, Steven H.; Blair, Ian A.; Hahn, Chang-Gyu

2012-01-01

Synaptic architecture and its adaptive changes require numerous molecular events that are both highly ordered and complex. A majority of neuropsychiatric illnesses are complex trait disorders, in which multiple etiologic factors converge at the synapse via many signaling pathways. Investigating the protein composition of synaptic microdomains from human patient brain tissues will yield valuable insights into the interactions of risk genes in many disorders. These types of studies in postmortem tissues have been limited by the lack of proper study paradigms. Thus, it is necessary not only to develop strategies to quantify protein and post-translational modifications at the synapse, but also to rigorously validate them for use in postmortem human brain tissues. In this study we describe the development of a liquid chromatography-selected reaction monitoring method, using a stable isotope-labeled neuronal proteome standard prepared from the brain tissue of a stable isotope-labeled mouse, for the multiplexed quantification of target synaptic proteins in mammalian samples. Additionally, we report the use of this method to validate a biochemical approach for the preparation of synaptic microdomain enrichments from human postmortem prefrontal cortex. Our data demonstrate that a targeted mass spectrometry approach with a true neuronal proteome standard facilitates accurate and precise quantification of over 100 synaptic proteins in mammalian samples, with the potential to quantify over 1000 proteins. Using this method, we found that protein enrichments in subcellular fractions prepared from human postmortem brain tissue were strikingly similar to those prepared from fresh mouse brain tissue. These findings demonstrate that biochemical fractionation methods paired with targeted proteomic strategies can be used in human brain tissues, with important implications for the study of neuropsychiatric disease. PMID:22942359

Minireview: Epigenetics of Obesity and Diabetes in Humans

PubMed Central

Slomko, Howard; Heo, Hye J.

2012-01-01

Understanding the determinants of human health and disease is overwhelmingly complex, particularly for common, late-onset, chronic disorders, such as obesity and diabetes. Elucidating the genetic and environmental factors that influence susceptibility to disruptions in energy homeostasis and metabolic regulation remain a challenge, and progress will entail the integration of multiple assessments of temporally dynamic environmental exposures in the context of each individual's genotype. To meet this challenge, researchers are increasingly exploring the epigenome, which is the malleable interface of gene-environment interactions. Epigenetic variation, whether innate or induced, contributes to variation in gene expression, the range of potential individual responses to internal and external cues, and risk for metabolic disease. Ultimately, advancement in our understanding of chronic disease susceptibility in humans will depend on refinement of exposure assessment tools and systems biology approaches to interpretation. In this review, we present recent progress in epigenetics of human obesity and diabetes, existing challenges, and the potential for new approaches to unravel the complex biology of metabolic dysregulation. PMID:22253427

Minireview: Epigenetics of obesity and diabetes in humans.

PubMed

Slomko, Howard; Heo, Hye J; Einstein, Francine H

2012-03-01

Understanding the determinants of human health and disease is overwhelmingly complex, particularly for common, late-onset, chronic disorders, such as obesity and diabetes. Elucidating the genetic and environmental factors that influence susceptibility to disruptions in energy homeostasis and metabolic regulation remain a challenge, and progress will entail the integration of multiple assessments of temporally dynamic environmental exposures in the context of each individual's genotype. To meet this challenge, researchers are increasingly exploring the epigenome, which is the malleable interface of gene-environment interactions. Epigenetic variation, whether innate or induced, contributes to variation in gene expression, the range of potential individual responses to internal and external cues, and risk for metabolic disease. Ultimately, advancement in our understanding of chronic disease susceptibility in humans will depend on refinement of exposure assessment tools and systems biology approaches to interpretation. In this review, we present recent progress in epigenetics of human obesity and diabetes, existing challenges, and the potential for new approaches to unravel the complex biology of metabolic dysregulation.

Patient-Specific Computational Modeling of Human Phonation

NASA Astrophysics Data System (ADS)

Xue, Qian; Zheng, Xudong; University of Maine Team

2013-11-01

Phonation is a common biological process resulted from the complex nonlinear coupling between glottal aerodynamics and vocal fold vibrations. In the past, the simplified symmetric straight geometric models were commonly employed for experimental and computational studies. The shape of larynx lumen and vocal folds are highly three-dimensional indeed and the complex realistic geometry produces profound impacts on both glottal flow and vocal fold vibrations. To elucidate the effect of geometric complexity on voice production and improve the fundamental understanding of human phonation, a full flow-structure interaction simulation is carried out on a patient-specific larynx model. To the best of our knowledge, this is the first patient-specific flow-structure interaction study of human phonation. The simulation results are well compared to the established human data. The effects of realistic geometry on glottal flow and vocal fold dynamics are investigated. It is found that both glottal flow and vocal fold dynamics present a high level of difference from the previous simplified model. This study also paved the important step toward the development of computer model for voice disease diagnosis and surgical planning. The project described was supported by Grant Number ROlDC007125 from the National Institute on Deafness and Other Communication Disorders (NIDCD).

Using Gene Ontology to describe the role of the neurexin-neuroligin-SHANK complex in human, mouse and rat and its relevance to autism.

PubMed

Patel, Sejal; Roncaglia, Paola; Lovering, Ruth C

2015-06-06

People with an autistic spectrum disorder (ASD) display a variety of characteristic behavioral traits, including impaired social interaction, communication difficulties and repetitive behavior. This complex neurodevelopment disorder is known to be associated with a combination of genetic and environmental factors. Neurexins and neuroligins play a key role in synaptogenesis and neurexin-neuroligin adhesion is one of several processes that have been implicated in autism spectrum disorders. In this report we describe the manual annotation of a selection of gene products known to be associated with autism and/or the neurexin-neuroligin-SHANK complex and demonstrate how a focused annotation approach leads to the creation of more descriptive Gene Ontology (GO) terms, as well as an increase in both the number of gene product annotations and their granularity, thus improving the data available in the GO database. The manual annotations we describe will impact on the functional analysis of a variety of future autism-relevant datasets. Comprehensive gene annotation is an essential aspect of genomic and proteomic studies, as the quality of gene annotations incorporated into statistical analysis tools affects the effective interpretation of data obtained through genome wide association studies, next generation sequencing, proteomic and transcriptomic datasets.

The neurobiology of social environmental risk for schizophrenia: an evolving research field.

PubMed

Akdeniz, Ceren; Tost, Heike; Meyer-Lindenberg, Andreas

2014-04-01

Schizophrenia is a severe and complex brain disorder that usually manifests in early adulthood and disturbs a wide range of human functions. More than 100 years after its initial description, the pathophysiology of the disorder is still incompletely understood. Many epidemiological studies strongly suggest a complex interaction between genetic and environmental risk factors for the development of the disorder. While there is considerable evidence for a social environmental component of this risk, the links between adverse social factors and altered brain function have just come into focus. In the present review, we first summarize epidemiological evidence for the significance of social environmental risk factors, outline the role of altered social stress processing in mental illness, and review the latest experimental evidence for the neural correlates of social environmental risk for schizophrenia. The studies we have discussed in this review provide a selection of the current work in the field. We suggest that many of the social environmental risk factors may impact on perceived social stress and engage neural circuits in the brain whose functional and structural architecture undergoes detrimental change in response to prolonged exposure. We conclude that multidisciplinary approaches involving various fields and thoroughly constructed longitudinal designs are necessary to capture complex structure of social environmental risks.

The Relationship of Complex Post-traumatic Stress Disorder and Post-traumatic Stress Disorder in a Culturally Distinct, Conflict-Affected Population: A Study among West Papuan Refugees Displaced to Papua New Guinea.

PubMed

Silove, Derrick; Tay, Alvin Kuowei; Kareth, Moses; Rees, Susan

2017-01-01

Controversy continues about the validity of the construct of complex post-traumatic stress disorder (C-PTSD). In particular, questions remain whether C-PTSD can be differentiated from post-traumatic stress disorder (PTSD) and, secondarily, other common mental disorders. The examination of these issues needs to be expanded to populations of diverse cultural backgrounds exposed to prolonged persecution. We undertake such an inquiry among a community sample of West Papuan refugees exposed to extensive persecution and trauma. We interviewed over 300 West Papuan refugees using the Refugee-Mental Health Assessment Package to record symptoms of PTSD, C-PTSD, major depressive disorder (MDD), and complex grief (CG). We used first- and second-order confirmatory factor analysis (CFA) to test aspects of the convergent and discriminant validity of C-PTSD. The CFA analysis supported both a one-factor and two-factor model of PTSD and C-PTSD. Nested model comparison tests provide support for the parsimonious one-factor model solution. A second-order CFA model of PTSD and C-PTSD produced a poor fit. The modified three-factor multi-disorder solution combining a traumatic stress (TS) factor (amalgamating PTSD and C-PTSD), MDD, and CG yielded a good fit only after removing three CG domains (estrangement, yearning, and behavioral change), a model that produced large standardized residuals (>0.20). The most parsimonious model yielded a single TS factor combining symptom domains of C-PTSD and PTSD in this culturally distinct community exposed to extensive persecution and conflict-related trauma. There may be grounds for expanding the scope of psychological treatments for refugees to encompass this wider TS response. Our findings are consistent with theoretical frameworks focusing on the wider TS reaction of refugees exposed to human rights-related traumas of mass conflict, persecution, and displacement.

Binding Patterns Associated Aß-HSP60 p458 Conjugate to HLA-DR-DRB Allele of Human in Alzheimer's Disease: An In Silico Approach.

PubMed

Padmadas, Naveen; Panda, Pritam Kumar; Durairaj, Sudarsanam

2018-03-01

Alzheimer's disease (AD) is a complex, irreversible, progressive brain disorder, which diminishes memory in a slow pace and thinking skills; ranked third by experts. It is a complex disorder that involves numerous cellular and subcellular alterations. The pathogenesis of AD is still unknown, but for better understanding, we proposed an in silico analysis to find out the binding patterns associated with HSP60. Several experimental conclusions have been drawn to understand the actual mechanism behind the forming of aggregation due to misfolding. Protein misfolding disorder is experimentally identified by the accumulation of protein aggregates at the intracellular or extracellular region of brain that adversely affects the cell functioning by disrupting the connection between the cells and ultimately leading to cell death. To unravel the mystery behind the mechanism of AD through computational approach, the current proposal shows the designing of Aß-HSP60 p458 conjugate followed by secondary structure analysis, which is further targeted to HLA-DR-DRB allele of human. The antigenicity of Aß (1-42) peptide is the major concern in our study predicted through PVS server, which provides an insight into the immunogenic behavior of Aß peptide. The mechanism involved in the interaction of HSP60-Aß conjugate with HLA-DR-DRB allele considering the fact that Aß (1-42) is highly immunogenic in human and interactions evoked highly robust T-cell response through MHC class II binding predictions. It was assisted by molecular dynamics simulation of predicted HSP60 structure followed by validation through Ramachandran plot analysis and protein-protein interaction of Aß (1-42) with HSP60.

A little rein on addiction.

PubMed

Mathuru, Ajay S

2018-06-01

Rewarding and aversive experiences influence emotions, motivate specific behaviors, and modify future action in animals. Multiple conserved vertebrate neural circuits have been discovered that act in a species-specific manner to reinforce behaviors that are rewarding, while attenuating those with an adverse outcome. A growing body of research now suggests that malfunction of the same circuits is an underlying cause for many human disorders and mental ailments. The habenula (Latin for "little rein") complex, an epithalamic structure that regulates midbrain monoaminergic activity has emerged in recent years as one such region in the vertebrate brain that modulates behavior. Its dysfunction, on the other hand, is implicated in a spectrum of psychiatric disorders in humans such as schizophrenia, depression and addiction. Here, I review the progress in identification of potential mechanisms involving the habenula in addiction. Copyright © 2017. Published by Elsevier Ltd.

Improvement of driving safety in road traffic system

NASA Astrophysics Data System (ADS)

Li, Ke-Ping; Gao, Zi-You

2005-05-01

A road traffic system is a complex system in which humans participate directly. In this system, human factors play a very important role. In this paper, a kind of control signal is designated at a given site (i.e., signal point) of the road. Under the effect of the control signal, the drivers will decrease their velocities when their vehicles pass the signal point. Our aim is to transit the traffic flow states from disorder to order and then improve the traffic safety. We have tested this technique for the two-lane traffic model that is based on the deterministic Nagel-Schreckenberg (NaSch) traffic model. The simulation results indicate that the traffic flow states can be transited from disorder to order. Different order states can be observed in the system and these states are safer.

Genetic and non-genetic animal models for autism spectrum disorders (ASD).

PubMed

Ergaz, Zivanit; Weinstein-Fudim, Liza; Ornoy, Asher

2016-09-01

Autism spectrum disorder (ASD) is associated, in addition to complex genetic factors, with a variety of prenatal, perinatal and postnatal etiologies. We discuss the known animal models, mostly in mice and rats, of ASD that helps us to understand the etiology, pathogenesis and treatment of human ASD. We describe only models where behavioral testing has shown autistic like behaviors. Some genetic models mimic known human syndromes like fragile X where ASD is part of the clinical picture, and others are without defined human syndromes. Among the environmentally induced ASD models in rodents, the most common model is the one induced by valproic acid (VPA) either prenatally or early postnatally. VPA induces autism-like behaviors following single exposure during different phases of brain development, implying that the mechanism of action is via a general biological mechanism like epigenetic changes. Maternal infection and inflammation are also associated with ASD in man and animal models. Copyright © 2016 Elsevier Inc. All rights reserved.

Mouse models for human hair loss disorders

PubMed Central

Porter, Rebecca M

2003-01-01

The outer surface of the hand, limb and body is covered by the epidermis, which is elaborated into a number of specialized appendages, evolved not only to protect and reinforce the skin but also for social signalling. The most prominent of these appendages is the hair follicle. Hair follicles are remarkable because of their prolific growth characteristics and their complexity of differentiation. After initial embryonic morphogenesis, the hair follicle undergoes repeated cycles of regression and regeneration throughout the lifetime of the organism. Studies of mouse mutants with hair loss phenotypes have suggested that the mechanisms controlling the hair cycle probably involve many of the major signalling molecules used elsewhere in development, although the complete pathway of hair follicle growth control is not yet understood. Mouse studies have also led to the discovery of genes underlying several human disorders. Future studies of mouse hair-loss mutants are likely to benefit the understanding of human hair loss as well as increasing our knowledge of mechanisms controlling morphogenesis and tumorigenesis. PMID:12587927

Application of induced pluripotent stem cells to understand neurobiological basis of bipolar disorder and schizophrenia.

PubMed

Liu, Yao-Nan; Lu, Si-Yao; Yao, Jun

2017-09-01

The etiology of neuropsychiatric disorders, such as schizophrenia and bipolar disorder, usually involves complex combinations of genetic defects/variations and environmental impacts, which hindered, for a long time, research efforts based on animal models and patients' non-neuronal cells or post-mortem tissues. However, the development of human induced pluripotent stem cell (iPSC) technology by the Yamanaka group was immediately applied to establish cell research models for neuronal disorders. Since then, techniques to achieve highly efficient differentiation of different types of neural cells following iPSC modeling have made much progress. The fast-growing iPSC and neural differentiation techniques have brought valuable insights into the pathology and neurobiology of neuropsychiatric disorders. In this article, we first review the application of iPSC technology in modeling neuronal disorders and discuss the progress in the accompanying neural differentiation. Then, we summarize the progress in iPSC-based research that has been accomplished so far regarding schizophrenia and bipolar disorder. © 2017 The Authors. Psychiatry and Clinical Neurosciences © 2017 Japanese Society of Psychiatry and Neurology.

Mitochondrial iron-sulfur cluster biogenesis from molecular understanding to clinical disease

PubMed Central

Alfadhel, Majid; Nashabat, Marwan; Ali, Qais Abu; Hundallah, Khalid

2017-01-01

Iron–sulfur clusters (ISCs) are known to play a major role in various protein functions. Located in the mitochondria, cytosol, endoplasmic reticulum and nucleus, they contribute to various core cellular functions. Until recently, only a few human diseases related to mitochondrial ISC biogenesis defects have been described. Such diseases include Friedreich ataxia, combined oxidative phosphorylation deficiency 19, infantile complex II/III deficiency defect, hereditary myopathy with lactic acidosis and mitochondrial muscle myopathy, lipoic acid biosynthesis defects, multiple mitochondrial dysfunctions syndromes and non ketotic hyperglycinemia due to glutaredoxin 5 gene defect. Disorders of mitochondrial import, export and translation, including sideroblastic anemia with ataxia, EVEN-PLUS syndrome and mitochondrial complex I deficiency due to nucleotide-binding protein-like protein gene defect, have also been implicated in ISC biogenesis defects. With advances in next generation sequencing technologies, more disorders related to ISC biogenesis defects are expected to be elucidated. In this article, we aim to shed the light on mitochondrial ISC biogenesis, related proteins and their function, pathophysiology, clinical phenotypes of related disorders, diagnostic approach, and future implications. PMID:28064324

Genetic testing for patients with renal disease: procedures, pitfalls, and ethical considerations.

PubMed

Korf, B R

1999-07-01

The Human Genome Project is rapidly producing insights into the molecular basis of human genetic disorders. The most immediate clinical benefit is the advent of new diagnostic methods. Molecular diagnostic tools are available for several genetic renal disorders and are in development for many more. Two general approaches to molecular diagnosis are linkage-based testing and direct mutation detection. The former is used when the gene has not been cloned but has been mapped in relation to polymorphic loci. Linkage-based testing is also helpful when a large diversity of mutations makes direct detection difficult. Limitations include the need to study multiple family members, the need for informative polymorphisms, and genetic heterogeneity. Direct mutation detection is limited by genetic heterogeneity and the need to distinguish nonpathogenic allelic variants from pathogenic mutations. Molecular testing raises a number of complex ethical issues, including those associated with prenatal or presymptomatic diagnosis. In addition, there are concerns about informed consent, privacy, genetic discrimination, and technology transfer for newly developed tests. Health professionals need to be aware of the technical and ethical implications of these new methods of testing, as well as the complexities in test interpretation, as molecular approaches are increasingly integrated into medical practice.

HERV Envelope Proteins: Physiological Role and Pathogenic Potential in Cancer and Autoimmunity

PubMed Central

Grandi, Nicole; Tramontano, Enzo

2018-01-01

Human endogenous retroviruses (HERVs) are relics of ancient infections accounting for about the 8% of our genome. Despite their persistence in human DNA led to the accumulation of mutations, HERVs are still contributing to the human transcriptome, and a growing number of findings suggests that their expression products may have a role in various diseases. Among HERV products, the envelope proteins (Env) are currently highly investigated for their pathogenic properties, which could likely be participating to several disorders with complex etiology, particularly in the contexts of autoimmunity and cancer. In fact, HERV Env proteins have been shown, on the one side, to trigger both innate and adaptive immunity, prompting inflammatory, cytotoxic and apoptotic reactions; and, on the other side, to prevent the immune response activation, presenting immunosuppressive properties and acting as immune downregulators. In addition, HERV Env proteins have been shown to induce abnormal cell-cell fusion, possibly contributing to tumor development and metastasizing processes. Remarkably, even highly defective HERV env genes and alternative env splicing variants can provide further mechanisms of pathogenesis. A well-known example is the HERV-K(HML2) env gene that, depending on the presence or the absence of a 292-bp deletion, can originate two proteins of different length (Np9 and Rec) proposed to have oncogenic properties. The understanding of their involvement in complex pathological disorders made HERV Env proteins potential targets for therapeutic interventions. Of note, a monoclonal antibody directed against a HERV-W Env is currently under clinical trial as therapeutic approach for multiple sclerosis, representing the first HERV-based treatment. The present review will focus on the current knowledge of the HERV Env expression, summarizing its role in human physiology and its possible pathogenic effects in various cancer and autoimmune disorders. It moreover analyzes HERV Env possible exploitation for the development of innovative therapeutic strategies. PMID:29593697

Bridging the gap: large animal models in neurodegenerative research.

PubMed

Eaton, S L; Wishart, T M

2017-08-01

The world health organisation has declared neurological disorders as one of the greatest public health risks in the world today. Yet, despite this growing concern, the mechanisms underpinning many of these conditions are still poorly understood. This may in part be due to the seemingly diverse nature of the initiating insults ranging from genetic (such as the Ataxia's and Lysosomal storage disorders) through to protein misfolding and aggregation (i.e. Prions), and those of a predominantly unknown aetiology (i.e. Alzheimer's and Parkinson's disease). However, efforts to elucidate mechanistic regulation are also likely to be hampered because of the complexity of the human nervous system, the apparent selective regional vulnerability and differential degenerative progression. The key to elucidating these aetiologies is determining the regional molecular cascades, which are occurring from the early through to terminal stages of disease progression. Whilst much molecular data have been captured at the end stage of disease from post-mortem analysis in humans, the very early stages of disease are often conspicuously asymptomatic, and even if they were not, repeated sampling from multiple brain regions of "affected" patients and "controls" is neither ethical nor possible. Model systems therefore become fundamental for elucidating the mechanisms governing these complex neurodegenerative conditions. However, finding a model that precisely mimics the human condition can be challenging and expensive. Whilst cellular and invertebrate models are frequently used in neurodegenerative research and have undoubtedly yielded much useful data, the comparatively simplistic nature of these systems makes insights gained from such a stand alone model limited when it comes to translation. Given the recent advances in gene editing technology, the options for novel model generation in higher order species have opened up new and exciting possibilities for the field. In this review, we therefore explain some of the reasons why larger animal models often appear to give a more robust recapitulation of human neurological disorders and why they may be a critical stepping stone for effective therapeutic translation.

RAGE splicing variants in mammals.

PubMed

Sterenczak, Katharina Anna; Nolte, Ingo; Murua Escobar, Hugo

2013-01-01

The receptor for advanced glycation end products (RAGE) is a multiligand receptor of environmental stressors which plays key roles in pathophysiological processes, including immune/inflammatory disorders, Alzheimer's disease, diabetic arteriosclerosis, tumorigenesis, and metastasis. Besides the full-length RAGE protein in humans nearly 20 natural occurring RAGE splicing variants were described on mRNA and protein level. These naturally occurring isoforms are characterized by either N-terminally or C-terminally truncations and are discussed as possible regulators of the full-length RAGE receptor either by competitive ligand binding or by displacing the full-length protein in the membrane. Accordingly, expression deregulations of the naturally occurring isoforms were supposed to have significant effect on RAGE-mediated disorders. Thereby the soluble C-truncated RAGE isoforms present in plasma and tissues are the mostly focused isoforms in research and clinics. Deregulations of the circulating levels of soluble RAGE forms were reported in several RAGE-associated pathological disorders including for example atherosclerosis, diabetes, renal failure, Alzheimer's disease, and several cancer types. Regarding other mammalian species, the canine RAGE gene showed high similarities to the corresponding human structures indicating RAGE to be evolutionary highly conserved between both species. Similar to humans the canine RAGE showed a complex and extensive splicing activity leading to a manifold pattern of RAGE isoforms. Due to the similarities seen in several canine and human diseases-including cancer-comparative structural and functional analyses allow the development of RAGE and ligand-specific therapeutic approaches beneficial for human and veterinary medicine.

Multilayer modeling and analysis of human brain networks

PubMed Central

2017-01-01

Abstract Understanding how the human brain is structured, and how its architecture is related to function, is of paramount importance for a variety of applications, including but not limited to new ways to prevent, deal with, and cure brain diseases, such as Alzheimer’s or Parkinson’s, and psychiatric disorders, such as schizophrenia. The recent advances in structural and functional neuroimaging, together with the increasing attitude toward interdisciplinary approaches involving computer science, mathematics, and physics, are fostering interesting results from computational neuroscience that are quite often based on the analysis of complex network representation of the human brain. In recent years, this representation experienced a theoretical and computational revolution that is breaching neuroscience, allowing us to cope with the increasing complexity of the human brain across multiple scales and in multiple dimensions and to model structural and functional connectivity from new perspectives, often combined with each other. In this work, we will review the main achievements obtained from interdisciplinary research based on magnetic resonance imaging and establish de facto, the birth of multilayer network analysis and modeling of the human brain. PMID:28327916

Cerebellar Development and Disease

PubMed Central

Gleeson, Joseph G.

2008-01-01

Recent Advances The molecular control of cell type specification within the developing cerebellum as well as the genetic causes of the most common human developmental cerebellar disorders have long remained mysterious. Recent genetic lineage and loss-of-function data from mice have revealed unique and non-overlapping anatomical origins for GABAergic neurons from ventricular zone precursors and glutamatergic cell from rhombic lip precursors, mirroring distinct origins for these neurotransmitter-specific cell types in the cerebral cortex. Mouse studies elucidating the role of Ptf1a as a cerebellar ventricular zone GABerigic fate switch were actually preceded by the recognition that PTF1A mutations in humans cause cerebellar agenesis, a birth defect of the human cerebellum. Indeed, several genes for congenital human cerebellar malformations have recently been identified, including genes causing Joubert syndrome, Dandy-Walker malformation and Ponto-cerebellar hypoplasia. These studies have pointed to surprisingly complex roles for transcriptional regulation, mitochondrial function and neuronal cilia in patterning, homeostasis and cell proliferation during cerebellar development. Together mouse and human studies are synergistically advancing our understanding of the developmental mechanisms that generate the uniquely complex mature cerebellum. PMID:18513948

The human lexinome: Genes of language and reading

PubMed Central

Gibson, Christopher J.; Gruen, Jeffrey R.

2008-01-01

Within the human genome, genetic mapping studies have identified ten regions of different chromosomes, known as DYX loci, in genetic linkage with dyslexia, and two, known as SLI loci, in genetic linkage with Specific Language Impairment. Further genetic studies have identified four dyslexia genes within the DYX loci: DYX1C1 on 15q, KIAA0319 and DCDC2 on 6p22, and ROBO1on 13q. FOXP2 on 7q has been implicated in the development of Speech-Language Disorder. No genes for Specific Language impairment have yet been identified within the two SLI loci. Functional studies have shown that all four dyslexia genes play roles in brain development, and ongoing molecular studies are attempting to elucidate how these genes exert their effects at a subcellular level. Taken together, these genes and loci likely represent only a fraction of the human lexinome, a term we introduce here to refer to the collection of all the genetic and protein elements involved in the development of human language, expression, and reading. Learning outcomes The reader will become familiar with (i) methods for identifying genes for complex diseases, (ii) the application of these methods in the elucidation of genes underlying disorders of language and reading, and (iii) the cellular pathways through which polymorphisms in these genes may contribute to the development of the disorders. PMID:18466916

Human Neuroimaging of Oxytocin and Vasopressin in Social Cognition

PubMed Central

Zink, Caroline F; Meyer-Lindenberg, Andreas

2012-01-01

The neuropeptides oxytocin and vasopressin have increasingly been identified as modulators of human social behaviors and associated with neuropsychiatric disorders characterized by social dysfunction, such as autism. Identifying the human brain regions that are impacted by oxytocin and vasopressin in a social context is essential to fully characterize the role of oxytocin and vasopressin in complex human social cognition. Advances in human non-invasive neuroimaging techniques and genetics have enabled scientists to begin to elucidate the neurobiological basis of the influence of oxytocin and vasopressin on human social behaviors. Here we review the findings to-date from investigations of the acute and chronic effects of oxytocin and vasopressin on neural activity underlying social cognitive processes using “pharmacological fMRI” and “imaging genetics”, respectively. PMID:22326707

How informative is the mouse for human gut microbiota research?

PubMed Central

Nguyen, Thi Loan Anh; Vieira-Silva, Sara; Liston, Adrian; Raes, Jeroen

2015-01-01

The microbiota of the human gut is gaining broad attention owing to its association with a wide range of diseases, ranging from metabolic disorders (e.g. obesity and type 2 diabetes) to autoimmune diseases (such as inflammatory bowel disease and type 1 diabetes), cancer and even neurodevelopmental disorders (e.g. autism). Having been increasingly used in biomedical research, mice have become the model of choice for most studies in this emerging field. Mouse models allow perturbations in gut microbiota to be studied in a controlled experimental setup, and thus help in assessing causality of the complex host-microbiota interactions and in developing mechanistic hypotheses. However, pitfalls should be considered when translating gut microbiome research results from mouse models to humans. In this Special Article, we discuss the intrinsic similarities and differences that exist between the two systems, and compare the human and murine core gut microbiota based on a meta-analysis of currently available datasets. Finally, we discuss the external factors that influence the capability of mouse models to recapitulate the gut microbiota shifts associated with human diseases, and investigate which alternative model systems exist for gut microbiota research. PMID:25561744

How informative is the mouse for human gut microbiota research?

PubMed

Nguyen, Thi Loan Anh; Vieira-Silva, Sara; Liston, Adrian; Raes, Jeroen

2015-01-01

The microbiota of the human gut is gaining broad attention owing to its association with a wide range of diseases, ranging from metabolic disorders (e.g. obesity and type 2 diabetes) to autoimmune diseases (such as inflammatory bowel disease and type 1 diabetes), cancer and even neurodevelopmental disorders (e.g. autism). Having been increasingly used in biomedical research, mice have become the model of choice for most studies in this emerging field. Mouse models allow perturbations in gut microbiota to be studied in a controlled experimental setup, and thus help in assessing causality of the complex host-microbiota interactions and in developing mechanistic hypotheses. However, pitfalls should be considered when translating gut microbiome research results from mouse models to humans. In this Special Article, we discuss the intrinsic similarities and differences that exist between the two systems, and compare the human and murine core gut microbiota based on a meta-analysis of currently available datasets. Finally, we discuss the external factors that influence the capability of mouse models to recapitulate the gut microbiota shifts associated with human diseases, and investigate which alternative model systems exist for gut microbiota research. © 2015. Published by The Company of Biologists Ltd.

Human mitochondrial DNA: roles of inherited and somatic mutations

PubMed Central

Schon, Eric A.; DiMauro, Salvatore; Hirano, Michio

2014-01-01

Mutations in the human mitochondrial genome are known to cause an array of diverse disorders, most of which are maternally inherited, and all of which are associated with defects in oxidative energy metabolism. It is now emerging that somatic mutations in mitochondrial DNA (mtDNA) are also linked to other complex traits, including neurodegenerative diseases, ageing and cancer. Here we discuss insights into the roles of mtDNA mutations in a wide variety of diseases, highlighting the interesting genetic characteristics of the mitochondrial genome and challenges in studying its contribution to pathogenesis. PMID:23154810

Williams syndrome as a model of genetically determined right-hemisphere dominance.

PubMed

Bogdanov, N N; Solonichenko, V G

1997-01-01

Studies were carried out on the dermatoglyphics (skin ridge marks) on the hands of children with Williams syndrome; this is an inherited disease with cardiovascular pathology and a characteristic facial phenotype ("elf" facies), along with specific mental and cognitive disturbances. The results suggest a characteristic dermatoglyphic type with the presence of complex whorls on the fingers and a clear predominance of marks of greater complexity on the left hand; this is a very rare trait in normal people and in those with other inherited nervous system disorders. The features of the dermatoglyphic pattern serve as a characteristic marker of a genetically determined state of the human central nervous system, and suggests directions for neurophysiological studies of children with Williams syndrome as a unique model for analysis of higher nervous function in humans.

The intrinsically disordered C-terminal domain of the measles virus nucleoprotein interacts with the C-terminal domain of the phosphoprotein via two distinct sites and remains predominantly unfolded

PubMed Central

Bourhis, Jean-Marie; Receveur-Bréchot, Véronique; Oglesbee, Michael; Zhang, Xinsheng; Buccellato, Matthew; Darbon, Hervé; Canard, Bruno; Finet, Stéphanie; Longhi, Sonia

2005-01-01

Measles virus is a negative-sense, single-stranded RNA virus within theMononegavirales order,which includes several human pathogens, including rabies, Ebola, Nipah, and Hendra viruses. Themeasles virus nucleoprotein consists of a structured N-terminal domain, and of an intrinsically disordered C-terminal domain, NTAIL (aa 401–525), which undergoes induced folding in the presence of the C-terminal domain (XD, aa 459–507) of the viral phosphoprotein. With in NTAIL, an α-helical molecular recognition element (α-MoRE, aa 488–499) involved in binding to P and in induced folding was identified and then observed in the crystal structure of XD. Using small-angle X-ray scattering, we have derived a low-resolution structural model of the complex between XD and NTAIL, which shows that most of NTAIL remains disordered in the complex despite P-induced folding within the α-MoRE. The model consists of an extended shape accommodating the multiple conformations adopted by the disordered N-terminal region of NTAIL, and of a bulky globular region, corresponding to XD and to the C terminus of NTAIL (aa 486–525). Using surface plasmon resonance, circular dichroism, fluorescence spectroscopy, and heteronuclear magnetic resonance, we show that NTAIL has an additional site (aa 517–525) involved in binding to XD but not in the unstructured-to-structured transition. This work provides evidence that intrinsically disordered domains can establish complex interactions with their partners, and can contact them through multiple sites that do not all necessarily gain regular secondary structure. PMID:16046624

Insights into Chronic Functional Movement Disorders: The Value of Qualitative Psychiatric Interviews.

PubMed

Epstein, Steven A; Maurer, Carine W; LaFaver, Kathrin; Ameli, Rezvan; Sinclair, Stephen; Hallett, Mark

Patients with functional movement disorders (FMDs) are commonly seen by neurologists and psychosomatic medicine psychiatrists. Research literature provides scant information about the subjective experiences of individuals with this often chronic problem. To enhance our understanding of psychologic aspects of FMDs by conducting qualitative interviews of research subjects. In total, 36 patients with FMDs were recruited from the Human Motor Control clinic at the National Institutes of Health. Each subject participated in a qualitative psychiatric interview and a structured diagnostic psychiatric interview. Of our 36 subjects, 28 had current or lifetime psychiatric disorders in addition to conversion disorder and 22 had current disorders. Qualitative interviews provided rich information on patients' understanding of their illnesses and impaired cognitive processing of emotions. Our study supports the addition of open-ended qualitative interviews to delineate emotional dynamics and conceptual frameworks among such patients. Exploratory interviews generate enhanced understanding of such complex patients, above and beyond that gained by assessing DSM diagnostic comorbidities. Copyright © 2016 The Academy of Psychosomatic Medicine. All rights reserved.

Translational Chemistry Meets Gluten-Related Disorders.

PubMed

Lammers, Karen M; Herrera, Maria G; Dodero, Veronica I

2018-03-01

Gluten-related disorders are a complex group of diseases that involve the activation of the immune system triggered by the ingestion of gluten. Among these, celiac disease, with a prevalence of 1 %, is the most investigated, but recently, a new pathology, named nonceliac gluten sensitivity, was reported with a general prevalence of 7 %. Finally, there other less-prevalent gluten-related diseases such as wheat allergy, gluten ataxia, and dermatitis herpetiformis (with an overall prevalence of less than 0.1 %). As mentioned, the common molecular trigger is gluten, a complex mixture of storage proteins present in wheat, barley, and a variety of oats that are not fully degraded by humans. The most-studied protein related to disease is gliadin, present in wheat, which possesses in its sequence many pathological fragments. Despite a lot of effort to treat these disorders, the only effective method is a long-life gluten-free diet. This Review summarizes the actual knowledge of gluten-related disorders from a translational chemistry point of view. We discuss what is currently known from the literature about the interaction of gluten with the gut and the critical host responses it evokes and, finally, connect them to our current and novel molecular understanding of the supramolecular organization of gliadin and the 33-mer gliadin peptide fragment under physiological conditions.

X-linked juvenile retinoschisis: mutations at the retinoschisis and Norrie disease gene loci?

PubMed

Hiraoka, M; Rossi, F; Trese, M T; Shastry, B S

2001-01-01

Juvenile retinoschisis (RS) and Norrie disease (ND) are X-linked recessive retinal disorders. Both disorders, in the majority of cases, are monogenic and are caused by mutations in the RS and ND genes, respectively. Here we report the identification of a family in which mutations in both the RS and ND genes are segregating with RS pathology. Although the mutations identified in this report were not functionally characterized with regard to their pathogenicity, it is likely that both of them are involved in RS pathology in the family analyzed. This suggests the complexity and digenic nature of monogenic human disorders in some cases. If this proves to be a widespread problem, it will complicate the strategies used to identify the genes involved in diseases and to develop methods for intervention.

Discovery of biochemical biomarkers for aggression: A role for metabolomics in psychiatry.

PubMed

Hagenbeek, Fiona A; Kluft, Cornelis; Hankemeier, Thomas; Bartels, Meike; Draisma, Harmen H M; Middeldorp, Christel M; Berger, Ruud; Noto, Antonio; Lussu, Milena; Pool, René; Fanos, Vassilios; Boomsma, Dorret I

2016-07-01

Human aggression encompasses a wide range of behaviors and is related to many psychiatric disorders. We introduce the different classification systems of aggression and related disorders as a basis for discussing biochemical biomarkers and then present an overview of studies in humans (published between 1990 and 2015) that reported statistically significant associations of biochemical biomarkers with aggression, DSM-IV disorders involving aggression, and their subtypes. The markers are of different types, including inflammation markers, neurotransmitters, lipoproteins, and hormones from various classes. Most studies focused on only a limited portfolio of biomarkers, frequently a specific class only. When integrating the data, it is clear that compounds from several biological pathways have been found to be associated with aggressive behavior, indicating complexity and the need for a broad approach. In the second part of the paper, using examples from the aggression literature and psychiatric metabolomics studies, we argue that a better understanding of aggression would benefit from a more holistic approach such as provided by metabolomics. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

[Role of environment in complex diseases: air pollution and food contaminants].

PubMed

Scheen, A J; Giet, D

2012-01-01

Our polluted environment exposes human beings, along their life, to various toxic compounds that could trigger and aggravate different complex diseases. Such a phenomenon is well recognized for cardiovascular diseases, respiratory diseases and cancers, but other chronic inflammatory disorders may also been implicated. The most common factors, but also the most toxic, and thereby the most extensively investigated, are air pollutants (both indoor and outdoor pollution) and various contaminants present in drinking water and food (organic compounds, chemical products, heavy metals, ...). The complex interrelationships between food and pollutants, on the one hand, and between gene and environmental pollutants, including the influence of epigenetics, on the other hand, deserve further careful studies.

The age of anxiety: role of animal models of anxiolytic action in drug discovery

PubMed Central

Cryan, John F; Sweeney, Fabian F

2011-01-01

Anxiety disorders are common, serious and a growing health problem worldwide. However, the causative factors, aetiology and underlying mechanisms of anxiety disorders, as for most psychiatric disorders, remain relatively poorly understood. Animal models are an important aid in giving insight into the aetiology, neurobiology and, ultimately, the therapy of human anxiety disorders. The approach, however, is challenged with a number of complexities. In particular, the heterogeneous nature of anxiety disorders in humans coupled with the associated multifaceted and descriptive diagnostic criteria, creates challenges in both animal modelling and in clinical research. In this paper, we describe some of the more widely used approaches for assessing the anxiolytic activity of known and potential therapeutic agents. These include ethological, conflict-based, hyponeophagia, vocalization-based, physiological and cognitive-based paradigms. Developments in the characterization of translational models are also summarized, as are the challenges facing researchers in their drug discovery efforts in developing new anxiolytic drugs, not least the ever-shifting clinical conceptualization of anxiety disorders. In conclusion, to date, although animal models of anxiety have relatively good validity, anxiolytic drugs with novel mechanisms have been slow to emerge. It is clear that a better alignment of the interactions between basic and clinical scientists is needed if this is to change. LINKED ARTICLES This article is part of a themed issue on Translational Neuropharmacology. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.164.issue-4 PMID:21545412

Genetic Variation in Cardiomyopathy and Cardiovascular Disorders.

PubMed

McNally, Elizabeth M; Puckelwartz, Megan J

2015-01-01

With the wider deployment of massively-parallel, next-generation sequencing, it is now possible to survey human genome data for research and clinical purposes. The reduced cost of producing short-read sequencing has now shifted the burden to data analysis. Analysis of genome sequencing remains challenged by the complexity of the human genome, including redundancy and the repetitive nature of genome elements and the large amount of variation in individual genomes. Public databases of human genome sequences greatly facilitate interpretation of common and rare genetic variation, although linking database sequence information to detailed clinical information is limited by privacy and practical issues. Genetic variation is a rich source of knowledge for cardiovascular disease because many, if not all, cardiovascular disorders are highly heritable. The role of rare genetic variation in predicting risk and complications of cardiovascular diseases has been well established for hypertrophic and dilated cardiomyopathy, where the number of genes that are linked to these disorders is growing. Bolstered by family data, where genetic variants segregate with disease, rare variation can be linked to specific genetic variation that offers profound diagnostic information. Understanding genetic variation in cardiomyopathy is likely to help stratify forms of heart failure and guide therapy. Ultimately, genetic variation may be amenable to gene correction and gene editing strategies.

Modeling anorexia nervosa: transcriptional insights from human iPSC-derived neurons

PubMed Central

Negraes, P D; Cugola, F R; Herai, R H; Trujillo, C A; Cristino, A S; Chailangkarn, T; Muotri, A R; Duvvuri, V

2017-01-01

Anorexia nervosa (AN) is a complex and multifactorial disorder occurring predominantly in women. Despite having the highest mortality among psychiatric conditions, it still lacks robust and effective treatment. Disorders such as AN are most likely syndromes with multiple genetic contributions, however, genome-wide studies have been underpowered to reveal associations with this uncommon illness. Here, we generated induced pluripotent stem cells (iPSCs) from adolescent females with AN and unaffected controls. These iPSCs were differentiated into neural cultures and subjected to extensive transcriptome analysis. Within a small cohort of patients who presented for treatment, we identified a novel gene that appears to contribute to AN pathophysiology, TACR1 (tachykinin 1 receptor). The participation of tachykinins in a variety of biological processes and their interactions with other neurotransmitters suggest novel mechanisms for how a disrupted tachykinin system might contribute to AN symptoms. Although TACR1 has been associated with psychiatric conditions, especially anxiety disorders, we believe this report is its first association with AN. Moreover, our human iPSC approach is a proof-of-concept that AN can be modeled in vitro with a full human genetic complement, and represents a new tool for understanding the elusive molecular and cellular mechanisms underlying the disease. PMID:28291261

Advances in Electronic-Nose Technologies for the Detection of Volatile Biomarker Metabolites in the Human Breath

PubMed Central

Wilson, Alphus D.

2015-01-01

Recent advancements in the use of electronic-nose (e-nose) devices to analyze human breath profiles for the presence of specific volatile metabolites, known as biomarkers or chemical bio-indicators of specific human diseases, metabolic disorders and the overall health status of individuals, are providing the potential for new noninvasive tools and techniques useful to point-of-care clinical disease diagnoses. This exciting new area of electronic disease detection and diagnosis promises to yield much faster and earlier detection of human diseases and disorders, allowing earlier, more effective treatments, resulting in more rapid patient recovery from various afflictions. E-nose devices are particularly suited for the field of disease diagnostics, because they are sensitive to a wide range of volatile organic compounds (VOCs) and can effectively distinguish between different complex gaseous mixtures via analysis of electronic aroma sensor-array output profiles of volatile metabolites present in the human breath. This review provides a summary of some recent developments of electronic-nose technologies, particularly involving breath analysis, with the potential for providing many new diagnostic applications for the detection of specific human diseases associated with different organs in the body, detectable from e-nose analyses of aberrant disease-associated VOCs present in air expired from the lungs. PMID:25738426

Oxytocin in animal models of autism spectrum disorder.

PubMed

Peñagarikano, Olga

2017-02-01

Autism spectrum disorder is a behavioral disorder characterized by impairments in social interaction and communication together with the presence of stereotyped behaviors and restricted interests. Although highly genetic, its etiology is complex which correlates with the extensive heterogeneity found in its clinical manifestation, adding to the challenge of understanding its pathophysiology and develop targeted pharmacotherapies. The neuropeptide oxytocin is part of a highly conserved system involved in the regulation of social behavior, and both animal and human research have shown that variation in the oxytocin system accounts for interindividual differences in the expression of social behaviors in mammals. In autism, recent studies in human patients and animal models are starting to reveal that alterations in the oxytocin system are more common than previously anticipated. Genetic variation in the key players involved in the system (i.e., oxytocin receptor, oxytocin, and CD38) has been found associated with autism in humans, and animal models of the disorder converge in an altered oxytocin system and/or dysfunction in oxytocin related biological processes. Furthermore, oxytocin administration exerts a behavioral and neurobiological response, and thus, the oxytocin system has become a promising potential therapeutical target for autism. Animal models represent a valuable tool to aid in the research into the potential therapeutic use of oxytocin. In this review, I aim to discuss the main findings related to oxytocin research in autism with a focus on findings in animal models. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 202-213, 2017. © 2016 Wiley Periodicals, Inc.

Understanding the genetics of autoimmune disease: two loci that regulate late onset Addison’s disease in Portuguese Water Dogs

PubMed Central

Chase, K.; Sargan, D.; Miller, K.; Ostrander, E. A.; Lark, K. G.

2009-01-01

Summary Addison’s disease, an immune-mediated disorder caused by destruction of the adrenal glands, is a rare disorder of Western European populations. Studies indicate that the disorder is polygenic in nature, involving specific alleles of the CTLA-4, DRB1*04 and DQ, Cyp27B1, VDR and MIC-A and -B loci. A similar immune form of Addison’s disease occurs in several breeds of domestic dog, with frequencies ranging from 1.5 to 9.0%. The high frequency of the disease in domestic dog breeds likely reflects the small number of founders associated with many breeds, subsequent inbreeding, and the frequent use of popular sires. The Portuguese Water Dog (PWD) is a significantly affected breed. An analysis of 11 384 PWDs surveyed between 1985 and 1996 suggests a breed-specific disease incidence of 1.5%. As with humans, the disease is typically of late onset. This study involves a genetic comparison of Addison’s disease in the PWD to the analogous disease in humans. The study is facilitated by the existence of complete pedigrees and a relatively high degree of inbreeding among PWDs. The breed originated from 31 founders, with 10 animals responsible for 90% of the current gene pool. We describe, specifically, the identification of two disease-associated loci, on Canis familiaris (CFA) chromosomes CFA12 and 37, which are syntenic with the human DRB1 histocompatibility locus alleles HLA-DRB1* 04 and DRB1*0301, and to a locus for immunosuppression syntenic with CTLA-4. Strong similarities exist therefore in the complex genetic background of Addison’s disease in humans and in the PWD. With the completion of the canine and human genome sequence, the purebred dog is set to become an important comparative model for Addison’s as well as other human immune disorders. PMID:16712648

Human swallowing simulation based on videofluorography images using Hamiltonian MPS method

NASA Astrophysics Data System (ADS)

Kikuchi, Takahiro; Michiwaki, Yukihiro; Kamiya, Tetsu; Toyama, Yoshio; Tamai, Tasuku; Koshizuka, Seiichi

2015-09-01

In developed nations, swallowing disorders and aspiration pneumonia have become serious problems. We developed a method to simulate the behavior of the organs involved in swallowing to clarify the mechanisms of swallowing and aspiration. The shape model is based on anatomically realistic geometry, and the motion model utilizes forced displacements based on realistic dynamic images to reflect the mechanisms of human swallowing. The soft tissue organs are modeled as nonlinear elastic material using the Hamiltonian MPS method. This method allows for stable simulation of the complex swallowing movement. A penalty method using metaballs is employed to simulate contact between organ walls and smooth sliding along the walls. We performed four numerical simulations under different analysis conditions to represent four cases of swallowing, including a healthy volunteer and a patient with a swallowing disorder. The simulation results were compared to examine the epiglottic downfolding mechanism, which strongly influences the risk of aspiration.

Biological restoration of central nervous system architecture and function: part 3-stem cell- and cell-based applications and realities in the biological management of central nervous system disorders: traumatic, vascular, and epilepsy disorders.

PubMed

Farin, Azadeh; Liu, Charles Y; Langmoen, Iver A; Apuzzo, Michael L J

2009-11-01

STEM CELL THERAPY has emerged as a promising novel therapeutic endeavor for traumatic brain injury, spinal cord injury, stroke, and epilepsy in experimental studies. A few preliminary clinical trials have further supported its safety and early efficacy after transplantation into humans. Although not yet clinically available for central nervous system disorders, stem cell technology is expected to evolve into one of the most powerful tools in the biological management of complex central nervous system disorders, many of which currently have limited treatment modalities. The identification of stem cells, discovery of neurogenesis, and application of stem cells to treat central nervous system disorders represent a dramatic evolution and expansion of the neurosurgeon's capabilities into the neurorestoration and neuroregeneration realms. In Part 3 of a 5-part series on stem cells, we discuss the theory, experimental evidence, and clinical data pertaining to the use of stem cells for the treatment of traumatic, vascular, and epileptic disorders.

Early Life Stress, Mood, and Anxiety Disorders.

PubMed

Syed, Shariful A; Nemeroff, Charles B

2017-02-01

Early life stress has been shown to exert profound short- and long-term effects on human physiology both in the central nervous system and peripherally. Early life stress has demonstrated clear association with many psychiatric disorders including major depression, posttraumatic stress disorder, and bipolar disorder. The Diagnostic and Statistics Manuel of Mental Disorders (DSM) diagnostic categorical system has served as a necessary framework for clinical service, delivery, and research, however has not been completely matching the neurobiological research perspective. Early life stress presents a complex dynamic featuring a wide spectrum of physiologic alterations: from epigenetic alterations, inflammatory changes, to dysregulation of the hypothalamic pituitary axis and has further added to the challenge of identifying biomarkers associated with psychiatric disorders. The National Institute of Mental Health's proposed Research Domain Criteria initiative incorporates a dimensional approach to assess discrete domains and constructs of behavioral function that are subserved by identifiable neural circuits. The current neurobiology of early life stress is reviewed in accordance with dimensional organization of Research Domain Criteria matrix and how the findings as a whole fit within the Research Domain Criteria frameworks.

Klotho: a humeral mediator in CSF and plasma that influences longevity and susceptibility to multiple complex disorders, including depression.

PubMed

Pavlatou, M G; Remaley, A T; Gold, P W

2016-08-30

Klotho is a hormone secreted into human cerebrospinal fluid (CSF), plasma and urine that promotes longevity and influences the onset of several premature senescent phenotypes in mice and humans, including atherosclerosis, cardiovascular disease, stroke and osteoporosis. Preliminary studies also suggest that Klotho possesses tumor suppressor properties. Klotho's roles in these phenomena were first suggested by studies demonstrating that a defect in the Klotho gene in mice results in a significant decrease in lifespan. The Klotho-deficient mouse dies prematurely at 8-9 weeks of age. At 4-5 weeks of age, a syndrome resembling human ageing emerges consisting of atherosclerosis, osteoporosis, cognitive disturbances and alterations of hippocampal architecture. Several deficits in Klotho-deficient mice are likely to contribute to these phenomena. These include an inability to defend against oxidative stress in the central nervous system and periphery, decreased capacity to generate nitric oxide to sustain normal endothelial reactivity, defective Klotho-related mediation of glycosylation and ion channel regulation, increased insulin/insulin-like growth factor signaling and a disturbed calcium and phosphate homeostasis accompanied by altered vitamin D levels and ectopic calcification. Identifying the mechanisms by which Klotho influences multiple important pathways is an emerging field in human biology that will contribute significantly to understanding basic physiologic processes and targets for the treatment of complex diseases. Because many of the phenomena seen in Klotho-deficient mice occur in depressive illness, major depression and bipolar disorder represent illnesses potentially associated with Klotho dysregulation. Klotho's presence in CSF, blood and urine should facilitate its study in clinical populations.

Cross-β Polymerization of Low Complexity Sequence Domains.

PubMed

Kato, Masato; McKnight, Steven L

2017-03-01

Most transcription factors and RNA regulatory proteins encoded by eukaryotic genomes ranging from yeast to humans contain polypeptide domains variously described as intrinsically disordered, prion-like, or of low complexity (LC). These LC domains exist in an unfolded state when DNA and RNA regulatory proteins are studied in biochemical isolation from cells. Upon incubation in the purified state, many of these LC domains polymerize into homogeneous, labile amyloid-like fibers. Here, we consider several lines of evidence that may favor biologic utility for LC domain polymers. Copyright © 2017 Cold Spring Harbor Laboratory Press; all rights reserved.

Bridging Animal and Human Models

PubMed Central

Barkley-Levenson, Amanda M.; Crabbe, John C.

2012-01-01

Genetics play an important role in the development and course of alcohol abuse, and understanding genetic contributions to this disorder may lead to improved preventative and therapeutic strategies in the future. Studies both in humans and in animal models are necessary to fully understand the neurobiology of alcoholism from the molecular to the cognitive level. By dissecting the complex facets of alcoholism into discrete, well-defined phenotypes that are measurable in both human populations and animal models of the disease, researchers will be better able to translate findings across species and integrate the knowledge obtained from various disciplines. Some of the key areas of alcoholism research where consilience between human and animal studies is possible are alcohol withdrawal severity, sensitivity to rewards, impulsivity, and dysregulated alcohol consumption. PMID:23134048

Risk-prone individuals prefer the wrong options on a rat version of the Iowa Gambling Task.

PubMed

Rivalan, Marion; Ahmed, Serge H; Dellu-Hagedorn, Françoise

2009-10-15

Decision making in complex and conflicting situations, as measured in the widely used Iowa Gambling Task (IGT), can be profoundly impaired in psychiatric disorders, such as attention-deficit/hyperactivity disorder, drug addiction, and also in healthy individuals for whom immediate gratification prevails over long-term gain. The cognitive processes underlying these deficits are poorly understood, in part due to a lack of suitable animal models assessing complex decision making with good construct validity. We developed a rat gambling task analogous to the IGT that tracks, for the first time, the ongoing decision process within a single session in an operant cage. Rats could choose between various options. Disadvantageous options, as opposed to advantageous ones, offered bigger immediate food reward but were followed by longer, unpredictable penalties (time-out). The majority of rats can evaluate and deduce favorable options more or less rapidly according to task complexity, whereas others systematically choose disadvantageously. These interindividual differences are stable over time and do not depend on task difficulty or on the level of food restriction. We find that poor decision making does not result from a failure to acquire relevant information but from hypersensitivity to reward and higher risk taking in anxiogenic situations. These results suggest that rats, as well as human poor performers, share similar traits to those observed in decision-making related psychiatric disorders. These traits could constitute risk factors of developing such disorders. The rapid identification of poor decision makers using the rat gambling task should promote the discovery of the specific brain dysfunctions that cause maladapted decision making.

Insights into Fanconi Anaemia from the structure of human FANCE

PubMed Central

Nookala, Ravi K.; Hussain, Shobbir; Pellegrini, Luca

2007-01-01

Fanconi Anaemia (FA) is a cancer predisposition disorder characterized by spontaneous chromosome breakage and high cellular sensitivity to genotoxic agents. In response to DNA damage, a multi-subunit assembly of FA proteins, the FA core complex, monoubiquitinates the downstream FANCD2 protein. The FANCE protein plays an essential role in the FA process of DNA repair as the FANCD2-binding component of the FA core complex. Here we report a crystallographic and biological study of human FANCE. The first structure of a FA protein reveals the presence of a repeated helical motif that provides a template for the structural rationalization of other proteins defective in Fanconi Anaemia. The portion of FANCE defined by our crystallographic analysis is sufficient for interaction with FANCD2, yielding structural information into the mode of FANCD2 recruitment to the FA core complex. Disease-associated mutations disrupt the FANCE–FANCD2 interaction, providing structural insight into the molecular mechanisms of FA pathogenesis. PMID:17308347

Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia

PubMed Central

Boisson, Bertrand; Laplantine, Emmanuel; Dobbs, Kerry; Cobat, Aurélie; Tarantino, Nadine; Hazen, Melissa; Lidov, Hart G.W.; Hopkins, Gregory; Du, Likun; Belkadi, Aziz; Chrabieh, Maya; Itan, Yuval; Picard, Capucine; Fournet, Jean-Christophe; Eibel, Hermann; Tsitsikov, Erdyni; Pai, Sung-Yun; Abel, Laurent; Al-Herz, Waleed; Israel, Alain

2015-01-01

Inherited, complete deficiency of human HOIL-1, a component of the linear ubiquitination chain assembly complex (LUBAC), underlies autoinflammation, infections, and amylopectinosis. We report the clinical description and molecular analysis of a novel inherited disorder of the human LUBAC complex. A patient with multiorgan autoinflammation, combined immunodeficiency, subclinical amylopectinosis, and systemic lymphangiectasia, is homozygous for a mutation in HOIP, the gene encoding the catalytic component of LUBAC. The missense allele (L72P, in the PUB domain) is at least severely hypomorphic, as it impairs HOIP expression and destabilizes the whole LUBAC complex. Linear ubiquitination and NF-κB activation are impaired in the patient’s fibroblasts stimulated by IL-1β or TNF. In contrast, the patient’s monocytes respond to IL-1β more vigorously than control monocytes. However, the activation and differentiation of the patient’s B cells are impaired in response to CD40 engagement. These cellular and clinical phenotypes largely overlap those of HOIL-1-deficient patients. Clinical differences between HOIL-1- and HOIP-mutated patients may result from differences between the mutations, the loci, or other factors. Our findings show that human HOIP is essential for the assembly and function of LUBAC and for various processes governing inflammation and immunity in both hematopoietic and nonhematopoietic cells. PMID:26008899

The genome projects: implications for dental practice and education.

PubMed

Wright, J T; Hart, T C

2002-05-01

Information from the Human Genome Project (HGP) and the integration of information from related areas of study and technology will dramatically change health care for the craniofacial complex. Approaches to risk assessment and diagnosis, prevention, early intervention, and management of craniofacial conditions are and will continue to evolve through the application of this new knowledge. While this information will advance our health care abilities, it is clear that the dental profession will face challenges regarding the acquisition, application, transfer, and effective and efficient use of this knowledge with regards to dental research, dental education, and clinical practice. Unraveling the human genomic sequence now allows accurate diagnosis of numerous craniofacial conditions. However, the greatest oral disease burden results from dental caries and periodontal disease that are complex disorders having both hereditary and environmental factors determining disease risk, progression, and course. Disease risk assessment, prevention, and therapy, based on knowledge from the HGP, will likely vary markedly for the different complex conditions affecting the head and neck. Integration of Information from the human genome, comparative and microbial genomics, proteomics, bioinformatics, and related technologies will provide the basis for proactive prevention and intervention and novel and more efficient treatment approaches. Oral health care practitioners will increasingly require knowledge of human genetics and the application of new molecular-based diagnostic and therapeutic technologies.

Oxytocin and social cognition in rhesus macaques: Implications for understanding and treating human psychopathology

PubMed Central

Chang, Steve W. C.; Platt, Michael L.

2013-01-01

Converging evidence from humans and non-human animals indicates that the neurohypophysial hormone oxytocin (OT) evolved to serve a specialized function in social behavior in mammals. Although OT-based therapies are currently being evaluated as remedies for social deficits in neuropsychiatric disorders, precisely how OT regulates complex social processes remains largely unknown. Here we describe how a non-human primate model can be used to understand the mechanisms by which OT regulates social cognition and thereby inform its clinical application in humans. We focus primarily on recent advances in our understanding of OT-mediated social cognition in rhesus macaques (Macaca mulatta), supplemented by discussion of recent work in humans, other primates, and rodents. Together, these studies endorse the hypothesis that OT promotes social exploration both by amplifying social motivation and by attenuating social vigilance. PMID:24231551

Integrated Genomic and Network-Based Analyses of Complex Diseases and Human Disease Network.

PubMed

Al-Harazi, Olfat; Al Insaif, Sadiq; Al-Ajlan, Monirah A; Kaya, Namik; Dzimiri, Nduna; Colak, Dilek

2016-06-20

A disease phenotype generally reflects various pathobiological processes that interact in a complex network. The highly interconnected nature of the human protein interaction network (interactome) indicates that, at the molecular level, it is difficult to consider diseases as being independent of one another. Recently, genome-wide molecular measurements, data mining and bioinformatics approaches have provided the means to explore human diseases from a molecular basis. The exploration of diseases and a system of disease relationships based on the integration of genome-wide molecular data with the human interactome could offer a powerful perspective for understanding the molecular architecture of diseases. Recently, subnetwork markers have proven to be more robust and reliable than individual biomarker genes selected based on gene expression profiles alone, and achieve higher accuracy in disease classification. We have applied one of these methodologies to idiopathic dilated cardiomyopathy (IDCM) data that we have generated using a microarray and identified significant subnetworks associated with the disease. In this paper, we review the recent endeavours in this direction, and summarize the existing methodologies and computational tools for network-based analysis of complex diseases and molecular relationships among apparently different disorders and human disease network. We also discuss the future research trends and topics of this promising field. Copyright © 2015 Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, and Genetics Society of China. Published by Elsevier Ltd. All rights reserved.

A source, a cascade, a schizoid: a heuristic proposal from the Longitudinal Study of Personality Disorders.

PubMed

Lenzenweger, Mark F

2010-11-01

It is argued that personality pathology represents the final emergent product of a complex interaction of underlying neurobehavioral systems as well as environment inputs. A number of factors may be involved in the developmental pathway and a cascading of effects is plausible, although a unifying cascade for all personality disorders is not likely. The present study suggests a possible cascade relevant to one personality disorder: schizoid personality disorder in emerging adulthood. In brief, it is hypothesized that the absence of a relationship characterized by a rich degree of psychological proximal process in early childhood, which is associated with nurturance and the facilitation of more complex development, predicts impairment in the actualization of the affiliation system (i.e., that system that facilitates interpersonal connectedness and social bonds in human beings and is under substantial genetic influence), and this impairment in the affiliation system predicts the appearance of schizoid personality disorder symptoms in emerging adulthood (late teens/early 20s), which persists over time into emerging adulthood. The impairment in the affiliation system is argued to proceed through childhood sociality as reflected in temperament on through adult personality as reflected in communal positive emotion. Furthermore, it is also hypothesized that the relationship between proximal processes and the affiliation system maintains irrespective of other childhood temperament factors that might adversely impact early parent/caregiver and child relations. The data for a preliminary illustration of this possible cascade are drawn from The Longitudinal Study of Personality Disorders, which is a prospective, multiwave study of personality disorders, personality, and temperament in a large sample of adults drawn from a nonclinical population.

Cortical–Subcortical Interactions in Hypersomnia Disorders: Mechanisms Underlying Cognitive and Behavioral Aspects of the Sleep–Wake Cycle

PubMed Central

Larson-Prior, Linda J.; Ju, Yo-El; Galvin, James E.

2014-01-01

Subcortical circuits mediating sleep–wake functions have been well characterized in animal models, and corroborated by more recent human studies. Disruptions in these circuits have been identified in hypersomnia disorders (HDs) such as narcolepsy and Kleine–Levin Syndrome, as well as in neurodegenerative disorders expressing excessive daytime sleepiness. However, the behavioral expression of sleep–wake functions is not a simple on-or-off state determined by subcortical circuits, but encompasses a complex range of behaviors determined by the interaction between cortical networks and subcortical circuits. While conceived as disorders of sleep, HDs are equally disorders of wake, representing a fundamental instability in neural state characterized by lapses of alertness during wake. These episodic lapses in alertness and wakefulness are also frequently seen in neurodegenerative disorders where electroencephalogram demonstrates abnormal function in cortical regions associated with cognitive fluctuations (CFs). Moreover, functional connectivity MRI shows instability of cortical networks in individuals with CFs. We propose that the inability to stabilize neural state due to disruptions in the sleep–wake control networks is common to the sleep and cognitive dysfunctions seen in hypersomnia and neurodegenerative disorders. PMID:25309500

The pathological consequences of impaired genome integrity in humans; disorders of the DNA replication machinery.

PubMed

O'Driscoll, Mark

2017-01-01

Accurate and efficient replication of the human genome occurs in the context of an array of constitutional barriers, including regional topological constraints imposed by chromatin architecture and processes such as transcription, catenation of the helical polymer and spontaneously generated DNA lesions, including base modifications and strand breaks. DNA replication is fundamentally important for tissue development and homeostasis; differentiation programmes are intimately linked with stem cell division. Unsurprisingly, impairments of the DNA replication machinery can have catastrophic consequences for genome stability and cell division. Functional impacts on DNA replication and genome stability have long been known to play roles in malignant transformation through a variety of complex mechanisms, and significant further insights have been gained from studying model organisms in this context. Congenital hypomorphic defects in components of the DNA replication machinery have been and continue to be identified in humans. These disorders present with a wide range of clinical features. Indeed, in some instances, different mutations in the same gene underlie different clinical presentations. Understanding the origin and molecular basis of these features opens a window onto the range of developmental impacts of suboptimal DNA replication and genome instability in humans. Here, I will briefly overview the basic steps involved in DNA replication and the key concepts that have emerged from this area of research, before switching emphasis to the pathological consequences of defects within the DNA replication network; the human disorders. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Relevance of Rodent Models of Depression in Clinical Practice: Can We Overcome the Obstacles in Translational Neuropsychiatry?

PubMed

Söderlund, Johan; Lindskog, Maria

2018-04-23

The diagnosis of a mental disorder generally depends on clinical observations and phenomenological symptoms reported by the patient. The definition of a given diagnosis is criteria based and relies on the ability to accurately interpret subjective symptoms and complex behavior. This type of diagnosis comprises a challenge to translate to reliable animal models, and these translational uncertainties hamper the development of new treatments. In this review, we will discuss how depressive-like behavior can be induced in rodents, and the relationship between these models and depression in humans. Specifically, we suggest similarities between triggers of depressive-like behavior in animal models and human conditions known to increase the risk of depression, for example exhaustion and bullying. Although we acknowledge the potential problems in comparing animal findings to human conditions, such comparisons are useful for understanding the complexity of depression, and we highlight the need to develop clinical diagnoses and animal models in parallel to overcome translational uncertainties.

Strategies for the Integration of Cough and Swallow to Maintain Airway Protection in Humans.

PubMed

Huff, Alyssa; Reed, Mitchell D; Smith, Barbara K; Brown, Edward H; Ovechkin, Alexander V; Pitts, Teresa

2018-06-20

Airway protective behaviors, like cough and swallow, deteriorate in many populations suffering from neurologic disorders. While coordination of these behaviors has been investigated in an animal model, it has not been tested in humans. We used a novel protocol, adapted from previous work in the cat, to assess cough and swallow independently and their coordination strategies in seven healthy males (26 ± 6 years). Surface electromyograms of the submental complex and external oblique complex, spirometry, and thoracic and abdominal wall kinematics, were used to evaluate the timing of swallow, cough, and breathing as well as lung volume (LV) during these behaviors. Unlike the cat, there was significant variability in the cough-swallow phase preference; however, there was a targeted LV range in which swallow occurred. These results give insight into the differences between the cat and human models in airway protective strategies related to the coordination of cough and swallow behaviors, allowing for better understanding of dystussia and dysphagia.

Human Trafficking, Mental Illness, and Addiction: Avoiding Diagnostic Overshadowing.

PubMed

Stoklosa, Hanni; MacGibbon, Marti; Stoklosa, Joseph

2017-01-01

This article reviews an emergency department-based clinical vignette of a trafficked patient with co-occurring pregnancy-related, mental health, and substance use disorder issues. The authors, including a survivor of human trafficking, draw on their backgrounds in addiction care, human trafficking, emergency medicine, and psychiatry to review the literature on relevant general health and mental health consequences of trafficking and propose an approach to the clinical complexities this case presents. In their discussion, the authors explicate the deleterious role of implicit bias and diagnostic overshadowing in trafficked patients with co-occurring addiction and mental illness. Finally, the authors propose a trauma-informed, multidisciplinary response to potentially trafficked patients. © 2017 American Medical Association. All Rights Reserved.

An approach to congenital malformations of the head and neck.

PubMed

Isaacson, Glenn

2007-02-01

It is easy to be overwhelmed when faced with the hundreds of cataloged anomalies of the head and neck region. For any individual defect there may be variation in phenotype, associated anomalies, and cause. To help organize these various disorders, dysmorphologists have grouped them into "syndromes", "sequences" and "associations" based on our level of understanding of their etiologies. Recently, completion of the human genome project has added a new level of complexity to the study of human malformations by providing a flood of new information about the genetic origins of established syndromes. The article describes the dysmorphologist's approach to the child with one or more anomalies and provides a glimpse into the future of human genetics.

Influence of complex childhood diseases on variation in growth and skeletal development.

PubMed

Zemel, Babette S

2017-03-01

The study of human growth and skeletal development by human biologists is framed by the larger theoretical concerns regarding the underpinnings of population variation and human evolution. This unique perspective is directly relevant to the assessment of child health and well-being at the individual and group level, as well as the construction of growth charts. Environmental, behavioral (nutrition and physical activity), and disease-related factors can prevent attainment of full genetic potential for growth. Undernutrition is most often the cause of growth faltering and poor skeletal development. Disease related factors, such as malabsorption, inflammation, and immobility also have profound effects. These effects will be illustrated with examples from diseases such as cystic fibrosis, inflammatory bowel disease, and Down syndrome. The need for separate growth charts for children with genetic disorders is often controversial because of potential medical and/or nutritional complications associated with some disorders. Children with Alagille syndrome and Down syndrome will be used to illustrate the advantages and limitations of syndrome-specific charts. This overview of health and disease effects on growth and skeletal development provides insights into the plasticity of human growth and its sensitivity to overall health and well-being. © 2017 Wiley Periodicals, Inc.

Drosophila mutants of the autism candidate gene neurobeachin (rugose) exhibit neuro-developmental disorders, aberrant synaptic properties, altered locomotion, and impaired adult social behavior and activity patterns.

PubMed

Wise, Alexandria; Tenezaca, Luis; Fernandez, Robert W; Schatoff, Emma; Flores, Julian; Ueda, Atsushi; Zhong, Xiaotian; Wu, Chun-Fang; Simon, Anne F; Venkatesh, Tadmiri

2015-01-01

Autism spectrum disorder (ASD) is a neurodevelopmental disorder in humans characterized by complex behavioral deficits, including intellectual disability, impaired social interactions, and hyperactivity. ASD exhibits a strong genetic component with underlying multigene interactions. Candidate gene studies have shown that the neurobeachin (NBEA) gene is disrupted in human patients with idiopathic autism ( Castermans et al., 2003 ). The NBEA gene spans the common fragile site FRA 13A and encodes a signal scaffold protein ( Savelyeva et al., 2006 ). In mice, NBEA has been shown to be involved in the trafficking and function of a specific subset of synaptic vesicles. ( Medrihan et al., 2009 ; Savelyeva et al., 2006 ). Rugose (rg) is the Drosophila homolog of the mammalian and human NBEA. Our previous genetic and molecular analyses have shown that rg encodes an A kinase anchor protein (DAKAP 550), which interacts with components of the epidermal growth factor receptor or EGFR and Notch-mediated signaling pathways, facilitating cross talk between these and other pathways ( Shamloula et al., 2002 ). We now present functional data from studies on the larval neuromuscular junction that reveal abnormal synaptic architecture and physiology. In addition, adult rg loss-of-function mutants exhibit defective social interactions, impaired habituation, aberrant locomotion, and hyperactivity. These results demonstrate that Drosophila NBEA (rg) mutants exhibit phenotypic characteristics reminiscent of human ASD and thus could serve as a genetic model for studying ASDs.

The chromatin basis of neurodevelopmental disorders: Rethinking dysfunction along the molecular and temporal axes.

PubMed

Gabriele, Michele; Lopez Tobon, Alejandro; D'Agostino, Giuseppe; Testa, Giuseppe

2018-06-08

The complexity of the human brain emerges from a long and finely tuned developmental process orchestrated by the crosstalk between genome and environment. Vis à vis other species, the human brain displays unique functional and morphological features that result from this extensive developmental process that is, unsurprisingly, highly vulnerable to both genetically and environmentally induced alterations. One of the most striking outcomes of the recent surge of sequencing-based studies on neurodevelopmental disorders (NDDs) is the emergence of chromatin regulation as one of the two domains most affected by causative mutations or Copy Number Variations besides synaptic function, whose involvement had been largely predicted for obvious reasons. These observations place chromatin dysfunction at the top of the molecular pathways hierarchy that ushers in a sizeable proportion of NDDs and that manifest themselves through synaptic dysfunction and recurrent systemic clinical manifestation. Here we undertake a conceptual investigation of chromatin dysfunction in NDDs with the aim of systematizing the available evidence in a new framework: first, we tease out the developmental vulnerabilities in human corticogenesis as a structuring entry point into the causation of NDDs; second, we provide a much needed clarification of the multiple meanings and explanatory frameworks revolving around "epigenetics", highlighting those that are most relevant for the analysis of these disorders; finally we go in-depth into paradigmatic examples of NDD-causing chromatin dysregulation, with a special focus on human experimental models and datasets. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Deriving excitatory neurons of the neocortex from pluripotent stem cells

PubMed Central

Hansen, David V.; Rubenstein, John L.R.; Kriegstein, Arnold R.

2011-01-01

The human cerebral cortex is an immensely complex structure that subserves critical functions that can be disrupted in developmental and degenerative disorders. Recent innovations in cellular reprogramming and differentiation techniques have provided new ways to study the cellular components of the cerebral cortex. Here we discuss approaches to generate specific subtypes of excitatory cortical neurons from pluripotent stem cells. We review spatial and temporal aspects of cortical neuron specification that can guide efforts to produce excitatory neuron subtypes with increased resolution. Finally, we discuss distinguishing features of human cortical development and their translational ramifications for cortical stem cell technologies. PMID:21609822

GARLIC: a bioinformatic toolkit for aetiologically connecting diseases and cell type-specific regulatory maps

PubMed Central

Nikolić, Miloš; Papantonis, Argyris

2017-01-01

Abstract Genome-wide association studies (GWAS) have emerged as a powerful tool to uncover the genetic basis of human common diseases, which often show a complex, polygenic and multi-factorial aetiology. These studies have revealed that 70–90% of all single nucleotide polymorphisms (SNPs) associated with common complex diseases do not occur within genes (i.e. they are non-coding), making the discovery of disease-causative genetic variants and the elucidation of the underlying pathological mechanisms far from straightforward. Based on emerging evidences suggesting that disease-associated SNPs are frequently found within cell type-specific regulatory sequences, here we present GARLIC (GWAS-based Prediction Toolkit for Connecting Diseases and Cell Types), a user-friendly, multi-purpose software with an associated database and online viewer that, using global maps of cis-regulatory elements, can aetiologically connect human diseases with relevant cell types. Additionally, GARLIC can be used to retrieve potential disease-causative genetic variants overlapping regulatory sequences of interest. Overall, GARLIC can satisfy several important needs within the field of medical genetics, thus potentially assisting in the ultimate goal of uncovering the elusive and complex genetic basis of common human disorders. PMID:28007912

The dysbindin gene in major depression: an association study.

PubMed

Zill, Peter; Baghai, Thomas C; Engel, Rolf; Zwanzger, Peter; Schüle, Cornelius; Eser, Daniela; Behrens, Stefanie; Rupprecht, Rainer; Möller, Hans-Jürgen; Ackenheil, Manfred; Bondy, Brigitta

2004-08-15

The pathophysiological mechanisms, as well as the molecular loci of antidepressant drug action have not yet been established, but recent models proposed that several adaptive mechanisms in signal transduction cascades beyond the receptor and reuptake systems are involved in antidepressant action and play an important role in the etiology of affective disorders. In this context, the dysbindin gene (dystrobrevin-binding-protein 1, DTNBP1), which was recently reported to be associated with schizophrenia seems to be an interesting candidate gene for affective disorders. Dysbindin is widely expressed in the human brain and binds to the dystrophin-associated protein complex (DPC) which appears to be involved in signal transduction pathways, which have been repeatedly investigated and described as altered or disturbed in affective disorders [McLeod et al. [2003: Psychopharmacol Bull 35:24-41]; Brambilla et al. [2003: Mol Psychiatry 8:721-737

A new view of “dream enactment” in REM sleep behavior disorder

PubMed Central

Blumberg, Mark S.; Plumeau, Alan M.

2015-01-01

SUMMARY REM sleep behavior disorder (RBD) is a disorder in which patients exhibit increased muscle tone and exaggerated myoclonic twitching during REM sleep. In addition, violent movements of the limbs, and complex behaviors that can sometimes appear to involve the enactment of dreams, are associated with RBD. These behaviors are widely thought to result from a dysfunction involving atonia-producing neural circuitry in the brainstem, thereby unmasking cortically generated dreams. Here we scrutinize the assumptions that led to this interpretation of RBD. In particular, we challenge the assumption that motor cortex produces twitches during REM sleep, thus calling into question the related assumption that motor cortex is primarily responsible for all of the pathological movements of RBD. Moreover, motor cortex is not even necessary to produce complex behavior; for example, stimulation of some brainstem structures can produce defensive and aggressive behaviors in rats and monkeys that are striking similar to those reported in human patients with RBD. Accordingly, we suggest an interpretation of RBD that focuses increased attention on the brainstem as a source of the pathological movements and that considers sensory feedback from moving limbs as an important influence on the content of dream mentation. PMID:26802823

Gene therapy restores auditory and vestibular function in a mouse model of Usher syndrome type 1c.

PubMed

Pan, Bifeng; Askew, Charles; Galvin, Alice; Heman-Ackah, Selena; Asai, Yukako; Indzhykulian, Artur A; Jodelka, Francine M; Hastings, Michelle L; Lentz, Jennifer J; Vandenberghe, Luk H; Holt, Jeffrey R; Géléoc, Gwenaëlle S

2017-03-01

Because there are currently no biological treatments for hearing loss, we sought to advance gene therapy approaches to treat genetic deafness. We focused on Usher syndrome, a devastating genetic disorder that causes blindness, balance disorders and profound deafness, and studied a knock-in mouse model, Ush1c c.216G>A, for Usher syndrome type IC (USH1C). As restoration of complex auditory and balance function is likely to require gene delivery systems that target auditory and vestibular sensory cells with high efficiency, we delivered wild-type Ush1c into the inner ear of Ush1c c.216G>A mice using a synthetic adeno-associated viral vector, Anc80L65, shown to transduce 80-90% of sensory hair cells. We demonstrate recovery of gene and protein expression, restoration of sensory cell function, rescue of complex auditory function and recovery of hearing and balance behavior to near wild-type levels. The data represent unprecedented recovery of inner ear function and suggest that biological therapies to treat deafness may be suitable for translation to humans with genetic inner ear disorders.

Single Molecule Study of the Intrinsically Disordered FG-Repeat Nucleoporin 153

PubMed Central

Milles, Sigrid; Lemke, Edward A.

2011-01-01

Nucleoporins (Nups), which are intrinsically disordered, form a selectivity filter inside the nuclear pore complex, taking a central role in the vital nucleocytoplasmic transport mechanism. These Nups display a complex and nonrandom amino-acid architecture of phenylalanine glycine (FG)-repeat clusters and intra-FG linkers. How such heterogeneous sequence composition relates to function and could give rise to a transport mechanism is still unclear. Here we describe a combined chemical biology and single-molecule fluorescence approach to study the large human Nup153 FG-domain. In order to obtain insights into the properties of this domain beyond the average behavior, we probed the end-to-end distance (RE) of several ∼50-residues long FG-repeat clusters in the context of the whole protein domain. Despite the sequence heterogeneity of these FG-clusters, we detected a reoccurring and consistent compaction from a relaxed coil behavior under denaturing conditions (RE/RE,RC = 0.99 ± 0.15 with RE,RC corresponding to ideal relaxed coil behavior) to a collapsed state under native conditions (RE/RE,RC = 0.79 ± 0.09). We then analyzed the properties of this protein on the supramolecular level, and determined that this human FG-domain was in fact able to form a hydrogel with physiological permeability barrier properties. PMID:21961597

Altered neuronal network and rescue in a human MECP2 duplication model

PubMed Central

Nageshappa, Savitha; Carromeu, Cassiano; Trujillo, Cleber A.; Mesci, Pinar; Espuny-Camacho, Ira; Pasciuto, Emanuela; Vanderhaeghen, Pierre; Verfaillie, Catherine; Raitano, Susanna; Kumar, Anujith; Carvalho, Claudia M.B.; Bagni, Claudia; Ramocki, Melissa B.; Araujo, Bruno H. S.; Torres, Laila B.; Lupski, James R.; Van Esch, Hilde; Muotri, Alysson R.

2015-01-01

Increased dosage of MeCP2 results in a dramatic neurodevelopmental phenotype with onset at birth. We generated induced pluripotent stem cells (iPSC) from patients with the MECP2 duplication syndrome (MECP2dup), carrying different duplication sizes, to study the impact of increased MeCP2 dosage in human neurons. We show that cortical neurons derived from these different MECP2dup iPSC lines have increase synaptogenesis and dendritic complexity. Additionally, using multi-electrodes arrays, we show that neuronal network synchronization was altered in MECP2dup-derived neurons. Given MeCP2 function at the epigenetic level, we tested if these alterations were reversible using a library of compounds with defined activity on epigenetic pathways. One histone deacetylase inhibitor, NCH-51, was validated as a potential clinical candidate. Interestingly, this compound has never been considered before as a therapeutic alternative for neurological disorders. Our model recapitulates early stages of the human MECP2 duplication syndrome and represents a promising cellular tool to facilitate therapeutic drug screening for severe neurodevelopmental disorders. PMID:26347316

A Reverse-Translational Approach to Bipolar Disorder: Rodent and human studies in the Behavioral Pattern Monitor

PubMed Central

Young, Jared W.; Minassian, Arpi; Paulus, Martin P.; Geyer, Mark A.; Perry, William

2007-01-01

Mania is the defining feature of Bipolar Disorder (BD). There has been limited progress in understanding the neurobiological underpinnings of BD mania and developing novel therapeutics, in part due to a paucity of relevant animal models with translational potential. Hyperactivity is a cardinal symptom of mania, traditionally measured in humans using observer-rated scales. Multivariate assessment of unconditioned locomotor behavior using the rat Behavioral Pattern Monitor (BPM) developed in our laboratory has shown that hyperactivity includes complex multifaceted behaviors. The BPM has been used to demonstrate differential effects of drugs on locomotor activity and exploratory behavior in rats. Studies of genetically engineered mice in a mouse BPM have confirmed its utility as a cross-species tool. In a “reverse-translational” approach to this work, we developed the human BPM to characterize motor activity in BD patients. Increased activity, object interactions, and altered locomotor patterns provide multidimensional phenotypes to model in the rodent BPM. This unique approach to modeling BD provides an opportunity to identify the neurobiology underlying BD mania and test novel antimanic agents. PMID:17706782

Synaptic scaffold evolution generated components of vertebrate cognitive complexity

PubMed Central

Nithianantharajah, J.; Komiyama, N.H.; McKechanie, A.; Johnstone, M.; Blackwood, D. H.; St Clair, D.; Emes, R.D.; van de Lagemaat, L. N.; Saksida, L.M.; Bussey, T.J.; Grant, S.G.N.

2014-01-01

The origins and evolution of higher cognitive functions including complex forms of learning, attention and executive functions are unknown. A potential mechanism driving the evolution of vertebrate cognition early in the vertebrate lineage (550 My ago) was genome duplication and subsequent diversification of postsynaptic genes. Here we report the first genetic analysis of a vertebrate gene family in cognitive functions measured using computerized touchscreens. Comparison of mice carrying mutations in all four Dlg paralogs show simple associative learning required Dlg4, while Dlg2 and Dlg3 diversified to play opposing roles in complex cognitive processes. Exploiting the translational utility of touchscreens in humans and mice, testing Dlg2 mutations in both species showed Dlg2’s role in complex learning, cognitive flexibility and attention has been highly conserved over 100 My. Dlg family mutations underlie psychiatric disorders suggesting genome evolution expanded the complexity of vertebrate cognition at the cost of susceptibility to mental illness. PMID:23201973

The beneficial role of Naringin- a citrus bioflavonoid, against oxidative stress-induced neurobehavioral disorders and cognitive dysfunction in rodents: A systematic review and meta-analysis.

PubMed

Viswanatha, Gollapalle Lakshminarayanashastry; Shylaja, H; Moolemath, Yogananda

2017-10-01

Naringin is a bioflavonoid, very abundantly found in citrus species. In literature, naringin has been scientifically well documented for its beneficial effects in various neurological disorders. In this systematic review and meta-analysis, we have made an attempt to correlate the protective role of naringin against oxidative stress-induced neurological disorders in rodents. The systematic search was performed using electronic databases; the search was mainly focused on the role of naringin in oxidative stress-induced neuropathological conditions in rodents. While, the meta-analysis was performed on the effect of naringin on oxidative stress markers [superoxide dismutase (SOD), catalase (CAT), glutathione-S-transferase (GST), reduced glutathione (GSH), lipid peroxidation (LPO)], nitrite, mitochondrial complexes (I to IV) and enzymes (acetylcholinesterase, Na + -K + -ATPase, Ca 2+ -ATPase, and Mg 2+ -ATPase) in the rodent brain. The data was analyzed using Review Manager Software. Based on the inclusion and exclusion criteria, twenty studies were selected. The meta-analysis revealed that, naringin could significantly inhibit various physical and chemical stimuli- induced neurological perturbances in the rodent brain, mediated through oxidative stress. Further, naringin also significantly restored the levels of all the oxidative stress markers (oxidative, nitrosative, enzymes, and mitochondrial complexes) in different parts of the rodent brain. This systematic review and meta-analysis supports the available scientific evidence on the beneficial role of naringin in the management of various neurological ailments. However, further studies involving human subjects is recommended to establish the safety and therapeutic efficacy in humans. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Production and perception rules underlying visual patterns: effects of symmetry and hierarchy.

PubMed

Westphal-Fitch, Gesche; Huber, Ludwig; Gómez, Juan Carlos; Fitch, W Tecumseh

2012-07-19

Formal language theory has been extended to two-dimensional patterns, but little is known about two-dimensional pattern perception. We first examined spontaneous two-dimensional visual pattern production by humans, gathered using a novel touch screen approach. Both spontaneous creative production and subsequent aesthetic ratings show that humans prefer ordered, symmetrical patterns over random patterns. We then further explored pattern-parsing abilities in different human groups, and compared them with pigeons. We generated visual plane patterns based on rules varying in complexity. All human groups tested, including children and individuals diagnosed with autism spectrum disorder (ASD), were able to detect violations of all production rules tested. Our ASD participants detected pattern violations with the same speed and accuracy as matched controls. Children's ability to detect violations of a relatively complex rotational rule correlated with age, whereas their ability to detect violations of a simple translational rule did not. By contrast, even with extensive training, pigeons were unable to detect orientation-based structural violations, suggesting that, unlike humans, they did not learn the underlying structural rules. Visual two-dimensional patterns offer a promising new formally-grounded way to investigate pattern production and perception in general, widely applicable across species and age groups.

Production and perception rules underlying visual patterns: effects of symmetry and hierarchy

PubMed Central

Westphal-Fitch, Gesche; Huber, Ludwig; Gómez, Juan Carlos; Fitch, W. Tecumseh

2012-01-01

Formal language theory has been extended to two-dimensional patterns, but little is known about two-dimensional pattern perception. We first examined spontaneous two-dimensional visual pattern production by humans, gathered using a novel touch screen approach. Both spontaneous creative production and subsequent aesthetic ratings show that humans prefer ordered, symmetrical patterns over random patterns. We then further explored pattern-parsing abilities in different human groups, and compared them with pigeons. We generated visual plane patterns based on rules varying in complexity. All human groups tested, including children and individuals diagnosed with autism spectrum disorder (ASD), were able to detect violations of all production rules tested. Our ASD participants detected pattern violations with the same speed and accuracy as matched controls. Children's ability to detect violations of a relatively complex rotational rule correlated with age, whereas their ability to detect violations of a simple translational rule did not. By contrast, even with extensive training, pigeons were unable to detect orientation-based structural violations, suggesting that, unlike humans, they did not learn the underlying structural rules. Visual two-dimensional patterns offer a promising new formally-grounded way to investigate pattern production and perception in general, widely applicable across species and age groups. PMID:22688636

Animal models in translational studies of PTSD.

PubMed

Daskalakis, Nikolaos P; Yehuda, Rachel; Diamond, David M

2013-09-01

Understanding the neurobiological mechanisms of post-traumatic stress disorder (PTSD) is of vital importance for developing biomarkers and more effective pharmacotherapy for this disorder. The design of bidirectional translational studies addressing all facets of PTSD is needed. Animal models of PTSD are needed not only to capture the complexity of PTSD behavioral characteristics, but also to address experimentally the influence of variety of factors which might determine an individual's vulnerability or resilience to trauma, e.g., genetic predisposition, early-life experience and social support. The current review covers recent translational approaches to bridge the gap between human and animal PTSD research and to create a framework for discovery of biomarkers and novel therapeutics. Published by Elsevier Ltd.

Concepts and Updates in the Evaluation and Diagnosis of Common Disorders of Sexual Development.

PubMed

Rawal, Amar Y; Austin, Paul F

2015-12-01

Our understanding of disorders of sexual differentiation (DSD) has evolved from aberrations of human genital development to a broad group of complex disorders of etiological and functional significance. The unique challenge of DSD conditions is that they create a cause for significant angst and concern for both parents and physician, as they frequently lead to questions with regards to gender assignment, surgically corrective options, long-term outlook regarding gender identity, and reproductive potential. To further add to the burden, many patients who present with genital abnormalities do not have a clear explanation as to the underlying basis of their disorder. This review looks at DSD from a pediatric urology point of view with emphasis on evaluation, diagnosis, and algorithm for work-up. We also discuss novel genetic analysis techniques and their value in diagnosis. Overall, this is an all-encompassing review on a diagnostic approach to DSD, with inclusion of recent developments and controversies, which will benefit urologists and other physicians alike.

Skin Barrier Disruption - A Requirement for Allergen Sensitization?

PubMed Central

De Benedetto, Anna; Kubo, Akiharu; Beck, Lisa A.

2011-01-01

For at least half a century, noninvasive techniques have been available to quantify skin barrier function, and these have shown that a number of human skin conditions and disorders are associated with defects in skin permeability. In the last decade, several genes responsible for skin barrier defects observed in both monogenetic and complex, polygenic disorders have been elucidated and functionally characterized. This has led to an explosion of work in the last six years that has identified pathways connecting epidermal barrier disruption and antigen uptake as well as the quality and/or magnitude of the antigen-specific adaptive immune response. This review will introduce the notion that diseases arise from the dynamic crosstalk that occurs between the skin barrier and immune system using atopic dermatitis or eczema as the disease prototype. Nevertheless, the concepts put forth are highly relevant to a number of antigen-driven disorders for which skin barrier is at least transiently compromised such as psoriasis, allergic contact dermatitis and blistering disorders. PMID:22217737

Mirror me: Imitative responses in adults with autism.

PubMed

Schunke, Odette; Schöttle, Daniel; Vettorazzi, Eik; Brandt, Valerie; Kahl, Ursula; Bäumer, Tobias; Ganos, Christos; David, Nicole; Peiker, Ina; Engel, Andreas K; Brass, Marcel; Münchau, Alexander

2016-02-01

Dysfunctions of the human mirror neuron system have been postulated to underlie some deficits in autism spectrum disorders including poor imitative performance and impaired social skills. Using three reaction time experiments addressing mirror neuron system functions under simple and complex conditions, we examined 20 adult autism spectrum disorder participants and 20 healthy controls matched for age, gender and education. Participants performed simple finger-lifting movements in response to (1) biological finger and non-biological dot movement stimuli, (2) acoustic stimuli and (3) combined visual-acoustic stimuli with different contextual (compatible/incompatible) and temporal (simultaneous/asynchronous) relation. Mixed model analyses revealed slower reaction times in autism spectrum disorder. Both groups responded faster to biological compared to non-biological stimuli (Experiment 1) implying intact processing advantage for biological stimuli in autism spectrum disorder. In Experiment 3, both groups had similar 'interference effects' when stimuli were presented simultaneously. However, autism spectrum disorder participants had abnormally slow responses particularly when incompatible stimuli were presented consecutively. Our results suggest imitative control deficits rather than global imitative system impairments. © The Author(s) 2015.

Musculoskeletal modelling of human ankle complex: Estimation of ankle joint moments.

PubMed

Jamwal, Prashant K; Hussain, Shahid; Tsoi, Yun Ho; Ghayesh, Mergen H; Xie, Sheng Quan

2017-05-01

A musculoskeletal model for the ankle complex is vital in order to enhance the understanding of neuro-mechanical control of ankle motions, diagnose ankle disorders and assess subsequent treatments. Motions at the human ankle and foot, however, are complex due to simultaneous movements at the two joints namely, the ankle joint and the subtalar joint. The musculoskeletal elements at the ankle complex, such as ligaments, muscles and tendons, have intricate arrangements and exhibit transient and nonlinear behaviour. This paper develops a musculoskeletal model of the ankle complex considering the biaxial ankle structure. The model provides estimates of overall mechanical characteristics (motion and moments) of ankle complex through consideration of forces applied along ligaments and muscle-tendon units. The dynamics of the ankle complex and its surrounding ligaments and muscle-tendon units is modelled and formulated into a state space model to facilitate simulations. A graphical user interface is also developed during this research in order to include the visual anatomical information by converting it to quantitative information on coordinates. Validation of the ankle model was carried out by comparing its outputs with those published in literature as well as with experimental data obtained from an existing parallel ankle rehabilitation robot. Qualitative agreement was observed between the model and measured data for both, the passive and active ankle motions during trials in terms of displacements and moments. Copyright © 2017 Elsevier Ltd. All rights reserved.

Network complexity as a measure of information processing across resting-state networks: evidence from the Human Connectome Project

PubMed Central

McDonough, Ian M.; Nashiro, Kaoru

2014-01-01

An emerging field of research focused on fluctuations in brain signals has provided evidence that the complexity of those signals, as measured by entropy, conveys important information about network dynamics (e.g., local and distributed processing). While much research has focused on how neural complexity differs in populations with different age groups or clinical disorders, substantially less research has focused on the basic understanding of neural complexity in populations with young and healthy brain states. The present study used resting-state fMRI data from the Human Connectome Project (Van Essen et al., 2013) to test the extent that neural complexity in the BOLD signal, as measured by multiscale entropy (1) would differ from random noise, (2) would differ between four major resting-state networks previously associated with higher-order cognition, and (3) would be associated with the strength and extent of functional connectivity—a complementary method of estimating information processing. We found that complexity in the BOLD signal exhibited different patterns of complexity from white, pink, and red noise and that neural complexity was differentially expressed between resting-state networks, including the default mode, cingulo-opercular, left and right frontoparietal networks. Lastly, neural complexity across all networks was negatively associated with functional connectivity at fine scales, but was positively associated with functional connectivity at coarse scales. The present study is the first to characterize neural complexity in BOLD signals at a high temporal resolution and across different networks and might help clarify the inconsistencies between neural complexity and functional connectivity, thus informing the mechanisms underlying neural complexity. PMID:24959130

Open reading frames associated with cancer in the dark matter of the human genome.

PubMed

Delgado, Ana Paula; Brandao, Pamela; Chapado, Maria Julia; Hamid, Sheilin; Narayanan, Ramaswamy

2014-01-01

The uncharacterized proteins (open reading frames, ORFs) in the human genome offer an opportunity to discover novel targets for cancer. A systematic analysis of the dark matter of the human proteome for druggability and biomarker discovery is crucial to mining the genome. Numerous data mining tools are available to mine these ORFs to develop a comprehensive knowledge base for future target discovery and validation. Using the Genetic Association Database, the ORFs of the human dark matter proteome were screened for evidence of association with neoplasms. The Phenome-Genome Integrator tool was used to establish phenotypic association with disease traits including cancer. Batch analysis of the tools for protein expression analysis, gene ontology and motifs and domains was used to characterize the ORFs. Sixty-two ORFs were identified for neoplasm association. The expression Quantitative Trait Loci (eQTL) analysis identified thirteen ORFs related to cancer traits. Protein expression, motifs and domain analysis and genome-wide association studies verified the relevance of these OncoORFs in diverse tumors. The OncoORFs are also associated with a wide variety of human diseases and disorders. Our results link the OncoORFs to diverse diseases and disorders. This suggests a complex landscape of the uncharacterized proteome in human diseases. These results open the dark matter of the proteome to novel cancer target research. Copyright© 2014, International Institute of Anticancer Research (Dr. John G. Delinasios), All rights reserved.

Identification of multiple genetic loci in the mouse controlling immobility time in the tail suspension and forced swimming tests.

PubMed

Abou-Elnaga, Ahmed F; Torigoe, Daisuke; Fouda, Mohamed M; Darwish, Ragab A; Abou-Ismail, Usama A; Morimatsu, Masami; Agui, Takashi

2015-05-01

Depression is one of the most famous psychiatric disorders in humans in all over the countries and considered a complex neurobehavioral trait and difficult to identify causal genes. Tail suspension test (TST) and forced swimming test (FST) are widely used for assessing depression-like behavior and antidepressant activity in mice. A variety of antidepressant agents are known to reduce immobility time in both TST and FST. To identify genetic determinants of immobility duration in both tests, we analyzed 101 F2 mice from an intercross between C57BL/6 and DBA/2 strains. Quantitative trait locus (QTL) mapping using 106 microsatellite markers revealed three loci (two significant and one suggestive) and five suggestive loci controlling immobility time in the TST and FST, respectively. Results of QTL analysis suggest a broad description of the genetic architecture underlying depression, providing underpinnings for identifying novel molecular targets for antidepressants to clear the complex genetic mechanisms of depressive disorders.

Enhancer Variants Synergistically Drive Dysfunction of a Gene Regulatory Network In Hirschsprung Disease

DOE PAGES

Chatterjee, Sumantra; Kapoor, Ashish; Akiyama, Jennifer A.; ...

2016-09-29

Common sequence variants in cis-regulatory elements (CREs) are suspected etiological causes of complex disorders. We previously identified an intronic enhancer variant in the RET gene disrupting SOX10 binding and increasing Hirschsprung disease (HSCR) risk 4-fold. We now show that two other functionally independent CRE variants, one binding Gata2 and the other binding Rarb, also reduce Ret expression and increase risk 2- and 1.7-fold. By studying human and mouse fetal gut tissues and cell lines, we demonstrate that reduced RET expression propagates throughout its gene regulatory network, exerting effects on both its positive and negative feedback components. We also provide evidencemore » that the presence of a combination of CRE variants synergistically reduces RET expression and its effects throughout the GRN. These studies show how the effects of functionally independent non-coding variants in a coordinated gene regulatory network amplify their individually small effects, providing a model for complex disorders.« less

Dlgap1 knockout mice exhibit alterations of the postsynaptic density and selective reductions in sociability.

PubMed

Coba, M P; Ramaker, M J; Ho, E V; Thompson, S L; Komiyama, N H; Grant, S G N; Knowles, J A; Dulawa, S C

2018-02-02

The scaffold protein DLGAP1 is localized at the post-synaptic density (PSD) of glutamatergic neurons and is a component of supramolecular protein complexes organized by PSD95. Gain-of-function variants of DLGAP1 have been associated with obsessive-compulsive disorder (OCD), while haploinsufficient variants have been linked to autism spectrum disorder (ASD) and schizophrenia in human genetic studies. We tested male and female Dlgap1 wild type (WT), heterozygous (HT), and knockout (KO) mice in a battery of behavioral tests: open field, dig, splash, prepulse inhibition, forced swim, nest building, social approach, and sucrose preference. We also used biochemical approaches to examine the role of DLGAP1 in the organization of PSD protein complexes. Dlgap1 KO mice were most notable for disruption of protein interactions in the PSD, and deficits in sociability. Other behavioral measures were largely unaffected. Our data suggest that Dlgap1 knockout leads to PSD disruption and reduced sociability, consistent with reports of DLGAP1 haploinsufficient variants in schizophrenia and ASD.

The Impact of Neuroimmune Alterations in Autism Spectrum Disorder

PubMed Central

Gottfried, Carmem; Bambini-Junior, Victorio; Francis, Fiona; Riesgo, Rudimar; Savino, Wilson

2015-01-01

Autism spectrum disorder (ASD) involves a complex interplay of both genetic and environmental risk factors, with immune alterations and synaptic connection deficiency in early life. In the past decade, studies of ASD have substantially increased, in both humans and animal models. Immunological imbalance (including autoimmunity) has been proposed as a major etiological component in ASD, taking into account increased levels of pro-inflammatory cytokines observed in postmortem brain from patients, as well as autoantibody production. Also, epidemiological studies have established a correlation of ASD with family history of autoimmune diseases; associations with major histocompatibility complex haplotypes and abnormal levels of immunological markers in the blood. Moreover, the use of animal models to study ASD is providing increasing information on the relationship between the immune system and the pathophysiology of ASD. Herein, we will discuss the accumulating literature for ASD, giving special attention to the relevant aspects of factors that may be related to the neuroimmune interface in the development of ASD, including changes in neuroplasticity. PMID:26441683

Enhancer Variants Synergistically Drive Dysfunction of a Gene Regulatory Network In Hirschsprung Disease

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

Chatterjee, Sumantra; Kapoor, Ashish; Akiyama, Jennifer A.

Common sequence variants in cis-regulatory elements (CREs) are suspected etiological causes of complex disorders. We previously identified an intronic enhancer variant in the RET gene disrupting SOX10 binding and increasing Hirschsprung disease (HSCR) risk 4-fold. We now show that two other functionally independent CRE variants, one binding Gata2 and the other binding Rarb, also reduce Ret expression and increase risk 2- and 1.7-fold. By studying human and mouse fetal gut tissues and cell lines, we demonstrate that reduced RET expression propagates throughout its gene regulatory network, exerting effects on both its positive and negative feedback components. We also provide evidencemore » that the presence of a combination of CRE variants synergistically reduces RET expression and its effects throughout the GRN. These studies show how the effects of functionally independent non-coding variants in a coordinated gene regulatory network amplify their individually small effects, providing a model for complex disorders.« less

Music: a unique window into the world of autism.

PubMed

Molnar-Szakacs, Istvan; Heaton, Pamela

2012-04-01

Understanding emotions is fundamental to our ability to navigate the complex world of human social interaction. Individuals with autism spectrum disorders (ASD) experience difficulties with the communication and understanding of emotions within the social domain. Their ability to interpret other people's nonverbal, facial, and bodily expressions of emotion is strongly curtailed. However, there is evidence to suggest that many individuals with ASD show a strong and early preference for music and are able to understand simple and complex musical emotions in childhood and adulthood. The dissociation between emotion recognition abilities in musical and social domains in individuals with ASD provides us with the opportunity to consider the nature of emotion processing difficulties characterizing this disorder. There has recently been a surge of interest in musical abilities in individuals with ASD, and this has motivated new behavioral and neuroimaging studies. Here, we review this new work. We conclude by providing some questions for future directions. © 2012 New York Academy of Sciences.

Interactions Between Anandamide and Corticotropin-Releasing Factor Signaling Modulate Human Amygdala Function and Risk for Anxiety Disorders: An Imaging Genetics Strategy for Modeling Molecular Interactions.

PubMed

Demers, Catherine H; Drabant Conley, Emily; Bogdan, Ryan; Hariri, Ahmad R

2016-09-01

Preclinical models reveal that stress-induced amygdala activity and impairment in fear extinction reflect reductions in anandamide driven by corticotropin-releasing factor receptor type 1 (CRF1) potentiation of the anandamide catabolic enzyme fatty acid amide hydrolase. Here, we provide clinical translation for the importance of these molecular interactions using an imaging genetics strategy to examine whether interactions between genetic polymorphisms associated with differential anandamide (FAAH rs324420) and CRF1 (CRHR1 rs110402) signaling modulate amygdala function and anxiety disorder diagnosis. Analyses revealed that individuals with a genetic background predicting relatively high anandamide and CRF1 signaling exhibited blunted basolateral amygdala habituation, which further mediated increased risk for anxiety disorders among these same individuals. The convergence of preclinical and clinical data suggests that interactions between anandamide and CRF1 represent a fundamental molecular mechanism regulating amygdala function and anxiety. Our results further highlight the potential of imaging genetics to powerfully translate complex preclinical findings to clinically meaningful human phenotypes. Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

A review of craniofacial disorders caused by spliceosomal defects.

PubMed

Lehalle, D; Wieczorek, D; Zechi-Ceide, R M; Passos-Bueno, M R; Lyonnet, S; Amiel, J; Gordon, C T

2015-11-01

The spliceosome is a large ribonucleoprotein complex that removes introns from pre-mRNA transcripts. Mutations in EFTUD2, encoding a component of the major spliceosome, have recently been identified as the cause of mandibulofacial dysostosis, Guion-Almeida type (MFDGA), characterized by mandibulofacial dysostosis, microcephaly, external ear malformations and intellectual disability. Mutations in several other genes involved in spliceosomal function or linked aspects of mRNA processing have also recently been identified in human disorders with specific craniofacial malformations: SF3B4 in Nager syndrome, an acrofacial dysostosis (AFD); SNRPB in cerebrocostomandibular syndrome, characterized by Robin sequence and rib defects; EIF4A3 in the AFD Richieri-Costa-Pereira syndrome, characterized by Robin sequence, median mandibular cleft and limb defects; and TXNL4A in Burn-McKeown syndrome, involving specific craniofacial dysmorphisms. Here, we review phenotypic and molecular aspects of these syndromes. Given the apparent sensitivity of craniofacial development to defects in mRNA processing, it is possible that mutations in other proteins involved in spliceosomal function will emerge in the future as causative for related human disorders. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Computer-based simulation of the Bielschowsky head-tilt test using the SEE++ software system.

PubMed

Kaltofen, Thomas; Buchberger, Michael; Priglinger, Siegfried

2008-01-01

Latest measurements of the vestibulo-ocular reflex (VOR) allowed the integration of the simulation of the Bielschowsky head-tilt test (BHTT) into the SEE++ software system. SEE++ realizes a biomechanical model of the human eye in order to simulate eye motility disorders and strabismus surgeries. With the addition of the BHTT it can now also be used for differential-diagnostic simulations of complex disorders (e.g., superior oblique palsies). In order to simulate the BHTT in SEE++, the user can freely choose the desired head-tilt angle from -45 degrees to +45 degrees. The chosen angle is shown in the 3D view with a human body model and is also used in the calculation of the Hess-Lancaster test. The integration of the BHTT offers an additional improvement of the possibilities for simulating eye motility disorders. Moreover, SEE++ allows the creation of a video of the "virtual patient" while tilting the head from one side to the other, which shows dynamic changes in the simulated Hess-diagrams. Comparisons of simulation results with patient-measured data showed a good correlation between the simulated and the measured data. Further comparisons with patient data are planned.

The expanding syndrome of amyotrophic lateral sclerosis: a clinical and molecular odyssey

PubMed Central

Turner, Martin R; Swash, Michael

2015-01-01

Recent advances in understanding amyotrophic lateral sclerosis (ALS) have delivered new questions. Disappointingly, the initial enthusiasm for transgenic mouse models of the disease has not been followed by rapid advances in therapy or prevention. Monogenic models may have inadvertently masked the true complexity of the human disease. ALS has evolved into a multisystem disorder, involving a final common pathway accessible via multiple upstream aetiological tributaries. Nonetheless, there is a common clinical core to ALS, as clear today as it was to Charcot and others. We stress the continuing relevance of clinical observations amid the increasing molecular complexity of ALS. PMID:25644224

Different patterns of morphological changes in the hippocampus and dentate gyrus accompany the differential expression of disability following nerve injury.

PubMed

Kalman, Eszter; Keay, Kevin A

2014-12-01

Physical and psychological trauma which results in mood disorders and the disruption of complex behaviours is associated with reductions in hippocampal volume. Clinical evaluation of neuropathic pain reveals mood and behavioural change in a significant number of patients. A rat model of neuropathic injury results in complex behavioural changes in a subpopulation (~30%) of injured rats; these changes are co-morbid with a range of other 'disabilities'. The specific objective of this study was to determine in rats the morphology of the hippocampus and dentate gyrus in individuals with and without complex behavioural disruptions following a constriction injury of the sciatic nerve, and to determine whether rats that develop disabilities following nerve injury have a reduced hippocampal volume compared with injured rats with no disabilities. The social behaviours of nerve-injured rats were evaluated before and after nerve injury. The morphology of the hippocampus of rats with and without behavioural disruptions was compared in serial histological sections. Single-housing and repeated social-interaction testing had no effect on the morphology of either the hippocampus or the dentate gyrus. Rats with transient or ongoing disability identified by behavioural disruption following sciatic nerve injury, show bilateral reductions in hippocampal volume, and lateralised reduction in the dentate gyrus (left side). Disabled rats display a combination of behavioural and physiological changes, which resemble many of the criteria used clinically to diagnose mood disorders. They also show reductions in the volume of the hippocampus similar to people with clinically diagnosed mood disorders. The sciatic nerve injury model reveals a similarity to the human neuropathic pain presentation presenting an anatomically specific focus for the investigation of the neural mechanisms underpinning the co-morbidity of chronic pain and mood disorder. © 2014 Anatomical Society.

Influence of religious aspects and personal beliefs on psychological behavior: focus on anxiety disorders

PubMed Central

Agorastos, Agorastos; Demiralay, Cüneyt; Huber, Christian G

2014-01-01

The current paper presents literature relevant to the relationship of religiosity, spirituality, and personal beliefs with mental health and, in particular, anxiety disorders as an empirical narrative review, providing an overview on the most important and clinically relevant research results on the topic. The relationship between religiosity/spirituality, personal beliefs (ie, magical ideation and paranormal beliefs), and mental health has lately been studied extensively, and results have indicated significant associations among these variables. However, scientific approaches to this field are complex and multidimensional, partly leading to poor operationalization, incomparable data, and contradictory results. Literature demonstrates that higher religiosity/spirituality and magical ideation scores have often been associated with increased obsessive–compulsive traits. Similar results could not be confidently replicated for other anxiety disorders. However, it is still unclear if these differences suggest a specific association with obsessive–compulsive traits and reflect deviating etiopathogenetic and cognitive aspects between obsessive–compulsive disorder and other anxiety disorders, or if these results are biased through other factors. Religiosity/spirituality and personal beliefs constitute important parameters of human experience and deserve greater consideration in the psychotherapeutic treatment of psychiatric disorders. PMID:24648780

Dopamine in the medial amygdala network mediates human bonding.

PubMed

Atzil, Shir; Touroutoglou, Alexandra; Rudy, Tali; Salcedo, Stephanie; Feldman, Ruth; Hooker, Jacob M; Dickerson, Bradford C; Catana, Ciprian; Barrett, Lisa Feldman

2017-02-28

Research in humans and nonhuman animals indicates that social affiliation, and particularly maternal bonding, depends on reward circuitry. Although numerous mechanistic studies in rodents demonstrated that maternal bonding depends on striatal dopamine transmission, the neurochemistry supporting maternal behavior in humans has not been described so far. In this study, we tested the role of central dopamine in human bonding. We applied a combined functional MRI-PET scanner to simultaneously probe mothers' dopamine responses to their infants and the connectivity between the nucleus accumbens (NAcc), the amygdala, and the medial prefrontal cortex (mPFC), which form an intrinsic network (referred to as the "medial amygdala network") that supports social functioning. We also measured the mothers' behavioral synchrony with their infants and plasma oxytocin. The results of this study suggest that synchronous maternal behavior is associated with increased dopamine responses to the mother's infant and stronger intrinsic connectivity within the medial amygdala network. Moreover, stronger network connectivity is associated with increased dopamine responses within the network and decreased plasma oxytocin. Together, these data indicate that dopamine is involved in human bonding. Compared with other mammals, humans have an unusually complex social life. The complexity of human bonding cannot be fully captured in nonhuman animal models, particularly in pathological bonding, such as that in autistic spectrum disorder or postpartum depression. Thus, investigations of the neurochemistry of social bonding in humans, for which this study provides initial evidence, are warranted.

Unraveling the autoimmune translational research process layer by layer

PubMed Central

Blumberg, Richard S; Dittel, Bonnie; Hafler, David; von Herrath, Matthias; Nestle, Frank O

2015-01-01

Autoimmune diseases have a complex etiology and despite great progress having been made in our comprehension of these disorders, there has been limited success in the development of approved medications based on these insights. Development of drugs and strategies for application in translational research and medicine are hampered by an inadequate molecular definition of the human autoimmune phenotype and the organizational models that are necessary to clarify this definition. PMID:22227670

New technologies provide insights into genetic basis of psychiatric disorders and explain their co-morbidity.

PubMed

Rudan, Igor

2010-06-01

The completion of Human Genome Project and the "HapMap" project was followed by translational activities from companies within the private sector. This led to the introduction of genome-wide scans based on hundreds of thousands of single nucleotide polymorphysms (SNP). These scans were based on common genetic variants in human populations. This new and powerful technology was then applied to the existing DNA-based datasets with information on psychiatric disorders. As a result, an unprecedented amount of novel scientific insights related to the underlying biology and genetics of psychiatric disorders was obtained. The dominant design of these studies, so called "genome-wide association studies" (GWAS), used statistical methods which minimized the risk of false positive reports and provided much greater power to detect genotype-phenotype associations. All findings were entirely data-driven rather than hypothesis-driven, which often made it difficult for researchers to understand or interpret the findings. Interestingly, this work in genetics is indicating how non-specific some genes are for psychiatric disorders, having associations in common for schizophrenia, bipolar disorder and autism. This suggests that the earlier stages of psychiatric disorders may be multi-valent and that early detection, coupled with a clearer understanding of the environmental factors, may allow prevention. At the present time, the rich "harvest" from GWAS still has very limited power to predict the variation in psychiatric disease status at individual level, typically explaining less than 5% of the total risk variance. The most recent studies of common genetic variation implicated the role of major histocompatibility complex in schizophrenia and other disorders. They also provided molecular evidence for a substantial polygenic component to the risk of psychiatric diseases, involving thousands of common alleles of very small effect. The studies of structural genetic variation, such as copy number variants (CNV), coupled with the efforts targeting rare genetic variation (using the emerging whole-genome "deep" sequencing technologies) will become the area of the greatest interest in the field of genetic epidemiology. This will be complemented by the studies of epigenetic phoenomena, changes of expression at a large scale and understanding gene-gene interactions in complex networks using systems biology approaches. A deeper understanding of the underlying biology of psychiatric disorders is essential to improve diagnoses and therapies of these diseases. New technologies - genome-wide association studies, imaging and the optical manipulation of neural circuits - are promising to provide novel insights and lead to new treatments.

Substrate Binding and Catalytic Mechanism of Human Choline Acetyltransferase

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

Kim,A.; Rylett, J.; Shilton, B.

2006-01-01

Choline acetyltransferase (ChAT) catalyzes the synthesis of the neurotransmitter acetylcholine from choline and acetyl-CoA, and its presence is a defining feature of cholinergic neurons. We report the structure of human ChAT to a resolution of 2.2 {angstrom} along with structures for binary complexes of ChAT with choline, CoA, and a nonhydrolyzable acetyl-CoA analogue, S-(2-oxopropyl)-CoA. The ChAT-choline complex shows which features of choline are important for binding and explains how modifications of the choline trimethylammonium group can be tolerated by the enzyme. A detailed model of the ternary Michaelis complex fully supports the direct transfer of the acetyl group from acetyl-CoAmore » to choline through a mechanism similar to that seen in the serine hydrolases for the formation of an acyl-enzyme intermediate. Domain movements accompany CoA binding, and a surface loop, which is disordered in the unliganded enzyme, becomes localized and binds directly to the phosphates of CoA, stabilizing the complex. Interactions between this surface loop and CoA may function to lower the K{sub M} for CoA and could be important for phosphorylation-dependent regulation of ChAT activity.« less

Genetic errors of the human CARD-BCL10-MALT1 (CBM) complex: molecular, immunological, and clinical heterogeneity

PubMed Central

de Diego, Rebeca Pérez; Sánchez-Ramón, Silvia; López-Collazo, Eduardo; Martínez-Barricarte, Rubén; Cubillos-Zapata, Carolina; Cerdán, Antonio Ferreira; Casanova, Jean-Laurent; Puel, Anne

2016-01-01

Three members of the caspase recruitment domain (CARD) family of adaptors (CARD9, CARD10, and CARD11) are known to form heterotrimers with B-cell lymphoma 10 (BCL10) and mucosa-associated lymphoid tissue lymphoma-translocation gene 1 (MALT1). These three CARD-BCL10-MALT1 (CBM) complexes activate NF-κB in both the innate and adaptive arms of immunity. Human inherited defects of the three components of the CBM complex, including the two adaptors CARD9 and CARD11 and the two core components BCL10 and MALT1, have recently been reported. Bi-allelic loss-of-function (LOF) mutant alleles underlie several different immunological and clinical phenotypes, which can be assigned to two distinct categories. Isolated invasive fungal infections, of unclear cellular basis, are associated with CARD9 deficiency, whereas a broad range of clinical manifestations, including those characteristic of T- and B-lymphocyte defects, are associated with CARD11, MALT1 and BCL10 deficiencies. Interestingly, humans with these mutations have some features in common with the corresponding knockout mice, but other features are different between humans and mice. Moreover, germline and somatic gain-of-function (GOF) mutations of MALT1, BCL10 and CARD11 have also been found in other patients with lymphoproliferative disorders. This broad range of germline and somatic CBM lesions, including LOF and GOF mutations, highlights the contribution of each of the components of the CBM to human immunity. PMID:26277595

Targets for Drug Therapy for Autism Spectrum Disorder: Challenges and Future Directions.

PubMed

Lacivita, Enza; Perrone, Roberto; Margari, Lucia; Leopoldo, Marcello

2017-11-22

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by persistent deficits in social communication and interaction and restricted, repetitive patterns of behavior, interests, and activities. Various factors are involved in the etiopathogenesis of ASD, including genetic factors, environmental toxins and stressors, impaired immune responses, mitochondrial dysfunction, and neuroinflammation. The heterogeneity in the phenotype among ASD patients and the complex etiology of the condition have long impeded the advancement of the development of pharmacological therapies. In the recent years, the integration of findings from mouse models to human genetics resulted in considerable progress toward the understanding of ASD pathophysiology. Currently, strategies to treat core symptoms of ASD are directed to correct synaptic dysfunctions, abnormalities in central oxytocin, vasopressin, and serotonin neurotransmission, and neuroinflammation. Here, we present a survey of the studies that have suggested molecular targets for drug development for ASD and the state-of-the-art of medicinal chemistry efforts in related areas.

Invisalign(®) treatment of patients with craniomandibular disorders.

PubMed

Schupp, Werner; Haubrich, Julia; Neumann, Iris

2010-09-01

The temporomandibular joint is one of the most complex joint systems in the human body. Craniomandibular disorders (CMD) are a common condition in which symptoms and signs may vary within a single individual and from one person to another. As anatomic and functional aspects of the craniomandibular system (CMS) and the upper cervical spine are closely interconnected, CMD need a close interdisciplinary approach combining orthopedics, manual medicine, orthodontics and dentistry. Splints as a therapeutic treatment instrument in CMD patients are widely accepted. The association of splint therapy and the Invisalign(®) system not only provides comfortable and almost invisible treatment but also constitutes a powerful instrument for the orthodontic treatment of the CMD patient. To this end, precise knowledge of the temporomandibular joint, temporomandibular disorders and treatment using removable and fixed splints is indispensable. Copyright © 2010 CEO. Published by Elsevier Masson SAS. All rights reserved.

Caring for the Trafficked Patient: Ethical Challenges and Recommendations for Health Care Professionals.

PubMed

Macias-Konstantopoulos, Wendy L

2017-01-01

Human trafficking is an egregious human rights violation with profound negative physical and psychological consequences, including communicable diseases, substance use disorders, and mental illnesses. The health needs of this population are multiple, complex, and influenced by past and present experiences of abuse, neglect, and exploitation. Effective health care services for trafficked patients require clinicians to consider individual patients' needs, wishes, goals, priorities, risks, and vulnerabilities as well as public health implications and even resource allocation. Applying the bioethical principles of respect for autonomy, nonmaleficence, beneficence, and justice, this article considers the ethics of care model as a trauma-informed framework for providing health care to human trafficking victims and survivors. © 2017 American Medical Association. All Rights Reserved.

Molecular biology and genetics of embryonic eyelid development.

PubMed

Rubinstein, Tal J; Weber, Adam C; Traboulsi, Elias I

2016-09-01

The embryology of the eyelid is a complex process that includes interactions between the surface ectoderm and mesenchymal tissues. In the mouse and human, the eyelids form and fuse before birth; they open prenatally in the human and postnatally in the mouse. In the mouse, cell migration is stimulated by different growth factors such as FGF10, TGF-α, Activin B, and HB-EGF. These growth factors modulate downstream BMP4 signaling, the ERK cascade, and JNK/c-JUN. Several mechanisms, such as the Wnt/β-catenin signaling pathway, may inhibit and regulate eyelid fusion. Eyelid opening, on the other hand, is driven by the BMP/Smad signaling system. Several human genetic disorders result from dysregulation of the above molecular pathways.

Quantitative and Systems Pharmacology 3. Network-Based Identification of New Targets for Natural Products Enables Potential Uses in Aging-Associated Disorders.

PubMed

Fang, Jiansong; Gao, Li; Ma, Huili; Wu, Qihui; Wu, Tian; Wu, Jun; Wang, Qi; Cheng, Feixiong

2017-01-01

Aging that refers the accumulation of genetic and physiology changes in cells and tissues over a lifetime has been shown a high risk of developing various complex diseases, such as neurodegenerative disease, cardiovascular disease and cancer. Over the past several decades, natural products have been demonstrated as anti-aging interveners via extending lifespan and preventing aging-associated disorders. In this study, we developed an integrated systems pharmacology infrastructure to uncover new indications for aging-associated disorders by natural products. Specifically, we incorporated 411 high-quality aging-associated human genes or human-orthologous genes from mus musculus (MM), saccharomyces cerevisiae (SC), c aenorhabditis elegans (CE), and drosophila melanogaster (DM). We constructed a global drug-target network of natural products by integrating both experimental and computationally predicted drug-target interactions (DTI). We further built the statistical network models for identification of new anti-aging indications of natural products through integration of the curated aging-associated genes and drug-target network of natural products. High accuracy was achieved on the network models. We showcased several network-predicted anti-aging indications of four typical natural products (caffeic acid, metformin, myricetin, and resveratrol) with new mechanism-of-actions. In summary, this study offers a powerful systems pharmacology infrastructure to identify natural products for treatment of aging-associated disorders.

Prefrontal Cortex and Social Cognition in Mouse and Man

PubMed Central

Bicks, Lucy K.; Koike, Hiroyuki; Akbarian, Schahram; Morishita, Hirofumi

2015-01-01

Social cognition is a complex process that requires the integration of a wide variety of behaviors, including salience, reward-seeking, motivation, knowledge of self and others, and flexibly adjusting behavior in social groups. Not surprisingly, social cognition represents a sensitive domain commonly disrupted in the pathology of a variety of psychiatric disorders including Autism Spectrum Disorder (ASD) and Schizophrenia (SCZ). Here, we discuss convergent research from animal models to human disease that implicates the prefrontal cortex (PFC) as a key regulator in social cognition, suggesting that disruptions in prefrontal microcircuitry play an essential role in the pathophysiology of psychiatric disorders with shared social deficits. We take a translational perspective of social cognition, and review three key behaviors that are essential to normal social processing in rodents and humans, including social motivation, social recognition, and dominance hierarchy. A shared prefrontal circuitry may underlie these behaviors. Social cognition deficits in animal models of neurodevelopmental disorders like ASD and SCZ have been linked to an altered balance of excitation and inhibition (E/I ratio) within the cortex generally, and PFC specifically. A clear picture of the mechanisms by which altered E/I ratio in the PFC might lead to disruptions of social cognition across a variety of behaviors is not well understood. Future studies should explore how disrupted developmental trajectory of prefrontal microcircuitry could lead to altered E/I balance and subsequent deficits in the social domain. PMID:26635701

Quantitative and Systems Pharmacology 3. Network-Based Identification of New Targets for Natural Products Enables Potential Uses in Aging-Associated Disorders

PubMed Central

Fang, Jiansong; Gao, Li; Ma, Huili; Wu, Qihui; Wu, Tian; Wu, Jun; Wang, Qi; Cheng, Feixiong

2017-01-01

Aging that refers the accumulation of genetic and physiology changes in cells and tissues over a lifetime has been shown a high risk of developing various complex diseases, such as neurodegenerative disease, cardiovascular disease and cancer. Over the past several decades, natural products have been demonstrated as anti-aging interveners via extending lifespan and preventing aging-associated disorders. In this study, we developed an integrated systems pharmacology infrastructure to uncover new indications for aging-associated disorders by natural products. Specifically, we incorporated 411 high-quality aging-associated human genes or human-orthologous genes from mus musculus (MM), saccharomyces cerevisiae (SC), caenorhabditis elegans (CE), and drosophila melanogaster (DM). We constructed a global drug-target network of natural products by integrating both experimental and computationally predicted drug-target interactions (DTI). We further built the statistical network models for identification of new anti-aging indications of natural products through integration of the curated aging-associated genes and drug-target network of natural products. High accuracy was achieved on the network models. We showcased several network-predicted anti-aging indications of four typical natural products (caffeic acid, metformin, myricetin, and resveratrol) with new mechanism-of-actions. In summary, this study offers a powerful systems pharmacology infrastructure to identify natural products for treatment of aging-associated disorders. PMID:29093681

MicroRNAs in CAG trinucleotide repeat expansion disorders: an integrated review of the literature.

PubMed

Dumitrescu, Laura; Popescu, Bogdan O

2015-01-01

MicroRNAs are small RNAs involved in gene silencing. They play important roles in transcriptional regulation and are selectively and abundantly expressed in the central nervous system. A considerable amount of the human genome is comprised of tandem repeating nucleotide streams. Several diseases are caused by above-threshold expansion of certain trinucleotide repeats occurring in a protein-coding or non-coding region. Though monogenic, CAG trinucleotide repeat expansion disorders have a complex pathogenesis, various combinations of multiple coexisting pathways resulting in one common final consequence: selective neurodegeneration. Mutant protein and mutant transcript gain of toxic function are considered to be the core pathogenic mechanisms. The profile of microRNAs in CAG trinucleotide repeat disorders is scarcely described, however microRNA dysregulation has been identified in these diseases and microRNA-related intereference with gene expression is considered to be involved in their pathogenesis. Better understanding of microRNAs functions and means of manipulation promises to offer further insights into the pathogenic pathways of CAG repeat expansion disorders, to point out new potential targets for drug intervention and to provide some of the much needed etiopathogenic therapeutic agents. A number of disease-modifying microRNA silencing strategies are under development, but several implementation impediments still have to be resolved. CAG targeting seems feasible and efficient in animal models and is an appealing approach for clinical practice. Preliminary human trials are just beginning.

Complexity and multifractality of neuronal noise in mouse and human hippocampal epileptiform dynamics

NASA Astrophysics Data System (ADS)

Serletis, Demitre; Bardakjian, Berj L.; Valiante, Taufik A.; Carlen, Peter L.

2012-10-01

Fractal methods offer an invaluable means of investigating turbulent nonlinearity in non-stationary biomedical recordings from the brain. Here, we investigate properties of complexity (i.e. the correlation dimension, maximum Lyapunov exponent, 1/fγ noise and approximate entropy) and multifractality in background neuronal noise-like activity underlying epileptiform transitions recorded at the intracellular and local network scales from two in vitro models: the whole-intact mouse hippocampus and lesional human hippocampal slices. Our results show evidence for reduced dynamical complexity and multifractal signal features following transition to the ictal epileptiform state. These findings suggest that pathological breakdown in multifractal complexity coincides with loss of signal variability or heterogeneity, consistent with an unhealthy ictal state that is far from the equilibrium of turbulent yet healthy fractal dynamics in the brain. Thus, it appears that background noise-like activity successfully captures complex and multifractal signal features that may, at least in part, be used to classify and identify brain state transitions in the healthy and epileptic brain, offering potential promise for therapeutic neuromodulatory strategies for afflicted patients suffering from epilepsy and other related neurological disorders. This paper is based on chapter 5 of Serletis (2010 PhD Dissertation Department of Physiology, Institute of Biomaterials and Biomedical Engineering, University of Toronto).

Genome-wide association identifies candidate genes that influence the human electroencephalogram

PubMed Central

Hodgkinson, Colin A.; Enoch, Mary-Anne; Srivastava, Vibhuti; Cummins-Oman, Justine S.; Ferrier, Cherisse; Iarikova, Polina; Sankararaman, Sriram; Yamini, Goli; Yuan, Qiaoping; Zhou, Zhifeng; Albaugh, Bernard; White, Kenneth V.; Shen, Pei-Hong; Goldman, David

2010-01-01

Complex psychiatric disorders are resistant to whole-genome analysis due to genetic and etiological heterogeneity. Variation in resting electroencephalogram (EEG) is associated with common, complex psychiatric diseases including alcoholism, schizophrenia, and anxiety disorders, although not diagnostic for any of them. EEG traits for an individual are stable, variable between individuals, and moderately to highly heritable. Such intermediate phenotypes appear to be closer to underlying molecular processes than are clinical symptoms, and represent an alternative approach for the identification of genetic variation that underlies complex psychiatric disorders. We performed a whole-genome association study on alpha (α), beta (β), and theta (θ) EEG power in a Native American cohort of 322 individuals to take advantage of the genetic and environmental homogeneity of this population isolate. We identified three genes (SGIP1, ST6GALNAC3, and UGDH) with nominal association to variability of θ or α power. SGIP1 was estimated to account for 8.8% of variance in θ power, and this association was replicated in US Caucasians, where it accounted for 3.5% of the variance. Bayesian analysis of prior probability of association based upon earlier linkage to chromosome 1 and enrichment for vesicle-related transport proteins indicates that the association of SGIP1 with θ power is genuine. We also found association of SGIP1 with alcoholism, an effect that may be mediated via the same brain mechanisms accessed by θ EEG, and which also provides validation of the use of EEG as an endophenotype for alcoholism. PMID:20421487

Atomic description of the immune complex involved in heparin-induced thrombocytopenia

DOE PAGES

Cai, Zheng; Yarovoi, Serge V.; Zhu, Zhiqiang; ...

2015-09-22

Heparin-induced thrombocytopenia (HIT) is an autoimmune thrombotic disorder caused by immune complexes containing platelet factor 4 (PF4), antibodies to PF4 and heparin or cellular glycosaminoglycans (GAGs). Here we solve the crystal structures of the: (1) PF4 tetramer/fondaparinux complex, (2) PF4 tetramer/KKO-Fab complex (a murine monoclonal HIT-like antibody) and (3) PF4 monomer/RTO-Fab complex (a non-HIT anti-PF4 monoclonal antibody). Fondaparinux binds to the ‘closed’ end of the PF4 tetramer and stabilizes its conformation. This interaction in turn stabilizes the epitope for KKO on the ‘open’ end of the tetramer. Fondaparinux and KKO thereby collaborate to ‘stabilize’ the ternary pathogenic immune complex. Bindingmore » of RTO to PF4 monomers prevents PF4 tetramerization and inhibits KKO and human HIT IgG-induced platelet activation and platelet aggregation in vitro, and thrombus progression in vivo. Lastly, the atomic structures provide a basis to develop new diagnostics and non-anticoagulant therapeutics for HIT.« less

The HSPB8-BAG3 chaperone complex is upregulated in astrocytes in the human brain affected by protein aggregation diseases.

PubMed

Seidel, K; Vinet, J; Dunnen, W F A den; Brunt, E R; Meister, M; Boncoraglio, A; Zijlstra, M P; Boddeke, H W G M; Rüb, U; Kampinga, H H; Carra, S

2012-02-01

HSPB8 is a small heat shock protein that forms a complex with the co-chaperone BAG3. Overexpression of the HSPB8-BAG3 complex in cells stimulates autophagy and facilitates the clearance of mutated aggregation-prone proteins, whose accumulation is a hallmark of many neurodegenerative disorders. HSPB8-BAG3 could thus play a protective role in protein aggregation diseases and might be specifically upregulated in response to aggregate-prone protein-mediated toxicity. Here we analysed HSPB8-BAG3 expression levels in post-mortem human brain tissue from patients suffering of the following protein conformation disorders: Alzheimer's disease, Parkinson's disease, Huntington's disease and spinocerebellar ataxia type 3 (SCA3). Western blotting and immunohistochemistry techniques were used to analyse HSPB8 and BAG3 expression levels in fibroblasts from SCA3 patients and post-mortem brain tissues, respectively. In all diseases investigated, we observed a strong upregulation of HSPB8 and a moderate upregulation of BAG3 specifically in astrocytes in the cerebral areas affected by neuronal damage and degeneration. Intriguingly, no significant change in the HSPB8-BAG3 expression levels was observed within neurones, irrespective of their localization or of the presence of proteinaceous aggregates. We propose that the upregulation of HSPB8 and BAG3 may enhance the ability of astrocytes to clear aggregated proteins released from neurones and cellular debris, maintain the local tissue homeostasis and/or participate in the cytoskeletal remodelling that astrocytes undergo during astrogliosis. © 2011 The Authors. Neuropathology and Applied Neurobiology © 2011 British Neuropathological Society.

Comparative studies of placentation and immunology in non-human primates suggest a scenario for the evolution of deep trophoblast invasion and an explanation for human pregnancy disorders.

PubMed

Carter, Anthony M

2011-04-01

Deep trophoblast invasion in the placental bed has been considered the hallmark of human pregnancy. It occurs by two routes, interstitial and endovascular, and results in transformation of the walls of the spiral arteries as they traverse the decidua and the inner third of the myometrium. Disturbances in this process are associated with reproductive disorders such preeclampsia. In contrast, trophoblast invasion in Old World monkeys occurs only by the endovascular route and seldom reaches the myometrium. Recently, it was shown that this pattern is maintained in gibbons, but that the human arrangement also occurs in chimpanzee and gorilla. There is an interesting parallel with results from placental immunology regarding the evolution of the major histocompatability complex class I antigen HLA-C and its cognate receptors. HLA-C is not present in Old World monkeys or gibbons. It emerged in the orangutan and became polymorphic in the lineage leading to gorilla, bonobo, chimpanzee, and human. Interaction between HLA-C1 and HLA-C2 on the surface of trophoblast and killer immunoglobulin-like receptors (KIRs) expressed by uterine natural killer cells are important regulators of trophoblast invasion. Evolution of this system in great apes may have been one prerequisite for deep trophoblast invasion but seems to have come at a price. The evidence now suggests that certain combinations of maternal genotype for KIRs and fetal genotype for HLA-C imply an increased risk of preeclampsia, fetal growth restriction, and recurrent abortion. The fetal genotype is in part derived from the father providing an explanation for the paternal contribution to reproductive disorders.

Paternal Age Effect Mutations and Selfish Spermatogonial Selection: Causes and Consequences for Human Disease

PubMed Central

Goriely, Anne; Wilkie, Andrew O.M.

2012-01-01

Advanced paternal age has been associated with an increased risk for spontaneous congenital disorders and common complex diseases (such as some cancers, schizophrenia, and autism), but the mechanisms that mediate this effect have been poorly understood. A small group of disorders, including Apert syndrome (caused by FGFR2 mutations), achondroplasia, and thanatophoric dysplasia (FGFR3), and Costello syndrome (HRAS), which we collectively term “paternal age effect” (PAE) disorders, provides a good model to study the biological and molecular basis of this phenomenon. Recent evidence from direct quantification of PAE mutations in sperm and testes suggests that the common factor in the paternal age effect lies in the dysregulation of spermatogonial cell behavior, an effect mediated molecularly through the growth factor receptor-RAS signal transduction pathway. The data show that PAE mutations, although arising rarely, are positively selected and expand clonally in normal testes through a process akin to oncogenesis. This clonal expansion, which is likely to take place in the testes of all men, leads to the relative enrichment of mutant sperm over time—explaining the observed paternal age effect associated with these disorders—and in rare cases to the formation of testicular tumors. As regulation of RAS and other mediators of cellular proliferation and survival is important in many different biological contexts, for example during tumorigenesis, organ homeostasis and neurogenesis, the consequences of selfish mutations that hijack this process within the testis are likely to extend far beyond congenital skeletal disorders to include complex diseases, such as neurocognitive disorders and cancer predisposition. PMID:22325359

Auditory-Motor Interactions in Pediatric Motor Speech Disorders: Neurocomputational Modeling of Disordered Development

PubMed Central

Terband, H.; Maassen, B.; Guenther, F.H.; Brumberg, J.

2014-01-01

Background/Purpose Differentiating the symptom complex due to phonological-level disorders, speech delay and pediatric motor speech disorders is a controversial issue in the field of pediatric speech and language pathology. The present study investigated the developmental interaction between neurological deficits in auditory and motor processes using computational modeling with the DIVA model. Method In a series of computer simulations, we investigated the effect of a motor processing deficit alone (MPD), and the effect of a motor processing deficit in combination with an auditory processing deficit (MPD+APD) on the trajectory and endpoint of speech motor development in the DIVA model. Results Simulation results showed that a motor programming deficit predominantly leads to deterioration on the phonological level (phonemic mappings) when auditory self-monitoring is intact, and on the systemic level (systemic mapping) if auditory self-monitoring is impaired. Conclusions These findings suggest a close relation between quality of auditory self-monitoring and the involvement of phonological vs. motor processes in children with pediatric motor speech disorders. It is suggested that MPD+APD might be involved in typically apraxic speech output disorders and MPD in pediatric motor speech disorders that also have a phonological component. Possibilities to verify these hypotheses using empirical data collected from human subjects are discussed. PMID:24491630

Host genetic variation impacts microbiome composition across human body sites.

PubMed

Blekhman, Ran; Goodrich, Julia K; Huang, Katherine; Sun, Qi; Bukowski, Robert; Bell, Jordana T; Spector, Timothy D; Keinan, Alon; Ley, Ruth E; Gevers, Dirk; Clark, Andrew G

2015-09-15

The composition of bacteria in and on the human body varies widely across human individuals, and has been associated with multiple health conditions. While microbial communities are influenced by environmental factors, some degree of genetic influence of the host on the microbiome is also expected. This study is part of an expanding effort to comprehensively profile the interactions between human genetic variation and the composition of this microbial ecosystem on a genome- and microbiome-wide scale. Here, we jointly analyze the composition of the human microbiome and host genetic variation. By mining the shotgun metagenomic data from the Human Microbiome Project for host DNA reads, we gathered information on host genetic variation for 93 individuals for whom bacterial abundance data are also available. Using this dataset, we identify significant associations between host genetic variation and microbiome composition in 10 of the 15 body sites tested. These associations are driven by host genetic variation in immunity-related pathways, and are especially enriched in host genes that have been previously associated with microbiome-related complex diseases, such as inflammatory bowel disease and obesity-related disorders. Lastly, we show that host genomic regions associated with the microbiome have high levels of genetic differentiation among human populations, possibly indicating host genomic adaptation to environment-specific microbiomes. Our results highlight the role of host genetic variation in shaping the composition of the human microbiome, and provide a starting point toward understanding the complex interaction between human genetics and the microbiome in the context of human evolution and disease.

The lod score method.

PubMed

Rice, J P; Saccone, N L; Corbett, J

2001-01-01

The lod score method originated in a seminal article by Newton Morton in 1955. The method is broadly concerned with issues of power and the posterior probability of linkage, ensuring that a reported linkage has a high probability of being a true linkage. In addition, the method is sequential, so that pedigrees or lod curves may be combined from published reports to pool data for analysis. This approach has been remarkably successful for 50 years in identifying disease genes for Mendelian disorders. After discussing these issues, we consider the situation for complex disorders, where the maximum lod score (MLS) statistic shares some of the advantages of the traditional lod score approach but is limited by unknown power and the lack of sharing of the primary data needed to optimally combine analytic results. We may still learn from the lod score method as we explore new methods in molecular biology and genetic analysis to utilize the complete human DNA sequence and the cataloging of all human genes.

An Organismal CNV Mutator Phenotype Restricted to Early Human Development.

PubMed

Liu, Pengfei; Yuan, Bo; Carvalho, Claudia M B; Wuster, Arthur; Walter, Klaudia; Zhang, Ling; Gambin, Tomasz; Chong, Zechen; Campbell, Ian M; Coban Akdemir, Zeynep; Gelowani, Violet; Writzl, Karin; Bacino, Carlos A; Lindsay, Sarah J; Withers, Marjorie; Gonzaga-Jauregui, Claudia; Wiszniewska, Joanna; Scull, Jennifer; Stankiewicz, Paweł; Jhangiani, Shalini N; Muzny, Donna M; Zhang, Feng; Chen, Ken; Gibbs, Richard A; Rautenstrauss, Bernd; Cheung, Sau Wai; Smith, Janice; Breman, Amy; Shaw, Chad A; Patel, Ankita; Hurles, Matthew E; Lupski, James R

2017-02-23

De novo copy number variants (dnCNVs) arising at multiple loci in a personal genome have usually been considered to reflect cancer somatic genomic instabilities. We describe a multiple dnCNV (MdnCNV) phenomenon in which individuals with genomic disorders carry five to ten constitutional dnCNVs. These CNVs originate from independent formation incidences, are predominantly tandem duplications or complex gains, exhibit breakpoint junction features reminiscent of replicative repair, and show increased de novo point mutations flanking the rearrangement junctions. The active CNV mutation shower appears to be restricted to a transient perizygotic period. We propose that a defect in the CNV formation process is responsible for the "CNV-mutator state," and this state is dampened after early embryogenesis. The constitutional MdnCNV phenomenon resembles chromosomal instability in various cancers. Investigations of this phenomenon may provide unique access to understanding genomic disorders, structural variant mutagenesis, human evolution, and cancer biology. Copyright © 2017 Elsevier Inc. All rights reserved.

Genome-wide association mapping identifies multiple loci for a canine SLE-related disease complex.

PubMed

Wilbe, Maria; Jokinen, Päivi; Truvé, Katarina; Seppala, Eija H; Karlsson, Elinor K; Biagi, Tara; Hughes, Angela; Bannasch, Danika; Andersson, Göran; Hansson-Hamlin, Helene; Lohi, Hannes; Lindblad-Toh, Kerstin

2010-03-01

The unique canine breed structure makes dogs an excellent model for studying genetic diseases. Within a dog breed, linkage disequilibrium is extensive, enabling genome-wide association (GWA) with only around 15,000 SNPs and fewer individuals than in human studies. Incidences of specific diseases are elevated in different breeds, indicating that a few genetic risk factors might have accumulated through drift or selective breeding. In this study, a GWA study with 81 affected dogs (cases) and 57 controls from the Nova Scotia duck tolling retriever breed identified five loci associated with a canine systemic lupus erythematosus (SLE)-related disease complex that includes both antinuclear antibody (ANA)-positive immune-mediated rheumatic disease (IMRD) and steroid-responsive meningitis-arteritis (SRMA). Fine mapping with twice as many dogs validated these loci. Our results indicate that the homogeneity of strong genetic risk factors within dog breeds allows multigenic disorders to be mapped with fewer than 100 cases and 100 controls, making dogs an excellent model in which to identify pathways involved in human complex diseases.

Identifying gene networks underlying the neurobiology of ethanol and alcoholism.

PubMed

Wolen, Aaron R; Miles, Michael F

2012-01-01

For complex disorders such as alcoholism, identifying the genes linked to these diseases and their specific roles is difficult. Traditional genetic approaches, such as genetic association studies (including genome-wide association studies) and analyses of quantitative trait loci (QTLs) in both humans and laboratory animals already have helped identify some candidate genes. However, because of technical obstacles, such as the small impact of any individual gene, these approaches only have limited effectiveness in identifying specific genes that contribute to complex diseases. The emerging field of systems biology, which allows for analyses of entire gene networks, may help researchers better elucidate the genetic basis of alcoholism, both in humans and in animal models. Such networks can be identified using approaches such as high-throughput molecular profiling (e.g., through microarray-based gene expression analyses) or strategies referred to as genetical genomics, such as the mapping of expression QTLs (eQTLs). Characterization of gene networks can shed light on the biological pathways underlying complex traits and provide the functional context for identifying those genes that contribute to disease development.

Increased Treatment Complexity for Major Depressive Disorder for Inpatients With Comorbid Personality Disorder.

PubMed

Wiegand, Hauke F; Godemann, Frank

2017-05-01

The study examined inpatient treatment for major depressive disorder (MDD) when it is complicated by comorbid personality disorder. In this descriptive analysis of a large data sample from 2013 (German VIPP data set) of 58,913 cases from 75 hospitals, three groups were compared: patients with MDD, patients with MDD and a comorbid personality disorder, and patients with a main diagnosis of personality disorder. Compared with MDD patients, those with comorbid personality disorder had higher rates of recurrent depression and nearly twice as many readmissions within one year, despite longer mean length of stay. Records of patients with comorbidities more often indicated accounting codes for "complex diagnostic procedures," "crisis intervention," and "constant observation." Patients with comorbid disorders differed from patients with a main diagnosis of personality disorder in treatment indicator characteristics and distribution of personality disorder diagnoses. Personality disorder comorbidity made MDD treatment more complex, and recurrence of MDD episodes and hospital readmission occurred more often than if patients had a sole MDD diagnosis.

Mn2+ exerts stronger structural effects than the Mn-citrate complex on the human erythrocyte membrane and molecular models.

PubMed

Suwalsky, M; Villena, F; Sotomayor, C P

2010-01-01

While traces of manganese (Mn) take part in important and essential functions in biology, elevated exposures have been shown to cause significant toxicity. Chronic exposure to the metal leads to manganese neurotoxicity (or manganism), a brain disorder that resembles Parkinsonism. Toxic effect mechanisms of Mn is not understood, toxic concentrations of manganese are not well defined and blood manganese concentration at which neurotoxicity occurs has not been identified. There are reports indicating that the most abundant Mn-species in Mn carriers within blood is the Mn-citrate complex. Despite the well-documented information about the toxic effects of Mn, there are scarce reports concerning the effects of manganese compounds on both structure and functions of cell membranes, particularly those of human erythrocytes. With the aim to better understand the molecular mechanisms of the interaction of Mn with cell membranes, MnCl(2), and the Mn-citrate complex were incubated with intact erythrocytes, isolated unsealead human erythrocyte membranes (IUM), and molecular models of the erythrocyte membrane. These consisted in bilayers of dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylethanolamine (DMPE), phospholipid classes present in the outer and inner monolayers of the erythrocyte membrane, respectively. The capacity of the Mn compounds to perturb the bilayer structures of DMPC and DMPE was evaluated by X-ray diffraction, IUM were studied by fluorescence spectroscopy, and intact human erythrocytes were observed by scanning electron microscopy (SEM). In all these systems it was found that Mn(2+) exerted considerable higher structural perturbations than the Mn-citrate complex.

Autism Phenotypes in Tuberous Sclerosis Complex: Diagnostic and Treatment Considerations.

PubMed

Gipson, Tanjala T; Poretti, Andrea; Thomas, Emily A; Jenkins, Kosunique T; Desai, Sonal; Johnston, Michael V

2015-12-01

Tuberous sclerosis complex is a multisystem, chronic genetic condition characterized by systemic growth of benign tumors and often accompanied by epilepsy, autism spectrum disorders, and intellectual disability. Nonetheless, the neurodevelopmental phenotype of these patients is not often detailed. The authors describe 3 individuals with tuberous sclerosis complex who share common characteristics that can help to identify a distinct profile of autism spectrum disorder. These findings include typical cognitive development, expressive and pragmatic language deficits, and anxiety. The authors also describe features specific to tuberous sclerosis complex that require consideration before diagnosing an autism spectrum disorder. Identifying distinct profiles of autism spectrum disorder in tuberous sclerosis complex can help optimize treatment across the life span. © The Author(s) 2015.

Considering Valproate as a Risk Factor for Rapid Exacerbation of Complex Movement Disorder in Progressed Stages of Late-Infantile CLN2 Disease.

PubMed

Johannsen, Jessika; Nickel, Miriam; Schulz, Angela; Denecke, Jonas

2016-06-01

Neuronal ceroid lipofuscinosis type 2 (CLN2 disease, OMIM 204500) is a rare autosomal-recessive lysosomal storage disorder. It is one of the most common neurodegenerative disorders in childhood. Symptoms include epilepsy, rapid motor and language regression, dementia, visual loss, and a complex movement disorder in later stages of the disease. We report on two children with genetically confirmed late-infantile CLN2 disease who developed a severe exacerbation of their complex movement disorder leading to hyperthermia, hyper-CK-emia and decreased level of consciousness over several weeks despite different therapeutic approaches. Both patients were on long-term antiepileptic treatment with valproate and only after the withdrawal of valproate, the movement disorder disappeared and level of consciousness improved. These observations emphasize that valproate has to be considered as a possible risk factor in patients in later stages of late-infantile CLN2 disease who develop a rapidly progressive complex movement disorder. Georg Thieme Verlag KG Stuttgart · New York.

Genes uniquely expressed in human growth plate chondrocytes uncover a distinct regulatory network.

PubMed

Li, Bing; Balasubramanian, Karthika; Krakow, Deborah; Cohn, Daniel H

2017-12-20

Chondrogenesis is the earliest stage of skeletal development and is a highly dynamic process, integrating the activities and functions of transcription factors, cell signaling molecules and extracellular matrix proteins. The molecular mechanisms underlying chondrogenesis have been extensively studied and multiple key regulators of this process have been identified. However, a genome-wide overview of the gene regulatory network in chondrogenesis has not been achieved. In this study, employing RNA sequencing, we identified 332 protein coding genes and 34 long non-coding RNA (lncRNA) genes that are highly selectively expressed in human fetal growth plate chondrocytes. Among the protein coding genes, 32 genes were associated with 62 distinct human skeletal disorders and 153 genes were associated with skeletal defects in knockout mice, confirming their essential roles in skeletal formation. These gene products formed a comprehensive physical interaction network and participated in multiple cellular processes regulating skeletal development. The data also revealed 34 transcription factors and 11,334 distal enhancers that were uniquely active in chondrocytes, functioning as transcriptional regulators for the cartilage-selective genes. Our findings revealed a complex gene regulatory network controlling skeletal development whereby transcription factors, enhancers and lncRNAs participate in chondrogenesis by transcriptional regulation of key genes. Additionally, the cartilage-selective genes represent candidate genes for unsolved human skeletal disorders.

The Gut Microbiome and Mental Health: Implications for Anxiety- and Trauma-Related Disorders.

PubMed

Malan-Muller, Stefanie; Valles-Colomer, Mireia; Raes, Jeroen; Lowry, Christopher A; Seedat, Soraya; Hemmings, Sian M J

2018-02-01

Biological psychiatry research has long focused on the brain in elucidating the neurobiological mechanisms of anxiety- and trauma-related disorders. This review challenges this assumption and suggests that the gut microbiome and its interactome also deserve attention to understand brain disorders and develop innovative treatments and diagnostics in the 21st century. The recent, in-depth characterization of the human microbiome spurred a paradigm shift in human health and disease. Animal models strongly suggest a role for the gut microbiome in anxiety- and trauma-related disorders. The microbiota-gut-brain (MGB) axis sits at the epicenter of this new approach to mental health. The microbiome plays an important role in the programming of the hypothalamic-pituitary-adrenal (HPA) axis early in life, and stress reactivity over the life span. In this review, we highlight emerging findings of microbiome research in psychiatric disorders, focusing on anxiety- and trauma-related disorders specifically, and discuss the gut microbiome as a potential therapeutic target. 16S rRNA sequencing has enabled researchers to investigate and compare microbial composition between individuals. The functional microbiome can be studied using methods involving metagenomics, metatranscriptomics, metaproteomics, and metabolomics, as discussed in the present review. Other factors that shape the gut microbiome should be considered to obtain a holistic view of the factors at play in the complex interactome linked to the MGB. In all, we underscore the importance of microbiome science, and gut microbiota in particular, as emerging critical players in mental illness and maintenance of mental health. This new frontier of biological psychiatry and postgenomic medicine should be embraced by the mental health community as it plays an ever-increasing transformative role in integrative and holistic health research in the next decade.

Tourette Syndrome: Overview and Classroom Interventions. A Complex Neurobehavioral Disorder Which May Involve Learning Problems, Attention Deficit Hyperactivity Disorder, Obsessive Compulsive Symptoms, and Stereotypical Behaviors.

ERIC Educational Resources Information Center

Fisher, Ramona A.; Collins, Edward C.

Tourette Syndrome is conceptualized as a neurobehavioral disorder, with behavioral aspects that are sometimes difficult for teachers to understand and deal with. The disorder has five layers of complexity: (1) observable multiple motor, vocal, and cognitive tics and sensory involvement; (2) Attention Deficit Hyperactivity Disorder; (3)…

Organoid technology for brain and therapeutics research.

PubMed

Wang, Zhi; Wang, Shu-Na; Xu, Tian-Ying; Miao, Zhu-Wei; Su, Ding-Feng; Miao, Chao-Yu

2017-10-01

Brain is one of the most complex organs in human. The current brain research is mainly based on the animal models and traditional cell culture. However, the inherent species differences between humans and animals as well as the gap between organ level and cell level make it difficult to study human brain development and associated disorders through traditional technologies. Recently, the brain organoids derived from pluripotent stem cells have been reported to recapitulate many key features of human brain in vivo, for example recapitulating the zone of putative outer radial glia cells. Brain organoids offer a new platform for scientists to study brain development, neurological diseases, drug discovery and personalized medicine, regenerative medicine, and so on. Here, we discuss the progress, applications, advantages, limitations, and prospects of brain organoid technology in neurosciences and related therapeutics. © 2017 John Wiley & Sons Ltd.

Genome-wide analysis identifies 12 loci influencing human reproductive behavior.

PubMed

Barban, Nicola; Jansen, Rick; de Vlaming, Ronald; Vaez, Ahmad; Mandemakers, Jornt J; Tropf, Felix C; Shen, Xia; Wilson, James F; Chasman, Daniel I; Nolte, Ilja M; Tragante, Vinicius; van der Laan, Sander W; Perry, John R B; Kong, Augustine; Ahluwalia, Tarunveer S; Albrecht, Eva; Yerges-Armstrong, Laura; Atzmon, Gil; Auro, Kirsi; Ayers, Kristin; Bakshi, Andrew; Ben-Avraham, Danny; Berger, Klaus; Bergman, Aviv; Bertram, Lars; Bielak, Lawrence F; Bjornsdottir, Gyda; Bonder, Marc Jan; Broer, Linda; Bui, Minh; Barbieri, Caterina; Cavadino, Alana; Chavarro, Jorge E; Turman, Constance; Concas, Maria Pina; Cordell, Heather J; Davies, Gail; Eibich, Peter; Eriksson, Nicholas; Esko, Tõnu; Eriksson, Joel; Falahi, Fahimeh; Felix, Janine F; Fontana, Mark Alan; Franke, Lude; Gandin, Ilaria; Gaskins, Audrey J; Gieger, Christian; Gunderson, Erica P; Guo, Xiuqing; Hayward, Caroline; He, Chunyan; Hofer, Edith; Huang, Hongyan; Joshi, Peter K; Kanoni, Stavroula; Karlsson, Robert; Kiechl, Stefan; Kifley, Annette; Kluttig, Alexander; Kraft, Peter; Lagou, Vasiliki; Lecoeur, Cecile; Lahti, Jari; Li-Gao, Ruifang; Lind, Penelope A; Liu, Tian; Makalic, Enes; Mamasoula, Crysovalanto; Matteson, Lindsay; Mbarek, Hamdi; McArdle, Patrick F; McMahon, George; Meddens, S Fleur W; Mihailov, Evelin; Miller, Mike; Missmer, Stacey A; Monnereau, Claire; van der Most, Peter J; Myhre, Ronny; Nalls, Mike A; Nutile, Teresa; Kalafati, Ioanna Panagiota; Porcu, Eleonora; Prokopenko, Inga; Rajan, Kumar B; Rich-Edwards, Janet; Rietveld, Cornelius A; Robino, Antonietta; Rose, Lynda M; Rueedi, Rico; Ryan, Kathleen A; Saba, Yasaman; Schmidt, Daniel; Smith, Jennifer A; Stolk, Lisette; Streeten, Elizabeth; Tönjes, Anke; Thorleifsson, Gudmar; Ulivi, Sheila; Wedenoja, Juho; Wellmann, Juergen; Willeit, Peter; Yao, Jie; Yengo, Loic; Zhao, Jing Hua; Zhao, Wei; Zhernakova, Daria V; Amin, Najaf; Andrews, Howard; Balkau, Beverley; Barzilai, Nir; Bergmann, Sven; Biino, Ginevra; Bisgaard, Hans; Bønnelykke, Klaus; Boomsma, Dorret I; Buring, Julie E; Campbell, Harry; Cappellani, Stefania; Ciullo, Marina; Cox, Simon R; Cucca, Francesco; Toniolo, Daniela; Davey-Smith, George; Deary, Ian J; Dedoussis, George; Deloukas, Panos; van Duijn, Cornelia M; de Geus, Eco J C; Eriksson, Johan G; Evans, Denis A; Faul, Jessica D; Sala, Cinzia Felicita; Froguel, Philippe; Gasparini, Paolo; Girotto, Giorgia; Grabe, Hans-Jörgen; Greiser, Karin Halina; Groenen, Patrick J F; de Haan, Hugoline G; Haerting, Johannes; Harris, Tamara B; Heath, Andrew C; Heikkilä, Kauko; Hofman, Albert; Homuth, Georg; Holliday, Elizabeth G; Hopper, John; Hyppönen, Elina; Jacobsson, Bo; Jaddoe, Vincent W V; Johannesson, Magnus; Jugessur, Astanand; Kähönen, Mika; Kajantie, Eero; Kardia, Sharon L R; Keavney, Bernard; Kolcic, Ivana; Koponen, Päivikki; Kovacs, Peter; Kronenberg, Florian; Kutalik, Zoltan; La Bianca, Martina; Lachance, Genevieve; Iacono, William G; Lai, Sandra; Lehtimäki, Terho; Liewald, David C; Lindgren, Cecilia M; Liu, Yongmei; Luben, Robert; Lucht, Michael; Luoto, Riitta; Magnus, Per; Magnusson, Patrik K E; Martin, Nicholas G; McGue, Matt; McQuillan, Ruth; Medland, Sarah E; Meisinger, Christa; Mellström, Dan; Metspalu, Andres; Traglia, Michela; Milani, Lili; Mitchell, Paul; Montgomery, Grant W; Mook-Kanamori, Dennis; de Mutsert, Renée; Nohr, Ellen A; Ohlsson, Claes; Olsen, Jørn; Ong, Ken K; Paternoster, Lavinia; Pattie, Alison; Penninx, Brenda W J H; Perola, Markus; Peyser, Patricia A; Pirastu, Mario; Polasek, Ozren; Power, Chris; Kaprio, Jaakko; Raffel, Leslie J; Räikkönen, Katri; Raitakari, Olli; Ridker, Paul M; Ring, Susan M; Roll, Kathryn; Rudan, Igor; Ruggiero, Daniela; Rujescu, Dan; Salomaa, Veikko; Schlessinger, David; Schmidt, Helena; Schmidt, Reinhold; Schupf, Nicole; Smit, Johannes; Sorice, Rossella; Spector, Tim D; Starr, John M; Stöckl, Doris; Strauch, Konstantin; Stumvoll, Michael; Swertz, Morris A; Thorsteinsdottir, Unnur; Thurik, A Roy; Timpson, Nicholas J; Tung, Joyce Y; Uitterlinden, André G; Vaccargiu, Simona; Viikari, Jorma; Vitart, Veronique; Völzke, Henry; Vollenweider, Peter; Vuckovic, Dragana; Waage, Johannes; Wagner, Gert G; Wang, Jie Jin; Wareham, Nicholas J; Weir, David R; Willemsen, Gonneke; Willeit, Johann; Wright, Alan F; Zondervan, Krina T; Stefansson, Kari; Krueger, Robert F; Lee, James J; Benjamin, Daniel J; Cesarini, David; Koellinger, Philipp D; den Hoed, Marcel; Snieder, Harold; Mills, Melinda C

2016-12-01

The genetic architecture of human reproductive behavior-age at first birth (AFB) and number of children ever born (NEB)-has a strong relationship with fitness, human development, infertility and risk of neuropsychiatric disorders. However, very few genetic loci have been identified, and the underlying mechanisms of AFB and NEB are poorly understood. We report a large genome-wide association study of both sexes including 251,151 individuals for AFB and 343,072 individuals for NEB. We identified 12 independent loci that are significantly associated with AFB and/or NEB in a SNP-based genome-wide association study and 4 additional loci associated in a gene-based effort. These loci harbor genes that are likely to have a role, either directly or by affecting non-local gene expression, in human reproduction and infertility, thereby increasing understanding of these complex traits.

Characterization of linear mimetic peptides of Interleukin-22 from dissection of protein interfaces.

PubMed

La Manna, Sara; Scognamiglio, Pasqualina Liana; Di Natale, Concetta; Leone, Marilisa; Mercurio, Flavia Anna; Malfitano, Anna Maria; Cianfarani, Francesca; Madonna, Stefania; Caravella, Sergio; Albanesi, Cristina; Novellino, Ettore; Marasco, Daniela

2017-07-01

Interleukin-22 (IL-22) belongs to the family of IL-10 cytokines and is involved in a wide number of human diseases, including inflammatory disorders and cancer pathology. The ligand-receptor complex IL-22/IL-22R plays a key role in several pathways especially in the regulation and resolution of immune responses. The identification of novel compounds able to modulate IL-22/IL-22R complex could open the route to new therapeutic strategies in multiple human diseases. In this study, we designed and characterized IL-22 derived peptides at protein interface regions: several sequences revealed able to interfere with the protein complex with IC 50 in the micromolar range as evaluated through Surface Plasmon Resonance (SPR) experiments. Their conformational characterization was carried out through Circular Dichroism (CD) and Nuclear Magnetic Resonance (NMR) spectroscopies, shedding new light into the features of IL-22 fragments and on structural determinants of IL-22/IL-22R1 recognition. Finally, several peptides were tested on human keratinocyte cultures for evaluating their ability to mimic the activation of molecular pathways downstream to IL-22R in response to IL-22 binding. Copyright © 2017 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

A complex selection signature at the human AVPR1B gene.

PubMed

Cagliani, Rachele; Fumagalli, Matteo; Pozzoli, Uberto; Riva, Stefania; Cereda, Matteo; Comi, Giacomo P; Pattini, Linda; Bresolin, Nereo; Sironi, Manuela

2009-06-01

The vasopressin receptor type 1b (AVPR1B) is mainly expressed by pituitary corticotropes and it mediates the stimulatory effects of AVP on ACTH release; common AVPR1B haplotypes have been involved in mood and anxiety disorders in humans, while rodents lacking a functional receptor gene display behavioral defects and altered stress responses. Here we have analyzed the two exons of the gene and the data we present suggest that AVPR1B has been subjected to natural selection in humans. In particular, analysis of exon 2 strongly suggests the action of balancing selection in African populations and Europeans: the region displays high nucleotide diversity, an excess of intermediate-frequency alleles, a higher level of within-species diversity compared to interspecific divergence and a genealogy with common haplotypes separated by deep branches. This relatively unambiguous situation coexists with unusual features across exon 1, raising the possibility that a nonsynonymous variant (Gly191Arg) in this region has been subjected to directional selection. Although the underlying selective pressure(s) remains to be identified, we consider this to be among the first documented examples of a gene involved in mood disorders and subjected to natural selection in humans; this observation might add support to the long-debated idea that depression/low mood might have played an adaptive role during human evolution.

A complex selection signature at the human AVPR1B gene

PubMed Central

Cagliani, Rachele; Fumagalli, Matteo; Pozzoli, Uberto; Riva, Stefania; Cereda, Matteo; Comi, Giacomo P; Pattini, Linda; Bresolin, Nereo; Sironi, Manuela

2009-01-01

Background The vasopressin receptor type 1b (AVPR1B) is mainly expressed by pituitary corticotropes and it mediates the stimulatory effects of AVP on ACTH release; common AVPR1B haplotypes have been involved in mood and anxiety disorders in humans, while rodents lacking a functional receptor gene display behavioral defects and altered stress responses. Results Here we have analyzed the two exons of the gene and the data we present suggest that AVPR1B has been subjected to natural selection in humans. In particular, analysis of exon 2 strongly suggests the action of balancing selection in African populations and Europeans: the region displays high nucleotide diversity, an excess of intermediate-frequency alleles, a higher level of within-species diversity compared to interspecific divergence and a genealogy with common haplotypes separated by deep branches. This relatively unambiguous situation coexists with unusual features across exon 1, raising the possibility that a nonsynonymous variant (Gly191Arg) in this region has been subjected to directional selection. Conclusion Although the underlying selective pressure(s) remains to be identified, we consider this to be among the first documented examples of a gene involved in mood disorders and subjected to natural selection in humans; this observation might add support to the long-debated idea that depression/low mood might have played an adaptive role during human evolution. PMID:19486526

Design of Peptide Immunotherapies for MHC Class-II-Associated Autoimmune Disorders

PubMed Central

2013-01-01

Autoimmune disorders, that occur when autoreactive immune cells are induced to activate their responses against self-tissues, affect one percent of the world population and represent one of the top 10 leading causes of death. The major histocompatibility complex (MHC) is a principal susceptibility locus for many human autoimmune diseases, in which self-tissue antigens providing targets for pathogenic lymphocytes are bound to HLA molecules encoded by disease-associated alleles. In spite of the attempts to design strategies for inhibition of antigen presentation targeting the MHC-peptide/TCR complex via generation of blocking antibodies, altered peptide ligands (APL), or inhibitors of costimulatory molecules, potent therapies with minimal side effects have yet to be developed. Copaxone (glatiramer acetate, GA) is a random synthetic amino acid copolymer that reduces the relapse rate by about 30% in relapsing-remitting multiple sclerosis (MS) patients. Based on the elucidated binding motifs of Copaxone and of the anchor residues of the immunogenic myelin basic protein (MBP) peptide to HLA-DR molecules, novel copolymers have been designed and proved to be more effective in suppressing MS-like disease in mice. In this report, we describe the rationale for design of second-generation synthetic random copolymers as candidate drugs for a number of MHC class-II-associated autoimmune disorders. PMID:24324511

Genetic disorders of vitamin B12 metabolism: eight complementation groups – eight genes

PubMed Central

Froese, D. Sean; Gravel, Roy A.

2010-01-01

Vitamin B12 (cobalamin, Cbl) is an essential nutrient in human metabolism. Genetic diseases of vitamin B12 utilisation constitute an important fraction of inherited newborn disease. Functionally, B12 is the cofactor for methionine synthase and methylmalonyl CoA mutase. To function as a cofactor, B12 must be metabolised through a complex pathway that modifies its structure and takes it through subcellular compartments of the cell. Through the study of inherited disorders of vitamin B12 utilisation, the genes for eight complementation groups have been identified, leading to the determination of the general structure of vitamin B12 processing and providing methods for carrier testing, prenatal diagnosis and approaches to treatment. PMID:21114891

Intestinal Effector T Cells in Health and Disease

PubMed Central

Maynard, Craig L.; Weaver, Casey T.

2011-01-01

Summary Crohn’s disease and ulcerative colitis are the two major forms of chronic relapsing inflammatory disorders of the human intestines collectively referred to as inflammatory bowel disease (IBD). Though a complex set of autoinflammatory disorders that can be precipitated by diverse genetic and environmental factors, a feature that appears common to IBD pathogenesis is a dysregulated effector T cell response to the commensal microbiota. Due to the heightened effector T cell activity in IBD, developmental and functional pathways that give rise to these cells are potential targets for therapeutic intervention. In this review, we highlight recent advances in our understanding of effector T cell biology in the context of intestinal immune regulation and speculate on their potential clinical significance. PMID:19766082

GlcNAc-1-P-transferase–tunicamycin complex structure reveals basis for inhibition of N-glycosylation

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

Yoo, Jiho; Mashalidis, Ellene H.; Kuk, Alvin C. Y.

N-linked glycosylation is a predominant post-translational modification of protein in eukaryotes, and its dysregulation is the etiology of several human disorders. The enzyme UDP-N-acetylglucosamine:dolichyl-phosphate N-acetylglucosaminephosphotransferase (GlcNAc-1-P-transferase or GPT) catalyzes the first and committed step of N-linked glycosylation in the endoplasmic reticulum membrane, and it is the target of the natural product tunicamycin. Tunicamycin has potent antibacterial activity, inhibiting the bacterial cell wall synthesis enzyme MraY, but its usefulness as an antibiotic is limited by off-target inhibition of human GPT. Our understanding of how tunicamycin inhibits N-linked glycosylation and efforts to selectively target MraY are hampered by a lack of structuralmore » information. Here we present crystal structures of human GPT in complex with tunicamycin. In conclusion, structural and functional analyses reveal the difference between GPT and MraY in their mechanisms of inhibition by tunicamycin. We demonstrate that this difference could be exploited to design MraY-specific inhibitors as potential antibiotics.« less

Application of Sequence-Dependent Electrophoresis Fingerprinting in Exploring Biodiversity and Population Dynamics of Human Intestinal Microbiota: What Can Be Revealed?

PubMed Central

Huys, Geert; Vanhoutte, Tom; Vandamme, Peter

2008-01-01

Sequence-dependent electrophoresis (SDE) fingerprinting techniques such as denaturing gradient gel electrophoresis (DGGE) have become commonplace in the field of molecular microbial ecology. The success of the SDE technology lays in the fact that it allows visualization of the predominant members of complex microbial ecosystems independent of their culturability and without prior knowledge on the complexity and diversity of the ecosystem. Mainly using the prokaryotic 16S rRNA gene as PCR amplification target, SDE-based community fingerprinting turned into one of the leading molecular tools to unravel the diversity and population dynamics of human intestinal microbiota. The first part of this review covers the methodological concept of SDE fingerprinting and the technical hurdles for analyzing intestinal samples. Subsequently, the current state-of-the-art of DGGE and related techniques to analyze human intestinal microbiota from healthy individuals and from patients with intestinal disorders is surveyed. In addition, the applicability of SDE analysis to monitor intestinal population changes upon nutritional or therapeutic interventions is critically evaluated. PMID:19277102

The Structure of the Human Centrin 2-Xeroderma Pigmentosum Group C Protein Complex

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

Thompson,J.; Ryan, Z.; Salisbury, J.

2006-01-01

Human centrin-2 plays a key role in centrosome function and stimulates nucleotide excision repair by binding to the xeroderma pigmentosum group C protein. To determine the structure of human centrin-2 and to develop an understanding of molecular interactions between centrin and xeroderma pigmentosum group C protein, we characterized the crystal structure of calcium-loaded full-length centrin-2 complexed with a xeroderma pigmentosum group C peptide. Our structure shows that the carboxyl-terminal domain of centrin-2 binds this peptide and two calcium atoms, whereas the amino-terminal lobe is in a closed conformation positioned distantly by an ordered {alpha}-helical linker. A stretch of the amino-terminalmore » domain unique to centrins appears disordered. Two xeroderma pigmentosum group C peptides both bound to centrin-2 also interact to form an {alpha}-helical coiled-coil. The interface between centrin-2 and each peptide is predominantly nonpolar, and key hydrophobic residues of XPC have been identified that lead us to propose a novel binding motif for centrin.« less

The pink gene encodes the Drosophila orthologue of the human Hermansky-Pudlak syndrome 5 (HPS5) gene.

PubMed

Syrzycka, Monika; McEachern, Lori A; Kinneard, Jennifer; Prabhu, Kristel; Fitzpatrick, Kathleen; Schulze, Sandra; Rawls, John M; Lloyd, Vett K; Sinclair, Donald A R; Honda, Barry M

2007-06-01

Hermansky-Pudlak syndrome (HPS) consists of a set of human autosomal recessive disorders, with symptoms resulting from defects in genes required for protein trafficking in lysosome-related organelles such as melanosomes and platelet dense granules. A number of human HPS genes and rodent orthologues have been identified whose protein products are key components of 1 of 4 different protein complexes (AP-3 or BLOC-1, -2, and -3) that are key participants in the process. Drosophila melanogaster has been a key model organism in demonstrating the in vivo significance of many genes involved in protein trafficking pathways; for example, mutations in the "granule group" genes lead to changes in eye colour arising from improper protein trafficking to pigment granules in the developing eye. An examination of the chromosomal positioning of Drosophila HPS gene orthologues suggested that CG9770, the Drosophila HPS5 orthologue, might correspond to the pink locus. Here we confirm this gene assignment, making pink the first eye colour gene in flies to be identified as a BLOC complex gene.

Neuromagnetic Evidence of Spatially Distributed Sources Underlying Epileptiform Spikes in the Human Brain

NASA Astrophysics Data System (ADS)

Barth, Daniel S.; Sutherling, William; Engle, Jerome; Beatty, Jackson

1984-01-01

Neuromagnetic measurements were performed on 17 subjects with focal seizure disorders. In all of the subjects, the interictal spike in the scalp electroencephalogram was associated with an orderly extracranial magnetic field pattern. In eight of these subjects, multiple current sources underlay the magnetic spike complex. The multiple sources within a given subject displayed a fixed chronological sequence of discharge, demonstrating a high degree of spatial and temporal organization within the interictal focus.

Current Standards of Care and Long Term Outcomes for Thalassemia and Sickle Cell Disease.

PubMed

Chonat, Satheesh; Quinn, Charles T

2017-01-01

Thalassemia and sickle cell disease (SCD) are disorders of hemoglobin that affect millions of people worldwide. The carrier states for these diseases arose as common, balanced polymorphisms during human history because they afforded protection against severe forms of malaria. These complex, multisystem diseases are reviewed here with a focus on current standards of clinical management and recent research findings. The importance of a comprehensive, multidisciplinary and lifelong system of care is also emphasized.

Single molecule study of the intrinsically disordered FG-repeat nucleoporin 153.

PubMed

Milles, Sigrid; Lemke, Edward A

2011-10-05

Nucleoporins (Nups), which are intrinsically disordered, form a selectivity filter inside the nuclear pore complex, taking a central role in the vital nucleocytoplasmic transport mechanism. These Nups display a complex and nonrandom amino-acid architecture of phenylalanine glycine (FG)-repeat clusters and intra-FG linkers. How such heterogeneous sequence composition relates to function and could give rise to a transport mechanism is still unclear. Here we describe a combined chemical biology and single-molecule fluorescence approach to study the large human Nup153 FG-domain. In order to obtain insights into the properties of this domain beyond the average behavior, we probed the end-to-end distance (R(E)) of several ∼50-residues long FG-repeat clusters in the context of the whole protein domain. Despite the sequence heterogeneity of these FG-clusters, we detected a reoccurring and consistent compaction from a relaxed coil behavior under denaturing conditions (R(E)/R(E,RC) = 0.99 ± 0.15 with R(E,RC) corresponding to ideal relaxed coil behavior) to a collapsed state under native conditions (R(E)/R(E,RC) = 0.79 ± 0.09). We then analyzed the properties of this protein on the supramolecular level, and determined that this human FG-domain was in fact able to form a hydrogel with physiological permeability barrier properties. Copyright © 2011 Biophysical Society. Published by Elsevier Inc. All rights reserved.

The association of posttraumatic stress disorder, complex posttraumatic stress disorder, and borderline personality disorder from a network analytical perspective.

PubMed

Knefel, Matthias; Tran, Ulrich S; Lueger-Schuster, Brigitte

2016-10-01

Posttraumatic Stress Disorder (PTSD), Complex PTSD, and Borderline Personality Disorder (BPD) share etiological risk factors and an overlapping set of associated symptoms. Since the ICD-11 proposal for trauma-related disorders, the relationship of these disorders has to be clarified. A novel approach to psychopathology, network analysis, allows for a detailed analysis of comorbidity on symptom level. Symptoms were assessed in adult survivors of childhood abuse (N=219) using the newly developed ICD-11 Trauma-Questionnaire and the SCID-II. The psychopathological network was analyzed using the network approach. PTSD and Complex PTSD symptoms were strongly connected within disorders and to a lesser degree between disorders. Symptoms of BPD were weakly connected to others. Re-experiencing and dissociation were the most central symptoms. Mental disorders are no discrete entities, clear boundaries are unlikely to be found. The psychopathological network revealed central symptoms that might be important targets for specific first interventions. Copyright © 2016 Elsevier Ltd. All rights reserved.

A Comparison of the Different Animal Models of Fetal Alcohol Spectrum Disorders and Their Use in Studying Complex Behaviors

PubMed Central

Patten, Anna R.; Fontaine, Christine J.; Christie, Brian R.

2014-01-01

Prenatal ethanol exposure (PNEE) has been linked to widespread impairments in brain structure and function. There are a number of animal models that are used to study the structural and functional deficits caused by PNEE, including, but not limited to invertebrates, fish, rodents, and non-human primates. Animal models enable a researcher to control important variables such as the route of ethanol administration, as well as the timing, frequency and amount of ethanol exposure. Each animal model and system of exposure has its place, depending on the research question being undertaken. In this review, we will examine the different routes of ethanol administration and the various animal models of fetal alcohol spectrum disorders (FASD) that are commonly used in research, emphasizing their strengths and limitations. We will also present an up-to-date summary on the effects of prenatal/neonatal ethanol exposure on behavior across the lifespan, focusing on learning and memory, olfaction, social, executive, and motor functions. Special emphasis will be placed where the various animal models best represent deficits observed in the human condition and offer a viable test bed to examine potential therapeutics for human beings with FASD. PMID:25232537

Clinical mitochondrial genetics

PubMed Central

Chinnery, P.; Howell, N.; Andrews, R.; Turnbull, D.

1999-01-01

The last decade has been an age of enlightenment as far as mitochondrial pathology is concerned. Well established nuclear genetic diseases, such as Friedreich's ataxia,12 Wilson disease,3 and autosomal recessive hereditary spastic paraplegia,4 have been shown to have a mitochondrial basis, and we are just starting to unravel the complex nuclear genetic disorders which directly cause mitochondrial dysfunction (table 1). However, in addition to the 3 billion base pair nuclear genome, each human cell typically contains thousands of copies of a small, 16.5 kb circular molecule of double stranded DNA (fig 1). Mitochondrial DNA (mtDNA) accounts for only 1% of the total cellular nucleic acid content. It encodes for 13 polypeptides which are essential for aerobic metabolism and defects of the mitochondrial genome are an important cause of human disease.9293 Since the characterisation of the first pathogenic mtDNA defects in 1988,513 over 50 point mutations and well over 100 rearrangements of the mitochondrial genome have been associated with human disease9495 (http://www.gen.emory.edu/mitomap.html). These disorders form the focus of this article.


Keywords: mitochondrial DNA; mitochondrial disease; heteroplasmy; genetic counselling PMID:10874629

Reconstruction of a Functional Human Gene Network, with an Application for Prioritizing Positional Candidate Genes

PubMed Central

Franke, Lude; Bakel, Harm van; Fokkens, Like; de Jong, Edwin D.; Egmont-Petersen, Michael; Wijmenga, Cisca

2006-01-01

Most common genetic disorders have a complex inheritance and may result from variants in many genes, each contributing only weak effects to the disease. Pinpointing these disease genes within the myriad of susceptibility loci identified in linkage studies is difficult because these loci may contain hundreds of genes. However, in any disorder, most of the disease genes will be involved in only a few different molecular pathways. If we know something about the relationships between the genes, we can assess whether some genes (which may reside in different loci) functionally interact with each other, indicating a joint basis for the disease etiology. There are various repositories of information on pathway relationships. To consolidate this information, we developed a functional human gene network that integrates information on genes and the functional relationships between genes, based on data from the Kyoto Encyclopedia of Genes and Genomes, the Biomolecular Interaction Network Database, Reactome, the Human Protein Reference Database, the Gene Ontology database, predicted protein-protein interactions, human yeast two-hybrid interactions, and microarray coexpressions. We applied this network to interrelate positional candidate genes from different disease loci and then tested 96 heritable disorders for which the Online Mendelian Inheritance in Man database reported at least three disease genes. Artificial susceptibility loci, each containing 100 genes, were constructed around each disease gene, and we used the network to rank these genes on the basis of their functional interactions. By following up the top five genes per artificial locus, we were able to detect at least one known disease gene in 54% of the loci studied, representing a 2.8-fold increase over random selection. This suggests that our method can significantly reduce the cost and effort of pinpointing true disease genes in analyses of disorders for which numerous loci have been reported but for which most of the genes are unknown. PMID:16685651

"Complex" Posttraumatic Stress Disorder/Disorders of Extreme Stress (CP/DES) in Sexually Abused Children: An Exloratory Study.

ERIC Educational Resources Information Center

Hall, Darlene Kordich

1999-01-01

Compares three groups of young sexually abused children on seven "Complex" Posttraumatic Stress Disorder/Disorders of Extreme Stress (CP/DES) indices. As cumulative number of types of trauma increased, the number of CP/DES symptoms rose. Results suggest that CP/DES also characterizes sexually abused children, especially those who have…

Pervasive pleiotropy between psychiatric disorders and immune disorders revealed by integrative analysis of multiple GWAS

PubMed Central

Wang, Qian; Yang, Can; Gelernter, Joel; Zhao, Hongyu

2015-01-01

Although some existing epidemiological observations and molecular experiments suggested that brain disorders in the realm of psychiatry may be influenced by immune dysregulation, the degree of genetic overlap between psychiatric disorders and immune disorders has not been well established. We investigated this issue by integrative analysis of genome-wide association studies of 18 complex human traits/diseases (five psychiatric disorders, seven immune disorders, and others) and multiple genome-wide annotation resources (Central nervous system genes, immune-related expression-quantitative trait loci (eQTL) and DNase I hypertensive sites from 98 cell-lines). We detected pleiotropy in 24 of the 35 psychiatric-immune disorder pairs. The strongest pleiotropy was observed for schizophrenia-rheumatoid arthritis with MHC region included in the analysis (p = 3.9 × 10−285), and schizophrenia-Crohns disease with MHC region excluded (p = 1.1 × 10−36). Significant enrichment (>1.4 fold) of immune-related eQTL was observed in four psychiatric disorders. Genomic regions responsible for pleiotropy between psychiatric disorders and immune disorders were detected. The MHC region on chromosome 6 appears to be the most important with other regions, such as cytoband 1p13.2, also playing significant roles in pleiotropy. We also found that most alleles shared between schizophrenia and Crohns disease have the same effect direction, with similar trend found for other disorder pairs, such as bipolar-Crohn’s disease. Our results offer a novel birds-eye view of the genetic relationship and demonstrate strong evidence for pervasive pleiotropy between psychiatric disorders and immune disorders. Our findings might open new routes for prevention and treatment strategies for these disorders based on a new appreciation of the importance of immunological mechanisms in mediating risk of many psychiatric diseases. PMID:26340901

Altered Astrocyte-Neuron Interactions and Epileptogenesis in Tuberous Sclerosis Complex Disorder

DTIC Science & Technology

2015-06-01

Tsc1-deficient astrocytes on neuronal morphology and neuronal activity associated with seizures . 2. KEY WORDS epilepsy , seizure , tuberous sclerosis...AWARD NUMBER: W81XWH-12-1-0196 TITLE: Altered Astrocyte-Neuron Interactions and Epileptogenesis in Tuberous Sclerosis Complex Disorder PRINCIPAL...TITLE AND SUBTITLE Altered Astrocyte-Neuron Interactions and Epileptogenesis in Tuberous Sclerosis Complex Disorder 5a. CONTRACT NUMBER 5b. GRANT

Cat-Map: putting cataract on the map

PubMed Central

Bennett, Thomas M.; Hejtmancik, J. Fielding

2010-01-01

Lens opacities, or cataract(s), may be inherited as a classic Mendelian disorder usually with early-onset or, more commonly, acquired with age as a multi-factorial or complex trait. Many genetic forms of cataract have been described in mice and other animal models. Considerable progress has been made in mapping and identifying the genes and mutations responsible for inherited forms of cataract, and genetic determinants of age-related cataract are beginning to be discovered. To provide a convenient and accurate summary of current information focused on the increasing genetic complexity of Mendelian and age-related cataract we have created an online chromosome map and reference database for cataract in humans and mice (Cat-Map). PMID:21042563

Complex posttraumatic stress disorder: The need to consolidate a distinct clinical syndrome or to reevaluate features of psychiatric disorders following interpersonal trauma?

PubMed

Giourou, Evangelia; Skokou, Maria; Andrew, Stuart P; Alexopoulou, Konstantina; Gourzis, Philippos; Jelastopulu, Eleni

2018-03-22

Complex posttraumatic stress disorder (Complex PTSD) has been recently proposed as a distinct clinical entity in the WHO International Classification of Diseases, 11 th version, due to be published, two decades after its first initiation. It is described as an enhanced version of the current definition of PTSD, with clinical features of PTSD plus three additional clusters of symptoms namely emotional dysregulation, negative self-cognitions and interpersonal hardship, thus resembling the clinical features commonly encountered in borderline personality disorder (BPD). Complex PTSD is related to complex trauma which is defined by its threatening and entrapping context, generally interpersonal in nature. In this manuscript, we review the current findings related to traumatic events predisposing the above-mentioned disorders as well as the biological correlates surrounding them, along with their clinical features. Furthermore, we suggest that besides the present distinct clinical diagnoses (PTSD; Complex PTSD; BPD), there is a cluster of these comorbid disorders, that follow a continuum of trauma and biological severity on a spectrum of common or similar clinical features and should be treated as such. More studies are needed to confirm or reject this hypothesis, particularly in clinical terms and how they correlate to clinical entities' biological background, endorsing a shift from the phenomenologically only classification of psychiatric disorders towards a more biologically validated classification.

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

Cai, Zheng; Yarovoi, Serge V.; Zhu, Zhiqiang

Heparin-induced thrombocytopenia (HIT) is an autoimmune thrombotic disorder caused by immune complexes containing platelet factor 4 (PF4), antibodies to PF4 and heparin or cellular glycosaminoglycans (GAGs). Here we solve the crystal structures of the: (1) PF4 tetramer/fondaparinux complex, (2) PF4 tetramer/KKO-Fab complex (a murine monoclonal HIT-like antibody) and (3) PF4 monomer/RTO-Fab complex (a non-HIT anti-PF4 monoclonal antibody). Fondaparinux binds to the ‘closed’ end of the PF4 tetramer and stabilizes its conformation. This interaction in turn stabilizes the epitope for KKO on the ‘open’ end of the tetramer. Fondaparinux and KKO thereby collaborate to ‘stabilize’ the ternary pathogenic immune complex. Bindingmore » of RTO to PF4 monomers prevents PF4 tetramerization and inhibits KKO and human HIT IgG-induced platelet activation and platelet aggregation in vitro, and thrombus progression in vivo. Lastly, the atomic structures provide a basis to develop new diagnostics and non-anticoagulant therapeutics for HIT.« less

Open Science Meets Stem Cells: A New Drug Discovery Approach for Neurodegenerative Disorders

PubMed Central

Han, Chanshuai; Chaineau, Mathilde; Chen, Carol X.-Q.; Beitel, Lenore K.; Durcan, Thomas M.

2018-01-01

Neurodegenerative diseases are a challenge for drug discovery, as the biological mechanisms are complex and poorly understood, with a paucity of models that faithfully recapitulate these disorders. Recent advances in stem cell technology have provided a paradigm shift, providing researchers with tools to generate human induced pluripotent stem cells (iPSCs) from patient cells. With the potential to generate any human cell type, we can now generate human neurons and develop “first-of-their-kind” disease-relevant assays for small molecule screening. Now that the tools are in place, it is imperative that we accelerate discoveries from the bench to the clinic. Using traditional closed-door research systems raises barriers to discovery, by restricting access to cells, data and other research findings. Thus, a new strategy is required, and the Montreal Neurological Institute (MNI) and its partners are piloting an “Open Science” model. One signature initiative will be that the MNI biorepository will curate and disseminate patient samples in a more accessible manner through open transfer agreements. This feeds into the MNI open drug discovery platform, focused on developing industry-standard assays with iPSC-derived neurons. All cell lines, reagents and assay findings developed in this open fashion will be made available to academia and industry. By removing the obstacles many universities and companies face in distributing patient samples and assay results, our goal is to accelerate translational medical research and the development of new therapies for devastating neurodegenerative disorders. PMID:29467610

Open Science Meets Stem Cells: A New Drug Discovery Approach for Neurodegenerative Disorders.

PubMed

Han, Chanshuai; Chaineau, Mathilde; Chen, Carol X-Q; Beitel, Lenore K; Durcan, Thomas M

2018-01-01

Neurodegenerative diseases are a challenge for drug discovery, as the biological mechanisms are complex and poorly understood, with a paucity of models that faithfully recapitulate these disorders. Recent advances in stem cell technology have provided a paradigm shift, providing researchers with tools to generate human induced pluripotent stem cells (iPSCs) from patient cells. With the potential to generate any human cell type, we can now generate human neurons and develop "first-of-their-kind" disease-relevant assays for small molecule screening. Now that the tools are in place, it is imperative that we accelerate discoveries from the bench to the clinic. Using traditional closed-door research systems raises barriers to discovery, by restricting access to cells, data and other research findings. Thus, a new strategy is required, and the Montreal Neurological Institute (MNI) and its partners are piloting an "Open Science" model. One signature initiative will be that the MNI biorepository will curate and disseminate patient samples in a more accessible manner through open transfer agreements. This feeds into the MNI open drug discovery platform, focused on developing industry-standard assays with iPSC-derived neurons. All cell lines, reagents and assay findings developed in this open fashion will be made available to academia and industry. By removing the obstacles many universities and companies face in distributing patient samples and assay results, our goal is to accelerate translational medical research and the development of new therapies for devastating neurodegenerative disorders.

Increased burden of deleterious variants in essential genes in autism spectrum disorder.

PubMed

Ji, Xiao; Kember, Rachel L; Brown, Christopher D; Bućan, Maja

2016-12-27

Autism spectrum disorder (ASD) is a heterogeneous, highly heritable neurodevelopmental syndrome characterized by impaired social interaction, communication, and repetitive behavior. It is estimated that hundreds of genes contribute to ASD. We asked if genes with a strong effect on survival and fitness contribute to ASD risk. Human orthologs of genes with an essential role in pre- and postnatal development in the mouse [essential genes (EGs)] are enriched for disease genes and under strong purifying selection relative to human orthologs of mouse genes with a known nonlethal phenotype [nonessential genes (NEGs)]. This intolerance to deleterious mutations, commonly observed haploinsufficiency, and the importance of EGs in development suggest a possible cumulative effect of deleterious variants in EGs on complex neurodevelopmental disorders. With a comprehensive catalog of 3,915 mammalian EGs, we provide compelling evidence for a stronger contribution of EGs to ASD risk compared with NEGs. By examining the exonic de novo and inherited variants from 1,781 ASD quartet families, we show a significantly higher burden of damaging mutations in EGs in ASD probands compared with their non-ASD siblings. The analysis of EGs in the developing brain identified clusters of coexpressed EGs implicated in ASD. Finally, we suggest a high-priority list of 29 EGs with potential ASD risk as targets for future functional and behavioral studies. Overall, we show that large-scale studies of gene function in model organisms provide a powerful approach for prioritization of genes and pathogenic variants identified by sequencing studies of human disease.

Increased burden of deleterious variants in essential genes in autism spectrum disorder

PubMed Central

Kember, Rachel L.; Brown, Christopher D.; Bućan, Maja

2016-01-01

Autism spectrum disorder (ASD) is a heterogeneous, highly heritable neurodevelopmental syndrome characterized by impaired social interaction, communication, and repetitive behavior. It is estimated that hundreds of genes contribute to ASD. We asked if genes with a strong effect on survival and fitness contribute to ASD risk. Human orthologs of genes with an essential role in pre- and postnatal development in the mouse [essential genes (EGs)] are enriched for disease genes and under strong purifying selection relative to human orthologs of mouse genes with a known nonlethal phenotype [nonessential genes (NEGs)]. This intolerance to deleterious mutations, commonly observed haploinsufficiency, and the importance of EGs in development suggest a possible cumulative effect of deleterious variants in EGs on complex neurodevelopmental disorders. With a comprehensive catalog of 3,915 mammalian EGs, we provide compelling evidence for a stronger contribution of EGs to ASD risk compared with NEGs. By examining the exonic de novo and inherited variants from 1,781 ASD quartet families, we show a significantly higher burden of damaging mutations in EGs in ASD probands compared with their non-ASD siblings. The analysis of EGs in the developing brain identified clusters of coexpressed EGs implicated in ASD. Finally, we suggest a high-priority list of 29 EGs with potential ASD risk as targets for future functional and behavioral studies. Overall, we show that large-scale studies of gene function in model organisms provide a powerful approach for prioritization of genes and pathogenic variants identified by sequencing studies of human disease. PMID:27956632

Identification of Atg3 as an intrinsically disordered polypeptide yields insights into the molecular dynamics of autophagy-related proteins in yeast.

PubMed

Popelka, Hana; Uversky, Vladimir N; Klionsky, Daniel J

2014-06-01

The mechanism of autophagy relies on complex cell signaling and regulatory processes. Each cell contains many proteins that lack a rigid 3-dimensional structure under physiological conditions. These dynamic proteins, called intrinsically disordered proteins (IDPs) and protein regions (IDPRs), are predominantly involved in cell signaling and regulation. Yet, very little is known about their presence among proteins of the core autophagy machinery. In this work, we characterized the autophagy protein Atg3 from yeast and human along with 2 variants to show that Atg3 is an IDPRs-containing protein and that disorder/order predicted for these proteins from their amino acid sequence corresponds to their experimental characteristics. Based on this consensus, we applied the same prediction methods to all known Atg proteins from Saccharomyces cerevisiae. The data presented here provide an insight into the structural dynamics of each Atg protein. They also show that intrinsic disorder at various levels has to be taken into consideration for about half of the Atg proteins. This work should become a useful tool that will facilitate and encourage exploration of protein intrinsic disorder in autophagy.

Dopamine in the medial amygdala network mediates human bonding

PubMed Central

Touroutoglou, Alexandra; Rudy, Tali; Salcedo, Stephanie; Feldman, Ruth; Hooker, Jacob M.; Dickerson, Bradford C.; Catana, Ciprian; Barrett, Lisa Feldman

2017-01-01

Research in humans and nonhuman animals indicates that social affiliation, and particularly maternal bonding, depends on reward circuitry. Although numerous mechanistic studies in rodents demonstrated that maternal bonding depends on striatal dopamine transmission, the neurochemistry supporting maternal behavior in humans has not been described so far. In this study, we tested the role of central dopamine in human bonding. We applied a combined functional MRI-PET scanner to simultaneously probe mothers’ dopamine responses to their infants and the connectivity between the nucleus accumbens (NAcc), the amygdala, and the medial prefrontal cortex (mPFC), which form an intrinsic network (referred to as the “medial amygdala network”) that supports social functioning. We also measured the mothers’ behavioral synchrony with their infants and plasma oxytocin. The results of this study suggest that synchronous maternal behavior is associated with increased dopamine responses to the mother’s infant and stronger intrinsic connectivity within the medial amygdala network. Moreover, stronger network connectivity is associated with increased dopamine responses within the network and decreased plasma oxytocin. Together, these data indicate that dopamine is involved in human bonding. Compared with other mammals, humans have an unusually complex social life. The complexity of human bonding cannot be fully captured in nonhuman animal models, particularly in pathological bonding, such as that in autistic spectrum disorder or postpartum depression. Thus, investigations of the neurochemistry of social bonding in humans, for which this study provides initial evidence, are warranted. PMID:28193868

Association of a MAOA gene variant with generalized anxiety disorder, but not with panic disorder or major depression.

PubMed

Tadic, A; Rujescu, D; Szegedi, A; Giegling, I; Singer, P; Möller, H-J; Dahmen, N

2003-02-01

This study was conducted to detect a possible association of a T941G single nucleotide polymorphism (SNP) in the monoamine oxidase A (MAOA) gene with generalized anxiety disorder (GAD), panic disorder (PD), or major depression (MD). Fifty GAD patients (34 females and 16 males), 38 PD patients (21 females and 17 males), and 108 MD patients (80 females and 28 males) were included. The comparison group consisted of 276 (132 females and 144 males) unrelated healthy individuals. The 941T allele was over-represented in patients suffering from GAD (chi(2) = 6.757; df = 1; P < 0.01, not corrected for multiple testing) when compared to healthy volunteers. No association was observed in MD or PD. This is the first study specifically analyzing the MAOA G941T polymorphism in GAD and thus needs to be replicated in an independent sample. However, the results are in line with previous data suggesting an association between the MAOA locus and regulation of complex human behavior. Copyright 2003 Wiley-Liss, Inc.

Automatic detection of articulation disorders in children with cleft lip and palate.

PubMed

Maier, Andreas; Hönig, Florian; Bocklet, Tobias; Nöth, Elmar; Stelzle, Florian; Nkenke, Emeka; Schuster, Maria

2009-11-01

Speech of children with cleft lip and palate (CLP) is sometimes still disordered even after adequate surgical and nonsurgical therapies. Such speech shows complex articulation disorders, which are usually assessed perceptually, consuming time and manpower. Hence, there is a need for an easy to apply and reliable automatic method. To create a reference for an automatic system, speech data of 58 children with CLP were assessed perceptually by experienced speech therapists for characteristic phonetic disorders at the phoneme level. The first part of the article aims to detect such characteristics by a semiautomatic procedure and the second to evaluate a fully automatic, thus simple, procedure. The methods are based on a combination of speech processing algorithms. The semiautomatic method achieves moderate to good agreement (kappa approximately 0.6) for the detection of all phonetic disorders. On a speaker level, significant correlations between the perceptual evaluation and the automatic system of 0.89 are obtained. The fully automatic system yields a correlation on the speaker level of 0.81 to the perceptual evaluation. This correlation is in the range of the inter-rater correlation of the listeners. The automatic speech evaluation is able to detect phonetic disorders at an experts'level without any additional human postprocessing.

Pharmacotherapeutics for substance-use disorders: a focus on dopaminergic medications

PubMed Central

Verrico, Christopher D; Haile, Colin N; Newton, Thomas F; Kosten, Thomas R; De La Garza, Richard

2015-01-01

Introduction Illicit substance-use is a substantial public health concern, contributing over $150 billion in costs annually to Americans. A complex disease, a substance-use disorder affects neural circuits involved in reinforcement, motivation, learning and memory, and inhibitory control. Areas covered The modulatory influence of dopamine in mesocorticolimbic circuits contributes to encoding the primary reinforcing effects of substances and numerous studies suggest that aberrant signaling within these circuits contributes to the development of a substance-use disorder in some individuals. Decades of research focused on the clinical development of medications that directly target dopamine receptors has led to recent studies of agonist-like dopaminergic treatments for stimulant-use disorders and, more recently, cannabis-use disorder. Human studies evaluating the efficacy of dopaminergic agonist-like medications to reduce reinforcing effects and substance-use provide some insight into the design of future pharmacotherapy trials. A search of PubMed using specific brain regions, medications, and/or the terms ‘dopamine’, ‘cognition’, ‘reinforcement’, ‘cocaine’, ‘methamphetamine’, ‘amphetamine’, ‘cannabis’, ‘treatment/pharmacotherapy’, ‘addiction/abuse/dependence’ identified articles relevant to this review. Expert opinion Conceptualization of substance-use disorders and their treatment continues to evolve. Current efforts increasingly focus on a strategy fostering combination pharmacotherapies that target multiple neurotransmitter systems. PMID:24033127

[Nutritional aspects of attention-deficit/hyperactive disorder].

PubMed

Quintero, J; Rodríguez-Quirós, J; Correas-Lauffer, J; Pérez-Templado, J

Attention-deficit/hyperactive disorder (ADHD) has received in the past years a lot of attention from the paediatrician's specialties. Even though the studies of its etiopathology have advanced, mainly the ones related with genetics and neuroimaging, the final cause today is still unclear. It has been related to many factors such as diet, like some allergies to additives, toxicity to heavy metals and other toxic substances from the environment, due to low protein diets with a high carbohydrate content, unbalanced minerals, essential fatty acids and phospholipid deficit, amino acid deficits, thyroid disorders, and vitamin B complex disorders and phytochemicals. The way our lifestyle has changed in general and the diet in particular nowadays is being considered as a hypothesis for many disorders and health problems, but what about ADHD? One of the changes that we want to emphasize is related to vegetable fat and oils that dominate human consumption and the reduction income of fatty acids from the omega-3 family, including alpha-linolenic acid, eicosapentaenoic acid and docosapentaenoic acid. The fact is even worse when the amount of omega-6 increases and the ratio between both changes. It is a fact that these kinds of nutrients play an important role in the nervous system development. In this paper the essential fatty acids in neuropsychiatric disorders in general, ADHD in particular, is reviewed.

Regulation of the Dopamine and Vesicular Monoamine Transporters: Pharmacological Targets and Implications for Disease.

PubMed

German, Christopher L; Baladi, Michelle G; McFadden, Lisa M; Hanson, Glen R; Fleckenstein, Annette E

2015-10-01

Dopamine (DA) plays a well recognized role in a variety of physiologic functions such as movement, cognition, mood, and reward. Consequently, many human disorders are due, in part, to dysfunctional dopaminergic systems, including Parkinson's disease, attention deficit hyperactivity disorder, and substance abuse. Drugs that modify the DA system are clinically effective in treating symptoms of these diseases or are involved in their manifestation, implicating DA in their etiology. DA signaling and distribution are primarily modulated by the DA transporter (DAT) and by vesicular monoamine transporter (VMAT)-2, which transport DA into presynaptic terminals and synaptic vesicles, respectively. These transporters are regulated by complex processes such as phosphorylation, protein-protein interactions, and changes in intracellular localization. This review provides an overview of 1) the current understanding of DAT and VMAT2 neurobiology, including discussion of studies ranging from those conducted in vitro to those involving human subjects; 2) the role of these transporters in disease and how these transporters are affected by disease; and 3) and how selected drugs alter the function and expression of these transporters. Understanding the regulatory processes and the pathologic consequences of DAT and VMAT2 dysfunction underlies the evolution of therapeutic development for the treatment of DA-related disorders. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

Effects of LSD on grooming behavior in serotonin transporter heterozygous (Sert⁺/⁻) mice.

PubMed

Kyzar, Evan J; Stewart, Adam Michael; Kalueff, Allan V

2016-01-01

Serotonin (5-HT) plays a crucial role in the brain, modulating mood, cognition and reward. The serotonin transporter (SERT) is responsible for the reuptake of 5-HT from the synaptic cleft and regulates serotonin signaling in the brain. In humans, SERT genetic variance is linked to the pathogenesis of various psychiatric disorders, including anxiety, autism spectrum disorders (ASD) and obsessive-compulsive disorder (OCD). Rodent self-grooming is a complex, evolutionarily conserved patterned behavior relevant to stress, ASD and OCD. Genetic ablation of mouse Sert causes various behavioral deficits, including increased anxiety and grooming behavior. The hallucinogenic drug lysergic acid diethylamide (LSD) is a potent serotonergic agonist known to modulate human and animal behavior. Here, we examined heterozygous Sert(+/-) mouse behavior following acute administration of LSD (0.32 mg/kg). Overall, Sert(+/-) mice displayed a longer duration of self-grooming behavior regardless of LSD treatment. In contrast, LSD increased serotonin-sensitive behaviors, such as head twitching, tremors and backwards gait behaviors in both Sert(+/+) and Sert(+/-) mice. There were no significant interactions between LSD treatment and Sert gene dosage in any of the behavioral domains measured. These results suggest that Sert(+/-) mice may respond to the behavioral effects of LSD in a similar manner to wild-type mice. Copyright © 2015 Elsevier B.V. All rights reserved.

Regulation of the Dopamine and Vesicular Monoamine Transporters: Pharmacological Targets and Implications for Disease

PubMed Central

German, Christopher L.; Baladi, Michelle G.; McFadden, Lisa M.; Hanson, Glen R.

2015-01-01

Dopamine (DA) plays a well recognized role in a variety of physiologic functions such as movement, cognition, mood, and reward. Consequently, many human disorders are due, in part, to dysfunctional dopaminergic systems, including Parkinson’s disease, attention deficit hyperactivity disorder, and substance abuse. Drugs that modify the DA system are clinically effective in treating symptoms of these diseases or are involved in their manifestation, implicating DA in their etiology. DA signaling and distribution are primarily modulated by the DA transporter (DAT) and by vesicular monoamine transporter (VMAT)-2, which transport DA into presynaptic terminals and synaptic vesicles, respectively. These transporters are regulated by complex processes such as phosphorylation, protein–protein interactions, and changes in intracellular localization. This review provides an overview of 1) the current understanding of DAT and VMAT2 neurobiology, including discussion of studies ranging from those conducted in vitro to those involving human subjects; 2) the role of these transporters in disease and how these transporters are affected by disease; and 3) and how selected drugs alter the function and expression of these transporters. Understanding the regulatory processes and the pathologic consequences of DAT and VMAT2 dysfunction underlies the evolution of therapeutic development for the treatment of DA-related disorders. PMID:26408528

Actin Out: Regulation of the Synaptic Cytoskeleton

PubMed Central

Spence, Erin F.; Soderling, Scott H.

2015-01-01

The small size of dendritic spines belies the elaborate role they play in excitatory synaptic transmission and ultimately complex behaviors. The cytoskeletal architecture of the spine is predominately composed of actin filaments. These filaments, which at first glance might appear simple, are also surprisingly complex. They dynamically assemble into different structures and serve as a platform for orchestrating the elaborate responses of the spine during spinogenesis and experience-dependent plasticity. Multiple mutations associated with human neurodevelopmental and psychiatric disorders involve genes that encode regulators of the synaptic cytoskeleton. A major, unresolved question is how the disruption of specific actin filament structures leads to the onset and progression of complex synaptic and behavioral phenotypes. This review will cover established and emerging mechanisms of actin cytoskeletal remodeling and how this influences specific aspects of spine biology that are implicated in disease. PMID:26453304

The Fanconi anemia pathway promotes replication-dependent DNA interstrand crosslink repair

PubMed Central

Knipscheer, Puck; Räschle, Markus; Smogorzewska, Agata; Enoiu, Milica; Ho, The Vinh; Schärer, Orlando D.; Elledge, Stephen J.; Walter, Johannes C.

2010-01-01

Fanconi anemia is a human cancer predisposition syndrome caused by mutations in thirteen Fanc genes. The disorder is characterized by genomic instability and cellular hypersensitivity to chemicals that generate DNA interstrand crosslinks (ICLs). A central event in the activation of the Fanconi anemia pathway is the mono-ubiquitylation of the FANCI-FANCD2 complex, but how this complex confers ICL resistance remains enigmatic. We make use of a cell-free system to show that the FANCI-FANCD2 complex is required for replication-dependent ICL repair. Removal of FANCD2 from extracts inhibits nucleolytic incisions near the ICL as well as translesion DNA synthesis past the lesion. Reversal of these defects requires ubiquitylated FANCI-FANCD2. Our results show that multiple steps of the essential S phase ICL repair mechanism fail when the Fanconi anemia pathway is compromised. PMID:19965384

Inhibition of copper-mediated aggregation of human γD-crystallin by Schiff bases.

PubMed

Chauhan, Priyanka; Muralidharan, Sai Brinda; Velappan, Anand Babu; Datta, Dhrubajyoti; Pratihar, Sanjay; Debnath, Joy; Ghosh, Kalyan Sundar

2017-06-01

Protein aggregation, due to the imbalance in the concentration of Cu 2+ and Zn 2+ ions is found to be allied with various physiological disorders. Copper is known to promote the oxidative damage of β/γ-crystallins in aged eye lens and causes their aggregation leading to cataract. Therefore, synthesis of a small-molecule 'chelator' for Cu 2+ with complementary antioxidant effect will find potential applications against aggregation of β/γ-crystallins. In this paper, we have reported the synthesis of different Schiff bases and studied their Cu 2+ complexation ability (using UV-Vis, FT-IR and ESI-MS) and antioxidant activity. Further based on their copper complexation efficiency, Schiff bases were used to inhibit Cu 2+ -mediated aggregation of recombinant human γD-crystallin (HGD) and β/γ-crystallins (isolated from cataractous human eye lens). Among these synthesized molecules, compound 8 at a concentration of 100 μM had shown ~95% inhibition of copper (100 μM)-induced aggregation. Compound 8 also showed a positive cooperative effect at a concentration of 5-15 μM on the inhibitory activity of human αA-crystallin (HAA) during Cu 2+ -induced aggregation of HGD. It eventually inhibited the aggregation process by additional ~20%. However, ~50% inhibition of copper-mediated aggregation of β/γ-crystallins (isolated from cataractous human eye lens) was recorded by compound 8 (100 μM). Although the reductive aminated products of the imines showed better antioxidant activity due to their lower copper complexing ability, they were found to be non-effective against Cu 2+ -mediated aggregation of HGD.

Basic mechanisms of gabitril (tiagabine) and future potential developments.

PubMed

Meldrum, B S; Chapman, A G

1999-01-01

Gabitril (tiagabine) is a potent selective inhibitor of the principal neuronal gamma-aminobutyric acid (GABA) transporter (GAT-1) in the cortex and hippocampus. By slowing the reuptake of synaptically-released GABA, it prolongs inhibitory postsynaptic potentials. In animal models of epilepsy, tiagabine is particularly effective against kindled (limbic) seizures and against reflexly-induced generalized convulsive seizures. These data are predictive of its efficacy in complex partial seizures in humans. Possible clinical applications outside the field of epilepsy include bipolar disorder and pain.

Current Standards of Care and Long Term Outcomes for Thalassemia and Sickle Cell Disease

PubMed Central

Chonat, Satheesh

2017-01-01

Thalassemia and sickle cell disease (SCD) are disorders of hemoglobin that affect millions of people worldwide. The carrier states for these diseases arose as common, balanced polymorphisms during human history because they afforded protection against severe forms of malaria. These complex, multisystem diseases are reviewed here with a focus on current standards of clinical management and recent research findings. The importance of a comprehensive, multidisciplinary and lifelong system of care is also emphasized. PMID:29127677

Modeling the complex pathology of Alzheimer’s disease in Drosophila

PubMed Central

Fernandez-Funez, Pedro; de Mena, Lorena; Rincon-Limas, Diego E.

2015-01-01

Alzheimer’s disease (AD) is the leading cause of dementia and the most common neurodegenerative disorder. AD is mostly a sporadic disorder and its main risk factor is age, but mutations in three genes that promote the accumulation of the amyloid-β (Aβ42) peptide revealed the critical role of Amyloid precursor protein (APP) processing in AD. Neurofibrillary tangles enriched in tau are the other pathological hallmark of AD, but the lack of causative tau mutations still puzzles researchers. Here, we describe the contribution of a powerful invertebrate model, the fruit fly Drosophila melanogaster, to uncovering the function and pathogenesis of human APP, Aβ42, and tau. APP and tau participate in many complex cellular processes, although their main function is microtubule stabilization and the to-and-fro transport of axonal vesicles. Additionally, expression of secreted Aβ42 induces prominent neuronal death in Drosophila, a critical feature of AD, making this model a popular choice for identifying intrinsic and extrinsic factors mediating Aβ42 neurotoxicity. Overall, Drosophila has made significant contributions to better understand the complex pathology of AD, although additional insight can be expected from combining multiple transgenes, performing genome-wide loss-of-function screens, and testing anti-tau therapies alone or in combination with Aβ42. PMID:26024860

Oxidized Base Damage and Single-Strand Break Repair in Mammalian Genomes: Role of Disordered Regions and Posttranslational Modifications in Early Enzymes

PubMed Central

Hegde, Muralidhar L.; Izumi, Tadahide; Mitra, Sankar

2012-01-01

Oxidative genome damage induced by reactive oxygen species includes oxidized bases, abasic (AP) sites, and single-strand breaks, all of which are repaired via the evolutionarily conserved base excision repair/single-strand break repair (BER/SSBR) pathway. BER/SSBR in mammalian cells is complex, with preferred and backup sub-pathways, and is linked to genome replication and transcription. The early BER/SSBR enzymes, namely, DNA glycosylases (DGs) and the end-processing proteins such as abasic endonuclease 1 (APE1), form complexes with downstream repair (and other noncanonical) proteins via pairwise interactions. Furthermore, a unique feature of mammalian early BER/ SSBR enzymes is the presence of a disordered terminal extension that is absent in their Escherichia coli prototypes. These nonconserved segments usually contain organelle-targeting signals, common interaction interfaces, and sites of posttranslational modifications that may be involved in regulating their repair function including lesion scanning. Finally, the linkage of BER/SSBR deficiency to cancer, aging, and human neurodegenerative diseases, and therapeutic targeting of BER/SSBR are discussed. PMID:22749145

Genetics, environmental factors and the emerging role of epigenetics in neurodegenerative diseases.

PubMed

Migliore, Lucia; Coppedè, Fabio

2009-07-10

In the present review we summarize recent advances in the understanding of the interaction between genetics and environmental factors involved in complex multi-factorial neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD) and Amyotrophic Lateral Sclerosis (ALS). The discovery of several genes responsible for the familial forms has led to a better comprehension of the molecular pathways involved in the selective neuronal degeneration which is specific for each of these disorders. However, the vast majority of the cases occurs as sporadic forms, likely resulting from complex gene-gene and gene-environment interplay. Several environmental factors, including, pesticides, metals, head injuries, lifestyles and dietary habits have been associated with increased disease risk or even with protection. Hundreds of genetic variants have been investigated as possible risk factors for the sporadic forms, but results are often conflicting, not repeated or inconclusive. New approaches to environmental health research are revealing us that at the basis there could be chemically induced changes in gene regulation and emphasise the importance of understanding the susceptibility of the human epigenome to dietary and other environmental effects.

Chemical perturbation of an intrinsically disordered region of TFIID distinguishes two modes of transcription initiation

PubMed Central

Zhang, Zhengjian; Boskovic, Zarko; Hussain, Mahmud M; Hu, Wenxin; Inouye, Carla; Kim, Han-Je; Abole, A Katherine; Doud, Mary K; Lewis, Timothy A; Koehler, Angela N; Schreiber, Stuart L; Tjian, Robert

2015-01-01

Intrinsically disordered proteins/regions (IDPs/IDRs) are proteins or peptide segments that fail to form stable 3-dimensional structures in the absence of partner proteins. They are abundant in eukaryotic proteomes and are often associated with human diseases, but their biological functions have been elusive to study. In this study, we report the identification of a tin(IV) oxochloride-derived cluster that binds an evolutionarily conserved IDR within the metazoan TFIID transcription complex. Binding arrests an isomerization of promoter-bound TFIID that is required for the engagement of Pol II during the first (de novo) round of transcription initiation. However, the specific chemical probe does not affect reinitiation, which requires the re-entry of Pol II, thus, mechanistically distinguishing these two modes of transcription initiation. This work also suggests a new avenue for targeting the elusive IDRs by harnessing certain features of metal-based complexes for mechanistic studies, and for the development of novel pharmaceutical interventions. DOI: http://dx.doi.org/10.7554/eLife.07777.001 PMID:26314865

How Preclinical Models Evolved to Resemble the Diagnostic Criteria of Drug Addiction.

PubMed

Belin-Rauscent, Aude; Fouyssac, Maxime; Bonci, Antonello; Belin, David

2016-01-01

Drug addiction is a complex neuropsychiatric disorder that affects a subset of the individuals who take drugs. It is characterized by maladaptive drug-seeking habits that are maintained despite adverse consequences and intense drug craving. The pathophysiology and etiology of addiction is only partially understood despite extensive research because of the gap between current preclinical models of addiction and the clinical criteria of the disorder. This review presents a brief overview, based on selected methodologies, of how behavioral models have evolved over the last 50 years to the development of recent preclinical models of addiction that more closely mimic diagnostic criteria of addiction. It is hoped that these new models will increase our understanding of the complex neurobiological mechanisms whereby some individuals switch from controlled drug use to compulsive drug-seeking habits and relapse to these maladaptive habits. Additionally, by paving the way to bridge the gap that exists between biobehavioral research on addiction and the human situation, these models may provide new perspectives for the development of novel and effective therapeutic strategies for drug addiction. Published by Elsevier Inc.

How preclinical models evolved to resemble the diagnostic criteria of drug addiction

PubMed Central

Belin-Rauscent, Aude; Fouyssac, Maxime; Bonci, Antonello; Belin, David

2015-01-01

Drug addiction is a complex neuropsychiatric disorder that affects a subset of the individuals who take drugs. It is characterized by maladaptive drug-seeking habits that are maintained despite adverse consequences and intense drug craving. Despite extensive research, the pathophysiology and aetiology of addiction is only partially understood, due to the gap between current preclinical models of addiction and the clinical criteria of the disorder. Here we give a brief overview, based on selected methodologies, of how behavioral models have evolved over the last fifty years to the development of recent preclinical models of addiction that more closely mimic diagnostic criteria of addiction. These new models will hopefully increase our understanding of the complex neurobiological mechanisms whereby some individuals switch from controlled drug use to compulsive drug-seeking habits and relapse to these maladaptive habits. Additional, by paving the way to bridge the gap that exists between biobehavioral research on addiction and the human situation, these models may provide new perspectives for the development of novel and effective therapeutic strategies for drug addiction. PMID:25747744

Levels of Social Sharing and Clinical Implications for Severe Social Withdrawal in Patients with Personality Disorders.

PubMed

Colle, Livia; Pellecchia, Giovanni; Moroni, Fabio; Carcione, Antonino; Nicolò, Giuseppe; Semerari, Antonio; Procacci, Michele

2017-01-01

Social sharing capacities have attracted attention from a number of fields of social cognition and have been variously defined and analyzed in numerous studies. Social sharing consists in the subjective awareness that aspects of the self's experience are held in common with other individuals. The definition of social sharing must take a variety of elements into consideration: the motivational element, the contents of the social sharing experience, the emotional responses it evokes, the behavioral outcomes, and finally, the circumstances and the skills which enable social sharing. The primary objective of this study is to explore some of the diverse forms of human social sharing and to classify them according to levels of complexity. We identify four different types of social sharing, categorized according to the nature of the content being shared and the complexity of the mindreading skills required. The second objective of this study is to consider possible applications of this graded model of social sharing experience in clinical settings. Specifically, this model may support the development of graded, focused clinical interventions for patients with personality disorders characterized by severe social withdrawal.

Recording In Vivo Human Colonic Motility: What Have We Learnt Over the Past 100 Years?

PubMed

Dinning, Phil G

To understand the abnormalities that underpin functional gut disorders we must first gain insight into the normal patterns of gut motility. While detailed information continually builds on the motor patterns (and mechanisms that control them) of the human esophagus and anorectum, our knowledge of normal and abnormal motility in the more inaccessible regions of the gut remains poor. This particularly true of the human colon. Investigation of in vivo colonic motor patterns is achieved through measures of transit (radiology, scintigraphy and, more recently, "smart pills") or by direct real-time recording of colonic contractility (intraluminal manometry). This short review will provide an overview of findings from the past and present and attempt to piece together the complex nature of colonic motor patterns. In doing so it will build a profile of human colonic motility and determine the likely mechanisms that control this motility.

Genome-wide analysis identifies 12 loci influencing human reproductive behavior

PubMed Central

Barban, Nicola; Jansen, Rick; de Vlaming, Ronald; Vaez, Ahmad; Mandemakers, Jornt J.; Tropf, Felix C.; Shen, Xia; Wilson, James F.; Chasman, Daniel I.; Nolte, Ilja M.; Tragante, Vinicius; van der Laan, Sander W.; Perry, John R. B.; Kong, Augustine; Ahluwalia, Tarunveer; Albrecht, Eva; Yerges-Armstrong, Laura; Atzmon, Gil; Auro, Kirsi; Ayers, Kristin; Bakshi, Andrew; Ben-Avraham, Danny; Berger, Klaus; Bergman, Aviv; Bertram, Lars; Bielak, Lawrence F.; Bjornsdottir, Gyda; Bonder, Marc Jan; Broer, Linda; Bui, Minh; Barbieri, Caterina; Cavadino, Alana; Chavarro, Jorge E; Turman, Constance; Concas, Maria Pina; Cordell, Heather J.; Davies, Gail; Eibich, Peter; Eriksson, Nicholas; Esko, Tõnu; Eriksson, Joel; Falahi, Fahimeh; Felix, Janine F.; Fontana, Mark Alan; Franke, Lude; Gandin, Ilaria; Gaskins, Audrey J.; Gieger, Christian; Gunderson, Erica P.; Guo, Xiuqing; Hayward, Caroline; He, Chunyan; Hofer, Edith; Huang, Hongyan; Joshi, Peter K.; Kanoni, Stavroula; Karlsson, Robert; Kiechl, Stefan; Kifley, Annette; Kluttig, Alexander; Kraft, Peter; Lagou, Vasiliki; Lecoeur, Cecile; Lahti, Jari; Li-Gao, Ruifang; Lind, Penelope A.; Liu, Tian; Makalic, Enes; Mamasoula, Crysovalanto; Matteson, Lindsay; Mbarek, Hamdi; McArdle, Patrick F.; McMahon, George; Meddens, S. Fleur W.; Mihailov, Evelin; Miller, Mike; Missmer, Stacey A.; Monnereau, Claire; van der Most, Peter J.; Myhre, Ronny; Nalls, Mike A.; Nutile, Teresa; Panagiota, Kalafati Ioanna; Porcu, Eleonora; Prokopenko, Inga; Rajan, Kumar B.; Rich-Edwards, Janet; Rietveld, Cornelius A.; Robino, Antonietta; Rose, Lynda M.; Rueedi, Rico; Ryan, Kathy; Saba, Yasaman; Schmidt, Daniel; Smith, Jennifer A.; Stolk, Lisette; Streeten, Elizabeth; Tonjes, Anke; Thorleifsson, Gudmar; Ulivi, Sheila; Wedenoja, Juho; Wellmann, Juergen; Willeit, Peter; Yao, Jie; Yengo, Loic; Zhao, Jing Hua; Zhao, Wei; Zhernakova, Daria V.; Amin, Najaf; Andrews, Howard; Balkau, Beverley; Barzilai, Nir; Bergmann, Sven; Biino, Ginevra; Bisgaard, Hans; Bønnelykke, Klaus; Boomsma, Dorret I.; Buring, Julie E.; Campbell, Harry; Cappellani, Stefania; Ciullo, Marina; Cox, Simon R.; Cucca, Francesco; Daniela, Toniolo; Davey-Smith, George; Deary, Ian J.; Dedoussis, George; Deloukas, Panos; van Duijn, Cornelia M.; de Geus, Eco JC.; Eriksson, Johan G.; Evans, Denis A.; Faul, Jessica D.; Felicita, Sala Cinzia; Froguel, Philippe; Gasparini, Paolo; Girotto, Giorgia; Grabe, Hans-Jörgen; Greiser, Karin Halina; Groenen, Patrick J.F.; de Haan, Hugoline G.; Haerting, Johannes; Harris, Tamara B.; Heath, Andrew C.; Heikkilä, Kauko; Hofman, Albert; Homuth, Georg; Holliday, Elizabeth G; Hopper, John; Hypponen, Elina; Jacobsson, Bo; Jaddoe, Vincent W. V.; Johannesson, Magnus; Jugessur, Astanand; Kähönen, Mika; Kajantie, Eero; Kardia, Sharon L.R.; Keavney, Bernard; Kolcic, Ivana; Koponen, Päivikki; Kovacs, Peter; Kronenberg, Florian; Kutalik, Zoltan; La Bianca, Martina; Lachance, Genevieve; Iacono, William; Lai, Sandra; Lehtimäki, Terho; Liewald, David C; Lindgren, Cecilia; Liu, Yongmei; Luben, Robert; Lucht, Michael; Luoto, Riitta; Magnus, Per; Magnusson, Patrik K.E.; Martin, Nicholas G.; McGue, Matt; McQuillan, Ruth; Medland, Sarah E.; Meisinger, Christa; Mellström, Dan; Metspalu, Andres; Michela, Traglia; Milani, Lili; Mitchell, Paul; Montgomery, Grant W.; Mook-Kanamori, Dennis; de Mutsert, Renée; Nohr, Ellen A; Ohlsson, Claes; Olsen, Jørn; Ong, Ken K.; Paternoster, Lavinia; Pattie, Alison; Penninx, Brenda WJH; Perola, Markus; Peyser, Patricia A.; Pirastu, Mario; Polasek, Ozren; Power, Chris; Kaprio, Jaakko; Raffel, Leslie J.; Räikkönen, Katri; Raitakari, Olli; Ridker, Paul M.; Ring, Susan M.; Roll, Kathryn; Rudan, Igor; Ruggiero, Daniela; Rujescu, Dan; Salomaa, Veikko; Schlessinger, David; Schmidt, Helena; Schmidt, Reinhold; Schupf, Nicole; Smit, Johannes; Sorice, Rossella; Spector, Tim D.; Starr, John M.; Stöckl, Doris; Strauch, Konstantin; Stumvoll, Michael; Swertz, Morris A.; Thorsteinsdottir, Unnur; Thurik, A. Roy; Timpson, Nicholas J.; Tönjes, Anke; Tung, Joyce Y.; Uitterlinden, André G.; Vaccargiu, Simona; Viikari, Jorma; Vitart, Veronique; Völzke, Henry; Vollenweider, Peter; Vuckovic, Dragana; Waage, Johannes; Wagner, Gert G.; Wang, Jie Jin; Wareham, Nicholas J.; Weir, David R.; Willemsen, Gonneke; Willeit, Johann; Wright, Alan F.; Zondervan, Krina T.; Stefansson, Kari; Krueger, Robert F.; Lee, James J.; Benjamin, Daniel J.; Cesarini, David; Koellinger, Philipp D.; den Hoed, Marcel; Snieder, Harold; Mills, Melinda C.

2017-01-01

The genetic architecture of human reproductive behavior – age at first birth (AFB) and number of children ever born (NEB) – has a strong relationship with fitness, human development, infertility and risk of neuropsychiatric disorders. However, very few genetic loci have been identified and the underlying mechanisms of AFB and NEB are poorly understood. We report the largest genome-wide association study to date of both sexes including 251,151 individuals for AFB and 343,072 for NEB. We identified 12 independent loci that are significantly associated with AFB and/or NEB in a SNP-based genome-wide association study, and four additional loci in a gene-based effort. These loci harbor genes that are likely to play a role – either directly or by affecting non-local gene expression – in human reproduction and infertility, thereby increasing our understanding of these complex traits. PMID:27798627

Modeling Autism by SHANK Gene Mutations in Mice

PubMed Central

Jiang, Yong-hui; Ehlers, Michael D.

2013-01-01

Summary Shank family proteins (Shank1, Shank2, and Shank3) are synaptic scaffolding proteins that organize an extensive protein complex at the postsynaptic density (PSD) of excitatory glutamatergic synapses. Recent human genetic studies indicate that SHANK family genes (SHANK1, SHANK2, and SHANK3) are causative genes for idiopathic autism spectrum disorders (ASD). Neurobiological studies of Shank mutations in mice support a general hypothesis of synaptic dysfunction in the pathophysiology of ASD. However, the molecular diversity of SHANK family gene products, as well as the heterogeneity in human and mouse phenotypes, pose challenges to modeling human SHANK mutations. Here, we review the molecular genetics of SHANK mutations in human ASD and discuss recent findings where such mutations have been modeled in mice. Conserved features of synaptic dysfunction and corresponding behaviors in Shank mouse mutants may help dissect the pathophysiology of ASD, but also highlight divergent phenotypes that arise from different mutations in the same gene. PMID:23583105

Attention-deficit hyperactivity disorder (ADHD) and tuberous sclerosis complex.

PubMed

D'Agati, Elisa; Moavero, Romina; Cerminara, Caterina; Curatolo, Paolo

2009-10-01

The neurobiological basis of attention-deficit hyperactivity disorder (ADHD) in tuberous sclerosis complex is still largely unknown. Cortical tubers may disrupt several brain networks that control different types of attention. Frontal lobe dysfunction due to seizures or epileptiform electroencephalographic discharges may perturb the development of brain systems that underpin attentional and hyperactive functions during a critical early stage of brain maturation. Comorbidity of attention-deficit hyperactivity disorder (ADHD) with mental retardation and autism spectrum disorders is frequent in children with tuberous sclerosis. Attention-deficit hyperactivity disorder (ADHD) may also reflect a direct effect of the abnormal genetic program. Treatment of children with tuberous sclerosis complex with combined symptoms of attention-deficit hyperactivity disorder (ADHD) and epilepsy may represent a challenge for clinicians, because antiepileptic therapy and drugs used to treat attention-deficit hyperactivity disorder (ADHD) may aggravate the clinical picture of each other.

Evaluation of the Nicotinic Acetylcholine Receptor-Associated Proteome at Baseline and Following Nicotine Exposure in Human and Mouse Cortex.

PubMed

McClure-Begley, Tristan D; Esterlis, Irina; Stone, Kathryn L; Lam, TuKiet T; Grady, Sharon R; Colangelo, Christopher M; Lindstrom, Jon M; Marks, Michael J; Picciotto, Marina R

2016-01-01

Nicotinic acetylcholine receptors (nAChRs) support the initiation and maintenance of smoking, but the long-term changes occurring in the protein complex as a result of smoking and the nicotine in tobacco are not known. Human studies and animal models have also demonstrated that increasing cholinergic tone increases behaviors related to depression, suggesting that the nAChR-associated proteome could be altered in individuals with mood disorders. We therefore immunopurified nAChRs and associated proteins for quantitative proteomic assessment of changes in protein-protein interactions of high-affinity nAChRs containing the β2 subunit (β2*-nAChRs) from either cortex of mice treated with saline or nicotine, or postmortem human temporal cortex tissue from tobacco-exposed and nonexposed individuals, with a further comparison of diagnosed mood disorder to control subjects. We observed significant effects of nicotine exposure on the β2*-nAChR-associated proteome in human and mouse cortex, particularly in the abundance of the nAChR subunits themselves, as well as putative interacting proteins that make up core components of neuronal excitability (Na/K ATPase subunits), presynaptic neurotransmitter release (syntaxins, SNAP25, synaptotagmin), and a member of a known nAChR protein chaperone family (14-3-3ζ). These findings identify candidate-signaling proteins that could mediate changes in cholinergic signaling via nicotine or tobacco use. Further analysis of identified proteins will determine whether these interactions are essential for primary function of nAChRs at presynaptic terminals. The identification of differences in the nAChR-associated proteome and downstream signaling in subjects with various mood disorders may also identify novel etiological mechanisms and reveal new treatment targets.

Developing a 3-choice serial reaction time task for examining neural and cognitive function in an equine model.

PubMed

Roberts, Kirsty; Hemmings, Andrew J; McBride, Sebastian D; Parker, Matthew O

2017-12-01

Large animal models of human neurological disorders are advantageous compared to rodent models due to their neuroanatomical complexity, longevity and their ability to be maintained in naturalised environments. Some large animal models spontaneously develop behaviours that closely resemble the symptoms of neural and psychiatric disorders. The horse is an example of this; the domestic form of this species consistently develops spontaneous stereotypic behaviours akin to the compulsive and impulsive behaviours observed in human neurological disorders such as Tourette's syndrome. The ability to non-invasively probe normal and abnormal equine brain function through cognitive testing may provide an extremely useful methodological tool to assess brain changes associated with certain human neurological and psychiatric conditions. An automated operant system with the ability to present visual and auditory stimuli as well as dispense salient food reward was developed. To validate the system, ten horses were trained and tested using a standard cognitive task (three choice serial reaction time task (3-CSRTT)). All animals achieved total learning criterion and performed six probe sessions. Learning criterion was met within 16.30±0.79 sessions over a three day period. During six probe sessions, level of performance was maintained at 80.67±0.57% (mean±SEM) accuracy. This is the first mobile fully automated system developed to examine cognitive function in the horse. A fully-automated operant system for mobile cognitive function of a large animal model has been designed and validated. Horses pose an interesting complementary model to rodents for the examination of human neurological dysfunction. Copyright © 2017 Elsevier B.V. All rights reserved.

MECR Mutations Cause Childhood-Onset Dystonia and Optic Atrophy, a Mitochondrial Fatty Acid Synthesis Disorder.

PubMed

Heimer, Gali; Kerätär, Juha M; Riley, Lisa G; Balasubramaniam, Shanti; Eyal, Eran; Pietikäinen, Laura P; Hiltunen, J Kalervo; Marek-Yagel, Dina; Hamada, Jeffrey; Gregory, Allison; Rogers, Caleb; Hogarth, Penelope; Nance, Martha A; Shalva, Nechama; Veber, Alvit; Tzadok, Michal; Nissenkorn, Andreea; Tonduti, Davide; Renaldo, Florence; Kraoua, Ichraf; Panteghini, Celeste; Valletta, Lorella; Garavaglia, Barbara; Cowley, Mark J; Gayevskiy, Velimir; Roscioli, Tony; Silberstein, Jonathon M; Hoffmann, Chen; Raas-Rothschild, Annick; Tiranti, Valeria; Anikster, Yair; Christodoulou, John; Kastaniotis, Alexander J; Ben-Zeev, Bruria; Hayflick, Susan J

2016-12-01

Mitochondrial fatty acid synthesis (mtFAS) is an evolutionarily conserved pathway essential for the function of the respiratory chain and several mitochondrial enzyme complexes. We report here a unique neurometabolic human disorder caused by defective mtFAS. Seven individuals from five unrelated families presented with childhood-onset dystonia, optic atrophy, and basal ganglia signal abnormalities on MRI. All affected individuals were found to harbor recessive mutations in MECR encoding the mitochondrial trans-2-enoyl-coenzyme A-reductase involved in human mtFAS. All six mutations are extremely rare in the general population, segregate with the disease in the families, and are predicted to be deleterious. The nonsense c.855T>G (p.Tyr285 ∗ ), c.247_250del (p.Asn83Hisfs ∗ 4), and splice site c.830+2_830+3insT mutations lead to C-terminal truncation variants of MECR. The missense c.695G>A (p.Gly232Glu), c.854A>G (p.Tyr285Cys), and c.772C>T (p.Arg258Trp) mutations involve conserved amino acid residues, are located within the cofactor binding domain, and are predicted by structural analysis to have a destabilizing effect. Yeast modeling and complementation studies validated the pathogenicity of the MECR mutations. Fibroblast cell lines from affected individuals displayed reduced levels of both MECR and lipoylated proteins as well as defective respiration. These results suggest that mutations in MECR cause a distinct human disorder of the mtFAS pathway. The observation of decreased lipoylation raises the possibility of a potential therapeutic strategy. Copyright © 2016 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

The Role of the New mTOR Complex, mTORC2, in Autism Spectrum Disorders

DTIC Science & Technology

2015-10-01

1 AWARD NUMBER: W81XWH-13-1-0380 TITLE: "The Role of the New mTOR Complex, mTORC2, in Autism Spectrum Disorders " PRINCIPAL INVESTIGATOR: Mauro...34The Role of the New mTOR Complex, mTORC2, in Autism Spectrum Disorders " 5a. CONTRACT NUMBER W81XWH-13-1-0380 5b. GRANT NUMBER 5c. PROGRAM...Pten. These insights hold the promise for new mTORC2-based treatment of ASD. 15. SUBJECT TERMS Autism Spectrum Disorder (ASD), mTORC2, mTORC1

Emotional and Cognitive Self-regulation, an EEG Study

ClinicalTrials.gov

2016-08-08

Posttraumatic Stress Disorder PTSD); Complex Posttraumatic Stress Disorder (cPTSD); Dissociative Disorder Not Otherwise Specified (DDNOS); Dissociative Identity Disorder (DID); Borderline Personality Disorder (BPD)

Inhibition of amyloid peptide fibril formation by gold-sulfur complexes.

PubMed

Wang, Wenji; Zhao, Cong; Zhu, Dengsen; Gong, Gehui; Du, Weihong

2017-06-01

Amyloid-related diseases are characterized by protein conformational change and amyloid fibril deposition. Metal complexes are potential inhibitors of amyloidosis. Nitrogen-coordinated gold complexes have been used to disaggregate prion neuropeptide (PrP106-126) and human islet amyloid polypeptide (hIAPP). However, the roles of metal complexes in peptide fibril formation and related bioactivity require further exploration. In this work, we investigated the interactions of amyloid peptides PrP106-126 and hIAPP with two tetracoordinated gold-sulfur complexes, namely, dichloro diethyl dithiocarbamate gold complex and dichloro pyrrolidine dithiocarbamate gold complex. We also determined the effects of these complexes on peptide-induced cytotoxicity. Thioflavin T assay, morphological characterization, and particle size analysis indicated that the two gold-sulfur complexes effectively inhibited the fibrillation of the amyloid peptides, which led to the formation of nanoscale particles. The complexes reduced the cytotoxicity induced by the amyloid peptides. Intrinsic fluorescence, nuclear magnetic resonance, and mass spectrometry revealed that the complexes interacted with PrP106-126 and hIAPP via metal coordination and hydrophobic interaction, which improved the inhibition and binding of the two gold-sulfur compounds. Our study provided new insights into the use of tetracoordinated gold-sulfur complexes as drug candidates against protein conformational disorders. Copyright © 2017 Elsevier Inc. All rights reserved.

Methods for protein complex prediction and their contributions towards understanding the organisation, function and dynamics of complexes.

PubMed

Srihari, Sriganesh; Yong, Chern Han; Patil, Ashwini; Wong, Limsoon

2015-09-14

Complexes of physically interacting proteins constitute fundamental functional units responsible for driving biological processes within cells. A faithful reconstruction of the entire set of complexes is therefore essential to understand the functional organisation of cells. In this review, we discuss the key contributions of computational methods developed till date (approximately between 2003 and 2015) for identifying complexes from the network of interacting proteins (PPI network). We evaluate in depth the performance of these methods on PPI datasets from yeast, and highlight their limitations and challenges, in particular at detecting sparse and small or sub-complexes and discerning overlapping complexes. We describe methods for integrating diverse information including expression profiles and 3D structures of proteins with PPI networks to understand the dynamics of complex formation, for instance, of time-based assembly of complex subunits and formation of fuzzy complexes from intrinsically disordered proteins. Finally, we discuss methods for identifying dysfunctional complexes in human diseases, an application that is proving invaluable to understand disease mechanisms and to discover novel therapeutic targets. We hope this review aptly commemorates a decade of research on computational prediction of complexes and constitutes a valuable reference for further advancements in this exciting area. Copyright © 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Crystal structure of the human cytosolic sialidase Neu2. Evidence for the dynamic nature of substrate recognition.

PubMed

Chavas, Leonard M G; Tringali, Cristina; Fusi, Paola; Venerando, Bruno; Tettamanti, Guido; Kato, Ryuichi; Monti, Eugenio; Wakatsuki, Soichi

2005-01-07

Gangliosides play key roles in cell differentiation, cell-cell interactions, and transmembrane signaling. Sialidases hydrolyze sialic acids to produce asialo compounds, which is the first step of degradation processes of glycoproteins and gangliosides. Sialidase involvement has been implicated in some lysosomal storage disorders such as sialidosis and galactosialidosis. Neu2 is a recently identified human cytosolic sialidase. Here we report the first high resolution x-ray structures of mammalian sialidase, human Neu2, in its apo form and in complex with an inhibitor, 2-deoxy-2,3-dehydro-N-acetylneuraminic acid (DANA). The structure shows the canonical six-blade beta-propeller observed in viral and bacterial sialidases with its active site in a shallow crevice. In the complex structure, the inhibitor lies in the catalytic crevice surrounded by ten amino acids. In particular, the arginine triad, conserved among sialidases, aids in the proper positioning of the carboxylate group of DANA within the active site region. The tyrosine residue, Tyr(334), conserved among mammalian and bacterial sialidases as well as in viral neuraminidases, facilitates the enzymatic reaction by stabilizing a putative carbonium ion in the transition state. The loops containing Glu(111) and the catalytic aspartate Asp(46) are disordered in the apo form but upon binding of DANA become ordered to adopt two short alpha-helices to cover the inhibitor, illustrating the dynamic nature of substrate recognition. The N-acetyl and glycerol moieties of DANA are recognized by Neu2 residues not shared by bacterial sialidases and viral neuraminidases, which can be regarded as a key structural difference for potential drug design against bacteria, influenza, and other viruses.

Targets for future clinical trials in Huntington's disease: what's in the pipeline?

PubMed

Wild, Edward J; Tabrizi, Sarah J

2014-09-15

The known genetic cause of Huntington's disease (HD) has fueled considerable progress in understanding its pathobiology and the development of therapeutic approaches aimed at correcting specific changes linked to the causative mutation. Among the most promising is reducing expression of mutant huntingtin protein (mHTT) with RNA interference or antisense oligonucleotides; human trials are now being planned. Zinc-finger transcriptional repression is another innovative method to reduce mHTT expression. Modulation of mHTT phosphorylation, chaperone upregulation, and autophagy enhancement represent attempts to alter cellular homeostasis to favor removal of mHTT. Inhibition of histone deacetylases (HDACs) remains of interest; recent work affirms HDAC4 as a target but questions the assumed centrality of its catalytic activity in HD. Phosphodiesterase inhibition, aimed at restoring synaptic function, has progressed rapidly to human trials. Deranged cellular signaling provides several tractable targets, but specificity and complexity are challenges. Restoring neurotrophic support in HD remains a key potential therapeutic approach. with several approaches being pursued, including brain-derived neurotrophic factor (BDNF) mimesis through tyrosine receptor kinase B (TrkB) agonism and monoclonal antibodies. An increasing understanding of the role of glial cells in HD has led to several new therapeutic avenues, including kynurenine monooxygenase inhibition, immunomodulation by laquinimod, CB2 agonism, and others. The complex metabolic derangements in HD remain under study, but no clear therapeutic strategy has yet emerged. We conclude that many exciting therapeutics are progressing through the development pipeline, and combining a better understanding of HD biology in human patients, with concerted medicinal chemistry efforts, will be crucial for bringing about an era of effective therapies. © 2014 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Tuberous sclerosis associated neuropsychiatric disorders (TAND) and the TAND Checklist.

PubMed

de Vries, Petrus J; Whittemore, Vicky H; Leclezio, Loren; Byars, Anna W; Dunn, David; Ess, Kevin C; Hook, Dena; King, Bryan H; Sahin, Mustafa; Jansen, Anna

2015-01-01

Tuberous sclerosis complex is a multisystem genetic disorder with a range of physical manifestations that require evaluation, surveillance, and management. Individuals with tuberous sclerosis complex also have a range of behavioral, psychiatric, intellectual, academic, neuropsychologic, and psychosocial difficulties. These may represent the greatest burden of the disease. Around 90% of individuals with tuberous sclerosis complex will have some of these difficulties during their lifetime, yet only about 20% ever receive evaluation and treatment. The Neuropsychiatry Panel at the 2012 Tuberous Sclerosis Complex International Consensus Conference expressed concern about the significant "treatment gap" and about confusion regarding terminology relating to the biopsychosocial difficulties associated with tuberous sclerosis complex. The Tuberous Sclerosis Complex Neuropsychiatry Panel coined the term TAND-tuberous sclerosis complex-associated neuropsychiatric disorders-to bring together these multidimensional manifestations of the disorder, and recommended annual screening for TAND. In addition, the Panel agreed to develop a TAND Checklist as a guide for screening. Here, we present an outline of the conceptualization of TAND, rationale for the structure of the TAND Checklist, and include the full US English version of the TAND Checklist. We hope that the unified term TAND and the TAND Checklist will raise awareness of the importance of tuberous sclerosis complex-associated neuropsychiatric disorders and of the major burden of disease associated with it, provide a shared language and a simple tool to describe and evaluate the different levels of TAND, alert clinical teams and families or individuals of the importance of screening, assessment, and treatment of TAND, and provide a shared framework for future studies of tuberous sclerosis complex-associated neuropsychiatric disorders. Copyright © 2015 Elsevier Inc. All rights reserved.

[Dissolving anxiety as an essential ingredient for any therapy].

PubMed

Radics, Judit

2014-06-01

Anxiety frequently develops in human life and it is usually useful for the organism. Anxiety helps accomodation to the social environment, however, it may be harmful when it is intensive and long-lasting. It can also cause psychosomatic diseases. Anxiety may present itself as mild or moderate stress, psychosomatic diseases or psychiatric disorders. In the general practice, about one third of the patients suffer from anxiety, but it is not easy to identify these patients because of the frequent somatic complaints which may cover anxiety symptoms. The prevalence of anxiety disorders is between 12.6% and 17.2% per year and, in a considerable proportion of patients, both anxiety and depression are present. Therapy of anxiety is complex including psychopharmacotherapy (antidepressants, anxiolytics, hypnotics), psychotherapy and life style changes.

Agmatine: clinical applications after 100 years in translation.

PubMed

Piletz, John E; Aricioglu, Feyza; Cheng, Juei-Tang; Fairbanks, Carolyn A; Gilad, Varda H; Haenisch, Britta; Halaris, Angelos; Hong, Samin; Lee, Jong Eun; Li, Jin; Liu, Ping; Molderings, Gerhard J; Rodrigues, Ana Lúcia S; Satriano, Joseph; Seong, Gong Je; Wilcox, George; Wu, Ning; Gilad, Gad M

2013-09-01

Agmatine (decarboxylated arginine) has been known as a natural product for over 100 years, but its biosynthesis in humans was left unexplored owing to long-standing controversy. Only recently has the demonstration of agmatine biosynthesis in mammals revived research, indicating its exceptional modulatory action at multiple molecular targets, including neurotransmitter systems, nitric oxide (NO) synthesis and polyamine metabolism, thus providing bases for broad therapeutic applications. This timely review, a concerted effort by 16 independent research groups, draws attention to the substantial preclinical and initial clinical evidence, and highlights challenges and opportunities, for the use of agmatine in treating a spectrum of complex diseases with unmet therapeutic needs, including diabetes mellitus, neurotrauma and neurodegenerative diseases, opioid addiction, mood disorders, cognitive disorders and cancer. Copyright © 2013 Elsevier Ltd. All rights reserved.

The Development of Eating Behavior - Biology and Context

PubMed Central

Gahagan, Sheila

2012-01-01

Eating is necessary for survival, gives great pleasure and can be perturbed leading to undernutrition, overnutrition and eating disorders. The development of feeding in humans relies on complex interplay between homeostatic mechanisms; neural reward systems; and child motor, sensory and socio-emotional capability. Furthermore, parenting, social influences and the food environment influence the development of eating behavior. The rapid expansion of new knowledge in this field, from basic science to clinical and community-based research, is expected to lead to urgently needed research in support of effective, evidence-based prevention and treatment strategies for undernutrition, overnutrition and eating disorders in early childhood. Using a biopsychosocial approach, this review covers current knowledge of the development of eating behavior from the brain to the individual child, taking into account important contextual influences. PMID:22472944

Generation of a high-fidelity antibody against nerve growth factor using library scanning mutagenesis and validation with structures of the initial and optimized Fab-antigen complexes

PubMed Central

La Porte, Sherry L; Eigenbrot, Charles; Ultsch, Mark; Ho, Wei-Hsien; Foletti, Davide; Forgie, Alison; Lindquist, Kevin C; Shelton, David L; Pons, Jaume

2014-01-01

Nerve growth factor (NGF) is indispensable during normal embryonic development and critical for the amplification of pain signals in adults. Intervention in NGF signaling holds promise for the alleviation of pain resulting from human diseases such as osteoarthritis, cancer and chronic lower back disorders. We developed a fast, high-fidelity method to convert a hybridoma-derived NGF-targeted mouse antibody into a clinical candidate. This method, termed Library Scanning Mutagenesis (LSM), resulted in the ultra-high affinity antibody tanezumab, a first-in-class anti-hyperalgesic specific for an NGF epitope. Functional and structural comparisons between tanezumab and the mouse 911 precursor antibody using neurotrophin-specific cell survival assays and X-ray crystal structures of both Fab-antigen complexes illustrated high fidelity retention of the NGF epitope. These results suggest the potential for wide applicability of the LSM method for optimization of well-characterized antibodies during humanization. PMID:24830649

Evolution of disorder in Mediator complex and its functional relevance

PubMed Central

Nagulapalli, Malini; Maji, Sourobh; Dwivedi, Nidhi; Dahiya, Pradeep; Thakur, Jitendra K.

2016-01-01

Mediator, an important component of eukaryotic transcriptional machinery, is a huge multisubunit complex. Though the complex is known to be conserved across all the eukaryotic kingdoms, the evolutionary topology of its subunits has never been studied. In this study, we profiled disorder in the Mediator subunits of 146 eukaryotes belonging to three kingdoms viz., metazoans, plants and fungi, and attempted to find correlation between the evolution of Mediator complex and its disorder. Our analysis suggests that disorder in Mediator complex have played a crucial role in the evolutionary diversification of complexity of eukaryotic organisms. Conserved intrinsic disordered regions (IDRs) were identified in only six subunits in the three kingdoms whereas unique patterns of IDRs were identified in other Mediator subunits. Acquisition of novel molecular recognition features (MoRFs) through evolution of new subunits or through elongation of the existing subunits was evident in metazoans and plants. A new concept of ‘junction-MoRF’ has been introduced. Evolutionary link between CBP and Med15 has been provided which explain the evolution of extended-IDR in CBP from Med15 KIX-IDR junction-MoRF suggesting role of junction-MoRF in evolution and modulation of protein–protein interaction repertoire. This study can be informative and helpful in understanding the conserved and flexible nature of Mediator complex across eukaryotic kingdoms. PMID:26590257

Molecular Basis for Structural Heterogeneity of an Intrinsically Disordered Protein Bound to a Partner by Combined ESI-IM-MS and Modeling

NASA Astrophysics Data System (ADS)

D'Urzo, Annalisa; Konijnenberg, Albert; Rossetti, Giulia; Habchi, Johnny; Li, Jinyu; Carloni, Paolo; Sobott, Frank; Longhi, Sonia; Grandori, Rita

2015-03-01

Intrinsically disordered proteins (IDPs) form biologically active complexes that can retain a high degree of conformational disorder, escaping structural characterization by conventional approaches. An example is offered by the complex between the intrinsically disordered NTAIL domain and the phosphoprotein X domain (PXD) from measles virus (MeV). Here, distinct conformers of the complex are detected by electrospray ionization-mass spectrometry (ESI-MS) and ion mobility (IM) techniques yielding estimates for the solvent-accessible surface area (SASA) in solution and the average collision cross-section (CCS) in the gas phase. Computational modeling of the complex in solution, based on experimental constraints, provides atomic-resolution structural models featuring different levels of compactness. The resulting models indicate high structural heterogeneity. The intermolecular interactions are predominantly hydrophobic, not only in the ordered core of the complex, but also in the dynamic, disordered regions. Electrostatic interactions become involved in the more compact states. This system represents an illustrative example of a hydrophobic complex that could be directly detected in the gas phase by native mass spectrometry. This work represents the first attempt to modeling the entire NTAIL domain bound to PXD at atomic resolution.

Considering PTSD From the Perspective of Brain Processes: A Psychological Construction Approach

PubMed Central

Suvak, Michael K.; Barrett, Lisa Feldman

2011-01-01

Posttraumatic stress disorder (PTSD) is a complex psychiatric disorder that involves symptoms from various domains that appear to be produced by the combination of several mechanisms. The authors contend that existing neural accounts fail to provide a viable model that explains the emergence and maintenance of PTSD and the associated heterogeneity in the expression of this disorder (cf. Garfinkel & Liberzon, 2009). They introduce a psychological construction approach as a novel framework to probe the brain basis of PTSD, where distributed networks within the human brain are thought to correspond to the basic psychological ingredients of the mind. The authors posit that it is the combination of these ingredients that produces the heterogeneous symptom clusters in PTSD. Their goal is show that a constructionist approach has significant heuristic value in understanding the emergence and maintenance of PTSD symptoms, and leads to different and perhaps more useful conjectures about the origins and maintenance of the syndrome than the traditional hyperreactive fear account. PMID:21298725

Marker chromosome genomic structure and temporal origin implicate a chromoanasynthesis event in a family with pleiotropic psychiatric phenotypes.

PubMed

Grochowski, Christopher M; Gu, Shen; Yuan, Bo; Tcw, Julia; Brennand, Kristen J; Sebat, Jonathan; Malhotra, Dheeraj; McCarthy, Shane; Rudolph, Uwe; Lindstrand, Anna; Chong, Zechen; Levy, Deborah L; Lupski, James R; Carvalho, Claudia M B

2018-04-25

Small supernumerary marker chromosomes (sSMC) are chromosomal fragments difficult to characterize genomically. Here, we detail a proband with schizoaffective disorder and a mother with bipolar disorder with psychotic features who present with a marker chromosome that segregates with disease. We explored the architecture of this marker and investigated its temporal origin. Array comparative genomic hybridization (aCGH) analysis revealed three duplications and three triplications that spanned the short arm of chromosome 9, suggestive of a chromoanasynthesis-like event. Segregation of marker genotypes, phased using sSMC mosaicism in the mother, provided evidence that it was generated during a germline-level event in the proband's maternal grandmother. Whole-genome sequencing (WGS) was performed to resolve the structure and junctions of the chromosomal fragments, revealing further complexities. While structural variations have been previously associated with neuropsychiatric disorders and marker chromosomes, here we detail the precise architecture, human life-cycle genesis, and propose a DNA replicative/repair mechanism underlying formation. © 2018 Wiley Periodicals, Inc.

An intrinsic vasopressin system in the olfactory bulb is involved in social recognition

PubMed Central

Tobin, Vicky A.; Hashimoto, Hirofumi; Wacker, Douglas W.; Takayanagi, Yuki; Langnaese, Kristina; Caquineau, Celine; Noack, Julia; Landgraf, Rainer; Onaka, Tatsushi; Leng, Gareth; Meddle, Simone L.; Engelmann, Mario; Ludwig, Mike

2010-01-01

Many peptides, when released as chemical messengers within the brain, have powerful influences on complex behaviours. Most strikingly, vasopressin and oxytocin, once thought of as circulating hormones whose actions were confined to peripheral organs, are now known to be released in the brain where they play fundamentally important roles in social behaviours1. In humans, disruptions of these peptide systems have been linked to several neurobehavioural disorders, including Prader-Willi syndrome, affective disorders, and obsessive-compulsive disorder, and polymorphisms of the vasopressin V1a receptor have been linked to autism2,3. Here we report that the rat olfactory bulb contains a large population of interneurones which express vasopressin, that blocking the actions of vasopressin in the olfactory bulb impairs the social recognition abilities of rats, and that vasopressin agonists and antagonists can modulate the processing of information by olfactory bulb neurones. The findings indicate that social information is processed in part by a vasopressin system intrinsic to the olfactory system. PMID:20182426

Genetic approaches for the study of PTSD: Advances and challenges

PubMed Central

Banerjee, Sunayana B.; Morrison, Filomene G.; Ressler, Kerry J.

2017-01-01

Post-traumatic stress disorder (PTSD) is a highly debilitating stress and anxiety-related disorder that occurs in response to specific trauma or abuse. Genetic risk factors may account for up to 30–40% of the heritability of PTSD. Understanding the gene pathways that are associated with PTSD, and how those genes interact with the fear and stress circuitry to mediate risk and resilience for PTSD will enable the development of targeted therapies to prevent the occurrence of or decrease the severity of this complex multi-gene disorder. This review will summarize recent research on genetic approaches to understanding PTSD risk and resilience in human populations, including candidate genes and their epigenetic modifications, genome-wide association studies and neural imaging genetics approaches. Despite challenges faced within this field of study such as inconsistent results and replications, genetic approaches still offer exciting opportunities for the identification and development of novel therapeutic targets and therapies in the future. PMID:28242325

Small intestinal bacterial overgrowth syndrome

PubMed Central

Bures, Jan; Cyrany, Jiri; Kohoutova, Darina; Förstl, Miroslav; Rejchrt, Stanislav; Kvetina, Jaroslav; Vorisek, Viktor; Kopacova, Marcela

2010-01-01

Human intestinal microbiota create a complex polymicrobial ecology. This is characterised by its high population density, wide diversity and complexity of interaction. Any dysbalance of this complex intestinal microbiome, both qualitative and quantitative, might have serious health consequence for a macro-organism, including small intestinal bacterial overgrowth syndrome (SIBO). SIBO is defined as an increase in the number and/or alteration in the type of bacteria in the upper gastrointestinal tract. There are several endogenous defence mechanisms for preventing bacterial overgrowth: gastric acid secretion, intestinal motility, intact ileo-caecal valve, immunoglobulins within intestinal secretion and bacteriostatic properties of pancreatic and biliary secretion. Aetiology of SIBO is usually complex, associated with disorders of protective antibacterial mechanisms (e.g. achlorhydria, pancreatic exocrine insufficiency, immunodeficiency syndromes), anatomical abnormalities (e.g. small intestinal obstruction, diverticula, fistulae, surgical blind loop, previous ileo-caecal resections) and/or motility disorders (e.g. scleroderma, autonomic neuropathy in diabetes mellitus, post-radiation enteropathy, small intestinal pseudo-obstruction). In some patients more than one factor may be involved. Symptoms related to SIBO are bloating, diarrhoea, malabsorption, weight loss and malnutrition. The gold standard for diagnosing SIBO is still microbial investigation of jejunal aspirates. Non-invasive hydrogen and methane breath tests are most commonly used for the diagnosis of SIBO using glucose or lactulose. Therapy for SIBO must be complex, addressing all causes, symptoms and complications, and fully individualised. It should include treatment of the underlying disease, nutritional support and cyclical gastro-intestinal selective antibiotics. Prognosis is usually serious, determined mostly by the underlying disease that led to SIBO. PMID:20572300

Disruption of self-organized actions in monkeys with progressive MPTP-induced parkinsonism. I. Effects of task complexity.

PubMed

Pessiglione, Mathias; Guehl, Dominique; Hirsch, Etienne C; Féger, Jean; Tremblay, Léon

2004-01-01

Parkinson's disease (PD) is characterized by motor symptoms, usually accompanied by cognitive deficits. The question addressed in this study is whether complexity of routine actions can exacerbate parkinsonian disorders that are often considered to be motor symptoms. To examine this question, we trained four vervet monkeys (Cercopithecus aethiops) to perform three multiple-choice retrieval tasks. In order of ascending complexity, rewards were freely available (task 1), covered with transparent sliding plaques (task 2), and covered with opaque sliding plaques cued by symbols (task 3). Thus, from task 1 to task 2 we added a motor difficulty--the recall of context-adapted movement; and from task 2 to task 3 we added a cognitive difficulty: the recall of symbol-reward associations. The more complex the task, the longer it took to learn, but after extensive training the performance was stable in all tasks, with similar retrieval durations. The monkeys then received systemic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) injections (0.3-0.4 mg/kg) every 4-7 days, until the first motor symptoms appeared. In the course of MPTP intoxication, the behavioural performance declined while the motor symptoms were absent or mild--the retrieval duration increased, and non-initiated choices and hesitations between choices became frequent. Interestingly, this decline was in proportion to task complexity, and was particularly pronounced with the cognitive difficulty. Furthermore, freezing appeared only with the cognitive difficulty. We therefore suggest that everyday cognitive difficulties may exacerbate hypokinesia (lack of initiation, abnormal slowness) and executive disorders (hesitations, freezing) in the early stages of human PD.

Metabolic flexibility of mitochondrial respiratory chain disorders predicted by computer modelling.

PubMed

Zieliński, Łukasz P; Smith, Anthony C; Smith, Alexander G; Robinson, Alan J

2016-11-01

Mitochondrial respiratory chain dysfunction causes a variety of life-threatening diseases affecting about 1 in 4300 adults. These diseases are genetically heterogeneous, but have the same outcome; reduced activity of mitochondrial respiratory chain complexes causing decreased ATP production and potentially toxic accumulation of metabolites. Severity and tissue specificity of these effects varies between patients by unknown mechanisms and treatment options are limited. So far most research has focused on the complexes themselves, and the impact on overall cellular metabolism is largely unclear. To illustrate how computer modelling can be used to better understand the potential impact of these disorders and inspire new research directions and treatments, we simulated them using a computer model of human cardiomyocyte mitochondrial metabolism containing over 300 characterised reactions and transport steps with experimental parameters taken from the literature. Overall, simulations were consistent with patient symptoms, supporting their biological and medical significance. These simulations predicted: complex I deficiencies could be compensated using multiple pathways; complex II deficiencies had less metabolic flexibility due to impacting both the TCA cycle and the respiratory chain; and complex III and IV deficiencies caused greatest decreases in ATP production with metabolic consequences that parallel hypoxia. Our study demonstrates how results from computer models can be compared to a clinical phenotype and used as a tool for hypothesis generation for subsequent experimental testing. These simulations can enhance understanding of dysfunctional mitochondrial metabolism and suggest new avenues for research into treatment of mitochondrial disease and other areas of mitochondrial dysfunction. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Protein Misfolding, Amyloid Formation, and Human Disease: A Summary of Progress Over the Last Decade.

PubMed

Chiti, Fabrizio; Dobson, Christopher M

2017-06-20

Peptides and proteins have been found to possess an inherent tendency to convert from their native functional states into intractable amyloid aggregates. This phenomenon is associated with a range of increasingly common human disorders, including Alzheimer and Parkinson diseases, type II diabetes, and a number of systemic amyloidoses. In this review, we describe this field of science with particular reference to the advances that have been made over the last decade in our understanding of its fundamental nature and consequences. We list the proteins that are known to be deposited as amyloid or other types of aggregates in human tissues and the disorders with which they are associated, as well as the proteins that exploit the amyloid motif to play specific functional roles in humans. In addition, we summarize the genetic factors that have provided insight into the mechanisms of disease onset. We describe recent advances in our knowledge of the structures of amyloid fibrils and their oligomeric precursors and of the mechanisms by which they are formed and proliferate to generate cellular dysfunction. We show evidence that a complex proteostasis network actively combats protein aggregation and that such an efficient system can fail in some circumstances and give rise to disease. Finally, we anticipate the development of novel therapeutic strategies with which to prevent or treat these highly debilitating and currently incurable conditions.

The Human CHRNA7 and CHRFAM7A Genes: A Review of the Genetics, Regulation, and Function

PubMed Central

Sinkus, Melissa L.; Graw, Sharon; Freedman, Robert; Ross, Randal G.; Lester, Henry A.; Leonard, Sherry

2015-01-01

The human α7 neuronal nicotinic acetylcholine receptor gene (CHRNA7) is ubiquitously expressed in both the central nervous system and in the periphery. CHRNA7 is genetically linked to multiple disorders with cognitive deficits, including schizophrenia, bipolar disorder, ADHD, epilepsy, Alzheimer’s disease, and Rett syndrome. The regulation of CHRNA7 is complex; more than a dozen mechanisms are known, one of which is a partial duplication of the parent gene. Exons 5-10 of CHRNA7 on chromosome 15 were duplicated and inserted 1.6 Mb upstream of CHRNA7, interrupting an earlier partial duplication of two other genes. The chimeric CHRFAM7A gene product, dupα7, assembles with α7 subunits, resulting in a dominant negative regulation of function. The duplication is human specific, occurring neither in primates nor in rodents. The duplicated α7 sequence in exons 5-10 of CHRFAM7A is almost identical to CHRNA7, and thus is not completely queried in high throughput genetic studies (GWAS). Further, pre-clinical animal models of the α7nAChR utilized in drug development research do not have CHRFAM7A (dupα7) and cannot fully model human drug responses. The wide expression of CHRNA7, its multiple functions and modes of regulation present challenges for study of this gene in disease. PMID:25701707

Irrational beliefs, biases and gambling: exploring the role of animal models in elucidating vulnerabilities for the development of pathological gambling.

PubMed

Cocker, P J; Winstanley, C A

2015-02-15

Gambling is a heterogeneous and complex disorder. Multiple factors may lead to problem gambling, yet one of the most important appears to be the increased presence of cognitive biases or distortions. These biases are thought to precipitate gambling as they can lead to dysfunctional decision making under risk or ambiguity. Modelling these cognitive perturbations in animals can improve our understanding of their neurobiological bases, and potentially stimulate novel treatment options. The first aim of this review is to give a broad overview of some of the cognitive biases that are most commonly associated with gambling. Secondly, we will discuss several animal models that we have developed in which rodent decision-making appears hallmarked by the same cognitive inconsistencies as human choice. In particular, we will discuss two tasks that capture elements of risk and loss averse decision making, and another in which rats appear susceptible to the 'near-miss' effect. To date, findings from both human and non-human studies suggest that these different biases are neuropharmacologically and neurostructurally dissociable, and that dopamine plays a key role in their expression. Lastly, we will briefly discuss areas in both human and animal research where limitations within the field may be hampering a more complete understanding of pathological gambling as a disorder. Copyright © 2014 Elsevier B.V. All rights reserved.

Antidiabetic Effects of Chamomile Flowers Extract in Obese Mice through Transcriptional Stimulation of Nutrient Sensors of the Peroxisome Proliferator-Activated Receptor (PPAR) Family

PubMed Central

Weidner, Christopher; Wowro, Sylvia J.; Rousseau, Morten; Freiwald, Anja; Kodelja, Vitam; Abdel-Aziz, Heba; Kelber, Olaf; Sauer, Sascha

2013-01-01

Given the significant increases in the incidence of metabolic diseases, efficient strategies for preventing and treating of these common disorders are urgently needed. This includes the development of phytopharmaceutical products or functional foods to prevent or cure metabolic diseases. Plant extracts from edible biomaterial provide a potential resource of structurally diverse molecules that can synergistically interfere with complex disorders. In this study we describe the safe application of ethanolic chamomile (Matricaria recutita) flowers extract (CFE) for the treatment and prevention of type 2 diabetes and associated disorders. We show in vitro that this extract activates in particular nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) and its isotypes. In a cellular context, in human primary adipocytes CFE administration (300 µg/ml) led to specific expression of target genes of PPARγ, whereas in human hepatocytes CFE-induced we detected expression changes of genes that were regulated by PPARα. In vivo treatment of insulin-resistant high-fat diet (HFD)-fed C57BL/6 mice with CFE (200 mg/kg/d) for 6 weeks considerably reduced insulin resistance, glucose intolerance, plasma triacylglycerol, non-esterified fatty acids (NEFA) and LDL/VLDL cholesterol. Co-feeding of lean C57BL/6 mice a HFD with 200 mg/kg/d CFE for 20 weeks showed effective prevention of fatty liver formation and hepatic inflammation, indicating additionally hepatoprotective effects of the extract. Moreover, CFE treatment did not reveal side effects, which have otherwise been associated with strong synthetic PPAR-targeting molecules, such as weight gain, liver disorders, hemodilution or bone cell turnover. Taken together, modulation of PPARs and other factors by chamomile flowers extract has the potential to prevent or treat type 2 diabetes and related disorders. PMID:24265809

Modeling a model: Mouse genetics, 22q11.2 Deletion Syndrome, and disorders of cortical circuit development

PubMed Central

Meechan, Daniel W.; Maynard, Thomas M.; Fernandez, Alejandra; Karpinski, Beverly A.; Rothblat, Lawrence A.; LaMantia, Anthony S.

2015-01-01

Understanding the developmental etiology of autistic spectrum disorders, attention deficit/hyperactivity disorder and schizophrenia remains a major challenge for establishing new diagnostic and therapeutic approaches to these common, difficult-to-treat diseases that compromise neural circuits in the cerebral cortex. One aspect of this challenge is the breadth and overlap of ASD, ADHD, and SCZ deficits; another is the complexity of mutations associated with each, and a third is the difficulty of analyzing disrupted development in at-risk or affected human fetuses. The identification of distinct genetic syndromes that include behavioral deficits similar to those in ASD, ADHC and SCZ provides a critical starting point for meeting this challenge. We summarize clinical and behavioral impairments in children and adults with one such genetic syndrome, the 22q11.2 Deletion Syndrome, routinely called 22q11DS, caused by micro-deletions of between 1.5 and 3.0 MB on human chromosome 22. Among many syndromic features, including cardiovascular and craniofacial anomalies, 22q11DS patients have a high incidence of brain structural, functional, and behavioral deficits that reflect cerebral cortical dysfunction and fall within the spectrum that defines ASD, ADHD, and SCZ. We show that developmental pathogenesis underlying this apparent genetic “model” syndrome in patients can be defined and analyzed mechanistically using genomically accurate mouse models of the deletion that causes 22q11DS. We conclude that “modeling a model”, in this case 22q11DS as a model for idiopathic ASD, ADHD and SCZ, as well as other behavioral disorders like anxiety frequently seen in 22q11DS patients, in genetically engineered mice provides a foundation for understanding the causes and improving diagnosis and therapy for these disorders of cortical circuit development. PMID:25866365

Antidiabetic effects of chamomile flowers extract in obese mice through transcriptional stimulation of nutrient sensors of the peroxisome proliferator-activated receptor (PPAR) family.

PubMed

Weidner, Christopher; Wowro, Sylvia J; Rousseau, Morten; Freiwald, Anja; Kodelja, Vitam; Abdel-Aziz, Heba; Kelber, Olaf; Sauer, Sascha

2013-01-01

Given the significant increases in the incidence of metabolic diseases, efficient strategies for preventing and treating of these common disorders are urgently needed. This includes the development of phytopharmaceutical products or functional foods to prevent or cure metabolic diseases. Plant extracts from edible biomaterial provide a potential resource of structurally diverse molecules that can synergistically interfere with complex disorders. In this study we describe the safe application of ethanolic chamomile (Matricaria recutita) flowers extract (CFE) for the treatment and prevention of type 2 diabetes and associated disorders. We show in vitro that this extract activates in particular nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) and its isotypes. In a cellular context, in human primary adipocytes CFE administration (300 µg/ml) led to specific expression of target genes of PPARγ, whereas in human hepatocytes CFE-induced we detected expression changes of genes that were regulated by PPARα. In vivo treatment of insulin-resistant high-fat diet (HFD)-fed C57BL/6 mice with CFE (200 mg/kg/d) for 6 weeks considerably reduced insulin resistance, glucose intolerance, plasma triacylglycerol, non-esterified fatty acids (NEFA) and LDL/VLDL cholesterol. Co-feeding of lean C57BL/6 mice a HFD with 200 mg/kg/d CFE for 20 weeks showed effective prevention of fatty liver formation and hepatic inflammation, indicating additionally hepatoprotective effects of the extract. Moreover, CFE treatment did not reveal side effects, which have otherwise been associated with strong synthetic PPAR-targeting molecules, such as weight gain, liver disorders, hemodilution or bone cell turnover. Taken together, modulation of PPARs and other factors by chamomile flowers extract has the potential to prevent or treat type 2 diabetes and related disorders.

Correction of the consequences of mitochondrial 3243A>G mutation in the MT-TL1 gene causing the MELAS syndrome by tRNA import into mitochondria

PubMed Central

Karicheva, Olga Z.; Kolesnikova, Olga A.; Schirtz, Tom; Vysokikh, Mikhail Y.; Mager-Heckel, Anne-Marie; Lombès, Anne; Boucheham, Abdeldjalil; Krasheninnikov, Igor A.; Martin, Robert P.; Entelis, Nina; Tarassov, Ivan

2011-01-01

Mutations in human mitochondrial DNA are often associated with incurable human neuromuscular diseases. Among these mutations, an important number have been identified in tRNA genes, including 29 in the gene MT-TL1 coding for the tRNALeu(UUR). The m.3243A>G mutation was described as the major cause of the MELAS syndrome (mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes). This mutation was reported to reduce tRNALeu(UUR) aminoacylation and modification of its anti-codon wobble position, which results in a defective mitochondrial protein synthesis and reduced activities of respiratory chain complexes. In the present study, we have tested whether the mitochondrial targeting of recombinant tRNAs bearing the identity elements for human mitochondrial leucyl-tRNA synthetase can rescue the phenotype caused by MELAS mutation in human transmitochondrial cybrid cells. We demonstrate that nuclear expression and mitochondrial targeting of specifically designed transgenic tRNAs results in an improvement of mitochondrial translation, increased levels of mitochondrial DNA-encoded respiratory complexes subunits, and significant rescue of respiration. These findings prove the possibility to direct tRNAs with changed aminoacylation specificities into mitochondria, thus extending the potential therapeutic strategy of allotopic expression to address mitochondrial disorders. PMID:21724600

Correction of the consequences of mitochondrial 3243A>G mutation in the MT-TL1 gene causing the MELAS syndrome by tRNA import into mitochondria.

PubMed

Karicheva, Olga Z; Kolesnikova, Olga A; Schirtz, Tom; Vysokikh, Mikhail Y; Mager-Heckel, Anne-Marie; Lombès, Anne; Boucheham, Abdeldjalil; Krasheninnikov, Igor A; Martin, Robert P; Entelis, Nina; Tarassov, Ivan

2011-10-01

Mutations in human mitochondrial DNA are often associated with incurable human neuromuscular diseases. Among these mutations, an important number have been identified in tRNA genes, including 29 in the gene MT-TL1 coding for the tRNA(Leu(UUR)). The m.3243A>G mutation was described as the major cause of the MELAS syndrome (mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes). This mutation was reported to reduce tRNA(Leu(UUR)) aminoacylation and modification of its anti-codon wobble position, which results in a defective mitochondrial protein synthesis and reduced activities of respiratory chain complexes. In the present study, we have tested whether the mitochondrial targeting of recombinant tRNAs bearing the identity elements for human mitochondrial leucyl-tRNA synthetase can rescue the phenotype caused by MELAS mutation in human transmitochondrial cybrid cells. We demonstrate that nuclear expression and mitochondrial targeting of specifically designed transgenic tRNAs results in an improvement of mitochondrial translation, increased levels of mitochondrial DNA-encoded respiratory complexes subunits, and significant rescue of respiration. These findings prove the possibility to direct tRNAs with changed aminoacylation specificities into mitochondria, thus extending the potential therapeutic strategy of allotopic expression to address mitochondrial disorders.

CARMA2sh and ULK2 control pathogen-associated molecular patterns recognition in human keratinocytes: psoriasis-linked CARMA2sh mutants escape ULK2 censorship.

PubMed

Scudiero, Ivan; Mazzone, Pellegrino; D'Andrea, Luca E; Ferravante, Angela; Zotti, Tiziana; Telesio, Gianluca; De Rubis, Gabriele; Reale, Carla; Pizzulo, Maddalena; Muralitharan, Shanmugakonar; Vito, Pasquale; Stilo, Romania

2017-02-23

The molecular complexes formed by specific members of the family of CARMA proteins, the CARD domain-containing adapter molecule BCL10 and MALT1 (CBM complex) represent a central hub in regulating activation of the pleiotropic transcription factor NF-κB. Recently, missense mutations in CARMA2sh have been shown to cause psoriasis in a dominant manner and with high penetrancy. Here, we demonstrate that in human keratinocytes CARMA2sh plays an essential role in the signal transduction pathway that connects pathogen-associated molecular patterns recognition to NF-κB activation. We also find that the serine/threonine kinase ULK2 binds to and phosphorylates CARMA2sh, thereby inhibiting its capacity to activate NF-κB by promoting lysosomal degradation of BCL10, which is essential for CARMA2sh-mediated NF-κB signaling. Remarkably, CARMA2sh mutants associated with psoriasis escape ULK2 inhibition. Finally, we show that a peptide blocking CARD-mediated BCL10 interactions reduces the capacity of psoriasis-linked CARMA2sh mutants to activate NF-κB. Our work elucidates a fundamental signaling mechanism operating in human keratinocytes and opens to novel potential tools for the therapeutical treatment of human skin disorders.

RING E3 mechanism for ubiquitin ligation to a disordered substrate visualized for human anaphase-promoting complex

DOE PAGES

Brown, Nicholas G.; VanderLinden, Ryan; Watson, Edmond R.; ...

2015-03-30

For many E3 ligases, a mobile RING (Really Interesting New Gene) domain stimulates ubiquitin (Ub) transfer from a thioester-linked E2~Ub intermediate to a lysine on a remotely bound disordered substrate. One such E3 is the gigantic, multisubunit 1.2-MDa anaphase-promoting complex/cyclosome (APC), which controls cell division by ubiquitinating cell cycle regulators to drive their timely degradation. Intrinsically disordered substrates are typically recruited via their KEN-box, D-box, and/or other motifs binding to APC and a coactivator such as CDH1. On the opposite side of the APC, the dynamic catalytic core contains the cullin-like subunit APC2 and its RING partner APC11, which collaboratesmore » with the E2 UBCH10 (UBE2C) to ubiquitinate substrates. However, how dynamic RING–E2~Ub catalytic modules such as APC11–UBCH10~Ub collide with distally tethered disordered substrates remains poorly understood. In this paper, we report structural mechanisms of UBCH10 recruitment to APC CDH1 and substrate ubiquitination. Unexpectedly, in addition to binding APC11’s RING, UBCH10 is corecruited via interactions with APC2, which we visualized in a trapped complex representing an APC CDH1–UBCH10~Ub–substrate intermediate by cryo-electron microscopy, and in isolation by X-ray crystallography. To our knowledge, this is the first structural view of APC, or any cullin–RING E3, with E2 and substrate juxtaposed, and it reveals how tripartite cullin–RING–E2 interactions establish APC’s specificity for UBCH10 and harness a flexible catalytic module to drive ubiquitination of lysines within an accessible zone. Finally, we propose that multisite interactions reduce the degrees of freedom available to dynamic RING E3–E2~Ub catalytic modules, condense the search radius for target lysines, increase the chance of active-site collision with conformationally fluctuating substrates, and enable regulation.« less

HERVs Expression in Autism Spectrum Disorders

PubMed Central

Balestrieri, Emanuela; Arpino, Carla; Matteucci, Claudia; Sorrentino, Roberta; Pica, Francesca; Alessandrelli, Riccardo; Coniglio, Antonella; Curatolo, Paolo; Rezza, Giovanni; Macciardi, Fabio; Garaci, Enrico; Gaudi, Simona; Sinibaldi-Vallebona, Paola

2012-01-01

Background Autistic Spectrum Disorder (ASD) is a heterogeneous neurodevelopmental disorder, resulting from complex interactions among genetic, genomic and environmental factors. Here we have studied the expression of Human Endogenous Retroviruses (HERVs), non-coding DNA elements with potential regulatory functions, and have tested their possible implication in autism. Methods The presence of retroviral mRNAs from four HERV families (E, H, K and W), widely implicated in complex diseases, was evaluated in peripheral blood mononuclear cells (PBMCs) from ASD patients and healthy controls (HCs) by qualitative RT-PCR. We also analyzed the expression of the env sequence from HERV-H, HERV-W and HERV-K families in PBMCs at the time of sampling and after stimulation in culture, in both ASD and HC groups, by quantitative Real-time PCR. Differences between groups were evaluated using statistical methods. Results The percentage of HERV-H and HERV-W positive samples was higher among ASD patients compared to HCs, while HERV-K was similarly represented and HERV-E virtually absent in both groups. The quantitative evaluation shows that HERV-H and HERV-W are differentially expressed in the two groups, with HERV-H being more abundantly expressed and, conversely, HERV-W, having lower abundance, in PBMCs from ASDs compared to healthy controls. PMBCs from ASDs also showed an increased potential to up-regulate HERV-H expression upon stimulation in culture, unlike HCs. Furthermore we report a negative correlation between expression levels of HERV-H and age among ASD patients and a statistically significant higher expression in ASD patients with Severe score in Communication and Motor Psychoeducational Profile-3. Conclusions Specific HERV families have a distinctive expression profile in ASD patients compared to HCs. We propose that HERV-H expression be explored in larger samples of individuals with autism spectrum in order to determine its utility as a novel biological trait of this complex disorder. PMID:23155411

Leptin regulates dopamine responses to sustained stress in humans.

PubMed

Burghardt, Paul R; Love, Tiffany M; Stohler, Christian S; Hodgkinson, Colin; Shen, Pei-Hong; Enoch, Mary-Anne; Goldman, David; Zubieta, Jon-Kar

2012-10-31

Neural systems that identify and respond to salient stimuli are critical for survival in a complex and changing environment. In addition, interindividual differences, including genetic variation and hormonal and metabolic status likely influence the behavioral strategies and neuronal responses to environmental challenges. Here, we examined the relationship between leptin allelic variation and plasma leptin levels with DAD2/3R availability in vivo as measured with [(11)C]raclopride PET at baseline and during a standardized pain stress challenge. Allelic variation in the leptin gene was associated with varying levels of dopamine release in response to the pain stressor, but not with baseline D2/3 receptor availability. Circulating leptin was also positively associated with stress-induced dopamine release. These results show that leptin serves as a regulator of neuronal function in humans and provides an etiological mechanism for differences in dopamine neurotransmission in response to salient stimuli as related to metabolic function. The capacity for leptin to influence stress-induced dopaminergic function is of importance for pathological states where dopamine is thought to play an integral role, such as mood, substance-use disorders, eating disorders, and obesity.

Manifestation of Hyperandrogenism in the Continuous Light Exposure-Induced PCOS Rat Model

PubMed Central

Kang, Xuezhi; Jia, Lina; Shen, Xueyong

2015-01-01

Polycystic ovary syndrome (PCOS) is a complex endocrine and metabolic disorder, and its pathogenesis has yet to be completely clarified. A fully convincing animal model has not been established for PCOS. In earlier studies, researchers have shown that the exposure of rats to continuous light can induce PCOS; nevertheless, hyperandrogenism, a key characteristic observed in human PCOS, has not been reported previously. In the present study, we found that (1) body weights decreased in female rats in a continuous light environment with both ovarian and uterine augmentation; (2) the estrous cycle in rats under continuous light environment was disordered, and polycystic ovary-like changes occurred, accompanied with fur loss and lethargy; and (3) serum testosterone levels in rats in a continuous light environment significantly increased. Our data suggest that continuous light can lead to the occurrence of PCOS in female rats without the need for drugs; this is a reasonable PCOS animal model that is more consistent with the natural disease state in humans; and poor sleep habits or negligence of sleep hygiene may be an important lifestyle factor in pathogenesis of PCOS. PMID:26064969

Role of Genetic Factors in the Pathogenesis of Radial Deficiencies in Humans

PubMed Central

Elmakky, Amira; Stanghellini, Ilaria; Landi, Antonio; Percesepe, Antonio

2015-01-01

Radial deficiencies (RDs), defined as under/abnormal development or absence of any of the structures of the forearm, radial carpal bones and thumb, occur with a live birth incidence ranging from 1 out of 30,000 to 1 out 6,000 newborns and represent about one third/one fourth of all the congenital upper limb anomalies. About half of radial disorders have a mendelian cause and pattern of inheritance, whereas the remaining half appears sporadic with no known gene involved. In sporadic forms certain anomalies, such as thumb or radial hypoplasia, may occur either alone or in association with systemic conditions, like vertebral abnormalities or renal defects. All the cases with a mendelian inheritance are syndromic forms, which include cardiac defects (in Holt-Oram syndrome), bone marrow failure (in Fanconi anemia), platelet deficiency (in thrombocytopenia-absent-radius syndrome), ocular motility impairment (in Okihiro syndrome). The genetics of radial deficiencies is complex, characterized by genetic heterogeneity and high inter- and intra-familial clinical variability: this review will analyze the etiopathogenesis and the genotype/phenotype correlations of the main radial deficiency disorders in humans. PMID:26962299

Assessing Anxiety in Nonhuman Primates

PubMed Central

Coleman, Kristine; Pierre, Peter J.

2014-01-01

Anxiety can be broadly described as a psychological state in which normally innocuous environmental stimuli trigger negative emotional expectations. Human anxiety disorders are multidimensional and may be organic or acquired, situational or pervasive. The broad ranging nature of the anxiety phenotype speaks to the need for models that identify its various components and root causes to develop effective clinical treatments. The cross-species comparative approach to modeling anxiety disorders in animals aims to understand mechanisms that both contribute to and modulate anxiety. Nonhuman primate models provide an important bridge from nonprimate model systems because of the complexity of nonhuman primates’ biobehavioral capacities and their commonalities with human emotion. The broad goal of this review is to provide an overview of various procedures available to study anxiety in the nonhuman primate, with a focus on the behavioral aspects of anxiety. Commonly used methods covered in this review include assessing animals in their home environment or in response to an ethologically relevant threat, associative conditioning and startle response tests, and cognitive bias tests. We also discuss how these procedures can help veterinarians and researchers care for captive nonhuman primates. PMID:25225310

Prenatal exposure of a girl with autism spectrum disorder to 'horsetail' (Equisetum arvense) herbal remedy and alcohol: a case report

PubMed Central

2011-01-01

Introduction Autism is a complex neurodevelopmental disorder in which the interactions of genetic, epigenetic and environmental influences are thought to play a causal role. In humans, throughout embryonic and fetal life, brain development is exquisitely susceptible to injury caused by exposure to toxic chemicals present in the environment. Although the use of herbal supplements during pregnancy is relatively common, little information is available on their association with fetal neurodevelopment. This is, to the best of our knowledge, the first report in the literature to associate a new plausible mechanism of neurodevelopmental toxicity with a case of autism spectrum disorder through a vitamin deficiency potentiated by concomitant use of herbal supplements and ethanol exposure. Case presentation We describe the pediatric environmental history of a three-year-old Caucasian girl with an autism spectrum disorder. We utilized her pediatric environmental history to evaluate constitutional, genetic, and environmental factors pertinent to manifestation of neurodevelopment disorders. Both parents reported prenatal exposure to several risk factors of interest. A year prior to conception the mother began a weight loss diet and ingested 1200 mg/day of 'horsetail' (Equisetum arvense) herbal remedies containing thiaminase, an enzyme that with long-term use can lead to vitamin deficiency. The mother reported a significant weight loss during the pregnancy and a deficiency of B-complex vitamins. Thiamine (vitamin B1) deficiency could have been potentiated by the horsetail's thiaminase activity and ethanol exposure during pregnancy. No other risk factors were identified. Conclusions A detailed and careful pediatric environmental history, which includes daily intake, herbal remedies and ethanol exposure, should be obtained from all patients with autism spectrum disorder. Maternal consumption of ethanol and of herbal supplements with suspected or potential toxicity should be avoided during pregnancy. The prospective parents should perform preconception planning before pregnancy. PMID:21453474

Crystal Structure of the Human Pol α B Subunit in Complex with the C-terminal Domain of the Catalytic Subunit*

PubMed Central

Suwa, Yoshiaki; Gu, Jianyou; Baranovskiy, Andrey G.; Babayeva, Nigar D.; Pavlov, Youri I.; Tahirov, Tahir H.

2015-01-01

In eukaryotic DNA replication, short RNA-DNA hybrid primers synthesized by primase-DNA polymerase α (Prim-Pol α) are needed to start DNA replication by the replicative DNA polymerases, Pol δ and Pol ϵ. The C terminus of the Pol α catalytic subunit (p180C) in complex with the B subunit (p70) regulates the RNA priming and DNA polymerizing activities of Prim-Pol α. It tethers Pol α and primase, facilitating RNA primer handover from primase to Pol α. To understand these regulatory mechanisms and to reveal the details of human Pol α organization, we determined the crystal structure of p70 in complex with p180C. The structured portion of p70 includes a phosphodiesterase (PDE) domain and an oligonucleotide/oligosaccharide binding (OB) domain. The N-terminal domain and the linker connecting it to the PDE domain are disordered in the reported crystal structure. The p180C adopts an elongated asymmetric saddle shape, with a three-helix bundle in the middle and zinc-binding modules (Zn1 and Zn2) on each side. The extensive p180C-p70 interactions involve 20 hydrogen bonds and a number of hydrophobic interactions resulting in an extended buried surface of 4080 Å2. Importantly, in the structure of the p180C-p70 complex with full-length p70, the residues from the N-terminal to the OB domain contribute to interactions with p180C. The comparative structural analysis revealed both the conserved features and the differences between the human and yeast Pol α complexes. PMID:25847248

Intricate Crystal Structure of Dihydrolipoamide Dehydrogenase (E3) with its Binding Protein: Multiple Copies, Dynamic and Static Disorders

NASA Technical Reports Server (NTRS)

Makal, A.; Hong, Y. S.; Potter, R.; Vettaikkorumakankauv, A. K.; Korotchkina, L. G.; Patel, M. S.; Ciszak, E.

2004-01-01

Human E3 and binding protein E3BP are two components of the pyruvate dehydrogenase complex. Crystallization of E3 with 221-amino acid fragment of E3BP (E3BPdd) led to crystals that diffracted to a resolution of 2.6 Angstroms. Structure determination involved molecular replacement using a dimer of E3 homolog as a search model and de novo building of the E3BPdd peptide. Solution was achieved by inclusion of one E3 dimer at a time, followed by refinement until five E3 dimers were located. This complete content of E3 provided electron density maps suitable for tracing nine peptide chains of E3BPdd, eight of them being identified with partial occupancies. Final content of the asymmetric unit consists of five E3 dimers, each binding one E3BPdd molecule. In four of these molecular complexes, E3BPdd is in static disorder resulting in E3BPdd binding to either one or the other monomer of the E3 dimer. However, E3BPdd of the fifth E3 dimer forms specific contacts that lock it at one monomer. In addition to this static disorder, E3BPdd reveals high mobility in the limited space of the crystal lattice. Support from NIH and NASA.

[Locomotive syndrome and frailty. Musculoskeletal ambulation disorder symptom complex and locomotive syndrome].

PubMed

Yamamoto, Noriaki

2012-04-01

Musculoskeletal ambulation disorder symptom complex is the new concept of musculoskeletal disorders with disability in walking and balance, which lead to the high risk of fall and lower activity in elderly. Locomotive syndrome is another concept to aware of healthy locomotive organ for early prevention of orthopedic disease.

Gut microbiota and obesity.

PubMed

Gérard, Philippe

2016-01-01

The human intestine harbors a complex bacterial community called the gut microbiota. This microbiota is specific to each individual despite the existence of several bacterial species shared by the majority of adults. The influence of the gut microbiota in human health and disease has been revealed in the recent years. Particularly, the use of germ-free animals and microbiota transplant showed that the gut microbiota may play a causal role in the development of obesity and associated metabolic disorders, and lead to identification of several mechanisms. In humans, differences in microbiota composition, functional genes and metabolic activities are observed between obese and lean individuals suggesting a contribution of the gut microbiota to these phenotypes. Finally, the evidence linking gut bacteria to host metabolism could allow the development of new therapeutic strategies based on gut microbiota modulation to treat or prevent obesity.

Synthesis, Delivery and Regulation of Eukaryotic Heme and Fe-S Cluster Cofactors

PubMed Central

Barupala, Dulmini P.; Dzul, Stephen P.; Riggs-Gelasco, Pamela Jo; Stemmler, Timothy L.

2016-01-01

In humans, the bulk of iron in the body (over 75%) is directed towards heme- or Fe-S cluster cofactor synthesis, and the complex, highly regulated pathways in place to accomplish biosynthesis have evolved to safely assemble and load these cofactors into apoprotein partners. In eukaryotes, heme biosynthesis is both initiated and finalized within the mitochondria, while cellular Fe-S cluster assembly is controlled by correlated pathways both within the mitochondria and within the cytosol. Iron plays a vital role in a wide array of metabolic processes and defects in iron cofactor assembly leads to human diseases. This review describes progress towards our molecular-level understanding of cellular heme and Fe-S cluster biosynthesis, focusing on the regulation and mechanistic details that are essential for understanding human disorders related to the breakdown in these essential pathways. PMID:26785297

Redox proteomics and the dynamic molecular landscape of the aging brain.

PubMed

Perluigi, Marzia; Swomley, Aaron M; Butterfield, D Allan

2014-01-01

It is well established that the risk to develop neurodegenerative disorders increases with chronological aging. Accumulating studies contributed to characterize the age-dependent changes either at gene and protein expression level which, taken together, show that aging of the human brain results from the combination of the normal decline of multiple biological functions with environmental factors that contribute to defining disease risk of late-life brain disorders. Finding the "way out" of the labyrinth of such complex molecular interactions may help to fill the gap between "normal" brain aging and development of age-dependent diseases. To this purpose, proteomics studies are a powerful tool to better understand where to set the boundary line of healthy aging and age-related disease by analyzing the variation of protein expression levels and the major post translational modifications that determine "protein" physio/pathological fate. Increasing attention has been focused on oxidative modifications due to the crucial role of oxidative stress in aging, in addition to the fact that this type of modification is irreversible and may alter protein function. Redox proteomics studies contributed to decipher the complexity of brain aging by identifying the proteins that were increasingly oxidized and eventually dysfunctional as a function of age. The purpose of this review is to summarize the most important findings obtained by applying proteomics approaches to murine models of aging with also a brief overview of some human studies, in particular those related to dementia. Copyright © 2014. Published by Elsevier B.V.

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

PubMed Central

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

2017-01-01

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

The epigenetic lorax: gene–environment interactions in human health

PubMed Central

Latham, Keith E; Sapienza, Carmen; Engel, Nora

2012-01-01

Over the last decade, we have witnessed an explosion of information on genetic factors underlying common human diseases and disorders. This ‘human genomics’ information revolution has occurred as a backdrop to a rapid increase in the rates of many human disorders and diseases. For example, obesity, Type 2 diabetes, asthma, autism spectrum disorder and attention deficit hyperactivity disorder have increased at rates that cannot be due to changes in the genetic structure of the population, and are difficult to ascribe to changes in diagnostic criteria or ascertainment. A likely cause of the increased incidence of these disorders is increased exposure to environmental factors that modify gene function. Many environmental factors that have epidemiological association with common human disorders are likely to exert their effects through epigenetic alterations. This general mechanism of gene–environment interaction poses special challenges for individuals, educators, scientists and public policy makers in defining, monitoring and mitigating exposures. PMID:22920179

Multiple autoimmune diseases syndrome in Italian Greyhounds: preliminary studies of genome-wide diversity and possible associations within the dog leukocyte antigen (DLA) complex.

PubMed

Pedersen, Niels C; Liu, Hongwei; Greenfield, Daniel L; Echols, Layle Griffioen

2012-01-15

A disorder manifested by multiple autoimmune disorders, and resembling autoimmune polyendocrine syndrome type 2 (APS-2) in humans, may exist in Italian Greyhounds. The incidence of this disorder is increasing and its potential impact on the health of the breed is becoming of great concern. The aims of the present study were to document the existence of this syndrome, conduct a preliminary assessment of genetic diversity across the breed and within affected and unaffected dogs, determine whether the disorder associates with the dog leukocyte antigen (DLA) complex, and demonstrate similarities to APS-2 of humans. To these ends, information on disease, pedigrees, and blood or buccal swab samples were collected from affected and healthy Italian Greyhounds and extracted DNA analyzed. Analysis of Y chromosome markers and mitochondrial DNA sequences showed that Italian Greyhounds evolved from a single patriline and two major and four minor matrilines. A panel of 24 highly polymorphic simple tandem repeat (STR) markers across 20 autosomes demonstrated that affected and unaffected dogs were not distinguishable from the population as a whole by heterozygosity, F-statistics, and principal component analysis (PCA). However, analysis of allele frequencies at each STR loci identified regions of increased or decreased disease risk on four chromosomes. A similar genetic analysis using 109 single nucleotide polymorphisms (SNPs) across the DLA region showed differences between affected and unaffected dogs. PCA and zygosity mapping of DLA SNPs from unrelated dogs demonstrated two distinct subpopulations among the affected individuals. One population was very homozygous and the other closely resembled unaffected dogs in its heterozygosity, suggesting the evolution of a disease prone bloodline as a result of non-random selection. Exon 2 sequencing of the DLA class II genes demonstrated 5-8 alleles at each locus and 14 three loci haplotypes. Two specific haplotypes containing DRB1*00203 or DRB1*02901 were associated with increased disease risk in about one-third of affected dogs. However, high density SNP association mapping across the DLA region and CFA12 did not corroborate the association. Copyright © 2011 Elsevier B.V. All rights reserved.

Platelet Activation in Human Immunodeficiency Virus Type-1 Patients Is Not Altered with Cocaine Abuse

PubMed Central

Kiebala, Michelle; Singh, Meera V.; Piepenbrink, Michael S.; Qiu, Xing; Kobie, James J.; Maggirwar, Sanjay B.

2015-01-01

Recent work has indicated that platelets, which are anucleate blood cells, significantly contribute to inflammatory disorders. Importantly, platelets also likely contribute to various inflammatory secondary disorders that are increasingly associated with Human Immunodeficiency Virus Type-1 (HIV) infection including neurological impairments and cardiovascular complications. Indeed, HIV infection is often associated with increased levels of platelet activators. Additionally, cocaine, a drug commonly abused by HIV-infected individuals, leads to increased platelet activation in humans. Considering that orchestrated signaling mechanisms are essential for platelet activation, and that nuclear factor-kappa B (NF-κB) inhibitors can alter platelet function, the role of NF-κB signaling in platelet activation during HIV infection warrants further investigation. Here we tested the hypothesis that inhibitory kappa B kinase complex (IKK) activation would be central for platelet activation induced by HIV and cocaine. Whole blood from HIV-positive and HIV-negative individuals, with or without cocaine abuse was used to assess platelet activation via flow cytometry whereas IKK activation was analyzed by performing immunoblotting and in vitro kinase assays. We demonstrate that increased platelet activation in HIV patients, as measured by CD62P expression, is not altered with reported cocaine use. Furthermore, cocaine and HIV do not activate platelets in whole blood when treated ex vivo. Finally, HIV-induced platelet activation does not involve the NF-κB signaling intermediate, IKKβ. Platelet activation in HIV patients is not altered with cocaine abuse. These results support the notion that non-IKK targeting approaches will be better suited for the treatment of HIV-associated inflammatory disorders. PMID:26076359

Cortical representations of communication sounds.

PubMed

Heiser, Marc A; Cheung, Steven W

2008-10-01

This review summarizes recent research into cortical processing of vocalizations in animals and humans. There has been a resurgent interest in this topic accompanied by an increased number of studies using animal models with complex vocalizations and new methods in human brain imaging. Recent results from such studies are discussed. Experiments have begun to reveal the bilateral cortical fields involved in communication sound processing and the transformations of neural representations that occur among those fields. Advances have also been made in understanding the neuronal basis of interaction between developmental exposures and behavioral experiences with vocalization perception. Exposure to sounds during the developmental period produces large effects on brain responses, as do a variety of specific trained tasks in adults. Studies have also uncovered a neural link between the motor production of vocalizations and the representation of vocalizations in cortex. Parallel experiments in humans and animals are answering important questions about vocalization processing in the central nervous system. This dual approach promises to reveal microscopic, mesoscopic, and macroscopic principles of large-scale dynamic interactions between brain regions that underlie the complex phenomenon of vocalization perception. Such advances will yield a greater understanding of the causes, consequences, and treatment of disorders related to speech processing.

Resting state brain networks in the prairie vole.

PubMed

Ortiz, Juan J; Portillo, Wendy; Paredes, Raul G; Young, Larry J; Alcauter, Sarael

2018-01-19

Resting state functional magnetic resonance imaging (rsfMRI) has shown the hierarchical organization of the human brain into large-scale complex networks, referred as resting state networks. This technique has turned into a promising translational research tool after the finding of similar resting state networks in non-human primates, rodents and other animal models of great value for neuroscience. Here, we demonstrate and characterize the presence of resting states networks in Microtus ochrogaster, the prairie vole, an extraordinary animal model to study complex human-like social behavior, with potential implications for the research of normal social development, addiction and neuropsychiatric disorders. Independent component analysis of rsfMRI data from isoflurane-anestethized prairie voles resulted in cortical and subcortical networks, including primary motor and sensory networks, but also included putative salience and default mode networks. We further discuss how future research could help to close the gap between the properties of the large scale functional organization and the underlying neurobiology of several aspects of social cognition. These results contribute to the evidence of preserved resting state brain networks across species and provide the foundations to explore the use of rsfMRI in the prairie vole for basic and translational research.

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

Perriot, Romain; Uberuaga, Blas P.; Zamora, Richard J.

Diffusion in complex oxides is critical to ionic transport, radiation damage evolution, sintering, and aging. In complex oxides such as pyrochlores, anionic diffusion is dramatically affected by cation disorder. However, little is known about how disorder influences cation transport. Here, we report results from classical and accelerated molecular dynamics simulations of vacancy-mediated cation diffusion in Gd 2Ti 2O 7 pyrochlore, on the microsecond timescale. We find that diffusion is slow at low levels of disorder, while higher disorder allows for fast diffusion, which is then accompanied by antisite annihilation and reordering, and thus a slowing of cation transport. Cation diffusivitymore » is therefore not constant, but decreases as the material reorders. We also show that fast cation diffusion is triggered by the formation of a percolation network of antisites. This is in contrast with observations from other complex oxides and disordered media models, suggesting a fundamentally different relation between disorder and mass transport.« less

Abundance of intrinsic structural disorder in the histone H1 subtypes.

PubMed

Kowalski, Andrzej

2015-12-01

The intrinsically disordered proteins consist of partially structured regions linked to the unstructured stretches, which consequently form the transient and dynamic conformational ensembles. They undergo disorder to order transition upon binding their partners. Intrinsic disorder is attributed to histones H1, perceived as assemblers of chromatin structure and the regulators of DNA and proteins activity. In this work, the comparison of intrinsic disorder abundance in the histone H1 subtypes was performed both by the analysis of their amino acid composition and by the prediction of disordered stretches, as well as by identifying molecular recognition features (MoRFs) and ANCHOR protein binding regions (APBR) that are responsible for recognition and binding. Both human and model organisms-animals, plants, fungi and protists-have H1 histone subtypes with the properties typical of disordered state. They possess a significantly higher content of hydrophilic and charged amino acid residues, arranged in the long regions, covering over half of the whole amino acid residues in chain. Almost complete disorder corresponds to histone H1 terminal domains, including MoRFs and ANCHOR. Those motifs were also identified in a more ordered histone H1 globular domain. Compared to the control (globular and fibrous) proteins, H1 histones demonstrate the increased folding rate and a higher proportion of low-complexity segments. The results of this work indicate that intrinsic disorder is an inherent structural property of histone H1 subtypes and it is essential for establishing a protein conformation which defines functional outcomes affecting on DNA- and/or partner protein-dependent cell processes. Copyright © 2015 Elsevier Ltd. All rights reserved.

Synapse alterations in autism: Review of animal model findings.

PubMed

Zatkova, Martina; Bakos, Jan; Hodosy, Julius; Ostatnikova, Daniela

2016-06-01

Recent research has produced an explosion of experimental data on the complex neurobiological mechanisms of developmental disorders including autism. Animal models are one approach to studying the phenotypic features and molecular basis of autism. In this review, we describe progress in understanding synaptogenesis and alterations to this process with special emphasis on the cell adhesion molecules and scaffolding proteins implicated in autism. Genetic mouse model experiments are discussed in relation to alterations to selected synaptic proteins and consequent behavioral deficits measured in animal experiments. Pubmed databases were used to search for original and review articles on animal and human clinical studies on autism. The cell adhesion molecules, neurexin, neurolignin and the Shank family of proteins are important molecular targets associated with autism. The heterogeneity of the autism spectrum of disorders limits interpretation of information acquired from any single animal model or animal test. We showed synapse-specific/ model-specific defects associated with a given genotype in these models. Characterization of mouse models with genetic variations may help study the mechanisms of autism in humans. However, it will be necessary to apply new analytic paradigms in using genetically modified mice for understanding autism etiology in humans. Further studies are needed to create animal models with mutations that match the molecular and neural bases of autism.

Evidence for percolation diffusion of cations and reordering in disordered pyrochlore from accelerated molecular dynamics

DOE PAGES

Perriot, Romain; Uberuaga, Blas P.; Zamora, Richard J.; ...

2017-09-20

Diffusion in complex oxides is critical to ionic transport, radiation damage evolution, sintering, and aging. In complex oxides such as pyrochlores, anionic diffusion is dramatically affected by cation disorder. However, little is known about how disorder influences cation transport. Here, we report results from classical and accelerated molecular dynamics simulations of vacancy-mediated cation diffusion in Gd 2Ti 2O 7 pyrochlore, on the microsecond timescale. We find that diffusion is slow at low levels of disorder, while higher disorder allows for fast diffusion, which is then accompanied by antisite annihilation and reordering, and thus a slowing of cation transport. Cation diffusivitymore » is therefore not constant, but decreases as the material reorders. We also show that fast cation diffusion is triggered by the formation of a percolation network of antisites. This is in contrast with observations from other complex oxides and disordered media models, suggesting a fundamentally different relation between disorder and mass transport.« less

Evolution of disorder in Mediator complex and its functional relevance.

PubMed

Nagulapalli, Malini; Maji, Sourobh; Dwivedi, Nidhi; Dahiya, Pradeep; Thakur, Jitendra K

2016-02-29

Mediator, an important component of eukaryotic transcriptional machinery, is a huge multisubunit complex. Though the complex is known to be conserved across all the eukaryotic kingdoms, the evolutionary topology of its subunits has never been studied. In this study, we profiled disorder in the Mediator subunits of 146 eukaryotes belonging to three kingdoms viz., metazoans, plants and fungi, and attempted to find correlation between the evolution of Mediator complex and its disorder. Our analysis suggests that disorder in Mediator complex have played a crucial role in the evolutionary diversification of complexity of eukaryotic organisms. Conserved intrinsic disordered regions (IDRs) were identified in only six subunits in the three kingdoms whereas unique patterns of IDRs were identified in other Mediator subunits. Acquisition of novel molecular recognition features (MoRFs) through evolution of new subunits or through elongation of the existing subunits was evident in metazoans and plants. A new concept of 'junction-MoRF' has been introduced. Evolutionary link between CBP and Med15 has been provided which explain the evolution of extended-IDR in CBP from Med15 KIX-IDR junction-MoRF suggesting role of junction-MoRF in evolution and modulation of protein-protein interaction repertoire. This study can be informative and helpful in understanding the conserved and flexible nature of Mediator complex across eukaryotic kingdoms. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

[Complex Trauma-related Disorders in Research and Practice].

PubMed

Metzner, Franka; Pahlke, Stephanie; Diesing, Alice; Marin, Nina; Klasen, Fionna; Pawils, Silke; Schulte-Markwort, Michael; Richter-Appelt, Hertha

2018-03-01

Complex Trauma-related Disorders in Research and Practice Frequent traumata in childhood and adolescence are long-term or repeated interpersonal traumata caused by perpetrators in the close environment of the minors. For the description of the extensive symptoms after interpersonal Type II traumata, the complex trauma-related disorders Complex Posttraumatic Stress Disorder (CPTSD) or Disorder of Extreme Stress Not Otherwise Specified (DESNOS) and the Developmental Trauma Disorder (DTD) are being discussed for inclusion in the classification systems for mental disorders. Scientific knowledge and practical experiences regarding CPTSD, DESNOS and DTD in children and adolescents up to 18 years were examined by 1) a Systematic Review of 1,070 publications identified by database research and additional search strategies, and 2) a nationwide online survey of 374 psychotherapists and psychiatrists for children and adolescents in Germany. Of 13 included empirical studies (8 CPTSD or DESNOS, 5 DTD), 9 were conducted in the USA, 4 based on file coding and 3 on secondary data analysis and only 7 reported diagnosis rates (range: 0-78 %). Of the interviewed therapists, 100 % considered the CPTSD as being met with at least one patient with interpersonal traumata up to 18 years of age in 2014 and 99 % gave this estimate for the DTD. Two thirds of therapists rated the diagnostic option CPTSD and DTD as "very often" or "often" helpful for their therapeutic work with children and adolescents. While empirical data available is to be considered insufficient and characterized by methodological limitations, the relevance of complex trauma-related disorders is perceived as high by practitioners.

Phonological complexity in school-aged children who stutter and exhibit a language disorder.

PubMed

Wolk, Lesley; LaSalle, Lisa R

2015-03-01

The Index of Phonological Complexity and the Word Complexity Measure are two measures of the phonological complexity of a word. Other phonological measures such as phonological neighborhood density have been used to compare stuttered versus fluent words. It appears that in preschoolers who stutter, the length and complexity of the utterance is more influential than the phonetic features of the stuttered word. The present hypothesis was that in school-age children who stutter, stuttered words would be more phonologically complex than fluent words, when the length and complexity of the utterance containing them is comparable. School-age speakers who stutter were hypothesized to differ from those with a concomitant language disorder. Sixteen speakers, six females and ten males (M age=12;3; Range=7;7 to 19;5) available from an online database, were divided into eight who had a concomitant language disorder (S+LD) and eight age- and sex-matched speakers who did not (S-Only). When all stuttered content words were identified, S+LD speakers produced more repetitions, and S-Only speakers produced more inaudible sound prolongations. When stuttered content words were matched to fluent content words and when talker groups were combined, stuttered words were significantly (p≤0.01) higher in both the Index of Phonological Complexity and the Word Complexity Measure and lower in density ("sparser") than fluent words. Results corroborate those of previous researchers. Future research directions are suggested, such as cross-sectional designs to evaluate developmental patterns of phonological complexity and stuttering plus language disordered connections. The reader will be able to: (a) Define and describe phonological complexity; (b) Define phonological neighborhood density and summarize the literature on the topic; (c) Describe the Index of Phonological Complexity (IPC) for a given word; (d) Describe the Word Complexity Measure (WCM) for a given word; (e) Summarize two findings from the current study and describe how each relates to studies of phonological complexity and fluency disorders. Copyright © 2014 Elsevier Inc. All rights reserved.

Thoracic Outlet Syndrome

MedlinePlus

... including rotator cuff injuries, cervical disc disorders, fibromyalgia, multiple sclerosis, complex regional pain syndrome, and tumors of the ... including rotator cuff injuries, cervical disc disorders, fibromyalgia, multiple sclerosis, complex regional pain syndrome, and tumors of the ...

Genome-Wide Methylome Analyses Reveal Novel Epigenetic Regulation Patterns in Schizophrenia and Bipolar Disorder

PubMed Central

Li, Yongsheng; Camarillo, Cynthia; Xu, Juan; Arana, Tania Bedard; Xiao, Yun; Zhao, Zheng; Chen, Hong; Ramirez, Mercedes; Zavala, Juan; Escamilla, Michael A.; Armas, Regina; Mendoza, Ricardo; Ontiveros, Alfonso; Nicolini, Humberto; Jerez Magaña, Alvaro Antonio; Rubin, Lewis P.; Li, Xia; Xu, Chun

2015-01-01

Schizophrenia (SZ) and bipolar disorder (BP) are complex genetic disorders. Their appearance is also likely informed by as yet only partially described epigenetic contributions. Using a sequencing-based method for genome-wide analysis, we quantitatively compared the blood DNA methylation landscapes in SZ and BP subjects to control, both in an understudied population, Hispanics along the US-Mexico border. Remarkably, we identified thousands of differentially methylated regions for SZ and BP preferentially located in promoters 3′-UTRs and 5′-UTRs of genes. Distinct patterns of aberrant methylation of promoter sequences were located surrounding transcription start sites. In these instances, aberrant methylation occurred in CpG islands (CGIs) as well as in flanking regions as well as in CGI sparse promoters. Pathway analysis of genes displaying these distinct aberrant promoter methylation patterns showed enhancement of epigenetic changes in numerous genes previously related to psychiatric disorders and neurodevelopment. Integration of gene expression data further suggests that in SZ aberrant promoter methylation is significantly associated with altered gene transcription. In particular, we found significant associations between (1) promoter CGIs hypermethylation with gene repression and (2) CGI 3′-shore hypomethylation with increased gene expression. Finally, we constructed a specific methylation analysis platform that facilitates viewing and comparing aberrant genome methylation in human neuropsychiatric disorders. PMID:25734057

Mental disorder is a cause of crime: the cornerstone of forensic psychiatry.

PubMed

Anckarsäter, Henrik; Radovic, Susanna; Svennerlind, Christer; Höglund, Pontus; Radovic, Filip

2009-01-01

The assumption that mental disorder is a cause of crime is the foundation of forensic psychiatry, but conceptual, epistemological, and empirical analyses show that neither mental nor crime, or the causation implied, are clear-cut concepts. "Mental" denotes heterogeneous aspects of a person such as inner experiences, cognitive abilities, and behaviour patterns described in a non-physical vocabulary. In psychology and psychiatry, mental describes law-bound, caused aspects of human functioning that are predictable and generalizable. Problems defined as mental disorders are end-points of dimensional inter-individual differences rather than natural categories. Deficits in cognitive faculties, such as attention, verbal understanding, impulse control, and reality assessment, may be susceptibility factors that relate to behaviours (such as crimes) by increasing the probability (risk) for a negative behaviour or constitute causes in the sense of INUS conditions (Insufficient but Non-redundant parts of Unnecessary but Sufficient conditions). Attributing causes to complex behaviours such as crimes is not an unbiased process, and mental disorders will attract disproportionate attention when it comes to explanations of behaviours that we wish to distance ourselves from. Only by rigorous interpretation of what psychiatry actually can inform us about, using empirical analyses of quantified aggressive antisocial behaviours and their possible explanatory factors, can we gain a clearer notion of the relationship between mental disorder and crime.

Female reproductive disorders: the roles of endocrine-disrupting compounds and developmental timing

PubMed Central

Crain, D. Andrew; Janssen, Sarah J.; Edwards, Thea M.; Heindel, Jerrold; Ho, Shuk-mei; Hunt, Patricia; Iguchi, Taisen; Juul, Anders; McLachlan, John A.; Schwartz, Jackie; Skakkebaek, Niels; Soto, Ana M.; Swan, Shanna; Walker, Cheryl; Woodruff, Teresa K.; Woodruff, Tracey J.; Giudice, Linda C.; Guillette, Louis J.

2014-01-01

Objective To evaluate the possible role of endocrine-disrupting compounds (EDCs) on female reproductive disorders emphasizing developmental plasticity and the complexity of endocrine-dependent ontogeny of reproductive organs. Declining conception rates and the high incidence of female reproductive disruptions warrant evaluation of the impact of EDCs on female reproductive health. Design Publications related to the contribution of EDCs to disorders of the ovary (aneuploidy, polycystic ovary syndrome, and altered cyclicity), uterus (endometriosis, uterine fibroids, fetal growth restriction, and pregnancy loss), breast (breast cancer, reduced duration of lactation), and pubertal timing were identified, reviewed, and summarized at a workshop. Conclusion(s) The data reviewed illustrate that EDCs contribute to numerous human female reproductive disorders and emphasize the sensitivity of early life-stage exposures. Many research gaps are identified that limit full understanding of the contribution of EDCs to female reproductive problems. Moreover, there is an urgent need to reduce the incidence of these reproductive disorders, which can be addressed by correlative studies on early life exposure and adult reproductive dysfunction together with tools to assess the specific exposures and methods to block their effects. This review of the EDC literature as it relates to female health provides an important platform on which women’s health can be improved. PMID:18929049

Involvement of Neuroinflammation during Brain Development in Social Cognitive Deficits in Autism Spectrum Disorder and Schizophrenia.

PubMed

Nakagawa, Yutaka; Chiba, Kenji

2016-09-01

Development of social cognition, a unique and high-order function, depends on brain maturation from childhood to adulthood in humans. Autism spectrum disorder (ASD) and schizophrenia have similar social cognitive deficits, although age of onset in each disorder is different. Pathogenesis of these disorders is complex and contains several features, including genetic risk factors, environmental risk factors, and sites of abnormalities in the brain. Although several hypotheses have been postulated, they seem to be insufficient to explain how brain alterations associated with symptoms in these disorders develop at distinct developmental stages. Development of ASD appears to be related to cerebellar dysfunction and subsequent thalamic hyperactivation in early childhood. By contrast, schizophrenia seems to be triggered by thalamic hyperactivation in late adolescence, whereas hippocampal aberration has been possibly initiated in childhood. One of the possible culprits is metal homeostasis disturbances that can induce dysfunction of blood-cerebrospinal fluid barrier. Thalamic hyperactivation is thought to be induced by microglia-mediated neuroinflammation and abnormalities of intracerebral environment. Consequently, it is likely that the thalamic hyperactivation triggers dysregulation of the dorsolateral prefrontal cortex for lower brain regions related to social cognition. In this review, we summarize the brain aberration in ASD and schizophrenia and provide a possible mechanism underlying social cognitive deficits in these disorders based on their distinct ages of onset. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

Case Study: Skinny Genes? An Interdisciplinary Look at a Complex Behavioral Disorder

ERIC Educational Resources Information Center

Gow, Joan-Beth; Carpino, Lisa A.

2018-01-01

Anorexia nervosa is a complex behavioral disorder with the highest risk of death of any psychological disorder. Between 15% and 20% of those suffering from anorexia die from complications that are attributed either directly or indirectly to self-starvation. Heritability for anorexia is around 0.5, meaning about 50% of the risk for anorexia is…

Commentary on the Inclusion of Persistent Complex Bereavement-Related Disorder in DSM-5

ERIC Educational Resources Information Center

Boelen, Paul A.; Prigerson, Holly G.

2012-01-01

The DSM-5 Anxiety, Obsessive-Compulsive Spectrum, Posttraumatic, and Dissociative Disorders Work Group has proposed criteria for Persistent Complex Bereavement-Related Disorder (PCBRD) for inclusion in the appendix of DSM-5. The authors feel that it is important that dysfunctional grief will become a formal condition in DSM-5 because that would…

Stabilizing Group Treatment for Complex Posttraumatic Stress Disorder Related to Childhood Abuse Based on Psycho-Education and Cognitive Behavioral Therapy: A Pilot Study

ERIC Educational Resources Information Center

Dorrepaal, Ethy; Thomaes, Kathleen; Smit, Johannes H.; van Balkom, Anton J. L. M.; van Dyck, Richard; Veltman, Dick J.; Draijer, Nel

2010-01-01

Objective: This study tests a Stabilizing Group Treatment protocol, designed for the management of the long-term sequelae of child abuse, that is, Complex Posttraumatic Stress Disorder (Complex PTSD). Evidence-based treatment for this subgroup of PTSD patients is largely lacking. This stabilizing treatment aims at improving Complex PTSD using…

The measles virus N(TAIL)-XD complex: an illustrative example of fuzziness.

PubMed

Longhi, Sonia

2012-01-01

In this chapter, I focus on the biochemical and structural characterization of the complex between the intrinsically disordered C-terminal domain of the measles virus nucleoprotein (N(TAIL)) and the C-terminal X domain (XD) of the viral phosphoprotein (P). I summarize the main experimental data available so far pointing out the prevalently disordered nature of N(TAIL) even after complex formation and the role of the flexible C-terminal appendage in the binding reaction. I finally discuss the possible functional role of these residual disordered regions within the complex in terms of their ability to capture other regulatory, binding partners.

Fanconi anemia protein, FANCA, associates with BRG1, a component of the human SWI/SNF complex.

PubMed

Otsuki, T; Furukawa, Y; Ikeda, K; Endo, H; Yamashita, T; Shinohara, A; Iwamatsu, A; Ozawa, K; Liu, J M

2001-11-01

Fanconi anemia (FA) is a genetic disorder that predisposes to hematopoietic failure, birth defects and cancer. We identified an interaction between the FA protein, FANCA and brm-related gene 1 (BRG1) product. BRG1 is a subunit of the SWI/SNF complex, which remodels chromatin structure through a DNA-dependent ATPase activity. FANCA was demonstrated to associate with the endogenous SWI/SNF complex. We also found a significant increase in the molecular chaperone, glucose-regulated protein 94 (GRP94) among BRG1-associated factors isolated from a FANCA-mutant cell line, which was not seen in either a normal control cell line or the mutant line complemented by wild-type FANCA. Despite this specific difference, FANCA did not appear to be absolutely required for in vitro chromatin remodeling. Finally, we demonstrated co-localization in the nucleus between transfected FANCA and BRG1. The physiological action of FANCA on the SWI/SNF complex remains to be clarified, but our work suggests that FANCA may recruit the SWI/SNF complex to target genes, thereby enabling coupled nuclear functions such as transcription and DNA repair.

Human immunodeficiency virus endocrinopathy

PubMed Central

Sinha, Uma; Sengupta, Nilanjan; Mukhopadhyay, Prasanta; Roy, Keshab Sinha

2011-01-01

Human immunodeficiency virus (HIV) endocrinopathy encompasses a broad spectrum of disorders. Almost all the endocrine organs are virtually affected by HIV infection. HIV can directly alter glandular function. More commonly secondary endocrine dysfunction occurs due to opportunistic infections and neoplasms in immunocompromised state. The complex interaction between HIV infection and endocrine system may be manifested as subtle biochemical and hormonal perturbation to overt glandular failure. Antiretroviral therapy as well as other essential medications often result in adverse endocrinal consequences. Apart from adrenal insufficiency, hypogonadism, diabetes and bone loss, AIDS wasting syndrome and HIV lipodystrophy need special reference. Endocrinal evaluation should proceed as in other patients with suspected endocrine dysfunction. Available treatment options have been shown to improve quality of life and long-term mortality in AIDS patients. PMID:22028995

Analysis of Brain Recurrence

NASA Astrophysics Data System (ADS)

Frilot, Clifton; Kim, Paul Y.; Carrubba, Simona; McCarty, David E.; Chesson, Andrew L.; Marino, Andrew A.

Analysis of Brain Recurrence (ABR) is a method for extracting physiologically significant information from the electroencephalogram (EEG), a non-stationary electrical output of the brain, the ultimate complex dynamical system. ABR permits quantification of temporal patterns in the EEG produced by the non-autonomous differential laws that govern brain metabolism. In the context of appropriate experimental and statistical designs, ABR is ideally suited to the task of interpreting the EEG. Present applications of ABR include discovery of a human magnetic sense, increased mechanistic understanding of neuronal membrane processes, diagnosis of degenerative neurological disease, detection of changes in brain metabolism caused by weak environmental electromagnetic fields, objective characterization of the quality of human sleep, and evaluation of sleep disorders. ABR has important beneficial implications for the development of clinical and experimental neuroscience.

Defining the diverse spectrum of inversions, complex structural variation, and chromothripsis in the morbid human genome.

PubMed

Collins, Ryan L; Brand, Harrison; Redin, Claire E; Hanscom, Carrie; Antolik, Caroline; Stone, Matthew R; Glessner, Joseph T; Mason, Tamara; Pregno, Giulia; Dorrani, Naghmeh; Mandrile, Giorgia; Giachino, Daniela; Perrin, Danielle; Walsh, Cole; Cipicchio, Michelle; Costello, Maura; Stortchevoi, Alexei; An, Joon-Yong; Currall, Benjamin B; Seabra, Catarina M; Ragavendran, Ashok; Margolin, Lauren; Martinez-Agosto, Julian A; Lucente, Diane; Levy, Brynn; Sanders, Stephan J; Wapner, Ronald J; Quintero-Rivera, Fabiola; Kloosterman, Wigard; Talkowski, Michael E

2017-03-06

Structural variation (SV) influences genome organization and contributes to human disease. However, the complete mutational spectrum of SV has not been routinely captured in disease association studies. We sequenced 689 participants with autism spectrum disorder (ASD) and other developmental abnormalities to construct a genome-wide map of large SV. Using long-insert jumping libraries at 105X mean physical coverage and linked-read whole-genome sequencing from 10X Genomics, we document seven major SV classes at ~5 kb SV resolution. Our results encompass 11,735 distinct large SV sites, 38.1% of which are novel and 16.8% of which are balanced or complex. We characterize 16 recurrent subclasses of complex SV (cxSV), revealing that: (1) cxSV are larger and rarer than canonical SV; (2) each genome harbors 14 large cxSV on average; (3) 84.4% of large cxSVs involve inversion; and (4) most large cxSV (93.8%) have not been delineated in previous studies. Rare SVs are more likely to disrupt coding and regulatory non-coding loci, particularly when truncating constrained and disease-associated genes. We also identify multiple cases of catastrophic chromosomal rearrangements known as chromoanagenesis, including somatic chromoanasynthesis, and extreme balanced germline chromothripsis events involving up to 65 breakpoints and 60.6 Mb across four chromosomes, further defining rare categories of extreme cxSV. These data provide a foundational map of large SV in the morbid human genome and demonstrate a previously underappreciated abundance and diversity of cxSV that should be considered in genomic studies of human disease.

Predictability and Robustness in the Manipulation of Dynamically Complex Objects

PubMed Central

Hasson, Christopher J.

2017-01-01

Manipulation of complex objects and tools is a hallmark of many activities of daily living, but how the human neuromotor control system interacts with such objects is not well understood. Even the seemingly simple task of transporting a cup of coffee without spilling creates complex interaction forces that humans need to compensate for. Predicting the behavior of an underactuated object with nonlinear fluid dynamics based on an internal model appears daunting. Hence, this research tests the hypothesis that humans learn strategies that make interactions predictable and robust to inaccuracies in neural representations of object dynamics. The task of moving a cup of coffee is modeled with a cart-and-pendulum system that is rendered in a virtual environment, where subjects interact with a virtual cup with a rolling ball inside using a robotic manipulandum. To gain insight into human control strategies, we operationalize predictability and robustness to permit quantitative theory-based assessment. Predictability is quantified by the mutual information between the applied force and the object dynamics; robustness is quantified by the energy margin away from failure. Three studies are reviewed that show how with practice subjects develop movement strategies that are predictable and robust. Alternative criteria, common for free movement, such as maximization of smoothness and minimization of force, do not account for the observed data. As manual dexterity is compromised in many individuals with neurological disorders, the experimental paradigm and its analyses are a promising platform to gain insights into neurological diseases, such as dystonia and multiple sclerosis, as well as healthy aging. PMID:28035560

Eating disorder emergencies: understanding the medical complexities of the hospitalized eating disordered patient.

PubMed

Cartwright, Martina M

2004-12-01

Eating disorders are maladaptive eating behaviors that typically develop in adolescence and early adulthood. Psychiatric maladies and comorbid conditions, especially insulin-dependent diabetes mellitus, frequently co-exist with eating disorders. Serious medical complications affecting all organs and tissues can develop and result in numerous emergent hospitalizations. This article reviews the pathophysiologies of anorexia nervosa, bulimia nervosa, and orthorexia nervosa and discusses the complexities associated with the treatment of medical complications seen in these patients.

What Difference Does It Make? Implicit, Explicit and Complex Social Cognition in Autism Spectrum Disorders

ERIC Educational Resources Information Center

Schaller, Ulrich M.; Rauh, Reinhold

2017-01-01

We tested social cognition abilities of adolescents with autism spectrum disorders (ASD) and neurotypically developed peers (NTD). A multi-faceted test-battery including facial emotion categorization (FEC), classical false belief tasks (FBT), and complex social cognition (SC), yielded significantly lower accuracy rates for FEC and complex SC tasks…

[Obsessive-compulsive disorders in forensic-psychiatric opinions].

PubMed

Kocur, Józef; Trendak, Wiesława

2009-01-01

Obsessive-compulsive disorders and disorders within their spectrum pose a serious diagnostic and therapeutic problem, as the symptoms that appear along with the disorders result from dysfunction of the emotional, motivational and cognitive sphere. The dysfunction is determined by complex genetic, neurochemical and neurophysiological factors. Exacerbation of the symptoms may weaken the control over the disturbed impulses and compulsions, which in turn may lead to violation of law. Therefore, a forensic-psychiatric evaluation in cases related to patients suffering from obsessive-compulsive disorders has to include very complex relations between the type and the circumstances of the committed act or the undertaken actions and the type and intensity of these disorders.

The Golden Retriever Lifetime Study: establishing an observational cohort study with translational relevance for human health

PubMed Central

Guy, Michael K.; Page, Rodney L.; Jensen, Wayne A.; Olson, Patricia N.; Haworth, J. David; Searfoss, Erin E.; Brown, Diane E.

2015-01-01

The Golden Retriever Lifetime Study (GRLS) is the first prospective longitudinal study attempted in veterinary medicine to identify the major dietary, genetic and environmental risk factors for cancer and other important diseases in dogs. The GRLS is an observational study that will follow a cohort of 3000 purebred Golden Retrievers throughout their lives via annual online questionnaires from the dog owner and annual physical examinations and collection of biological samples by the primary care veterinarian. The field of comparative medicine investigating naturally occurring disorders in pets is specifically relevant to the many diseases that have a genetic basis for disease in both animals and humans, including cancer, blindness, metabolic and behavioural disorders and some neurodegenerative disorders. The opportunity for the GRLS to provide high-quality data for translational comparative medical initiatives in several disease categories is great. In particular, the opportunity to develop a lifetime dataset of lifestyle and activity, environmental exposure and diet history combined with simultaneous annual biological sample sets and detailed health outcomes will provide disease incidence data for this cohort of geographically dispersed dogs and associations with a wide variety of potential risk factors. The GRLS will provide a lifetime historical context, repeated biological sample sets and outcomes necessary to interrogate complex associations between genes and environmental influences and cancer. PMID:26056371

Characterisation of CDKL5 Transcript Isoforms in Human and Mouse

PubMed Central

Dando, Owen; Landsberger, Nicoletta; Kilstrup-Nielsen, Charlotte; Kind, Peter C.; Bailey, Mark E. S.; Cobb, Stuart R.

2016-01-01

Mutations in the X-linked Cyclin-Dependent Kinase-Like 5 gene (CDKL5) cause early onset infantile spasms and subsequent severe developmental delay in affected children. Deleterious mutations have been reported to occur throughout the CDKL5 coding region. Several studies point to a complex CDKL5 gene structure in terms of exon usage and transcript expression. Improvements in molecular diagnosis and more extensive research into the neurobiology of CDKL5 and pathophysiology of CDKL5 disorders necessitate an updated analysis of the gene. In this study, we have analysed human and mouse CDKL5 transcript patterns both bioinformatically and experimentally. We have characterised the predominant brain isoform of CDKL5, a 9.7 kb transcript comprised of 18 exons with a large 6.6 kb 3’-untranslated region (UTR), which we name hCDKL5_1. In addition we describe new exonic regions and a range of novel splice and UTR isoforms. This has enabled the description of an updated gene model in both species and a standardised nomenclature system for CDKL5 transcripts. Profiling revealed tissue- and brain development stage-specific differences in expression between transcript isoforms. These findings provide an essential backdrop for the diagnosis of CDKL5-related disorders, for investigations into the basic biology of this gene and its protein products, and for the rational design of gene-based and molecular therapies for these disorders. PMID:27315173

Characterisation of CDKL5 Transcript Isoforms in Human and Mouse.

PubMed

Hector, Ralph D; Dando, Owen; Landsberger, Nicoletta; Kilstrup-Nielsen, Charlotte; Kind, Peter C; Bailey, Mark E S; Cobb, Stuart R

2016-01-01

Mutations in the X-linked Cyclin-Dependent Kinase-Like 5 gene (CDKL5) cause early onset infantile spasms and subsequent severe developmental delay in affected children. Deleterious mutations have been reported to occur throughout the CDKL5 coding region. Several studies point to a complex CDKL5 gene structure in terms of exon usage and transcript expression. Improvements in molecular diagnosis and more extensive research into the neurobiology of CDKL5 and pathophysiology of CDKL5 disorders necessitate an updated analysis of the gene. In this study, we have analysed human and mouse CDKL5 transcript patterns both bioinformatically and experimentally. We have characterised the predominant brain isoform of CDKL5, a 9.7 kb transcript comprised of 18 exons with a large 6.6 kb 3'-untranslated region (UTR), which we name hCDKL5_1. In addition we describe new exonic regions and a range of novel splice and UTR isoforms. This has enabled the description of an updated gene model in both species and a standardised nomenclature system for CDKL5 transcripts. Profiling revealed tissue- and brain development stage-specific differences in expression between transcript isoforms. These findings provide an essential backdrop for the diagnosis of CDKL5-related disorders, for investigations into the basic biology of this gene and its protein products, and for the rational design of gene-based and molecular therapies for these disorders.

Oxytocin and vasopressin: linking pituitary neuropeptides and their receptors to social neurocircuits

PubMed Central

Baribeau, Danielle A.; Anagnostou, Evdokia

2015-01-01

Oxytocin and vasopressin are pituitary neuropeptides that have been shown to affect social processes in mammals. There is growing interest in these molecules and their receptors as potential precipitants of, and/or treatments for, social deficits in neurodevelopmental disorders, including autism spectrum disorder. Numerous behavioral-genetic studies suggest that there is an association between these peptides and individual social abilities; however, an explanatory model that links hormonal activity at the receptor level to complex human behavior remains elusive. The following review summarizes the known associations between the oxytocin and vasopressin neuropeptide systems and social neurocircuits in the brain. Following a micro- to macro- level trajectory, current literature on the synthesis and secretion of these peptides, and the structure, function and distribution of their respective receptors is first surveyed. Next, current models regarding the mechanism of action of these peptides on microcircuitry and other neurotransmitter systems are discussed. Functional neuroimaging evidence on the acute effects of exogenous administration of these peptides on brain activity is then reviewed. Overall, a model in which the local neuromodulatory effects of pituitary neuropeptides on brainstem and basal forebrain regions strengthen signaling within social neurocircuits proves appealing. However, these findings are derived from animal models; more research is needed to clarify the relevance of these mechanisms to human behavior and treatment of social deficits in neuropsychiatric disorders. PMID:26441508

Oxytocin and vasopressin: linking pituitary neuropeptides and their receptors to social neurocircuits.

PubMed

Baribeau, Danielle A; Anagnostou, Evdokia

2015-01-01

Oxytocin and vasopressin are pituitary neuropeptides that have been shown to affect social processes in mammals. There is growing interest in these molecules and their receptors as potential precipitants of, and/or treatments for, social deficits in neurodevelopmental disorders, including autism spectrum disorder. Numerous behavioral-genetic studies suggest that there is an association between these peptides and individual social abilities; however, an explanatory model that links hormonal activity at the receptor level to complex human behavior remains elusive. The following review summarizes the known associations between the oxytocin and vasopressin neuropeptide systems and social neurocircuits in the brain. Following a micro- to macro- level trajectory, current literature on the synthesis and secretion of these peptides, and the structure, function and distribution of their respective receptors is first surveyed. Next, current models regarding the mechanism of action of these peptides on microcircuitry and other neurotransmitter systems are discussed. Functional neuroimaging evidence on the acute effects of exogenous administration of these peptides on brain activity is then reviewed. Overall, a model in which the local neuromodulatory effects of pituitary neuropeptides on brainstem and basal forebrain regions strengthen signaling within social neurocircuits proves appealing. However, these findings are derived from animal models; more research is needed to clarify the relevance of these mechanisms to human behavior and treatment of social deficits in neuropsychiatric disorders.

Investigating Neuromagnetic Brain Responses against Chromatic Flickering Stimuli by Wavelet Entropies

PubMed Central

Bhagat, Mayank; Bhushan, Chitresh; Saha, Goutam; Shimjo, Shinsuke; Watanabe, Katsumi; Bhattacharya, Joydeep

2009-01-01

Background Photosensitive epilepsy is a type of reflexive epilepsy triggered by various visual stimuli including colourful ones. Despite the ubiquitous presence of colorful displays, brain responses against different colour combinations are not properly studied. Methodology/Principal Findings Here, we studied the photosensitivity of the human brain against three types of chromatic flickering stimuli by recording neuromagnetic brain responses (magnetoencephalogram, MEG) from nine adult controls, an unmedicated patient, a medicated patient, and two controls age-matched with patients. Dynamical complexities of MEG signals were investigated by a family of wavelet entropies. Wavelet entropy is a newly proposed measure to characterize large scale brain responses, which quantifies the degree of order/disorder associated with a multi-frequency signal response. In particular, we found that as compared to the unmedicated patient, controls showed significantly larger wavelet entropy values. We also found that Renyi entropy is the most powerful feature for the participant classification. Finally, we also demonstrated the effect of combinational chromatic sensitivity on the underlying order/disorder in MEG signals. Conclusions/Significance Our results suggest that when perturbed by potentially epileptic-triggering stimulus, healthy human brain manages to maintain a non-deterministic, possibly nonlinear state, with high degree of disorder, but an epileptic brain represents a highly ordered state which making it prone to hyper-excitation. Further, certain colour combination was found to be more threatening than other combinations. PMID:19779630

Investigating neuromagnetic brain responses against chromatic flickering stimuli by wavelet entropies.

PubMed

Bhagat, Mayank; Bhushan, Chitresh; Saha, Goutam; Shimjo, Shinsuke; Watanabe, Katsumi; Bhattacharya, Joydeep

2009-09-25

Photosensitive epilepsy is a type of reflexive epilepsy triggered by various visual stimuli including colourful ones. Despite the ubiquitous presence of colorful displays, brain responses against different colour combinations are not properly studied. Here, we studied the photosensitivity of the human brain against three types of chromatic flickering stimuli by recording neuromagnetic brain responses (magnetoencephalogram, MEG) from nine adult controls, an unmedicated patient, a medicated patient, and two controls age-matched with patients. Dynamical complexities of MEG signals were investigated by a family of wavelet entropies. Wavelet entropy is a newly proposed measure to characterize large scale brain responses, which quantifies the degree of order/disorder associated with a multi-frequency signal response. In particular, we found that as compared to the unmedicated patient, controls showed significantly larger wavelet entropy values. We also found that Renyi entropy is the most powerful feature for the participant classification. Finally, we also demonstrated the effect of combinational chromatic sensitivity on the underlying order/disorder in MEG signals. Our results suggest that when perturbed by potentially epileptic-triggering stimulus, healthy human brain manages to maintain a non-deterministic, possibly nonlinear state, with high degree of disorder, but an epileptic brain represents a highly ordered state which making it prone to hyper-excitation. Further, certain colour combination was found to be more threatening than other combinations.

The gut microbiota and the emergence of autoimmunity: relevance to major psychiatric disorders

PubMed Central

Severance, EG; Tveiten, D; Lindström, LH; Yolken, RH; Reichelt, KL

2017-01-01

Background Autoimmune phenotypes are prevalent in major psychiatric disorders. Disequilibria of cellular processes occurring in the gastrointestinal (GI) tract likely contribute to immune dysfunction in psychiatric disorders. As the venue of a complex community of resident microbes, the gut in a homeostatic state equates with a functional digestive system, cellular barrier stability and properly regulated recognition of self and non-self antigens. When gut processes become disrupted as a result of environmental or genetic factors, autoimmunity may ensue. Methods Here, we review the issues pertinent to autoimmunity and the microbiome in psychiatric disorders and show that many of the reported immune risk factors for the development of these brain disorders are in fact related and consistent with dysfunctions occurring in the gut. We review the few human microbiome studies that have been done in people with psychiatric disorders and supplement this information with mechanistic data gleaned from experimental rodent studies. Results These investigations demonstrate changes in behavior and brain biochemistry directly attributable to alterations in the gut microbiome. We present a model by which autoantigens are produced by extrinsically-derived food and microbial factors bound to intrinsic components of the gut including receptors present in the enteric nervous system. Conclusion This new focus on examining activities outside of the CNS for relevance to the etiology and pathophysiology of psychiatric disorders may require new modalities or a re-evaluation of pharmaceutical targets found in peripheral systems. PMID:27634185

[The facets of creativity in the light of bipolar mood alterations].

PubMed

Szakács, Réka

2018-01-30

The link between creativity, as the highest expression form of human achievement, and bipolar disorder came into focus of scientific investigations and research. Accomplished writers, composers and visual artists show a substantially higher rate of affective disorders, prodominantly bipolar mood disorders, comparing to the general population. Then again, patients afflicted with bipolar II subtype (hypomania and depression), as well as persons presenting the mildest form of bipolar mood swings (cyclothymia) possess higher creative skills. It evokes therefore that certain forms and mood states of bipolar disorder, notably hypomania might convey cognitive, emotional/affective, and motivational benefits to creativity. The aim of this paper is to display expression forms of creativity (writing, visual art, scientific work) as well as productivity (literary and scientific work output, number of artworks and exhibitions, awards) in the light of clinically diagnosed mood states at an eminent creative individual, treated for bipolar II disorder. Analysing the affective states, we found a striking relation between hypomanic episodes and visual artistic creativity and achievement, as well as scientific performance, whereas mild-moderate depressed mood promoted literary work. Severe depression and mixed states were not associated with creative activities, and intriguingly, long-term stabilised euthymic mood, exempted from marked affective lability, is disadvantageous regarding creativity. It seems, thereby, that mood functions as a sluice of creativity. Nevertheless, it is likely that there is a complex interaction between bipolar mood disorder spectrum and psychological factors promoting creativity, influenced also by individual variability due to medication, comorbid conditions, and course of disorder.

Toward a 3D model of human brain development for studying gene/environment interactions

PubMed Central

2013-01-01

This project aims to establish and characterize an in vitro model of the developing human brain for the purpose of testing drugs and chemicals. To accurately assess risk, a model needs to recapitulate the complex interactions between different types of glial cells and neurons in a three-dimensional platform. Moreover, human cells are preferred over cells from rodents to eliminate cross-species differences in sensitivity to chemicals. Previously, we established conditions to culture rat primary cells as three-dimensional aggregates, which will be humanized and evaluated here with induced pluripotent stem cells (iPSCs). The use of iPSCs allows us to address gene/environment interactions as well as the potential of chemicals to interfere with epigenetic mechanisms. Additionally, iPSCs afford us the opportunity to study the effect of chemicals during very early stages of brain development. It is well recognized that assays for testing toxicity in the developing brain must consider differences in sensitivity and susceptibility that arise depending on the time of exposure. This model will reflect critical developmental processes such as proliferation, differentiation, lineage specification, migration, axonal growth, dendritic arborization and synaptogenesis, which will probably display differences in sensitivity to different types of chemicals. Functional endpoints will evaluate the complex cell-to-cell interactions that are affected in neurodevelopment through chemical perturbation, and the efficacy of drug intervention to prevent or reverse phenotypes. The model described is designed to assess developmental neurotoxicity effects on unique processes occurring during human brain development by leveraging human iPSCs from diverse genetic backgrounds, which can be differentiated into different cell types of the central nervous system. Our goal is to demonstrate the feasibility of the personalized model using iPSCs derived from individuals with neurodevelopmental disorders caused by known mutations and chromosomal aberrations. Notably, such a human brain model will be a versatile tool for more complex testing platforms and strategies as well as research into central nervous system physiology and pathology. PMID:24564953

Identifying novel interventional strategies for psychiatric disorders: integrating genomics, 'enviromics' and gene-environment interactions in valid preclinical models.

PubMed

McOmish, Caitlin E; Burrows, Emma L; Hannan, Anthony J

2014-10-01

Psychiatric disorders affect a substantial proportion of the population worldwide. This high prevalence, combined with the chronicity of the disorders and the major social and economic impacts, creates a significant burden. As a result, an important priority is the development of novel and effective interventional strategies for reducing incidence rates and improving outcomes. This review explores the progress that has been made to date in establishing valid animal models of psychiatric disorders, while beginning to unravel the complex factors that may be contributing to the limitations of current methodological approaches. We propose some approaches for optimizing the validity of animal models and developing effective interventions. We use schizophrenia and autism spectrum disorders as examples of disorders for which development of valid preclinical models, and fully effective therapeutics, have proven particularly challenging. However, the conclusions have relevance to various other psychiatric conditions, including depression, anxiety and bipolar disorders. We address the key aspects of construct, face and predictive validity in animal models, incorporating genetic and environmental factors. Our understanding of psychiatric disorders is accelerating exponentially, revealing extraordinary levels of genetic complexity, heterogeneity and pleiotropy. The environmental factors contributing to individual, and multiple, disorders also exhibit breathtaking complexity, requiring systematic analysis to experimentally explore the environmental mediators and modulators which constitute the 'envirome' of each psychiatric disorder. Ultimately, genetic and environmental factors need to be integrated via animal models incorporating the spatiotemporal complexity of gene-environment interactions and experience-dependent plasticity, thus better recapitulating the dynamic nature of brain development, function and dysfunction. © 2014 The British Pharmacological Society.

Substance use disorders: Psychoneuroimmunological mechanisms and new targets for therapy

PubMed Central

Loftis, Jennifer M.; Huckans, Marilyn

2013-01-01

An estimated 76.4 million people worldwide meet criteria for alcohol use disorders, and 15.3 million meet criteria for drug use disorders. Given the high rates of addiction and the associated health, economic, and social costs, it is essential to develop a thorough understanding of the impact of substance abuse on mental and physical health outcomes and to identify new treatment approaches for substance use disorders (SUDs). Psychoneuroimmunology is a rapidly expanding, multidisciplinary area of research that may be of particular importance to addiction medicine, as its focus is on the dynamic and complex interactions among behavioral factors, the central nervous system, and the endocrine and immune systems (Ader, 2001). This review, therefore, focuses on: 1) the psychoneuroimmunologic effects of SUDs by substance type and use pattern, and 2) the current and future treatment strategies, including barriers that can impede successful recovery outcomes. Evidence-based psychosocial and pharmacotherapeutic treatments are reviewed. Psychological factors and central nervous system correlates that impact treatment adherence and response are discussed. Several novel therapeutic approaches that are currently under investigation are introduced; translational data from animal and human studies is presented, highlighting immunotherapy as a promising new direction for addiction medicine. PMID:23631821

Inflammasome mediated autoinflammatory disorders

PubMed Central

Wilson, Shruti P.; Cassel, Suzanne L.

2013-01-01

The nucleotide-binding domain leucine-rich repeat containing (NLR) family of receptors are members of the innate immune system with a critical role in host defense. These molecules are key to driving inflammatory responses to abnormal cellular conditions. A number of the NLRs serve this role upon activation by forming a multi-protein complex called an inflammasome. The inflammasome drives the processing and release of cytokines such as the pro-inflammatory cytokines interleukin (IL)-1β and IL-18. The important function of NLR molecules in autoinflammatory disorders has recently been recognized in part through the identification of the role of IL-1β in pathogenesis of several autoinflammatory diseases. Cryopyrin-associated periodic syndromes (CAPS) were the first autoinflammatory disorders found to be directly mediated by dysfunctional inflammasome activation. This finding has subsequently led to studies in both murine models and humans that have revealed several other inflammatory conditions associated with activation of NLR containing inflammasomes. Understanding of the molecular pathophysiology of these autoinflammatory disorders has further guided the successful development of targeted therapy against IL-1. In this review, we will provide an overview of the inflammasomes and describe the important role they play in the development and manifestations of autoinflammatory diseases. PMID:20861596

Quantifying the propagation of distress and mental disorders in social networks.

PubMed

Scatà, Marialisa; Di Stefano, Alessandro; La Corte, Aurelio; Liò, Pietro

2018-03-22

Heterogeneity of human beings leads to think and react differently to social phenomena. Awareness and homophily drive people to weigh interactions in social multiplex networks, influencing a potential contagion effect. To quantify the impact of heterogeneity on spreading dynamics, we propose a model of coevolution of social contagion and awareness, through the introduction of statistical estimators, in a weighted multiplex network. Multiplexity of networked individuals may trigger propagation enough to produce effects among vulnerable subjects experiencing distress, mental disorder, which represent some of the strongest predictors of suicidal behaviours. The exposure to suicide is emotionally harmful, since talking about it may give support or inadvertently promote it. To disclose the complex effect of the overlapping awareness on suicidal ideation spreading among disordered people, we also introduce a data-driven approach by integrating different types of data. Our modelling approach unveils the relationship between distress and mental disorders propagation and suicidal ideation spreading, shedding light on the role of awareness in a social network for suicide prevention. The proposed model is able to quantify the impact of overlapping awareness on suicidal ideation spreading and our findings demonstrate that it plays a dual role on contagion, either reinforcing or delaying the contagion outbreak.

Survival, differentiation, and neuroprotective mechanisms of human stem cells complexed with neurotrophin-3-releasing pharmacologically active microcarriers in an ex vivo model of Parkinson's disease.

PubMed

Daviaud, Nicolas; Garbayo, Elisa; Sindji, Laurence; Martínez-Serrano, Alberto; Schiller, Paul C; Montero-Menei, Claudia N

2015-06-01

Stem cell-based regenerative therapies hold great potential for the treatment of degenerative disorders such as Parkinson's disease (PD). We recently reported the repair and functional recovery after treatment with human marrow-isolated adult multilineage inducible (MIAMI) cells adhered to neurotrophin-3 (NT3) releasing pharmacologically active microcarriers (PAMs) in hemiparkinsonian rats. In order to comprehend this effect, the goal of the present work was to elucidate the survival, differentiation, and neuroprotective mechanisms of MIAMI cells and human neural stem cells (NSCs), both adhering to NT3-releasing PAMs in an ex vivo organotypic model of nigrostriatal degeneration made from brain sagittal slices. It was shown that PAMs led to a marked increase in MIAMI cell survival and neuronal differentiation when releasing NT3. A significant neuroprotective effect of MIAMI cells adhering to PAMs was also demonstrated. NSCs barely had a neuroprotective effect and differentiated mostly into dopaminergic neuronal cells when adhering to PAM-NT3. Moreover, those cells were able to release dopamine in a sufficient amount to induce a return to baseline levels. Reverse transcription-quantitative polymerase chain reaction and enzyme-linked immunosorbent assay analyses identified vascular endothelial growth factor (VEGF) and stanniocalcin-1 as potential mediators of the neuroprotective effect of MIAMI cells and NSCs, respectively. It was also shown that VEGF locally stimulated tissue vascularization, which might improve graft survival, without excluding a direct neuroprotective effect of VEGF on dopaminergic neurons. These results indicate a prospective interest of human NSC/PAM and MIAMI cell/PAM complexes in tissue engineering for PD. Stem cell-based regenerative therapies hold great potential for the treatment of degenerative disorders such as Parkinson's disease (PD). The present work elucidates and compares the survival, differentiation, and neuroprotective mechanisms of marrow-isolated adult multilineage inducible cells and human neural stem cells both adhered to neurotrophin-3-releasing pharmacologically active microcarriers in an ex vivo organotypic model of PD made from brain sagittal slices. ©AlphaMed Press.

mTOR signaling: at the crossroads of plasticity, memory and disease.

PubMed

Hoeffer, Charles A; Klann, Eric

2010-02-01

Mammalian target of rapamycin (mTOR) is a protein kinase involved in translation control and long-lasting synaptic plasticity. mTOR functions as the central component of two multi-protein signaling complexes, mTORC1 and mTORC2, which can be distinguished from each other based on their unique compositions and substrates. Although the majority of evidence linking mTOR function to synaptic plasticity comes from studies utilizing rapamycin, studies in genetically modified mice also suggest that mTOR couples receptors to the translation machinery for establishing long-lasting synaptic changes that are the basis for higher order brain function, including long-term memory. Finally, perturbation of the mTOR signaling cascade appears to be a common pathophysiological feature of human neurological disorders, including mental retardation syndromes and autism spectrum disorders. (c) 2009 Elsevier Ltd. All rights reserved.

[Charles Miller Fisher: the grandmaster of neurological observation].

PubMed

Fukutake, Toshio

2014-11-01

Charles Miller Fisher is widely regarded as the father of modern stroke neurology. He discovered almost all pathomechanisms of cerebral infarction, including embolism from atrial fibrillation, carotid artery disease, and lacunar infarcts and their syndromes, by the most meticulous clinico-pathological observations. Moreover, his work provided the basis for treatments such as anticoagulation, antiplatelet therapy, and carotid endarterectomy. He also contributed greatly to several topics of General Neurology; for example, migraine, normal pressure hydrocephalus, and Miller Fisher syndrome. In his late years, he tried to expand the neurological field to the more complex disorders of human behavior, including hysteria, dementia, and ill-defined pain syndromes. He thus became known as the grandmaster of refined neurological observation. His lifelong detailed studies were crucially important in helping neurologists all over the world recognize disorders and syndromes that had not previously been understood.

Interactive Social Neuroscience to Study Autism Spectrum Disorder

PubMed Central

Rolison, Max J.; Naples, Adam J.; McPartland, James C.

2015-01-01

Individuals with autism spectrum disorder (ASD) demonstrate difficulty with social interactions and relationships, but the neural mechanisms underlying these difficulties remain largely unknown. While social difficulties in ASD are most apparent in the context of interactions with other people, most neuroscience research investigating ASD have provided limited insight into the complex dynamics of these interactions. The development of novel, innovative “interactive social neuroscience” methods to study the brain in contexts with two interacting humans is a necessary advance for ASD research. Studies applying an interactive neuroscience approach to study two brains engaging with one another have revealed significant differences in neural processes during interaction compared to observation in brain regions that are implicated in the neuropathology of ASD. Interactive social neuroscience methods are crucial in clarifying the mechanisms underlying the social and communication deficits that characterize ASD. PMID:25745371

Immune complex-mediated autoimmunity in a patient With Smith-Magenis syndrome (del 17p11.2).

PubMed

Yang, Jianying; Chandrasekharappa, Settara C; Vilboux, Thierry; Smith, Ann C M; Peterson, Erik J

2014-08-01

Smith-Magenis syndrome (SMS) is a sporadic congenital disorder involving multiple organ systems caused by chromosome 17p11.2 deletions. Smith-Magenis syndrome features craniofacial and skeletal anomalies, cognitive impairment, and neurobehavioral abnormalities. In addition, some SMS patients may exhibit hypogammaglobulinemia. We report the first case of SMS-associated autoimmunity in a woman who presented with adult onset of multiple autoimmune disorders, including systemic lupus erythematosus, antiphospholipid antibody syndrome, and autoimmune hepatitis. Molecular analysis using single-nucleotide polymorphism array confirmed a de novo 3.8-Mb deletion (breakpoints, chr17: 16,660,721-20,417,975), resulting in haploinsufficiency for TACI (transmembrane activator and CAML interactor). Our data are consistent with potential loss of function for the BAFF (B cell-activating factor) receptor TACI as a contributing factor to human autoimmune phenomena.

mTOR Signaling: At the Crossroads of Plasticity, Memory, and Disease

PubMed Central

Hoeffer, Charles A.; Klann, Eric

2009-01-01

Mammalian target of rapamycin (mTOR) is a protein kinase involved in translation control and long-lasting synaptic plasticity. mTOR functions as the central component of two multi-protein signaling complexes, mTORC1 and mTORC2, which can be distinguished from each other based on their unique compositions and substrates. Although majority of evidence linking mTOR function to synaptic plasticity comes from studies utilizing rapamycin, studies in genetically-modified mice also suggest that mTOR couples receptors to the translation machinery for establishing long-lasting synaptic changes that are the basis for higher order brain function, including long-term memory. Finally, perturbation of the mTOR signaling cascade appears to be a common pathophysiological feature of human neurological disorders, including mental retardation syndromes and autism spectrum disorders. PMID:19963289

Molecular targets of alcohol action: translational research for pharmacotherapy development and screening

PubMed Central

Gorini, Giorgio; Bell, Richard L.; Mayfield, R. Dayne

2016-01-01

Summary Alcohol abuse and dependence are multifaceted disorders with neurobiological, psychological, and environmental components. Research on other complex neuropsychiatric diseases suggests that genetically influenced intermediate characteristics affect the risk for heavy alcohol consumption and its consequences. Diverse therapeutic interventions can be developed through identification of reliable biomarkers for this disorder and new pharmacological targets for its treatment. Advances in the fields of genomics and proteomics offer a number of possible targets for the development of new therapeutic approaches. This brain-focused review highlights studies identifying neurobiological systems associated with these targets and possible pharmacotherapies, summarizing evidence from clinically relevant animal and human studies, as well as sketching improvements and challenges facing the fields of proteomics and genomics. Concluding thoughts on using results from these profiling technologies for medication development are also presented. PMID:21199775

Interactive social neuroscience to study autism spectrum disorder.

PubMed

Rolison, Max J; Naples, Adam J; McPartland, James C

2015-03-01

Individuals with autism spectrum disorder (ASD) demonstrate difficulty with social interactions and relationships, but the neural mechanisms underlying these difficulties remain largely unknown. While social difficulties in ASD are most apparent in the context of interactions with other people, most neuroscience research investigating ASD have provided limited insight into the complex dynamics of these interactions. The development of novel, innovative "interactive social neuroscience" methods to study the brain in contexts with two interacting humans is a necessary advance for ASD research. Studies applying an interactive neuroscience approach to study two brains engaging with one another have revealed significant differences in neural processes during interaction compared to observation in brain regions that are implicated in the neuropathology of ASD. Interactive social neuroscience methods are crucial in clarifying the mechanisms underlying the social and communication deficits that characterize ASD.

AP1S3 mutations are associated with pustular psoriasis and impaired Toll-like receptor 3 trafficking.

PubMed

Setta-Kaffetzi, Niovi; Simpson, Michael A; Navarini, Alexander A; Patel, Varsha M; Lu, Hui-Chun; Allen, Michael H; Duckworth, Michael; Bachelez, Hervé; Burden, A David; Choon, Siew-Eng; Griffiths, Christopher E M; Kirby, Brian; Kolios, Antonios; Seyger, Marieke M B; Prins, Christa; Smahi, Asma; Trembath, Richard C; Fraternali, Franca; Smith, Catherine H; Barker, Jonathan N; Capon, Francesca

2014-05-01

Adaptor protein complex 1 (AP-1) is an evolutionary conserved heterotetramer that promotes vesicular trafficking between the trans-Golgi network and the endosomes. The knockout of most murine AP-1 complex subunits is embryonically lethal, so the identification of human disease-associated alleles has the unique potential to deliver insights into gene function. Here, we report two founder mutations (c.11T>G [p.Phe4Cys] and c.97C>T [p.Arg33Trp]) in AP1S3, the gene encoding AP-1 complex subunit σ1C, in 15 unrelated individuals with a severe autoinflammatory skin disorder known as pustular psoriasis. Because the variants are predicted to destabilize the 3D structure of the AP-1 complex, we generated AP1S3-knockdown cell lines to investigate the consequences of AP-1 deficiency in skin keratinocytes. We found that AP1S3 silencing disrupted the endosomal translocation of the innate pattern-recognition receptor TLR-3 (Toll-like receptor 3) and resulted in a marked inhibition of downstream signaling. These findings identify pustular psoriasis as an autoinflammatory phenotype caused by defects in vesicular trafficking and demonstrate a requirement of AP-1 for Toll-like receptor homeostasis. Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Dependent personality features in a complex case of borderline personality disorder.

PubMed

Nirestean, Tudor; Lukacs, Emese; Nirestean, Aurel; Gabos Grecu, Iosif

2016-11-01

Borderline personality disorder is a complex disease model as it encompasses a diversity of pathological personality traits and psychopathological symptoms. It is not surprising, therefore, that it is often manifested by personality disorders across all three clusters and accompanied by other mental (Axis I) disorders. This melange makes both psychological treatment and pharmacotherapy especially challenging, and this paper describes the case of a particularly complex case of a 33-year-old Romanian patient, who has a history of severe deprivation in childhood, mood and substance use disorder in association with borderline pathology. In the course of treatment from many sources and interventions, it has become clear that dependence is a key component of the pathology and has been rewarded with a degree of success in management. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Protein disorder in the human diseasome: unfoldomics of human genetic diseases

PubMed Central

Midic, Uros; Oldfield, Christopher J; Dunker, A Keith; Obradovic, Zoran; Uversky, Vladimir N

2009-01-01

Background Intrinsically disordered proteins lack stable structure under physiological conditions, yet carry out many crucial biological functions, especially functions associated with regulation, recognition, signaling and control. Recently, human genetic diseases and related genes were organized into a bipartite graph (Goh KI, Cusick ME, Valle D, Childs B, Vidal M, et al. (2007) The human disease network. Proc Natl Acad Sci U S A 104: 8685–8690). This diseasome network revealed several significant features such as the common genetic origin of many diseases. Methods and findings We analyzed the abundance of intrinsic disorder in these diseasome network proteins by means of several prediction algorithms, and we analyzed the functional repertoires of these proteins based on prior studies relating disorder to function. Our analyses revealed that (i) Intrinsic disorder is common in proteins associated with many human genetic diseases; (ii) Different disease classes vary in the IDP contents of their associated proteins; (iii) Molecular recognition features, which are relatively short loosely structured protein regions within mostly disordered sequences and which gain structure upon binding to partners, are common in the diseasome, and their abundance correlates with the intrinsic disorder level; (iv) Some disease classes have a significant fraction of genes affected by alternative splicing, and the alternatively spliced regions in the corresponding proteins are predicted to be highly disordered; and (v) Correlations were found among the various diseasome graph-related properties and intrinsic disorder. Conclusion These observations provide the basis for the construction of the human-genetic-disease-associated unfoldome. PMID:19594871

Acute movement disorders in the medical setting.

PubMed

Zawar, Ifrah; Caro, Mario A; Feldman, Lara; Jimenez, Xavier F

2016-07-01

Objective Psychosomatic medicine psychiatrists are often tasked with the evaluation and treatment of complex neuropsychiatric states which may be motoric in phenotype. Little energy has been dedicated to understanding acute movement disorders in the hospital environment. Method Recognizing the importance of frontal-subcortical (corticostriatothalamocortical) circuitry and basal ganglia structures, we present a case series of acute movement disorder phenotypes resulting from underlying medical conditions, commonly-administered medications, or the interaction of both. We organize these scenarios into neurodegenerative disorders, primary psychiatric disorders, neuroinflammation, and polypharmacy, demonstrating a clinical example of each followed by background references on a variety of clinical states and medications contributing to acute movement disorders. In addition, we offer visual illustration of implicated neurocircuitry as well as proposed neurotransmitter imbalances involving glutamate, gamma aminobutyric acid, and dopamine. Furthermore, we review the various clinical syndromes and medications involved in the development of acute movement disorders. Results Acute movement disorder's involve complex interactions between frontal-subcortical circuits and acute events. Given the complexity of interactions, psychopharmacological considerations become critical, as some treatments may alleviate acute movement disorders while others will exacerbate them. Conclusion Integrating underlying medical conditions and acutely administered (or discontinued) pharmacological agents offers an interactional, neuromedical approach to acute movement disorders that is critical to the work of psychosomatic medicine.

A Non-Degenerate Code of Deleterious Variants in Mendelian Loci Contributes to Complex Disease Risk

PubMed Central

Blair, David R.; Lyttle, Christopher S.; Mortensen, Jonathan M.; Bearden, Charles F.; Jensen, Anders Boeck; Khiabanian, Hossein; Melamed, Rachel; Rabadan, Raul; Bernstam, Elmer V.; Brunak, Søren; Jensen, Lars Juhl; Nicolae, Dan; Shah, Nigam H.; Grossman, Robert L.; Cox, Nancy J.; White, Kevin P.; Rzhetsky, Andrey

2013-01-01

Summary Whereas countless highly penetrant variants have been associated with Mendelian disorders, the genetic etiologies underlying complex diseases remain largely unresolved. Here, we examine the extent to which Mendelian variation contributes to complex disease risk by mining the medical records of over 110 million patients. We detect thousands of associations between Mendelian and complex diseases, revealing a non-degenerate, phenotypic code that links each complex disorder to a unique collection of Mendelian loci. Using genome-wide association results, we demonstrate that common variants associated with complex diseases are enriched in the genes indicated by this “Mendelian code.” Finally, we detect hundreds of comorbidity associations among Mendelian disorders, and we use probabilistic genetic modeling to demonstrate that Mendelian variants likely contribute non-additively to the risk for a subset of complex diseases. Overall, this study illustrates a complementary approach for mapping complex disease loci and provides unique predictions concerning the etiologies of specific diseases. PMID:24074861

XX Disorder of Sex Development is associated with an insertion on chromosome 9 and downregulation of RSPO1 in dogs (Canis lupus familiaris).

PubMed

Meyers-Wallen, Vicki N; Boyko, Adam R; Danko, Charles G; Grenier, Jennifer K; Mezey, Jason G; Hayward, Jessica J; Shannon, Laura M; Gao, Chuan; Shafquat, Afrah; Rice, Edward J; Pujar, Shashikant; Eggers, Stefanie; Ohnesorg, Thomas; Sinclair, Andrew H

2017-01-01

Remarkable progress has been achieved in understanding the mechanisms controlling sex determination, yet the cause for many Disorders of Sex Development (DSD) remains unknown. Of particular interest is a rare XX DSD subtype in which individuals are negative for SRY, the testis determining factor on the Y chromosome, yet develop testes or ovotestes, and both of these phenotypes occur in the same family. This is a naturally occurring disorder in humans (Homo sapiens) and dogs (C. familiaris). Phenotypes in the canine XX DSD model are strikingly similar to those of the human XX DSD subtype. The purposes of this study were to identify 1) a variant associated with XX DSD in the canine model and 2) gene expression alterations in canine embryonic gonads that could be informative to causation. Using a genome wide association study (GWAS) and whole genome sequencing (WGS), we identified a variant on C. familiaris autosome 9 (CFA9) that is associated with XX DSD in the canine model and in affected purebred dogs. This is the first marker identified for inherited canine XX DSD. It lies upstream of SOX9 within the canine ortholog for the human disorder, which resides on 17q24. Inheritance of this variant indicates that XX DSD is a complex trait in which breed genetic background affects penetrance. Furthermore, the homozygous variant genotype is associated with embryonic lethality in at least one breed. Our analysis of gene expression studies (RNA-seq and PRO-seq) in embryonic gonads at risk of XX DSD from the canine model identified significant RSPO1 downregulation in comparison to XX controls, without significant upregulation of SOX9 or other known testis pathway genes. Based on these data, a novel mechanism is proposed in which molecular lesions acting upstream of RSPO1 induce epigenomic gonadal mosaicism.

XX Disorder of Sex Development is associated with an insertion on chromosome 9 and downregulation of RSPO1 in dogs (Canis lupus familiaris)

PubMed Central

Boyko, Adam R.; Grenier, Jennifer K.; Mezey, Jason G.; Hayward, Jessica J.; Shannon, Laura M.; Gao, Chuan; Shafquat, Afrah; Rice, Edward J.; Eggers, Stefanie; Ohnesorg, Thomas; Sinclair, Andrew H.

2017-01-01

Remarkable progress has been achieved in understanding the mechanisms controlling sex determination, yet the cause for many Disorders of Sex Development (DSD) remains unknown. Of particular interest is a rare XX DSD subtype in which individuals are negative for SRY, the testis determining factor on the Y chromosome, yet develop testes or ovotestes, and both of these phenotypes occur in the same family. This is a naturally occurring disorder in humans (Homo sapiens) and dogs (C. familiaris). Phenotypes in the canine XX DSD model are strikingly similar to those of the human XX DSD subtype. The purposes of this study were to identify 1) a variant associated with XX DSD in the canine model and 2) gene expression alterations in canine embryonic gonads that could be informative to causation. Using a genome wide association study (GWAS) and whole genome sequencing (WGS), we identified a variant on C. familiaris autosome 9 (CFA9) that is associated with XX DSD in the canine model and in affected purebred dogs. This is the first marker identified for inherited canine XX DSD. It lies upstream of SOX9 within the canine ortholog for the human disorder, which resides on 17q24. Inheritance of this variant indicates that XX DSD is a complex trait in which breed genetic background affects penetrance. Furthermore, the homozygous variant genotype is associated with embryonic lethality in at least one breed. Our analysis of gene expression studies (RNA-seq and PRO-seq) in embryonic gonads at risk of XX DSD from the canine model identified significant RSPO1 downregulation in comparison to XX controls, without significant upregulation of SOX9 or other known testis pathway genes. Based on these data, a novel mechanism is proposed in which molecular lesions acting upstream of RSPO1 induce epigenomic gonadal mosaicism. PMID:29053721

Small-world human brain networks: Perspectives and challenges.

PubMed

Liao, Xuhong; Vasilakos, Athanasios V; He, Yong

2017-06-01

Modelling the human brain as a complex network has provided a powerful mathematical framework to characterize the structural and functional architectures of the brain. In the past decade, the combination of non-invasive neuroimaging techniques and graph theoretical approaches enable us to map human structural and functional connectivity patterns (i.e., connectome) at the macroscopic level. One of the most influential findings is that human brain networks exhibit prominent small-world organization. Such a network architecture in the human brain facilitates efficient information segregation and integration at low wiring and energy costs, which presumably results from natural selection under the pressure of a cost-efficiency balance. Moreover, the small-world organization undergoes continuous changes during normal development and ageing and exhibits dramatic alterations in neurological and psychiatric disorders. In this review, we survey recent advances regarding the small-world architecture in human brain networks and highlight the potential implications and applications in multidisciplinary fields, including cognitive neuroscience, medicine and engineering. Finally, we highlight several challenging issues and areas for future research in this rapidly growing field. Copyright © 2017 Elsevier Ltd. All rights reserved.

Is it a tic or Tourette's? Clues for differentiating simple from more complex tic disorders.

PubMed

Evidente, V G

2000-10-01

Tics are characterized by sterotyped, purposeless, and irregularly repetitive movements and usually can be classified as chronic motor or vocal tic disorders, transient tic disorders, or Tourette's syndrome. The latter is a complex disorder associated with multiple tics and often accompanied by other conditions, such as ADHD and obsessive-compulsive disorder. Treatment can be difficult, and drug therapy should begin with agents least likely to cause problems for the patient. Education of the patient and family and support from the physician and other care providers are essential elements of effective management.

Human difference in the genomic era: Facilitating a socially responsible dialogue

PubMed Central

2010-01-01

Background The study of human genetic variation has been advanced by research such as genome-wide association studies, which aim to identify variants associated with common, complex diseases and traits. Significant strides have already been made in gleaning information on susceptibility, treatment, and prevention of a number of disorders. However, as genetic researchers continue to uncover underlying differences between individuals, there is growing concern that observed population-level differences will be inappropriately generalized as inherent to particular racial or ethnic groups and potentially perpetuate negative stereotypes. Discussion We caution that imprecision of language when conveying research conclusions, compounded by the potential distortion of findings by the media, can lead to the stigmatization of racial and ethnic groups. Summary It is essential that the scientific community and with those reporting and disseminating research findings continue to foster a socially responsible dialogue about genetic variation and human difference. PMID:20504336

Muscle Coordination and Locomotion in Humans.

PubMed

Sylos-Labini, Francesca; Zago, Myrka; Guertin, Pierre A; Lacquaniti, Francesco; Ivanenko, Yury P

2017-01-01

Locomotion is a semi-automatic daily task. Several studies show that muscle activity is fairly stereotyped during normal walking. Nevertheless, each human leg contains over 50 muscles and locomotion requires flexibility in order to adapt to different conditions as, for instance, different speeds, gaits, turning, obstacle avoidance, altered gravity levels, etc. Therefore, locomotor control has to deal with a certain level of flexibility and non-linearity. In this review, we describe and discuss different findings dealing with both simplicity and variability of the muscular control, as well as with its maturation during development. Despite complexity and redundancy, muscle activity patterns and spatiotemporal maps of spinal motoneuron output during human locomotion show both stereotypical features as well as functional re-organization. Flexibility and different solutions to adjust motor patterns should be considered when considering new rehabilitation strategies to treat disorders involving deficits in gait. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Multi-platform ’Omics Analysis of Human Ebola Virus Disease Pathogenesis

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

Eisfeld, Amie J.; Halfmann, Peter J.; Wendler, Jason P.

The pathogenesis of human Ebola virus disease (EVD) is complex. EVD is characterized by high levels of virus replication and dissemination, dysregulated immune responses, extensive virus- and host-mediated tissue damage, and disordered coagulation. To clarify how host responses contribute to EVD pathophysiology, we performed multi-platform ’omics analysis of peripheral blood mononuclear cells and plasma from EVD patients. Our results indicate that EVD molecular signatures overlap with those of sepsis, imply that pancreatic enzymes contribute to tissue damage in fatal EVD, and suggest that Ebola virus infection may induce aberrant neutrophils whose activity could explain hallmarks of fatal EVD. Moreover, integratedmore » biomarker prediction identified putative biomarkers from different data platforms that differentiated survivors and fatalities early after infection. This work reveals insight into EVD pathogenesis, suggests an effective approach for biomarker identification, and provides an important community resource for further analysis of human EVD severity.« less

Multi-platform 'Omics Analysis of Human Ebola Virus Disease Pathogenesis.

PubMed

Eisfeld, Amie J; Halfmann, Peter J; Wendler, Jason P; Kyle, Jennifer E; Burnum-Johnson, Kristin E; Peralta, Zuleyma; Maemura, Tadashi; Walters, Kevin B; Watanabe, Tokiko; Fukuyama, Satoshi; Yamashita, Makoto; Jacobs, Jon M; Kim, Young-Mo; Casey, Cameron P; Stratton, Kelly G; Webb-Robertson, Bobbie-Jo M; Gritsenko, Marina A; Monroe, Matthew E; Weitz, Karl K; Shukla, Anil K; Tian, Mingyuan; Neumann, Gabriele; Reed, Jennifer L; van Bakel, Harm; Metz, Thomas O; Smith, Richard D; Waters, Katrina M; N'jai, Alhaji; Sahr, Foday; Kawaoka, Yoshihiro

2017-12-13

The pathogenesis of human Ebola virus disease (EVD) is complex. EVD is characterized by high levels of virus replication and dissemination, dysregulated immune responses, extensive virus- and host-mediated tissue damage, and disordered coagulation. To clarify how host responses contribute to EVD pathophysiology, we performed multi-platform 'omics analysis of peripheral blood mononuclear cells and plasma from EVD patients. Our results indicate that EVD molecular signatures overlap with those of sepsis, imply that pancreatic enzymes contribute to tissue damage in fatal EVD, and suggest that Ebola virus infection may induce aberrant neutrophils whose activity could explain hallmarks of fatal EVD. Moreover, integrated biomarker prediction identified putative biomarkers from different data platforms that differentiated survivors and fatalities early after infection. This work reveals insight into EVD pathogenesis, suggests an effective approach for biomarker identification, and provides an important community resource for further analysis of human EVD severity. Copyright © 2017 Elsevier Inc. All rights reserved.

Synthesis, delivery and regulation of eukaryotic heme and Fe-S cluster cofactors.

PubMed

Barupala, Dulmini P; Dzul, Stephen P; Riggs-Gelasco, Pamela Jo; Stemmler, Timothy L

2016-02-15

In humans, the bulk of iron in the body (over 75%) is directed towards heme- or Fe-S cluster cofactor synthesis, and the complex, highly regulated pathways in place to accomplish biosynthesis have evolved to safely assemble and load these cofactors into apoprotein partners. In eukaryotes, heme biosynthesis is both initiated and finalized within the mitochondria, while cellular Fe-S cluster assembly is controlled by correlated pathways both within the mitochondria and within the cytosol. Iron plays a vital role in a wide array of metabolic processes and defects in iron cofactor assembly leads to human diseases. This review describes progress towards our molecular-level understanding of cellular heme and Fe-S cluster biosynthesis, focusing on the regulation and mechanistic details that are essential for understanding human disorders related to the breakdown in these essential pathways. Copyright © 2016 Elsevier Inc. All rights reserved.

Levels of Social Sharing and Clinical Implications for Severe Social Withdrawal in Patients with Personality Disorders

PubMed Central

Colle, Livia; Pellecchia, Giovanni; Moroni, Fabio; Carcione, Antonino; Nicolò, Giuseppe; Semerari, Antonio; Procacci, Michele

2017-01-01

Social sharing capacities have attracted attention from a number of fields of social cognition and have been variously defined and analyzed in numerous studies. Social sharing consists in the subjective awareness that aspects of the self’s experience are held in common with other individuals. The definition of social sharing must take a variety of elements into consideration: the motivational element, the contents of the social sharing experience, the emotional responses it evokes, the behavioral outcomes, and finally, the circumstances and the skills which enable social sharing. The primary objective of this study is to explore some of the diverse forms of human social sharing and to classify them according to levels of complexity. We identify four different types of social sharing, categorized according to the nature of the content being shared and the complexity of the mindreading skills required. The second objective of this study is to consider possible applications of this graded model of social sharing experience in clinical settings. Specifically, this model may support the development of graded, focused clinical interventions for patients with personality disorders characterized by severe social withdrawal. PMID:29255430

Tuberous Sclerosis Associated Neuropsychiatric Disorders (TAND) and the TAND Checklist

PubMed Central

de Vries, Petrus J.; Whittemore, Vicky H.; Leclezio, Loren; Byars, Anna W.; Dunn, David; Ess, Kevin C.; Hook, Dena; King, Bryan H.; Sahin, Mustafa; Jansen, Anna

2015-01-01

BACKGROUND Tuberous sclerosis complex is a multisystem genetic disorder with a range of physical manifestations that require evaluation, surveillance, and management. Individuals with tuberous sclerosis complex also have a range of behavioral, psychiatric, intellectual, academic, neuropsychologic, and psychosocial difficulties. These may represent the greatest burden of the disease. Around 90% of individuals with tuberous sclerosis complex will have some of these difficulties during their lifetime, yet only about 20% ever receive evaluation and treatment. The Neuropsychiatry Panel at the 2012 Tuberous Sclerosis Complex International Consensus Conference expressed concern about the significant “treatment gap” and about confusion regarding terminology relating to the biopsychosocial difficulties associated with tuberous sclerosis complex. METHODS The Tuberous Sclerosis Complex Neuropsychiatry Panel coined the term TAND—tuberous sclerosis complex-associated neuropsychiatric disorders—to bring together these multidimensional manifestations of the disorder, and recommended annual screening for TAND. In addition, the Panel agreed to develop a TAND Checklist as a guide for screening. RESULTS Here, we present an outline of the conceptualization of TAND, rationale for the structure of the TAND Checklist, and include the full US English version of the TAND Checklist. CONCLUSION We hope that the unified term TAND and the TAND Checklist will raise awareness of the importance of tuberous sclerosis complex-associated neuropsychiatric disorders and of the major burden of disease associated with it, provide a shared language and a simple tool to describe and evaluate the different levels of TAND, alert clinical teams and families or individuals of the importance of screening, assessment, and treatment of TAND, and provide a shared framework for future studies of tuberous sclerosis complex-associated neuropsychiatric disorders. PMID:25532776

Linking Human Health and Livestock Health: A “One-Health” Platform for Integrated Analysis of Human Health, Livestock Health, and Economic Welfare in Livestock Dependent Communities

PubMed Central

Thumbi, S. M.; Njenga, M. Kariuki; Marsh, Thomas L.; Noh, Susan; Otiang, Elkanah; Munyua, Peninah; Ochieng, Linus; Ogola, Eric; Yoder, Jonathan; Audi, Allan; Montgomery, Joel M.; Bigogo, Godfrey; Breiman, Robert F.; Palmer, Guy H.; McElwain, Terry F.

2015-01-01

Background For most rural households in sub-Saharan Africa, healthy livestock play a key role in averting the burden associated with zoonotic diseases, and in meeting household nutritional and socio-economic needs. However, there is limited understanding of the complex nutritional, socio-economic, and zoonotic pathways that link livestock health to human health and welfare. Here we describe a platform for integrated human health, animal health and economic welfare analysis designed to address this challenge. We provide baseline epidemiological data on disease syndromes in humans and the animals they keep, and provide examples of relationships between human health, animal health and household socio-economic status. Method We designed a study to obtain syndromic disease data in animals along with economic and behavioral information for 1500 rural households in Western Kenya already participating in a human syndromic disease surveillance study. Data collection started in February 2013, and each household is visited bi-weekly and data on four human syndromes (fever, jaundice, diarrhea and respiratory illness) and nine animal syndromes (death, respiratory, reproductive, musculoskeletal, nervous, urogenital, digestive, udder disorders, and skin disorders in cattle, sheep, goats and chickens) are collected. Additionally, data from a comprehensive socio-economic survey is collected every 3 months in each of the study households. Findings Data from the first year of study showed 93% of the households owned at least one form of livestock (55%, 19%, 41% and 88% own cattle, sheep, goats and chickens respectively). Digestive disorders, mainly diarrhea episodes, were the most common syndromes observed in cattle, goats and sheep, accounting for 56% of all livestock syndromes, followed by respiratory illnesses (18%). In humans, respiratory illnesses accounted for 54% of all illnesses reported, followed by acute febrile illnesses (40%) and diarrhea illnesses (5%). While controlling for household size, the incidence of human illness increased 1.31-fold for every 10 cases of animal illness or death observed (95% CI 1.16–1.49). Access and utilization of animal source foods such as milk and eggs were positively associated with the number of cattle and chickens owned by the household. Additionally, health care seeking was correlated with household incomes and wealth, which were in turn correlated with livestock herd size. Conclusion This study platform provides a unique longitudinal dataset that allows for the determination and quantification of linkages between human and animal health, including the impact of healthy animals on human disease averted, malnutrition, household educational attainment, and income levels. PMID:25798951

Linking human health and livestock health: a "one-health" platform for integrated analysis of human health, livestock health, and economic welfare in livestock dependent communities.

PubMed

Thumbi, S M; Njenga, M Kariuki; Marsh, Thomas L; Noh, Susan; Otiang, Elkanah; Munyua, Peninah; Ochieng, Linus; Ogola, Eric; Yoder, Jonathan; Audi, Allan; Montgomery, Joel M; Bigogo, Godfrey; Breiman, Robert F; Palmer, Guy H; McElwain, Terry F

2015-01-01

For most rural households in sub-Saharan Africa, healthy livestock play a key role in averting the burden associated with zoonotic diseases, and in meeting household nutritional and socio-economic needs. However, there is limited understanding of the complex nutritional, socio-economic, and zoonotic pathways that link livestock health to human health and welfare. Here we describe a platform for integrated human health, animal health and economic welfare analysis designed to address this challenge. We provide baseline epidemiological data on disease syndromes in humans and the animals they keep, and provide examples of relationships between human health, animal health and household socio-economic status. We designed a study to obtain syndromic disease data in animals along with economic and behavioral information for 1500 rural households in Western Kenya already participating in a human syndromic disease surveillance study. Data collection started in February 2013, and each household is visited bi-weekly and data on four human syndromes (fever, jaundice, diarrhea and respiratory illness) and nine animal syndromes (death, respiratory, reproductive, musculoskeletal, nervous, urogenital, digestive, udder disorders, and skin disorders in cattle, sheep, goats and chickens) are collected. Additionally, data from a comprehensive socio-economic survey is collected every 3 months in each of the study households. Data from the first year of study showed 93% of the households owned at least one form of livestock (55%, 19%, 41% and 88% own cattle, sheep, goats and chickens respectively). Digestive disorders, mainly diarrhea episodes, were the most common syndromes observed in cattle, goats and sheep, accounting for 56% of all livestock syndromes, followed by respiratory illnesses (18%). In humans, respiratory illnesses accounted for 54% of all illnesses reported, followed by acute febrile illnesses (40%) and diarrhea illnesses (5%). While controlling for household size, the incidence of human illness increased 1.31-fold for every 10 cases of animal illness or death observed (95% CI 1.16-1.49). Access and utilization of animal source foods such as milk and eggs were positively associated with the number of cattle and chickens owned by the household. Additionally, health care seeking was correlated with household incomes and wealth, which were in turn correlated with livestock herd size. This study platform provides a unique longitudinal dataset that allows for the determination and quantification of linkages between human and animal health, including the impact of healthy animals on human disease averted, malnutrition, household educational attainment, and income levels.

NMR backbone assignments of the tyrosine kinase domain of human fibroblast growth factor receptor 3 in apo state and in complex with inhibitor PD173074.

PubMed

Sanfelice, Domenico; Koss, Hans; Bunney, Tom D; Thompson, Gary S; Farrell, Brendan; Katan, Matilda; Breeze, Alexander L

2018-03-26

Fibroblast growth factors receptors (FGFR) are transmembrane protein tyrosine kinases involved in many cellular process, including growth, differentiation and angiogenesis. Dysregulation of FGFR enzymatic activity is associated with developmental disorders and cancers; therefore FGFRs have become attractive targets for drug discovery, with a number of agents in late-stage clinical trials. Here, we present the backbone resonance assignments of FGFR3 tyrosine kinase domain in the ligand-free form and in complex with the canonical FGFR kinase inhibitor PD173074. Analysis of chemical shift changes upon inhibitor binding highlights a characteristic pattern of allosteric network perturbations that is of relevance for future drug discovery activities aimed at development of conformationally-selective FGFR inhibitors.

Power-law scaling for macroscopic entropy and microscopic complexity: Evidence from human movement and posture

NASA Astrophysics Data System (ADS)

Hong, S. Lee; Bodfish, James W.; Newell, Karl M.

2006-03-01

We investigated the relationship between macroscopic entropy and microscopic complexity of the dynamics of body rocking and sitting still across adults with stereotyped movement disorder and mental retardation (profound and severe) against controls matched for age, height, and weight. This analysis was performed through the examination of center of pressure (COP) motion on the mediolateral (side-to-side) and anteroposterior (fore-aft) dimensions and the entropy of the relative phase between the two dimensions of motion. Intentional body rocking and stereotypical body rocking possessed similar slopes for their respective frequency spectra, but differences were revealed during maintenance of sitting postures. The dynamics of sitting in the control group produced lower spectral slopes and higher complexity (approximate entropy). In the controls, the higher complexity found on each dimension of motion was related to a weaker coupling between dimensions. Information entropy of the relative phase between the two dimensions of COP motion and irregularity (complexity) of their respective motions fitted a power-law function, revealing a relationship between macroscopic entropy and microscopic complexity across both groups and behaviors. This power-law relation affords the postulation that the organization of movement and posture dynamics occurs as a fractal process.

Human exposure to endocrine disrupting chemicals: effects on the male and female reproductive systems.

PubMed

Sifakis, Stavros; Androutsopoulos, Vasilis P; Tsatsakis, Aristeidis M; Spandidos, Demetrios A

2017-04-01

Endocrine disrupting chemicals (EDCs) comprise a group of chemical compounds that have been examined extensively due to the potential harmful effects in the health of human populations. During the past decades, particular focus has been given to the harmful effects of EDCs to the reproductive system. The estimation of human exposure to EDCs can be broadly categorized into occupational and environmental exposure, and has been a major challenge due to the structural diversity of the chemicals that are derived by many different sources at doses below the limit of detection used by conventional methodologies. Animal and in vitro studies have supported the conclusion that endocrine disrupting chemicals affect the hormone dependent pathways responsible for male and female gonadal development, either through direct interaction with hormone receptors or via epigenetic and cell-cycle regulatory modes of action. In human populations, the majority of the studies point towards an association between exposure to EDCs and male and/or female reproduction system disorders, such as infertility, endometriosis, breast cancer, testicular cancer, poor sperm quality and/or function. Despite promising discoveries, a causal relationship between the reproductive disorders and exposure to specific toxicants is yet to be established, due to the complexity of the clinical protocols used, the degree of occupational or environmental exposure, the determination of the variables measured and the sample size of the subjects examined. Future studies should focus on a uniform system of examining human populations with regard to the exposure to specific EDCs and the direct effect on the reproductive system. Copyright © 2017 Elsevier B.V. All rights reserved.

An Intrinsically Disordered APLF Links Ku, DNA-PKcs, and XRCC4-DNA Ligase IV in an Extended Flexible Non-homologous End Joining Complex

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

Hammel, Michal; Yu, Yaping; Radhakrishnan, Sarvan K.

DNA double-strand break (DSB) repair by non-homologous end joining (NHEJ) in human cells is initiated by Ku heterodimer binding to a DSB, followed by recruitment of core NHEJ factors including DNA-dependent protein kinase catalytic subunit (DNA-PKcs), XRCC4-like factor (XLF), and XRCC4 (X4)-DNA ligase IV (L4). Ku also interacts with accessory factors such as aprataxin and polynucleotide kinase/phosphatase-like factor (APLF). But, how these factors interact to tether, process, and ligate DSB ends while allowing regulation and chromatin interactions remains enigmatic. Here, small angle X-ray scattering (SAXS) and mutational analyses show APLF is largely an intrinsically disordered protein that binds Ku, Ku/DNA-PKcsmore » (DNA-PK), and X4L4 within an extended flexible NHEJ core complex. X4L4 assembles with Ku heterodimers linked to DNA-PKcs via flexible Ku80 C-terminal regions (Ku80CTR) in a complex stabilized through APLF interactions with Ku, DNA-PK, and X4L4. Our collective results unveil the solution architecture of the six-protein complex and suggest cooperative assembly of an extended flexible NHEJ core complex that supports APLF accessibility while possibly providing flexible attachment of the core complex to chromatin. The resulting dynamic tethering furthermore, provides geometric access of L4 catalytic domains to the DNA ends during ligation and of DNA-PKcs for targeted phosphorylation of other NHEJ proteins as well as trans-phosphorylation of DNA-PKcs on the opposing DSB without disrupting the core ligation complex. Overall the results shed light on evolutionary conservation of Ku, X4, and L4 activities, while explaining the observation that Ku80CTR and DNA-PKcs only occur in a subset of higher eukaryotes.« less

An Intrinsically Disordered APLF Links Ku, DNA-PKcs, and XRCC4-DNA Ligase IV in an Extended Flexible Non-homologous End Joining Complex

DOE PAGES

Hammel, Michal; Yu, Yaping; Radhakrishnan, Sarvan K.; ...

2016-11-14

DNA double-strand break (DSB) repair by non-homologous end joining (NHEJ) in human cells is initiated by Ku heterodimer binding to a DSB, followed by recruitment of core NHEJ factors including DNA-dependent protein kinase catalytic subunit (DNA-PKcs), XRCC4-like factor (XLF), and XRCC4 (X4)-DNA ligase IV (L4). Ku also interacts with accessory factors such as aprataxin and polynucleotide kinase/phosphatase-like factor (APLF). But, how these factors interact to tether, process, and ligate DSB ends while allowing regulation and chromatin interactions remains enigmatic. Here, small angle X-ray scattering (SAXS) and mutational analyses show APLF is largely an intrinsically disordered protein that binds Ku, Ku/DNA-PKcsmore » (DNA-PK), and X4L4 within an extended flexible NHEJ core complex. X4L4 assembles with Ku heterodimers linked to DNA-PKcs via flexible Ku80 C-terminal regions (Ku80CTR) in a complex stabilized through APLF interactions with Ku, DNA-PK, and X4L4. Our collective results unveil the solution architecture of the six-protein complex and suggest cooperative assembly of an extended flexible NHEJ core complex that supports APLF accessibility while possibly providing flexible attachment of the core complex to chromatin. The resulting dynamic tethering furthermore, provides geometric access of L4 catalytic domains to the DNA ends during ligation and of DNA-PKcs for targeted phosphorylation of other NHEJ proteins as well as trans-phosphorylation of DNA-PKcs on the opposing DSB without disrupting the core ligation complex. Overall the results shed light on evolutionary conservation of Ku, X4, and L4 activities, while explaining the observation that Ku80CTR and DNA-PKcs only occur in a subset of higher eukaryotes.« less

Mutations in B4GALNT1 (GM2 synthase) underlie a new disorder of ganglioside biosynthesis.

PubMed

Harlalka, Gaurav V; Lehman, Anna; Chioza, Barry; Baple, Emma L; Maroofian, Reza; Cross, Harold; Sreekantan-Nair, Ajith; Priestman, David A; Al-Turki, Saeed; McEntagart, Meriel E; Proukakis, Christos; Royle, Louise; Kozak, Radoslaw P; Bastaki, Laila; Patton, Michael; Wagner, Karin; Coblentz, Roselyn; Price, Joy; Mezei, Michelle; Schlade-Bartusiak, Kamilla; Platt, Frances M; Hurles, Matthew E; Crosby, Andrew H

2013-12-01

Glycosphingolipids are ubiquitous constituents of eukaryotic plasma membranes, and their sialylated derivatives, gangliosides, are the major class of glycoconjugates expressed by neurons. Deficiencies in their catabolic pathways give rise to a large and well-studied group of inherited disorders, the lysosomal storage diseases. Although many glycosphingolipid catabolic defects have been defined, only one proven inherited disease arising from a defect in ganglioside biosynthesis is known. This disease, because of defects in the first step of ganglioside biosynthesis (GM3 synthase), results in a severe epileptic disorder found at high frequency amongst the Old Order Amish. Here we investigated an unusual neurodegenerative phenotype, most commonly classified as a complex form of hereditary spastic paraplegia, present in families from Kuwait, Italy and the Old Order Amish. Our genetic studies identified mutations in B4GALNT1 (GM2 synthase), encoding the enzyme that catalyzes the second step in complex ganglioside biosynthesis, as the cause of this neurodegenerative phenotype. Biochemical profiling of glycosphingolipid biosynthesis confirmed a lack of GM2 in affected subjects in association with a predictable increase in levels of its precursor, GM3, a finding that will greatly facilitate diagnosis of this condition. With the description of two neurological human diseases involving defects in two sequentially acting enzymes in ganglioside biosynthesis, there is the real possibility that a previously unidentified family of ganglioside deficiency diseases exist. The study of patients and animal models of these disorders will pave the way for a greater understanding of the role gangliosides play in neuronal structure and function and provide insights into the development of effective treatment therapies.

The Pleiotropic MET Receptor Network: Circuit Development and the Neural-Medical Interface of Autism.

PubMed

Eagleson, Kathie L; Xie, Zhihui; Levitt, Pat

2017-03-01

People with autism spectrum disorder and other neurodevelopmental disorders (NDDs) are behaviorally and medically heterogeneous. The combination of polygenicity and gene pleiotropy-the influence of one gene on distinct phenotypes-raises questions of how specific genes and their protein products interact to contribute to NDDs. A preponderance of evidence supports developmental and pathophysiological roles for the MET receptor tyrosine kinase, a multifunctional receptor that mediates distinct biological responses depending upon cell context. MET influences neuron architecture and synapse maturation in the forebrain and regulates homeostasis in gastrointestinal and immune systems, both commonly disrupted in NDDs. Peak expression of synapse-enriched MET is conserved across rodent and primate forebrain, yet regional differences in primate neocortex are pronounced, with enrichment in circuits that participate in social information processing. A functional risk allele in the MET promoter, enriched in subgroups of children with autism spectrum disorder, reduces transcription and disrupts socially relevant neural circuits structurally and functionally. In mice, circuit-specific deletion of Met causes distinct atypical behaviors. MET activation increases dendritic complexity and nascent synapse number, but synapse maturation requires reductions in MET. MET mediates its specific biological effects through different intracellular signaling pathways and has a complex protein interactome that is enriched in autism spectrum disorder and other NDD candidates. The interactome is coregulated in developing human neocortex. We suggest that a gene as pleiotropic and highly regulated as MET, together with its interactome, is biologically relevant in normal and pathophysiological contexts, affecting central and peripheral phenotypes that contribute to NDD risk and clinical symptoms. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

[Basic disorders in human communication].

PubMed

Peñaloza-López, Y; Gutiérrez-Silva, J; Andrade-Illañez, E N; Fierro-Evans, M A; Hernández-López, X

1989-01-01

This paper specifies the areas and disorders that concern human communication medicine. The frequency of the diverse disorders is analyzed in relation to age and sex, and the distribution in group ages of several disabling diseases is also discussed.

Testing Brain Overgrowth and Synaptic Models of Autism Using NPC’s and Neurons from Patient-Derived IPS Cells

DTIC Science & Technology

2014-10-01

Release; Distribution Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT Autism and autism spectrum disorders (ASD) are complex neurodevelopmental ...1. INTRODUCTION: Autism and autism spectrum disorders (ASD) are complex neurodevelopmental diseases that affect about 1% of children in the...and neurons. 2. KEYWORDS: Autism spectrum disorder, ASD, neurodevelopmental disease, disease modeling, induced pluripotent stem cell, iPS

Functional Analysis of Human Hub Proteins and Their Interactors Involved in the Intrinsic Disorder-Enriched Interactions

PubMed Central

Hu, Gang; Wu, Zhonghua

2017-01-01

Some of the intrinsically disordered proteins and protein regions are promiscuous interactors that are involved in one-to-many and many-to-one binding. Several studies have analyzed enrichment of intrinsic disorder among the promiscuous hub proteins. We extended these works by providing a detailed functional characterization of the disorder-enriched hub protein-protein interactions (PPIs), including both hubs and their interactors, and by analyzing their enrichment among disease-associated proteins. We focused on the human interactome, given its high degree of completeness and relevance to the analysis of the disease-linked proteins. We quantified and investigated numerous functional and structural characteristics of the disorder-enriched hub PPIs, including protein binding, structural stability, evolutionary conservation, several categories of functional sites, and presence of over twenty types of posttranslational modifications (PTMs). We showed that the disorder-enriched hub PPIs have a significantly enlarged number of disordered protein binding regions and long intrinsically disordered regions. They also include high numbers of targeting, catalytic, and many types of PTM sites. We empirically demonstrated that these hub PPIs are significantly enriched among 11 out of 18 considered classes of human diseases that are associated with at least 100 human proteins. Finally, we also illustrated how over a dozen specific human hubs utilize intrinsic disorder for their promiscuous PPIs. PMID:29257115

Impact of the gut microbiota on inflammation, obesity, and metabolic disease.

PubMed

Boulangé, Claire L; Neves, Ana Luisa; Chilloux, Julien; Nicholson, Jeremy K; Dumas, Marc-Emmanuel

2016-04-20

The human gut harbors more than 100 trillion microbial cells, which have an essential role in human metabolic regulation via their symbiotic interactions with the host. Altered gut microbial ecosystems have been associated with increased metabolic and immune disorders in animals and humans. Molecular interactions linking the gut microbiota with host energy metabolism, lipid accumulation, and immunity have also been identified. However, the exact mechanisms that link specific variations in the composition of the gut microbiota with the development of obesity and metabolic diseases in humans remain obscure owing to the complex etiology of these pathologies. In this review, we discuss current knowledge about the mechanistic interactions between the gut microbiota, host energy metabolism, and the host immune system in the context of obesity and metabolic disease, with a focus on the importance of the axis that links gut microbes and host metabolic inflammation. Finally, we discuss therapeutic approaches aimed at reshaping the gut microbial ecosystem to regulate obesity and related pathologies, as well as the challenges that remain in this area.

Auditory-motor interactions in pediatric motor speech disorders: neurocomputational modeling of disordered development.

PubMed

Terband, H; Maassen, B; Guenther, F H; Brumberg, J

2014-01-01

Differentiating the symptom complex due to phonological-level disorders, speech delay and pediatric motor speech disorders is a controversial issue in the field of pediatric speech and language pathology. The present study investigated the developmental interaction between neurological deficits in auditory and motor processes using computational modeling with the DIVA model. In a series of computer simulations, we investigated the effect of a motor processing deficit alone (MPD), and the effect of a motor processing deficit in combination with an auditory processing deficit (MPD+APD) on the trajectory and endpoint of speech motor development in the DIVA model. Simulation results showed that a motor programming deficit predominantly leads to deterioration on the phonological level (phonemic mappings) when auditory self-monitoring is intact, and on the systemic level (systemic mapping) if auditory self-monitoring is impaired. These findings suggest a close relation between quality of auditory self-monitoring and the involvement of phonological vs. motor processes in children with pediatric motor speech disorders. It is suggested that MPD+APD might be involved in typically apraxic speech output disorders and MPD in pediatric motor speech disorders that also have a phonological component. Possibilities to verify these hypotheses using empirical data collected from human subjects are discussed. The reader will be able to: (1) identify the difficulties in studying disordered speech motor development; (2) describe the differences in speech motor characteristics between SSD and subtype CAS; (3) describe the different types of learning that occur in the sensory-motor system during babbling and early speech acquisition; (4) identify the neural control subsystems involved in speech production; (5) describe the potential role of auditory self-monitoring in developmental speech disorders. Copyright © 2014 Elsevier Inc. All rights reserved.

A Multilevel Functional Study of a SNAP25 At-Risk Variant for Bipolar Disorder and Schizophrenia.

PubMed

Houenou, Josselin; Boisgontier, Jennifer; Henrion, Annabelle; d'Albis, Marc-Antoine; Dumaine, Anne; Linke, Julia; Wessa, Michèle; Daban, Claire; Hamdani, Nora; Delavest, Marine; Llorca, Pierre-Michel; Lançon, Christophe; Schürhoff, Franck; Szöke, Andrei; Le Corvoisier, Philippe; Barau, Caroline; Poupon, Cyril; Etain, Bruno; Leboyer, Marion; Jamain, Stéphane

2017-10-25

The synaptosomal-associated protein SNAP25 is a key player in synaptic vesicle docking and fusion and has been associated with multiple psychiatric conditions, including schizophrenia, bipolar disorder, and attention-deficit/hyperactivity disorder. We recently identified a promoter variant in SNAP25 , rs6039769 , that is associated with early-onset bipolar disorder and a higher gene expression level in human prefrontal cortex. In the current study, we showed that this variant was associated both in males and females with schizophrenia in two independent cohorts. We then combined in vitro and in vivo approaches in humans to understand the functional impact of the at-risk allele. Thus, we showed in vitro that the rs6039769 C allele was sufficient to increase the SNAP25 transcription level. In a postmortem expression analysis of 33 individuals affected with schizophrenia and 30 unaffected control subjects, we showed that the SNAP25b / SNAP25a ratio was increased in schizophrenic patients carrying the rs6039769 at-risk allele. Last, using genetics imaging in a cohort of 71 subjects, we showed that male risk carriers had an increased amygdala-ventromedial prefrontal cortex functional connectivity and a larger amygdala than non-risk carriers. The latter association has been replicated in an independent cohort of 121 independent subjects. Altogether, results from these multilevel functional studies are bringing strong evidence for the functional consequences of this allelic variation of SNAP25 on modulating the development and plasticity of the prefrontal-limbic network, which therefore may increase the vulnerability to both early-onset bipolar disorder and schizophrenia. SIGNIFICANCE STATEMENT Functional characterization of disease-associated variants is a key challenge in understanding neuropsychiatric disorders and will open an avenue in the development of personalized treatments. Recent studies have accumulated evidence that the SNARE complex, and more specifically the SNAP25 protein, may be involved in psychiatric disorders. Here, our multilevel functional studies are bringing strong evidence for the functional consequences of an allelic variation of SNAP25 on modulating the development and plasticity of the prefrontal-limbic network. These results demonstrate a common genetically driven functional alteration of a synaptic mechanism both in schizophrenia and early-onset bipolar disorder and confirm the shared genetic vulnerability between these two disorders. Copyright © 2017 the authors 0270-6474/17/3710390-09$15.00/0.

High-resolution temporal and regional mapping of MAPT expression and splicing in human brain development.

PubMed

Hefti, Marco M; Farrell, Kurt; Kim, SoongHo; Bowles, Kathryn R; Fowkes, Mary E; Raj, Towfique; Crary, John F

2018-01-01

The microtubule associated protein tau plays a critical role in the pathogenesis of neurodegenerative disease. Recent studies suggest that tau also plays a role in disorders of neuronal connectivity, including epilepsy and post-traumatic stress disorder. Animal studies have shown that the MAPT gene, which codes for the tau protein, undergoes complex pre-mRNA alternative splicing to produce multiple isoforms during brain development. Human data, particularly on temporal and regional variation in tau splicing during development are however lacking. In this study, we present the first detailed examination of the temporal and regional sequence of MAPT alternative splicing in the developing human brain. We used a novel computational analysis of large transcriptomic datasets (total n = 502 patients), quantitative polymerase chain reaction (qPCR) and western blotting to examine tau expression and splicing in post-mortem human fetal, pediatric and adult brains. We found that MAPT exons 2 and 10 undergo abrupt shifts in expression during the perinatal period that are unique in the canonical human microtubule-associated protein family, while exon 3 showed small but significant temporal variation. Tau isoform expression may be a marker of neuronal maturation, temporally correlated with the onset of axonal growth. Immature brain regions such as the ganglionic eminence and rhombic lip had very low tau expression, but within more mature regions, there was little variation in tau expression or splicing. We thus demonstrate an abrupt, evolutionarily conserved shift in tau isoform expression during the human perinatal period that may be due to tau expression in maturing neurons. Alternative splicing of the MAPT pre-mRNA may play a vital role in normal brain development across multiple species and provides a basis for future investigations into the developmental and pathological functions of the tau protein.

A humanoid mouse model of autism.

PubMed

Takumi, Toru

2010-10-01

Even now fruit of the human genome project is available, we have difficulties to approach neuropsychiatric disorders at the molecular level. Autism is a complex psychiatric illness but has received considerable attention as a developmental brain disorder not only from basic researchers but also from society. Substantial evidence suggests that chromosomal abnormalities contribute to autism risk. The duplication of human chromosome 15q11-13 is known to be the most frequent cytogenetic abnormality in autism. We succeeded to generate mice with a 6.3-Mb-wide interstitial duplication in mouse chromosome 7c that is highly syntenic to human 15q11-13 by using a Cre-loxP-based chromosome-engineering technique. The only paternally duplicated mice display autistic behavioral features such as poor social interaction and stereotypical behavior, and exhibit a developmental abnormality in ultrasonic vocalizations as well as anxiety. The detailed analysis focusing on a non-coding small nucleolar RNA, MBII52, within the duplicated region, revealed that the paternally duplicated mice alter the editing ratio of serotonin (5-HT) 2c receptor pre-mRNA and intracellular calcium responses by a 5-HT2c receptor specific agonist are changed in neurons. This result may explain one of molecular mechanisms of abnormal behaviors in the paternal duplicated mice. The first chromosome-engineered mouse model for human chromosome 15q11-13 duplication fulfills not only face validity of human autistic phenotypes but also construct validity based on human chromosome abnormality. This model will be a founder mouse for forward genetics of autistic disease and an invaluable tool for its therapeutic development. Copyright © 2010 Elsevier B.V. All rights reserved.

Genetics Home Reference: seasonal affective disorder

MedlinePlus

... seasonal affective disorder are complex. A shortage of sunlight contributes to the development of the disorder in the fall and winter months, and too much sunlight is associated with seasonal affective disorder in the ...

Crystal Structure of Human [Beta]-Hexosaminidase B: Understanding the Molecular Basis of Sandhoff and Tay-Sachs Disease

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

Mark, Brian L.; Mahuran, Don J.; Cherney, Maia M.

2010-12-01

In humans, two major {beta}-hexosaminidase isoenzymes exist: Hex A and Hex B. Hex A is a heterodimer of subunits {alpha} and {beta} (60% identity), whereas Hex B is a homodimer of {beta}-subunits. Interest in human {beta}-hexosaminidase stems from its association with Tay-Sachs and Sandhoff disease; these are prototypical lysosomal storage disorders resulting from the abnormal accumulation of G{sub M2}-ganglioside (G{sub M2}). Hex A degrades G{sub M2} by removing a terminal N-acetyl-D-galactosamine ({beta}-GalNAc) residue, and this activity requires the G{sub M2}-activator, a protein which solubilizes the ganglioside for presentation to Hex A. We present here the crystal structure of human Hexmore » B, alone (2.4 {angstrom}) and in complex with the mechanistic inhibitors GalNAc-isofagomine (2.2 {angstrom}) or NAG-thiazoline (2.5 {angstrom}). From these, and the known X-ray structure of the G{sub M2}-activator, we have modeled Hex A in complex with the activator and ganglioside. Together, our crystallographic and modeling data demonstrate how {alpha} and {beta}-subunits dimerize to form either Hex A or Hex B, how these isoenzymes hydrolyze diverse substrates, and how many documented point mutations cause Sandhoff disease ({beta}-subunit mutations) and Tay-Sachs disease ({alpha}-subunit mutations).« less

MicroRNA-211 Regulates Oxidative Phosphorylation and Energy Metabolism in Human Vitiligo.

PubMed

Sahoo, Anupama; Lee, Bongyong; Boniface, Katia; Seneschal, Julien; Sahoo, Sanjaya K; Seki, Tatsuya; Wang, Chunyan; Das, Soumen; Han, Xianlin; Steppie, Michael; Seal, Sudipta; Taieb, Alain; Perera, Ranjan J

2017-09-01

Vitiligo is a common chronic skin disorder characterized by loss of epidermal melanocytes and progressive depigmentation. Vitiligo has complex immune, genetic, environmental, and biochemical causes, but the exact molecular mechanisms of vitiligo development and progression, particularly those related to metabolic control, are poorly understood. In this study we characterized the human vitiligo cell line PIG3V and the normal human melanocyte line HEM-l by RNA sequencing, targeted metabolomics, and shotgun lipidomics. Melanocyte-enriched microRNA-211, a known metabolic switch in nonpigmented melanoma cells, was severely down-regulated in vitiligo cell line PIG3V and skin biopsy samples from vitiligo patients, whereas its predicted targets PPARGC1A, RRM2, and TAOK1 were reciprocally up-regulated. microRNA-211 binds to PGC1-α 3' untranslated region locus and represses it. Although mitochondrial numbers were constant, mitochondrial complexes I, II, and IV and respiratory responses were defective in vitiligo cells. Nanoparticle-coated microRNA-211 partially augmented the oxygen consumption rate in PIG3V cells. The lower oxygen consumption rate, changes in lipid and metabolite profiles, and increased reactive oxygen species production observed in vitiligo cells appear to be partly due to abnormal regulation of microRNA-211 and its target genes. These genes represent potential biomarkers and therapeutic targets in human vitiligo. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Dystonia and Paroxysmal Dyskinesias: Under-Recognized Movement Disorders in Domestic Animals? A Comparison with Human Dystonia/Paroxysmal Dyskinesias.

PubMed

Richter, Angelika; Hamann, Melanie; Wissel, Jörg; Volk, Holger A

2015-01-01

Dystonia is defined as a neurological syndrome characterized by involuntary sustained or intermittent muscle contractions causing twisting, often repetitive movements, and postures. Paroxysmal dyskinesias are episodic movement disorders encompassing dystonia, chorea, athetosis, and ballism in conscious individuals. Several decades of research have enhanced the understanding of the etiology of human dystonia and dyskinesias that are associated with dystonia, but the pathophysiology remains largely unknown. The spontaneous occurrence of hereditary dystonia and paroxysmal dyskinesia is well documented in rodents used as animal models in basic dystonia research. Several hyperkinetic movement disorders, described in dogs, horses and cattle, show similarities to these human movement disorders. Although dystonia is regarded as the third most common movement disorder in humans, it is often misdiagnosed because of the heterogeneity of etiology and clinical presentation. Since these conditions are poorly known in veterinary practice, their prevalence may be underestimated in veterinary medicine. In order to attract attention to these movement disorders, i.e., dystonia and paroxysmal dyskinesias associated with dystonia, and to enhance interest in translational research, this review gives a brief overview of the current literature regarding dystonia/paroxysmal dyskinesia in humans and summarizes similar hereditary movement disorders reported in domestic animals.

Aberrant expression of long noncoding RNAs in autistic brain.

PubMed

Ziats, Mark N; Rennert, Owen M

2013-03-01

The autism spectrum disorders (ASD) have a significant hereditary component, but the implicated genetic loci are heterogeneous and complex. Consequently, there is a gap in understanding how diverse genomic aberrations all result in one clinical ASD phenotype. Gene expression studies from autism brain tissue have demonstrated that aberrantly expressed protein-coding genes may converge onto common molecular pathways, potentially reconciling the strong heritability and shared clinical phenotypes with the genomic heterogeneity of the disorder. However, the regulation of gene expression is extremely complex and governed by many mechanisms, including noncoding RNAs. Yet no study in ASD brain tissue has assessed for changes in regulatory long noncoding RNAs (lncRNAs), which represent a large proportion of the human transcriptome, and actively modulate mRNA expression. To assess if aberrant expression of lncRNAs may play a role in the molecular pathogenesis of ASD, we profiled over 33,000 annotated lncRNAs and 30,000 mRNA transcripts from postmortem brain tissue of autistic and control prefrontal cortex and cerebellum by microarray. We detected over 200 differentially expressed lncRNAs in ASD, which were enriched for genomic regions containing genes related to neurodevelopment and psychiatric disease. Additionally, comparison of differences in expression of mRNAs between prefrontal cortex and cerebellum within individual donors showed ASD brains had more transcriptional homogeneity. Moreover, this was also true of the lncRNA transcriptome. Our results suggest that further investigation of lncRNA expression in autistic brain may further elucidate the molecular pathogenesis of this disorder.

Psycho-Cognitive Intervention for ASD from Cross-Species Behavioral Analyses of Infants, Chicks and Common Marmosets.

PubMed

Koshiba, Mamiko; Karino, Genta; Mimura, Koki; Nakamura, Shun; Yui, Kunio; Kunikata, Tetsuya; Yamanouchi, Hideo

2016-01-01

Educational treatment to support social development of children with autism spectrum disorder (ASD) is an important topic in developmental psychiatry. However, it remains difficult to objectively quantify the socio-emotional development of ASD children. To address this problem, we developed a novel analytical method that assesses subjects' complex behaviors using multivariate analysis, 'Behavior Output analysis for Quantitative Emotional State Translation' (BOUQUET). Here, we examine the potential for psycho-cognitive ASD therapy based on comparative evaluations of clinical (human) and experimental (animal) models. Our observations of ASD children (vs. their normally developing siblings) and the domestic chick in socio-sensory deprivation models show the importance of unimodal sensory stimulation, particularly important for tactile- and auditory-biased socialization. Identifying psycho-cognitive elements in early neural development, human newborn infants in neonatal intensive care unit as well as a New World monkey, the common marmoset, also prompted us to focus on the development of voluntary movement against gravity. In summary, striking behavioral similarities between children with ASD and domestic chicks' socio-sensory deprivation models support the role of multimodal sensory-motor integration as a prerequisite step for normal development of socio-emotional and psycho-cognitive functions. Data obtained in the common marmoset model also suggest that switching from primitive anti-gravity reflexes to complex voluntary movement may be a critical milestone for psycho-cognitive development. Combining clinical findings with these animal models, and using multivariate integrative analyses may facilitate the development of effective interventions to improve social functions in infants and in children with neurodevelopmental disorders.

Epigenetic regulation of osteogenesis: human embryonic palatal mesenchymal cells.

PubMed

Barkhordarian, Andre; Sison, Jay; Cayabyab, Riana; Mahanian, Nicole; Chiappelli, Francesco

2011-01-06

Mesenchymal stem cells (MSCs) provide an appropriate model to study epigenetic changes during osteogenesis and bone regeneration due to their differentiation potential. Since there are no unique markers for MSCs, methods of identification are limited. The complex morphology of human embryonic palatal mesenchyme stem cell (HEPM) requires analysis of fractal dimensions to provide an objective quantification of self-similarity, a statistical transformation of cellular shape and border complexity. We propose the hypothesis of a study to compare and contrast sequential steps of osteogenic differentiation in HEPMs both phenotypically using immunocytochemistry, and morphometrically using fractal analysis from undifferentiated passage 1 (P1) to passage 7 (P7) cells. The proof-of-concept is provided by results we present here that identify and compare the modulation of expression of certain epigenetic biomarkers (alkaline phosphatase, ALP; stromal interaction molecule-1, STRO-1; runt-related transcription factor-2, RUNX2), which are established markers of osteogenesis in bone marrow studies, of osteoblastic/skeletal morphogenesis, and of osteoblast maturation. We show that Osteoinductive medium (OIM) modulates the rate of differentiation of HEPM into Run-2+ cells, the most differentiated subpopulation, followed by ALP+ and STRO-1+ cells. Taken together, our phenotypical and morphometric data demonstrate the feasibility of using HEPM to assess osteogenic differentiation from an early undifferentiated to a differentiated stage. This research model may lay the foundation for future studies aimed at characterizing the epigenetic characteristics of osteoimmunological disorders and dysfunctions (e.g., osteoarthritis, temporomandibular joint disorders), so that proteomic profiling can aid the diagnosis and monitor the prognosis of these and other osteoimmunopathologies.

[Vojta's method as the early neurodevelopmental diagnosis and therapy concept].

PubMed

Banaszek, Grazyna

2010-01-01

Vaclav Vojta (1917-2000) developed an early diagnostic method of the neurodevelopmental disorder of infants and came up with therapeutic concept consisting in releasing of global motor complexes by means of the stimulation of proper areas on patients body. In the diagnostics apart from very careful observation of the spontaneous movement of the infant and examination of the reflexes that are characteristic for the first weeks of human's life, Vojta applied the examination of the 7 postural reactions. Presence of the trouble in patterns and dynamics of the postural reactions Vojta called Central Nervous Coordination Disorder--CNCD and regarded as work diagnosis or alarm signal indicating necessity of application of the therapy, especially when asymmetry of the muscle tone and primitive reflexes beyond their physiological appearance period are observed or the number of the abnormal reactions exceeds 5. Global motor complexes as reflex locomotion--crawling and rotation--consist of all the partial motion patterns, which are gradually used by healthy infant in the process of postural and motor ontogenesis. Providing the central nervous system with proper external stimulation allows to, using neuronal plasticity, recreate an access to the human's postural development program and gradually replace pathological motor patterns by those more regular. Exercises repeated several times a day rebuilt support, erectile and vertical mechanisms, improve automatic postural control and phase lower limb movement. Affecting especially on autochtonic muscles of the spine exercises balance synergic cooperation of muscle groups in the trunk and those surrounding key body joints. This way they correct body's posture and peripheral motion and pathology of the outlasted primitive reflexes gradually withdraws.

Diagnosis of complex acid-base disorders: physician performance versus the microcomputer.

PubMed

Schreck, D M; Zacharias, D; Grunau, C F

1986-02-01

Patients with acid-base disturbances that are often complex frequently present to the emergency department. The sometimes hectic nature of the ED can preclude the appropriate quantitative analysis required by these disorders, especially when mixed disturbances are present. A computer program using generally accepted acid-base and electrolyte formulae was developed for use on the Apple II+ or IBM-PC microcomputer. Each of a series of 35 acid-base disturbances incorporating single, double, and triple disorders was correctly identified by the computer in less than 45 seconds. Problem sets based on the same 35 disturbances were presented to 21 physician-subjects at various levels of training from the emergency medicine, internal medicine, pediatrics, surgery, and family practice specialties. Although the physicians were given unlimited time and the necessary formulae to reach a diagnosis, they were requested to perform their analyses in the same fashion used in the ED. Although times varied widely, no physician spent more than five minutes on any problem. The physician correct response rates were 86%, 49%, and 17% for single, double, and triple disorders, respectively. The primary disorder correct response rate was 89% for double disorders and 94% for triple disorders. The primary and secondary disorder correct response rate was 58% for triple disorders. The data suggest that the microcomputer may be beneficial in the rapid assessment of complex disorders.

A novel diagnostic tool reveals mitochondrial pathology in human diseases and aging.

PubMed

Scheibye-Knudsen, Morten; Scheibye-Alsing, Karsten; Canugovi, Chandrika; Croteau, Deborah L; Bohr, Vilhelm A

2013-03-01

The inherent complex and pleiotropic phenotype of mitochondrial diseases poses a significant diagnostic challenge for clinicians as well as an analytical barrier for scientists. To overcome these obstacles we compiled a novel database, www.mitodb.com, containing the clinical features of primary mitochondrial diseases. Based on this we developed a number of qualitative and quantitative measures, enabling us to determine whether a disorder can be characterized as mitochondrial. These included a clustering algorithm, a disease network, a mitochondrial barcode and two scoring algorithms. Using these tools we detected mitochondrial involvement in a number of diseases not previously recorded as mitochondrial. As a proof of principle Cockayne syndrome, ataxia with oculomotor apraxia 1 (AOA1), spinocerebellar ataxia with axonal neuropathy 1 (SCAN1) and ataxia-telangiectasia have recently been shown to have mitochondrial dysfunction and those diseases showed strong association with mitochondrial disorders. We next evaluated mitochondrial involvement in aging and detected two distinct categories of accelerated aging disorders, one of them being associated with mitochondrial dysfunction. Normal aging seemed to associate stronger with the mitochondrial diseases than the non-mitochondrial partially supporting a mitochondrial theory of aging.

An outbreak of illness among aerospace workers.

PubMed Central

Sparks, P. J.; Simon, G. E.; Katon, W. J.; Altman, L. C.; Ayars, G. H.; Johnson, R. L.

1990-01-01

A multispecialty panel of physicians evaluated a case series of 53 composite-materials workers in a large aircraft manufacturing facility who filed workers' compensation claims for illness labeled by the media as the "aerospace syndrome." Possible skin and respiratory tract exposures included formaldehyde, phenol, particulates, epoxy resins, and trace organic solvents, but measured concentrations were well below all regulatory and consensus standards. Most workers had histories of transient skin or respiratory tract irritation consistent with the known potential toxicity of these materials. None of the workers tested had immunoglobulin IgG or IgE antibodies to human serum albumin complexed with formaldehyde. A majority (74%) met DSM-III-R [Diagnostic and Statistical Manual of Mental Disorders, 3rd edition, revised] criteria for major depression, panic disorder, or both. Most of these psychiatric disorders were of a recent onset, correlating in time with the use of phenol- and formaldehyde-impregnated composite material. Psychosocial factors were thought to have played a major role in the high prevalence of illness in this group and should be evaluated directly in well-controlled epidemiologic studies of similar crisis-building situations in the future. PMID:2098006

Oxytocin and vasopressin systems in genetic syndromes and neurodevelopmental disorders

PubMed Central

Francis, S.M.; Sagar, A.; Levin-Decanini, T.; Liu, W.; Carter, C.S.; Jacob, S.

2015-01-01

Oxytocin (OT) and arginine vasopressin (AVP) are two small, related neuropeptide hormones found in many mammalian species, including humans. Dysregulation of these neuropeptides have been associated with changes in behavior, especially social interactions. We review how the OT and AVP systems have been investigated in Autism Spectrum Disorder (ASD), Prader–Willi Syndrome (PWS), Williams Syndrome (WS) and Fragile X syndrome (FXS). All of these neurodevelopmental disorders (NDD) are marked by social deficits. While PWS, WS and FXS have identified genetic mutations, ASD stems from multiple genes with complex interactions. Animal models of NDD are invaluable for studying the role and relatedness of OT and AVP in the developing brain. We present data from a FXS mouse model affecting the fragile X mental retardation 1 (Fmr1) gene, resulting in decreased OT and AVP staining cells in some brain regions. Reviewing the research about OT and AVP in these NDD suggests that altered OT pathways may be downstream from different etiological factors and perturbations in development. This has implications for ongoing studies of the therapeutic application of OT in NDD. PMID:24462936

Melatonin in Children with Autism Spectrum Disorders: How Does the Evidence Fit Together?

PubMed

Veatch, Olivia J; Goldman, Suzanne E; Adkins, Karen W; Malow, Beth A

Autism spectrum disorders (ASD) are prevalent neurodevelopmental conditions, affecting 1 in 68 children in the United States alone. Sleep disturbance, particularly insomnia, is very common in children diagnosed with ASD, with evidence supporting overlapping neurobiological and genetic underpinnings. One of the most well studied mechanisms related to ASD and insomnia is dysregulation of the melatonin pathway, which has been observed in many individuals with ASD compared to typically developing controls. Furthermore, variation in genes whose products regulate endogenous melatonin modify sleep patterns in humans and have also been implicated in some cases of ASD. However, the relationship between comorbid insomnia, melatonin processing, and genes that regulate endogenous melatonin levels in ASD is complex and requires further study to fully elucidate. The aim of this review is to provide an overview of the current findings related to the effects of genetic variation in the melatonergic pathway on risk for expression of sleep disorders in children with ASD. In addition, functional findings related to endogenous levels of melatonin and pharmacokinetic profiles in this patient population are evaluated.

Structure/function implications in a dynamic complex of the intrinsically disordered Sic1 with the Cdc4 subunit of an SCF ubiquitin ligase

PubMed Central

Mittag, Tanja; Marsh, Joseph; Grishaev, Alexander; Orlicky, Stephen; Lin, Hong; Sicheri, Frank; Tyers, Mike; Forman-Kay, Julie D.

2010-01-01

Summary Intrinsically disordered proteins can form highly dynamic complexes with partner proteins. One such dynamic complex involves the intrinsically disordered Sic1 with its partner Cdc4 in regulation of yeast cell cycle progression. Phosphorylation of six N-terminal Sic1 sites leads to equilibrium engagement of each phosphorylation site with the primary binding pocket in Cdc4, the substrate recognition subunit of a ubiquitin ligase. ENSEMBLE calculations utilizing experimental NMR and small-angle x-ray scattering data reveal significant transient structure in both phosphorylation states of the isolated ensembles (Sic1 and pSic1) that modulates their electrostatic potential, suggesting a structural basis for the proposed strong contribution of electrostatics to binding. A structural model of the dynamic pSic1-Cdc4 complex demonstrates the spatial arrangements in the ubiquitin ligase complex. These results provide a physical picture of a protein that is predominantly disordered in both its free and bound states, enabling aspects of its structure/function relationship to be elucidated. PMID:20399186

Complex Psychiatric Comorbidity of Treatment-Seeking Youth With Autism Spectrum Disorder and Anxiety Symptoms

PubMed Central

HEPBURN, SUSAN L.; STERN, JESSICA A.; BLAKELEY-SMITH, AUDREY; KIMEL, LILA K.; REAVEN, JUDITH A.

2015-01-01

Anxiety disorders and other co-occurring psychiatric disorders significantly impact adaptive functioning for many children with autism spectrum disorder (ASD). This descriptive study examines the complexity of psychiatric comorbidity in treatment-seeking youth with ASD and anxiety symptoms. Forty-two parents of 8- to 14-year-old children with ASD and anxiety symptoms completed a structured psychiatric interview (K-SADS) and provided information about the child’s past and current psychological functioning as part of a screening process to enter an anxiety intervention program. Overall, comorbidity was very complex, with children obtaining an average of 4 psychiatric diagnoses (including anxiety disorders) on a structured clinical interview (range = 0–9). Onset and course differed by psychiatric disorder. Complexity of comorbidity did not differ significantly by age, sex, or autism severity. Despite clinical significance of the symptoms reported, few children were currently (or ever) engaged in mental health treatment or group psychosocial intervention. Although the specificity of the current sample limits the generalizability of these results, findings suggest that treatment-seeking children with ASD and anxiety often present with additional psychiatric symptoms, which supports a transdiagnostic approach to research and intervention in this area. Accurate assessment of comorbidity may provide valuable information for families and clinicians regarding individualized treatment approaches. PMID:25960821

Schizophrenia and Human Self-Domestication: An Evolutionary Linguistics Approach.

PubMed

Benítez-Burraco, Antonio; Di Pietro, Lorena; Barba, Marta; Lattanzi, Wanda

2017-01-01

Schizophrenia (SZ) is a pervasive neurodevelopmental disorder that entails social and cognitive deficits, including marked language problems. Its complex multifactorial etiopathogenesis, including genetic and environmental factors, is still widely uncertain. SZ incidence has always been high and quite stable in human populations, across time and regardless of cultural implications, for unclear reasons. It has been hypothesized that SZ pathophysiology may involve the biological components that changed during the recent human evolutionary history, and led to our distinctive mode of cognition, which includes language skills. In this paper we explore this hypothesis, focusing on the self-domestication of the human species. This has been claimed to account for many human-specific distinctive traits, including aspects of our behavior and cognition, and to favor the emergence of complex languages through cultural evolution. The "domestication syndrome" in mammals comprises the constellation of traits exhibited by domesticated strains, seemingly resulting from the hypofunction of the neural crest. It is our intention to show that people with SZ exhibit more marked domesticated traits at the morphological, physiological, and behavioral levels. We also show that genes involved in domestication and neural crest development and function comprise nearly 20% of SZ candidates, most of which exhibit altered expression profiles in the brain of SZ patients, specifically in areas involved in language processing. Based on these observations, we conclude that SZ may represent an abnormal ontogenetic itinerary for the human faculty of language, resulting, at least in part, from changes in genes important for the domestication syndrome and primarily involving the neural crest. © 2017 S. Karger AG, Basel.

Can vocal conditioning trigger a semiotic ratchet in marmosets?

PubMed

Turesson, Hjalmar K; Ribeiro, Sidarta

2015-01-01

The complexity of human communication has often been taken as evidence that our language reflects a true evolutionary leap, bearing little resemblance to any other animal communication system. The putative uniqueness of the human language poses serious evolutionary and ethological challenges to a rational explanation of human communication. Here we review ethological, anatomical, molecular, and computational results across several species to set boundaries for these challenges. Results from animal behavior, cognitive psychology, neurobiology, and semiotics indicate that human language shares multiple features with other primate communication systems, such as specialized brain circuits for sensorimotor processing, the capability for indexical (pointing) and symbolic (referential) signaling, the importance of shared intentionality for associative learning, affective conditioning and parental scaffolding of vocal production. The most substantial differences lie in the higher human capacity for symbolic compositionality, fast vertical transmission of new symbols across generations, and irreversible accumulation of novel adaptive behaviors (cultural ratchet). We hypothesize that increasingly-complex vocal conditioning of an appropriate animal model may be sufficient to trigger a semiotic ratchet, evidenced by progressive sign complexification, as spontaneous contact calls become indexes, then symbols and finally arguments (strings of symbols). To test this hypothesis, we outline a series of conditioning experiments in the common marmoset (Callithrix jacchus). The experiments are designed to probe the limits of vocal communication in a prosocial, highly vocal primate 35 million years far from the human lineage, so as to shed light on the mechanisms of semiotic complexification and cultural transmission, and serve as a naturalistic behavioral setting for the investigation of language disorders.

Can vocal conditioning trigger a semiotic ratchet in marmosets?

PubMed Central

Turesson, Hjalmar K.; Ribeiro, Sidarta

2015-01-01

The complexity of human communication has often been taken as evidence that our language reflects a true evolutionary leap, bearing little resemblance to any other animal communication system. The putative uniqueness of the human language poses serious evolutionary and ethological challenges to a rational explanation of human communication. Here we review ethological, anatomical, molecular, and computational results across several species to set boundaries for these challenges. Results from animal behavior, cognitive psychology, neurobiology, and semiotics indicate that human language shares multiple features with other primate communication systems, such as specialized brain circuits for sensorimotor processing, the capability for indexical (pointing) and symbolic (referential) signaling, the importance of shared intentionality for associative learning, affective conditioning and parental scaffolding of vocal production. The most substantial differences lie in the higher human capacity for symbolic compositionality, fast vertical transmission of new symbols across generations, and irreversible accumulation of novel adaptive behaviors (cultural ratchet). We hypothesize that increasingly-complex vocal conditioning of an appropriate animal model may be sufficient to trigger a semiotic ratchet, evidenced by progressive sign complexification, as spontaneous contact calls become indexes, then symbols and finally arguments (strings of symbols). To test this hypothesis, we outline a series of conditioning experiments in the common marmoset (Callithrix jacchus). The experiments are designed to probe the limits of vocal communication in a prosocial, highly vocal primate 35 million years far from the human lineage, so as to shed light on the mechanisms of semiotic complexification and cultural transmission, and serve as a naturalistic behavioral setting for the investigation of language disorders. PMID:26500583

Mutations in the mitochondrial cysteinyl-tRNA synthase gene, CARS2, lead to a severe epileptic encephalopathy and complex movement disorder.

PubMed

Coughlin, Curtis R; Scharer, Gunter H; Friederich, Marisa W; Yu, Hung-Chun; Geiger, Elizabeth A; Creadon-Swindell, Geralyn; Collins, Abigail E; Vanlander, Arnaud V; Coster, Rudy Van; Powell, Christopher A; Swanson, Michael A; Minczuk, Michal; Van Hove, Johan L K; Shaikh, Tamim H

2015-08-01

Mitochondrial disease is often suspected in cases of severe epileptic encephalopathy especially when a complex movement disorder, liver involvement and progressive developmental regression are present. Although mutations in either mitochondrial DNA or POLG are often present, other nuclear defects in mitochondrial DNA replication and protein translation have been associated with a severe epileptic encephalopathy. We identified a proband with an epileptic encephalopathy, complex movement disorder and a combined mitochondrial respiratory chain enzyme deficiency. The child presented with neurological regression, complex movement disorder and intractable seizures. A combined deficiency of mitochondrial complexes I, III and IV was noted in liver tissue, along with increased mitochondrial DNA content in skeletal muscle. Incomplete assembly of complex V, using blue native polyacrylamide gel electrophoretic analysis and complex I, using western blotting, suggested a disorder of mitochondrial transcription or translation. Exome sequencing identified compound heterozygous mutations in CARS2, a mitochondrial aminoacyl-tRNA synthetase. Both mutations affect highly conserved amino acids located within the functional ligase domain of the cysteinyl-tRNA synthase. A specific decrease in the amount of charged mt-tRNA(Cys) was detected in patient fibroblasts compared with controls. Retroviral transfection of the wild-type CARS2 into patient skin fibroblasts led to the correction of the incomplete assembly of complex V, providing functional evidence for the role of CARS2 mutations in disease aetiology. Our findings indicate that mutations in CARS2 result in a mitochondrial translational defect as seen in individuals with mitochondrial epileptic encephalopathy. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

What Makes a Good Homeostat? Influencing circadian and sleep-wake regulation for prevention and intervention in mood and anxiety disorders

PubMed Central

Frank, Ellen; Benabou, Marion; Bentzley, Brandon; Bianchi, Matt; Goldstein, Tina; Konopka, Genevieve; Maywood, Elizabeth; Pritchett, David; Sheaves, Bryony; Thomas, Jessica

2015-01-01

All living organisms depend on homeostasis, the complex set of interacting metabolic chemical reactions for maintaining life and well-being. This is no less true for psychiatric well-being than for physical well-being. Indeed, a focus on homeostasis forces us to see how inextricably linked mental and physical well-being are. This paper focuses on these linkages. In particular, it addresses the ways in which understanding of disturbed homeostasis may aid in creating classes of patients with mood and anxiety disorders based on such phenotypes. At the cellular level, we may be able to compensate for the inability to study living brain tissue through the study of homeostatic mechanisms in fibroblasts, pluripotent human cells, and mitochondria and determine how homeostasis is disturbed at the level of these peripheral tissues through exogenous stress. We also emphasize the remarkable opportunities for enhancing knowledge in this area that are offered by advances in technology. The study of human behavior, especially when combined with our greatly improved capacity to study unique but isolated populations, offers particularly clear windows into the relationships among genetic, environmental, and behavioral contributions to homeostasis. PMID:25532787

A Multiphase Flow in the Antroduodenal Portion of the Gastrointestinal Tract: A Mathematical Model

PubMed Central

Trusov, P. V.

2016-01-01

A group of authors has developed a multilevel mathematical model that focuses on functional disorders in a human body associated with various chemical, physical, social, and other factors. At this point, the researchers have come up with structure, basic definitions and concepts of a mathematical model at the “macrolevel” that allow describing processes in a human body as a whole. Currently we are working at the “mesolevel” of organs and systems. Due to complexity of the tasks, this paper deals with only one meso-fragment of a digestive system model. It describes some aspects related to modeling multiphase flow in the antroduodenal portion of the gastrointestinal tract. Biochemical reactions, dissolution of food particles, and motor, secretory, and absorbing functions of the tract are taken into consideration. The paper outlines some results concerning influence of secretory function disorders on food dissolution rate and tract contents acidity. The effect which food density has on inflow of food masses from a stomach to a bowel is analyzed. We assume that the future development of the model will include digestive enzymes and related reactions of lipolysis, proteolysis, and carbohydrates breakdown. PMID:27413393

Identification of a novel PPARβ/δ/miR-21-3p axis in UV-induced skin inflammation.

PubMed

Degueurce, Gwendoline; D'Errico, Ilenia; Pich, Christine; Ibberson, Mark; Schütz, Frédéric; Montagner, Alexandra; Sgandurra, Marie; Mury, Lionel; Jafari, Paris; Boda, Akash; Meunier, Julien; Rezzonico, Roger; Brembilla, Nicolò Costantino; Hohl, Daniel; Kolios, Antonios; Hofbauer, Günther; Xenarios, Ioannis; Michalik, Liliane

2016-08-01

Although excessive exposure to UV is widely recognized as a major factor leading to skin perturbations and cancer, the complex mechanisms underlying inflammatory skin disorders resulting from UV exposure remain incompletely characterized. The nuclear hormone receptor PPARβ/δ is known to control mouse cutaneous repair and UV-induced skin cancer development. Here, we describe a novel PPARβ/δ-dependent molecular cascade involving TGFβ1 and miR-21-3p, which is activated in the epidermis in response to UV exposure. We establish that the passenger miRNA miR-21-3p, that we identify as a novel UV-induced miRNA in the epidermis, plays a pro-inflammatory function in keratinocytes and that its high level of expression in human skin is associated with psoriasis and squamous cell carcinomas. Finally, we provide evidence that inhibition of miR-21-3p reduces UV-induced cutaneous inflammation in ex vivo human skin biopsies, thereby underlining the clinical relevance of miRNA-based topical therapies for cutaneous disorders. © 2016 The Authors. Published under the terms of the CC BY 4.0 license.

Discovery of candidate KEN-box motifs using cell cycle keyword enrichment combined with native disorder prediction and motif conservation.

PubMed

Michael, Sushama; Travé, Gilles; Ramu, Chenna; Chica, Claudia; Gibson, Toby J

2008-02-15

KEN-box-mediated target selection is one of the mechanisms used in the proteasomal destruction of mitotic cell cycle proteins via the APC/C complex. While annotating the Eukaryotic Linear Motif resource (ELM, http://elm.eu.org/), we found that KEN motifs were significantly enriched in human protein entries with cell cycle keywords in the UniProt/Swiss-Prot database-implying that KEN-boxes might be more common than reported. Matches to short linear motifs in protein database searches are not, per se, significant. KEN-box enrichment with cell cycle Gene Ontology terms suggests that collectively these motifs are functional but does not prove that any given instance is so. Candidates were surveyed for native disorder prediction using GlobPlot and IUPred and for motif conservation in homologues. Among >25 strong new candidates, the most notable are human HIPK2, CHFR, CDC27, Dab2, Upf2, kinesin Eg5, DNA Topoisomerase 1 and yeast Cdc5 and Swi5. A similar number of weaker candidates were present. These proteins have yet to be tested for APC/C targeted destruction, providing potential new avenues of research.

Influencing circadian and sleep-wake regulation for prevention and intervention in mood and anxiety disorders: what makes a good homeostat?

PubMed

Frank, Ellen; Benabou, Marion; Bentzley, Brandon; Bianchi, Matt; Goldstein, Tina; Konopka, Genevieve; Maywood, Elizabeth; Pritchett, David; Sheaves, Bryony; Thomas, Jessica

2014-12-01

All living organisms depend on homeostasis, the complex set of interacting metabolic chemical reactions for maintaining life and well-being. This is no less true for psychiatric well-being than for physical well-being. Indeed, a focus on homeostasis forces us to see how inextricably linked mental and physical well-being are. This paper focuses on these linkages. In particular, it addresses the ways in which understanding of disturbed homeostasis may aid in creating classes of patients with mood and anxiety disorders based on such phenotypes. At the cellular level, we may be able to compensate for the inability to study living brain tissue through the study of homeostatic mechanisms in fibroblasts, pluripotent human cells, and mitochondria and determine how homeostasis is disturbed at the level of these peripheral tissues through exogenous stress. We also emphasize the remarkable opportunities for enhancing knowledge in this area that are offered by advances in technology. The study of human behavior, especially when combined with our greatly improved capacity to study unique but isolated populations, offers particularly clear windows into the relationships among genetic, environmental, and behavioral contributions to homeostasis. © 2014 New York Academy of Sciences.

Nature Neuroscience Review

PubMed Central

Maze, Ian; Shen, Li; Zhang, Bin; Garcia, Benjamin A.; Shao, Ningyi; Mitchell, Amanda; Sun, HaoSheng; Akbarian, Schahram; Allis, C. David; Nestler, Eric J.

2014-01-01

Over the past decade, rapid advances in epigenomics research have extensively characterized critical roles for chromatin regulatory events during normal periods of eukaryotic cell development and plasticity, as well as part of aberrant processes implicated in human disease. Application of such approaches to studies of the central nervous system (CNS), however, is more recent. Here, we provide a comprehensive overview of currently available tools to analyze neuroepigenomics data, as well as a discussion of pending challenges specific to the field of neuroscience. Integration of numerous unbiased genome-wide and proteomic approaches will be necessary to fully understand the neuroepigenome and the extraordinarily complex nature of the human brain. This will be critical to the development of future diagnostic and therapeutic strategies aimed at alleviating the vast array of heterogeneous and genetically distinct disorders of the CNS. PMID:25349914

The Gut Microbiome: A New Frontier in Autism Research

PubMed Central

Mulle, Jennifer G.; Sharp, William G.; Cubells, Joseph F.

2013-01-01

The human gut harbors a complex community of microbes that profoundly influence many aspects of growth and development, including development of the nervous system. Advances in high-throughput DNA sequencing methods have led to rapidly expanding knowledge about this gut microbiome. Here, we review fundamental emerging data on the human gut microbiome, with a focus on potential interactions between the microbiome and autism spectrum disorders (ASD) and consider research on atypical patterns of feeding and nutrition in ASD and how they might interact with the microbiome. Finally we selectively survey results from studies in rodents on the impact of the microbiome on neurobehavioral development. The evidence reviewed here suggests that a deeper understanding of the gut microbiome could open up new avenues of research on ASD, including potential novel treatment strategies. PMID:23307560

Glucocorticoid receptor signaling in health and disease

PubMed Central

Kadmiel, Mahita; Cidlowski, John A.

2013-01-01

Glucocorticoids are steroid hormones regulated in a circadian and stres-associated manner to maintain various metabolic and homeostatic functions that are necessary for life. Synthetic glucocorticoids are widely prescribed drugs for many conditions including asthma, chronic obstructive pulmonary disease (COPD), and inflammatory disorders of the eye. Research in the last few years has begun to unravel the profound complexity of glucocorticoid signaling and has contributed remarkably to improved therapeutic strategies. Glucocorticoids signal through the glucocorticoid receptor, a member of the superfamily of nuclear receptors, in both genomic and non-genomic ways in almost every tissue in the human body. In this review, we will provide an update on glucocorticoid receptor signaling and highlight the role of GR signaling in physiological and pathophysiological conditions in the major organ systems in the human body. PMID:23953592

Genes for normal sleep and sleep disorders.

PubMed

Tafti, Mehdi; Maret, Stéphanie; Dauvilliers, Yves

2005-01-01

Sleep and wakefulness are complex behaviors that are influenced by many genetic and environmental factors, which are beginning to be discovered. The contribution of genetic components to sleep disorders is also increasingly recognized as important. Point mutations in the prion protein, period 2, and the prepro-hypocretin/orexin gene have been found as the cause of a few sleep disorders but the possibility that other gene defects may contribute to the pathophysiology of major sleep disorders is worth in-depth investigations. However, single gene disorders are rare and most common disorders are complex in terms of their genetic susceptibility, environmental effects, gene-gene, and gene-environment interactions. We review here the current progress in the genetics of normal and pathological sleep.

Functional coupling between adenosine A1 receptors and G-proteins in rat and postmortem human brain membranes determined with conventional guanosine-5'-O-(3-[35S]thio)triphosphate ([35S]GTPγS) binding or [35S]GTPγS/immunoprecipitation assay.

PubMed

Odagaki, Yuji; Kinoshita, Masakazu; Ota, Toshio; Meana, J Javier; Callado, Luis F; Matsuoka, Isao; García-Sevilla, Jesús A

2018-06-01

Adenosine signaling plays a complex role in multiple physiological processes in the brain, and its dysfunction has been implicated in pathophysiology of neuropsychiatric diseases such as schizophrenia and affective disorders. In the present study, the coupling between adenosine A 1 receptor and G-protein was assessed by means of two [ 35 S]GTPγS binding assays, i.e., conventional filtration method and [ 35 S]GTPγS binding/immunoprecipitation in rat and human brain membranes. The latter method provides information about adenosine A 1 receptor-mediated Gα i-3 activation in rat as well as human brain membranes. On the other hand, adenosine-stimulated [ 35 S]GTPγS binding determined with conventional assay derives from functional activation of Gα i/o proteins (not restricted only to Gα i-3 ) coupled to adenosine A 1 receptors. The determination of adenosine concentrations in the samples used in the present study indicates the possibility that the assay mixture under our experimental conditions contains residual endogenous adenosine at nanomolar concentrations, which was also suggested by the results on the effects of adenosine receptor antagonists on basal [ 35 S]GTPγS binding level. The effects of adenosine deaminase (ADA) on basal binding also support the presence of adenosine. Nevertheless, the varied patterns of ADA discouraged us from adding ADA into assay medium routinely. The concentration-dependent increases elicited by adenosine were determined in 40 subjects without any neuropsychiatric disorders. The increases in %E max values determined by conventional assay according to aging and postmortem delay should be taken into account in future studies focusing on the effects of psychiatric disorders on adenosine A 1 receptor/G-protein interaction in postmortem human brain tissue.

The serotonergic system and anxiety.

PubMed

Gordon, Joshua A; Hen, Rene

2004-01-01

The wide use of serotonin reuptake inhibitors and serotonin receptor agonists in anxiety disorders has suggested a key role for the modulatory neurotransmitter in anxiety. However, serotonin's specific role is still uncertain. This article reviews the literature concerning how and where serotonergic agents modulate anxiety. Varying and sometimes conflicting data from human and animal studies argue for both anxiolytic and anxiogenic roles for serotonin, depending on the specific disorder, structure, or behavioral task studied. However, recent data from molecular genetic studies in the mouse point toward two important roles for the serotonin 1A receptor. In development, serotonin acts through this receptor to promote development of the circuitry necessary for normal anxiety-like behaviors. In adulthood, serotonin reuptake inhibitors act through the same receptor to stimulate neurogenesis and reduce anxiety-like behaviors. These studies highlight that the complex serotonin system likely plays various roles in the regulation of anxiety both during development and in adulthood.

A systems biology-led insight into the role of the proteome in neurodegenerative diseases.

PubMed

Fasano, Mauro; Monti, Chiara; Alberio, Tiziana

2016-09-01

Multifactorial disorders are the result of nonlinear interactions of several factors; therefore, a reductionist approach does not appear to be appropriate. Proteomics is a global approach that can be efficiently used to investigate pathogenetic mechanisms of neurodegenerative diseases. Here, we report a general introduction about the systems biology approach and mechanistic insights recently obtained by over-representation analysis of proteomics data of cellular and animal models of Alzheimer's disease, Parkinson's disease and other neurodegenerative disorders, as well as of affected human tissues. Expert commentary: As an inductive method, proteomics is based on unbiased observations that further require validation of generated hypotheses. Pathway databases and over-representation analysis tools allow researchers to assign an expectation value to pathogenetic mechanisms linked to neurodegenerative diseases. The systems biology approach based on omics data may be the key to unravel the complex mechanisms underlying neurodegeneration.

LncRNAs: key players and novel insights into diabetes mellitus

PubMed Central

He, Xiaoyun; Ou, Chunlin; Xiao, Yanhua; Han, Qing; Li, Hao; Zhou, Suxian

2017-01-01

Long non-coding RNAs (LncRNAs) are a class of endogenous RNA molecules, which have a transcribing length of over 200 nt, lack a complete functional open reading frame (ORF), and rarely encode a functional short peptide. Recent studies have revealed that disruption of LncRNAs levels correlates with several human diseases, including diabetes mellitus (DM), a complex multifactorial metabolic disorder affecting more than 400 million people worldwide. LncRNAs are emerging as pivotal regulators in various biological processes, in the progression of DM and its associated complications, involving pancreatic β-cell disorder, insulin resistance, and epigenetic regulation, etc. Further investigation into the mechanisms of action of LncRNAs in DM will be of great value in the thorough understanding of pathogenesis. However, prior to successful application of LncRNAs, further search for molecular biomarkers and drug targets to provide a new strategy for DM prevention, early diagnosis, and therapy is warranted. PMID:29050364

Some aspects of the anemia of chronic disorders modeled and analyzed by petri net based approach.

PubMed

Formanowicz, Dorota; Sackmann, Andrea; Kozak, Adam; Błażewicz, Jacek; Formanowicz, Piotr

2011-06-01

Anemia of chronic disorders is a very important phenomenon and iron is a crucial factor of this complex process. To better understand this process and its influence on some other factors we have built a mathematical model of the human body iron homeostasis, which possibly most exactly would reflect the metabolism of iron in the case of anemia and inflammation. The model has been formulated in the language of Petri net theory, which allows for its simulation and precise analysis. The obtained results of the analysis of the model's behavior, concerning the influence of anemia and inflammation on the transferrin receptors, and hepcidin concentration changes are the valuable complements to the knowledge following from clinical research. This analysis is one of the first attempts to investigate properties and behavior of a not fully understood biological system on a basis of its Petri net based model.

Personalized nutrition and obesity.

PubMed

Qi, Lu

2014-08-01

The past few decades have witnessed a rapid rise in nutrition-related disorders such as obesity in the United States and over the world. Traditional nutrition research has associated various foods and nutrients with obesity. Recent advances in genomics have led to identification of the genetic variants determining body weight and related dietary factors such as intakes of energy and macronutrients. In addition, compelling evidence has lent support to interactions between genetic variations and dietary factors in relation to obesity and weight change. Moreover, recently emerging data from other 'omics' studies such as epigenomics and metabolomics suggest that more complex interplays between the global features of human body and dietary factors may exist at multiple tiers in affecting individuals' susceptibility to obesity; and a concept of 'personalized nutrition' has been proposed to integrate this novel knowledge with traditional nutrition research, with the hope ultimately to endorse person-centric diet intervention to mitigate obesity and related disorders.

Personalized nutrition and obesity

PubMed Central

Qi, Lu

2017-01-01

The past few decades have witnessed a rapid rise in nutrition-related disorders such as obesity in the United States and over the world. Traditional nutrition research has associated various foods and nutrients with obesity. Recent advances in genomics have led to identification of the genetic variants determining body weight and related dietary factors such as intakes of energy and macronutrients. In addition, compelling evidence has lent support to interactions between genetic variations and dietary factors in relation to obesity and weight change. Moreover, recently emerging data from other ‘omics’ studies such as epigenomics and metabolomics suggest that more complex interplays between the global features of human body and dietary factors may exist at multiple tiers in affecting individuals’ susceptibility to obesity; and a concept of ‘personalized nutrition’ has been proposed to integrate this novel knowledge with traditional nutrition research, with the hope ultimately to endorse person-centric diet intervention to mitigate obesity and related disorders. PMID:24716734

A random set scoring model for prioritization of disease candidate genes using protein complexes and data-mining of GeneRIF, OMIM and PubMed records.

PubMed

Jiang, Li; Edwards, Stefan M; Thomsen, Bo; Workman, Christopher T; Guldbrandtsen, Bernt; Sørensen, Peter

2014-09-24

Prioritizing genetic variants is a challenge because disease susceptibility loci are often located in genes of unknown function or the relationship with the corresponding phenotype is unclear. A global data-mining exercise on the biomedical literature can establish the phenotypic profile of genes with respect to their connection to disease phenotypes. The importance of protein-protein interaction networks in the genetic heterogeneity of common diseases or complex traits is becoming increasingly recognized. Thus, the development of a network-based approach combined with phenotypic profiling would be useful for disease gene prioritization. We developed a random-set scoring model and implemented it to quantify phenotype relevance in a network-based disease gene-prioritization approach. We validated our approach based on different gene phenotypic profiles, which were generated from PubMed abstracts, OMIM, and GeneRIF records. We also investigated the validity of several vocabulary filters and different likelihood thresholds for predicted protein-protein interactions in terms of their effect on the network-based gene-prioritization approach, which relies on text-mining of the phenotype data. Our method demonstrated good precision and sensitivity compared with those of two alternative complex-based prioritization approaches. We then conducted a global ranking of all human genes according to their relevance to a range of human diseases. The resulting accurate ranking of known causal genes supported the reliability of our approach. Moreover, these data suggest many promising novel candidate genes for human disorders that have a complex mode of inheritance. We have implemented and validated a network-based approach to prioritize genes for human diseases based on their phenotypic profile. We have devised a powerful and transparent tool to identify and rank candidate genes. Our global gene prioritization provides a unique resource for the biological interpretation of data from genome-wide association studies, and will help in the understanding of how the associated genetic variants influence disease or quantitative phenotypes.

Functional significance of rare neuroligin 1 variants found in autism

PubMed Central

Nakanishi, Moe; Nomura, Jun; Ji, Xiao; Tamada, Kota; Arai, Takashi; Takahashi, Eiki; Bućan, Maja

2017-01-01

Genetic mutations contribute to the etiology of autism spectrum disorder (ASD), a common, heterogeneous neurodevelopmental disorder characterized by impairments in social interaction, communication, and repetitive and restricted patterns of behavior. Since neuroligin3 (NLGN3), a cell adhesion molecule at the neuronal synapse, was first identified as a risk gene for ASD, several additional variants in NLGN3 and NLGN4 were found in ASD patients. Moreover, synaptopathies are now known to cause several neuropsychiatric disorders including ASD. In humans, NLGNs consist of five family members, and neuroligin1 (NLGN1) is a major component forming a complex on excitatory glutamatergic synapses. However, the significance of NLGN1 in neuropsychiatric disorders remains unknown. Here, we systematically examine five missense variants of NLGN1 that were detected in ASD patients, and show molecular and cellular alterations caused by these variants. We show that a novel NLGN1 Pro89Leu (P89L) missense variant found in two ASD siblings leads to changes in cellular localization, protein degradation, and to the impairment of spine formation. Furthermore, we generated the knock-in P89L mice, and we show that the P89L heterozygote mice display abnormal social behavior, a core feature of ASD. These results, for the first time, implicate rare variants in NLGN1 as functionally significant and support that the NLGN synaptic pathway is of importance in the etiology of neuropsychiatric disorders. PMID:28841651

Functional significance of rare neuroligin 1 variants found in autism.

PubMed

Nakanishi, Moe; Nomura, Jun; Ji, Xiao; Tamada, Kota; Arai, Takashi; Takahashi, Eiki; Bućan, Maja; Takumi, Toru

2017-08-01

Genetic mutations contribute to the etiology of autism spectrum disorder (ASD), a common, heterogeneous neurodevelopmental disorder characterized by impairments in social interaction, communication, and repetitive and restricted patterns of behavior. Since neuroligin3 (NLGN3), a cell adhesion molecule at the neuronal synapse, was first identified as a risk gene for ASD, several additional variants in NLGN3 and NLGN4 were found in ASD patients. Moreover, synaptopathies are now known to cause several neuropsychiatric disorders including ASD. In humans, NLGNs consist of five family members, and neuroligin1 (NLGN1) is a major component forming a complex on excitatory glutamatergic synapses. However, the significance of NLGN1 in neuropsychiatric disorders remains unknown. Here, we systematically examine five missense variants of NLGN1 that were detected in ASD patients, and show molecular and cellular alterations caused by these variants. We show that a novel NLGN1 Pro89Leu (P89L) missense variant found in two ASD siblings leads to changes in cellular localization, protein degradation, and to the impairment of spine formation. Furthermore, we generated the knock-in P89L mice, and we show that the P89L heterozygote mice display abnormal social behavior, a core feature of ASD. These results, for the first time, implicate rare variants in NLGN1 as functionally significant and support that the NLGN synaptic pathway is of importance in the etiology of neuropsychiatric disorders.

Plasmodium coatneyi in Rhesus Macaques Replicates the Multisystemic Dysfunction of Severe Malaria in Humans

PubMed Central

Cabrera-Mora, Monica; Garcia, AnaPatricia; Orkin, Jack; Strobert, Elizabeth; Barnwell, John W.; Galinski, Mary R.

2013-01-01

Severe malaria, a leading cause of mortality among children and nonimmune adults, is a multisystemic disorder characterized by complex clinical syndromes that are mechanistically poorly understood. The interplay of various parasite and host factors is critical in the pathophysiology of severe malaria. However, knowledge regarding the pathophysiological mechanisms and pathways leading to the multisystemic disorders of severe malaria in humans is limited. Here, we systematically investigate infections with Plasmodium coatneyi, a simian malaria parasite that closely mimics the biological characteristics of P. falciparum, and develop baseline data and protocols for studying erythrocyte turnover and severe malaria in greater depth. We show that rhesus macaques (Macaca mulatta) experimentally infected with P. coatneyi develop anemia, coagulopathy, and renal and metabolic dysfunction. The clinical course of acute infections required suppressive antimalaria chemotherapy, fluid support, and whole-blood transfusion, mimicking the standard of care for the management of severe malaria cases in humans. Subsequent infections in the same animals progressed with a mild illness in comparison, suggesting that immunity played a role in reducing the severity of the disease. Our results demonstrate that P. coatneyi infection in rhesus macaques can serve as a highly relevant model to investigate the physiological pathways and molecular mechanisms of malaria pathogenesis in naïve and immune individuals. Together with high-throughput postgenomic technologies, such investigations hold promise for the identification of new clinical interventions and adjunctive therapies. PMID:23509137