Hidden Structural Codes in Protein Intrinsic Disorder.

Science.gov (United States)

Borkosky, Silvia S; Camporeale, Gabriela; Chemes, Lucía B; Risso, Marikena; Noval, María Gabriela; Sánchez, Ignacio E; Alonso, Leonardo G; de Prat Gay, Gonzalo

2017-10-17

Intrinsic disorder is a major structural category in biology, accounting for more than 30% of coding regions across the domains of life, yet consists of conformational ensembles in equilibrium, a major challenge in protein chemistry. Anciently evolved papillomavirus genomes constitute an unparalleled case for sequence to structure-function correlation in cases in which there are no folded structures. E7, the major transforming oncoprotein of human papillomaviruses, is a paradigmatic example among the intrinsically disordered proteins. Analysis of a large number of sequences of the same viral protein allowed for the identification of a handful of residues with absolute conservation, scattered along the sequence of its N-terminal intrinsically disordered domain, which intriguingly are mostly leucine residues. Mutation of these led to a pronounced increase in both α-helix and β-sheet structural content, reflected by drastic effects on equilibrium propensities and oligomerization kinetics, and uncovers the existence of local structural elements that oppose canonical folding. These folding relays suggest the existence of yet undefined hidden structural codes behind intrinsic disorder in this model protein. Thus, evolution pinpoints conformational hot spots that could have not been identified by direct experimental methods for analyzing or perturbing the equilibrium of an intrinsically disordered protein ensemble.

Expected packing density allows prediction of both amyloidogenic and disordered regions in protein chains

Energy Technology Data Exchange (ETDEWEB)

Galzitskaya, Oxana V; Garbuzynskiy, Sergiy O; Lobanov, Michail Yu [Institute of Protein Research, Russian Academy of Sciences, 142290, Pushchino, Moscow Region (Russian Federation)

2007-07-18

The determination of factors that influence conformational changes in proteins is very important for the identification of potentially amyloidogenic and disordered regions in polypeptide chains. In our work we introduce a new parameter, mean packing density, to detect both amyloidogenic and disordered regions in a protein sequence. It has been shown that regions with strong expected packing density are responsible for amyloid formation. Our predictions are consistent with known disease-related amyloidogenic regions for 9 of 12 amyloid-forming proteins and peptides in which the positions of amyloidogenic regions have been revealed experimentally. Our findings support the concept that the mechanism of formation of amyloid fibrils is similar for different peptides and proteins. Moreover, we have demonstrated that regions with weak expected packing density are responsible for the appearance of disordered regions. Our method has been tested on datasets of globular proteins and long disordered protein segments, and it shows improved performance over other widely used methods. Thus, we demonstrate that the expected packing density is a useful value for predicting both disordered and amyloidogenic regions of a protein based on sequence alone. Our results are important for understanding the structural characteristics of protein folding and misfolding.

Temperature-induced transitions in disordered proteins probed by NMR spectroscopy

DEFF Research Database (Denmark)

Kjærgaard, Magnus; Poulsen, Flemming Martin; Kragelund, Birthe Brandt

2012-01-01

Intrinsically disordered proteins are abundant in nature and perform many important physiological functions. Multidimensional NMR spectroscopy has been crucial for the understanding of the conformational properties of disordered proteins and is increasingly used to probe their conformational...... ensembles. Compared to folded proteins, disordered proteins are more malleable and more easily perturbed by environmental factors. Accordingly, the experimental conditions and especially the temperature modify the structural and functional properties of disordered proteins. NMR spectroscopy allows analysis...... of temperature-induced structural changes at residue resolution using secondary chemical shift analysis, paramagnetic relaxation enhancement, and residual dipolar couplings. This chapter discusses practical aspects of NMR studies of temperature-induced structural changes in disordered proteins....

Interplay between chaperones and protein disorder promotes the evolution of protein networks.

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Sebastian Pechmann

2014-06-01

Full Text Available Evolution is driven by mutations, which lead to new protein functions but come at a cost to protein stability. Non-conservative substitutions are of interest in this regard because they may most profoundly affect both function and stability. Accordingly, organisms must balance the benefit of accepting advantageous substitutions with the possible cost of deleterious effects on protein folding and stability. We here examine factors that systematically promote non-conservative mutations at the proteome level. Intrinsically disordered regions in proteins play pivotal roles in protein interactions, but many questions regarding their evolution remain unanswered. Similarly, whether and how molecular chaperones, which have been shown to buffer destabilizing mutations in individual proteins, generally provide robustness during proteome evolution remains unclear. To this end, we introduce an evolutionary parameter λ that directly estimates the rate of non-conservative substitutions. Our analysis of λ in Escherichia coli, Saccharomyces cerevisiae, and Homo sapiens sequences reveals how co- and post-translationally acting chaperones differentially promote non-conservative substitutions in their substrates, likely through buffering of their destabilizing effects. We further find that λ serves well to quantify the evolution of intrinsically disordered proteins even though the unstructured, thus generally variable regions in proteins are often flanked by very conserved sequences. Crucially, we show that both intrinsically disordered proteins and highly re-wired proteins in protein interaction networks, which have evolved new interactions and functions, exhibit a higher λ at the expense of enhanced chaperone assistance. Our findings thus highlight an intricate interplay of molecular chaperones and protein disorder in the evolvability of protein networks. Our results illuminate the role of chaperones in enabling protein evolution, and underline the

Marked variability in the extent of protein disorder within and between viral families.

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Ravindra Pushker

Full Text Available Intrinsically disordered regions in eukaryotic proteomes contain key signaling and regulatory modules and mediate interactions with many proteins. Many viral proteomes encode disordered proteins and modulate host factors through the use of short linear motifs (SLiMs embedded within disordered regions. However, the degree of viral protein disorder across different viruses is not well understood, so we set out to establish the constraints acting on viruses, in terms of their use of disordered protein regions. We surveyed predicted disorder across 2,278 available viral genomes in 41 families, and correlated the extent of disorder with genome size and other factors. Protein disorder varies strikingly between viral families (from 2.9% to 23.1% of residues, and also within families. However, this substantial variation did not follow the established trend among their hosts, with increasing disorder seen across eubacterial, archaebacterial, protists, and multicellular eukaryotes. For example, among large mammalian viruses, poxviruses and herpesviruses showed markedly differing disorder (5.6% and 17.9%, respectively. Viral families with smaller genome sizes have more disorder within each of five main viral types (ssDNA, dsDNA, ssRNA+, dsRNA, retroviruses, except for negative single-stranded RNA viruses, where disorder increased with genome size. However, surveying over all viruses, which compares tiny and enormous viruses over a much bigger range of genome sizes, there is no strong association of genome size with protein disorder. We conclude that there is extensive variation in the disorder content of viral proteomes. While a proportion of this may relate to base composition, to extent of gene overlap, and to genome size within viral types, there remain important additional family and virus-specific effects. Differing disorder strategies are likely to impact on how different viruses modulate host factors, and on how rapidly viruses can evolve novel

Interaction between -Synuclein and Other Proteins in Neurodegenerative Disorders

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Kurt A. Jellinger

2011-01-01

Full Text Available Protein aggregation is a common characteristic of many neurodegenerative disorders, and the interaction between pathological/toxic proteins to cause neurodegeneration is a hot topic of current neuroscience research. Despite clinical, genetic, and experimental differences, evidence increasingly indicates considerable overlap between synucleinopathies and tauopathies or other protein-misfolding diseases. Inclusions, characteristics of these disorders, also occurring in other neurodegenerative diseases, suggest interactions of pathological proteins engaging common downstream pathways. Novel findings that have shifted our understanding in the role of pathologic proteins in the pathogenesis of Parkinson and Alzheimer diseases have confirmed correlations/overlaps between these and other neurodegenerative disorders. The synergistic effects of α-synuclein, hyperphosphorylated tau, amyloid-β, and other pathologic proteins, and the underlying molecular pathogenic mechanisms, including induction and spread of protein aggregates, are critically reviewed, suggesting a dualism or triad of neurodegeneration in protein-misfolding disorders, although the etiology of most of these processes is still mysterious.

What Are Related Disorders?

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... The Marfan Foundation Marfan & Related Disorders What is Marfan Syndrome? What are Related Disorders? What are the Signs? ... Contact Us Donate Marfan & Related Disorders What is Marfan Syndrome? What are Related Disorders? What are the Signs? ...

Functional anthology of intrinsic disorder. 1. Biological processes and functions of proteins with long disordered regions.

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Xie, Hongbo; Vucetic, Slobodan; Iakoucheva, Lilia M; Oldfield, Christopher J; Dunker, A Keith; Uversky, Vladimir N; Obradovic, Zoran

2007-05-01

Identifying relationships between function, amino acid sequence, and protein structure represents a major challenge. In this study, we propose a bioinformatics approach that identifies functional keywords in the Swiss-Prot database that correlate with intrinsic disorder. A statistical evaluation is employed to rank the significance of these correlations. Protein sequence data redundancy and the relationship between protein length and protein structure were taken into consideration to ensure the quality of the statistical inferences. Over 200,000 proteins from the Swiss-Prot database were analyzed using this approach. The predictions of intrinsic disorder were carried out using PONDR VL3E predictor of long disordered regions that achieves an accuracy of above 86%. Overall, out of the 710 Swiss-Prot functional keywords that were each associated with at least 20 proteins, 238 were found to be strongly positively correlated with predicted long intrinsically disordered regions, whereas 302 were strongly negatively correlated with such regions. The remaining 170 keywords were ambiguous without strong positive or negative correlation with the disorder predictions. These functions cover a large variety of biological activities and imply that disordered regions are characterized by a wide functional repertoire. Our results agree well with literature findings, as we were able to find at least one illustrative example of functional disorder or order shown experimentally for the vast majority of keywords showing the strongest positive or negative correlation with intrinsic disorder. This work opens a series of three papers, which enriches the current view of protein structure-function relationships, especially with regards to functionalities of intrinsically disordered proteins, and provides researchers with a novel tool that could be used to improve the understanding of the relationships between protein structure and function. The first paper of the series describes our

Molecular signaling involving intrinsically disordered proteins in prostate cancer

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Anna Russo

2016-01-01

Full Text Available Investigations on cellular protein interaction networks (PINs reveal that proteins that constitute hubs in a PIN are notably enriched in Intrinsically Disordered Proteins (IDPs compared to proteins that constitute edges, highlighting the role of IDPs in signaling pathways. Most IDPs rapidly undergo disorder-to-order transitions upon binding to their biological targets to perform their function. Conformational dynamics enables IDPs to be versatile and to interact with a broad range of interactors under normal physiological conditions where their expression is tightly modulated. IDPs are involved in many cellular processes such as cellular signaling, transcriptional regulation, and splicing; thus, their high-specificity/low-affinity interactions play crucial roles in many human diseases including cancer. Prostate cancer (PCa is one of the leading causes of cancer-related mortality in men worldwide. Therefore, identifying molecular mechanisms of the oncogenic signaling pathways that are involved in prostate carcinogenesis is crucial. In this review, we focus on the aspects of cellular pathways leading to PCa in which IDPs exert a primary role.

Functional Anthology of Intrinsic Disorder. I. Biological Processes and Functions of Proteins with Long Disordered Regions

Science.gov (United States)

Xie, Hongbo; Vucetic, Slobodan; Iakoucheva, Lilia M.; Oldfield, Christopher J.; Dunker, A. Keith; Uversky, Vladimir N.; Obradovic, Zoran

2008-01-01

Identifying relationships between function, amino acid sequence and protein structure represents a major challenge. In this study we propose a bioinformatics approach that identifies functional keywords in the Swiss-Prot database that correlate with intrinsic disorder. A statistical evaluation is employed to rank the significance of these correlations. Protein sequence data redundancy and the relationship between protein length and protein structure were taken into consideration to ensure the quality of the statistical inferences. Over 200,000 proteins from Swiss-Prot database were analyzed using this approach. The predictions of intrinsic disorder were carried out using PONDR VL3E predictor of long disordered regions that achieves an accuracy of above 86%. Overall, out of the 710 Swiss-Prot functional keywords that were each associated with at least 20 proteins, 238 were found to be strongly positively correlated with predicted long intrinsically disordered regions, whereas 302 were strongly negatively correlated with such regions. The remaining 170 keywords were ambiguous without strong positive or negative correlation with the disorder predictions. These functions cover a large variety of biological activities and imply that disordered regions are characterized by a wide functional repertoire. Our results agree well with literature findings, as we were able to find at least one illustrative example of functional disorder or order shown experimentally for the vast majority of keywords showing the strongest positive or negative correlation with intrinsic disorder. This work opens a series of three papers, which enriches the current view of protein structure-function relationships, especially with regards to functionalities of intrinsically disordered proteins and provides researchers with a novel tool that could be used to improve the understanding of the relationships between protein structure and function. The first paper of the series describes our statistical

Microsecond molecular dynamics simulations of intrinsically disordered proteins involved in the oxidative stress response

NARCIS (Netherlands)

Cino, E.A.; Wong-ekkabut, J.; Karttunen, M.E.J.; Choy, W.-Y.

2011-01-01

Intrinsically disordered proteins (IDPs) are abundant in cells and have central roles in protein-protein interaction networks. Interactions between the IDP Prothymosin alpha (ProTa) and the Neh2 domain of Nuclear factor erythroid 2-related factor 2 (Nrf2), with a common binding partner, Kelch-like

Functional Advantages of Conserved Intrinsic Disorder in RNA-Binding Proteins.

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Varadi, Mihaly; Zsolyomi, Fruzsina; Guharoy, Mainak; Tompa, Peter

2015-01-01

Proteins form large macromolecular assemblies with RNA that govern essential molecular processes. RNA-binding proteins have often been associated with conformational flexibility, yet the extent and functional implications of their intrinsic disorder have never been fully assessed. Here, through large-scale analysis of comprehensive protein sequence and structure datasets we demonstrate the prevalence of intrinsic structural disorder in RNA-binding proteins and domains. We addressed their functionality through a quantitative description of the evolutionary conservation of disordered segments involved in binding, and investigated the structural implications of flexibility in terms of conformational stability and interface formation. We conclude that the functional role of intrinsically disordered protein segments in RNA-binding is two-fold: first, these regions establish extended, conserved electrostatic interfaces with RNAs via induced fit. Second, conformational flexibility enables them to target different RNA partners, providing multi-functionality, while also ensuring specificity. These findings emphasize the functional importance of intrinsically disordered regions in RNA-binding proteins.

Functional Advantages of Conserved Intrinsic Disorder in RNA-Binding Proteins.

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Mihaly Varadi

Full Text Available Proteins form large macromolecular assemblies with RNA that govern essential molecular processes. RNA-binding proteins have often been associated with conformational flexibility, yet the extent and functional implications of their intrinsic disorder have never been fully assessed. Here, through large-scale analysis of comprehensive protein sequence and structure datasets we demonstrate the prevalence of intrinsic structural disorder in RNA-binding proteins and domains. We addressed their functionality through a quantitative description of the evolutionary conservation of disordered segments involved in binding, and investigated the structural implications of flexibility in terms of conformational stability and interface formation. We conclude that the functional role of intrinsically disordered protein segments in RNA-binding is two-fold: first, these regions establish extended, conserved electrostatic interfaces with RNAs via induced fit. Second, conformational flexibility enables them to target different RNA partners, providing multi-functionality, while also ensuring specificity. These findings emphasize the functional importance of intrinsically disordered regions in RNA-binding proteins.

Intrinsically disordered segments and the evolution of protein half-life

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Babu, M.

2013-03-01

Precise turnover of proteins is essential for cellular homeostasis and is primarily mediated by the proteasome. Thus, a fundamental question is: What features make a protein an efficient substrate for degradation? Here I will present results that proteins with a long terminal disordered segment or internal disordered segments have a significantly shorter half-life in yeast. This relationship appears to be evolutionarily conserved in mouse and human. Furthermore, upon gene duplication, divergence in the length of terminal disorder or variation in the number of internal disordered segments results in significant alteration of the half-life of yeast paralogs. Many proteins that exhibit such changes participate in signaling, where altered protein half-life will likely influence their activity. We suggest that variation in the length and number of disordered segments could serve as a remarkably simple means to evolve protein half-life and may serve as an underappreciated source of genetic variation with important phenotypic consequences. MMB acknowledges the Medical Research Council for funding his research program.

[Renal diseases related to MYH9 disorders].

Science.gov (United States)

Galeano, Dario; Zanoli, Luca; L'Imperio, Vincenzo; Fatuzzo, Pasquale; Granata, Antonio

2017-04-01

Mutations in MYH9 gene encoding the nonmuscle myosin heavy chain IIA (NMMHC-IIA) are related to a number of rare autosomal-dominant disorders which has been known as May-Hegglin disease, Sebastian syndrome, Fechtner syndrome and Epstein syndrome. Their common clinical features are congenital macrothrombocytopaenia and polymorphonuclear inclusion bodies, in addition to a variable risk of developing proteinuria, chronic kidney disease progressing toward end stage, sensorineural deafness and presenile cataracts. The term MYH9 related disease (MYH9-RD) describes the variable expression of a single illness encompassing all previously mentioned hereditary disorders. Renal involvement in MYH9- RD has been observed in 30% of patients. Mutant MYH9 protein, expressed in podocytes, mesangial and tubular cells, plays a main role in foot process effacement and in development of nephropathy. Interestingly, the MYH9 gene is currently under investigation also for his possible contribution to many other non-hereditary glomerulopathies such as focal global glomerulosclerosis (hypertensive nephrosclerosis), idiopathic focal segmental glomerulosclerosis, C1q nephropathy and HIV-associated nephropathy. In this review we are aimed to describe renal diseases related to MYH9 disorders, from the hereditary disease to the acquired disorders, in which MYH9-gene acts as a "renal failure susceptibility gene". Copyright by Società Italiana di Nefrologia SIN, Rome, Italy.

Extreme disorder in an ultrahigh-affinity protein complex

DEFF Research Database (Denmark)

Borgia, Alessandro; Borgia, Madeleine B; Bugge, Katrine

2018-01-01

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...... 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...... 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...

Intrinsically disordered proteins as molecular shields†

Science.gov (United States)

Chakrabortee, Sohini; Tripathi, Rashmi; Watson, Matthew; Kaminski Schierle, Gabriele S.; Kurniawan, Davy P.; Kaminski, Clemens F.; Wise, Michael J.; Tunnacliffe, Alan

2017-01-01

The broad family of LEA proteins are intrinsically disordered proteins (IDPs) with several potential roles in desiccation tolerance, or anhydrobiosis, one of which is to limit desiccation-induced aggregation of cellular proteins. We show here that this activity, termed molecular shield function, is distinct from that of a classical molecular chaperone, such as HSP70 – while HSP70 reduces aggregation of citrate synthase (CS) on heating, two LEA proteins, a nematode group 3 protein, AavLEA1, and a plant group 1 protein, Em, do not; conversely, the LEA proteins reduce CS aggregation on desiccation, while HSP70 lacks this ability. There are also differences in interaction with client proteins – HSP70 can be co-immunoprecipitated with a polyglutamine-containing client, consistent with tight complex formation, whereas the LEA proteins can not, although a loose interaction is observed by Förster resonance energy transfer. In a further exploration of molecular shield function, we demonstrate that synthetic polysaccharides, like LEA proteins, are able to reduce desiccation-induced aggregation of a water-soluble proteome, consistent with a steric interference model of anti-aggregation activity. If molecular shields operate by reducing intermolecular cohesion rates, they should not protect against intramolecular protein damage. This was tested using the monomeric red fluorescent protein, mCherry, which does not undergo aggregation on drying, but the absorbance and emission spectra of its intrinsic fluorophore are dramatically reduced, indicative of intramolecular conformational changes. As expected, these changes are not prevented by AavLEA1, except for a slight protection at high molar ratios, and an AavLEA1-mCherry fusion protein is damaged to the same extent as mCherry alone. A recent hypothesis proposed that proteomes from desiccation-tolerant species contain a higher degree of disorder than intolerant examples, and that this might provide greater intrinsic stability

Intrinsically disordered proteins as molecular shields.

Science.gov (United States)

Chakrabortee, Sohini; Tripathi, Rashmi; Watson, Matthew; Schierle, Gabriele S Kaminski; Kurniawan, Davy P; Kaminski, Clemens F; Wise, Michael J; Tunnacliffe, Alan

2012-01-01

The broad family of LEA proteins are intrinsically disordered proteins (IDPs) with several potential roles in desiccation tolerance, or anhydrobiosis, one of which is to limit desiccation-induced aggregation of cellular proteins. We show here that this activity, termed molecular shield function, is distinct from that of a classical molecular chaperone, such as HSP70 - while HSP70 reduces aggregation of citrate synthase (CS) on heating, two LEA proteins, a nematode group 3 protein, AavLEA1, and a plant group 1 protein, Em, do not; conversely, the LEA proteins reduce CS aggregation on desiccation, while HSP70 lacks this ability. There are also differences in interaction with client proteins - HSP70 can be co-immunoprecipitated with a polyglutamine-containing client, consistent with tight complex formation, whereas the LEA proteins can not, although a loose interaction is observed by Förster resonance energy transfer. In a further exploration of molecular shield function, we demonstrate that synthetic polysaccharides, like LEA proteins, are able to reduce desiccation-induced aggregation of a water-soluble proteome, consistent with a steric interference model of anti-aggregation activity. If molecular shields operate by reducing intermolecular cohesion rates, they should not protect against intramolecular protein damage. This was tested using the monomeric red fluorescent protein, mCherry, which does not undergo aggregation on drying, but the absorbance and emission spectra of its intrinsic fluorophore are dramatically reduced, indicative of intramolecular conformational changes. As expected, these changes are not prevented by AavLEA1, except for a slight protection at high molar ratios, and an AavLEA1-mCherry fusion protein is damaged to the same extent as mCherry alone. A recent hypothesis proposed that proteomes from desiccation-tolerant species contain a higher degree of disorder than intolerant examples, and that this might provide greater intrinsic stability

Genome-wide analysis of protein disorder in Arabidopsis thaliana: implications for plant environmental adaptation.

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Pietrosemoli, Natalia; García-Martín, Juan A; Solano, Roberto; Pazos, Florencio

2013-01-01

Intrinsically disordered proteins/regions (IDPs/IDRs) are currently recognized as a widespread phenomenon having key cellular functions. Still, many aspects of the function of these proteins need to be unveiled. IDPs conformational flexibility allows them to recognize and interact with multiple partners, and confers them larger interaction surfaces that may increase interaction speed. For this reason, molecular interactions mediated by IDPs/IDRs are particularly abundant in certain types of protein interactions, such as those of signaling and cell cycle control. We present the first large-scale study of IDPs in Arabidopsis thaliana, the most widely used model organism in plant biology, in order to get insight into the biological roles of these proteins in plants. The work includes a comparative analysis with the human proteome to highlight the differential use of disorder in both species. Results show that while human proteins are in general more disordered, certain functional classes, mainly related to environmental response, are significantly more enriched in disorder in Arabidopsis. We propose that because plants cannot escape from environmental conditions as animals do, they use disorder as a simple and fast mechanism, independent of transcriptional control, for introducing versatility in the interaction networks underlying these biological processes so that they can quickly adapt and respond to challenging environmental conditions.

Comprehensive large-scale assessment of intrinsic protein disorder.

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Walsh, Ian; Giollo, Manuel; Di Domenico, Tomás; Ferrari, Carlo; Zimmermann, Olav; Tosatto, Silvio C E

2015-01-15

Intrinsically disordered regions are key for the function of numerous proteins. Due to the difficulties in experimental disorder characterization, many computational predictors have been developed with various disorder flavors. Their performance is generally measured on small sets mainly from experimentally solved structures, e.g. Protein Data Bank (PDB) chains. MobiDB has only recently started to collect disorder annotations from multiple experimental structures. MobiDB annotates disorder for UniProt sequences, allowing us to conduct the first large-scale assessment of fast disorder predictors on 25 833 different sequences with X-ray crystallographic structures. In addition to a comprehensive ranking of predictors, this analysis produced the following interesting observations. (i) The predictors cluster according to their disorder definition, with a consensus giving more confidence. (ii) Previous assessments appear over-reliant on data annotated at the PDB chain level and performance is lower on entire UniProt sequences. (iii) Long disordered regions are harder to predict. (iv) Depending on the structural and functional types of the proteins, differences in prediction performance of up to 10% are observed. The datasets are available from Web site at URL: http://mobidb.bio.unipd.it/lsd. Supplementary data are available at Bioinformatics online. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Gluten-related disorders: certainties, questions and doubts.

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Valenti, Simona; Corica, Domenico; Ricciardi, Luisa; Romano, Claudio

2017-11-01

In the last decade, the ingestion of gluten, a heterogeneous complex of proteins present in wheat, rice, barley and probably in oats, has been associated with clinical disorders, such as celiac disease, wheat allergy and recently to non-celiac gluten sensitivity or wheat intolerance syndrome. Gluten-related disorders, which are becoming epidemiologically relevant with an estimated global prevalence of about 5%, require the exclusion of gluten from the diet. For the past 5 years, an important shift in the availability of gluten-free products, together with increased consumption in the general population, has been recorded and is estimated to be about 12-25%. Many people follow a self-prescribed gluten-free diet, despite the fact that the majority have not first been previously excluded, or confirmed, as having gluten disorders. They rely on claims that a gluten-free diet improves general health. In this review, we provide an overview of the clinical disorders related to gluten or wheat ingestion, pointing out the current certainties, open questions, possible answers and several doubts in the management of these conditions. KEY MESSAGE Incidence of gluten-related disorders is increased in the last decade and self-diagnosis is frequent with inappropriate starting of a gluten-free diet. Gluten and wheat are considered as the most important triggers to coeliac disease, wheat allergy and non-celiac gluten sensitivity. Pediatricians, allergologist and gastroenterologist are involved in the management of these conditions and appropriate diagnostic protocols are required.

Content of intrinsic disorder influences the outcome of cell-free protein synthesis.

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Tokmakov, Alexander A; Kurotani, Atsushi; Ikeda, Mariko; Terazawa, Yumiko; Shirouzu, Mikako; Stefanov, Vasily; Sakurai, Tetsuya; Yokoyama, Shigeyuki

2015-09-11

Cell-free protein synthesis is used to produce proteins with various structural traits. Recent bioinformatics analyses indicate that more than half of eukaryotic proteins possess long intrinsically disordered regions. However, no systematic study concerning the connection between intrinsic disorder and expression success of cell-free protein synthesis has been presented until now. To address this issue, we examined correlations of the experimentally observed cell-free protein expression yields with the contents of intrinsic disorder bioinformatically predicted in the expressed sequences. This analysis revealed strong relationships between intrinsic disorder and protein amenability to heterologous cell-free expression. On the one hand, elevated disorder content was associated with the increased ratio of soluble expression. On the other hand, overall propensity for detectable protein expression decreased with disorder content. We further demonstrated that these tendencies are rooted in some distinct features of intrinsically disordered regions, such as low hydrophobicity, elevated surface accessibility and high abundance of sequence motifs for proteolytic degradation, including sites of ubiquitination and PEST sequences. Our findings suggest that identification of intrinsically disordered regions in the expressed amino acid sequences can be of practical use for predicting expression success and optimizing cell-free protein synthesis.

Modeling disordered regions in proteins using Rosetta.

Directory of Open Access Journals (Sweden)

Ray Yu-Ruei Wang

Full Text Available Protein structure prediction methods such as Rosetta search for the lowest energy conformation of the polypeptide chain. However, the experimentally observed native state is at a minimum of the free energy, rather than the energy. The neglect of the missing configurational entropy contribution to the free energy can be partially justified by the assumption that the entropies of alternative folded states, while very much less than unfolded states, are not too different from one another, and hence can be to a first approximation neglected when searching for the lowest free energy state. The shortcomings of current structure prediction methods may be due in part to the breakdown of this assumption. Particularly problematic are proteins with significant disordered regions which do not populate single low energy conformations even in the native state. We describe two approaches within the Rosetta structure modeling methodology for treating such regions. The first does not require advance knowledge of the regions likely to be disordered; instead these are identified by minimizing a simple free energy function used previously to model protein folding landscapes and transition states. In this model, residues can be either completely ordered or completely disordered; they are considered disordered if the gain in entropy outweighs the loss of favorable energetic interactions with the rest of the protein chain. The second approach requires identification in advance of the disordered regions either from sequence alone using for example the DISOPRED server or from experimental data such as NMR chemical shifts. During Rosetta structure prediction calculations the disordered regions make only unfavorable repulsive contributions to the total energy. We find that the second approach has greater practical utility and illustrate this with examples from de novo structure prediction, NMR structure calculation, and comparative modeling.

Describing intrinsically disordered proteins at atomic resolution by NMR

International Nuclear Information System (INIS)

Ringkjobing Jensen, Malene; Blackledge, Martin; Ruigrok, Rob WH

2013-01-01

There is growing interest in the development of physical methods to study the conformational behaviour and biological activity of intrinsically disordered proteins (IDPs). In this review recent advances in the elucidation of quantitative descriptions of disordered proteins from nuclear magnetic resonance spectroscopy are presented. Ensemble approaches are particularly well adapted to map the conformational energy landscape sampled by the protein at atomic resolution. Significant advances in development of calibrated approaches to the statistical representation of the conformational behaviour of IDPs are presented, as well as applications to some biologically important systems where disorder plays a crucial role. (authors)

Sleep-related movement disorders.

Science.gov (United States)

Merlino, Giovanni; Gigli, Gian Luigi

2012-06-01

Several movement disorders may occur during nocturnal rest disrupting sleep. A part of these complaints is characterized by relatively simple, non-purposeful and usually stereotyped movements. The last version of the International Classification of Sleep Disorders includes these clinical conditions (i.e. restless legs syndrome, periodic limb movement disorder, sleep-related leg cramps, sleep-related bruxism and sleep-related rhythmic movement disorder) under the category entitled sleep-related movement disorders. Moreover, apparently physiological movements (e.g. alternating leg muscle activation and excessive hypnic fragmentary myoclonus) can show a high frequency and severity impairing sleep quality. Clinical and, in specific cases, neurophysiological assessments are required to detect the presence of nocturnal movement complaints. Patients reporting poor sleep due to these abnormal movements should undergo non-pharmacological or pharmacological treatments.

Neurofilaments Function as Shock Absorbers: Compression Response Arising from Disordered Proteins

Science.gov (United States)

Kornreich, Micha; Malka-Gibor, Eti; Zuker, Ben; Laser-Azogui, Adi; Beck, Roy

2016-09-01

What can cells gain by using disordered, rather than folded, proteins in the architecture of their skeleton? Disordered proteins take multiple coexisting conformations, and often contain segments which act as random-walk-shaped polymers. Using x-ray scattering we measure the compression response of disordered protein hydrogels, which are the main stress-responsive component of neuron cells. We find that at high compression their mechanics are dominated by gaslike steric and ionic repulsions. At low compression, specific attractive interactions dominate. This is demonstrated by the considerable hydrogel expansion induced by the truncation of critical short protein segments. Accordingly, the floppy disordered proteins form a weakly cross-bridged hydrogel, and act as shock absorbers that sustain large deformations without failure.

Extreme disorder in an ultrahigh-affinity protein complex

Science.gov (United States)

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.

Functional Advantages of Conserved Intrinsic Disorder in RNA-Binding Proteins

OpenAIRE

Varadi, Mihaly; Zsolyomi, Fruzsina; Guharoy, Mainak; Tompa, Peter

2015-01-01

Proteins form large macromolecular assemblies with RNA that govern essential molecular processes. RNA-binding proteins have often been associated with conformational flexibility, yet the extent and functional implications of their intrinsic disorder have never been fully assessed. Here, through large-scale analysis of comprehensive protein sequence and structure datasets we demonstrate the prevalence of intrinsic structural disorder in RNA-binding proteins and domains. We addressed their func...

Transiently disordered tails accelerate folding of globular proteins.

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Mallik, Saurav; Ray, Tanaya; Kundu, Sudip

2017-07-01

Numerous biological proteins exhibit intrinsic disorder at their termini, which are associated with multifarious functional roles. Here, we show the surprising result that an increased percentage of terminal short transiently disordered regions with enhanced flexibility (TstDREF) is associated with accelerated folding rates of globular proteins. Evolutionary conservation of predicted disorder at TstDREFs and drastic alteration of folding rates upon point-mutations suggest critical regulatory role(s) of TstDREFs in shaping the folding kinetics. TstDREFs are associated with long-range intramolecular interactions and the percentage of native secondary structural elements physically contacted by TstDREFs exhibit another surprising positive correlation with folding kinetics. These results allow us to infer probable molecular mechanisms behind the TstDREF-mediated regulation of folding kinetics that challenge protein biochemists to assess by direct experimental testing. © 2017 Federation of European Biochemical Societies.

Dancing Protein Clouds: The Strange Biology and Chaotic Physics of Intrinsically Disordered Proteins.

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Uversky, Vladimir N

2016-03-25

Biologically active but floppy proteins represent a new reality of modern protein science. These intrinsically disordered proteins (IDPs) and hybrid proteins containing ordered and intrinsically disordered protein regions (IDPRs) constitute a noticeable part of any given proteome. Functionally, they complement ordered proteins, and their conformational flexibility and structural plasticity allow them to perform impossible tricks and be engaged in biological activities that are inaccessible to well folded proteins with their unique structures. The major goals of this minireview are to show that, despite their simplified amino acid sequences, IDPs/IDPRs are complex entities often resembling chaotic systems, are structurally and functionally heterogeneous, and can be considered an important part of the structure-function continuum. Furthermore, IDPs/IDPRs are everywhere, and are ubiquitously engaged in various interactions characterized by a wide spectrum of binding scenarios and an even wider spectrum of structural and functional outputs. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Conformational disorder in folded and intrinsically disordered proteins from nuclear magnetic resonance

International Nuclear Information System (INIS)

Salmon, Loic

2010-01-01

Biological macromolecules are, by essence, dynamical systems. While the importance of this flexibility is nowadays well established, the accurate characterization of the conformational disorder of these systems remains an important challenge. Nuclear magnetic resonance spectroscopy is a unique tool to probe these motions at atomic level, through the analysis of spin relaxation or residual dipolar couplings. The latter allows all motions occurring at timescales faster than the millisecond to be investigated, including physiologically important timescales. The information presents in those couplings is interpreted here using mainly analytical approaches in order to quantify the amounts of dynamics present in folded protein, to determine the direction of those motions and to obtain structural information within this conformational disorder. These analytical approaches are complemented by numerical methods, that allowed the observation of phenomena from a different point of view or the investigation of other systems such as intrinsically disordered proteins. All of these studies demonstrate an important complementarity between structural order and conformational disorder. (author)

Genome-Wide Prediction of Intrinsic Disorder; Sequence Alignment of Intrinsically Disordered Proteins

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Midic, Uros

2012-01-01

Intrinsic disorder (ID) is defined as a lack of stable tertiary and/or secondary structure under physiological conditions in vitro. Intrinsically disordered proteins (IDPs) are highly abundant in nature. IDPs possess a number of crucial biological functions, being involved in regulation, recognition, signaling and control, e.g. their functional…

Intrinsically disordered proteins aggregate at fungal cell-to-cell channels and regulate intercellular connectivity.

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Lai, Julian; Koh, Chuan Hock; Tjota, Monika; Pieuchot, Laurent; Raman, Vignesh; Chandrababu, Karthik Balakrishna; Yang, Daiwen; Wong, Limsoon; Jedd, Gregory

2012-09-25

Like animals and plants, multicellular fungi possess cell-to-cell channels (septal pores) that allow intercellular communication and transport. Here, using a combination of MS of Woronin body-associated proteins and a bioinformatics approach that identifies related proteins based on composition and character, we identify 17 septal pore-associated (SPA) proteins that localize to the septal pore in rings and pore-centered foci. SPA proteins are not homologous at the primary sequence level but share overall physical properties with intrinsically disordered proteins. Some SPA proteins form aggregates at the septal pore, and in vitro assembly assays suggest aggregation through a nonamyloidal mechanism involving mainly α-helical and disordered structures. SPA loss-of-function phenotypes include excessive septation, septal pore degeneration, and uncontrolled Woronin body activation. Together, our data identify the septal pore as a complex subcellular compartment and focal point for the assembly of unstructured proteins controlling diverse aspects of intercellular connectivity.

Changes in predicted protein disorder tendency may contribute to disease risk

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Hu Yang

2011-12-01

Full Text Available Abstract Background Recent studies suggest that many proteins or regions of proteins lack 3D structure. Defined as intrinsically disordered proteins, these proteins/peptides are functionally important. Recent advances in next generation sequencing technologies enable genome-wide identification of novel nucleotide variations in a specific population or cohort. Results Using the exonic single nucleotide variations (SNVs identified in the 1,000 Genomes Project and distributed by the Genetic Analysis Workshop 17, we systematically analysed the genetic and predicted disorder potential features of the non-synonymous variations. The result of experiments suggests that a significant change in the tendency of a protein region to be structured or disordered caused by SNVs may lead to malfunction of such a protein and contribute to disease risk. Conclusions After validation with functional SNVs on the traits distributed by GAW17, we conclude that it is valuable to consider structure/disorder tendencies while prioritizing and predicting mechanistic effects arising from novel genetic variations.

Mutation in Parkinson disease-associated, G-protein-coupled receptor 37 (GPR37/PaelR is related to autism spectrum disorder.

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Eriko Fujita-Jimbo

Full Text Available Little is known about the molecular pathogenesis of Autism spectrum disorder (ASD, a neurodevelopmental disorder. Here we identified two mutations in the G-protein-coupled receptor 37 gene (GPR37 localized on chromosome 7q31-33, called the AUTS1 region, of ASD patients; 1585-1587 ttc del (Del312F in one Japanese patient and G2324A (R558Q in one Caucasian patient. The Del312F was located in the conserved transmembrane domain, and the R558Q was located in a conserved region just distal to the last transmembrane domain. In addition, a potential ASD-related GPR37 variant, T589M, was found in 7 affected Caucasian men from five different families. Our results suggested that some alleles in GPR37 were related to the deleterious effect of ASD. GPR37 is associated with the dopamine transporter to modulate dopamine uptake, and regulates behavioral responses to dopaminergic drugs. Thus, dopaminergic neurons may be involved in the ASD. However, we also detected the Del321F mutation in the patient's unaffected father and R558Q in not only an affected brother but also an unaffected mother. The identification of unaffected parents that carried the mutated alleles suggested that the manifestation of ASD was also influenced by factors other than these mutations, including endoplasmic reticulum stress of the mutated proteins or gender. Our study will provide the new insight into the molecular pathogenesis of ASD.

Protein disorder in plants: a view from the chloroplast

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Yruela Inmaculada

2012-09-01

Full Text Available Abstract Background The intrinsically unstructured state of some proteins, observed in all living organisms, is essential for basic cellular functions. In this field the available information from plants is limited but it has been reached a point where these proteins can be comprehensively classified on the basis of disorder, function and evolution. Results Our analysis of plant genomes confirms that nuclear-encoded proteins follow the same trend than other multi-cellular eukaryotes; however, chloroplast- and mitochondria- encoded proteins conserve the patterns of Archaea and Bacteria, in agreement with their phylogenetic origin. Based on current knowledge about gene transference from the chloroplast to the nucleus, we report a strong correlation between the rate of disorder of transferred and nuclear-encoded proteins, even for polypeptides that play functional roles back in the chloroplast. We further investigate this trend by reviewing the set of chloroplast ribosomal proteins, one of the most representative transferred gene clusters, finding that the ribosomal large subunit, assembled from a majority of nuclear-encoded proteins, is clearly more unstructured than the small one, which integrates mostly plastid-encoded proteins. Conclusions Our observations suggest that the evolutionary dynamics of the plant nucleus adds disordered segments to genes alike, regardless of their origin, with the notable exception of proteins currently encoded in both genomes, probably due to functional constraints.

Malignancy in Noonan syndrome and related disorders.

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Smpokou, P; Zand, D J; Rosenbaum, K N; Summar, M L

2015-12-01

Noonan syndrome (NS) and related disorders, such as NS with multiple lentigines (formerly called LEOPARD syndrome), cardiofaciocutaneous syndrome, and Costello syndrome, constitute an important group of developmental malformation syndromes with variable clinical and molecular features. Their underlying pathophysiologic mechanism involves dysregulation of the Ras/mitogen-activated protein kinase signaling pathway, an essential mediator of developmental and growth processes in the prenatal and postnatal setting. Malignant tumor development is an important complication encountered in other RASopathies, such as neurofibromatosis type 1, but the neoplastic risks and incidence of malignant tumors are less clearly defined in NS and related disorders of the Noonan spectrum. Malignant tumor development remains an important complication variably seen in the RASopathies and, thus, a clear understanding of the underlying risks is essential for appropriate clinical care in this patient population. This review discusses previously published reports of malignancies in individuals with RASopathies of the Noonan spectrum. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

High GC content causes orphan proteins to be intrinsically disordered.

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Walter Basile

2017-03-01

Full Text Available De novo creation of protein coding genes involves the formation of short ORFs from noncoding regions; some of these ORFs might then become fixed in the population. These orphan proteins need to, at the bare minimum, not cause serious harm to the organism, meaning that they should for instance not aggregate. Therefore, although the creation of short ORFs could be truly random, the fixation should be subjected to some selective pressure. The selective forces acting on orphan proteins have been elusive, and contradictory results have been reported. In Drosophila young proteins are more disordered than ancient ones, while the opposite trend is present in yeast. To the best of our knowledge no valid explanation for this difference has been proposed. To solve this riddle we studied structural properties and age of proteins in 187 eukaryotic organisms. We find that, with the exception of length, there are only small differences in the properties between proteins of different ages. However, when we take the GC content into account we noted that it could explain the opposite trends observed for orphans in yeast (low GC and Drosophila (high GC. GC content is correlated with codons coding for disorder promoting amino acids. This leads us to propose that intrinsic disorder is not a strong determining factor for fixation of orphan proteins. Instead these proteins largely resemble random proteins given a particular GC level. During evolution the properties of a protein change faster than the GC level causing the relationship between disorder and GC to gradually weaken.

Work-related voice disorder

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Paulo Eduardo Przysiezny

2015-04-01

Full Text Available INTRODUCTION: Dysphonia is the main symptom of the disorders of oral communication. However, voice disorders also present with other symptoms such as difficulty in maintaining the voice (asthenia, vocal fatigue, variation in habitual vocal fundamental frequency, hoarseness, lack of vocal volume and projection, loss of vocal efficiency, and weakness when speaking. There are several proposals for the etiologic classification of dysphonia: functional, organofunctional, organic, and work-related voice disorder (WRVD.OBJECTIVE: To conduct a literature review on WRVD and on the current Brazilian labor legislation.METHODS: This was a review article with bibliographical research conducted on the PubMed and Bireme databases, using the terms "work-related voice disorder", "occupational dysphonia", "dysphonia and labor legislation", and a review of labor and social security relevant laws.CONCLUSION: WRVD is a situation that frequently is listed as a reason for work absenteeism, functional rehabilitation, or for prolonged absence from work. Currently, forensic physicians have no comparative parameters to help with the analysis of vocal disorders. In certain situations WRVD may cause, work disability. This disorder may be labor-related, or be an adjuvant factor to work-related diseases.

Wrecked regulation of intrinsically disordered proteins in diseases: Pathogenicity of deregulated regulators

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Vladimir N. Uversky

2014-07-01

Full Text Available Biologically active proteins without stable tertiary structure are common in all known proteomes. Functions of these intrinsically disordered proteins (IDPs are typically related to regulation, signaling and control. Cellular levels of these important regulators are tightly regulated by a variety mechanisms ranging from firmly controlled expression to precisely targeted degradation. Functions of IDPs are controlled by binding to specific partners, alternative splicing, and posttranslational modifications among other means. In the norm, right amounts of precisely activated IDPs have to be present in right time at right places. Wrecked regulation brings havoc to the ordered world of disordered proteins, leading to protein misfolding, misidentification, and missignaling that give rise to numerous human diseases, such as cancer, cardiovascular disease, neurodegenerative diseases, and diabetes. Among factors inducing pathogenic transformations of IDPs are various cellular mechanisms, such as chromosomal translocations, damaged splicing, altered expression, frustrated posttranslational modifications, aberrant proteolytic degradation, and defective trafficking. This review presents some of the aspects of deregulated regulation of IDPs leading to human diseases.

Attention-deficit/hyperactivity disorder symptoms and stress-related biomarkers.

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Vogel, S W N; Bijlenga, D; Verduijn, J; Bron, T I; Beekman, A T F; Kooij, J J S; Penninx, B W J H

2017-05-01

The current study examined whether (a) Attention-Deficit/Hyperactivity Disorder (ADHD) symptoms were associated with dysregulation of stress-related mechanisms, and (b) whether ADHD symptoms interact with affective disorders in their association with dysregulated stress-related mechanisms. Data were obtained from 2307 subjects participating in the Netherlands Study of Depression and Anxiety. Stress-related mechanisms were reflected by the following biomarkers: (1) hypothalamic-pituitary-adrenal axis indicators (salivary cortisol awakening curve, evening cortisol, cortisol suppression after a 0.5mg dexamethasone suppression test (DST)); (2) autonomic nervous system measures (heart rate, pre-ejection period, respiratory sinus arrhythmia); (3) inflammatory markers (C-reactive protein, interleukin-6, tumor necrosis factor-alpha); (4) brain-derived neurotrophic factor. ADHD symptoms were measured using Conners' Adult ADHD Rating Scale and used both dichotomous (High ADHD symptoms (yes/no)) and continuous (Inattentive symptoms, Hyperactive/Impulsive symptoms, and the ADHD index). Regression analyses showed associations between High ADHD symptoms, Inattentive symptoms, the ADHD index and a higher cortisol awakening curve, between Hyperactive/Impulsive symptoms and less cortisol suppression after DST, and between Inattentive symptoms and a longer pre-ejection period. However, the associations with the cortisol awakening curve disappeared after adjustment for depressive and anxiety disorders. No associations were observed between ADHD symptoms and inflammatory markers or BDNF. ADHD symptoms did not interact with affective disorders in dysregulation of stress-related mechanisms. Some associations were observed between ADHD symptoms, the HPA-axis, and the pre-ejection period, but these were mostly driven by depressive and anxiety disorders. This study found no evidence that ADHD symptomatology was associated with dysregulations in inflammatory markers and BDNF. Consequently

Identification of Inhibitors of Biological Interactions Involving Intrinsically Disordered Proteins

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Daniela Marasco

2015-04-01

Full Text Available Protein–protein interactions involving disordered partners have unique features and represent prominent targets in drug discovery processes. Intrinsically Disordered Proteins (IDPs are involved in cellular regulation, signaling and control: they bind to multiple partners and these high-specificity/low-affinity interactions play crucial roles in many human diseases. Disordered regions, terminal tails and flexible linkers are particularly abundant in DNA-binding proteins and play crucial roles in the affinity and specificity of DNA recognizing processes. Protein complexes involving IDPs are short-lived and typically involve short amino acid stretches bearing few “hot spots”, thus the identification of molecules able to modulate them can produce important lead compounds: in this scenario peptides and/or peptidomimetics, deriving from structure-based, combinatorial or protein dissection approaches, can play a key role as hit compounds. Here, we propose a panoramic review of the structural features of IDPs and how they regulate molecular recognition mechanisms focusing attention on recently reported drug-design strategies in the field of IDPs.

An Overview of Practical Applications of Protein Disorder Prediction and Drive for Faster, More Accurate Predictions.

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Deng, Xin; Gumm, Jordan; Karki, Suman; Eickholt, Jesse; Cheng, Jianlin

2015-07-07

Protein disordered regions are segments of a protein chain that do not adopt a stable structure. Thus far, a variety of protein disorder prediction methods have been developed and have been widely used, not only in traditional bioinformatics domains, including protein structure prediction, protein structure determination and function annotation, but also in many other biomedical fields. The relationship between intrinsically-disordered proteins and some human diseases has played a significant role in disorder prediction in disease identification and epidemiological investigations. Disordered proteins can also serve as potential targets for drug discovery with an emphasis on the disordered-to-ordered transition in the disordered binding regions, and this has led to substantial research in drug discovery or design based on protein disordered region prediction. Furthermore, protein disorder prediction has also been applied to healthcare by predicting the disease risk of mutations in patients and studying the mechanistic basis of diseases. As the applications of disorder prediction increase, so too does the need to make quick and accurate predictions. To fill this need, we also present a new approach to predict protein residue disorder using wide sequence windows that is applicable on the genomic scale.

An Overview of Practical Applications of Protein Disorder Prediction and Drive for Faster, More Accurate Predictions

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Xin Deng

2015-07-01

Full Text Available Protein disordered regions are segments of a protein chain that do not adopt a stable structure. Thus far, a variety of protein disorder prediction methods have been developed and have been widely used, not only in traditional bioinformatics domains, including protein structure prediction, protein structure determination and function annotation, but also in many other biomedical fields. The relationship between intrinsically-disordered proteins and some human diseases has played a significant role in disorder prediction in disease identification and epidemiological investigations. Disordered proteins can also serve as potential targets for drug discovery with an emphasis on the disordered-to-ordered transition in the disordered binding regions, and this has led to substantial research in drug discovery or design based on protein disordered region prediction. Furthermore, protein disorder prediction has also been applied to healthcare by predicting the disease risk of mutations in patients and studying the mechanistic basis of diseases. As the applications of disorder prediction increase, so too does the need to make quick and accurate predictions. To fill this need, we also present a new approach to predict protein residue disorder using wide sequence windows that is applicable on the genomic scale.

The dynamic multisite interactions between two intrinsically disordered proteins

KAUST Repository

Wu, Shaowen

2017-05-11

Protein interactions involving intrinsically disordered proteins (IDPs) comprise a variety of binding modes, from the well characterized folding upon binding to dynamic fuzzy complex. To date, most studies concern the binding of an IDP to a structured protein, while the Interaction between two IDPs is poorly understood. In this study, we combined NMR, smFRET, and molecular dynamics (MD) simulation to characterize the interaction between two IDPs, the C-terminal domain (CTD) of protein 4.1G and the nuclear mitotic apparatus (NuMA) protein. It is revealed that CTD and NuMA form a fuzzy complex with remaining structural disorder. Multiple binding sites on both proteins were identified by MD and mutagenesis studies. Our study provides an atomic scenario in which two IDPs bearing multiple binding sites interact with each other in dynamic equilibrium. The combined approach employed here could be widely applicable for investigating IDPs and their dynamic interactions.

Intrinsically Disordered Segments Affect Protein Half-Life in the Cell and during Evolution

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Robin van der Lee

2014-09-01

Full Text Available Precise control of protein turnover is essential for cellular homeostasis. The ubiquitin-proteasome system is well established as a major regulator of protein degradation, but an understanding of how inherent structural features influence the lifetimes of proteins is lacking. We report that yeast, mouse, and human proteins with terminal or internal intrinsically disordered segments have significantly shorter half-lives than proteins without these features. The lengths of the disordered segments that affect protein half-life are compatible with the structure of the proteasome. Divergence in terminal and internal disordered segments in yeast proteins originating from gene duplication leads to significantly altered half-life. Many paralogs that are affected by such changes participate in signaling, where altered protein half-life will directly impact cellular processes and function. Thus, natural variation in the length and position of disordered segments may affect protein half-life and could serve as an underappreciated source of genetic variation with important phenotypic consequences.

Homer1a protein expression in schizophrenia, bipolar disorder, and major depression.

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Leber, Stefan L; Llenos, Ida C; Miller, Christine L; Dulay, Jeannette R; Haybaeck, Johannes; Weis, Serge

2017-10-01

In recent years, there was growing interest in postsynaptic density proteins in the central nervous system. Of the most important candidates of this specialized region are proteins belonging to the Homer protein family. This family of scaffolding proteins is suspected to participate in the pathogenesis of a variety of diseases. The present study aims to compare Homer1a expression in the hippocampus and cingulate gyrus of patients with major psychiatric disorders including schizophrenia, bipolar disorder and major depression. Immunohistochemistry was used to analyze changes of Homer1a protein expression in the hippocampal formation and the cingulate gyrus from the respective disease groups. Glial cells of the cingulate gyrus gray matter showed decreased Homer1a levels in bipolar disorder when compared to controls. The same results were seen when comparing cingulate gyrus gray matter glial cells in bipolar disorder with major depression. Stratum oriens glial cells of the hippocampus showed decreased Homer1a levels in bipolar disorder when compared to controls and major depression. Stratum lacunosum glial cells showed decreased Homer1a levels in bipolar disorder when compared to major depression. In stratum oriens interneurons Homer1a levels were increased in all disease groups when compared to controls. Stratum lucidum axons showed decreased Homer1a levels in bipolar disorder when compared to controls. Our data demonstrate altered Homer1a levels in specific brain regions and cell types of patients suffering from schizophrenia, bipolar disorder and major depression. These findings support the role of Homer proteins as interesting candidates in neuropsychiatric pathophysiology and treatment.

Related Addictive Disorders.

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Buck, Tina; Sales, Amos

This paper provides an overview of addiction related to substance abuse. It provides basic information, prevalence, diagnostic criteria, assessment tools, and treatment issues for eating disorders, compulsive gambling, sex addictions, and work addictions. Eating disorders such as anorexia nervosa and bulimia nervosa, especially affect adolescents.…

Gene Prioritization by Integrated Analysis of Protein Structural and Network Topological Properties for the Protein-Protein Interaction Network of Neurological Disorders

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Yashna Paul

2016-01-01

Full Text Available Neurological disorders are known to show similar phenotypic manifestations like anxiety, depression, and cognitive impairment. There is a need to identify shared genetic markers and molecular pathways in these diseases, which lead to such comorbid conditions. Our study aims to prioritize novel genetic markers that might increase the susceptibility of patients affected with one neurological disorder to other diseases with similar manifestations. Identification of pathways involving common candidate markers will help in the development of improved diagnosis and treatments strategies for patients affected with neurological disorders. This systems biology study for the first time integratively uses 3D-structural protein interface descriptors and network topological properties that characterize proteins in a neurological protein interaction network, to aid the identification of genes that are previously not known to be shared between these diseases. Results of protein prioritization by machine learning have identified known as well as new genetic markers which might have direct or indirect involvement in several neurological disorders. Important gene hubs have also been identified that provide an evidence for shared molecular pathways in the neurological disease network.

What's in a name? : Why these proteins are intrinsically disordered: Why these proteins are intrinsically disordered

NARCIS (Netherlands)

Dunker, A Keith; Babu, M Madan; Barbar, Elisar; Blackledge, Martin; Bondos, Sarah E; Dosztányi, Zsuzsanna; Dyson, H Jane; Forman-Kay, Julie; Fuxreiter, Monika; Gsponer, Jörg; Han, Kyou-Hoon; Jones, David T; Longhi, Sonia; Metallo, Steven J; Nishikawa, Ken; Nussinov, Ruth; Obradovic, Zoran; Pappu, Rohit V; Rost, Burkhard; Selenko, Philipp; Subramaniam, Vinod; Sussman, Joel L; Tompa, Peter; Uversky, Vladimir N

2013-01-01

"What's in a name? That which we call a rose By any other name would smell as sweet." From "Romeo and Juliet", William Shakespeare (1594) This article opens a series of publications on disambiguation of the basic terms used in the field of intrinsically disordered proteins. We start from the

Animal Models of Hemophilia and Related Bleeding Disorders

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Lozier, Jay N.; Nichols, Timothy C.

2013-01-01

Animal models of hemophilia and related diseases are important for development of novel treatments and to understand the pathophysiology of bleeding disorders in humans. Testing in animals with the equivalent human disorder provides informed estimates of doses and measures of efficacy, which aids in design of human trials. Many models of hemophilia A, hemophilia B, and von Willebrand disease have been developed from animals with spontaneous mutations (hemophilia A dogs, rats, sheep; hemophilia B dogs; and von Willebrand disease pigs and dogs), or by targeted gene disruption in mice to create hemophilia A, B, or VWD models. Animal models have been used to generate new insights into the pathophysiology of each bleeding disorder and also to perform pre-clinical assessments of standard protein replacement therapies as well as novel gene transfer technology. Both the differences between species and differences in underlying causative mutations must be considered in choosing the best animal for a specific scientific study PMID:23956467

Partner-Mediated Polymorphism of an Intrinsically Disordered Protein.

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Bignon, Christophe; Troilo, Francesca; Gianni, Stefano; Longhi, Sonia

2017-11-29

Intrinsically disordered proteins (IDPs) recognize their partners through molecular recognition elements (MoREs). The MoRE of the C-terminal intrinsically disordered domain of the measles virus nucleoprotein (N TAIL ) is partly pre-configured as an α-helix in the free form and undergoes α-helical folding upon binding to the X domain (XD) of the viral phosphoprotein. Beyond XD, N TAIL also binds the major inducible heat shock protein 70 (hsp70). So far, no structural information is available for the N TAIL /hsp70 complex. Using mutational studies combined with a protein complementation assay based on green fluorescent protein reconstitution, we have investigated both N TAIL /XD and N TAIL /hsp70 interactions. Although the same N TAIL region binds the two partners, the binding mechanisms are different. Hsp70 binding is much more tolerant of MoRE substitutions than XD, and the majority of substitutions lead to an increased N TAIL /hsp70 interaction strength. Furthermore, while an increased and a decreased α-helicity of the MoRE lead to enhanced and reduced interaction strength with XD, respectively, the impact on hsp70 binding is negligible, suggesting that the MoRE does not adopt an α-helical conformation once bound to hsp70. Here, by showing that the α-helical conformation sampled by the free form of the MoRE does not systematically commit it to adopt an α-helical conformation in the bound form, we provide an example of partner-mediated polymorphism of an IDP and of the relative insensitiveness of the bound structure to the pre-recognition state. The present results therefore contribute to shed light on the molecular mechanisms by which IDPs recognize different partners. Copyright © 2017 Elsevier Ltd. All rights reserved.

The Ising model for prediction of disordered residues from protein sequence alone

International Nuclear Information System (INIS)

Lobanov, Michail Yu; Galzitskaya, Oxana V

2011-01-01

Intrinsically disordered regions serve as molecular recognition elements, which play an important role in the control of many cellular processes and signaling pathways. It is useful to be able to predict positions of disordered residues and disordered regions in protein chains using protein sequence alone. A new method (IsUnstruct) based on the Ising model for prediction of disordered residues from protein sequence alone has been developed. According to this model, each residue can be in one of two states: ordered or disordered. The model is an approximation of the Ising model in which the interaction term between neighbors has been replaced by a penalty for changing between states (the energy of border). The IsUnstruct has been compared with other available methods and found to perform well. The method correctly finds 77% of disordered residues as well as 87% of ordered residues in the CASP8 database, and 72% of disordered residues as well as 85% of ordered residues in the DisProt database

ProteinSplit: splitting of multi-domain proteins using prediction of ordered and disordered regions in protein sequences for virtual structural genomics

International Nuclear Information System (INIS)

Wyrwicz, Lucjan S; Koczyk, Grzegorz; Rychlewski, Leszek; Plewczynski, Dariusz

2007-01-01

The annotation of protein folds within newly sequenced genomes is the main target for semi-automated protein structure prediction (virtual structural genomics). A large number of automated methods have been developed recently with very good results in the case of single-domain proteins. Unfortunately, most of these automated methods often fail to properly predict the distant homology between a given multi-domain protein query and structural templates. Therefore a multi-domain protein should be split into domains in order to overcome this limitation. ProteinSplit is designed to identify protein domain boundaries using a novel algorithm that predicts disordered regions in protein sequences. The software utilizes various sequence characteristics to assess the local propensity of a protein to be disordered or ordered in terms of local structure stability. These disordered parts of a protein are likely to create interdomain spacers. Because of its speed and portability, the method was successfully applied to several genome-wide fold annotation experiments. The user can run an automated analysis of sets of proteins or perform semi-automated multiple user projects (saving the results on the server). Additionally the sequences of predicted domains can be sent to the Bioinfo.PL Protein Structure Prediction Meta-Server for further protein three-dimensional structure and function prediction. The program is freely accessible as a web service at http://lucjan.bioinfo.pl/proteinsplit together with detailed benchmark results on the critical assessment of a fully automated structure prediction (CAFASP) set of sequences. The source code of the local version of protein domain boundary prediction is available upon request from the authors

Alanine and proline content modulate global sensitivity to discrete perturbations in disordered proteins.

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Perez, Romel B; Tischer, Alexander; Auton, Matthew; Whitten, Steven T

2014-12-01

Molecular transduction of biological signals is understood primarily in terms of the cooperative structural transitions of protein macromolecules, providing a mechanism through which discrete local structure perturbations affect global macromolecular properties. The recognition that proteins lacking tertiary stability, commonly referred to as intrinsically disordered proteins (IDPs), mediate key signaling pathways suggests that protein structures without cooperative intramolecular interactions may also have the ability to couple local and global structure changes. Presented here are results from experiments that measured and tested the ability of disordered proteins to couple local changes in structure to global changes in structure. Using the intrinsically disordered N-terminal region of the p53 protein as an experimental model, a set of proline (PRO) and alanine (ALA) to glycine (GLY) substitution variants were designed to modulate backbone conformational propensities without introducing non-native intramolecular interactions. The hydrodynamic radius (R(h)) was used to monitor changes in global structure. Circular dichroism spectroscopy showed that the GLY substitutions decreased polyproline II (PP(II)) propensities relative to the wild type, as expected, and fluorescence methods indicated that substitution-induced changes in R(h) were not associated with folding. The experiments showed that changes in local PP(II) structure cause changes in R(h) that are variable and that depend on the intrinsic chain propensities of PRO and ALA residues, demonstrating a mechanism for coupling local and global structure changes. Molecular simulations that model our results were used to extend the analysis to other proteins and illustrate the generality of the observed PRO and alanine effects on the structures of IDPs. © 2014 Wiley Periodicals, Inc.

The dynamic multisite interactions between two intrinsically disordered proteins

KAUST Repository

Wu, Shaowen; Wang, Dongdong; Liu, Jin; Feng, Yitao; Weng, Jingwei; Li, Yu; Gao, Xin; Liu, Jianwei; Wang, Wenning

2017-01-01

Protein interactions involving intrinsically disordered proteins (IDPs) comprise a variety of binding modes, from the well characterized folding upon binding to dynamic fuzzy complex. To date, most studies concern the binding of an IDP to a

RNA chaperoning and intrinsic disorder in the core proteins of Flaviviridae.

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Ivanyi-Nagy, Roland; Lavergne, Jean-Pierre; Gabus, Caroline; Ficheux, Damien; Darlix, Jean-Luc

2008-02-01

RNA chaperone proteins are essential partners of RNA in living organisms and viruses. They are thought to assist in the correct folding and structural rearrangements of RNA molecules by resolving misfolded RNA species in an ATP-independent manner. RNA chaperoning is probably an entropy-driven process, mediated by the coupled binding and folding of intrinsically disordered protein regions and the kinetically trapped RNA. Previously, we have shown that the core protein of hepatitis C virus (HCV) is a potent RNA chaperone that can drive profound structural modifications of HCV RNA in vitro. We now examined the RNA chaperone activity and the disordered nature of core proteins from different Flaviviridae genera, namely that of HCV, GBV-B (GB virus B), WNV (West Nile virus) and BVDV (bovine viral diarrhoea virus). Despite low-sequence similarities, all four proteins demonstrated general nucleic acid annealing and RNA chaperone activities. Furthermore, heat resistance of core proteins, as well as far-UV circular dichroism spectroscopy suggested that a well-defined 3D protein structure is not necessary for core-induced RNA structural rearrangements. These data provide evidence that RNA chaperoning-possibly mediated by intrinsically disordered protein segments-is conserved in Flaviviridae core proteins. Thus, besides nucleocapsid formation, core proteins may function in RNA structural rearrangements taking place during virus replication.

Protein secondary structure appears to be robust under in silico evolution while protein disorder appears not to be.

KAUST Repository

Schaefer, Christian

2010-01-16

MOTIVATION: The mutation of amino acids often impacts protein function and structure. Mutations without negative effect sustain evolutionary pressure. We study a particular aspect of structural robustness with respect to mutations: regular protein secondary structure and natively unstructured (intrinsically disordered) regions. Is the formation of regular secondary structure an intrinsic feature of amino acid sequences, or is it a feature that is lost upon mutation and is maintained by evolution against the odds? Similarly, is disorder an intrinsic sequence feature or is it difficult to maintain? To tackle these questions, we in silico mutated native protein sequences into random sequence-like ensembles and monitored the change in predicted secondary structure and disorder. RESULTS: We established that by our coarse-grained measures for change, predictions and observations were similar, suggesting that our results were not biased by prediction mistakes. Changes in secondary structure and disorder predictions were linearly proportional to the change in sequence. Surprisingly, neither the content nor the length distribution for the predicted secondary structure changed substantially. Regions with long disorder behaved differently in that significantly fewer such regions were predicted after a few mutation steps. Our findings suggest that the formation of regular secondary structure is an intrinsic feature of random amino acid sequences, while the formation of long-disordered regions is not an intrinsic feature of proteins with disordered regions. Put differently, helices and strands appear to be maintained easily by evolution, whereas maintaining disordered regions appears difficult. Neutral mutations with respect to disorder are therefore very unlikely.

Protein secondary structure appears to be robust under in silico evolution while protein disorder appears not to be.

KAUST Repository

Schaefer, Christian; Schlessinger, Avner; Rost, Burkhard

2010-01-01

MOTIVATION: The mutation of amino acids often impacts protein function and structure. Mutations without negative effect sustain evolutionary pressure. We study a particular aspect of structural robustness with respect to mutations: regular protein secondary structure and natively unstructured (intrinsically disordered) regions. Is the formation of regular secondary structure an intrinsic feature of amino acid sequences, or is it a feature that is lost upon mutation and is maintained by evolution against the odds? Similarly, is disorder an intrinsic sequence feature or is it difficult to maintain? To tackle these questions, we in silico mutated native protein sequences into random sequence-like ensembles and monitored the change in predicted secondary structure and disorder. RESULTS: We established that by our coarse-grained measures for change, predictions and observations were similar, suggesting that our results were not biased by prediction mistakes. Changes in secondary structure and disorder predictions were linearly proportional to the change in sequence. Surprisingly, neither the content nor the length distribution for the predicted secondary structure changed substantially. Regions with long disorder behaved differently in that significantly fewer such regions were predicted after a few mutation steps. Our findings suggest that the formation of regular secondary structure is an intrinsic feature of random amino acid sequences, while the formation of long-disordered regions is not an intrinsic feature of proteins with disordered regions. Put differently, helices and strands appear to be maintained easily by evolution, whereas maintaining disordered regions appears difficult. Neutral mutations with respect to disorder are therefore very unlikely.

Distribution of language-related Cntnap2 protein in neural circuits critical for vocal learning.

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Condro, Michael C; White, Stephanie A

2014-01-01

Variants of the contactin associated protein-like 2 (Cntnap2) gene are risk factors for language-related disorders including autism spectrum disorder, specific language impairment, and stuttering. Songbirds are useful models for study of human speech disorders due to their shared capacity for vocal learning, which relies on similar cortico-basal ganglia circuitry and genetic factors. Here we investigate Cntnap2 protein expression in the brain of the zebra finch, a songbird species in which males, but not females, learn their courtship songs. We hypothesize that Cntnap2 has overlapping functions in vocal learning species, and expect to find protein expression in song-related areas of the zebra finch brain. We further expect that the distribution of this membrane-bound protein may not completely mirror its mRNA distribution due to the distinct subcellular localization of the two molecular species. We find that Cntnap2 protein is enriched in several song control regions relative to surrounding tissues, particularly within the adult male, but not female, robust nucleus of the arcopallium (RA), a cortical song control region analogous to human layer 5 primary motor cortex. The onset of this sexually dimorphic expression coincides with the onset of sensorimotor learning in developing males. Enrichment in male RA appears due to expression in projection neurons within the nucleus, as well as to additional expression in nerve terminals of cortical projections to RA from the lateral magnocellular nucleus of the nidopallium. Cntnap2 protein expression in zebra finch brain supports the hypothesis that this molecule affects neural connectivity critical for vocal learning across taxonomic classes. Copyright © 2013 Wiley Periodicals, Inc.

Deciphering RNA-Recognition Patterns of Intrinsically Disordered Proteins

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Ambuj Srivastava

2018-05-01

Full Text Available Intrinsically disordered regions (IDRs and protein (IDPs are highly flexible owing to their lack of well-defined structures. A subset of such proteins interacts with various substrates; including RNA; frequently adopting regular structures in the final complex. In this work; we have analysed a dataset of protein–RNA complexes undergoing disorder-to-order transition (DOT upon binding. We found that DOT regions are generally small in size (less than 3 residues for RNA binding proteins. Like structured proteins; positively charged residues are found to interact with RNA molecules; indicating the dominance of electrostatic and cation-π interactions. However, a comparison of binding frequency shows that interface hydrophobic and aromatic residues have more interactions in only DOT regions than in a protein. Further; DOT regions have significantly higher exposure to water than their structured counterparts. Interactions of DOT regions with RNA increase the sheet formation with minor changes in helix forming residues. We have computed the interaction energy for amino acids–nucleotide pairs; which showed the preference of His–G; Asn–U and Ser–U at for the interface of DOT regions. This study provides insights to understand protein–RNA interactions and the results could also be used for developing a tool for identifying DOT regions in RNA binding proteins.

Lower glutamic acid decarboxylase 65kD mRNA and protein levels in the prefrontal cortex in schizoaffective disorder but not schizophrenia

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Glausier, JR; Kimoto, S; Fish, KN; Lewis, DA

2014-01-01

Background Altered GABA signaling in the prefrontal cortex (PFC) has been associated with cognitive dysfunction in schizophrenia and schizoaffective disorder. PFC levels of the GABA-synthesizing enzyme glutamic acid decarboxylase 67kD (GAD67) has been consistently reported to be lower in these disorders, but the status of the second GABA-synthesizing enzyme, GAD65, remains unclear. Methods GAD65 mRNA levels were quantified in PFC area 9 by quantitative polymerase chain reaction from 62 subjects with schizophrenia or schizoaffective disorder and 62 matched healthy comparison subjects. GAD65 relative protein levels were quantified in a subset of subject pairs by confocal immunofluorescence microscopy. Results Mean GAD65 mRNA levels were 13.6% lower in schizoaffective disorder subjects, but did not differ in schizophrenia subjects, relative to their matched healthy comparison subjects. In the subjects with schizoaffective disorder, mean GAD65 protein levels were 19.4% lower and were correlated with GAD65 mRNA levels. Lower GAD65 mRNA and protein measures within schizoaffective disorder subjects was not attributable to factors commonly comorbid with the diagnosis. Conclusions In concert with previous studies, these findings suggest that schizoaffective disorder is associated with lower levels of both GAD65 and GAD67 mRNA and protein in the PFC, whereas subjects with schizophrenia have lower mean levels of only GAD67 mRNA and protein. Because cognitive function is generally better preserved in subjects with schizoaffective disorder relative to subjects with schizophrenia, these findings may support an interpretation that GAD65 down-regulation provides a homeostatic response complementary to GAD67 down-regulation expression that serves to reduce inhibition in the face of lower PFC network activity. PMID:24993056

Intrinsic disorder in Viral Proteins Genome-Linked: experimental and predictive analyses

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Van Dorsselaer Alain

2009-02-01

Full Text Available Abstract Background VPgs are viral proteins linked to the 5' end of some viral genomes. Interactions between several VPgs and eukaryotic translation initiation factors eIF4Es are critical for plant infection. However, VPgs are not restricted to phytoviruses, being also involved in genome replication and protein translation of several animal viruses. To date, structural data are still limited to small picornaviral VPgs. Recently three phytoviral VPgs were shown to be natively unfolded proteins. Results In this paper, we report the bacterial expression, purification and biochemical characterization of two phytoviral VPgs, namely the VPgs of Rice yellow mottle virus (RYMV, genus Sobemovirus and Lettuce mosaic virus (LMV, genus Potyvirus. Using far-UV circular dichroism and size exclusion chromatography, we show that RYMV and LMV VPgs are predominantly or partly unstructured in solution, respectively. Using several disorder predictors, we show that both proteins are predicted to possess disordered regions. We next extend theses results to 14 VPgs representative of the viral diversity. Disordered regions were predicted in all VPg sequences whatever the genus and the family. Conclusion Based on these results, we propose that intrinsic disorder is a common feature of VPgs. The functional role of intrinsic disorder is discussed in light of the biological roles of VPgs.

Salt-bridge networks within globular and disordered proteins: characterizing trends for designable interactions.

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Basu, Sankar; Mukharjee, Debasish

2017-07-01

There has been considerable debate about the contribution of salt bridges to the stabilization of protein folds, in spite of their participation in crucial protein functions. Salt bridges appear to contribute to the activity-stability trade-off within proteins by bringing high-entropy charged amino acids into close contacts during the course of their functions. The current study analyzes the modes of association of salt bridges (in terms of networks) within globular proteins and at protein-protein interfaces. While the most common and trivial type of salt bridge is the isolated salt bridge, bifurcated salt bridge appears to be a distinct salt-bridge motif having a special topology and geometry. Bifurcated salt bridges are found ubiquitously in proteins and interprotein complexes. Interesting and attractive examples presenting different modes of interaction are highlighted. Bifurcated salt bridges appear to function as molecular clips that are used to stitch together large surface contours at interacting protein interfaces. The present work also emphasizes the key role of salt-bridge-mediated interactions in the partial folding of proteins containing long stretches of disordered regions. Salt-bridge-mediated interactions seem to be pivotal to the promotion of "disorder-to-order" transitions in small disordered protein fragments and their stabilization upon binding. The results obtained in this work should help to guide efforts to elucidate the modus operandi of these partially disordered proteins, and to conceptualize how these proteins manage to maintain the required amount of disorder even in their bound forms. This work could also potentially facilitate explorations of geometrically specific designable salt bridges through the characterization of composite salt-bridge networks. Graphical abstract ᅟ.

Predicting binding within disordered protein regions to structurally characterised peptide-binding domains.

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Waqasuddin Khan

Full Text Available Disordered regions of proteins often bind to structured domains, mediating interactions within and between proteins. However, it is difficult to identify a priori the short disordered regions involved in binding. We set out to determine if docking such peptide regions to peptide binding domains would assist in these predictions.We assembled a redundancy reduced dataset of SLiM (Short Linear Motif containing proteins from the ELM database. We selected 84 sequences which had an associated PDB structures showing the SLiM bound to a protein receptor, where the SLiM was found within a 50 residue region of the protein sequence which was predicted to be disordered. First, we investigated the Vina docking scores of overlapping tripeptides from the 50 residue SLiM containing disordered regions of the protein sequence to the corresponding PDB domain. We found only weak discrimination of docking scores between peptides involved in binding and adjacent non-binding peptides in this context (AUC 0.58.Next, we trained a bidirectional recurrent neural network (BRNN using as input the protein sequence, predicted secondary structure, Vina docking score and predicted disorder score. The results were very promising (AUC 0.72 showing that multiple sources of information can be combined to produce results which are clearly superior to any single source.We conclude that the Vina docking score alone has only modest power to define the location of a peptide within a larger protein region known to contain it. However, combining this information with other knowledge (using machine learning methods clearly improves the identification of peptide binding regions within a protein sequence. This approach combining docking with machine learning is primarily a predictor of binding to peptide-binding sites, and is not intended as a predictor of specificity of binding to particular receptors.

Microsecond molecular dynamics simulations of intrinsically disordered proteins involved in the oxidative stress response.

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Elio A Cino

Full Text Available Intrinsically disordered proteins (IDPs are abundant in cells and have central roles in protein-protein interaction networks. Interactions between the IDP Prothymosin alpha (ProTα and the Neh2 domain of Nuclear factor erythroid 2-related factor 2 (Nrf2, with a common binding partner, Kelch-like ECH-associated protein 1(Keap1, are essential for regulating cellular response to oxidative stress. Misregulation of this pathway can lead to neurodegenerative diseases, premature aging and cancer. In order to understand the mechanisms these two disordered proteins employ to bind to Keap1, we performed extensive 0.5-1.0 microsecond atomistic molecular dynamics (MD simulations and isothermal titration calorimetry experiments to investigate the structure/dynamics of free-state ProTα and Neh2 and their thermodynamics of bindings. The results show that in their free states, both ProTα and Neh2 have propensities to form bound-state-like β-turn structures but to different extents. We also found that, for both proteins, residues outside the Keap1-binding motifs may play important roles in stabilizing the bound-state-like structures. Based on our findings, we propose that the binding of disordered ProTα and Neh2 to Keap1 occurs synergistically via preformed structural elements (PSEs and coupled folding and binding, with a heavy bias towards PSEs, particularly for Neh2. Our results provide insights into the molecular mechanisms Neh2 and ProTα bind to Keap1, information that is useful for developing therapeutics to enhance the oxidative stress response.

Lower glutamic acid decarboxylase 65-kDa isoform messenger RNA and protein levels in the prefrontal cortex in schizoaffective disorder but not schizophrenia.

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Glausier, Jill R; Kimoto, Sohei; Fish, Kenneth N; Lewis, David A

2015-01-15

Altered gamma-aminobutyric acid (GABA) signaling in the prefrontal cortex (PFC) has been associated with cognitive dysfunction in patients with schizophrenia and schizoaffective disorder. Levels of the GABA-synthesizing enzyme glutamic acid decarboxylase 67-kDa isoform (GAD67) in the PFC have been consistently reported to be lower in patients with these disorders, but the status of the second GABA-synthesizing enzyme, glutamic acid decarboxylase 65-kDa isoform (GAD65), remains unclear. GAD65 messenger RNA (mRNA) levels were quantified in PFC area 9 by quantitative polymerase chain reaction from 62 subjects with schizophrenia or schizoaffective disorder and 62 matched healthy comparison subjects. In a subset of subject pairs, GAD65 relative protein levels were quantified by confocal immunofluorescence microscopy. Mean GAD65 mRNA levels were 13.6% lower in subjects with schizoaffective disorder but did not differ in subjects with schizophrenia relative to their matched healthy comparison subjects. In the subjects with schizoaffective disorder, mean GAD65 protein levels were 19.4% lower and were correlated with GAD65 mRNA levels. Lower GAD65 mRNA and protein levels within subjects with schizoaffective disorder were not attributable to factors commonly comorbid with the diagnosis. In concert with previous studies, these findings suggest that schizoaffective disorder is associated with lower levels of both GAD65 and GAD67 mRNA and protein in the PFC, whereas subjects with schizophrenia have lower mean levels of only GAD67 mRNA and protein. Because cognitive function is generally better preserved in patients with schizoaffective disorder relative to patients with schizophrenia, these findings may support an interpretation that GAD65 downregulation provides a homeostatic response complementary to GAD67 downregulation that serves to reduce inhibition in the face of lower PFC network activity. Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc

Understanding diffusion of intrinsically disordered proteins in polymer solutions: A disorder plus collapse model

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Juan Wang

2017-11-01

Full Text Available Understanding diffusion of intrinsically disordered proteins (IDPs under crowded environments is of ubiquitous importance to modelling related dynamics in biological systems. In the present work, we proposed a theoretical framework to study the diffusion behavior of IDPs in polymer solutions. IDP is modeled as an ensemble of particles with a wide range of gyration radius subject to Flory-Fisk distribution, where the collapse effect which leads to the shrink of IDP due to polymer crowding is included. The diffusion coefficient of IDP is calculated as the average, denoted by 〈D〉, over the values of the particle samples. By properly incorporating the scaling relations for diffusion coefficient of nanoparticle (NP in polymer solutions, we are able to evaluate 〈D〉 straightforwardly and reveal the disorder and collapse effects on IDP’s diffusion in an explicit manner. Particular attentions are paid on comparison between the diffusion coefficient of an IDP and that of a NP. Results demonstrate that both disorder and collapse can enhance IDP diffusion rate. Our analysis shows that the crossover behavior reported by experiments can be actually a general phenomenon, namely, while a NP with smaller size than that of an IDP diffuses faster in simple solutions, the IDP may become the faster one under crowded conditions. We apply our theory to analyze the diffusion of several types of IDP in a few different polymer solutions. Good agreements between the theoretical results and the experimental data are obtained.

Disease-associated mutations disrupt functionally important regions of intrinsic protein disorder.

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Vladimir Vacic

Full Text Available The effects of disease mutations on protein structure and function have been extensively investigated, and many predictors of the functional impact of single amino acid substitutions are publicly available. The majority of these predictors are based on protein structure and evolutionary conservation, following the assumption that disease mutations predominantly affect folded and conserved protein regions. However, the prevalence of the intrinsically disordered proteins (IDPs and regions (IDRs in the human proteome together with their lack of fixed structure and low sequence conservation raise a question about the impact of disease mutations in IDRs. Here, we investigate annotated missense disease mutations and show that 21.7% of them are located within such intrinsically disordered regions. We further demonstrate that 20% of disease mutations in IDRs cause local disorder-to-order transitions, which represents a 1.7-2.7 fold increase compared to annotated polymorphisms and neutral evolutionary substitutions, respectively. Secondary structure predictions show elevated rates of transition from helices and strands into loops and vice versa in the disease mutations dataset. Disease disorder-to-order mutations also influence predicted molecular recognition features (MoRFs more often than the control mutations. The repertoire of disorder-to-order transition mutations is limited, with five most frequent mutations (R→W, R→C, E→K, R→H, R→Q collectively accounting for 44% of all deleterious disorder-to-order transitions. As a proof of concept, we performed accelerated molecular dynamics simulations on a deleterious disorder-to-order transition mutation of tumor protein p63 and, in agreement with our predictions, observed an increased α-helical propensity of the region harboring the mutation. Our findings highlight the importance of mutations in IDRs and refine the traditional structure-centric view of disease mutations. The results of this study

Protein intrinsic disorder in Arabidopsis NAC transcription factors

DEFF Research Database (Denmark)

O'Shea, Charlotte; Jensen, Mikael Kryger; Stender, Emil G.P.

2015-01-01

of differences in binding mechanisms. Although substitution of both hydrophobic and acidic residues of the ANAC046 MoRF region abolished binding, substitution of other residues, even with α-helix-breaking proline, was less disruptive. Together, the biophysical analyses suggest that RCD1-ANAC046 complex formation......Protein ID (intrinsic disorder) plays a significant, yet relatively unexplored role in transcription factors (TFs). In the present paper, analysis of the transcription regulatory domains (TRDs) of six phylogenetically representative, plant-specific NAC [no apical meristem, ATAF (Arabidopsis...

Disorder Prediction Methods, Their Applicability to Different Protein Targets and Their Usefulness for Guiding Experimental Studies

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Jennifer D. Atkins

2015-08-01

Full Text Available The role and function of a given protein is dependent on its structure. In recent years, however, numerous studies have highlighted the importance of unstructured, or disordered regions in governing a protein’s function. Disordered proteins have been found to play important roles in pivotal cellular functions, such as DNA binding and signalling cascades. Studying proteins with extended disordered regions is often problematic as they can be challenging to express, purify and crystallise. This means that interpretable experimental data on protein disorder is hard to generate. As a result, predictive computational tools have been developed with the aim of predicting the level and location of disorder within a protein. Currently, over 60 prediction servers exist, utilizing different methods for classifying disorder and different training sets. Here we review several good performing, publicly available prediction methods, comparing their application and discussing how disorder prediction servers can be used to aid the experimental solution of protein structure. The use of disorder prediction methods allows us to adopt a more targeted approach to experimental studies by accurately identifying the boundaries of ordered protein domains so that they may be investigated separately, thereby increasing the likelihood of their successful experimental solution.

OPAL: prediction of MoRF regions in intrinsically disordered protein sequences.

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Sharma, Ronesh; Raicar, Gaurav; Tsunoda, Tatsuhiko; Patil, Ashwini; Sharma, Alok

2018-06-01

Intrinsically disordered proteins lack stable 3-dimensional structure and play a crucial role in performing various biological functions. Key to their biological function are the molecular recognition features (MoRFs) located within long disordered regions. Computationally identifying these MoRFs from disordered protein sequences is a challenging task. In this study, we present a new MoRF predictor, OPAL, to identify MoRFs in disordered protein sequences. OPAL utilizes two independent sources of information computed using different component predictors. The scores are processed and combined using common averaging method. The first score is computed using a component MoRF predictor which utilizes composition and sequence similarity of MoRF and non-MoRF regions to detect MoRFs. The second score is calculated using half-sphere exposure (HSE), solvent accessible surface area (ASA) and backbone angle information of the disordered protein sequence, using information from the amino acid properties of flanks surrounding the MoRFs to distinguish MoRF and non-MoRF residues. OPAL is evaluated using test sets that were previously used to evaluate MoRF predictors, MoRFpred, MoRFchibi and MoRFchibi-web. The results demonstrate that OPAL outperforms all the available MoRF predictors and is the most accurate predictor available for MoRF prediction. It is available at http://www.alok-ai-lab.com/tools/opal/. ashwini@hgc.jp or alok.sharma@griffith.edu.au. Supplementary data are available at Bioinformatics online.

The PROSECCO server for chemical shift predictions in ordered and disordered proteins.

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Sanz-Hernández, Máximo; De Simone, Alfonso

2017-11-01

The chemical shifts measured in solution-state and solid-state nuclear magnetic resonance (NMR) are powerful probes of the structure and dynamics of protein molecules. The exploitation of chemical shifts requires methods to correlate these data with the protein structures and sequences. We present here an approach to calculate accurate chemical shifts in both ordered and disordered proteins using exclusively the information contained in their sequences. Our sequence-based approach, protein sequences and chemical shift correlations (PROSECCO), achieves the accuracy of the most advanced structure-based methods in the characterization of chemical shifts of folded proteins and improves the state of the art in the study of disordered proteins. Our analyses revealed fundamental insights on the structural information carried by NMR chemical shifts of structured and unstructured protein states.

Relative deprivation and disordered gambling in youths.

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Elgar, Frank J; Canale, Natale; Wohl, Michael J A; Lenzi, Michela; Vieno, Alessio

2018-03-07

Previous research has found that area-level income inequality and individual-level relative deprivation both contribute to disordered gambling in adults. However, the socioeconomic factors that contribute to disordered gambling in youths and protective factors in their social environment have not been fully explored. This study examined the association between relative deprivation and youth disordered gambling and the potential moderating role of social support in this association. We used data on family material assets and self-reported symptoms of disordered gambling symptoms in 19 321 participants of the 2013/2014 Italian Health Behaviour in School-aged Children study. Relative deprivation was measured using the Yitzhaki index and classmates as a social reference group. Its association with disordered gambling was tested using multilevel negative binomial regression analyses. We also tested moderated effects of relative deprivation on disordered gambling by four sources of social support: families, peers, teachers and classmates. Relative deprivation related to a fourfold increase in the rate of disordered gambling symptoms (incidence rate ratio=4.18) after differences in absolute family wealth and other variables were statistically controlled. Symptoms were also more prevalent in males, first-generation immigrants and less supported youth. Peer support moderated the association between relative deprivation and symptoms, suggesting that high deprivation and low peer support have interactive links to disordered gambling. Relative deprivation among classmates relate to youth symptoms of disordered gambling. Youth who live in economically unequal settings and perceive a lack of social support may be at greatest risk. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

[Topiramate in substance-related and addictive disorders].

Science.gov (United States)

Cohen, Johan; Dervaux, Alain; Laqueille, Xavier

2014-09-01

Drug treatments used in substance use disorders are not effective in all patients. To assess the effectiveness of topiramate use in the treatment of substance use disorders. Medline database from January 1966 to December 2013, Cochrane database and clinicaltrials.gov. We used keywords topiramate, addiction, substance abuse, alcohol, tobacco, nicotine, cocaine, methamphetamine, opiate, heroin, benzodiazepine, cannabis, bulimia nervosa, binge eating disorder, gambling. All clinical trials were included. Animal trials, laboratory tests, reviews, answers to writers, case-reports, case series and publications unrelated to the topic were excluded. Twenty-eight articles investigating the efficacy of topiramate in substance use were included. In alcohol-related disorder, several trials and a meta-analysis showed a reduction of days of consumption. In a single-center trial on tobacco-related disorder, topiramate was not found effective in reducing the carbon monoxide expired. In cocaine-related disorder, one single-center trial showed a reduction of days of consumption and two single-center trials have found a trend in favour of topiramate. In alcohol and cocaine co-dependency, a single-center trial found a trend in favour of topiramate. In methamphetamine-related disorder, a multicenter trial found a trend in favour of topiramate. In bulimia nervosa, two single-center trials showed a reduction in binge eating and compensatory behaviours. In binge eating disorder, several trials showed a reduction of binge eating and weight. In gambling, one single-center trial did not show any significant results. There were no randomized controlled trials found in opioid-related disorder, benzodiazepines-related disorder, and cannabis-related disorder. Definition of abstinence and methods to assess the efficacy of topiramate differed between trials. The methodological quality of included trials was variable, especially with no double-blind procedure in eight trials. Topiramate showed

Non-breathing-related sleep disorders following stroke.

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Marquez-Romero, J M; Morales-Ramírez, M; Arauz, A

2014-01-01

It has been shown that sleep-related breathing disorders, especially sleep apnea, are very common in patients who have had a stroke, and that they also reduce the potential for neurological recovery. Nevertheless, other sleep disorders caused by stroke (excessive daytime sleepiness, insomnia, sleep related movement disorders) can also cause or increase stroke-related disability, and this fact is less commonly known. Studies with polysomnography have shown many abnormalities in sleep architecture during the acute phase of stroke; these abnormalities have a negative impact on the patient's quality of life although they tend to improve with time. This also happens with other sleep disorders occurring as the result of a stroke (insomnia, narcolepsy, restless legs syndrome, periodic limb movement disorder and REM sleep behavior disorder), which are nevertheless potentially treatable. In this article, we briefly review the physiopathology and epidemiology of the disorders listed above in order to raise awareness about the importance of these disorders and the effects they elicit in stroke patients. Sleep disorders that are not breathing-related have scarcely been studied in stroke patients despite the fact that almost all such disorders may present as a result of a cerebrovascular event. Copyright © 2012 Sociedad Española de Neurología. Published by Elsevier Espana. All rights reserved.

Multiple structure-intrinsic disorder interactions regulate and coordinate Hox protein function

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Bondos, Sarah

During animal development, Hox transcription factors determine fate of developing tissues to generate diverse organs and appendages. Hox proteins are famous for their bizarre mutant phenotypes, such as replacing antennae with legs. Clearly, the functions of individual Hox proteins must be distinct and reliable in vivo, or the organism risks malformation or death. However, within the Hox protein family, the DNA-binding homeodomains are highly conserved and the amino acids that contact DNA are nearly invariant. These observations raise the question: How do different Hox proteins correctly identify their distinct target genes using a common DNA binding domain? One possible means to modulate DNA binding is through the influence of the non-homeodomain protein regions, which differ significantly among Hox proteins. However genetic approaches never detected intra-protein interactions, and early biochemical attempts were hindered because the special features of ``intrinsically disordered'' sequences were not appreciated. We propose the first-ever structural model of a Hox protein to explain how specific contacts between distant, intrinsically disordered regions of the protein and the homeodomain regulate DNA binding and coordinate this activity with other Hox molecular functions.

Marfan Syndrome and Related Disorders: 25 Years of Gene Discovery.

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Verstraeten, Aline; Alaerts, Maaike; Van Laer, Lut; Loeys, Bart

2016-06-01

Marfan syndrome (MFS) is a rare, autosomal-dominant, multisystem disorder, presenting with skeletal, ocular, skin, and cardiovascular symptoms. Significant clinical overlap with other systemic connective tissue diseases, including Loeys-Dietz syndrome (LDS), Shprintzen-Goldberg syndrome (SGS), and the MASS phenotype, has been documented. In MFS and LDS, the cardiovascular manifestations account for the major cause of patient morbidity and mortality, rendering them the main target for therapeutic intervention. Over the past decades, gene identification studies confidently linked the aforementioned syndromes, as well as nonsyndromic aneurysmal disease, to genetic defects in proteins related to the transforming growth factor (TGF)-β pathway, greatly expanding our knowledge on the disease mechanisms and providing us with novel therapeutic targets. As a result, the focus of the developing pharmacological treatment strategies is shifting from hemodynamic stress management to TGF-β antagonism. In this review, we discuss the insights that have been gained in the molecular biology of MFS and related disorders over the past 25 years. © 2016 WILEY PERIODICALS, INC.

[Effects of Electroacupuncture Intervention on Oxygen Free Radicals and Expression of Apoptosis-related Proteins in Rats with Ischemic Learning and Memory Disorder].

Science.gov (United States)

Hou, Zhi-tao; Sun, Zhong-ren; Liu, Song-tao; Xiong, Sheng-biao; Liu, Yi-tian; Han, Xiao-xia; Sun, Hong-fang; Han, Yu-sheng; Yin, Hong-na; Xu, Jin-qiao; Li, Dong-dong

2015-12-01

To observe the effect of electroacupuncture (EA) therapy on levels of oxygen free radicals (OFR) and hippocampal apoptosis-related protein expression in ischemic learning-memory disorder rats so as to investigate its mechanisms underlying improvement of ischemic learning-memory impairment. A total of 60 SD rats were randomly divided into sham operation (sham), model, medication, and EA groups, with 15 rats in each group. The learning-memory disorder model was made by occlusion of bilateral carotid arteries. EA (2- 3 Hz, 2 mA) was applied to "Zhi San Zhen" ["Shenting" (GV 24) and bilateral "Benshen" (GB 13)] for 30 min, once a day for 3 weeks. The rats of the medication group were treated by lavage of Aricept (0.03 mg . kg(-1) . d(-1)), once daily for 3 weeks. The rats' learning-memory ability was detected by Morris water maze tests and the state of hippocampal apoptosis cells was observed by light microscope after TUNEL staining and the expression of hippocampal Bcl-2, Bax and Caspase-3 proteins was detected by immunohistochemistry. Serum and hippocampal superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activity and malondialdehyde (MDA) contents were detected by chemical colorimetric analysis. Compared with the sham group, the escape latencies (place-navigation) after modeling were evidently prolonged, and the times of target-platform crossing in 90 sec (spatial probe test) considerably reduced in the model group (Plearning-memory ability. After the treatment for 21 d, the increased escape latency and the reduced target-platform crossing time in both EA and medication groups were reversed in comparison with the model group (Pmemory ability, and the effect of the EA group was significantly superior to that of the medication group (Plearning-memory ability in ischemic learning-memory disorder rats which may be associated with its effects in reducing blood and hippocampal OFR contents and hippocampal cellular apoptosis.

[Prevalence of sleep-related breathing disorders of inpatients with psychiatric disorders].

Science.gov (United States)

Behr, M; Acker, J; Cohrs, S; Deuschle, M; Danker-Hopfe, H; Göder, R; Norra, C; Richter, K; Riemann, D; Schilling, C; Weeß, H-G; Wetter, T C; Wollenburg, L M; Pollmächer, T

2018-06-06

Sleep-related breathing disorders seriously impair well-being and increase the risk for relevant somatic and psychiatric disorders. Moreover, risk factors for sleep-related breathing disorders are highly prevalent in psychiatric patients. The aim of this study was for the first time in Germany to study the prevalence of obstructive sleep apnea syndrome (OSAS) as the most common form of sleep-related breathing disorder in patients with psychiatric disorders. In 10 psychiatric hospitals in Germany and 1 hospital in Switzerland, a total of 249 inpatients underwent an 8‑channel sleep polygraphy to investigate the prevalence of sleep apnea in this group of patients. With a conspicuous screening result of 23.7% of the subjects, a high prevalence of sleep-related breathing disorders was found to occur among this group of patients. Male gender, higher age and high body mass index (BMI) were identified as positive risk factors for the detection of OSAS. The high prevalence indicates that sleep apnea is a common sleep disorder among psychiatric patients. Although OSAS can lead to substantial disorders of the mental state and when untreated is accompanied by serious somatic health problems, screening procedures are not part of the routine work-up in psychiatric hospitals; therefore, sleep apnea is presumably underdiagnosed in psychiatric patients. In view of the results of this and previous studies, this topic complex should be the subject of further research studies.

Disorder and function: a review of the dehydrin protein family

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Steffen P Graether

2014-10-01

Full Text Available Dehydration proteins (dehydrins are group 2 members of the late embryogenesis abundant (LEA protein family. The protein architecture of dehydrins can be described by the presence of three types of conserved sequence motifs that have been named the K-, Y- and S-segments. By definition, a dehydrin must contain at least one copy of the lysine-rich K-segment. Abiotic stresses such as drought, cold, and salinity cause the upregulation of dehydrin mRNA and protein levels. Despite the large body of genetic and protein evidence of the importance of these proteins in stress response, the in vivo protective mechanism is not fully known. In vitro experimental evidence from biochemical assays and localization experiments suggest multiple roles for dehydrins, including membrane protection, cryoprotection of enzymes, and protection from reactive oxygen species. Membrane binding by dehydrins is likely to be as a peripheral membrane protein, since the protein sequences are highly hydrophilic and contain many charged amino acids. Because of this, dehydrins in solution are intrinsically disordered proteins, that is, they have no well-defined secondary or tertiary structure. Despite their disorder, dehydrins have been shown to gain structure when bound to ligands such as membranes, and to possibly change their oligomeric state when bound to ions. We review what is currently known about dehydrin sequences and their structures, and examine the various ligands that have been shown to bind to this family of proteins.

DeepCNF-D: Predicting Protein Order/Disorder Regions by Weighted Deep Convolutional Neural Fields

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Sheng Wang

2015-07-01

Full Text Available Intrinsically disordered proteins or protein regions are involved in key biological processes including regulation of transcription, signal transduction, and alternative splicing. Accurately predicting order/disorder regions ab initio from the protein sequence is a prerequisite step for further analysis of functions and mechanisms for these disordered regions. This work presents a learning method, weighted DeepCNF (Deep Convolutional Neural Fields, to improve the accuracy of order/disorder prediction by exploiting the long-range sequential information and the interdependency between adjacent order/disorder labels and by assigning different weights for each label during training and prediction to solve the label imbalance issue. Evaluated by the CASP9 and CASP10 targets, our method obtains 0.855 and 0.898 AUC values, which are higher than the state-of-the-art single ab initio predictors.

DSS1/Sem1, a multifunctional and intrinsically disordered protein

DEFF Research Database (Denmark)

Kragelund, Birthe Brandt; Schenstrøm, Signe Marie; Rebula, Caio A.

2016-01-01

DSS1/Sem1 is a versatile intrinsically disordered protein. Besides being a bona fide subunit of the 26S proteasome, DSS1 associates with other protein complexes, including BRCA2-RPA, involved in homologous recombination; the Csn12-Thp3 complex, involved in RNA splicing; the integrator, involved...

DisoMCS: Accurately Predicting Protein Intrinsically Disordered Regions Using a Multi-Class Conservative Score Approach.

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Zhiheng Wang

Full Text Available The precise prediction of protein intrinsically disordered regions, which play a crucial role in biological procedures, is a necessary prerequisite to further the understanding of the principles and mechanisms of protein function. Here, we propose a novel predictor, DisoMCS, which is a more accurate predictor of protein intrinsically disordered regions. The DisoMCS bases on an original multi-class conservative score (MCS obtained by sequence-order/disorder alignment. Initially, near-disorder regions are defined on fragments located at both the terminus of an ordered region connecting a disordered region. Then the multi-class conservative score is generated by sequence alignment against a known structure database and represented as order, near-disorder and disorder conservative scores. The MCS of each amino acid has three elements: order, near-disorder and disorder profiles. Finally, the MCS is exploited as features to identify disordered regions in sequences. DisoMCS utilizes a non-redundant data set as the training set, MCS and predicted secondary structure as features, and a conditional random field as the classification algorithm. In predicted near-disorder regions a residue is determined as an order or a disorder according to the optimized decision threshold. DisoMCS was evaluated by cross-validation, large-scale prediction, independent tests and CASP (Critical Assessment of Techniques for Protein Structure Prediction tests. All results confirmed that DisoMCS was very competitive in terms of accuracy of prediction when compared with well-established publicly available disordered region predictors. It also indicated our approach was more accurate when a query has higher homologous with the knowledge database.The DisoMCS is available at http://cal.tongji.edu.cn/disorder/.

Mindfulness mediates the relation between disordered eating-related cognitions and psychological distress.

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Masuda, Akihiko; Wendell, Johanna W

2010-12-01

The present study investigated whether mindfulness mediates the relation between disordered eating-related cognitions and negative psychological outcomes within a non-clinical college sample. Disordered eating-related cognitions were positively associated with general psychological ill-health and emotional distress in interpersonal contexts and inversely related to mindfulness. Mindfulness, which was also inversely related to general psychological ill-health and emotional distress, was found to partially mediate the relations between disordered eating-related cognitions and the two predicted variables. Copyright © 2010 Elsevier Ltd. All rights reserved.

Low Proportion of Dietary Plant Protein among Athletes with Premenstrual Syndrome-Related Performance Impairment.

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Yamada, Keiko; Takeda, Takashi

2018-02-01

Premenstrual syndrome (PMS) is psychosomatic disorder that are limited to the late luteal phase in the menstrual cycle. PMS could impair athletic performance. To investigate associations between proportions of dietary plant and animal protein and PMS-related impairment of athletic performance, we surveyed 135 female athletes aged 18-23 years attending Kindai University. Participants belonged to authorized university clubs, all of which have high rankings in Japanese university sports. Participants completed self-administered questionnaires on diet history, demographics, and PMS-related impairment of athletic performance. Total protein, animal protein, and plant protein intake were examined, and the proportion of dietary plant protein was calculated for each participant. We divided athletes into two groups: those without PMS-related impairment of athletic performance (n = 117) and those with PMS-related performance impairment (n = 18). A t-test was used to compare mean values and multivariable adjusted mean values between groups; adjustment variables were energy intake, body mass index, and daily training duration. Total protein intake was not significantly different between the groups. However, athletes whose performance was affected by PMS reported higher intake of animal protein (mean 50.6 g) than athletes whose performance was unaffected by PMS (mean 34.9 g). Plant protein intake was lower among athletes with PMS-related impairment (mean 25.4 g) than among athletes without impairment (mean 26.9 g). The proportion of dietary plant protein was lower among athletes with PMS-related impairment (39.3%) than those without impairment (45.9%). A low proportion of dietary plant protein may cause PMS-related athletic impairment among athletes.

Parental educational practices in relation to children's anxiety disorder-related behavior.

Science.gov (United States)

Mellon, Robert C; Moutavelis, Adrianos G

2011-08-01

Schoolchildren reported their parents' use of aversive control and positive reinforcement contingencies in their educational interventions, as well as parental non-responsiveness to their requests for educational assistance. They also reported their own levels of six dimensions of anxiety disorder-related phenomena. Both parental use of aversive control and non-responsiveness were directly related to overall levels of child anxiety disorder-related behavior; these correlations were more robust than those observed in previous investigations of more diffuse dimensions of parenting style and trait anxiety. Panic disorder/agoraphobia and Generalized anxiety disorder were the dimensions most strongly correlated with both parental aversive control and non-responsiveness, while Compulsive behavior was uniquely uncorrelated with parental non-responsiveness and uniquely correlated with parental use of positive reinforcement contingencies. Differences in the magnitudes of correlations between anxiety disorder-related dimensions and parental educational practices are interpreted in terms of the probable differential effectiveness of their constituent behaviors in terminating parent-mediated negative reinforcers. Copyright © 2011 Elsevier Ltd. All rights reserved.

In Silico Analysis of Correlations between Protein Disorder and Post-Translational Modifications in Algae.

Science.gov (United States)

Kurotani, Atsushi; Sakurai, Tetsuya

2015-08-20

Recent proteome analyses have reported that intrinsically disordered regions (IDRs) of proteins play important roles in biological processes. In higher plants whose genomes have been sequenced, the correlation between IDRs and post-translational modifications (PTMs) has been reported. The genomes of various eukaryotic algae as common ancestors of plants have also been sequenced. However, no analysis of the relationship to protein properties such as structure and PTMs in algae has been reported. Here, we describe correlations between IDR content and the number of PTM sites for phosphorylation, glycosylation, and ubiquitination, and between IDR content and regions rich in proline, glutamic acid, serine, and threonine (PEST) and transmembrane helices in the sequences of 20 algae proteomes. Phosphorylation, O-glycosylation, ubiquitination, and PEST preferentially occurred in disordered regions. In contrast, transmembrane helices were favored in ordered regions. N-glycosylation tended to occur in ordered regions in most of the studied algae; however, it correlated positively with disordered protein content in diatoms. Additionally, we observed that disordered protein content and the number of PTM sites were significantly increased in the species-specific protein clusters compared to common protein clusters among the algae. Moreover, there were specific relationships between IDRs and PTMs among the algae from different groups.

In Silico Analysis of Correlations between Protein Disorder and Post-Translational Modifications in Algae

Directory of Open Access Journals (Sweden)

Atsushi Kurotani

2015-08-01

Full Text Available Recent proteome analyses have reported that intrinsically disordered regions (IDRs of proteins play important roles in biological processes. In higher plants whose genomes have been sequenced, the correlation between IDRs and post-translational modifications (PTMs has been reported. The genomes of various eukaryotic algae as common ancestors of plants have also been sequenced. However, no analysis of the relationship to protein properties such as structure and PTMs in algae has been reported. Here, we describe correlations between IDR content and the number of PTM sites for phosphorylation, glycosylation, and ubiquitination, and between IDR content and regions rich in proline, glutamic acid, serine, and threonine (PEST and transmembrane helices in the sequences of 20 algae proteomes. Phosphorylation, O-glycosylation, ubiquitination, and PEST preferentially occurred in disordered regions. In contrast, transmembrane helices were favored in ordered regions. N-glycosylation tended to occur in ordered regions in most of the studied algae; however, it correlated positively with disordered protein content in diatoms. Additionally, we observed that disordered protein content and the number of PTM sites were significantly increased in the species-specific protein clusters compared to common protein clusters among the algae. Moreover, there were specific relationships between IDRs and PTMs among the algae from different groups.

Correlation of chemical shifts predicted by molecular dynamics simulations for partially disordered proteins

Energy Technology Data Exchange (ETDEWEB)

Karp, Jerome M.; Erylimaz, Ertan; Cowburn, David, E-mail: cowburn@cowburnlab.org, E-mail: David.cowburn@einstein.yu.edu [Albert Einstein College of Medicine of Yeshiva University, Department of Biochemistry (United States)

2015-01-15

There has been a longstanding interest in being able to accurately predict NMR chemical shifts from structural data. Recent studies have focused on using molecular dynamics (MD) simulation data as input for improved prediction. Here we examine the accuracy of chemical shift prediction for intein systems, which have regions of intrinsic disorder. We find that using MD simulation data as input for chemical shift prediction does not consistently improve prediction accuracy over use of a static X-ray crystal structure. This appears to result from the complex conformational ensemble of the disordered protein segments. We show that using accelerated molecular dynamics (aMD) simulations improves chemical shift prediction, suggesting that methods which better sample the conformational ensemble like aMD are more appropriate tools for use in chemical shift prediction for proteins with disordered regions. Moreover, our study suggests that data accurately reflecting protein dynamics must be used as input for chemical shift prediction in order to correctly predict chemical shifts in systems with disorder.

SIRT2 as a therapeutic target for age-related disorders

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RIta eMachado de Oliveira

2012-05-01

Full Text Available Sirtuin proteins are conserved regulators of aging that have recently emerged as important modifiers of several diseases which commonly occur later in life, such as cancer, diabetes, cardiovascular and neurodegenerative diseases. In mammals, there are seven sirtuins (SIRT1-7, which display diversity in subcellular localization and function. SIRT1 has received much of attention due to its possible impact on longevity, while important biological and therapeutic roles of other sirtuins have been underestimated and just recently recognized. Here we focus on SIRT2, a member of the sirtuin family, and discuss its role in cellular and tissue-specific functions. This review summarizes the main scientific advances on SIRT2 protein biology and explores its potential as a therapeutic target for treatment of age-related disorders.

Role of Matricellular Proteins in Disorders of the Central Nervous System.

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Jayakumar, A R; Apeksha, A; Norenberg, M D

2017-03-01

Matricellular proteins (MCPs) are actively expressed non-structural proteins present in the extracellular matrix, which rapidly turnover and possess regulatory roles, as well as mediate cell-cell interactions. MCPs characteristically contain binding sites for other extracellular proteins, cell surface receptors, growth factors, cytokines and proteases, that provide structural support for surrounding cells. MCPs are present in most organs, including brain, and play a major role in cell-cell interactions and tissue repair. Among the MCPs found in brain include thrombospondin-1/2, secreted protein acidic and rich in cysteine family (SPARC), including Hevin/SC1, Tenascin C and CYR61/Connective Tissue Growth Factor/Nov family of proteins, glypicans, galectins, plasminogen activator inhibitor (PAI-1), autotaxin, fibulin and perisostin. This review summarizes the potential role of MCPs in the pathogenesis of major neurological disorders, including Alzheimer's disease, amyotrophic lateral sclerosis, ischemia, trauma, hepatic encephalopathy, Down's syndrome, autism, multiple sclerosis, brain neoplasms, Parkinson's disease and epilepsy. Potential therapeutic opportunities of MCP's for these disorders are also considered in this review.

Consequences of occupational food-related hand dermatoses with a focus on protein contact dermatitis

DEFF Research Database (Denmark)

Vester, Lotte; Thyssen, Jacob P; Menné, Torkil

2012-01-01

Background. Protein contact dermatitis is a frequent disorder among hand eczema patients who have occupational food contact. Knowledge about the consequences of having protein contact dermatitis is lacking. Objectives. To investigate the consequences of having occupational skin disease on the hands...... resulting from food handling, with a focus on protein contact dermatitis. Material and methods. One hundred and seventy-eight patients who were identified as having skin disease related to occupational food exposure and who answered a questionnaire concerning the consequences of their skin disease were......%, respectively, of the patients with other occupational food-related hand dermatoses (p = 0.02). Sixty-two per cent and 43%, respectively, had to change job because of skin problems (p = 0.02). Atopic dermatitis was equally common in the two groups. Conclusion. We found that the patients with protein contact...

The FKBP51-Glucocorticoid Receptor Balance in Stress-Related Mental Disorders.

Science.gov (United States)

Fries, Gabriel R; Gassen, Nils C; Schmidt, Ulrike; Rein, Theo

2015-01-01

The immunophilin FK506 binding protein 51 (FKBP51) has emerged as one of the most intensely investigated proteins in stress-related mental disorders. It was originally characterized as Hsp90 cochaperone and part of the receptor-chaperone heterocomplex that governs the activity of steroid receptors. It turned out that the presence of FKBP51 in this heterocomplex leads to diminished activity of the corticosteroid receptors. In particular, based on its inhibitory action on the glucocorticoid receptor (GR), FKBP51 was included in a candidate gene approach to discover gene polymorphisms that might be relevant for the development and treatment of major depression. The discovery that polymorphisms in the gene coding for FKBP51 were linked to the treatment response of depressed patients intensified the research on the role of FKBP51 in stress-related diseases worldwide. It has become evident that FKBP51 is not only a regulator of GR action, but also a GR target. The function of this ultrashort intracellular feedback loop is critically important for cellular and physiological stress regulation as it does not only calibrate the function of GR, but also the levels of FKBP51. Given the pleiotropic functions of FKBP51, its levels might be equally important for mental disorders as GR function and hence for the development of potential FKBP51 drug targets.

Intrinsically Disordered Proteins and the Origins of Multicellular Organisms

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Dunker, A. Keith

In simple multicellular organisms all of the cells are in direct contact with the surrounding milieu, whereas in complex multicellular organisms some cells are completely surrounded by other cells. Current phylogenetic trees indicate that complex multicellular organisms evolved independently from unicellular ancestors about 10 times, and only among the eukaryotes, including once for animals, twice each for green, red, and brown algae, and thrice for fungi. Given these multiple independent evolutionary lineages, we asked two questions: 1. Which molecular functions underpinned the evolution of multicellular organisms?; and, 2. Which of these molecular functions depend on intrinsically disordered proteins (IDPs)? Compared to unicellularity, multicellularity requires the advent of molecules for cellular adhesion, for cell-cell communication and for developmental programs. In addition, the developmental programs need to be regulated over space and time. Finally, each multicellular organism has cell-specific biochemistry and physiology. Thus, the evolution of complex multicellular organisms from unicellular ancestors required five new classes of functions. To answer the second question we used Key-words in Swiss Protein ranked for associations with predictions of protein structure or disorder. With a Z-score of 18.8 compared to random-function proteins, à differentiation was the biological process most strongly associated with IDPs. As expected from this result, large numbers of individual proteins associated with differentiation exhibit substantial regions of predicted disorder. For the animals for which there is the most readily available data all five of the underpinning molecular functions for multicellularity were found to depend critically on IDP-based mechanisms and other evidence supports these ideas. While the data are more sparse, IDPs seem to similarly underlie the five new classes of functions for plants and fungi as well, suggesting that IDPs were indeed

Specific alterations in plasma proteins during depressed, manic, and euthymic states of bipolar disorder

Energy Technology Data Exchange (ETDEWEB)

Song, Y.R. [Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing (China); Chongqing Key Laboratory of Neurobiology, Chongqing (China); Institute of Neuroscience and the Collaborative Innovation Center for Brain Science, Chongqing Medical University, Chongqing (China); Wu, B. [Chongqing Key Laboratory of Neurobiology, Chongqing (China); Institute of Neuroscience and the Collaborative Innovation Center for Brain Science, Chongqing Medical University, Chongqing (China); Yang, Y.T.; Chen, J. [Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing (China); Chongqing Key Laboratory of Neurobiology, Chongqing (China); Institute of Neuroscience and the Collaborative Innovation Center for Brain Science, Chongqing Medical University, Chongqing (China); Zhang, L.J.; Zhang, Z.W. [Chongqing Key Laboratory of Neurobiology, Chongqing (China); Institute of Neuroscience and the Collaborative Innovation Center for Brain Science, Chongqing Medical University, Chongqing (China); Shi, H.Y. [Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing (China); Chongqing Key Laboratory of Neurobiology, Chongqing (China); Institute of Neuroscience and the Collaborative Innovation Center for Brain Science, Chongqing Medical University, Chongqing (China); Huang, C.L.; Pan, J.X. [Chongqing Key Laboratory of Neurobiology, Chongqing (China); Institute of Neuroscience and the Collaborative Innovation Center for Brain Science, Chongqing Medical University, Chongqing (China); Xie, P. [Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing (China); Chongqing Key Laboratory of Neurobiology, Chongqing (China); Institute of Neuroscience and the Collaborative Innovation Center for Brain Science, Chongqing Medical University, Chongqing (China)

2015-09-08

Bipolar disorder (BD) is a common psychiatric mood disorder affecting more than 1-2% of the general population of different European countries. Unfortunately, there is no objective laboratory-based test to aid BD diagnosis or monitor its progression, and little is known about the molecular basis of BD. Here, we performed a comparative proteomic study to identify differentially expressed plasma proteins in various BD mood states (depressed BD, manic BD, and euthymic BD) relative to healthy controls. A total of 10 euthymic BD, 20 depressed BD, 15 manic BD, and 20 demographically matched healthy control subjects were recruited. Seven high-abundance proteins were immunodepleted in plasma samples from the 4 experimental groups, which were then subjected to proteome-wide expression profiling by two-dimensional electrophoresis and matrix-assisted laser desorption/ionization-time-of-flight/time-of-flight tandem mass spectrometry. Proteomic results were validated by immunoblotting and bioinformatically analyzed using MetaCore. From a total of 32 proteins identified with 1.5-fold changes in expression compared with healthy controls, 16 proteins were perturbed in BD independent of mood state, while 16 proteins were specifically associated with particular BD mood states. Two mood-independent differential proteins, apolipoprotein (Apo) A1 and Apo L1, suggest that BD pathophysiology may be associated with early perturbations in lipid metabolism. Moreover, down-regulation of one mood-dependent protein, carbonic anhydrase 1 (CA-1), suggests it may be involved in the pathophysiology of depressive episodes in BD. Thus, BD pathophysiology may be associated with early perturbations in lipid metabolism that are independent of mood state, while CA-1 may be involved in the pathophysiology of depressive episodes.

Specific alterations in plasma proteins during depressed, manic, and euthymic states of bipolar disorder

International Nuclear Information System (INIS)

Song, Y.R.; Wu, B.; Yang, Y.T.; Chen, J.; Zhang, L.J.; Zhang, Z.W.; Shi, H.Y.; Huang, C.L.; Pan, J.X.; Xie, P.

2015-01-01

Bipolar disorder (BD) is a common psychiatric mood disorder affecting more than 1-2% of the general population of different European countries. Unfortunately, there is no objective laboratory-based test to aid BD diagnosis or monitor its progression, and little is known about the molecular basis of BD. Here, we performed a comparative proteomic study to identify differentially expressed plasma proteins in various BD mood states (depressed BD, manic BD, and euthymic BD) relative to healthy controls. A total of 10 euthymic BD, 20 depressed BD, 15 manic BD, and 20 demographically matched healthy control subjects were recruited. Seven high-abundance proteins were immunodepleted in plasma samples from the 4 experimental groups, which were then subjected to proteome-wide expression profiling by two-dimensional electrophoresis and matrix-assisted laser desorption/ionization-time-of-flight/time-of-flight tandem mass spectrometry. Proteomic results were validated by immunoblotting and bioinformatically analyzed using MetaCore. From a total of 32 proteins identified with 1.5-fold changes in expression compared with healthy controls, 16 proteins were perturbed in BD independent of mood state, while 16 proteins were specifically associated with particular BD mood states. Two mood-independent differential proteins, apolipoprotein (Apo) A1 and Apo L1, suggest that BD pathophysiology may be associated with early perturbations in lipid metabolism. Moreover, down-regulation of one mood-dependent protein, carbonic anhydrase 1 (CA-1), suggests it may be involved in the pathophysiology of depressive episodes in BD. Thus, BD pathophysiology may be associated with early perturbations in lipid metabolism that are independent of mood state, while CA-1 may be involved in the pathophysiology of depressive episodes

Thermodiffusion as a close-to-interface effect that matters in non-isothermal (dis)orderly protein aggregations

Energy Technology Data Exchange (ETDEWEB)

Gadomski, A., E-mail: agad@utp.edu.pl; Kruszewska, N., E-mail: nkruszewska@utp.edu.pl

2014-08-01

The goal of this discussion letter is to argue how and why an inherent nanoscale thermodiffusion (Soret-type) effect can be relevant in (dis)orderly protein aggregation. We propose a model in which the aggregation of proteins, in the presence of temperature gradient, is described in terms of Smoluchowski dynamics in the phase space of nuclei sizes. The Soret coefficient of the aggregation is proportional to the variations of the aggregation free energy over temperature. The free energy is related to the (interface) boundary condition of the system. When boundary condition is of equilibrium Gibbs–Thomson type, with a well-stated surface tension of the nucleus, to the system can be assigned a negative Soret effect. On the contrary, when a non-equilibrium perturbing (salting-out) term enters the boundary condition, a positive Soret effect may manifest. A zero-value Soret regime is expected to occur in between, yielding very soft (“fragile”) non-Kossel protein-type crystals. - Highlights: • Comprehension for non-isothermal formation of (dis)orderly protein aggregation. • Classification of temperature-sensitive morphologies in colloid-type aggregation. • Morphologies split into near-equilibrium and nonequilibrium structural outcomes. • Classification on mesoscopic nonequilibrium thermodynamics near local equilibrium.

Unfoldomics of prostate cancer: on the abundance and roles of intrinsically disordered proteins in prostate cancer

Science.gov (United States)

Landau, Kevin S; Na, Insung; Schenck, Ryan O; Uversky, Vladimir N

2016-01-01

Prostatic diseases such as prostate cancer and benign prostatic hyperplasia are highly prevalent among men. The number of studies focused on the abundance and roles of intrinsically disordered proteins in prostate cancer is rather limited. The goal of this study is to analyze the prevalence and degree of disorder in proteins that were previously associated with the prostate cancer pathogenesis and to compare these proteins to the entire human proteome. The analysis of these datasets provides means for drawing conclusions on the roles of disordered proteins in this common male disease. We also hope that the results of our analysis can potentially lead to future experimental studies of these proteins to find novel pathways associated with this disease. PMID:27453073

Rotational order–disorder structure of fluorescent protein FP480

International Nuclear Information System (INIS)

Pletnev, Sergei; Morozova, Kateryna S.; Verkhusha, Vladislav V.; Dauter, Zbigniew

2009-01-01

An analysis of the rotational order–disorder structure of fluorescent protein FP480 is presented. In the last decade, advances in instrumentation and software development have made crystallography a powerful tool in structural biology. Using this method, structural information can now be acquired from pathological crystals that would have been abandoned in earlier times. In this paper, the order–disorder (OD) structure of fluorescent protein FP480 is discussed. The structure is composed of tetramers with 222 symmetry incorporated into the lattice in two different ways, namely rotated 90° with respect to each other around the crystal c axis, with tetramer axes coincident with crystallographic twofold axes. The random distribution of alternatively oriented tetramers in the crystal creates a rotational OD structure with statistically averaged I422 symmetry, although the presence of very weak and diffuse additional reflections suggests that the randomness is only approximate

Sequence charge decoration dictates coil-globule transition in intrinsically disordered proteins.

Science.gov (United States)

Firman, Taylor; Ghosh, Kingshuk

2018-03-28

We present an analytical theory to compute conformations of heteropolymers-applicable to describe disordered proteins-as a function of temperature and charge sequence. The theory describes coil-globule transition for a given protein sequence when temperature is varied and has been benchmarked against the all-atom Monte Carlo simulation (using CAMPARI) of intrinsically disordered proteins (IDPs). In addition, the model quantitatively shows how subtle alterations of charge placement in the primary sequence-while maintaining the same charge composition-can lead to significant changes in conformation, even as drastic as a coil (swelled above a purely random coil) to globule (collapsed below a random coil) and vice versa. The theory provides insights on how to control (enhance or suppress) these changes by tuning the temperature (or solution condition) and charge decoration. As an application, we predict the distribution of conformations (at room temperature) of all naturally occurring IDPs in the DisProt database and notice significant size variation even among IDPs with a similar composition of positive and negative charges. Based on this, we provide a new diagram-of-states delineating the sequence-conformation relation for proteins in the DisProt database. Next, we study the effect of post-translational modification, e.g., phosphorylation, on IDP conformations. Modifications as little as two-site phosphorylation can significantly alter the size of an IDP with everything else being constant (temperature, salt concentration, etc.). However, not all possible modification sites have the same effect on protein conformations; there are certain "hot spots" that can cause maximal change in conformation. The location of these "hot spots" in the parent sequence can readily be identified by using a sequence charge decoration metric originally introduced by Sawle and Ghosh. The ability of our model to predict conformations (both expanded and collapsed states) of IDPs at a high

Long Distance Modulation of Disorder-to-Order Transitions in Protein Allostery.

Science.gov (United States)

Wang, Jingheng; Custer, Gregory; Beckett, Dorothy; Matysiak, Silvina

2017-08-29

Elucidation of the molecular details of allosteric communication between distant sites in a protein is key to understanding and manipulating many biological regulatory processes. Although protein disorder is acknowledged to play an important thermodynamic role in allostery, the molecular mechanisms by which this disorder is harnessed for long distance communication are known for a limited number of systems. Transcription repression by the Escherichia coli biotin repressor, BirA, is allosterically activated by binding of the small molecule effector biotinoyl-5'-AMP. The effector acts by promoting BirA dimerization, which is a prerequisite for sequence-specific binding to the biotin biosynthetic operon operator sequence. A 30 Å distance separates the effector binding and dimerization surfaces in BirA, and previous studies indicate that allostery is mediated, in part, by disorder-to-order transitions on the two coupled sites. In this work, combined experimental and computational methods have been applied to investigate the molecular basis of allosteric communication in BirA. Double-mutant cycle analysis coupled with thermodynamic measurements indicates functional coupling between residues in disordered loops on the two distant surfaces. All atom molecular dynamics simulations reveal that this coupling occurs through long distance reciprocal modulation of the structure and dynamics of disorder-to-order transitions on the two surfaces.

Improving protein disorder prediction by deep bidirectional long short-term memory recurrent neural networks.

Science.gov (United States)

Hanson, Jack; Yang, Yuedong; Paliwal, Kuldip; Zhou, Yaoqi

2017-03-01

Capturing long-range interactions between structural but not sequence neighbors of proteins is a long-standing challenging problem in bioinformatics. Recently, long short-term memory (LSTM) networks have significantly improved the accuracy of speech and image classification problems by remembering useful past information in long sequential events. Here, we have implemented deep bidirectional LSTM recurrent neural networks in the problem of protein intrinsic disorder prediction. The new method, named SPOT-Disorder, has steadily improved over a similar method using a traditional, window-based neural network (SPINE-D) in all datasets tested without separate training on short and long disordered regions. Independent tests on four other datasets including the datasets from critical assessment of structure prediction (CASP) techniques and >10 000 annotated proteins from MobiDB, confirmed SPOT-Disorder as one of the best methods in disorder prediction. Moreover, initial studies indicate that the method is more accurate in predicting functional sites in disordered regions. These results highlight the usefulness combining LSTM with deep bidirectional recurrent neural networks in capturing non-local, long-range interactions for bioinformatics applications. SPOT-disorder is available as a web server and as a standalone program at: http://sparks-lab.org/server/SPOT-disorder/index.php . j.hanson@griffith.edu.au or yuedong.yang@griffith.edu.au or yaoqi.zhou@griffith.edu.au. Supplementary data is available at Bioinformatics online. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com

From Sequence and Forces to Structure, Function and Evolution of Intrinsically Disordered Proteins

Science.gov (United States)

Forman-Kay, Julie D.; Mittag, Tanja

2015-01-01

Intrinsically disordered proteins (IDPs), which lack persistent structure, are a challenge to structural biology due to the inapplicability of standard methods for characterization of folded proteins as well as their deviation from the dominant structure/function paradigm. Their widespread presence and involvement in biological function, however, has spurred the growing acceptance of the importance of IDPs and the development of new tools for studying their structure, dynamics and function. The interplay of folded and disordered domains or regions for function and the existence of a continuum of protein states with respect to conformational energetics, motional timescales and compactness is shaping a unified understanding of structure-dynamics-disorder/function relationships. On the 20th anniversary of this journal, Structure, we provide a historical perspective on the investigation of IDPs and summarize the sequence features and physical forces that underlie their unique structural, functional and evolutionary properties. PMID:24010708

Intrinsically Disordered Proteins in a Physics-Based World

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Jianhan Chen

2010-12-01

Full Text Available Intrinsically disordered proteins (IDPs are a newly recognized class of functional proteins that rely on a lack of stable structure for function. They are highly prevalent in biology, play fundamental roles, and are extensively involved in human diseases. For signaling and regulation, IDPs often fold into stable structures upon binding to specific targets. The mechanisms of these coupled binding and folding processes are of significant importance because they underlie the organization of regulatory networks that dictate various aspects of cellular decision-making. This review first discusses the challenge in detailed experimental characterization of these heterogeneous and dynamics proteins and the unique and exciting opportunity for physics-based modeling to make crucial contributions, and then summarizes key lessons from recent de novo simulations of the structure and interactions of several regulatory IDPs.

Folding propensity of intrinsically disordered proteins by osmotic stress

International Nuclear Information System (INIS)

Mansouri, Amanda L.; Grese, Laura N.; Rowe, Erica L.

2016-01-01

Proteins imparted with intrinsic disorder conduct a range of essential cellular functions. To better understand the folding and hydration properties of intrinsically disordered proteins (IDPs), we used osmotic stress to induce conformational changes in nuclear co-activator binding domain (NCBD) and activator for thyroid hormone and retinoid receptor (ACTR). Osmotic stress was applied by the addition of small and polymeric osmolytes, where we discovered that water contributions to NCBD folding always exceeded those for ACTR. Both NCBD and ACTR were found to gain a-helical structure with increasing osmotic stress, consistent with their folding upon NCBD/ACTR complex formation. Using small-angle neutron scattering (SANS), we further characterized NCBD structural changes with the osmolyte ethylene glycol. Here a large reduction in overall size initially occurred before substantial secondary structural change. In conclusion, by focusing on folding propensity, and linked hydration changes, we uncover new insights that may be important for how IDP folding contributes to binding.

Reduced expression of G protein-coupled receptor kinases in schizophrenia but not in schizoaffective disorder

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Bychkov, ER; Ahmed, MR; Gurevich, VV; Benovic, JL; Gurevich, EV

2011-01-01

Alterations of multiple G protein-mediated signaling pathways are detected in schizophrenia. G protein-coupled receptor kinases (GRKs) and arrestins terminate signaling by G protein-coupled receptors exerting powerful influence on receptor functions. Modifications of arrestin and/or GRKs expression may contribute to schizophrenia pathology. Cortical expression of arrestins and GRKs was measured postmortem in control and subjects with schizophrenia or schizoaffective disorder. Additionally, arrestin/GRK expression was determined in elderly patients with schizophrenia and age-matched control. Patients with schizophrenia, but not schizoaffective disorder, displayed reduced concentration of arrestin and GRK mRNAs and GRK3 protein. Arrestins and GRK significantly decreased with age. In elderly patients, GRK6 was reduced, with other GRKs and arrestins unchanged. Reduced cortical concentration of GRKs in schizophrenia (resembling that in aging) may result in altered G protein-dependent signaling, thus contributing to prefrontal deficits in schizophrenia. The data suggest distinct molecular mechanisms underlying schizophrenia and schizoaffective disorder. PMID:21784156

Engineering Aromatic-Aromatic Interactions To Nucleate Folding in Intrinsically Disordered Regions of Proteins.

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Balakrishnan, Swati; Sarma, Siddhartha P

2017-08-22

Aromatic interactions are an important force in protein folding as they combine the stability of a hydrophobic interaction with the selectivity of a hydrogen bond. Much of our understanding of aromatic interactions comes from "bioinformatics" based analyses of protein structures and from the contribution of these interactions to stabilizing secondary structure motifs in model peptides. In this study, the structural consequences of aromatic interactions on protein folding have been explored in engineered mutants of the molten globule protein apo-cytochrome b 5 . Structural changes from disorder to order due to aromatic interactions in two variants of the protein, viz., WF-cytb5 and FF-cytb5, result in significant long-range secondary and tertiary structure. The results show that 54 and 52% of the residues in WF-cytb5 and FF-cytb5, respectively, occupy ordered regions versus 26% in apo-cytochrome b 5 . The interactions between the aromatic groups are offset-stacked and edge-to-face for the Trp-Phe and Phe-Phe mutants, respectively. Urea denaturation studies indicate that both mutants have a C m higher than that of apo-cytochrome b 5 and are more stable to chaotropic agents than apo-cytochrome b 5 . The introduction of these aromatic residues also results in "trimer" interactions with existing aromatic groups, reaffirming the selectivity of the aromatic interactions. These studies provide insights into the aromatic interactions that drive disorder-to-order transitions in intrinsically disordered regions of proteins and will aid in de novo protein design beyond small peptide scaffolds.

Bipolar Disorder and Alcoholism: Are They Related?

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... Are they related? Is there a connection between bipolar disorder and alcoholism? Answers from Daniel K. Hall-Flavin, M.D. Bipolar disorder and alcoholism often occur together. Although the association ...

Intrinsic disorder here, there, and everywhere, and nowhere to escape from it.

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Uversky, Vladimir N

2017-09-01

The concept of protein intrinsic disorder persistently penetrates into all areas of modern protein science. It cannot be ignored anymore, and cannot be shrugged off, as it represents a vital feature (or, more correctly, a broad spectrum of important features), which, when added to and mixed with features arising from the well established protein structure-function paradigm, complete the picture of a functioning protein. The field of protein intrinsic disorder is very dynamic and fast developing. This Multi-Author Review represents a snapshot of this field by introducing some recent advances. Articles assembled in this Multi-Author Review introduce some of the new aspects of intrinsic disorder, outline some fascinating ideas related to the intrinsically disordered proteins, their structure, and functionality, and show challenges related to the analysis of proteins carrying intrinsic disorder.

G Protein-Linked Signaling Pathways in Bipolar and Major Depressive Disorders

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Hiroaki eTomita

2013-12-01

Full Text Available The G-protein linked signaling system (GPLS comprises a large number of G-proteins, G protein-coupled receptors (GPCRs, GPCR ligands, and downstream effector molecules. G-proteins interact with both GPCRs and downstream effectors such as cyclic adenosine monophosphate (cAMP, phosphatidylinositols, and ion channels. The GPLS is implicated in the pathophysiology and pharmacology of both major depressive disorder (MDD and bipolar disorder (BPD. This study evaluated whether GPLS is altered at the transcript level. The gene expression in the dorsolateral prefrontal (DLPFC and anterior cingulate (ACC were compared from MDD, BPD, and control subjects using Affymetrix Gene Chips and real time quantitative PCR. High quality brain tissue was used in the study to control for confounding effects of agonal events, tissue pH, RNA integrity, gender, and age. GPLS signaling transcripts were altered especially in the ACC of BPD and MDD subjects. Transcript levels of molecules which repress cAMP activity were increased in BPD and decreased in MDD. Two orphan GPCRs, GPRC5B and GPR37, showed significantly decreased expression levels in MDD, and significantly increased expression levels in BPD. Our results suggest opposite changes in BPD and MDD in the GPLS, ‘activated’ cAMP signaling activity in BPD and ‘blunted’ cAMP signaling activity in MDD. GPRC5B and GPR37 both appear to have behavioral effects, and are also candidate genes for neurodegenerative disorders. In the context of the opposite changes observed in BPD and MDD, these GPCRs warrant further study of their brain effects.

On the potential of using peculiarities of the protein intrinsic disorder distribution in mitochondrial cytochrome b to identify the source of animal meats

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Yacoub, Haitham A.; Sadek, Mahmoud A.; Uversky, Vladimir N.

2017-01-01

ABSTRACT This study was conducted to identify the source of animal meat based on the peculiarities of protein intrinsic disorder distribution in mitochondrial cytochrome b (mtCyt-b). The analysis revealed that animal and avian species can be discriminated based on the proportions of the two groups of residues, Leu+Ile, and Ser+Pro+Ala, in the amino acid sequences of their mtCyt-b. Although levels of the overall intrinsic disorder in mtCyt-b is not very high, the peculiarities of disorder distribution within the sequences of mtCyt-b from different species varies in a rather specific way. In fact, positions and intensities of disorder/flexibility “signals” in the corresponding disorder profiles are relatively unique for avian and animal species. Therefore, it is possible to devise a set of simple rules based on the peculiarities of disorder profiles of their mtCyt-b proteins to discriminate among species. This intrinsic disorder-based analysis represents a new technique that could be used to provide a promising solution for identification of the source of meats. PMID:28331777

Innovative scattering analysis shows that hydrophobic disordered proteins are expanded in water

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Riback, Joshua A.; Bowman, Micayla A.; Zmyslowski, Adam M.; Knoverek, Catherine R.; Jumper, John M.; Hinshaw, James R.; Kaye, Emily B.; Freed, Karl F.; Clark, Patricia L.; Sosnick, Tobin R.

2017-10-12

A substantial fraction of the proteome is intrinsically disordered, and even well-folded proteins adopt non-native geometries during synthesis, folding, transport, and turnover. Characterization of intrinsically disordered proteins (IDPs) is challenging, in part because of a lack of accurate physical models and the difficulty of interpreting experimental results. We have developed a general method to extract the dimensions and solvent quality (self-interactions) of IDPs from a single small-angle x-ray scattering measurement. We applied this procedure to a variety of IDPs and found that even IDPs with low net charge and high hydrophobicity remain highly expanded in water, contrary to the general expectation that protein-like sequences collapse in water. Our results suggest that the unfolded state of most foldable sequences is expanded; we conjecture that this property was selected by evolution to minimize misfolding and aggregation.

State-related alterations of gene expression in bipolar disorder

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Munkholm, Klaus; Vinberg, Maj; Berk, Michael

2012-01-01

Munkholm K, Vinberg M, Berk M, Kessing LV. State-related alterations of gene expression in bipolar disorder: a systematic review. Bipolar Disord 2012: 14: 684-696. © 2012 The Authors. Journal compilation © 2012 John Wiley & Sons A/S. Objective:  Alterations in gene expression in bipolar disorder...... have been found in numerous studies. It is unclear whether such alterations are related to specific mood states. As a biphasic disorder, mood state-related alterations in gene expression have the potential to point to markers of disease activity, and trait-related alterations might indicate...... vulnerability pathways. This review therefore evaluated the evidence for whether gene expression in bipolar disorder is state or trait related. Methods:  A systematic review, using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guideline for reporting systematic reviews, based...

Serum protein profiling and proteomics in autistic spectrum disorder using magnetic bead-assisted mass spectrometry.

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Taurines, Regina; Dudley, Edward; Conner, Alexander C; Grassl, Julia; Jans, Thomas; Guderian, Frank; Mehler-Wex, Claudia; Warnke, Andreas; Gerlach, Manfred; Thome, Johannes

2010-04-01

The pathophysiology of autistic spectrum disorder (ASD) is not fully understood and there are no diagnostic or predictive biomarkers. Proteomic profiling has been used in the past for biomarker research in several non-psychiatric and psychiatric disorders and could provide new insights, potentially presenting a useful tool for generating such biomarkers in autism. Serum protein pre-fractionation with C8-magnetic beads and protein profiling by matrix-assisted laser desorption/ionisation-time of flight-mass spectrometry (MALDI-ToF-MS) were used to identify possible differences in protein profiles in patients and controls. Serum was obtained from 16 patients (aged 8-18) and age-matched controls. Three peaks in the MALDI-ToF-MS significantly differentiated the ASD sample from the control group. Sub-grouping the ASD patients into children with and without comorbid Attention Deficit and Hyperactivity Disorder, ADHD (ASD/ADHD+ patients, n = 9; ASD/ADHD- patients, n = 7), one peak distinguished the ASD/ADHD+ patients from controls and ASD/ADHD- patients. Our results suggest that altered protein levels in peripheral blood of patients with ASD might represent useful biomarkers for this devastating psychiatric disorder.

Sequence charge decoration dictates coil-globule transition in intrinsically disordered proteins

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Firman, Taylor; Ghosh, Kingshuk

2018-03-01

We present an analytical theory to compute conformations of heteropolymers—applicable to describe disordered proteins—as a function of temperature and charge sequence. The theory describes coil-globule transition for a given protein sequence when temperature is varied and has been benchmarked against the all-atom Monte Carlo simulation (using CAMPARI) of intrinsically disordered proteins (IDPs). In addition, the model quantitatively shows how subtle alterations of charge placement in the primary sequence—while maintaining the same charge composition—can lead to significant changes in conformation, even as drastic as a coil (swelled above a purely random coil) to globule (collapsed below a random coil) and vice versa. The theory provides insights on how to control (enhance or suppress) these changes by tuning the temperature (or solution condition) and charge decoration. As an application, we predict the distribution of conformations (at room temperature) of all naturally occurring IDPs in the DisProt database and notice significant size variation even among IDPs with a similar composition of positive and negative charges. Based on this, we provide a new diagram-of-states delineating the sequence-conformation relation for proteins in the DisProt database. Next, we study the effect of post-translational modification, e.g., phosphorylation, on IDP conformations. Modifications as little as two-site phosphorylation can significantly alter the size of an IDP with everything else being constant (temperature, salt concentration, etc.). However, not all possible modification sites have the same effect on protein conformations; there are certain "hot spots" that can cause maximal change in conformation. The location of these "hot spots" in the parent sequence can readily be identified by using a sequence charge decoration metric originally introduced by Sawle and Ghosh. The ability of our model to predict conformations (both expanded and collapsed states) of IDPs at

Clinical identification of the simple sleep-related movement disorders.

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Walters, Arthur S

2007-04-01

Simple sleep-related movement disorders must be distinguished from daytime movement disorders that persist during sleep, sleep-related epilepsy, and parasomnias, which are generally characterized by activity that appears to be simultaneously complex, goal-directed, and purposeful but is outside the conscious awareness of the patient and, therefore, inappropriate. Once it is determined that the patient has a simple sleep-related movement disorder, the part of the body affected by the movement and the age of the patient give clues as to which sleep-related movement disorder is present. In some cases, all-night polysomnography with accompanying video may be necessary to make the diagnosis. Hypnic jerks (ie, sleep starts), bruxism, rhythmic movement disorder (ie, head banging/body rocking), and nocturnal leg cramps are discussed in addition to less well-appreciated disorders such as benign sleep myoclonus of infancy, excessive fragmentary myoclonus, and hypnagogic foot tremor/alternating leg muscle activation.

Behavioral, Pharmacological, and Immunological Abnormalities after Streptococcal Exposure: A Novel Rat Model of Sydenham Chorea and Related Neuropsychiatric Disorders

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Brimberg, Lior; Benhar, Itai; Mascaro-Blanco, Adita; Alvarez, Kathy; Lotan, Dafna; Winter, Christine; Klein, Julia; Moses, Allon E; Somnier, Finn E; Leckman, James F; Swedo, Susan E; Cunningham, Madeleine W; Joel, Daphna

2012-01-01

Group A streptococcal (GAS) infections and autoimmunity are associated with the onset of a spectrum of neuropsychiatric disorders in children, with the prototypical disorder being Sydenham chorea (SC). Our aim was to develop an animal model that resembled the behavioral, pharmacological, and immunological abnormalities of SC and other streptococcal-related neuropsychiatric disorders. Male Lewis rats exposed to GAS antigen exhibited motor symptoms (impaired food manipulation and beam walking) and compulsive behavior (increased induced-grooming). These symptoms were alleviated by the D2 blocker haloperidol and the selective serotonin reuptake inhibitor paroxetine, respectively, drugs that are used to treat motor symptoms and compulsions in streptococcal-related neuropsychiatric disorders. Streptococcal exposure resulted in antibody deposition in the striatum, thalamus, and frontal cortex, and concomitant alterations in dopamine and glutamate levels in cortex and basal ganglia, consistent with the known pathophysiology of SC and related neuropsychiatric disorders. Autoantibodies (IgG) of GAS rats reacted with tubulin and caused elevated calcium/calmodulin-dependent protein kinase II signaling in SK-N-SH neuronal cells, as previously found with sera from SC and related neuropsychiatric disorders. Our new animal model translates directly to human disease and led us to discover autoantibodies targeted against dopamine D1 and D2 receptors in the rat model as well as in SC and other streptococcal-related neuropsychiatric disorders. PMID:22534626

Discovery of Cryoprotective Activity in Human Genome-Derived Intrinsically Disordered Proteins

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Naoki Matsuo

2018-01-01

Full Text Available Intrinsically disordered proteins (IDPs are an emerging phenomenon. They may have a high degree of flexibility in their polypeptide chains, which lack a stable 3D structure. Although several biological functions of IDPs have been proposed, their general function is not known. The only finding related to their function is the genetically conserved YSK2 motif present in plant dehydrins. These proteins were shown to be IDPs with the YSK2 motif serving as a core region for the dehydrins’ cryoprotective activity. Here we examined the cryoprotective activity of randomly selected IDPs toward the model enzyme lactate dehydrogenase (LDH. All five IDPs that were examined were in the range of 35–45 amino acid residues in length and were equally potent at a concentration of 50 μg/mL, whereas folded proteins, the PSD-95/Dlg/ZO-1 (PDZ domain, and lysozymes had no potency. We further examined their cryoprotective activity toward glutathione S-transferase as an example of the other enzyme, and toward enhanced green fluorescent protein as a non-enzyme protein example. We further examined the lyophilization protective activity of the peptides toward LDH, which revealed that some IDPs showed a higher activity than that of bovine serum albumin (BSA. Based on these observations, we propose that cryoprotection is a general feature of IDPs. Our findings may become a clue to various industrial applications of IDPs in the future.

Understanding the Role of Intrinsic Disorder of Viral Proteins in the Oncogenicity of Different Types of HPV.

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Tamarozzi, Elvira Regina; Giuliatti, Silvana

2018-01-09

Intrinsic disorder is very important in the biological function of several proteins, and is directly linked to their foldability during interaction with their targets. There is a close relationship between the intrinsically disordered proteins and the process of carcinogenesis involving viral pathogens. Among these pathogens, we have highlighted the human papillomavirus (HPV) in this study. HPV is currently among the most common sexually transmitted infections, besides being the cause of several types of cancer. HPVs are divided into two groups, called high- and low-risk, based on their oncogenic potential. The high-risk HPV E6 protein has been the target of much research, in seeking treatments against HPV, due to its direct involvement in the process of cell cycle control. To understand the role of intrinsic disorder of the viral proteins in the oncogenic potential of different HPV types, the structural characteristics of intrinsically disordered regions of high and low-risk HPV E6 proteins were analyzed. In silico analyses of primary sequences, prediction of tertiary structures, and analyses of molecular dynamics allowed the observation of the behavior of such disordered regions in these proteins, thereby proving a direct relationship of structural variation with the degree of oncogenicity of HPVs. The results obtained may contribute to the development of new therapies, targeting the E6 oncoprotein, for the treatment of HPV-associated diseases.

ER stress signaling and neurodegeneration: At the intersection between Alzheimer's disease and Prion-related disorders.

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Torres, Mauricio; Matamala, José Manuel; Duran-Aniotz, Claudia; Cornejo, Victor Hugo; Foley, Andrew; Hetz, Claudio

2015-09-02

Alzheimer's and Prion diseases are two neurodegenerative conditions sharing different pathophysiological characteristics. Disease symptoms are associated with the abnormal accumulation of protein aggregates, which are generated by the misfolding and oligomerization of specific proteins. Recent functional studies uncovered a key role of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) in the occurrence of synaptic dysfunction and neurodegeneration in Prion-related disorders and Alzheimer's disease. Here we review common pathological features of both diseases, emphasizing the link between amyloid formation, its pathogenesis and alterations in ER proteostasis. The potential benefits of targeting the UPR as a therapeutic strategy is also discussed. Copyright © 2014 Elsevier B.V. All rights reserved.

Stress Related Oral Disorders - A Review

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D Nagabhushana

2004-01-01

However, relatively few studies have been carried out on the relationship of emotional factors to diseases of the oral mucosa. So, here is an article which tries to briefly review the psychosomatic (stress related disorders related to the oral cavity.

An Extended Guinier Analysis for Intrinsically Disordered Proteins.

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Zheng, Wenwei; Best, Robert B

2018-03-21

Guinier analysis allows model-free determination of the radius of gyration (R g ) of a biomolecule from X-ray or neutron scattering data, in the limit of very small scattering angles. Its range of validity is well understood for globular proteins, but is known to be more restricted for unfolded or intrinsically disordered proteins (IDPs). We have used ensembles of disordered structures from molecular dynamics simulations to investigate which structural properties cause deviations from the Guinier approximation at small scattering angles. We find that the deviation from the Guinier approximation is correlated with the polymer scaling exponent ν describing the unfolded ensemble. We therefore introduce an empirical, ν-dependent, higher-order correction term, to augment the standard Guinier analysis. We test the new fitting scheme using all-atom simulation data for several IDPs and experimental data for both an IDP and a destabilized mutant of a folded protein. In all cases tested, we achieve an accuracy of the inferred R g within ∼3% of the true R g . The method is straightforward to implement and extends the range of validity to a maximum qR g of ∼2 versus ∼1.1 for Guinier analysis. Compared with the Guinier or Debye approaches, our method allows data from wider angles with lower noise to be used to analyze scattering data accurately. In addition to R g , our fitting scheme also yields estimates of the scaling exponent ν in excellent agreement with the reference ν determined from the underlying molecular ensemble. Published by Elsevier Ltd.

CDKL5 protein substitution therapy rescues neurological phenotypes of a mouse model of CDKL5 disorder.

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Trazzi, Stefania; De Franceschi, Marianna; Fuchs, Claudia; Bastianini, Stefano; Viggiano, Rocchina; Lupori, Leonardo; Mazziotti, Raffaele; Medici, Giorgio; Lo Martire, Viviana; Ren, Elisa; Rimondini, Roberto; Zoccoli, Giovanna; Bartesaghi, Renata; Pizzorusso, Tommaso; Ciani, Elisabetta

2018-05-01

Cyclin-dependent kinase like-5 (CDKL5) disorder is a rare neurodevelopmental disease caused by mutations in the CDKL5 gene. The consequent misexpression of the CDKL5 protein in the nervous system leads to a severe phenotype characterized by intellectual disability, motor impairment, visual deficits and early-onset epilepsy. No therapy is available for CDKL5 disorder. It has been reported that a protein transduction domain (TAT) is able to deliver macromolecules into cells and even into the brain when fused to a given protein. We demonstrate that TAT-CDKL5 fusion protein is efficiently internalized by target cells and retains CDKL5 activity. Intracerebroventricular infusion of TAT-CDKL5 restored hippocampal development, hippocampus-dependent memory and breathing pattern in Cdkl5-null mice. Notably, systemically administered TAT-CDKL5 protein passed the blood-brain-barrier, reached the CNS, and rescued various neuroanatomical and behavioral defects, including breathing pattern and visual responses. Our results suggest that CDKL5 protein therapy may be an effective clinical tool for the treatment of CDKL5 disorder.

Applying chaperones to protein-misfolding disorders: molecular chaperones against α-synuclein in Parkinson's disease.

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Chaari, Ali; Hoarau-Véchot, Jessica; Ladjimi, Moncef

2013-09-01

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the accumulation of a protein called α-synuclein (α-syn) into inclusions known as lewy bodies (LB) within neurons. This accumulation is also due to insufficient formation and activity of dopamine produced in certain neurons within the substantia nigra. Lewy bodies are the pathological hallmark of the idiopathic disorder and the cascade that allows α-synuclein to misfold, aggregate and form these inclusions has been the subject of intensive research. Targeting these early steps of oligomerization is one of the main therapeutic approaches in order to develop neurodegenerative-modifying agents. Because the folding and refolding of alpha synuclein is the key point of this cascade, we are interested in this review to summarize the role of some molecular chaperones proteins such as Hsp70, Hsp90 and small heat shock proteins (sHsp) and Hsp 104. Hsp70 and its co-chaperone, Hsp70 and small heat shock proteins can prevent neurodegeneration by preventing α-syn misfolding, oligomerization and aggregation in vitro and in Parkinson disease animal models. Hsp104 is able to resolve disordered protein aggregates and cross beta amyloid conformers. Together, these chaperones have a complementary effect and can be a target for therapeutic intervention in PD. Published by Elsevier B.V.

Abnormal brain activation and connectivity to standardized disorder-related visual scenes in social anxiety disorder.

Science.gov (United States)

Heitmann, Carina Yvonne; Feldker, Katharina; Neumeister, Paula; Zepp, Britta Maria; Peterburs, Jutta; Zwitserlood, Pienie; Straube, Thomas

2016-04-01

Our understanding of altered emotional processing in social anxiety disorder (SAD) is hampered by a heterogeneity of findings, which is probably due to the vastly different methods and materials used so far. This is why the present functional magnetic resonance imaging (fMRI) study investigated immediate disorder-related threat processing in 30 SAD patients and 30 healthy controls (HC) with a novel, standardized set of highly ecologically valid, disorder-related complex visual scenes. SAD patients rated disorder-related as compared with neutral scenes as more unpleasant, arousing and anxiety-inducing than HC. On the neural level, disorder-related as compared with neutral scenes evoked differential responses in SAD patients in a widespread emotion processing network including (para-)limbic structures (e.g. amygdala, insula, thalamus, globus pallidus) and cortical regions (e.g. dorsomedial prefrontal cortex (dmPFC), posterior cingulate cortex (PCC), and precuneus). Functional connectivity analysis yielded an altered interplay between PCC/precuneus and paralimbic (insula) as well as cortical regions (dmPFC, precuneus) in SAD patients, which emphasizes a central role for PCC/precuneus in disorder-related scene processing. Hyperconnectivity of globus pallidus with amygdala, anterior cingulate cortex (ACC) and medial prefrontal cortex (mPFC) additionally underlines the relevance of this region in socially anxious threat processing. Our findings stress the importance of specific disorder-related stimuli for the investigation of altered emotion processing in SAD. Disorder-related threat processing in SAD reveals anomalies at multiple stages of emotion processing which may be linked to increased anxiety and to dysfunctionally elevated levels of self-referential processing reported in previous studies. © 2016 Wiley Periodicals, Inc.

Intercellular protein-protein interactions at synapses.

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Yang, Xiaofei; Hou, Dongmei; Jiang, Wei; Zhang, Chen

2014-06-01

Chemical synapses are asymmetric intercellular junctions through which neurons send nerve impulses to communicate with other neurons or excitable cells. The appropriate formation of synapses, both spatially and temporally, is essential for brain function and depends on the intercellular protein-protein interactions of cell adhesion molecules (CAMs) at synaptic clefts. The CAM proteins link pre- and post-synaptic sites, and play essential roles in promoting synapse formation and maturation, maintaining synapse number and type, accumulating neurotransmitter receptors and ion channels, controlling neuronal differentiation, and even regulating synaptic plasticity directly. Alteration of the interactions of CAMs leads to structural and functional impairments, which results in many neurological disorders, such as autism, Alzheimer's disease and schizophrenia. Therefore, it is crucial to understand the functions of CAMs during development and in the mature neural system, as well as in the pathogenesis of some neurological disorders. Here, we review the function of the major classes of CAMs, and how dysfunction of CAMs relates to several neurological disorders.

Small-angle scattering studies of intrinsically disordered proteins and their complexes

DEFF Research Database (Denmark)

Cordeiro, Tiago N.; Herranz-Trillo, Fátima; Urbanek, Annika

2017-01-01

Intrinsically Disordered Proteins (IDPs) perform a broad range of biological functions. Their relevance has motivated intense research activity seeking to characterize their sequence/structure/function relationships. However, the conformational plasticity of these molecules hampers the applicatio...

Lysinuric protein intolerance (LPI): a multi organ disease by far more complex than a classic urea cycle disorder.

Science.gov (United States)

Ogier de Baulny, Hélène; Schiff, Manuel; Dionisi-Vici, Carlo

2012-05-01

Lysinuric protein intolerance (LPI) is an inherited defect of cationic amino acid (lysine, arginine and ornithine) transport at the basolateral membrane of intestinal and renal tubular cells caused by mutations in SLC7A7 encoding the y(+)LAT1 protein. LPI has long been considered a relatively benign urea cycle disease, when appropriately treated with low-protein diet and l-citrulline supplementation. However, the severe clinical course of this disorder suggests that LPI should be regarded as a severe multisystem disease with uncertain outcome. Specifically, immune dysfunction potentially attributable to nitric oxide (NO) overproduction secondary to arginine intracellular trapping (due to defective efflux from the cell) might be a crucial pathophysiological route explaining many of LPI complications. The latter comprise severe lung disease with pulmonary alveolar proteinosis, renal disease, hemophagocytic lymphohistiocytosis with subsequent activation of macrophages, various auto-immune disorders and an incompletely characterized immune deficiency. These results have several therapeutic implications, among which lowering the l-citrulline dosage may be crucial, as excessive citrulline may worsen intracellular arginine accumulation. Copyright © 2012 Elsevier Inc. All rights reserved.

p15PAF is an intrinsically disordered protein with nonrandom structural preferences at sites of interaction with other proteins.

Science.gov (United States)

De Biasio, Alfredo; Ibáñez de Opakua, Alain; Cordeiro, Tiago N; Villate, Maider; Merino, Nekane; Sibille, Nathalie; Lelli, Moreno; Diercks, Tammo; Bernadó, Pau; Blanco, Francisco J

2014-02-18

We present to our knowledge the first structural characterization of the proliferating-cell-nuclear-antigen-associated factor p15(PAF), showing that it is monomeric and intrinsically disordered in solution but has nonrandom conformational preferences at sites of protein-protein interactions. p15(PAF) is a 12 kDa nuclear protein that acts as a regulator of DNA repair during DNA replication. The p15(PAF) gene is overexpressed in several types of human cancer. The nearly complete NMR backbone assignment of p15(PAF) allowed us to measure 86 N-H(N) residual dipolar couplings. Our residual dipolar coupling analysis reveals nonrandom conformational preferences in distinct regions, including the proliferating-cell-nuclear-antigen-interacting protein motif (PIP-box) and the KEN-box (recognized by the ubiquitin ligase that targets p15(PAF) for degradation). In accordance with these findings, analysis of the (15)N R2 relaxation rates shows a relatively reduced mobility for the residues in these regions. The agreement between the experimental small angle x-ray scattering curve of p15(PAF) and that computed from a statistical coil ensemble corrected for the presence of local secondary structural elements further validates our structural model for p15(PAF). The coincidence of these transiently structured regions with protein-protein interaction and posttranslational modification sites suggests a possible role for these structures as molecular recognition elements for p15(PAF). Copyright © 2014 Biophysical Society. Published by Elsevier Inc. All rights reserved.

Crosslines, fluorophores in the AGE-related cross-linked proteins.

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Ienaga, K; Nakamura, K; Hochi, T; Nakazawa, Y; Fukunaga, Y; Kakita, H; Nakano, K

1995-01-01

We can summarize our results as follows: (1) A pair of fluorescent crosslines were isolated from the Maillard reaction mixture; (2) AGE-proteins contained crossline-like structures, and (3) crossline-like immunoreactivities were accumulated in renal tissues of diabetic rats. From these results we concluded that fluorophores in AGE proteins have crossline-like structures and we had the first indication that XLs could be markers for renal disorders.

Comparative Genomics and Disorder Prediction Identify Biologically Relevant SH3 Protein Interactions.

Directory of Open Access Journals (Sweden)

2005-08-01

Full Text Available Protein interaction networks are an important part of the post-genomic effort to integrate a part-list view of the cell into system-level understanding. Using a set of 11 yeast genomes we show that combining comparative genomics and secondary structure information greatly increases consensus-based prediction of SH3 targets. Benchmarking of our method against positive and negative standards gave 83% accuracy with 26% coverage. The concept of an optimal divergence time for effective comparative genomics studies was analyzed, demonstrating that genomes of species that diverged very recently from Saccharomyces cerevisiae(S. mikatae, S. bayanus, and S. paradoxus, or a long time ago (Neurospora crassa and Schizosaccharomyces pombe, contain less information for accurate prediction of SH3 targets than species within the optimal divergence time proposed. We also show here that intrinsically disordered SH3 domain targets are more probable sites of interaction than equivalent sites within ordered regions. Our findings highlight several novel S. cerevisiae SH3 protein interactions, the value of selection of optimal divergence times in comparative genomics studies, and the importance of intrinsic disorder for protein interactions. Based on our results we propose novel roles for the S. cerevisiae proteins Abp1p in endocytosis and Hse1p in endosome protein sorting.

Comparative genomics and disorder prediction identify biologically relevant SH3 protein interactions.

Directory of Open Access Journals (Sweden)

Pedro Beltrao

2005-08-01

Full Text Available Protein interaction networks are an important part of the post-genomic effort to integrate a part-list view of the cell into system-level understanding. Using a set of 11 yeast genomes we show that combining comparative genomics and secondary structure information greatly increases consensus-based prediction of SH3 targets. Benchmarking of our method against positive and negative standards gave 83% accuracy with 26% coverage. The concept of an optimal divergence time for effective comparative genomics studies was analyzed, demonstrating that genomes of species that diverged very recently from Saccharomyces cerevisiae(S. mikatae, S. bayanus, and S. paradoxus, or a long time ago (Neurospora crassa and Schizosaccharomyces pombe, contain less information for accurate prediction of SH3 targets than species within the optimal divergence time proposed. We also show here that intrinsically disordered SH3 domain targets are more probable sites of interaction than equivalent sites within ordered regions. Our findings highlight several novel S. cerevisiae SH3 protein interactions, the value of selection of optimal divergence times in comparative genomics studies, and the importance of intrinsic disorder for protein interactions. Based on our results we propose novel roles for the S. cerevisiae proteins Abp1p in endocytosis and Hse1p in endosome protein sorting.

Large-scale analysis of intrinsic disorder flavors and associated functions in the protein sequence universe.

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Necci, Marco; Piovesan, Damiano; Tosatto, Silvio C E

2016-12-01

Intrinsic disorder (ID) in proteins has been extensively described for the last decade; a large-scale classification of ID in proteins is mostly missing. Here, we provide an extensive analysis of ID in the protein universe on the UniProt database derived from sequence-based predictions in MobiDB. Almost half the sequences contain an ID region of at least five residues. About 9% of proteins have a long ID region of over 20 residues which are more abundant in Eukaryotic organisms and most frequently cover less than 20% of the sequence. A small subset of about 67,000 (out of over 80 million) proteins is fully disordered and mostly found in Viruses. Most proteins have only one ID, with short ID evenly distributed along the sequence and long ID overrepresented in the center. The charged residue composition of Das and Pappu was used to classify ID proteins by structural propensities and corresponding functional enrichment. Swollen Coils seem to be used mainly as structural components and in biosynthesis in both Prokaryotes and Eukaryotes. In Bacteria, they are confined in the nucleoid and in Viruses provide DNA binding function. Coils & Hairpins seem to be specialized in ribosome binding and methylation activities. Globules & Tadpoles bind antigens in Eukaryotes but are involved in killing other organisms and cytolysis in Bacteria. The Undefined class is used by Bacteria to bind toxic substances and mediate transport and movement between and within organisms in Viruses. Fully disordered proteins behave similarly, but are enriched for glycine residues and extracellular structures. © 2016 The Protein Society.

Shank synaptic scaffold proteins: keys to understanding the pathogenesis of autism and other synaptic disorders.

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Sala, Carlo; Vicidomini, Cinzia; Bigi, Ilaria; Mossa, Adele; Verpelli, Chiara

2015-12-01

Shank/ProSAP proteins are essential to synaptic formation, development, and function. Mutations in the family of SHANK genes are strongly associated with autism spectrum disorders (ASD) and other neurodevelopmental and neuropsychiatric disorders, such as intellectual disability (ID), and schizophrenia. Thus, the term 'Shankopathies' identifies a number of neuronal diseases caused by alteration of Shank protein expression leading to abnormal synaptic development. With this review we want to summarize the major genetic, molecular, behavior and electrophysiological studies that provide new clues into the function of Shanks and pave the way for the discovery of new therapeutic drugs targeted to treat patients with SHANK mutations and also patients affected by other neurodevelopmental and neuropsychiatric disorders. Shank/ProSAP proteins are essential to synaptic formation, development, and function. Mutations in the family of SHANK genes are strongly associated with autism spectrum disorders (ASD) and other neurodevelopmental and neuropsychiatric disorders, such as intellectual disability (ID), and schizophrenia (SCZ). With this review we want to summarize the major genetic, molecular, behavior and electrophysiological studies that provide new clues into the function of Shanks and pave the way for the discovery of new therapeutic drugs targeted to treat patients with SHANK mutations. © 2015 International Society for Neurochemistry.

Relation of periodontitis and metabolic syndrome with gestational glucose metabolism disorder.

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Bullon, Pedro; Jaramillo, Reyes; Santos-Garcia, Rocio; Rios-Santos, Vicente; Ramirez, Maria; Fernandez-Palacin, Ana; Fernandez-Riejos, Patricia

2014-02-01

Gestational diabetes mellitus (GDM) and metabolic syndrome have been related to periodontitis. This study's objective is to establish the relationship between them in pregnant women affected by gestational glucose metabolism disorder. In 188 pregnant women with positive O'Sullivan test (POT) results, an oral glucose tolerance test (OGTT) was performed to diagnose GDM. The mother's periodontal parameters, age, prepregnancy weight and height and body mass index (BMI), blood pressure, gestational age, and birth weight were recorded at 24 to 28 weeks of pregnancy, as well as levels of glucose, C-reactive protein, triglycerides, glycated hemoglobin (HbA1c), and total, low-density lipoprotein, high-density lipoprotein (HDL), and very-low-density lipoprotein (VLDL) cholesterol levels. Prepregnancy weight, prepregnancy BMI, systolic and diastolic blood pressure, VLDL cholesterol, and glucose parameters were higher in GDM compared with POT (P periodontitis than in patients without periodontitis (P c, triglycerides, and 1- and 2-hour OGTT were positively related with probing depth and clinical attachment level; blood glucose was related only to bleeding on probing (P c, basal OGTT, and 1- and 2-hour OGTT were positively related to prepregnancy BMI and blood pressure; HDL cholesterol was negatively related to prepregnancy BMI; C-reactive protein was positively related to prepregnancy BMI and diastolic blood pressure (P periodontal disease and some biochemical parameters such as lipid and glucose data in pregnancy, and also among metabolic syndrome and biochemical parameters.

Anxiety sensitivity mediates relations between emotional disorders and smoking.

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Zvolensky, Michael J; Farris, Samantha G; Leventhal, Adam M; Schmidt, Norman B

2014-09-01

Research has documented consistent and robust relations between emotional disorders (i.e., depressive and anxiety disorders) and smoking. Yet, it is presently unclear whether anxiety sensitivity--the fear of aversive internal anxiety states--accounts for the relations between emotional disorders and various smoking processes, including nicotine dependence, perceived barriers to smoking cessation, and severity of problematic symptoms during past cessation attempts. Participants (N = 465) were treatment-seeking daily tobacco smokers recruited as part of a larger tobacco-cessation study. Baseline (pretreatment) data were utilized. Emotional disorders were assessed via clinical diagnostic interview; self-report measures were used to assess anxiety sensitivity and 3 criterion variables: nicotine dependence, barriers to smoking cessation, and severity of problematic symptoms while quitting in past attempts. Emotional disorders were predictive of higher levels of nicotine dependence, greater perceived barriers to cessation, and greater severity of problematic symptoms while attempting to quit in the past; each of these relations were accounted for by the indirect effect of anxiety sensitivity. The present findings suggest that anxiety sensitivity may be an important transdiagnostic construct in explicating the nature of the relations between emotional disorders and various smoking processes.

Bioinformatics analysis identifies several intrinsically disordered human E3 ubiquitin-protein ligases

Directory of Open Access Journals (Sweden)

Wouter Boomsma

2016-02-01

Full Text Available The ubiquitin-proteasome system targets misfolded proteins for degradation. Since the accumulation of such proteins is potentially harmful for the cell, their prompt removal is important. E3 ubiquitin-protein ligases mediate substrate ubiquitination by bringing together the substrate with an E2 ubiquitin-conjugating enzyme, which transfers ubiquitin to the substrate. For misfolded proteins, substrate recognition is generally delegated to molecular chaperones that subsequently interact with specific E3 ligases. An important exception is San1, a yeast E3 ligase. San1 harbors extensive regions of intrinsic disorder, which provide both conformational flexibility and sites for direct recognition of misfolded targets of vastly different conformations. So far, no mammalian ortholog of San1 is known, nor is it clear whether other E3 ligases utilize disordered regions for substrate recognition. Here, we conduct a bioinformatics analysis to examine >600 human and S. cerevisiae E3 ligases to identify enzymes that are similar to San1 in terms of function and/or mechanism of substrate recognition. An initial sequence-based database search was found to detect candidates primarily based on the homology of their ordered regions, and did not capture the unique disorder patterns that encode the functional mechanism of San1. However, by searching specifically for key features of the San1 sequence, such as long regions of intrinsic disorder embedded with short stretches predicted to be suitable for substrate interaction, we identified several E3 ligases with these characteristics. Our initial analysis revealed that another remarkable trait of San1 is shared with several candidate E3 ligases: long stretches of complete lysine suppression, which in San1 limits auto-ubiquitination. We encode these characteristic features into a San1 similarity-score, and present a set of proteins that are plausible candidates as San1 counterparts in humans. In conclusion, our work

Autism and Related Disorders

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McPartland, James; Volkmar, Fred R.

2012-01-01

The Pervasive Developmental Disorders are a group of neurodevelopmental disorders that include Autistic Disorder, Asperger’s Disorder, Pervasive Developmental Disorder - Not Otherwise Specified (PDD-NOS), Childhood Disintegrative Disorder (CDD), and Rett’s Disorder. All feature childhood onset with a constellation of symptoms spanning social interaction and communication and including atypical behavior patterns. The first three disorders (Autistic Disorder, Asperger’s Disorder, and PDD-NOS) are currently referred to as Autism Spectrum Disorders, reflecting divergent phenotypic and etiologic characteristics compared to Rett’s Disorder and CDD. This chapter reviews relevant research and clinical information relevant to appropriate medical diagnosis and treatment. PMID:22608634

Epigenetic mechanisms of alcoholism and stress-related disorders.

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Palmisano, Martina; Pandey, Subhash C

2017-05-01

Stress-related disorders, such as anxiety, early life stress, and posttraumatic stress disorder appear to be important factors in promoting alcoholism, as alcohol consumption can temporarily attenuate the negative affective symptoms of these disorders. Several molecules involved in signaling pathways may contribute to the neuroadaptation induced during alcohol dependence and stress disorders, and among these, brain-derived neurotrophic factor (BDNF), corticotropin releasing factor (CRF), neuropeptide Y (NPY) and opioid peptides (i.e., nociceptin and dynorphin) are involved in the interaction of stress and alcohol. In fact, alterations in the expression and function of these molecules have been associated with the pathophysiology of stress-related disorders and alcoholism. In recent years, various studies have focused on the epigenetic mechanisms that regulate chromatin architecture, thereby modifying gene expression. Interestingly, epigenetic modifications in specific brain regions have been shown to be associated with the neurobiology of psychiatric disorders, including alcoholism and stress. In particular, the enzymes responsible for chromatin remodeling (i.e., histone deacetylases and methyltransferases, DNA methyltransferases) have been identified as common molecular mechanisms for the interaction of stress and alcohol and have become promising therapeutic targets to treat or prevent alcoholism and associated emotional disorders. Published by Elsevier Inc.

Of piglets, dietary proteins, and pancreatic proteases

NARCIS (Netherlands)

Makkink, C.A.

1993-01-01

Newly weaned piglets often show digestive disorders, frequently resulting in diarrhoea. These disorders may be related to the dietary protein source, since young piglets are less capable of digesting proteins of vegetable origin than older pigs. This study was undertaken to investigate the

Antisocial personality disorder and borderline symptoms are differentially related to impulsivity and course of illness in bipolar disorder.

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Swann, Alan C; Lijffijt, Marijn; Lane, Scott D; Steinberg, Joel L; Moeller, F Gerard

2013-06-01

Interactions between characteristics of bipolar and Axis II cluster B disorders are clinically and diagnostically challenging. Characteristics associated with personality disorders may be dimensional aspects of bipolar disorder. We investigated relationships among antisocial personality disorder (ASPD) or borderline personality disorder symptoms, impulsivity, and course of illness in bipolar disorder. Subjects with bipolar disorder were recruited from the community. Diagnosis was by structured clinical interview for DSM-IV (SCID-I and -II), psychiatric symptom assessment by the change version of the schedule for affective disorders and schizophrenia (SADS-C), severity of Axis II symptoms by ASPD and borderline personality disorder SCID-II symptoms, and impulsivity by the Barratt impulsiveness scale (BIS-11). ASPD and borderline symptoms were not related to clinical state or affective symptoms. Borderline symptoms correlated with BIS-11 impulsivity scores, and predicted history of suicide attempts independently of the relationship to impulsivity. ASPD symptoms were more strongly related to course of illness, including early onset, frequent episodes, and substance-related disorders. These effects persisted after allowance for gender and substance-use disorder history. Personality disorder symptoms appear to be dimensional, trait-like characteristics of bipolar disorder. ASPD and Borderline symptoms are differentially related to impulsivity and course of illness. Copyright © 2012 Elsevier B.V. All rights reserved.

Antisocial Personality Disorder and Borderline Symptoms are Differentially Related to Impulsivity and Course of Illness in Bipolar Disorder

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Swann, Alan C.; Lijffijt, Marijn; Lane, Scott D.; Steinberg, Joel L.; Moeller, F. Gerard

2012-01-01

Background Interactions between characteristics of bipolar and Axis II cluster B disorders are clinically and diagnostically challenging. Characteristics associated with personality disorders may be dimensional aspects of bipolar disorder. We investigated relationships among antisocial personality disorder (ASPD) or borderline personality disorder symptoms, impulsivity, and course of illness in bipolar disorder. Methods Subjects with bipolar disorder were recruited from the community. Diagnosis was by Structured Clinical Interview for DSM-IV (SCID-I and –II), psychiatric symptom assessment by the Change version of the Schedule for Affective Disorders and Schizophrenia (SADS-C), severity of axis II symptoms by ASPD and borderline personality disorder SCID-II symptoms, and impulsivity by the Barratt Impulsiveness Scale (BIS-11). Results ASPD and borderline symptoms were not related to clinical state or affective symptoms. Borderline symptoms correlated with BIS-11 impulsivity scores, and predicted history of suicide attempts independently of the relationship to impulsivity. ASPD symptoms were more strongly related to course of illness, including early onset, frequent episodes, and substance-related disorders. These effects persisted after allowance for gender and substance-use disorder history. Conclusions Personality disorder symptoms appear to be dimensional, trait-like characteristics of bipolar disorder. ASPD and Borderline symptoms are differentially related to impulsivity and course of illness. PMID:22835849

Rasal2 deficiency reduces adipogenesis and occurrence of obesity-related disorders

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Xiaoqiang Zhu

2017-06-01

Full Text Available Objective: Identification of additional regulatory factors involved in the onset of obesity is important to understand the mechanisms underlying this prevailing disease and its associated metabolic disorders and to develop therapeutic strategies. Through isolation and analysis of a mutant, we aimed to uncover the function of a Ras-GAP gene, Rasal2 (Ras protein activator like 2, in the development of obesity and related metabolic disorders and to obtain valuable insights regarding the mechanism underlying the function. Methods: An obesity-based genetic screen was performed to identify an insertional mutation that disrupts the expression of Rasal2 (Rasal2PB/PB mice. Important metabolic parameters, such as fat mass and glucose tolerance, were measured in Rasal2PB/PB mice. The impact of Rasal2 on adipogenesis was evaluated in the mutant mice and in 3T3-L1 preadipocytes treated with Rasal2 siRNA. Ras and ERK activities were then evaluated in Rasal2-deficient preadipocytes or mice, and their functional relationships with Rasal2 on adipogenesis were investigated by employing Ras and MEK inhibitors. Results: Rasal2PB/PB mice showed drastic decrease in Rasal2 expression and a lean phenotype. The mutant mice displayed decreased adiposity and resistance to high-fat diet induced metabolic disorders. Further analysis indicated that Rasal2 deficiency leads to impaired adipogenesis in vivo and in vitro. Moreover, while Rasal2 deficiency resulted in increased activity of both Ras and ERK in preadipocytes, reducing Ras, but not ERK, suppressed the impaired adipogenesis. Conclusions: Rasal2 promotes adipogenesis, which may critically contribute to its role in the development of obesity and related metabolic disorders and may do so by repressing Ras activity in an ERK-independent manner. Keywords: Ras, ERK, Ras-GAP, Glucose tolerance, High-fat diet, Diabetes

Parathyroid hormone-related protein blood test

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... ency/article/003691.htm Parathyroid hormone-related protein blood test To use the sharing features on this page, ... measures the level of a hormone in the blood, called parathyroid hormone-related protein. How the Test is Performed A blood sample is needed . How ...

Paraphilia-related disorders and personality disorders in sexual homicide perpetrators

OpenAIRE

Martin P. Kafka; Niels Habermann; Andreas Hill; Peer Briken; Wolfgang Berner

2010-01-01

We investigated the relationship between paraphilias (PA), paraphilia-related disorders (PRD), and personality disorders retrospectively in a sample of 161 sexual murderers. Four groups were compared: (1) sexual murderers without a PA or a PRD diagnosis (n=47), (2) sexual murderers with at least one PRD but no PA (n=29), (3) murderers with at least one PA but no PRDs (n=29), and finally, (4) those with a combination of both (PA + PRD, n=56). The PA + PRD group showed a significantly higher pr...

Anxiety and Related Disorders and Concealment in Sexual Minority Young Adults.

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Cohen, Jeffrey M; Blasey, Christine; Barr Taylor, C; Weiss, Brandon J; Newman, Michelle G

2016-01-01

Sexual minorities face greater exposure to discrimination and rejection than heterosexuals. Given these threats, sexual minorities may engage in sexual orientation concealment in order to avoid danger. This social stigma and minority stress places sexual minorities at risk for anxiety and related disorders. Given that three fourths of anxiety disorder onset occurs before the age of 24, the current study investigated the symptoms of generalized anxiety disorder, social phobia, panic disorder, posttraumatic stress disorder, and depression in sexual minority young adults relative to their heterosexual peers. Secondarily, the study investigated sexual orientation concealment as a predictor of anxiety and related disorders. A sample of 157 sexual minority and 157 heterosexual young adults matched on age and gender completed self-report measures of the aforementioned disorders, and indicated their level of sexual orientation concealment. Results revealed that sexual minority young adults reported greater symptoms relative to heterosexuals across all outcome measures. There were no interactions between sexual minority status and gender, however, women had higher symptoms across all disorders. Sexual minority young women appeared to be at the most risk for clinical levels of anxiety and related disorders. In addition, concealment of sexual orientation significantly predicted symptoms of social phobia. Implications are offered for the cognitive and behavioral treatment of anxiety and related disorders in this population. Copyright © 2015. Published by Elsevier Ltd.

ECM Proteins Glycosylation and Relation to Diabetes

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Pernodet, Nadine; Bloomberg, Ayla; Sood, Vandana; Slutsky, Lenny; Ge, Shouren; Clark, Richard; Rafailovich, Miriam

2004-03-01

The chemical modification and crosslinking of proteins by sugar glycosylation contribute to the aging of tissue proteins, and acceleration of this reaction during hyperglycemia is implicated in the pathogenesis of diabetic complications, such as disorder of the wound healing. Advanced glycation endproducts (AGEs) formation and protein crosslinking are irreversible processes that alter the structural and functional properties of proteins, lipid components and nucleic acids. And the mechanism, by which it happens, is not clear. Fibrinogen and fibronectin are plasma proteins, which play a major role in human wound healing. Fibrinogen converts to an insoluble fibrin "gel" following a cut, which eventually forms a clot to prevent blood loss, to direct cell adhesion and migration for forming scars. Fibronectin is a critical protein for cell adhesion and migration in wound healing. The effects of glucose on the binding of these plasma proteins from the extra cellular matrix (ECM) were followed at different concentrations by atomic force microscopy and lateral force modulation to measure the mechanical response of the samples. Glucose solutions (1, 2, and 3mg/mL) were incubated with the protein (100 mg/ml) and silicon (Si) substrates spun with sulfonated polystyrene (SPS) 28% for five days. Data showed that not only the organization of the protein on the surface was affected but also its mechanical properties. At 3 mg/mL glucose, Fn fibers were observed to be harder than those of the control, in good agreement with our hypothesis that glycosylation hardens tissues by crosslinking of proteins in the ECM and might cause fibers to break more easily.

The Genetics of Stress-Related Disorders: PTSD, Depression, and Anxiety Disorders

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Smoller, Jordan W

2016-01-01

Research into the causes of psychopathology has largely focused on two broad etiologic factors: genetic vulnerability and environmental stressors. An important role for familial/heritable factors in the etiology of a broad range of psychiatric disorders was established well before the modern era of genomic research. This review focuses on the genetic basis of three disorder categories—posttraumatic stress disorder (PTSD), major depressive disorder (MDD), and the anxiety disorders—for which environmental stressors and stress responses are understood to be central to pathogenesis. Each of these disorders aggregates in families and is moderately heritable. More recently, molecular genetic approaches, including genome-wide studies of genetic variation, have been applied to identify specific risk variants. In this review, I summarize evidence for genetic contributions to PTSD, MDD, and the anxiety disorders including genetic epidemiology, the role of common genetic variation, the role of rare and structural variation, and the role of gene–environment interaction. Available data suggest that stress-related disorders are highly complex and polygenic and, despite substantial progress in other areas of psychiatric genetics, few risk loci have been identified for these disorders. Progress in this area will likely require analysis of much larger sample sizes than have been reported to date. The phenotypic complexity and genetic overlap among these disorders present further challenges. The review concludes with a discussion of prospects for clinical translation of genetic findings and future directions for research. PMID:26321314

Intramolecular three-colour single pair FRET of intrinsically disordered proteins with increased dynamic range.

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Milles, Sigrid; Koehler, Christine; Gambin, Yann; Deniz, Ashok A; Lemke, Edward A

2012-10-01

Single molecule observation of fluorescence resonance energy transfer can be used to provide insight into the structure and dynamics of proteins. Using a straightforward triple-colour labelling strategy, we present a measurement and analysis scheme that can simultaneously study multiple regions within single intrinsically disordered proteins.

[Complex Trauma-related Disorders in Research and Practice].

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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.

Obsessive-compulsive disorder and its related disorders: a reappraisal of obsessive-compulsive spectrum concepts.

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Murphy, Dennis L; Timpano, Kiara R; Wheaton, Michael G; Greenberg, Benjamin D; Miguel, Euripedes C

2010-01-01

Obsessive-compulsive disorder (OCD) is a clinical syndrome whose hallmarks are excessive, anxiety-evoking thoughts and compulsive behaviors that are generally recognized as unreasonable, but which cause significant distress and impairment. When these are the exclusive symptoms, they constitute uncomplicated OCD. OCD may also occur in the context of other neuropsychiatric disorders, most commonly other anxiety and mood disorders. The question remains as to whether these combinations of disorders should be regarded as independent, cooccurring disorders or as different manifestations of an incompletely understood constellation of OCD spectrum disorders with a common etiology. Additional considerations are given here to two potential etiology-based subgroups: (i) an environmentally based group in which OCD occurs following apparent causal events such as streptococcal infections, brain injury, or atypical neuroleptic treatment; and (ii) a genomically based group in which OCD is related to chromosomal anomalies or specific genes. Considering the status of current research, the concept of OCD and OCD-related spectrum conditions seems fluid in 2010, and in need of ongoing reappraisal.

Hypothesis review: are clathrin-mediated endocytosis and clathrin-dependent membrane and protein trafficking core pathophysiological processes in schizophrenia and bipolar disorder?

LENUS (Irish Health Repository)

2012-02-01

Clathrin-mediated endocytosis (CME) is the best-characterized mechanism governing cellular membrane and protein trafficking. In this hypothesis review, we integrate recent evidence implicating CME and related cellular trafficking mechanisms in the pathophysiology of psychotic disorders such as schizophrenia and bipolar disorder. The evidence includes proteomic and genomic findings implicating proteins and genes of the clathrin interactome. Additionally, several important candidate genes for schizophrenia, such as dysbindin, are involved in processes closely linked to CME and membrane trafficking. We discuss that key aspects of psychosis neuropathology such as synaptic dysfunction, white matter changes and aberrant neurodevelopment are all influenced by clathrin-dependent processes, and that other cellular trafficking mechanisms previously linked to psychoses interact with the clathrin interactome in important ways. Furthermore, many antipsychotic drugs have been shown to affect clathrin-interacting proteins. We propose that the targeted pharmacological manipulation of the clathrin interactome may offer fruitful opportunities for novel treatments of schizophrenia.Molecular Psychiatry advance online publication, 11 October 2011; doi:10.1038\\/mp.2011.123.

Plasma cell morphology in multiple myeloma and related disorders.

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Ribourtout, B; Zandecki, M

2015-06-01

Normal and reactive plasma cells (PC) are easy to ascertain on human bone marrow films, due to their small mature-appearing nucleus and large cytoplasm, the latter usually deep blue after Giemsa staining. Cytoplasm is filled with long strands of rough endoplasmic reticulum and one large Golgi apparatus (paranuclear hof), demonstrating that PC are dedicated mainly to protein synthesis and excretion (immunoglobulin). Deregulation of the genome may induce clonal expansion of one PC that will lead to immunoglobulin overproduction and eventually to one among the so-called PC neoplasms. In multiple myeloma (MM), the number of PC is over 10% in most patients studied. Changes in the morphology of myeloma PC may be inconspicuous as compared to normal PC (30-50% patients). In other instances PC show one or several morphological changes. One is related to low amount of cytoplasm, defining lymphoplasmacytoid myeloma (10-15% patients). In other cases (40-50% patients), named immature myeloma cases, nuclear-cytoplasmic asynchrony is observed: presence of one nucleolus, finely dispersed chromatin and/or irregular nuclear contour contrast with a still large and blue (mature) cytoplasm. A peculiar morphological change, corresponding to the presence of very immature PC named plasmablasts, is observed in 10-15% cases. Several prognostic morphological classifications have been published, as mature myeloma is related to favorable outcome and immature myeloma, peculiarly plasmablastic myeloma, is related to dismal prognosis. However, such classifications are no longer included in current prognostic schemes. Changes related to the nucleus are very rare in monoclonal gammopathy of unknown significance (MGUS). In contrast, anomalies related to the cytoplasm of PC, including color (flaming cells), round inclusions (Mott cells, Russell bodies), Auer rod-like or crystalline inclusions, are reported in myeloma cases as well as in MGUS and at times in reactive disorders. They do not correspond

The Impact of O-Glycan Chemistry on the Stability of Intrinsically Disordered Proteins

Energy Technology Data Exchange (ETDEWEB)

Beckham, Gregg T [National Renewable Energy Laboratory (NREL), Golden, CO (United States); Prates, Erica T [National Renewable Energy Laboratory (NREL), Golden, CO (United States); Crowley, Michael F [National Renewable Energy Laboratory (NREL), Golden, CO (United States); Guan, Xiaoyang [University of Colorado; Li, Yaohao [University of Colorado; Wang, Xinfeng [University of Colorado; Chaffey, Patrick K. [University of Colorado; Skaf, Munir S. [University of Campinas; Tan, Zhongping [University of Colorado

2018-03-02

Protein glycosylation is a diverse post-translational modification that serves myriad biological functions. O-linked glycans in particular vary widely in extent and chemistry in eukaryotes, with secreted proteins from fungi and yeast commonly exhibiting O-mannosylation in intrinsically disordered regions of proteins, likely for proteolysis protection, among other functions. However, it is not well understood why mannose is often the preferred glycan, and more generally, if the neighboring protein sequence and glycan have coevolved to protect against proteolysis in glycosylated intrinsically disordered proteins (IDPs). Here, we synthesized variants of a model IDP, specifically a natively O-mannosylated linker from a fungal enzyme, with a-O-linked mannose, glucose, and galactose moieties, along with a non-glycosylated linker. Upon exposure to thermolysin, O-mannosylation, by far, provides the highest extent of proteolysis protection. To explain this observation, extensive molecular dynamics simulations were conducted, revealing that the axial configuration of the C2-hydroxyl group (2-OH) of a-mannose adjacent to the glycan-peptide bond strongly influences the conformational features of the linker. Specifically, a-mannose restricts the torsions of the IDP main chain more than other glycans whose equatorial 2-OH groups exhibit interactions that favor perpendicular glycan-protein backbone orientation. We suggest that IDP stiffening due to O-mannosylation impairs protease action, with contributions from protein-glycan interactions, protein flexibility, and protein stability. Our results further imply that resistance to proteolysis is an important driving force for evolutionary selection of a-mannose in eukaryotic IDPs, and more broadly, that glycan motifs for proteolysis protection likely coevolve with the protein sequence to which they attach.

Striatal-enriched Tyrosine Protein Phosphatase (STEP) in the Mechanisms of Depressive Disorders.

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Kulikova, Elizabeth; Kulikov, Alexander

2017-08-30

Striatal-enriched tyrosine protein phosphatase (STEP) is expressed mainly in the brain. Its dysregulation is associated with Alzheimer's and Huntington's diseases, schizophrenia, fragile X syndrome, drug abuse and stroke/ischemia. However, an association between STEP and depressive disorders is still obscure. The review discusses the theoretical foundations and experimental facts concerning possible relationship between STEP dysregulation and depression risk. STEP dephosphorylates and inactivates several key neuronal signaling proteins such as extracellular signal-regulating kinase 1 and 2 (ERK1/2), stress activated protein kinases p38, the Src family tyrosine kinases Fyn, Pyk2, NMDA and AMPA glutamate receptors. The inactivation of these proteins decreases the expression of brain derived neurotrophic factor (BDNF) necessary for neurogenesis and neuronal survival. The deficit of BDNF results in progressive degeneration of neurons in the hippocampus and cortex and increases depression risk. At the same time, a STEP inhibitor, 8-(trifluoromethyl)-1,2,3,4,5-benzopentathiepin-6-amine hydrochloride (TC-2153), increases BDNF expression in the hippocampus and attenuated the depressivelike behavior in mice. Thus, STEP is involved in the mechanism of depressive disorders and it is a promising molecular target for atypical antidepressant drugs of new generation. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Protein function prediction using neighbor relativity in protein-protein interaction network.

Science.gov (United States)

Moosavi, Sobhan; Rahgozar, Masoud; Rahimi, Amir

2013-04-01

There is a large gap between the number of discovered proteins and the number of functionally annotated ones. Due to the high cost of determining protein function by wet-lab research, function prediction has become a major task for computational biology and bioinformatics. Some researches utilize the proteins interaction information to predict function for un-annotated proteins. In this paper, we propose a novel approach called "Neighbor Relativity Coefficient" (NRC) based on interaction network topology which estimates the functional similarity between two proteins. NRC is calculated for each pair of proteins based on their graph-based features including distance, common neighbors and the number of paths between them. In order to ascribe function to an un-annotated protein, NRC estimates a weight for each neighbor to transfer its annotation to the unknown protein. Finally, the unknown protein will be annotated by the top score transferred functions. We also investigate the effect of using different coefficients for various types of functions. The proposed method has been evaluated on Saccharomyces cerevisiae and Homo sapiens interaction networks. The performance analysis demonstrates that NRC yields better results in comparison with previous protein function prediction approaches that utilize interaction network. Copyright © 2012 Elsevier Ltd. All rights reserved.

Clinical, molecular, and pharmacological aspects of FMR1 related disorders.

Science.gov (United States)

Pugin, A; Faundes, V; Santa María, L; Curotto, B; Aliaga, S; Salas, I; Soto, P; Bravo, P; Peña, M I; Alliende, M A

2017-05-01

Fragile X syndrome, the most common inherited cause of intellectual disability, is associated with a broad spectrum of disorders across different generations of a single family. This study reviews the clinical manifestations of fragile X-associated disorders as well as the spectrum of mutations of the fragile X mental retardation 1 gene (FMR1) and the neurobiology of the fragile X mental retardation protein (FMRP), and also provides an overview of the potential therapeutic targets and genetic counselling. This disorder is caused by expansion of the CGG repeat (>200 repeats) in the 5 prime untranslated region of FMR1, resulting in a deficit or absence of FMRP. FMRP is an RNA-binding protein that regulates the translation of several genes that are important in synaptic plasticity and dendritic maturation. It is believed that CGG repeat expansions in the premutation range (55 to 200 repeats) elicit an increase in mRNA levels of FMR1, which may cause neuronal toxicity. These changes manifest clinically as developmental problems such as autism and learning disabilities as well as neurodegenerative diseases including fragile X-associated tremor/ataxia syndrome (FXTAS). Advances in identifying the molecular basis of fragile X syndrome may help us understand the causes of neuropsychiatric disorders, and they will probably contribute to development of new and specific treatments. Copyright © 2014 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

Proteins with Intrinsically Disordered Domains Are Preferentially Recruited to Polyglutamine Aggregates.

Directory of Open Access Journals (Sweden)

Maggie P Wear

Full Text Available Intracellular protein aggregation is the hallmark of several neurodegenerative diseases. Aggregates formed by polyglutamine (polyQ-expanded proteins, such as Huntingtin, adopt amyloid-like structures that are resistant to denaturation. We used a novel purification strategy to isolate aggregates formed by human Huntingtin N-terminal fragments with expanded polyQ tracts from both yeast and mammalian (PC-12 cells. Using mass spectrometry we identified the protein species that are trapped within these polyQ aggregates. We found that proteins with very long intrinsically-disordered (ID domains (≥ 100 amino acids and RNA-binding proteins were disproportionately recruited into aggregates. The removal of the ID domains from selected proteins was sufficient to eliminate their recruitment into polyQ aggregates. We also observed that several neurodegenerative disease-linked proteins were reproducibly trapped within the polyQ aggregates purified from mammalian cells. Many of these proteins have large ID domains and are found in neuronal inclusions in their respective diseases. Our study indicates that neurodegenerative disease-associated proteins are particularly vulnerable to recruitment into polyQ aggregates via their ID domains. Also, the high frequency of ID domains in RNA-binding proteins may explain why RNA-binding proteins are frequently found in pathological inclusions in various neurodegenerative diseases.

The intrinsically disordered structural platform of the plant defence hub protein RPM1-interacting protein 4 provides insights into its mode of action in the host-pathogen interface and evolution of the nitrate-induced domain protein family.

Science.gov (United States)

Sun, Xiaolin; Greenwood, David R; Templeton, Matthew D; Libich, David S; McGhie, Tony K; Xue, Bin; Yoon, Minsoo; Cui, Wei; Kirk, Christopher A; Jones, William T; Uversky, Vladimir N; Rikkerink, Erik H A

2014-09-01

Arabidopsis thaliana (At) RPM1-interacting protein 4 (RIN4), targeted by many defence-suppressing bacterial type III effectors and monitored by several resistance proteins, regulates plant immune responses to pathogen-associated molecular patterns and type III effectors. Little is known about the overall protein structure of AtRIN4, especially in its unbound form, and the relevance of structure to its diverse biological functions. AtRIN4 contains two nitrate-induced (NOI) domains and is a member of the NOI family. Using experimental and bioinformatic approaches, we demonstrate that the unbound AtRIN4 is intrinsically disordered under physiological conditions. The intrinsically disordered polypeptide chain of AtRIN4 is interspersed with molecular recognition features (MoRFs) and anchor-identified long-binding regions, potentially allowing it to undergo disorder-to-order transitions upon binding to partner(s). A poly-l-proline II structure, often responsible for protein recognition, is also identified in AtRIN4. By performing bioinformatics analyses on RIN4 homologues from different plant species and the NOI proteins from Arabidopsis, we infer the conservation of intrinsic disorder, MoRFs and long-binding regions of AtRIN4 in other plant species and the NOI family. Intrinsic disorder and MoRFs could provide RIN4 proteins with the binding promiscuity and plasticity required to act as hubs in a pivotal position within plant defence signalling cascades. © 2014 FEBS.

Three-dimensional interactive atlas of cranial nerve-related disorders.

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Nowinski, W L; Chua, B C

2013-06-01

Anatomical knowledge of the cranial nerves (CN) is fundamental in education, research and clinical practice. Moreover, understanding CN-related pathology with underlying neuroanatomy and the resulting neurological deficits is of vital importance. To facilitate CN knowledge anatomy and pathology understanding, we created an atlas of CN-related disorders, which is a three-dimensional (3D) interactive tool correlating CN pathology with the underlying surface and sectional neuroanatomy as well as the resulting neurological deficits. A computer platform was developed with: 1) anatomy browser along with the normal brain atlas (built earlier); 2) simulator of CN lesions; 3) tools to label CN-related pathology; and 4) CN pathology database with lesions and disorders, and the resulting signs, symptoms and/or syndromes. The normal neuroanatomy comprises about 2,300 3D components subdivided into modules. Cranial nerves contain more than 600 components: all 12 pairs of cranial nerves (CN I - CN XII) and the brainstem CN nuclei. The CN pathology database was populated with 36 lesions compiled from clinical textbooks. The initial view of each disorder was preset in terms of lesion location and size, surrounding surface and sectional neuroanatomy, and disorder and neuroanatomy labeling. Moreover, path selection from a CN nucleus to a targeted organ further enhances pathology-anatomy relationships. This atlas of CN-related disorders is potentially useful to a wide variety of users ranging from medical students and residents to general practitioners, neuroradiologists and neurologists, as it contains both normal brain anatomy and CN-related pathology correlated with neurological disorders presented in a visual and interactive way.

Familial recurrences of FOXG1-related disorder: Evidence for mosaicism.

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McMahon, Kelly Q; Papandreou, Apostolos; Ma, Mandy; Barry, Brenda J; Mirzaa, Ghayda M; Dobyns, William B; Scott, Richard H; Trump, Natalie; Kurian, Manju A; Paciorkowski, Alex R

2015-12-01

FOXG1-related disorders are caused by heterozygous mutations in FOXG1 and result in a spectrum of neurodevelopmental phenotypes including postnatal microcephaly, intellectual disability with absent speech, epilepsy, chorea, and corpus callosum abnormalities. The recurrence risk for de novo mutations in FOXG1-related disorders is assumed to be low. Here, we describe three unrelated sets of full siblings with mutations in FOXG1 (c.515_577del63, c.460dupG, and c.572T > G), representing familial recurrence of the disorder. In one family, we have documented maternal somatic mosaicism for the FOXG1 mutation, and all of the families presumably represent parental gonadal (or germline) mosaicism. To our knowledge, mosaicism has not been previously reported in FOXG1-related disorders. Therefore, this report provides evidence that germline mosaicism for FOXG1 mutations is a likely explanation for familial recurrence and should be considered during recurrence risk counseling for families of children with FOXG1-related disorders. © 2015 Wiley Periodicals, Inc.

A human phenome-interactome network of protein complexes implicated in genetic disorders

DEFF Research Database (Denmark)

Hansen, Kasper Lage; Karlberg, Erik, Olof, Linnart; Størling, Zenia, Marian

2007-01-01

the known disease-causing protein as the top candidate, and in 870 intervals with no identified disease-causing gene, provides novel candidates implicated in disorders such as retinitis pigmentosa, epithelial ovarian cancer, inflammatory bowel disease, amyotrophic lateral sclerosis, Alzheimer disease, type...

Instrument-related Skin Disorders in Musicians.

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Patruno, Cataldo; Napolitano, Maddalena; La Bella, Serena; Ayala, Fabio; Balato, Nicola; Cantelli, Mariateresa; Balato, Anna

2016-01-01

Among artists, musicians may suffer from occupational skin problems; notwithstanding, these conditions have been rarely reviewed. The characteristics of individual performer and the type of instrument will determine the kind of disease. Moreover, the hours that the musician spent to advance artistic skill may influence the severity. The frequency and risk factors of instrument-related skin disorders in musicians from southern Italy were analyzed. An observational study was conducted in 628 musicians. A questionnaire including questions related to age, sex, instrument played, musical activity, previous or current skin disorders, and impact of skin symptoms on music making was submitted. Of 628 musicians, 199 (31.7%) reported suffering from at least 1 skin disease. Cutaneous diseases likely directly correlated with the use of the musical instrument were found in 129 (20.5%) of the 628 subjects. In particular, different patterns of irritant contact dermatitis were found. Skin conditions may be a significant problem in professional instrumentalists. They are mainly related to musical activity. Preventive measures should be established.

Adherence issues in inherited metabolic disorders treated by low natural protein diets

DEFF Research Database (Denmark)

MaCdonald, A; van Rijn, M; Feillet, F

2012-01-01

Common inborn errors of metabolism treated by low natural protein diets [amino acid (AA) disorders, organic acidemias and urea cycle disorders] are responsible for a collection of diverse clinical symptoms, each condition presenting at different ages with variable severity. Precursor......-free or essential L-AAs are important in all these conditions. Optimal long-term outcome depends on early diagnosis and good metabolic control, but because of the rarity and severity of conditions, randomized controlled trials are scarce. In all of these disorders, it is commonly described that dietary adherence...... on their neuropsychological profile. There are little data about their ability to self-manage their own diet or the success of any formal educational programs that may have been implemented. Trials conducted in non-phenylketonuria (PKU) patients are rare, and the development of specialist L-AAs for non-PKU AA disorders has...

Clinical aspects and treatment of taste and smell disorders

NARCIS (Netherlands)

F.K.L. Spijkervet; R. Weissenbruch; A. Visser; Dr. Harriët Jager-Wittenaar; A. van Nieuw Amerongen; A. Vissink

2013-01-01

Taste and smell perception are closely related. Many chemosensory disorders which result in faulty taste are in fact smell disorders. Causes of chemosensory disorders which call for attention are ageing, medication, natural proteins, burning mouth syndrome, nerve injuries, aerate disorders in the

Synaptic proteins and receptors defects in autism spectrum disorders

OpenAIRE

Chen, Jianling; Yu, Shunying; Fu, Yingmei; Li, Xiaohong

2014-01-01

Recent studies have found that hundreds of genetic variants, including common and rare variants, rare and de novo mutations, and common polymorphisms have contributed to the occurrence of autism spectrum disorders (ASDs). The mutations in a number of genes such as neurexin, neuroligin, postsynaptic density protein 95 (PSD-95), SH3 and multiple ankyrin repeat domains 3 (SHANK3), synapsin, gephyrin, cadherin (CDH) and protocadherin (PCDH), thousand-and-one-amino acid 2 kinase (TAOK2), and conta...

Relational Aggression in Children with Preschool Onset (PO) Psychiatric Disorders

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Belden, Andy C.; Gaffrey, Michael S.; Luby, Joan L.

2012-01-01

Objective The role of preschool onset (PO) psychiatric disorders as correlates and/or risk factors for relational aggression during kindergarten or 1st grade was tested in a sample of N = 146 preschool-age children (3 to 5.11). Method Axis-I diagnoses and symptom scores were derived using the Preschool Age Psychiatric Assessment. Children’s roles in relational aggression as aggressor, victim, aggressive-victim, or non-aggressor/non-victim were determined at preschool and again 24 months later at elementary school entry. Results Preschoolers diagnosed with PO-psychiatric disorders were 3 times as likely as the healthy preschoolers to be classified aggressors, victims, or aggressive-victims. Children diagnosed with PO-disruptive, depressive, and/or anxiety disorders were at least 6 times as likely as children without PO-psychiatric disorders to become aggressive-victims during elementary school after covarying for other key risk factors. Conclusions Findings suggested that PO-psychiatric disorders differentiated preschool and school-age children’s roles in relational aggression based on teacher-report. Recommendations for future research and preventative intervention aimed at minimizing the development of relational aggression in early childhood by identifying and targeting PO-psychiatric disorders are made. PMID:22917202

Sex-related and non-sex-related comorbidity subtypes of tic disorders: a latent class approach.

Science.gov (United States)

Rodgers, S; Müller, M; Kawohl, W; Knöpfli, D; Rössler, W; Castelao, E; Preisig, M; Ajdacic-Gross, V

2014-05-01

Recent evidence suggests that there may be more than one Gilles de la Tourette syndrome (GTS)/tic disorder phenotype. However, little is known about the common patterns of these GTS/tic disorder-related comorbidities. In addition, sex-specific phenomenological data of GTS/tic disorder-affected adults are rare. Therefore, this community-based study used latent class analyses (LCA) to investigate sex-related and non-sex-related subtypes of GTS/tic disorders and their most common comorbidities. The data were drawn from the PsyCoLaus study (n = 3691), a population-based survey conducted in Lausanne, Switzerland. LCA were performed on the data of 80 subjects manifesting motor/vocal tics during their childhood/adolescence. Comorbid attention-deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder, depressive, phobia and panic symptoms/syndromes comprised the selected indicators. The resultant classes were characterized by psychosocial correlates. In LCA, four latent classes provided the best fit to the data. We identified two male-related classes. The first class exhibited both ADHD and depression. The second class comprised males with only depression. Class three was a female-related class depicting obsessive thoughts/compulsive acts, phobias and panic attacks. This class manifested high psychosocial impairment. Class four had a balanced sex proportion and comorbid symptoms/syndromes such as phobias and panic attacks. The complementary occurrence of comorbid obsessive thoughts/compulsive acts and ADHD impulsivity was remarkable. To the best of our knowledge, this is the first study applying LCA to community data of GTS symptoms/tic disorder-affected persons. Our findings support the utility of differentiating GTS/tic disorder subphenotypes on the basis of comorbid syndromes. © 2013 The Author(s) European Journal of Neurology © 2013 EFNS.

Liquid demixing of intrinsically disordered proteins is seeded by poly(ADP-ribose)

DEFF Research Database (Denmark)

Altmeyer, Matthias; Neelsen, Kai J; Teloni, Federico

2015-01-01

disordered proteins at DNA break sites. Demixing, which relies on electrostatic interactions between positively charged RGG repeats and negatively charged PAR, is amplified by aggregation-prone prion-like domains, and orchestrates the earliest cellular responses to DNA breakage. We propose that PAR...

Phase behaviour of disordered proteins underlying low density and high permeability of liquid organelles

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Wei, Ming-Tzo; Elbaum-Garfinkle, Shana; Holehouse, Alex S.; Chen, Carlos Chih-Hsiung; Feric, Marina; Arnold, Craig B.; Priestley, Rodney D.; Pappu, Rohit V.; Brangwynne, Clifford P.

2017-11-01

Many intracellular membraneless organelles form via phase separation of intrinsically disordered proteins (IDPs) or regions (IDRs). These include the Caenorhabditis elegans protein LAF-1, which forms P granule-like droplets in vitro. However, the role of protein disorder in phase separation and the macromolecular organization within droplets remain elusive. Here, we utilize a novel technique, ultrafast-scanning fluorescence correlation spectroscopy, to measure the molecular interactions and full coexistence curves (binodals), which quantify the protein concentration within LAF-1 droplets. The binodals of LAF-1 and its IDR display a number of unusual features, including 'high concentration' binodal arms that correspond to remarkably dilute droplets. We find that LAF-1 and other in vitro and intracellular droplets are characterized by an effective mesh size of ∼3-8 nm, which determines the size scale at which droplet properties impact molecular diffusion and permeability. These findings reveal how specific IDPs can phase separate to form permeable, low-density (semi-dilute) liquids, whose structural features are likely to strongly impact biological function.

Narcissistic disorder and the failure of symbolisation: a Relational Affective Hypothesis.

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Mizen, C S

2014-09-01

The psychoanalytic concept of narcissistic disorder is broader than that of Narcissistic Personality Disorder (DSM-5 [1]), underlying a range of Personality Disorders (PD) and their co-morbidities. Existing Mentalisation, Psychoanalytic and Cognitive models, fail to account fully for the emerging evidence of biological, developmental, relational and defensive contributions to narcissistic disorder, nor do they account for the common and variant features of co-morbidities namely Anorexia Nervosa, Somatisation, Substance Misuse and Autistic Spectrum Disorder. Alexithymia and concrete modes of relating are common findings in narcissistic disorder and these co-morbid conditions. Current models do not provide a comprehensive account, on the basis of neuro-scientific and developmental evidence, of how affective feelings come to be represented in words and the association between narcissistic disorders and failures of symbolisation. In this paper I propose an empirically based Relational Affective Hypothesis that narcissistic disorder and its comorbidities represent failures at specific points on a representational function pathway through which subcortical affect and visceral feeling in a relational context become the basis for abstraction and language. The elucidation of this pathway allows investigation of the contribution of biological, social and psychogenic factors in narcissistic disorders. It also brings a new understanding of the neurological underpinning of psychodynamic defences in narcissistic disorders. Research and novel treatment implications are briefly considered. Copyright © 2014 Elsevier Ltd. All rights reserved.

A functional CD86 polymorphism associated with asthma and related allergic disorders

DEFF Research Database (Denmark)

Corydon, Thomas Juhl; Haagerup, Annette; Jensen, Thomas Gryesten

2007-01-01

BACKGROUND: Several studies have documented a substantial genetic component in the aetiology of allergic diseases and a number of atopy susceptibility loci have been suggested. One of these loci is 3q21, at which linkage to multiple atopy phenotypes has been reported. This region harbours the CD8......, and specifically the Ile179Val polymorphism, may be a novel aetiological factor in the development of asthma and related allergic disorders....... gene encoding the costimulatory B7.2 protein. The costimulatory system, consisting of receptor proteins, cytokines and associated factors, activates T cells and regulates the immune response upon allergen challenge. METHODS: We sequenced the CD86 gene in patients with atopy from 10 families that showed...... evidence of linkage to 3q21. Identified polymorphisms were analysed in a subsequent family-based association study of two independent Danish samples, respectively comprising 135 and 100 trios of children with atopy and their parents. Functional analysis of the costimulatory effect on cytokine production...

The Classification of Hysteria and Related Disorders: Historical and Phenomenological Considerations

Science.gov (United States)

North, Carol S.

2015-01-01

This article examines the history of the conceptualization of dissociative, conversion, and somatoform syndromes in relation to one another, chronicles efforts to classify these and other phenomenologically-related psychopathology in the American diagnostic system for mental disorders, and traces the subsequent divergence in opinions of dissenting sectors on classification of these disorders. This article then considers the extensive phenomenological overlap across these disorders in empirical research, and from this foundation presents a new model for the conceptualization of these disorders. The classification of disorders formerly known as hysteria and phenomenologically-related syndromes has long been contentious and unsettled. Examination of the long history of the conceptual difficulties, which remain inherent in existing classification schemes for these disorders, can help to address the continuing controversy. This review clarifies the need for a major conceptual revision of the current classification of these disorders. A new phenomenologically-based classification scheme for these disorders is proposed that is more compatible with the agnostic and atheoretical approach to diagnosis of mental disorders used by the current classification system. PMID:26561836

The Classification of Hysteria and Related Disorders: Historical and Phenomenological Considerations

Directory of Open Access Journals (Sweden)

Carol S. North

2015-11-01

Full Text Available This article examines the history of the conceptualization of dissociative, conversion, and somatoform syndromes in relation to one another, chronicles efforts to classify these and other phenomenologically-related psychopathology in the American diagnostic system for mental disorders, and traces the subsequent divergence in opinions of dissenting sectors on classification of these disorders. This article then considers the extensive phenomenological overlap across these disorders in empirical research, and from this foundation presents a new model for the conceptualization of these disorders. The classification of disorders formerly known as hysteria and phenomenologically-related syndromes has long been contentious and unsettled. Examination of the long history of the conceptual difficulties, which remain inherent in existing classification schemes for these disorders, can help to address the continuing controversy. This review clarifies the need for a major conceptual revision of the current classification of these disorders. A new phenomenologically-based classification scheme for these disorders is proposed that is more compatible with the agnostic and atheoretical approach to diagnosis of mental disorders used by the current classification system.

Detecting remote sequence homology in disordered proteins: discovery of conserved motifs in the N-termini of Mononegavirales phosphoproteins.

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David Karlin

Full Text Available Paramyxovirinae are a large group of viruses that includes measles virus and parainfluenza viruses. The viral Phosphoprotein (P plays a central role in viral replication. It is composed of a highly variable, disordered N-terminus and a conserved C-terminus. A second viral protein alternatively expressed, the V protein, also contains the N-terminus of P, fused to a zinc finger. We suspected that, despite their high variability, the N-termini of P/V might all be homologous; however, using standard approaches, we could previously identify sequence conservation only in some Paramyxovirinae. We now compared the N-termini using sensitive sequence similarity search programs, able to detect residual similarities unnoticeable by conventional approaches. We discovered that all Paramyxovirinae share a short sequence motif in their first 40 amino acids, which we called soyuz1. Despite its short length (11-16aa, several arguments allow us to conclude that soyuz1 probably evolved by homologous descent, unlike linear motifs. Conservation across such evolutionary distances suggests that soyuz1 plays a crucial role and experimental data suggest that it binds the viral nucleoprotein to prevent its illegitimate self-assembly. In some Paramyxovirinae, the N-terminus of P/V contains a second motif, soyuz2, which might play a role in blocking interferon signaling. Finally, we discovered that the P of related Mononegavirales contain similarly overlooked motifs in their N-termini, and that their C-termini share a previously unnoticed structural similarity suggesting a common origin. Our results suggest several testable hypotheses regarding the replication of Mononegavirales and suggest that disordered regions with little overall sequence similarity, common in viral and eukaryotic proteins, might contain currently overlooked motifs (intermediate in length between linear motifs and disordered domains that could be detected simply by comparing orthologous proteins.

Endoplasmic reticulum stress in obesity and obesity-related disorders: An expanded view.

Science.gov (United States)

Pagliassotti, Michael J; Kim, Paul Y; Estrada, Andrea L; Stewart, Claire M; Gentile, Christopher L

2016-09-01

The endoplasmic reticulum (ER) is most notable for its central roles in calcium ion storage, lipid biosynthesis, and protein sorting and processing. By virtue of its extensive membrane contact sites that connect the ER to most other organelles and to the plasma membrane, the ER can also regulate diverse cellular processes including inflammatory and insulin signaling, nutrient metabolism, and cell proliferation and death via a signaling pathway called the unfolded protein response (UPR). Chronic UPR activation has been observed in liver and/or adipose tissue of dietary and genetic murine models of obesity, and in human obesity and non-alcoholic fatty liver disease (NAFLD). Activation of the UPR in obesity and obesity-related disorders likely has two origins. One linked to classic ER stress involving the ER lumen and one linked to alterations to the ER membrane environment. This review discusses both of these origins and also considers the role of post-translational protein modifications, such as acetylation and palmitoylation, and ER-mitochondrial interactions to obesity-mediated impairments in the ER and activation of the UPR. Copyright © 2016 Elsevier Inc. All rights reserved.

Molecular modeling of the elastomeric properties of repeating units and building blocks of resilin, a disordered elastic protein.

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Khandaker, Md Shahriar K; Dudek, Daniel M; Beers, Eric P; Dillard, David A; Bevan, David R

2016-08-01

The mechanisms responsible for the properties of disordered elastomeric proteins are not well known. To better understand the relationship between elastomeric behavior and amino acid sequence, we investigated resilin, a disordered rubber-like protein, found in specialized regions of the cuticle of insects. Resilin of Drosophila melanogaster contains Gly-rich repetitive motifs comprised of the amino acids, PSSSYGAPGGGNGGR, which confer elastic properties to resilin. The repetitive motifs of insect resilin can be divided into smaller partially conserved building blocks: PSS, SYGAP, GGGN and GGR. Using molecular dynamics (MD) simulations, we studied the relative roles of SYGAP, and its less common variants SYSAP and TYGAP, on the elastomeric properties of resilin. Results showed that SYGAP adopts a bent structure that is one-half to one-third the end-to-end length of the other motifs having an equal number of amino acids but containing SYSAP or TYGAP substituted for SYGAP. The bent structure of SYGAP forms due to conformational freedom of glycine, and hydrogen bonding within the motif apparently plays a role in maintaining this conformation. These structural features of SYGAP result in higher extensibility compared to other motifs, which may contribute to elastic properties at the macroscopic level. Overall, the results are consistent with a role for the SYGAP building block in the elastomeric properties of these disordered proteins. What we learned from simulating the repetitive motifs of resilin may be applicable to the biology and mechanics of other elastomeric biomaterials, and may provide us the deeper understanding of their unique properties. Copyright © 2016 Elsevier Ltd. All rights reserved.

Repeat-mediated epigenetic dysregulation of the FMR1 gene in the fragile X-related disorders.

Science.gov (United States)

Usdin, Karen; Kumari, Daman

2015-01-01

The fragile X-related disorders are members of the Repeat Expansion Diseases, a group of genetic conditions resulting from an expansion in the size of a tandem repeat tract at a specific genetic locus. The repeat responsible for disease pathology in the fragile X-related disorders is CGG/CCG and the repeat tract is located in the 5' UTR of the FMR1 gene, whose protein product FMRP, is important for the proper translation of dendritic mRNAs in response to synaptic activation. There are two different pathological FMR1 allele classes that are distinguished only by the number of repeats. Premutation alleles have 55-200 repeats and confer risk of fragile X-associated tremor/ataxia syndrome and fragile X-associated primary ovarian insufficiency. Full mutation alleles on the other hand have >200 repeats and result in fragile X syndrome, a disorder that affects learning and behavior. Different symptoms are seen in carriers of premutation and full mutation alleles because the repeat number has paradoxical effects on gene expression: Epigenetic changes increase transcription from premutation alleles and decrease transcription from full mutation alleles. This review will cover what is currently known about the mechanisms responsible for these changes in FMR1 expression and how they may relate to other Repeat Expansion Diseases that also show repeat-mediated changes in gene expression.

Generating intrinsically disordered protein conformational ensembles from a Markov chain

Science.gov (United States)

Cukier, Robert I.

2018-03-01

Intrinsically disordered proteins (IDPs) sample a diverse conformational space. They are important to signaling and regulatory pathways in cells. An entropy penalty must be payed when an IDP becomes ordered upon interaction with another protein or a ligand. Thus, the degree of conformational disorder of an IDP is of interest. We create a dichotomic Markov model that can explore entropic features of an IDP. The Markov condition introduces local (neighbor residues in a protein sequence) rotamer dependences that arise from van der Waals and other chemical constraints. A protein sequence of length N is characterized by its (information) entropy and mutual information, MIMC, the latter providing a measure of the dependence among the random variables describing the rotamer probabilities of the residues that comprise the sequence. For a Markov chain, the MIMC is proportional to the pair mutual information MI which depends on the singlet and pair probabilities of neighbor residue rotamer sampling. All 2N sequence states are generated, along with their probabilities, and contrasted with the probabilities under the assumption of independent residues. An efficient method to generate realizations of the chain is also provided. The chain entropy, MIMC, and state probabilities provide the ingredients to distinguish different scenarios using the terminologies: MoRF (molecular recognition feature), not-MoRF, and not-IDP. A MoRF corresponds to large entropy and large MIMC (strong dependence among the residues' rotamer sampling), a not-MoRF corresponds to large entropy but small MIMC, and not-IDP corresponds to low entropy irrespective of the MIMC. We show that MorFs are most appropriate as descriptors of IDPs. They provide a reasonable number of high-population states that reflect the dependences between neighbor residues, thus classifying them as IDPs, yet without very large entropy that might lead to a too high entropy penalty.

The relation among perfectionism, obsessive-compulsive personality disorder and obsessive-compulsive disorder in individuals with eating disorders.

Science.gov (United States)

Halmi, Katherine A; Tozzi, Federica; Thornton, Laura M; Crow, Scott; Fichter, Manfred M; Kaplan, Allan S; Keel, Pamela; Klump, Kelly L; Lilenfeld, Lisa R; Mitchell, James E; Plotnicov, Katherine H; Pollice, Christine; Rotondo, Alessandro; Strober, Michael; Woodside, D Blake; Berrettini, Wade H; Kaye, Walter H; Bulik, Cynthia M

2005-12-01

Perfectionism and obsessionality are core features of eating disorders (ED), yet the nature of their relation remains unknown. Understanding the relation between these traits may enhance our ability to identify relevant behavioral endophenotypes for ED. Six-hundred seven individuals with anorexia and bulimia nervosa from the International Price Foundation Genetic Study were assessed for perfectionism, obsessive-compulsive personality disorder (OCPD), and obsessive-compulsive disorder (OCD). No differences were found across ED subtypes in the prevalence of OCPD and OCD, nor with the association between OCD and OCPD. Perfectionism scores were highest in individuals with OCPD whether alone or in combination with OCD. Perfectionism appears to be more closely associated with obsessive-compulsive personality symptoms rather than OCD. The pairing of perfectionism with OCPD may be a relevant core behavioral feature underlying vulnerability to ED. Copyright 2005 by Wiley Periodicals, Inc.

Endoplasmic Reticulum (ER Stress and Endocrine Disorders

Directory of Open Access Journals (Sweden)

Daisuke Ariyasu

2017-02-01

Full Text Available The endoplasmic reticulum (ER is the organelle where secretory and membrane proteins are synthesized and folded. Unfolded proteins that are retained within the ER can cause ER stress. Eukaryotic cells have a defense system called the “unfolded protein response” (UPR, which protects cells from ER stress. Cells undergo apoptosis when ER stress exceeds the capacity of the UPR, which has been revealed to cause human diseases. Although neurodegenerative diseases are well-known ER stress-related diseases, it has been discovered that endocrine diseases are also related to ER stress. In this review, we focus on ER stress-related human endocrine disorders. In addition to diabetes mellitus, which is well characterized, several relatively rare genetic disorders such as familial neurohypophyseal diabetes insipidus (FNDI, Wolfram syndrome, and isolated growth hormone deficiency type II (IGHD2 are discussed in this article.

Endoplasmic Reticulum (ER) Stress and Endocrine Disorders

Science.gov (United States)

Ariyasu, Daisuke; Yoshida, Hiderou; Hasegawa, Yukihiro

2017-01-01

The endoplasmic reticulum (ER) is the organelle where secretory and membrane proteins are synthesized and folded. Unfolded proteins that are retained within the ER can cause ER stress. Eukaryotic cells have a defense system called the “unfolded protein response” (UPR), which protects cells from ER stress. Cells undergo apoptosis when ER stress exceeds the capacity of the UPR, which has been revealed to cause human diseases. Although neurodegenerative diseases are well-known ER stress-related diseases, it has been discovered that endocrine diseases are also related to ER stress. In this review, we focus on ER stress-related human endocrine disorders. In addition to diabetes mellitus, which is well characterized, several relatively rare genetic disorders such as familial neurohypophyseal diabetes insipidus (FNDI), Wolfram syndrome, and isolated growth hormone deficiency type II (IGHD2) are discussed in this article. PMID:28208663

Inborn Errors of Metabolism with Hyperammonemia: Urea Cycle Defects and Related Disorders.

Science.gov (United States)

Summar, Marshall L; Mew, Nicholas Ah

2018-04-01

The urea cycle disorders are a group of inherited biochemical diseases caused by a complete or partial deficiency of any one of the enzymes or transport proteins required to convert toxic ammonia into urea and to produce arginine and citrulline. The clinical manifestations of these disorders are mostly the result of acute or chronic hyperammonemia, which affects the central nervous system. Affected individuals can also develop hepatic dysfunction. These disorders can present at any age from the immediate newborn to later in life. Early diagnosis and treatment are key to improving outcomes. Copyright © 2017 Elsevier Inc. All rights reserved.

I-Metaiodobenzylguanidine Myocardial Scintigraphy in Lewy Body-Related Disorders: A Literature Review

Directory of Open Access Journals (Sweden)

Eun Joo Chung

2015-05-01

Full Text Available Lewy body-related disorders are characterized by the presence of Lewy bodies and Lewy neurites, which have abnormal aggregations of α-synuclein in the nigral and extranigral areas, including in the heart. 123I-metaiodobenzylguanidine (MIBG scintigraphy is a well-known tool to evaluate cardiac sympathetic denervation in the Lewy body-related disorders. MIBG scintigraphy showed low uptake of MIBG in the Lewy body-related disorders, including Parkinson’s disease, dementia with Lewy bodies, pure autonomic failure and rapid eye movement sleep behavior disorder. This review summarizes previous results on the diagnostic applications of MIBG scintigraphy in Lewy body-related disorders.

Relative contribution of attention-deficit hyperactivity disorder, obsessive-compulsive disorder, and tic severity to social and behavioral problems in tic disorders

NARCIS (Netherlands)

Hoekstra, PJ; Steenhuis, MP; Troost, PW; Korf, J; Kallenberg, CGM; Minderaa, RB

The aim of this study was to investigate social and behavioral problems related to attention-deficit hyperactivity disorder (ADHD), obsessions and compulsions, and tic severity in children with a tic disorder. Parents of 58 children with a tic disorder with and without different forms of ADHD

Psychosis and relapse in bipolar disorder are related to GRM3 ...

African Journals Online (AJOL)

; mGluR3; G72 protein; HumanDysfunction in glutamate signalling is thought to play a role in the pathophysiology of bipolar disorder (BD). There is evidence of associations between single nucleotide polymorphisms (SNPs) in GRM3, GRIN2B, ...

Combinations of SNPs Related to Signal Transduction in Bipolar Disorder

DEFF Research Database (Denmark)

Koefoed, Pernille; Andreassen, Ole A; Bennike, Bente

2011-01-01

of complex diseases, it may be useful to look at combinations of genotypes. Genes related to signal transmission, e.g., ion channel genes, may be of interest in this respect in the context of bipolar disorder. In the present study, we analysed 803 SNPs in 55 genes related to aspects of signal transmission...... and calculated all combinations of three genotypes from the 3×803 SNP genotypes for 1355 controls and 607 patients with bipolar disorder. Four clusters of patient-specific combinations were identified. Permutation tests indicated that some of these combinations might be related to bipolar disorder. The WTCCC...... in the clusters in the two datasets. The present analyses of the combinations of SNP genotypes support a role for both genetic heterogeneity and interactions in the genetic architecture of bipolar disorder....

A compound heterozygous mutation in DPAGT1 results in a congenital disorder of glycosylation with a relatively mild phenotype

NARCIS (Netherlands)

Iqbal, Z.; Shahzad, M.; Vissers, L.E.L.M.; Scherpenzeel, M. van; Gilissen, C.; Razzaq, A.; Zahoor, M.Y.; Khan, S.N.; Kleefstra, T.; Veltman, J.A.; Brouwer, A.P.M. de; Lefeber, D.J.; Bokhoven, H. van; Riazuddin, S.

2013-01-01

Congenital disorders of glycosylation (CDG) are a large group of recessive multisystem disorders caused by impaired protein or lipid glycosylation. The CDG-I subgroup is characterized by protein N-glycosylation defects originating in the endoplasmic reticulum. The genetic defect is known for 17

Occupational imbalance and the role of perceived stress in predicting stress-related disorders.

Science.gov (United States)

Håkansson, Carita; Ahlborg, Gunnar

2017-03-02

Stress-related disorders are the main reason for sick leave in many European countries. The aim of the present study was to explore whether perceived occupational imbalance predicts stress-related disorders, potential gender differences, and to explore the mediating role of perceived stress. Longitudinal data on 2223 employees in a public organization in Sweden were collected by surveys, and analyzed by logistic regression. Occupational imbalance predicted stress-related disorders among both women and men. However, what aspects of occupational imbalance which predicted stress-related disorders differ by gender. Perceived stress was not a mediator in these associations. How women and men perceived their occupational balance affected the risk of stress-related disorders. The results may be used to develop effective strategies to decrease stress-related disorders.

Synaptic proteins and receptors defects in autism spectrum disorders

Directory of Open Access Journals (Sweden)

Jianling eChen

2014-09-01

Full Text Available Recent studies have found that hundreds of genetic variants, including common and rare variants, rare and de novo mutations, and common polymorphisms have contributed to the occurrence of autism spectrum disorders (ASDs. The mutations in a number of genes such as neurexin, neuroligin, postsynaptic density protein 95 (PSD-95, SH3 and multiple ankyrin repeat domains 3 (SHANK3, synapsin, gephyrin, cadherin (CDH and protocadherin (PCDH, thousand-and-one-amino acid 2 kinase (TAOK2, and contactin (CNTN, have been shown to play important roles in the development and function of synapses. In addition, synaptic receptors, such as gamma-aminobutyric acid (GABA receptors and glutamate receptors, have also been associated with ASDs. This review will primarily focus on the defects of synaptic proteins and receptors associated with ASDs and their roles in the pathogenesis of ASDs via synaptic pathways.

FRA-1 protein overexpression is a feature of hyperplastic and neoplastic breast disorders

International Nuclear Information System (INIS)

Chiappetta, Gennaro; Pierantoni, Giovanna Maria; Fusco, Alfredo; Ferraro, Angelo; Botti, Gerardo; Monaco, Mario; Pasquinelli, Rosa; Vuttariello, Emilia; Arnaldi, Liliane; Di Bonito, Maurizio; D'Aiuto, Giuseppe

2007-01-01

Fos-related antigen 1 (FRA-1) is an immediate early gene encoding a member of AP-1 family of transcription factors involved in cell proliferation, differentiation, apoptosis, and other biological processes. fra-1 gene overexpression has an important role in the process of cellular transformation, and our previous studies suggest FRA-1 protein detection as a useful tool for the diagnosis of thyroid neoplasias. Here we investigate the expression of the FRA-1 protein in benign and malignant breast tissues by immunohistochemistry, Western blot, RT-PCR and qPCR analysis, to evaluate its possible help in the diagnosis and prognosis of breast neoplastic diseases. We investigate the expression of the FRA-1 protein in 70 breast carcinomas and 30 benign breast diseases by immunohistochemistry, Western blot, RT-PCR and qPCR analysis. FRA-1 protein was present in all of the carcinoma samples with an intense staining in the nucleus. Positive staining was also found in most of fibroadenomas, but in this case the staining was present both in the nucleus and cytoplasm, and the number of positive cells was lower than in carcinomas. Similar results were obtained from the analysis of breast hyperplasias, with no differences in FRA-1 expression level between typical and atypical breast lesions; however the FRA-1 protein localization is mainly nuclear in the atypical hyperplasias. In situ breast carcinomas showed a pattern of FRA-1 protein expression very similar to that observed in atypical hyperplasias. Conversely, no FRA-1 protein was detectable in 6 normal breast tissue samples used as controls. RT-PCR and qPCR analysis confirmed these results. Similar results were obtained analysing FRA-1 expression in fine needle aspiration biopsy (FNAB) samples. The data shown here suggest that FRA-1 expression, including its intracellular localization, may be considered a useful marker for hyperplastic and neoplastic proliferative breast disorders

Work-related musculoskeletal disorders : prevention report

NARCIS (Netherlands)

Podniece, Z.; Heuvel, S. van den; Blatter, B.

2008-01-01

Work-related musculoskeletal disorders (MSDs) can interfere with activities at work and can lead to reduced productivity, sickness absence and chronic occupational disability. The aim of this report is to systematic evaluate the effectiveness of interventions at the workplace since 2002 and to

Narcissistic personality disorder: relations with distress and functional impairment.

Science.gov (United States)

Miller, Joshua D; Campbell, W Keith; Pilkonis, Paul A

2007-01-01

This study examined the construct validity of narcissistic personality disorder (NPD) by examining the relations between NPD and measures of psychologic distress and functional impairment both concurrently and prospectively across 2 samples. In particular, the goal was to address whether NPD typically "meets" criterion C of the DSM-IV definition of Personality Disorder, which requires that the symptoms lead to clinically significant distress or impairment in functioning. Sample 1 (n = 152) was composed of individuals receiving psychiatric treatment, whereas sample 2 (n = 151) was composed of both psychiatric patients (46%) and individuals from the community. Narcissistic personality disorder was linked to ratings of depression, anxiety, and several measures of impairment both concurrently and at 6-month follow-up. However, the relations between NPD and psychologic distress were (a) small, especially in concurrent measurements, and (b) largely mediated by impaired functioning. Narcissistic personality disorder was most strongly related to causing pain and suffering to others, and this relationship was significant even when other Cluster B personality disorders were controlled. These findings suggest that NPD is a maladaptive personality style which primarily causes dysfunction and distress in interpersonal domains. The behavior of narcissistic individuals ultimately leads to problems and distress for the narcissistic individuals and for those with whom they interact.

Aripiprazole-induced sleep-related eating disorder: a case report.

Science.gov (United States)

Kobayashi, Nobuyuki; Takano, Masahiro

2018-04-05

Sleep-related eating disorder is characterized by parasomnia with recurrent episodes of nocturnal eating or drinking during the main sleep period. Several drugs, including atypical antipsychotics, induce sleep-related eating disorder. However, aripiprazole has not previously been associated with sleep-related eating disorder. A 41-year-old Japanese man visited our clinic complaining of depression. The patient was treated with sertraline, which was titrated up to 100 mg for 4 weeks. A sleep inducer and an anxiolytic were coadministered. His depressive mood slightly improved, but it continued for an additional 4 months. Subsequently, aripiprazole (3 mg) was added as an adjunctive therapy. After 3 weeks, the patient's mother found that the patient woke up and ate food at night. The next morning, the patient was amnesic for this event, felt full, and wondered why the bags of food were empty. This episode lasted for 2 days. The patient gained 5 kg during these 3 weeks. After the aripiprazole dose was reduced to 1.5 mg, the patient's nocturnal eating episodes rapidly and completely disappeared. To the best of our knowledge, this is first report of sleep-related eating disorder induced by aripiprazole, and it indicates that this disorder should be considered a possible side effect of aripiprazole. Although aripiprazole is used mainly in patients with schizophrenia, its recently documented use as an adjunctive therapy in patients with depression might induce hitherto unknown side effects.

Epilepsy and outcome in FOXG1-related disorders

Science.gov (United States)

Seltzer, Laurie E.; Ma, Mandy; Ahmed, Sohnee; Bertrand, Mary; Dobyns, William B.; Wheless, James; Paciorkowski, Alex R.

2014-01-01

Summary Objective FOXG1-related disorders are associated with severe intellectual disability, absent speech with autistic features, and epilepsy. Children with deletions or intragenic mutations of FOXG1 also have postnatal microcephaly, morphologic abnormalities of the corpus callosum, and choreiform movements. Duplications of 14q12 often present with infantile spasms, and have subsequent intellectual disability with autistic features. Long term epilepsy outcome and response to treatment has not been studied systematically in a well-described cohort of subjects with FOXG1-related disorders. We report on the epilepsy features and developmental outcome of 23 new subjects with deletions or intragenic mutations of FOXG1, and 7 subjects with duplications. Methods Subjects had either chromosomal microarray or FOXG1 gene sequencing performed as part of routine clinical care. Development and epilepsy follow-up data were collected from medical records from treating neurologists and through telephone parental interviews using standardized questionnaires. Results Epilepsy was diagnosed in 87% of the subjects with FOXG1-related disorders. The mean age of epilepsy diagnosis in FOXG1 duplications was significantly younger than those with deletions/intragenic mutations (p=0.0002). All of the duplication FOXG1 children with infantile spasms responded to hormonal therapy and only one required long-term anti-epileptic therapy. In contrast, more children with deletions/intragenic mutations required anti-epileptic drugs on follow-up (p<0.0005). All subjects with FOXG1-related disorders had neurodevelopmental disabilities after 3 years of age, regardless of the epilepsy type or intractability of seizures. All had impaired verbal language and social contact, and three duplication subjects were formally diagnosed with autism. Subjects with deletion/intragenic mutations however had significantly worse ambulation (p=0.04) and functional hand use (p<0.0005). Significance Epilepsy and

Chronic obstructive pulmonary disease and sleep related disorders.

Science.gov (United States)

Tsai, Sheila C

2017-03-01

Sleep related disorders are common and under-recognized in the chronic obstructive pulmonary disease (COPD) population. COPD symptoms can disrupt sleep. Similarly, sleep disorders can affect COPD. This review highlights the common sleep disorders seen in COPD patients, their impact, and potential management. Treatment of sleep disorders may improve quality of life in COPD patients. Optimizing inhaler therapy improves sleep quality. Increased inflammatory markers are noted in patients with the overlap syndrome of COPD and obstructive sleep apnea versus COPD alone. There are potential benefits of noninvasive positive pressure ventilation therapy for overlap syndrome patients with hypercapnia. Nocturnal supplemental oxygen may be beneficial in certain COPD subtypes. Nonbenzodiazepine hypnotic therapy for insomnia has shown benefit without associated respiratory failure or worsening respiratory symptoms. Melatonin may provide mild hypnotic and antioxidant benefits. This article discusses the impact of sleep disorders on COPD patients and the potential benefits of managing sleep disorders on respiratory disease control and quality of life.

Treatment of cardiovascular disorders using the cell differentiation signaling protein Nell1

Science.gov (United States)

Culiat, Cymbeline T

2014-05-13

It has been identified in accordance with the present invention that Nell1 is essential for normal cardiovascular development by promoting proper formation of the heart and blood vessels. The present invention therefore provides therapeutic methods for treating cardiovascular disorders by employing a Nell1 protein or nucleic acid molecule.

Fibrillin abnormalities and prognosis in Marfan syndrome and related disorders

Energy Technology Data Exchange (ETDEWEB)

Aoyama, T.; Furthmayr, H.; Francke, U.; Gasner, C. [Stanford Univ. Medical Center, CA (United States)

1995-08-28

Marfan syndrome (MFS), a multisystem autosomal-dominant disorder, is characterized by mutations of the fibrillin-1 (FBN1) gene and by abnormal patterns of synthesis, secretion, and matrix deposition of the fibrillin protein. To determine the sensitivity and specificity of fibrillin protein abnormalities in the diagnosis of MFS, we studied dermal fibroblasts from 57 patients with classical MFS, 15 with equivocal MFS, 8 with single-organ manifestations, and 16 with other connective tissue disorders including homocystinuria and Ehlers-Danlos syndrome. Abnormal fibrillin metabolism was identified in 70 samples that were classified into four different groups based on quantitation of fibrillin synthesis and matrix deposition. Significant correlations were found for phenotypic features including arachnodactyly, striae distensae, cardiovascular manifestations, and fibrillin groups II and IV, which included 70% of the MFS patients. In addition, these two groups were associated with shortened {open_quotes}event-free{close_quotes} survival and more severe cardiovascular complications than groups I and III. The latter included most of the equivocal MFS/single manifestation patients with fibrillin abnormalities. Our results indicate that fibrillin defects at the protein level per se are not specific for MFS, but that the drastically reduced fibrillin deposition, caused by a dominant-negative effect of abnormal fibrillin molecules in individuals defined as groups II and IV, is of prognostic and possibly diagnostic significance. 25 refs., 3 figs., 6 tabs.

Should OCD leave the anxiety disorders in DSM-V? The case for obsessive compulsive-related disorders.

Science.gov (United States)

Hollander, Eric; Braun, Ashley; Simeon, Daphne

2008-01-01

Recently in 2006, a group of experts in obsessive compulsive disorder (OCD) and obsessive compulsive-related disorders (OCRDs) convened in Washington, DC, to review existing data on the relationships between these various disorders, and to suggest approaches to address the gaps in our knowledge, in preparation for the upcoming Diagnostic and Statistical Manual (Fifth Edition) (DSM-V). As a result of this meeting, the Research Planning Agenda for DSM-V: OCRD Work Group suggested removing OCD from the anxiety disorders, where it is currently found. This proposal is in accordance with the current International Classification of Mental Disorders (ICD-10) classification of OCD as a separate category from the anxiety disorders. Although the ICD-10 places both OCD and the anxiety disorders under the umbrella category of "neurotic, stress-related, and somatoform disorders," they are two separate categories, distinct from one another. As OCD and other putative OCRDs share aspects of phenomenology, comorbidity, neurotransmitter/peptide systems, neurocircuitry, familial and genetic factors, and treatment response, it was proposed to create a new category in DSM-V entitled OCRDs. Alternatively, the OCRDs might be conceptualized as a new category within the broader category of anxiety disorders. Future studies are needed to better define the relationships among these disorders, and to study boundary issues for this proposed category. There are both advantages and disadvantages in creating a new diagnostic category in DSM-V, and these are discussed in this article.

Attachment insecurity, mentalization and their relation to symptoms in eating disorder patients.

Science.gov (United States)

Kuipers, Greet S; van Loenhout, Zara; van der Ark, L Andries; Bekker, Marrie H J

2016-01-01

To investigate the relationships of attachment security and mentalization with core and co-morbid symptoms in eating disorder patients. We compared 51 eating disorder patients at the start of intensive treatment and 20 healthy controls on attachment, mentalization, eating disorder symptoms, depression, anxiety, personality disorders, psycho-neuroticism, autonomy problems and self-injurious behavior, using the Adult Attachment Interview, the SCID-I and II and several questionnaires. Compared with the controls, the eating disorder patients showed a higher prevalence of insecure attachment; eating disorder patients more often than controls received the AAI classification Unresolved for loss or abuse. They also had a lower level of mentalization and more autonomy problems. In the patient group eating disorder symptoms, depression, anxiety, psycho-neuroticism and autonomy problems were neither related to attachment security nor to mentalization; self-injurious behavior was associated with lesser attachment security and lower mentalization; borderline personality disorder was related to lower mentalization. In the control group no relations were found between attachment, mentalization and psychopathologic variables. Eating disorder patients' low level of mentalization suggests the usefulness of Mentalization Based Treatment techniques for eating disorder treatment, especially in case of self-injurious behavior and/or co-morbid borderline personality disorder.

Substance use disorders in adolescent and young adult relatives of probands with bipolar disorder: What drives the increased risk?

Science.gov (United States)

Hulvershorn, Leslie A; King, Jennifer; Monahan, Patrick O; Wilcox, Holly C; Mitchell, Philip B; Fullerton, Janice M; Edenberg, Howard J; Roberts, Gloria M P; Kamali, Masoud; Glowinski, Anne L; Ghaziuddin, Neera; McInnis, Melvin; Iyer-Eimerbrink, Priya A; Nurnberger, John I

2017-10-01

Adults with bipolar disorder (BD) have higher rates of substance use disorders (SUDs) compared to the general population. SUD rates in young offspring/relatives of BD probands, as well as factors which drive those rates, are not as well-characterized. We aimed to examine SUD prevalence among adolescent/young adult offspring and relatives of probands with and without BD. Data were collected from five sites in the US and Australia during 2006-2011. Youth offspring/relatives ("Relatives of BD probands;" n=267; mean age=16.8years; ±2.9S.D.), identified through a proband family member with DSM-IV BD (Type I or II), were compared to offspring/relatives of control probands ("relatives of control probands;" n=149; mean age=17.4years; ±2.9S.D.). Logistic regression with generalized estimating equations was used to compare the groups across a range of substance use and SUD variables. Odds ratios were calculated for lifetime prevalence of substance outcomes. Bivariate analyses showed DSM-IV SUDs were more prevalent among relatives of BD probands than among relatives of control probands (29% vs. 18%; p=0.01). Generalized estimating equation models showed BD mood and childhood-onset externalizing disorders in adolescent and young adult relatives to each significantly increase the odds (OR=2.80-3.17; p<0.02) for the development of several substance variables among all relatives, whereas the risk of SUDs in relatives was not increased when the relatives had no mood or externalizing disorders themselves. Relatives of BD probands with lifetime mood and externalizing disorders report more substance use/SUDs than relatives of control probands. In contrast, SUD outcomes in relatives of BD probands without mood or externalizing disorders were no different from control relatives without psychopathology. Early recognition and treatment of psychiatric disorders may lead to less substance use in this highly vulnerable population. Copyright © 2017 Elsevier Inc. All rights reserved.

Review on risk factors related to lower back disorders at workplace

Science.gov (United States)

A' Tifah Jaffar, Nur; Nasrull Abdol Rahman, Mohd

2017-08-01

This review examines the evidence of the occurrence of risk exposure on work-related lower back disorders in the workplace. This review also investigates potential interactions between the risk factors in the workplace which include heavy physical work risk factor, static work postures risk factor, frequent bending and twisting risk factor, lifting risk factor, pushing and pulling risk factor, repetitive work risk factor, vibration risk factor, psychological and psychosocial risk factor that may be associated with symptoms of musculoskeletal disorders of lower back. These risk factors can reinforce each other and their influence can also be mediated by cultural or social factors. A systematic review of the literature was carried out by searching using databases and the searching strategy was used combined keyword for risk factors, work-related lower back disorders, heavy physical work, static work postures, frequent bending and twisting, lifting, pushing and pulling, repetitive work, vibration, psychological and psychosocial risk factor. A total of 67 articles were identified and reviewed. The risk factors identified that related for low back disorder are seven which are heavy physical work, static work postures, frequent bending and twisting, lifting, pushing and pulling, repetitive work, vibration, psychological and psychosocial risk factor and the level of evidence supporting the relationship with lower back disorders also described such as strong, moderate, insufficient, limited and no evidence. This result confirms that, existing of higher physical and psychosocial demand related to reported risk factors of low back disorders. The result also showed that previous reviews had evaluated relationship between risk factors of low back disorders and specific types of musculoskeletal disorders. This review also highlights the scarves evidence regarding some of the frequently reported risk factors for work related lower back disorders.

Intrinsic disorder in pathogen effectors: protein flexibility as an evolutionary hallmark in a molecular arms race.

Science.gov (United States)

Marín, Macarena; Uversky, Vladimir N; Ott, Thomas

2013-09-01

Effector proteins represent a refined mechanism of bacterial pathogens to overcome plants' innate immune systems. These modular proteins often manipulate host physiology by directly interfering with immune signaling of plant cells. Even if host cells have developed efficient strategies to perceive the presence of pathogenic microbes and to recognize intracellular effector activity, it remains an open question why only few effectors are recognized directly by plant resistance proteins. Based on in-silico genome-wide surveys and a reevaluation of published structural data, we estimated that bacterial effectors of phytopathogens are highly enriched in long-disordered regions (>50 residues). These structurally flexible segments have no secondary structure under physiological conditions but can fold in a stimulus-dependent manner (e.g., during protein-protein interactions). The high abundance of intrinsic disorder in effectors strongly suggests positive evolutionary selection of this structural feature and highlights the dynamic nature of these proteins. We postulate that such structural flexibility may be essential for (1) effector translocation, (2) evasion of the innate immune system, and (3) host function mimicry. The study of these dynamical regions will greatly complement current structural approaches to understand the molecular mechanisms of these proteins and may help in the prediction of new effectors.

Immunohistochemical identification of messenger RNA-related proteins in basophilic inclusions of adult-onset atypical motor neuron disease.

Science.gov (United States)

Fujita, Kengo; Ito, Hidefumi; Nakano, Satoshi; Kinoshita, Yoshimi; Wate, Reika; Kusaka, Hirofumi

2008-10-01

This report concerns an immunohistochemical investigation on RNA-related proteins in the basophilic inclusions (BIs) from patients with adult-onset atypical motor neuron disease. Formalin-fixed, paraffin-embedded sections of the motor cortex and the lumbar spinal cord were examined. The BIs appeared blue in color with H&E and Nissl stain, and pink with methylgreen-pyronin stain. Ribonuclease pretreatment abolished the methylgreen-pyronin staining, suggesting that the BIs contained RNA. Immunohistochemically, the BIs were distinctly labeled with the antibodies against poly(A)-binding protein 1, T cell intracellular antigen 1, and ribosomal protein S6. These proteins are essential constituents of stress granules. In contrast, the BIs were not immunoreactive for ribosomal protein L28 and decapping enzyme 1, which are core components of transport ribonucleoprotein particles and processing bodies, respectively. Moreover, the BIs were not immunopositive for TDP-43. Our results imply that translation attenuation could be involved in the processes of BI formation in this disorder.

Serum levels of carbonylated and nitrosylated proteins in mobbing victims with workplace adjustment disorders.

Science.gov (United States)

Di Rosa, A E; Gangemi, S; Cristani, M; Fenga, C; Saitta, S; Abenavoli, E; Imbesi, S; Speciale, A; Minciullo, P L; Spatari, G; Abbate, S; Saija, A; Cimino, F

2009-12-01

Today the most important problem in the work place is psychological abuse, which may affect the health because of high levels of stress and anxiety. There is evidence that most psychiatric disorders are associated with increased oxidative stress but nothing is reported about the presence of oxidative stress in mobbing victims. This study has been carried out in a group of 19 patients affected by workplace mobbing-due adjustment disorders, in comparison with 38 healthy subjects, to evaluate whether oxidative stress may be induced by mobbing. Serum levels of protein carbonyl groups and of nitrosylated proteins, biological markers of oxidative stress conditions, were higher than those measured in healthy subjects. These findings may contribute to a better understanding of the redox homeostasis dysregulation occurring in victims of workplace mobbing.

Effect of soy protein on obesity-linked renal and pancreatic disorders in female rats

International Nuclear Information System (INIS)

Osman, H.F.; El-Sherbiny, E.M.

2006-01-01

The purpose of this study was to identify the effect of soy protein based diet on renal and pancreatic disorders in female obese rats. Animals assigned into group I in which 30 rats fed on a balanced diet. Group II contained 30 rats fed on a diet containing 30% fats for 4 weeks. At the end of the 4 th week, one-half of each group was treated as group III which contain 15 rats (half of group I) fed on diet containing 25% soy protein for 3 weeks and represents soy protein group, and the other half served as control. Group IV contained 15 rats (half of group II) fed on a diet containing 25% soy protein for 3 weeks and served as obese + soy protein group, and the other half fed on a normal balanced diet for 3 weeks and represents the obese group. Body weights of rats were recorded every week during the experimental period. Renal and pancreatic functions were measured as urea, creatinine, glomerular filtration rate (creatinine clearance), ammonia, sodium and potassium ions, total protein, albumin, globulin, glucose, insulin and alpha-amylase activity. Feeding with soy protein led to a very high significant increase in urea while creatinine was significantly decreased and creatinine clearance was significantly increased in the groups fed on soy protein. Ammonia concentration was increased in all groups and there was non-significant alteration in sodium and potassium ion concentrations. In soy protein groups (groups III and IV), total protein, albumin and globulin levels were increased. Glucose level was increased in obese rats and significantly decreased in groups III and IV. In group IV, insulin level was decreased which implicated to insulin excess in obesity. Soy protein decreased alpha-amylase activity in groups III and IV as compared to control rats. From these results, soy protein have a direct and protective effect on glomerular disorders and pancreatic secretions. This may be due to isoflavone contents in soy which can modulate the disturbance in metabolism

Plasma kynurenine and related measures in tic disorder patients

NARCIS (Netherlands)

Hoekstra, Pieter J.; Anderson, George M.; Troost, Pieter W.; Kallenberg, Cees G. M.; Minderaa, Ruud B.

Objective Increased plasma kynurenine has been reported in tic disorder patients, and this observation has been suggested to be indicative of immune dysregulation. In the present study, we examined plasma levels of kynurenine and related molecules in a group of tic disorder patients. Methods Plasma

Seroreactive marker for inflammatory bowel disease and associations with antibodies to dietary proteins in bipolar disorder.

Science.gov (United States)

Severance, Emily G; Gressitt, Kristin L; Yang, Shuojia; Stallings, Cassie R; Origoni, Andrea E; Vaughan, Crystal; Khushalani, Sunil; Alaedini, Armin; Dickerson, Faith B; Yolken, Robert H

2014-05-01

Immune sensitivity to wheat glutens and bovine milk caseins may affect a subset of individuals with bipolar disorder. Digested byproducts of these foods are exorphins that have the potential to impact brain physiology through action at opioid receptors. Inflammation in the gastrointestinal (GI) tract might accelerate exposure of food antigens to systemic circulation and help explain elevated gluten and casein antibody levels in individuals with bipolar disorder. We measured a marker of GI inflammation, anti-Saccharomyces cerevisiae antibodies (ASCA), in non-psychiatric controls (n = 207), in patients with bipolar disorder without a recent onset of psychosis (n = 226), and in patients with bipolar disorder with a recent onset of psychosis (n = 38). We compared ASCA levels to antibodies against gluten, casein, Epstein-Barr virus (EBV), herpes simplex virus 1 (HSV-1), influenza A, influenza B, measles, and Toxoplasma gondii. Elevated ASCA conferred a 3.5-4.4-fold increased odds ratio of disease association (age-, race-, and gender-corrected multinomial logistic regressions, p ≤ 0.00001) that was independent of type of medication received. ASCA correlated with food antibodies in both bipolar disorder groups (R(2)  = 0.29-0.59, p ≤ 0.0005), and with measles and T. gondii immunoglobulin G (IgG) in the recent onset psychosis bipolar disorder group (R(2)  = 0.31-0.36, p ≤ 0.004-0.01). Elevated seropositivity of a GI-related marker and its association with antibodies to food-derived proteins and self-reported GI symptoms suggest a GI comorbidity in at least a subgroup of individuals with bipolar disorder. Marker seroreactivity may also represent part of an overall heightened activated immune state inherent to this mood disorder. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

[Substance-related and addictive disorders in the DSM-5].

Science.gov (United States)

Thomasius, Rainer; Sack, Peter-Michael; Strittmatter, Esther; Kaess, Michael

2014-03-01

This paper concerns the revised classification of Substance-Related and Addictive Disorders in the fifth edition of the American Psychiatric Association's (APA) Diagnostic and Statistical Manual of Mental Disorders (DSM-5). In DSM-5, substance use disorders are diagnosed on a continuum of severity specified by explicit operationalized diagnostic criteria. "Gambling disorder" is the only behavioral addiction added to the DSM. Furthermore, preliminary criteria for "Caffeine Use Disorder" and "Internet Gaming Disorder" have now been defined in the manual. Adopting the DSM-5 criteria catalogue within the German treatment system for children and adolescents with substance use disorders or at risk for developing substance use disorders would be of great significance. Since the diagnostic threshold is lower, more patients would be eligible for treatment. Thus, early intervention in the area of substance use disorders should be strengthened, a development that appears to be highly desirable from the perspective of child and adolescent psychiatry. The current Section III diagnoses, with their now comprehensive diagnostic criteria, facilitate more internationally compatible research.

Prevalence of interpersonal trauma exposure and trauma-related disorders in severe mental illness.

Science.gov (United States)

Mauritz, Maria W; Goossens, Peter J J; Draijer, Nel; van Achterberg, Theo

2013-01-01

Interpersonal trauma exposure and trauma-related disorders in people with severe mental illness (SMI) are often not recognized in clinical practice. To substantiate the prevalence of interpersonal trauma exposure and trauma-related disorders in people with SMI. We conducted a systematic review of four databases (1980-2010) and then described and analysed 33 studies in terms of primary diagnosis and instruments used to measure trauma exposure and trauma-related disorders. Population-weighted mean prevalence rates in SMI were physical abuse 47% (range 25-72%), sexual abuse 37% (range 24-49%), and posttraumatic stress disorder (PTSD) 30% (range 20-47%). Compared to men, women showed a higher prevalence of sexual abuse in schizophrenia spectrum disorder, bipolar disorder, and mixed diagnosis groups labelled as having SMI. Prevalence rates of interpersonal trauma and trauma-related disorders were significantly higher in SMI than in the general population. Emotional abuse and neglect, physical neglect, complex PTSD, and dissociative disorders have been scarcely examined in SMI.

Error-Related Negativity and Tic History in Pediatric Obsessive-Compulsive Disorder

Science.gov (United States)

Hanna, Gregory L.; Carrasco, Melisa; Harbin, Shannon M.; Nienhuis, Jenna K.; LaRosa, Christina E.; Chen, Poyu; Fitzgerald, Kate D.; Gehring, William J.

2012-01-01

Objective: The error-related negativity (ERN) is a negative deflection in the event-related potential after an incorrect response, which is often increased in patients with obsessive-compulsive disorder (OCD). However, the relation of the ERN to comorbid tic disorders has not been examined in patients with OCD. This study compared ERN amplitudes…

Prevalence of Work Related Musculoskeletal Disorders Among ...

African Journals Online (AJOL)

Journal Home > Vol 4, No 4 (2014) > ... Background: Work related musculoskeletal disorders (MSDs) are one of the common occupational ... of the doctor, duration of practice, working hours per week, physical activity and working environment.

[Trauma and stressor-related disorders: diagnostic conceptualization in DSM-5].

Science.gov (United States)

Kapfhammer, H P

2014-05-01

The Diagnostic and Statistical Manual of Mental Disorders 5 (DSM-5) includes a distinct diagnostic group of trauma and stressor-related disorders that has been set apart from anxiety disorders. From a perspective of adult psychiatry this new disorder category includes posttraumatic stress disorder (PTSD), acute stress disorder (ASD), and adjustment disorders. The PTSD is based on narrower trauma criteria that focus on acute life-threatening situations, serious injury, or sexual violence by way of direct confrontation, witnessing or indirect confrontation. Indirect confrontation, however, is reserved only for violent or accidental events that occurred to close family members or friends. The former A2 criterion of an intense emotional reaction to trauma has been removed. A deliberately broad approach to clinical PTSD phenomenology has created an empirically driven new cluster of persistent negative alterations in cognition and mood due to experiencing traumatic events. The ASD has been reconceptualized as an intense stress syndrome with a clear need of acute treatment during the early course after traumatic exposure. Adjustment disorders continue to emphasize maladaptive emotional and behavioral responses to unspecific, non-traumatic stressors in an intensity that is beyond social or cultural norms. Neither complex PTSD nor prolonged grief disorders have received an independent diagnostic status within DSM-5. With respect to stress-related disorders major divergences between DSM-5 and the future International Classification of Diseases 11 (ICD-11) are to be expected.

Major depressive disorder: insight into candidate cerebrospinal fluid protein biomarkers from proteomics studies.

Science.gov (United States)

Al Shweiki, Mhd Rami; Oeckl, Patrick; Steinacker, Petra; Hengerer, Bastian; Schönfeldt-Lecuona, Carlos; Otto, Markus

2017-06-01

Major Depressive Disorder (MDD) is the leading cause of global disability, and an increasing body of literature suggests different cerebrospinal fluid (CSF) proteins as biomarkers of MDD. The aim of this review is to summarize the suggested CSF biomarkers and to analyze the MDD proteomics studies of CSF and brain tissues for promising biomarker candidates. Areas covered: The review includes the human studies found by a PubMed search using the following terms: 'depression cerebrospinal fluid biomarker', 'major depression biomarker CSF', 'depression CSF biomarker', 'proteomics depression', 'proteomics biomarkers in depression', 'proteomics CSF biomarker in depression', and 'major depressive disorder CSF'. The literature analysis highlights promising biomarker candidates and demonstrates conflicting results on others. It reveals 42 differentially regulated proteins in MDD that were identified in more than one proteomics study. It discusses the diagnostic potential of the biomarker candidates and their association with the suggested pathologies. Expert commentary: One ultimate goal of finding biomarkers for MDD is to improve the diagnostic accuracy to achieve better treatment outcomes; due to the heterogeneous nature of MDD, using bio-signatures could be a good strategy to differentiate MDD from other neuropsychiatric disorders. Notably, further validation studies of the suggested biomarkers are still needed.

Military-related trauma is associated with eating disorder symptoms in male veterans.

Science.gov (United States)

Arditte Hall, Kimberly A; Bartlett, Brooke A; Iverson, Katherine M; Mitchell, Karen S

2017-11-01

Eating disorders are understudied among male veterans, who may be at increased risk due to the high rates of trauma exposure and experiences of multiple traumatization in this population. This study sought to examine the associations between specific types of trauma (i.e., childhood physical abuse, adult physical assault, childhood sexual abuse, adult sexual assault, and military-related trauma) and eating disorder symptoms in a large, nationally-representative sample of trauma-exposed male veterans. Survey data were collected from N = 642 male veterans. Traumatic experiences in childhood and adulthood were assessed using the Trauma History Screen and the National Stressful Events Survey. Eating disorder symptoms were assessed with the Eating Disorder Diagnostic Scale. Analyses also controlled for age and body mass index. Multiple traumatization was associated with increased eating disorder symptoms. However, military-related trauma was the only trauma type that was uniquely associated with eating disorder symptoms when controlling for other trauma types. Examination of different types of military-related trauma indicated that this association was not driven by exposure to combat. Noncombat, military-related trauma was associated with eating disorder symptom severity in male veterans. Results highlight the need for better assessment of eating disorder symptoms in this population. © 2017 Wiley Periodicals, Inc.

DNA origami scaffold for studying intrinsically disordered proteins of the nuclear pore complex

NARCIS (Netherlands)

Ketterer, Philip; Ananth, Adithya N; Laman Trip, Diederik S; Mishra, Ankur; Bertosin, Eva; Ganji, Mahipal; van der Torre, Jaco; Onck, Patrick; Dietz, Hendrik; Dekker, Cees

2018-01-01

The nuclear pore complex (NPC) is the gatekeeper for nuclear transport in eukaryotic cells. A key component of the NPC is the central shaft lined with intrinsically disordered proteins (IDPs) known as FG-Nups, which control the selective molecular traffic. Here, we present an approach to realize

Digested disorder: Quarterly intrinsic disorder digest (January/February/March, 2013).

Science.gov (United States)

Uversky, Vladimir N

2013-01-01

The current literature on intrinsically disordered proteins is blooming. A simple PubMed search for "intrinsically disordered protein OR natively unfolded protein" returns about 1,800 hits (as of June 17, 2013), with many papers published quite recently. To keep interested readers up to speed with this literature, we are starting a "Digested Disorder" project, which will encompass a series of reader's digest type of publications aiming at the objective representation of the research papers and reviews on intrinsically disordered proteins. The only two criteria for inclusion in this digest are the publication date (a paper should be published within the covered time frame) and topic (a paper should be dedicated to any aspect of protein intrinsic disorder). The current digest covers papers published during the period of January, February and March of 2013. The papers are grouped hierarchically by topics they cover, and for each of the included paper a short description is given on its major findings.

Heat shock protein 10 (Hsp10) in immune-related diseases: one coin, two sides

Science.gov (United States)

Jia, Haibo; Halilou, Amadou I.; Hu, Liang; Cai, Wenqian; Liu, Jing; Huang, Bo

2011-01-01

Heat shock protein 10 (Hsp10) in eukaryotes, originally identified as a mitochondrial chaperone, now is also known to be present in cytosol, cell surface, extracellular space and peripheral blood. Functionally besides participating in mitochondrial protein folding in association with Hsp60, Hsp10 appears to be related to pregnancy, cancer and autoimmune inhibition. Hsp10 can be released to peripheral blood at very early time point of pregnancy and given another name called early pregnancy factor (EPF), which seems to play a critical role in developing a pregnant niche. In malignant disorders, Hsp10 is usually abnormally expressed in the cytosol of malignant cells and further released to extracellular space, resulting in tumor-promoting effect from various aspects. Furthermore, distinct from other heat shock protein members, whose soluble form is recognized as danger signal by immune cells and triggers immune responses, Hsp10 after release, however, is designed to be an inhibitory signal by limiting immune response. This review discusses how Hsp10 participates in various physiological and pathological processes from basic protein molecule folding to pregnancy, cancer and autoimmune diseases, and emphasizes how important the location is for the function exertion of a molecule. PMID:21969171

Trauma in relation to psychological characteristics in women with eating disorders

Directory of Open Access Journals (Sweden)

Bernadetta Izydorczyk

2017-05-01

Full Text Available Background The aim of the article was to present the results of the author’s own study that sought relationships between having experienced psychological trauma and the psychological characteristics of people with eating disorders. The basic research question was the following: To what degree are the traumatic events experienced by females with various types of eating disorders related to these females’ psychological characteristics? Participants and procedure The sample comprised 120 females with eating disorders: 30 females aged between 20 and 26 diagnosed with bulimia nervosa, 31 females diagnosed with binge-eating disorder and 59 females aged between 20 and 26 diagnosed with anorexia nervosa. The research was carried out in the years 2007-2012 in outpatient clinics treating neuroses and eating disorders and mental health outpatient clinics in Poland. The study employed a clinical and psychometric (i.e., questionnaires for measuring psychological characteristics approach. Results Statistical analysis confirmed the existence of significant differences between the females with eating disorders who have experienced relational trauma(s in their lives (particularly in their childhood and adolescence and those who did not reveal such experience. The females with anorexia and bulimia who have also experienced psychological, physical or sexual violence revealed a significantly different, higher level of bulimic thinking and tendencies for excessively uncontrolled, impulsive behaviors towards food and nutrition (i.e., vomit-provoking and other forms of body purgation, e.g. using purgative drugs and others than did females with no relational trauma experience. Conclusions The frequency of relational trauma occurrence was significantly higher for females with bulimia and bulimic anorexia. For females with restrictive anorexia and binge-eating disorder, no significantly frequent occurrence of trauma was observed. Diagnosing the occurrence of

[The epidemiological study of work-related musculoskeletal disorders and related factors among automobile assembly workers].

Science.gov (United States)

Wang, Zhong-Xu; Qin, Ru-Li; Li, Yu-Zhen; Zhang, Xue-Yan; Jia, Ning; Zhang, Qiu-Ling; Li, Gang; Zhao, Jie; Li, Huan-Huan; Jiang, Hai-Qiang

2011-08-01

To investigate the work-related musculoskeletal disorders among automobile assembly workers, to discusses the related risk factors and their relationship. The selected 1508 automobile assembly workers from a north car manufacturing company were regarded as the study object. The hazard zone jobs checklist, Nordic musculoskeletal symptom questionnaire (NMQ) and pain questionnaire were used to perform the epidemiological cross-sectional and retrospective survey and study for the General status, awkward ergonomics factors and related influencing factors, and musculoskeletal disorders of workers. The predominant body sites of occurring WMSDs among automobile assembly workers were mainly low back, wrist, neck and shoulders, the predominant workshop section of occurring WMSDs were mostly concentrated in engine compartment, interior ornament, door cover, chassis and debugging section. The predominant body site of WMSDs among engine compartment and chassis section workers was low back, interior ornament workers were low back and wrist, door cover workers was wrist, chassis workers was low back, debugging workers were neck and low back. Neck musculoskeletal disorders had the trend with the increase of a body height; Smoking may increase the occurrence of musculoskeletal disorders. The WMSDs appears to be a serious ergonomic proble assem among automobile assembly workers, predominant occurring site of WMSDs is with different workshop section, its characteristics is quite obvious, probably related to its existing awkward work position or activities. The worker height and smoking habits may be important factors which affect musculoskeletal disorders happen.

Voice disorders in teachers and their associations with work-related factors: a systematic review.

Science.gov (United States)

Cantor Cutiva, Lady Catherine; Vogel, Ineke; Burdorf, Alex

2013-01-01

To provide a quantitative assessment of the occurrence of voice disorders among teachers and to identify associated work-related and individual factors in the teaching profession. A systematic review was conducted using three computerized databases on the occurrence of voice disorders among teachers and their associations with work-related and individual factors. Some of the keywords used were: "teacher", "voice disorder", "voice problem", and "dysphonia". Information regarding the occurrence of voice disorders and associations between work-related and individual factors and voice disorders were extracted from each paper. Occurrence and associations were expressed in prevalence and odds ratios, respectively. In total, 23 publications met the criteria for inclusion. All publications were cross-sectional studies. Prevalence estimates varied widely, reflecting disparity in definitions of "voice problem". Teachers had a significantly increased occurrence of voice disorders compared to other occupations. Several work-related and individual factors were consistently associated with voice disorders, most notably high levels of noise in classrooms, being a physical education instructor, and habitual use of a loud speaking voice. This review shows that teachers report voice disorders more often than non-teachers. Various work-related and individual factors are associated with reported voice disorders. Longitudinal studies are urgently required to get more insight into the development of voice disorders, their work-related determinants, and the consequences of these voice disorders for functioning and work performance among teachers. Describe the occurrence of voice disorders among teachers. Identify some work-related factors of voice disorders among teachers. Interpret the quality of the publications to describe or analyze the relationship between working conditions and voice disorders among teachers. Copyright © 2013 Elsevier Inc. All rights reserved.

The role of metals in protein conformational disorders - The case of prion protein and Aβ -peptide

International Nuclear Information System (INIS)

De Santis, E; Minicozzi, V; Morante, S; Rossi, G C; Stellato, F

2016-01-01

Protein conformational disorders are members of a vast class of pathologies in which endogenous proteins or peptides undergo a misfolding process by switching from the physiological soluble configuration to a pathological fibrillar insoluble state. An important, but not yet fully elucidated, role in the process appears to be played by transition metal ions, mainly copper and zinc. X-ray absorption spectroscopy is one of the most suitable techniques for the structural characterization of biological molecules in complex with metal. Owing to its chemical selectivity and sensitivity to the local atomic geometry around the absorber, it can be successfully used to study the environment of metal ions in complex with proteins and peptides in physiological conditions. In this paper we present X-ray absorption spectroscopy studies of the metal ions coordination modes in systems where metals are complexed with specific amyloidogenic proteins and peptides. In particular, we show results concerning the Amyloid β peptide, that is involved in Alzheimer's disease, and the Prion protein, that is responsible for the Transmissible Spongiform Encephalopathy. Our findings suggest that the copper and zinc ions may play a crucial role in the aggregation and fibril formation process of these two biomolecules. Elucidating this kind of interaction could be a key preliminary step before any viable therapy can be conceived or designed. (paper)

The role of metals in protein conformational disorders - The case of prion protein and Aβ -peptide

Science.gov (United States)

De Santis, E.; Minicozzi, V.; Morante, S.; Rossi, G. C.; Stellato, F.

2016-02-01

Protein conformational disorders are members of a vast class of pathologies in which endogenous proteins or peptides undergo a misfolding process by switching from the physiological soluble configuration to a pathological fibrillar insoluble state. An important, but not yet fully elucidated, role in the process appears to be played by transition metal ions, mainly copper and zinc. X-ray absorption spectroscopy is one of the most suitable techniques for the structural characterization of biological molecules in complex with metal. Owing to its chemical selectivity and sensitivity to the local atomic geometry around the absorber, it can be successfully used to study the environment of metal ions in complex with proteins and peptides in physiological conditions. In this paper we present X-ray absorption spectroscopy studies of the metal ions coordination modes in systems where metals are complexed with specific amyloidogenic proteins and peptides. In particular, we show results concerning the Amyloid β peptide, that is involved in Alzheimer's disease, and the Prion protein, that is responsible for the Transmissible Spongiform Encephalopathy. Our findings suggest that the copper and zinc ions may play a crucial role in the aggregation and fibril formation process of these two biomolecules. Elucidating this kind of interaction could be a key preliminary step before any viable therapy can be conceived or designed.

Annotating activation/inhibition relationships to protein-protein interactions using gene ontology relations.

Science.gov (United States)

Yim, Soorin; Yu, Hasun; Jang, Dongjin; Lee, Doheon

2018-04-11

Signaling pathways can be reconstructed by identifying 'effect types' (i.e. activation/inhibition) of protein-protein interactions (PPIs). Effect types are composed of 'directions' (i.e. upstream/downstream) and 'signs' (i.e. positive/negative), thereby requiring directions as well as signs of PPIs to predict signaling events from PPI networks. Here, we propose a computational method for systemically annotating effect types to PPIs using relations between functional information of proteins. We used regulates, positively regulates, and negatively regulates relations in Gene Ontology (GO) to predict directions and signs of PPIs. These relations indicate both directions and signs between GO terms so that we can project directions and signs between relevant GO terms to PPIs. Independent test results showed that our method is effective for predicting both directions and signs of PPIs. Moreover, our method outperformed a previous GO-based method that did not consider the relations between GO terms. We annotated effect types to human PPIs and validated several highly confident effect types against literature. The annotated human PPIs are available in Additional file 2 to aid signaling pathway reconstruction and network biology research. We annotated effect types to PPIs by using regulates, positively regulates, and negatively regulates relations in GO. We demonstrated that those relations are effective for predicting not only signs, but also directions of PPIs. The usefulness of those relations suggests their potential applications to other types of interactions such as protein-DNA interactions.

Haptoglobin-related protein is a high-affinity hemoglobin-binding plasma protein

DEFF Research Database (Denmark)

Nielsen, Marianne Jensby; Petersen, Steen Vang; Jacobsen, Christian

2006-01-01

Haptoglobin-related protein (Hpr) is a primate-specific plasma protein associated with apolipoprotein L-I (apoL-I)-containing high-density lipoprotein (HDL) particles shown to be a part of the innate immune defense. Despite the assumption hitherto that Hpr does not bind to hemoglobin, the present...

DNA origami scaffold for studying intrinsically disordered proteins of the nuclear pore complex

NARCIS (Netherlands)

Ketterer, Philip; Ananth, A.N.; Laman Trip, J.D.S.; Mishra, Ankur; Bertosin, Eva; Ganji, M.; van der Torre, J.; Onck, Patrick; Dietz, Hendrik; Dekker, C.

2018-01-01

The nuclear pore complex (NPC) is the gatekeeper for nuclear transport in eukaryotic cells. A key component of the NPC is the central shaft lined with intrinsically disordered proteins (IDPs) known as FG-Nups, which control the selective molecular traffic. Here, we present an approach to realize

Prevalence of interpersonal trauma exposure and trauma-related disorders in severe mental illness

Directory of Open Access Journals (Sweden)

Maria W. Mauritz

2013-04-01

Full Text Available Background: Interpersonal trauma exposure and trauma-related disorders in people with severe mental illness (SMI are often not recognized in clinical practice. Objective: To substantiate the prevalence of interpersonal trauma exposure and trauma-related disorders in people with SMI. Methods: We conducted a systematic review of four databases (1980–2010 and then described and analysed 33 studies in terms of primary diagnosis and instruments used to measure trauma exposure and trauma-related disorders. Results: Population-weighted mean prevalence rates in SMI were physical abuse 47% (range 25–72%, sexual abuse 37% (range 24–49%, and posttraumatic stress disorder (PTSD 30% (range 20–47%. Compared to men, women showed a higher prevalence of sexual abuse in schizophrenia spectrum disorder, bipolar disorder, and mixed diagnosis groups labelled as having SMI. Conclusions: Prevalence rates of interpersonal trauma and trauma-related disorders were significantly higher in SMI than in the general population. Emotional abuse and neglect, physical neglect, complex PTSD, and dissociative disorders have been scarcely examined in SMI.

[Actigraphy in Bipolar Disorder and First Degree Relatives].

Science.gov (United States)

Andrade Carrillo, Rommel; Gómez Cano, Sujey; Palacio Ortiz, Juan David; García Valencia, Jenny

2015-01-01

Bipolar disorder is a disabling disease that involves a significant economic costs to the health system, making it is essential to investigate possible early predictors such as changes in sleep-wake cycle in high-risk populations. To review the available literature on alterations in the sleep-wake cycle and circadian rhythm in patients with bipolar disorder and their first degree relatives. A literature search was performed in the data bases, Access Medicine, ClinicalKey, EMBASE, JAMA, Lilacs, OVID, Oxford Journals, ScienceDirect, SciELO, APA y PsycNET. Articles in both English and Spanish were reviewed, without limits by study type. Actigraphy is a non-invasive, useful method for assessing sleep-wake cycle disturbances in the active phases of bipolar disorder, and during euthymia periods. Actigraphy showed good sensitivity to predict true sleep, but low specificity, compared with polysomnography. Although studies in bipolar offspring and relatives are scarce, they show sleep changes similar to bipolar patients. Actigraphy may be a good screening tool of sleep/wake cycle in patients with bipolar disorders, because it is economic, non-invasive and sensitive. Longitudinal studies are required to evaluate its potential use as a risk marker. Copyright © 2014 Asociación Colombiana de Psiquiatría. Publicado por Elsevier España. All rights reserved.

Intrinsically disordered regions may lower the hydration free energy in proteins: a case study of nudix hydrolase in the bacterium Deinococcus radiodurans.

Directory of Open Access Journals (Sweden)

Omar Awile

Full Text Available The proteome of the radiation- and desiccation-resistant bacterium D. radiodurans features a group of proteins that contain significant intrinsically disordered regions that are not present in non-extremophile homologues. Interestingly, this group includes a number of housekeeping and repair proteins such as DNA polymerase III, nudix hydrolase and rotamase. Here, we focus on a member of the nudix hydrolase family from D. radiodurans possessing low-complexity N- and C-terminal tails, which exhibit sequence signatures of intrinsic disorder and have unknown function. The enzyme catalyzes the hydrolysis of oxidatively damaged and mutagenic nucleotides, and it is thought to play an important role in D. radiodurans during the recovery phase after exposure to ionizing radiation or desiccation. We use molecular dynamics simulations to study the dynamics of the protein, and study its hydration free energy using the GB/SA formalism. We show that the presence of disordered tails significantly decreases the hydration free energy of the whole protein. We hypothesize that the tails increase the chances of the protein to be located in the remaining water patches in the desiccated cell, where it is protected from the desiccation effects and can function normally. We extrapolate this to other intrinsically disordered regions in proteins, and propose a novel function for them: intrinsically disordered regions increase the "surface-properties" of the folded domains they are attached to, making them on the whole more hydrophilic and potentially influencing, in this way, their localization and cellular activity.

Relative quantification of protein-protein interactions using a dual luciferase reporter pull-down assay system.

Directory of Open Access Journals (Sweden)

Shuaizheng Jia

Full Text Available The identification and quantitative analysis of protein-protein interactions are essential to the functional characterization of proteins in the post-proteomics era. The methods currently available are generally time-consuming, technically complicated, insensitive and/or semi-quantitative. The lack of simple, sensitive approaches to precisely quantify protein-protein interactions still prevents our understanding of the functions of many proteins. Here, we develop a novel dual luciferase reporter pull-down assay by combining a biotinylated Firefly luciferase pull-down assay with a dual luciferase reporter assay. The biotinylated Firefly luciferase-tagged protein enables rapid and efficient isolation of a putative Renilla luciferase-tagged binding protein from a relatively small amount of sample. Both of these proteins can be quantitatively detected using the dual luciferase reporter assay system. Protein-protein interactions, including Fos-Jun located in the nucleus; MAVS-TRAF3 in cytoplasm; inducible IRF3 dimerization; viral protein-regulated interactions, such as MAVS-MAVS and MAVS-TRAF3; IRF3 dimerization; and protein interaction domain mapping, are studied using this novel assay system. Herein, we demonstrate that this dual luciferase reporter pull-down assay enables the quantification of the relative amounts of interacting proteins that bind to streptavidin-coupled beads for protein purification. This study provides a simple, rapid, sensitive, and efficient approach to identify and quantify relative protein-protein interactions. Importantly, the dual luciferase reporter pull-down method will facilitate the functional determination of proteins.

Effects of nitrogen and irrigation on gluten protein composition and their relationship to yellow berry disorder in wheat (triticum aestivum)

International Nuclear Information System (INIS)

Wong, B.R.; Felix, F.R.; Chavez, T

2014-01-01

In Mexico and the rest of the world, the presence of yellow berry (YB) in wheat grains (Triticum aestivum) has been related with poor quality, this defect is associated with low protein content in the grains. However, the quality of the wheat depends not only on the protein content, but also on the composition of the gluten proteins. The effect of the various agronomic factors on the composition of wheat gluten has been a subject of study worldwide. However, in Mexico, wheat quality still remains an issue, as there is a lack of knowledge regarding the optimal agronomic conditions to produce wheat with good-quality gluten. For this reason, the effects of nitrogen (N) rates and irrigations on the amount of gliadin subclasses, glutenin subunits (two main groups) and grain protein content as well as the relation of these proteins to the YB content in wheat grains were investigated. The experiment was conducted on arable farmland in the Valley of Empalme, Sonora, Mexico (27 degree 58' N, 110 degree 49' W; 10 m altitude), during the fall-winter period of 2009-2010. Tarachi, the hard wheat cultivar studied, was selected for its relative susceptibility to the presence of elevated YB content in mature wheat kernels. Three levels of N (75, 150 or 250 kg ha-1) and three levels of irrigation (1, 2 or 3 auxiliary irrigations) were studied. Using a N rate of 150 kg ha-1 with 3 auxiliary irrigations, wheat with good-quality gluten was obtained. The results suggest that the YB disorder is primarily related to the amount of protein in the wheat grain. (author)

Actin, actin-binding proteins, and actin-related proteins in the nucleus.

Science.gov (United States)

Kristó, Ildikó; Bajusz, Izabella; Bajusz, Csaba; Borkúti, Péter; Vilmos, Péter

2016-04-01

Extensive research in the past decade has significantly broadened our view about the role actin plays in the life of the cell and added novel aspects to actin research. One of these new aspects is the discovery of the existence of nuclear actin which became evident only recently. Nuclear activities including transcriptional activation in the case of all three RNA polymerases, editing and nuclear export of mRNAs, and chromatin remodeling all depend on actin. It also became clear that there is a fine-tuned equilibrium between cytoplasmic and nuclear actin pools and that this balance is ensured by an export-import system dedicated to actin. After over half a century of research on conventional actin and its organizing partners in the cytoplasm, it was also an unexpected finding that the nucleus contains more than 30 actin-binding proteins and new classes of actin-related proteins which are not able to form filaments but had evolved nuclear-specific functions. The actin-binding and actin-related proteins in the nucleus have been linked to RNA transcription and processing, nuclear transport, and chromatin remodeling. In this paper, we attempt to provide an overview of the wide range of information that is now available about actin, actin-binding, and actin-related proteins in the nucleus.

DMPD: Protein kinase C epsilon: a new target to control inflammation andimmune-mediated disorders. [Dynamic Macrophage Pathway CSML Database

Lifescience Database Archive (English)

Full Text Available 14643884 Protein kinase C epsilon: a new target to control inflammation andimmune-m...g) (.html) (.csml) Show Protein kinase C epsilon: a new target to control inflammation andimmune-mediated di...sorders. PubmedID 14643884 Title Protein kinase C epsilon: a new target to contro

Structure and stability insights into tumour suppressor p53 evolutionary related proteins.

Directory of Open Access Journals (Sweden)

Bruno Pagano

Full Text Available The p53 family of genes and their protein products, namely, p53, p63 and p73, have over one billion years of evolutionary history. Advances in computational biology and genomics are enabling studies of the complexities of the molecular evolution of p53 protein family to decipher the underpinnings of key biological conditions spanning from cancer through to various metabolic and developmental disorders and facilitate the design of personalised medicines. However, a complete understanding of the inherent nature of the thermodynamic and structural stability of the p53 protein family is still lacking. This is due, to a degree, to the lack of comprehensive structural information for a large number of homologous proteins and to an incomplete knowledge of the intrinsic factors responsible for their stability and how these might influence function. Here we investigate the thermal stability, secondary structure and folding properties of the DNA-binding domains (DBDs of a range of proteins from the p53 family using biophysical methods. While the N- and the C-terminal domains of the p53 family show sequence diversity and are normally targets for post-translational modifications and alternative splicing, the central DBD is highly conserved. Together with data obtained from Molecular Dynamics simulations in solution and with structure based homology modelling, our results provide further insights into the molecular properties of evolutionary related p53 proteins. We identify some marked structural differences within the p53 family, which could account for the divergence in biological functions as well as the subtleties manifested in the oligomerization properties of this family.

[Obesity-related metabolic disorders in childhood and adolescence].

Science.gov (United States)

Yeste, D; Carrascosa, A

2011-08-01

Obesity is the most frequent nutritional disorder in childhood and adolescence. The rise in its prevalence and severity has underlined the numerous and significant obesity-related metabolic disorders. Altered glucose metabolism, manifested as impaired glucose tolerance, appears early in severely obese children and adolescents. Obese young people with glucose intolerance are characterized by marked peripheral insulin resistance and relative beta-cell failure. Lipid deposition in muscle and the visceral compartment, and not only obesity per se, is related to increased peripheral insulin resistance, the triggering factor of the metabolic syndrome. Other elements of the metabolic syndrome, such as dyslipidaemia, and hypertension, are already present in obese youngsters and worsen with the degree of obesity. The long-term impact of obesity-related insulin resistance on cardiovascular morbidity in these patients is expected to emerge as these youngsters become young adults. Copyright © 2011 Asociación Española de Pediatría. Published by Elsevier Espana. All rights reserved.

High-resolution ultrasonography in assessment of nail-related disorders.

Science.gov (United States)

Singh, R; Bryson, D; Singh, H P; Jeyapalan, K; Dias, J J

2012-09-01

Disorders of the nail can pose a diagnostic challenge, and non-invasive imaging is frequently required to clarify diagnosis and delineate anatomy pre-operatively. We explored the use of high-resolution ultrasonography in the assessment of patients with nail disorders attending orthopaedic hand clinics. A search of a university teaching hospital musculoskeletal radiology database identified 36 patients (mean age 54.2 years) where ultrasonography was used to assess nail-related disorders between April 2003 and January 2007. Clinical, surgical and histological findings were correlated in these cases with ultrasound reports. Ultrasound findings correlated with the provisional diagnosis in 20 (61%) of 33 patients and provided a diagnosis in 3 patients where a provisional diagnosis was unavailable. In 7 of the 13 cases where the clinical diagnosis differed from ultrasound findings, a lump originally diagnosed as cystic in origin was shown to be solid on ultrasound. Different nail pathologies showed different characteristics on ultrasonography, including differences in vascularity, echogenicity, changes in nail structure/shape and extension into the nail bed, matrix, fold or evidence of bony erosion. The ultrasound findings correlated with histological analysis and intra-operative assessment in 10 of 15 patients who underwent operative treatment. Ultrasound provides important information on the anatomy of the nail apparatus and can differentiate solid and cystic lesions. It can be used as a diagnostic tool and can therefore help in pre-operative planning of nail-related disorders. In our series ultrasound supported or improved upon the clinical diagnosis in 31 (86%) out of the 36 patients presenting with nail-related disorders.

Limbic system associated membrane protein as a potential target for neuropsychiatric disorders

Directory of Open Access Journals (Sweden)

Eero eVasar

2013-03-01

Full Text Available The studies performed in laboratory animals and psychiatric patients suggest a possible role of limbic system associated membrane protein (LAMP in the mechanisms of psychiatric disorders. Stressful manipulations and genetic invalidation have revealed a role of the Lsamp gene in the regulation of anxiety in rodents. Besides that, Lsamp deficient mice display reduced aggressiveness and impaired adaptation in novel and stressful environments. The behavioural effects of amphetamine were blunted in genetically modified mice. Recent pharmacological and biochemical studies point towards altered function of GABA-, 5-hydroxytryptamine- and dopaminergic systems in Lsamp deficient mice. Moreover, we found an association between the gene polymorphisms of LSAMP and major depressive disorder. Patients suffering from major depressive disorder had significantly increased ratio between risk and protective haplotypes of the LSAMP gene compared to healthy volunteers. However, the impact of these haplotypes for the function of LAMP is not clear and remains to be elucidated in future studies.

MERA: a webserver for evaluating backbone torsion angle distributions in dynamic and disordered proteins from NMR data

Energy Technology Data Exchange (ETDEWEB)

Mantsyzov, Alexey B. [M.V. Lomonosov Moscow State University, Faculty of Fundamental Medicine (Russian Federation); Shen, Yang; Lee, Jung Ho [National Institutes of Health, Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases (United States); Hummer, Gerhard [Max Planck Institute of Biophysics (Germany); Bax, Ad, E-mail: bax@nih.gov [National Institutes of Health, Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases (United States)

2015-09-15

MERA (Maximum Entropy Ramachandran map Analysis from NMR data) is a new webserver that generates residue-by-residue Ramachandran map distributions for disordered proteins or disordered regions in proteins on the basis of experimental NMR parameters. As input data, the program currently utilizes up to 12 different parameters. These include three different types of short-range NOEs, three types of backbone chemical shifts ({sup 15}N, {sup 13}C{sup α}, and {sup 13}C′), six types of J couplings ({sup 3}J{sub HNHα}, {sup 3}J{sub C′C′}, {sup 3}J{sub C′Hα}, {sup 1}J{sub HαCα}, {sup 2}J{sub CαN} and {sup 1}J{sub CαN}), as well as the {sup 15}N-relaxation derived J(0) spectral density. The Ramachandran map distributions are reported in terms of populations of their 15° × 15° voxels, and an adjustable maximum entropy weight factor is available to ensure that the obtained distributions will not deviate more from a newly derived coil library distribution than required to account for the experimental data. MERA output includes the agreement between each input parameter and its distribution-derived value. As an application, we demonstrate performance of the program for several residues in the intrinsically disordered protein α-synuclein, as well as for several static and dynamic residues in the folded protein GB3.

Mechanisms of comorbidity, continuity, and discontinuity in anxiety-related disorders.

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McNaughton, Neil; Corr, Philip J

2016-11-01

We discuss comorbidity, continuity, and discontinuity of anxiety-related disorders from the perspective of a two-dimensional neuropsychology of fear (threat avoidance) and anxiety (threat approach). Pharmacological dissection of the "neurotic" disorders justifies both a categorical division between fear and anxiety and a subdivision of each mapped to a hierarchy of neural modules that process different immediacies of threat. It is critical that each module can generate normal responses, symptoms of another syndrome, or syndromal responses. We discuss the resultant possibilities for comorbid dysfunction of these modules both with each other and with some disorders not usually classified as anxiety related. The simplest case is symptomatic fear/anxiety comorbidity, where dysfunction in one module results in excess activity in a second, otherwise normal, module to generate symptoms and apparent comorbidity. More complex is syndromal fear/anxiety comorbidity, where more than one module is concurrently dysfunctional. Yet more complex are syndromal comorbidities of anxiety that go beyond the two dimensional fear/anxiety systems: depression, substance use disorder, and attention-deficit/hyperactivity disorder. Our account of attention-deficit/hyperactivity disorder-anxiety comorbidity entails discussion of the neuropsychology of externalizing disorders to account for the lack of anxiety comorbidity in some of these. Finally, we link the neuropsychology of disorder to personality variation, and to the development of a biomarker of variation in the anxiety system among individuals that, if extreme, may provide a means of unambiguously identifying the first of a range of anxiety syndromes.

Compulsivity-related neurocognitive performance deficits in gambling disorder: A systematic review and meta-analysis.

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van Timmeren, Tim; Daams, Joost G; van Holst, Ruth J; Goudriaan, Anna E

2018-01-01

Compulsivity is a core feature of addictive disorders, including gambling disorder. However, it is unclear to what extent this compulsive behavior in gambling disorder is associated with abnormal compulsivity-related neurocognitive functioning. Here, we summarize and synthesize the evidence for compulsive behavior, as assessed by compulsivity-related neurocognitive tasks, in individuals with gambling disorder compared to healthy controls (HCs). A total of 29 studies, comprising 41 task-results, were included in the systematic review; 32 datasets (n=1072 individuals with gambling disorder; n=1312 HCs) were also included in the meta-analyses, conducted for each cognitive task separately. Our meta-analyses indicate significant deficits in individuals with gambling disorder in cognitive flexibility, attentional set-shifting, and attentional bias. Overall, these findings support the idea that compulsivity-related performance deficits characterize gambling disorder. This association may provide a possible link between impairments in executive functions related to compulsive action. We discuss the practical relevance of these results, their implications for our understanding of gambling disorder and how they relate to neurobiological factors and other 'disorders of compulsivity'. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Sleep-Related Eating Disorder: A Case Report of a Progressed Night Eating Syndrome

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Sayed Shahabuddin Hoseini

2012-07-01

Full Text Available Night eating syndrome is a common disorder in eating behaviors that occurs in close relation to the night time sleep cycle. Although eating disorders are common in society, night eating syndrome has been left neglected by health care professionals. In this report we present a case of eating disorder that exhibits some novel features of night eating syndrome. Our case was a progressed type of eating disorder which may increase awareness among physicians about sleep-related eating disorders.

Impulse control and related disorders in Mexican Parkinson's disease patients.

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Rodríguez-Violante, Mayela; González-Latapi, Paulina; Cervantes-Arriaga, Amin; Camacho-Ordoñez, Azyadeh; Weintraub, Daniel

2014-08-01

Impulse control disorders (ICDs) are a relatively recent addition to the behavioral spectrum of PD-related non-motor symptoms. Social and economic factors may play a role on the ICD phenotype of PD patients. The aim of this study is to determine the prevalence and characterize the clinical profile of ICDs in a sample of low-income, low-education PD patients with no social security benefits from a Latin American country. We included 300 consecutive PD patients and 150 control subjects. The presence of ICD and related disorders was assessed using a structured interview. After the interview and neurological evaluation were concluded, all subjects completed the Questionnaire for Impulsive-compulsive Disorders in Parkinson's Disease-Rating Scale (QUIP-RS). Regarding ICDs and related disorders (hobbyism-punding), 25.6% (n = 77) of patients in the PD group and 16.6% (n = 25) in the control group fulfilled criteria for at least one ICD or related disorder (p = 0.032). There was a statistically significant difference in the QUIP-RS mean score between PD and control subjects (5.6 ± 9.7 and 2.7 ± 4.21, p = 0.001). The most common ICD was compulsive eating for both PD (8.6%) and control (2.6%) groups. The results of this study confirm that for this population, symptoms of an ICD are significantly more frequent in PD subjects than in control subjects. Nevertheless, socioeconomic differences may contribute to a lower overall frequency and distinct pattern of ICDs in PD patients compared with what has been reported in other countries. Copyright © 2014 Elsevier Ltd. All rights reserved.

The clinical expression of hereditary protein C and protein S deficiency: : a relation to clinical thrombotic risk-factors and to levels of protein C and protein S

NARCIS (Netherlands)

Henkens, C. M. A.; van der Meer, J.; Hillege, J. L.; Bom, V. J. J.; Halie, M. R.; van der Schaaf, W.

We investigated 103 first-degree relatives of 13 unrelated protein C or protein S deficient patients to assess the role of additional thrombotic risk factors and of protein C and protein S levels in the clinical expression of hereditary protein C and protein S deficiency. Fifty-seven relatives were

Understanding HIV-related posttraumatic stress disorder in South ...

African Journals Online (AJOL)

A number of epidemiological studies have attempted to measure the prevalence of HIV-related posttraumatic stress disorder (PTSD) in sub-Saharan Africa. A systematic review of the literature identified eight relevant studies that put current estimates of the prevalence of HIV-related PTSD between 4.2% and 40%. Even the ...

Axon guidance pathways served as common targets for human speech/language evolution and related disorders.

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Lei, Huimeng; Yan, Zhangming; Sun, Xiaohong; Zhang, Yue; Wang, Jianhong; Ma, Caihong; Xu, Qunyuan; Wang, Rui; Jarvis, Erich D; Sun, Zhirong

2017-11-01

Human and several nonhuman species share the rare ability of modifying acoustic and/or syntactic features of sounds produced, i.e. vocal learning, which is the important neurobiological and behavioral substrate of human speech/language. This convergent trait was suggested to be associated with significant genomic convergence and best manifested at the ROBO-SLIT axon guidance pathway. Here we verified the significance of such genomic convergence and assessed its functional relevance to human speech/language using human genetic variation data. In normal human populations, we found the affected amino acid sites were well fixed and accompanied with significantly more associated protein-coding SNPs in the same genes than the rest genes. Diseased individuals with speech/language disorders have significant more low frequency protein coding SNPs but they preferentially occurred outside the affected genes. Such patients' SNPs were enriched in several functional categories including two axon guidance pathways (mediated by netrin and semaphorin) that interact with ROBO-SLITs. Four of the six patients have homozygous missense SNPs on PRAME gene family, one youngest gene family in human lineage, which possibly acts upon retinoic acid receptor signaling, similarly as FOXP2, to modulate axon guidance. Taken together, we suggest the axon guidance pathways (e.g. ROBO-SLIT, PRAME gene family) served as common targets for human speech/language evolution and related disorders. Copyright © 2017 Elsevier Inc. All rights reserved.

A protein relational database and protein family knowledge bases to facilitate structure-based design analyses.

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Mobilio, Dominick; Walker, Gary; Brooijmans, Natasja; Nilakantan, Ramaswamy; Denny, R Aldrin; Dejoannis, Jason; Feyfant, Eric; Kowticwar, Rupesh K; Mankala, Jyoti; Palli, Satish; Punyamantula, Sairam; Tatipally, Maneesh; John, Reji K; Humblet, Christine

2010-08-01

The Protein Data Bank is the most comprehensive source of experimental macromolecular structures. It can, however, be difficult at times to locate relevant structures with the Protein Data Bank search interface. This is particularly true when searching for complexes containing specific interactions between protein and ligand atoms. Moreover, searching within a family of proteins can be tedious. For example, one cannot search for some conserved residue as residue numbers vary across structures. We describe herein three databases, Protein Relational Database, Kinase Knowledge Base, and Matrix Metalloproteinase Knowledge Base, containing protein structures from the Protein Data Bank. In Protein Relational Database, atom-atom distances between protein and ligand have been precalculated allowing for millisecond retrieval based on atom identity and distance constraints. Ring centroids, centroid-centroid and centroid-atom distances and angles have also been included permitting queries for pi-stacking interactions and other structural motifs involving rings. Other geometric features can be searched through the inclusion of residue pair and triplet distances. In Kinase Knowledge Base and Matrix Metalloproteinase Knowledge Base, the catalytic domains have been aligned into common residue numbering schemes. Thus, by searching across Protein Relational Database and Kinase Knowledge Base, one can easily retrieve structures wherein, for example, a ligand of interest is making contact with the gatekeeper residue.

Genetics Home Reference: FOXP2-related speech and language disorder

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... skills such as walking and tying shoelaces, and autism spectrum disorders, which are conditions characterized by impaired communication and social interaction. Related Information What does it mean if a disorder seems to run in my family? What is the prognosis of a genetic condition? ...

Bipolar and related disorders in DSM-5 and ICD-10.

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Kaltenboeck, Alexander; Winkler, Dietmar; Kasper, Siegfried

2016-08-01

Bipolar disorders are a group of psychiatric disorders with profound negative impact on affected patients. Even if their symptomatology has long been recognized, diagnostic criteria have changed over time and diagnosis often remains difficult. The Fifth Edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), issued in May 2013, comprises several changes regarding the diagnosis of bipolar disorders compared to the previous edition. Diagnostic categories and criteria for bipolar disorders show some concordance with the internationally also widely used Tenth Edition of the International Statistical Classification of Diseases and Related Health Problems (ICD-10). However, there are also major differences that are worth highlighting. The aim of the following text is to depict and discuss those.

Personality, emotion-related variables, and media pressure predict eating disorders via disordered eating in Lebanese university students.

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Sanchez-Ruiz, Maria Jose; El-Jor, Claire; Abi Kharma, Joelle; Bassil, Maya; Zeeni, Nadine

2017-04-18

Disordered eating behaviors are on the rise among youth. The present study investigates psychosocial and weight-related variables as predictors of eating disorders (ED) through disordered eating (DE) dimensions (namely restrained, external, and emotional eating) in Lebanese university students. The sample consisted of 244 undergraduates (143 female) aged from 18 to 31 years (M = 20.06; SD = 1.67). Using path analysis, two statistical models were built separately with restrained and emotional eating as dependent variables, and all possible direct and indirect pathways were tested for mediating effects. The variables tested for were media influence, perfectionism, trait emotional intelligence, and the Big Five dimensions. In the first model, media pressure, self-control, and extraversion predicted eating disorders via emotional eating. In the second model, media pressure and perfectionism predicted eating disorders via restrained eating. Findings from this study provide an understanding of the dynamics between DE, ED, and key personality, emotion-related, and social factors in youth. Lastly, implications and recommendations for future studies are advanced.

Diseases and disorders of muscle.

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Pearson, A M; Young, R B

1993-01-01

Muscle may suffer from a number of diseases or disorders, some being fatal to humans and animals. Their management or treatment depends on correct diagnosis. Although no single method may be used to identify all diseases, recognition depends on the following diagnostic procedures: (1) history and clinical examination, (2) blood biochemistry, (3) electromyography, (4) muscle biopsy, (5) nuclear magnetic resonance, (6) measurement of muscle cross-sectional area, (7) tests of muscle function, (8) provocation tests, and (9) studies on protein turnover. One or all of these procedures may prove helpful in diagnosis, but even then identification of the disorder may not be possible. Nevertheless, each of these procedures can provide useful information. Among the most common diseases in muscle are the muscular dystrophies, in which the newly identified muscle protein dystrophin is either absent or present at less than normal amounts in both Duchenne and Becker's muscular dystrophy. Although the identification of dystrophin represents a major breakthrough, treatment has not progressed to the experimental stage. Other major diseases of muscle include the inflammatory myopathies and neuropathies. Atrophy and hypertrophy of muscle and the relationship of aging, exercise, and fatigue all add to our understanding of the behavior of normal and abnormal muscle. Some other interesting related diseases and disorders of muscle include myasthenia gravis, muscular dysgenesis, and myclonus. Disorders of energy metabolism include those caused by abnormal glycolysis (Von Gierke's, Pompe's, Cori-Forbes, Andersen's, McArdle's, Hers', and Tauri's diseases) and by the acquired diseases of glycolysis (disorders of mitochondrial oxidation). Still other diseases associated with abnormal energy metabolism include lipid-related disorders (carnitine and carnitine palmitoyl-transferase deficiencies) and myotonic syndromes (myotonia congenita, paramyotonia congenita, hypokalemic and hyperkalemic

Markers of neuroinflammation and neuronal injury in bipolar disorder: Relation to prospective clinical outcomes.

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Isgren, Anniella; Sellgren, Carl; Ekman, Carl-Johan; Holmén-Larsson, Jessica; Blennow, Kaj; Zetterberg, Henrik; Jakobsson, Joel; Landén, Mikael

2017-10-01

Neuroimmune mechanisms have been linked to the pathophysiology of bipolar disorder based on studies of biomarkers in plasma, cerebrospinal fluid (CSF), and postmortem brain tissue. There are, however, no longitudinal studies investigating if CSF markers of neuroinflammation and neuronal injury predict clinical outcomes in patients with bipolar disorder. We have in previous studies found higher CSF concentrations of interleukin-8 (IL-8), monocyte chemoattractant protein 1 (MCP-1/CCL-2), chitinase-3-like protein 1 (CHI3L1/YKL-40), and neurofilament light chain (NF-L) in euthymic patients with bipolar disorder compared with controls. Here, we investigated the relationship of these CSF markers of neuroinflammation and neuronal injury with clinical outcomes in a prospective study. 77 patients with CSF analyzed at baseline were followed for 6-7years. Associations of baseline biomarkers with clinical outcomes (manic/hypomanic and depressive episodes, suicide attempts, psychotic symptoms, inpatient care, GAF score change) were investigated. Baseline MCP-1 concentrations were positively associated with manic/hypomanic episodes and inpatient care during follow-up. YKL-40 concentrations were negatively associated with manic/hypomanic episodes and with occurrence of psychotic symptoms. The prospective negative association between YKL-40 and manic/hypomanic episodes survived multiple testing correction. Concentrations of IL-8 and NF-L were not associated with clinical outcomes. High concentrations of these selected CSF markers of neuroinflammation and neuronal injury at baseline were not consistently associated with poor clinical outcomes in this prospective study. The assessed proteins may be involved in adaptive immune processes or reflect a state of vulnerability for bipolar disorder rather than being of predictive value for disease progression. Copyright © 2017 Elsevier Inc. All rights reserved.

State-related differences in heart rate variability in bipolar disorder

DEFF Research Database (Denmark)

Faurholt-Jepsen, Maria; Brage, Søren; Kessing, Lars Vedel

2017-01-01

Heart rate variability (HRV) is a validated measure of sympato-vagal balance in the autonomic nervous system. HRV appears decreased in patients with bipolar disorder (BD) compared with healthy individuals, but the extent of state-related alterations has been sparingly investigated. The present...... bipolar disorder and could...

Multiple-Localization and Hub Proteins

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Ota, Motonori; Gonja, Hideki; Koike, Ryotaro; Fukuchi, Satoshi

2016-01-01

Protein-protein interactions are fundamental for all biological phenomena, and protein-protein interaction networks provide a global view of the interactions. The hub proteins, with many interaction partners, play vital roles in the networks. We investigated the subcellular localizations of proteins in the human network, and found that the ones localized in multiple subcellular compartments, especially the nucleus/cytoplasm proteins (NCP), the cytoplasm/cell membrane proteins (CMP), and the nucleus/cytoplasm/cell membrane proteins (NCMP), tend to be hubs. Examinations of keywords suggested that among NCP, those related to post-translational modifications and transcription functions are the major contributors to the large number of interactions. These types of proteins are characterized by a multi-domain architecture and intrinsic disorder. A survey of the typical hub proteins with prominent numbers of interaction partners in the type revealed that most are either transcription factors or co-regulators involved in signaling pathways. They translocate from the cytoplasm to the nucleus, triggered by the phosphorylation and/or ubiquitination of intrinsically disordered regions. Among CMP and NCMP, the contributors to the numerous interactions are related to either kinase or ubiquitin ligase activity. Many of them reside on the cytoplasmic side of the cell membrane, and act as the upstream regulators of signaling pathways. Overall, these hub proteins function to transfer external signals to the nucleus, through the cell membrane and the cytoplasm. Our analysis suggests that multiple-localization is a crucial concept to characterize groups of hub proteins and their biological functions in cellular information processing. PMID:27285823

Biophysical characterization of the structural change of Nopp140, an intrinsically disordered protein, in the interaction with CK2α

International Nuclear Information System (INIS)

Na, Jung-Hyun; Lee, Won-Kyu; Kim, Yuyoung; Jeong, Cherlhyun; Song, Seung Soo; Cha, Sun-Shin; Han, Kyou-Hoon; Shin, Yeon-Kyun; Yu, Yeon Gyu

2016-01-01

Nucleolar phosphoprotein 140 (Nopp140) is a nucleolar protein, more than 80% of which is disordered. Previous studies have shown that the C-terminal region of Nopp140 (residues 568–596) interacts with protein kinase CK2α, and inhibits the catalytic activity of CK2. Although the region of Nopp140 responsible for the interaction with CK2α was identified, the structural features and the effect of this interaction on the structure of Nopp140 have not been defined due to the difficulty of structural characterization of disordered protein. In this study, the disordered feature of Nopp140 and the effect of CK2α on the structure of Nopp140 were examined using single-molecule fluorescence resonance energy transfer (smFRET) and electron paramagnetic resonance (EPR). The interaction with CK2α was increased conformational rigidity of the CK2α-interacting region of Nopp140 (Nopp140C), suggesting that the disordered and flexible conformation of Nopp140C became more rigid conformation as it binds to CK2α. In addition, site specific spin labeling and EPR analysis confirmed that the residues 574–589 of Nopp140 are critical for binding to CK2α. Similar technical approaches can be applied to analyze the conformational changes in other IDPs during their interactions with binding partners. - Highlights: • Nopp140 is intrinsically disordered protein (IDP). • Conformation of Nopp140 became more rigid conformation due to interaction with CK2α. • smFRET and EPR could be applied to analyze the structural changes of IDPs.

Biophysical characterization of the structural change of Nopp140, an intrinsically disordered protein, in the interaction with CK2α

Energy Technology Data Exchange (ETDEWEB)

Na, Jung-Hyun [Department of Chemistry, Kookmin University, Jeongneung-dong, Seongbuk-gu, Seoul 02707 (Korea, Republic of); Biomedical Research Institute, Korea Institute of Science and Technology, Seoul 02792 (Korea, Republic of); Department of Chemistry and Nano Science, Ewha Womans University, Seoul 03760 (Korea, Republic of); Lee, Won-Kyu [Department of Chemistry, Kookmin University, Jeongneung-dong, Seongbuk-gu, Seoul 02707 (Korea, Republic of); Kim, Yuyoung; Jeong, Cherlhyun [Biomedical Research Institute, Korea Institute of Science and Technology, Seoul 02792 (Korea, Republic of); Song, Seung Soo [Department of Chemistry, Kookmin University, Jeongneung-dong, Seongbuk-gu, Seoul 02707 (Korea, Republic of); Cha, Sun-Shin [Department of Chemistry and Nano Science, Ewha Womans University, Seoul 03760 (Korea, Republic of); Han, Kyou-Hoon [Division of Biosystems Research, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141 (Korea, Republic of); Shin, Yeon-Kyun [Biomedical Research Institute, Korea Institute of Science and Technology, Seoul 02792 (Korea, Republic of); Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University, Ames, IA 50011 (United States); Yu, Yeon Gyu, E-mail: ygyu@kookmin.ac.kr [Department of Chemistry, Kookmin University, Jeongneung-dong, Seongbuk-gu, Seoul 02707 (Korea, Republic of)

2016-08-19

Nucleolar phosphoprotein 140 (Nopp140) is a nucleolar protein, more than 80% of which is disordered. Previous studies have shown that the C-terminal region of Nopp140 (residues 568–596) interacts with protein kinase CK2α, and inhibits the catalytic activity of CK2. Although the region of Nopp140 responsible for the interaction with CK2α was identified, the structural features and the effect of this interaction on the structure of Nopp140 have not been defined due to the difficulty of structural characterization of disordered protein. In this study, the disordered feature of Nopp140 and the effect of CK2α on the structure of Nopp140 were examined using single-molecule fluorescence resonance energy transfer (smFRET) and electron paramagnetic resonance (EPR). The interaction with CK2α was increased conformational rigidity of the CK2α-interacting region of Nopp140 (Nopp140C), suggesting that the disordered and flexible conformation of Nopp140C became more rigid conformation as it binds to CK2α. In addition, site specific spin labeling and EPR analysis confirmed that the residues 574–589 of Nopp140 are critical for binding to CK2α. Similar technical approaches can be applied to analyze the conformational changes in other IDPs during their interactions with binding partners. - Highlights: • Nopp140 is intrinsically disordered protein (IDP). • Conformation of Nopp140 became more rigid conformation due to interaction with CK2α. • smFRET and EPR could be applied to analyze the structural changes of IDPs.

Spectral properties and scaling relations in off diagonally disordered chains

International Nuclear Information System (INIS)

Ure, J.E.; Majlis, N.

1987-07-01

We obtain the localization length L as a function of the energy E and the disorder width W for an off-diagonally disordered chain. This is done performing numerical simulations involving the continued fraction representations of the transfer matrix. The scaling relation L=W s is obtained with values of the exponent s in agreement with calculations of other authors. We also obtain the relation L ∼ |E| v for E → 0, and use it in the Herbert-Spencer-Thouless formula for L to describe the singularity of the density of states near E=0. We show that the slightest diagonal disorder obliterates this singularity. A practical method is presented to calculate the Green function by exploiting its continued fraction expansion. (author). 20 refs, 4 figs

Stress, glucocorticoids and memory: implications for treating fear-related disorders.

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de Quervain, Dominique; Schwabe, Lars; Roozendaal, Benno

2017-01-01

Glucocorticoid stress hormones are crucially involved in modulating mnemonic processing of emotionally arousing experiences. They enhance the consolidation of new memories, including those that extinguish older memories, but impair the retrieval of information stored in long-term memory. As strong aversive memories lie at the core of several fear-related disorders, including post-traumatic stress disorder and phobias, the memory-modulating properties of glucocorticoids have recently become of considerable translational interest. Clinical trials have provided the first evidence that glucocorticoid-based pharmacotherapies aimed at attenuating aversive memories might be helpful in the treatment of fear-related disorders. Here, we review important advances in the understanding of how glucocorticoids mediate stress effects on memory processes, and discuss the translational potential of these new conceptual insights.

Increased serum levels of high mobility group box 1 protein in patients with autistic disorder.

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Emanuele, Enzo; Boso, Marianna; Brondino, Natascia; Pietra, Stefania; Barale, Francesco; Ucelli di Nemi, Stefania; Politi, Pierluigi

2010-05-30

High mobility group box 1 (HMGB1) is a highly conserved, ubiquitous protein that functions as an activator for inducing the immune response and can be released from neurons after glutamate excitotoxicity. The objective of the present study was to measure serum levels of HMGB1 in patients with autistic disorder and to study their relationship with clinical characteristics. We enrolled 22 adult patients with autistic disorder (mean age: 28.1+/-7.7 years) and 28 age- and gender-matched healthy controls (mean age: 28.7+/-8.1 years). Serum levels of HMGB1 were measured by enzyme-linked immunosorbent assay (ELISA). Compared with healthy subjects, serum levels of HMGB1 were significantly higher in patients with autistic disorder (10.8+/-2.6 ng/mL versus 5.6+/-2.5 ng/mL, respectively, Pautistic disorder. Increased HMGB1 may be a biological correlate of the impaired reciprocal social interactions in this neurodevelopmental disorder. Copyright 2010 Elsevier Inc. All rights reserved.

Relations between protein production, protein quality and environmental factors in Pisum mutants

International Nuclear Information System (INIS)

Gottschalk, W.; Mueller, H.P.; Wolff, G.

1975-01-01

The seed protein content of 138 radiation-induced Pisum mutants was determined. The variability of this genetically well-defined material agrees approximately with that of the world collection of Pisum sativum. Some environmental factors to a great extent influence the protein production of the mutants and the initial line. Therefore, it is necessary to consider the relations between the genetically controlled protein production and its dependence upon the environmental factors. This is especially evident if the protein situation of the same genotypes cultivated under the moderate climatic conditions of middle Europe is compared with the subtropical conditions of India. A generally firm correlation between seed size and protein content could not be found in material regarding 148 different mutants of our assortment. Therefore, the selection of small-grained mutants does not result in a selection of protein-rich genotypes in Pisum sativum. Considering all the criteria positively and negatively influencing the protein production, a positive situation could be found in some mutants, especially in the fasciated ones. Furthermore, an improvement of the protein quality could be reached by a genetically conditioned alteration of the globulin-albumin ratio leading to an increase of some essential amino acids such as methionine and lysine. The combined action of mutant genes results in unexpected changes of the protein quantity as well as the quality of the recombinants in relation to their parental mutants. The comparison of some essential amino acids of our useful mutants with those of the varieties of other genera of the Leguminosae shows certain trends of biochemical alterations realized during evolutionary development of the family. (author)

Assisted reproductive technology (ART) treatment in women with schizophrenia or related psychotic disorder

DEFF Research Database (Denmark)

Ebdrup, Ninna H; Assens, Maria; Hougaard, Charlotte O

2014-01-01

To determine the prevalence rate of women with a diagnosis of schizophrenia or related psychotic disorder in assisted reproductive technology (ART) treatment and to study these women's fertility treatment outcome in comparison to women with no psychotic disorders.......To determine the prevalence rate of women with a diagnosis of schizophrenia or related psychotic disorder in assisted reproductive technology (ART) treatment and to study these women's fertility treatment outcome in comparison to women with no psychotic disorders....

Epidemic spreading model to characterize misfolded proteins propagation in aging and associated neurodegenerative disorders.

Science.gov (United States)

Iturria-Medina, Yasser; Sotero, Roberto C; Toussaint, Paule J; Evans, Alan C

2014-11-01

Misfolded proteins (MP) are a key component in aging and associated neurodegenerative disorders. For example, misfolded Amyloid-ß (Aß) and tau proteins are two neuropathogenic hallmarks of Alzheimer's disease. Mechanisms underlying intra-brain MP propagation/deposition remain essentially uncharacterized. Here, is introduced an epidemic spreading model (ESM) for MP dynamics that considers propagation-like interactions between MP agents and the brain's clearance response across the structural connectome. The ESM reproduces advanced Aß deposition patterns in the human brain (explaining 46∼56% of the variance in regional Aß loads, in 733 subjects from the ADNI database). Furthermore, this model strongly supports a) the leading role of Aß clearance deficiency and early Aß onset age during Alzheimer's disease progression, b) that effective anatomical distance from Aß outbreak region explains regional Aß arrival time and Aß deposition likelihood, c) the multi-factorial impact of APOE e4 genotype, gender and educational level on lifetime intra-brain Aß propagation, and d) the modulatory impact of Aß propagation history on tau proteins concentrations, supporting the hypothesis of an interrelated pathway between Aß pathophysiology and tauopathy. To our knowledge, the ESM is the first computational model highlighting the direct link between structural brain networks, production/clearance of pathogenic proteins and associated intercellular transfer mechanisms, individual genetic/demographic properties and clinical states in health and disease. In sum, the proposed ESM constitutes a promising framework to clarify intra-brain region to region transference mechanisms associated with aging and neurodegenerative disorders.

Epidemic spreading model to characterize misfolded proteins propagation in aging and associated neurodegenerative disorders.

Directory of Open Access Journals (Sweden)

Yasser Iturria-Medina

2014-11-01

Full Text Available Misfolded proteins (MP are a key component in aging and associated neurodegenerative disorders. For example, misfolded Amyloid-ß (Aß and tau proteins are two neuropathogenic hallmarks of Alzheimer's disease. Mechanisms underlying intra-brain MP propagation/deposition remain essentially uncharacterized. Here, is introduced an epidemic spreading model (ESM for MP dynamics that considers propagation-like interactions between MP agents and the brain's clearance response across the structural connectome. The ESM reproduces advanced Aß deposition patterns in the human brain (explaining 46∼56% of the variance in regional Aß loads, in 733 subjects from the ADNI database. Furthermore, this model strongly supports a the leading role of Aß clearance deficiency and early Aß onset age during Alzheimer's disease progression, b that effective anatomical distance from Aß outbreak region explains regional Aß arrival time and Aß deposition likelihood, c the multi-factorial impact of APOE e4 genotype, gender and educational level on lifetime intra-brain Aß propagation, and d the modulatory impact of Aß propagation history on tau proteins concentrations, supporting the hypothesis of an interrelated pathway between Aß pathophysiology and tauopathy. To our knowledge, the ESM is the first computational model highlighting the direct link between structural brain networks, production/clearance of pathogenic proteins and associated intercellular transfer mechanisms, individual genetic/demographic properties and clinical states in health and disease. In sum, the proposed ESM constitutes a promising framework to clarify intra-brain region to region transference mechanisms associated with aging and neurodegenerative disorders.

Movement disorders in paraneoplastic and autoimmune disease

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Panzer, Jessica; Dalmau, Josep

2013-01-01

Purpose of review The most relevant advances in immune-mediated movement disorders are described, with emphasis on the clinical–immunological associations, novel antigens, and treatment. Recent findings Many movement disorders previously considered idiopathic or degenerative are now recognized as immune-mediated. Some disorders are paraneoplastic, such as anti-CRMP5-associated chorea, anti-Ma2 hypokinesis and rigidity, anti-Yo cerebellar ataxia and tremor, and anti-Hu ataxia and pesudoathetosis. Other disorders such as Sydenham's chorea, or chorea related to systemic lupus erythematosus and antiphospholipid syndrome occur in association with multiple antibodies, are not paraneoplastic, and are triggered by molecular mimicry or unknown mechanisms. Recent studies have revealed a new category of disorders that can be paraneoplastic or not, and associate with antibodies against cell-surface or synaptic proteins. They include anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis, which may cause dyskinesias, chorea, ballismus or dystonia (NMDAR antibodies), the spectrum of Stiff-person syndrome/muscle rigidity (glutamic acid decarboxylase, amphiphysin, GABAA-receptor-associated protein, or glycine receptor antibodies), neuromyotonia (Caspr2 antibodies), and opsoclonus–myoclonus–ataxia (unknown antigens). Summary Neurologists should be aware that many movement disorders are immune-mediated. Recognition of these disorders is important because it may lead to the diagnosis of an occult cancer, and a substantial number of patients, mainly those with antibodies to cell-surface or synaptic proteins, respond to immunotherapy. PMID:21577108

Deciphering the Dynamic Interaction Profile of an Intrinsically Disordered Protein by NMR Exchange Spectroscopy.

Science.gov (United States)

Delaforge, Elise; Kragelj, Jaka; Tengo, Laura; Palencia, Andrés; Milles, Sigrid; Bouvignies, Guillaume; Salvi, Nicola; Blackledge, Martin; Jensen, Malene Ringkjøbing

2018-01-24

Intrinsically disordered proteins (IDPs) display a large number of interaction modes including folding-upon-binding, binding without major structural transitions, or binding through highly dynamic, so-called fuzzy, complexes. The vast majority of experimental information about IDP binding modes have been inferred from crystal structures of proteins in complex with short peptides of IDPs. However, crystal structures provide a mainly static view of the complexes and do not give information about the conformational dynamics experienced by the IDP in the bound state. Knowledge of the dynamics of IDP complexes is of fundamental importance to understand how IDPs engage in highly specific interactions without concomitantly high binding affinity. Here, we combine rotating-frame R 1ρ , Carr-Purcell-Meiboom Gill relaxation dispersion as well as chemical exchange saturation transfer to decipher the dynamic interaction profile of an IDP in complex with its partner. We apply the approach to the dynamic signaling complex formed between the mitogen-activated protein kinase (MAPK) p38α and the intrinsically disordered regulatory domain of the MAPK kinase MKK4. Our study demonstrates that MKK4 employs a subtle combination of interaction modes in order to bind to p38α, leading to a complex displaying significantly different dynamics across the bound regions.

Sleep-related breathing disorders and non-invasive ventilation

Directory of Open Access Journals (Sweden)

Agata Lax

2015-05-01

Full Text Available Non-invasive mechanical ventilation (NPPV was originally used in patients with acute respiratory impairment or exacerbations of chronic respiratory diseases, as an alternative to the endotracheal tube. Over the last thirty years NPPV has been also used at night in patients with stable chronic lung disease such as obstructive sleep apnea, the overlap syndrome (chronic obstructive pulmonary disease and obstructive sleep apnea, neuromuscular disorders, obesity-hypoventilation syndrome, and in other conditions such as sleep disorders associated with congestive heart failure (Cheyne-Stokes respiration. In this no-systematic review we discuss the different types of NPPV, the specific conditions in which they can be used and the indications, recommendations and evidence supporting the efficacy of NPPV. Optimizing patient acceptance and adherence to non-invasive ventilation treatment is challenging. The treatment of sleep-related disorders is a life-threatening condition. The optimal level of treatment should be determined in a sleep laboratory. Side effects directly affecting the patient’s adherence to treatment are known. The most common are nasopharyngeal symptoms including increased congestion and rhinorrhea; these effects are related to reduced humidity of inspired gas. Humidification of delivered gas may improve these symptoms.

Pre- and perinatal complications in relation to Tourette syndrome and co-occurring obsessive-compulsive disorder and attention-deficit/hyperactivity disorder

Science.gov (United States)

Abdulkadir, Mohamed; Tischfield, Jay A.; King, Robert A.; Fernandez, Thomas V.; Brown, Lawrence W.; Cheon, Keun-Ah; Coffey, Barbara J.; de Bruijn, Sebastian F. T. M.; Elzerman, Lonneke; Garcia-Delgar, Blanca; Gilbert, Donald L.; Grice, Dorothy E.; Hagstrøm, Julie; Hedderly, Tammy; Heyman, Isobel; Hong, Hyun Ju; Huyser, Chaim; Ibanez-Gomez, Laura; Kim, Young Key; Kim, Young-Shin; Koh, Yun-Joo; Kook, Sodahm; Kuperman, Samuel; Lamerz, Andreas; Leventhal, Bennett; Ludolph, Andrea G.; Madruga-Garrido, Marcos; Maras, Athanasios; Messchendorp, Marieke D.; Mir, Pablo; Morer, Astrid; Münchau, Alexander; Murphy, Tara L.; Openneer, Thaïra J. C.; Plessen, Kerstin J.; Rath, Judith J. G.; Roessner, Veit; Fründt, Odette; Shin, Eun-Young; Sival, Deborah A.; Song, Dong-Ho; Song, Jungeun; Stolte, Anne-Marie; Tübing, Jennifer; van den Ban, Els; Visscher, Frank; Wanderer, Sina; Woods, Martin; Zinner, Samuel H.; State, Matthew W.; Heiman, Gary A.; Hoekstra, Pieter J.; Dietrich, Andrea

2016-01-01

Pre- and perinatal complications have been implicated in the onset and clinical expression of Tourette syndrome albeit with considerable inconsistencies across studies. Also, little is known about their role in co-occurring obsessive-compulsive disorder (OCD) and attention–deficit/hyperactivity disorder (ADHD) in individuals with a tic disorder. Therefore, we aimed to investigate the role of pre- and perinatal complications in relation to the presence and symptom severity of chronic tic disorder and co-occurring OCD and ADHD using data of 1,113 participants from the Tourette International Collaborative Genetics study. This study included 586 participants with a chronic tic disorder and 527 unaffected family controls. We controlled for age and sex differences by creating propensity score matched subsamples for both case-control and within-case analyses. We found that premature birth (OR=1.72) and morning sickness requiring medical attention (OR=2.57) were associated with the presence of a chronic tic disorder. Also, the total number of pre- and perinatal complications was higher in those with a tic disorder (OR=1.07). Furthermore, neonatal complications were related to the presence (OR=1.46) and severity (b=2.27) of co-occurring OCD and also to ADHD severity (b=1.09). Delivery complications were only related to co-occurring OCD (OR=1.49). We conclude that early exposure to adverse situations during pregnancy is related to the presence of chronic tic disorders. Exposure at a later stage, at birth or during the first weeks of life, appears to be associated with co-occurring OCD and ADHD. PMID:27494079

A comparison of the capacity of DSM-IV and DSM-5 acute stress disorder definitions to predict posttraumatic stress disorder and related disorders.

Science.gov (United States)

Bryant, Richard A; Creamer, Mark; O'Donnell, Meaghan; Silove, Derrick; McFarlane, Alexander C; Forbes, David

2015-04-01

This study addresses the extent to which DSM-IV and DSM-5 definitions of acute stress disorder (ASD) predict subsequent posttraumatic stress disorder (PTSD) and related psychiatric disorders following trauma. Patients with randomized admissions to 5 hospitals across Australia (N = 596) were assessed in hospital and reassessed for PTSD at 3 (n = 508), 12 (n = 426), 24 (n = 439), and 72 (n = 314) months using the Clinician-Administered PTSD Scale; DSM-IV definition of PTSD was used at each assessment, and DSM-5 definition was used at 72 months. The Mini-International Neuropsychiatric Interview (MINI) was used at each assessment to assess anxiety, mood, and substance use disorders. Forty-five patients (8%) met DSM-IV criteria, and 80 patients (14%) met DSM-5 criteria for ASD. PTSD was diagnosed in 93 patients (9%) at 3, 82 patients (10%) at 12, 100 patients (12%) at 24, and 26 patients (8%) at 72 months; 19 patients (6%) met DSM-5 criteria for PTSD at 72 months. Comparable proportions of those diagnosed with ASD developed PTSD using DSM-IV (3 months = 46%, 12 months = 39%, 24 months = 32%, and 72 months = 25%) and DSM-5 (43%, 42%, 33%, and 24%) ASD definitions. Sensitivity was improved for DSM-5 relative to DSM-IV for depression (0.18 vs 0.30), panic disorder (0.19 vs 0.41), agoraphobia (0.14 vs 0.40), social phobia (0.12 vs 0.44), specific phobia (0.24 vs 0.58), obsessive-compulsive disorder (0.17 vs 0.47), and generalized anxiety disorder (0.20 vs 0.47). More than half of participants with DSM-5-defined ASD had a subsequent disorder. The DSM-5 criteria for ASD results in better identification of people who will subsequently develop PTSD or another psychiatric disorder relative to the DSM-IV criteria. Although prediction is modest, it suggests that the new ASD diagnosis can serve a useful function in acute trauma settings for triaging those who can benefit from either early intervention or subsequent monitoring. © Copyright 2015 Physicians Postgraduate Press, Inc.

High dimensional and high resolution pulse sequences for backbone resonance assignment of intrinsically disordered proteins

Energy Technology Data Exchange (ETDEWEB)

Zawadzka-Kazimierczuk, Anna; Kozminski, Wiktor, E-mail: kozmin@chem.uw.edu.pl [University of Warsaw, Faculty of Chemistry (Poland); Sanderova, Hana; Krasny, Libor [Institute of Microbiology, Academy of Sciences of the Czech Republic, Laboratory of Molecular Genetics of Bacteria, Department of Bacteriology (Czech Republic)

2012-04-15

Four novel 5D (HACA(N)CONH, HNCOCACB, (HACA)CON(CA)CONH, (H)NCO(NCA)CONH), and one 6D ((H)NCO(N)CACONH) NMR pulse sequences are proposed. The new experiments employ non-uniform sampling that enables achieving high resolution in indirectly detected dimensions. The experiments facilitate resonance assignment of intrinsically disordered proteins. The novel pulse sequences were successfully tested using {delta} subunit (20 kDa) of Bacillus subtilis RNA polymerase that has an 81-amino acid disordered part containing various repetitive sequences.

Programming molecular self-assembly of intrinsically disordered proteins containing sequences of low complexity

Science.gov (United States)

Simon, Joseph R.; Carroll, Nick J.; Rubinstein, Michael; Chilkoti, Ashutosh; López, Gabriel P.

2017-06-01

Dynamic protein-rich intracellular structures that contain phase-separated intrinsically disordered proteins (IDPs) composed of sequences of low complexity (SLC) have been shown to serve a variety of important cellular functions, which include signalling, compartmentalization and stabilization. However, our understanding of these structures and our ability to synthesize models of them have been limited. We present design rules for IDPs possessing SLCs that phase separate into diverse assemblies within droplet microenvironments. Using theoretical analyses, we interpret the phase behaviour of archetypal IDP sequences and demonstrate the rational design of a vast library of multicomponent protein-rich structures that ranges from uniform nano-, meso- and microscale puncta (distinct protein droplets) to multilayered orthogonally phase-separated granular structures. The ability to predict and program IDP-rich assemblies in this fashion offers new insights into (1) genetic-to-molecular-to-macroscale relationships that encode hierarchical IDP assemblies, (2) design rules of such assemblies in cell biology and (3) molecular-level engineering of self-assembled recombinant IDP-rich materials.

Premenstrual dysphoric disorder--review of actual findings about mental disorders related to menstrual cycle and possibilities of their therapy.

Science.gov (United States)

Zukov, I; Ptácek, R; Raboch, J; Domluvilová, D; Kuzelová, H; Fischer, S; Kozelek, P

2010-01-01

It is known that mood disorders in women explicitly relates to estrogen production. Except for these findings phenomenon as Premenstrual Syndrome and Premenstrual Dysphoric Disorder, directly connected to menstrual cycle in women, is widely discussed. Premenstrual dysphoric disorder (PMDD) is a set of subjectively unpleasant mental and somatic symptoms. It appears in luteal phase of ovarian cycle. During menstruation it remits and disappears up to one week from its termination. DSM IV classified PMDD into the category of "Other specific depressive disorders" and further revision DSM IV-TR classifies PMDD as a separate strictly defined psychiatric diagnosis. The International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10) does not include any specific category as PMDD or similar. The closest category F38.8 does not represent the core of the phenomenon because it relates only to general depressive symptomatology and does not give specific diagnostic criteria to menstrual cycle related mood disorders (Grady-Weliky, 2003). In the presented article, possible effectivity of PMDD treatment with the focus to antidepressants of SSRI type (Serotonin selective reuptake inhibitors) is discussed. In spite of interesting and significant findings, the treatment of PMDD and accordingly PMS is above all multidisciplinary question and it must be treated like that.

Validity of the Einstein Relation in Disordered Organic Semiconductors

NARCIS (Netherlands)

Wetzelaer, G. A. H.; Koster, L. J. A.; Blom, P. W. M.

2011-01-01

It is controversial whether energetic disorder in semiconductors is already sufficient to violate the classical Einstein relation, even in the case of thermal equilibrium. We demonstrate that the Einstein relation is violated only under nonequilibrium conditions due to deeply trapped carriers, as in

Negative Affective Experiences in Relation to Stages of Eating Disorder Recovery

Science.gov (United States)

Harney, Megan B.; Fitzsimmons-Crafr, Ellen E.; Maldonado, Christine R.; Bardone-Cone, Anna M.

2013-01-01

The purpose of this study was to examine a collection of negative affect symptoms in relation to stages of eating disorder recovery. Depressive symptoms, anxiety symptoms, loneliness, and perceived stress are known to be present in individuals with eating disorders; however, less is known about the presence of such constructs throughout the recovery process. Does this negative affect fog continue to linger in individuals who have recovered from an eating disorder? Female participants seen at some point for an eating disorder at a primary care clinic were categorized into one of three groups using a stringent definition of eating disorder recovery based on physical, behavioral, and psychological criteria: active eating disorder (n =53), partially recovered (n =15; psychological criteria not met), and fully recovered (n =20; all recovery criteria met). Additionally, data were obtained from 67 female controls who had no history of an eating disorder. Self-report data indicated that controls and women fully recovered from an eating disorder scored significantly lower than partially recovered and active eating disorder groups in perceived stress, depression, and anxiety. Controls and the fully recovered group were statistically indistinguishable from each other in these domains, as were the partially recovered and active eating disorder groups, suggesting an interesting divide depending on whether psychological criteria (e.g., normative levels of weight/shape concern) were met. In contrast, controls and fully recovered and partially recovered groups all reported feeling significantly less lonely relative to those with an active eating disorder suggesting that improved perceptions of interpersonal, social support may act as a stepping stone toward more comprehensive eating disorder recovery. Future research may want to longitudinally determine if an increase in actual or perceived social support facilitates the movement toward full recovery and whether this, in turn, has

Negative affective experiences in relation to stages of eating disorder recovery.

Science.gov (United States)

Harney, Megan B; Fitzsimmons-Craft, Ellen E; Maldonado, Christine R; Bardone-Cone, Anna M

2014-01-01

The purpose of this study was to examine a collection of negative affect symptoms in relation to stages of eating disorder recovery. Depressive symptoms, anxiety symptoms, loneliness, and perceived stress are known to be present in individuals with eating disorders; however, less is known about the presence of such constructs throughout the recovery process. Does this negative affect fog continue to linger in individuals who have recovered from an eating disorder? Female participants seen at some point for an eating disorder at a primary care clinic were categorized into one of three groups using a stringent definition of eating disorder recovery based on physical, behavioral, and psychological criteria: active eating disorder (n=53), partially recovered (n=15; psychological criteria not met), and fully recovered (n=20; all recovery criteria met). Additionally, data were obtained from 67 female controls who had no history of an eating disorder. Self-report data indicated that controls and women fully recovered from an eating disorder scored significantly lower than partially recovered and active eating disorder groups in perceived stress, depression, and anxiety. Controls and the fully recovered group were statistically indistinguishable from each other in these domains, as were the partially recovered and active eating disorder groups, suggesting an interesting divide depending on whether psychological criteria (e.g., normative levels of weight/shape concern) were met. In contrast, controls and fully recovered and partially recovered groups all reported feeling significantly less lonely relative to those with an active eating disorder suggesting that improved perceptions of interpersonal functioning and social support may act as a stepping stone toward more comprehensive eating disorder recovery. Future research may want to longitudinally determine if an increase in actual or perceived social support facilitates the movement toward full recovery and whether this

Etiopathogenetic Mechanisms of Pulmonary Hypertension in Sleep-Related Breathing Disorders

Directory of Open Access Journals (Sweden)

Ayodeji Adegunsoye

2012-01-01

Full Text Available Obstructive sleep apnea syndrome is a common disorder with significant health consequences and is on the rise in consonance with the obesity pandemic. In view of the association between sleep-disordered breathing and pulmonary hypertension as depicted by multiple studies, current clinical practice guidelines categorize obstructive sleep apnea as a risk factor for pulmonary hypertension and recommend an assessment for sleep disordered breathing in evaluating patients with pulmonary hypertension. The dysregulatory mechanisms associated with hypoxemic episodes observed in sleep related breathing disorders contribute to the onset of pulmonary hypertension and identification of these potentially treatable factors might help in the reduction of overall cardiovascular mortality.

Conduct disorder, war zone stress, and war-related posttraumatic stress disorder symptoms in American Indian Vietnam veterans.

Science.gov (United States)

Dillard, Denise; Jacobsen, Clemma; Ramsey, Scott; Manson, Spero

2007-02-01

This study examined whether conduct disorder (CD) was associated with war zone stress and war-related post-traumatic stress disorder (PTSD) symptoms in American Indian (AI) Vietnam veterans. Cross-sectional lay-interview data was analyzed for 591 male participants from the American Indian Vietnam Veterans Project. Logistic regression evaluated the association of CD with odds of high war zone stress and linear regression evaluated the association of CD and PTSD symptom severity. Childhood CD was not associated with increased odds of high war zone stress. Conduct disorder was associated with elevated war-related PTSD symptoms among male AI Vietnam Veterans independent of war zone stress level and other mediators. Future efforts should examine reasons for this association and if the association exists in other AI populations.

Discriminating binding mechanisms of an intrinsically disordered protein via a multi-state coarse-grained model

Energy Technology Data Exchange (ETDEWEB)

Knott, Michael [Department of Chemistry, Cambridge University, Lensfield Road, Cambridge CB2 1EW (United Kingdom); Best, Robert B., E-mail: robertbe@helix.nih.gov [Department of Chemistry, Cambridge University, Lensfield Road, Cambridge CB2 1EW (United Kingdom); Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-0520 (United States)

2014-05-07

Many proteins undergo a conformational transition upon binding to their cognate binding partner, with intrinsically disordered proteins (IDPs) providing an extreme example in which a folding transition occurs. However, it is often not clear whether this occurs via an “induced fit” or “conformational selection” mechanism, or via some intermediate scenario. In the first case, transient encounters with the binding partner favour transitions to the bound structure before the two proteins dissociate, while in the second the bound structure must be selected from a subset of unbound structures which are in the correct state for binding, because transient encounters of the incorrect conformation with the binding partner are most likely to result in dissociation. A particularly interesting situation involves those intrinsically disordered proteins which can bind to different binding partners in different conformations. We have devised a multi-state coarse-grained simulation model which is able to capture the binding of IDPs in alternate conformations, and by applying it to the binding of nuclear coactivator binding domain (NCBD) to either ACTR or IRF-3 we are able to determine the binding mechanism. By all measures, the binding of NCBD to either binding partner appears to occur via an induced fit mechanism. Nonetheless, we also show how a scenario closer to conformational selection could arise by choosing an alternative non-binding structure for NCBD.

Discriminating binding mechanisms of an intrinsically disordered protein via a multi-state coarse-grained model

International Nuclear Information System (INIS)

Knott, Michael; Best, Robert B.

2014-01-01

Many proteins undergo a conformational transition upon binding to their cognate binding partner, with intrinsically disordered proteins (IDPs) providing an extreme example in which a folding transition occurs. However, it is often not clear whether this occurs via an “induced fit” or “conformational selection” mechanism, or via some intermediate scenario. In the first case, transient encounters with the binding partner favour transitions to the bound structure before the two proteins dissociate, while in the second the bound structure must be selected from a subset of unbound structures which are in the correct state for binding, because transient encounters of the incorrect conformation with the binding partner are most likely to result in dissociation. A particularly interesting situation involves those intrinsically disordered proteins which can bind to different binding partners in different conformations. We have devised a multi-state coarse-grained simulation model which is able to capture the binding of IDPs in alternate conformations, and by applying it to the binding of nuclear coactivator binding domain (NCBD) to either ACTR or IRF-3 we are able to determine the binding mechanism. By all measures, the binding of NCBD to either binding partner appears to occur via an induced fit mechanism. Nonetheless, we also show how a scenario closer to conformational selection could arise by choosing an alternative non-binding structure for NCBD

Birth-Related Posttraumatic Stress Disorder: Implications for Early Intervention Services

Science.gov (United States)

Pizur-Barnekow, Kris; Doering, Jennifer J.; Willett, Marjorie; Ruminski, Christine; Spring, Molly

2014-01-01

The positive impact of healthy relationships on child development is widely accepted. A healthy relationship between mother and child is at risk when a mother experiences symptoms of birth-related posttraumatic stress disorder (PTSD). Mothers of children with special needs are at high risk for this disorder and early intervention (EI)…

Digested disorder: Quarterly intrinsic disorder digest (April-May-June, 2013).

Science.gov (United States)

DeForte, Shelly; Reddy, Krishna D; Uversky, Vladimir N

2013-01-01

The current literature on intrinsically disordered proteins is overwhelming. To keep interested readers up to speed with this literature, we continue a "Digested Disorder" project and represent a series of reader's digest type articles objectively representing the research papers and reviews on intrinsically disordered proteins. The only 2 criteria for inclusion in this digest are the publication date (a paper should be published within the covered time frame) and topic (a paper should be dedicated to any aspect of protein intrinsic disorder). The current digest issue covers papers published during the period of April, May, and June of 2013. The papers are grouped hierarchically by topics they cover, and for each of the included paper a short description is given on its major findings.

Multifunctional aspects of allopregnanolone in stress and related disorders.

Science.gov (United States)

Bali, Anjana; Jaggi, Amteshwar Singh

2014-01-03

Allopregnanolone (3α-hydroxy-5α-pregnan-20-one) is a major cholesterol-derived neurosteroid in the central nervous system and is synthesized from progesterone by steroidogenic enzymes, 5α-reductase (the rate-limiting enzyme) and 3α-hydroxysteroid dehydrogenase. The pathophysiological role of allopregnanolone in neuropsychiatric disorders has been highlighted in several investigations. The changes in neuroactive steroid levels are detected in stress and stress-related disorders including anxiety, panic and depression. The changes in allopregnanolone in response to acute stressor tend to restore the homeostasis by dampening the hyper-activated HPA axis. However, long standing stressors leading to development of neuropsychiatric disorders including depression and anxiety are associated with decrease in the allopregnanolone levels. GABAA receptor complex has been considered as the primary target of allopregnanolone and majority of its inhibitory actions are mediated through GABA potentiation or direct activation of GABA currents. The role of progesterone receptors in producing the late actions of allopregnanolone particularly in lordosis facilitation has also been described. Moreover, recent studies have also described the involvement of other multiple targets including brain-derived neurotrophic factor (BDNF), glutamate, dopamine, opioids, oxytocin, and calcium channels. The present review discusses the various aspects of allopregnanolone in stress and stress-related disorders including anxiety, depression and panic. © 2013.

Pre- and perinatal complications in relation to Tourette syndrome and co-occurring obsessive-compulsive disorder and attention-deficit/hyperactivity disorder.

Science.gov (United States)

Abdulkadir, Mohamed; Tischfield, Jay A; King, Robert A; Fernandez, Thomas V; Brown, Lawrence W; Cheon, Keun-Ah; Coffey, Barbara J; de Bruijn, Sebastian F T M; Elzerman, Lonneke; Garcia-Delgar, Blanca; Gilbert, Donald L; Grice, Dorothy E; Hagstrøm, Julie; Hedderly, Tammy; Heyman, Isobel; Hong, Hyun Ju; Huyser, Chaim; Ibanez-Gomez, Laura; Kim, Young Key; Kim, Young-Shin; Koh, Yun-Joo; Kook, Sodahm; Kuperman, Samuel; Lamerz, Andreas; Leventhal, Bennett; Ludolph, Andrea G; Madruga-Garrido, Marcos; Maras, Athanasios; Messchendorp, Marieke D; Mir, Pablo; Morer, Astrid; Münchau, Alexander; Murphy, Tara L; Openneer, Thaïra J C; Plessen, Kerstin J; Rath, Judith J G; Roessner, Veit; Fründt, Odette; Shin, Eun-Young; Sival, Deborah A; Song, Dong-Ho; Song, Jungeun; Stolte, Anne-Marie; Tübing, Jennifer; van den Ban, Els; Visscher, Frank; Wanderer, Sina; Woods, Martin; Zinner, Samuel H; State, Matthew W; Heiman, Gary A; Hoekstra, Pieter J; Dietrich, Andrea

2016-11-01

Pre- and perinatal complications have been implicated in the onset and clinical expression of Tourette syndrome albeit with considerable inconsistencies across studies. Also, little is known about their role in co-occurring obsessive-compulsive disorder (OCD) and attention-deficit/hyperactivity disorder (ADHD) in individuals with a tic disorder. Therefore, we aimed to investigate the role of pre- and perinatal complications in relation to the presence and symptom severity of chronic tic disorder and co-occurring OCD and ADHD using data of 1113 participants from the Tourette International Collaborative Genetics study. This study included 586 participants with a chronic tic disorder and 527 unaffected family controls. We controlled for age and sex differences by creating propensity score matched subsamples for both case-control and within-case analyses. We found that premature birth (OR = 1.72) and morning sickness requiring medical attention (OR = 2.57) were associated with the presence of a chronic tic disorder. Also, the total number of pre- and perinatal complications was higher in those with a tic disorder (OR = 1.07). Furthermore, neonatal complications were related to the presence (OR = 1.46) and severity (b = 2.27) of co-occurring OCD and also to ADHD severity (b = 1.09). Delivery complications were only related to co-occurring OCD (OR = 1.49). We conclude that early exposure to adverse situations during pregnancy is related to the presence of chronic tic disorders. Exposure at a later stage, at birth or during the first weeks of life, appears to be associated with co-occurring OCD and ADHD. Copyright © 2016 Elsevier Ltd. All rights reserved.

Dysthymic disorder: clinical characteristics in relation to age at onset.

Science.gov (United States)

Barzega, G; Maina, G; Venturello, S; Bogetto, F

2001-09-01

The variability in the clinical presentation of dysthymia has given rise to a rich debate in literature, and various hypotheses have been proposed. One is that the clinical presentation differs in relation to age at onset. The aim of the study was to evaluate differences in socio-demographic and clinical characteristics in a sample of patients with dysthymia (DSM-IV), in relation to age at onset. 84 consecutive outpatients with a diagnosis of dysthymia (DSM-IV) were studied. All subjects were evaluated by a semistructured clinical interview and the following rating scales: HAM-A, HAM-D, MADRS, Paykel's Interview for Recent Life Events. 23.8% of the sample had early-onset (dysthymia. Patients with early-onset disorder were significantly younger at the observation, more frequently female and single. They had a significantly longer duration of illness and in a significantly higher percentage had already received a specialist treatment before admission in the present trial. No differences in the frequency of symptoms were observed. A significantly higher percentage of patients with late-onset disease reported at least one stressful event in the year preceding the onset of dysthymia. A positive history of major depression was significantly more common among the early-onset group; social phobia, panic disorder and conversive disorder were also more frequent in this group. The late-onset patients frequently presented generalized anxiety disorder, substance abuse and somatization disorder. The study is retrospective and enrolls a limited number of cases. The present study agrees with other reports on the differences in clinical presentation of dysthymia according to age at onset. Although they are not actually related to age at onset, some interesting findings emerged in the symptomatological characterization of the disorder, referring to the diagnostic criteria proposed in DSM-IV.

Pre- and perinatal complications in relation to Tourette syndrome and co-occurring obsessive-compulsive disorder and attention-deficit/hyperactivity disorder

DEFF Research Database (Denmark)

Abdulkadir, Mohamed; Tischfield, Jay A; King, Robert A

2016-01-01

-deficit/hyperactivity disorder (ADHD) in individuals with a tic disorder. Therefore, we aimed to investigate the role of pre- and perinatal complications in relation to the presence and symptom severity of chronic tic disorder and co-occurring OCD and ADHD using data of 1113 participants from the Tourette International...... Collaborative Genetics study. This study included 586 participants with a chronic tic disorder and 527 unaffected family controls. We controlled for age and sex differences by creating propensity score matched subsamples for both case-control and within-case analyses. We found that premature birth (OR = 1.......72) and morning sickness requiring medical attention (OR = 2.57) were associated with the presence of a chronic tic disorder. Also, the total number of pre- and perinatal complications was higher in those with a tic disorder (OR = 1.07). Furthermore, neonatal complications were related to the presence (OR = 1...

Perceived quality of life in obsessive-compulsive disorder: related factors

Directory of Open Access Journals (Sweden)

Saiz-Ruiz Jeronimo

2006-05-01

Full Text Available Abstract Background Obsessive-compulsive disorder (OCD affects young adults and has great impact on the social, emotional and work spheres. Methods We measured perceived quality of life (QOL in OCD patients, in order to analyse socio-demographic and clinical factors that may be associated with QOL perception. 64 OCD outpatients were assessed with the Mini International Neuropsychiatric Interview for DSM-IV, the Yale-Brown Obsessions and Compulsions scale (Y-BOCS, Hamilton's depression scale and the SF-36 self-administered global QOL perception scale. Results We found a correlation among Hamilton's scale scores and all SF-36 subscales. The severity of the obsessive-compulsive disorder was correlated with all SF-36 subscales and with the highest scores in Hamilton's scale. The obsessions subscale was correlated to all SF-36 subscales, while the compulsions subscale was correlated only to social functioning, emotional role, mental health and vitality. Compulsions were not related to general health perception. There were significant differences between OCD patients and the Spanish general population in all SF-36 subscales except those related to physical health and pain. Gender, age, age of onset of the disorder, years of evolution and marital status of the patients did not significantly affect quality of life perception. Being employed was related to better scores in the subscale of physical role. Patients with medical comorbidity scored lower in the subscales of general health, social functioning and mental health. Patients with comorbid psychiatric disorders had worse scores in the subscales of pain, general health, social functioning and mental health. Conclusion Quality of life perception was different in OCD patients and the general population. Quality of life perception was related to severity of the disorder, physical and psychiatric comorbidity and employment status.

Group behavioral therapy for adolescents with tic-related and non-tic-related obsessive-compulsive disorder.

Science.gov (United States)

Himle, Joseph A; Fischer, Daniel J; Van Etten, Michelle L; Janeck, Amy S; Hanna, Gregory L

2003-01-01

Prior research supports the distinction between tic-related and non-tic-related obsessive-compulsive disorder (OCD) based on phenomenologic, etiologic, and neurobehavioral data. The present study examines whether response to psychosocial treatment differs in adolescents, depending on the presence of comorbid tics. Nineteen adolescents, 12-17 years of age, participated in 7-week, uncontrolled trial of group cognitive-behavioral treatment (CBT) for OCD. Eight of the patients had tic-related and eleven had non-tic-related OCD. The group CBT program included psycho-education, exposure and response prevention, cognitive strategies, and family involvement. Significant improvement was observed for all subjects on the Yale-Brown Obsessive Compulsive Scale ratings of obsessions, compulsions, and total OCD symptoms. Outcomes were similar for subjects with tic-related and non-tic-related OCD. These preliminary results suggest that the presence of comorbid tic disorders may not attenuate response to behavioral group treatment among adolescents. Copyright 2003 Wiley-Liss, Inc.

Psychosocial Factors and Work-related Musculoskeletal Disorders among Southeastern Asian Female Workers Living in Korea.

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Lee, Hyeonkyeong; Ahn, Hyunmi; Park, Chang Gi; Kim, Sun Jung; Moon, Sun Hye

2011-06-01

A rapid increase in the population of migrant workers in Korea has brought new challenges regarding the possible effects of acculturation on health. The purpose of this study was to examine the influence of acculturation- and work-related psychosocial factors on work-related musculoskeletal disorders among migrant female workers living in Korea. A cross-sectional survey design was used. A translated, structured questionnaire was administrated to 156 southeastern Asian female full-time workers living in Korea. About 35% of the participants experienced some type(s) of work-related musculoskeletal disorder(s), which were more prevalent in Vietnamese women than in Thai and Filipino women. Women who preferred to maintain their own heritage and to reject the host country heritage were at risk for work-related musculoskeletal disorders. Acculturation strategy and nationality were found to be significant factors associated with work-related musculoskeletal disorders. Health professionals need to accommodate acculturation contexts into risk assessment and intervention development for work-related musculoskeletal disorders separately for different nationalities.

Racial/ethnic variations in substance-related disorders among adolescents in the United States.

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Wu, Li-Tzy; Woody, George E; Yang, Chongming; Pan, Jeng-Jong; Blazer, Dan G

2011-11-01

While young racial/ethnic groups are the fastest growing population in the United States, data about substance-related disorders among adolescents of various racial/ethnic backgrounds are lacking. To examine the magnitude of past-year DSM-IV substance-related disorders (alcohol, marijuana, cocaine, inhalants, hallucinogens, heroin, analgesic opioids, stimulants, sedatives, and tranquilizers) among adolescents of white, Hispanic, African American, Native American, Asian or Pacific Islander, and multiple race/ethnicity. The 2005 to 2008 National Survey on Drug Use and Health. Academic research. Noninstitutionalized household adolescents aged 12 to 17 years. Substance-related disorders were assessed by standardized survey questions administered using the audio computer-assisted self-interviewing method. Of 72 561 adolescents aged 12 to 17 years, 37.0% used alcohol or drugs in the past year; 7.9% met criteria for a substance-related disorder, with Native Americans having the highest prevalence of use (47.5%) and disorder (15.0%). Analgesic opioids were the second most commonly used illegal drugs, following marijuana, in all racial/ethnic groups; analgesic opioid use was comparatively prevalent among adolescents of Native American (9.7%) and multiple race/ethnicity (8.8%). Among 27 705 past-year alcohol or drug users, Native Americans (31.5%), adolescents of multiple race/ethnicity (25.2%), adolescents of white race/ethnicity (22.9%), and Hispanics (21.0%) had the highest rates of substance-related disorders. Adolescents used marijuana more frequently than alcohol or other drugs, and 25.9% of marijuana users met criteria for marijuana abuse or dependence. After controlling for adolescents' age, socioeconomic variables, population density of residence, self-rated health, and survey year, adjusted analyses of adolescent substance users indicated elevated odds of substance-related disorders among Native Americans, adolescents of multiple race/ethnicity, adolescents of

Association of Oxidative Stress with Psychiatric Disorders.

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Hassan, Waseem; Noreen, Hamsa; Castro-Gomes, Vitor; Mohammadzai, Imdadullah; da Rocha, Joao Batista Teixeira; Landeira-Fernandez, J

2016-01-01

When concentrations of both reactive oxygen species and reactive nitrogen species exceed the antioxidative capability of an organism, the cells undergo oxidative impairment. Impairments in membrane integrity and lipid and protein oxidation, protein mutilation, DNA damage, and neuronal dysfunction are some of the fundamental consequences of oxidative stress. The purpose of this work was to review the associations between oxidative stress and psychological disorders. The search terms were the following: "oxidative stress and affective disorders," "free radicals and neurodegenerative disorders," "oxidative stress and psychological disorders," "oxidative stress, free radicals, and psychiatric disorders," and "association of oxidative stress." These search terms were used in conjunction with each of the diagnostic categories of the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders and World Health Organization's International Statistical Classification of Diseases and Related Health Problems. Genetic, pharmacological, biochemical, and preclinical therapeutic studies, case reports, and clinical trials were selected to explore the molecular aspects of psychological disorders that are associated with oxidative stress. We identified a broad spectrum of 83 degenerative syndromes and psychiatric disorders that were associated with oxidative stress. The multi-dimensional information identified herein supports the role of oxidative stress in various psychiatric disorders. We discuss the results from the perspective of developing novel therapeutic interventions.

Parental and Child Characteristics Related to Early-Onset Disordered Eating: A Systematic Review.

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Larsen, Pernille Stemann; Strandberg-Larsen, Katrine; Micali, Nadia; Andersen, Anne-Marie Nybo

2015-01-01

After participating in this activity, learners should be better able to: Evaluate the evidence regarding parental and child characteristics related to early-onset disordered eating. Eating disorders are rare in children, but disordered eating is common. Understanding the phenomenology of disordered eating in childhood can aid prevention of full-blown eating disorders. The purpose of this review is to systematically extract and synthesize the evidence on parental and child characteristics related to early-onset disordered eating. Systematic searches were conducted in PubMED/MEDLINE, EMBASE, and PsycInfo using the following search terms: eating disorder, disordered eating, problem eating, anorexia nervosa, bulimia nervosa, binge eating, child, preadolescent, and early onset. Studies published from 1990 to 2013 addressing parental and child characteristics of disordered eating in children aged 6 to 12 years were eligible for inclusion. The search was restricted to studies with cross-sectional, case-control, or longitudinal designs, studies in English, and with abstracts available. Forty-four studies fit these criteria. Most studies were based on community samples with a cross-sectional design. The included studies varied considerably in size, instruments used to assess early-onset disordered eating, and parental and child characteristics investigated. Important determinants included the following: higher body weight, previously reported disordered eating, body dissatisfaction, depression, parental disordered eating, and parental comments/concerns about child's weight and eating. The findings were inconsistent for sex, age, socioeconomic status, ethnicity, self-esteem/worth, and parental body weight. In conclusion, characteristics related to early-onset disordered eating have mainly been explored with a cross-sectional design. Full understanding of causal pathways will require good-quality longitudinal studies designed to address the influence of parental eating

Digested disorder: Quarterly intrinsic disorder digest (July-August-September, 2013).

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Reddy, Krishna D; DeForte, Shelly; Uversky, Vladimir N

2014-01-01

The current literature on intrinsically disordered proteins grows fast. To keep interested readers up to speed with this literature, we continue a "Digested Disorder" project and represent a new issue of reader's digest of the research papers and reviews on intrinsically disordered proteins. The only 2 criteria for inclusion in this digest are the publication date (a paper should be published within the covered time frame) and topic (a paper should be dedicated to any aspect of protein intrinsic disorder). The current digest issue covers papers published during the third quarter of 2013; i.e., during the period of June, July, and September of 2013. Similar to previous issues, the papers are grouped hierarchically by topics they cover, and for each of the included paper a short description is given on its major findings.

Prevalence of interpersonal trauma exposure and trauma-related disorders in severe mental illness

NARCIS (Netherlands)

Mauritz, M.W.; Goossens, P.J.J.; Draijer, N.; Achterberg, T. van

2013-01-01

BACKGROUND: Interpersonal trauma exposure and trauma-related disorders in people with severe mental illness (SMI) are often not recognized in clinical practice. OBJECTIVE: To substantiate the prevalence of interpersonal trauma exposure and trauma-related disorders in people with SMI. METHODS: We

Prevalence of interpersonal trauma exposure and trauma-related disorders in severe mental illness

NARCIS (Netherlands)

Mauritz, M.W.; Goossens, P.J.J.; Draijer, N.; van Achterberg, T.

2013-01-01

Background: Interpersonal trauma exposure and trauma-related disorders in people with severe mental illness (SMI) are often not recognized in clinical practice. Objective: To substantiate the prevalence of interpersonal trauma exposure and trauma-related disorders in people with SMI. Methods: We

Osmotin, a Pathogenesis-Related Protein

Czech Academy of Sciences Publication Activity Database

Viktorová, J.; Krásný, Lukáš; Kamlar, M.; Nováková, M.; Macková, M.; Macek, T.

2012-01-01

Roč. 13, č. 7 (2012), s. 672-681 ISSN 1389-2037 Grant - others:GA ČR(CZ) GAP501/11/1654; GA ČR(CZ) GA522/09/1693 Program:GA; GA Institutional support: RVO:61388971 Keywords : osmotin * pathogenesis-related proteins * antifungal activity Subject RIV: CE - Biochemistry Impact factor: 2.326, year: 2012

Regulation of Skeletal Muscle Plasticity by Protein Arginine Methyltransferases and Their Potential Roles in Neuromuscular Disorders

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Derek W. Stouth

2017-11-01

Full Text Available Protein arginine methyltransferases (PRMTs are a family of enzymes that catalyze the methylation of arginine residues on target proteins, thereby mediating a diverse set of intracellular functions that are indispensable for survival. Indeed, full-body knockouts of specific PRMTs are lethal and PRMT dysregulation has been implicated in the most prevalent chronic disorders, such as cancers and cardiovascular disease (CVD. PRMTs are now emerging as important mediators of skeletal muscle phenotype and plasticity. Since their first description in muscle in 2002, a number of studies employing wide varieties of experimental models support the hypothesis that PRMTs regulate multiple aspects of skeletal muscle biology, including development and regeneration, glucose metabolism, as well as oxidative metabolism. Furthermore, investigations in non-muscle cell types strongly suggest that proteins, such as peroxisome proliferator-activated receptor-γ coactivator-1α, E2F transcription factor 1, receptor interacting protein 140, and the tumor suppressor protein p53, are putative downstream targets of PRMTs that regulate muscle phenotype determination and remodeling. Recent studies demonstrating that PRMT function is dysregulated in Duchenne muscular dystrophy (DMD, spinal muscular atrophy (SMA, and amyotrophic lateral sclerosis (ALS suggests that altering PRMT expression and/or activity may have therapeutic value for neuromuscular disorders (NMDs. This review summarizes our understanding of PRMT biology in skeletal muscle, and identifies uncharted areas that warrant further investigation in this rapidly expanding field of research.

Body-Related Social Comparison and Disordered Eating among Adolescent Females with an Eating Disorder, Depressive Disorder, and Healthy Controls

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Daniel Le Grange

2012-09-01

Full Text Available The purpose of this study was to investigate the association between body-related social comparison (BRSC and eating disorders (EDs by: (a comparing the degree of BRSC in adolescents with an ED, depressive disorder (DD, and no psychiatric history; and (b investigating whether BRSC is associated with ED symptoms after controlling for symptoms of depression and self-esteem. Participants were 75 girls, aged 12–18 (25 per diagnostic group. To assess BRSC, participants reported on a 5-point Likert scale how often they compare their body to others’. Participants also completed a diagnostic interview, Eating Disorders Inventory-2 (EDI-2, Beck Depression Inventory-II (BDI-II, and Rosenberg Self-Esteem Scale (RSE. Compared to adolescents with a DD and healthy adolescents, adolescents with an ED engaged in significantly more BRSC (p ≤ 0.001. Collapsing across groups, BRSC was significantly positively correlated with ED symptoms (p ≤ 0.01, and these associations remained even after controlling for two robust predictors of both ED symptoms and social comparison, namely BDI-II and RSE. In conclusion, BRSC seems to be strongly related to EDs. Treatment for adolescents with an ED may focus on reducing BRSC.

Body-related social comparison and disordered eating among adolescent females with an eating disorder, depressive disorder, and healthy controls.

Science.gov (United States)

Hamel, Andrea E; Zaitsoff, Shannon L; Taylor, Andrew; Menna, Rosanne; Le Grange, Daniel

2012-09-01

The purpose of this study was to investigate the association between body-related social comparison (BRSC) and eating disorders (EDs) by: (a) comparing the degree of BRSC in adolescents with an ED, depressive disorder (DD), and no psychiatric history; and (b) investigating whether BRSC is associated with ED symptoms after controlling for symptoms of depression and self-esteem. Participants were 75 girls, aged 12-18 (25 per diagnostic group). To assess BRSC, participants reported on a 5-point Likert scale how often they compare their body to others'. Participants also completed a diagnostic interview, Eating Disorders Inventory-2 (EDI-2), Beck Depression Inventory-II (BDI-II), and Rosenberg Self-Esteem Scale (RSE). Compared to adolescents with a DD and healthy adolescents, adolescents with an ED engaged in significantly more BRSC (p ≤ 0.001). Collapsing across groups, BRSC was significantly positively correlated with ED symptoms (p ≤ 0.01), and these associations remained even after controlling for two robust predictors of both ED symptoms and social comparison, namely BDI-II and RSE. In conclusion, BRSC seems to be strongly related to EDs. Treatment for adolescents with an ED may focus on reducing BRSC.

Profiles of drug addicts in relation to personality variables and disorders.

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Carou, María; Romero, Estrella; Luengo, Mª Ángeles

2016-10-07

In recent decades, research has identified a set of impulsive/disinhibited personality variables closely associated with drug addiction. As well as this, disorders linked with these variables, such as ADHD and personality disorders, are being closely studied in the field of drug addiction. Although much knowledge has been accumulated about the relation of these variables and disorders taken separately, less is known about how these constructs allow identify-specific profiles within the drug dependent population to be identified. This work, on the basis of data collected on a sample of drug addicts in treatment, analyzes how impulsiveness, sensation seeking, self-control, ADHD and personality disorders contribute to identifying specific profiles of addicts. Cluster analysis allowed two profiles to be outlined according to these personality and psychopathology characteristics. Self-control, impulsiveness, impulsive and antisocial personality disorders, as well as scores in ADHD, emerge as the variables that contribute more to profile differentiation. One of these profiles (56.1% of participants) with a high disinhibition pattern, is associated with severe indicators of consumption and criminal career patterns. These results allow us to emphasize the role of personality and impulsiveness-related disorders in the identification of distinctive profiles within the addict population, and suggest the need to generate treatment strategies adapted to personal/psychopathology configurations of drug addicts.

Work-Related Upper Limb Disorders: A Case Report

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Zlatka Borisova Stoyneva

2015-03-01

Full Text Available In this study the complex interrelationship between physical factors, job stress, lifestyle and genetic factors on symptoms of work-related musculoskeletal disorders of the upper limbs is demonstrated by a case report and discussion of the literature. A 58 year old woman with long lasting complaints of the upper limbs with increasing intensity and duration, generalisation, combined with skin thickness, Raynaud’s phenomenon, joint disorders, arterial and pulmonary hypertension, metabolic lipid dysfunctions is presented. Occupational history proves continuous duration of service at a job with occupational physical static load with numerous repetitive monotonous systematic motions of fingers and hands as a weaver of Persian rugs followed by work at an automated loom and variable labour activities. Though the complaints dated since the time she was a manual weaver, the manifestations of generalized joint degenerative changes, system sclerosis with Raynaud’s phenomenon with similar upper extremities signs and symptoms discount upper limbs musculoskeletal disorder as caused only or mainly by occupational risk factors. The main principles and criteria for occupational diagnosis of musculoskeletal upper limb disorders and legislative requirements for their reglamentation are discussed.

Functional anthology of intrinsic disorder. 2. Cellular components, domains, technical terms, developmental processes, and coding sequence diversities correlated with long disordered regions.

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Vucetic, Slobodan; Xie, Hongbo; Iakoucheva, Lilia M; Oldfield, Christopher J; Dunker, A Keith; Obradovic, Zoran; Uversky, Vladimir N

2007-05-01

Biologically active proteins without stable ordered structure (i.e., intrinsically disordered proteins) are attracting increased attention. Functional repertoires of ordered and disordered proteins are very different, and the ability to differentiate whether a given function is associated with intrinsic disorder or with a well-folded protein is crucial for modern protein science. However, there is a large gap between the number of proteins experimentally confirmed to be disordered and their actual number in nature. As a result, studies of functional properties of confirmed disordered proteins, while helpful in revealing the functional diversity of protein disorder, provide only a limited view. To overcome this problem, a bioinformatics approach for comprehensive study of functional roles of protein disorder was proposed in the first paper of this series (Xie, H.; Vucetic, S.; Iakoucheva, L. M.; Oldfield, C. J.; Dunker, A. K.; Obradovic, Z.; Uversky, V. N. Functional anthology of intrinsic disorder. 1. Biological processes and functions of proteins with long disordered regions. J. Proteome Res. 2007, 5, 1882-1898). Applying this novel approach to Swiss-Prot sequences and functional keywords, we found over 238 and 302 keywords to be strongly positively or negatively correlated, respectively, with long intrinsically disordered regions. This paper describes approximately 90 Swiss-Prot keywords attributed to the cellular components, domains, technical terms, developmental processes, and coding sequence diversities possessing strong positive and negative correlation with long disordered regions.

Functional Anthology of Intrinsic Disorder. II. Cellular Components, Domains, Technical Terms, Developmental Processes and Coding Sequence Diversities Correlated with Long Disordered Regions

Science.gov (United States)

Vucetic, Slobodan; Xie, Hongbo; Iakoucheva, Lilia M.; Oldfield, Christopher J.; Dunker, A. Keith; Obradovic, Zoran; Uversky, Vladimir N.

2008-01-01

Biologically active proteins without stable ordered structure (i.e., intrinsically disordered proteins) are attracting increased attention. Functional repertoires of ordered and disordered proteins are very different, and the ability to differentiate whether a given function is associated with intrinsic disorder or with a well-folded protein is crucial for modern protein science. However, there is a large gap between the number of proteins experimentally confirmed to be disordered and their actual number in nature. As a result, studies of functional properties of confirmed disordered proteins, while helpful in revealing the functional diversity of protein disorder, provide only a limited view. To overcome this problem, a bioinformatics approach for comprehensive study of functional roles of protein disorder was proposed in the first paper of this series (Xie H., Vucetic S., Iakoucheva L.M., Oldfield C.J., Dunker A.K., Obradovic Z., Uversky V.N. (2006) Functional anthology of intrinsic disorder. I. Biological processes and functions of proteins with long disordered regions. J. Proteome Res.). Applying this novel approach to Swiss-Prot sequences and functional keywords, we found over 238 and 302 keywords to be strongly positively or negatively correlated, respectively, with long intrinsically disordered regions. This paper describes ~90 Swiss-Prot keywords attributed to the cellular components, domains, technical terms, developmental processes and coding sequence diversities possessing strong positive and negative correlation with long disordered regions. PMID:17391015

Potential role of anticonvulsants in the treatment of obsessive-compulsive and related disorders.

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Wang, Hee Ryung; Woo, Young Sup; Bahk, Won-Myong

2014-10-01

We reviewed the extant literature to evaluate the current evidence regarding the efficacy and safety of anticonvulsants in the treatment of obsessive-compulsive and related disorders. Relevant literature was accessed using the Cochrane database, embase and PubMed on 29 October 2013. Prospective studies examining the efficacy of anticonvulsants in obsessive-compulsive and related disorders were included. Case reports, case series, and retrospective studies were excluded. A total of 10 studies were included in this review. The studies of obsessive-compulsive disorder, except for two negative studies, showed favorable efficacy results of anticonvulsants. In one study on body dysmorphic disorder, levetiracetam showed favorable efficacy. In two lamotrigine studies for pathologic skin-picking, the efficacy findings were inconsistent. In one trichotillomania study, topiramate had reduced hair-pulling symptoms. Despite limited evidence, our review suggests that anticonvulsants have a potential role in the treatment of obsessive-compulsive and related disorders. © 2014 The Authors. Psychiatry and Clinical Neurosciences © 2014 Japanese Society of Psychiatry and Neurology.

Structural studies of human glioma pathogenesis-related protein 1

Energy Technology Data Exchange (ETDEWEB)

Asojo, Oluwatoyin A., E-mail: oasojo@unmc.edu [College of Medicine, Nebraska Medical Center, Omaha, NE 68198-6495 (United States); Koski, Raymond A.; Bonafé, Nathalie [L2 Diagnostics LLC, 300 George Street, New Haven, CT 06511 (United States); College of Medicine, Nebraska Medical Center, Omaha, NE 68198-6495 (United States)

2011-10-01

Structural analysis of a truncated soluble domain of human glioma pathogenesis-related protein 1, a membrane protein implicated in the proliferation of aggressive brain cancer, is presented. Human glioma pathogenesis-related protein 1 (GLIPR1) is a membrane protein that is highly upregulated in brain cancers but is barely detectable in normal brain tissue. GLIPR1 is composed of a signal peptide that directs its secretion, a conserved cysteine-rich CAP (cysteine-rich secretory proteins, antigen 5 and pathogenesis-related 1 proteins) domain and a transmembrane domain. GLIPR1 is currently being investigated as a candidate for prostate cancer gene therapy and for glioblastoma targeted therapy. Crystal structures of a truncated soluble domain of the human GLIPR1 protein (sGLIPR1) solved by molecular replacement using a truncated polyalanine search model of the CAP domain of stecrisp, a snake-venom cysteine-rich secretory protein (CRISP), are presented. The correct molecular-replacement solution could only be obtained by removing all loops from the search model. The native structure was refined to 1.85 Å resolution and that of a Zn{sup 2+} complex was refined to 2.2 Å resolution. The latter structure revealed that the putative binding cavity coordinates Zn{sup 2+} similarly to snake-venom CRISPs, which are involved in Zn{sup 2+}-dependent mechanisms of inflammatory modulation. Both sGLIPR1 structures have extensive flexible loop/turn regions and unique charge distributions that were not observed in any of the previously reported CAP protein structures. A model is also proposed for the structure of full-length membrane-bound GLIPR1.

Disorder-specific predictive classification of adolescents with attention deficit hyperactivity disorder (ADHD relative to autism using structural magnetic resonance imaging.

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Lena Lim

Full Text Available Attention Deficit Hyperactivity Disorder (ADHD is a neurodevelopmental disorder, but diagnosed by subjective clinical and rating measures. The study's aim was to apply Gaussian process classification (GPC to grey matter (GM volumetric data, to assess whether individual ADHD adolescents can be accurately differentiated from healthy controls based on objective, brain structure measures and whether this is disorder-specific relative to autism spectrum disorder (ASD.Twenty-nine adolescent ADHD boys and 29 age-matched healthy and 19 boys with ASD were scanned. GPC was applied to make disorder-specific predictions of ADHD diagnostic status based on individual brain structure patterns. In addition, voxel-based morphometry (VBM analysis tested for traditional univariate group level differences in GM.The pattern of GM correctly classified 75.9% of patients and 82.8% of controls, achieving an overall classification accuracy of 79.3%. Furthermore, classification was disorder-specific relative to ASD. The discriminating GM patterns showed higher classification weights for ADHD in earlier developing ventrolateral/premotor fronto-temporo-limbic and stronger classification weights for healthy controls in later developing dorsolateral fronto-striato-parieto-cerebellar networks. Several regions were also decreased in GM in ADHD relative to healthy controls in the univariate VBM analysis, suggesting they are GM deficit areas.The study provides evidence that pattern recognition analysis can provide significant individual diagnostic classification of ADHD patients and healthy controls based on distributed GM patterns with 79.3% accuracy and that this is disorder-specific relative to ASD. Findings are a promising first step towards finding an objective differential diagnostic tool based on brain imaging measures to aid with the subjective clinical diagnosis of ADHD.

Predictors of natively unfolded proteins: unanimous consensus score to detect a twilight zone between order and disorder in generic datasets

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Deiana Antonio

2010-04-01

Full Text Available Abstract Background Natively unfolded proteins lack a well defined three dimensional structure but have important biological functions, suggesting a re-assignment of the structure-function paradigm. To assess that a given protein is natively unfolded requires laborious experimental investigations, then reliable sequence-only methods for predicting whether a sequence corresponds to a folded or to an unfolded protein are of interest in fundamental and applicative studies. Many proteins have amino acidic compositions compatible both with the folded and unfolded status, and belong to a twilight zone between order and disorder. This makes difficult a dichotomic classification of protein sequences into folded and natively unfolded ones. In this work we propose an operational method to identify proteins belonging to the twilight zone by combining into a consensus score good performing single predictors of folding. Results In this methodological paper dichotomic folding indexes are considered: hydrophobicity-charge, mean packing, mean pairwise energy, Poodle-W and a new global index, that is called here gVSL2, based on the local disorder predictor VSL2. The performance of these indexes is evaluated on different datasets, in particular on a new dataset composed by 2369 folded and 81 natively unfolded proteins. Poodle-W, gVSL2 and mean pairwise energy have good performance and stability in all the datasets considered and are combined into a strictly unanimous combination score SSU, that leaves proteins unclassified when the consensus of all combined indexes is not reached. The unclassified proteins: i belong to an overlap region in the vector space of amino acidic compositions occupied by both folded and unfolded proteins; ii are composed by approximately the same number of order-promoting and disorder-promoting amino acids; iii have a mean flexibility intermediate between that of folded and that of unfolded proteins. Conclusions Our results show that

Health Related Quality of Life in Children with Autism Spectrum Disorders: The Clinical and Demographic Related Factors in Turkey

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Kose, Sezen; Erermis, Serpil; Ozturk, Onder; Ozbaran, Burcu; Demiral, Nagehan; Bildik, Tezan; Aydin, Cahide

2013-01-01

We aimed to investigate the Health Related Quality of Life and related clinical variables (HRQoL) of children with Autism Spectrum Disorders (ASD). We included 102 children with ASD (46 with autism, 38 with pervasive developmental disorder not otherwise specified (PDD-NOS) and 18 with Asperger's syndrome (AS)) and 39 typically developing children…

Antimony and sleep-related disorders: NHANES 2005-2008.

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Scinicariello, Franco; Buser, Melanie C; Feroe, Aliya G; Attanasio, Roberta

2017-07-01

Antimony is used as a flame-retardant in textiles and plastics, in semiconductors, pewter, and as pigments in paints, lacquers, glass and pottery. Subacute or chronic antimony poisoning has been reported to cause sleeplessness. The prevalence of short sleep duration (sleep apnea (OSA) affects 12-28 million US adults. Insufficient sleep and OSA have been linked to the development of several chronic conditions including diabetes, cardiovascular disease, obesity and depression, conditions that pose serious public health threats. To investigate whether there is an association between antimony exposure and sleep-related disorders in the US adult population using the National Health and Nutrition Examination Survey (NHANES) 2005-2008. We performed multivariate logistic regression to analyze the association of urinary antimony with several sleep disorders, including insufficient sleep and OSA, in adult (ages 20 years and older) participants of NHANES 2005-2008 (n=2654). We found that participants with higher urinary antimony levels had higher odds to experience insufficient sleep (≤6h/night) (OR 1.73; 95%CI; 1.04, 2.91) as well as higher odds to have increased sleep onset latency (>30min/night). Furthermore, we found that higher urinary antimony levels in participants were associated with OSA (OR 1.57; 95%CI; 1.05, 2.34), sleep problems, and day-time sleepiness. In this study, we found that urinary antimony was associated with higher odds to have insufficient sleep and OSA. Because of the public health implications of sleep disorders, further studies, especially a prospective cohort study, are warranted to evaluate the association between antimony exposure and sleep-related disorders. Copyright © 2017. Published by Elsevier Inc.

On the importance of polar interactions for complexes containing intrinsically disordered proteins.

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Eric T C Wong

Full Text Available There is a growing recognition for the importance of proteins with large intrinsically disordered (ID segments in cell signaling and regulation. ID segments in these proteins often harbor regions that mediate molecular recognition. Coupled folding and binding of the recognition regions has been proposed to confer high specificity to interactions involving ID segments. However, researchers recently questioned the origin of the interaction specificity of ID proteins because of the overrepresentation of hydrophobic residues in their interaction interfaces. Here, we focused on the role of polar and charged residues in interactions mediated by ID segments. Making use of the extended nature of most ID segments when in complex with globular proteins, we first identified large numbers of complexes between globular proteins and ID segments by using radius-of-gyration-based selection criteria. Consistent with previous studies, we found the interfaces of these complexes to be enriched in hydrophobic residues, and that these residues contribute significantly to the stability of the interaction interface. However, our analyses also show that polar interactions play a larger role in these complexes than in structured protein complexes. Computational alanine scanning and salt-bridge analysis indicate that interfaces in ID complexes are highly complementary with respect to electrostatics, more so than interfaces of globular proteins. Follow-up calculations of the electrostatic contributions to the free energy of binding uncovered significantly stronger Coulombic interactions in complexes harbouring ID segments than in structured protein complexes. However, they are counter-balanced by even higher polar-desolvation penalties. We propose that polar interactions are a key contributing factor to the observed high specificity of ID segment-mediated interactions.

Sex differences in stress-related psychiatric disorders: neurobiological perspectives.

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Bangasser, Debra A; Valentino, Rita J

2014-08-01

Stress is associated with the onset and severity of several psychiatric disorders that occur more frequently in women than men, including posttraumatic stress disorder (PTSD) and depression. Patients with these disorders present with dysregulation of several stress response systems, including the neuroendocrine response to stress, corticolimbic responses to negatively valenced stimuli, and hyperarousal. Thus, sex differences within their underlying circuitry may explain sex biases in disease prevalence. This review describes clinical studies that identify sex differences within the activity of these circuits, as well as preclinical studies that demonstrate cellular and molecular sex differences in stress responses systems. These studies reveal sex differences from the molecular to the systems level that increase endocrine, emotional, and arousal responses to stress in females. Exploring these sex differences is critical because this research can reveal the neurobiological underpinnings of vulnerability to stress-related psychiatric disorders and guide the development of novel pharmacotherapies. Copyright © 2014 Elsevier Inc. All rights reserved.

Resolving the ambiguity: Making sense of intrinsic disorder when PDB structures disagree.

Science.gov (United States)

DeForte, Shelly; Uversky, Vladimir N

2016-03-01

Missing regions in X-ray crystal structures in the Protein Data Bank (PDB) have played a foundational role in the study of intrinsically disordered protein regions (IDPRs), especially in the development of in silico predictors of intrinsic disorder. However, a missing region is only a weak indication of intrinsic disorder, and this uncertainty is compounded by the presence of ambiguous regions, where more than one structure of the same protein sequence "disagrees" in terms of the presence or absence of missing residues. The question is this: are these ambiguous regions intrinsically disordered, or are they the result of static disorder that arises from experimental conditions, ensembles of structures, or domain wobbling? A novel way of looking at ambiguous regions in terms of the pattern between multiple PDB structures has been demonstrated. It was found that the propensity for intrinsic disorder increases as the level of ambiguity decreases. However, it is also shown that ambiguity is more likely to occur as the protein region is placed within different environmental conditions, and even the most ambiguous regions as a set display compositional bias that suggests flexibility. The results suggested that ambiguity is a natural result for many IDPRs crystallized under different conditions and that static disorder and wobbling domains are relatively rare. Instead, it is more likely that ambiguity arises because many of these regions were conditionally or partially disordered. © 2016 The Protein Society.

Psychomotor development in infants with Prader-Willi syndrome and associations with sleep-related breathing disorders.

NARCIS (Netherlands)

Festen, D.A.M.; Wevers, M.; Weerd, A.W. de; Bossche, R.A. van den; Duivenvoorden, H.J.; Otten, B.J.; Wit, J.M.; Hokken-Koelega, A.C.S.

2007-01-01

Prader-Willi syndrome (PWS) is a neurogenetic disorder with hypotonia, psychomotor delay, obesity, short stature, and sleep-related breathing disorders. The aim of this study was to evaluate the association between psychomotor development and sleep-related breathing disorders in PWS infants. Bayley

Changes in cortical N-methyl-D-aspartate receptors and post-synaptic density protein 95 in schizophrenia, mood disorders and suicide.

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Dean, Brian; Gibbons, Andrew S; Boer, Simone; Uezato, Akihito; Meador-Woodruff, James; Scarr, Elizabeth; McCullumsmith, Robert E

2016-03-01

In humans, depending on dose, blocking the N-methyl-D-aspartate receptor (NMDAR) with ketamine can cause psychomimetic or antidepressant effects. The overall outcome for drugs such as ketamine depends on dose and the number of its available binding sites in the central nervous system, and to understand something of the latter variable we measure NMDAR in the frontal pole, dorsolateral prefrontal, anterior cingulate and parietal cortices from people with schizophrenia, bipolar disorder, major depressive disorders and age/sex matched controls. We measured levels of NMDARs (using [(3)H]MK-801 binding) and NMDAR sub-unit mRNAs (GRINs: using in situ hybridisation) as well as post-synaptic density protein 95 (anterior cingulate cortex only; not major depressive disorders: an NMDAR post-synaptic associated protein) in bipolar disorder, schizophrenia and controls. Compared to controls, levels of NMDAR were lower in the outer laminae of the dorsolateral prefrontal cortex (-17%, p = 0.01) in people with schizophrenia. In bipolar disorder, levels of NMDAR binding (laminae IV-VI; -19%, p disorders, levels of GRIN2D mRNA were higher in frontal pole (+22%, p suicide completers, levels of GRIN2B mRNA were higher in parietal cortex (+20%, p disorders and suicide completion and may contribute to different responses to ketamine. © The Royal Australian and New Zealand College of Psychiatrists 2015.

Eating-related Intrusive Thoughts Inventory: exploring the dimensionality of eating disorder symptoms.

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Perpiñá, Conxa; Roncero, María; Belloch, Amparo; Sánchez-Reales, Sergio

2011-08-01

The aims of this study were, first, to examine the structure and validity of the Eating-related Intrusive Thoughts Inventory (INPIAS), a self-report questionnaire designed to assess eating disorders related to intrusive thoughts (EDITs), and second, to explore the existence of a continuum ranging from normal to abnormal thought intrusions related to eating, weight, and shape. Participants were 574 (408 women) nonclinical community individuals. Analyses revealed that EDITs can be clustered into three sets: appearance-dieting, need to exercise, and thoughts-impulses related to eating disorders. EDITs' consequences showed a two-factor structure: emotional consequences/personal meaning and thought-action fusion responsibility; and four factors of strategies: "anxiety," suppression, obsessive-compulsive rituals, and distraction. The sample was then divided according to reported restrained eating. The High dietary restraint group reported a higher frequency of EDITs, whereas differences in the other factors were mediated by depression, anxiety, and obsessionality. The results suggest that eating disorder-related cognitions are experienced by nonclinical individuals, and distributed on a continuum.

A systematic review of the neural bases of psychotherapy for anxiety and related disorders.

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Brooks, Samantha J; Stein, Dan J

2015-09-01

Brain imaging studies over two decades have delineated the neural circuitry of anxiety and related disorders, particularly regions involved in fear processing and in obsessive-compulsive symptoms. The neural circuitry of fear processing involves the amygdala, anterior cingulate, and insular cortex, while cortico-striatal-thalamic circuitry plays a key role in obsessive-compulsive disorder. More recently, neuroimaging studies have examined how psychotherapy for anxiety and related disorders impacts on these neural circuits. Here we conduct a systematic review of the findings of such work, which yielded 19 functional magnetic resonance imaging studies examining the neural bases of cognitive-behavioral therapy (CBT) in 509 patients with anxiety and related disorders. We conclude that, although each of these related disorders is mediated by somewhat different neural circuitry, CBT may act in a similar way to increase prefrontal control of subcortical structures. These findings are consistent with an emphasis in cognitive-affective neuroscience on the potential therapeutic value of enhancing emotional regulation in various psychiatric conditions.

Canine models of inherited bleeding disorders in the development of coagulation assays, novel protein replacement and gene therapies.

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Nichols, T C; Hough, C; Agersø, H; Ezban, M; Lillicrap, D

2016-05-01

Animal models of inherited bleeding disorders are important for understanding disease pathophysiology and are required for preclinical assessment of safety prior to testing of novel therapeutics in human and veterinary medicine. Experiments in these animals represent important translational research aimed at developing safer and better treatments, such as plasma-derived and recombinant protein replacement therapies, gene therapies and immune tolerance protocols for antidrug inhibitory antibodies. Ideally, testing is done in animals with the analogous human disease to provide essential safety information, estimates of the correct starting dose and dose response (pharmacokinetics) and measures of efficacy (pharmacodynamics) that guide the design of human trials. For nearly seven decades, canine models of hemophilia, von Willebrand disease and other inherited bleeding disorders have not only informed our understanding of the natural history and pathophysiology of these disorders but also guided the development of novel therapeutics for use in humans and dogs. This has been especially important for the development of gene therapy, in which unique toxicities such as insertional mutagenesis, germ line gene transfer and viral toxicities must be assessed. There are several issues regarding comparative medicine in these species that have a bearing on these studies, including immune reactions to xenoproteins, varied metabolism or clearance of wild-type and modified proteins, and unique tissue tropism of viral vectors. This review focuses on the results of studies that have been performed in dogs with inherited bleeding disorders that closely mirror the human condition to develop safe and effective protein and gene-based therapies that benefit both species. © 2016 International Society on Thrombosis and Haemostasis.

Risk. Impact of having a first-degree relative with affective disorder

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Vinberg, Maj

2016-01-01

-risk twins and 5 low-risk twins) developed a psychiatric disorder during the 7-year follow-up period: 24 developed mood disorder (67%), 7 anxiety disorder (19%) and 5 (14%) substance abuse, schizophrenia or personality disorder. The results showed that familial risk, impaired stress tolerance and discrete......: the high-risk group comprised twins at risk of developing affective disorder (DZ or MZ twin; index co-twin affected); the low risk group (control group) comprised twins at low risk of developing affective disorder (DZ or MZ twin; index co-twin not affected). At baseline 234 participants were divided...... boundaries in order to have an impact on prevention. Furthermore, there is a need to move beyond the notion of ''magic bullets'', instead developing an integrated paradigm encompassing clusters of biomarkers related to behavioural measures of developmental psychopathology. Finally, as most psychiatric...

[Sleeping habits and sleep disorders during adolescence: relation to school performance].

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Salcedo Aguilar, F; Rodríguez Almonacid, F M; Monterde Aznar, M L; García Jiménez, M A; Redondo Martínez, P; Marcos Navarro, A I

2005-05-15

To determine the prevalence of sleep disorders in adolescence. To describe sleeping habits of adolescents in relation to sleep disorders and associated factors. To determine the relation between sleep disorders/inappropiate sleeping habits and school performance. Observational, descriptive, cross-sectional study. Secondary school of Cuenca (city in Spain). 1293 school children of first and fourth curses of secondary education. Structured questionnaire with opened and closed questions on sleeping habits during weekdays and at weekends and sleep disorders to be answered by the adolescents anonymously and on their own. Student's school performance with relation with to sleeping habits and sleep disorders were determined. 1155 students out of 1293 (response rate 89.33%) answered the questionnaire, 537 (45.9%) boys and 618 (54.1%) girls, 14 years old on average (between 11-18 years). On weekdays students went to bed at 23.17 h and got up at 7.46 h (average sleeping time =8 hours and 18 minutes). At weekends they went to bed at 1.02 h and got up at 10.42 h (average sleeping time =9 hours and 40 minutes). 45.4% of students said to sleep badly on Sunday night's. On average the number of subjects failed in class is higher with adolescents who complain about sleep (2.28 vs 1.91; P=.04), who are tired at waking up time (2.17 vs 1.97; P=.048) and who have morning sleepiness (2.17 vs 1.75; P=.004). Schools hours cause deficit sleeping time during weekdays which is partly made up for at weekend. At weekends there is an interruption of the adolescent's sleeping habits. School performance of adolescents with sleep disorders is lower.

Posttraumatic Stress Disorder Among Bereaved Relatives of Cancer Patients

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Elklit, Ask; Reinholt, N.; Nielsen, Louise Hjort

2010-01-01

The aim of this study was to assess post-traumatic stress disorder (PTSD) and predictors of PTSD in individuals who experienced the loss of a close relative to cancer. A total of 251 bereaved relatives ages 14 to 76 (M = 41.3, SD = 16.8) were recruited at a counseling service for cancer patients...

Total Thiols: Biomedical Importance And Their Alteration In Various Disorders

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Mungli Prakash

2009-09-01

Full Text Available Thiols are the organic compounds that contain a sulphydryl group. Among all the antioxidants that are available in the body, thiols constitute the major portion of the total body antioxidants and they play a significant role in defense against reactive oxygen species. Total thiols composed of both intracellular and extracellular thiols either in the free form as oxidized or reduced glutathione, or thiols bound to proteins. Among the thiols that are bound to proteins, albumin makes the major portion of the protein bound thiols, which binds to sufhydryl group at its cysteine-34 portion. Apart from their role in defense against free radicals, thiols share significant role in detoxification, signal transduction, apoptosis and various other functions at molecular level. The thiol status in the body can be assessed easily by determining the serum levels of thiols. Decreased levels of thiols has been noted in various medical disorders including chronic renal failure and other disorders related to kidney, cardiovascular disorders, stroke and other neurological disorders, diabetes mellitus, alcoholic cirrhosis and various other disorders. Therapy using thiols has been under investigation for certain disorders.

Environment-related health disorders. Experience and perspectives in the care of patients with environment-related health disorders; Umweltbezogene Gesundheitsstoerungen. Erfahrungen und Perspektiven umweltmedizinischer Patientenversorgung

Energy Technology Data Exchange (ETDEWEB)

Hornberg, C.; Malsch, A.K.F. [Bielefeld Univ. (Germany); Weissbach, W. [Universitaetsklinikum Aachen (Germany); Wiesmueller, G.A.

2004-08-15

Environmental medicine outpatient clinics, counseling centers, and practicing physicians have observed environment-related health disorders in patient groups of mixed age as well as for groups consisting only of adults or children. Practicing physicians suspected correlations between environmental factors and health disorders in 36-45% of cases, environmental medicine outpatient clinics and counseling centers in 4-34% for mixed-age groups, 0-24% for adults, and 9-13% for children. A comparison of these data is difficult due to differences in data acquisition, evaluation methods, and descriptive statistics used. Furthermore, data on children are insufficient. Patient-oriented environmental medicine faces a number of problems regarding determination of exposure, effects, and susceptibility, including a lack of scientifically verified cause-and-effect models as well as incorrect diagnoses, attributions, and conclusions. In view of the scope and intensity of environment-related health disorders, the topic cannot be ignored. A functioning program of environmental medicine counseling and patient care is needed for practicing physicians, universities and/or the public sector to deliver effective primary medical care in this field. As always, the building blocks of environmental medicine counseling are medical history, physical examination, differential diagnosis, human biomonitoring, and on-site inspection with environmental monitoring while also taking gender differences into account. Uniform basic documentation procedures and health science analyses will help to optimize patient care in environmental medicine. The value of a diagnostic algorithm in the care of patients with environment-related health disorders is beyond dispute. Last but not least, quality assurance and control are a sine qua non of patient-oriented environmental medicine. (orig.)

Binary classification of protein molecules into intrinsically disordered and ordered segments

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Gojobori Takashi

2011-06-01

Full Text Available Abstract Background Although structural domains in proteins (SDs are important, half of the regions in the human proteome are currently left with no SD assignments. These unassigned regions consist not only of novel SDs, but also of intrinsically disordered (ID regions since proteins, especially those in eukaryotes, generally contain a significant fraction of ID regions. As ID regions can be inferred from amino acid sequences, a method that combines SD and ID region assignments can determine the fractions of SDs and ID regions in any proteome. Results In contrast to other available ID prediction programs that merely identify likely ID regions, the DICHOT system we previously developed classifies the entire protein sequence into SDs and ID regions. Application of DICHOT to the human proteome revealed that residue-wise ID regions constitute 35%, SDs with similarity to PDB structures comprise 52%, while SDs with no similarity to PDB structures account for the remaining 13%. The last group consists of novel structural domains, termed cryptic domains, which serve as good targets of structural genomics. The DICHOT method applied to the proteomes of other model organisms indicated that eukaryotes generally have high ID contents, while prokaryotes do not. In human proteins, ID contents differ among subcellular localizations: nuclear proteins had the highest residue-wise ID fraction (47%, while mitochondrial proteins exhibited the lowest (13%. Phosphorylation and O-linked glycosylation sites were found to be located preferentially in ID regions. As O-linked glycans are attached to residues in the extracellular regions of proteins, the modification is likely to protect the ID regions from proteolytic cleavage in the extracellular environment. Alternative splicing events tend to occur more frequently in ID regions. We interpret this as evidence that natural selection is operating at the protein level in alternative splicing. Conclusions We classified

Prevalence of work-related musculoskeletal disorders among physical therapists

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Zaheen Iqbal

2015-08-01

Full Text Available Background: Health professions like dentistry, nursing and physical therapy have been reported at high risk for developing workrelated musculoskeletal disorders. Results of studies conducted in these occupational groups may help formulate prevention strategies. However, no such data among physical therapists has been reported in India. Material and Methods: We conducted an online survey among 100 physiotherapists in Delhi. Results: The response rate was 75%. The prevalence of work-related musculoskeletal disorders is found to be high since 92% of them reported to feel some pain after joining physical therapy which affects daily activities and even sometimes forces them to change their work. Physical therapists specialty, gender, furniture used in clinic and duration of patient contact are found to be related to the pain development (p < 0.05. Conclusions: We need to emphasize the role of ergonomics and techniques of patient handling in development of work-related pain symptoms. Med Pr 2015;66(4:459–469

C-reactive protein alterations in bipolar disorder: a meta-analysis.

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Dargél, Aroldo A; Godin, Ophelia; Kapczinski, Flávio; Kupfer, David J; Leboyer, Marion

2015-02-01

There is growing evidence that bipolar disorder (BD) is associated with inflammation, including abnormal levels of acute-phase C-reactive protein (CRP). Our meta-analysis was conducted to estimate the size of the association between CRP levels and BD, accounting also for subgroup differences (mood phases and treatment). MEDLINE, EMBASE, PsycINFO, and ISI Web of Science and references of identified articles were searched up to June 2013 using the keywords (bipolar disorder) AND (C-reactive protein OR CRP). English language studies measuring blood levels of CRP in patients with BD and control subjects were selected, 136 abstracts were reviewed, 20 articles retrieved, and 11 studies included. Two independent reviewers extracted data. All studies were included in the primary analyses, and between-group differences for subanalyses were also reported. This meta-analysis was performed using random-effects models. Eleven studies comprising 1,618 subjects were eligible for inclusion. Overall, CRP levels were significantly elevated in patients with BD versus controls (standardized mean difference [SMD] = 0.39; 95% CI, 0.24 to 0.55; P < .0001). CRP levels were significantly higher in manic (SMD = 0.73; 95% CI, 0.44 to 1.02; P < .001) and euthymic (SMD = 0.26; 95% CI, 0.01 to 0.51; P = .04), but not in depressed (SMD = 0.28; 95% CI, -0.17 to 0.73; P = .22) patients with BD compared to controls. CRP levels were unrelated to use of lithium or antipsychotic medication. This meta-analysis supports an association between increased CRP levels and BD. Given that an elevated level of CRP is a marker of low-grade inflammation and a risk factor for cardiovascular and malignant diseases, measurement of CRP level might be relevant to the clinical care of bipolar patients. © Copyright 2015 Physicians Postgraduate Press, Inc.

Digested disorder

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DeForte, Shelly; Reddy, Krishna D; Uversky, Vladimir N

2013-01-01

The current literature on intrinsically disordered proteins is overwhelming. To keep interested readers up to speed with this literature, we continue a “Digested Disorder” project and represent a series of reader’s digest type articles objectively representing the research papers and reviews on intrinsically disordered proteins. The only 2 criteria for inclusion in this digest are the publication date (a paper should be published within the covered time frame) and topic (a paper should be dedicated to any aspect of protein intrinsic disorder). The current digest issue covers papers published during the period of April, May, and June of 2013. The papers are grouped hierarchically by topics they cover, and for each of the included paper a short description is given on its major findings. PMID:28516028

DIBS: a repository of disordered binding sites mediating interactions with ordered proteins.

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Schad, Eva; Fichó, Erzsébet; Pancsa, Rita; Simon, István; Dosztányi, Zsuzsanna; Mészáros, Bálint

2018-02-01

Intrinsically Disordered Proteins (IDPs) mediate crucial protein-protein interactions, most notably in signaling and regulation. As their importance is increasingly recognized, the detailed analyses of specific IDP interactions opened up new opportunities for therapeutic targeting. Yet, large scale information about IDP-mediated interactions in structural and functional details are lacking, hindering the understanding of the mechanisms underlying this distinct binding mode. Here, we present DIBS, the first comprehensive, curated collection of complexes between IDPs and ordered proteins. DIBS not only describes by far the highest number of cases, it also provides the dissociation constants of their interactions, as well as the description of potential post-translational modifications modulating the binding strength and linear motifs involved in the binding. Together with the wide range of structural and functional annotations, DIBS will provide the cornerstone for structural and functional studies of IDP complexes. DIBS is freely accessible at http://dibs.enzim.ttk.mta.hu/. The DIBS application is hosted by Apache web server and was implemented in PHP. To enrich querying features and to enhance backend performance a MySQL database was also created. dosztanyi@caesar.elte.hu or bmeszaros@caesar.elte.hu. Supplementary data are available at Bioinformatics online. © The Author 2017. Published by Oxford University Press.

Health-Related Quality of Life in Obese Presurgery Patients with and without Binge Eating Disorder, and Subdiagnostic Binge Eating Disorders

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Rita Marie Sandberg

2013-01-01

Full Text Available Objective. To study health-related quality of life (HRQoL in obese presurgery patients with binge eating disorder (BED and with subdiagnostic binge eating disorder (SBED compared to patients without eating disorders or SBED. Method. Participants were patients referred to St. Olavs University Hospital, Norway, for bariatric surgery. Eating Disorders in Obesity (EDO questionnaire was used to diagnose BED and SBED. Short-Form Health Survey (SF-12 assessed health-related quality of life. Questionnaires were returned by 160 of 209 patients. The present study sample consisted of 143 patients (103 women and 40 men as 17 patients did not complete the SF-12. Results. Patients with BED and patients with SBED both had significantly lower mental HRQoL, but not physical HRQoL, compared to patients without eating disorders. Discussion. The findings indicate that obese presurgery patients with BED, and also SBED, may have special treatment needs in regard to their mental health.

Somatic Symptom and Related Disorders

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... A headache may mean a brain tumor. Body dysmorphic disorder occurs when a person becomes obsessed with ... body. Common concerns for people who have body dysmorphic disorder include: wrinkles hair loss weight gain size ...

Gluten-free diet in gluten-related disorders.

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Mulder, Chris J J; van Wanrooij, R L J; Bakker, S F; Wierdsma, N; Bouma, G

2013-01-01

A gluten-free diet (GFD) is recommended for all patients with coeliac disease (CD). The spectrum of gluten-related disorders in the early 1980s was simple: CD and dermatitis herpetiformis. In the last few years, wheat allergy, gluten ataxia and noncoeliac gluten sensitivity have become new gluten-related topics. Adherence to GFDs in CD is limited and factors influencing adherence are poorly understood. Noncoeliac gluten sensitivity has stimulated the GFD food industry not only in Australia but all over the world. This article provides an overview of GFD in daily practice. Copyright © 2013 S. Karger AG, Basel.

Prediction of the Ebola Virus Infection Related Human Genes Using Protein-Protein Interaction Network.

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Cao, HuanHuan; Zhang, YuHang; Zhao, Jia; Zhu, Liucun; Wang, Yi; Li, JiaRui; Feng, Yuan-Ming; Zhang, Ning

2017-01-01

Ebola hemorrhagic fever (EHF) is caused by Ebola virus (EBOV). It is reported that human could be infected by EBOV with a high fatality rate. However, association factors between EBOV and host still tend to be ambiguous. According to the "guilt by association" (GBA) principle, proteins interacting with each other are very likely to function similarly or the same. Based on this assumption, we tried to obtain EBOV infection-related human genes in a protein-protein interaction network using Dijkstra algorithm. We hope it could contribute to the discovery of novel effective treatments. Finally, 15 genes were selected as potential EBOV infection-related human genes. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Threat Related Selective Attention Predicts Treatment Success in Childhood Anxiety Disorders

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Legerstee, Jeroen S.; Tulen, Joke H. M.; Kallen, Victor L.; Dieleman, Gwen C.; Treffers, Philip D. A.; Verhulst, Frank C.; Utens, Elisabeth M. W. J.

2009-01-01

Threat-related selective attention was found to predict the success of the treatment of childhood anxiety disorders through administering a pictorial dot-probe task to 131 children with anxiety disorders prior to cognitive behavioral therapy. The diagnostic status of the subjects was evaluated with a semistructured clinical interview at both pre-…

A Relational Cultural Approach to Working with Clients with Eating Disorders

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Trepal, Heather C.; Boie, Ioana; Kress, Victoria E.

2012-01-01

The authors examine eating disorders through the conceptual framework of relational cultural theory (RCT). Taking into account the importance of relationships and connection, it is suggested that RCT may be a useful lens for conceptualizing and working with people who are experiencing eating disorders. Ways that RCT can be applied to enhance…

Conductance of single microRNAs chains related to the autism spectrum disorder

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Oliveira, J. I. N.; Albuquerque, E. L.; Fulco, U. L.; Mauriz, P. W.; Sarmento, R. G.; Caetano, E. W. S.; Freire, V. N.

2014-09-01

The charge transport properties of single-stranded microRNAs (miRNAs) chains associated to autism disorder were investigated. The computations were performed within a tight-binding model, together with a transfer matrix technique, with ionization energies and hopping parameters obtained by quantum chemistry method. Current-voltage (I× V) curves of twelve miRNA chains related to the autism spectrum disorders were calculated and analysed. We have obtained both semiconductor and insulator behavior, and a relationship between the current intensity and the autism-related miRNA bases sequencies, suggesting that a kind of electronic biosensor can be developed to distinguish different profiles of autism disorders.

Abnormal occipital event-related potentials in Parkinson's disease with concomitant REM sleep behavior disorder.

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Gaudreault, Pierre-Olivier; Gagnon, Jean-François; Montplaisir, Jacques; Vendette, Mélanie; Postuma, Ronald B; Gagnon, Katia; Gosselin, Nadia

2013-02-01

Rapid eye movement sleep behavior disorder is found in 33-46% of patients with Parkinson's disease and was shown to be associated with cognitive deficits. Our goal was to improve our understanding of the role of this sleep disorder in cerebral dysfunction occurring in Parkinson's disease using a visual cognitive task and event-related potentials. Sixteen patients with Parkinson's disease and rapid eye movement sleep behavior disorder, 15 patients with Parkinson's disease without rapid eye movement sleep behavior disorder and 16 healthy control subjects were included. The amplitude and latency of event-related potentials were compared between groups. No group differences were found for reaction times or accuracy. A Group effect was found for P2 wave amplitude; patients with rapid eye movement sleep behavior disorder had increased P2 in comparison with the control group (p disorder were associated with abnormal visual P2 component of event-related potentials. Although patients with Parkinson's disease alone were not significantly different from patients with combined Parkinson's disease and rapid eye movement sleep behavior disorder, their P2 amplitudes were not sufficiently abnormal to differ from that of control subjects. This study confirms that rapid eye movement sleep behavior disorder accentuates cerebral dysfunctions in Parkinson's disease. Copyright © 2012 Elsevier Ltd. All rights reserved.

DSM-V diagnostic criteria for bereavement-related disorders in children and adolescents: developmental considerations.

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Kaplow, Julie B; Layne, Christopher M; Pynoos, Robert S; Cohen, Judith A; Lieberman, Alicia

2012-01-01

Two bereavement-related disorders are proposed for the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-V): Adjustment Disorder Related to Bereavement, to be located in the main body of the text as an official diagnostic entity; and Bereavement-Related Disorder, including a Traumatic Death Specifier, to be located in the Appendix as an invitation for further research. These diagnoses currently do not include developmentally informed criteria, despite the importance of developmental processes in the ways children and adolescents grieve. In this article, we draw upon a selective review of the empirical literature and expert clinical knowledge to recommend developmentally informed modifications and specifiers of the proposed criteria for both bereavement disorders and strategies to improve future research. This article is derived from an invited report submitted to the DSM-V Posttraumatic Stress Disorder, Trauma, and Dissociative Disorders Sub-Work Group, and suggested modifications have received preliminary approval to be incorporated into the DSM-V at the time of this writing. Adoption of these proposals will have far-reaching consequences, given that DSM-V criteria will influence both critical treatment choices for bereaved youth and the next generation of research studies.

Overwork-related disorders in Japan: recent trends and development of a national policy to promote preventive measures.

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Yamauchi, Takashi; Yoshikawa, Toru; Takamoto, Masahiro; Sasaki, Takeshi; Matsumoto, Shun; Kayashima, Kotaro; Takeshima, Tadashi; Takahashi, Masaya

2017-06-08

Overwork-related disorders, such as cerebrovascular/cardiovascular diseases (CCVD) and mental disorders due to overwork, are a major occupational and public health issue worldwide, particularly in East Asian countries. This report discusses the recent trend of overwork-related disorders in Japan from the perspective of workers' compensated occupational diseases, as well as the development of a national policy for preventive measures against overwork-related disorders in Japan. Recently, the number of claimed and compensated cases of occupational mental disorders has increased substantially, particularly among young workers, as compared to those of occupational CCVD. In response to these situations and action from society, the Japanese Government passed the "Act on Promotion of Preventive Measures against Karoshi and Other Overwork-Related Health Disorders" in June 2014 to develop a national initiative towards the prevention of overwork-related disorders. Changes in the trend of overwork-related disorders in Japan under a legal foundation and an initiative by the central government should be closely monitored so that other countries can benefit from the experiences.

Internet gaming disorder, social network disorder and laterality: handedness relates to pathological use of social networks.

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Bouna-Pyrrou, Polyxeni; Mühle, Christiane; Kornhuber, Johannes; Lenz, Bernd

2015-08-01

The internet age bears new challenges that include health risks. It is agreed that excessive internet use may reach pathological levels. However, the concept of internet addiction lacks specificity and, therefore, warrants studies on its diagnostic and etiologic classification. This study was conducted to characterize the novel DSM-5 criteria for internet gaming disorder and the adapted criteria for the "social network disorder". Based on the established association of handedness and substance use disorders, we also explored whether internet use related to laterality. For this study, 3,287 volunteers participated in the online survey and gave particulars concerning their internet use in general, internet gaming and use of social networks, laterality markers (hand, foot, eye, ear, rotational preference in gymnastics, and head turning asymmetry) and health status. Of the participants, 1.1 % fulfilled the criteria for internet gaming disorder, and 1.8 % fulfilled the criteria for social network disorder. The applied criteria were highly correlated with the time spent on the respective internet activities (p social networks (p ≤ 4 × 10(-2)). The provided criteria proved to be user-friendly, comprehensible and well accepted. The results contribute to a better understanding of pathological internet gaming and social network use and provide evidence that biological markers of substance use disorders are involved in internet addiction.

Diagnosis of gluten related disorders: Celiac disease, wheat allergy and non-celiac gluten sensitivity.

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Elli, Luca; Branchi, Federica; Tomba, Carolina; Villalta, Danilo; Norsa, Lorenzo; Ferretti, Francesca; Roncoroni, Leda; Bardella, Maria Teresa

2015-06-21

Cereal crops and cereal consumption have had a vital role in Mankind's history. In the recent years gluten ingestion has been linked with a range of clinical disorders. Gluten-related disorders have gradually emerged as an epidemiologically relevant phenomenon with an estimated global prevalence around 5%. Celiac disease, wheat allergy and non-celiac gluten sensitivity represent different gluten-related disorders. Similar clinical manifestations can be observed in these disorders, yet there are peculiar pathogenetic pathways involved in their development. Celiac disease and wheat allergy have been extensively studied, while non-celiac gluten sensitivity is a relatively novel clinical entity, believed to be closely related to other gastrointestinal functional syndromes. The diagnosis of celiac disease and wheat allergy is based on a combination of findings from the patient's clinical history and specific tests, including serology and duodenal biopsies in case of celiac disease, or laboratory and functional assays for wheat allergy. On the other hand, non-celiac gluten sensitivity is still mainly a diagnosis of exclusion, in the absence of clear-cut diagnostic criteria. A multimodal pragmatic approach combining findings from the clinical history, symptoms, serological and histological tests is required in order to reach an accurate diagnosis. A thorough knowledge of the differences and overlap in clinical presentation among gluten-related disorders, and between them and other gastrointestinal disorders, will help clinicians in the process of differential diagnosis.

Relating DSM-5 section II and section III personality disorder diagnostic classification systems to treatment planning.

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Morey, Leslie C; Benson, Kathryn T

2016-07-01

Beginning with DSM-III, the inclusion of a "personality" axis was designed to encourage awareness of personality disorders and the treatment-related implications of individual differences, but since that time there is little accumulated evidence that the personality disorder categories provide substantial treatment-related guidance. The DSM-5 Personality and Personality Disorders Work Group sought to develop an Alternative Model for personality disorder, and this study examined whether this model is more closely related to clinicians' decision-making processes than the traditional categorical personality disorder diagnoses. A national sample of 337 clinicians provided complete personality disorder diagnostic information and several treatment-related clinical judgments about one of their patients. The dimensional concepts of the DSM-5 Alternative Model for personality disorders demonstrated stronger relationships than categorical DSM-IV/DSM-5 Section II diagnoses to 10 of 11 clinical judgments regarding differential treatment planning, optimal treatment intensity, and long-term prognosis. The constructs of the DSM-5 Alternative Model for personality disorders may provide more clinically useful information for treatment planning than the official categorical personality disorder diagnostic system retained in DSM-5 Section II. Copyright © 2016 Elsevier Inc. All rights reserved.

Intrinsically Disordered Side of the Zika Virus Proteome

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Rajanish Giri

2016-11-01

Full Text Available Over the last few decades, concepts of protein intrinsic disorder have been implicated in different biological processes. Recent studies have suggested that intrinsically disordered proteins (IDPs provide structural plasticity and functional diversity to viral proteins that are involved in rapid replication and immune evasion in host cells. In case of Zika virus, the roles of protein intrinsic disorder in mechanisms of pathogenesis are not completely understood. In this study, we have analyzed the prevalence of intrinsic disorder in Zika virus proteome (strain MR 766. Our analyses revealed that Zika virus polyprotein is enriched with intrinsically disordered protein regions (IDPRs and this finding is consistent with previous reports on the involvement of IDPs in shell formation and virulence of the Flaviviridae family. We found abundant IDPRs in Capsid, NS2B, NS3, NS4A, and NS5 proteins that are involved in mature particle formation and replication. In our view, the intrinsic disorder-focused analysis of ZIKV proteins could be important for the development of new disorder-based drugs.

Quetiapine-induced sleep-related eating disorder-like behavior: a case series

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Tamanna Sadeka

2012-11-01

Full Text Available Abstract Introduction Somnambulism or sleepwalking is a disorder of arousal from non-rapid eye movement sleep. The prevalence of sleep-related eating disorder has been found to be approximately between 1% and 5% among adults. Many cases of medication-related somnambulism and sleep-related eating disorder-like behavior have been reported in the literature. Quetiapine, an atypical antipsychotic medication, has been associated with somnambulism but has not yet been reported to be associated with sleep-related eating disorder. Case presentation Case 1 is a 51-year-old obese African American male veteran with a body mass index of 34.11kg/m2 and severe sleep apnea who has taken 150mg of quetiapine at bedtime for more than one year for depression. He developed sleepwalking three to four nights per week which resolved after stopping quetiapine while being compliant with bi-level positive pressure ventilation therapy. At one year follow-up, his body mass index was 32.57kg/m2. Case 2 is a 50-year-old African American female veteran with a body mass index of 30.5kg/m2 and mild sleep apnea who has taken 200mg of quetiapine daily for more than one year for depression. She was witnessed to sleepwalk three nights per week which resolved after discontinuing quetiapine while being treated with continuous positive airway pressure. At three months follow-up, her body mass index was 29.1kg/m2. Conclusion These cases illustrate that quetiapine may precipitate complex motor behavior including sleep-related eating disorder and somnambulism in susceptible patients. Atypical antipsychotics are commonly used in psychiatric and primary care practice, which means the population at risk of developing parasomnia may often go unrecognized. It is important to recognize this potential adverse effect of quetiapine and, to prevent injury and worsening obesity, discuss this with the patients who are prescribed these medications.

Alcohol use disorder-related sick leave and mortality: a cohort study.

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Wedegaertner, Felix; Geyer, Siegfried; Arnhold-Kerri, Sonja; Sittaro, Nicola-Alexander; te Wildt, Bert

2013-01-30

Alcohol use disorders (AUDs) are associated with the highest all-cause mortality rates of all mental disorders. The majority of patients with AUDs never receive inpatient treatment for their AUD, and there is lack of data about their mortality risks despite their constituting the majority of those affected. Absenteeism from work (sick leave) due to an AUD likely signals worsening. In this study, we assessed whether AUD-related sick leave was associated with mortality in a cohort of workers in Germany. 128,001 workers with health insurance were followed for a mean of 6.4 years. We examined the associations between 1) AUD-related sick leave managed on an outpatient basis and 2) AUD-related psychiatric inpatient treatment, and mortality using survival analysis, and Cox proportional hazard regression models (separately by sex) adjusted for age, education, and job code classification. We also stratified analyses by sick leave related to three groups of alcohol-related conditions (all determined by International Classification of Diseases 9th ed. (ICD-9) codes): alcohol abuse and dependence; alcohol-induced mental disorder; and alcohol-induced medical conditions. Outpatient-managed AUD-related sick leave was significantly associated with higher mortality (hazard ratio (HR) 2.90 (95% Confidence interval (CI) 2.24-3.75) for men, HR 5.83 (CI 2.90-11.75) for women). The magnitude of the association was similar for receipt of AUD-related psychiatric inpatient treatment (HR 3.2 (CI 2.76-3.78) for men, HR 6.5 (CI 4.41-9.47) for women). Compared to those without the conditions, higher mortality was observed consistently for outpatients and inpatients across the three groups of alcohol-related conditions. Those with alcohol-related medical conditions who had AUD-related psychiatric inpatient treatment appeared to have the highest mortality. Alcohol use disorder-related sick leave as documented in health insurance records is associated with higher mortality. Such sick leave does

Digested disorder

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Reddy, Krishna D; DeForte, Shelly; Uversky, Vladimir N

2014-01-01

The current literature on intrinsically disordered proteins grows fast. To keep interested readers up to speed with this literature, we continue a “Digested Disorder” project and represent a new issue of reader’s digest of the research papers and reviews on intrinsically disordered proteins. The only 2 criteria for inclusion in this digest are the publication date (a paper should be published within the covered time frame) and topic (a paper should be dedicated to any aspect of protein intrinsic disorder). The current digest issue covers papers published during the third quarter of 2013; i.e., during the period of June, July, and September of 2013. Similar to previous issues, the papers are grouped hierarchically by topics they cover, and for each of the included paper a short description is given on its major findings. PMID:28232877

Sleep, Plasticity and the Pathophysiology of Neurodevelopmental Disorders: The Potential Roles of Protein Synthesis and Other Cellular Processes

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Dante Picchioni

2014-03-01

Full Text Available Sleep is important for neural plasticity, and plasticity underlies sleep-dependent memory consolidation. It is widely appreciated that protein synthesis plays an essential role in neural plasticity. Studies of sleep-dependent memory and sleep-dependent plasticity have begun to examine alterations in these functions in populations with neurological and psychiatric disorders. Such an approach acknowledges that disordered sleep may have functional consequences during wakefulness. Although neurodevelopmental disorders are not considered to be sleep disorders per se, recent data has revealed that sleep abnormalities are among the most prevalent and common symptoms and may contribute to the progression of these disorders. The main goal of this review is to highlight the role of disordered sleep in the pathology of neurodevelopmental disorders and to examine some potential mechanisms by which sleep-dependent plasticity may be altered. We will also briefly attempt to extend the same logic to the other end of the developmental spectrum and describe a potential role of disordered sleep in the pathology of neurodegenerative diseases. We conclude by discussing ongoing studies that might provide a more integrative approach to the study of sleep, plasticity, and neurodevelopmental disorders.

Allergy-related disorders in the construction industry.

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Carino, Mauro; Romita, Paolo; Foti, Caterina

2013-01-01

Working conditions in the construction industry have improved in many industrialized countries, but heavy physical work with recurrent exposure to chemical agents, dust, and climatic influences still represents considerable risk for construction workers and may affect their health. The aim of this review is to analyze available data of the literature on allergy-related respiratory and skin disorders with emphasis on a preventive appraisal in order to produce statements and recommendations based on research evidence. The most common agents involved in the construction industry as a cause of occupational asthma (OA) in industrialized countries are isocyanates, wood dust, resins, glues, cobalt, and chromium. Allergic contact dermatitis (ACD) is an immunologic cell-mediated response to a sensitizing agent and the most common sensitizing agents associated with construction workers are epoxy resins, thiurams and thiazoles, and chromates. Medical surveillance must consider individual risk factors such as differences in individual susceptibility and sensitization to agents at workplace. Once work-related disorder is confirmed, adequate fitness for work should be assessed for the worker impaired by health condition. A reliable diagnosis of an index case is a sentinel event that may reveal risks for workers with similar exposure, leading to a revised risk assessment at the workplace that should reduce the risk and prevent further cases.

Protein Carbamylation: A Marker Reflecting Increased Age-Related Cell Oxidation

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Julia Carracedo

2018-05-01

Full Text Available Carbamylation is a post-translational modification of proteins that may partake in the oxidative stress-associated cell damage, and its increment has been recently proposed as a “hallmark of aging”. The molecular mechanisms associated with aging are related to an increased release of free radicals. We have studied whether carbamylated proteins from the peripheral blood of healthy subjects are related to oxidative damage and aging, taking into account the gender and the immune profile of the subjects. The study was performed in healthy human volunteers. The detection of protein carbamylation and malondialdehyde (MDA levels was evaluated using commercial kits. The immune profile was calculated using parameters of immune cell function. The results show that the individuals from the elderly group (60–79 years old have increased carbamylated protein and MDA levels. When considered by gender, only men between 60 and 79 years old showed significantly increased carbamylated proteins and MDA levels. When those subjects were classified by their immune profile, the carbamylated protein levels were higher in those with an older immune profile. In conclusion, the carbamylation of proteins in peripheral blood is related to age-associated oxidative damage and to an aging functional immunological signature. Our results suggest that carbamylated proteins may play an important role at the cellular level in the aging process.

Proteomic Analysis of Sauvignon Blanc Grape Skin, Pulp and Seed and Relative Quantification of Pathogenesis-Related Proteins.

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Bin Tian

Full Text Available Thaumatin-like proteins (TLPs and chitinases are the main constituents of so-called protein hazes which can form in finished white wine and which is a great concern of winemakers. These soluble pathogenesis-related (PR proteins are extracted from grape berries. However, their distribution in different grape tissues is not well documented. In this study, proteins were first separately extracted from the skin, pulp and seed of Sauvignon Blanc grapes, followed by trypsin digestion and analysis by liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS. Proteins identified included 75 proteins from Sauvignon Blanc grape skin, 63 from grape pulp and 35 from grape seed, mostly functionally classified as associated with metabolism and energy. Some were present exclusively in specific grape tissues; for example, proteins involved in photosynthesis were only detected in grape skin and proteins found in alcoholic fermentation were only detected in grape pulp. Moreover, proteins identified in grape seed were less diverse than those identified in grape skin and pulp. TLPs and chitinases were identified in both Sauvignon Blanc grape skin and pulp, but not in the seed. To relatively quantify the PR proteins, the protein extracts of grape tissues were seperated by HPLC first and then analysed by SDS-PAGE. The results showed that the protein fractions eluted at 9.3 min and 19.2 min under the chromatographic conditions of this study confirmed that these corresponded to TLPs and chitinases seperately. Thus, the relative quantification of TLPs and chitinases in protein extracts was carried out by comparing the area of corresponding peaks against the area of a thamautin standard. The results presented in this study clearly demonstrated the distribution of haze-forming PR proteins in grape berries, and the relative quantification of TLPs and chitinases could be applied in fast tracking of changes in PR proteins during grape growth and

Gambling disorder in financial markets: Clinical and treatment-related features.

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Shin, Young-Chul; Choi, Sam-Wook; Ha, Juwon; Choi, Jung-Seok; Kim, Dai-Jin