Structural classification of small, disulfide-rich protein domains.

PubMed

Cheek, Sara; Krishna, S Sri; Grishin, Nick V

2006-05-26

Disulfide-rich domains are small protein domains whose global folds are stabilized primarily by the formation of disulfide bonds and, to a much lesser extent, by secondary structure and hydrophobic interactions. Disulfide-rich domains perform a wide variety of roles functioning as growth factors, toxins, enzyme inhibitors, hormones, pheromones, allergens, etc. These domains are commonly found both as independent (single-domain) proteins and as domains within larger polypeptides. Here, we present a comprehensive structural classification of approximately 3000 small, disulfide-rich protein domains. We find that these domains can be arranged into 41 fold groups on the basis of structural similarity. Our fold groups, which describe broader structural relationships than existing groupings of these domains, bring together representatives with previously unacknowledged similarities; 18 of the 41 fold groups include domains from several SCOP folds. Within the fold groups, the domains are assembled into families of homologs. We define 98 families of disulfide-rich domains, some of which include newly detected homologs, particularly among knottin-like domains. On the basis of this classification, we have examined cases of convergent and divergent evolution of functions performed by disulfide-rich proteins. Disulfide bonding patterns in these domains are also evaluated. Reducible disulfide bonding patterns are much less frequent, while symmetric disulfide bonding patterns are more common than expected from random considerations. Examples of variations in disulfide bonding patterns found within families and fold groups are discussed.

Functional specialization in nucleotide sugar transporters occurred through differentiation of the gene cluster EamA (DUF6) before the radiation of Viridiplantae

PubMed Central

2011-01-01

Background The drug/metabolite transporter superfamily comprises a diversity of protein domain families with multiple functions including transport of nucleotide sugars. Drug/metabolite transporter domains are contained in both solute carrier families 30, 35 and 39 proteins as well as in acyl-malonyl condensing enzyme proteins. In this paper, we present an evolutionary analysis of nucleotide sugar transporters in relation to the entire superfamily of drug/metabolite transporters that considers crucial intra-protein duplication events that have shaped the transporters. We use a method that combines the strengths of hidden Markov models and maximum likelihood to find relationships between drug/metabolite transporter families, and branches within families. Results We present evidence that the triose-phosphate transporters, domain unknown function 914, uracil-diphosphate glucose-N-acetylglucosamine, and nucleotide sugar transporter families have evolved from a domain duplication event before the radiation of Viridiplantae in the EamA family (previously called domain unknown function 6). We identify previously unknown branches in the solute carrier 30, 35 and 39 protein families that emerged simultaneously as key physiological developments after the radiation of Viridiplantae, including the "35C/E" branch of EamA, which formed in the lineage of T. adhaerens (Animalia). We identify a second cluster of DMTs, called the domain unknown function 1632 cluster, which has non-cytosolic N- and C-termini, and thus appears to have been formed from a different domain duplication event. We identify a previously uncharacterized motif, G-X(6)-G, which is overrepresented in the fifth transmembrane helix of C-terminal domains. We present evidence that the family called fatty acid elongases are homologous to transporters, not enzymes as had previously been thought. Conclusions The nucleotide sugar transporters families were formed through differentiation of the gene cluster EamA (domain unknown function 6) before Viridiplantae, showing for the first time the significance of EamA. PMID:21569384

Functional Domains of NEAT1 Architectural lncRNA Induce Paraspeckle Assembly through Phase Separation.

PubMed

Yamazaki, Tomohiro; Souquere, Sylvie; Chujo, Takeshi; Kobelke, Simon; Chong, Yee Seng; Fox, Archa H; Bond, Charles S; Nakagawa, Shinichi; Pierron, Gerard; Hirose, Tetsuro

2018-06-21

A class of long noncoding RNAs (lncRNAs) has architectural functions in nuclear body construction; however, specific RNA domains dictating their architectural functions remain uninvestigated. Here, we identified the domains of the architectural NEAT1 lncRNA that construct paraspeckles. Systematic deletion of NEAT1 portions using CRISPR/Cas9 in haploid cells revealed modular domains of NEAT1 important for RNA stability, isoform switching, and paraspeckle assembly. The middle domain, containing functionally redundant subdomains, was responsible for paraspeckle assembly. Artificial tethering of the NONO protein to a NEAT1_2 mutant lacking the functional subdomains rescued paraspeckle assembly, and this required the NOPS dimerization domain of NONO. Paraspeckles exhibit phase-separated properties including susceptibility to 1,6-hexanediol treatment. RNA fragments of the NEAT1_2 subdomains preferentially bound NONO/SFPQ, leading to phase-separated aggregates in vitro. Thus, we demonstrate that the enrichment of NONO dimers on the redundant NEAT1_2 subdomains initiates construction of phase-separated paraspeckles, providing mechanistic insights into lncRNA-based nuclear body formation. Copyright © 2018 Elsevier Inc. All rights reserved.

The structure of the cyanobactin domain of unknown function from PatG in the patellamide gene cluster

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

Mann, Greg; Koehnke, Jesko; Bent, Andrew F.

The highly conserved domain of unknown function in the cyanobactin superfamily has a novel fold. The protein does not appear to bind the most plausible substrates, leaving questions as to its role. Patellamides are members of the cyanobactin family of ribosomally synthesized and post-translationally modified cyclic peptide natural products, many of which, including some patellamides, are biologically active. A detailed mechanistic understanding of the biosynthetic pathway would enable the construction of a biotechnological ‘toolkit’ to make novel analogues of patellamides that are not found in nature. All but two of the protein domains involved in patellamide biosynthesis have been characterized.more » The two domains of unknown function (DUFs) are homologous to each other and are found at the C-termini of the multi-domain proteins PatA and PatG. The domain sequence is found in all cyanobactin-biosynthetic pathways characterized to date, implying a functional role in cyanobactin biosynthesis. Here, the crystal structure of the PatG DUF domain is reported and its binding interactions with plausible substrates are investigated.« less

Interdependence of the rad50 hook and globular domain functions.

PubMed

Hohl, Marcel; Kochańczyk, Tomasz; Tous, Cristina; Aguilera, Andrés; Krężel, Artur; Petrini, John H J

2015-02-05

Rad50 contains a conserved Zn(2+) coordination domain (the Rad50 hook) that functions as a homodimerization interface. Hook ablation phenocopies Rad50 deficiency in all respects. Here, we focused on rad50 mutations flanking the Zn(2+)-coordinating hook cysteines. These mutants impaired hook-mediated dimerization, but recombination between sister chromatids was largely unaffected. This may reflect that cohesin-mediated sister chromatid interactions are sufficient for double-strand break repair. However, Mre11 complex functions specified by the globular domain, including Tel1 (ATM) activation, nonhomologous end joining, and DNA double-strand break end resection were affected, suggesting that dimerization exerts a broad influence on Mre11 complex function. These phenotypes were suppressed by mutations within the coiled-coil and globular ATPase domains, suggesting a model in which conformational changes in the hook and globular domains are transmitted via the extended coils of Rad50. We propose that transmission of spatial information in this manner underlies the regulation of Mre11 complex functions. Copyright © 2015 Elsevier Inc. All rights reserved.

Domains of awareness in schizophrenia.

PubMed

Gilleen, J; Greenwood, K; David, A S

2011-01-01

Patients with schizophrenia are often characterized as lacking insight or awareness into their illness and symptoms, yet despite considerable research, we still lack a full understanding of the factors involved in causing poor awareness. Within schizophrenia, there has been shown to be a fractionation across dimensions of awareness into mental illness: of being ill, of symptoms, and of treatment compliance. Recently, attention has turned to evidence of a fractionation between awareness of illness and of cognitive impairments and functioning. The current study investigated the degree of fractionation across a broad range of domains of function in schizophrenia and how each domain may be associated with neuropsychological functioning, clinical, mood, and demographic variables. Thirty-one mostly chronic stable patients with schizophrenia completed a battery of neuropsychological tests and measures of psychopathology, including mood. Cognitive insight and awareness of illness, symptoms, memory, and behavioral functioning were also measured. Insight and awareness were assessed using a combination of semistructured interview, observer-rated, self-rated, and objective measures, and included measures of the discrepancy between carer and self-ratings of impairment. Results revealed that awareness of functioning in each domain was largely independent and that awareness in each domain was predicted by different factors. Insight into symptoms was relatively poor while insight into cognitive deficits was preserved. Relative to neuropsychological variables, cognitive insight, comprising self-certainty and self-reflexivity, was a greater predictor of awareness. In conclusion, awareness is multiply fractionated and multiply determined. Therapeutic interventions could, therefore, produce beneficial changes within specific domains of awareness.

Domains of Awareness in Schizophrenia

PubMed Central

Gilleen, J.; Greenwood, K.; David, A. S.

2011-01-01

Patients with schizophrenia are often characterized as lacking insight or awareness into their illness and symptoms, yet despite considerable research, we still lack a full understanding of the factors involved in causing poor awareness. Within schizophrenia, there has been shown to be a fractionation across dimensions of awareness into mental illness: of being ill, of symptoms, and of treatment compliance. Recently, attention has turned to evidence of a fractionation between awareness of illness and of cognitive impairments and functioning. The current study investigated the degree of fractionation across a broad range of domains of function in schizophrenia and how each domain may be associated with neuropsychological functioning, clinical, mood, and demographic variables. Thirty-one mostly chronic stable patients with schizophrenia completed a battery of neuropsychological tests and measures of psychopathology, including mood. Cognitive insight and awareness of illness, symptoms, memory, and behavioral functioning were also measured. Insight and awareness were assessed using a combination of semistructured interview, observer-rated, self-rated, and objective measures, and included measures of the discrepancy between carer and self-ratings of impairment. Results revealed that awareness of functioning in each domain was largely independent and that awareness in each domain was predicted by different factors. Insight into symptoms was relatively poor while insight into cognitive deficits was preserved. Relative to neuropsychological variables, cognitive insight, comprising self-certainty and self-reflexivity, was a greater predictor of awareness. In conclusion, awareness is multiply fractionated and multiply determined. Therapeutic interventions could, therefore, produce beneficial changes within specific domains of awareness. PMID:20851850

CLAVATA1 Dominant-Negative Alleles Reveal Functional Overlap between Multiple Receptor Kinases That Regulate Meristem and Organ Development

PubMed Central

Diévart, Anne; Dalal, Monica; Tax, Frans E.; Lacey, Alexzandria D.; Huttly, Alison; Li, Jianming; Clark, Steven E.

2003-01-01

The CLAVATA1 (CLV1) receptor kinase controls stem cell number and differentiation at the Arabidopsis shoot and flower meristems. Other components of the CLV1 signaling pathway include the secreted putative ligand CLV3 and the receptor-like protein CLV2. We report evidence indicating that all intermediate and strong clv1 alleles are dominant negative and likely interfere with the activity of unknown receptor kinase(s) that have functional overlap with CLV1. clv1 dominant-negative alleles show major differences from dominant-negative alleles characterized to date in animal receptor kinase signaling systems, including the lack of a dominant-negative effect of kinase domain truncation and the ability of missense mutations in the extracellular domain to act in a dominant-negative manner. We analyzed chimeric receptor kinases by fusing CLV1 and BRASSINOSTEROID INSENSITIVE1 (BRI1) coding sequences and expressing these in clv1 null backgrounds. Constructs containing the CLV1 extracellular domain and the BRI1 kinase domain were strongly dominant negative in the regulation of meristem development. Furthermore, we show that CLV1 expressed within the pedicel can partially replace the function of the ERECTA receptor kinase. We propose the presence of multiple receptors that regulate meristem development in a functionally related manner whose interactions are driven by the extracellular domains and whose activation requires the kinase domain. PMID:12724544

Recombinant spider silk genetically functionalized with affinity domains.

PubMed

Jansson, Ronnie; Thatikonda, Naresh; Lindberg, Diana; Rising, Anna; Johansson, Jan; Nygren, Per-Åke; Hedhammar, My

2014-05-12

Functionalization of biocompatible materials for presentation of active protein domains is an area of growing interest. Herein, we describe a strategy for functionalization of recombinant spider silk via gene fusion to affinity domains of broad biotechnological use. Four affinity domains of different origin and structure; the IgG-binding domains Z and C2, the albumin-binding domain ABD, and the biotin-binding domain M4, were all successfully produced as soluble silk fusion proteins under nondenaturing purification conditions. Silk films and fibers produced from the fusion proteins were demonstrated to be chemically and thermally stable. Still, the bioactive domains are concluded to be folded and accessible, since their respective targets could be selectively captured from complex samples, including rabbit serum and human plasma. Interestingly, materials produced from mixtures of two different silk fusion proteins displayed combined binding properties, suggesting that tailor-made materials with desired stoichiometry and surface distributions of several binding domains can be produced. Further, use of the IgG binding ability as a general mean for presentation of desired biomolecules could be demonstrated for a human vascular endothelial growth factor (hVEGF) model system, via a first capture of anti-VEGF IgG to silk containing the Z-domain, followed by incubation with hVEGF. Taken together, this study demonstrates the potential of recombinant silk, genetically functionalized with affinity domains, for construction of biomaterials capable of presentation of almost any desired biomolecule.

Construct validity of the PROMIS® sexual function and satisfaction measures in patients with cancer

PubMed Central

2013-01-01

Background With data from a diverse sample of patients either in treatment for cancer or post-treatment for cancer, we examine inter-domain and cross-domain correlations among the core domains of the Patient-Reported Outcomes Measurement Information System Sexual Function and Satisfaction measures (PROMIS® SexFS) and the corresponding domains from conceptually-similar measures of sexual function, the International Index of Erectile Function and the Female Sexual Function Index. Findings Men (N=389) and women (N=430) were recruited from a tumor registry, oncology clinics, and an internet panel. The PROMIS SexFS, International Index of Erectile Function, and Female Sexual Function Index were used to collect participants’ self-reported sexual function. The domains shared among the measures include desire/interest in sexual activity, lubrication and vaginal discomfort/pain (women), erectile function (men), orgasm, and satisfaction. We examined correlations among different domains within the same instrument (discriminant validity) and correlations among similar domains measured by different instruments (convergent validity). Correlations demonstrating discriminant validity ranged from 0.38 to 0.73 for men and 0.48 to 0.74 for women, while correlations demonstrating convergent validity ranged from 0.62 to 0.83 for men and 0.71 to 0.92 for women. As expected, correlations demonstrating convergent validity were higher than correlations demonstrating discriminant validity, with one exception (orgasm for men). Conclusions Construct validity was supported by convergent and discriminant validity in a diverse sample of patients with cancer. For patients with cancer who may or may not have sexual dysfunction, the PROMIS SexFS measures provide a comprehensive assessment of key domains of sexual function and satisfaction. PMID:23497200

Domain atrophy creates rare cases of functional partial protein domains.

PubMed

Prakash, Ananth; Bateman, Alex

2015-04-30

Protein domains display a range of structural diversity, with numerous additions and deletions of secondary structural elements between related domains. We have observed a small number of cases of surprising large-scale deletions of core elements of structural domains. We propose a new concept called domain atrophy, where protein domains lose a significant number of core structural elements. Here, we implement a new pipeline to systematically identify new cases of domain atrophy across all known protein sequences. The output of this pipeline was carefully checked by hand, which filtered out partial domain instances that were unlikely to represent true domain atrophy due to misannotations or un-annotated sequence fragments. We identify 75 cases of domain atrophy, of which eight cases are found in a three-dimensional protein structure and 67 cases have been inferred based on mapping to a known homologous structure. Domains with structural variations include ancient folds such as the TIM-barrel and Rossmann folds. Most of these domains are observed to show structural loss that does not affect their functional sites. Our analysis has significantly increased the known cases of domain atrophy. We discuss specific instances of domain atrophy and see that there has often been a compensatory mechanism that helps to maintain the stability of the partial domain. Our study indicates that although domain atrophy is an extremely rare phenomenon, protein domains under certain circumstances can tolerate extreme mutations giving rise to partial, but functional, domains.

Domain duplication, divergence, and loss events in vertebrate Msx paralogs reveal phylogenomically informed disease markers

PubMed Central

Finnerty, John R; Mazza, Maureen E; Jezewski, Peter A

2009-01-01

Background Msx originated early in animal evolution and is implicated in human genetic disorders. To reconstruct the functional evolution of Msx and inform the study of human mutations, we analyzed the phylogeny and synteny of 46 metazoan Msx proteins and tracked the duplication, diversification and loss of conserved motifs. Results Vertebrate Msx sequences sort into distinct Msx1, Msx2 and Msx3 clades. The sister-group relationship between MSX1 and MSX2 reflects their derivation from the 4p/5q chromosomal paralogon, a derivative of the original "MetaHox" cluster. We demonstrate physical linkage between Msx and other MetaHox genes (Hmx, NK1, Emx) in a cnidarian. Seven conserved domains, including two Groucho repression domains (N- and C-terminal), were present in the ancestral Msx. In cnidarians, the Groucho domains are highly similar. In vertebrate Msx1, the N-terminal Groucho domain is conserved, while the C-terminal domain diverged substantially, implying a novel function. In vertebrate Msx2 and Msx3, the C-terminal domain was lost. MSX1 mutations associated with ectodermal dysplasia or orofacial clefting disorders map to conserved domains in a non-random fashion. Conclusion Msx originated from a MetaHox ancestor that also gave rise to Tlx, Demox, NK, and possibly EHGbox, Hox and ParaHox genes. Duplication, divergence or loss of domains played a central role in the functional evolution of Msx. Duplicated domains allow pleiotropically expressed proteins to evolve new functions without disrupting existing interaction networks. Human missense sequence variants reside within evolutionarily conserved domains, likely disrupting protein function. This phylogenomic evaluation of candidate disease markers will inform clinical and functional studies. PMID:19154605

Domain duplication, divergence, and loss events in vertebrate Msx paralogs reveal phylogenomically informed disease markers.

PubMed

Finnerty, John R; Mazza, Maureen E; Jezewski, Peter A

2009-01-20

Msx originated early in animal evolution and is implicated in human genetic disorders. To reconstruct the functional evolution of Msx and inform the study of human mutations, we analyzed the phylogeny and synteny of 46 metazoan Msx proteins and tracked the duplication, diversification and loss of conserved motifs. Vertebrate Msx sequences sort into distinct Msx1, Msx2 and Msx3 clades. The sister-group relationship between MSX1 and MSX2 reflects their derivation from the 4p/5q chromosomal paralogon, a derivative of the original "MetaHox" cluster. We demonstrate physical linkage between Msx and other MetaHox genes (Hmx, NK1, Emx) in a cnidarian. Seven conserved domains, including two Groucho repression domains (N- and C-terminal), were present in the ancestral Msx. In cnidarians, the Groucho domains are highly similar. In vertebrate Msx1, the N-terminal Groucho domain is conserved, while the C-terminal domain diverged substantially, implying a novel function. In vertebrate Msx2 and Msx3, the C-terminal domain was lost. MSX1 mutations associated with ectodermal dysplasia or orofacial clefting disorders map to conserved domains in a non-random fashion. Msx originated from a MetaHox ancestor that also gave rise to Tlx, Demox, NK, and possibly EHGbox, Hox and ParaHox genes. Duplication, divergence or loss of domains played a central role in the functional evolution of Msx. Duplicated domains allow pleiotropically expressed proteins to evolve new functions without disrupting existing interaction networks. Human missense sequence variants reside within evolutionarily conserved domains, likely disrupting protein function. This phylogenomic evaluation of candidate disease markers will inform clinical and functional studies.

Functions of intrinsic disorder in transmembrane proteins.

PubMed

Kjaergaard, Magnus; Kragelund, Birthe B

2017-09-01

Intrinsic disorder is common in integral membrane proteins, particularly in the intracellular domains. Despite this observation, these domains are not always recognized as being disordered. In this review, we will discuss the biological functions of intrinsically disordered regions of membrane proteins, and address why the flexibility afforded by disorder is mechanistically important. Intrinsically disordered regions are present in many common classes of membrane proteins including ion channels and transporters; G-protein coupled receptors (GPCRs), receptor tyrosine kinases and cytokine receptors. The functions of the disordered regions are many and varied. We will discuss selected examples including: (1) Organization of receptors, kinases, phosphatases and second messenger sources into signaling complexes. (2) Modulation of the membrane-embedded domain function by ball-and-chain like mechanisms. (3) Trafficking of membrane proteins. (4) Transient membrane associations. (5) Post-translational modifications most notably phosphorylation and (6) disorder-linked isoform dependent function. We finish the review by discussing the future challenges facing the membrane protein community regarding protein disorder.

Insulator function and topological domain border strength scale with architectural protein occupancy

PubMed Central

2014-01-01

Background Chromosome conformation capture studies suggest that eukaryotic genomes are organized into structures called topologically associating domains. The borders of these domains are highly enriched for architectural proteins with characterized roles in insulator function. However, a majority of architectural protein binding sites localize within topological domains, suggesting sites associated with domain borders represent a functionally different subclass of these regulatory elements. How topologically associating domains are established and what differentiates border-associated from non-border architectural protein binding sites remain unanswered questions. Results By mapping the genome-wide target sites for several Drosophila architectural proteins, including previously uncharacterized profiles for TFIIIC and SMC-containing condensin complexes, we uncover an extensive pattern of colocalization in which architectural proteins establish dense clusters at the borders of topological domains. Reporter-based enhancer-blocking insulator activity as well as endogenous domain border strength scale with the occupancy level of architectural protein binding sites, suggesting co-binding by architectural proteins underlies the functional potential of these loci. Analyses in mouse and human stem cells suggest that clustering of architectural proteins is a general feature of genome organization, and conserved architectural protein binding sites may underlie the tissue-invariant nature of topologically associating domains observed in mammals. Conclusions We identify a spectrum of architectural protein occupancy that scales with the topological structure of chromosomes and the regulatory potential of these elements. Whereas high occupancy architectural protein binding sites associate with robust partitioning of topologically associating domains and robust insulator function, low occupancy sites appear reserved for gene-specific regulation within topological domains. PMID:24981874

The evolution of filamin – A protein domain repeat perspective

PubMed Central

Light, Sara; Sagit, Rauan; Ithychanda, Sujay S.; Qin, Jun; Elofsson, Arne

2013-01-01

Particularly in higher eukaryotes, some protein domains are found in tandem repeats, performing broad functions often related to cellular organization. For instance, the eukaryotic protein filamin interacts with many proteins and is crucial for the cytoskeleton. The functional properties of long repeat domains are governed by the specific properties of each individual domain as well as by the repeat copy number. To provide better understanding of the evolutionary and functional history of repeating domains, we investigated the mode of evolution of the filamin domain in some detail. Among the domains that are common in long repeat proteins, sushi and spectrin domains evolve primarily through cassette tandem duplications while scavenger and immunoglobulin repeats appear to evolve through clustered tandem duplications. Additionally, immunoglobulin and filamin repeats exhibit a unique pattern where every other domain shows high sequence similarity. This pattern may be the result of tandem duplications, serve to avert aggregation between adjacent domains or it is the result of functional constraints. In filamin, our studies confirm the presence of interspersed integrin binding domains in vertebrates, while invertebrates exhibit more varied patterns, including more clustered integrin binding domains. The most notable case is leech filamin, which contains a 20 repeat expansion and exhibits unique dimerization topology. Clearly, invertebrate filamins are varied and contain examples of similar adjacent integrin-binding domains. Given that invertebrate integrin shows more similarity to the weaker filamin binder, integrin β3, it is possible that the distance between integrin-binding domains is not as crucial for invertebrate filamins as for vertebrates. PMID:22414427

The evolution of filamin-a protein domain repeat perspective.

PubMed

Light, Sara; Sagit, Rauan; Ithychanda, Sujay S; Qin, Jun; Elofsson, Arne

2012-09-01

Particularly in higher eukaryotes, some protein domains are found in tandem repeats, performing broad functions often related to cellular organization. For instance, the eukaryotic protein filamin interacts with many proteins and is crucial for the cytoskeleton. The functional properties of long repeat domains are governed by the specific properties of each individual domain as well as by the repeat copy number. To provide better understanding of the evolutionary and functional history of repeating domains, we investigated the mode of evolution of the filamin domain in some detail. Among the domains that are common in long repeat proteins, sushi and spectrin domains evolve primarily through cassette tandem duplications while scavenger and immunoglobulin repeats appear to evolve through clustered tandem duplications. Additionally, immunoglobulin and filamin repeats exhibit a unique pattern where every other domain shows high sequence similarity. This pattern may be the result of tandem duplications, serve to avert aggregation between adjacent domains or it is the result of functional constraints. In filamin, our studies confirm the presence of interspersed integrin binding domains in vertebrates, while invertebrates exhibit more varied patterns, including more clustered integrin binding domains. The most notable case is leech filamin, which contains a 20 repeat expansion and exhibits unique dimerization topology. Clearly, invertebrate filamins are varied and contain examples of similar adjacent integrin-binding domains. Given that invertebrate integrin shows more similarity to the weaker filamin binder, integrin β3, it is possible that the distance between integrin-binding domains is not as crucial for invertebrate filamins as for vertebrates. Copyright © 2012 Elsevier Inc. All rights reserved.

CD80 and CD86 IgC domains are important for quaternary structure, receptor binding and co-signaling function.

PubMed

Girard, Tanya; Gaucher, Denis; El-Far, Mohamed; Breton, Gaëlle; Sékaly, Rafick-Pierre

2014-09-01

CD86 and CD80, the ligands for the co-stimulatory molecules CD28 and CTLA-4, are members of the Ig superfamily. Their structure includes Ig variable-like (IgV) domains, Ig constant-like (IgC) domains and intracellular domains. Although crystallographic studies have clearly identified the IgV domain to be responsible for receptor interactions, earlier studies suggested that both Ig domains are required for full co-signaling function. Herein, we have used deletion and chimeric human CD80 and CD86 molecules in co-stimulation assays to study the impact of the multimeric state of IgV and IgC domains on receptor binding properties and on co-stimulatory function in a peptide-specific T cell activation model. We report for the first time the presence of CD80 dimers and CD86 monomers in living cells. Moreover, we show that the IgC domain of both molecules inhibits multimer formation and greatly affects binding to the co-receptors CD28 and CTLA-4. Finally, both IgC and intracellular domains are required for full co-signaling function. These findings reveal the distinct but complementary roles of CD80 and CD86 IgV and IgC domains in T cell activation. Copyright © 2014 Elsevier B.V. All rights reserved.

A Meta-analysis of Cerebellar Contributions to Higher Cognition from PET and fMRI studies

PubMed Central

Keren-Happuch, E; Chen, Shen-Hsing Annabel; Ho, Moon-Ho Ringo; Desmond, John E.

2013-01-01

A growing interest in cerebellar function and its involvement in higher cognition have prompted much research in recent years. Cerebellar presence in a wide range of cognitive functions examined within an increasing body of neuroimaging literature has been observed. We applied a meta-analytic approach, which employed the activation likelihood estimate method, to consolidate results of cerebellar involvement accumulated in different cognitive tasks of interest and systematically identified similarities among the studies. The current analysis included 88 neuroimaging studies demonstrating cerebellar activations in higher cognitive domains involving emotion, executive function, language, music, timing and working memory. While largely consistent with a prior meta-analysis by Stoodley and Schmahmann (2009), our results extended their findings to include music and timing domains to provide further insights into cerebellar involvement and elucidate its role in higher cognition. In addition, we conducted inter- and intra-domain comparisons for the cognitive domains of emotion, language and working memory. We also considered task differences within the domain of verbal working memory by conducting a comparison of the Sternberg with the n-back task, as well as an analysis of the differential components within the Sternberg task. Results showed a consistent cerebellar presence in the timing domain, providing evidence for a role in time keeping. Unique clusters identified within the domain further refine the topographic organization of the cerebellum. PMID:23125108

Network dysfunction predicts speech production after left hemisphere stroke.

PubMed

Geranmayeh, Fatemeh; Leech, Robert; Wise, Richard J S

2016-03-09

To investigate the role of multiple distributed brain networks, including the default mode, fronto-temporo-parietal, and cingulo-opercular networks, which mediate domain-general and task-specific processes during speech production after aphasic stroke. We conducted an observational functional MRI study to investigate the effects of a previous left hemisphere stroke on functional connectivity within and between distributed networks as patients described pictures. Study design included various baseline tasks, and we compared results to those of age-matched healthy participants performing the same tasks. We used independent component and psychophysiological interaction analyses. Although activity within individual networks was not predictive of speech production, relative activity between networks was a predictor of both within-scanner and out-of-scanner language performance, over and above that predicted from lesion volume, age, sex, and years of education. Specifically, robust functional imaging predictors were the differential activity between the default mode network and both the left and right fronto-temporo-parietal networks, respectively activated and deactivated during speech. We also observed altered between-network functional connectivity of these networks in patients during speech production. Speech production is dependent on complex interactions among widely distributed brain networks, indicating that residual speech production after stroke depends on more than the restoration of local domain-specific functions. Our understanding of the recovery of function following focal lesions is not adequately captured by consideration of ipsilesional or contralesional brain regions taking over lost domain-specific functions, but is perhaps best considered as the interaction between what remains of domain-specific networks and domain-general systems that regulate behavior. © 2016 American Academy of Neurology.

Network dysfunction predicts speech production after left hemisphere stroke

PubMed Central

Leech, Robert; Wise, Richard J.S.

2016-01-01

Objective: To investigate the role of multiple distributed brain networks, including the default mode, fronto-temporo-parietal, and cingulo-opercular networks, which mediate domain-general and task-specific processes during speech production after aphasic stroke. Methods: We conducted an observational functional MRI study to investigate the effects of a previous left hemisphere stroke on functional connectivity within and between distributed networks as patients described pictures. Study design included various baseline tasks, and we compared results to those of age-matched healthy participants performing the same tasks. We used independent component and psychophysiological interaction analyses. Results: Although activity within individual networks was not predictive of speech production, relative activity between networks was a predictor of both within-scanner and out-of-scanner language performance, over and above that predicted from lesion volume, age, sex, and years of education. Specifically, robust functional imaging predictors were the differential activity between the default mode network and both the left and right fronto-temporo-parietal networks, respectively activated and deactivated during speech. We also observed altered between-network functional connectivity of these networks in patients during speech production. Conclusions: Speech production is dependent on complex interactions among widely distributed brain networks, indicating that residual speech production after stroke depends on more than the restoration of local domain-specific functions. Our understanding of the recovery of function following focal lesions is not adequately captured by consideration of ipsilesional or contralesional brain regions taking over lost domain-specific functions, but is perhaps best considered as the interaction between what remains of domain-specific networks and domain-general systems that regulate behavior. PMID:26962070

A Functional Approach to Hyperspectral Image Analysis in the Cloud

NASA Astrophysics Data System (ADS)

Wilson, A.; Lindholm, D. M.; Coddington, O.; Pilewskie, P.

2017-12-01

Hyperspectral image volumes are very large. A hyperspectral image analysis (HIA) may use 100TB of data, a huge barrier to their use. Hylatis is a new NASA project to create a toolset for HIA. Through web notebook and cloud technology, Hylatis will provide a more interactive experience for HIA by defining and implementing concepts and operations for HIA, identified and vetted by subject matter experts, and callable within a general purpose language, particularly Python. Hylatis leverages LaTiS, a data access framework developed at LASP. With an OPeNDAP compliant interface plus additional server side capabilities, the LaTiS API provides a uniform interface to virtually any data source, and has been applied to various storage systems, including: file systems, databases, remote servers, and in various domains including: space science, systems administration and stock quotes. In the LaTiS architecture, data `adapters' read data into a data model, where server-side computations occur. Data `writers' write data from the data model into the desired format. The Hylatis difference is the data model. In LaTiS, data are represented as mathematical functions of independent and dependent variables. Domain semantics are not present at this level, but are instead present in higher software layers. The benefit of a domain agnostic, mathematical representation is having the power of math, particularly functional algebra, unconstrained by domain semantics. This agnosticism supports reusable server side functionality applicable in any domain, such as statistical, filtering, or projection operations. Algorithms to aggregate or fuse data can be simpler because domain semantics are separated from the math. Hylatis will map the functional model onto the Spark relational interface, thereby adding a functional interface to that big data engine.This presentation will discuss Hylatis goals, strategies, and current state.

Candidate Cell and Matrix Interaction Domains on the Collagen Fibril, the Predominant Protein of Vertebrates

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

Sweeney, Shawn M.; Orgel, Joseph P.; Fertala, Andrzej

Type I collagen, the predominant protein of vertebrates, polymerizes with type III and V collagens and non-collagenous molecules into large cable-like fibrils, yet how the fibril interacts with cells and other binding partners remains poorly understood. To help reveal insights into the collagen structure-function relationship, a data base was assembled including hundreds of type I collagen ligand binding sites and mutations on a two-dimensional model of the fibril. Visual examination of the distribution of functional sites, and statistical analysis of mutation distributions on the fibril suggest it is organized into two domains. The 'cell interaction domain' is proposed to regulatemore » dynamic aspects of collagen biology, including integrin-mediated cell interactions and fibril remodeling. The 'matrix interaction domain' may assume a structural role, mediating collagen cross-linking, proteoglycan interactions, and tissue mineralization. Molecular modeling was used to superimpose the positions of functional sites and mutations from the two-dimensional fibril map onto a three-dimensional x-ray diffraction structure of the collagen microfibril in situ, indicating the existence of domains in the native fibril. Sequence searches revealed that major fibril domain elements are conserved in type I collagens through evolution and in the type II/XI collagen fibril predominant in cartilage. Moreover, the fibril domain model provides potential insights into the genotype-phenotype relationship for several classes of human connective tissue diseases, mechanisms of integrin clustering by fibrils, the polarity of fibril assembly, heterotypic fibril function, and connective tissue pathology in diabetes and aging.« less

Mindfulness meditation practice and executive functioning: Breaking down the benefit.

PubMed

Gallant, Sara N

2016-02-01

This paper focuses on evidence for mindfulness meditation-related benefits to executive functioning, processes important for much of human volitional behaviour. Miyake et al. (2000) have shown that executive functions can be fractionated into three distinct domains including inhibition, working memory updating, and mental set shifting. Considering these separable domains, it is important to determine whether the effects of mindfulness can generalize to all three sub-functions or are specific to certain domains. To address this, the current review applied Miyake et al.'s (2000) fractionated model of executive functioning to the mindfulness literature. Empirical studies assessing the benefits of mindfulness to measures tapping the inhibition, updating, and shifting components of executive functioning were examined. Results suggest a relatively specific as opposed to general benefit resulting from mindfulness, with consistent inhibitory improvement, but more variable advantages to the updating and shifting domains. Recommendations surrounding application of mindfulness practice and future research are discussed. Copyright © 2016 Elsevier Inc. All rights reserved.

A mutation-led search for novel functional domains in MeCP2.

PubMed

Guy, Jacky; Alexander-Howden, Beatrice; FitzPatrick, Laura; DeSousa, Dina; Koerner, Martha V; Selfridge, Jim; Bird, Adrian

2018-04-27

Most missense mutations causing Rett syndrome affect domains of MeCP2 that have been shown to either bind methylated DNA or interact with a transcriptional co-repressor complex. Several mutations, however, including the C-terminal truncations that account for ∼10% of cases, fall outside these characterised domains. We studied the molecular consequences of four of these "non-canonical" mutations in cultured neurons and mice to see if they reveal additional essential domains without affecting known properties of MeCP2. The results show that the mutations partially or strongly deplete the protein and also in some cases interfere with co-repressor recruitment. These mutations therefore impact the activity of known functional domains and do not invoke new molecular causes of Rett syndrome. The finding that a stable C-terminal truncation does not compromise MeCP2 function raises the possibility that small molecules which stabilise these mutant proteins may be of therapeutic value.

MOCASSIN-prot: a multi-objective clustering approach for protein similarity networks.

PubMed

Keel, Brittney N; Deng, Bo; Moriyama, Etsuko N

2018-04-15

Proteins often include multiple conserved domains. Various evolutionary events including duplication and loss of domains, domain shuffling, as well as sequence divergence contribute to generating complexities in protein structures, and consequently, in their functions. The evolutionary history of proteins is hence best modeled through networks that incorporate information both from the sequence divergence and the domain content. Here, a game-theoretic approach proposed for protein network construction is adapted into the framework of multi-objective optimization, and extended to incorporate clustering refinement procedure. The new method, MOCASSIN-prot, was applied to cluster multi-domain proteins from ten genomes. The performance of MOCASSIN-prot was compared against two protein clustering methods, Markov clustering (TRIBE-MCL) and spectral clustering (SCPS). We showed that compared to these two methods, MOCASSIN-prot, which uses both domain composition and quantitative sequence similarity information, generates fewer false positives. It achieves more functionally coherent protein clusters and better differentiates protein families. MOCASSIN-prot, implemented in Perl and Matlab, is freely available at http://bioinfolab.unl.edu/emlab/MOCASSINprot. emoriyama2@unl.edu. Supplementary data are available at Bioinformatics online.

Application of WHO recommendations in outcome assessment of clinical series published in hand surgery journals with five years interval.

PubMed

Alarab, H; Dubert, T

2015-02-01

Outcome measurement is becoming increasingly important in hand surgery. The International classification of functioning, disability and health (ICF), is a WHO multi-dimensional approach to health condition including three domains: body "functions and structures", activities and participation. The aim of this study was to measure how often these three ICF domains were included in outcome measurements of the clinical series published in the American, European and French hand surgery journals. Our study included clinical series published in 2007 and 2012 in the American Journal Of Hand Surgery, European Journal Of Hand Surgery and Chirurgie de la Main. Analysis of each of these publications was done in two steps. First, we checked the presence or absence of the three domains of ICF in outcome measurement without considering the way it was measured. Then, we reported the use of evaluation instruments and/or quantitative measurement for each domain. We included 54 series in 2007 and 119 in 2012. The number of series reporting on the three domains and using at least one quantitative measurement for each domain represents 6% of articles in 2007 and 10% in 2012. This study shows that the quality of outcome measurement has improved over these 5 years, but remains poor according to the ICF recommendation. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

The basic tilted helix bundle domain of the prolyl isomerase FKBP25 is a novel double-stranded RNA binding module

PubMed Central

Dilworth, David; Bonnafous, Pierre; Edoo, Amiirah Bibi; Bourbigot, Sarah; Pesek-Jardim, Francy; Gudavicius, Geoff; Serpa, Jason J.; Petrotchenko, Evgeniy V.; Borchers, Christoph H.

2017-01-01

Abstract Prolyl isomerases are defined by a catalytic domain that facilitates the cis–trans interconversion of proline residues. In most cases, additional domains in these enzymes add important biological function, including recruitment to a set of protein substrates. Here, we report that the N-terminal basic tilted helix bundle (BTHB) domain of the human prolyl isomerase FKBP25 confers specific binding to double-stranded RNA (dsRNA). This binding is selective over DNA as well as single-stranded oligonucleotides. We find that FKBP25 RNA-association is required for its nucleolar localization and for the vast majority of its protein interactions, including those with 60S pre-ribosome and early ribosome biogenesis factors. An independent mobility of the BTHB and FKBP catalytic domains supports a model by which the N-terminus of FKBP25 is anchored to regions of dsRNA, whereas the FKBP domain is free to interact with neighboring proteins. Apart from the identification of the BTHB as a new dsRNA-binding module, this domain adds to the growing list of auxiliary functions used by prolyl isomerases to define their primary cellular targets. PMID:29036638

Free-electron gas at charged domain walls in insulating BaTiO3

PubMed Central

Sluka, Tomas; Tagantsev, Alexander K.; Bednyakov, Petr; Setter, Nava

2013-01-01

Hetero interfaces between metal-oxides display pronounced phenomena such as semiconductor-metal transitions, magnetoresistance, the quantum hall effect and superconductivity. Similar effects at compositionally homogeneous interfaces including ferroic domain walls are expected. Unlike hetero interfaces, domain walls can be created, displaced, annihilated and recreated inside a functioning device. Theory predicts the existence of 'strongly' charged domain walls that break polarization continuity, but are stable and conduct steadily through a quasi-two-dimensional electron gas. Here we show this phenomenon experimentally in charged domain walls of the prototypical ferroelectric BaTiO3. Their steady metallic-type conductivity, 109 times that of the parent matrix, evidence the presence of stable degenerate electron gas, thus adding mobility to functional interfaces. PMID:23651996

Resilience of biochemical activity in protein domains in the face of structural divergence.

PubMed

Zhang, Dapeng; Iyer, Lakshminarayan M; Burroughs, A Maxwell; Aravind, L

2014-06-01

Recent studies point to the prevalence of the evolutionary phenomenon of drastic structural transformation of protein domains while continuing to preserve their basic biochemical function. These transformations span a wide spectrum, including simple domains incorporated into larger structural scaffolds, changes in the structural core, major active site shifts, topological rewiring and extensive structural transmogrifications. Proteins from biological conflict systems, such as toxin-antitoxin, restriction-modification, CRISPR/Cas, polymorphic toxin and secondary metabolism systems commonly display such transformations. These include endoDNases, metal-independent RNases, deaminases, ADP ribosyltransferases, immunity proteins, kinases and E1-like enzymes. In eukaryotes such transformations are seen in domains involved in chromatin-related peptide recognition and protein/DNA-modification. Intense selective pressures from 'arms-race'-like situations in conflict and macromolecular modification systems could favor drastic structural divergence while preserving function. Published by Elsevier Ltd.

A hybrid two-component system protein from Azospirillum brasilense Sp7 was involved in chemotaxis.

PubMed

Cui, Yanhua; Tu, Ran; Wu, Lixian; Hong, Yuanyuan; Chen, Sanfeng

2011-09-20

We here report the sequence and functional analysis of org35 of Azospirillum brasilense Sp7, which was originally identified to be able to interact with NifA in yeast-two-hybrid system. The org35 encodes a hybrid two-component system protein, including N-terminal PAS domains, a histidine kinase (HPK) domain and a response regulator (RR) domain in C-terminal. To determine the function of the Org35, a deletion-insertion mutant in PAS domain [named Sp7353] and a complemental strain Sp7353C were constructed. The mutant had reduced chemotaxis ability compared to that of wild-type, and the complemental strain was similar to the wild-type strain. These data suggested that the A. brasilense org35 played a key role in chemotaxis. Variants containing different domains of the org35 were expressed, and the functions of these domains were studied in vitro. Phosphorylation assays in vitro demonstrated that the HPK domain of Org35 possessed the autokinase activity and that the phosphorylated HPK was able to transfer phosphate groups to the RR domain. The result indicated Org35 was a phosphorylation-communicating protein. Copyright © 2010 Elsevier GmbH. All rights reserved.

Cyberspace security system

DOEpatents

Abercrombie, Robert K; Sheldon, Frederick T; Ferragut, Erik M

2014-06-24

A system evaluates reliability, performance and/or safety by automatically assessing the targeted system's requirements. A cost metric quantifies the impact of failures as a function of failure cost per unit of time. The metrics or measurements may render real-time (or near real-time) outcomes by initiating active response against one or more high ranked threats. The system may support or may be executed in many domains including physical domains, cyber security domains, cyber-physical domains, infrastructure domains, etc. or any other domains that are subject to a threat or a loss.

F-BAR family proteins, emerging regulators for cell membrane dynamic changes-from structure to human diseases.

PubMed

Liu, Suxuan; Xiong, Xinyu; Zhao, Xianxian; Yang, Xiaofeng; Wang, Hong

2015-05-09

Eukaryotic cell membrane dynamics change in curvature during physiological and pathological processes. In the past ten years, a novel protein family, Fes/CIP4 homology-Bin/Amphiphysin/Rvs (F-BAR) domain proteins, has been identified to be the most important coordinators in membrane curvature regulation. The F-BAR domain family is a member of the Bin/Amphiphysin/Rvs (BAR) domain superfamily that is associated with dynamic changes in cell membrane. However, the molecular basis in membrane structure regulation and the biological functions of F-BAR protein are unclear. The pathophysiological role of F-BAR protein is unknown. This review summarizes the current understanding of structure and function in the BAR domain superfamily, classifies F-BAR family proteins into nine subfamilies based on domain structure, and characterizes F-BAR protein structure, domain interaction, and functional relevance. In general, F-BAR protein binds to cell membrane via F-BAR domain association with membrane phospholipids and initiates membrane curvature and scission via Src homology-3 (SH3) domain interaction with its partner proteins. This process causes membrane dynamic changes and leads to seven important cellular biological functions, which include endocytosis, phagocytosis, filopodium, lamellipodium, cytokinesis, adhesion, and podosome formation, via distinct signaling pathways determined by specific domain-binding partners. These cellular functions play important roles in many physiological and pathophysiological processes. We further summarize F-BAR protein expression and mutation changes observed in various diseases and developmental disorders. Considering the structure feature and functional implication of F-BAR proteins, we anticipate that F-BAR proteins modulate physiological and pathophysiological processes via transferring extracellular materials, regulating cell trafficking and mobility, presenting antigens, mediating extracellular matrix degradation, and transmitting signaling for cell proliferation.

Structure-informed insights for NLR functioning in plant immunity.

PubMed

Sukarta, Octavina C A; Slootweg, Erik J; Goverse, Aska

2016-08-01

To respond to foreign invaders, plants have evolved a cell autonomous multilayered immune system consisting of extra- and intracellular immune receptors. Nucleotide binding and oligomerization domain (NOD)-like receptors (NLRs) mediate recognition of pathogen effectors inside the cell and trigger a host specific defense response, often involving controlled cell death. NLRs consist of a central nucleotide-binding domain, which is flanked by an N-terminal CC or TIR domain and a C-terminal leucine-rich repeat domain (LRR). These multidomain proteins function as a molecular switch and their activity is tightly controlled by intra and inter-molecular interactions. In contrast to metazoan NLRs, the structural basis underlying NLR functioning as a pathogen sensor and activator of immune responses in plants is largely unknown. However, the first crystal structures of a number of plant NLR domains were recently obtained. In addition, biochemical and structure-informed analyses revealed novel insights in the cooperation between NLR domains and the formation of pre- and post activation complexes, including the coordinated activity of NLR pairs as pathogen sensor and executor of immune responses. Moreover, the discovery of novel integrated domains underscores the structural diversity of NLRs and provides alternative models for how these immune receptors function in plants. In this review, we will highlight these recent advances to provide novel insights in the structural, biochemical and molecular aspects involved in plant NLR functioning. Copyright © 2016 Elsevier Ltd. All rights reserved.

PDE and cognitive processing: beyond the memory domain.

PubMed

Heckman, P R A; Blokland, A; Ramaekers, J; Prickaerts, J

2015-03-01

Phosphodiesterase inhibitors (PDE-Is) enhance cAMP and/or cGMP signaling via reducing the degradation of these cyclic nucleotides. Both cAMP and cGMP signaling are essential for a variety of cellular functions and exert their effects both pre- and post-synaptically. Either of these second messengers relays and amplifies incoming signals at receptors on the cell surface making them important elements in signal transduction cascades and essential in cellular signaling in a variety of cell functions including neurotransmitter release and neuroprotection. Consequently, these processes can be influenced by PDE-Is as they increase cAMP and/or cGMP concentrations. PDE-Is have been considered as possible therapeutic agents to treat impaired memory function linked to several brain disorders, including depression, schizophrenia and Alzheimer's disease (AD). This review will, however, focus on the possible role of phosphodiesterases (PDEs) in cognitive decline beyond the memory domain. Here we will discuss the involvement of PDEs on three related domains: attention, information filtering (sensory- and sensorimotor gating) and response inhibition (drug-induced hyperlocomotion). Currently, these are emerging cognitive domains in the field of PDE research. Here we discuss experimental studies and the potential beneficial effects of PDE-I drugs on these cognitive domains, as effects of PDE-Is on these domains could potentially influence effects on memory performance. Overall, PDE4 seems to be the most promising target for all domains discussed in this review. Copyright © 2014 Elsevier Inc. All rights reserved.

PTEN Regulates Beta-Catenin in Androgen Signaling: Implication in Prostate Cancer Progression

DTIC Science & Technology

2007-03-01

Smad3 and Smad4 proteins contain a number of functional domains, including MH1, MH2, and the linker region (2). It appears that theMH2 domain is involved...domains or Smad4 linker region. These data demonstrate that the MH2 domains of Smad3 and Smad4 are involved in the interaction with hZimp10. hZimp10...length (FL), MH1 domain (MH1, 1–146 amino acids), linker domain (L, 147–308 amino acids), and MH2 domain (MH2, 309 –553 amino acids) and GST- Smad3 full

Paliperidone palmitate once-monthly maintains improvement in functioning domains of the Personal and Social Performance scale compared with placebo in subjects with schizoaffective disorder.

PubMed

Fu, Dong-Jing; Turkoz, Ibrahim; Walling, David; Lindenmayer, Jean-Pierre; Schooler, Nina R; Alphs, Larry

2018-02-01

Evaluate the effect of paliperidone palmitate once-monthly (PP1M) injectable on the specific functioning domains of the Personal and Social Performance (PSP) scale in patients with schizoaffective disorder (SCA) participating in a long-term study. This study (NCT01193153) included both in- and outpatient subjects with SCA experiencing an acute exacerbation of psychotic and mood symptoms. Subjects were treated with PP1M either as monotherapy or in combination with antidepressants or mood stabilizers during a 25-week open-label (OL) phase. Stabilized subjects were randomly assigned 1:1 (PP1M or placebo) into a 15-month double-blind (DB) relapse-prevention period. Functioning of the randomized subjects during OL and DB phases was evaluated using the PSP scale (four domains: socially useful activities, personal/social relationships, self-care, and disturbing/aggressive behaviors). Three statistical approaches were utilized to analyze PSP scores to assess robustness and consistency of findings. No adjustments were made for multiplicity. 334 of 667 enrolled subjects were stabilized with PP1M, randomly assigned to PP1M (n=164) or placebo (n=170) in the DB phase, and included in this analysis. Improvements in all PSP domain scores were observed during the OL phase and were maintained during the DB phase with PP1M, but decreased with placebo. Differences compared to placebo were significant in all four PSP domains during the DB phase (P≤0.008). The analysis in this study showed that PP1M improves functioning, as measured by the four PSP domain scores, in symptomatic subjects with SCA. Functioning was maintained compared with placebo. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Context-specific requirements of functional domains of the Spectraplakin Short stop in vivo.

PubMed

Bottenberg, Wolfgang; Sanchez-Soriano, Natalia; Alves-Silva, Juliana; Hahn, Ines; Mende, Michael; Prokop, Andreas

2009-07-01

Spectraplakins are large multifunctional cytoskeletal interacting molecules implicated in various processes, including gastrulation, wound healing, skin blistering and neuronal degeneration. It has been speculated that the various functional domains and regions found in Spectraplakins are used in context-specific manners, a model which would provide a crucial explanation for the multifunctional nature of Spectraplakins. Here we tested this possibility by studying domain requirements of the Drosophila Spectraplakin Short stop (Shot) in three different cellular contexts in vivo: (1) neuronal growth, which requires dynamic actin-microtubule interaction; (2) formation and maintenance of tendon cells, which depends on highly stabilised arrays of actin filaments and microtubules, and (3) compartmentalisation in neurons, which is likely to involve cortical F-actin networks. Using these cellular contexts for rescue experiments with Shot deletion constructs in shot mutant background, a number of differential domain requirements were uncovered. First, binding of Shot to F-actin through the first Calponin domain is essential in neuronal contexts but dispensable in tendon cells. This finding is supported by our analyses of shot(kakP2) mutant embryos, which produce only endogenous isoforms lacking the first Calponin domain. Thus, our data demonstrate a functional relevance for these isoforms in vivo. Second, we provide the first functional role for the Plakin domain of Shot, which has a strong requirement for compartmentalisation in neurons and axonal growth, demonstrating that Plakin domains of long Spectraplakin isoforms are of functional relevance. Like the Calponin domain, also the Plakin domain is dispensable in tendon cells, and the currently assumed role of Shot as a linker of microtubules to the tendon cell surface may have to be reconsidered. Third, we demonstrate a function of Shot as an actin-microtubule linker in dendritic growth, thus shedding new light into principal growth mechanisms of this neurite type. Taken together, our data clearly support the view that Spectraplakins function in tissue-specific modes in vivo, and even domains believed to be crucial for Spectraplakin function can be dispensable in specific contexts.

PEST domain mutations in Notch receptors comprise an oncogenic driver segment in triple-negative breast cancer sensitive to a γ-secretase inhibitor.

PubMed

Wang, Kai; Zhang, Qin; Li, Danan; Ching, Keith; Zhang, Cathy; Zheng, Xianxian; Ozeck, Mark; Shi, Stephanie; Li, Xiaorong; Wang, Hui; Rejto, Paul; Christensen, James; Olson, Peter

2015-03-15

To identify and characterize novel, activating mutations in Notch receptors in breast cancer and to determine response to the gamma secretase inhibitor (GSI) PF-03084014. We used several computational approaches, including novel algorithms, to analyze next-generation sequencing data and related omic datasets from The Cancer Genome Atlas (TCGA) breast cancer cohort. Patient-derived xenograft (PDX) models were sequenced, and Notch-mutant models were treated with PF-03084014. Gene-expression and functional analyses were performed to study the mechanism of activation through mutation and inhibition by PF-03084014. We identified mutations within and upstream of the PEST domains of NOTCH1, NOTCH2, and NOTCH3 in the TCGA dataset. Mutations occurred via several genetic mechanisms and compromised the function of the PEST domain, a negative regulatory domain commonly mutated in other cancers. Focal amplifications of NOTCH2 and NOTCH3 were also observed, as were heterodimerization or extracellular domain mutations at lower incidence. Mutations and amplifications often activated the Notch pathway as evidenced by increased expression of canonical Notch target genes, and functional mutations were significantly enriched in the triple-negative breast cancer subtype (TNBC). PDX models were also identified that harbored PEST domain mutations, and these models were highly sensitive to PF-03084014. This work suggests that Notch-altered breast cancer constitutes a bona fide oncogenic driver segment with the most common alteration being PEST domain mutations present in multiple Notch receptors. Importantly, functional studies suggest that this newly identified class can be targeted with Notch inhibitors, including GSIs. ©2015 American Association for Cancer Research.

Alphabet Soup

ERIC Educational Resources Information Center

Rebholz, Joachim A.

2017-01-01

Graphing functions is an important topic in algebra and precalculus high school courses. The functions that are usually discussed include polynomials, rational, exponential, and trigonometric functions along with their inverses. These functions can be used to teach different aspects of function theory: domain, range, monotonicity, inverse…

A functional analysis of TOEFAZ1 uncovers protein domains essential for cytokinesis in Trypanosoma brucei.

PubMed

Sinclair-Davis, Amy N; McAllaster, Michael R; de Graffenried, Christopher L

2017-11-15

The parasite Trypanosoma brucei is highly polarized, including a flagellum that is attached along the cell surface by the flagellum attachment zone (FAZ). During cell division, the new FAZ positions the cleavage furrow, which ingresses from the anterior tip of the cell towards the posterior. We recently identified TOEFAZ1 (for 'Tip of the Extending FAZ protein 1') as an essential protein in trypanosome cytokinesis. Here, we analyzed the localization and function of TOEFAZ1 domains by performing overexpression and RNAi complementation experiments. TOEFAZ1 comprises three domains with separable functions: an N-terminal α-helical domain that may be involved in FAZ recruitment, a central intrinsically disordered domain that keeps the morphogenic kinase TbPLK at the new FAZ tip, and a C-terminal zinc finger domain necessary for TOEFAZ1 oligomerization. Both the N-terminal and C-terminal domains are essential for TOEFAZ1 function, but TbPLK retention at the FAZ is not necessary for cytokinesis. The feasibility of alternative cytokinetic pathways that do not employ TOEFAZ1 are also assessed. Our results show that TOEFAZ1 is a multimeric scaffold for recruiting proteins that control the timing and location of cleavage furrow ingression. © 2017. Published by The Company of Biologists Ltd.

Evolutionary history and functional implications of protein domains and their combinations in eukaryotes.

PubMed

Itoh, Masumi; Nacher, Jose C; Kuma, Kei-ichi; Goto, Susumu; Kanehisa, Minoru

2007-01-01

In higher multicellular eukaryotes, complex protein domain combinations contribute to various cellular functions such as regulation of intercellular or intracellular signaling and interactions. To elucidate the characteristics and evolutionary mechanisms that underlie such domain combinations, it is essential to examine the different types of domains and their combinations among different groups of eukaryotes. We observed a large number of group-specific domain combinations in animals, especially in vertebrates. Examples include animal-specific combinations in tyrosine phosphorylation systems and vertebrate-specific combinations in complement and coagulation cascades. These systems apparently underwent extensive evolution in the ancestors of these groups. In extant animals, especially in vertebrates, animal-specific domains have greater connectivity than do other domains on average, and contribute to the varying number of combinations in each animal subgroup. In other groups, the connectivities of older domains were greater on average. To observe the global behavior of domain combinations during evolution, we traced the changes in domain combinations among animals and fungi in a network analysis. Our results indicate that there is a correlation between the differences in domain combinations among different phylogenetic groups and different global behaviors. Rapid emergence of animal-specific domains was observed in animals, contributing to specific domain combinations and functional diversification, but no such trends were observed in other clades of eukaryotes. We therefore suggest that the strategy for achieving complex multicellular systems in animals differs from that of other eukaryotes.

Characterization of DNA polymerase X from Thermus thermophilus HB8 reveals the POLXc and PHP domains are both required for 3'-5' exonuclease activity.

PubMed

Nakane, Shuhei; Nakagawa, Noriko; Kuramitsu, Seiki; Masui, Ryoji

2009-04-01

The X-family DNA polymerases (PolXs) comprise a highly conserved DNA polymerase family found in all kingdoms. Mammalian PolXs are known to be involved in several DNA-processing pathways including repair, but the cellular functions of bacterial PolXs are less known. Many bacterial PolXs have a polymerase and histidinol phosphatase (PHP) domain at their C-termini in addition to a PolX core (POLXc) domain, and possess 3'-5' exonuclease activity. Although both domains are highly conserved in bacteria, their molecular functions, especially for a PHP domain, are unknown. We found Thermus thermophilus HB8 PolX (ttPolX) has Mg(2+)/Mn(2+)-dependent DNA/RNA polymerase, Mn(2+)-dependent 3'-5' exonuclease and DNA-binding activities. We identified the domains of ttPolX by limited proteolysis and characterized their biochemical activities. The POLXc domain was responsible for the polymerase and DNA-binding activities but exonuclease activity was not detected for either domain. However, the POLXc and PHP domains interacted with each other and a mixture of the two domains had Mn(2+)-dependent 3'-5' exonuclease activity. Moreover, site-directed mutagenesis revealed catalytically important residues in the PHP domain for the 3'-5' exonuclease activity. Our findings provide a molecular insight into the functional domain organization of bacterial PolXs, especially the requirement of the PHP domain for 3'-5' exonuclease activity.

Physical Activity Throughout the Adult Life Span and Domain-Specific Cognitive Function in Old Age: A Systematic Review of Cross-Sectional and Longitudinal Data.

PubMed

Engeroff, Tobias; Ingmann, Tobias; Banzer, Winfried

2018-06-01

A growing body of literature suggests that physical activity might alleviate the age-related neurodegeneration and decline of cognitive function. However, most of this evidence is based on data investigating the association of exercise interventions or current physical activity behavior with cognitive function in elderly subjects. We performed a systematic review and hypothesize that physical activity during the adult life span is connected with maintained domain-specific cognitive functions during late adulthood defined as age 60+ years. We performed a systematic literature search up to November 2017 in PubMed, Web of Science, and Google Scholar without language limitations for studies analyzing the association of leisure physical activity during the adult life span (age 18+ years) and domain-specific cognitive functions in older adults (age 60+ years). The literature review yielded 14,294 articles and after applying inclusion and exclusion criteria, nine cross-sectional and 14 longitudinal studies were included. Moderate- and vigorous-intensity leisure physical activity was associated with global cognitive function and specific cognitive domains including executive functions and memory but not attention or working memory. Most studies assessed mid- to late-adulthood physical activity, thus information concerning the influence of young adult life-span physical activity is currently lacking. Observational evidence that moderate- and vigorous-intensity leisure physical activity is beneficially associated with maintained cognitive functions during old age is accumulating. Further studies are necessary to confirm a causal link by assessing objective physical activity data and the decline of cognitive functions at multiple time points during old age.

Functional link between plasma membrane spatiotemporal dynamics, cancer biology, and dietary membrane-altering agents.

PubMed

Erazo-Oliveras, Alfredo; Fuentes, Natividad R; Wright, Rachel C; Chapkin, Robert S

2018-06-02

The cell plasma membrane serves as a nexus integrating extra- and intracellular components, which together enable many of the fundamental cellular signaling processes that sustain life. In order to perform this key function, plasma membrane components assemble into well-defined domains exhibiting distinct biochemical and biophysical properties that modulate various signaling events. Dysregulation of these highly dynamic membrane domains can promote oncogenic signaling. Recently, it has been demonstrated that select membrane-targeted dietary bioactives (MTDBs) have the ability to remodel plasma membrane domains and subsequently reduce cancer risk. In this review, we focus on the importance of plasma membrane domain structural and signaling functionalities as well as how loss of membrane homeostasis can drive aberrant signaling. Additionally, we discuss the intricacies associated with the investigation of these membrane domain features and their associations with cancer biology. Lastly, we describe the current literature focusing on MTDBs, including mechanisms of chemoprevention and therapeutics in order to establish a functional link between these membrane-altering biomolecules, tuning of plasma membrane hierarchal organization, and their implications in cancer prevention.

Cognitive and psychomotor effects of risperidone in schizophrenia and schizoaffective disorder.

PubMed

Houthoofd, Sofie A M K; Morrens, Manuel; Sabbe, Bernard G C

2008-09-01

The aim of this review was to discuss data from double-blind, randomized controlled trials (RCTs) that have investigated the effects of oral and long-acting injectable risperidone on cognitive and psychomotor functioning in patients with schizophrenia or schizoaffective disorder. PubMed/MEDLINE and the Institute of Scientific Information Web of Science database were searched for relevant English-language double-blind RCTs published between March 2000 and July 2008, using the terms schizophrenia, schizoaffective disorder, cognition, risperidone, psychomotor, processing speed, attention, vigilance, working memory, verbal learning, visual learning, reasoning, problem solving, social cognition, MATRICS, and long-acting. Relevant studies included patients with schizophrenia or schizoaffective disorder. Cognitive domains were delineated at the Consensus Conferences of the National Institute of Mental Health-Measurement And Treatment Research to Improve Cognition in Schizophrenia (NIMH-MATRICS). The tests employed to assess each domain and psychomotor functioning, and the within-group and between-group comparisons of risperidone with haloperidol and other atypical antipsychotics, are presented. The results of individual tests were included when they were individually presented and interpretable for either drug; outcomes that were presented as cluster scores or factor structures were excluded. A total of 12 articles were included in this review. Results suggested that the use of oral risperidone appeared to be associated with within-group improvements on the cognitive domains of processing speed, attention/vigilance, verbal and visual learning and memory, and reasoning and problem solving in patients with schizophrenia or schizoaffective disorder. Risperidone and haloperidol seemed to generate similar beneficial effects (on the domains of processing speed, attention/vigilance, [verbal and nonverbal] working memory, and visual learning and memory, as well as psychomotor functioning), although the results for verbal fluency, verbal learning and memory, and reasoning and problem solving were not unanimous, and no comparative data on social cognition were available. Similar cognitive effects were found with risperidone, olanzapine, and quetiapine on the domains of verbal working memory and reasoning and problem solving, as well as verbal fluency. More research is needed on the domains in which study results were contradictory. For olanzapine versus risperidone, these were verbal and visual learning and memory and psychomotor functioning. No comparative data for olanzapine and risperidone were available for the social cognition domain. For quetiapine versus risperidone, the domains in which no unanimity was found were processing speed, attention/vigilance, nonverbal working memory, and verbal learning and memory. The limited available reports on risperidone versus clozapine suggest that: risperidone was associated with improved, and clozapine with worsened, performance on the nonverbal working memory domain; risperidone improved and clozapine did not improve reasoning and problem-solving performance; clozapine improved, and risperidone did not improve, social cognition performance. Use of long-acting injectable risperidone seemed to be associated with improved performance in the domains of attention/vigilance, verbal learning and memory, and reasoning and problem solving, as well as psychomotor functioning. The results for the nonverbal working memory domain were indeterminate, and no clear improvement was seen in the social cognition domain. The domains of processing speed, verbal working memory, and visual learning and memory, as well as verbal fluency, were not assessed. The results of this review of within-group comparisons of oral risperidone suggest that the agent appeared to be associated with improved functioning in the cognitive domains of processing speed, attention/vigilance, verbal and visual learning and memory, and reasoning and problem solving in patients with schizophrenia or schizoaffective disorder. Long-acting injectable risperidone seemed to be associated with improved functioning in the domains of attention/vigilance, verbal learning and memory, and reasoning and problem solving, as well as psychomotor functioning, in patients with schizophrenia or schizoaffective disorder.

The C-terminal extension of human RTEL1, mutated in Hoyeraal-Hreidarsson syndrome, contains harmonin-N-like domains.

PubMed

Faure, Guilhem; Revy, Patrick; Schertzer, Michael; Londono-Vallejo, Arturo; Callebaut, Isabelle

2014-06-01

Several studies have recently shown that germline mutations in RTEL1, an essential DNA helicase involved in telomere regulation and DNA repair, cause Hoyeraal-Hreidarsson syndrome (HHS), a severe form of dyskeratosis congenita. Using original new softwares, facilitating the delineation of the different domains of the protein and the identification of remote relationships for orphan domains, we outline here that the C-terminal extension of RTEL1, downstream of its catalytic domain and including several HHS-associated mutations, contains a yet unidentified tandem of harmonin-N-like domains, which may serve as a hub for partner interaction. This finding highlights the potential critical role of this region for the function of RTEL1 and gives insights into the impact that the identified mutations would have on the structure and function of these domains. © 2013 Wiley Periodicals, Inc.

Core outcome domains for clinical trials in non-specific low back pain.

PubMed

Chiarotto, Alessandro; Deyo, Richard A; Terwee, Caroline B; Boers, Maarten; Buchbinder, Rachelle; Corbin, Terry P; Costa, Leonardo O P; Foster, Nadine E; Grotle, Margreth; Koes, Bart W; Kovacs, Francisco M; Lin, Chung-Wei Christine; Maher, Chris G; Pearson, Adam M; Peul, Wilco C; Schoene, Mark L; Turk, Dennis C; van Tulder, Maurits W; Ostelo, Raymond W

2015-06-01

Inconsistent reporting of outcomes in clinical trials of patients with non-specific low back pain (NSLBP) hinders comparison of findings and the reliability of systematic reviews. A core outcome set (COS) can address this issue as it defines a minimum set of outcomes that should be reported in all clinical trials. In 1998, Deyo et al. recommended a standardized set of outcomes for LBP clinical research. The aim of this study was to update these recommendations by determining which outcome domains should be included in a COS for clinical trials in NSLBP. An International Steering Committee established the methodology to develop this COS. The OMERACT Filter 2.0 framework was used to draw a list of potential core domains that were presented in a Delphi study. Researchers, care providers and patients were invited to participate in three Delphi rounds and were asked to judge which domains were core. A priori criteria for consensus were established before each round and were analysed together with arguments provided by panellists on importance, overlap, aggregation and/or addition of potential core domains. The Steering Committee discussed the final results and made final decisions. A set of 280 experts was invited to participate in the Delphi; response rates in the three rounds were 52, 50 and 45%. Of 41 potential core domains presented in the first round, 13 had sufficient support to be presented for rating in the third round. Overall consensus was reached for the inclusion of three domains in this COS: 'physical functioning', 'pain intensity' and 'health-related quality of life'. Consensus on 'physical functioning' and 'pain intensity' was consistent across all stakeholders, 'health-related quality of life' was not supported by the patients, and all the other domains were not supported by two or more groups of stakeholders. Weighting all possible argumentations, the Steering Committee decided to include in the COS the three domains that reached overall consensus and the domain 'number of deaths'. The following outcome domains were included in this updated COS: 'physical functioning', 'pain intensity', 'health-related quality of life' and 'number of deaths'. The next step for the development of this COS will be to determine which measurement instruments best measure these domains.

GSDM family genes meet autophagy.

PubMed

Tamura, Masaru; Shiroishi, Toshihiko

2015-07-15

In the previous issue of Biochemical Journal, Shi et al. [(2015) 468, 325-336] report that Gasdermin (Gsdm) family proteins regulate autophagy activity, which is counter-balanced by the opposite functions of well-conserved N- and C-terminal domains of the proteins. The Gsdm family was originally identified as the causative gene of dominant skin mutations exhibiting alopecia. Each member of the Gsdm gene family shows characteristic expression patterns in the epithelium, which is tissue and differentiation stage-specific. Previous phenotype analyses of mutant mice, biochemical analyses of proteins and genome-wide association studies showed that the Gsdm gene family might be involved in epithelial cell development, apoptosis, inflammation, carcinogenesis and immune-related diseases. To date, however, their molecular function(s) remain unclear. Shi et al. found that mutations in the C-terminal domain of Gsdma3, a member of the Gsdm family, induce autophagy. Further studies revealed that the wild-type N-terminal domain has pro-autophagic activity and that the C-terminal domain conversely inhibits this N-terminal function. These opposite functions of the two domains were also observed in other Gsdm family members. Thus, their study provides a new insight into the function of Gsdm genes in epithelial cell lineage, causality of cancers and immune-related diseases including childhood-onset asthma. © 2015 Authors; published by Portland Press Limited.

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

Dai, Han; Shin, Ok-Ho; Machius, Mischa

The neuronal protein synaptotagmin 1 functions as a Ca{sup 2+} sensor in exocytosis via two Ca{sup 2+}-binding C{sub 2} domains. The very similar synaptotagmin 4, which includes all the predicted Ca{sup 2+}-binding residues in the C{sub 2}B domain but not in the C{sub 2}A domain, is also thought to function as a neuronal Ca{sup 2+} sensor. Here we show that, unexpectedly, both C{sub 2} domains of fly synaptotagmin 4 exhibit Ca{sup 2+}-dependent phospholipid binding, whereas neither C{sub 2} domain of rat synaptotagmin 4 binds Ca{sup 2+} or phospholipids efficiently. Crystallography reveals that changes in the orientations of critical Ca{sup 2+}more » ligands, and perhaps their flexibility, render the rat synaptotagmin 4 C{sub 2}B domain unable to form full Ca{sup 2+}-binding sites. These results indicate that synaptotagmin 4 is a Ca{sup 2+} sensor in the fly but not in the rat, that the Ca{sup 2+}-binding properties of C{sub 2} domains cannot be reliably predicted from sequence analyses, and that proteins clearly identified as orthologs may nevertheless have markedly different functional properties.« less

Multi-domain training in healthy old age: Hotel Plastisse as an iPad-based serious game to systematically compare multi-domain and single-domain training.

PubMed

Binder, Julia C; Zöllig, Jacqueline; Eschen, Anne; Mérillat, Susan; Röcke, Christina; Schoch, Sarah F; Jäncke, Lutz; Martin, Mike

2015-01-01

Finding effective training interventions for declining cognitive abilities in healthy aging is of great relevance, especially in view of the demographic development. Since it is assumed that transfer from the trained to untrained domains is more likely to occur when training conditions and transfer measures share a common underlying process, multi-domain training of several cognitive functions should increase the likelihood of such an overlap. In the first part, we give an overview of the literature showing that cognitive training using complex tasks, such as video games, leisure activities, or practicing a series of cognitive tasks, has shown promising results regarding transfer to a number of cognitive functions. These studies, however, do not allow direct inference about the underlying functions targeted by these training regimes. Custom-designed serious games allow to design training regimes according to specific cognitive functions and a target population's need. In the second part, we introduce the serious game Hotel Plastisse as an iPad-based training tool for older adults that allows the comparison of the simultaneous training of spatial navigation, visuomotor function, and inhibition to the training of each of these functions separately. Hotel Plastisse not only defines the cognitive functions of the multi-domain training clearly, but also implements training in an interesting learning environment including adaptive difficulty and feedback. We propose this novel training tool with the goal of furthering our understanding of how training regimes should be designed in order to affect cognitive functioning of older adults most broadly.

The rapidly evolving centromere-specific histone has stringent functional requirements in Arabidopsis thaliana.

PubMed

Ravi, Maruthachalam; Kwong, Pak N; Menorca, Ron M G; Valencia, Joel T; Ramahi, Joseph S; Stewart, Jodi L; Tran, Robert K; Sundaresan, Venkatesan; Comai, Luca; Chan, Simon W-L

2010-10-01

Centromeres control chromosome inheritance in eukaryotes, yet their DNA structure and primary sequence are hypervariable. Most animals and plants have megabases of tandem repeats at their centromeres, unlike yeast with unique centromere sequences. Centromere function requires the centromere-specific histone CENH3 (CENP-A in human), which replaces histone H3 in centromeric nucleosomes. CENH3 evolves rapidly, particularly in its N-terminal tail domain. A portion of the CENH3 histone-fold domain, the CENP-A targeting domain (CATD), has been previously shown to confer kinetochore localization and centromere function when swapped into human H3. Furthermore, CENP-A in human cells can be functionally replaced by CENH3 from distantly related organisms including Saccharomyces cerevisiae. We have used cenh3-1 (a null mutant in Arabidopsis thaliana) to replace endogenous CENH3 with GFP-tagged variants. A H3.3 tail domain-CENH3 histone-fold domain chimera rescued viability of cenh3-1, but CENH3's lacking a tail domain were nonfunctional. In contrast to human results, H3 containing the A. thaliana CATD cannot complement cenh3-1. GFP-CENH3 from the sister species A. arenosa functionally replaces A. thaliana CENH3. GFP-CENH3 from the close relative Brassica rapa was targeted to centromeres, but did not complement cenh3-1, indicating that kinetochore localization and centromere function can be uncoupled. We conclude that CENH3 function in A. thaliana, an organism with large tandem repeat centromeres, has stringent requirements for functional complementation in mitosis.

Multi-domain training in healthy old age: Hotel Plastisse as an iPad-based serious game to systematically compare multi-domain and single-domain training

PubMed Central

Binder, Julia C.; Zöllig, Jacqueline; Eschen, Anne; Mérillat, Susan; Röcke, Christina; Schoch, Sarah F.; Jäncke, Lutz; Martin, Mike

2015-01-01

Finding effective training interventions for declining cognitive abilities in healthy aging is of great relevance, especially in view of the demographic development. Since it is assumed that transfer from the trained to untrained domains is more likely to occur when training conditions and transfer measures share a common underlying process, multi-domain training of several cognitive functions should increase the likelihood of such an overlap. In the first part, we give an overview of the literature showing that cognitive training using complex tasks, such as video games, leisure activities, or practicing a series of cognitive tasks, has shown promising results regarding transfer to a number of cognitive functions. These studies, however, do not allow direct inference about the underlying functions targeted by these training regimes. Custom-designed serious games allow to design training regimes according to specific cognitive functions and a target population's need. In the second part, we introduce the serious game Hotel Plastisse as an iPad-based training tool for older adults that allows the comparison of the simultaneous training of spatial navigation, visuomotor function, and inhibition to the training of each of these functions separately. Hotel Plastisse not only defines the cognitive functions of the multi-domain training clearly, but also implements training in an interesting learning environment including adaptive difficulty and feedback. We propose this novel training tool with the goal of furthering our understanding of how training regimes should be designed in order to affect cognitive functioning of older adults most broadly. PMID:26257643

Discriminating electromagnetic radiation based on angle of incidence

DOEpatents

Hamam, Rafif E.; Bermel, Peter; Celanovic, Ivan; Soljacic, Marin; Yeng, Adrian Y. X.; Ghebrebrhan, Michael; Joannopoulos, John D.

2015-06-16

The present invention provides systems, articles, and methods for discriminating electromagnetic radiation based upon the angle of incidence of the electromagnetic radiation. In some cases, the materials and systems described herein can be capable of inhibiting reflection of electromagnetic radiation (e.g., the materials and systems can be capable of transmitting and/or absorbing electromagnetic radiation) within a given range of angles of incidence at a first incident surface, while substantially reflecting electromagnetic radiation outside the range of angles of incidence at a second incident surface (which can be the same as or different from the first incident surface). A photonic material comprising a plurality of periodically occurring separate domains can be used, in some cases, to selectively transmit and/or selectively absorb one portion of incoming electromagnetic radiation while reflecting another portion of incoming electromagnetic radiation, based upon the angle of incidence. In some embodiments, one domain of the photonic material can include an isotropic dielectric function, while another domain of the photonic material can include an anisotropic dielectric function. In some instances, one domain of the photonic material can include an isotropic magnetic permeability, while another domain of the photonic material can include an anisotropic magnetic permeability. In some embodiments, non-photonic materials (e.g., materials with relatively large scale features) can be used to selectively absorb incoming electromagnetic radiation based on angle of incidence.

Residual symptoms and specific functional impairments in euthymic patients with bipolar disorder.

PubMed

Samalin, Ludovic; de Chazeron, Ingrid; Vieta, Eduard; Bellivier, Frank; Llorca, Pierre-Michel

2016-03-01

The aims of the present study were to confirm the impact of residual symptoms on overall functioning in a large sample of euthymic patients with bipolar disorder in real-life conditions and to explore the relationship between residual symptoms and specific areas of functional impairment. This was a multicenter, cross-sectional, non-interventional study of euthymic outpatients with bipolar disorder. The Functioning Assessment Short Test was used to assess overall and specific domains of functioning (autonomy, occupational functioning, cognitive functioning, financial issues, interpersonal relationships, and leisure time). Various residual symptoms were assessed (residual mood symptoms, emotional dysregulation, sleep and sexual disorders, stigma, and perceived cognitive impairment). Logistic regression was used to determine the best model of association between functional domains and residual symptoms. Almost half of the 468 patients included (42%) had poor overall functioning. Residual depressive symptoms appeared to have an impact on overall functioning and in nearly all areas of functioning. In addition, specific residual symptoms had significantly more negative effects on some domains of functioning in euthymic patients with bipolar disorder (residual manic symptoms and occupational stigma on autonomy, emotional inhibition on occupational functioning, residual manic symptoms on financial issues, family stigma on interpersonal relationships, and sexual function and occupational stigma on leisure time). Our findings highlight the importance of evaluating overall functioning in clinical practice as well as functional domains. They also indicate that some residuals symptoms in patients with bipolar disorder should be targeted in personalized treatment plans, in order to improve functioning in the domains in which the patient is most impaired. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Translocation of the cytoplasmic domain of ADAM13 to the nucleus is essential for Calpain-8 expression and cranial neural crest cell migration

PubMed Central

Cousin, Hélène; Abbruzzese, Genevieve; Kerdavid, Erin; Gaultier, Alban; Alfandari, Dominique

2011-01-01

Summary ADAMs are transmembrane metalloproteases that control cell behavior by cleaving both cell adhesion and signaling molecules. The cytoplasmic domain of ADAMs can regulate the proteolytic activity by controlling the subcellular localization and/or the activation of the protease domain. Here we show that the cytoplasmic domain of ADAM13 is cleaved and translocates into the nucleus. Preventing this translocation renders the protein incapable of promoting cranial neural crest (CNC) cell migration in vivo, without affecting its proteolytic activity. In addition, the cytoplasmic domain of ADAM13 regulates the expression of multiple genes in CNC, including the protease Calpain8-a. Restoring the expression of Calpain8-a is sufficient to rescue CNC migration in the absence of the ADAM13 cytoplasmic domain. This study shows that the cytoplasmic domain of ADAM metalloproteases can perform essential functions in the nucleus of cells and may contribute substantially to the overall function of the protein. PMID:21316592

Topographical Organization of Attentional, Social, and Memory Processes in the Human Temporoparietal Cortex123

PubMed Central

Webb, Taylor W.; Kelly, Yin T.; Graziano, Michael S. A.

2016-01-01

Abstract The temporoparietal junction (TPJ) is activated in association with a large range of functions, including social cognition, episodic memory retrieval, and attentional reorienting. An ongoing debate is whether the TPJ performs an overarching, domain-general computation, or whether functions reside in domain-specific subdivisions. We scanned subjects with fMRI during five tasks known to activate the TPJ, probing social, attentional, and memory functions, and used data-driven parcellation (independent component analysis) to isolate task-related functional processes in the bilateral TPJ. We found that one dorsal component in the right TPJ, which was connected with the frontoparietal control network, was activated in all of the tasks. Other TPJ subregions were specific for attentional reorienting, oddball target detection, or social attribution of belief. The TPJ components that participated in attentional reorienting and oddball target detection appeared spatially separated, but both were connected with the ventral attention network. The TPJ component that participated in the theory-of-mind task was part of the default-mode network. Further, we found that the BOLD response in the domain-general dorsal component had a longer latency than responses in the domain-specific components, suggesting an involvement in distinct, perhaps postperceptual, computations. These findings suggest that the TPJ performs both domain-general and domain-specific computations that reside within spatially distinct functional components. PMID:27280153

Identification by Random Mutagenesis of Functional Domains in KREPB5 That Differentially Affect RNA Editing between Life Cycle Stages of Trypanosoma brucei

PubMed Central

McDermott, Suzanne M.; Carnes, Jason

2015-01-01

KREPB5 is an essential component of ∼20S editosomes in Trypanosoma brucei which contains a degenerate, noncatalytic RNase III domain. To explore the function of this protein, we used a novel approach to make and screen numerous conditional null T. brucei bloodstream form cell lines that express randomly mutagenized KREPB5 alleles. We identified nine single amino acid substitutions that could not complement the conditional loss of wild-type KREPB5. Seven of these were within the RNase III domain, and two were in the C-terminal region that has no homology to known motifs. Exclusive expression of these mutated KREPB5 alleles in the absence of wild-type allele expression resulted in growth inhibition, the loss of ∼20S editosomes, and inhibition of RNA editing in BF cells. Eight of these mutations were lethal in bloodstream form parasites but not in procyclic-form parasites, showing that multiple domains function in a life cycle-dependent manner. Amino acid changes at a substantial number of positions, including up to 7 per allele, allowed complementation and thus did not block KREPB5 function. Hence, the degenerate RNase III domain and a newly identified domain are critical for KREPB5 function and have differential effects between the life cycle stages of T. brucei that differentially edit mRNAs. PMID:26370513

Structural insights into SAM domain-mediated tankyrase oligomerization.

PubMed

DaRosa, Paul A; Ovchinnikov, Sergey; Xu, Wenqing; Klevit, Rachel E

2016-09-01

Tankyrase 1 (TNKS1; a.k.a. ARTD5) and tankyrase 2 (TNKS2; a.k.a ARTD6) are highly homologous poly(ADP-ribose) polymerases (PARPs) that function in a wide variety of cellular processes including Wnt signaling, Src signaling, Akt signaling, Glut4 vesicle translocation, telomere length regulation, and centriole and spindle pole maturation. Tankyrase proteins include a sterile alpha motif (SAM) domain that undergoes oligomerization in vitro and in vivo. However, the SAM domains of TNKS1 and TNKS2 have not been structurally characterized and the mode of oligomerization is not yet defined. Here we model the SAM domain-mediated oligomerization of tankyrase. The structural model, supported by mutagenesis and NMR analysis, demonstrates a helical, homotypic head-to-tail polymer that facilitates TNKS self-association. Furthermore, we show that TNKS1 and TNKS2 can form (TNKS1 SAM-TNKS2 SAM) hetero-oligomeric structures mediated by their SAM domains. Though wild-type tankyrase proteins have very low solubility, model-based mutations of the SAM oligomerization interface residues allowed us to obtain soluble TNKS proteins. These structural insights will be invaluable for the functional and biophysical characterization of TNKS1/2, including the role of TNKS oligomerization in protein poly(ADP-ribosyl)ation (PARylation) and PARylation-dependent ubiquitylation. © 2016 The Protein Society.

Functional innovation from changes in protein domains and their combinations.

PubMed

Lees, Jonathan G; Dawson, Natalie L; Sillitoe, Ian; Orengo, Christine A

2016-06-01

Domains are the functional building blocks of proteins. In this work we discuss how domains can contribute to the evolution of new functions. Domains themselves can evolve through various mechanisms, altering their intrinsic function. Domains can also facilitate functional innovations by combining with other domains to make novel proteins. We discuss the mechanisms by which domain and domain combinations support functional innovations. We highlight interesting examples where changes in domain combination promote changes at the domain level. Copyright © 2016 Elsevier Ltd. All rights reserved.

Does the Cambridge Automated Neuropsychological Test Battery (CANTAB) Distinguish Between Cognitive Domains in Healthy Older Adults?

PubMed

Lenehan, Megan E; Summers, Mathew J; Saunders, Nichole L; Summers, Jeffery J; Vickers, James C

2016-04-01

The Cambridge Neuropsychological Test Automated Battery (CANTAB) is a semiautomated computer interface for assessing cognitive function. We examined whether CANTAB tests measured specific cognitive functions, using established neuropsychological tests as a reference point. A sample of 500 healthy older (M = 60.28 years, SD = 6.75) participants in the Tasmanian Healthy Brain Project completed battery of CANTAB subtests and standard paper-based neuropsychological tests. Confirmatory factor analysis identified four factors: processing speed, verbal ability, episodic memory, and working memory. However, CANTAB tests did not consistently load onto the cognitive domain factors derived from traditional measures of the same function. These results indicate that five of the six CANTAB subtests examined did not load onto single cognitive functions. These CANTAB tests may lack the sensitivity to measure discrete cognitive functions in healthy populations or may measure other cognitive domains not included in the traditional neuropsychological battery. © The Author(s) 2015.

The dimer interface of the membrane type 1 matrix metalloproteinase hemopexin domain: crystal structure and biological functions.

PubMed

Tochowicz, Anna; Goettig, Peter; Evans, Richard; Visse, Robert; Shitomi, Yasuyuki; Palmisano, Ralf; Ito, Noriko; Richter, Klaus; Maskos, Klaus; Franke, Daniel; Svergun, Dmitri; Nagase, Hideaki; Bode, Wolfram; Itoh, Yoshifumi

2011-03-04

Homodimerization is an essential step for membrane type 1 matrix metalloproteinase (MT1-MMP) to activate proMMP-2 and to degrade collagen on the cell surface. To uncover the molecular basis of the hemopexin (Hpx) domain-driven dimerization of MT1-MMP, a crystal structure of the Hpx domain was solved at 1.7 Å resolution. Two interactions were identified as potential biological dimer interfaces in the crystal structure, and mutagenesis studies revealed that the biological dimer possesses a symmetrical interaction where blades II and III of molecule A interact with blades III and II of molecule B. The mutations of amino acids involved in the interaction weakened the dimer interaction of Hpx domains in solution, and incorporation of these mutations into the full-length enzyme significantly inhibited dimer-dependent functions on the cell surface, including proMMP-2 activation, collagen degradation, and invasion into the three-dimensional collagen matrix, whereas dimer-independent functions, including gelatin film degradation and two-dimensional cell migration, were not affected. These results shed light on the structural basis of MT1-MMP dimerization that is crucial to promote cellular invasion.

Calpain chronicle--an enzyme family under multidisciplinary characterization.

PubMed

Sorimachi, Hiroyuki; Hata, Shoji; Ono, Yasuko

2011-01-01

Calpain is an intracellular Ca2+-dependent cysteine protease (EC 3.4.22.17; Clan CA, family C02) discovered in 1964. It was also called CANP (Ca2+-activated neutral protease) as well as CASF, CDP, KAF, etc. until 1990. Calpains are found in almost all eukaryotes and a few bacteria, but not in archaebacteria. Calpains have a limited proteolytic activity, and function to transform or modulate their substrates' structures and activities; they are therefore called, "modulator proteases." In the human genome, 15 genes--CAPN1, CAPN2, etc.--encode a calpain-like protease domain. Their products are calpain homologs with divergent structures and various combinations of functional domains, including Ca2+-binding and microtubule-interaction domains. Genetic studies have linked calpain deficiencies to a variety of defects in many different organisms, including lethality, muscular dystrophies, gastropathy, and diabetes. This review of the study of calpains focuses especially on recent findings about their structure-function relationships. These discoveries have been greatly aided by the development of 3D structural studies and genetic models.

The C-Terminal Domain of the Virulence Factor MgtC Is a Divergent ACT Domain

PubMed Central

Yang, Yinshan; Labesse, Gilles; Carrère-Kremer, Séverine; Esteves, Kevin; Kremer, Laurent

2012-01-01

MgtC is a virulence factor of unknown function important for survival inside macrophages in several intracellular bacterial pathogens, including Mycobacterium tuberculosis. It is also involved in adaptation to Mg2+ deprivation, but previous work suggested that MgtC is not a Mg2+ transporter. In this study, we demonstrated that the amount of the M. tuberculosis MgtC protein is not significantly increased by Mg2+ deprivation. Members of the MgtC protein family share a conserved membrane N-terminal domain and a more divergent cytoplasmic C-terminal domain. To get insights into MgtC functional and structural organization, we have determined the nuclear magnetic resonance (NMR) structure of the C-terminal domain of M. tuberculosis MgtC. This structure is not affected by the Mg2+ concentration, indicating that it does not bind Mg2+. The structure of the C-terminal domain forms a βαββαβ fold found in small molecule binding domains called ACT domains. However, the M. tuberculosis MgtC ACT domain differs from canonical ACT domains because it appears to lack the ability to dimerize and to bind small molecules. We have shown, using a bacterial two-hybrid system, that the M. tuberculosis MgtC protein can dimerize and that the C-terminal domain somehow facilitates this dimerization. Taken together, these results indicate that M. tuberculosis MgtC does not have an intrinsic function related to Mg2+ uptake or binding but could act as a regulatory factor based on protein-protein interaction that could be facilitated by its ACT domain. PMID:22984256

Structure of a Novel DNA-binding Domain of Helicase-like Transcription Factor (HLTF) and Its Functional Implication in DNA Damage Tolerance.

PubMed

Hishiki, Asami; Hara, Kodai; Ikegaya, Yuzu; Yokoyama, Hideshi; Shimizu, Toshiyuki; Sato, Mamoru; Hashimoto, Hiroshi

2015-05-22

HLTF (helicase-like transcription factor) is a yeast RAD5 homolog found in mammals. HLTF has E3 ubiquitin ligase and DNA helicase activities, and plays a pivotal role in the template-switching pathway of DNA damage tolerance. HLTF has an N-terminal domain that has been designated the HIRAN (HIP116 and RAD5 N-terminal) domain. The HIRAN domain has been hypothesized to play a role in DNA binding; however, the structural basis of, and functional evidence for, the HIRAN domain in DNA binding has remained unclear. Here we show for the first time the crystal structure of the HIRAN domain of human HLTF in complex with DNA. The HIRAN domain is composed of six β-strands and two α-helices, forming an OB-fold structure frequently found in ssDNA-binding proteins, including in replication factor A (RPA). Interestingly, this study reveals that the HIRAN domain interacts with not only with a single-stranded DNA but also with a duplex DNA. Furthermore, the structure unexpectedly clarifies that the HIRAN domain specifically recognizes the 3'-end of DNA. These results suggest that the HIRAN domain functions as a sensor to the 3'-end of the primer strand at the stalled replication fork and that the domain facilitates fork regression. HLTF is recruited to a damaged site through the HIRAN domain at the stalled replication fork. Furthermore, our results have implications for the mechanism of template switching. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Cytochemistry of the functional domains of the nucleus in normal and in pathologic conditions.

PubMed

Maraldi, N M; Zini, N; Santi, S; Ognibene, A; Rizzoli, R; Mazzotti, G; Manzoli, F A

1998-01-01

By means of ultrastructural cytochemistry significant advances have been made in understanding the functional roles of many nuclear domains. This review gives schematic information about the main nuclear domains involved in replication, transcription, processing and transport of the transcripts in normal and in pathologic conditions. Particular attention is paid to a functional domain that appears to be involved in signal transduction. Data are reported on the intranuclear specific localization of key elements of the polyphosphoinositide signal transduction system in different cell types including human osteosarcoma cell lines. Compared with the compartmentalization of the cytoplasm, the nucleus has long been considered as relatively unstructured. On the other hand, fundamental nuclear functions, such as DNA replication and RNA transcription, can be molecularly characterized also in cell-free systems, suggesting that supramolecular organization is not so strictly required as for other cell functions occurring within intact cytoplasmic organelles. Nevertheless, a stringent organization is required for packing about 200 cm of DNA in the about 30 micron 3 of the nucleus. In the absence of membrane-delimited organelles, the nuclear organization is based on functional compartments, or domains, whose spatial localization involves the nuclear matrix, which shares many properties with the cytoskeleton. The nuclear domains are defined as structural compartments, not necessarily stable but dynamically variable, which perform specific metabolic functions through the partitioning of molecular complexes. Their identification has been made possible in the last few years by the development of specific nuclear probes for confocal and electron microscope immunocytochemistry. Therefore, the complex network of structures and enzymatic functions that make up the nucleus is in several cases yielding to molecular analysis, but a large part remains unknown (Strouboulis and Wolffe, 1996; Laemmli and Tjian, 1996). Rapid advances in understanding the functional role of the nuclear domains have been made recently: in particular, of the nuclear envelope, of the nucleolus, and of RNA splicing. In other cases, e.g. the precise localization of the nuclear domains involved in signal transduction, much remains to be clarified (Forbes and Johnson, 1997). It is conceivable that in the near future unexpected new nuclear domains will come to light and new nuclear functions may emerge, especially in field of post-transcriptional processing and transport of RNAs, and in the relationships between the nucleo-skeleton and enzymic fixed sites involved in replication, transcription and signal transduction. The aim of this review is to provide information about the morphological characteristics, the associated functions and the molecular composition of the main nuclear domains found to date. To simplify the exposition, the main data on each nuclear domain are reported in Tables, together with the principal references on the subject. Figures refer to original findings on some aspects of nuclear domain organization.

The PYRIN domain: A member of the death domain-fold superfamily

PubMed Central

Fairbrother, Wayne J.; Gordon, Nathaniel C.; Humke, Eric W.; O'Rourke, Karen M.; Starovasnik, Melissa A.; Yin, Jian-Ping; Dixit, Vishva M.

2001-01-01

PYRIN domains were identified recently as putative protein–protein interaction domains at the N-termini of several proteins thought to function in apoptotic and inflammatory signaling pathways. The ∼95 residue PYRIN domains have no statistically significant sequence homology to proteins with known three-dimensional structure. Using secondary structure prediction and potential-based fold recognition methods, however, the PYRIN domain is predicted to be a member of the six-helix bundle death domain-fold superfamily that includes death domains (DDs), death effector domains (DEDs), and caspase recruitment domains (CARDs). Members of the death domain-fold superfamily are well established mediators of protein–protein interactions found in many proteins involved in apoptosis and inflammation, indicating further that the PYRIN domains serve a similar function. An homology model of the PYRIN domain of CARD7/DEFCAP/NAC/NALP1, a member of the Apaf-1/Ced-4 family of proteins, was constructed using the three-dimensional structures of the FADD and p75 neurotrophin receptor DDs, and of the Apaf-1 and caspase-9 CARDs, as templates. Validation of the model using a variety of computational techniques indicates that the fold prediction is consistent with the sequence. Comparison of a circular dichroism spectrum of the PYRIN domain of CARD7/DEFCAP/NAC/NALP1 with spectra of several proteins known to adopt the death domain-fold provides experimental support for the structure prediction. PMID:11514682

A systematic analysis of the in vitro and in vivo functions of the HD-GYP domain proteins of Vibrio cholerae.

PubMed

McKee, Robert W; Kariisa, Ankunda; Mudrak, Benjamin; Whitaker, Courtney; Tamayo, Rita

2014-10-25

The second messenger cyclic diguanylate (c-di-GMP) plays a central role in bacterial adaptation to extracellular stimuli, controlling processes such as motility, biofilm development, cell development and, in some pathogens, virulence. The intracellular level of c-di-GMP is controlled by the complementary activities of diguanylate cyclases containing a GGDEF domain and two classes of c-di-GMP phosphodiesterases containing an EAL or HD-GYP hydrolytic domain. Compared to the GGDEF and EAL domains, the functions of HD-GYP domain family proteins are poorly characterized. The human diarrheal pathogen Vibrio cholerae encodes nine putative HD-GYP domain proteins. To determine the contributions of HD-GYP domain proteins to c-di-GMP signaling in V. cholerae, we systematically analyzed the enzymatic functionality of each protein and their involvement in processes known to be regulated by c-di-GMP: motility, biofilm development and virulence. Complementary in vitro and in vivo experiments showed that four HD-GYP domain proteins are active c-di-GMP phosphodiesterases: VC1295, VC1348, VCA0210 and VCA0681. Mutation of individual HD-GYP domain genes, as well as combinatorial mutations of multiple HD-GYP domain genes, had no effect on motility or biofilm formation of V. cholerae under the conditions tested. Furthermore, no single HD-GYP domain gene affected intestinal colonization by V. cholerae in an infant mouse model. However, inactivation of multiple HD-GYP domain genes, including the four encoding functional phosphodiesterases, significantly attenuated colonization. These results indicate that the HD-GYP family of c-di-GMP phosphodiesterases impacts signaling by this second messenger during infection. Altogether, this work greatly furthers the understanding of this important family of c-di-GMP metabolic enzymes and demonstrates a role for HD-GYP domain proteins in the virulence of V. cholerae.

Efficacy and tolerability of vardenafil for treatment of erectile dysfunction in patient subgroups.

PubMed

Porst, Hartmut; Young, Jay M; Schmidt, Abraham C; Buvat, Jacques

2003-09-01

To assess whether vardenafil would improve erectile function irrespective of etiology, baseline severity, or patient age. The consistency of the response over time was also evaluated. A multicenter, randomized, double-blind, placebo-controlled at-home study of vardenafil treatment (5, 10, and 20 mg) was performed. This secondary analysis compared the mean International Index of Erectile Function (IIEF) erectile function domain scores of various subgroups at 12 weeks of treatment. These populations included organic, psychogenic, or mixed etiologies; mild, moderate, or severe baseline severity; and four age groups (younger than 45, 45 to 55, 56 to 65, and older than 65 years). In addition, all IIEF domains were compared at sequential 4-week periods, before and during treatment. In the 580 men of the intent-to-treat population, the mean erectile function domain scores were statistically greater than placebo, irrespective of etiology, baseline severity, or age. This was seen at all dosages. Compared with placebo, vardenafil statistically improved the IIEF domain scores of erectile function, orgasmic function, intercourse satisfaction, and overall satisfaction after 4 weeks of treatment, and these improvements were maintained for 12 weeks. The rates of the most common adverse events (headache, flushing, and dyspepsia) were either constant or declined over time; they were generally mild to moderate and transient in nature. Vardenafil improved erectile function regardless of the general etiology, baseline severity of erectile dysfunction, or patient age. Improvements in erectile function and other key IIEF domains were consistently seen throughout the study.

Mammalian Per-Arnt-Sim proteins in environmental adaptation.

PubMed

McIntosh, Brian E; Hogenesch, John B; Bradfield, Christopher A

2010-01-01

The Per-Arnt-Sim (PAS) domain is conserved across the kingdoms of life and found in an ever-growing list of proteins. This domain can bind to and sense endogenous or xenobiotic small molecules such as molecular oxygen, cellular metabolites, or polyaromatic hydrocarbons. Members of this family are often found in pathways that regulate responses to environmental change; in mammals these include the hypoxia, circadian, and dioxin response pathways. These pathways function in development and throughout life to regulate cellular, organ, and whole-organism adaptive responses. Remarkably, in the case of the clock, this adaptation includes anticipation of environmental change. In this review, we summarize the roles of PAS domain-containing proteins in mammals. We provide structural evidence that functionally classifies both known and unknown biological roles. Finally, we discuss the role of PAS proteins in anticipation of and adaptation to environmental change.

A rho-binding protein kinase C-like activity is required for the function of protein kinase N in Drosophila development.

PubMed

Betson, Martha; Settleman, Jeffrey

2007-08-01

The Rho GTPases interact with multiple downstream effectors to exert their biological functions, which include important roles in tissue morphogenesis during the development of multicellular organisms. Among the Rho effectors are the protein kinase N (PKN) proteins, which are protein kinase C (PKC)-like kinases that bind activated Rho GTPases. The PKN proteins are well conserved evolutionarily, but their biological role in any organism is poorly understood. We previously determined that the single Drosophila ortholog of mammalian PKN proteins, Pkn, is a Rho/Rac-binding kinase essential for Drosophila development. By performing "rescue" studies with various Pkn mutant constructs, we have defined the domains of Pkn required for its role during Drosophila development. These studies suggested that Rho, but not Rac binding is important for Pkn function in development. In addition, we determined that the kinase domain of PKC53E, a PKC family kinase, can functionally substitute for the kinase domain of Pkn during development, thereby exemplifying the evolutionary strategy of "combining" functional domains to produce proteins with distinct biological activities. Interestingly, we also identified a requirement for Pkn in wing morphogenesis, thereby revealing the first postembryonic function for Pkn.

Changes in language white matter tract microarchitecture associated with cognitive deficits in patients with presumed low-grade glioma.

PubMed

Incekara, Fatih; Satoer, Djaina; Visch-Brink, Evy; Vincent, Arnaud; Smits, Marion

2018-06-08

OBJECTIVE The authors conducted a study to determine whether cognitive functioning of patients with presumed low-grade glioma is associated with white matter (WM) tract changes. METHODS The authors included 77 patients with presumed low-grade glioma who underwent awake surgery between 2005 and 2013. Diffusion tensor imaging with deterministic tractography was performed preoperatively to identify the arcuate, inferior frontooccipital, and uncinate fasciculi and to obtain the mean fractional anisotropy (FA) and mean diffusivity per tract. All patients were evaluated preoperatively using an extensive neuropsychological protocol that included assessments of the language, memory, and attention/executive function domains. Linear regression models were used to analyze each cognitive domain and each diffusion tensor imaging metric of the 3 WM tracts. RESULTS Significant correlations (corrected for multiple testing) were found between FA of the arcuate fasciculus and results of the repetition test for the language domain (β = 0.59, p < 0.0001) and between FA of the inferior frontooccipital fasciculus and results of the imprinting test for the memory domain (β = -0.55, p = 0.002) and the attention test for the attention and executive function domain (β = -0.62, p = 0.006). CONCLUSIONS In patients with glioma, language deficits in repetition of speech, imprinting, and attention deficits are associated with changes in the microarchitecture of the arcuate and inferior frontooccipital fasciculi.

Cognitive and sexual functions in patients with traumatic brain injury

PubMed Central

War, Firdous A.; Jamuna, R.; Arivazhagan, A.

2014-01-01

Background: Traumatic brain injury (TBI) has an immense psychosocial impact on an individual as well as on the close relatives. Sexuality is one among the functions which are usually found compromised post injury. The aim of present study was to examine cognitive and sexual functions post TBI. The objective of the study was to explore these domains and their relationship with each other. Tools: The tools used were sociodemographics record sheet, Edinburg handedness inventory, brief sexual function inventory, depression anxiety stress scales-21 and NIMHANS head injury battery. The sample consisted of 30 patients with mild-to-moderate TBI. All the subjects were tested individually in their regional language. Results: On cognitive domain, patients performed inadequately on all the tests; however, the percentage was higher in mental speed (43.3%), sustained attention (26.7%), verbal working memory (30%), response inhibition (36.7%), verbal memory (immediate and delayed) (43%) and visual (immediate, 23.3% and delayed, 26.7%). On the domain of sexual functions, all the four domains (sexual drive, erection, ejaculation and problem assessment) were affected however overall satisfaction (93.3%) was adequate. Among the four domains higher percentage of involvement was noted on problem assessment (70%), ejaculation (56.7%), and erection (46.7%). Significant correlation was found between mental speed, verbal working memory, planning, and visual memory with sexual drive, erection, ejaculation and overall satisfaction domains of sexual functioning. Negative correlation was found between motor speed and sustained attention with sexual drive, erection and ejaculation. Conclusion: Both cognitive and sexual functioning were found effected post TBI. However less emphasis is given to sexual functioning by the professionals. Educational intervention is needed to sensitize professional about this area and to include this area for better management. PMID:24891887

Politics drives human functioning, dignity, and quality of life.

PubMed

Barber, Brian K; Spellings, Carolyn; McNeely, Clea; Page, Paul D; Giacaman, Rita; Arafat, Cairo; Daher, Mahmoud; El Sarraj, Eyad; Mallouh, Mohammed Abu

2014-12-01

Too little is known about human functioning amidst chronic adversity. We addressed that need by studying adult Palestinians in the occupied Palestinian territories (oPt), a population that has experienced longstanding economic and political hardships. Fourteen group interviews were conducted in February, 2010 in Arabic by local fieldworkers with 68 participants representing the main stratifications of Palestinian society: gender, region, refugee status, and political affiliation. Interview tasks included each participant: describing someone doing well and not well, free listing domains of functioning, and prioritizing domains to the three most important. Thematic analyses highlighted the dominating role of the political domain of functioning (e.g., political structures, constraints, effects, identity, and activism) and the degree to which political conditions impacted all other realms of functioning (economic, education, family, psychological, etc.). The discussion links the findings to relevant theory and empirical work that has called attention to the need to include the political in frameworks of quality of life. It also emphasized that values, such as justice, rights, dignity and self-determination, that underlie political structures and policies, are key elements of human functioning. This is the case not only in the oPt, but in any society where power imbalances marginalize segments of the population. Copyright © 2014 Elsevier Ltd. All rights reserved.

Comprehensive analysis of the HEPN superfamily: identification of novel roles in intra-genomic conflicts, defense, pathogenesis and RNA processing

PubMed Central

2013-01-01

Background The major role of enzymatic toxins that target nucleic acids in biological conflicts at all levels has become increasingly apparent thanks in large part to the advances of comparative genomics. Typically, toxins evolve rapidly hampering the identification of these proteins by sequence analysis. Here we analyze an unexpectedly widespread superfamily of toxin domains most of which possess RNase activity. Results The HEPN superfamily is comprised of all α-helical domains that were first identified as being associated with DNA polymerase β-type nucleotidyltransferases in prokaryotes and animal Sacsin proteins. Using sensitive sequence and structure comparison methods, we vastly extend the HEPN superfamily by identifying numerous novel families and by detecting diverged HEPN domains in several known protein families. The new HEPN families include the RNase LS and LsoA catalytic domains, KEN domains (e.g. RNaseL and Ire1) and the RNase domains of RloC and PrrC. The majority of HEPN domains contain conserved motifs that constitute a metal-independent endoRNase active site. Some HEPN domains lacking this motif probably function as non-catalytic RNA-binding domains, such as in the case of the mannitol repressor MtlR. Our analysis shows that HEPN domains function as toxins that are shared by numerous systems implicated in intra-genomic, inter-genomic and intra-organismal conflicts across the three domains of cellular life. In prokaryotes HEPN domains are essential components of numerous toxin-antitoxin (TA) and abortive infection (Abi) systems and in addition are tightly associated with many restriction-modification (R-M) and CRISPR-Cas systems, and occasionally with other defense systems such as Pgl and Ter. We present evidence of multiple modes of action of HEPN domains in these systems, which include direct attack on viral RNAs (e.g. LsoA and RNase LS) in conjunction with other RNase domains (e.g. a novel RNase H fold domain, NamA), suicidal or dormancy-inducing attack on self RNAs (RM systems and possibly CRISPR-Cas systems), and suicidal attack coupled with direct interaction with phage components (Abi systems). These findings are compatible with the hypothesis on coupling of pathogen-targeting (immunity) and self-directed (programmed cell death and dormancy induction) responses in the evolution of robust antiviral strategies. We propose that altruistic cell suicide mediated by HEPN domains and other functionally similar RNases was essential for the evolution of kin and group selection and cell cooperation. HEPN domains were repeatedly acquired by eukaryotes and incorporated into several core functions such as endonucleolytic processing of the 5.8S-25S/28S rRNA precursor (Las1), a novel ER membrane-associated RNA degradation system (C6orf70), sensing of unprocessed transcripts at the nuclear periphery (Swt1). Multiple lines of evidence suggest that, similar to prokaryotes, HEPN proteins were recruited to antiviral, antitransposon, apoptotic systems or RNA-level response to unfolded proteins (Sacsin and KEN domains) in several groups of eukaryotes. Conclusions Extensive sequence and structure comparisons reveal unexpectedly broad presence of the HEPN domain in an enormous variety of defense and stress response systems across the tree of life. In addition, HEPN domains have been recruited to perform essential functions, in particular in eukaryotic rRNA processing. These findings are expected to stimulate experiments that could shed light on diverse cellular processes across the three domains of life. Reviewers This article was reviewed by Martijn Huynen, Igor Zhulin and Nick Grishin PMID:23768067

Comprehensive analysis of the HEPN superfamily: identification of novel roles in intra-genomic conflicts, defense, pathogenesis and RNA processing.

PubMed

Anantharaman, Vivek; Makarova, Kira S; Burroughs, A Maxwell; Koonin, Eugene V; Aravind, L

2013-06-15

The major role of enzymatic toxins that target nucleic acids in biological conflicts at all levels has become increasingly apparent thanks in large part to the advances of comparative genomics. Typically, toxins evolve rapidly hampering the identification of these proteins by sequence analysis. Here we analyze an unexpectedly widespread superfamily of toxin domains most of which possess RNase activity. The HEPN superfamily is comprised of all α-helical domains that were first identified as being associated with DNA polymerase β-type nucleotidyltransferases in prokaryotes and animal Sacsin proteins. Using sensitive sequence and structure comparison methods, we vastly extend the HEPN superfamily by identifying numerous novel families and by detecting diverged HEPN domains in several known protein families. The new HEPN families include the RNase LS and LsoA catalytic domains, KEN domains (e.g. RNaseL and Ire1) and the RNase domains of RloC and PrrC. The majority of HEPN domains contain conserved motifs that constitute a metal-independent endoRNase active site. Some HEPN domains lacking this motif probably function as non-catalytic RNA-binding domains, such as in the case of the mannitol repressor MtlR. Our analysis shows that HEPN domains function as toxins that are shared by numerous systems implicated in intra-genomic, inter-genomic and intra-organismal conflicts across the three domains of cellular life. In prokaryotes HEPN domains are essential components of numerous toxin-antitoxin (TA) and abortive infection (Abi) systems and in addition are tightly associated with many restriction-modification (R-M) and CRISPR-Cas systems, and occasionally with other defense systems such as Pgl and Ter. We present evidence of multiple modes of action of HEPN domains in these systems, which include direct attack on viral RNAs (e.g. LsoA and RNase LS) in conjunction with other RNase domains (e.g. a novel RNase H fold domain, NamA), suicidal or dormancy-inducing attack on self RNAs (RM systems and possibly CRISPR-Cas systems), and suicidal attack coupled with direct interaction with phage components (Abi systems). These findings are compatible with the hypothesis on coupling of pathogen-targeting (immunity) and self-directed (programmed cell death and dormancy induction) responses in the evolution of robust antiviral strategies. We propose that altruistic cell suicide mediated by HEPN domains and other functionally similar RNases was essential for the evolution of kin and group selection and cell cooperation. HEPN domains were repeatedly acquired by eukaryotes and incorporated into several core functions such as endonucleolytic processing of the 5.8S-25S/28S rRNA precursor (Las1), a novel ER membrane-associated RNA degradation system (C6orf70), sensing of unprocessed transcripts at the nuclear periphery (Swt1). Multiple lines of evidence suggest that, similar to prokaryotes, HEPN proteins were recruited to antiviral, antitransposon, apoptotic systems or RNA-level response to unfolded proteins (Sacsin and KEN domains) in several groups of eukaryotes. Extensive sequence and structure comparisons reveal unexpectedly broad presence of the HEPN domain in an enormous variety of defense and stress response systems across the tree of life. In addition, HEPN domains have been recruited to perform essential functions, in particular in eukaryotic rRNA processing. These findings are expected to stimulate experiments that could shed light on diverse cellular processes across the three domains of life. This article was reviewed by Martijn Huynen, Igor Zhulin and Nick Grishin.

APP is cleaved by Bace1 in pre-synaptic vesicles and establishes a pre-synaptic interactome, via its intracellular domain, with molecular complexes that regulate pre-synaptic vesicles functions.

PubMed

Del Prete, Dolores; Lombino, Franco; Liu, Xinran; D'Adamio, Luciano

2014-01-01

Amyloid Precursor Protein (APP) is a type I membrane protein that undergoes extensive processing by secretases, including BACE1. Although mutations in APP and genes that regulate processing of APP, such as PSENs and BRI2/ITM2B, cause dementias, the normal function of APP in synaptic transmission, synaptic plasticity and memory formation is poorly understood. To grasp the biochemical mechanisms underlying the function of APP in the central nervous system, it is important to first define the sub-cellular localization of APP in synapses and the synaptic interactome of APP. Using biochemical and electron microscopy approaches, we have found that APP is localized in pre-synaptic vesicles, where it is processed by Bace1. By means of a proteomic approach, we have characterized the synaptic interactome of the APP intracellular domain. We focused on this region of APP because in vivo data underline the central functional and pathological role of the intracellular domain of APP. Consistent with the expression of APP in pre-synaptic vesicles, the synaptic APP intracellular domain interactome is predominantly constituted by pre-synaptic, rather than post-synaptic, proteins. This pre-synaptic interactome of the APP intracellular domain includes proteins expressed on pre-synaptic vesicles such as the vesicular SNARE Vamp2/Vamp1 and the Ca2+ sensors Synaptotagmin-1/Synaptotagmin-2, and non-vesicular pre-synaptic proteins that regulate exocytosis, endocytosis and recycling of pre-synaptic vesicles, such as target-membrane-SNAREs (Syntaxin-1b, Syntaxin-1a, Snap25 and Snap47), Munc-18, Nsf, α/β/γ-Snaps and complexin. These data are consistent with a functional role for APP, via its carboxyl-terminal domain, in exocytosis, endocytosis and/or recycling of pre-synaptic vesicles.

Recombinant soluble adenovirus receptor

DOEpatents

Freimuth, Paul I.

2002-01-01

Disclosed are isolated polypeptides from human CAR (coxsackievirus and adenovirus receptor) protein which bind adenovirus. Specifically disclosed are amino acid sequences which corresponds to adenovirus binding domain D1 and the entire extracellular domain of human CAR protein comprising D1 and D2. In other aspects, the disclosure relates to nucleic acid sequences encoding these domains as well as expression vectors which encode the domains and bacterial cells containing such vectors. Also disclosed is an isolated fusion protein comprised of the D1 polypeptide sequence fused to a polypeptide sequence which facilitates folding of D1 into a functional, soluble domain when expressed in bacteria. The functional D1 domain finds application for example in a therapeutic method for treating a patient infected with a virus which binds to D1, and also in a method for identifying an antiviral compound which interferes with viral attachment. Also included is a method for specifically targeting a cell for infection by a virus which binds to D1.

Candidate Cell and Matrix Interaction Domains on the Collagen Fibril, the Predominant Protein of Vertebrates*S⃞

PubMed Central

Sweeney, Shawn M.; Orgel, Joseph P.; Fertala, Andrzej; McAuliffe, Jon D.; Turner, Kevin R.; Di Lullo, Gloria A.; Chen, Steven; Antipova, Olga; Perumal, Shiamalee; Ala-Kokko, Leena; Forlino, Antonella; Cabral, Wayne A.; Barnes, Aileen M.; Marini, Joan C.; Antonio, James D. San

2008-01-01

Type I collagen, the predominant protein of vertebrates, polymerizes with type III and V collagens and non-collagenous molecules into large cable-like fibrils, yet how the fibril interacts with cells and other binding partners remains poorly understood. To help reveal insights into the collagen structure-function relationship, a data base was assembled including hundreds of type I collagen ligand binding sites and mutations on a two-dimensional model of the fibril. Visual examination of the distribution of functional sites, and statistical analysis of mutation distributions on the fibril suggest it is organized into two domains. The “cell interaction domain” is proposed to regulate dynamic aspects of collagen biology, including integrin-mediated cell interactions and fibril remodeling. The “matrix interaction domain” may assume a structural role, mediating collagen cross-linking, proteoglycan interactions, and tissue mineralization. Molecular modeling was used to superimpose the positions of functional sites and mutations from the two-dimensional fibril map onto a three-dimensional x-ray diffraction structure of the collagen microfibril in situ, indicating the existence of domains in the native fibril. Sequence searches revealed that major fibril domain elements are conserved in type I collagens through evolution and in the type II/XI collagen fibril predominant in cartilage. Moreover, the fibril domain model provides potential insights into the genotype-phenotype relationship for several classes of human connective tissue diseases, mechanisms of integrin clustering by fibrils, the polarity of fibril assembly, heterotypic fibril function, and connective tissue pathology in diabetes and aging. PMID:18487200

Prediction of protein-protein interaction network using a multi-objective optimization approach.

PubMed

Chowdhury, Archana; Rakshit, Pratyusha; Konar, Amit

2016-06-01

Protein-Protein Interactions (PPIs) are very important as they coordinate almost all cellular processes. This paper attempts to formulate PPI prediction problem in a multi-objective optimization framework. The scoring functions for the trial solution deal with simultaneous maximization of functional similarity, strength of the domain interaction profiles, and the number of common neighbors of the proteins predicted to be interacting. The above optimization problem is solved using the proposed Firefly Algorithm with Nondominated Sorting. Experiments undertaken reveal that the proposed PPI prediction technique outperforms existing methods, including gene ontology-based Relative Specific Similarity, multi-domain-based Domain Cohesion Coupling method, domain-based Random Decision Forest method, Bagging with REP Tree, and evolutionary/swarm algorithm-based approaches, with respect to sensitivity, specificity, and F1 score.

Treatment effects in multiple cognitive domains in Alzheimer’s disease: a two-year cohort study

PubMed Central

2014-01-01

Introduction Despite widespread use of second-generation cholinesterase inhibitors for the symptomatic treatment of Alzheimer’s disease (AD), little is known about the long term effects of cholinergic treatment on global cognitive function and potential specific effects in different cognitive domains. The objectives of this study were to determine the association between cholinergic treatment and global cognitive function over one and two years in a cohort of patients with mild or moderate AD and identify potential differences in domain-specific cognitive outcomes within this cohort. Methods A cohort of patients meeting the revised National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria for mild or moderate AD, including patients both on treatment with a cholinesterase inhibitor and untreated controls (treated = 65, untreated = 65), were recruited from the Cognitive Neurology Clinic at Sunnybrook Health Sciences Centre, as part of the Sunnybrook Dementia Study. Patients were followed for one to two years and underwent standardized neuropsychological assessments to evaluate global and domain-specific cognitive function. Associations between cholinesterase inhibitor use and global and domain-specific cognitive outcome measures at one and two years of follow-up were estimated using mixed model linear regression, adjusting for age, education, and baseline mini mental state examination (MMSE). Results At one year, treated patients showed significantly less decline in global cognitive function, and treatment and time effects across tests of executive and visuospatial function. At two years, there was a significant trend towards less decline in global cognition for treated patients. Moreover, treated patients showed significant treatment and time effects across tests of executive functioning, memory, and visuospatial function. Conclusions The present study offers two important contributions to knowledge of the effectiveness of cholinesterase inhibitor treatment in patients with mild-moderate AD: 1) that second-generation cholinesterase inhibitors demonstrate long-term effectiveness for reducing global cognitive decline over one to two years of follow-up, and 2) that decline in function for cognitive domains, including executive function, memory, and visuospatial skill that are primarily mediated by frontal networks and by the cholinergic system, rather than memory, may be slowed by treatment targeting the cholinergic system. PMID:25484926

International patient and physician consensus on a psoriatic arthritis core outcome set for clinical trials.

PubMed

Orbai, Ana-Maria; de Wit, Maarten; Mease, Philip; Shea, Judy A; Gossec, Laure; Leung, Ying Ying; Tillett, William; Elmamoun, Musaab; Callis Duffin, Kristina; Campbell, Willemina; Christensen, Robin; Coates, Laura; Dures, Emma; Eder, Lihi; FitzGerald, Oliver; Gladman, Dafna; Goel, Niti; Grieb, Suzanne Dolwick; Hewlett, Sarah; Hoejgaard, Pil; Kalyoncu, Umut; Lindsay, Chris; McHugh, Neil; Shea, Bev; Steinkoenig, Ingrid; Strand, Vibeke; Ogdie, Alexis

2017-04-01

To identify a core set of domains (outcomes) to be measured in psoriatic arthritis (PsA) clinical trials that represent both patients' and physicians' priorities. We conducted (1) a systematic literature review (SLR) of domains assessed in PsA; (2) international focus groups to identify domains important to people with PsA; (3) two international surveys with patients and physicians to prioritise domains; (4) an international face-to-face meeting with patients and physicians using the nominal group technique method to agree on the most important domains; and (5) presentation and votes at the Outcome Measures in Rheumatology (OMERACT) conference in May 2016. All phases were performed in collaboration with patient research partners. We identified 39 unique domains through the SLR (24 domains) and international focus groups (34 domains). 50 patients and 75 physicians rated domain importance. During the March 2016 consensus meeting, 12 patients and 12 physicians agreed on 10 candidate domains. Then, 49 patients and 71 physicians rated these domains' importance. Five were important to >70% of both groups: musculoskeletal disease activity, skin disease activity, structural damage, pain and physical function. Fatigue and participation were important to >70% of patients. Patient global and systemic inflammation were important to >70% of physicians. The updated PsA core domain set endorsed by 90% of OMERACT 2016 participants includes musculoskeletal disease activity, skin disease activity, pain, patient global, physical function, health-related quality of life, fatigue and systemic inflammation. The updated PsA core domain set incorporates patients' and physicians' priorities and evolving PsA research. Next steps include identifying outcome measures that adequately assess these domains. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Functional health status of adolescents after the Fontan procedure -- comparison with their siblings.

PubMed

Manlhiot, Cedric; Knezevich, Stevan; Radojewski, Elizabeth; Cullen-Dean, Geraldine; Williams, William G; McCrindle, Brian W

2009-09-01

Studies have suggested that patients who have undergone the Fontan procedure experience lower functional health status and diminished exercise capacity compared with other children. To compare the functional health status of Fontan patients with and without siblings, assess whether there are any differences between Fontan patients and their siblings, and determine associated factors. A cross-sectional, single-centre, observational study was performed on Fontan patients 10 to 20 years of age, and their sibling closest in age, followed in a tertiary pediatric hospital. Functional health status was measured by the Child Health Questionnaire Child Form and the Pediatric Quality of Life Inventory. A total of 68 patients and 38 siblings were enrolled. Patients with siblings scored significantly lower on numerous domains of physical functional status than those without siblings. Compared with their matched siblings, Fontan patients reported significantly lower scores in all domains of the Pediatric Quality of Life Inventory and on physical (but not psychosocial) domains of the Child Health Questionnaire Child Form. Factors associated with increased patient-sibling differences included younger patient age, female sex, intracardiac lateral tunnel Fontan connection and lower ejection fraction at the time of study enrollment. Adolescents with Fontan physiology reported a lower functional health status in physical domains than their siblings, but had similar status in psychosocial domains. Having a sibling was associated with lower reported functional health status, suggesting an important effect of self-perceived physical limitations over true limitations.

Functional health status of adolescents after the Fontan procedure – comparison with their siblings

PubMed Central

Manlhiot, Cedric; Knezevich, Stevan; Radojewski, Elizabeth; Cullen-Dean, Geraldine; Williams, William G; McCrindle, Brian W

2009-01-01

BACKGROUND: Studies have suggested that patients who have undergone the Fontan procedure experience lower functional health status and diminished exercise capacity compared with other children. OBJECTIVES: To compare the functional health status of Fontan patients with and without siblings, assess whether there are any differences between Fontan patients and their siblings, and determine associated factors. METHODS: A cross-sectional, single-centre, observational study was performed on Fontan patients 10 to 20 years of age, and their sibling closest in age, followed in a tertiary pediatric hospital. Functional health status was measured by the Child Health Questionnaire Child Form and the Pediatric Quality of Life Inventory. RESULTS: A total of 68 patients and 38 siblings were enrolled. Patients with siblings scored significantly lower on numerous domains of physical functional status than those without siblings. Compared with their matched siblings, Fontan patients reported significantly lower scores in all domains of the Pediatric Quality of Life Inventory and on physical (but not psychosocial) domains of the Child Health Questionnaire Child Form. Factors associated with increased patient-sibling differences included younger patient age, female sex, intracardiac lateral tunnel Fontan connection and lower ejection fraction at the time of study enrollment. CONCLUSIONS: Adolescents with Fontan physiology reported a lower functional health status in physical domains than their siblings, but had similar status in psychosocial domains. Having a sibling was associated with lower reported functional health status, suggesting an important effect of self-perceived physical limitations over true limitations. PMID:19746247

Identification by Random Mutagenesis of Functional Domains in KREPB5 That Differentially Affect RNA Editing between Life Cycle Stages of Trypanosoma brucei.

PubMed

McDermott, Suzanne M; Carnes, Jason; Stuart, Kenneth

2015-12-01

KREPB5 is an essential component of ∼ 20S editosomes in Trypanosoma brucei which contains a degenerate, noncatalytic RNase III domain. To explore the function of this protein, we used a novel approach to make and screen numerous conditional null T. brucei bloodstream form cell lines that express randomly mutagenized KREPB5 alleles. We identified nine single amino acid substitutions that could not complement the conditional loss of wild-type KREPB5. Seven of these were within the RNase III domain, and two were in the C-terminal region that has no homology to known motifs. Exclusive expression of these mutated KREPB5 alleles in the absence of wild-type allele expression resulted in growth inhibition, the loss of ∼ 20S editosomes, and inhibition of RNA editing in BF cells. Eight of these mutations were lethal in bloodstream form parasites but not in procyclic-form parasites, showing that multiple domains function in a life cycle-dependent manner. Amino acid changes at a substantial number of positions, including up to 7 per allele, allowed complementation and thus did not block KREPB5 function. Hence, the degenerate RNase III domain and a newly identified domain are critical for KREPB5 function and have differential effects between the life cycle stages of T. brucei that differentially edit mRNAs. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

The conserved RNA recognition motif and C3H1 domain of the Not4 ubiquitin ligase regulate in vivo ligase function.

PubMed

Chen, Hongfeng; Sirupangi, Tirupataiah; Wu, Zhao-Hui; Johnson, Daniel L; Laribee, R Nicholas

2018-05-25

The Ccr4-Not complex controls RNA polymerase II (Pol II) dependent gene expression and proteasome function. The Not4 ubiquitin ligase is a Ccr4-Not subunit that has both a RING domain and a conserved RNA recognition motif and C3H1 domain (referred to as the RRM-C domain) with unknown function. We demonstrate that while individual Not4 RING or RRM-C mutants fail to replicate the proteasomal defects found in Not4 deficient cells, mutation of both exhibits a Not4 loss of function phenotype. Transcriptome analysis revealed that the Not4 RRM-C affects a specific subset of Pol II-regulated genes, including those involved in transcription elongation, cyclin-dependent kinase regulated nutrient responses, and ribosomal biogenesis. The Not4 RING, RRM-C, or RING/RRM-C mutations cause a generalized increase in Pol II binding at a subset of these genes, yet their impact on gene expression does not always correlate with Pol II recruitment which suggests Not4 regulates their expression through additional mechanisms. Intriguingly, we find that while the Not4 RRM-C is dispensable for Ccr4-Not association with RNA Pol II, the Not4 RING domain is required for these interactions. Collectively, these data elucidate previously unknown roles for the conserved Not4 RRM-C and RING domains in regulating Ccr4-Not dependent functions in vivo.

The Evolutionary History of Protein Domains Viewed by Species Phylogeny

PubMed Central

Yang, Song; Bourne, Philip E.

2009-01-01

Background Protein structural domains are evolutionary units whose relationships can be detected over long evolutionary distances. The evolutionary history of protein domains, including the origin of protein domains, the identification of domain loss, transfer, duplication and combination with other domains to form new proteins, and the formation of the entire protein domain repertoire, are of great interest. Methodology/Principal Findings A methodology is presented for providing a parsimonious domain history based on gain, loss, vertical and horizontal transfer derived from the complete genomic domain assignments of 1015 organisms across the tree of life. When mapped to species trees the evolutionary history of domains and domain combinations is revealed, and the general evolutionary trend of domain and combination is analyzed. Conclusions/Significance We show that this approach provides a powerful tool to study how new proteins and functions emerged and to study such processes as horizontal gene transfer among more distant species. PMID:20041107

Vestibular involvement in cognition: Visuospatial ability, attention, executive function, and memory.

PubMed

Bigelow, Robin T; Agrawal, Yuri

2015-01-01

A growing body of literature suggests the inner ear vestibular system has a substantial impact on cognitive function. The strongest evidence exists in connecting vestibular function to the cognitive domain of visuospatial ability, which includes spatial memory, navigation, mental rotation, and mental representation of three-dimensional space. Substantial evidence also exists suggesting the vestibular system has an impact on attention and cognitive processing ability. The cognitive domains of memory and executive function are also implicated in a number of studies. We will review the current literature, discuss possible causal links between vestibular dysfunction and cognitive performance, and suggest areas of future research.

Memory and executive functions in persons with type 2 diabetes: a meta-analysis.

PubMed

Sadanand, Shilpa; Balachandar, Rakesh; Bharath, Srikala

2016-02-01

Literature suggests that persons with type 2 diabetes mellitus (T2DM) are at risk for cognitive impairment, hence dementia. Common domains reported to be affected in those with T2DM are memory and executive functions. The extent of influence of T2DM on these domains has varied among studies. A systematic review and meta-analysis was carried out to understand whether sub-domains contributed to the variations observed in published research. We searched 'PubMed', 'ScienceDirect', 'SciVerseHub', 'Psychinfo', 'Proquest' 'Ebsco' and 'J-gate Plus' databases for published studies on cognition and T2DM among persons aged 50 years and older. Memory, executive functions and processing speed domain and sub-domain scores were extracted; effect sizes (Cohen's d) were calculated and analysed. Eight hundred seventeen articles were found. After various levels of filtering, 15 articles met the inclusion criteria for quantitative analyses. The analyses indicated that in comparison to controls, persons with T2DM showed decrements in episodic memory (d = -0.51), logical memory (d = -0.24), sub-domain of executive functions which included phonemic fluency (d = -0.35) and cognitive flexibility (d = 0.52), and speed of processing (d = -0.22). We found no difference in the sub-domains of verbal short-term memory and working memory. The meta-analysis revealed a detrimental effect of T2DM on cognitive sub-domains, namely, episodic memory and cognitive flexibility. There was a trend for the logical memory, phonemic fluency and processing speed to be affected. The analysis indicates that T2DM is a detrimental factor on certain cognitive sub-domains, rendering the person vulnerable to subsequent dementia. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

Engineering multi-functional bacterial outer membrane vesicles as modular nanodevices for biosensing and bioimaging.

PubMed

Chen, Qi; Rozovsky, Sharon; Chen, Wilfred

2017-07-04

Outer membrane vesicles (OMVs) are proteoliposomes derived from the outer membrane and periplasmic space of many Gram-negative bacteria including E. coli as part of their natural growth cycle. Inspired by the natural ability of E. coli to sort proteins to both the exterior and interior of OMVs, we reported here a one-pot synthesis approach to engineer multi-functionalized OMV-based sensors for both antigen binding and signal generation. SlyB, a native lipoprotein, was used a fusion partner to package nanoluciferase (Nluc) within OMVs, while a previously developed INP-Scaf3 surface scaffold was fused to the Z-domain for antibody recruiting. The multi-functionalized OMVs were used for thrombin detection with a detection limit of 0.5 nM, comparable to other detection methods. Using the cohesin domains inserted between the Z-domain and INP, these engineered OMVs were further functionalized with a dockerin-tagged GFP for cancer cell imaging.

The Proteome Folding Project: Proteome-scale prediction of structure and function

PubMed Central

Drew, Kevin; Winters, Patrick; Butterfoss, Glenn L.; Berstis, Viktors; Uplinger, Keith; Armstrong, Jonathan; Riffle, Michael; Schweighofer, Erik; Bovermann, Bill; Goodlett, David R.; Davis, Trisha N.; Shasha, Dennis; Malmström, Lars; Bonneau, Richard

2011-01-01

The incompleteness of proteome structure and function annotation is a critical problem for biologists and, in particular, severely limits interpretation of high-throughput and next-generation experiments. We have developed a proteome annotation pipeline based on structure prediction, where function and structure annotations are generated using an integration of sequence comparison, fold recognition, and grid-computing-enabled de novo structure prediction. We predict protein domain boundaries and three-dimensional (3D) structures for protein domains from 94 genomes (including human, Arabidopsis, rice, mouse, fly, yeast, Escherichia coli, and worm). De novo structure predictions were distributed on a grid of more than 1.5 million CPUs worldwide (World Community Grid). We generated significant numbers of new confident fold annotations (9% of domains that are otherwise unannotated in these genomes). We demonstrate that predicted structures can be combined with annotations from the Gene Ontology database to predict new and more specific molecular functions. PMID:21824995

Cardiac function and cognition in older community-dwelling cardiac patients.

PubMed

Eggermont, Laura H P; Aly, Mohamed F A; Vuijk, Pieter J; de Boer, Karin; Kamp, Otto; van Rossum, Albert C; Scherder, Erik J A

2017-11-01

Cognitive deficits have been reported in older cardiac patients. An underlying mechanism for these findings may be reduced cardiac function. The relationship between cardiac function as represented by different echocardiographic measures and different cognitive function domains in older cardiac patients remains unknown. An older (≥70 years) heterogeneous group of 117 community-dwelling cardiac patients under medical supervision by a cardiologist underwent thorough echocardiographic assessment including left ventricular ejection fraction, cardiac index, left atrial volume index, left ventricular mass index, left ventricular diastolic function, and valvular calcification. During a home visit, a neuropsychological assessment was performed within 7.1 ± 3.8 months after echocardiographic assessment; the neuropsychological assessment included three subtests of a word-learning test (encoding, recall, recognition) to examine one memory function domain and three executive function tests, including digit span backwards, Trail Making Test B minus A, and the Stroop colour-word test. Regression analyses showed no significant linear or quadratic associations between any of the echocardiographic functions and the cognitive function measures. None of the echocardiographic measures as representative of cardiac function was correlated with memory or executive function in this group of community-dwelling older cardiac patients. These findings contrast with those of previous studies. © 2017 Japanese Psychogeriatric Society.

The LRRK2 G2385R variant is a partial loss-of-function mutation that affects synaptic vesicle trafficking through altered protein interactions.

PubMed

Carrion, Maria Dolores Perez; Marsicano, Silvia; Daniele, Federica; Marte, Antonella; Pischedda, Francesca; Di Cairano, Eliana; Piovesana, Ester; von Zweydorf, Felix; Kremmer, Elisabeth; Gloeckner, Christian Johannes; Onofri, Franco; Perego, Carla; Piccoli, Giovanni

2017-07-14

Mutations in the Leucine-rich repeat kinase 2 gene (LRRK2) are associated with familial Parkinson's disease (PD). LRRK2 protein contains several functional domains, including protein-protein interaction domains at its N- and C-termini. In this study, we analyzed the functional features attributed to LRRK2 by its N- and C-terminal domains. We combined TIRF microscopy and synaptopHluorin assay to visualize synaptic vesicle trafficking. We found that N- and C-terminal domains have opposite impact on synaptic vesicle dynamics. Biochemical analysis demonstrated that different proteins are bound at the two extremities, namely β3-Cav2.1 at N-terminus part and β-Actin and Synapsin I at C-terminus domain. A sequence variant (G2385R) harboured within the C-terminal WD40 domain increases the risk for PD. Complementary biochemical and imaging approaches revealed that the G2385R variant alters strength and quality of LRRK2 interactions and increases fusion of synaptic vesicles. Our data suggest that the G2385R variant behaves like a loss-of-function mutation that mimics activity-driven events. Impaired scaffolding capabilities of mutant LRRK2 resulting in perturbed vesicular trafficking may arise as a common pathophysiological denominator through which different LRRK2 pathological mutations cause disease.

HIV-Associated Cognitive Impairment in Perinatally Infected Children: A Meta-analysis.

PubMed

Phillips, Nicole; Amos, Taryn; Kuo, Caroline; Hoare, Jacqueline; Ipser, Jonathan; Thomas, Kevin G F; Stein, Dan J

2016-11-01

Research shows, conclusively, that perinatal HIV infection has negative effects on cognitive functioning of children and adolescents. However, the extent of these cognitive impairments is unknown. Current literature does not document specific cognitive domains most affected in HIV-infected children and adolescents. To systematically review and meta-analyze the degree of cognitive impairment, and the specific cognitive domains affected, in children and adolescents with perinatally acquired HIV infection. We systematically searched 5 electronic bibliographic databases, namely: PubMed, PsychINFO, Academic Search Premier, Scopus, and WorldCat, by using a search protocol specifically designed for this study. Studies were selected on the basis of set a priori eligibility criteria. Titles, abstracts, and full texts were assessed by 2 independent reviewers. Data from included studies were extracted into Microsoft Excel by 2 independent reviewers. Twenty-two studies were identified for inclusion in the systematic review and of this, 6 studies were included in the meta-analysis. Results from the meta-analysis indicated that working memory and executive function were the domains most affected by the HIV virus. Only 27% of the included studies were suitable to enter into the meta-analysis. There was significant geographic bias in published studies, with only 32% (7/22) of included studies from sub-Saharan Africa. The evidence supports an association between HIV infection in children and adolescents and cognitive impairment in the domains of working memory, executive function and processing speed, with effect size estimates also providing some support for deficits in visual memory and visual-spatial ability. Copyright © 2016 by the American Academy of Pediatrics.

Distribution of PASTA domains in penicillin-binding proteins and serine/threonine kinases of Actinobacteria.

PubMed

Ogawara, Hiroshi

2016-09-01

PASTA domains (penicillin-binding protein and serine/threonine kinase-associated domains) have been identified in penicillin-binding proteins and serine/threonine kinases of Gram-positive Firmicutes and Actinobacteria. They are believed to bind β-lactam antibiotics, and be involved in peptidoglycan metabolism, although their biological function is not definitively clarified. Actinobacteria, especially Streptomyces species, are distinct in that they undergo complex cellular differentiation and produce various antibiotics including β-lactams. This review focuses on the distribution of PASTA domains in penicillin-binding proteins and serine/threonine kinases in Actinobacteria. In Actinobacteria, PASTA domains are detectable exclusively in class A but not in class B penicillin-binding proteins, in sharp contrast to the cases in other bacteria. In penicillin-binding proteins, PASTA domains distribute independently from taxonomy with some distribution bias. Particularly interesting thing is that no Streptomyces species have penicillin-binding protein with PASTA domains. Protein kinases in Actinobacteria possess 0 to 5 PASTA domains in their molecules. Protein kinases in Streptomyces can be classified into three groups: no PASTA domain, 1 PASTA domain and 4 PASTA domain-containing groups. The 4 PASTA domain-containing groups can be further divided into two subgroups. The serine/threonine kinases in different groups may perform different functions. The pocket region in one of these subgroup is more dense and extended, thus it may be involved in binding of ligands like β-lactams more efficiently.

Correlating structure and function during the evolution of fibrinogen-related domains

PubMed Central

Doolittle, Russell F; McNamara, Kyle; Lin, Kevin

2012-01-01

Fibrinogen-related domains (FReDs) are found in a variety of animal proteins with widely different functions, ranging from non-self recognition to clot formation. All appear to have a common surface where binding of one sort or other occurs. An examination of 19 completed animal genomes—including a sponge and sea anemone, six protostomes, and 11 deuterostomes—has allowed phylogenies to be constructed that show where various types of FReP (proteins containing FReDs) first made their appearance. Comparisons of sequences and structures also reveal particular features that correlate with function, including the influence of neighbor-domains. A particular set of insertions in the carboxyl-terminal subdomain was involved in the transition from structures known to bind sugars to those known to bind amino-terminal peptides. Perhaps not unexpectedly, FReDs with different functions have changed at different rates, with ficolins by far the fastest changing group. Significantly, the greatest amount of change in ficolin FReDs occurs in the third subdomain (“P domain”), the very opposite of the situation in most other vertebrate FReDs. The unbalanced style of change was also observed in FReDs from non-chordates, many of which have been implicated in innate immunity. PMID:23076991

The HD-GYP domain, cyclic di-GMP signaling, and bacterial virulence to plants.

PubMed

Dow, J Maxwell; Fouhy, Yvonne; Lucey, Jean F; Ryan, Robert P

2006-12-01

Cyclic di-GMP is an almost ubiquitous second messenger in bacteria that was first described as an allosteric activator of cellulose synthase but is now known to regulate a range of functions, including virulence in human and animal pathogens. Two protein domains, GGDEF and EAL, are implicated in the synthesis and degradation, respectively, of cyclic di-GMP. These domains are widely distributed in bacteria, including plant pathogens. The majority of proteins with GGDEF and EAL domains contain additional signal input domains, suggesting that their activities are responsive to environmental cues. Recent studies have demonstrated that a third domain, HD-GYP, is also active in cyclic di-GMP degradation. In the plant pathogen Xanthomonas campestris pv. campestris, a two-component signal transduction system comprising the HD-GYP domain regulatory protein RpfG and cognate sensor RpfC positively controls virulence. The signals recognized by RpfC may include the cell-cell signal DSF, which also acts to regulate virulence in X. campestris pv. campestris. Here, we review these recent advances in our understanding of cyclic di-GMP signaling with particular reference to one or more roles in the bacterial pathogenesis of plants.

On the maximum-entropy/autoregressive modeling of time series

NASA Technical Reports Server (NTRS)

Chao, B. F.

1984-01-01

The autoregressive (AR) model of a random process is interpreted in the light of the Prony's relation which relates a complex conjugate pair of poles of the AR process in the z-plane (or the z domain) on the one hand, to the complex frequency of one complex harmonic function in the time domain on the other. Thus the AR model of a time series is one that models the time series as a linear combination of complex harmonic functions, which include pure sinusoids and real exponentials as special cases. An AR model is completely determined by its z-domain pole configuration. The maximum-entropy/autogressive (ME/AR) spectrum, defined on the unit circle of the z-plane (or the frequency domain), is nothing but a convenient, but ambiguous visual representation. It is asserted that the position and shape of a spectral peak is determined by the corresponding complex frequency, and the height of the spectral peak contains little information about the complex amplitude of the complex harmonic functions.

The Hippocampus Supports Encoding of Between-Domain Associations within Working Memory

ERIC Educational Resources Information Center

Piekema, Carinne; Kessel, Roy P. C.; Rijpkema, Mark; Fernandez, Guillen

2009-01-01

It has been established that the medial temporal lobe, including the hippocampus, is crucial for associative memory. The aim of the current functional magnetic resonance imaging (fMRI) study was to investigate whether the hippocampus is differentially activated for associations between items processed in the same neocortical region (within-domain)…

Analysis instruments for the performance of Advanced Practice Nursing.

PubMed

Sevilla-Guerra, Sonia; Zabalegui, Adelaida

2017-11-29

Advanced Practice Nursing has been a reality in the international context for several decades and recently new nursing profiles have been developed in Spain as well that follow this model. The consolidation of these advanced practice roles has also led to of the creation of tools that attempt to define and evaluate their functions. This study aims to identify and explore the existing instruments that enable the domains of Advanced Practice Nursing to be defined. A review of existing international questionnaires and instruments was undertaken, including an analysis of the design process, the domains/dimensions defined, the main results and an exploration of clinimetric properties. Seven studies were analysed but not all proved to be valid, stable or reliable tools. One included tool was able to differentiate between the functions of the general nurse and the advanced practice nurse by the level of activities undertaken within the five domains described. These tools are necessary to evaluate the scope of advanced practice in new nursing roles that correspond to other international models of competencies and practice domains. Copyright © 2017 Elsevier España, S.L.U. All rights reserved.

Differential diagnosis of adults with ADHD: the role of executive function and self-regulation.

PubMed

Barkley, Russell A

2010-07-01

Adult ADHD is conceptualized as a disorder of age-inappropriate behavior that occurs because of maldevelopment of 2 related neuropsychological domains. The neuropsychological symptoms seen in adults with ADHD may be explained by deficits in executive function, which can be broadly defined as a set of neurocognitive processes that allow for the organization of behavior across time so as to attain future goals. Executive function is comprised of 2 broad domains: inhibition and metacognition. Inhibition encompasses the ability to inhibit motor, verbal, cognitive, and emotional activities. In turn, deficits in inhibition contribute to deficits in the development of 4 aspects of executive function in the domain of metacognition, which include nonverbal working memory, verbal working memory, planning and problem-solving, and emotional self-regulation. Understanding the ways in which deficits in executive function contribute to the symptoms of ADHD can help in differentiating ADHD from disorders that share similar characteristics. (c) Copyright 2010 Physicians Postgraduate Press, Inc.

Development and Initial Validation of the PROMIS(®) Sexual Function and Satisfaction Measures Version 2.0.

PubMed

Weinfurt, Kevin P; Lin, Li; Bruner, Deborah Watkins; Cyranowski, Jill M; Dombeck, Carrie B; Hahn, Elizabeth A; Jeffery, Diana D; Luecht, Richard M; Magasi, Susan; Porter, Laura S; Reese, Jennifer Barsky; Reeve, Bryce B; Shelby, Rebecca A; Smith, Ashley Wilder; Willse, John T; Flynn, Kathryn E

2015-09-01

The Patient-Reported Outcomes Measurement Information System (PROMIS)(®) Sexual Function and Satisfaction measure (SexFS) version 1.0 was developed with cancer populations. There is a need to expand the SexFS and provide evidence of its validity in diverse populations. The aim of this study was to describe the development of the SexFS v2.0 and present preliminary evidence for its validity. Development built on version 1.0, plus additional review of extant items, discussions with 15 clinical experts, 11 patient focus groups (including individuals with diabetes, heart disease, anxiety, depression, and/or are lesbian, gay, bisexual, or aged 65 or older), 48 cognitive interviews, and psychometric evaluation in a random sample of U.S. adults plus an oversample for specific sexual problems (2281 men, 1686 women). We examined differential item functioning (DIF) by gender and sexual activity. We examined convergent and known-groups validity. The final set of domains includes 11 scored scales (interest in sexual activity, lubrication, vaginal discomfort, clitoral discomfort, labial discomfort, erectile function, orgasm ability, orgasm pleasure, oral dryness, oral discomfort, satisfaction), and six nonscored item pools (screeners, sexual activities, anal discomfort, therapeutic aids, factors interfering with sexual satisfaction, bother). Domains from version 1.0 were reevaluated and improved. Domains considered applicable across gender and sexual activity status, namely interest, orgasm, and satisfaction, were found to have significant DIF. We identified subsets of items in each domain that provided consistent measurement across these important respondent groups. Convergent and known-groups validity was supported. The SexFS version 2.0 has several improvements and enhancements over version 1.0 and other extant measures, including expanded evidence for validity, scores centered around norms for sexually active U.S. adults, new domains, and a final set of items applicable for both men and women and those sexually active with a partner and without. The SexFS is customizable, allowing users to select relevant domains and items for their study. © 2015 International Society for Sexual Medicine.

The structure and dynamics of tandem WW domains in a negative regulator of notch signaling, Suppressor of deltex.

PubMed

Fedoroff, Oleg Y; Townson, Sharon A; Golovanov, Alexander P; Baron, Martin; Avis, Johanna M

2004-08-13

WW domains mediate protein recognition, usually though binding to proline-rich sequences. In many proteins, WW domains occur in tandem arrays. Whether or how individual domains within such arrays cooperate to recognize biological partners is, as yet, poorly characterized. An important question is whether functional diversity of different WW domain proteins is reflected in the structural organization and ligand interaction mechanisms of their multiple domains. We have determined the solution structure and dynamics of a pair of WW domains (WW3-4) from a Drosophila Nedd4 family protein called Suppressor of deltex (Su(dx)), a regulator of Notch receptor signaling. We find that the binding of a type 1 PPPY ligand to WW3 stabilizes the structure with effects propagating to the WW4 domain, a domain that is not active for ligand binding. Both WW domains adopt the characteristic triple-stranded beta-sheet structure, and significantly, this is the first example of a WW domain structure to include a domain (WW4) lacking the second conserved Trp (replaced by Phe). The domains are connected by a flexible linker, which allows a hinge-like motion of domains that may be important for the recognition of functionally relevant targets. Our results contrast markedly with those of the only previously determined three-dimensional structure of tandem WW domains, that of the rigidly oriented WW domain pair from the RNA-splicing factor Prp40. Our data illustrate that arrays of WW domains can exhibit a variety of higher order structures and ligand interaction mechanisms.

Development and Validation of Participation and Positive Psychologic Function Measures for Stroke Survivors

PubMed Central

Bode, Rita K.; Heinemann, Allen W.; Butt, Zeeshan; Stallings, Jena; Taylor, Caitlin; Rowe, Morgan; Roth, Elliot J.

2013-01-01

Bode RK, Heinemann AW, Butt Z, Stallings J, Taylor C, Rowe M, Roth EJ. Development and validation of participation and positive psychologic function measures for stroke survivors. Objective To evaluate the reliability and validity of Neurologic Quality of Life (NeuroQOL) item banks that assess quality-of-life (QOL) domains not typically included in poststroke measures. Design Secondary analysis of item responses to selected NeuroQOL domains. Setting Community. Participants Community-dwelling stroke survivors (n=111) who were at least 12 months poststroke. Interventions Not applicable. Main Outcome Measures Five measures developed for 3 NeuroQoL domains: ability to participate in social activities, satisfaction with participation in social activities, and positive psychologic function. Results A single bank was developed for the positive psychologic function domain, but 2 banks each were developed for the ability-to-participate and satisfaction-with-participation domains. The resulting item banks showed good psychometric properties and external construct validity with correlations with the legacy instruments, ranging from .53 to .71. Using these measures, stroke survivors in this sample reported an overall high level of QOL. Conclusions The NeuroQoL-derived measures are promising and valid methods for assessing aspects of QOL not typically measured in this population. PMID:20801251

Generalizing the correlated chromophore domain model of reversible photodegradation to include the effects of an applied electric field

NASA Astrophysics Data System (ADS)

Anderson, Benjamin; Kuzyk, Mark G.

2014-03-01

All observations of photodegradation and self-healing follow the predictions of the correlated chromophore domain model [Ramini et al., Polym. Chem. 4, 4948 (2013), 10.1039/c3py00263b]. In the present work, we generalize the domain model to describe the effects of an electric field by including induced dipole interactions between molecules in a domain by means of a self-consistent field approach. This electric field correction is added to the statistical mechanical model to calculate the distribution of domains that are central to healing. Also included in the model are the dynamics due to the formation of an irreversibly damaged species, which we propose involves damage to the polymer mediated through energy transfer from a dopant molecule after absorbing a photon. As in previous studies, the model with one-dimensional domains best explains all experimental data of the population as a function of time, temperature, intensity, concentration, and now applied electric field. Though the precise nature of a domain is yet to be determined, the fact that only one-dimensional domain models are consistent with observations suggests that they might be made of correlated dye molecules along polymer chains. Furthermore, the voltage-dependent measurements suggest that the largest polarizability axis of the molecules are oriented perpendicular to the chain.

On the detection of functionally coherent groups of protein domains with an extension to protein annotation

PubMed Central

McLaughlin, William A; Chen, Ken; Hou, Tingjun; Wang, Wei

2007-01-01

Background Protein domains coordinate to perform multifaceted cellular functions, and domain combinations serve as the functional building blocks of the cell. The available methods to identify functional domain combinations are limited in their scope, e.g. to the identification of combinations falling within individual proteins or within specific regions in a translated genome. Further effort is needed to identify groups of domains that span across two or more proteins and are linked by a cooperative function. Such functional domain combinations can be useful for protein annotation. Results Using a new computational method, we have identified 114 groups of domains, referred to as domain assembly units (DASSEM units), in the proteome of budding yeast Saccharomyces cerevisiae. The units participate in many important cellular processes such as transcription regulation, translation initiation, and mRNA splicing. Within the units the domains were found to function in a cooperative manner; and each domain contributed to a different aspect of the unit's overall function. The member domains of DASSEM units were found to be significantly enriched among proteins contained in transcription modules, defined as genes sharing similar expression profiles and presumably similar functions. The observation further confirmed the functional coherence of DASSEM units. The functional linkages of units were found in both functionally characterized and uncharacterized proteins, which enabled the assessment of protein function based on domain composition. Conclusion A new computational method was developed to identify groups of domains that are linked by a common function in the proteome of Saccharomyces cerevisiae. These groups can either lie within individual proteins or span across different proteins. We propose that the functional linkages among the domains within the DASSEM units can be used as a non-homology based tool to annotate uncharacterized proteins. PMID:17937820

Crystal Structure of a Two-domain Fragment of Hepatocyte Growth Factor Activator Inhibitor-1: FUNCTIONAL INTERACTIONS BETWEEN THE KUNITZ-TYPE INHIBITOR DOMAIN-1 AND THE NEIGHBORING POLYCYSTIC KIDNEY DISEASE-LIKE DOMAIN.

PubMed

Hong, Zebin; De Meulemeester, Laura; Jacobi, Annemarie; Pedersen, Jan Skov; Morth, J Preben; Andreasen, Peter A; Jensen, Jan K

2016-07-01

Hepatocyte growth factor activator inhibitor-1 (HAI-1) is a type I transmembrane protein and inhibitor of several serine proteases, including hepatocyte growth factor activator and matriptase. The protein is essential for development as knock-out mice die in utero due to placental defects caused by misregulated extracellular proteolysis. HAI-1 contains two Kunitz-type inhibitor domains (Kunitz), which are generally thought of as a functionally self-contained protease inhibitor unit. This is not the case for HAI-1, where our results reveal how interdomain interactions have evolved to stimulate the inhibitory activity of an integrated Kunitz. Here we present an x-ray crystal structure of an HAI-1 fragment covering the internal domain and Kunitz-1. The structure reveals not only that the previously uncharacterized internal domain is a member of the polycystic kidney disease domain family but also how the two domains engage in interdomain interactions. Supported by solution small angle x-ray scattering and a combination of site-directed mutagenesis and functional assays, we show that interdomain interactions not only stabilize the fold of the internal domain but also stimulate the inhibitory activity of Kunitz-1. By completing our structural characterization of the previously unknown N-terminal region of HAI-1, we provide new insight into the interplay between tertiary structure and the inhibitory activity of a multidomain protease inhibitor. We propose a previously unseen mechanism by which the association of an auxiliary domain stimulates the inhibitory activity of a Kunitz-type inhibitor (i.e. the first structure of an intramolecular interaction between a Kunitz and another domain). © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Cognitive Neuroscience of Attention Deficit Hyperactivity Disorder: Current Status and Working Hypotheses

ERIC Educational Resources Information Center

Vaidya, Chandan J.; Stollstorff, Melanie

2008-01-01

Cognitive neuroscience studies of Attention Deficit Hyperactivity Disorder (ADHD) suggest multiple loci of pathology with respect to both cognitive domains and neural circuitry. Cognitive deficits extend beyond executive functioning to include spatial, temporal, and lower-level "nonexecutive" functions. Atypical functional anatomy extends beyond…

Examining the relationship between specific cognitive processes and falls risk in older adults: a systematic review

PubMed Central

Hsu, Chun Liang; Nagamatsu, Lindsay S.; Davis, Jennifer C.; Liu-Ambrose, Teresa

2015-01-01

Purpose Recent evidence suggests that impaired cognition increases seniors’ risk of falling. The purpose of this review was to identify the cognitive domains that are significantly associated with falls or falls risk in older adults. Methods We conducted a systematic review of peer-reviewed journal articles published from 1948 to present, focusing on studies investigating different domains of cognitive function and their association with falls or falls risk in adults aged 60 years or older. In accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we completed a comprehensive search of MEDLINE, Pubmed, and EMBASE databases to identify studies examining the association between cognitive function and falls or falls risk. With an expert in the field, we developed a quality assessment questionnaire to rate the quality of the studies included in this systematic review. Results Twenty-five studies were included in the review. We categorized studies based on two related but distinct cognitive domains: 1) executive functions, or 2) dual-task ability. Twelve studies reported a significant association between executive functions and falls risk. Thirteen studies reported that dual-task performance is a predictor of falls or falls risk in older adults. Three studies did not report an association between cognition and falls risk. Conclusion Consistent evidence demonstrated that executive functions and dual-task performance were highly associated with falls or falls risk. The results from this review will aid healthcare professionals and researchers in developing innovative screening and treatment strategies for mitigating falls risk by targeting specific cognitive domains. PMID:22638707

Pre-injury psychosocial and demographic predictors of long-term functional outcomes post-TBI.

PubMed

Seagly, Katharine S; O'Neil, Rochelle L; Hanks, Robin A

2018-01-01

To determine whether pre-injury psychosocial and demographic factors differentially influence long-term functional outcomes post-TBI. Urban rehabilitation hospital. 149 individuals, ages 16-75, who sustained a mild complicated, moderate or severe TBI, were enrolled in a TBI Model System (TBIMS), and had functional outcome data five-15 years post-injury. Archival data were analysed with SPSS-18 using multiple regression to determine amount of variance accounted for in five functional domains. Predictors included age at injury, pre-injury education, Glasgow Coma Scale (GCS), pre-injury incarceration and psychiatric history. Craig Handicap Assessment and Reporting Technique (CHART), including Cognitive Independence, Physical Independence, Mobility, Occupation and Social Integration domains. Models were significant for Cognitive and Physical Independence, Mobility, and Occupation. Incarceration and psychiatric history accounted for the most variance in Cognitive and Physical Independence, over and above GCS and age at injury. Psychiatric history was also the strongest predictor of Occupation. Mobility was the only domain in which GCS accounted for the most variance. Pre-injury psychosocial and demographic factors may be more important than injury severity for predicting some long-term functional outcomes post-TBI. It would likely be beneficial to assess these factors in the inpatient setting, with input from a multidisciplinary team, as an early understanding of prognostic indicators can help guide treatment for optimal functional outcomes.

A Modern Understanding of the Traditional and Nontraditional Biological Functions of Angiotensin-Converting Enzyme

PubMed Central

Ong, Frank S.; Blackwell, Wendell-Lamar B.; Shah, Kandarp H.; Giani, Jorge F.; Gonzalez-Villalobos, Romer A.; Shen, Xiao Z.; Fuchs, Sebastien

2013-01-01

Angiotensin-converting enzyme (ACE) is a zinc-dependent peptidase responsible for converting angiotensin I into the vasoconstrictor angiotensin II. However, ACE is a relatively nonspecific peptidase that is capable of cleaving a wide range of substrates. Because of this, ACE and its peptide substrates and products affect many physiologic processes, including blood pressure control, hematopoiesis, reproduction, renal development, renal function, and the immune response. The defining feature of ACE is that it is composed of two homologous and independently catalytic domains, the result of an ancient gene duplication, and ACE-like genes are widely distributed in nature. The two ACE catalytic domains contribute to the wide substrate diversity of ACE and, by extension, the physiologic impact of the enzyme. Several studies suggest that the two catalytic domains have different biologic functions. Recently, the X-ray crystal structure of ACE has elucidated some of the structural differences between the two ACE domains. This is important now that ACE domain-specific inhibitors have been synthesized and characterized. Once widely available, these reagents will undoubtedly be powerful tools for probing the physiologic actions of each ACE domain. In turn, this knowledge should allow clinicians to envision new therapies for diseases not currently treated with ACE inhibitors. PMID:23257181

Molecular and functional characterization of clathrin- and AP-2-binding determinants within a disordered domain of auxilin.

PubMed

Scheele, Urte; Alves, Jurgen; Frank, Ronald; Duwel, Michael; Kalthoff, Christoph; Ungewickell, Ernst

2003-07-11

Uncoating of clathrin-coated vesicles requires the J-domain protein auxilin for targeting hsc70 to the clathrin coats and for stimulating the hsc70 ATPase activity. This results in the release of hsc70-complexed clathrin triskelia and concomitant dissociation of the coat. To understand the complex role of auxilin in uncoating and clathrin assembly in more detail, we analyzed the molecular organization of its clathrin-binding domain (amino acids 547-813). CD spectroscopy of auxilin fragments revealed that the clathrin-binding domain is almost completely disordered in solution. By systematic mapping using synthetic peptides and by site-directed mutagenesis, we identified short peptide sequences involved in clathrin heavy chain and AP-2 binding and evaluated their significance for the function of auxilin. Some of the binding determinants, including those containing sequences 674DPF and 636WDW, showed dual specificity for both clathrin and AP-2. In contrast, the two DLL motifs within the clathrin-binding domain were exclusively involved in clathrin binding. Surprisingly, they interacted not only with the N-terminal domain of the heavy chain, but also with the distal domain. Moreover, both DLL peptides proved to be essential for clathrin assembly and uncoating. In addition, we found that the motif 726NWQ is required for efficient clathrin assembly activity. Auxilin shares a number of protein-protein interaction motifs with other endocytic proteins, including AP180. We demonstrate that AP180 and auxilin compete for binding to the alpha-ear domain of AP-2. Like AP180, auxilin also directly interacts with the ear domain of beta-adaptin. On the basis of our data, we propose a refined model for the uncoating mechanism of clathrin-coated vesicles.

Predicting PDZ domain mediated protein interactions from structure

PubMed Central

2013-01-01

Background PDZ domains are structural protein domains that recognize simple linear amino acid motifs, often at protein C-termini, and mediate protein-protein interactions (PPIs) in important biological processes, such as ion channel regulation, cell polarity and neural development. PDZ domain-peptide interaction predictors have been developed based on domain and peptide sequence information. Since domain structure is known to influence binding specificity, we hypothesized that structural information could be used to predict new interactions compared to sequence-based predictors. Results We developed a novel computational predictor of PDZ domain and C-terminal peptide interactions using a support vector machine trained with PDZ domain structure and peptide sequence information. Performance was estimated using extensive cross validation testing. We used the structure-based predictor to scan the human proteome for ligands of 218 PDZ domains and show that the predictions correspond to known PDZ domain-peptide interactions and PPIs in curated databases. The structure-based predictor is complementary to the sequence-based predictor, finding unique known and novel PPIs, and is less dependent on training–testing domain sequence similarity. We used a functional enrichment analysis of our hits to create a predicted map of PDZ domain biology. This map highlights PDZ domain involvement in diverse biological processes, some only found by the structure-based predictor. Based on this analysis, we predict novel PDZ domain involvement in xenobiotic metabolism and suggest new interactions for other processes including wound healing and Wnt signalling. Conclusions We built a structure-based predictor of PDZ domain-peptide interactions, which can be used to scan C-terminal proteomes for PDZ interactions. We also show that the structure-based predictor finds many known PDZ mediated PPIs in human that were not found by our previous sequence-based predictor and is less dependent on training–testing domain sequence similarity. Using both predictors, we defined a functional map of human PDZ domain biology and predict novel PDZ domain function. Users may access our structure-based and previous sequence-based predictors at http://webservice.baderlab.org/domains/POW. PMID:23336252

ATP Binding to p97/VCP D1 Domain Regulates Selective Recruitment of Adaptors to Its Proximal N-Domain

PubMed Central

Chia, Wei Sheng; Chia, Diana Xueqi; Rao, Feng; Bar Nun, Shoshana; Geifman Shochat, Susana

2012-01-01

p97/Valosin-containing protein (VCP) is a member of the AAA-ATPase family involved in many cellular processes including cell division, intracellular trafficking and extraction of misfolded proteins in endoplasmic reticulum-associated degradation (ERAD). It is a homohexamer with each subunit containing two tandem D1 and D2 ATPase domains and N- and C-terminal regions that function as adaptor protein binding domains. p97/VCP is directed to its many different functional pathways by associating with various adaptor proteins. The regulation of the recruitment of the adaptor proteins remains unclear. Two adaptor proteins, Ufd1/Npl4 and p47, which bind exclusively to the p97/VCP N-domain and direct p97/VCP to either ERAD-related processes or homotypic fusion of Golgi fragments, were studied here. Surface plasmon resonance biosensor-based assays allowed the study of binding kinetics in real time. In competition experiments, it was observed that in the presence of ATP, Ufd1/Npl4 was able to compete more effectively with p47 for binding to p97/VCP. By using non-hydrolysable ATP analogues and the hexameric truncated p97/N-D1 fragment, it was shown that binding rather than hydrolysis of ATP to the proximal D1 domain strengthened the Ufd1/Npl4 association with the N-domain, thus regulating the recruitment of either Ufd1/Npl4 or p47. This novel role of ATP and an assigned function to the D1 AAA-ATPase domain link the multiple functions of p97/VCP to the metabolic status of the cell. PMID:23226521

A comprehensive assessment of memory, delay aversion, timing, inhibition, decision making and variability in attention deficit hyperactivity disorder: advancing beyond the three-pathway models.

PubMed

Coghill, D R; Seth, S; Matthews, K

2014-07-01

Although attention deficit hyperactivity disorder (ADHD) has been associated with a broad range of deficits across various neuropsychological domains, most studies have assessed only a narrow range of neuropsychological functions. Direct cross-domain comparisons are rare, with almost all studies restricted to less than four domains. Therefore, the relationships between these various domains remain undefined. In addition, almost all studies included previously medicated participants, limiting the conclusions that can be drawn. We present the first study to compare a large cohort of medication-naive boys with ADHD with healthy controls on a broad battery of neuropsychological tasks, assessing six key domains of neuropsychological functioning. The neuropsychological functioning of 83 medication-naive boys with well-characterized ADHD (mean age 8.9 years) was compared with that of 66 typically developing (TYP) boys (mean age 9.0 years) on a broad battery of validated neuropsychological tasks. Data reduction using complementary factor analysis (CFA) confirmed six distinct neuropsychological domains: working memory, inhibition, delay aversion, decision making, timing and response variability. Boys with ADHD performed less well across all six domains although, for each domain, only a minority of boys with ADHD had a deficit [effect size (% with deficit) ADHD versus TYP: working memory 0.95 (30.1), inhibition 0.61 (22.9), delay aversion 0.82 (36.1), decision making 0.55 (20.5), timing 0.71 (31.3), response variability 0.37 (18.1)]. The clinical syndrome of ADHD is neuropsychologically heterogeneous. These data highlight the complexity of the relationships between the different neuropsychological profiles associated with ADHD and the clinical symptoms and functional impairment.

ATP binding to p97/VCP D1 domain regulates selective recruitment of adaptors to its proximal N-domain.

PubMed

Chia, Wei Sheng; Chia, Diana Xueqi; Rao, Feng; Bar Nun, Shoshana; Geifman Shochat, Susana

2012-01-01

p97/Valosin-containing protein (VCP) is a member of the AAA-ATPase family involved in many cellular processes including cell division, intracellular trafficking and extraction of misfolded proteins in endoplasmic reticulum-associated degradation (ERAD). It is a homohexamer with each subunit containing two tandem D1 and D2 ATPase domains and N- and C-terminal regions that function as adaptor protein binding domains. p97/VCP is directed to its many different functional pathways by associating with various adaptor proteins. The regulation of the recruitment of the adaptor proteins remains unclear. Two adaptor proteins, Ufd1/Npl4 and p47, which bind exclusively to the p97/VCP N-domain and direct p97/VCP to either ERAD-related processes or homotypic fusion of Golgi fragments, were studied here. Surface plasmon resonance biosensor-based assays allowed the study of binding kinetics in real time. In competition experiments, it was observed that in the presence of ATP, Ufd1/Npl4 was able to compete more effectively with p47 for binding to p97/VCP. By using non-hydrolysable ATP analogues and the hexameric truncated p97/N-D1 fragment, it was shown that binding rather than hydrolysis of ATP to the proximal D1 domain strengthened the Ufd1/Npl4 association with the N-domain, thus regulating the recruitment of either Ufd1/Npl4 or p47. This novel role of ATP and an assigned function to the D1 AAA-ATPase domain link the multiple functions of p97/VCP to the metabolic status of the cell.

Functional, structural and phylogenetic analysis of domains underlying the Al sensitivity of the aluminum-activated malate/anion transporter, TaALMT1.

PubMed

Ligaba, Ayalew; Dreyer, Ingo; Margaryan, Armine; Schneider, David J; Kochian, Leon; Piñeros, Miguel

2013-12-01

Triticum aestivum aluminum-activated malate transporter (TaALMT1) is the founding member of a unique gene family of anion transporters (ALMTs) that mediate the efflux of organic acids. A small sub-group of root-localized ALMTs, including TaALMT1, is physiologically associated with in planta aluminum (Al) resistance. TaALMT1 exhibits significant enhancement of transport activity in response to extracellular Al. In this study, we integrated structure-function analyses of structurally altered TaALMT1 proteins expressed in Xenopus oocytes with phylogenic analyses of the ALMT family. Our aim is to re-examine the role of protein domains in terms of their potential involvement in the Al-dependent enhancement (i.e. Al-responsiveness) of TaALMT1 transport activity, as well as the roles of all its 43 negatively charged amino acid residues. Our results indicate that the N-domain, which is predicted to form the conductive pathway, mediates ion transport even in the absence of the C-domain. However, segments in both domains are involved in Al(3+) sensing. We identified two regions, one at the N-terminus and a hydrophobic region at the C-terminus, that jointly contribute to the Al-response phenotype. Interestingly, the characteristic motif at the N-terminus appears to be specific for Al-responsive ALMTs. Our study highlights the need to include a comprehensive phylogenetic analysis when drawing inferences from structure-function analyses, as a significant proportion of the functional changes observed for TaALMT1 are most likely the result of alterations in the overall structural integrity of ALMT family proteins rather than modifications of specific sites involved in Al(3+) sensing. © 2013 The Authors The Plant Journal © 2013 John Wiley & Sons Ltd.

A Novel Functional Role of Collagen Glycosylation

PubMed Central

Jürgensen, Henrik J.; Madsen, Daniel H.; Ingvarsen, Signe; Melander, Maria C.; Gårdsvoll, Henrik; Patthy, Laszlo; Engelholm, Lars H.; Behrendt, Niels

2011-01-01

Collagens make up the most abundant component of interstitial extracellular matrices and basement membranes. Collagen remodeling is a crucial process in many normal physiological events and in several pathological conditions. Some collagen subtypes contain specific carbohydrate side chains, the function of which is poorly known. The endocytic collagen receptor urokinase plasminogen activator receptor-associated protein (uPARAP)/Endo180 plays an important role in matrix remodeling through its ability to internalize collagen for lysosomal degradation. uPARAP/Endo180 is a member of the mannose receptor protein family. These proteins all include a fibronectin type II domain and a series of C-type lectin-like domains, of which only a minor part possess carbohydrate recognition activity. At least two of the family members, uPARAP/Endo180 and the mannose receptor, interact with collagens. The molecular basis for this interaction is known to involve the fibronectin type II domain but nothing is known about the function of the lectin domains in this respect. In this study, we have investigated a possible role of the single active lectin domain of uPARAP/Endo180 in the interaction with collagens. By expressing truncated recombinant uPARAP/Endo180 proteins and analyzing their interaction with collagens with high and low levels of glycosylation we demonstrated that this lectin domain interacts directly with glycosylated collagens. This interaction is functionally important because it was found to modulate the endocytic efficiency of the receptor toward highly glycosylated collagens such as basement membrane collagen IV. Surprisingly, this property was not shared by the mannose receptor, which internalized glycosylated collagens independently of its lectin function. This role of modulating its uptake efficiency by a specific receptor is a previously unrecognized function of collagen glycosylation. PMID:21768090

Domain wall nanoelectronics

NASA Astrophysics Data System (ADS)

Catalan, G.; Seidel, J.; Ramesh, R.; Scott, J. F.

2012-01-01

Domains in ferroelectrics were considered to be well understood by the middle of the last century: They were generally rectilinear, and their walls were Ising-like. Their simplicity stood in stark contrast to the more complex Bloch walls or Néel walls in magnets. Only within the past decade and with the introduction of atomic-resolution studies via transmission electron microscopy, electron holography, and atomic force microscopy with polarization sensitivity has their real complexity been revealed. Additional phenomena appear in recent studies, especially of magnetoelectric materials, where functional properties inside domain walls are being directly measured. In this paper these studies are reviewed, focusing attention on ferroelectrics and multiferroics but making comparisons where possible with magnetic domains and domain walls. An important part of this review will concern device applications, with the spotlight on a new paradigm of ferroic devices where the domain walls, rather than the domains, are the active element. Here magnetic wall microelectronics is already in full swing, owing largely to the work of Cowburn and of Parkin and their colleagues. These devices exploit the high domain wall mobilities in magnets and their resulting high velocities, which can be supersonic, as shown by Kreines’ and co-workers 30 years ago. By comparison, nanoelectronic devices employing ferroelectric domain walls often have slower domain wall speeds, but may exploit their smaller size as well as their different functional properties. These include domain wall conductivity (metallic or even superconducting in bulk insulating or semiconducting oxides) and the fact that domain walls can be ferromagnetic while the surrounding domains are not.

Life satisfaction of women of working age shortly after breast cancer surgery.

PubMed

Olsson, Mariann; Nilsson, Marie; Fugl-Meyer, Kerstin; Petersson, Lena-Marie; Wennman-Larsen, Agneta; Kjeldgård, Linnea; Alexanderson, Kristina

2017-03-01

To explore, among women of working age, satisfaction with life as a whole and with different life domains, and its associations with social and health variables, shortly after breast cancer surgery. This cross-sectional study included 605 women, aged 20-63 years, who had had breast cancer surgery with no distant metastasis, pre-surgical chemotherapy, or previous breast cancer. Associations between LiSat-11 and demographic and social factors as well as health- and treatment-related variables were analysed by multivariable logistic regression. Compared with Swedish reference levels, the women were, after breast cancer surgery, less satisfied with life, particularly sexual life. Women working shortly after breast cancer surgery were more often satisfied with life in provision domains compared with the reference population. Although most included variables showed associations with satisfaction, after adjustment for all significantly associated variables, only six variables-having children, being in work, having emotional and informational social support, and having good physical and emotional functioning-were positively associated with satisfaction with life as a whole. The odds ratios for satisfaction were higher in most life domains if the woman had social support and good emotional and cognitive functioning. One month after breast cancer surgery, satisfaction with different life domains was associated primarily with social support and health-related functioning. However, this soon after surgery, treatment-related variables showed no significant associations with life satisfaction. These results are useful for planning interventions to enhance e.g. social support and emotional as well as cognitive functioning.

Domain-swapping analysis of FtsI, FtsL, and FtsQ, bitopic membrane proteins essential for cell division in Escherichia coli.

PubMed Central

Guzman, L M; Weiss, D S; Beckwith, J

1997-01-01

FtsI, FtsL, and FtsQ are three membrane proteins required for assembly of the division septum in the bacterium Escherichia coli. Cells lacking any of these three proteins form long, aseptate filaments that eventually lyse. FtsI, FtsL, and FtsQ are not homologous but have similar overall structures: a small cytoplasmic domain, a single membrane-spanning segment (MSS), and a large periplasmic domain that probably encodes the primary functional activities of these proteins. The periplasmic domain of FtsI catalyzes transpeptidation and is involved in the synthesis of septal peptidoglycan. The precise functions of FtsL and FtsQ are not known. To ask whether the cytoplasmic domain and MSS of each protein serve only as a membrane anchor or have instead a more sophisticated function, we have used molecular genetic techniques to swap these domains among the three Fts proteins and one membrane protein not involved in cell division, MalF. In the cases of FtsI and FtsL, replacement of the cytoplasmic domain and/or MSS resulted in the loss of the ability to support cell division. For FtsQ, MSS swaps supported cell division but cytoplasmic domain swaps did not. We discuss several potential interpretations of these results, including that the essential domains of FtsI, FtsL, and FtsQ have a role in regulating the localization and/or activity of these proteins to ensure that septum formation occurs at the right place in the cell and at the right time during the division cycle. PMID:9260951

Intrinsic, Functional, and Structural Properties of β-Thymosins and β-Thymosin/WH2 Domains in the Regulation and Coordination of Actin Self-Assembly Dynamics and Cytoskeleton Remodeling.

PubMed

Renault, L

2016-01-01

β-Thymosins are a family of heat-stable multifunctional polypeptides that are expressed as small proteins of about 5kDa (~45 amino acids) almost exclusively in multicellular animals. They were first isolated from the thymus. As full-length or truncated polypeptides, they appear to stimulate a broad range of extracellular activities in various signaling pathways, including tissue repair and regeneration, inflammation, cell migration, and immune defense. However, their cell surface receptors and structural mechanisms of regulations in these multiple pathways remain still poorly understood. Besides their extracellular activities, they belong to a larger family of small, intrinsically disordered actin-binding domains called WH2/β-thymosin domains that have been identified in more than 1800 multidomain proteins found in different taxonomic domains of life and involved in various actin-based motile processes including cell morphogenesis, motility, adhesions, tissue development, intracellular trafficking, or pathogen infections. This review briefly surveys the main recent findings to understand how these small, intrinsically disordered but functional domains can interact with many unrelated partners and can thus integrate and coordinate various intracellular activities in actin self-assembly dynamics and cell signaling pathways linked to their cytoskeleton remodeling. © 2016 Elsevier Inc. All rights reserved.

Presynaptic establishment of the synaptic cleft extracellular matrix is required for post-synaptic differentiation

PubMed Central

Rohrbough, Jeffrey; Rushton, Emma; Woodruff, Elvin; Fergestad, Tim; Vigneswaran, Krishanthan; Broadie, Kendal

2007-01-01

Formation and regulation of excitatory glutamatergic synapses is essential for shaping neural circuits throughout development. In a Drosophila genetic screen for synaptogenesis mutants, we identified mind the gap (mtg), which encodes a secreted, extracellular N-glycosaminoglycan-binding protein. MTG is expressed neuronally and detected in the synaptic cleft, and is required to form the specialized transsynaptic matrix that links the presynaptic active zone with the post-synaptic glutamate receptor (GluR) domain. Null mtg embryonic mutant synapses exhibit greatly reduced GluR function, and a corresponding loss of localized GluR domains. All known post-synaptic signaling/scaffold proteins functioning upstream of GluR localization are also grossly reduced or mislocalized in mtg mutants, including the dPix–dPak–Dock cascade and the Dlg/PSD-95 scaffold. Ubiquitous or neuronally targeted mtg RNA interference (RNAi) similarly reduce post-synaptic assembly, whereas post-synaptically targeted RNAi has no effect, indicating that presynaptic MTG induces and maintains the post-synaptic pathways driving GluR domain formation. These findings suggest that MTG is secreted from the presynaptic terminal to shape the extracellular synaptic cleft domain, and that the cleft domain functions to mediate transsynaptic signals required for post-synaptic development. PMID:17901219

Leucine-Rich Repeat Kinase 2 Binds to Neuronal Vesicles through Protein Interactions Mediated by Its C-Terminal WD40 Domain

PubMed Central

Piccoli, Giovanni; Onofri, Franco; Cirnaru, Maria Daniela; Kaiser, Christoph J. O.; Jagtap, Pravinkumar; Kastenmüller, Andreas; Pischedda, Francesca; Marte, Antonella; von Zweydorf, Felix; Vogt, Andreas; Giesert, Florian; Pan, Lifeng; Antonucci, Flavia; Kiel, Christina; Zhang, Mingjie; Weinkauf, Sevil; Sattler, Michael; Sala, Carlo; Matteoli, Michela; Ueffing, Marius

2014-01-01

Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) are associated with familial and sporadic Parkinson's disease (PD). LRRK2 is a complex protein that consists of multiple domains, including predicted C-terminal WD40 repeats. In this study, we analyzed functional and molecular features conferred by the WD40 domain. Electron microscopic analysis of the purified LRRK2 C-terminal domain revealed doughnut-shaped particles, providing experimental evidence for its WD40 fold. We demonstrate that LRRK2 WD40 binds and sequesters synaptic vesicles via interaction with vesicle-associated proteins. In fact, a domain-based pulldown approach combined with mass spectrometric analysis identified LRRK2 as being part of a highly specific protein network involved in synaptic vesicle trafficking. In addition, we found that a C-terminal sequence variant associated with an increased risk of developing PD, G2385R, correlates with a reduced binding affinity of LRRK2 WD40 to synaptic vesicles. Our data demonstrate a critical role of the WD40 domain within LRRK2 function. PMID:24687852

Structural Basis for Endosomal Targeting by the Bro1 Domain

PubMed Central

Kim, Jaewon; Sitaraman, Sujatha; Hierro, Aitor; Beach, Bridgette M.; Odorizzi, Greg; Hurley, James H.

2010-01-01

Summary Proteins delivered to the lysosome or the yeast vacuole via late endosomes are sorted by the ESCRT complexes and by associated proteins, including Alix and its yeast homolog Bro1. Alix, Bro1, and several other late endosomal proteins share a conserved 160 residue Bro1 domain whose boundaries, structure, and function have not been characterized. The crystal structure of the Bro1 domain of Bro1 reveals a folded core of 367 residues. The extended Bro1 domain is necessary and sufficient for binding to the ESCRT-III subunit Snf7 and for the recruitment of Bro1 to late endosomes. The structure resembles a boomerang with its concave face filled in and contains a triple tetratricopeptide repeat domain as a substructure. Snf7 binds to a conserved hydrophobic patch on Bro1 that is required for protein complex formation and for the protein-sorting function of Bro1. These results define a conserved mechanism whereby Bro1 domain-containing proteins are targeted to endosomes by Snf7 and its orthologs. PMID:15935782

Hydrogel Tethering Enhances Interdomain Stabilization of Single-Chain Antibodies.

PubMed

Xiong, Yijia; Ford, Nicole R; Hecht, Karen A; Roesijadi, Guritno; Squier, Thomas C

2017-11-15

Here, we identify the importance of molecular crowding agents in the functional stabilization of scFv antibodies. Antibodies were tethered through an engineered calmodulin (CaM)-binding peptide into a stimulus-responsive hydrogel composed of poly(ethylene glycol) (PEG)-functionalized CaM. Macromolecular crowding is modulated by transient heating, which decreases effective pore sizes. Using a fluorescent ligand bound to the scFv, frequency-domain fluorescence spectroscopy was used to assess the structural coupling between the V H and the V L domains and relationships with functional stabilization. There is minimal structural coupling between the V H and the V L domains in solution, as is apparent from the substantial rotational mobility for the bound ligand, that is suggestive of an independent mobility for the V H and the V L domains. In comparison, the hydrogel matrix acts to structurally couple the V H and the V L domains, resulting in a reduction in rotational mobility and a retention of ligand binding in the presence of 8.0 M urea. Under these same conditions, ligand binding is disrupted for scFv antibodies in solution. Increases in the stabilization of scFv antibodies in hydrogels is not simply the result of molecular crowding because decreases in pore size act to destabilize ligand binding. Rather, our results suggest that the functional stabilization of the scFv antibody within the PEG hydrogel matrix includes important factors involving protein solvation that stabilize interdomain interactions between the V H and the V L domains necessary for ligand binding.

Iterative and function-continuation Fourier deconvolution methods for enhancing mass spectrometer resolution

NASA Technical Reports Server (NTRS)

Ioup, J. W.; Ioup, G. E.; Rayborn, G. H., Jr.; Wood, G. M., Jr.; Upchurch, B. T.

1984-01-01

Mass spectrometer data in the form of ion current versus mass-to-charge ratio often include overlapping mass peaks, especially in low- and medium-resolution instruments. Numerical deconvolution of such data effectively enhances the resolution by decreasing the overlap of mass peaks. In this paper two approaches to deconvolution are presented: a function-domain iterative technique and a Fourier transform method which uses transform-domain function-continuation. Both techniques include data smoothing to reduce the sensitivity of the deconvolution to noise. The efficacy of these methods is demonstrated through application to representative mass spectrometer data and the deconvolved results are discussed and compared to data obtained from a spectrometer with sufficient resolution to achieve separation of the mass peaks studied. A case for which the deconvolution is seriously affected by Gibbs oscillations is analyzed.

Neurocognition in early-onset schizophrenia and schizoaffective disorders.

PubMed

Hooper, Stephen R; Giuliano, Anthony J; Youngstrom, Eric A; Breiger, David; Sikich, Linmarie; Frazier, Jean A; Findling, Robert L; McClellan, Jon; Hamer, Robert M; Vitiello, Benedetto; Lieberman, Jeffrey A

2010-01-01

We examined the neuropsychological functioning of youth enrolled in the NIMH funded trial, Treatment of Early-Onset Schizophrenia Spectrum Disorders (TEOSS). We compared the baseline neuropsychological functioning of youth with schizophrenia (SZ, n = 79) to those with schizoaffective disorder (SA, n = 40), and examined the relationship of different variables of illness severity and adaptive behavior to neuropsychological functioning. Participants ranged in age from 8 to 19 years. Diagnostic status was confirmed via structured interview over multiple time points. Domains of neuropsychological functioning included fine-motor, attention, working memory, problem-solving efficiency, inhibitory control, and social cognition. Other variables included intelligence (IQ), academic achievement skills, adaptive behavior, and different measures of illness severity. The two groups did not differ on IQ or on any of the neuropsychological domains. The SZ group performed significantly lower in spelling. A high proportion of individuals in both groups reflected significant intellectual and academic achievement skill deficits. Significant correlations were found between the neurocognitive domains and both illness severity and adaptive behavior variables. There were few differences between the SZ and SA groups on IQ, achievement, or neuropsychological functioning; however, both groups showed significantly high rates of deficits in IQ and basic academic skills. Correlations of the neurocognitive functions with illness severity and adaptive behavior were small to moderate in magnitude. These findings continue to implicate the importance of neurocognitive functioning as a key area of vulnerability in the study of youth with schizophrenia spectrum disorders.

Concomitant prediction of function and fold at the domain level with GO-based profiles.

PubMed

Lopez, Daniel; Pazos, Florencio

2013-01-01

Predicting the function of newly sequenced proteins is crucial due to the pace at which these raw sequences are being obtained. Almost all resources for predicting protein function assign functional terms to whole chains, and do not distinguish which particular domain is responsible for the allocated function. This is not a limitation of the methodologies themselves but it is due to the fact that in the databases of functional annotations these methods use for transferring functional terms to new proteins, these annotations are done on a whole-chain basis. Nevertheless, domains are the basic evolutionary and often functional units of proteins. In many cases, the domains of a protein chain have distinct molecular functions, independent from each other. For that reason resources with functional annotations at the domain level, as well as methodologies for predicting function for individual domains adapted to these resources are required.We present a methodology for predicting the molecular function of individual domains, based on a previously developed database of functional annotations at the domain level. The approach, which we show outperforms a standard method based on sequence searches in assigning function, concomitantly predicts the structural fold of the domains and can give hints on the functionally important residues associated to the predicted function.

Knowledge Representation Standards and Interchange Formats for Causal Graphs

NASA Technical Reports Server (NTRS)

Throop, David R.; Malin, Jane T.; Fleming, Land

2005-01-01

In many domains, automated reasoning tools must represent graphs of causally linked events. These include fault-tree analysis, probabilistic risk assessment (PRA), planning, procedures, medical reasoning about disease progression, and functional architectures. Each of these fields has its own requirements for the representation of causation, events, actors and conditions. The representations include ontologies of function and cause, data dictionaries for causal dependency, failure and hazard, and interchange formats between some existing tools. In none of the domains has a generally accepted interchange format emerged. The paper makes progress towards interoperability across the wide range of causal analysis methodologies. We survey existing practice and emerging interchange formats in each of these fields. Setting forth a set of terms and concepts that are broadly shared across the domains, we examine the several ways in which current practice represents them. Some phenomena are difficult to represent or to analyze in several domains. These include mode transitions, reachability analysis, positive and negative feedback loops, conditions correlated but not causally linked and bimodal probability distributions. We work through examples and contrast the differing methods for addressing them. We detail recent work in knowledge interchange formats for causal trees in aerospace analysis applications in early design, safety and reliability. Several examples are discussed, with a particular focus on reachability analysis and mode transitions. We generalize the aerospace analysis work across the several other domains. We also recommend features and capabilities for the next generation of causal knowledge representation standards.

Botulinum neurotoxin structure, engineering, and novel cellular trafficking and targeting.

PubMed

Singh, B R

2006-04-01

Botulinum neurotoxins are multifaceted molecules, which are truly unique not only in their mode of action, but also their utility as a drug carrier either across the gut wall or to the nerve terminals. The molecule is divided in clear functional domains that can operate independently. This feature can be used to employ them as cargo carrier by linking other drugs or vaccines with the binding and translocation domains of BoNT. While the domain structures are largely independent of each other, the dynamic structure of these domains, especially that of the enzymatic domain (L chain), is quite different from the reported crystal structures for several BoNT serotypes and their enzymatic domain. This review discusses the comparative structures of BoNT in crystal and solution for their relevance to the molecular mechanism of BoNT action, especially in view of our recent discovery that the enzymatically active structure of the BoNT exists as a molten-globule and that of the endopeptidase domain as a novel PRIME conformation. Finally, a non-exhaustive discussion has been included to explain the long-lasting biological effects of certain serotypes of BoNT, based on the current knowledge of the structure-function of different serotypes of botulinum neurotoxins.

Membrane re-modelling by BAR domain superfamily proteins via molecular and non-molecular factors.

PubMed

Nishimura, Tamako; Morone, Nobuhiro; Suetsugu, Shiro

2018-04-17

Lipid membranes are structural components of cell surfaces and intracellular organelles. Alterations in lipid membrane shape are accompanied by numerous cellular functions, including endocytosis, intracellular transport, and cell migration. Proteins containing Bin-Amphiphysin-Rvs (BAR) domains (BAR proteins) are unique, because their structures correspond to the membrane curvature, that is, the shape of the lipid membrane. BAR proteins present at high concentration determine the shape of the membrane, because BAR domain oligomers function as scaffolds that mould the membrane. BAR proteins co-operate with various molecular and non-molecular factors. The molecular factors include cytoskeletal proteins such as the regulators of actin filaments and the membrane scission protein dynamin. Lipid composition, including saturated or unsaturated fatty acid tails of phospholipids, also affects the ability of BAR proteins to mould the membrane. Non-molecular factors include the external physical forces applied to the membrane, such as tension and friction. In this mini-review, we will discuss how the BAR proteins orchestrate membrane dynamics together with various molecular and non-molecular factors. © 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

Effect of ageing on neurocognitive function by stage of HIV infection: evidence from the Multicenter AIDS Cohort Study.

PubMed

Goodkin, Karl; Miller, Eric N; Cox, Christopher; Reynolds, Sandra; Becker, James T; Martin, Eileen; Selnes, Ola A; Ostrow, David G; Sacktor, Ned C

2017-09-01

The demographics of the HIV epidemic in the USA have shifted towards older age. We aimed to establish the relationship between the processes of ageing and HIV infection in neurocognitive impairment. With longitudinal data from the Multicenter AIDS Cohort Study, a long-term prospective cohort study of the natural and treated history of HIV infection among men who have sex with men in the USA, we examined the effect of ageing, HIV infection (by disease stage), and their interaction on five neurocognitive domains: information processing speed, executive function, episodic memory, working memory, and motor function. We controlled for duration of serostatus in a subanalysis, as well as comorbidities and other factors that affect cognition. Analyses were by linear mixed models for longitudinal data. 5086 participants (47 886 visits) were included in the analytic sample (2278 HIV-seropositive participants contributed 20 477 visits and 2808 HIV-seronegative control participants contributed 27 409 visits). In an a-priori multivariate analysis with control variables including comorbidities and time since seroconversion, significant, direct negative effects of ageing were noted on all neurocognitive domains (p<0·0001 for all). Similar effects were noted for late-stage HIV disease progression on information processing speed (p=0·002), executive function (p<0·0001), motor function (p<0·0001), and working memory (p=0·001). Deleterious interaction effects were also noted in the domains of episodic memory (p=0·03) and motor function (p=0·02). A greater than expected effect of ageing on episodic memory and motor function with advanced stages of HIV infection suggests that these two domains are most susceptible to the progression of neurocognitive impairment caused by ageing in individuals with HIV. This deficit pattern suggests differential damage to the hippocampus and basal ganglia (specifically nigrostriatal pathways). Older individuals with HIV infection should be targeted for regular screening for HIV-associate neurocognitive disorder, particularly with tests referable to the episodic memory and motor domains. National Institute of Mental Health. Copyright © 2017 Elsevier Ltd. All rights reserved.

Development of the NIH PROMIS® Sexual Function and Satisfaction Measures in Patients with Cancer

PubMed Central

Flynn, Kathryn E.; Lin, Li; Cyranowski, Jill M.; Reeve, Bryce B.; Reese, Jennifer Barsky; Jeffery, Diana D.; Smith, Ashley Wilder; Porter, Laura S.; Dombeck, Carrie B.; Bruner, Deborah Watkins; Keefe, Francis J.; Weinfurt, Kevin P.

2013-01-01

Introduction We describe the development and validation of the PROMIS Sexual Function and Satisfaction (PROMIS SexFS) measures version 1.0 for cancer populations. Aim To develop a customizable self-report measure of sexual function and satisfaction as part of the U.S. National Institutes of Health PROMIS® Network. Methods Our multidisciplinary working group followed a comprehensive protocol for developing psychometrically robust patient reported outcome (PRO) measures including qualitative (scale development) and quantitative (psychometric evaluation) development. We performed an extensive literature review, conducted 16 focus groups with cancer patients and multiple discussions with clinicians, and evaluated candidate items in cognitive testing with patients. We administered items to 819 cancer patients. Items were calibrated using item response theory and evaluated for reliability and validity. Main Outcome Measures The PROMIS Sexual Function and Satisfaction (PROMIS SexFS) measures version 1.0 include 79 items in 11 domains: interest in sexual activity, lubrication, vaginal discomfort, erectile function, global satisfaction with sex life, orgasm, anal discomfort, therapeutic aids, sexual activities, interfering factors, and screener questions. Results In addition to content validity (patients indicate that items cover important aspects of their experiences) and face validity (patients indicate that items measure sexual function and satisfaction), the measure shows evidence for discriminant validity (domains discriminate between groups expected to be different), convergent validity (strong correlations between scores on PROMIS and scores on conceptually-similar older measures of sexual function), as well as favorable test-retest reliability among people not expected to change (inter-class correlations from 2 administrations of the instrument, 1 month apart). Conclusions The PROMIS SexFS offers researchers a reliable and valid set of tools to measure self-reported sexual function and satisfaction among diverse men and women. The measures are customizable; researchers can select the relevant domains and items comprising those domains for their study. PMID:23387911

A comprehensive analysis of the Omp85/TpsB protein superfamily structural diversity, taxonomic occurrence, and evolution

PubMed Central

Heinz, Eva; Lithgow, Trevor

2014-01-01

Members of the Omp85/TpsB protein superfamily are ubiquitously distributed in Gram-negative bacteria, and function in protein translocation (e.g., FhaC) or the assembly of outer membrane proteins (e.g., BamA). Several recent findings are suggestive of a further level of variation in the superfamily, including the identification of the novel membrane protein assembly factor TamA and protein translocase PlpD. To investigate the diversity and the causal evolutionary events, we undertook a comprehensive comparative sequence analysis of the Omp85/TpsB proteins. A total of 10 protein subfamilies were apparent, distinguished in their domain structure and sequence signatures. In addition to the proteins FhaC, BamA, and TamA, for which structural and functional information is available, are families of proteins with so far undescribed domain architectures linked to the Omp85 β-barrel domain. This study brings a classification structure to a dynamic protein superfamily of high interest given its essential function for Gram-negative bacteria as well as its diverse domain architecture, and we discuss several scenarios of putative functions of these so far undescribed proteins. PMID:25101071

Self-reported walking ability predicts functional mobility performance in frail older adults.

PubMed

Alexander, N B; Guire, K E; Thelen, D G; Ashton-Miller, J A; Schultz, A B; Grunawalt, J C; Giordani, B

2000-11-01

To determine how self-reported physical function relates to performance in each of three mobility domains: walking, stance maintenance, and rising from chairs. Cross-sectional analysis of older adults. University-based laboratory and community-based congregate housing facilities. Two hundred twenty-one older adults (mean age, 79.9 years; range, 60-102 years) without clinical evidence of dementia (mean Folstein Mini-Mental State score, 28; range, 24-30). We compared the responses of these older adults on a questionnaire battery used by the Established Populations for the Epidemiologic Study of the Elderly (EPESE) project, to performance on mobility tasks of graded difficulty. Responses to the EPESE battery included: (1) whether assistance was required to perform seven Katz activities of daily living (ADL) items, specifically with walking and transferring; (2) three Rosow-Breslau items, including the ability to walk up stairs and walk a half mile; and (3) five Nagi items, including difficulty stooping, reaching, and lifting objects. The performance measures included the ability to perform, and time taken to perform, tasks in three summary score domains: (1) walking ("Walking," seven tasks, including walking with an assistive device, turning, stair climbing, tandem walking); (2) stance maintenance ("Stance," six tasks, including unipedal, bipedal, tandem, and maximum lean); and (3) chair rise ("Chair Rise," six tasks, including rising from a variety of seat heights with and without the use of hands for assistance). A total score combines scores in each Walking, Stance, and Chair Rise domain. We also analyzed how cognitive/ behavioral factors such as depression and self-efficacy related to the residuals from the self-report and performance-based ANOVA models. Rosow-Breslau items have the strongest relationship with the three performance domains, Walking, Stance, and Chair Rise (eta-squared ranging from 0.21 to 0.44). These three performance domains are as strongly related to one Katz ADL item, walking (eta-squared ranging from 0.15 to 0.33) as all of the Katz ADL items combined (eta-squared ranging from 0.21 to 0.35). Tests of problem solving and psychomotor speed, the Trails A and Trails B tests, are significantly correlated with the residuals from the self-report and performance-based ANOVA models. Compared with the rest of the EPESE self-report items, self-report items related to walking (such as Katz walking and Rosow-Breslau items) are better predictors of functional mobility performance on tasks involving walking, stance maintenance, and rising from chairs. Compared with other self-report items, self-reported walking ability may be the best predictor of overall functional mobility.

Differential distribution of voltage-gated ion channels in cortical neurons: implications for epilepsy.

PubMed

Child, Nicholas D; Benarroch, Eduardo E

2014-03-18

Neurons contain different functional somatodendritic and axonal domains, each with a characteristic distribution of voltage-gated ion channels, synaptic inputs, and function. The dendritic tree of a cortical pyramidal neuron has 2 distinct domains, the basal and the apical dendrites, both containing dendritic spines; the different domains of the axon are the axonal initial segment (AIS), axon proper (which in myelinated axons includes the node of Ranvier, paranodes, juxtaparanodes, and internodes), and the axon terminals. In the cerebral cortex, the dendritic spines of the pyramidal neurons receive most of the excitatory synapses; distinct populations of γ-aminobutyric acid (GABA)ergic interneurons target specific cellular domains and thus exert different influences on pyramidal neurons. The multiple synaptic inputs reaching the somatodendritic region and generating excitatory postsynaptic potentials (EPSPs) and inhibitory postsynaptic potentials (IPSPs) sum and elicit changes in membrane potential at the AIS, the site of initiation of the action potential.

Structure of Serum Amyloid A Suggests a Mechanism for Selective Lipoprotein Binding and Functions: SAA as a Hub in Macromolecular Interaction Networks

PubMed Central

Frame, Nicholas M.; Gursky, Olga

2016-01-01

Serum amyloid A is a major acute-phase plasma protein that modulates innate immunity and cholesterol homeostasis. We combine sequence analysis with x-ray crystal structures to postulate that SAA acts as an intrinsically disordered hub mediating interactions among proteins, lipids and proteoglycans. A structural model of lipoprotein-bound SAA monomer is proposed wherein two α-helices from the N-domain form a concave hydrophobic surface that binds lipoproteins. A C-domain, connected to the N-domain via a flexible linker, binds polar/charged ligands including cell receptors, bridging them with lipoproteins and re-routing cholesterol transport. Our model is supported by the SAA cleavage in the inter-domain linker to generate the 1–76 fragment deposited in reactive amyloidosis. This model sheds new light on functions of this enigmatic protein. PMID:26918388

The Importance of Social Cognition in Improving Functional Outcomes in Schizophrenia

PubMed Central

Javed, Afzal; Charles, Asha

2018-01-01

Social cognition has become recognized as an important driver of functional outcomes and overall recovery in patients with schizophrenia, mediating the relationship between neurocognition and social functioning. Since antipsychotic therapy targeting remission of clinical symptoms has been shown to have a limited impact on social cognition, there has been an increasing drive to develop therapeutic strategies to specifically improve social cognition in schizophrenia. We sought to review current evidence relating to social cognition in schizophrenia and its clinical implications, including interventions designed to target the core domains of social cognition (emotion processing, theory of mind, attributional bias, and social perception) as a means of improving functional outcomes and thereby increasing the likelihood of recovery. Relevant articles were identified by conducting a literature search in PubMed using the search terms “schizophrenia” AND “cognition” AND “social functioning,” limited to Title/Abstract, over a time period of the past 10 years. Current evidence demonstrates that schizophrenia is associated with impairments in all four core domains of social cognition, during the pre-first-episode, first-episode, early, and chronic phases of the disease, and that such impairments are important determinants of functional outcome. Interventions targeting the four core domains of social cognition comprise psychosocial approaches (social cognition training programs) and pharmacological therapies. Social cognition training programs targeting multiple and specific core domains of social cognition have shown promise in improving social cognition skills, which, in some cases, has translated into improvements in functional outcomes. Use of some psychosocial interventions has additionally resulted in improvements in clinical symptoms and/or quality of life. Pharmacological therapies, including oxytocin and certain antipsychotics, have yielded more mixed results, due in part to the confounding impact of factors including variation in receptor genetics, bioavailability, pharmacokinetics, and drug–drug interactions, and inconsistencies between study designs and medication dosages. Additional research is required to advance our understanding of the role of social cognition in schizophrenia, and to further establish the utility of targeted interventions in this setting. PMID:29740360

The prefrontal landscape: implications of functional architecture for understanding human mentation and the central executive.

PubMed

Goldman-Rakic, P S

1996-10-29

The functional architecture of prefrontal cortex is central to our understanding of human mentation and cognitive prowess. This region of the brain is often treated as an undifferentiated structure, on the one hand, or as a mosaic of psychological faculties, on the other. This paper focuses on the working memory processor as a specialization of prefrontal cortex and argues that the different areas within prefrontal cortex represent iterations of this function for different information domains, including spatial cognition, object cognition and additionally, in humans, semantic processing. According to this parallel processing architecture, the 'central executive' could be considered an emergent property of multiple domain-specific processors operating interactively. These processors are specializations of different prefrontal cortical areas, each interconnected both with the domain-relevant long-term storage sites in posterior regions of the cortex and with appropriate output pathways.

DNA Sequence Analysis of Sry Alleles (Subgenus Mus) Implicates Misregulation as the Cause of C57bl/6j-Y(pos) Sex Reversal and Defines the Sry Functional Unit

PubMed Central

Albrecht, K. H.; Eicher, E. M.

1997-01-01

The Sry (sex determining region, Y chromosome) open reading frame from mice representing four species of the genus Mus was sequenced in an effort to understand the conditional dysfunction of some M. domesticus Sry alleles when present on the C57BL/6J inbred strain genetic background and to delimit the functionally important protein regions. Twenty-two Sry alleles were sequenced, most from wild-derived Y chromosomes, including 11 M. domesticus alleles, seven M. musculus alleles and two alleles each from the related species M. spicilegus and M. spretus. We found that the HMG domain (high mobility group DNA binding domain) and the unique regions are well conserved, while the glutamine repeat cluster (GRC) region is quite variable. No correlation was found between the predicted protein isoforms and the ability of a Sry allele to allow differentiation of ovarian tissue when on the C57BL/6J genetic background, strongly suggesting that the cause of this sex reversal is not the Sry protein itself, but rather the regulation of SRY expression. Furthermore, our interspecies sequence analysis provides compelling evidence that the M. musculus and M. domesticus SRY functional domain is contained in the first 143 amino acids, which includes the HMG domain and adjacent unique region (UR-2). PMID:9383069

Measuring the Effect of Soil-Transmitted Helminth Infections on Cognitive Function in Children: Systematic Review and Critical Appraisal of Evidence.

PubMed

Owada, Kei; Nielsen, Mark; Lau, Colleen L; Clements, Archie C A; Yakob, Laith; Soares Magalhães, Ricardo J

2017-01-01

Recently the role of soil-transmitted helminth (STH) infections in children's cognitive developmental impairment has been under scrutiny. We conducted a systematic review of the evidence for associations between STH infections and cognitive function of children using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocol. We aimed to identify the domains of cognitive function in three age strata (<24months, 24-59months and ≥60months) and critically appraise the general design protocol of the studies, with a focus on the cognitive function measurement tools used. A total of 42 papers fulfilled the inclusion criteria, including 10 studies from a recent Cochrane review. Our findings demonstrate variation in tested domains, lack of consistency in the use of measurement tools and analysis of results. Cognitive function measures in children aged under 59months have been mainly limited to domains of gross motor, fine motor and language skills, whereas in children aged 60months and above most studies tested domains such as memory and processing speed. Even within the same age group the results on the association between STH infections and measures of cognitive development were often conflicting. The current study highlights the need for methodological consensus in the use of measurement tools and data analysis protocols if the effect of STH infections on cognitive function domains in children is to be correctly established. This will be an imperative next step to generate conclusive evidence of the role of STH infections in cognitive development in children. Copyright © 2017 Elsevier Ltd. All rights reserved.

Rasch analysis of the UK Functional Assessment Measure in patients with complex disability after stroke.

PubMed

Medvedev, Oleg N; Turner-Stokes, Lynne; Ashford, Stephen; Siegert, Richard J

2018-02-28

To determine whether the UK Functional Assessment Measure (UK FIM+FAM) fits the Rasch model in stroke patients with complex disability and, if so, to derive a conversion table of Rasch-transformed interval level scores. The sample included a UK multicentre cohort of 1,318 patients admitted for specialist rehabilitation following a stroke. Rasch analysis was conducted for the 30-item scale including 3 domains of items measuring physical, communication and psychosocial functions. The fit of items to the Rasch model was examined using 3 different analytical approaches referred to as "pathways". The best fit was achieved in the pathway where responses from motor, communication and psychosocial domains were summarized into 3 super-items and where some items were split because of differential item functioning (DIF) relative to left and right hemisphere location (χ2 (10) = 14.48, p = 0.15). Re-scoring of items showing disordered thresholds did not significantly improve the overall model fit. The UK FIM+FAM with domain super-items satisfies expectations of the unidimensional Rasch model without the need for re-scoring. A conversion table was produced to convert the total scale scores into interval-level data based on person estimates of the Rasch model. The clinical benefits of interval-transformed scores require further evaluation.

Orthologs in Arabidopsis thaliana of the Hsp70 interacting protein Hip

PubMed Central

Webb, Mary Alice; Cavaletto, John M.; Klanrit, Preekamol; Thompson, Gary A.

2001-01-01

The Hsp70-interacting protein Hip binds to the adenosine triphosphatase domain of Hsp70, stabilizing it in the adenosine 5′-diphosphate–ligated conformation and promoting binding of target polypeptides. In mammalian cells, Hip is a component of the cytoplasmic chaperone heterocomplex that regulates signal transduction via interaction with hormone receptors and protein kinases. Analysis of the complete genome sequence of the model flowering plant Arabidopsis thaliana revealed 2 genes encoding Hip orthologs. The deduced sequence of AtHip-1 consists of 441 amino acid residues and is 42% identical to human Hip. AtHip-1 contains the same functional domains characterized in mammalian Hip, including an N-terminal dimerization domain, an acidic domain, 3 tetratricopeptide repeats flanked by a highly charged region, a series of degenerate GGMP repeats, and a C-terminal region similar to the Sti1/Hop/p60 protein. The deduced amino acid sequence of AtHip-2 consists of 380 amino acid residues. AtHip-2 consists of a truncated Hip-like domain that is 46% identical to human Hip, followed by a C-terminal domain related to thioredoxin. AtHip-2 is 63% identical to another Hip-thioredoxin protein recently identified in Vitis labrusca (grape). The truncated Hip domain in AtHip-2 includes the amino terminus, the acidic domain, and tetratricopeptide repeats with flanking charged region. Analyses of expressed sequence tag databases indicate that both AtHip-1 and AtHip-2 are expressed in A thaliana and that orthologs of Hip are also expressed widely in other plants. The similarity between AtHip-1 and its mammalian orthologs is consistent with a similar role in plant cells. The sequence of AtHip-2 suggests the possibility of additional unique chaperone functions. PMID:11599566

Gaining the Patient Reported Outcomes Measurement Information System (PROMIS) Perspective in Chronic Kidney Disease: a Midwest Pediatric Nephrology Consortium study

PubMed Central

Selewski, David T.; Massengill, Susan F.; Troost, Jonathan P.; Wickman, Larysa; Messer, Kassandra L.; Herreshoff, Emily; Bowers, Corinna; Ferris, Maria E.; Mahan, John D.; Greenbaum, Larry A.; MacHardy, Jackie; Kapur, Gaurav; Chand, Deepa H.; Goebel, Jens; Barletta, Gina Marie; Geary, Denis; Kershaw, David B.; Pan, Cynthia G.; Gbadegesin, Rasheed; Hidalgo, Guillermo; Lane, Jerome C.; Leiser, Jeffrey D.; Song, Peter X.; Thissen, David; Liu, Yang; Gross, Heather E.; DeWalt, Darren A.; Gipson, Debbie S.

2014-01-01

Background and Objectives Chronic kidney disease is a persistent chronic health condition commonly seen in pediatric nephrology programs. Our study aims to evaluate the sensitivity of the Patient Reported Outcomes Measurement Information System (PROMIS) pediatric instrument to indicators of disease severity and activity in pediatric chronic kidney disease. Methods This cross sectional study included 233 children 8–17 years old with chronic kidney disease from 16 participating institutions in North America. Disease activity indicators, including hospitalization in the previous 6 months, edema, and number of medications consumed daily, as well as disease severity indicators of kidney function and coexisting medical conditions were captured. PROMIS domains, including depression, anxiety, social-peer relationships, pain interference, fatigue, mobility, and upper extremity function, were administered via web-based questionnaires. Absolute effect sizes (AES) were generated to demonstrate the impact of disease on domain scores. Four children were excluded because of missing GFR estimations. Results 221 of the 229 children included in the final analysis completed the entire PROMIS questionnaire. Unadjusted PROMIS domains were responsive to chronic kidney disease activity indicators and number of coexisting conditions. PROMIS domain scores were worse in the presence of recent hospitalizations (depression AES 0.33, anxiety AES 0.42, pain interference AES 0.46, fatigue AES 0.50, mobility AES 0.49), edema (depression AES 0.50, anxiety AES 0.60, pain interference AES 0.77, mobility AES 0.54) and coexisting medical conditions (social peer-relationships AES 0.66, fatigue AES 0.83, mobility AES 0.60, upper extremity function AES 0.48). Conclusions The PROMIS pediatric domains of depression, anxiety, social-peer relationships, pain interference, and mobility were sensitive to the clinical status of children with chronic kidney disease in this multi-center cross sectional study. We demonstrated that a number of important clinical characteristics including recent history of hospitalization and edema affected patient perceptions of depression, anxiety, pain interference, fatigue and mobility. The PROMIS instruments provide a potentially valuable tool to study the impact of chronic kidney disease. Additional studies will be required to assess responsiveness in PROMIS score with changes in disease status over time. PMID:24908324

Evaluation of sexual function in women with type 2 diabetes mellitus.

PubMed

Fatemi, Seyedeh Seddigeh; Taghavi, Seyed Morteza

2009-01-01

Sexual health is an important, but often neglected, component of diabetes care. In contrast to erectile dysfunction among men with diabetes, female sexual dysfunction has not been well studied among diabetic women. The aim of this study was to assess the prevalence of sexual dysfunction in women with type 2 diabetes compared to that in an age-matched control group. In all, 50 married women with type 2 diabetes attending the outpatient endocrine clinic of Ghaem Hospital between April 2007 and March 2008 were selected. Fasting plasma glucose and glycosylated haemoglobin were measured and sexual function was assessed by questionnaire. Scores in each domain of sexual function were compared with those of 40 non-diabetic controls. Sexual function scores for the sexual drive, arousal, vaginal lubrication, orgasm and overall satisfaction domains were all lower in the diabetic women (p value < 0.05). Duration of diabetes and age correlated negatively with all domains of sexual function. There was no significant relationship between sexual function and body mass index (BMI), glycaemic control, education or employment status. Diabetes significantly impairs the sexual performance of diabetic women. Determinants of sexual function include age and duration of diabetes.

Multiple roles of phosphoinositide-specific phospholipase C isozymes.

PubMed

Suh, Pann-Ghill; Park, Jae-Il; Manzoli, Lucia; Cocco, Lucio; Peak, Joanna C; Katan, Matilda; Fukami, Kiyoko; Kataoka, Tohru; Yun, Sanguk; Ryu, Sung Ho

2008-06-30

Phosphoinositide-specific phospholipase C is an effector molecule in the signal transduction process. It generates two second messengers, inositol-1,4,5-trisphosphate and diacylglycerol from phosphatidylinositol 4,5-bisphosphate. Currently, thirteen mammal PLC isozymes have been identified, and they are divided into six groups: PLC-beta, -gamma, -delta, -epsilon, -zeta and -eta. Sequence analysis studies demonstrated that each isozyme has more than one alternative splicing variant. PLC isozymes contain the X and Y domains that are responsible for catalytic activity. Several other domains including the PH domain, the C2 domain and EF hand motifs are involved in various biological functions of PLC isozymes as signaling proteins. The distribution of PLC isozymes is tissue and organ specific. Recent studies on isolated cells and knockout mice depleted of PLC isozymes have revealed their distinct phenotypes. Given the specificity in distribution and cellular localization, it is clear that each PLC isozyme bears a unique function in the modulation of physiological responses. In this review, we discuss the structural organization, enzymatic properties and molecular diversity of PLC splicing variants and study functional and physiological roles of each isozyme.

Description of waves in inhomogeneous domains using Heun's equation

NASA Astrophysics Data System (ADS)

Bednarik, M.; Cervenka, M.

2018-04-01

There are a number of model equations describing electromagnetic, acoustic or quantum waves in inhomogeneous domains and some of them are of the same type from the mathematical point of view. This isomorphism enables us to use a unified approach to solving the corresponding equations. In this paper, the inhomogeneity is represented by a trigonometric spatial distribution of a parameter determining the properties of an inhomogeneous domain. From the point of view of modeling, this trigonometric parameter function can be smoothly connected to neighboring constant-parameter regions. For this type of distribution, exact local solutions of the model equations are represented by the local Heun functions. As the interval for which the solution is sought includes two regular singular points. For this reason, a method is proposed which resolves this problem only based on the local Heun functions. Further, the transfer matrix for the considered inhomogeneous domain is determined by means of the proposed method. As an example of the applicability of the presented solutions the transmission coefficient is calculated for the locally periodic structure which is given by an array of asymmetric barriers.

Crystal Structure of the Ternary Complex of a NaV C-Terminal Domain, a Fibroblast Growth Factor Homologous Factor, and Calmodulin

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

Wang, Chaojian; Chung, Ben C.; Yan, Haidun

2012-11-13

Voltage-gated Na{sup +} (Na{sub V}) channels initiate neuronal action potentials. Na{sub V} channels are composed of a transmembrane domain responsible for voltage-dependent Na{sup +} conduction and a cytosolic C-terminal domain (CTD) that regulates channel function through interactions with many auxiliary proteins, including fibroblast growth factor homologous factors (FHFs) and calmodulin (CaM). Most ion channel structural studies have focused on mechanisms of permeation and voltage-dependent gating but less is known about how intracellular domains modulate channel function. Here we report the crystal structure of the ternary complex of a human NaV CTD, an FHF, and Ca{sup 2+}-free CaM at 2.2 {angstrom}.more » Combined with functional experiments based on structural insights, we present a platform for understanding the roles of these auxiliary proteins in NaV channel regulation and the molecular basis of mutations that lead to neuronal and cardiac diseases. Furthermore, we identify a critical interaction that contributes to the specificity of individual NaV CTD isoforms for distinctive FHFs.« less

Standardizing patient-reported outcomes assessment in cancer clinical trials: a patient-reported outcomes measurement information system initiative.

PubMed

Garcia, Sofia F; Cella, David; Clauser, Steven B; Flynn, Kathryn E; Lad, Thomas; Lai, Jin-Shei; Reeve, Bryce B; Smith, Ashley Wilder; Stone, Arthur A; Weinfurt, Kevin

2007-11-10

Patient-reported outcomes (PROs), such as symptom scales or more broad-based health-related quality-of-life measures, play an important role in oncology clinical trials. They frequently are used to help evaluate cancer treatments, as well as for supportive and palliative oncology care. To be most beneficial, these PROs must be relevant to patients and clinicians, valid, and easily understood and interpreted. The Patient-Reported Outcomes Measurement Information System (PROMIS) Network, part of the National Institutes of Health Roadmap Initiative, aims to improve appreciably how PROs are selected and assessed in clinical research, including clinical trials. PROMIS is establishing a publicly available resource of standardized, accurate, and efficient PRO measures of major self-reported health domains (eg, pain, fatigue, emotional distress, physical function, social function) that are relevant across chronic illnesses including cancer. PROMIS is also developing measures of self-reported health domains specifically targeted to cancer, such as sleep/wake function, sexual function, cognitive function, and the psychosocial impacts of the illness experience (ie, stress response and coping; shifts in self-concept, social interactions, and spirituality). We outline the qualitative and quantitative methods by which PROMIS measures are being developed and adapted for use in clinical oncology research. At the core of this activity is the formation and application of item banks using item response theory modeling. We also present our work in the fatigue domain, including a short-form measure, as a sample of PROMIS methodology and work to date. Plans for future validation and application of PROMIS measures are discussed.

Culture and biology interplay: An introduction.

PubMed

Causadias, José M; Telzer, Eva H; Lee, Richard M

2017-01-01

Culture and biology have evolved together, influence each other, and concurrently shape behavior, affect, cognition, and development. This special section highlights 2 major domains of the interplay between culture and biology. The first domain is neurobiology of cultural experiences-how cultural, ethnic, and racial experiences influence limbic systems and neuroendocrine functioning-and the second domain is cultural neuroscience-the connections between cultural processes and brain functioning. We include 3 studies on neurobiology of cultural experiences that examine the associations between racial discrimination and heart rate variability (Hill et al., 2016), economic and sociocultural stressors and cortisol levels (Mendoza, Dmitrieva, Perreira, & Watamura, 2016), and unfair treatment and allostatic load (Ong, Williams, Nwizu, & Gruenewald, 2016). We also include 2 studies on cultural neuroscience that investigate cultural group differences and similarities in beliefs, practices, and neural basis of emotion regulation (Qu & Telzer, 2016), and reflected and direct self-appraisals (Pfeifer et al., 2016). We discuss pending challenges and future directions for this emerging field. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

Characterization of a novel transcriptionally active domain in the transforming growth factor beta-regulated Smad3 protein.

PubMed

Prokova, Vassiliki; Mavridou, Sofia; Papakosta, Paraskevi; Kardassis, Dimitris

2005-01-01

Transforming growth factor beta (TGFbeta) regulates transcriptional responses via activation of cytoplasmic effector proteins termed Smads. Following their phosphorylation by the type I TGFbeta receptor, Smads form oligomers and translocate to the nucleus where they activate the transcription of TGFbeta target genes in cooperation with nuclear cofactors and coactivators. In the present study, we have undertaken a deletion analysis of human Smad3 protein in order to characterize domains that are essential for transcriptional activation in mammalian cells. With this analysis, we showed that Smad3 contains two domains with transcriptional activation function: the MH2 domain and a second middle domain that includes the linker region and the first two beta strands of the MH2 domain. Using a protein-protein interaction assay based on biotinylation in vivo, we were able to show that a Smad3 protein bearing an internal deletion in the middle transactivation domain is characterized by normal oligomerization and receptor activation properties. However, this mutant has reduced transactivation capacity on synthetic or natural promoters and is unable to interact physically and functionally with the histone acetyltransferase p/CAF. The loss of interaction with p/CAF or other coactivators could account, at least in part, for the reduced transactivation capacity of this Smad3 mutant. Our data support an essential role of the previously uncharacterized middle region of Smad3 for nuclear functions, such as transcriptional activation and interaction with coactivators.

Notch intracellular domain deficiency in nuclear localization activity retains the ability to enhance neural stem cell character and block neurogenesis in mammalian brain development.

PubMed

Jang, Jiwon; Byun, Sung-Hyun; Han, Dasol; Lee, Junsub; Kim, Juwan; Lee, Nayeon; Kim, Inhee; Park, Soojeong; Ha, Soobong; Kwon, Mookwang; Ahn, Jyhyun; Chung, Woo-Jae; Kweon, Dae-Hyuk; Cho, Jae Youl; Kim, Sunyoung; Yoon, Keejung

2014-12-01

Notch has a broad range of regulatory functions in many developmental processes, including hematopoiesis, neurogenesis, and angiogenesis. Notch has several key functional regions such as the RBP-Jκ/CBF1 association module (RAM) domain, nuclear localization signals (NLS), and ankyrin (ANK) repeats. However, previous reports assessing the level of importance of these domains in the Notch signaling pathway are controversial. In this study, we have assessed the level of contribution of each Notch domain to the regulation of mammalian neural stem cells in vivo as well as in vitro. Reporter assays and real-time polymerase chain reactions show that the ANK repeats and RAM domain are indispensable to the transactivation of Notch target genes, whereas a nuclear export signal (NES)-fused Notch intracellular domain (NICD) mutant defective in nuclear localization exerts a level of activity comparable to unmodified NICD. Transactivational ability appears to be tightly coupled to Notch functions during brain development. Unlike ANK repeats and RAM domain deletion mutants, NES-NICD recapitulates NICD features such as promotion of astrogenesis at the expense of neurogenesis in vitro and enhancement of neural stem cell character in vivo. Our data support the previous observation that intranuclear localization is not essential to the oncogenesis of Notch1 in certain types of cells and imply the importance of the noncanonical Notch signaling pathway in the regulation of mammalian neural stem cells.

Comprehensive analysis of orthologous protein domains using the HOPS database.

PubMed

Storm, Christian E V; Sonnhammer, Erik L L

2003-10-01

One of the most reliable methods for protein function annotation is to transfer experimentally known functions from orthologous proteins in other organisms. Most methods for identifying orthologs operate on a subset of organisms with a completely sequenced genome, and treat proteins as single-domain units. However, it is well known that proteins are often made up of several independent domains, and there is a wealth of protein sequences from genomes that are not completely sequenced. A comprehensive set of protein domain families is found in the Pfam database. We wanted to apply orthology detection to Pfam families, but first some issues needed to be addressed. First, orthology detection becomes impractical and unreliable when too many species are included. Second, shorter domains contain less information. It is therefore important to assess the quality of the orthology assignment and avoid very short domains altogether. We present a database of orthologous protein domains in Pfam called HOPS: Hierarchical grouping of Orthologous and Paralogous Sequences. Orthology is inferred in a hierarchic system of phylogenetic subgroups using ortholog bootstrapping. To avoid the frequent errors stemming from horizontally transferred genes in bacteria, the analysis is presently limited to eukaryotic genes. The results are accessible in the graphical browser NIFAS, a Java tool originally developed for analyzing phylogenetic relations within Pfam families. The method was tested on a set of curated orthologs with experimentally verified function. In comparison to tree reconciliation with a complete species tree, our approach finds significantly more orthologs in the test set. Examples for investigating gene fusions and domain recombination using HOPS are given.

Effects of mutations in the Arabidopsis Cold Shock Domain Protein 3 (AtCSP3) gene on leaf cell expansion.

PubMed

Yang, Yongil; Karlson, Dale

2012-08-01

The cold shock domain is among the most evolutionarily conserved nucleic acid binding domains from prokaryotes to higher eukaryotes, including plants. Although eukaryotic cold shock domain proteins have been extensively studied as transcriptional and post-transcriptional regulators during various developmental processes, their functional roles in plants remains poorly understood. In this study, AtCSP3 (At2g17870), which is one of four Arabidopsis thaliana c old s hock domain proteins (AtCSPs), was functionally characterized. Quantitative RT-PCR analysis confirmed high expression of AtCSP3 in reproductive and meristematic tissues. A homozygous atcsp3 loss-of-function mutant exhibits an overall reduced seedling size, stunted and orbicular rosette leaves, reduced petiole length, and curled leaf blades. Palisade mesophyll cells are smaller and more circular in atcsp3 leaves. Cell size analysis indicated that the reduced size of the circular mesophyll cells appears to be generated by a reduction of cell length along the leaf-length axis, resulting in an orbicular leaf shape. It was also determined that leaf cell expansion is impaired for lateral leaf development in the atcsp3 loss-of-function mutant, but leaf cell proliferation is not affected. AtCSP3 loss-of-function resulted in a dramatic reduction of LNG1 transcript, a gene that is involved in two-dimensional leaf polarity regulation. Transient subcellular localization of AtCSP3 in onion epidermal cells confirmed a nucleocytoplasmic localization pattern. Collectively, these data suggest that AtCSP3 is functionally linked to the regulation of leaf length by affecting LNG1 transcript accumulation during leaf development. A putative function of AtCSP3 as an RNA binding protein is also discussed in relation to leaf development.

Atlas international de la vitalite linguistique. Volume 2: L'Europe Occidentale = International Atlas of Language Vitality. Volume 2: Western Europe.

ERIC Educational Resources Information Center

McConnell, Grant D., Ed.; Gendron, Jean-Denis, Ed.

The atlas offers a cartography of language functions, quantitatively measured in vitality rates, for Western Europe. The atlas has three parts: vitality by language; vitality by domain; and vitality by country. Eighty-three minority languages are covered. Domains considered include: global; religion; schools; mass media; administration; courts;…

The Dimer Interface of the Membrane Type 1 Matrix Metalloproteinase Hemopexin Domain

PubMed Central

Tochowicz, Anna; Goettig, Peter; Evans, Richard; Visse, Robert; Shitomi, Yasuyuki; Palmisano, Ralf; Ito, Noriko; Richter, Klaus; Maskos, Klaus; Franke, Daniel; Svergun, Dmitri; Nagase, Hideaki; Bode, Wolfram; Itoh, Yoshifumi

2011-01-01

Homodimerization is an essential step for membrane type 1 matrix metalloproteinase (MT1-MMP) to activate proMMP-2 and to degrade collagen on the cell surface. To uncover the molecular basis of the hemopexin (Hpx) domain-driven dimerization of MT1-MMP, a crystal structure of the Hpx domain was solved at 1.7 Å resolution. Two interactions were identified as potential biological dimer interfaces in the crystal structure, and mutagenesis studies revealed that the biological dimer possesses a symmetrical interaction where blades II and III of molecule A interact with blades III and II of molecule B. The mutations of amino acids involved in the interaction weakened the dimer interaction of Hpx domains in solution, and incorporation of these mutations into the full-length enzyme significantly inhibited dimer-dependent functions on the cell surface, including proMMP-2 activation, collagen degradation, and invasion into the three-dimensional collagen matrix, whereas dimer-independent functions, including gelatin film degradation and two-dimensional cell migration, were not affected. These results shed light on the structural basis of MT1-MMP dimerization that is crucial to promote cellular invasion. PMID:21193411

Acetyllysine-binding and function of bromodomain-containing proteins in chromatin.

PubMed

Dyson, M H; Rose, S; Mahadevan, L C

2001-08-01

Acetylated histones are generally associated with active chromatin. The bromodomain has recently been identified as a protein module capable of binding to acetylated lysine residues, and hence is able to mediate the recruitment of factors to acetylated chromatin. Functional studies of bromodomain-containing proteins indicate how this domain contributes to the activity of a number of nuclear factors including histone acetyltransferases and chromatin remodelling complexes. Here, we review the characteristics of acetyllysine-binding by bromodomains, discuss associated domains found in these proteins, and address the function of the bromodomain in the context of chromatin. Finally, the modulation of bromodomain binding by neighbouring post-translational modifications within histone tails might provide a mechanism through which combinations of covalent marks could exert control on chromatin function.

Evolution of the snake body form reveals homoplasy in amniote Hox gene function.

PubMed

Head, Jason J; Polly, P David

2015-04-02

Hox genes regulate regionalization of the axial skeleton in vertebrates, and changes in their expression have been proposed to be a fundamental mechanism driving the evolution of new body forms. The origin of the snake-like body form, with its deregionalized pre-cloacal axial skeleton, has been explained as either homogenization of Hox gene expression domains, or retention of standard vertebrate Hox domains with alteration of downstream expression that suppresses development of distinct regions. Both models assume a highly regionalized ancestor, but the extent of deregionalization of the primaxial domain (vertebrae, dorsal ribs) of the skeleton in snake-like body forms has never been analysed. Here we combine geometric morphometrics and maximum-likelihood analysis to show that the pre-cloacal primaxial domain of elongate, limb-reduced lizards and snakes is not deregionalized compared with limbed taxa, and that the phylogenetic structure of primaxial morphology in reptiles does not support a loss of regionalization in the evolution of snakes. We demonstrate that morphometric regional boundaries correspond to mapped gene expression domains in snakes, suggesting that their primaxial domain is patterned by a normally functional Hox code. Comparison of primaxial osteology in fossil and modern amniotes with Hox gene distributions within Amniota indicates that a functional, sequentially expressed Hox code patterned a subtle morphological gradient along the anterior-posterior axis in stem members of amniote clades and extant lizards, including snakes. The highly regionalized skeletons of extant archosaurs and mammals result from independent evolution in the Hox code and do not represent ancestral conditions for clades with snake-like body forms. The developmental origin of snakes is best explained by decoupling of the primaxial and abaxial domains and by increases in somite number, not by changes in the function of primaxial Hox genes.

Impact of brain-derived neurotrophic factor genetic polymorphism on cognition: A systematic review.

PubMed

Toh, Yi Long; Ng, Terence; Tan, Megan; Tan, Azrina; Chan, Alexandre

2018-06-01

Brain-derived neurotrophic factor (BDNF) has an important role in the neurogenesis and neuroplasticity of the brain. This systematic review was designed to examine the association between BDNF Val66Met (rs6265) polymorphism and four cognitive domains-attention and concentration, executive function, verbal fluency, and memory, respectively. Primary literature search was performed using search engines such as PubMed and Scopus. Observational studies that evaluated the neurocognitive performances in relation to BDNF polymorphism within human subjects were included in this review, while animal studies, overlapping studies, and meta-analysis were excluded. Forty of 82 reviewed studies (48.8%) reported an association between Val66Met polymorphism and neurocognitive domains. The proportion of the studies showing positive findings in cognitive performances between Val/Val homozygotes and Met carriers was comparable, at 30.5% and 18.3%, respectively. The highest percentage of positive association between Val66Met polymorphism and neurocognition was reported under the memory domain, with 26 of 63 studies (41.3%), followed by 18 of 47 studies (38.3%) under the executive function domain and four of 23 studies (17.4%) under the attention and concentration domain. There were no studies showing an association between Val66Met polymorphism and verbal fluency. In particular, Val/Val homozygotes performed better in tasks related to the memory domain, while Met carriers performed better in terms of executive function, in both healthy individuals and clinical populations. While numerous studies report an association between Val66Met polymorphism and neurocognitive changes in executive function and memory domains, the effect of Met allele has not been clearly established. © 2018 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.

Core Domains for Clinical Research in Acute Respiratory Failure Survivors: An International Modified Delphi Consensus Study.

PubMed

Turnbull, Alison E; Sepulveda, Kristin A; Dinglas, Victor D; Chessare, Caroline M; Bingham, Clifton O; Needham, Dale M

2017-06-01

To identify the "core domains" (i.e., patient outcomes, health-related conditions, or aspects of health) that relevant stakeholders agree are essential to assess in all clinical research studies evaluating the outcomes of acute respiratory failure survivors after hospital discharge. A two-round consensus process, using a modified Delphi methodology, with participants from 16 countries, including patient and caregiver representatives. Prior to voting, participants were asked to review 1) results from surveys of clinical researchers, acute respiratory failure survivors, and caregivers that rated the importance of 19 preliminary outcome domains and 2) results from a qualitative study of acute respiratory failure survivors' outcomes after hospital discharge, as related to the 19 preliminary outcome domains. Participants also were asked to suggest any additional potential domains for evaluation in the first Delphi survey. Web-based surveys of participants representing four stakeholder groups relevant to clinical research evaluating postdischarge outcomes of acute respiratory failure survivors: clinical researchers, clinicians, patients and caregivers, and U.S. federal research funding organizations. None. None. Survey response rates were 97% and 99% in round 1 and round 2, respectively. There were seven domains that met the a priori consensus criteria to be designated as core domains: physical function, cognition, mental health, survival, pulmonary function, pain, and muscle and/or nerve function. This study generated a consensus-based list of core domains that should be assessed in all clinical research studies evaluating acute respiratory failure survivors after hospital discharge. Identifying appropriate measurement instruments to assess these core domains is an important next step toward developing a set of core outcome measures for this field of research.

The APSES family proteins in fungi: Characterizations, evolution and functions.

PubMed

Zhao, Yong; Su, Hao; Zhou, Jing; Feng, Huihua; Zhang, Ke-Qin; Yang, Jinkui

2015-08-01

The APSES protein family belongs to transcriptional factors of the basic helix-loop-helix (bHLH) class, the originally described members (APSES: Asm1p, Phd1p, Sok2p, Efg1p and StuAp) are used to designate this group of proteins, and they have been identified as key regulators of fungal development and other biological processes. APSES proteins share a highly conserved DNA-binding domain (APSES domain) of about 100 amino acids, whose central domain is predicted to form a typical bHLH structure. Besides APSES domain, several APSES proteins also contain additional domains, such as KilA-N and ankyrin repeats. In recent years, an increasing number of APSES proteins have been identified from diverse fungi, and they involve in numerous biological processes, such as sporulation, cellular differentiation, mycelial growth, secondary metabolism and virulence. Most fungi, including Aspergillus fumigatus, Aspergillus nidulans, Candida albicans, Fusarium graminearum, and Neurospora crassa, contain five APSES proteins. However, Cryptococcus neoformans only contains two APSES proteins, and Saccharomyces cerevisiae contains six APSES proteins. The phylogenetic analysis showed the APSES domains from different fungi were grouped into four clades (A, B, C and D), which is consistent with the result of homologous alignment of APSES domains using DNAman. The roles of APSES proteins in clade C have been studied in detail, while little is known about the roles of other APSES proteins in clades A, B and D. In this review, the biochemical properties and functional domains of APSES proteins are predicted and compared, and the phylogenetic relationship among APSES proteins from various fungi are analyzed based on the APSES domains. Moreover, the functions of APSES proteins in different fungi are summarized and discussed. Copyright © 2014 Elsevier Inc. All rights reserved.

Cognition Predicts Quality of Life Among Patients With End-Stage Liver Disease.

PubMed

Paulson, Daniel; Shah, Mona; Miller-Matero, Lisa Renee; Eshelman, Anne; Abouljoud, Marwan

2016-01-01

Impaired cognitive functioning and poor quality of life (QoL) are both common among patients with end-stage liver disease; however, it is unclear how these are related. This study examines how specific cognitive domains predict QoL among liver transplant candidates by replicating Stewart and colleagues' (2010) 3-factor model of cognitive functioning, and determining how variability in these cognitive domains predicts mental health and physical QoL. The sample included 246 patients with end-stage liver disease who were candidates for liver transplant at a large, Midwestern health care center. Measures, including the Repeatable Battery for the Assessment of Neuropsychological Status, Trail Making Test, Shipley Institute of Living Scale, Short-Form Health Survey-36 Version 2, and Hospital Anxiety and Depression Scale, comprised latent variables representing global intellectual functioning, psychomotor speed, and learning and memory functioning. Confirmatory factor analysis results indicate that the 3-factor solution model comprised of global intellectual functioning, psychomotor speed, and learning and memory functioning fit the data well. Addition of physical and mental health QoL latent factors resulted in a structural model also with good fit. Results related physical QoL to global intellectual functioning, and mental health QoL to global intellectual functioning and psychomotor functioning. Findings elucidate a relationship between cognition and QoL and support the use of routine neuropsychological screening with end-stage liver disease patients, specifically examining the cognitive domains of global intellectual, psychomotor, and learning and memory functioning. Subsequently, screening results may inform implementation of targeted interventions to improve QoL. Copyright © 2016 The Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved.

Fragments of Bacterial Endoglycosidase S and Immunoglobulin G Reveal Subdomains of Each That Contribute to Deglycosylation*

PubMed Central

Dixon, Emma V.; Claridge, Jolyon K.; Harvey, David J.; Baruah, Kavitha; Yu, Xiaojie; Vesiljevic, Snezana; Mattick, Susan; Pritchard, Laura K.; Krishna, Benjamin; Scanlan, Christopher N.; Schnell, Jason R.; Higgins, Matthew K.; Zitzmann, Nicole; Crispin, Max

2014-01-01

Endoglycosidase S (EndoS) is a glycoside-hydrolase secreted by the bacterium Streptococcus pyogenes. EndoS preferentially hydrolyzes the N-linked glycans from the Fc region of IgG during infection. This hydrolysis impedes Fc functionality and contributes to the immune evasion strategy of S. pyogenes. Here, we investigate the mechanism of human serum IgG deactivation by EndoS. We expressed fragments of IgG1 and demonstrated that EndoS was catalytically active against all of them including the isolated CH2 domain of the Fc domain. Similarly, we sought to investigate which domains within EndoS could contribute to activity. Bioinformatics analysis of the domain organization of EndoS confirmed the previous predictions of a chitinase domain and leucine-rich repeat but also revealed a putative carbohydrate binding module (CBM) followed by a C-terminal region. Using expressed fragments of EndoS, circular dichroism of the isolated CBM, and a CBM-C-terminal region fusion revealed folded domains dominated by β sheet and α helical structure, respectively. Nuclear magnetic resonance analysis of the CBM with monosaccharides was suggestive of carbohydrate binding functionality. Functional analysis of truncations of EndoS revealed that, whereas the C-terminal of EndoS is dispensable for activity, its deletion impedes the hydrolysis of IgG glycans. PMID:24668806

Inference of domain-disease associations from domain-protein, protein-disease and disease-disease relationships.

PubMed

Zhang, Wangshu; Coba, Marcelo P; Sun, Fengzhu

2016-01-11

Protein domains can be viewed as portable units of biological function that defines the functional properties of proteins. Therefore, if a protein is associated with a disease, protein domains might also be associated and define disease endophenotypes. However, knowledge about such domain-disease relationships is rarely available. Thus, identification of domains associated with human diseases would greatly improve our understanding of the mechanism of human complex diseases and further improve the prevention, diagnosis and treatment of these diseases. Based on phenotypic similarities among diseases, we first group diseases into overlapping modules. We then develop a framework to infer associations between domains and diseases through known relationships between diseases and modules, domains and proteins, as well as proteins and disease modules. Different methods including Association, Maximum likelihood estimation (MLE), Domain-disease pair exclusion analysis (DPEA), Bayesian, and Parsimonious explanation (PE) approaches are developed to predict domain-disease associations. We demonstrate the effectiveness of all the five approaches via a series of validation experiments, and show the robustness of the MLE, Bayesian and PE approaches to the involved parameters. We also study the effects of disease modularization in inferring novel domain-disease associations. Through validation, the AUC (Area Under the operating characteristic Curve) scores for Bayesian, MLE, DPEA, PE, and Association approaches are 0.86, 0.84, 0.83, 0.83 and 0.79, respectively, indicating the usefulness of these approaches for predicting domain-disease relationships. Finally, we choose the Bayesian approach to infer domains associated with two common diseases, Crohn's disease and type 2 diabetes. The Bayesian approach has the best performance for the inference of domain-disease relationships. The predicted landscape between domains and diseases provides a more detailed view about the disease mechanisms.

Functional diversity of Csk, Chk, and Src SH2 domains due to a single residue variation.

PubMed

Ayrapetov, Marina K; Nam, Nguyen Hai; Ye, Guofeng; Kumar, Anil; Parang, Keykavous; Sun, Gongqin

2005-07-08

The C-terminal Src kinase (Csk) family of protein tyrosine kinases contains two members: Csk and Csk homologous kinase (Chk). Both phosphorylate and inactivate Src family kinases. Recent reports suggest that the Src homology (SH) 2 domains of Csk and Chk may bind to different phosphoproteins, which provides a basis for different cellular functions for Csk and Chk. To verify and characterize such a functional divergence, we compared the binding properties of the Csk, Chk, and Src SH2 domains and investigated the structural basis for the functional divergence. First, the study demonstrated striking functional differences between the Csk and Chk SH2 domains and revealed functional similarities between the Chk and Src SH2 domains. Second, structural analysis and mutagenic studies revealed that the functional differences among the three SH2 domains were largely controlled by one residue, Glu127 in Csk, Ile167 in Chk, and Lys200 in Src. Mutating these residues in the Csk or Chk SH2 domain to the Src counterpart resulted in dramatic gain of function similar to Src SH2 domain, whereas mutating Lys200 in Src SH2 domain to Glu (the Csk counterpart) resulted in loss of Src SH2 function. Third, a single point mutation of E127K rendered Csk responsive to activation by a Src SH2 domain ligand. Finally, the optimal phosphopeptide sequence for the Chk SH2 domain was determined. These results provide a compelling explanation for the functional differences between two homologous protein tyrosine kinases and reveal a new structure-function relationship for the SH2 domains.

DCA_Tools

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

Summers, Michael S

2017-11-08

HPC software for ab-initio, condensed-matter physics, quantum mechanics calculations needs to be built on top of well tested libraries some of which address requirements unique to the programming domain. During the development of the DCA++ code, that we use in our research, we have developed a collection of libraries that may be of use to other computational scientists working in the same or similar domains. The libraries include: a) a pythonic input-language system, b) tensors whose shape is constructed from generalized dimension objects such at time domains. frequency domains, momentum domains, vertex domains et. al. and c) linear algebra operationsmore » that resolve to BLA/LAPACK operations when possible. This supports the implementation of Greens functions and operations on them such as are used in condensed matter physics.« less

Same but not alike: Structure, flexibility and energetics of domains in multi-domain proteins are influenced by the presence of other domains

PubMed Central

Vishwanath, Sneha

2018-01-01

The majority of the proteins encoded in the genomes of eukaryotes contain more than one domain. Reasons for high prevalence of multi-domain proteins in various organisms have been attributed to higher stability and functional and folding advantages over single-domain proteins. Despite these advantages, many proteins are composed of only one domain while their homologous domains are part of multi-domain proteins. In the study presented here, differences in the properties of protein domains in single-domain and multi-domain systems and their influence on functions are discussed. We studied 20 pairs of identical protein domains, which were crystallized in two forms (a) tethered to other proteins domains and (b) tethered to fewer protein domains than (a) or not tethered to any protein domain. Results suggest that tethering of domains in multi-domain proteins influences the structural, dynamic and energetic properties of the constituent protein domains. 50% of the protein domain pairs show significant structural deviations while 90% of the protein domain pairs show differences in dynamics and 12% of the residues show differences in the energetics. To gain further insights on the influence of tethering on the function of the domains, 4 pairs of homologous protein domains, where one of them is a full-length single-domain protein and the other protein domain is a part of a multi-domain protein, were studied. Analyses showed that identical and structurally equivalent functional residues show differential dynamics in homologous protein domains; though comparable dynamics between in-silico generated chimera protein and multi-domain proteins were observed. From these observations, the differences observed in the functions of homologous proteins could be attributed to the presence of tethered domain. Overall, we conclude that tethered domains in multi-domain proteins not only provide stability or folding advantages but also influence pathways resulting in differences in function or regulatory properties. PMID:29432415

Same but not alike: Structure, flexibility and energetics of domains in multi-domain proteins are influenced by the presence of other domains.

PubMed

Vishwanath, Sneha; de Brevern, Alexandre G; Srinivasan, Narayanaswamy

2018-02-01

The majority of the proteins encoded in the genomes of eukaryotes contain more than one domain. Reasons for high prevalence of multi-domain proteins in various organisms have been attributed to higher stability and functional and folding advantages over single-domain proteins. Despite these advantages, many proteins are composed of only one domain while their homologous domains are part of multi-domain proteins. In the study presented here, differences in the properties of protein domains in single-domain and multi-domain systems and their influence on functions are discussed. We studied 20 pairs of identical protein domains, which were crystallized in two forms (a) tethered to other proteins domains and (b) tethered to fewer protein domains than (a) or not tethered to any protein domain. Results suggest that tethering of domains in multi-domain proteins influences the structural, dynamic and energetic properties of the constituent protein domains. 50% of the protein domain pairs show significant structural deviations while 90% of the protein domain pairs show differences in dynamics and 12% of the residues show differences in the energetics. To gain further insights on the influence of tethering on the function of the domains, 4 pairs of homologous protein domains, where one of them is a full-length single-domain protein and the other protein domain is a part of a multi-domain protein, were studied. Analyses showed that identical and structurally equivalent functional residues show differential dynamics in homologous protein domains; though comparable dynamics between in-silico generated chimera protein and multi-domain proteins were observed. From these observations, the differences observed in the functions of homologous proteins could be attributed to the presence of tethered domain. Overall, we conclude that tethered domains in multi-domain proteins not only provide stability or folding advantages but also influence pathways resulting in differences in function or regulatory properties.

Development of the NIH PROMIS ® Sexual Function and Satisfaction measures in patients with cancer.

PubMed

Flynn, Kathryn E; Lin, Li; Cyranowski, Jill M; Reeve, Bryce B; Reese, Jennifer Barsky; Jeffery, Diana D; Smith, Ashley Wilder; Porter, Laura S; Dombeck, Carrie B; Bruner, Deborah Watkins; Keefe, Francis J; Weinfurt, Kevin P

2013-02-01

We describe the development and validation of the Patient-Reported Outcomes Measurement Information System(®) Sexual Function and Satisfaction (PROMIS(®) SexFS; National Institutes of Health) measures, version 1.0, for cancer populations. To develop a customizable self-report measure of sexual function and satisfaction as part of the U.S. National Institutes of Health PROMIS Network. Our multidisciplinary working group followed a comprehensive protocol for developing psychometrically robust patient-reported outcome measures including qualitative (scale development) and quantitative (psychometric evaluation) development. We performed an extensive literature review, conducted 16 focus groups with cancer patients and multiple discussions with clinicians, and evaluated candidate items in cognitive testing with patients. We administered items to 819 cancer patients. Items were calibrated using item-response theory and evaluated for reliability and validity. The PROMIS SexFS measures, version 1.0, include 81 items in 11 domains: Interest in Sexual Activity, Lubrication, Vaginal Discomfort, Erectile Function, Global Satisfaction with Sex Life, Orgasm, Anal Discomfort, Therapeutic Aids, Sexual Activities, Interfering Factors, and Screener Questions. In addition to content validity (patients indicate that items cover important aspects of their experiences) and face validity (patients indicate that items measure sexual function and satisfaction), the measure shows evidence for discriminant validity (domains discriminate between groups expected to be different) and convergent validity (strong correlations between scores on PROMIS and scores on conceptually similar older measures of sexual function), as well as favorable test-retest reliability among people not expected to change (interclass correlations from two administrations of the instrument, 1 month apart). The PROMIS SexFS offers researchers a reliable and valid set of tools to measure self-reported sexual function and satisfaction among diverse men and women. The measures are customizable; researchers can select the relevant domains and items comprising those domains for their study. © 2013 International Society for Sexual Medicine.

Loss of a Trans-Splicing nad1 Intron from Geraniaceae and Transfer of the Maturase Gene matR to the Nucleus in Pelargonium

PubMed Central

Grewe, Felix; Zhu, Andan; Mower, Jeffrey P.

2016-01-01

The mitochondrial nad1 gene of seed plants has a complex structure, including four introns in cis or trans configurations and a maturase gene (matR) hosted within the final intron. In the geranium family (Geraniaceae), however, sequencing of representative species revealed that three of the four introns, including one in a trans configuration and another that hosts matR, were lost from the nad1 gene in their common ancestor. Despite the loss of the host intron, matR has been retained as a freestanding gene in most genera of the family, indicating that this maturase has additional functions beyond the splicing of its host intron. In the common ancestor of Pelargonium, matR was transferred to the nuclear genome, where it was split into two unlinked genes that encode either its reverse transcriptase or maturase domain. Both nuclear genes are transcribed and contain predicted mitochondrial targeting signals, suggesting that they express functional proteins that are imported into mitochondria. The nuclear localization and split domain structure of matR in the Pelargonium nuclear genome offers a unique opportunity to assess the function of these two domains using transgenic approaches. PMID:27664178

Specific cognitive functions and depressive symptoms as predictors of activities of daily living in older adults with heterogeneous cognitive backgrounds

PubMed Central

de Paula, Jonas J.; Diniz, Breno S.; Bicalho, Maria A.; Albuquerque, Maicon Rodrigues; Nicolato, Rodrigo; de Moraes, Edgar N.; Romano-Silva, Marco A.; Malloy-Diniz, Leandro F.

2015-01-01

Cognitive functioning influences activities of daily living (ADL). However, studies reporting the association between ADL and neuropsychological performance show inconsistent results regarding what specific cognitive domains are related to each specific functional domains. Additionally, whether depressive symptoms are associated with a worse functional performance in older adults is still under explored. We investigated if specific cognitive domains and depressive symptoms would affect different aspects of ADL. Participants were 274 older adults (96 normal aging participants, 85 patients with mild cognitive impairment, and 93 patients probable with mild Alzheimer’s disease dementia) with low formal education (∼4 years). Measures of ADL included three complexity levels: Self-care, Instrumental-Domestic, and Instrumental-Complex. The specific cognitive functions were evaluated through a factorial strategy resulting in four cognitive domains: Executive Functions, Language/Semantic Memory, Episodic Memory, and Visuospatial Abilities. The Geriatric Depression Scale measured depressive symptoms. Multiple linear regression analysis showed executive functions and episodic memory as significant predictors of Instrumental-Domestic ADL, and executive functions, episodic memory and language/semantic memory as predictors of Instrumental-Complex ADL (22 and 28% of explained variance, respectively). Ordinal regression analysis showed the influence of specific cognitive functions and depressive symptoms on each one of the instrumental ADL. We observed a heterogeneous pattern of association with explained variance ranging from 22 to 38%. Different instrumental ADL had specific cognitive predictors and depressive symptoms were predictive of ADL involving social contact. Our results suggest a specific pattern of influence depending on the specific instrumental daily living activity. PMID:26257644

Executive Functions Contribute Uniquely to Reading Competence in Minority Youth

ERIC Educational Resources Information Center

Jacobson, Lisa A.; Koriakin, Taylor; Lipkin, Paul; Boada, Richard; Frijters, Jan C.; Lovett, Maureen W.; Hill, Dina; Willcutt, Erik; Gottwald, Stephanie; Wolf, Maryanne; Bosson-Heenan, Joan; Gruen, Jeffrey R.; Mahone, E. Mark

2017-01-01

Competent reading requires various skills beyond those for basic word reading (i.e., core language skills, rapid naming, phonological processing). Contributing "higher-level" or domain-general processes include information processing speed and executive functions (working memory, strategic problem solving, attentional switching).…

Plasma membrane organization promotes virulence of the human fungal pathogen Candida albicans

PubMed Central

Douglas, Lois M.; Konopka, James. B.

2017-01-01

Candida albicans is a human fungal pathogen capable of causing lethal systemic infections. The plasma membrane plays key roles in virulence because it not only functions as a protective barrier, it also mediates dynamic functions including secretion of virulence factors, cell wall synthesis, invasive hyphal morphogenesis, endocytosis, and nutrient uptake. Consistent with this functional complexity, the plasma membrane is composed of a wide array of lipids and proteins. These components are organized into distinct domains that will be the topic of this review. Some of the plasma membrane domains that will be described are known to act as scaffolds or barriers to diffusion, such as MCC/eisosomes, septins, and sites of contact with the endoplasmic reticulum. Other zones mediate dynamic processes, including secretion, endocytosis, and a special region at hyphal tips that facilitates rapid growth. The highly organized architecture of the plasma membrane facilitates the coordination of diverse functions and promotes the pathogenesis of C. albicans. PMID:26920878

Plasma membrane organization promotes virulence of the human fungal pathogen Candida albicans.

PubMed

Douglas, Lois M; Konopka, James B

2016-03-01

Candida albicans is a human fungal pathogen capable of causing lethal systemic infections. The plasma membrane plays key roles in virulence because it not only functions as a protective barrier, it also mediates dynamic functions including secretion of virulence factors, cell wall synthesis, invasive hyphal morphogenesis, endocytosis, and nutrient uptake. Consistent with this functional complexity, the plasma membrane is composed of a wide array of lipids and proteins. These components are organized into distinct domains that will be the topic of this review. Some of the plasma membrane domains that will be described are known to act as scaffolds or barriers to diffusion, such as MCC/eisosomes, septins, and sites of contact with the endoplasmic reticulum. Other zones mediate dynamic processes, including secretion, endocytosis, and a special region at hyphal tips that facilitates rapid growth. The highly organized architecture of the plasma membrane facilitates the coordination of diverse functions and promotes the pathogenesis of C. albicans.

Cognition and Context: Rural-Urban Differences in Cognitive Aging Among Older Mexican Adults.

PubMed

Saenz, Joseph L; Downer, Brian; Garcia, Marc A; Wong, Rebeca

2017-04-01

To describe differences in cognitive functioning across rural and urban areas among older Mexican adults. We include respondents aged 50+ in the 2012 Mexican Health and Aging Study (MHAS). Cognitive functioning by domain is regressed as a function of community size. The role of educational attainment in explaining rural/urban differences in cognitive functioning is examined. Respondents residing in more rural areas performed worse across five cognitive domains. The majority, but not all, of the association between community size and cognitive functioning was explained by lower education in rural areas. Respondents residing in more rural areas were disadvantaged in terms of cognitive functioning compared with those residing in more urban areas. Poorer cognitive functioning in late life may be the result of historical educational disadvantage in rural areas or selection through migration from rural to urban regions for employment.

A Preliminary Core Domain Set for Clinical Trials of Shoulder Disorders: A Report from the OMERACT 2016 Shoulder Core Outcome Set Special Interest Group.

PubMed

Buchbinder, Rachelle; Page, Matthew J; Huang, Hsiaomin; Verhagen, Arianne P; Beaton, Dorcas; Kopkow, Christian; Lenza, Mario; Jain, Nitin B; Richards, Bethan; Richards, Pamela; Voshaar, Marieke; van der Windt, Danielle; Gagnier, Joel J

2017-12-01

The Outcome Measures in Rheumatology (OMERACT) Shoulder Core Outcome Set Special Interest Group (SIG) was established to develop a core outcome set (COS) for clinical trials of shoulder disorders. In preparation for OMERACT 2016, we systematically examined all outcome domains and measurement instruments reported in 409 randomized trials of interventions for shoulder disorders published between 1954 and 2015. Informed by these data, we conducted an international Delphi consensus study including shoulder trial experts, clinicians, and patients to identify key domains that should be included in a shoulder disorder COS. Findings were discussed at a stakeholder premeeting of OMERACT. At OMERACT 2016, we sought consensus on a preliminary core domain set and input into next steps. There were 13 and 15 participants at the premeeting and the OMERACT 2016 SIG meeting, respectively (9 attended both meetings). Consensus was reached on a preliminary core domain set consisting of an inner core of 4 domains: pain, physical function/activity, global perceived effect, and adverse events including death. A middle core consisted of 3 domains: emotional well-being, sleep, and participation (recreation and work). An outer core of research required to inform the final COS was also formulated. Our next steps are to (1) analyze whether participation (recreation and work) should be in the inner core, (2) conduct a third Delphi round to finalize definitions and wording of domains and reach final endorsement for the domains, and (3) determine which instruments fulfill the OMERACT criteria for measuring each domain.

Theoretical Insights Reveal Novel Motions in Csk’s SH3 Domain That Control Kinase Activation

PubMed Central

Barkho, Sulyman; Pierce, Levi C. T.; Li, Sheng; Adams, Joseph A.; Jennings, Patricia A.

2015-01-01

The Src family of tyrosine kinases (SFKs) regulate numerous aspects of cell growth and differentiation and are under the principal control of the C-terminal Src Kinase (Csk). Although Csk and SFKs share conserved kinase, SH2 and SH3 domains, they differ considerably in three-dimensional structure, regulatory mechanism, and the intrinsic kinase activities. Although the SH2 and SH3 domains are known to up- or down-regulate tyrosine kinase function, little is known about the global motions in the full-length kinase that govern these catalytic variations. We use a combination of accelerated Molecular Dynamics (aMD) simulations and experimental methods to provide a new view of functional motions in the Csk scaffold. These computational studies suggest that high frequency vibrations in the SH2 domain are coupled through the N-terminal lobe of the kinase domain to motions in the SH3 domain. The effects of these reflexive movements on the kinase domain can be viewed using both Deuterium Exchange Mass Spectrometry (DXMS) and steady-state kinetic methods. Removal of several contacts, including a crystallographically unobserved N-terminal segment, between the SH3 and kinase domains short-circuit these coupled motions leading to reduced catalytic efficiency and stability of N-lobe motifs within the kinase domain. The data expands the model of Csk’s activation whereby separate domains productively interact with two diametrically opposed surfaces of the kinase domain. Such reversible transitions may organize the active structure of the tyrosine kinase domain of Csk. PMID:26030592

An information theory framework for dynamic functional domain connectivity.

PubMed

Vergara, Victor M; Miller, Robyn; Calhoun, Vince

2017-06-01

Dynamic functional network connectivity (dFNC) analyzes time evolution of coherent activity in the brain. In this technique dynamic changes are considered for the whole brain. This paper proposes an information theory framework to measure information flowing among subsets of functional networks call functional domains. Our method aims at estimating bits of information contained and shared among domains. The succession of dynamic functional states is estimated at the domain level. Information quantity is based on the probabilities of observing each dynamic state. Mutual information measurement is then obtained from probabilities across domains. Thus, we named this value the cross domain mutual information (CDMI). Strong CDMIs were observed in relation to the subcortical domain. Domains related to sensorial input, motor control and cerebellum form another CDMI cluster. Information flow among other domains was seldom found. Other methods of dynamic connectivity focus on whole brain dFNC matrices. In the current framework, information theory is applied to states estimated from pairs of multi-network functional domains. In this context, we apply information theory to measure information flow across functional domains. Identified CDMI clusters point to known information pathways in the basal ganglia and also among areas of sensorial input, patterns found in static functional connectivity. In contrast, CDMI across brain areas of higher level cognitive processing follow a different pattern that indicates scarce information sharing. These findings show that employing information theory to formally measured information flow through brain domains reveals additional features of functional connectivity. Copyright © 2017 Elsevier B.V. All rights reserved.

Generating Dynamic Persistence in the Time Domain

NASA Astrophysics Data System (ADS)

Guerrero, A.; Smith, L. A.; Smith, L. A.; Kaplan, D. T.

2001-12-01

Many dynamical systems present long-range correlations. Physically, these systems vary from biological to economical, including geological or urban systems. Important geophysical candidates for this type of behaviour include weather (or climate) and earthquake sequences. Persistence is characterised by slowly decaying correlation function; that, in theory, never dies out. The Persistence exponent reflects the degree of memory in the system and much effort has been expended creating and analysing methods that successfully estimate this parameter and model data that exhibits persistence. The most widely used methods for generating long correlated time series are not dynamical systems in the time domain, but instead are derived from a given spectral density. Little attention has been drawn to modelling persistence in the time domain. The time domain approach has the advantage that an observation at certain time can be calculated using previous observations which is particularly suitable when investigating the predictability of a long memory process. We will describe two of these methods in the time domain. One is a traditional approach using fractional ARIMA (autoregressive and moving average) models; the second uses a novel approach to extending a given series using random Fourier basis functions. The statistical quality of the two methods is compared, and they are contrasted with weather data which shows, reportedly, persistence. The suitability of this approach both for estimating predictability and for making predictions is discussed.

Multidimensional Patient Impression of Change Following Interdisciplinary Pain Management.

PubMed

Gagnon, Christine M; Scholten, Paul; Atchison, James

2018-04-20

To assess patient impression of change following interdisciplinary pain management utilizing a newly developed Multidimensional Patient Impression of Change (MPIC) questionnaire. A heterogeneous group of chronic pain patients (N = 601) participated in an interdisciplinary treatment program. Programs included individual and group therapies (pain psychology, physical therapy, occupational therapy, relaxation training/biofeedback, aerobic conditioning, patient education and medical management). Patients completed measures of pain, mood, coping, physical functioning and pain acceptance both prior to and at completion of their treatment programs. The newly developed MPIC is an expansion to the Patient Global Impression of Change (PGIC) including seven additional domains (Pain, Mood, Sleep, Physical Functioning, Cope with Pain, Manage Pain Flare-ups, and Medication Effectiveness). The MPIC was administered to the patients post-treatment. There were statistically significant pre- to post-treatment improvements found on all outcome measures. The majority of these improvements were significantly correlated with all domains of the MPIC. The original PGIC item was significantly associated with all of the new MPIC domains and the domains were significantly associated with each other; but there were variations in the distribution of responses highlighting variation of perceived improvements among the domains. Our results support the use of the MPIC as a quick and easy post-treatment assessment screening tool. Future research is needed to examine relevant correlates to Medication Effectiveness. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Classification of proteins with shared motifs and internal repeats in the ECOD database

PubMed Central

Kinch, Lisa N.; Liao, Yuxing

2016-01-01

Abstract Proteins and their domains evolve by a set of events commonly including the duplication and divergence of small motifs. The presence of short repetitive regions in domains has generally constituted a difficult case for structural domain classifications and their hierarchies. We developed the Evolutionary Classification Of protein Domains (ECOD) in part to implement a new schema for the classification of these types of proteins. Here we document the ways in which ECOD classifies proteins with small internal repeats, widespread functional motifs, and assemblies of small domain‐like fragments in its evolutionary schema. We illustrate the ways in which the structural genomics project impacted the classification and characterization of new structural domains and sequence families over the decade. PMID:26833690

ATTENTION FUNCTIONING IN CHILDREN WITH PRENATAL DRUG EXPOSURE.

PubMed

Jaeger, Dominique A; Suchan, Boris; Schölmerich, Axel; Schneider, Dominik T; Gawehn, Nina

2015-01-01

Children born to drug abusers are exposed to teratogenic influences on intrauterine brain development and undergo postnatal withdrawal. We investigated the interplay of different domains and levels of attention functioning in 24 prenatally exposed and 25 nonexposed children who were 5 to 6 years old. Assessment included parent ratings and neuropsychological and electrophysiological methods. Exposed children had a higher prevalence of attention deficit hyperactivity symptoms, tended to have poorer performance in an attention test battery, and showed EEG alterations in P3 and N2c. Findings suggest long-term effects of prenatal drug exposure on specific domains and on different levels of attention functioning. © 2015 Michigan Association for Infant Mental Health.

HMMerThread: detecting remote, functional conserved domains in entire genomes by combining relaxed sequence-database searches with fold recognition.

PubMed

Bradshaw, Charles Richard; Surendranath, Vineeth; Henschel, Robert; Mueller, Matthias Stefan; Habermann, Bianca Hermine

2011-03-10

Conserved domains in proteins are one of the major sources of functional information for experimental design and genome-level annotation. Though search tools for conserved domain databases such as Hidden Markov Models (HMMs) are sensitive in detecting conserved domains in proteins when they share sufficient sequence similarity, they tend to miss more divergent family members, as they lack a reliable statistical framework for the detection of low sequence similarity. We have developed a greatly improved HMMerThread algorithm that can detect remotely conserved domains in highly divergent sequences. HMMerThread combines relaxed conserved domain searches with fold recognition to eliminate false positive, sequence-based identifications. With an accuracy of 90%, our software is able to automatically predict highly divergent members of conserved domain families with an associated 3-dimensional structure. We give additional confidence to our predictions by validation across species. We have run HMMerThread searches on eight proteomes including human and present a rich resource of remotely conserved domains, which adds significantly to the functional annotation of entire proteomes. We find ∼4500 cross-species validated, remotely conserved domain predictions in the human proteome alone. As an example, we find a DNA-binding domain in the C-terminal part of the A-kinase anchor protein 10 (AKAP10), a PKA adaptor that has been implicated in cardiac arrhythmias and premature cardiac death, which upon stress likely translocates from mitochondria to the nucleus/nucleolus. Based on our prediction, we propose that with this HLH-domain, AKAP10 is involved in the transcriptional control of stress response. Further remotely conserved domains we discuss are examples from areas such as sporulation, chromosome segregation and signalling during immune response. The HMMerThread algorithm is able to automatically detect the presence of remotely conserved domains in proteins based on weak sequence similarity. Our predictions open up new avenues for biological and medical studies. Genome-wide HMMerThread domains are available at http://vm1-hmmerthread.age.mpg.de.

HMMerThread: Detecting Remote, Functional Conserved Domains in Entire Genomes by Combining Relaxed Sequence-Database Searches with Fold Recognition

PubMed Central

Bradshaw, Charles Richard; Surendranath, Vineeth; Henschel, Robert; Mueller, Matthias Stefan; Habermann, Bianca Hermine

2011-01-01

Conserved domains in proteins are one of the major sources of functional information for experimental design and genome-level annotation. Though search tools for conserved domain databases such as Hidden Markov Models (HMMs) are sensitive in detecting conserved domains in proteins when they share sufficient sequence similarity, they tend to miss more divergent family members, as they lack a reliable statistical framework for the detection of low sequence similarity. We have developed a greatly improved HMMerThread algorithm that can detect remotely conserved domains in highly divergent sequences. HMMerThread combines relaxed conserved domain searches with fold recognition to eliminate false positive, sequence-based identifications. With an accuracy of 90%, our software is able to automatically predict highly divergent members of conserved domain families with an associated 3-dimensional structure. We give additional confidence to our predictions by validation across species. We have run HMMerThread searches on eight proteomes including human and present a rich resource of remotely conserved domains, which adds significantly to the functional annotation of entire proteomes. We find ∼4500 cross-species validated, remotely conserved domain predictions in the human proteome alone. As an example, we find a DNA-binding domain in the C-terminal part of the A-kinase anchor protein 10 (AKAP10), a PKA adaptor that has been implicated in cardiac arrhythmias and premature cardiac death, which upon stress likely translocates from mitochondria to the nucleus/nucleolus. Based on our prediction, we propose that with this HLH-domain, AKAP10 is involved in the transcriptional control of stress response. Further remotely conserved domains we discuss are examples from areas such as sporulation, chromosome segregation and signalling during immune response. The HMMerThread algorithm is able to automatically detect the presence of remotely conserved domains in proteins based on weak sequence similarity. Our predictions open up new avenues for biological and medical studies. Genome-wide HMMerThread domains are available at http://vm1-hmmerthread.age.mpg.de. PMID:21423752

The signaling helix: a common functional theme in diverse signaling proteins

PubMed Central

Anantharaman, Vivek; Balaji, S; Aravind, L

2006-01-01

Background The mechanism by which the signals are transmitted between receptor and effector domains in multi-domain signaling proteins is poorly understood. Results Using sensitive sequence analysis methods we identify a conserved helical segment of around 40 residues in a wide range of signaling proteins, including numerous sensor histidine kinases such as Sln1p, and receptor guanylyl cyclases such as the atrial natriuretic peptide receptor and nitric oxide receptors. We term this helical segment the signaling (S)-helix and present evidence that it forms a novel parallel coiled-coil element, distinct from previously known helical segments in signaling proteins, such as the Dimerization-Histidine phosphotransfer module of histidine kinases, the intra-cellular domains of the chemotaxis receptors, inter-GAF domain helical linkers and the α-helical HAMP module. Analysis of domain architectures allowed us to reconstruct the domain-neighborhood graph for the S-helix, which showed that the S-helix almost always occurs between two signaling domains. Several striking patterns in the domain neighborhood of the S-helix also became evident from the graph. It most often separates diverse N-terminal sensory domains from various C-terminal catalytic signaling domains such as histidine kinases, cNMP cyclase, PP2C phosphatases, NtrC-like AAA+ ATPases and diguanylate cyclases. It might also occur between two sensory domains such as PAS domains and occasionally between a DNA-binding HTH domain and a sensory domain. The sequence conservation pattern of the S-helix revealed the presence of a unique constellation of polar residues in the dimer-interface positions within the central heptad of the coiled-coil formed by the S-helix. Conclusion Combining these observations with previously reported mutagenesis studies on different S-helix-containing proteins we suggest that it functions as a switch that prevents constitutive activation of linked downstream signaling domains. However, upon occurrence of specific conformational changes due to binding of ligand or other sensory inputs in a linked upstream domain it transmits the signal to the downstream domain. Thus, the S-helix represents one of the most prevalent functional themes involved in the flow of signals between modules in diverse prokaryote-type multi-domain signaling proteins. Reviewers This article was reviewed by Frank Eisenhaber, Arcady Mushegian and Sandor Pongor. PMID:16953892

Coiled-coil length: Size does matter.

PubMed

Surkont, Jaroslaw; Diekmann, Yoan; Ryder, Pearl V; Pereira-Leal, Jose B

2015-12-01

Protein evolution is governed by processes that alter primary sequence but also the length of proteins. Protein length may change in different ways, but insertions, deletions and duplications are the most common. An optimal protein size is a trade-off between sequence extension, which may change protein stability or lead to acquisition of a new function, and shrinkage that decreases metabolic cost of protein synthesis. Despite the general tendency for length conservation across orthologous proteins, the propensity to accept insertions and deletions is heterogeneous along the sequence. For example, protein regions rich in repetitive peptide motifs are well known to extensively vary their length across species. Here, we analyze length conservation of coiled-coils, domains formed by an ubiquitous, repetitive peptide motif present in all domains of life, that frequently plays a structural role in the cell. We observed that, despite the repetitive nature, the length of coiled-coil domains is generally highly conserved throughout the tree of life, even when the remaining parts of the protein change, including globular domains. Length conservation is independent of primary amino acid sequence variation, and represents a conservation of domain physical size. This suggests that the conservation of domain size is due to functional constraints. © 2015 Wiley Periodicals, Inc.

On domain modelling of the service system with its application to enterprise information systems

NASA Astrophysics Data System (ADS)

Wang, J. W.; Wang, H. F.; Ding, J. L.; Furuta, K.; Kanno, T.; Ip, W. H.; Zhang, W. J.

2016-01-01

Information systems are a kind of service systems and they are throughout every element of a modern industrial and business system, much like blood in our body. Types of information systems are heterogeneous because of extreme uncertainty in changes in modern industrial and business systems. To effectively manage information systems, modelling of the work domain (or domain) of information systems is necessary. In this paper, a domain modelling framework for the service system is proposed and its application to the enterprise information system is outlined. The framework is defined based on application of a general domain modelling tool called function-context-behaviour-principle-state-structure (FCBPSS). The FCBPSS is based on a set of core concepts, namely: function, context, behaviour, principle, state and structure and system decomposition. Different from many other applications of FCBPSS in systems engineering, the FCBPSS is applied to both infrastructure and substance systems, which is novel and effective to modelling of service systems including enterprise information systems. It is to be noted that domain modelling of systems (e.g. enterprise information systems) is a key to integration of heterogeneous systems and to coping with unanticipated situations facing to systems.

The association between familial ASD diagnosis, autism symptomatology and developmental functioning in young children.

PubMed

Estabillo, Jasper A; Matson, Johnny L; Jiang, Xinrui

2016-10-01

Few studies have directly compared individuals with and without a relative diagnosed with ASD on various domains. The present study aimed to examine the relationship between familial ASD diagnosis and the exhibition of ASD symptoms in young children with and without ASD diagnoses. Participants included 8353 children aged 17-37 months old and their families. They were divided into four groups based on individual and family diagnosis, then compared on autism symptomatology and developmental domains. No differences were found between ASD groups on overall scores and each of the factor domains, indicating no association between family ASD diagnosis and ASD symptomatology or developmental functioning. Disparate results were found for atypically developing groups with and without relatives diagnosed with ASD. Implications of these results are discussed.

Task force report: the macroenvironment and community mental health.

PubMed

Monahan, J; Vaux, A

1980-01-01

The U.S. President's Commission on Mental Health (1978) has called for a broader conception of mental health and the factors that influence it. The "macro"-social environment is emerging as one area of concern. The influence of two macroenvironmental domains, the physical and economic, on several areas of human functioning is documented in this article. Topics in the physical domain include noise and crowding; and in the economic domain, socio-economic status, unemployment, and economic change. The implications of this research for community mental health practice is described.

Recombinant Domain V of Human Perlecan Is a Bioactive Vascular Proteoglycan.

PubMed

Rnjak-Kovacina, Jelena; Tang, Fengying; Lin, Xiaoting; Whitelock, John M; Lord, Megan S

2017-12-01

The C-terminal domain V of the extracellular matrix proteoglycan perlecan plays unique and often divergent roles in a number of biological processes, including angiogenesis, vascular cell interactions, wound healing, and autophagy. Recombinant forms of domain V have been proposed as therapeutic agents for the treatment of cancer, stroke, and the development of cardiovascular devices and bioartificial tissues. However, the effect of domain V appears to be related to the differences in domain V structure and function observed in different expression systems and environments and exactly how this occurs is not well understood. In this study, the sequence from amino acid 3626 to 4391 of the perlecan protein core, which includes domain V, is expressed in HEK-293 cells and purified as a secreted product from conditioned media. This recombinant domain V (rDV) is expressed as a proteoglycan decorated with heparan sulfate and chondroitin sulfate chains and supports endothelial cell interactions to the same extent as full-length perlecan. This expression system serves as an important model of recombinant proteoglycan expression, as well as a source of biologically active rDV for therapeutic applications. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Using the International Classification of Functioning, Disability and Health (ICF) to describe children referred to special care or paediatric dental services.

PubMed

Faulks, Denise; Norderyd, Johanna; Molina, Gustavo; Macgiolla Phadraig, Caoimhin; Scagnet, Gabriela; Eschevins, Caroline; Hennequin, Martine

2013-01-01

Children in dentistry are traditionally described in terms of medical diagnosis and prevalence of oral disease. This approach gives little information regarding a child's capacity to maintain oral health or regarding the social determinants of oral health. The biopsychosocial approach, embodied in the International Classification of Functioning, Disability and Health - Child and Youth version (ICF-CY) (WHO), provides a wider picture of a child's real-life experience, but practical tools for the application of this model are lacking. This article describes the preliminary empirical study necessary for development of such a tool - an ICF-CY Core Set for Oral Health. An ICF-CY questionnaire was used to identify the medical, functional, social and environmental context of 218 children and adolescents referred to special care or paediatric dental services in France, Sweden, Argentina and Ireland (mean age 8 years ± 3.6 yrs). International Classification of Disease (ICD-10) diagnoses included disorders of the nervous system (26.1%), Down syndrome (22.0%), mental retardation (17.0%), autistic disorders (16.1%), and dental anxiety alone (11.0%). The most frequently impaired items in the ICF Body functions domain were 'Intellectual functions', 'High-level cognitive functions', and 'Attention functions'. In the Activities and Participation domain, participation restriction was frequently reported for 25 items including 'Handling stress', 'Caring for body parts', 'Looking after one's health' and 'Speaking'. In the Environment domain, facilitating items included 'Support of friends', 'Attitude of friends' and 'Support of immediate family'. One item was reported as an environmental barrier - 'Societal attitudes'. The ICF-CY can be used to highlight common profiles of functioning, activities, participation and environment shared by children in relation to oral health, despite widely differing medical, social and geographical contexts. The results of this empirical study might be used to develop an ICF-CY Core Set for Oral Health - a holistic but practical tool for clinical and epidemiological use.

How It Matters when It Happens: Life Changes Related to Functional Loss in Younger and Older Adults

ERIC Educational Resources Information Center

Boerner, Kathrin; Wang, Shu-Wen

2010-01-01

This study examined the impact of loss of vision on important life domains depending on life context. The sample included two groups dealing with vision impairment: middle-aged (n = 44) and older adults (n = 107). Findings showed important group differences in extent, type, and facet of life changes across and within four life domains:…

The Arabidopsis PLAT domain protein1 is critically involved in abiotic stress tolerance.

PubMed

Hyun, Tae Kyung; van der Graaff, Eric; Albacete, Alfonso; Eom, Seung Hee; Großkinsky, Dominik K; Böhm, Hannah; Janschek, Ursula; Rim, Yeonggil; Ali, Walid Wahid; Kim, Soo Young; Roitsch, Thomas

2014-01-01

Despite the completion of the Arabidopsis genome sequence, for only a relatively low percentage of the encoded proteins experimental evidence concerning their function is available. Plant proteins that harbour a single PLAT (Polycystin, Lipoxygenase, Alpha-toxin and Triacylglycerol lipase) domain and belong to the PLAT-plant-stress protein family are ubiquitously present in monocot and dicots. However, the function of PLAT-plant-stress proteins is still poorly understood. Therefore, we have assessed the function of the uncharacterised Arabidopsis PLAT-plant-stress family members through a combination of functional genetic and physiological approaches. PLAT1 overexpression conferred increased abiotic stress tolerance, including cold, drought and salt stress, while loss-of-function resulted in opposite effects on abiotic stress tolerance. Strikingly, PLAT1 promoted growth under non-stressed conditions. Abiotic stress treatments induced PLAT1 expression and caused expansion of its expression domain. The ABF/ABRE transcription factors, which are positive mediators of abscisic acid signalling, activate PLAT1 promoter activity in transactivation assays and directly bind to the ABRE elements located in this promoter in electrophoretic mobility shift assays. This suggests that PLAT1 represents a novel downstream target of the abscisic acid signalling pathway. Thus, we showed that PLAT1 critically functions as positive regulator of abiotic stress tolerance, but also is involved in regulating plant growth, and thereby assigned a function to this previously uncharacterised PLAT domain protein. The functional data obtained for PLAT1 support that PLAT-plant-stress proteins in general could be promising targets for improving abiotic stress tolerance without yield penalty.

The Arabidopsis PLAT Domain Protein1 Is Critically Involved in Abiotic Stress Tolerance

PubMed Central

Eom, Seung Hee; Großkinsky, Dominik K.; Böhm, Hannah; Janschek, Ursula; Rim, Yeonggil; Ali, Walid Wahid; Kim, Soo Young; Roitsch, Thomas

2014-01-01

Despite the completion of the Arabidopsis genome sequence, for only a relatively low percentage of the encoded proteins experimental evidence concerning their function is available. Plant proteins that harbour a single PLAT (Polycystin, Lipoxygenase, Alpha-toxin and Triacylglycerol lipase) domain and belong to the PLAT-plant-stress protein family are ubiquitously present in monocot and dicots. However, the function of PLAT-plant-stress proteins is still poorly understood. Therefore, we have assessed the function of the uncharacterised Arabidopsis PLAT-plant-stress family members through a combination of functional genetic and physiological approaches. PLAT1 overexpression conferred increased abiotic stress tolerance, including cold, drought and salt stress, while loss-of-function resulted in opposite effects on abiotic stress tolerance. Strikingly, PLAT1 promoted growth under non-stressed conditions. Abiotic stress treatments induced PLAT1 expression and caused expansion of its expression domain. The ABF/ABRE transcription factors, which are positive mediators of abscisic acid signalling, activate PLAT1 promoter activity in transactivation assays and directly bind to the ABRE elements located in this promoter in electrophoretic mobility shift assays. This suggests that PLAT1 represents a novel downstream target of the abscisic acid signalling pathway. Thus, we showed that PLAT1 critically functions as positive regulator of abiotic stress tolerance, but also is involved in regulating plant growth, and thereby assigned a function to this previously uncharacterised PLAT domain protein. The functional data obtained for PLAT1 support that PLAT-plant-stress proteins in general could be promising targets for improving abiotic stress tolerance without yield penalty. PMID:25396746

The function of the yeast molecular chaperone Sse1 is mechanistically distinct from the closely related hsp70 family.

PubMed

Shaner, Lance; Trott, Amy; Goeckeler, Jennifer L; Brodsky, Jeffrey L; Morano, Kevin A

2004-05-21

The Sse1/Hsp110 molecular chaperones are a poorly understood subgroup of the Hsp70 chaperone family. Hsp70 can refold denatured polypeptides via a C-terminal peptide binding domain (PBD), which is regulated by nucleotide cycling in an N-terminal ATPase domain. However, unlike Hsp70, both Sse1 and mammalian Hsp110 bind unfolded peptide substrates but cannot refold them. To test the in vivo requirement for interdomain communication, SSE1 alleles carrying amino acid substitutions in the ATPase domain were assayed for their ability to complement sse1Delta yeast. Surprisingly, all mutants predicted to abolish ATP hydrolysis (D8N, K69Q, D174N, D203N) complemented the temperature sensitivity of sse1Delta and lethality of sse1Deltasse2Delta cells, whereas mutations in predicted ATP binding residues (G205D, G233D) were non-functional. Complementation ability correlated well with ATP binding assessed in vitro. The extreme C terminus of the Hsp70 family is required for substrate targeting and heterocomplex formation with other chaperones, but mutant Sse1 proteins with a truncation of up to 44 C-terminal residues that were not included in the PBD were active. Remarkably, the two domains of Sse1, when expressed in trans, functionally complement the sse1Delta growth phenotype and interact by coimmunoprecipitation analysis. In addition, a functional PBD was required to stabilize the Sse1 ATPase domain, and stabilization also occurred in trans. These data represent the first structure-function analysis of this abundant but ill defined chaperone, and establish several novel aspects of Sse1/Hsp110 function relative to Hsp70.

A mutational analysis of the cytosolic domain of the tomato Cf-9 disease-resistance protein shows that membrane-proximal residues are important for Avr9-dependent necrosis.

PubMed

Chakrabarti, Apratim; Velusamy, Thilaga; Tee, Choon Yang; Jones, David A

2016-05-01

The tomato Cf-9 gene encodes a membrane-anchored glycoprotein that imparts race-specific resistance against the tomato leaf mould fungus Cladosporium fulvum in response to the avirulence protein Avr9. Although the N-terminal half of the extracellular leucine-rich repeat (eLRR) domain of the Cf-9 protein determines its specificity for Avr9, the C-terminal half, including its small cytosolic domain, is postulated to be involved in signalling. The cytosolic domain of Cf-9 carries several residues that are potential sites for ubiquitinylation or phosphorylation, or signals for endocytic uptake. A targeted mutagenesis approach was employed to investigate the roles of these residues and cellular processes in Avr9-dependent necrosis triggered by Cf-9. Our results indicate that the membrane-proximal region of the cytosolic domain of Cf-9 plays an important role in Cf-9-mediated necrosis, and two amino acids within this region, a threonine (T835) and a proline (P838), are particularly important for Cf-9 function. An alanine mutation of T835 had no effect on Cf-9 function, but an aspartic acid mutation, which mimics phosphorylation, reduced Cf-9 function. We therefore postulate that phosphorylation/de-phosphorylation of T835 could act as a molecular switch to determine whether Cf-9 is in a primed or inactive state. Yeast two-hybrid analysis was used to show that the cytosolic domain of Cf-9 interacts with the cytosolic domain of tomato VAP27. This interaction could be disrupted by an alanine mutation of P838, whereas interaction with CITRX remained unaffected. We therefore postulate that a proline-induced kink in the membrane-proximal region of the cytosolic domain of Cf-9 may be important for interaction with VAP27, which may, in turn, be important for Cf-9 function. © 2015 BSPP AND JOHN WILEY & SONS LTD.

Ribosomal small subunit domains radiate from a central core

NASA Astrophysics Data System (ADS)

Gulen, Burak; Petrov, Anton S.; Okafor, C. Denise; Vander Wood, Drew; O'Neill, Eric B.; Hud, Nicholas V.; Williams, Loren Dean

2016-02-01

The domain architecture of a large RNA can help explain and/or predict folding, function, biogenesis and evolution. We offer a formal and general definition of an RNA domain and use that definition to experimentally characterize the rRNA of the ribosomal small subunit. Here the rRNA comprising a domain is compact, with a self-contained system of molecular interactions. A given rRNA helix or stem-loop must be allocated uniquely to a single domain. Local changes such as mutations can give domain-wide effects. Helices within a domain have interdependent orientations, stabilities and interactions. With these criteria we identify a core domain (domain A) of small subunit rRNA. Domain A acts as a hub, linking the four peripheral domains and imposing orientational and positional restraints on the other domains. Experimental characterization of isolated domain A, and mutations and truncations of it, by methods including selective 2‧OH acylation analyzed by primer extension and circular dichroism spectroscopy are consistent with our architectural model. The results support the utility of the concept of an RNA domain. Domain A, which exhibits structural similarity to tRNA, appears to be an essential core of the small ribosomal subunit.

Frequency-Domain Identification Of Aeroelastic Modes

NASA Technical Reports Server (NTRS)

Acree, C. W., Jr.; Tischler, Mark B.

1991-01-01

Report describes flight measurements and frequency-domain analyses of aeroelastic vibrational modes of wings of XV-15 tilt-rotor aircraft. Begins with description of flight-test methods. Followed by brief discussion of methods of analysis, which include Fourier-transform computations using chirp z transformers, use of coherence and other spectral functions, and methods and computer programs to obtain frequencies and damping coefficients from measurements. Includes brief description of results of flight tests and comparisions among various experimental and theoretical results. Ends with section on conclusions and recommended improvements in techniques.

Cognitive performance and electrophysiological indices of cognitive control: a validation study of conflict adaptation.

PubMed

Clayson, Peter E; Larson, Michael J

2012-05-01

Psychiatric and neurologic disorders are associated with deficits in the postconflict recruitment of cognitive control. The primary aim of this study was to validate the relationship between cognitive functioning and indices of conflict adaptation. Event-related potentials were obtained from 89 healthy individuals who completed an Eriksen flanker task. Neuropsychological domains tested included memory, verbal fluency, and attention/executive functioning. Behavioral measures and N2 amplitudes showed significant conflict adaptation (i.e., previous-trial congruencies influenced current-trial measures). Higher scores on the attention/executive functioning and verbal fluency domains were associated with larger incongruent-trial N2 conflict adaptation; measures of cognitive functioning were not related to behavioral indices. This study provides initial validation of N2 conflict adaptation effects as cognitive function-related aspects of cognitive control. Copyright © 2012 Society for Psychophysiological Research.

Structure of a Spumaretrovirus Gag Central Domain Reveals an Ancient Retroviral Capsid

PubMed Central

Dutta, Moumita; Pollard, Dominic J.; Goldstone, David C.; Ramos, Andres; Müllers, Erik; Stirnnagel, Kristin; Stanke, Nicole; Lindemann, Dirk; Taylor, William R.; Rosenthal, Peter B.

2016-01-01

The Spumaretrovirinae, or foamy viruses (FVs) are complex retroviruses that infect many species of monkey and ape. Despite little sequence homology, FV and orthoretroviral Gag proteins perform equivalent functions, including genome packaging, virion assembly, trafficking and membrane targeting. However, there is a paucity of structural information for FVs and it is unclear how disparate FV and orthoretroviral Gag molecules share the same function. To probe the functional overlap of FV and orthoretroviral Gag we have determined the structure of a central region of Gag from the Prototype FV (PFV). The structure comprises two all α-helical domains NtDCEN and CtDCEN that although they have no sequence similarity, we show they share the same core fold as the N- (NtDCA) and C-terminal domains (CtDCA) of archetypal orthoretroviral capsid protein (CA). Moreover, structural comparisons with orthoretroviral CA align PFV NtDCEN and CtDCEN with NtDCA and CtDCA respectively. Further in vitro and functional virological assays reveal that residues making inter-domain NtDCEN—CtDCEN interactions are required for PFV capsid assembly and that intact capsid is required for PFV reverse transcription. These data provide the first information that relates the Gag proteins of Spuma and Orthoretrovirinae and suggests a common ancestor for both lineages containing an ancient CA fold. PMID:27829070

Insights into Hox protein function from a large scale combinatorial analysis of protein domains.

PubMed

Merabet, Samir; Litim-Mecheri, Isma; Karlsson, Daniel; Dixit, Richa; Saadaoui, Mehdi; Monier, Bruno; Brun, Christine; Thor, Stefan; Vijayraghavan, K; Perrin, Laurent; Pradel, Jacques; Graba, Yacine

2011-10-01

Protein function is encoded within protein sequence and protein domains. However, how protein domains cooperate within a protein to modulate overall activity and how this impacts functional diversification at the molecular and organism levels remains largely unaddressed. Focusing on three domains of the central class Drosophila Hox transcription factor AbdominalA (AbdA), we used combinatorial domain mutations and most known AbdA developmental functions as biological readouts to investigate how protein domains collectively shape protein activity. The results uncover redundancy, interactivity, and multifunctionality of protein domains as salient features underlying overall AbdA protein activity, providing means to apprehend functional diversity and accounting for the robustness of Hox-controlled developmental programs. Importantly, the results highlight context-dependency in protein domain usage and interaction, allowing major modifications in domains to be tolerated without general functional loss. The non-pleoitropic effect of domain mutation suggests that protein modification may contribute more broadly to molecular changes underlying morphological diversification during evolution, so far thought to rely largely on modification in gene cis-regulatory sequences.

Insights into Hox Protein Function from a Large Scale Combinatorial Analysis of Protein Domains

PubMed Central

Karlsson, Daniel; Dixit, Richa; Saadaoui, Mehdi; Monier, Bruno; Brun, Christine; Thor, Stefan; Vijayraghavan, K.; Perrin, Laurent; Pradel, Jacques; Graba, Yacine

2011-01-01

Protein function is encoded within protein sequence and protein domains. However, how protein domains cooperate within a protein to modulate overall activity and how this impacts functional diversification at the molecular and organism levels remains largely unaddressed. Focusing on three domains of the central class Drosophila Hox transcription factor AbdominalA (AbdA), we used combinatorial domain mutations and most known AbdA developmental functions as biological readouts to investigate how protein domains collectively shape protein activity. The results uncover redundancy, interactivity, and multifunctionality of protein domains as salient features underlying overall AbdA protein activity, providing means to apprehend functional diversity and accounting for the robustness of Hox-controlled developmental programs. Importantly, the results highlight context-dependency in protein domain usage and interaction, allowing major modifications in domains to be tolerated without general functional loss. The non-pleoitropic effect of domain mutation suggests that protein modification may contribute more broadly to molecular changes underlying morphological diversification during evolution, so far thought to rely largely on modification in gene cis-regulatory sequences. PMID:22046139

Tetraspanins and Transmembrane Adaptor Proteins As Plasma Membrane Organizers-Mast Cell Case.

PubMed

Halova, Ivana; Draber, Petr

2016-01-01

The plasma membrane contains diverse and specialized membrane domains, which include tetraspanin-enriched domains (TEMs) and transmembrane adaptor protein (TRAP)-enriched domains. Recent biophysical, microscopic, and functional studies indicated that TEMs and TRAP-enriched domains are involved in compartmentalization of physicochemical events of such important processes as immunoreceptor signal transduction and chemotaxis. Moreover, there is evidence of a cross-talk between TEMs and TRAP-enriched domains. In this review we discuss the presence and function of such domains and their crosstalk using mast cells as a model. The combined data based on analysis of selected mast cell-expressed tetraspanins [cluster of differentiation (CD)9, CD53, CD63, CD81, CD151)] or TRAPs [linker for activation of T cells (LAT), non-T cell activation linker (NTAL), and phosphoprotein associated with glycosphingolipid-enriched membrane microdomains (PAG)] using knockout mice or specific antibodies point to a diversity within these two families and bring evidence of the important roles of these molecules in signaling events. An example of this diversity is physical separation of two TRAPs, LAT and NTAL, which are in many aspects similar but show plasma membrane location in different microdomains in both non-activated and activated cells. Although our understanding of TEMs and TRAP-enriched domains is far from complete, pharmaceutical applications of the knowledge about these domains are under way.

Operational Definition of Active and Healthy Aging (AHA): The European Innovation Partnership (EIP) on AHA Reference Site Questionnaire: Montpellier October 20-21, 2014, Lisbon July 2, 2015.

PubMed

Bousquet, Jean; Malva, Joao; Nogues, Michel; Mañas, Leocadio Rodriguez; Vellas, Bruno; Farrell, John

2015-12-01

A core operational definition of active and healthy aging (AHA) is needed to conduct comparisons. A conceptual AHA framework proposed by the European Innovation Partnership on Active and Healthy Ageing Reference Site Network includes several items such as functioning (individual capability and underlying body systems), well-being, activities and participation, and diseases (including noncommunicable diseases, frailty, mental and oral health disorders). The instruments proposed to assess the conceptual framework of AHA have common applicability and availability attributes. The approach includes core and optional domains/instruments depending on the needs and the questions. A major common domain is function, as measured by the World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0). WHODAS 2.0 can be used across all diseases and healthy individuals. It covers many of the AHA dimensions proposed by the Reference Site network. However, WHODAS 2.0 does not include all dimensions proposed for AHA assessment. The second common domain is health-related quality of life (HRQoL). A report of the AHA questionnaire in the form of a spider net has been proposed to facilitate usual comparisons across individuals and groups of interest. Copyright © 2015. Published by Elsevier Inc.

Structural and Functional Studies of gpX of Escherichia coli Phage P2 Reveal a Widespread Role for LysM Domains in the Baseplates of Contractile-Tailed Phages

PubMed Central

Fatehi Hassanabad, Mostafa; Chang, Tom; Pirani, Nawaz; Bona, Diane; Edwards, Aled M.

2013-01-01

A variety of bacterial pathogenicity determinants, including the type VI secretion system and the virulence cassettes from Photorhabdus and Serratia, share an evolutionary origin with contractile-tailed myophages. The well-characterized Escherichia coli phage P2 provides an excellent system for studies related to these systems, as its protein composition appears to represent the “minimal” myophage tail. In this study, we used nuclear magnetic resonance (NMR) spectroscopy to determine the solution structure of gpX, a 68-residue tail baseplate protein. Although the sequence and structure of gpX are similar to those of LysM domains, which are a large family associated with peptidoglycan binding, we did not detect a peptidoglycan-binding activity for gpX. However, bioinformatic analysis revealed that half of all myophages, including all that possess phage T4-like baseplates, encode a tail protein with a LysM-like domain, emphasizing a widespread role for this domain in baseplate function. While phage P2 gpX comprises only a single LysM domain, many myophages display LysM domain fusions with other tail proteins, such as the DNA circulation protein found in Mu-like phages and gp53 of T4-like phages. Electron microscopy of P2 phage particles with an incorporated gpX-maltose binding protein fusion revealed that gpX is located at the top of the baseplate, near the junction of the baseplate and tail tube. gpW, the orthologue of phage T4 gp25, was also found to localize to this region. A general colocalization of LysM-like domains and gpW homologues in diverse phages is supported by our bioinformatic analysis. PMID:24097944

Context Influences on the Subjective Experience of Aging: The Impact of Culture and Domains of Functioning.

PubMed

O'Brien, Erica L; Hess, Thomas M; Kornadt, Anna E; Rothermund, Klaus; Fung, Helene; Voss, Peggy

2017-08-01

Attitudes about aging influence how people feel about their aging and affect psychological and health outcomes in later life. Given cross-cultural variability in such attitudes, the subjective experience of aging (e.g., subjective age [SA]) may also vary, potentially accounting for culture-specific patterns of aging-related outcomes. Our study explored cultural variation in SA and its determinants. American (N = 569), Chinese (N = 492), and German (N = 827) adults aged 30-95 years completed a questionnaire that included instruments measuring basic demographic information, SA, beliefs about thresholds of old age, control over life changes, and age dependency of changes in eight different life domains (i.e., family, work). Analyses revealed consistency across cultures in the domain-specificity of SA, but differences in the amount of shared variance across domains (e.g., Chinese adults exhibited greater homogeneity across domains than did Americans and Germans). Cultural differences were also observed in levels of SA in some domains, which were attenuated by domain-specific beliefs (e.g., control). Interestingly, beliefs about aging accounted for more cultural variation in SA than did sociodemographic factors (e.g., education). Our results demonstrate that subjective perceptions of aging and everyday functioning may be best understood from a perspective focused on context (i.e., culture, life domain). Given its important relation to functioning, examination of cross-cultural differences in the subjective experience of aging may highlight factors that determine variations in aging-related outcomes that then could serve as targets of culture-specific interventions promoting well-being in later life. © The Author 2017. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

S1-S3 counter charges in the voltage sensor module of a mammalian sodium channel regulate fast inactivation.

PubMed

Groome, James R; Winston, Vern

2013-05-01

The movement of positively charged S4 segments through the electric field drives the voltage-dependent gating of ion channels. Studies of prokaryotic sodium channels provide a mechanistic view of activation facilitated by electrostatic interactions of negatively charged residues in S1 and S2 segments, with positive counterparts in the S4 segment. In mammalian sodium channels, S4 segments promote domain-specific functions that include activation and several forms of inactivation. We tested the idea that S1-S3 countercharges regulate eukaryotic sodium channel functions, including fast inactivation. Using structural data provided by bacterial channels, we constructed homology models of the S1-S4 voltage sensor module (VSM) for each domain of the mammalian skeletal muscle sodium channel hNaV1.4. These show that side chains of putative countercharges in hNaV1.4 are oriented toward the positive charge complement of S4. We used mutagenesis to define the roles of conserved residues in the extracellular negative charge cluster (ENC), hydrophobic charge region (HCR), and intracellular negative charge cluster (INC). Activation was inhibited with charge-reversing VSM mutations in domains I-III. Charge reversal of ENC residues in domains III (E1051R, D1069K) and IV (E1373K, N1389K) destabilized fast inactivation by decreasing its probability, slowing entry, and accelerating recovery. Several INC mutations increased inactivation from closed states and slowed recovery. Our results extend the functional characterization of VSM countercharges to fast inactivation, and support the premise that these residues play a critical role in domain-specific gating transitions for a mammalian sodium channel.

Domain organization, genomic structure, evolution, and regulation of expression of the aggrecan gene family.

PubMed

Schwartz, N B; Pirok, E W; Mensch, J R; Domowicz, M S

1999-01-01

Proteoglycans are complex macromolecules, consisting of a polypeptide backbone to which are covalently attached one or more glycosaminoglycan chains. Molecular cloning has allowed identification of the genes encoding the core proteins of various proteoglycans, leading to a better understanding of the diversity of proteoglycan structure and function, as well as to the evolution of a classification of proteoglycans on the basis of emerging gene families that encode the different core proteins. One such family includes several proteoglycans that have been grouped with aggrecan, the large aggregating chondroitin sulfate proteoglycan of cartilage, based on a high number of sequence similarities within the N- and C-terminal domains. Thus far these proteoglycans include versican, neurocan, and brevican. It is now apparent that these proteins, as a group, are truly a gene family with shared structural motifs on the protein and nucleotide (mRNA) levels, and with nearly identical genomic organizations. Clearly a common ancestral origin is indicated for the members of the aggrecan family of proteoglycans. However, differing patterns of amplification and divergence have also occurred within certain exons across species and family members, leading to the class-characteristic protein motifs in the central carbohydrate-rich region exclusively. Thus the overall domain organization strongly suggests that sequence conservation in the terminal globular domains underlies common functions, whereas differences in the central portions of the genes account for functional specialization among the members of this gene family.

Biological roles and functional mechanisms of arenavirus Z protein in viral replication.

PubMed

Wang, Jialong; Danzy, Shamika; Kumar, Naveen; Ly, Hinh; Liang, Yuying

2012-09-01

Arenaviruses can cause severe hemorrhagic fever diseases in humans, with limited prophylactic or therapeutic measures. A small RING-domain viral protein Z has been shown to mediate the formation of virus-like particles and to inhibit viral RNA synthesis, although its biological roles in an infectious viral life cycle have not been directly addressed. By taking advantage of the available reverse genetics system for a model arenavirus, Pichinde virus (PICV), we provide the direct evidence for the essential biological roles of the Z protein's conserved residues, including the G2 myristylation site, the conserved C and H residues of RING domain, and the poorly characterized C-terminal L79 and P80 residues. Dicodon substitutions within the late (L) domain (PSAPPYEP) of the PICV Z protein, although producing viable mutant viruses, have significantly reduced virus growth, a finding suggestive of an important role for the intact L domain in viral replication. Further structure-function analyses of both PICV and Lassa fever virus Z proteins suggest that arenavirus Z proteins have similar molecular mechanisms in mediating their multiple functions, with some interesting variations, such as the role of the G2 residue in blocking viral RNA synthesis. In summary, our studies have characterized the biological roles of the Z protein in an infectious arenavirus system and have shed important light on the distinct functions of its domains in virus budding and viral RNA regulation, the knowledge of which may lead to the development of novel antiviral drugs.

Autistic traits and neuropsychological performance in 6- to-10-year-old children: a population-based study.

PubMed

Hyseni, Fjola; Blanken, Laura M E; Muetzel, Ryan; Verhulst, Frank C; Tiemeier, Henning; White, Tonya

2018-04-23

Clinical studies of children with autism spectrum disorder (ASD) provide evidence for poorer neuropsychological performance within specific domains compared to age, gender, and sometimes IQ-matched controls. Since recent evidence suggests that autistic symptoms form a spectrum that extends into the general population, it was our goal to evaluate the nature of the relationship between autistic traits and neuropsychological performance across the continuum in the general population. We examined neuropsychological performance across five different domains in 1019 6-to-10-year-old children participating in a population-based study of child development. Autistic traits were assessed when the children were 6 years of age using the Social Responsiveness Scale and ASD diagnoses were obtained via medical records. Neuropsychological functioning was measured using the NEPSY-II-NL and included the domains of attention and executive function, memory and learning, sensorimotor functioning, language, and visuospatial functioning. We found that children with higher autistic traits showed significantly lower neuropsychological performance in all domains investigated and that this association remained even after excluding children with the highest autistic traits or confirmed ASD. When comparing 41 children with confirmed ASD diagnosis to typically developing controls, children with ASD showed significantly lower neuropsychological performance across all domains. Taken together, our results suggest that children with both ASD and subclinical autistic traits have lower neuropsychological performance. Thus, this may provide an understanding of why some children without an ASD diagnosis may require some additional assistance within academic settings.

Structure of the Newcastle disease virus hemagglutinin-neuraminidase (HN) ectodomain reveals a four-helix bundle stalk

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

Yuan, Ping; Swanson, Kurt A.; Leser, George P.

2014-10-02

The paramyxovirus hemagglutinin-neuraminidase (HN) protein plays multiple roles in viral entry and egress, including binding to sialic acid receptors, activating the fusion (F) protein to activate membrane fusion and viral entry, and cleaving sialic acid from carbohydrate chains. HN is an oligomeric integral membrane protein consisting of an N-terminal transmembrane domain, a stalk region, and an enzymatically active neuraminidase (NA) domain. Structures of the HN NA domains have been solved previously; however, the structure of the stalk region has remained elusive. The stalk region contains specificity determinants for F interactions and activation, underlying the requirement for homotypic F and HNmore » interactions in viral entry. Mutations of the Newcastle disease virus HN stalk region have been shown to affect both F activation and NA activities, but a structural basis for understanding these dual affects on HN functions has been lacking. Here, we report the structure of the Newcastle disease virus HN ectodomain, revealing dimers of NA domain dimers flanking the N-terminal stalk domain. The stalk forms a parallel tetrameric coiled-coil bundle (4HB) that allows classification of extensive mutational data, providing insight into the functional roles of the stalk region. Mutations that affect both F activation and NA activities map predominantly to the 4HB hydrophobic core, whereas mutations that affect only F-protein activation map primarily to the 4HB surface. Two of four NA domains interact with the 4HB stalk, and residues at this interface in both the stalk and NA domain have been implicated in HN function.« less

Border patrol: insights into the unique role of perlecan/heparan sulfate proteoglycan 2 at cell and tissue borders.

PubMed

Farach-Carson, Mary C; Warren, Curtis R; Harrington, Daniel A; Carson, Daniel D

2014-02-01

The extracellular matrix proteoglycan (ECM) perlecan, also known as heparan sulfate proteoglycan 2 or HSPG2, is one of the largest (>200 nm) and oldest (>550 M years) extracellular matrix molecules. In vertebrates, perlecan's five-domain structure contains numerous independently folding modules with sequence similarities to other ECM proteins, all connected like cars into one long, diverse complex train following a unique N-terminal domain I decorated with three long glycosaminoglycan chains, and an additional glycosaminoglycan attachment site in the C-terminal domain V. In lower invertebrates, perlecan is not typically a proteoglycan, possessing the majority of the core protein modules, but lacking domain I where the attachment sites for glycosaminoglycan chains are located. This suggests that uniting the heparan sulfate binding growth factor functions of domain I and the core protein functions of the rest of the molecule in domains II-V occurred later in evolution for a new functional purpose. In this review, we surveyed several decades of pertinent literature to ask a fundamental question: Why did nature design this protein uniquely as an extraordinarily long multifunctional proteoglycan with a single promoter regulating expression, rather than separating these functions into individual proteins that could be independently regulated? We arrived at the conclusion that the concentration of perlecan at functional borders separating tissues and tissue layers is an ancient key function of the core protein. The addition of the heparan sulfate chains in domain I likely occurred as an additional means of binding the core protein to other ECM proteins in territorial matrices and basement membranes, and as a means to reserve growth factors in an on-site depot to assist with rapid repair of those borders when compromised, such as would occur during wounding. We propose a function for perlecan that extends its role from that of an extracellular scaffold, as we previously suggested, to that of a critical agent for establishing and patrolling tissue borders in complex tissues in metazoans. We also propose that understanding these unique functions of the individual portions of the perlecan molecule can provide new insights and tools for engineering of complex multi-layered tissues including providing the necessary cues for establishing neotissue borders. © 2013.

Border Patrol: Insights into the Unique Role of Perlecan/Heparan Sulfate Proteoglycan2 at Cell and Tissue Borders

PubMed Central

Farach-Carson, Mary C.; Warren, Curtis R.; Harrington, Daniel A.; Carson, Daniel D.

2013-01-01

The extracellular matrix proteoglycan (ECM) perlecan, also known as heparan sulfate proteoglycan 2 or HSPG2, is one of the largest (>200 nm) and oldest (>550M years) extracellular matrix molecules. In vertebrates, perlecan’s five-domain structure contains numerous independently folding modules with sequence similarities to other ECM proteins, all connected like cars into one long, diverse complex train following a unique N-terminal domain I decorated with three long glycosaminoglycan chains, and an additional glycosaminoglycan attachment site in the C-terminal domain V. In lower invertebrates, perlecan is not typically a proteoglycan, possessing the majority of the core protein modules, but lacking domain I where the attachment sites for glycosaminoglycan chains are located. This suggests that uniting the heparan sulfate binding growth factor functions of domain I and the core protein functions of the rest of the molecule in domains II-V occurred later in evolution for a new functional purpose. In this review, we surveyed several decades of pertinent literature to ask a fundamental question: Why did nature design this protein uniquely as an extraordinarily long multifunctional proteoglycan with a single promoter regulating expression, rather than separating these functions into individual proteins that could be independently regulated? We arrived at the conclusion that the concentration of perlecan at functional borders separating tissues and tissue layers is an ancient key function of the core protein. The addition of the heparan sulfate chains in domain I likely occurred as an additional means of binding the core protein to other ECM proteins in territorial matrices and basement membranes, and as a means to reserve growth factors in an on-site depot to assist with rapid repair of those borders when compromised, such as would occur during wounding. We propose a function for perlecan that extends its role from that of an extracellular scaffold, as we previously suggested, to that of a critical agent for establishing and patrolling tissue borders in complex tissues in metazoans. We also propose that understanding these unique functions of the individual portions of the perlecan molecule can provide new insights and tools for engineering of complex multi-layered tissues including providing the necessary cues for establishing neotissue borders. PMID:24001398

Clinical symptoms predict concurrent social and global functioning in an early psychosis sample.

PubMed

Cacciotti-Saija, Cristina; Langdon, Robyn; Ward, Philip B; Hickie, Ian B; Guastella, Adam J

2018-04-01

Although well established in chronic schizophrenia, the key determinants of functioning remain unknown during the early phase of a psychotic disorder. The aim of this study was to comprehensively examine the social cognitive, basic neurocognitive and clinical predictors of concurrent social functioning and global functioning in an early psychosis sample. This study examined the relationship between social cognition, basic neurocognition and clinical symptoms with concurrent functioning in 51 early psychosis individuals. Assessments included a range of self-report, observational and clinician-rated measures of cognitive, symptom severity and functioning domains. Results revealed a significant association between self-reported social function and lower levels of both social interaction anxiety and negative psychotic symptoms. A significant association was also observed between lower levels of negative psychotic symptoms and observed social functioning. Lastly, results demonstrated a significant association between reduced negative psychotic symptoms and clinician-rated global functioning. Clinical domains such as negative symptoms and social interaction anxiety significantly contribute to an optimal model predicting outcome during the early phase of a psychotic disorder. These clinical features may also provide useful markers of an individual's capacity for social participation. Clinical implications include the need for early targeted intervention to address social anxiety and negative psychotic symptoms to facilitate optimum patient outcome. © 2015 Wiley Publishing Asia Pty Ltd.

UNIX helps integrate control packages for combined cycle

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

Forbes, H.W.

1994-05-01

This article describes the use of integrated UNIX based control systems in a combined-cycle power plant. The topics of the article include equipment configuration, control domains and functions for the gas turbine, steam turbine, balance of plant, unit-coordination, and plant master control, device gateway functions, and data-acquisition environment.

Disability and recovery in schizophrenia: a systematic review of cognitive behavioral therapy interventions.

PubMed

Nowak, Izabela; Sabariego, Carla; Świtaj, Piotr; Anczewska, Marta

2016-07-11

Schizophrenia is a disabling disease that impacts all major life areas. There is a growing need for meeting the challenge of disability from a perspective that extends symptomatic reduction. Therefore, this study aimed to systematically review the extent to which traditional and "third wave" cognitive - behavioral (CBT) interventions address the whole scope of disabilities experienced by people with lived experience of schizophrenia using the WHO's International Classification of Functioning, Disability and Health (ICF) as a frame of reference. It also explores if current CBT interventions focus on recovery and what is their impact on disability domains. Medline and PsycINFO databases were searched for studies published in English between January 2009 and December 2015. Abstracts and full papers were screened against pre-defined selection criteria by two reviewers. Methodological quality of included studies was assessed by two independent raters using the Effective Public Health Practice Project Quality assessment tool for quantitative studies (EPHPP) guidelines. A total of 50 studies were included, 35 studies evaluating traditional CBT interventions and 15 evaluating "third wave" approaches. Overall, traditional CBT interventions addressed more disability domains than "third wave" approaches and mostly focused on mental functions reflecting schizophrenia psychopathology. Seven studies met the inclusion criteria of recovery-oriented interventions. The majority of studies evaluating these interventions had however a high risk of bias, therefore evidence on their effectiveness is inconclusive. Traditional CBT interventions address more disability domains than "third wave" therapies, however both approaches focus mostly on mental functions that reflect schizophrenia psychopathology. There are also few interventions that focus on recovery. These results indicate that CBT interventions going beyond symptom reduction are still needed. Recovery-focused CBT interventions seem to be a promising treatment approach as they target disability from a broader perspective including activity and participation domains. Although their effectiveness is inconclusive, they reflect users' views of recovery and trends towards improvement of mood, negative symptoms and functioning are shown.

Longitudinal assessment of neuropsychological function in major depression.

PubMed

Douglas, Katie M; Porter, Richard J

2009-12-01

Neuropsychological impairment is a core component of major depression, yet its relationship to clinical state is unclear. The aims of the present review were to determine which neuropsychological domains and tasks were most sensitive to improvement in clinical state in major depression and to highlight the methodological issues in such research. Studies that included a baseline and at least one follow-up neuropsychological testing session in adults with major depression were identified using MEDLINE, Web of Science and ScienceDirect databases. Thirty studies were included in the review. Findings in younger adult populations suggested that improvement in mood was most strongly related to improved verbal memory and verbal fluency, while measures of executive functioning and attention tended to remain impaired across treatment. In late-life major depression, improved psychomotor speed was most closely related to treatment response, but there was much inconsistency between study findings, which may be due to methodological issues. In major depression, particular neuropsychological domains are more strongly related to clinical state than others. The findings from the present review suggest that the domains most sensitive to clinical state are verbal learning and memory, verbal fluency and psychomotor speed. In contrast, measures of attention and executive functioning perhaps represent more trait-like markers of major depression. With further methodologically sound research, the changes in neuropsychological function associated with treatment response may provide a means of evaluating different treatment strategies in major depression.

Structure-guided Mutational Analysis of the OB, HhH, and BRCT Domains of Escherichia coli DNA Ligase*S⃞

PubMed Central

Wang, Li Kai; Nair, Pravin A.; Shuman, Stewart

2008-01-01

NAD+-dependent DNA ligases (LigAs) are ubiquitous in bacteria and essential for growth. LigA enzymes have a modular structure in which a central catalytic core composed of nucleotidyltransferase and oligonucleotide-binding (OB) domains is linked via a tetracysteine zinc finger to distal helix-hairpin-helix (HhH) and BRCT (BRCA1-like C-terminal) domains. The OB and HhH domains contribute prominently to the protein clamp formed by LigA around nicked duplex DNA. Here we conducted a structure-function analysis of the OB and HhH domains of Escherichia coli LigA by alanine scanning and conservative substitutions, entailing 43 mutations at 22 amino acids. We thereby identified essential functional groups in the OB domain that engage the DNA phosphodiester backbone flanking the nick (Arg333); penetrate the minor grove and distort the nick (Val383 and Ile384); or stabilize the OB fold (Arg379). The essential constituents of the HhH domain include: four glycines (Gly455, Gly489, Gly521, Gly553), which bind the phosphate backbone across the minor groove at the outer margins of the LigA-DNA interface; Arg487, which penetrates the minor groove at the outer margin on the 3 ®-OH side of the nick; and Arg446, which promotes protein clamp formation via contacts to the nucleotidyltransferase domain. We find that the BRCT domain is required in its entirety for effective nick sealing and AMP-dependent supercoil relaxation. PMID:18515356

Prefrontal contributions to domain-general executive control processes during temporal context retrieval.

PubMed

Rajah, M Natasha; Ames, Blaine; D'Esposito, Mark

2008-03-07

Neuroimaging studies have reported increased prefrontal cortex (PFC) activity during temporal context retrieval versus recognition memory. However, it remains unclear if these activations reflect PFC contributions to domain-general executive control processes or domain-specific retrieval processes. To gain a better understanding of the functional roles of these various PFC regions during temporal context retrieval we propose it is necessary to examine PFC activity across tasks from different domains, in which parallel manipulations are included targeting specific cognitive processes. In the current fMRI study, we examined domain-general and domain-specific PFC contributions to temporal context retrieval by increasing stimulus (but maintaining response number) and increasing response number (but maintaining stimulus number) across temporal context memory and ordering control tasks, for faces. The control task required subjects to order faces from youngest to oldest. Our behavioral results indicate that the combination of increased stimulus and response numbers significantly increased task difficulty for temporal context retrieval and ordering tasks. Across domains, increasing stimulus number, while maintaining response numbers, caused greater right lateral premotor cortex (BA 6/8) activity; whereas increasing response number, while maintaining stimulus number, caused greater domain-general left DLPFC (BA 9) and VLPFC (BA 44/45) activity. In addition, we found domain-specific right DLPFC (BA 9) activity only during retrieval events. These results highlight the functional heterogeneity of frontal cortex, and suggest its involvement in temporal context retrieval is related to its role in various cognitive control processes.

Structure-guided mutational analysis of the OB, HhH, and BRCT domains of Escherichia coli DNA ligase.

PubMed

Wang, Li Kai; Nair, Pravin A; Shuman, Stewart

2008-08-22

NAD(+)-dependent DNA ligases (LigAs) are ubiquitous in bacteria and essential for growth. LigA enzymes have a modular structure in which a central catalytic core composed of nucleotidyltransferase and oligonucleotide-binding (OB) domains is linked via a tetracysteine zinc finger to distal helix-hairpin-helix (HhH) and BRCT (BRCA1-like C-terminal) domains. The OB and HhH domains contribute prominently to the protein clamp formed by LigA around nicked duplex DNA. Here we conducted a structure-function analysis of the OB and HhH domains of Escherichia coli LigA by alanine scanning and conservative substitutions, entailing 43 mutations at 22 amino acids. We thereby identified essential functional groups in the OB domain that engage the DNA phosphodiester backbone flanking the nick (Arg(333)); penetrate the minor grove and distort the nick (Val(383) and Ile(384)); or stabilize the OB fold (Arg(379)). The essential constituents of the HhH domain include: four glycines (Gly(455), Gly(489), Gly(521), Gly(553)), which bind the phosphate backbone across the minor groove at the outer margins of the LigA-DNA interface; Arg(487), which penetrates the minor groove at the outer margin on the 3 (R)-OH side of the nick; and Arg(446), which promotes protein clamp formation via contacts to the nucleotidyltransferase domain. We find that the BRCT domain is required in its entirety for effective nick sealing and AMP-dependent supercoil relaxation.

The coxsackievirus-adenovirus receptor reveals complex homophilic and heterophilic interactions on neural cells.

PubMed

Patzke, Christopher; Max, Klaas E A; Behlke, Joachim; Schreiber, Jadwiga; Schmidt, Hannes; Dorner, Armin A; Kröger, Stephan; Henning, Mechthild; Otto, Albrecht; Heinemann, Udo; Rathjen, Fritz G

2010-02-24

The coxsackievirus-adenovirus receptor (CAR) is a member of the Ig superfamily strongly expressed in the developing nervous system. Our histological investigations during development reveal an initial uniform distribution of CAR on all neural cells with a concentration on membranes that face the margins of the nervous system (e.g., the basal laminae and the ventricular side). At more advanced stages, CAR becomes downregulated and restricted to specific regions including areas rich in axonal and dendritic surfaces. To study the function of CAR on neural cells, we used the fiber knob of the adenovirus, extracellular CAR domains, blocking antibodies to CAR, as well as CAR-deficient neural cells. Blocking antibodies were found to inhibit neurite extension in retina organ and retinal explant cultures, whereas the application of the recombinant fiber knob of the adenovirus subtype Ad2 or extracellular CAR domains promoted neurite extension and adhesion to extracellular matrices. We observed a promiscuous interaction of CAR with extracellular matrix glycoproteins, which was deduced from analytical ultracentrifugation experiments, affinity chromatography, and adhesion assays. The membrane proximal Ig domain of CAR, termed D2, was found to bind to a fibronectin fragment, including the heparin-binding domain 2, which promotes neurite extension of wild type, but not of CAR-deficient neural cells. In contrast to heterophilic interactions, homophilic association of CAR involves both Ig domains, as was revealed by ultracentrifugation, chemical cross-linking, and adhesion studies. The results of these functional and binding studies are correlated to a U-shaped homodimer of the complete extracellular domains of CAR detected by x-ray crystallography.

Olfactory performance segregates effects of anhedonia and anxiety on social function in patients with schizophrenia

PubMed Central

Cieslak, Kristina; Walsh-Messinger, Julie; Stanford, Arielle; Vaez-Azizi, Leila; Antonius, Daniel; Harkavy-Friedman, Jill; Goetz, Deborah; Goetz, Raymond R.; Malaspina, Dolores

2015-01-01

Background Social dysfunction is common among individuals with schizophrenia. While often attributed to anhedonia, social dysfunction could also result from unrecognized anxiety. We examined the contributions of anhedonia and anxiety to social function using olfactory function to examine whether the domains had separate underpinnings. Methods We assessed anhedonia, anxiety and social function as well as olfactory function in well-characterized patients with schizophrenia or schizoaffective disorder and healthy controls. Results We included 56 patients and 37 controls in our study. Patients exhibited significantly higher levels of anhedonia and anxiety than controls, and the domains were highly correlated in patients. The combination of anhedonia and anxiety more strongly predicted social dysfunction than either measure alone. Smell identification was differentially related to the symptoms, with better performance predicting less anhedonia but more social fear in male patients. Limitations The use of self-report measures precludes differentiation between recollected or recounted experience. Aside from smell identification and odour threshold, additional measures of olfaction may be considered for future studies. Conclusion Anhedonia and anxiety were strongly correlated and both negatively impacted social function. The olfactory biomarker results support the conclusion that these domains are separate. Social function in patients with schizophrenia may improve with interventions for anxiety, even in the presence of marked negative symptoms. PMID:26107162

Oligomerization but Not Membrane Bending Underlies the Function of Certain F-BAR Proteins in Cell Motility and Cytokinesis.

PubMed

McDonald, Nathan A; Vander Kooi, Craig W; Ohi, Melanie D; Gould, Kathleen L

2015-12-21

F-BAR proteins function in diverse cellular processes by linking membranes to the actin cytoskeleton. Through oligomerization, multiple F-BAR domains can bend membranes into tubules, though the physiological importance of F-BAR-to-F-BAR assemblies is not yet known. Here, we investigate the F-BAR domain of the essential cytokinetic scaffold, Schizosaccharomyces pombe Cdc15, during cytokinesis. Challenging a widely held view that membrane deformation is a fundamental property of F-BARs, we report that the Cdc15 F-BAR binds, but does not deform, membranes in vivo or in vitro, and six human F-BAR domains-including those from Fer and RhoGAP4-share this property. Nevertheless, tip-to-tip interactions between F-BAR dimers are critical for Cdc15 oligomerization and high-avidity membrane binding, stabilization of contractile ring components at the medial cortex, and the fidelity of cytokinesis. F-BAR oligomerization is also critical for Fer and RhoGAP4 physiological function, demonstrating its broad importance to F-BAR proteins that function without membrane bending. Copyright © 2015 Elsevier Inc. All rights reserved.

Supra-domains: evolutionary units larger than single protein domains.

PubMed

Vogel, Christine; Berzuini, Carlo; Bashton, Matthew; Gough, Julian; Teichmann, Sarah A

2004-02-20

Domains are the evolutionary units that comprise proteins, and most proteins are built from more than one domain. Domains can be shuffled by recombination to create proteins with new arrangements of domains. Using structural domain assignments, we examined the combinations of domains in the proteins of 131 completely sequenced organisms. We found two-domain and three-domain combinations that recur in different protein contexts with different partner domains. The domains within these combinations have a particular functional and spatial relationship. These units are larger than individual domains and we term them "supra-domains". Amongst the supra-domains, we identified some 1400 (1203 two-domain and 166 three-domain) combinations that are statistically significantly over-represented relative to the occurrence and versatility of the individual component domains. Over one-third of all structurally assigned multi-domain proteins contain these over-represented supra-domains. This means that investigation of the structural and functional relationships of the domains forming these popular combinations would be particularly useful for an understanding of multi-domain protein function and evolution as well as for genome annotation. These and other supra-domains were analysed for their versatility, duplication, their distribution across the three kingdoms of life and their functional classes. By examining the three-dimensional structures of several examples of supra-domains in different biological processes, we identify two basic types of spatial relationships between the component domains: the combined function of the two domains is such that either the geometry of the two domains is crucial and there is a tight constraint on the interface, or the precise orientation of the domains is less important and they are spatially separate. Frequently, the role of the supra-domain becomes clear only once the three-dimensional structure is known. Since this is the case for only a quarter of the supra-domains, we provide a list of the most important unknown supra-domains as potential targets for structural genomics projects.

Evaluating, Comparing, and Interpreting Protein Domain Hierarchies

PubMed Central

2014-01-01

Abstract Arranging protein domain sequences hierarchically into evolutionarily divergent subgroups is important for investigating evolutionary history, for speeding up web-based similarity searches, for identifying sequence determinants of protein function, and for genome annotation. However, whether or not a particular hierarchy is optimal is often unclear, and independently constructed hierarchies for the same domain can often differ significantly. This article describes methods for statistically evaluating specific aspects of a hierarchy, for probing the criteria underlying its construction and for direct comparisons between hierarchies. Information theoretical notions are used to quantify the contributions of specific hierarchical features to the underlying statistical model. Such features include subhierarchies, sequence subgroups, individual sequences, and subgroup-associated signature patterns. Underlying properties are graphically displayed in plots of each specific feature's contributions, in heat maps of pattern residue conservation, in “contrast alignments,” and through cross-mapping of subgroups between hierarchies. Together, these approaches provide a deeper understanding of protein domain functional divergence, reveal uncertainties caused by inconsistent patterns of sequence conservation, and help resolve conflicts between competing hierarchies. PMID:24559108

Changes in the folding landscape of the WW domain provide a molecular mechanism for an inherited genetic syndrome.

PubMed

Pucheta-Martinez, Encarna; D'Amelio, Nicola; Lelli, Moreno; Martinez-Torrecuadrada, Jorge L; Sudol, Marius; Saladino, Giorgio; Gervasio, Francesco Luigi

2016-07-26

WW domains are small domains present in many human proteins with a wide array of functions and acting through the recognition of proline-rich sequences. The WW domain belonging to polyglutamine tract-binding protein 1 (PQBP1) is of particular interest due to its direct involvement in several X chromosome-linked intellectual disabilities, including Golabi-Ito-Hall (GIH) syndrome, where a single point mutation (Y65C) correlates with the development of the disease. The mutant cannot bind to its natural ligand WBP11, which regulates mRNA processing. In this work we use high-field high-resolution NMR and enhanced sampling molecular dynamics simulations to gain insight into the molecular causes the disease. We find that the wild type protein is partially unfolded exchanging among multiple beta-strand-like conformations in solution. The Y65C mutation further destabilizes the residual fold and primes the protein for the formation of a disulphide bridge, which could be at the origin of the loss of function.

Changes in the folding landscape of the WW domain provide a molecular mechanism for an inherited genetic syndrome

NASA Astrophysics Data System (ADS)

Pucheta-Martinez, Encarna; D'Amelio, Nicola; Lelli, Moreno; Martinez-Torrecuadrada, Jorge L.; Sudol, Marius; Saladino, Giorgio; Gervasio, Francesco Luigi

2016-07-01

WW domains are small domains present in many human proteins with a wide array of functions and acting through the recognition of proline-rich sequences. The WW domain belonging to polyglutamine tract-binding protein 1 (PQBP1) is of particular interest due to its direct involvement in several X chromosome-linked intellectual disabilities, including Golabi-Ito-Hall (GIH) syndrome, where a single point mutation (Y65C) correlates with the development of the disease. The mutant cannot bind to its natural ligand WBP11, which regulates mRNA processing. In this work we use high-field high-resolution NMR and enhanced sampling molecular dynamics simulations to gain insight into the molecular causes the disease. We find that the wild type protein is partially unfolded exchanging among multiple beta-strand-like conformations in solution. The Y65C mutation further destabilizes the residual fold and primes the protein for the formation of a disulphide bridge, which could be at the origin of the loss of function.

Pair correlation functions for identifying spatial correlation in discrete domains

NASA Astrophysics Data System (ADS)

Gavagnin, Enrico; Owen, Jennifer P.; Yates, Christian A.

2018-06-01

Identifying and quantifying spatial correlation are important aspects of studying the collective behavior of multiagent systems. Pair correlation functions (PCFs) are powerful statistical tools that can provide qualitative and quantitative information about correlation between pairs of agents. Despite the numerous PCFs defined for off-lattice domains, only a few recent studies have considered a PCF for discrete domains. Our work extends the study of spatial correlation in discrete domains by defining a new set of PCFs using two natural and intuitive definitions of distance for a square lattice: the taxicab and uniform metric. We show how these PCFs improve upon previous attempts and compare between the quantitative data acquired. We also extend our definitions of the PCF to other types of regular tessellation that have not been studied before, including hexagonal, triangular, and cuboidal. Finally, we provide a comprehensive PCF for any tessellation and metric, allowing investigation of spatial correlation in irregular lattices for which recognizing correlation is less intuitive.

Sirt1 carboxyl-domain is an ATP-repressible domain that is transferrable to other proteins

PubMed Central

Kang, Hyeog; Oka, Shinichi; Lee, Duck-Yeon; Park, Junhong; Aponte, Angel M.; Jung, Young-Sang; Bitterman, Jacob; Zhai, Peiyong; He, Yi; Kooshapur, Hamed; Ghirlando, Rodolfo; Tjandra, Nico; Lee, Sean B.; Kim, Myung K.; Sadoshima, Junichi; Chung, Jay H.

2017-01-01

Sirt1 is an NAD+-dependent protein deacetylase that regulates many physiological functions, including stress resistance, adipogenesis, cell senescence and energy production. Sirt1 can be activated by energy deprivation, but the mechanism is poorly understood. Here, we report that Sirt1 is negatively regulated by ATP, which binds to the C-terminal domain (CTD) of Sirt1. ATP suppresses Sirt1 activity by impairing the CTD's ability to bind to the deacetylase domain as well as its ability to function as the substrate recruitment site. ATP, but not NAD+, causes a conformational shift to a less compact structure. Mutations that prevent ATP binding increase Sirt1's ability to promote stress resistance and inhibit adipogenesis under high-ATP conditions. Interestingly, the CTD can be attached to other proteins, thereby converting them into energy-regulated proteins. These discoveries provide insight into how extreme energy deprivation can impact Sirt1 activity and underscore the complex nature of Sirt1 structure and regulation. PMID:28504272

The International Index of Erectile Function: development of an adapted tool for use in HIV-positive men who have sex with men.

PubMed

Coyne, Katherine; Mandalia, Sundhiya; McCullough, Sonya; Catalan, Jose; Noestlinger, Christiana; Colebunders, Robert; Asboe, David

2010-02-01

Erectile dysfunction is common in HIV-positive men who have sex with men (MSM). A standardized scale is needed to assess erectile function in clinical practice and research studies. The International Index of Erectile Function (IIEF) is a widely accepted tool for assessing erectile function designed for heterosexual men. We modified the tool for MSM. We present an analysis of internal consistency of the questionnaire in an HIV-positive cohort. The adapted questionnaire included modified questions within each of the five domains of the IIEF: (i) erectile function, (ii) intercourse satisfaction, (iii) orgasmic function, (iv) sexual desire, and (v) overall satisfaction with sex. MSM at seven European HIV treatment centers completed the questionnaire. Responses were analyzed for internal consistency using standardized Cronbach's alpha values within each of the five domains. A factor analysis was performed to confirm the domain structure of the questionnaire. Data from 486 MSM were analyzed. The factor analysis supported the domain structure described. Questions about erectile function, orgasmic function, and sexual desire performed well, with Cronbach's alpha values of 0.82, 0.83, and 0.89, respectively. Questions concerning intercourse satisfaction were less consistent (Cronbach's alpha 0.55) because frequency of attempts at sexual intercourse did not correlate with other responses. Responses about satisfaction with sex with a regular partner diverged from satisfaction with overall sex life. Frequency of morning erections diverged from other aspects of erectile function, whereas erections with masturbation correlated better. Internal consistency was high overall. This tool is suitable for HIV-positive MSM and can be used in screening, research, and monitoring treatment response.

Transcriptomic Signature of the SHATTERPROOF2 Expression Domain Reveals the Meristematic Nature of Arabidopsis Gynoecial Medial Domain1[OPEN

PubMed Central

Villarino, Gonzalo H.; Hu, Qiwen; Flores-Vergara, Miguel; Sehra, Bhupinder; Brumos, Javier; Stepanova, Anna N.; Sundberg, Eva; Heber, Steffen

2016-01-01

Plant meristems, like animal stem cell niches, maintain a pool of multipotent, undifferentiated cells that divide and differentiate to give rise to organs. In Arabidopsis (Arabidopsis thaliana), the carpel margin meristem is a vital meristematic structure that generates ovules from the medial domain of the gynoecium, the female floral reproductive structure. The molecular mechanisms that specify this meristematic region and regulate its organogenic potential are poorly understood. Here, we present a novel approach to analyze the transcriptional signature of the medial domain of the Arabidopsis gynoecium, highlighting the developmental stages that immediately proceed ovule initiation, the earliest stages of seed development. Using a floral synchronization system and a SHATTERPROOF2 (SHP2) domain-specific reporter, paired with FACS and RNA sequencing, we assayed the transcriptome of the gynoecial medial domain with temporal and spatial precision. This analysis reveals a set of genes that are differentially expressed within the SHP2 expression domain, including genes that have been shown previously to function during the development of medial domain-derived structures, including the ovules, thus validating our approach. Global analyses of the transcriptomic data set indicate a similarity of the pSHP2-expressing cell population to previously characterized meristematic domains, further supporting the meristematic nature of this gynoecial tissue. Our method identifies additional genes including novel isoforms, cis-natural antisense transcripts, and a previously unrecognized member of the REPRODUCTIVE MERISTEM family of transcriptional regulators that are potential novel regulators of medial domain development. This data set provides genome-wide transcriptional insight into the development of the carpel margin meristem in Arabidopsis. PMID:26983993

Structure and function of NADPH-cytochrome P450 reductase and nitric oxide synthase reductase domain

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

Iyanagi, Takashi

2005-12-09

NADPH-cytochrome P450 reductase (CPR) and the nitric oxide synthase (NOS) reductase domains are members of the FAD-FMN family of proteins. The FAD accepts two reducing equivalents from NADPH (dehydrogenase flavin) and FMN acts as a one-electron carrier (flavodoxin-type flavin) for the transfer from NADPH to the heme protein, in which the FMNH {sup {center_dot}}/FMNH{sub 2} couple donates electrons to cytochrome P450 at constant oxidation-reduction potential. Although the interflavin electron transfer between FAD and FMN is not strictly regulated in CPR, electron transfer is activated in neuronal NOS reductase domain upon binding calmodulin (CaM), in which the CaM-bound activated form canmore » function by a similar mechanism to that of CPR. The oxygenated form and spin state of substrate-bound cytochrome P450 in perfused rat liver are also discussed in terms of stepwise one-electron transfer from CPR. This review provides a historical perspective of the microsomal mixed-function oxidases including CPR and P450. In addition, a new model for the redox-linked conformational changes during the catalytic cycle for both CPR and NOS reductase domain is also discussed.« less

Exploring the evolution of protein function in Archaea.

PubMed

Goncearenco, Alexander; Berezovsky, Igor N

2012-05-30

Despite recent progress in studies of the evolution of protein function, the questions what were the first functional protein domains and what were their basic building blocks remain unresolved. Previously, we introduced the concept of elementary functional loops (EFLs), which are the functional units of enzymes that provide elementary reactions in biochemical transformations. They are presumably descendants of primordial catalytic peptides. We analyzed distant evolutionary connections between protein functions in Archaea based on the EFLs comprising them. We show examples of the involvement of EFLs in new functional domains, as well as reutilization of EFLs and functional domains in building multidomain structures and protein complexes. Our analysis of the archaeal superkingdom yields the dominating mechanisms in different periods of protein evolution, which resulted in several levels of the organization of biochemical function. First, functional domains emerged as combinations of prebiotic peptides with the very basic functions, such as nucleotide/phosphate and metal cofactor binding. Second, domain recombination brought to the evolutionary scene the multidomain proteins and complexes. Later, reutilization and de novo design of functional domains and elementary functional loops complemented evolution of protein function.

Patients' perspectives on quality of life after burn.

PubMed

Kool, Marianne B; Geenen, Rinie; Egberts, Marthe R; Wanders, Hendriët; Van Loey, Nancy E

2017-06-01

The concept quality of life (QOL) refers to both health-related outcomes and one's skills to reach these outcomes, which is not yet incorporated in the burn-related QOL conceptualisation. The aim of this study was to obtain a comprehensive overview of relevant burn-specific domains of QOL from the patient's perspective and to determine its hierarchical structure. Concept mapping was used comprising a focus group (n=6), interviews (n=25), and a card-sorting task (n=24) in burn survivors. Participants sorted aspects of QOL based on content similarity after which hierarchical cluster analysis was used to determine the hierarchical structure of burn-related QOL. Ninety-nine aspects of burn-related QOL were selected from the interviews, written on cards, and sorted. The hierarchical structure of burn-related QOL showed a core distinction between resilience and vulnerability. Resilience comprised the domains positive coping and social sharing. Vulnerability included 5 domains subdivided in 13 subdomains: the psychological domain included trauma-related symptoms, cognitive symptoms, negative emotions, body perception and depressive mood; the economical domain comprised finance and work; the social domain included stigmatisation/invalidation; the physical domain comprised somatic symptoms, scars, and functional limitations; and the intimate/sexual domain comprised the relationship with partner, and anxiety/avoidance in sexual life. From the patient's perspective, QOL following burns includes a variety of vulnerability and resilience factors, which forms a fresh basis for the development of a screening instrument. Whereas some factors are well known, this study also revealed overlooked problem and resilience areas that could be considered in client-centred clinical practice in order to customize self-management support. Copyright © 2016 Elsevier Ltd and ISBI. All rights reserved.

The use of cell microinjection for the in vivo analysis of viral transcriptional regulatory protein domains.

PubMed

Green, Maurice; Thorburn, Andrew; Kern, Robert; Loewenstein, Paul M

2007-01-01

Microinjection of mammalian cells provides a powerful method for analyzing in vivo functions of viral genes and viral gene products. By microinjection, a controlled amount (ranging from several to many thousands of copies) of a viral or cellular gene, a protein product of a gene, a polypeptide fragment encoding a specific protein domain, or an RNA molecule can be delivered into a target cell and the functional consequences analyzed. Microinjection can be used to deliver antibody targeted to a specific protein domain in order to analyze the requirement of the protein for specific cell functions such as cell cycle progression, transcription of specific genes, or intracellular transport. This chapter describes examples of the successful use of microinjection to probe adenovirus E1A regulatory mechanisms. Detailed methods are provided for manual and semiautomatic microinjection of mammalian cells as well as bioassay protocols for microinjected cells including immunofluorescence, colorimetic, in situ hybridization, and autoradiography.

Archaeal MCM has separable processivity, substrate choice and helicase domains

PubMed Central

Barry, Elizabeth R.; McGeoch, Adam T.; Kelman, Zvi; Bell, Stephen D.

2007-01-01

The mini-chromosome maintenance (MCM) complex is the principal candidate for the replicative helicase of archaea and eukaryotes. Here, we describe a functional dissection of the roles of the three principal structural modules of the homomultimeric MCM of the hyperthermophilic archaeon Sulfolobus solfataricus. Our results include the first analysis of the central AAA+ domain in isolation. This domain possesses ATPase and helicase activity, defining this as the minimal helicase domain. Reconstitution experiments show that the helicase activity of the AAA+ domain can be stimulated by addition of the isolated N-terminal half in trans. Addition of the N-terminus influences both the processivity of the helicase and the choice of substrate that can be melted by the ATPase domain. The degenerate helix-turn-helix domain at the C-terminus of MCM exerts a negative effect on the helicase activity of the complex. These results provide the first evidence for extensive regulatory inter-domain communication within the MCM complex. PMID:17259218

High-Throughput Quantification of SH2 Domain-Phosphopeptide Interactions with Cellulose-Peptide Conjugate Microarrays.

PubMed

Engelmann, Brett W

2017-01-01

The Src Homology 2 (SH2) domain family primarily recognizes phosphorylated tyrosine (pY) containing peptide motifs. The relative affinity preferences among competing SH2 domains for phosphopeptide ligands define "specificity space," and underpins many functional pY mediated interactions within signaling networks. The degree of promiscuity exhibited and the dynamic range of affinities supported by individual domains or phosphopeptides is best resolved by a carefully executed and controlled quantitative high-throughput experiment. Here, I describe the fabrication and application of a cellulose-peptide conjugate microarray (CPCMA) platform to the quantitative analysis of SH2 domain specificity space. Included herein are instructions for optimal experimental design with special attention paid to common sources of systematic error, phosphopeptide SPOT synthesis, microarray fabrication, analyte titrations, data capture, and analysis.

Association of social-environmental factors with cognitive function in children with sickle cell disease.

PubMed

Yarboi, Janet; Compas, Bruce E; Brody, Gene H; White, Desiree; Rees Patterson, Jenny; Ziara, Kristen; King, Allison

2017-04-01

The aim of this study was to examine the relationship between cognitive function in pediatric sickle cell disease (SCD) patients and mothers' reports of social-environmental stress, depressive symptoms, and parenting. A total of 65 children with SCD completed comprehensive neuropsychological testing to assess several domains of cognitive functioning, including general intellectual ability, academic achievement, and executive function. Mothers reported on demographics, social-environmental stress, depressive symptoms, and parenting. As predicted, children with SCD significantly underperformed relative to normative data on measures of cognitive function. Associations between maternal social-environmental stress, maternal depressive symptoms, and parenting were mixed. The results show partial support for the hypothesis that greater stress and depressive symptoms and less positive parenting are associated with poorer cognitive function in children with SCD. Linear regression analyses showed that maternal financial stress was the strongest predictor across all domains of cognitive function. The findings replicate and extend past research, reaffirming that children with SCD are at risk for cognitive impairment across multiple domains. Additionally, social-environmental stress, particularly financial strain, is linked to mothers' depressive symptoms and parenting behaviors as well as children's cognitive function. Future studies using direct observations of parenting behaviors are needed. These findings, along with recent research on parenting interventions, may inform the development of concrete, teachable parenting and coping skills to improve cognitive functioning in children with SCD.

Axonal Membranes and Their Domains: Assembly and Function of the Axon Initial Segment and Node of Ranvier

PubMed Central

Nelson, Andrew D.; Jenkins, Paul M.

2017-01-01

Neurons are highly specialized cells of the nervous system that receive, process and transmit electrical signals critical for normal brain function. Here, we review the intricate organization of axonal membrane domains that facilitate rapid action potential conduction underlying communication between complex neuronal circuits. Two critical excitable domains of vertebrate axons are the axon initial segment (AIS) and the nodes of Ranvier, which are characterized by the high concentrations of voltage-gated ion channels, cell adhesion molecules and specialized cytoskeletal networks. The AIS is located at the proximal region of the axon and serves as the site of action potential initiation, while nodes of Ranvier, gaps between adjacent myelin sheaths, allow rapid propagation of the action potential through saltatory conduction. The AIS and nodes of Ranvier are assembled by ankyrins, spectrins and their associated binding partners through the clustering of membrane proteins and connection to the underlying cytoskeleton network. Although the AIS and nodes of Ranvier share similar protein composition, their mechanisms of assembly are strikingly different. Here we will cover the mechanisms of formation and maintenance of these axonal excitable membrane domains, specifically highlighting the similarities and differences between them. We will also discuss recent advances in super resolution fluorescence imaging which have elucidated the arrangement of the submembranous axonal cytoskeleton revealing a surprising structural organization necessary to maintain axonal organization and function. Finally, human mutations in axonal domain components have been associated with a growing number of neurological disorders including severe cognitive dysfunction, epilepsy, autism, neurodegenerative diseases and psychiatric disorders. Overall, this review highlights the assembly, maintenance and function of axonal excitable domains, particularly the AIS and nodes of Ranvier, and how abnormalities in these processes may contribute to disease. PMID:28536506

Modulation of chaperone function and cochaperone interaction by novobiocin in the C-terminal domain of Hsp90: evidence that coumarin antibiotics disrupt Hsp90 dimerization.

PubMed

Allan, Rudi K; Mok, Danny; Ward, Bryan K; Ratajczak, Thomas

2006-03-17

The C-terminal domain of Hsp90 displays independent chaperone activity, mediates dimerization, and contains the MEEVD motif essential for interaction with tetratricopeptide repeat-containing immunophilin cochaperones assembled in mature steroid receptor complexes. An alpha-helical region, upstream of the MEEVD peptide, helps form the dimerization interface and includes a hydrophobic microdomain that contributes to the Hsp90 interaction with the immunophilin cochaperones and corresponds to the binding site for novobiocin, a coumarin-related Hsp90 inhibitor. Mutation of selected residues within the hydrophobic microdomain significantly impacted the chaperone function of a recombinant C-terminal Hsp90 fragment and novobiocin inhibited wild-type chaperone activity. Prior incubation of the Hsp90 fragment with novobiocin led to a direct blockade of immunophilin cochaperone binding. However, the drug had little influence on the pre-formed Hsp90-immunophilin complex, suggesting that bound cochaperones mask the novobiocin-binding site. We observed a differential effect of the drug on Hsp90-immunophilin interaction, suggesting that the immunophilins make distinct contacts within the C-terminal domain to specifically modulate Hsp90 function. Novobiocin also precluded the interaction of full-length Hsp90 with the p50(cdc37) cochaperone, which targets the N-terminal nucleotide-binding domain, and is prevalent in Hsp90 complexes with protein kinase substrates. Novobiocin therefore acts locally and allosterically to induce conformational changes within multiple regions of the Hsp90 protein. We provide evidence that coumermycin A1, a coumarin structurally related to novobiocin, interferes with dimerization of the Hsp90 C-terminal domain. Coumarin-based inhibitors then may antagonize Hsp90 function by inducing a conformation favoring separation of the C-terminal domains and release of substrate.

Recommendation for measuring clinical outcome in distal radius fractures: a core set of domains for standardized reporting in clinical practice and research.

PubMed

Goldhahn, Jörg; Beaton, Dorcas; Ladd, Amy; Macdermid, Joy; Hoang-Kim, Amy

2014-02-01

Lack of standardization of outcome measurement has hampered an evidence-based approach to clinical practice and research. We adopted a process of reviewing evidence on current use of measures and appropriate theoretical frameworks for health and disability to inform a consensus process that was focused on deriving the minimal set of core domains in distal radius fracture. We agreed on the following seven core recommendations: (1) pain and function were regarded as the primary domains, (2) very brief measures were needed for routine administration in clinical practice, (3) these brief measures could be augmented by additional measures that provide more detail or address additional domains for clinical research, (4) measurement of pain should include measures of both intensity and frequency as core attributes, (5) a numeric pain scale, e.g. visual analogue scale or visual numeric scale or the pain subscale of the patient-reported wrist evaluation (PRWE) questionnaires were identified as reliable, valid and feasible measures to measure these concepts, (6) for function, either the Quick Disability of the arm, shoulder and hand questionnaire or PRWE-function subscale was identified as reliable, valid and feasible measures, and (7) a measure of participation and treatment complications should be considered core outcomes for both clinical practice and research. We used a sound methodological approach to form a comprehensive foundation of content for outcomes in the area of distal radius fractures. We recommend the use of symptom and function as separate domains in the ICF core set in clinical research or practice for patients with wrist fracture. Further research is needed to provide more definitive measurement properties of measures across all domains.

Evolutionary versatility of eukaryotic protein domains revealed by their bigram networks

PubMed Central

2011-01-01

Background Protein domains are globular structures of independently folded polypeptides that exert catalytic or binding activities. Their sequences are recognized as evolutionary units that, through genome recombination, constitute protein repertoires of linkage patterns. Via mutations, domains acquire modified functions that contribute to the fitness of cells and organisms. Recent studies have addressed the evolutionary selection that may have shaped the functions of individual domains and the emergence of particular domain combinations, which led to new cellular functions in multi-cellular animals. This study focuses on modeling domain linkage globally and investigates evolutionary implications that may be revealed by novel computational analysis. Results A survey of 77 completely sequenced eukaryotic genomes implies a potential hierarchical and modular organization of biological functions in most living organisms. Domains in a genome or multiple genomes are modeled as a network of hetero-duplex covalent linkages, termed bigrams. A novel computational technique is introduced to decompose such networks, whereby the notion of domain "networking versatility" is derived and measured. The most and least "versatile" domains (termed "core domains" and "peripheral domains" respectively) are examined both computationally via sequence conservation measures and experimentally using selected domains. Our study suggests that such a versatility measure extracted from the bigram networks correlates with the adaptivity of domains during evolution, where the network core domains are highly adaptive, significantly contrasting the network peripheral domains. Conclusions Domain recombination has played a major part in the evolution of eukaryotes attributing to genome complexity. From a system point of view, as the results of selection and constant refinement, networks of domain linkage are structured in a hierarchical modular fashion. Domains with high degree of networking versatility appear to be evolutionary adaptive, potentially through functional innovations. Domain bigram networks are informative as a model of biological functions. The networking versatility indices extracted from such networks for individual domains reflect the strength of evolutionary selection that the domains have experienced. PMID:21849086

Evolutionary versatility of eukaryotic protein domains revealed by their bigram networks.

PubMed

Xie, Xueying; Jin, Jing; Mao, Yongyi

2011-08-18

Protein domains are globular structures of independently folded polypeptides that exert catalytic or binding activities. Their sequences are recognized as evolutionary units that, through genome recombination, constitute protein repertoires of linkage patterns. Via mutations, domains acquire modified functions that contribute to the fitness of cells and organisms. Recent studies have addressed the evolutionary selection that may have shaped the functions of individual domains and the emergence of particular domain combinations, which led to new cellular functions in multi-cellular animals. This study focuses on modeling domain linkage globally and investigates evolutionary implications that may be revealed by novel computational analysis. A survey of 77 completely sequenced eukaryotic genomes implies a potential hierarchical and modular organization of biological functions in most living organisms. Domains in a genome or multiple genomes are modeled as a network of hetero-duplex covalent linkages, termed bigrams. A novel computational technique is introduced to decompose such networks, whereby the notion of domain "networking versatility" is derived and measured. The most and least "versatile" domains (termed "core domains" and "peripheral domains" respectively) are examined both computationally via sequence conservation measures and experimentally using selected domains. Our study suggests that such a versatility measure extracted from the bigram networks correlates with the adaptivity of domains during evolution, where the network core domains are highly adaptive, significantly contrasting the network peripheral domains. Domain recombination has played a major part in the evolution of eukaryotes attributing to genome complexity. From a system point of view, as the results of selection and constant refinement, networks of domain linkage are structured in a hierarchical modular fashion. Domains with high degree of networking versatility appear to be evolutionary adaptive, potentially through functional innovations. Domain bigram networks are informative as a model of biological functions. The networking versatility indices extracted from such networks for individual domains reflect the strength of evolutionary selection that the domains have experienced.

Chemical Shift Assignments of the C-terminal Eps15 Homology Domain-3 EH Domain*

PubMed Central

Caplan, Steve; Sorgen, Paul L.

2013-01-01

The C-terminal Eps15 homology (EH) domain 3 (EHD3) belongs to a eukaryotic family of endocytic regulatory proteins and is involved in the recycling of various receptors from the early endosome to the endocytic recycling compartment or in retrograde transport from the endosomes to the Golgi. EH domains are highly conserved in the EHD family and function as protein-protein interaction units that bind to Asn-Pro-Phe (NPF) motif-containing proteins. The EH domain of EHD1 was the first C-terminal EH domain from the EHD family to be solved by NMR. The differences observed between this domain and proteins with N-terminal EH domains helped describe a mechanism for the differential binding of NPF-containing proteins. Here, structural studies were expanded to include the EHD3 EH domain. While the EHD1 and EHD3 EH domains are highly homologous, they have different protein partners. A comparison of these structures will help determine the selectivity in protein binding between the EHD family members and lead to a better understanding of their unique roles in endocytic regulation. PMID:23754701

Phosphotyrosine recognition domains: the typical, the atypical and the versatile

PubMed Central

2012-01-01

SH2 domains are long known prominent players in the field of phosphotyrosine recognition within signaling protein networks. However, over the years they have been joined by an increasing number of other protein domain families that can, at least with some of their members, also recognise pTyr residues in a sequence-specific context. This superfamily of pTyr recognition modules, which includes substantial fractions of the PTB domains, as well as much smaller, or even single member fractions like the HYB domain, the PKCδ and PKCθ C2 domains and RKIP, represents a fascinating, medically relevant and hence intensely studied part of the cellular signaling architecture of metazoans. Protein tyrosine phosphorylation clearly serves a plethora of functions and pTyr recognition domains are used in a similarly wide range of interaction modes, which encompass, for example, partner protein switching, tandem recognition functionalities and the interaction with catalytically active protein domains. If looked upon closely enough, virtually no pTyr recognition and regulation event is an exact mirror image of another one in the same cell. Thus, the more we learn about the biology and ultrastructural details of pTyr recognition domains, the more does it become apparent that nature cleverly combines and varies a few basic principles to generate a sheer endless number of sophisticated and highly effective recognition/regulation events that are, under normal conditions, elegantly orchestrated in time and space. This knowledge is also valuable when exploring pTyr reader domains as diagnostic tools, drug targets or therapeutic reagents to combat human diseases. PMID:23134684

Interaction mode between catalytic and regulatory subunits in glucosidase II involved in ER glycoprotein quality control.

PubMed

Satoh, Tadashi; Toshimori, Takayasu; Noda, Masanori; Uchiyama, Susumu; Kato, Koichi

2016-11-01

The glycoside hydrolase family 31 (GH31) α-glucosidases play vital roles in catabolic and regulated degradation, including the α-subunit of glucosidase II (GIIα), which catalyzes trimming of the terminal glucose residues of N-glycan in glycoprotein processing coupled with quality control in the endoplasmic reticulum (ER). Among the known GH31 enzymes, only GIIα functions with its binding partner, regulatory β-subunit (GIIβ), which harbors a lectin domain for substrate recognition. Although the structural data have been reported for GIIα and the GIIβ lectin domain, the interaction mode between GIIα and GIIβ remains unknown. Here, we determined the structure of a complex formed between GIIα and the GIIα-binding domain of GIIβ, thereby providing a structural basis underlying the functional extension of this unique GH31 enzyme. © 2016 The Protein Society.

FERM proteins in animal morphogenesis.

PubMed

Tepass, Ulrich

2009-08-01

Proteins containing a FERM domain are ubiquitous components of the cytocortex of animal cells where they are engaged in structural, transport, and signaling functions. Recent years have seen a wealth of genetic studies in model organisms that explore FERM protein function in development and tissue organization. In addition, mutations in several FERM protein-encoding genes have been associated with human diseases. This review will provide a brief overview of the FERM domain structure and the FERM protein superfamily and then discuss recent advances in our understanding of the mechanism of function and developmental requirement of several FERM proteins including Moesin, Myosin-VIIA, Myosin-XV, Coracle/Band4.1 as well as Yurt and its vertebrate homologs Mosaic Eyes and EPB41L5/YMO1/Limulus.

FARE-CAFE: a database of functional and regulatory elements of cancer-associated fusion events.

PubMed

Korla, Praveen Kumar; Cheng, Jack; Huang, Chien-Hung; Tsai, Jeffrey J P; Liu, Yu-Hsuan; Kurubanjerdjit, Nilubon; Hsieh, Wen-Tsong; Chen, Huey-Yi; Ng, Ka-Lok

2015-01-01

Chromosomal translocation (CT) is of enormous clinical interest because this disorder is associated with various major solid tumors and leukemia. A tumor-specific fusion gene event may occur when a translocation joins two separate genes. Currently, various CT databases provide information about fusion genes and their genomic elements. However, no database of the roles of fusion genes, in terms of essential functional and regulatory elements in oncogenesis, is available. FARE-CAFE is a unique combination of CTs, fusion proteins, protein domains, domain-domain interactions, protein-protein interactions, transcription factors and microRNAs, with subsequent experimental information, which cannot be found in any other CT database. Genomic DNA information including, for example, manually collected exact locations of the first and second break points, sequences and karyotypes of fusion genes are included. FARE-CAFE will substantially facilitate the cancer biologist's mission of elucidating the pathogenesis of various types of cancer. This database will ultimately help to develop 'novel' therapeutic approaches. Database URL: http://ppi.bioinfo.asia.edu.tw/FARE-CAFE. © The Author(s) 2015. Published by Oxford University Press.

OST-HTH: a novel predicted RNA-binding domain

PubMed Central

2010-01-01

Background The mechanism by which the arthropod Oskar and vertebrate TDRD5/TDRD7 proteins nucleate or organize structurally related ribonucleoprotein (RNP) complexes, the polar granule and nuage, is poorly understood. Using sequence profile searches we identify a novel domain in these proteins that is widely conserved across eukaryotes and bacteria. Results Using contextual information from domain architectures, sequence-structure superpositions and available functional information we predict that this domain is likely to adopt the winged helix-turn-helix fold and bind RNA with a potential specificity for dsRNA. We show that in eukaryotes this domain is often combined in the same polypeptide with protein-protein- or lipid- interaction domains that might play a role in anchoring these proteins to specific cytoskeletal structures. Conclusions Thus, proteins with this domain might have a key role in the recognition and localization of dsRNA, including miRNAs, rasiRNAs and piRNAs hybridized to their targets. In other cases, this domain is fused to ubiquitin-binding, E3 ligase and ubiquitin-like domains indicating a previously under-appreciated role for ubiquitination in regulating the assembly and stability of nuage-like RNP complexes. Both bacteria and eukaryotes encode a conserved family of proteins that combines this predicted RNA-binding domain with a previously uncharacterized domain (DUF88). We present evidence that it is an RNAse belonging to the superfamily that includes the 5'->3' nucleases, PIN and NYN domains and might be recruited to degrade certain RNAs. Reviewers This article was reviewed by Sandor Pongor and Arcady Mushegian. PMID:20302647

Functional and topological characteristics of mammalian regulatory domains

PubMed Central

Symmons, Orsolya; Uslu, Veli Vural; Tsujimura, Taro; Ruf, Sandra; Nassari, Sonya; Schwarzer, Wibke; Ettwiller, Laurence; Spitz, François

2014-01-01

Long-range regulatory interactions play an important role in shaping gene-expression programs. However, the genomic features that organize these activities are still poorly characterized. We conducted a large operational analysis to chart the distribution of gene regulatory activities along the mouse genome, using hundreds of insertions of a regulatory sensor. We found that enhancers distribute their activities along broad regions and not in a gene-centric manner, defining large regulatory domains. Remarkably, these domains correlate strongly with the recently described TADs, which partition the genome into distinct self-interacting blocks. Different features, including specific repeats and CTCF-binding sites, correlate with the transition zones separating regulatory domains, and may help to further organize promiscuously distributed regulatory influences within large domains. These findings support a model of genomic organization where TADs confine regulatory activities to specific but large regulatory domains, contributing to the establishment of specific gene expression profiles. PMID:24398455

Vortex Domain Structure in Ferroelectric Nanoplatelets and Control of its Transformation by Mechanical Load

PubMed Central

Chen, W. J.; Zheng, Yue; Wang, Biao

2012-01-01

Vortex domain patterns in low-dimensional ferroelectrics and multiferroics have been extensively studied with the aim of developing nanoscale functional devices. However, control of the vortex domain structure has not been investigated systematically. Taking into account effects of inhomogeneous electromechanical fields, ambient temperature, surface and size, we demonstrate significant influence of mechanical load on the vortex domain structure in ferroelectric nanoplatelets. Our analysis shows that the size and number of dipole vortices can be controlled by mechanical load, and yields rich temperature-stress (T-S) phase diagrams. Simulations also reveal that transformations between “vortex states” induced by the mechanical load are possible, which is totally different from the conventional way controlled on the vortex domain by the electric field. These results are relevant to application of vortex domain structures in ferroelectric nanodevices, and suggest a novel route to applications including memories, mechanical sensors and transducers. PMID:23150769

Molecular basis for TPR domain-mediated regulation of protein phosphatase 5.

PubMed

Yang, Jing; Roe, S Mark; Cliff, Matthew J; Williams, Mark A; Ladbury, John E; Cohen, Patricia T W; Barford, David

2005-01-12

Protein phosphatase 5 (Ppp5) is a serine/threonine protein phosphatase comprising a regulatory tetratricopeptide repeat (TPR) domain N-terminal to its phosphatase domain. Ppp5 functions in signalling pathways that control cellular responses to stress, glucocorticoids and DNA damage. Its phosphatase activity is suppressed by an autoinhibited conformation maintained by the TPR domain and a C-terminal subdomain. By interacting with the TPR domain, heat shock protein 90 (Hsp90) and fatty acids including arachidonic acid stimulate phosphatase activity. Here, we describe the structure of the autoinhibited state of Ppp5, revealing mechanisms of TPR-mediated phosphatase inhibition and Hsp90- and arachidonic acid-induced stimulation of phosphatase activity. The TPR domain engages with the catalytic channel of the phosphatase domain, restricting access to the catalytic site. This autoinhibited conformation of Ppp5 is stabilised by the C-terminal alphaJ helix that contacts a region of the Hsp90-binding groove on the TPR domain. Hsp90 activates Ppp5 by disrupting TPR-phosphatase domain interactions, permitting substrate access to the constitutively active phosphatase domain, whereas arachidonic acid prompts an alternate conformation of the TPR domain, destabilising the TPR-phosphatase domain interface.

Multiple Functional Domains of Enterococcus faecalis Aggregation Substance Asc10 Contribute to Endocarditis Virulence ▿ †

PubMed Central

Chuang, Olivia N.; Schlievert, Patrick M.; Wells, Carol L.; Manias, Dawn A.; Tripp, Timothy J.; Dunny, Gary M.

2009-01-01

Aggregation substance proteins encoded by sex pheromone plasmids increase the virulence of Enterococcus faecalis in experimental pathogenesis models, including infectious endocarditis models. These large surface proteins may contain multiple functional domains involved in various interactions with other bacterial cells and with the mammalian host. Aggregation substance Asc10, encoded by plasmid pCF10, is induced during growth in the mammalian bloodstream, and pCF10 carriage gives E. faecalis a significant selective advantage in this environment. We employed a rabbit model to investigate the role of various functional domains of Asc10 in endocarditis. The data suggested that the bacterial load of the infected tissue was the best indicator of virulence. Isogenic strains carrying either no plasmid, wild-type pCF10, a pCF10 derivative with an in-frame deletion of the prgB gene encoding Asc10, or pCF10 derivatives expressing other alleles of prgB were examined in this model. Previously identified aggregation domains contributed to the virulence associated with the wild-type protein, and a strain expressing an Asc10 derivative in which glycine residues in two RGD motifs were changed to alanine residues showed the greatest reduction in virulence. Remarkably, this strain and the strain carrying the pCF10 derivative with the in-frame deletion of prgB were both significantly less virulent than an isogenic plasmid-free strain. The data demonstrate that multiple functional domains are important in Asc10-mediated interactions with the host during the course of experimental endocarditis and that in the absence of a functional prgB gene, pCF10 carriage is actually disadvantageous in vivo. PMID:18955479

The EBNA-2 N-Terminal Transactivation Domain Folds into a Dimeric Structure Required for Target Gene Activation.

PubMed

Friberg, Anders; Thumann, Sybille; Hennig, Janosch; Zou, Peijian; Nössner, Elfriede; Ling, Paul D; Sattler, Michael; Kempkes, Bettina

2015-05-01

Epstein-Barr virus (EBV) is a γ-herpesvirus that may cause infectious mononucleosis in young adults. In addition, epidemiological and molecular evidence links EBV to the pathogenesis of lymphoid and epithelial malignancies. EBV has the unique ability to transform resting B cells into permanently proliferating, latently infected lymphoblastoid cell lines. Epstein-Barr virus nuclear antigen 2 (EBNA-2) is a key regulator of viral and cellular gene expression for this transformation process. The N-terminal region of EBNA-2 comprising residues 1-58 appears to mediate multiple molecular functions including self-association and transactivation. However, it remains to be determined if the N-terminus of EBNA-2 directly provides these functions or if these activities merely depend on the dimerization involving the N-terminal domain. To address this issue, we determined the three-dimensional structure of the EBNA-2 N-terminal dimerization (END) domain by heteronuclear NMR-spectroscopy. The END domain monomer comprises a small fold of four β-strands and an α-helix which form a parallel dimer by interaction of two β-strands from each protomer. A structure-guided mutational analysis showed that hydrophobic residues in the dimer interface are required for self-association in vitro. Importantly, these interface mutants also displayed severely impaired self-association and transactivation in vivo. Moreover, mutations of solvent-exposed residues or deletion of the α-helix do not impair dimerization but strongly affect the functional activity, suggesting that the EBNA-2 dimer presents a surface that mediates functionally important intra- and/or intermolecular interactions. Our study shows that the END domain is a novel dimerization fold that is essential for functional activity. Since this specific fold is a unique feature of EBNA-2 it might provide a novel target for anti-viral therapeutics.

Inositol Pentakisphosphate Isomers Bind PH Domains with Varying Specificity and Inhibit Phosphoinositide Interactions

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

S Jackson; S Al-Saigh; C Schultz

2011-12-31

PH domains represent one of the most common domains in the human proteome. These domains are recognized as important mediators of protein-phosphoinositide and protein-protein interactions. Phosphoinositides are lipid components of the membrane that function as signaling molecules by targeting proteins to their sites of action. Phosphoinositide based signaling pathways govern a diverse range of important cellular processes including membrane remodeling, differentiation, proliferation and survival. Myo-Inositol phosphates are soluble signaling molecules that are structurally similar to the head groups of phosphoinositides. These molecules have been proposed to function, at least in part, by regulating PH domain-phosphoinositide interactions. Given the structural similaritymore » of inositol phosphates we were interested in examining the specificity of PH domains towards the family of myo-inositol pentakisphosphate isomers. In work reported here we demonstrate that the C-terminal PH domain of pleckstrin possesses the specificity required to discriminate between different myo-inositol pentakisphosphate isomers. The structural basis for this specificity was determined using high-resolution crystal structures. Moreover, we show that while the PH domain of Grp1 does not possess this high degree of specificity, the PH domain of protein kinase B does. These results demonstrate that some PH domains possess enough specificity to discriminate between myo-inositol pentakisphosphate isomers allowing for these molecules to differentially regulate interactions with phosphoinositides. Furthermore, this work contributes to the growing body of evidence supporting myo-inositol phosphates as regulators of important PH domain-phosphoinositide interactions. Finally, in addition to expanding our knowledge of cellular signaling, these results provide a basis for developing tools to probe biological pathway.« less

Evolution of posterior parietal cortex and parietal-frontal networks for specific actions in primates.

PubMed

Kaas, Jon H; Stepniewska, Iwona

2016-02-15

Posterior parietal cortex (PPC) is an extensive region of the human brain that develops relatively late and is proportionally large compared with that of monkeys and prosimian primates. Our ongoing comparative studies have led to several conclusions about the evolution of this posterior parietal region. In early placental mammals, PPC likely was a small multisensory region much like PPC of extant rodents and tree shrews. In early primates, PPC likely resembled that of prosimian galagos, in which caudal PPC (PPCc) is visual and rostral PPC (PPCr) has eight or more multisensory domains where electrical stimulation evokes different complex motor behaviors, including reaching, hand-to-mouth, looking, protecting the face or body, and grasping. These evoked behaviors depend on connections with functionally matched domains in premotor cortex (PMC) and motor cortex (M1). Domains in each region compete with each other, and a serial arrangement of domains allows different factors to influence motor outcomes successively. Similar arrangements of domains have been retained in New and Old World monkeys, and humans appear to have at least some of these domains. The great expansion and prolonged development of PPC in humans suggest the addition of functionally distinct territories. We propose that, across primates, PMC and M1 domains are second and third levels in a number of parallel, interacting networks for mediating and selecting one type of action over others. © 2015 Wiley Periodicals, Inc.

Structural Interface Forms and Their Involvement in Stabilization of Multidomain Proteins or Protein Complexes.

PubMed

Dygut, Jacek; Kalinowska, Barbara; Banach, Mateusz; Piwowar, Monika; Konieczny, Leszek; Roterman, Irena

2016-10-18

The presented analysis concerns the inter-domain and inter-protein interface in protein complexes. We propose extending the traditional understanding of the protein domain as a function of local compactness with an additional criterion which refers to the presence of a well-defined hydrophobic core. Interface areas in selected homodimers vary with respect to their contribution to share as well as individual (domain-specific) hydrophobic cores. The basic definition of a protein domain, i.e., a structural unit characterized by tighter packing than its immediate environment, is extended in order to acknowledge the role of a structured hydrophobic core, which includes the interface area. The hydrophobic properties of interfaces vary depending on the status of interacting domains-In this context we can distinguish: (1) Shared hydrophobic cores (spanning the whole dimer); (2) Individual hydrophobic cores present in each monomer irrespective of whether the dimer contains a shared core. Analysis of interfaces in dystrophin and utrophin indicates the presence of an additional quasi-domain with a prominent hydrophobic core, consisting of fragments contributed by both monomers. In addition, we have also attempted to determine the relationship between the type of interface (as categorized above) and the biological function of each complex. This analysis is entirely based on the fuzzy oil drop model.

Identification of the essential protein domains for Mib2 function during the development of the Drosophila larval musculature and adult flight muscles.

PubMed

Domsch, Katrin; Acs, Andreas; Obermeier, Claudia; Nguyen, Hanh T; Reim, Ingolf

2017-01-01

The proper differentiation and maintenance of myofibers is fundamental to a functional musculature. Disruption of numerous mostly structural factors leads to perturbations of these processes. Among the limited number of known regulatory factors for these processes is Mind bomb2 (Mib2), a muscle-associated E3 ubiquitin ligase, which was previously established to be required for maintaining the integrity of larval muscles. In this study, we have examined the mechanistic aspects of Mib2 function by performing a detailed functional dissection of the Mib2 protein. We show that the ankyrin repeats, in its entirety, and the hitherto uncharacterized Mib-specific domains (MIB), are important for the major function of Mib2 in skeletal and visceral muscles in the Drosophila embryo. Furthermore, we characterize novel mib2 alleles that have arisen from a forward genetic screen aimed at identifying regulators of myogenesis. Two of these alleles are viable, but flightless hypomorphic mib2 mutants, and harbor missense mutations in the MIB domain and RING finger, respectively. Functional analysis of these new alleles, including in vivo imaging, demonstrates that Mib2 plays an additional important role in the development of adult thorax muscles, particularly in maintaining the larval templates for the dorsal longitudinal indirect flight muscles during metamorphosis.

Does neuropsychological performance in OCD relate to different symptoms? A meta-analysis comparing the symmetry and obsessing dimensions.

PubMed

Bragdon, Laura B; Gibb, Brandon E; Coles, Meredith E

2018-06-19

Investigations of neuropsychological functioning in obsessive-compulsive disorder (OCD) have produced mixed results for deficits in executive functioning (EF), attention, and memory. One potential explanation for varied findings may relate to the heterogeneity of symptom presentations, and different clinical or neurobiological characteristics may underlie these different symptoms. We investigated differences in neuropsychological functioning between two symptoms groups, obsessing/checking (O/C) and symmetry/ordering (S/O), based on data suggesting an association with different motivations: harm avoidance and incompleteness, respectively. Ten studies (with 628 patients) were included and each investigation assessed at least one of 14 neuropsychological domains. The S/O domain demonstrated small, negative correlations with overall neuropsychological functioning, performance in EF, memory, visuospatial ability, cognitive flexibility, and verbal working memory. O/C symptoms demonstrated small, negative correlations with memory and verbal memory performance. A comparison of functioning between symptom groups identified large effect sizes showing that the S/O dimension was more strongly related to poorer neuropsychological performance overall, and in the domains of attention, visuospatial ability, and the subdomain of verbal working memory. Findings support existing evidence suggesting that different OCD symptoms, and their associated core motivations, relate to unique patterns of neuropsychological functioning, and, potentially dysfunction in different neural circuits. © 2018 Wiley Periodicals, Inc.

Correlates of sexual function in male and female patients with multiple sclerosis.

PubMed

Lew-Starowicz, Michal; Rola, Rafal

2014-09-01

Many factors have been suggested to contribute to sexual dysfunction (SD) in multiple sclerosis (MS) patients, but the research on their impact on sexual functioning (SF) and sexual quality of life (SQoL) remains scant. The aim of this study was to investigate correlates of SF and SQoL in MS patients, as well as possible gender differences. 204 MS patients were interviewed, completed the questionnaires, and underwent neurological assessment. Primary outcome measures included the International Index of Erectile Function, the Female Sexual Function Questionnaire, the Sexual Quality of Life Questionnaire, the Beck Depression Inventory, and the Expanded Disability Status Scale. The course and duration of the disease did not predict patients' SF. Negative correlations were found for brainstem symptoms with orgasmic function and overall satisfaction in men and between cognitive functioning and the partner domain in women. Interestingly, brainstem symptoms correlated positively with the arousal domain in women. More than half (52.1%) of patients fulfilled Beck Depression Inventory criteria for depression, and these patients showed more SD than nondepressive individuals. The strongest negative correlations with depressive symptoms were found for desire, erectile function, and overall satisfaction with sexual life in men and for orgasm and sexual enjoyment in women. Deterioration in particular domains of SF was clearly related with diminished SQoL. The main gender difference was a strong influence of decreased desire on SQoL in women and no such correlation in men. Negative assessment of the relationship with partner significantly affected all domains of SF and SQoL in MS women and the desire domain in MS men. Several correlates of SF in MS patients were found. The role of brainstem symptoms needs further investigation. Clinicians should pay close attention to depressive symptoms and relationship factors in MS patients who suffer from SD. © 2014 International Society for Sexual Medicine.

Changes at the KinA PAS-A Dimerization Interface Influence Histidine Kinase Function

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

Lee, James; Tomchick, Diana R.; Brautigam, Chad A.

2008-11-12

The Bacillus subtilis KinA protein is a histidine protein kinase that controls the commitment of this organism to sporulate in response to nutrient deprivation and several other conditions. Prior studies indicated that the N-terminal Per-ARNT-Sim domain (PAS-A) plays a critical role in the catalytic activity of this enzyme, as demonstrated by the significant decrease of the autophosphorylation rate of a KinA protein lacking this domain. On the basis of the environmental sensing role played by PAS domains in a wide range of proteins, including other bacterial sensor kinases, it has been suggested that the PAS-A domain plays an important regulatorymore » role in KinA function. We have investigated this potential by using a combination of biophysical and biochemical methods to examine PAS-A structure and function, both in isolation and within the intact protein. Here, we present the X-ray crystal structure of the KinA PAS-A domain, showing that it crystallizes as a homodimer using {beta}-sheet/{beta}-sheet packing interactions as observed for several other PAS domain complexes. Notably, we observed two dimers with tertiary and quaternary structure differences in the crystalline lattice, indicating significant structural flexibility in these domains. To confirm that KinA PAS-A also forms dimers in solution, we used a combination of NMR spectroscopy, gel filtration chromatography, and analytical ultracentrifugation, the results of which are all consistent with the crystallographic results. We experimentally tested the importance of several residues at the dimer interface using site-directed mutagenesis, finding changes in the PAS-A domain that significantly alter KinA enzymatic activity in vitro and in vivo. These results support the importance of PAS domains within KinA and other histidine kinases and suggest possible routes for natural or artificial regulation of kinase activity.« less

The X-ray Crystallographic Structure and Activity Analysis of a Pseudomonas-Specific Subfamily of the HAD Enzyme Superfamily Evidences a Novel Biochemical Function

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

Peisach,E.; Wang, L.; Burroughs, A.

2008-01-01

The haloacid dehalogenase (HAD) superfamily is a large family of proteins dominated by phosphotransferases. Thirty-three sequence families within the HAD superfamily (HADSF) have been identified to assist in function assignment. One such family includes the enzyme phosphoacetaldehyde hydrolase (phosphonatase). Phosphonatase possesses the conserved Rossmanniod core domain and a C1-type cap domain. Other members of this family do not possess a cap domain and because the cap domain of phosphonatase plays an important role in active site desolvation and catalysis, the function of the capless family members must be unique. A representative of the capless subfamily, PSPTO{_}2114, from the plant pathogenmore » Pseudomonas syringae, was targeted for catalytic activity and structure analyses. The X-ray structure of PSPTO{_}2114 reveals a capless homodimer that conserves some but not all of the intersubunit contacts contributed by the core domains of the phosphonatase homodimer. The region of the PSPTO{_}2114 that corresponds to the catalytic scaffold of phosphonatase (and other HAD phosphotransfereases) positions amino acid residues that are ill suited for Mg+2 cofactor binding and mediation of phosphoryl group transfer between donor and acceptor substrates. The absence of phosphotransferase activity in PSPTO{_}2114 was confirmed by kinetic assays. To explore PSPTO{_}2114 function, the conservation of sequence motifs extending outside of the HADSF catalytic scaffold was examined. The stringently conserved residues among PSPTO{_}2114 homologs were mapped onto the PSPTO{_}2114 three-dimensional structure to identify a surface region unique to the family members that do not possess a cap domain. The hypothesis that this region is used in protein-protein recognition is explored to define, for the first time, HADSF proteins which have acquired a function other than that of a catalyst. Proteins 2008.« less

A cross-cultural comparison of the coexistence and domain superiority of individuating and relating autonomy.

PubMed

Yeh, Kuang-Hui; Bedford, Olwen; Yang, Yung-Jui

2009-06-01

The consensus definition of autonomy in the psychological literature emphasizes self-governance through free volition, not separation or independence from others. Since the concept of self may differ cross-culturally, several researchers have tried to incorporate types of self into the notion of autonomy; however, only the dual model of autonomy has been able to do this while retaining an emphasis on volition. The dual model describes two distinct forms of autonomy-individuating and relating-each with superior function in a specific domain of individual functioning. Individuating autonomy represents a volitional capacity to act against social constraints and offers a route to achieve an independent self-identity by expressing individualistic attributes and distinctions. Relating autonomy represents a volitional capacity to act by emphasizing the harmony of self-in-relation-to-others, the quality of interpersonal relationships, and self-transcendence. These two forms of autonomy have been shown to coexist at the individual level in a Taiwanese sample. This study takes the next step, with a cross-cultural test of the coexistence and domain superiority hypotheses of individuating and relating autonomy. Participants included 306 college students from Taiwan and 183 college students from the United States. Structural equation modelling by multigroup analyses confirmed the cross-cultural equivalence of the two-factor individuating autonomy and relating autonomy measurement model. Across both samples the two forms of autonomy were shown to be mutually inclusive and not exclusive or independent. The domain-superior function of each form of autonomy was also confirmed cross-culturally; each form of autonomy has a dominant, but not necessarily exclusive, domain of functioning. Specifically, individuating autonomy was more associated with intrapersonal than interpersonal domain dependent variables, while relating autonomy was more associated with interpersonal than intrapersonal domain dependent variables. Limitations of the study and considerations for future research are discussed.

Evidence-based Assessment of Cognitive Functioning in Pediatric Psychology

PubMed Central

Brown, Ronald T.; Cavanagh, Sarah E.; Vess, Sarah F.; Segall, Mathew J.

2008-01-01

Objective To review the evidence base for measures of cognitive functioning frequently used within the field of pediatric psychology. Methods From a list of 47 measures identified by the Society of Pediatric Psychology (Division 54) Evidence-Based Assessment Task Force Workgroup, 27 measures were included in the review. Measures were organized, reviewed, and evaluated according to general domains of functioning (e.g., attention/executive functioning, memory). Results Twenty-two of 27 measures reviewed demonstrated psychometric properties that met “Well-established” criteria as set forth by the Assessment Task Force. Psychometric properties were strongest for measures of general cognitive ability and weakest for measures of visual-motor functioning and attention. Conclusions We report use of “Well-established” measures of overall cognitive functioning, nonverbal intelligence, academic achievement, language, and memory and learning. For several specific tests in the domains of visual-motor functioning and attention, additional psychometric data are needed for measures to meet criteria as “Well established.” PMID:18194973

Transfer Function Identification Using Orthogonal Fourier Transform Modeling Functions

NASA Technical Reports Server (NTRS)

Morelli, Eugene A.

2013-01-01

A method for transfer function identification, including both model structure determination and parameter estimation, was developed and demonstrated. The approach uses orthogonal modeling functions generated from frequency domain data obtained by Fourier transformation of time series data. The method was applied to simulation data to identify continuous-time transfer function models and unsteady aerodynamic models. Model fit error, estimated model parameters, and the associated uncertainties were used to show the effectiveness of the method for identifying accurate transfer function models from noisy data.

Updating the Psoriatic Arthritis (PsA) Core Domain Set: A Report from the PsA Workshop at OMERACT 2016.

PubMed

Orbai, Ana-Maria; de Wit, Maarten; Mease, Philip J; Callis Duffin, Kristina; Elmamoun, Musaab; Tillett, William; Campbell, Willemina; FitzGerald, Oliver; Gladman, Dafna D; Goel, Niti; Gossec, Laure; Hoejgaard, Pil; Leung, Ying Ying; Lindsay, Chris; Strand, Vibeke; van der Heijde, Désirée M; Shea, Bev; Christensen, Robin; Coates, Laura; Eder, Lihi; McHugh, Neil; Kalyoncu, Umut; Steinkoenig, Ingrid; Ogdie, Alexis

2017-10-01

To include the patient perspective in accordance with the Outcome Measures in Rheumatology (OMERACT) Filter 2.0 in the updated Psoriatic Arthritis (PsA) Core Domain Set for randomized controlled trials (RCT) and longitudinal observational studies (LOS). At OMERACT 2016, research conducted to update the PsA Core Domain Set was presented and discussed in breakout groups. The updated PsA Core Domain Set was voted on and endorsed by OMERACT participants. We conducted a systematic literature review of domains measured in PsA RCT and LOS, and identified 24 domains. We conducted 24 focus groups with 130 patients from 7 countries representing 5 continents to identify patient domains. We achieved consensus through 2 rounds of separate surveys with 50 patients and 75 physicians, and a nominal group technique meeting with 12 patients and 12 physicians. We conducted a workshop and breakout groups at OMERACT 2016 in which findings were presented and discussed. The updated PsA Core Domain Set endorsed with 90% agreement by OMERACT 2016 participants included musculoskeletal disease activity, skin disease activity, fatigue, pain, patient's global assessment, physical function, health-related quality of life, and systemic inflammation, which were recommended for all RCT and LOS. These were important, but not required in all RCT and LOS: economic cost, emotional well-being, participation, and structural damage. Independence, sleep, stiffness, and treatment burden were on the research agenda. The updated PsA Core Domain Set was endorsed at OMERACT 2016. Next steps for the PsA working group include evaluation of PsA outcome measures and development of a PsA Core Outcome Measurement Set.

Domain architecture conservation in orthologs

PubMed Central

2011-01-01

Background As orthologous proteins are expected to retain function more often than other homologs, they are often used for functional annotation transfer between species. However, ortholog identification methods do not take into account changes in domain architecture, which are likely to modify a protein's function. By domain architecture we refer to the sequential arrangement of domains along a protein sequence. To assess the level of domain architecture conservation among orthologs, we carried out a large-scale study of such events between human and 40 other species spanning the entire evolutionary range. We designed a score to measure domain architecture similarity and used it to analyze differences in domain architecture conservation between orthologs and paralogs relative to the conservation of primary sequence. We also statistically characterized the extents of different types of domain swapping events across pairs of orthologs and paralogs. Results The analysis shows that orthologs exhibit greater domain architecture conservation than paralogous homologs, even when differences in average sequence divergence are compensated for, for homologs that have diverged beyond a certain threshold. We interpret this as an indication of a stronger selective pressure on orthologs than paralogs to retain the domain architecture required for the proteins to perform a specific function. In general, orthologs as well as the closest paralogous homologs have very similar domain architectures, even at large evolutionary separation. The most common domain architecture changes observed in both ortholog and paralog pairs involved insertion/deletion of new domains, while domain shuffling and segment duplication/deletion were very infrequent. Conclusions On the whole, our results support the hypothesis that function conservation between orthologs demands higher domain architecture conservation than other types of homologs, relative to primary sequence conservation. This supports the notion that orthologs are functionally more similar than other types of homologs at the same evolutionary distance. PMID:21819573

Protein domain analysis of genomic sequence data reveals regulation of LRR related domains in plant transpiration in Ficus.

PubMed

Lang, Tiange; Yin, Kangquan; Liu, Jinyu; Cao, Kunfang; Cannon, Charles H; Du, Fang K

2014-01-01

Predicting protein domains is essential for understanding a protein's function at the molecular level. However, up till now, there has been no direct and straightforward method for predicting protein domains in species without a reference genome sequence. In this study, we developed a functionality with a set of programs that can predict protein domains directly from genomic sequence data without a reference genome. Using whole genome sequence data, the programming functionality mainly comprised DNA assembly in combination with next-generation sequencing (NGS) assembly methods and traditional methods, peptide prediction and protein domain prediction. The proposed new functionality avoids problems associated with de novo assembly due to micro reads and small single repeats. Furthermore, we applied our functionality for the prediction of leucine rich repeat (LRR) domains in four species of Ficus with no reference genome, based on NGS genomic data. We found that the LRRNT_2 and LRR_8 domains are related to plant transpiration efficiency, as indicated by the stomata index, in the four species of Ficus. The programming functionality established in this study provides new insights for protein domain prediction, which is particularly timely in the current age of NGS data expansion.

Comparing longitudinal assessments of quality of life by patient and parent in newly diagnosed children with cancer: the value of both raters' perspectives.

PubMed

Parsons, Susan K; Fairclough, Diane L; Wang, Jim; Hinds, Pamela S

2012-06-01

Health-related quality of life (HRQoL) information from children facing rare and/or life-threatening disease serves important clinical functions. Longitudinal HRQoL ratings from 222 child-parent dyads collected at four time points during the first 16 weeks of cancer treatment are presented. Patient and parent HRQoL reports at the domain level, based on the Pediatric Quality of Life Inventory™ 4.0 Generic Core Scales, were compared over time, and variation in child/parent agreement by age, treatment intensity, and time on treatment was explored. Analyses included consideration of missingness, differences between child and parent group mean domain scores averaged over assessments, agreement between individual child and parent, compared to group averages, and within-subject changes between assessments. Children consistently reported higher functioning than their parents with differences varying by child age and HRQoL domain and diminishing over time. No differences were found by intensity of treatment. The between-subject correlation ranged from 0.61 (social functioning) to 0.86 (physical functioning) across time. Agreement within groups, defined by age, treatment intensity, and time were generally similar. Results indicate moderate-to-good child/parent agreement with variability by domain of HRQoL. Findings underscore the complexity of self- and proxy-based report and support the use of information from both raters.

Validation of a mobility item bank for older patients in primary care.

PubMed

Cabrero-García, Julio; Ramos-Pichardo, Juan Diego; Muñoz-Mendoza, Carmen Luz; Cabañero-Martínez, María José; González-Llopis, Lorena; Reig-Ferrer, Abilio

2012-12-05

To develop and validate an item bank to measure mobility in older people in primary care and to analyse differential item functioning (DIF) and differential bundle functioning (DBF) by sex. A pool of 48 mobility items was administered by interview to 593 older people attending primary health care practices. The pool contained four domains based on the International Classification of Functioning: changing and maintaining body position, carrying, lifting and pushing, walking and going up and down stairs. The Late Life Mobility item bank consisted of 35 items, and measured with a reliability of 0.90 or more across the full spectrum of mobility, except at the higher end of better functioning. No evidence was found of non-uniform DIF but uniform DIF was observed, mainly for items in the changing and maintaining body position and carrying, lifting and pushing domains. The walking domain did not display DBF, but the other three domains did, principally the carrying, lifting and pushing items. During the design and validation of an item bank to measure mobility in older people, we found that strength (carrying, lifting and pushing) items formed a secondary dimension that produced DBF. More research is needed to determine how best to include strength items in a mobility measure, or whether it would be more appropriate to design separate measures for each construct.

Poly(A) polymerase contains multiple functional domains.

PubMed Central

Raabe, T; Murthy, K G; Manley, J L

1994-01-01

Poly(A) polymerase (PAP) contains regions of similarity with several known protein domains. Through site-directed mutagenesis, we provide evidence that PAP contains a functional ribonucleoprotein-type RNA binding domain (RBD) that is responsible for primer binding, making it the only known polymerase to contain such a domain. The RBD is adjacent to, and probably overlaps with, an apparent catalytic region responsible for polymerization. Despite the presence of sequence similarities, this catalytic domain appears to be distinct from the conserved polymerase module found in a large number of RNA-dependent polymerases. PAP contains two nuclear localization signals (NLSs) in its C terminus, each by itself similar to the consensus bipartite NLS found in many nuclear proteins. Mutagenesis experiments indicate that both signals, which are separated by nearly 140 residues, play important roles in directing PAP exclusively to the nucleus. Surprisingly, basic amino acids in the N-terminal-most NLS are also essential for AAUAAA-dependent polyadenylation but not for nonspecific poly(A) synthesis, suggesting that this region of PAP is involved in interactions both with nuclear targeting proteins and with nuclear polyadenylation factors. The serine/threonine-rich C terminus is multiply phosphorylated, including at sites affected by mutations in either NLS. Images PMID:8164653

Dissection of Swa2p/Auxilin Domain Requirements for Cochaperoning Hsp70 Clathrin-uncoating Activity In Vivo

PubMed Central

Xiao, Jing; Kim, Leslie S.

2006-01-01

The auxilin family of J-domain proteins load Hsp70 onto clathrin-coated vesicles (CCVs) to drive uncoating. In vitro, auxilin function requires its ability to bind clathrin and stimulate Hsp70 ATPase activity via its J-domain. To test these requirements in vivo, we performed a mutational analysis of Swa2p, the yeast auxilin ortholog. Swa2p is a modular protein with three N-terminal clathrin-binding (CB) motifs, a ubiquitin association (UBA) domain, a tetratricopeptide repeat (TPR) domain, and a C-terminal J-domain. In vitro, clathrin binding is mediated by multiple weak interactions, but a Swa2p truncation lacking two CB motifs and the UBA domain retains nearly full function in vivo. Deletion of all CB motifs strongly abrogates clathrin disassembly but does not eliminate Swa2p function in vivo. Surprisingly, mutation of the invariant HPD motif within the J-domain to AAA only partially affects Swa2p function. Similarly, a TPR point mutation (G388R) causes a modest phenotype. However, Swa2p function is abolished when these TPR and J mutations are combined. The TPR and J-domains are not functionally redundant because deletion of either domain renders Swa2p nonfunctional. These data suggest that the TPR and J-domains collaborate in a bipartite interaction with Hsp70 to regulate its activity in clathrin disassembly. PMID:16687570

Benchmarking health IT among OECD countries: better data for better policy

PubMed Central

Adler-Milstein, Julia; Ronchi, Elettra; Cohen, Genna R; Winn, Laura A Pannella; Jha, Ashish K

2014-01-01

Objective To develop benchmark measures of health information and communication technology (ICT) use to facilitate cross-country comparisons and learning. Materials and methods The effort is led by the Organisation for Economic Co-operation and Development (OECD). Approaches to definition and measurement within four ICT domains were compared across seven OECD countries in order to identify functionalities in each domain. These informed a set of functionality-based benchmark measures, which were refined in collaboration with representatives from more than 20 OECD and non-OECD countries. We report on progress to date and remaining work to enable countries to begin to collect benchmark data. Results The four benchmarking domains include provider-centric electronic record, patient-centric electronic record, health information exchange, and tele-health. There was broad agreement on functionalities in the provider-centric electronic record domain (eg, entry of core patient data, decision support), and less agreement in the other three domains in which country representatives worked to select benchmark functionalities. Discussion Many countries are working to implement ICTs to improve healthcare system performance. Although many countries are looking to others as potential models, the lack of consistent terminology and approach has made cross-national comparisons and learning difficult. Conclusions As countries develop and implement strategies to increase the use of ICTs to promote health goals, there is a historic opportunity to enable cross-country learning. To facilitate this learning and reduce the chances that individual countries flounder, a common understanding of health ICT adoption and use is needed. The OECD-led benchmarking process is a crucial step towards achieving this. PMID:23721983

Amino acid mutations in the caldesmon COOH-terminal functional domain increase force generation in bladder smooth muscle

PubMed Central

Deng, Maoxian; Boopathi, Ettickan; Hypolite, Joseph A.; Raabe, Tobias; Chang, Shaohua; Zderic, Stephen; Wein, Alan J.

2013-01-01

Caldesmon (CaD), a component of smooth muscle thin filaments, binds actin, tropomyosin, calmodulin, and myosin and inhibits actin-activated ATP hydrolysis by smooth muscle myosin. Internal deletions of the chicken CaD functional domain that spans from amino acids (aa) 718 to 731, which corresponds to aa 512–530 including the adjacent aa sequence in mouse CaD, lead to diminished CaD-induced inhibition of actin-activated ATP hydrolysis by myosin. Transgenic mice with mutations of five aa residues (Lys523 to Gln, Val524 to Leu, Ser526 to Thr, Pro527 to Cys, and Lys529 to Ser), which encompass the ATPase inhibitory determinants located in exon 12, were generated by homologous recombination. Homozygous (−/−) animals did not develop, but heterozygous (+/−) mice carrying the expected mutations in the CaD ATPase inhibitory domain (CaD mutant) matured and reproduced normally. The peak force produced in response to KCl and electrical field stimulation by the detrusor smooth muscle from the CaD mutant was high compared with that of the wild type. CaD mutant mice revealed nonvoiding contractions during bladder filling on awake cystometry, suggesting that the CaD ATPase inhibitory domain suppresses force generation during the filling phase and this suppression is partially released by mutations in 50% of CaD in heterozygous. Our data show for the first time a functional phenotype, at the intact smooth muscle tissue and in vivo organ levels, following mutation of a functional domain at the COOH-terminal region of CaD. PMID:23986516

Benchmarking health IT among OECD countries: better data for better policy.

PubMed

Adler-Milstein, Julia; Ronchi, Elettra; Cohen, Genna R; Winn, Laura A Pannella; Jha, Ashish K

2014-01-01

To develop benchmark measures of health information and communication technology (ICT) use to facilitate cross-country comparisons and learning. The effort is led by the Organisation for Economic Co-operation and Development (OECD). Approaches to definition and measurement within four ICT domains were compared across seven OECD countries in order to identify functionalities in each domain. These informed a set of functionality-based benchmark measures, which were refined in collaboration with representatives from more than 20 OECD and non-OECD countries. We report on progress to date and remaining work to enable countries to begin to collect benchmark data. The four benchmarking domains include provider-centric electronic record, patient-centric electronic record, health information exchange, and tele-health. There was broad agreement on functionalities in the provider-centric electronic record domain (eg, entry of core patient data, decision support), and less agreement in the other three domains in which country representatives worked to select benchmark functionalities. Many countries are working to implement ICTs to improve healthcare system performance. Although many countries are looking to others as potential models, the lack of consistent terminology and approach has made cross-national comparisons and learning difficult. As countries develop and implement strategies to increase the use of ICTs to promote health goals, there is a historic opportunity to enable cross-country learning. To facilitate this learning and reduce the chances that individual countries flounder, a common understanding of health ICT adoption and use is needed. The OECD-led benchmarking process is a crucial step towards achieving this.

Crystal Structure of a Two-domain Fragment of Hepatocyte Growth Factor Activator Inhibitor-1

PubMed Central

Hong, Zebin; De Meulemeester, Laura; Jacobi, Annemarie; Pedersen, Jan Skov; Morth, J. Preben; Andreasen, Peter A.; Jensen, Jan K.

2016-01-01

Hepatocyte growth factor activator inhibitor-1 (HAI-1) is a type I transmembrane protein and inhibitor of several serine proteases, including hepatocyte growth factor activator and matriptase. The protein is essential for development as knock-out mice die in utero due to placental defects caused by misregulated extracellular proteolysis. HAI-1 contains two Kunitz-type inhibitor domains (Kunitz), which are generally thought of as a functionally self-contained protease inhibitor unit. This is not the case for HAI-1, where our results reveal how interdomain interactions have evolved to stimulate the inhibitory activity of an integrated Kunitz. Here we present an x-ray crystal structure of an HAI-1 fragment covering the internal domain and Kunitz-1. The structure reveals not only that the previously uncharacterized internal domain is a member of the polycystic kidney disease domain family but also how the two domains engage in interdomain interactions. Supported by solution small angle x-ray scattering and a combination of site-directed mutagenesis and functional assays, we show that interdomain interactions not only stabilize the fold of the internal domain but also stimulate the inhibitory activity of Kunitz-1. By completing our structural characterization of the previously unknown N-terminal region of HAI-1, we provide new insight into the interplay between tertiary structure and the inhibitory activity of a multidomain protease inhibitor. We propose a previously unseen mechanism by which the association of an auxiliary domain stimulates the inhibitory activity of a Kunitz-type inhibitor (i.e. the first structure of an intramolecular interaction between a Kunitz and another domain). PMID:27189939

Protein sorting by lipid phase-like domains supports emergent signaling function in B lymphocyte plasma membranes.

PubMed

Stone, Matthew B; Shelby, Sarah A; Núñez, Marcos F; Wisser, Kathleen; Veatch, Sarah L

2017-02-01

Diverse cellular signaling events, including B cell receptor (BCR) activation, are hypothesized to be facilitated by domains enriched in specific plasma membrane lipids and proteins that resemble liquid-ordered phase-separated domains in model membranes. This concept remains controversial and lacks direct experimental support in intact cells. Here, we visualize ordered and disordered domains in mouse B lymphoma cell membranes using super-resolution fluorescence localization microscopy, demonstrate that clustered BCR resides within ordered phase-like domains capable of sorting key regulators of BCR activation, and present a minimal, predictive model where clustering receptors leads to their collective activation by stabilizing an extended ordered domain. These results provide evidence for the role of membrane domains in BCR signaling and a plausible mechanism of BCR activation via receptor clustering that could be generalized to other signaling pathways. Overall, these studies demonstrate that lipid mediated forces can bias biochemical networks in ways that broadly impact signal transduction.

Tyrosine Phosphorylation of the Lyn Src Homology 2 (SH2) Domain Modulates Its Binding Affinity and Specificity*

PubMed Central

Jin, Lily L.; Wybenga-Groot, Leanne E.; Tong, Jiefei; Taylor, Paul; Minden, Mark D.; Trudel, Suzanne; McGlade, C. Jane; Moran, Michael F.

2015-01-01

Src homology 2 (SH2) domains are modular protein structures that bind phosphotyrosine (pY)-containing polypeptides and regulate cellular functions through protein-protein interactions. Proteomics analysis showed that the SH2 domains of Src family kinases are themselves tyrosine phosphorylated in blood system cancers, including acute myeloid leukemia, chronic lymphocytic leukemia, and multiple myeloma. Using the Src family kinase Lyn SH2 domain as a model, we found that phosphorylation at the conserved SH2 domain residue Y194 impacts the affinity and specificity of SH2 domain binding to pY-containing peptides and proteins. Analysis of the Lyn SH2 domain crystal structure supports a model wherein phosphorylation of Y194 on the EF loop modulates the binding pocket that engages amino acid side chains at the pY+2/+3 position. These data indicate another level of regulation wherein SH2-mediated protein-protein interactions are modulated by SH2 kinases and phosphatases. PMID:25587033

Older adults' perceptions of ageing and their health and functioning: a systematic review of observational studies.

PubMed

Warmoth, Krystal; Tarrant, Mark; Abraham, Charles; Lang, Iain A

2016-07-01

Many older people perceive ageing negatively, describing it in terms of poor or declining health and functioning. These perceptions may be related to older adults' health. The aim of this review was to synthesise existing research on the relationship between older adults' perceptions of ageing and their health and functioning. A systematic search was conducted of five electronic databases (ASSIA, CINAHL, IBSS, MEDLINE and PsycINFO). Citations within identified reports were also searched. Observational studies were included if they included perceptions of ageing and health-related measures involving participants aged 60 years and older. Study selection, data extraction and quality appraisal were conducted using predefined criteria. Twenty-eight reports met the criteria for inclusion. Older adults' perceptions of ageing were assessed with a variety of measures. Perceptions were related to health and functioning across seven health domains: memory and cognitive performance, physical and physiological performance, medical conditions and outcomes, disability, care-seeking, self-rated health, quality of life and death. How ageing is perceived by older adults is related to their health and functioning in multiple domains. However, higher quality and longitudinal studies are needed to further investigate this relationship.

Applied Routh approximation

NASA Technical Reports Server (NTRS)

Merrill, W. C.

1978-01-01

The Routh approximation technique for reducing the complexity of system models was applied in the frequency domain to a 16th order, state variable model of the F100 engine and to a 43d order, transfer function model of a launch vehicle boost pump pressure regulator. The results motivate extending the frequency domain formulation of the Routh method to the time domain in order to handle the state variable formulation directly. The time domain formulation was derived and a characterization that specifies all possible Routh similarity transformations was given. The characterization was computed by solving two eigenvalue-eigenvector problems. The application of the time domain Routh technique to the state variable engine model is described, and some results are given. Additional computational problems are discussed, including an optimization procedure that can improve the approximation accuracy by taking advantage of the transformation characterization.

Procedural Learning and Individual Differences in Language

PubMed Central

Lee, Joanna C.; Tomblin, J. Bruce

2014-01-01

The aim of the current study was to examine different aspects of procedural memory in young adults who varied with regard to their language abilities. We selected a sample of procedural memory tasks, each of which represented a unique type of procedural learning, and has been linked, at least partially, to the functionality of the corticostriatal system. The findings showed that variance in language abilities is associated with performance on different domains of procedural memory, including the motor domain (as shown in the pursuit rotor task), the cognitive domain (as shown in the weather prediction task), and the linguistic domain (as shown in the nonword repetition priming task). These results implicate the corticostriatal system in individual differences in language. PMID:26190949

The electronic patient record: a strategic planning framework.

PubMed

Gordon, D B; Marafioti, S; Carter, M; Kunov, H; Dolan, A

1995-01-01

Sunnybrook Health Science Center (Sunnybrook) is a multifacility academic teaching center. In May 1994, Sunnybrook struck an electronic patient record taskforce to develop a strategic plan for the implementation of a comprehensive, facility wide electronic patient record (EPR). The taskforce sought to create a conceptual framework which provides context and integrates decision-making related to the comprehensive electronic patient record. The EPR is very much broader in scope than the traditional paper-based record. It is not restricted to simply reporting individual patient data. By the Institute of Medicine's definition, the electronic patient record resides in a system specifically designed to support users through availability of complete and accurate data, practitioner reminders and alerts, clinical decision support systems, links to bodies of medical knowledge, and other aids [1]. It is a comprehensive resource for patient care. The taskforce proposed a three domain model for determining how the EPR affects Sunnybrook. The EPR enables Sunnybrook to have a high performance team structure (domain 1), to function as an integrated organization (domain 2), and to reach out and develop new relationships with external organizations to become an extended enterprise (domain 3) [2]. Domain 1: Sunnybrook's high performance teams or patient service units' (PSUs) are decentralized, autonomous operating units that provide care to patients grouped by 'like' diagnosis and resource needs. The EPR must provide functions and applications which promote patient focused care, such as cross functional charting and care maps, group scheduling, clinical email, and a range of enabling technologies for multiskilled workers. Domain 2: In the integrated organization domain, the EPR should facilitate closer linkages between the arrangement of PSUs into clinical teams and with other facilities within the center in order to provide a longitudinal record that covers a continuum of care. Domain 3: In the inter-enterprise domain, the EPR must allow for patient information to be exchanged with external providers including referring doctors, laboratories, and other hospitals via community health information networks (CHINs). Sunnybrook will prioritize the development of first domain functionality within the corporate constraints imposed by the integrated organization domain. Inter-enterprise computing will be less of a priority until Sunnybrook has developed a critical mass of the electronic patient record internally. The three domain description is a useful model for describing the relationship between the electronic patient record enabling technologies and the Sunnybrook organizational structures. The taskforce has used this model to determine EPR development guidelines and implementation priorities.

Determinants of Living Well With Aphasia in the First Year Poststroke: A Prospective Cohort Study.

PubMed

Worrall, Linda E; Hudson, Kyla; Khan, Asaduzzaman; Ryan, Brooke; Simmons-Mackie, Nina

2017-02-01

To determine factors that contribute to living well with aphasia in the first 12 months poststroke. Prospective longitudinal cohort study. Hospitalized care, ambulatory care, and general community. A referred sample of people (N=58) with a first incidence of aphasia after stroke was assessed at 3, 6, 9, and 12 months postonset. Participants were recruited through speech-language pathologists in 2 capital cities in Australia. Presence of aphasia was determined through the Western Aphasia Battery-Revised by an experienced speech-language pathologist. Not applicable. The main outcomes were the 5 domains of the Assessment for Living with Aphasia at 3, 6, 9, and 12 months poststroke. The independent variables included demographics, physical functioning, social network, mood, aphasia severity, and a self-rating of successfully living with aphasia at the same time points. Mixed effects modeling was used to determine which factors contributed to the trajectory of each of the 5 domains of participation, impairment, environment, personal factors, and life with aphasia. Higher household income, larger social network size, being a woman, and having milder aphasia were positively associated with the participation domain. Graduate or postgraduate educational levels, low mood, and poor physical functioning were negatively associated with the participation domain. Factors positively associated with other domains included higher income, self-ratings of successfully living with aphasia, and aphasia severity. Low mood was consistently negatively associated with all of the domains. Psychosocial determinants were the most significant predictors of living well with aphasia in the first 12 months postonset. Aphasia rehabilitation needs to attend more to these factors to optimize outcomes. Copyright © 2016 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.

The Popeye Domain Containing Genes and Their Function as cAMP Effector Proteins in Striated Muscle.

PubMed

Brand, Thomas

2018-03-13

The Popeye domain containing (POPDC) genes encode transmembrane proteins, which are abundantly expressed in striated muscle cells. Hallmarks of the POPDC proteins are the presence of three transmembrane domains and the Popeye domain, which makes up a large part of the cytoplasmic portion of the protein and functions as a cAMP-binding domain. Interestingly, despite the prediction of structural similarity between the Popeye domain and other cAMP binding domains, at the protein sequence level they strongly differ from each other suggesting an independent evolutionary origin of POPDC proteins. Loss-of-function experiments in zebrafish and mouse established an important role of POPDC proteins for cardiac conduction and heart rate adaptation after stress. Loss-of function mutations in patients have been associated with limb-girdle muscular dystrophy and AV-block. These data suggest an important role of these proteins in the maintenance of structure and function of striated muscle cells.

A Conceptual Foundation for Measures of Physical Function and Behavioral Health Function for Social Security Work Disability Evaluation

PubMed Central

Marfeo, Elizabeth E.; Haley, Stephen M.; Jette, Alan M.; Eisen, Susan V.; Ni, Pengsheng; Bogusz, Kara; Meterko, Mark; McDonough, Christine M.; Chan, Leighton; Brandt, Diane E.; Rasch, Elizabeth K.

2014-01-01

Physical and mental impairments represent the two largest health condition categories for which workers receive Social Security disability benefits. Comprehensive assessment of physical and mental impairments should include aspects beyond medical conditions such as a person’s underlying capabilities as well as activity demands relevant to the context of work. The objective of this paper is to describe the initial conceptual stages of developing new measurement instruments of behavioral health and physical functioning relevant for Social Security work disability evaluation purposes. To outline a clear conceptualization of the constructs to be measured, two content models were developed using structured and informal qualitative approaches. We performed a structured literature review focusing on work disability and incorporating aspects of the International Classification of Functioning, Disability, and Health (ICF) as a unifying taxonomy for framework development. Expert interviews provided advice and consultation to enhance face validity of the resulting content models. The content model for work-related behavioral health function identifies five major domains (1) Behavior Control, (2) Basic Interactions, (3) Temperament and Personality, (4) Adaptability, and (5) Workplace Behaviors. The content model describing physical functioning includes three domains (1) Changing and Maintaining Body Position, (2) Whole Body Mobility, and (3) Carrying, Moving and Handling Objects. These content models informed subsequent measurement properties including item development, measurement scale construction, and provided conceptual coherence guiding future empirical inquiry. The proposed measurement approaches show promise to comprehensively and systematically assess physical and behavioral health functioning relevant to work. PMID:23548543

Structural insights into SAM domain‐mediated tankyrase oligomerization

PubMed Central

DaRosa, Paul A.; Ovchinnikov, Sergey

2016-01-01

Abstract Tankyrase 1 (TNKS1; a.k.a. ARTD5) and tankyrase 2 (TNKS2; a.k.a ARTD6) are highly homologous poly(ADP‐ribose) polymerases (PARPs) that function in a wide variety of cellular processes including Wnt signaling, Src signaling, Akt signaling, Glut4 vesicle translocation, telomere length regulation, and centriole and spindle pole maturation. Tankyrase proteins include a sterile alpha motif (SAM) domain that undergoes oligomerization in vitro and in vivo. However, the SAM domains of TNKS1 and TNKS2 have not been structurally characterized and the mode of oligomerization is not yet defined. Here we model the SAM domain‐mediated oligomerization of tankyrase. The structural model, supported by mutagenesis and NMR analysis, demonstrates a helical, homotypic head‐to‐tail polymer that facilitates TNKS self‐association. Furthermore, we show that TNKS1 and TNKS2 can form (TNKS1 SAM‐TNKS2 SAM) hetero‐oligomeric structures mediated by their SAM domains. Though wild‐type tankyrase proteins have very low solubility, model‐based mutations of the SAM oligomerization interface residues allowed us to obtain soluble TNKS proteins. These structural insights will be invaluable for the functional and biophysical characterization of TNKS1/2, including the role of TNKS oligomerization in protein poly(ADP‐ribosyl)ation (PARylation) and PARylation‐dependent ubiquitylation. PMID:27328430

Protein Domain-Level Landscape of Cancer-Type-Specific Somatic Mutations

PubMed Central

Yang, Fan; Petsalaki, Evangelia; Rolland, Thomas; Hill, David E.; Vidal, Marc; Roth, Frederick P.

2015-01-01

Identifying driver mutations and their functional consequences is critical to our understanding of cancer. Towards this goal, and because domains are the functional units of a protein, we explored the protein domain-level landscape of cancer-type-specific somatic mutations. Specifically, we systematically examined tumor genomes from 21 cancer types to identify domains with high mutational density in specific tissues, the positions of mutational hotspots within these domains, and the functional and structural context where possible. While hotspots corresponding to specific gain-of-function mutations are expected for oncoproteins, we found that tumor suppressor proteins also exhibit strong biases toward being mutated in particular domains. Within domains, however, we observed the expected patterns of mutation, with recurrently mutated positions for oncogenes and evenly distributed mutations for tumor suppressors. For example, we identified both known and new endometrial cancer hotspots in the tyrosine kinase domain of the FGFR2 protein, one of which is also a hotspot in breast cancer, and found new two hotspots in the Immunoglobulin I-set domain in colon cancer. Thus, to prioritize cancer mutations for further functional studies aimed at more precise cancer treatments, we have systematically correlated mutations and cancer types at the protein domain level. PMID:25794154

The distance function effect on k-nearest neighbor classification for medical datasets.

PubMed

Hu, Li-Yu; Huang, Min-Wei; Ke, Shih-Wen; Tsai, Chih-Fong

2016-01-01

K-nearest neighbor (k-NN) classification is conventional non-parametric classifier, which has been used as the baseline classifier in many pattern classification problems. It is based on measuring the distances between the test data and each of the training data to decide the final classification output. Since the Euclidean distance function is the most widely used distance metric in k-NN, no study examines the classification performance of k-NN by different distance functions, especially for various medical domain problems. Therefore, the aim of this paper is to investigate whether the distance function can affect the k-NN performance over different medical datasets. Our experiments are based on three different types of medical datasets containing categorical, numerical, and mixed types of data and four different distance functions including Euclidean, cosine, Chi square, and Minkowsky are used during k-NN classification individually. The experimental results show that using the Chi square distance function is the best choice for the three different types of datasets. However, using the cosine and Euclidean (and Minkowsky) distance function perform the worst over the mixed type of datasets. In this paper, we demonstrate that the chosen distance function can affect the classification accuracy of the k-NN classifier. For the medical domain datasets including the categorical, numerical, and mixed types of data, K-NN based on the Chi square distance function performs the best.

Influence of androgen receptor CAG polymorphism on sexual function recovery after testosterone therapy in late-onset hypogonadism.

PubMed

Tirabassi, Giacomo; Corona, Giovanni; Biagioli, Andrea; Buldreghini, Eddi; delli Muti, Nicola; Maggi, Mario; Balercia, Giancarlo

2015-02-01

Androgen receptor (AR) CAG polymorphism has been found to influence sexual function. However, no study has evaluated its potential to condition sexual function recovery after testosterone replacement therapy (TRT) in a large cohort of hypogonadic subjects. To evaluate the role of this polymorphism in sexual function improvement after TRT in late-onset hypogonadism (LOH). Seventy-three men affected by LOH were retrospectively considered. Evaluations were performed before TRT started (time 0) and before the sixth undecanoate testosterone injection. International Index of Erectile Function (IIEF) questionnaire (erectile function [EF], orgasmic function [OF], sexual desire [SD], intercourse satisfaction [IS], overall satisfaction [OS], and total IIEF-15 score); total and free testosterone and estradiol; AR gene CAG repeat number. TRT induced a significant increase in total and free testosterone and estradiol. All IIEF domains significantly improved after TRT. AR CAG repeats negatively and significantly correlated with all the variations (Δ-) of sexual function domains, except for Δ-OS. Conversely, Δ-total testosterone was found to be positively and significantly correlated with sexual function domain variations, except for Δ-IS and Δ-OS. Δ-estradiol did not correlate significantly with any of the variations of sexual function domains. After inclusion in generalized linear models, the number of AR gene CAG triplets was found to be independently and negatively associated with Δ-EF, Δ-SD, Δ-IS, and Δ-Total IIEF-15 score, whereas Δ-total testosterone was independently and positively associated with Δ-EF, Δ-OF, Δ-SD, and Δ-Total IIEF-15 score. However, after including time 0 total testosterone in the model, AR gene CAG triplets remained independently and negatively associated only with Δ-EF and Δ-Total IIEF-15 score, whereas Δ-total testosterone was independently and positively associated only with Δ-EF. Longer length of AR gene CAG repeat tract seems to lower TRT-induced improvement of sexual function in LOH. © 2014 International Society for Sexual Medicine.

Identification and analysis of mutational hotspots in oncogenes and tumour suppressors.

PubMed

Baeissa, Hanadi; Benstead-Hume, Graeme; Richardson, Christopher J; Pearl, Frances M G

2017-03-28

The key to interpreting the contribution of a disease-associated mutation in the development and progression of cancer is an understanding of the consequences of that mutation both on the function of the affected protein and on the pathways in which that protein is involved. Protein domains encapsulate function and position-specific domain based analysis of mutations have been shown to help elucidate their phenotypes. In this paper we examine the domain biases in oncogenes and tumour suppressors, and find that their domain compositions substantially differ. Using data from over 30 different cancers from whole-exome sequencing cancer genomic projects we mapped over one million mutations to their respective Pfam domains to identify which domains are enriched in any of three different classes of mutation; missense, indels or truncations. Next, we identified the mutational hotspots within domain families by mapping small mutations to equivalent positions in multiple sequence alignments of protein domainsWe find that gain of function mutations from oncogenes and loss of function mutations from tumour suppressors are normally found in different domain families and when observed in the same domain families, hotspot mutations are located at different positions within the multiple sequence alignment of the domain. By considering hotspots in tumour suppressors and oncogenes independently, we find that there are different specific positions within domain families that are particularly suited to accommodate either a loss or a gain of function mutation. The position is also dependent on the class of mutation.We find rare mutations co-located with well-known functional mutation hotspots, in members of homologous domain superfamilies, and we detect novel mutation hotspots in domain families previously unconnected with cancer. The results of this analysis can be accessed through the MOKCa database (http://strubiol.icr.ac.uk/extra/MOKCa).

Outer Membrane Targeting of Passenger Proteins by the Vacuolating Cytotoxin Autotransporter of Helicobacter pylori

PubMed Central

Fischer, Wolfgang; Buhrdorf, Renate; Gerland, Elke; Haas, Rainer

2001-01-01

Helicobacter pylori produces a number of proteins associated with the outer membrane, including adhesins and the vacuolating cytotoxin. These proteins are supposed to integrate into the outer membrane by β-barrel structures, characteristic of the family of autotransporter proteins. By using the SOMPES (shuttle vector-based outer membrane protein expression) system for outer membrane protein production, we were able to functionally express in H. pylori the cholera toxin B subunit genetically fused to the C-terminal VacA domain. We demonstrate that the fusion protein is translocated to the H. pylori outer membrane and that the CtxB domain is exposed on the H. pylori surface. Thus, we provide the first experimental evidence that the C-terminal β-domain of VacA can transport a foreign passenger protein to the H. pylori surface and hence acts as a functional autotransporter. PMID:11598049

The dynamic landscape of the cell nucleus.

PubMed

Austin, Christopher M; Bellini, Michel

2010-01-01

While the cell nucleus was described for the first time almost two centuries ago, our modern view of the nuclear architecture is primarily based on studies from the last two decades. This surprising late start coincides with the development of new, powerful strategies to probe for the spatial organization of nuclear activities in both fixed and live cells. As a result, three major principles have emerged: first, the nucleus is not just a bag filled with nucleic acids and proteins. Rather, many distinct functional domains, including the chromosomes, resides within the confines of the nuclear envelope. Second, all these nuclear domains are highly dynamic, with molecules exchanging rapidly between them and the surrounding nucleoplasm. Finally, the motion of molecules within the nucleoplasm appears to be mostly driven by random diffusion. Here, the emerging roles of several subnuclear domains are discussed in the context of the dynamic functions of the cell nucleus.

The impact of subjective cognitive fatigue and depression on cognitive function in patients with multiple sclerosis.

PubMed

Golan, Daniel; Doniger, Glen M; Wissemann, Karl; Zarif, Myassar; Bumstead, Barbara; Buhse, Marijean; Fafard, Lori; Lavi, Idit; Wilken, Jeffrey; Gudesblatt, Mark

2018-02-01

The association between subjective cognitive fatigue and objective cognitive dysfunction in patients with multiple sclerosis (PwMS) has been studied, with conflicting results. To explore the impact of fatigue on cognitive function, while controlling for the influence of depression, disability, comorbidities, and psychotropic medications. PwMS completed a computerized cognitive testing battery with age- and education-adjusted cognitive domain scores. Disability (Expanded Disability Status Scale (EDSS)), cognitive fatigue, and depression were concurrently evaluated. In all, 699 PwMS were included. Both cognitive fatigue and depression were significantly and negatively correlated with the same cognitive domains: information processing speed, executive function, attention, motor function, and memory (-0.15 ⩽ r ⩽ -0.14 for cognitive fatigue; -0.24 ⩽ r ⩽ -0.19 for depression). Multivariate analysis revealed significant but small independent correlations only between depression and neuropsychological test results, while cognitive fatigue had no independent correlation with objective cognitive function except for a trend toward impaired motor function in highly fatigued PwMS. Depression and cognitive fatigue accounted for no more than 6% of the variance in objective cognitive domain scores. Cognitive fatigue is not independently related to objective cognitive impairment. Depression may influence cognitive function of PwMS primarily when it is severe. Cognitive impairment in PwMS should not be ascribed to fatigue or mild depression.

Factors associated with DSM-5 severity level ratings for autism spectrum disorder.

PubMed

Mazurek, Micah O; Lu, Frances; Macklin, Eric A; Handen, Benjamin L

2018-02-01

The newest edition of the Diagnostic and Statistical Manual of Mental Disorders (5th ed., DSM-5) introduced substantial changes to the diagnostic criteria for autism spectrum disorder, including new severity level ratings for social communication and restricted and repetitive behavior domains. The purpose of this study was to evaluate the use of these new severity ratings and to examine their relation to other measures of severity and clinical features. Participants included 248 children with autism spectrum disorder who received diagnostic evaluations at one of six Autism Treatment Network sites. Higher severity ratings in both domains were associated with younger age, lower intelligence quotient, and greater Autism Diagnostic Observation Schedule-Second Edition domain-specific symptom severity. Greater restricted and repetitive behavior severity was associated with higher parent-reported stereotyped behaviors. Severity ratings were not associated with emotional or behavioral problems. The new DSM-5 severity ratings in both domains were significantly associated with behavioral observations of autism severity but not with measures of other behavioral or emotional symptoms. However, the strong associations between intelligence quotient and DSM-5 severity ratings in both domains suggest that clinicians may be including cognitive functioning in their overall determination of severity. Further research is needed to examine clinician decision-making and interpretation of these specifiers.

Motor Skills and Exercise Capacity Are Associated with Objective Measures of Cognitive Functions and Academic Performance in Preadolescent Children.

PubMed

Geertsen, Svend Sparre; Thomas, Richard; Larsen, Malte Nejst; Dahn, Ida Marie; Andersen, Josefine Needham; Krause-Jensen, Matilde; Korup, Vibeke; Nielsen, Claus Malta; Wienecke, Jacob; Ritz, Christian; Krustrup, Peter; Lundbye-Jensen, Jesper

2016-01-01

To investigate associations between motor skills, exercise capacity and cognitive functions, and evaluate how they correlate to academic performance in mathematics and reading comprehension using standardised, objective tests. This cross-sectional study included 423 Danish children (age: 9.29±0.35 years, 209 girls). Fine and gross motor skills were evaluated in a visuomotor accuracy-tracking task, and a whole-body coordination task, respectively. Exercise capacity was estimated from the Yo-Yo intermittent recovery level 1 children's test (YYIR1C). Selected tests from the Cambridge Neuropsychological Test Automated Battery (CANTAB) were used to assess different domains of cognitive functions, including sustained attention, spatial working memory, episodic and semantic memory, and processing speed. Linear mixed-effects models were used to investigate associations between these measures and the relationship with standard tests of academic performance in mathematics and reading comprehension. Both fine and gross motor skills were associated with better performance in all five tested cognitive domains (all P<0.001), whereas exercise capacity was only associated with better sustained attention (P<0.046) and spatial working memory (P<0.038). Fine and gross motor skills (all P<0.001), exercise capacity and cognitive functions such as working memory, episodic memory, sustained attention and processing speed were all associated with better performance in mathematics and reading comprehension. The data demonstrate that fine and gross motor skills are positively correlated with several aspects of cognitive functions and with academic performance in both mathematics and reading comprehension. Moreover, exercise capacity was associated with academic performance and performance in some cognitive domains. Future interventions should investigate associations between changes in motor skills, exercise capacity, cognitive functions, and academic performance to elucidate the causality of these associations.

Motor Skills and Exercise Capacity Are Associated with Objective Measures of Cognitive Functions and Academic Performance in Preadolescent Children

PubMed Central

Thomas, Richard; Larsen, Malte Nejst; Dahn, Ida Marie; Andersen, Josefine Needham; Krause-Jensen, Matilde; Korup, Vibeke; Nielsen, Claus Malta; Wienecke, Jacob; Ritz, Christian; Krustrup, Peter; Lundbye-Jensen, Jesper

2016-01-01

Objective To investigate associations between motor skills, exercise capacity and cognitive functions, and evaluate how they correlate to academic performance in mathematics and reading comprehension using standardised, objective tests. Methods This cross-sectional study included 423 Danish children (age: 9.29±0.35 years, 209 girls). Fine and gross motor skills were evaluated in a visuomotor accuracy-tracking task, and a whole-body coordination task, respectively. Exercise capacity was estimated from the Yo-Yo intermittent recovery level 1 children's test (YYIR1C). Selected tests from the Cambridge Neuropsychological Test Automated Battery (CANTAB) were used to assess different domains of cognitive functions, including sustained attention, spatial working memory, episodic and semantic memory, and processing speed. Linear mixed-effects models were used to investigate associations between these measures and the relationship with standard tests of academic performance in mathematics and reading comprehension. Results Both fine and gross motor skills were associated with better performance in all five tested cognitive domains (all P<0.001), whereas exercise capacity was only associated with better sustained attention (P<0.046) and spatial working memory (P<0.038). Fine and gross motor skills (all P<0.001), exercise capacity and cognitive functions such as working memory, episodic memory, sustained attention and processing speed were all associated with better performance in mathematics and reading comprehension. Conclusions The data demonstrate that fine and gross motor skills are positively correlated with several aspects of cognitive functions and with academic performance in both mathematics and reading comprehension. Moreover, exercise capacity was associated with academic performance and performance in some cognitive domains. Future interventions should investigate associations between changes in motor skills, exercise capacity, cognitive functions, and academic performance to elucidate the causality of these associations. PMID:27560512

Disease Severity and Domain Specific Arthritis Self-Efficacy: Relationships to Pain and Functioning in Rheumatoid Arthritis Patients

PubMed Central

Somers, Tamara J.; Shelby, Rebecca A.; Keefe, Francis J.; Godiwala, Neha; Lumley, Mark A.; Mosley-Williams, Angelia; Rice, John R.; Caldwell, David

2010-01-01

Objective Examining the degree to which disease severity and domains of self-efficacy (pain, function, other symptoms) explain pain and functioning in rheumatoid arthritis patients. Methods Patients (N=263) completed the Arthritis Impact Measurements Scales-2 to assess pain and functioning (physical, affective, and social), the Arthritis Self-Efficacy Scale to assess three self-efficacy domains (pain, physical function, other); disease severity was assessed with C-reactive protein, physician's rating, abnormal joint count. Structural equation modeling was used to examine hypotheses: 1) does disease severity have a direct relationship with pain and each area of functioning, 2) does disease severity have a direct relationship with each arthritis self-efficacy domain, and 3) do the self-efficacy domains mediate the relationship between disease severity and RA pain and each area of functioning. Results Disease severity was related to pain, physical functioning, and each self-efficacy domain (β's=.28-.56; p's<.001). Each self-efficacy domain was related to its respective domain of functioning (e.g., self-efficacy for pain was related to pain) (β's=.36-.54; p's<.001). Self-efficacy mediated the relationship between disease severity and pain and functioning (β's=.12-.19; p's<.001). Self-efficacy for pain control and to perform functional tasks accounted for 32-42% of disease severity's total effect on their respective outcomes (e.g., self-efficacy for pain control accounted for 32% of disease severity's total effect on pain). Variance accounted for by the total model was 52% for pain, 53% for physical functioning, and 44% for affective and social functioning. Conclusions Disease severity and self-efficacy both impact RA functioning and intervening in these areas may lead to better outcomes. PMID:20535796

Protein domain organisation: adding order.

PubMed

Kummerfeld, Sarah K; Teichmann, Sarah A

2009-01-29

Domains are the building blocks of proteins. During evolution, they have been duplicated, fused and recombined, to produce proteins with novel structures and functions. Structural and genome-scale studies have shown that pairs or groups of domains observed together in a protein are almost always found in only one N to C terminal order and are the result of a single recombination event that has been propagated by duplication of the multi-domain unit. Previous studies of domain organisation have used graph theory to represent the co-occurrence of domains within proteins. We build on this approach by adding directionality to the graphs and connecting nodes based on their relative order in the protein. Most of the time, the linear order of domains is conserved. However, using the directed graph representation we have identified non-linear features of domain organization that are over-represented in genomes. Recognising these patterns and unravelling how they have arisen may allow us to understand the functional relationships between domains and understand how the protein repertoire has evolved. We identify groups of domains that are not linearly conserved, but instead have been shuffled during evolution so that they occur in multiple different orders. We consider 192 genomes across all three kingdoms of life and use domain and protein annotation to understand their functional significance. To identify these features and assess their statistical significance, we represent the linear order of domains in proteins as a directed graph and apply graph theoretical methods. We describe two higher-order patterns of domain organisation: clusters and bi-directionally associated domain pairs and explore their functional importance and phylogenetic conservation. Taking into account the order of domains, we have derived a novel picture of global protein organization. We found that all genomes have a higher than expected degree of clustering and more domain pairs in forward and reverse orientation in different proteins relative to random graphs with identical degree distributions. While these features were statistically over-represented, they are still fairly rare. Looking in detail at the proteins involved, we found strong functional relationships within each cluster. In addition, the domains tended to be involved in protein-protein interaction and are able to function as independent structural units. A particularly striking example was the human Jak-STAT signalling pathway which makes use of a set of domains in a range of orders and orientations to provide nuanced signaling functionality. This illustrated the importance of functional and structural constraints (or lack thereof) on domain organisation.

Generalization of the Schwarz–Christoffel mapping to multiply connected polygonal domains

PubMed Central

Vasconcelos, Giovani L.

2014-01-01

A generalization of the Schwarz–Christoffel mapping to multiply connected polygonal domains is obtained by making a combined use of two preimage domains, namely, a rectilinear slit domain and a bounded circular domain. The conformal mapping from the circular domain to the polygonal region is written as an indefinite integral whose integrand consists of a product of powers of the Schottky-Klein prime functions, which is the same irrespective of the preimage slit domain, and a prefactor function that depends on the choice of the rectilinear slit domain. A detailed derivation of the mapping formula is given for the case where the preimage slit domain is the upper half-plane with radial slits. Representation formulae for other canonical slit domains are also obtained but they are more cumbersome in that the prefactor function contains arbitrary parameters in the interior of the circular domain. PMID:24910523

Generalization of the Schwarz-Christoffel mapping to multiply connected polygonal domains.

PubMed

Vasconcelos, Giovani L

2014-06-08

A generalization of the Schwarz-Christoffel mapping to multiply connected polygonal domains is obtained by making a combined use of two preimage domains, namely, a rectilinear slit domain and a bounded circular domain. The conformal mapping from the circular domain to the polygonal region is written as an indefinite integral whose integrand consists of a product of powers of the Schottky-Klein prime functions, which is the same irrespective of the preimage slit domain, and a prefactor function that depends on the choice of the rectilinear slit domain. A detailed derivation of the mapping formula is given for the case where the preimage slit domain is the upper half-plane with radial slits. Representation formulae for other canonical slit domains are also obtained but they are more cumbersome in that the prefactor function contains arbitrary parameters in the interior of the circular domain.

Fission yeast Lem2 and Man1 perform fundamental functions of the animal cell nuclear lamina.

PubMed

Gonzalez, Yanira; Saito, Akira; Sazer, Shelley

2012-01-01

In animal cells the nuclear lamina, which consists of lamins and lamin-associated proteins, serves several functions: it provides a structural scaffold for the nuclear envelope and tethers proteins and heterochromatin to the nuclear periphery. In yeast, proteins and large heterochromatic domains including telomeres are also peripherally localized, but there is no evidence that yeast have lamins or a fibrous nuclear envelope scaffold. Nonetheless, we found that the Lem2 and Man1 proteins of the fission yeast Schizosaccharomyces pombe, evolutionarily distant relatives of the Lap2/Emerin/Man1 (LEM) sub-family of animal cell lamin-associated proteins, perform fundamental functions of the animal cell lamina. These integral inner nuclear membrane localized proteins, with nuclear localized DNA binding Helix-Extension-Helix (HEH) domains, impact nuclear envelope structure and integrity, are essential for the enrichment of telomeres at the nuclear periphery and by means of their HEH domains anchor chromatin, most likely transcriptionally repressed heterochromatin, to the nuclear periphery. These data indicate that the core functions of the nuclear lamina are conserved between fungi and animal cells and can be performed in fission yeast, without lamins or other intermediate filament proteins.

Rehabilitation priorities for individuals with Prader-Willi Syndrome.

PubMed

Pituch, Keenan A; Green, Vanessa A; Didden, Robert; Lang, Russell; O'Reilly, Mark F; Lancioni, Giulio E; Whittle, Lisa; Hodis, Flaviu; Sigafoos, Jeff

2010-01-01

To identify rehabilitation priorities that parents have for their children, including their adult-aged children, with Prader-Willi Syndrome (PWS) and to determine the relation between these priorities and the child's levels of adaptive behaviour functioning. Parents involved in organisations related to PWS were invited to complete an online survey. The survey listed 54 skills/behaviours (e.g. toileting, expresses wants and needs and tantrums) representing 10 adaptive functioning domains (e.g. self-care, communication and problem behaviour). Parents rated their child's current level of ability/performance with respect to each skill/behaviour and indicated the extent to which training/treatment was a priority. Fifty-eight surveys were completed during the 4-month data collection period. Parents identified nine high-priority skills/behaviours from five different adaptive functioning domains. For most domains, parent priorities showed a significant linear relation to the children's adaptive behaviour deficits, in that priorities reflected areas where the child had the greatest deficits and the most problematic behaviours. Rehabilitation professionals should focus on the eating issues that arise in PWS and identify the adaptive functioning deficits of these individuals because such deficits are high-priority areas for parents.

Pattern, growth, and aging in aggregation kinetics of a Vicsek-like active matter model

NASA Astrophysics Data System (ADS)

Das, Subir K.

2017-01-01

Via molecular dynamics simulations, we study kinetics in a Vicsek-like phase-separating active matter model. Quantitative results, for isotropic bicontinuous pattern, are presented on the structure, growth, and aging. These are obtained via the two-point equal-time density-density correlation function, the average domain length, and the two-time density autocorrelation function. Both the correlation functions exhibit basic scaling properties, implying self-similarity in the pattern dynamics, for which the average domain size exhibits a power-law growth in time. The equal-time correlation has a short distance behavior that provides reasonable agreement between the corresponding structure factor tail and the Porod law. The autocorrelation decay is a power-law in the average domain size. Apart from these basic similarities, the overall quantitative behavior of the above-mentioned observables is found to be vastly different from those of the corresponding passive limit of the model which also undergoes phase separation. The functional forms of these have been quantified. An exceptionally rapid growth in the active system occurs due to fast coherent motion of the particles, mean-squared-displacements of which exhibit multiple scaling regimes, including a long time ballistic one.

Individual Differences in Executive Function and Central Coherence Predict Developmental Changes in Theory of Mind in Autism

ERIC Educational Resources Information Center

Pellicano, Elizabeth

2010-01-01

There is strong evidence to suggest that individuals with autism show atypicalities in multiple cognitive domains, including theory of mind (ToM), executive function (EF), and central coherence (CC). In this study, the longitudinal relationships among these 3 aspects of cognition in autism were investigated. Thirty-seven cognitively able children…

A concept ideation framework for medical device design.

PubMed

Hagedorn, Thomas J; Grosse, Ian R; Krishnamurty, Sundar

2015-06-01

Medical device design is a challenging process, often requiring collaboration between medical and engineering domain experts. This collaboration can be best institutionalized through systematic knowledge transfer between the two domains coupled with effective knowledge management throughout the design innovation process. Toward this goal, we present the development of a semantic framework for medical device design that unifies a large medical ontology with detailed engineering functional models along with the repository of design innovation information contained in the US Patent Database. As part of our development, existing medical, engineering, and patent document ontologies were modified and interlinked to create a comprehensive medical device innovation and design tool with appropriate properties and semantic relations to facilitate knowledge capture, enrich existing knowledge, and enable effective knowledge reuse for different scenarios. The result is a Concept Ideation Framework for Medical Device Design (CIFMeDD). Key features of the resulting framework include function-based searching and automated inter-domain reasoning to uniquely enable identification of functionally similar procedures, tools, and inventions from multiple domains based on simple semantic searches. The significance and usefulness of the resulting framework for aiding in conceptual design and innovation in the medical realm are explored via two case studies examining medical device design problems. Copyright © 2015 Elsevier Inc. All rights reserved.

Streamline integration as a method for two-dimensional elliptic grid generation

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

Wiesenberger, M., E-mail: Matthias.Wiesenberger@uibk.ac.at; Held, M.; Einkemmer, L.

We propose a new numerical algorithm to construct a structured numerical elliptic grid of a doubly connected domain. Our method is applicable to domains with boundaries defined by two contour lines of a two-dimensional function. Furthermore, we can adapt any analytically given boundary aligned structured grid, which specifically includes polar and Cartesian grids. The resulting coordinate lines are orthogonal to the boundary. Grid points as well as the elements of the Jacobian matrix can be computed efficiently and up to machine precision. In the simplest case we construct conformal grids, yet with the help of weight functions and monitor metricsmore » we can control the distribution of cells across the domain. Our algorithm is parallelizable and easy to implement with elementary numerical methods. We assess the quality of grids by considering both the distribution of cell sizes and the accuracy of the solution to elliptic problems. Among the tested grids these key properties are best fulfilled by the grid constructed with the monitor metric approach. - Graphical abstract: - Highlights: • Construct structured, elliptic numerical grids with elementary numerical methods. • Align coordinate lines with or make them orthogonal to the domain boundary. • Compute grid points and metric elements up to machine precision. • Control cell distribution by adaption functions or monitor metrics.« less

A dual process perspective on advances in cognitive science and alcohol use disorder.

PubMed

Lindgren, Kristen P; Hendershot, Christian S; Ramirez, Jason J; Bernat, Edward; Rangel-Gomez, Mauricio; Peterson, Kirsten P; Murphy, James G

2018-04-11

There is a tremendous global and national (US) burden associated with alcohol misuse and alcohol use disorder (AUD). Further, of the mental health disorders, AUD has the widest treatment gap. Thus, there is a critical need for improved understanding of the etiology, maintenance, and treatment of AUD. The application of cognitive science to the study of AUD has a longstanding history of attempting to meet this need. In this selective review, we identified and focused on four domains of recent (i.e., in the last decade) applications of cognitive science to the study of AUD: implicit cognitive biases, executive function, behavioral economic approaches to alcohol decision making, and functional connectivity neuroimaging. We highlighted advances within these four domains and considered them in the context of dual process models of addiction, which focus on the contribution and interplay of two complementary neurocognitive systems (impulsive and control systems). Findings across the domains were generally consistent with dual process models. They also suggest the need for further model refinements, including integrating behavioral economic approaches and findings from functional connectivity neuroimaging studies. Research evaluating candidate interventions associated with these domains is emergent but promising, suggesting important directions for future research. Copyright © 2018 Elsevier Ltd. All rights reserved.

Conserved features in TamA enable interaction with TamB to drive the activity of the translocation and assembly module

PubMed Central

Selkrig, Joel; Belousoff, Matthew J.; Headey, Stephen J.; Heinz, Eva; Shiota, Takuya; Shen, Hsin-Hui; Beckham, Simone A.; Bamert, Rebecca S.; Phan, Minh-Duy; Schembri, Mark A.; Wilce, Matthew C.J.; Scanlon, Martin J.; Strugnell, Richard A.; Lithgow, Trevor

2015-01-01

The biogenesis of membranes from constituent proteins and lipids is a fundamental aspect of cell biology. In the case of proteins assembled into bacterial outer membranes, an overarching question concerns how the energy required for protein insertion and folding is accessed at this remote location of the cell. The translocation and assembly module (TAM) is a nanomachine that functions in outer membrane biogenesis and virulence in diverse bacterial pathogens. Here we demonstrate the interactions through which TamA and TamB subunits dock to bridge the periplasm, and unite the outer membrane aspects to the inner membrane of the bacterial cell. We show that specific functional features in TamA have been conserved through evolution, including residues surrounding the lateral gate and an extensive surface of the POTRA domains. Analysis by nuclear magnetic resonance spectroscopy and small angle X-ray scattering document the characteristic structural features of these POTRA domains and demonstrate rigidity in solution. Quartz crystal microbalance measurements pinpoint which POTRA domain specifically docks the TamB subunit of the nanomachine. We speculate that the POTRA domain of TamA functions as a lever arm in order to drive the activity of the TAM, assembling proteins into bacterial outer membranes. PMID:26243377

Aperiodic topological order in the domain configurations of functional materials

NASA Astrophysics Data System (ADS)

Huang, Fei-Ting; Cheong, Sang-Wook

2017-03-01

In numerous functional materials, such as steels, ferroelectrics and magnets, new functionalities can be achieved through the engineering of the domain structures, which are associated with the ordering of certain parameters within the material. The recent progress in technologies that enable imaging at atomic-scale spatial resolution has transformed our understanding of domain topology, revealing that, along with simple stripe-like or irregularly shaped domains, intriguing vortex-type topological domain configurations also exist. In this Review, we present a new classification scheme of 'Zm Zn domains with Zl vortices' for 2D macroscopic domain structures with m directional variants and n translational antiphases. This classification, together with the concepts of topological protection and topological charge conservation, can be applied to a wide range of materials, such as multiferroics, improper ferroelectrics, layered transition metal dichalcogenides and magnetic superconductors, as we discuss using selected examples. The resulting topological considerations provide a new basis for the understanding of the formation, kinetics, manipulation and property optimization of domains and domain boundaries in functional materials.

Further insight into BRUTUS domain composition and functionality

PubMed Central

Matthiadis, Anna; Long, Terri A.

2016-01-01

ABSTRACT BRUTUS (BTS) is a hemerythrin (HHE) domain containing E3 ligase that facilitates the degradation of POPEYE-like (PYEL) proteins in a proteasomal-dependent manner. Deletion of BTS HHE domains enhances BTS stability in the presence of iron and also complements loss of BTS function, suggesting that the HHE domains are critical for protein stability but not for enzymatic function. The RING E3 domain plays an essential role in BTS' capacity to both interact with PYEL proteins and to act as an E3 ligase. Here we show that removal of the RING domain does not complement loss of BTS function. We conclude that enzymatic activity of BTS via the RING domain is essential for response to iron deficiency in plants. Further, we analyze possible BTS domain structure evolution and predict that the combination of domains found in BTS is specific to photosynthetic organisms, potentially indicative of a role for BTS and its orthologs in mitigating the iron-related challenges presented by photosynthesis. PMID:27359166

Further insight into BRUTUS domain composition and functionality.

PubMed

Matthiadis, Anna; Long, Terri A

2016-08-02

BRUTUS (BTS) is a hemerythrin (HHE) domain containing E3 ligase that facilitates the degradation of POPEYE-like (PYEL) proteins in a proteasomal-dependent manner. Deletion of BTS HHE domains enhances BTS stability in the presence of iron and also complements loss of BTS function, suggesting that the HHE domains are critical for protein stability but not for enzymatic function. The RING E3 domain plays an essential role in BTS' capacity to both interact with PYEL proteins and to act as an E3 ligase. Here we show that removal of the RING domain does not complement loss of BTS function. We conclude that enzymatic activity of BTS via the RING domain is essential for response to iron deficiency in plants. Further, we analyze possible BTS domain structure evolution and predict that the combination of domains found in BTS is specific to photosynthetic organisms, potentially indicative of a role for BTS and its orthologs in mitigating the iron-related challenges presented by photosynthesis.

Structure and regulatory role of the C-terminal winged helix domain of the archaeal minichromosome maintenance complex

PubMed Central

Wiedemann, Christoph; Szambowska, Anna; Häfner, Sabine; Ohlenschläger, Oliver; Gührs, Karl-Heinz; Görlach, Matthias

2015-01-01

The minichromosome maintenance complex (MCM) represents the replicative DNA helicase both in eukaryotes and archaea. Here, we describe the solution structure of the C-terminal domains of the archaeal MCMs of Sulfolobus solfataricus (Sso) and Methanothermobacter thermautotrophicus (Mth). Those domains consist of a structurally conserved truncated winged helix (WH) domain lacking the two typical ‘wings’ of canonical WH domains. A less conserved N-terminal extension links this WH module to the MCM AAA+ domain forming the ATPase center. In the Sso MCM this linker contains a short α-helical element. Using Sso MCM mutants, including chimeric constructs containing Mth C-terminal domain elements, we show that the ATPase and helicase activity of the Sso MCM is significantly modulated by the short α-helical linker element and by N-terminal residues of the first α-helix of the truncated WH module. Finally, based on our structural and functional data, we present a docking-derived model of the Sso MCM, which implies an allosteric control of the ATPase center by the C-terminal domain. PMID:25712103

Pyrimidinone-Peptoid Hybrid Molecules with Distinct Effects on Molecular Chaperone Function and Cell Proliferation

PubMed Central

Wright, Christine M.; Chovatiya, Raj J.; Jameson, Nora E.; Turner, David M.; Zhu, Guangyu; Werner, Stefan; Huryn, Donna M.; Pipas, James M.; Day, Billy W.; Wipf, Peter; Brodsky, Jeffrey L.

2008-01-01

The Hsp70 molecular chaperones are ATPases that play critical roles in the pathogenesis of many human diseases, including breast cancer. Hsp70 ATP hydrolysis is relatively weak, but is stimulated by J domain-containing proteins. We identified pyrimidinone-peptoid hybrid molecules that inhibit cell proliferation with greater potency than previously described Hsp70 modulators. In many cases, anti-proliferative activity correlated with inhibition of J domain stimulation of Hsp70. PMID:18164205

Supplementary motor area as key structure for domain-general sequence processing: A unified account.

PubMed

Cona, Giorgia; Semenza, Carlo

2017-01-01

The Supplementary Motor Area (SMA) is considered as an anatomically and functionally heterogeneous region and is implicated in several functions. We propose that SMA plays a crucial role in domain-general sequence processes, contributing to the integration of sequential elements into higher-order representations regardless of the nature of such elements (e.g., motor, temporal, spatial, numerical, linguistic, etc.). This review emphasizes the domain-general involvement of the SMA, as this region has been found to support sequence operations in a variety of cognitive domains that, albeit different, share an inherent sequence processing. These include action, time and spatial processing, numerical cognition, music and language processing, and working memory. In this light, we reviewed and synthesized recent neuroimaging, stimulation and electrophysiological studies in order to compare and reconcile the distinct sources of data by proposing a unifying account for the role of the SMA. We also discussed the differential contribution of the pre-SMA and SMA-proper in sequence operations, and possible neural mechanisms by which such operations are executed. Copyright © 2016 Elsevier Ltd. All rights reserved.

Changes in the folding landscape of the WW domain provide a molecular mechanism for an inherited genetic syndrome

PubMed Central

Pucheta-Martinez, Encarna; D’Amelio, Nicola; Lelli, Moreno; Martinez-Torrecuadrada, Jorge L.; Sudol, Marius; Saladino, Giorgio; Gervasio, Francesco Luigi

2016-01-01

WW domains are small domains present in many human proteins with a wide array of functions and acting through the recognition of proline-rich sequences. The WW domain belonging to polyglutamine tract-binding protein 1 (PQBP1) is of particular interest due to its direct involvement in several X chromosome-linked intellectual disabilities, including Golabi-Ito-Hall (GIH) syndrome, where a single point mutation (Y65C) correlates with the development of the disease. The mutant cannot bind to its natural ligand WBP11, which regulates mRNA processing. In this work we use high-field high-resolution NMR and enhanced sampling molecular dynamics simulations to gain insight into the molecular causes the disease. We find that the wild type protein is partially unfolded exchanging among multiple beta-strand-like conformations in solution. The Y65C mutation further destabilizes the residual fold and primes the protein for the formation of a disulphide bridge, which could be at the origin of the loss of function. PMID:27456546

The TFIIH subunit Tfb3 regulates cullin neddylation

PubMed Central

Rabut, Gwenaël; Le Dez, Gaëlle; Verma, Rati; Makhnevych, Taras; Knebel, Axel; Kurz, Thimo; Boone, Charles; Deshaies, Raymond J.; Peter, Matthias

2011-01-01

Summary Cullin proteins are scaffolds for the assembly of multi-subunit ubiquitin ligases, which ubiquitylate a large number of proteins involved in widely-varying cellular functions. Multiple mechanisms cooperate to regulate cullin activity, including neddylation of their C-terminal domain. Interestingly, we found that the yeast Cul4-type cullin Rtt101 is not only neddylated but also ubiquitylated, and both modifications promote Rtt101 function in vivo. Surprisingly, proper modification of Rtt101 neither correlated with catalytic activity of the RING-domain of Hrt1 nor did it require the Nedd8 ligase Dcn1. Instead, ubiquitylation of Rtt101 was dependent on the ubiquitin-conjugating enzyme Ubc4, while efficient neddylation involves the RING-domain protein Tfb3, a subunit of the transcription factor TFIIH. Tfb3 also controls Cul3 neddylation and activity in vivo, and physically interacts with Ubc4 and the Nedd8-conjugating enzyme Ubc12 as well as the Hrt1/Rtt101 complex. Together, these results suggest that the conserved RING-domain protein Tfb3 controls activation of a subset of cullins. PMID:21816351

Building a patchwork - The yeast plasma membrane as model to study lateral domain formation.

PubMed

Schuberth, Christian; Wedlich-Söldner, Roland

2015-04-01

The plasma membrane (PM) has to fulfill a wide range of biological functions including selective uptake of substances, signal transduction and modulation of cell polarity and cell shape. To allow efficient regulation of these processes many resident proteins and lipids of the PM are laterally segregated into different functional domains. A particularly striking example of lateral segregation has been described for the budding yeast PM, where integral membrane proteins as well as lipids exhibit very slow translational mobility and form a patchwork of many overlapping micron-sized domains. Here we discuss the molecular and physical mechanisms contributing to the formation of a multi-domain membrane and review our current understanding of yeast PM organization. Many of the fundamental principles underlying membrane self-assembly and organization identified in yeast are expected to equally hold true in other organisms, even for the more transient and elusive organization of the PM in mammalian cells. This article is part of a Special Issue entitled: Nanoscale membrane organisation and signalling. Copyright © 2014 Elsevier B.V. All rights reserved.

Cognitive Deficits as a Mediator of Poor Occupational Function in Remitted Major Depressive Disorder Patients

PubMed Central

Woo, Young Sup; Rosenblat, Joshua D.; Kakar, Ron; Bahk, Won-Myong; McIntyre, Roger S.

2016-01-01

Cognitive deficits in major depressive disorder (MDD) patients have been described in numerous studies. However, few reports have aimed to describe cognitive deficits in the remitted state of MDD and the mediational effect of cognitive deficits on occupational outcome. The aim of the current review is to synthesize the literature on the mediating and moderating effects of specific domains of cognition on occupational impairment among people with remitted MDD. In addition, predictors of cognitive deficits found to be vocationally important will be examined. Upon examination of the extant literature, attention, executive function and verbal memory are areas of consistent impairment in remitted MDD patients. Cognitive domains shown to have considerable impact on vocational functioning include deficits in memory, attention, learning and executive function. Factors that adversely affect cognitive function related to occupational accommodation include higher age, late age at onset, residual depressive symptoms, history of melancholic/psychotic depression, and physical/psychiatric comorbidity, whereas higher levels of education showed a protective effect against cognitive deficit. Cognitive deficits are a principal mediator of occupational impairment in remitted MDD patients. Therapeutic interventions specifically targeting cognitive deficits in MDD are needed, even in the remitted state, to improve functional recovery, especially in patients who have a higher risk of cognitive deficit. PMID:26792035

Using Ecological Momentary Assessment to Investigate Short-Term Variations in Sexual Functioning in a Sample of Peri-Menopausal Women from Iran

PubMed Central

Pakpour, Amir H.; Yekaninejad, Mir Saeed; Pallich, Gianandrea; Burri, Andrea

2015-01-01

The investigation of short-term changes in female sexual functioning has received little attention so far. The aims of the study were to gain empirical knowledge on within-subject and within- and across-variable fluctuations in women’s sexual functioning over time. More specifically, to investigate the stability of women´s self-reported sexual functioning and the moderating effects of contextual and interpersonal factors. A convenience sample of 206 women, recruited across eight Health care Clinics in Rasht, Iran. Ecological momentary assessment was used to examine fluctuations of sexual functioning over a six week period. A shortened version of the Female Sexual Function Index (FSFI) was applied to assess sexual functioning. Self-constructed questions were included to assess relationship satisfaction, partner’s sexual performance and stress levels. Mixed linear two-level model analyses revealed a link between orgasm and relationship satisfaction (Beta = 0.125, P = 0.074) with this link varying significantly between women. Analyses further revealed a significant negative association between stress and all six domains of women’s sexual functioning. Women not only reported differing levels of stress over the course of the assessment period, but further differed from each other in how much stress they experienced and how much this influenced their sexual response. Orgasm and sexual satisfaction were both significantly associated with all other domains of sexual function (P<0.001). And finally, a link between partner performance and all domains of women`s sexual functioning (P<0.001) could be detected. Except for lubrication (P = 0.717), relationship satisfaction had a significant effect on all domains of the sexual response (P<0.001). Overall, our findings support the new group of criteria introduced in the DSM-5, called “associated features” such as partner factors and relationship factors. Consideration of these criteria is important and necessary for clinicians when diagnosing FSD. PMID:25692787

Assessment of nutritional status in the elderly: a proposed function-driven model.

PubMed

Engelheart, Stina; Brummer, Robert

2018-01-01

There is no accepted or standardized definition of 'malnutrition'. Hence, there is also no definition of what constitutes an adequate nutritional status. In elderly people, assessment of nutritional status is complex and is complicated by multi-morbidity and disabilities combined with nutrition-related problems, such as dysphagia, decreased appetite, fatigue, and muscle weakness. We propose a nutritional status model that presents nutritional status from a comprehensive functional perspective. This model visualizes the complexity of the nutritional status in elderly people. The presented model could be interpreted as the nutritional status is conditional to a person's optimal function or situation. Another way of looking at it might be that a person's nutritional status affects his or her optimal situation. The proposed model includes four domains: (1) physical function and capacity; (2) health and somatic disorders; (3) food and nutrition; and (4) cognitive, affective, and sensory function. Each domain has a major impact on nutritional status, which in turn has a major impact on the outcome of each domain. Nutritional status is a multifaceted concept and there exist several knowledge gaps in the diagnosis, prevention, and optimization of treatment of inadequate nutritional status in elderly people. The nutritional status model may be useful in nutritional assessment research, as well as in the clinical setting.

NovelFam3000 – Uncharacterized human protein domains conserved across model organisms

PubMed Central

Kemmer, Danielle; Podowski, Raf M; Arenillas, David; Lim, Jonathan; Hodges, Emily; Roth, Peggy; Sonnhammer, Erik LL; Höög, Christer; Wasserman, Wyeth W

2006-01-01

Background Despite significant efforts from the research community, an extensive portion of the proteins encoded by human genes lack an assigned cellular function. Most metazoan proteins are composed of structural and/or functional domains, of which many appear in multiple proteins. Once a domain is characterized in one protein, the presence of a similar sequence in an uncharacterized protein serves as a basis for inference of function. Thus knowledge of a domain's function, or the protein within which it arises, can facilitate the analysis of an entire set of proteins. Description From the Pfam domain database, we extracted uncharacterized protein domains represented in proteins from humans, worms, and flies. A data centre was created to facilitate the analysis of the uncharacterized domain-containing proteins. The centre both provides researchers with links to dispersed internet resources containing gene-specific experimental data and enables them to post relevant experimental results or comments. For each human gene in the system, a characterization score is posted, allowing users to track the progress of characterization over time or to identify for study uncharacterized domains in well-characterized genes. As a test of the system, a subset of 39 domains was selected for analysis and the experimental results posted to the NovelFam3000 system. For 25 human protein members of these 39 domain families, detailed sub-cellular localizations were determined. Specific observations are presented based on the analysis of the integrated information provided through the online NovelFam3000 system. Conclusion Consistent experimental results between multiple members of a domain family allow for inferences of the domain's functional role. We unite bioinformatics resources and experimental data in order to accelerate the functional characterization of scarcely annotated domain families. PMID:16533400

The prokaryotic antecedents of the ubiquitin-signaling system and the early evolution of ubiquitin-like β-grasp domains

PubMed Central

Iyer, Lakshminarayan M; Burroughs, A Maxwell; Aravind, L

2006-01-01

Background Ubiquitin (Ub)-mediated signaling is one of the hallmarks of all eukaryotes. Prokaryotic homologs of Ub (ThiS and MoaD) and E1 ligases have been studied in relation to sulfur incorporation reactions in thiamine and molybdenum/tungsten cofactor biosynthesis. However, there is no evidence for entire protein modification systems with Ub-like proteins and deconjugation by deubiquitinating enzymes in prokaryotes. Hence, the evolutionary assembly of the eukaryotic Ub-signaling apparatus remains unclear. Results We systematically analyzed prokaryotic Ub-related β-grasp fold proteins using sensitive sequence profile searches and structural analysis. Consequently, we identified novel Ub-related proteins beyond the characterized ThiS, MoaD, TGS, and YukD domains. To understand their functional associations, we sought and recovered several conserved gene neighborhoods and domain architectures. These included novel associations involving diverse sulfur metabolism proteins, siderophore biosynthesis and the gene encoding the transfer mRNA binding protein SmpB, as well as domain fusions between Ub-like domains and PIN-domain related RNAses. Most strikingly, we found conserved gene neighborhoods in phylogenetically diverse bacteria combining genes for JAB domains (the primary de-ubiquitinating isopeptidases of the proteasomal complex), along with E1-like adenylating enzymes and different Ub-related proteins. Further sequence analysis of other conserved genes in these neighborhoods revealed several Ub-conjugating enzyme/E2-ligase related proteins. Genes for an Ub-like protein and a JAB domain peptidase were also found in the tail assembly gene cluster of certain caudate bacteriophages. Conclusion These observations imply that members of the Ub family had already formed strong functional associations with E1-like proteins, UBC/E2-related proteins, and JAB peptidases in the bacteria. Several of these Ub-like proteins and the associated protein families are likely to function together in signaling systems just as in eukaryotes. PMID:16859499

Characterizing Cognitive Performance in a Large Longitudinal Study of Aging with Computerized Semantic Indices of Verbal Fluency

PubMed Central

Pakhomov, Serguei VS; Eberly, Lynn; Knopman, David

2016-01-01

A computational approach for estimating several indices of performance on the animal category verbal fluency task was validated, and examined in a large longitudinal study of aging. The performance indices included the traditional verbal fluency score, size of semantic clusters, density of repeated words, as well as measures of semantic and lexical diversity. Change over time in these measures was modeled using mixed effects regression in several groups of participants, including those that remained cognitively normal throughout the study (CN) and those that were diagnosed with mild cognitive impairment (MCI) or Alzheimer’s disease (AD) dementia at some point subsequent to the baseline visit. The results of the study show that, with the exception of mean cluster size, the indices showed significantly greater declines in the MCI and AD dementia groups as compared to CN participants. Examination of associations between the indices and cognitive domains of memory, attention and visuospatial functioning showed that the traditional verbal fluency scores were associated with declines in all three domains, whereas semantic and lexical diversity measures were associated with declines only in the visuospatial domain. Baseline repetition density was associated with declines in memory and visuospatial domains. Examination of lexical and semantic diversity measures in subgroups with high vs. low attention scores (but normal functioning in other domains) showed that the performance of individuals with low attention was influenced more by word frequency rather than strength of semantic relatedness between words. These findings suggest that various automatically semantic indices may be used to examine various aspects of cognitive performance affected by dementia. PMID:27245645

Psychotic experiences and disability: Findings from the Collaborative Psychiatric Epidemiology Surveys.

PubMed

Oh, Hans; Koyanagi, Ai; Kelleher, Ian; DeVylder, Jordan

2018-03-01

Psychotic experiences are associated with a number of poor clinical outcomes, including multimorbid psychopathology, suicidal behavior, and poor treatment response. We wished to investigate the relationship between psychotic experiences and disability, including the following domains: cognition, mobility, self-care, social interaction, role functioning, and days out of role. We used three nationally representative and racially/ethnically diverse samples of the general US adult population: the National Comorbidity Survey Replication (NCS-R), the National Latino and Asian American Survey (NLAAS), and the National Survey of American Life (NSAL). Multi-variable logistic regression analyses were used to assess the associations between lifetime psychotic experiences (visual and auditory hallucinatory experiences and delusional ideation; WHO Composite International Diagnostic Interview psychosis screen) and 30-day impairments in functioning across disability domains (using the WHO Disability Assessment Schedule II). In all three samples, models were adjusted for socio-demographics and co-occurring psychiatric disorders. In the NCS-R, models were also adjusted for chronic health conditions. Across all three studies, our adjusted models showed that people with disability had anywhere from about 1.5 to over 3 times the odds of reporting lifetime psychotic experiences, depending on the domain. This was true for each disability domain, except self-care in the NLAAS and in the NSAL. Psychotic experiences are markers of risk for disability across a wide range of domains. This may explain the elevated rates of service utilization among individuals who report psychotic experiences and supports the need to assess for and respond to psychotic experiences even in the absence of psychotic disorder. Copyright © 2017 Elsevier B.V. All rights reserved.

A Note on a Sampling Theorem for Functions over GF(q)n Domain

NASA Astrophysics Data System (ADS)

Ukita, Yoshifumi; Saito, Tomohiko; Matsushima, Toshiyasu; Hirasawa, Shigeichi

In digital signal processing, the sampling theorem states that any real valued function ƒ can be reconstructed from a sequence of values of ƒ that are discretely sampled with a frequency at least twice as high as the maximum frequency of the spectrum of ƒ. This theorem can also be applied to functions over finite domain. Then, the range of frequencies of ƒ can be expressed in more detail by using a bounded set instead of the maximum frequency. A function whose range of frequencies is confined to a bounded set is referred to as bandlimited function. And a sampling theorem for bandlimited functions over Boolean domain has been obtained. Here, it is important to obtain a sampling theorem for bandlimited functions not only over Boolean domain (GF(q)n domain) but also over GF(q)n domain, where q is a prime power and GF(q) is Galois field of order q. For example, in experimental designs, although the model can be expressed as a linear combination of the Fourier basis functions and the levels of each factor can be represented by GF(q)n, the number of levels often take a value greater than two. However, the sampling theorem for bandlimited functions over GF(q)n domain has not been obtained. On the other hand, the sampling points are closely related to the codewords of a linear code. However, the relation between the parity check matrix of a linear code and any distinct error vectors has not been obtained, although it is necessary for understanding the meaning of the sampling theorem for bandlimited functions. In this paper, we generalize the sampling theorem for bandlimited functions over Boolean domain to a sampling theorem for bandlimited functions over GF(q)n domain. We also present a theorem for the relation between the parity check matrix of a linear code and any distinct error vectors. Lastly, we clarify the relation between the sampling theorem for functions over GF(q)n domain and linear codes.

The extracellular Leucine-Rich Repeat superfamily; a comparative survey and analysis of evolutionary relationships and expression patterns

PubMed Central

Dolan, Jackie; Walshe, Karen; Alsbury, Samantha; Hokamp, Karsten; O'Keeffe, Sean; Okafuji, Tatsuya; Miller, Suzanne FC; Tear, Guy; Mitchell, Kevin J

2007-01-01

Background Leucine-rich repeats (LRRs) are highly versatile and evolvable protein-ligand interaction motifs found in a large number of proteins with diverse functions, including innate immunity and nervous system development. Here we catalogue all of the extracellular LRR (eLRR) proteins in worms, flies, mice and humans. We use convergent evidence from several transmembrane-prediction and motif-detection programs, including a customised algorithm, LRRscan, to identify eLRR proteins, and a hierarchical clustering method based on TribeMCL to establish their evolutionary relationships. Results This yields a total of 369 proteins (29 in worm, 66 in fly, 135 in mouse and 139 in human), many of them of unknown function. We group eLRR proteins into several classes: those with only LRRs, those that cluster with Toll-like receptors (Tlrs), those with immunoglobulin or fibronectin-type 3 (FN3) domains and those with some other domain. These groups show differential patterns of expansion and diversification across species. Our analyses reveal several clusters of novel genes, including two Elfn genes, encoding transmembrane proteins with eLRRs and an FN3 domain, and six genes encoding transmembrane proteins with eLRRs only (the Elron cluster). Many of these are expressed in discrete patterns in the developing mouse brain, notably in the thalamus and cortex. We have also identified a number of novel fly eLRR proteins with discrete expression in the embryonic nervous system. Conclusion This study provides the necessary foundation for a systematic analysis of the functions of this class of genes, which are likely to include prominently innate immunity, inflammation and neural development, especially the specification of neuronal connectivity. PMID:17868438

A domain-specific compiler for a parallel multiresolution adaptive numerical simulation environment

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

Rajbhandari, Samyam; Kim, Jinsung; Krishnamoorthy, Sriram

This paper describes the design and implementation of a layered domain-specific compiler to support MADNESS---Multiresolution ADaptive Numerical Environment for Scientific Simulation. MADNESS is a high-level software environment for the solution of integral and differential equations in many dimensions, using adaptive and fast harmonic analysis methods with guaranteed precision. MADNESS uses k-d trees to represent spatial functions and implements operators like addition, multiplication, differentiation, and integration on the numerical representation of functions. The MADNESS runtime system provides global namespace support and a task-based execution model including futures. MADNESS is currently deployed on massively parallel supercomputers and has enabled many science advances.more » Due to the highly irregular and statically unpredictable structure of the k-d trees representing the spatial functions encountered in MADNESS applications, only purely runtime approaches to optimization have previously been implemented in the MADNESS framework. This paper describes a layered domain-specific compiler developed to address some performance bottlenecks in MADNESS. The newly developed static compile-time optimizations, in conjunction with the MADNESS runtime support, enable significant performance improvement for the MADNESS framework.« less

GCR1, a transcriptional activator in Saccharomyces cerevisiae, complexes with RAP1 and can function without its DNA binding domain.

PubMed Central

Tornow, J; Zeng, X; Gao, W; Santangelo, G M

1993-01-01

In Saccharomyces cerevisiae, efficient expression of glycolytic and translational component genes requires two DNA binding proteins, RAP1 (which binds to UASRPG) and GCR1 (which binds to the CT box). We generated deletions in GCR1 to test the validity of several different models for GCR1 function. We report here that the C-terminal half of GCR1, which includes the domain required for DNA binding to the CT box in vitro, can be removed without affecting GCR1-dependent transcription of either the glycolytic gene ADH1 or the translational component genes TEF1 and TEF2. We have also identified an activation domain within a segment of the GCR1 protein (the N-terminal third) that is essential for in vivo function. RAP1 and GCR1 can be co-immunoprecipitated from whole cell extracts, suggesting that they form a complex in vivo. The data are most consistent with a model in which GCR1 is attracted to DNA through contact with RAP1. Images PMID:8508768

Septins - active GTPases or just GTP-binding proteins?

PubMed

Abbey, Megha; Gaestel, Matthias; Menon, Manoj B

2018-05-10

Septins are conserved cytoskeletal proteins with unique filament forming capabilities and roles in cytokinesis and cell morphogenesis. Septins undergo hetero-oligomerization and assemble into higher order structures including filaments, rings and cages. Hetero- and homotypic interactions of septin isoforms involve alternating GTPase (G)-domain interfaces and those mediated by N- and C-terminal extensions. While most septins bind GTP, display weak GTP-hydrolysis activity and incorporate guanine nucleotides in their interaction interfaces, studies using GTPase-inactivating mutations have failed to conclusively establish a crucial role for GTPase activity in mediating septin functions. In this mini-review, we will critically assess the role of GTP-binding and -hydrolysis on septin assembly and function. The relevance of G-domain activity will also be discussed in the context of human septin mutations as well as the development of specific small-molecules targeting septin polymerization. As structural determinants of septin oligomer interfaces, G-domains are attractive targets for ligand-based inhibition of septin assembly. Whether such an intervention can predictably alter septin function is a major question for future research. This article is protected by copyright. All rights reserved. © 2018 Wiley Periodicals, Inc.

Directed evolution can rapidly improve the activity of chimeric assembly-line enzymes

PubMed Central

Fischbach, Michael A.; Lai, Jonathan R.; Roche, Eric D.; Walsh, Christopher T.; Liu, David R.

2007-01-01

Nonribosomal peptides (NRPs) are produced by NRP synthetase (NRPS) enzymes that function as molecular assembly lines. The modular architecture of NRPSs suggests that a domain responsible for activating a building block could be replaced with a domain from a foreign NRPS to create a chimeric assembly line that produces a new variant of a natural NRP. However, such chimeric NRPS modules are often heavily impaired, impeding efforts to create novel NRP variants by swapping domains from different modules or organisms. Here we show that impaired chimeric NRPSs can be functionally restored by directed evolution. Using rounds of mutagenesis coupled with in vivo screens for NRP production, we rapidly isolated variants of two different chimeric NRPSs with ≈10-fold improvements in enzyme activity and product yield, including one that produces new derivatives of the potent NRP/polyketide antibiotic andrimid. Because functional restoration in these examples required only modest library sizes (103 to 104 clones) and three or fewer rounds of screening, our approach may be widely applicable even for NRPSs from genetically challenging hosts. PMID:17620609

Binding Rate Constants Reveal Distinct Features of Disordered Protein Domains.

PubMed

Dogan, Jakob; Jonasson, Josefin; Andersson, Eva; Jemth, Per

2015-08-04

Intrinsically disordered proteins (IDPs) are abundant in the proteome and involved in key cellular functions. However, experimental data about the binding kinetics of IDPs as a function of different environmental conditions are scarce. We have performed an extensive characterization of the ionic strength dependence of the interaction between the molten globular nuclear co-activator binding domain (NCBD) of CREB binding protein and five different protein ligands, including the intrinsically disordered activation domain of p160 transcriptional co-activators (SRC1, TIF2, ACTR), the p53 transactivation domain, and the folded pointed domain (PNT) of transcription factor ETS-2. Direct comparisons of the binding rate constants under identical conditions show that the association rate constant, kon, for interactions between NCBD and disordered protein domains is high at low salt concentrations (90-350 × 10(6) M(-1) s(-1) at 4 °C) but is reduced significantly (10-30-fold) with an increasing ionic strength and reaches a plateau around physiological ionic strength. In contrast, the kon for the interaction between NCBD and the folded PNT domain is only 7 × 10(6) M(-1) s(-1) (4 °C and low salt) and displays weak ionic strength dependence, which could reflect a distinctly different association that relies less on electrostatic interactions. Furthermore, the basal rate constant (in the absence of electrostatic interactions) is high for the NCBD interactions, exceeding those typically observed for folded proteins. One likely interpretation is that disordered proteins have a large number of possible collisions leading to a productive on-pathway encounter complex, while folded proteins are more restricted in terms of orientation. Our results highlight the importance of electrostatic interactions in binding involving IDPs and emphasize the significance of including ionic strength as a factor in studies that compare the binding properties of IDPs to those of ordered proteins.

Threading structural model of the manganese-stabilizing protein PsbO reveals presence of two possible beta-sandwich domains.

PubMed

Pazos, F; Heredia, P; Valencia, A; de las Rivas, J

2001-12-01

The manganese-stabilizing protein (PsbO) is an essential component of photosystem II (PSII) and is present in all oxyphotosynthetic organisms. PsbO allows correct water splitting and oxygen evolution by stabilizing the reactions driven by the manganese cluster. Despite its important role, its structure and detailed functional mechanism are still unknown. In this article we propose a structural model based on fold recognition and molecular modeling. This model has additional support from a study of the distribution of characteristics of the PsbO sequence family, such as the distribution of conserved, apolar, tree-determinants, and correlated positions. Our threading results consistently showed PsbO as an all-beta (beta) protein, with two homologous beta domains of approximately 120 amino acids linked by a flexible Proline-Glycine-Glycine (PGG) motif. These features are compatible with a general elongated and flexible architecture, in which the two domains form a sandwich-type structure with Greek key topology. The first domain is predicted to include 8 to 9 beta-strands, the second domain 6 to 7 beta-strands. An Ig-like beta-sandwich structure was selected as a template to build the 3-D model. The second domain has, between the strands, long-loops rich in Pro and Gly that are difficult to model. One of these long loops includes a highly conserved region (between P148 and P174) and a short alpha-helix (between E181 and N188)). These regions are characteristic parts of PsbO and show that the second domain is not so similar to the template. Overall, the model was able to account for much of the experimental data reported by several authors, and it would allow the detection of key residues and regions that are proposed in this article as essential for the structure and function of PsbO. Copyright 2001 Wiley-Liss, Inc.

J domain independent functions of J proteins.

PubMed

Ajit Tamadaddi, Chetana; Sahi, Chandan

2016-07-01

Heat shock proteins of 40 kDa (Hsp40s), also called J proteins, are obligate partners of Hsp70s. Via their highly conserved and functionally critical J domain, J proteins interact and modulate the activity of their Hsp70 partners. Mutations in the critical residues in the J domain often result in the null phenotype for the J protein in question. However, as more J proteins have been characterized, it is becoming increasingly clear that a significant number of J proteins do not "completely" rely on their J domains to carry out their cellular functions, as previously thought. In some cases, regions outside the highly conserved J domain have become more important making the J domain dispensable for some, if not for all functions of a J protein. This has profound effects on the evolution of such J proteins. Here we present selected examples of J proteins that perform J domain independent functions and discuss this in the context of evolution of J proteins with dispensable J domains and J-like proteins in eukaryotes.

Domain size and structure in exchange coupled [Co/Pt]/NiO/[Co/Pt] multilayers.

PubMed

Baruth, A; Adenwalla, S

2011-09-21

We investigate the competing effects of interlayer exchange coupling and magnetostatic coupling in the magnetic heterostructure ([Co/Pt]/NiO/[Co/Pt]) with perpendicular magnetic anisotropy (PMA). This particular heterostructure is unique among coupled materials with PMA in directly exhibiting both ferromagnetic and antiferromagnetic coupling, oscillating between the two as a function of spacer layer thickness. By systematically tuning the coupling interactions via a wedge-shaped NiO spacer layer, we explore the energetics that dictate magnetic domain formation using high resolution magnetic force microscopy coupled with the magneto-optical Kerr effect. This technique probes the microscopic and macroscopic magnetic behavior as a continuous function of thickness and the interlayer exchange coupling, including the regions where interlayer coupling goes through zero. We see significant changes in domain structure based on the sign of coupling, and also show that magnetic domain size is directly related to the magnitude of the interlayer exchange coupling energy, which generally dominates over the magnetostatic interactions. When magnetostatic interactions become comparable to the interlayer exchange coupling, a delicate interplay between the differing energy contributions is apparent and energy scales are extracted. The results are of intense interest to the magnetic recording industry and also illustrate a relatively new avenue of undiscovered physics, primarily dealing with the delicate balance of energies in the formation of magnetic domains for coupled systems with PMA, defining limits on domain size as well as the interplay between roughness, domains and magnetic coupling.

Geriatric Assessment and Functional Decline in Older Patients with Lung Cancer.

PubMed

Decoster, L; Kenis, C; Schallier, D; Vansteenkiste, J; Nackaerts, K; Vanacker, L; Vandewalle, N; Flamaing, J; Lobelle, J P; Milisen, K; De Grève, J; Wildiers, H

2017-10-01

Older patients with lung cancer are a heterogeneous population making treatment decisions complex. This study aims to evaluate the value of geriatric assessment (GA) as well as the evolution of functional status (FS) in older patients with lung cancer, and to identify predictors associated with functional decline and overall survival (OS). At baseline, GA was performed in patients ≥70 years with newly diagnosed lung cancer. FS measured by activities of daily living (ADL) and instrumental activities of daily living (IADL) was reassessed at follow-up to define functional decline and OS was collected. Predictors for functional decline and OS were determined. Two hundred and forty-five patients were included in this study. At baseline, GA deficiencies were present in all domains and ADL and IADL were impaired in 51 and 63% of patients, respectively. At follow-up, functional decline in ADL was observed in 23% and in IADL in 45% of patients. In multivariable analysis, radiotherapy was predictive for ADL decline. No other predictors for ADL or IADL decline were identified. Stage and baseline performance status were predictive for OS. Older patients with lung cancer present with multiple deficiencies covering all geriatric domains. During treatment, functional decline is observed in almost half of the patients. None of the specific domains of the GA were predictive for functional decline or survival, probably because of the high impact of the aggressiveness of this tumor type leading to a poor prognosis.

The role of the GAF and central domains of the transcriptional activator VnfA in Azotobacter vinelandii.

PubMed

Yoshimitsu, Kyohei; Takatani, Nobuyuki; Miura, Yukio; Watanabe, Yoshihito; Nakajima, Hiroshi

2011-09-01

VnfA is a transcriptional activator that is required for the expression of the structural genes encoding nitrogenase-2 in Azotobacter vinelandii. VnfA consists of three domains: an N-terminal regulatory domain termed GAF, including a Cys-rich motif; a central domain from the AAA+ family; and a C-terminal domain for DNA binding. Previously, we reported that transcriptionally active VnfA harboring an Fe-S cluster (presumably of the 3Fe-4S type) as a prosthetic group and the Cys-rich motif were possibly associated with coordination of the Fe-S cluster. In the present study, we have investigated the roles of the GAF and central domains in the regulatory function of VnfA using truncated variants: ΔN15(VnfA) and ΔGAF(VnfA) that lack the N-terminal 15 residues and whole GAF domain, respectively, and GAF(VnfA) consisting of only the GAF domain. ΔN15(VnfA) and ΔGAF(VnfA) lost the ability to bind the Fe-S cluster, whereas GAF(VnfA) was still able to bind to the cluster, consistent with the hypothesis that the Cys-rich motif is essential for Fe-S cluster binding. The GAF domain showed an inhibitory effect on the transcriptional activity of VnfA, which was reversed in the presence of the Fe-S cluster, and reactivated upon disassembly of the cluster. The inhibitory activity of the GAF domain acts on the NTPase activity of the central domain, whereas the binding ability of VnfA to DNA was not significantly affected, when VnfA retains its tetrameric conformation. The results imply that a major pathway, by which VnfA function is regulated, operates via the control of NTPase activity by the GAF domain. © 2011 The Authors Journal compilation © 2011 FEBS.

Pan-Cancer Analysis of Mutation Hotspots in Protein Domains.

PubMed

Miller, Martin L; Reznik, Ed; Gauthier, Nicholas P; Aksoy, Bülent Arman; Korkut, Anil; Gao, Jianjiong; Ciriello, Giovanni; Schultz, Nikolaus; Sander, Chris

2015-09-23

In cancer genomics, recurrence of mutations in independent tumor samples is a strong indicator of functional impact. However, rare functional mutations can escape detection by recurrence analysis owing to lack of statistical power. We enhance statistical power by extending the notion of recurrence of mutations from single genes to gene families that share homologous protein domains. Domain mutation analysis also sharpens the functional interpretation of the impact of mutations, as domains more succinctly embody function than entire genes. By mapping mutations in 22 different tumor types to equivalent positions in multiple sequence alignments of domains, we confirm well-known functional mutation hotspots, identify uncharacterized rare variants in one gene that are equivalent to well-characterized mutations in another gene, detect previously unknown mutation hotspots, and provide hypotheses about molecular mechanisms and downstream effects of domain mutations. With the rapid expansion of cancer genomics projects, protein domain hotspot analysis will likely provide many more leads linking mutations in proteins to the cancer phenotype. Copyright © 2015 Elsevier Inc. All rights reserved.

Imaging of surface spin textures on bulk crystals by scanning electron microscopy

NASA Astrophysics Data System (ADS)

Akamine, Hiroshi; Okumura, So; Farjami, Sahar; Murakami, Yasukazu; Nishida, Minoru

2016-11-01

Direct observation of magnetic microstructures is vital for advancing spintronics and other technologies. Here we report a method for imaging surface domain structures on bulk samples by scanning electron microscopy (SEM). Complex magnetic domains, referred to as the maze state in CoPt/FePt alloys, were observed at a spatial resolution of less than 100 nm by using an in-lens annular detector. The method allows for imaging almost all the domain walls in the mazy structure, whereas the visualisation of the domain walls with the classical SEM method was limited. Our method provides a simple way to analyse surface domain structures in the bulk state that can be used in combination with SEM functions such as orientation or composition analysis. Thus, the method extends applications of SEM-based magnetic imaging, and is promising for resolving various problems at the forefront of fields including physics, magnetics, materials science, engineering, and chemistry.

Complex biomembrane mimetics on the sub-nanometer scale

DOE PAGES

Heberle, Frederick A.; Pabst, Georg

2017-07-17

Biomimetic lipid vesicles are indispensable tools for gaining insight into the biophysics of cell physiology on the molecular level. The level of complexity of these model systems has steadily increased, and now spans from domain forming lipid mixtures to asymmetric lipid bilayers. We review recent progress in the development and application of elastic neutron and X-ray scattering techniques for studying these systems in situ and under physiologically relevant conditions on the nanometer to sub-nanometer length scales. Particularly we focus on: (i) structural details of coexisting liquid-ordered and liquid-disordered domains, including their thickness and lipid packing mismatch as a function ofmore » a size transition from nanoscopic to macroscopic domains; (ii) membrane-mediated protein partitioning into lipid domains; (iii) the role of the aqueous medium in tuning interactions between membranes and domains; and (iv) leaflet specific structure in asymmetric bilayers and passive lipid flip-flop.« less

Complex biomembrane mimetics on the sub-nanometer scale

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

Heberle, Frederick A.; Pabst, Georg

Biomimetic lipid vesicles are indispensable tools for gaining insight into the biophysics of cell physiology on the molecular level. The level of complexity of these model systems has steadily increased, and now spans from domain forming lipid mixtures to asymmetric lipid bilayers. We review recent progress in the development and application of elastic neutron and X-ray scattering techniques for studying these systems in situ and under physiologically relevant conditions on the nanometer to sub-nanometer length scales. Particularly we focus on: (i) structural details of coexisting liquid-ordered and liquid-disordered domains, including their thickness and lipid packing mismatch as a function ofmore » a size transition from nanoscopic to macroscopic domains; (ii) membrane-mediated protein partitioning into lipid domains; (iii) the role of the aqueous medium in tuning interactions between membranes and domains; and (iv) leaflet specific structure in asymmetric bilayers and passive lipid flip-flop.« less

Computational Study on the Inhibitor Binding Mode and Allosteric Regulation Mechanism in Hepatitis C Virus NS3/4A Protein

PubMed Central

Xue, Weiwei; Yang, Ying; Wang, Xiaoting; Liu, Huanxiang; Yao, Xiaojun

2014-01-01

HCV NS3/4A protein is an attractive therapeutic target responsible for harboring serine protease and RNA helicase activities during the viral replication. Small molecules binding at the interface between the protease and helicase domains can stabilize the closed conformation of the protein and thus block the catalytic function of HCV NS3/4A protein via an allosteric regulation mechanism. But the detailed mechanism remains elusive. Here, we aimed to provide some insight into the inhibitor binding mode and allosteric regulation mechanism of HCV NS3/4A protein by using computational methods. Four simulation systems were investigated. They include: apo state of HCV NS3/4A protein, HCV NS3/4A protein in complex with an allosteric inhibitor and the truncated form of the above two systems. The molecular dynamics simulation results indicate HCV NS3/4A protein in complex with the allosteric inhibitor 4VA adopts a closed conformation (inactive state), while the truncated apo protein adopts an open conformation (active state). Further residue interaction network analysis suggests the communication of the domain-domain interface play an important role in the transition from closed to open conformation of HCV NS3/4A protein. However, the inhibitor stabilizes the closed conformation through interaction with several key residues from both the protease and helicase domains, including His57, Asp79, Asp81, Asp168, Met485, Cys525 and Asp527, which blocks the information communication between the functional domains interface. Finally, a dynamic model about the allosteric regulation and conformational changes of HCV NS3/4A protein was proposed and could provide fundamental insights into the allosteric mechanism of HCV NS3/4A protein function regulation and design of new potent inhibitors. PMID:24586263

A viral suppressor of RNA silencing inhibits ARGONAUTE 1 function by precluding target RNA binding to pre-assembled RISC

PubMed Central

Kenesi, Erzsébet; Lózsa, Rita

2017-01-01

Abstract In most eukaryotes, RNA silencing is an adaptive immune system regulating key biological processes including antiviral defense. To evade this response, viruses of plants, worms and insects have evolved viral suppressors of RNA silencing proteins (VSRs). Various VSRs, such as P1 from Sweet potato mild mottle virus (SPMMV), inhibit the activity of RNA-induced silencing complexes (RISCs) including an ARGONAUTE (AGO) protein loaded with a small RNA. However, the specific mechanisms explaining this class of inhibition are unknown. Here, we show that SPMMV P1 interacts with AGO1 and AGO2 from Arabidopsis thaliana, but solely interferes with AGO1 function. Moreover, a mutational analysis of a newly identified zinc finger domain in P1 revealed that this domain could represent an effector domain as it is required for P1 suppressor activity but not for AGO1 binding. Finally, a comparative analysis of the target RNA binding capacity of AGO1 in the presence of wild-type or suppressor-defective P1 forms revealed that P1 blocks target RNA binding to AGO1. Our results describe the negative regulation of RISC, the small RNA containing molecular machine. PMID:28499009

Structure-Function Relationship of the Bik1-Bim1 Complex.

PubMed

Stangier, Marcel M; Kumar, Anil; Chen, Xiuzhen; Farcas, Ana-Maria; Barral, Yves; Steinmetz, Michel O

2018-04-03

In budding yeast, the microtubule plus-end tracking proteins Bik1 (CLIP-170) and Bim1 (EB1) form a complex that interacts with partners involved in spindle positioning, including Stu2 and Kar9. Here, we show that the CAP-Gly and coiled-coil domains of Bik1 interact with the C-terminal ETF peptide of Bim1 and the C-terminal tail region of Stu2, respectively. The crystal structures of the CAP-Gly domain of Bik1 (Bik1CG) alone and in complex with an ETF peptide revealed unique, functionally relevant CAP-Gly elements, establishing Bik1CG as a specific C-terminal phenylalanine recognition domain. Unlike the mammalian CLIP-170-EB1 complex, Bik1-Bim1 forms ternary complexes with the EB1-binding motifs SxIP and LxxPTPh, which are present in diverse proteins, including Kar9. Perturbation of the Bik1-Bim1 interaction in vivo affected Bik1 localization and astral microtubule length. Our results provide insight into the role of the Bik1-Bim1 interaction for cell division, and demonstrate that the CLIP-170-EB1 module is evolutionarily flexible. Copyright © 2018 Elsevier Ltd. All rights reserved.

Hydrogen exchange differences between chemoreceptor signaling complexes localize to functionally important subdomains.

PubMed

Koshy, Seena S; Li, Xuni; Eyles, Stephen J; Weis, Robert M; Thompson, Lynmarie K

2014-12-16

The goal of understanding mechanisms of transmembrane signaling, one of many key life processes mediated by membrane proteins, has motivated numerous studies of bacterial chemotaxis receptors. Ligand binding to the receptor causes a piston motion of an α helix in the periplasmic and transmembrane domains, but it is unclear how the signal is then propagated through the cytoplasmic domain to control the activity of the associated kinase CheA. Recent proposals suggest that signaling in the cytoplasmic domain involves opposing changes in dynamics in different subdomains. However, it has been difficult to measure dynamics within the functional system, consisting of extended arrays of receptor complexes with two other proteins, CheA and CheW. We have combined hydrogen exchange mass spectrometry with vesicle template assembly of functional complexes of the receptor cytoplasmic domain to reveal that there are significant signaling-associated changes in exchange, and these changes localize to key regions of the receptor involved in the excitation and adaptation responses. The methylation subdomain exhibits complex changes that include slower hydrogen exchange in complexes in a kinase-activating state, which may be partially consistent with proposals that this subdomain is stabilized in this state. The signaling subdomain exhibits significant protection from hydrogen exchange in complexes in a kinase-activating state, suggesting a tighter and/or larger interaction interface with CheA and CheW in this state. These first measurements of the stability of protein subdomains within functional signaling complexes demonstrate the promise of this approach for measuring functionally important protein dynamics within the various physiologically relevant states of multiprotein complexes.

Hydrogen Exchange Differences between Chemoreceptor Signaling Complexes Localize to Functionally Important Subdomains

PubMed Central

2015-01-01

The goal of understanding mechanisms of transmembrane signaling, one of many key life processes mediated by membrane proteins, has motivated numerous studies of bacterial chemotaxis receptors. Ligand binding to the receptor causes a piston motion of an α helix in the periplasmic and transmembrane domains, but it is unclear how the signal is then propagated through the cytoplasmic domain to control the activity of the associated kinase CheA. Recent proposals suggest that signaling in the cytoplasmic domain involves opposing changes in dynamics in different subdomains. However, it has been difficult to measure dynamics within the functional system, consisting of extended arrays of receptor complexes with two other proteins, CheA and CheW. We have combined hydrogen exchange mass spectrometry with vesicle template assembly of functional complexes of the receptor cytoplasmic domain to reveal that there are significant signaling-associated changes in exchange, and these changes localize to key regions of the receptor involved in the excitation and adaptation responses. The methylation subdomain exhibits complex changes that include slower hydrogen exchange in complexes in a kinase-activating state, which may be partially consistent with proposals that this subdomain is stabilized in this state. The signaling subdomain exhibits significant protection from hydrogen exchange in complexes in a kinase-activating state, suggesting a tighter and/or larger interaction interface with CheA and CheW in this state. These first measurements of the stability of protein subdomains within functional signaling complexes demonstrate the promise of this approach for measuring functionally important protein dynamics within the various physiologically relevant states of multiprotein complexes. PMID:25420045

Validity and reliability of CHOICE Health Experience Questionnaire: Thai version.

PubMed

Aiyasanon, Nipa; Premasathian, Nalinee; Nimmannit, Akarin; Jetanavanich, Pantip; Sritippayawan, Suchai

2009-09-01

Assess the reliability and validity of the Thai translation of the CHOICE Health Experience Questionnaire (CHEQ), which is the English-language questionnaire, developed specifically for End-stage-renal disease (ESRD) patients. The CHEQ comprised of two parts, nine general domains of SF-36 (physical function, role-physical, bodily pain, mental health, role-emotional, social function, vitality, general health, and report transition) and 16 dialysis specific domains of the CHEQ (role-physical, mental health, general health, freedom, travel restriction, cognitive function, financial function, restriction diet and fluids, recreation, work, body image, symptoms, sex, sleep, access, and quality of life). The authors translated the CHEQ questionnaire into Thai and confirmed the accuracy by back translation. Pilot study sample was 10 Thai ESRD patients. Then the CHEQ (Thai) was applied to 110 Thai ESRD patients. Twenty-three patients had chronic peritoneal dialysis patients and 87 were chronic intermittent hemodialysis patients. Statistical analysis included descriptive statistics, Mann-Whitney U test, Student's t-test, and Cronbach's alpha. Construct validity was satisfactory with the significant difference less than 0.001 between the low and high group. The reliability coefficient for the Cronbach's alpha of the total scale of the CHEQ (Thai) was 0.98. The Cronbach 's alphas were greater than 0.7 for all domains, range from 0.58 to 0.92, except the social function and quality of life domain (alpha = 0.66 and 0.575). The CHEQ (Thai) is reliable and valid for assessment of Thai ESRD patients receiving chronic dialysis. Its properties are similar to those reported in the original version.

Functional, Responsive Materials Assembled from Recombinant Oleosin

NASA Astrophysics Data System (ADS)

Hammer, Daniel

Biological cells are surrounded by a plasma membrane made primarily of phospholipids that form a bilayer. This membrane is permselective and compartmentalizes the cell. A simple form of artificial cell is the vesicle, in which a phospholipid bilayer membrane surrounds an aqueous solution. However, there is no a priori reason why a membrane needs to be made of phospholipids. It could be made of any surfactant that forms a bilayer. We have assembled membranes and other structures from the recombinant plant protein oleosin. The ability to assemble from a recombinant protein means that every molecule is identical, we have complete control over the sequence, and hence can build in designer functionality with high fidelity, including adhesion and enzymatic activity. Such incorporation is trivial using the tools of molecular biology. We find that while many variants of oleosin make membranes, others make micelles and sheets. We show how the type of supramolecular structure can be altered by the conditions of solvent, such as ionic strength, and the architecture of the surfactant itself. We show that protease cleavable domains can be incorporated within oleosin, and be engineered to protect other functional domains such as adhesive motifs, to make responsive materials whose activity and shape depend on the action of proteases. We will also present the idea of making ``Franken''-oleosins, where large domains of native oleosin are replaced with domains from other functional proteins, to make hybrids conferred by the donor protein. Thus, we can view oleosin as a template upon which a vast array of designer functionalities can be imparted..

Neuropsychological functioning in preschool-age children with sickle cell disease: the role of illness-related and psychosocial factors.

PubMed

Tarazi, Reem A; Grant, Mitzie L; Ely, Elizabeth; Barakat, Lamia P

2007-03-01

Cognitive and academic deficits have been identified in school-aged children with sickle cell disease (SCD). However, there have been very few identified studies that examine neuropsychological functioning in preschool-age children with SCD. It is important to understand effects of SCD from a developmental perspective and to consider the contribution of environmental factors in this at-risk population. Neuropsychological functioning of preschool-age children with SCD and no history of overt stroke (n = 26) was examined across several domains (language, immediate memory/brief attention, visuospatial/visuoconstructional, motor/visuomotor). The mean Full Scale IQ for the sample was 89.0. Performance on the Immediate Memory/ Brief Attention domain was significantly higher than the other domains, although the pattern of performance was relatively consistent, with mean standard scores ranging from 88.0 to 95.0. Disease severity was not significantly related to cognitive functioning in this group of young children with SCD. Socioeconomic status (SES) was significantly correlated with most domain scores and, based on regression analyses, accounted for 18% to 47% of the variance in functioning. Psychosocial factors, such as number of children living in the home and parental stress levels, were negatively associated with Motor/Visuomotor skills, and weekly hours in school/day care was positively associated with language-related skills. Results suggest that, at this young age, psychosocial risk factors appear to be appropriate targets for intervention, with the goal of improving long-term outcome in children with SCD. Further investigations should include comparison to a matched control group.

Gain-of-function mutations in interleukin-7 receptor-α (IL7R) in childhood acute lymphoblastic leukemias

PubMed Central

Shochat, Chen; Tal, Noa; Bandapalli, Obul R.; Palmi, Chiara; Ganmore, Ithamar; te Kronnie, Geertruy; Cario, Gunnar; Cazzaniga, Giovanni; Kulozik, Andreas E.; Stanulla, Martin; Schrappe, Martin; Biondi, Andrea; Basso, Giuseppe; Bercovich, Dani; Muckenthaler, Martina U.

2011-01-01

Interleukin-7 receptor α (IL7R) is required for normal lymphoid development. Loss-of-function mutations in this gene cause autosomal recessive severe combined immune deficiency. Here, we describe somatic gain-of-function mutations in IL7R in pediatric B and T acute lymphoblastic leukemias. The mutations cause either a serine-to-cysteine substitution at amino acid 185 in the extracellular domain (4 patients) or in-frame insertions and deletions in the transmembrane domain (35 patients). In B cell precursor leukemias, the mutations were associated with the aberrant expression of cytokine receptor-like factor 2 (CRLF2), and the mutant IL-7R proteins formed a functional receptor with CRLF2 for thymic stromal lymphopoietin (TSLP). Biochemical and functional assays reveal that these IL7R mutations are activating mutations conferring cytokine-independent growth of progenitor lymphoid cells. A cysteine, included in all but three of the mutated IL-7R alleles, is essential for the constitutive activation of the receptor. This is the first demonstration of gain-of-function mutations of IL7R. Our current and recent observations of mutations in IL7R and CRLF2, respectively suggest that the addition of cysteine to the juxtamembranous domains is a general mechanism for mutational activation of type I cytokine receptors in leukemia. PMID:21536738

Identification of the essential protein domains for Mib2 function during the development of the Drosophila larval musculature and adult flight muscles

PubMed Central

Domsch, Katrin; Acs, Andreas; Obermeier, Claudia; Nguyen, Hanh T.

2017-01-01

The proper differentiation and maintenance of myofibers is fundamental to a functional musculature. Disruption of numerous mostly structural factors leads to perturbations of these processes. Among the limited number of known regulatory factors for these processes is Mind bomb2 (Mib2), a muscle-associated E3 ubiquitin ligase, which was previously established to be required for maintaining the integrity of larval muscles. In this study, we have examined the mechanistic aspects of Mib2 function by performing a detailed functional dissection of the Mib2 protein. We show that the ankyrin repeats, in its entirety, and the hitherto uncharacterized Mib-specific domains (MIB), are important for the major function of Mib2 in skeletal and visceral muscles in the Drosophila embryo. Furthermore, we characterize novel mib2 alleles that have arisen from a forward genetic screen aimed at identifying regulators of myogenesis. Two of these alleles are viable, but flightless hypomorphic mib2 mutants, and harbor missense mutations in the MIB domain and RING finger, respectively. Functional analysis of these new alleles, including in vivo imaging, demonstrates that Mib2 plays an additional important role in the development of adult thorax muscles, particularly in maintaining the larval templates for the dorsal longitudinal indirect flight muscles during metamorphosis. PMID:28282454

Fibromyalgia syndrome module at OMERACT 9: domain construct.

PubMed

Mease, Philip; Arnold, Lesley M; Choy, Ernest H; Clauw, Daniel J; Crofford, Leslie J; Glass, Jennifer M; Martin, Susan A; Morea, Jessica; Simon, Lee; Strand, C Vibeke; Williams, David A

2009-10-01

The objective of the module was to (1) establish a core domain set for fibromyalgia (FM) assessment in clinical trials and practice, (2) review outcome measure performance characteristics, (3) discuss development of a responder index for assessment of FM in clinical trials, (4) review objective markers, (5) review the domain of cognitive dysfunction, and (6) establish a research agenda for outcomes research. Presentations at the module included: (1) Results of univariate and multivariate analysis of 10 FM clinical trials of 4 drugs, mapping key domains identified in previous patient focus group: Delphi exercises and a clinician/researcher Delphi exercise, and breakout discussions to vote on possible essential domains and reliable measures; (2) Updates regarding outcome measure status; (3) Update on objective markers to measure FM disease state; and (4) Review of the issue of cognitive dysfunction (dyscognition) in FM. Consensus was reached as follows: (1) Greater than 70% of OMERACT participants agreed that pain, tenderness, fatigue, patient global, multidimensional function and sleep disturbance domains should be measured in all FM clinical trials; dyscognition and depression should be measured in some trials; and stiffness, anxiety, functional imaging, and cerebrospinal fluid biomarkers were identified as domains of research interest. (2) FM domain outcome measures have generally proven to be reliable, discriminative, and feasible. More sophisticated and comprehensive measures are in development, as is a responder index for FM. (3) Increasing numbers of objective markers are being developed for FM assessment. (4) Cognitive dysfunction assessment by self-assessed and applied outcome measures is being developed. In conclusion, a multidimensional symptom core set is proposed for evaluation of FM in clinical trials. Research on improved measures of single domains and composite measures is ongoing.

The reliability and validity of the English version of the Evaluation of Daily Activity Questionnaire for people with rheumatoid arthritis

PubMed Central

Tennant, Alan; Tyson, Sarah F.; Nordenskiöld, Ulla; Hawkins, Ruth; Prior, Yeliz

2015-01-01

Objectives. The Evaluation of Daily Activity Questionnaire (EDAQ) includes 138 items in 14 domains identified as important by people with RA. The aim of this study was to test the validity and reliability of the English EDAQ. Methods. A total of 502 participants completed two questionnaires 3 weeks apart. The first consisted of the EDAQ, HAQ, RA Quality of Life (RAQoL) and the Medical Outcomes Scale (MOS) 36-item Short-Form Health Survey (SF-36v2), and the second consisted of the EDAQ only. The 14 EDAQ domains were tested for: unidimensionality—using confirmatory factor analysis; fit, response dependency, invariance across groups (differential item functioning)—using Rasch analysis; internal consistency [Person Separation Index (PSI)]; concurrent validity—by correlations with the HAQ, SF-36v2 and RAQoL; and test–retest reliability (Spearman’s correlations). Results. Confirmatory factor analysis of the 14 EDAQ domains indicated unidimensionality, after adjustment for local dependency in each domain. All domains achieved a root mean square error of approximation <0.10 and satisfied Rasch model expectations for local dependency. DIF by age, gender and employment status was largely absent. The PSI was consistent with individual use (PSI = 0.94 for all 14 domains). For all domains, except Caring, concurrent validity was good: HAQ (rs = 0.72–0.91), RAQoL (rs = 0.67–0.82) and SF36v2 Physical Function scale (rs = −0.60 to −0.84) and test–retest reliability was good (rs = 0.70–0.89). Conclusion. Analysis supported a 14-domain, two-component structure (Self care and Mobility) of the EDAQ, where each domain, and both components, satisfied Rasch model requirements, and have robust reliability and validity. PMID:25863045

Up-regulation of Hyperpolarization-activated Cyclic Nucleotide-gated Channel 3 (HCN3) by Specific Interaction with K+ Channel Tetramerization Domain-containing Protein 3 (KCTD3)*

PubMed Central

Cao-Ehlker, Xiaochun; Zong, Xiangang; Hammelmann, Verena; Gruner, Christian; Fenske, Stefanie; Michalakis, Stylianos; Wahl-Schott, Christian; Biel, Martin

2013-01-01

Most ion channels consist of the principal ion-permeating core subunit(s) and accessory proteins that are assembled with the channel core. The biological functions of the latter proteins are diverse and include the regulation of the biophysical properties of the ion channel, its connection to signaling pathways and the control of its cell surface expression. There is recent evidence that native hyperpolarization-activated cyclic nucleotide-gated channel complexes (HCN1–4) also contain accessory subunits, among which TRIP8b (tetratricopeptide repeat-containing Rab8b-interacting protein) has been most extensively studied. Here, we identify KCTD3, a so far uncharacterized member of the potassium channel tetramerization-domain containing (KCTD) protein family as an HCN3-interacting protein. KCTD3 is widely expressed in brain and some non-neuronal tissues and colocalizes with HCN3 in specific regions of the brain including hypothalamus. Within the HCN channel family, KCTD3 specifically binds to HCN3 and leads to a profound up-regulation of cell surface expression and current density of this channel. HCN3 can also functionally interact with TRIP8b; however, we found no evidence for channel complexes containing both TRIP8b and KCTD3. The C terminus of HCN3 is crucially required for functional interaction with KCTD3. Replacement of the cytosolic C terminus of HCN2 by the corresponding domain of HCN3 renders HCN2 sensitive to regulation by KCTD3. The C-terminal-half of KCTD3 is sufficient for binding to HCN3. However, the complete protein including the N-terminal tetramerization domain is needed for HCN3 current up-regulation. Together, our experiments indicate that KCTD3 is an accessory subunit of native HCN3 complexes. PMID:23382386

Structure-function analyses reveal the molecular architecture and neutralization mechanism of a bacterial HEPN-MNT toxin-antitoxin system.

PubMed

Jia, Xuanyan; Yao, Jianyun; Gao, Zengqiang; Liu, Guangfeng; Dong, Yu-Hui; Wang, Xiaoxue; Zhang, Heng

2018-05-04

Toxin-antitoxin (TA) loci in bacteria are small genetic modules that regulate various cellular activities, including cell growth and death. The two-gene module encoding a HEPN (higher eukaryotes and prokaryotes nucleotide-binding) domain and a cognate MNT (minimal nucleotidyltransferase) domain have been predicted to represent a novel type II TA system prevalent in archaea and bacteria. However, the neutralization mechanism and cellular targets of the TA family remain unclear. The toxin SO_3166 having a HEPN domain and its cognate antitoxin SO_3165 with an MNT domain constitute a typical type II TA system that regulates cell motility and confers plasmid stability in the bacterium Shewanella oneidensis Here, we report the crystal structure and solution conformation of the SO_3166-SO_3165 pair, representing the first complex structures in this TA family. The structures revealed that SO_3165 and SO_3166 form a tight heterooctamer (at a 2:6 ratio), an organization that is very rare in other TA systems. We also observed that SO_3166 dimerization enables the formation of a deep cleft at the HEPN-domain interface harboring a composite R X 4-6H active site that functions as an RNA-cleaving RNase. SO_3165 bound SO_3166 mainly through its two α-helices (α2 and α4), functioning as molecular recognition elements. Moreover, their insertion into the SO_3166 cleft sterically blocked the R X 4-6H site or narrowed the cleft to inhibit RNA substrate binding. Structure-based mutagenesis confirmed the important roles of these α-helices in SO_3166 binding and inhibition. Our structure-function analysis provides first insights into the neutralization mechanism of the HEPN-MNT TA family. © 2018 Jia et al.

The FHA domain determines Drosophila Chk2/Mnk localization to key mitotic structures and is essential for early embryonic DNA damage responses.

PubMed

Takada, Saeko; Collins, Eric R; Kurahashi, Kayo

2015-05-15

DNA damage responses, including mitotic centrosome inactivation, cell-cycle delay in mitosis, and nuclear dropping from embryo cortex, maintain genome integrity in syncytial Drosophila embryos. A conserved signaling kinase, Chk2, known as Mnk/Loki, is essential for the responses. Here we demonstrate that functional EGFP-Mnk expressed from a transgene localizes to the nucleus, centrosomes, interkinetochore/centromere region, midbody, and pseudocleavage furrows without DNA damage and in addition forms numerous foci/aggregates on mitotic chromosomes upon DNA damage. We expressed EGFP-tagged Mnk deletion or point mutation variants and investigated domain functions of Mnk in vivo. A triple mutation in the phosphopeptide-binding site of the forkhead-associated (FHA) domain disrupted normal Mnk localization except to the nucleus. The mutation also disrupted Mnk foci formation on chromosomes upon DNA damage. FHA mutations and deletion of the SQ/TQ-cluster domain (SCD) abolished Mnk transphosphorylations and autophosphorylations, indicative of kinase activation after DNA damage. A potent NLS was found at the C-terminus, which is required for normal Mnk function. We propose that the FHA domain in Mnk plays essential dual functions in mediating embryonic DNA damage responses by means of its phosphopeptide-binding ability: activating Mnk in the nucleus upon DNA damage and recruiting Mnk to multiple subcellular structures independently of DNA damage. © 2015 Takada et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).

Cognitive Deficits in Executive Functions and Decision-Making Impairments Cluster Gambling Disorder Sub-types.

PubMed

Mallorquí-Bagué, Núria; Tolosa-Sola, Iris; Fernández-Aranda, Fernándo; Granero, Roser; Fagundo, Ana Beatriz; Lozano-Madrid, María; Mestre-Bach, Gemma; Gómez-Peña, Mónica; Aymamí, Neus; Borrás-González, Indira; Sánchez-González, Jessica; Baño, Marta; Del Pino-Gutiérrez, Amparo; Menchón, José M; Jiménez-Murcia, Susana

2018-03-01

To identify Gambling Disorder (GD) subtypes, in a population of men seeking treatment for GD, according to specific executive function domains (i.e., cognitive flexibility, inhibition and working memory as well as decision making) which are usually impaired in addictive behaviors. A total of 145 males ranging from 18 to 65 years diagnosed with GD were included in this study. All participants completed: (a) a set of questionnaires to assess psychopathological symptoms, personality and impulsivity traits, and (b) a battery of neuropsychological measures to test different executive functioning domains. Two clusters were identified based on the individual performance on the neuropsychological assessment. Cluster 1 [n = 106; labeled as Low Impaired Executive Function (LIEF)] was composed by patients with poor results in the neuropsychological assessment; cluster 2 patients [n = 46; labeled as High Impaired Executive Function (HIEF)] presented significantly higher deficits on the assessed domains and performed worse than the ones of LIEF cluster. Regarding the characterization of these two clusters, patients in cluster 2 were significantly older, unemployed and registered higher mean age of GD onset than patients in cluster 1. Additionally, patients in cluster 2 also obtained higher psychopathological symptoms, impulsivity (in both positive and negative urgency as well as sensation seeking) and some specific personality traits (higher harm avoidance as well as lower self-directedness and cooperativeness) than patients in cluster 1. The results of this study describe two different GD subtypes based on different cognitive domains (i.e., executive function performance). These two GD subtypes display different impulsivity and personality traits as well as clinical symptoms. The results provide new insight into the etiology and characterization of GD and have the potential to help improving current treatments.

Nucleic acid sequences encoding D1 and D1/D2 domains of human coxsackievirus and adenovirus receptor (CAR)

DOEpatents

Freimuth, Paul I.

2010-04-06

The invention provides recombinant human CAR (coxsackievirus and adenovirus receptor) polypeptides which bind adenovirus. Specifically, polypeptides corresponding to adenovirus binding domain D1 and the entire extracellular domain of human CAR protein comprising D1 and D2 are provided. In another aspect, the invention provides nucleic acid sequences encoding these domains and expression vectors for producing the domains and bacterial cells containing such vectors. The invention also includes an isolated fusion protein comprised of the D1 polypeptide fused to a polypeptide which facilitates folding of D1 when expressed in bacteria. The functional D1 domain finds application in a therapeutic method for treating a patient infected with a CAR D1-binding virus, and also in a method for identifying an antiviral compound which interferes with viral attachment. The invention also provides a method for specifically targeting a cell for infection by a virus which binds to D1.

Parkin binds the Rpn10 subunit of 26S proteasomes through its ubiquitin-like domain

PubMed Central

Sakata, Eri; Yamaguchi, Yoshiki; Kurimoto, Eiji; Kikuchi, Jun; Yokoyama, Shigeyuki; Yamada, Shingo; Kawahara, Hiroyuki; Yokosawa, Hideyoshi; Hattori, Nobutaka; Mizuno, Yoshikuni; Tanaka, Keiji; Kato, Koichi

2003-01-01

Parkin, a product of the causative gene of autosomal-recessive juvenile parkinsonism (AR-JP), is a RING-type E3 ubiquitin ligase and has an amino-terminal ubiquitin-like (Ubl) domain. Although a single mutation that causes an Arg to Pro substitution at position 42 of the Ubl domain (the Arg 42 mutation) has been identified in AR-JP patients, the function of this domain is not clear. In this study, we determined the three-dimensional structure of the Ubl domain of parkin by NMR, in particular by extensive use of backbone 15N-1H residual dipolar-coupling data. Inspection of chemical-shift-perturbation data showed that the parkin Ubl domain binds the Rpn10 subunit of 26S proteasomes via the region of parkin that includes position 42. Our findings suggest that the Arg 42 mutation induces a conformational change in the Rpn10-binding site of Ubl, resulting in impaired proteasomal binding of parkin, which could be the cause of AR-JP. PMID:12634850

TIR-only protein RBA1 recognizes a pathogen effector to regulate cell death in Arabidopsis

PubMed Central

Anderson, Ryan G.; Cherkis, Karen A.; Law, Terry F.; Liu, Qingli L.; Machius, Mischa; Nimchuk, Zachary L.; Yang, Li; Chung, Eui-Hwan; El Kasmi, Farid; Hyunh, Michael; Sondek, John E.; Dangl, Jeffery L.

2017-01-01

Detection of pathogens by plants is mediated by intracellular nucleotide-binding site leucine-rich repeat (NLR) receptor proteins. NLR proteins are defined by their stereotypical multidomain structure: an N-terminal Toll–interleukin receptor (TIR) or coiled-coil (CC) domain, a central nucleotide-binding (NB) domain, and a C-terminal leucine-rich repeat (LRR). The plant innate immune system contains a limited NLR repertoire that functions to recognize all potential pathogens. We isolated Response to the bacterial type III effector protein HopBA1 (RBA1), a gene that encodes a TIR-only protein lacking all other canonical NLR domains. RBA1 is sufficient to trigger cell death in response to HopBA1. We generated a crystal structure for HopBA1 and found that it has similarity to a class of proteins that includes esterases, the heme-binding protein ChaN, and an uncharacterized domain of Pasteurella multocida toxin. Self-association, coimmunoprecipitation with HopBA1, and function of RBA1 require two previously identified TIR–TIR dimerization interfaces. Although previously described as distinct in other TIR proteins, in RBA1 neither of these interfaces is sufficient when the other is disrupted. These data suggest that oligomerization of RBA1 is required for function. Our identification of RBA1 demonstrates that “truncated” NLRs can function as pathogen sensors, expanding our understanding of both receptor architecture and the mechanism of activation in the plant immune system. PMID:28137883

Noncoding RNAs of the Ultrabithorax Domain of the Drosophila Bithorax Complex

PubMed Central

Pease, Benjamin; Borges, Ana C.; Bender, Welcome

2013-01-01

RNA transcripts without obvious coding potential are widespread in many creatures, including the fruit fly, Drosophila melanogaster. Several noncoding RNAs have been identified within the Drosophila bithorax complex. These first appear in blastoderm stage embryos, and their expression patterns indicate that they are transcribed only from active domains of the bithorax complex. It has been suggested that these noncoding RNAs have a role in establishing active domains, perhaps by setting the state of Polycomb Response Elements A comprehensive survey across the proximal half of the bithorax complex has now revealed nine distinct noncoding RNA transcripts, including four within the Ultrabithorax transcription unit. At the blastoderm stage, the noncoding transcripts collectively span ∼75% of the 135 kb surveyed. Recombination-mediated cassette exchange was used to invert the promoter of one of the noncoding RNAs, a 23-kb transcript from the bxd domain of the bithorax complex. The resulting animals fail to make the normal bxd noncoding RNA and show no transcription across the bxd Polycomb Response Element in early embryos. The mutant flies look normal; the regulation of the bxd domain appears unaffected. Thus, the bxd noncoding RNA has no apparent function. PMID:24077301

Structural studies and molecular dynamics simulations suggest a processive mechanism of exolytic lytic transglycosylase from Campylobacter jejuni.

PubMed

Vijayaraghavan, Jagamya; Kumar, Vijay; Krishnan, Nikhil P; Kaufhold, Ross T; Zeng, Ximin; Lin, Jun; van den Akker, Focco

2018-01-01

The bacterial soluble lytic transglycosylase (LT) breaks down the peptidoglycan (PG) layer during processes such as cell division. We present here crystal structures of the soluble LT Cj0843 from Campylobacter jejuni with and without bulgecin A inhibitor in the active site. Cj0843 has a doughnut shape similar but not identical to that of E. coli SLT70. The C-terminal catalytic domain is preceded by an L-domain, a large helical U-domain, a flexible linker, and a small N-terminal NU-domain. The flexible linker allows the NU-domain to reach over and complete the circular shape, using residues conserved in the Epsilonproteobacteria LT family. The inner surface of the Cj0843 doughnut is mostly positively charged including a pocket that has 8 Arg/Lys residues. Molecular dynamics simulations with PG strands revealed a potential functional role for this pocket in anchoring the negatively charged terminal tetrapeptide of the PG during several steps in the reaction including homing and aligning the PG strand for exolytic cleavage, and subsequent ratcheting of the PG strand to enhance processivity in degrading PG strands.

The Escherichia coli Subtilase Cytotoxin A Subunit Specifically Cleaves Cell-surface GRP78 Protein and Abolishes COOH-terminal-dependent Signaling

PubMed Central

Ray, Rupa; de Ridder, Gustaaf G.; Eu, Jerry P.; Paton, Adrienne W.; Paton, James C.; Pizzo, Salvatore V.

2012-01-01

GRP78, a molecular chaperone with critical endoplasmic reticulum functions, is aberrantly expressed on the surface of cancer cells, including prostate and melanoma. Here it functions as a pro-proliferative and anti-apoptotic signaling receptor via NH2-terminal domain ligation. Auto-antibodies to this domain may appear in cancer patient serum where they are a poor prognostic indicator. Conversely, GRP78 COOH-terminal domain ligation is pro-apoptotic and anti-proliferative. There is no method to disrupt cell-surface GRP78 without compromising the total GRP78 pool, making it difficult to study cell-surface GRP78 function. We studied six cell lines representing three cancer types. One cell line per group expresses high levels of cell-surface GRP78, and the other expresses low levels (human hepatoma: Hep3B and HepG2; human prostate cancer: PC3 and 1-LN; murine melanoma: B16F0 and B16F1). We investigated the effect of Escherichia coli subtilase cytoxin catalytic subunit (SubA) on GRP78. We report that SubA specifically cleaves cell-surface GRP78 on HepG2, 1-LN, and B16F1 cells without affecting intracellular GRP78. B16F0 cells (GRP78low) have lower amounts of cleaved cell-surface GRP78. SubA has no effect on Hep3B and PC3 cells. The predicted 28-kDa GRP78 COOH-terminal fragment is released into the culture medium by SubA treatment, and COOH-terminal domain signal transduction is abrogated, whereas pro-proliferative signaling mediated through NH2-terminal domain ligation is unaffected. These experiments clarify cell-surface GRP78 topology and demonstrate that the COOH-terminal domain is necessary for pro-apoptotic signal transduction occurring upon COOH-terminal antibody ligation. SubA is a powerful tool to specifically probe the functions of cell-surface GRP78. PMID:22851173

The Escherichia coli subtilase cytotoxin A subunit specifically cleaves cell-surface GRP78 protein and abolishes COOH-terminal-dependent signaling.

PubMed

Ray, Rupa; de Ridder, Gustaaf G; Eu, Jerry P; Paton, Adrienne W; Paton, James C; Pizzo, Salvatore V

2012-09-21

GRP78, a molecular chaperone with critical endoplasmic reticulum functions, is aberrantly expressed on the surface of cancer cells, including prostate and melanoma. Here it functions as a pro-proliferative and anti-apoptotic signaling receptor via NH(2)-terminal domain ligation. Auto-antibodies to this domain may appear in cancer patient serum where they are a poor prognostic indicator. Conversely, GRP78 COOH-terminal domain ligation is pro-apoptotic and anti-proliferative. There is no method to disrupt cell-surface GRP78 without compromising the total GRP78 pool, making it difficult to study cell-surface GRP78 function. We studied six cell lines representing three cancer types. One cell line per group expresses high levels of cell-surface GRP78, and the other expresses low levels (human hepatoma: Hep3B and HepG2; human prostate cancer: PC3 and 1-LN; murine melanoma: B16F0 and B16F1). We investigated the effect of Escherichia coli subtilase cytoxin catalytic subunit (SubA) on GRP78. We report that SubA specifically cleaves cell-surface GRP78 on HepG2, 1-LN, and B16F1 cells without affecting intracellular GRP78. B16F0 cells (GRP78(low)) have lower amounts of cleaved cell-surface GRP78. SubA has no effect on Hep3B and PC3 cells. The predicted 28-kDa GRP78 COOH-terminal fragment is released into the culture medium by SubA treatment, and COOH-terminal domain signal transduction is abrogated, whereas pro-proliferative signaling mediated through NH(2)-terminal domain ligation is unaffected. These experiments clarify cell-surface GRP78 topology and demonstrate that the COOH-terminal domain is necessary for pro-apoptotic signal transduction occurring upon COOH-terminal antibody ligation. SubA is a powerful tool to specifically probe the functions of cell-surface GRP78.

CDD/SPARCLE: functional classification of proteins via subfamily domain architectures.

PubMed

Marchler-Bauer, Aron; Bo, Yu; Han, Lianyi; He, Jane; Lanczycki, Christopher J; Lu, Shennan; Chitsaz, Farideh; Derbyshire, Myra K; Geer, Renata C; Gonzales, Noreen R; Gwadz, Marc; Hurwitz, David I; Lu, Fu; Marchler, Gabriele H; Song, James S; Thanki, Narmada; Wang, Zhouxi; Yamashita, Roxanne A; Zhang, Dachuan; Zheng, Chanjuan; Geer, Lewis Y; Bryant, Stephen H

2017-01-04

NCBI's Conserved Domain Database (CDD) aims at annotating biomolecular sequences with the location of evolutionarily conserved protein domain footprints, and functional sites inferred from such footprints. An archive of pre-computed domain annotation is maintained for proteins tracked by NCBI's Entrez database, and live search services are offered as well. CDD curation staff supplements a comprehensive collection of protein domain and protein family models, which have been imported from external providers, with representations of selected domain families that are curated in-house and organized into hierarchical classifications of functionally distinct families and sub-families. CDD also supports comparative analyses of protein families via conserved domain architectures, and a recent curation effort focuses on providing functional characterizations of distinct subfamily architectures using SPARCLE: Subfamily Protein Architecture Labeling Engine. CDD can be accessed at https://www.ncbi.nlm.nih.gov/Structure/cdd/cdd.shtml. Published by Oxford University Press on behalf of Nucleic Acids Research 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Modelling protein functional domains in signal transduction using Maude

NASA Technical Reports Server (NTRS)

Sriram, M. G.

2003-01-01

Modelling of protein-protein interactions in signal transduction is receiving increased attention in computational biology. This paper describes recent research in the application of Maude, a symbolic language founded on rewriting logic, to the modelling of functional domains within signalling proteins. Protein functional domains (PFDs) are a critical focus of modern signal transduction research. In general, Maude models can simulate biological signalling networks and produce specific testable hypotheses at various levels of abstraction. Developing symbolic models of signalling proteins containing functional domains is important because of the potential to generate analyses of complex signalling networks based on structure-function relationships.

Universal depinning transition of domain walls in ultrathin ferromagnets

NASA Astrophysics Data System (ADS)

Diaz Pardo, R.; Savero Torres, W.; Kolton, A. B.; Bustingorry, S.; Jeudy, V.

2017-05-01

We present a quantitative and comparative study of magnetic-field-driven domain-wall depinning transition in different ferromagnetic ultrathin films over a wide range of temperature. We reveal a universal scaling function accounting for both drive and thermal effects on the depinning transition, including critical exponents. The consistent description we obtain for both the depinning and subthreshold thermally activated creep motion should shed light on the universal glassy dynamics of thermally fluctuating elastic objects pinned by disordered energy landscapes.

System modeling with the DISC framework: evidence from safety-critical domains.

PubMed

Reiman, Teemu; Pietikäinen, Elina; Oedewald, Pia; Gotcheva, Nadezhda

2012-01-01

The objective of this paper is to illustrate the development and application of the Design for Integrated Safety Culture (DISC) framework for system modeling by evaluating organizational potential for safety in nuclear and healthcare domains. The DISC framework includes criteria for good safety culture and a description of functions that the organization needs to implement in order to orient the organization toward the criteria. Three case studies will be used to illustrate the utilization of the DISC framework in practice.

Identification and Functional Analysis of ZIC3 Mutations in Heterotaxy and Related Congenital Heart Defects

PubMed Central

Ware, Stephanie M.; Peng, Jianlan; Zhu, Lirong; Fernbach, Susan; Colicos, Suzanne; Casey, Brett; Towbin, Jeffrey; Belmont, John W.

2004-01-01

Mutations in the zinc finger transcription factor ZIC3 cause X-linked heterotaxy and have also been identified in patients with isolated congenital heart disease (CHD). To determine the relative contribution of ZIC3 mutations to both heterotaxy and isolated CHD, we screened the coding region of ZIC3 in 194 unrelated patients, including 61 patients with classic heterotaxy, 93 patients with heart defects characteristic of heterotaxy, and 11 patients with situs inversus totalis. Five novel ZIC3 mutations in three classic heterotaxy kindreds and two sporadic CHD cases were identified. None of these alleles was found in 97 ethnically matched control samples. On the basis of these analyses, we conclude that the phenotypic spectrum of ZIC3 mutations should be expanded to include affected females and CHD not typical for heterotaxy. This screening of a cohort of patients with sporadic heterotaxy indicates that ZIC3 mutations account for ∼1% of affected individuals. Missense and nonsense mutations were found in the highly conserved zinc finger–binding domain and in the N-terminal protein domain. Functional analysis of all currently known ZIC3 point mutations indicates that mutations in the putative zinc finger DNA binding domain and in the N-terminal domain result in loss of reporter gene transactivation. It is surprising that transfection studies demonstrate aberrant cytoplasmic localization resulting from mutations between amino acids 253–323 of the ZIC3 protein, indicating that the pathogenesis of a subset of ZIC3 mutations results at least in part from failure of appropriate nuclear localization. These results further expand the phenotypic and genotypic spectrum of ZIC3 mutations and provide initial mechanistic insight into their functional consequences. PMID:14681828

Translation, Validation and Reliability of the Kidney Diseases Quality of Life-Short Form (KDQOL-SF Form) Tool in Urdu.

PubMed

Anees, Muhammad; Ibrahim, Muhammad; Imtiaz, Marium; Batool, Shazia; Elahi, Irfan; Malik, Muzammil Riaz

2016-08-01

To translate, validate and assess the reliability of kidney disease quality of life - short form (KDQOL-SF-36) in Urdu, national language of Pakistan. Amulticentric descriptive cross-sectional study. Department of Nephrology, Mayo Hospital, Lahore, from February to July 2015. Patients of end-stage renal disease (ESRD) on maintenance hemodialysis (MHD) for more than three months, were included in the study. Patients of ESRD not on dialysis, and those with acute renal failure were excluded. The English version of KDQOL-SF-36 was translated in Urdu and then translated back in English; further validation was done by a senior professor of Punjab University, Lahore. One hundred and thirty patients were included in the study. Fifty patients were from Mayo Hospital, 35 from Shalamar Hospital and 50 from Shaikh Zayed Hospital, Lahore. The internal consistency reliability coefficient for overall scale was 0.84. Twelve sub-scales (symptoms, effect of kidney disease, burden of kidney disease, cognitive function, quality of social interaction, sexual function, social support, physical functioning, role physical, pain, emotional well-being and role emotional) had more than 0.70 internal consistency reliability coefficient. Overall mean score of the domains i.e kidney disease component score (KDCS), physical component score (PCS), and mental component score (MCS) was 60.62 ±17.61, 43.12 ±19.54, and 49.27 ±14.52, respectively. Asignificant positive relationship was observed between KDCS and MCS domains, KDCS and PCS domains, PCS, and MCS domains. The Urdu version of KDQOL-SF-36 is a reliable and valid version to measure QOLin kidney disease patients on dialysis in Pakistan.

Functional Elements on SIRPα IgV domain Mediate Cell Surface Binding to CD47

PubMed Central

Liu, Yuan; Tong, Qiao; Zhou, Yubin; Lee, Hsiau-Wei; Yang, Jenny J.; Bühring, Hans-Jörg; Chen, Yi-Tien; Ha, Binh; Chen, Celia X-J.; Zen, Ke

2007-01-01

Summary SIRPα and SIRPβ1, the two major isoforms of the signal regulatory protein (SIRP) family, are co-expressed in human leukocytes but mediate distinct extracellular binding interactions and divergent cell signaling responses. Previous studies have demonstrated that binding of SIRPα with CD47, another important cell surface molecule, through the extracellular IgV domain regulates important leukocyte functions including macrophage recognition, leukocyte adhesion and transmigration. Although SIRPβ1 shares highly homologous extracellular IgV structure with SIRPα, it does not bind to CD47. In this study, we defined key amino acid residues exclusively expressing in the IgV domain of SIRPα, but not SIRPβ1, which determine the extracellular binding interaction of SIRPα to CD47. These key residues include Gln67, a small hydrophobic amino acid (Ala or Val) at the 57th position and Met102. We found that Gln67 and Ala/Val57 are critical. Mutation of either of these residues abates SIRPα directly binding to CD47. Functional cell adhesion and leukocyte transmigration assays further demonstrated central roles of Gln67 and Ala/Val57 in SIRPα extracellular binding mediated cell interactions and cell migration. Another SIRPα-specific residue, Met102, appears to assist SIRPα IgV binding through Gln67 and Ala/Val57. An essential role of these amino acids in SIRPα binding to CD47 was further confirmed by introducing these residues into the SIRPβ1 IgV domain, which dramatically converts SIRPβ1 into a CD47-binding molecule. Our results thus revealed the molecular basis by which SIRPα selectively binds to CD47 and shed new light into the structural mechanisms of SIRP isoform mediated distinctive extracellular interactions and cellular responses. PMID:17070842

Functional elements on SIRPalpha IgV domain mediate cell surface binding to CD47.

PubMed

Liu, Yuan; Tong, Qiao; Zhou, Yubin; Lee, Hsiau-Wei; Yang, Jenny J; Bühring, Hans-Jörg; Chen, Yi-Tien; Ha, Binh; Chen, Celia X-J; Yang, Yang; Zen, Ke

2007-01-19

SIRPalpha and SIRPbeta1, the two major isoforms of the signal regulatory protein (SIRP) family, are co-expressed in human leukocytes but mediate distinct extracellular binding interactions and divergent cell signaling responses. Previous studies have demonstrated that binding of SIRPalpha with CD47, another important cell surface molecule, through the extracellular IgV domain regulates important leukocyte functions including macrophage recognition, leukocyte adhesion and transmigration. Although SIRPbeta1 shares highly homologous extracellular IgV structure with SIRPalpha, it does not bind to CD47. Here, we defined key amino acid residues exclusively expressing in the IgV domain of SIRPalpha, but not SIRPbeta1, which determine the extracellular binding interaction of SIRPalpha to CD47. These key residues include Gln67, a small hydrophobic amino acid (Ala or Val) at the 57th position and Met102. We found that Gln67 and Ala/Val57 are critical. Mutation of either of these residues abates SIRPalpha directly binding to CD47. Functional cell adhesion and leukocyte transmigration assays further demonstrated central roles of Gln67 and Ala/Val57 in SIRPalpha extracellular binding mediated cell interactions and cell migration. Another SIRPalpha-specific residue, Met102, appears to assist SIRPalpha IgV binding through Gln67 and Ala/Val57. An essential role of these amino acid residues in SIRPalpha binding to CD47 was further confirmed by introducing these residues into the SIRPbeta1 IgV domain, which dramatically converts SIRPbeta1 into a CD47-binding molecule. Our results thus revealed the molecular basis by which SIRPalpha binds to CD47 and shed new light into the structural mechanisms of SIRP isoform mediated distinctive extracellular interactions and cellular responses.

Linking late cognitive outcome with glioma surgery location using resection cavity maps.

PubMed

Hendriks, Eef J; Habets, Esther J J; Taphoorn, Martin J B; Douw, Linda; Zwinderman, Aeilko H; Vandertop, W Peter; Barkhof, Frederik; Klein, Martin; De Witt Hamer, Philip C

2018-05-01

Patients with a diffuse glioma may experience cognitive decline or improvement upon resective surgery. To examine the impact of glioma location, cognitive alteration after glioma surgery was quantified and related to voxel-based resection probability maps. A total of 59 consecutive patients (range 18-67 years of age) who had resective surgery between 2006 and 2011 for a supratentorial nonenhancing diffuse glioma (grade I-III, WHO 2007) were included in this observational cohort study. Standardized neuropsychological examination and MRI were obtained before and after surgery. Intraoperative stimulation mapping guided resections towards neurological functions (language, sensorimotor function, and visual fields). Maps of resected regions were constructed in standard space. These resection cavity maps were compared between patients with and without new cognitive deficits (z-score difference >1.5 SD between baseline and one year after resection), using a voxel-wise randomization test and calculation of false discovery rates. Brain regions significantly associated with cognitive decline were classified in standard cortical and subcortical anatomy. Cognitive improvement in any domain occurred in 10 (17%) patients, cognitive decline in any domain in 25 (42%), and decline in more than one domain in 10 (17%). The most frequently affected subdomains were attention in 10 (17%) patients and information processing speed in 9 (15%). Resection regions associated with decline in more than one domain were predominantly located in the right hemisphere. For attention decline, no specific region could be identified. For decline in information speed, several regions were found, including the frontal pole and the corpus callosum. Cognitive decline after resective surgery of diffuse glioma is prevalent, in particular, in patients with a tumor located in the right hemisphere without cognitive function mapping. © The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.

Relationship between CYP1A2 Localization and Lipid Microdomain Formation as a Function of Lipid Composition

PubMed Central

Brignac-Huber, Lauren M.; Reed, James R.; Eyer, Marilyn K.

2013-01-01

Cytochrome P450 (P450) function requires the interaction of P450 and NADPH-cytochrome P450 reductase (CPR) in membranes, and is frequently studied using reconstituted systems composed solely of phosphatidylcholine. There is increasing evidence that other endoplasmic reticulum (ER) lipids can affect P450 structure, activity, and interactions with CPR. Some of these lipid effects have been attributed to the formation of organized liquid-ordered (lo) domains. The goal of this study was to determine if lo domains were formed in P450 reconstituted systems mimicking the ER membrane. CYP1A2, when incorporated in “ER-like” lipid vesicles, displayed detergent insolubility after treatment with Brij 98 and centrifugation in a sucrose gradient. Lipid probes were employed to identify domain formation in both ER-like vesicles and model membranes known to form lo domains. Changes in fluorescence resonance energy transfer (FRET) using an established donor/acceptor FRET pair in both ER-like and model lo-forming systems demonstrated the coexistence of lo- and liquid-disordered domains as a function of cholesterol and sphingomyelin content. Similarly, 6-dodecanoyl-2-dimethylaminonaphthalene (laurdan), a probe that reports on membrane organization, showed that cholesterol and sphingomyelin increased membrane order. Finally, brominated-phosphatidylcholine allowed for monitoring of the location of both CPR and CYP1A2 within the lo regions of ER-like systems. Taken together, the results demonstrate that ER-like vesicles generate microdomains, and both CYP1A2 and CPR predominantly localize into lo membrane regions. Probe fluorescent responses suggest that lipid microdomains form in these vesicles whether or not enzymes are included in the reconstituted systems. Thus, it does not appear that the proteins are critical for stabilizing lo domains. PMID:23963955

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

Antolin, J.; Instituto Carlos I de Fisica Teorica y Computacional, Universidad de Granada, ES-18071 Granada; Bouvrie, P. A.

An alternative one-parameter measure of divergence is proposed, quantifying the discrepancy among general probability densities. Its main mathematical properties include (i) comparison among an arbitrary number of functions, (ii) the possibility of assigning different weights to each function according to its relevance on the comparative procedure, and (iii) ability to modify the relative contribution of different regions within the domain. Applications to the study of atomic density functions, in both conjugated spaces, show the versatility and universality of this divergence.

Advances in functional brain imaging technology and developmental neuro-psychology: their applications in the Jungian analytic domain.

PubMed

Petchkovsky, Leon

2017-06-01

Analytical psychology shares with many other psychotherapies the important task of repairing the consequences of developmental trauma. The majority of analytic patients come from compromised early developmental backgrounds: they may have experienced neglect, abuse, or failures of empathic resonance from their carers. Functional brain imagery techniques including Quantitative Electroencephalogram (QEEG), and functional Magnetic Resonance Imagery (fMRI), allow us to track mental processes in ways beyond verbal reportage and introspection. This independent perspective is useful for developing new psychodynamic hypotheses, testing current ones, providing diagnostic markers, and monitoring treatment progress. Jung, with the Word Association Test, grasped these principles 100 years ago. Brain imaging techniques have contributed to powerful recent advances in our understanding of neurodevelopmental processes in the first three years of life. If adequate nurturance is compromised, a range of difficulties may emerge. This has important implications for how we understand and treat our psychotherapy clients. The paper provides an overview of functional brain imaging and advances in developmental neuropsychology, and looks at applications of some of these findings (including neurofeedback) in the Jungian psychotherapy domain. © 2017, The Society of Analytical Psychology.

The General Definition of the p97/Valosin-containing Protein (VCP)-interacting Motif (VIM) Delineates a New Family of p97 Cofactors*

PubMed Central

Stapf, Christopher; Cartwright, Edward; Bycroft, Mark; Hofmann, Kay; Buchberger, Alexander

2011-01-01

Cellular functions of the essential, ubiquitin-selective AAA ATPase p97/valosin-containing protein (VCP) are controlled by regulatory cofactors determining substrate specificity and fate. Most cofactors bind p97 through a ubiquitin regulatory X (UBX) or UBX-like domain or linear sequence motifs, including the hitherto ill defined p97/VCP-interacting motif (VIM). Here, we present the new, minimal consensus sequence RX5AAX2R as a general definition of the VIM that unites a novel family of known and putative p97 cofactors, among them UBXD1 and ZNF744/ANKZF1. We demonstrate that this minimal VIM consensus sequence is necessary and sufficient for p97 binding. Using NMR chemical shift mapping, we identified several residues of the p97 N-terminal domain (N domain) that are critical for VIM binding. Importantly, we show that cellular stress resistance conferred by the yeast VIM-containing cofactor Vms1 depends on the physical interaction between its VIM and the critical N domain residues of the yeast p97 homolog, Cdc48. Thus, the VIM-N domain interaction characterized in this study is required for the physiological function of Vms1 and most likely other members of the newly defined VIM family of cofactors. PMID:21896481

Caveolins and caveolae in ocular physiology and pathophysiology.

PubMed

Gu, Xiaowu; Reagan, Alaina M; McClellan, Mark E; Elliott, Michael H

2017-01-01

Caveolae are specialized, invaginated plasma membrane domains that are defined morphologically and by the expression of signature proteins called, caveolins. Caveolae and caveolins are abundant in a variety of cell types including vascular endothelium, glia, and fibroblasts where they play critical roles in transcellular transport, endocytosis, mechanotransduction, cell proliferation, membrane lipid homeostasis, and signal transduction. Given these critical cellular functions, it is surprising that ablation of the caveolae organelle does not result in lethality suggesting instead that caveolae and caveolins play modulatory roles in cellular homeostasis. Caveolar components are also expressed in ocular cell types including retinal vascular cells, Müller glia, retinal pigment epithelium (RPE), conventional aqueous humor outflow cells, the corneal epithelium and endothelium, and the lens epithelium. In the eye, studies of caveolae and other membrane microdomains (i.e., "lipid rafts") have lagged behind what is a substantial body of literature outside vision science. However, interest in caveolae and their molecular components has increased with accumulating evidence of important roles in vision-related functions such as blood-retinal barrier homeostasis, ocular inflammatory signaling, pathogen entry at the ocular surface, and aqueous humor drainage. The recent association of CAV1/2 gene loci with primary open angle glaucoma and intraocular pressure has further enhanced the need to better understand caveolar functions in the context of ocular physiology and disease. Herein, we provide the first comprehensive review of literature on caveolae, caveolins, and other membrane domains in the context of visual system function. This review highlights the importance of caveolae domains and their components in ocular physiology and pathophysiology and emphasizes the need to better understand these important modulators of cellular function. Copyright © 2016 Elsevier Ltd. All rights reserved.

Effects of environmental noise on cognitive (dys)functions in schizophrenia: A pilot within-subjects experimental study

PubMed Central

Wright, Bernice; Peters, Emmanuelle; Ettinger, Ulrich; Kuipers, Elizabeth; Kumari, Veena

2016-01-01

Cognitive impairment, particularly in attention, memory and executive function domains, is commonly present and associated with poor functional outcomes in schizophrenia. In healthy adults, environmental noise adversely affects many cognitive domains, including those known to be compromised in schizophrenia. This pilot study examined whether environmental noise causes further cognitive deterioration in a small sample of people with schizophrenia. Eighteen outpatients with schizophrenia on stable doses of antipsychotics and 18 age and sex-matched healthy participants were assessed on a comprehensive cognitive battery including measures of psychomotor speed, attention, executive functioning, working memory, and verbal learning and memory under three different conditions [quiet: ~ 30 dB(A); urban noise: building site noise, 68–78 dB(A); and social noise: background babble and footsteps from a crowded hall without any discernible words, 68–78 dB(A)], 7–14 days apart, with counter-balanced presentation of noise conditions across participants of both groups. The results showed widespread cognitive impairment in patients under all conditions, and noise-induced impairments of equal magnitude on specific cognitive functions in both groups. Both patient and healthy participant groups showed significant disruption of delayed verbal recall and recognition by urban and social noise, and of working memory by social noise, relative to the quiet condition. Performance under urban and social noise did not differ significantly from each other for any cognitive measure in either group. We conclude that noise has adverse effects on the verbal and working memory domains in schizophrenia patients and healthy participants. This may be particularly problematic for patients as it worsens their pre-existing cognitive deficits. PMID:27017491

Effects of environmental noise on cognitive (dys)functions in schizophrenia: A pilot within-subjects experimental study.

PubMed

Wright, Bernice; Peters, Emmanuelle; Ettinger, Ulrich; Kuipers, Elizabeth; Kumari, Veena

2016-05-01

Cognitive impairment, particularly in attention, memory and executive function domains, is commonly present and associated with poor functional outcomes in schizophrenia. In healthy adults, environmental noise adversely affects many cognitive domains, including those known to be compromised in schizophrenia. This pilot study examined whether environmental noise causes further cognitive deterioration in a small sample of people with schizophrenia. Eighteen outpatients with schizophrenia on stable doses of antipsychotics and 18 age and sex-matched healthy participants were assessed on a comprehensive cognitive battery including measures of psychomotor speed, attention, executive functioning, working memory, and verbal learning and memory under three different conditions [quiet: ~30dB(A); urban noise: building site noise, 68-78dB(A); and social noise: background babble and footsteps from a crowded hall without any discernible words, 68-78dB(A)], 7-14days apart, with counter-balanced presentation of noise conditions across participants of both groups. The results showed widespread cognitive impairment in patients under all conditions, and noise-induced impairments of equal magnitude on specific cognitive functions in both groups. Both patient and healthy participant groups showed significant disruption of delayed verbal recall and recognition by urban and social noise, and of working memory by social noise, relative to the quiet condition. Performance under urban and social noise did not differ significantly from each other for any cognitive measure in either group. We conclude that noise has adverse effects on the verbal and working memory domains in schizophrenia patients and healthy participants. This may be particularly problematic for patients as it worsens their pre-existing cognitive deficits. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Caveolins and caveolae in ocular physiology and pathophysiology

PubMed Central

Gu, Xiaowu; Reagan, Alaina M.; McClellan, Mark E.; Elliott, Michael H.

2016-01-01

Caveolae are specialized, invaginated plasma membrane domains that are defined morphologically and by the expression of signature proteins called, caveolins. Caveolae and caveolins are abundant in a variety of cell types including vascular endothelium, glia, and fibroblasts where they play critical roles in transcellular transport, endocytosis, mechanotransduction, cell proliferation, membrane lipid homeostasis, and signal transduction. Given these critical cellular functions, it is surprising that ablation of the caveolae organelle does not result in lethality suggesting instead that caveolae and caveolins play modulatory roles in cellular homeostasis. Caveolar components are also expressed in ocular cell types including retinal vascular cells, Müller glia, retinal pigment epithelium (RPE), conventional aqueous humor outflow cells, the corneal epithelium and endothelium, and the lens epithelium. In the eye, studies of caveolae and other membrane microdomains (i.e., “lipid rafts”) have lagged behind what is a substantial body of literature outside vision science. However, interest in caveolae and their molecular components has increased with accumulating evidence of important roles in vision-related functions such as blood-retinal barrier homeostasis, ocular inflammatory signalling, pathogen entry at the ocular surface, and aqueous humor drainage. The recent association of CAV1/2 gene loci with primary open angle glaucoma and intraocular pressure has further enhanced the need to better understand caveolar functions in the context of ocular physiology and disease. Herein, we provide the first comprehensive review of literature on caveolae, caveolins, and other membrane domains in the context of visual system function. This review highlights the importance of caveolae domains and their components in ocular physiology and pathophysiology and emphasizes the need to better understand these important modulators of cellular function. PMID:27664379

Conceptual foundation for measures of physical function and behavioral health function for Social Security work disability evaluation.

PubMed

Marfeo, Elizabeth E; Haley, Stephen M; Jette, Alan M; Eisen, Susan V; Ni, Pengsheng; Bogusz, Kara; Meterko, Mark; McDonough, Christine M; Chan, Leighton; Brandt, Diane E; Rasch, Elizabeth K

2013-09-01

Physical and mental impairments represent the 2 largest health condition categories for which workers receive Social Security disability benefits. Comprehensive assessment of physical and mental impairments should include aspects beyond medical conditions such as a person's underlying capabilities as well as activity demands relevant to the context of work. The objective of this article is to describe the initial conceptual stages of developing new measurement instruments of behavioral health and physical functioning relevant for Social Security work disability evaluation purposes. To outline a clear conceptualization of the constructs to be measured, 2 content models were developed using structured and informal qualitative approaches. We performed a structured literature review focusing on work disability and incorporating aspects of the International Classification of Functioning, Disability and Health as a unifying taxonomy for framework development. Expert interviews provided advice and consultation to enhance face validity of the resulting content models. The content model for work-related behavioral health function identifies 5 major domains: (1) behavior control, (2) basic interactions, (3) temperament and personality, (4) adaptability, and (5) workplace behaviors. The content model describing physical functioning includes 3 domains: (1) changing and maintaining body position, (2) whole-body mobility, and (3) carrying, moving, and handling objects. These content models informed subsequent measurement properties including item development and measurement scale construction, and provided conceptual coherence guiding future empirical inquiry. The proposed measurement approaches show promise to comprehensively and systematically assess physical and behavioral health functioning relevant to work. Copyright © 2013 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.

The domain organization of the bacterial intermediate filament-like protein crescentin is important for assembly and function

PubMed Central

Cabeen, Matthew T; Herrmann, Harald; Jacobs-Wagner, Christine

2011-01-01

Crescentin is a bacterial filament-forming protein that exhibits domain organization features found in metazoan intermediate filament (IF) proteins. Structure-function studies of eukaryotic IFs have been hindered by a lack of simple genetic systems and easily quantifiable phenotypes. Here we exploit the characteristic localization of the crescentin structure along the inner curvature of Caulobacter crescentus cells and the loss of cell curvature associated with impaired crescentin function to analyze the importance of the domain organization of crescentin. By combining biochemistry and ultrastructural analysis in vitro with cellular localization and functional studies, we show that crescentin requires its distinctive domain organization, and furthermore that different structural elements have distinct structural and functional contributions. The head domain can be functionally subdivided into two subdomains; the first (amino-terminal) is required for function but not assembly, while the second is necessary for structure assembly. The rod domain is similarly required for structure assembly, and the linker L1 appears important to prevent runaway assembly into nonfunctional aggregates. The data also suggest that the stutter and the tail domain have critical functional roles in stabilizing crescentin structures against disassembly by monovalent cations in the cytoplasm. This study suggests that the IF-like behavior of crescentin is a consequence of its domain organization, implying that the IF protein layout is an adaptable cytoskeletal motif, much like the actin and tubulin folds, that is broadly exploited for various functions throughout life from bacteria to humans. © 2011 Wiley-Liss, Inc. PMID:21360832

Using the International Classification of Functioning, Disability, and Health to identify outcome domains for a core outcome set for aphasia: a comparison of stakeholder perspectives.

PubMed

Wallace, Sarah J; Worrall, Linda; Rose, Tanya; Le Dorze, Guylaine

2017-11-12

This study synthesised the findings of three separate consensus processes exploring the perspectives of key stakeholder groups about important aphasia treatment outcomes. This process was conducted to generate recommendations for outcome domains to be included in a core outcome set for aphasia treatment trials. International Classification of Functioning, Disability, and Health codes were examined to identify where the groups of: (1) people with aphasia, (2) family members, (3) aphasia researchers, and (4) aphasia clinicians/managers, demonstrated congruence in their perspectives regarding important treatment outcomes. Codes were contextualized using qualitative data. Congruence across three or more stakeholder groups was evident for ICF chapters: Mental functions; Communication; and Services, systems, and policies. Quality of life was explicitly identified by clinicians/managers and researchers, while people with aphasia and their families identified outcomes known to be determinants of quality of life. Core aphasia outcomes include: language, emotional wellbeing, communication, patient-reported satisfaction with treatment and impact of treatment, and quality of life. International Classification of Functioning, Disability, and Health coding can be used to compare stakeholder perspectives and identify domains for core outcome sets. Pairing coding with qualitative data may ensure important nuances of meaning are retained. Implications for rehabilitation The outcomes measured in treatment research should be relevant to stakeholders and support health care decision making. Core outcome sets (agreed, minimum set of outcomes, and outcome measures) are increasingly being used to ensure the relevancy and consistency of the outcomes measured in treatment studies. Important aphasia treatment outcomes span all components of the International Classification of Functioning, Disability, and Health. Stakeholders demonstrated congruence in the identification of important outcomes which related Mental functions; Communication; Services, systems, and policies; and Quality of life. A core outcome set for aphasia treatment research should include measures relating to: language, emotional wellbeing, communication, patient-reported satisfaction with treatment and impact of treatment, and quality of life. Coding using the International Classification of Functioning, Disability, and Health, presents a novel methodology for the comparison of stakeholder perspectives to inform recommendations for outcome constructs to be included in a core outcome set. Coding can be paired with qualitative data to ensure nuances of meaning are retained.

Signal Processing, Analysis, & Display

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

Lager, Darrell; Azevado, Stephen

1986-06-01

SIG is a general-purpose signal processing, analysis, and display program. Its main purpose is to perform manipulations on time- and frequency-domain signals. However, it has been designed to ultimately accommodate other representations for data such as multiplexed signals and complex matrices. Two user interfaces are provided in SIG - a menu mode for the unfamiliar user and a command mode for more experienced users. In both modes errors are detected as early as possible and are indicated by friendly, meaningful messages. An on-line HELP package is also included. A variety of operations can be performed on time- and frequency-domain signalsmore » including operations on the samples of a signal, operations on the entire signal, and operations on two or more signals. Signal processing operations that can be performed are digital filtering (median, Bessel, Butterworth, and Chebychev), ensemble average, resample, auto and cross spectral density, transfer function and impulse response, trend removal, convolution, Fourier transform and inverse window functions (Hamming, Kaiser-Bessel), simulation (ramp, sine, pulsetrain, random), and read/write signals. User definable signal processing algorithms are also featured. SIG has many options including multiple commands per line, command files with arguments,commenting lines, defining commands, and automatic execution for each item in a repeat sequence. Graphical operations on signals and spectra include: x-y plots of time signals; real, imaginary, magnitude, and phase plots of spectra; scaling of spectra for continuous or discrete domain; cursor zoom; families of curves; and multiple viewports.« less

SIG. Signal Processing, Analysis, & Display

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

Hernandez, J.; Lager, D.; Azevedo, S.

1992-01-22

SIG is a general-purpose signal processing, analysis, and display program. Its main purpose is to perform manipulations on time- and frequency-domain signals. However, it has been designed to ultimately accommodate other representations for data such as multiplexed signals and complex matrices. Two user interfaces are provided in SIG - a menu mode for the unfamiliar user and a command mode for more experienced users. In both modes errors are detected as early as possible and are indicated by friendly, meaningful messages. An on-line HELP package is also included. A variety of operations can be performed on time- and frequency-domain signalsmore » including operations on the samples of a signal, operations on the entire signal, and operations on two or more signals. Signal processing operations that can be performed are digital filtering (median, Bessel, Butterworth, and Chebychev), ensemble average, resample, auto and cross spectral density, transfer function and impulse response, trend removal, convolution, Fourier transform and inverse window functions (Hamming, Kaiser-Bessel), simulation (ramp, sine, pulsetrain, random), and read/write signals. User definable signal processing algorithms are also featured. SIG has many options including multiple commands per line, command files with arguments,commenting lines, defining commands, and automatic execution for each item in a repeat sequence. Graphical operations on signals and spectra include: x-y plots of time signals; real, imaginary, magnitude, and phase plots of spectra; scaling of spectra for continuous or discrete domain; cursor zoom; families of curves; and multiple viewports.« less

Extensions of PDZ domains as important structural and functional elements.

PubMed

Wang, Conan K; Pan, Lifeng; Chen, Jia; Zhang, Mingjie

2010-08-01

'Divide and conquer' has been the guiding strategy for the study of protein structure and function. Proteins are divided into domains with each domain having a canonical structural definition depending on its type. In this review, we push forward with the interesting observation that many domains have regions outside of their canonical definition that affect their structure and function; we call these regions 'extensions'. We focus on the highly abundant PDZ (PSD-95, DLG1 and ZO-1) domain. Using bioinformatics, we find that many PDZ domains have potential extensions and we developed an openly-accessible website to display our results ( http://bcz102.ust.hk/pdzex/ ). We propose, using well-studied PDZ domains as illustrative examples, that the roles of PDZ extensions can be classified into at least four categories: 1) protein dynamics-based modulation of target binding affinity, 2) provision of binding sites for macro-molecular assembly, 3) structural integration of multi-domain modules, and 4) expansion of the target ligand-binding pocket. Our review highlights the potential structural and functional importance of domain extensions, highlighting the significance of looking beyond the canonical boundaries of protein domains in general.

Novel functions of CCM1 delimit the relationship of PTB/PH domains.

PubMed

Zhang, Jun; Dubey, Pallavi; Padarti, Akhil; Zhang, Aileen; Patel, Rinkal; Patel, Vipulkumar; Cistola, David; Badr, Ahmed

2017-10-01

Three NPXY motifs and one FERM domain in CCM1 makes it a versatile scaffold protein for tethering the signaling components together within the CCM signaling complex (CSC). The cellular role of CCM1 protein remains inadequately expounded. Both phosphotyrosine binding (PTB) and pleckstrin homology (PH) domains were recognized as structurally related but functionally distinct domains. By utilizing molecular cloning, protein binding assays and RT-qPCR to identify novel cellular partners of CCM1 and its cellular expression patterns; by screening candidate PTB/PH proteins and subsequently structurally simulation in combining with current X-ray crystallography and NMR data to defined the essential structure of PTB/PH domain for NPXY-binding and the relationship among PTB, PH and FERM domain(s). We identified a group of 28 novel cellular partners of CCM1, all of which contain either PTB or PH domain(s), and developed a novel classification system for these PTB/PH proteins based on their relationship with different NPXY motifs of CCM1. Our results demonstrated that CCM1 has a wide spectrum of binding to different PTB/PH proteins and perpetuates their specificity to interact with certain PTB/PH domains through selective combination of three NPXY motifs. We also demonstrated that CCM1 can be assembled into oligomers through intermolecular interaction between its F3 lobe in FERM domain and one of the three NPXY motifs. Despite being embedded in FERM domain as F3 lobe, F3 module acts as a fully functional PH domain to interact with NPXY motif. The most salient feature of the study was that both PTB and PH domains are structurally and functionally comparable, suggesting that PTB domain is likely evolved from PH domain with polymorphic structural additions at its N-terminus. A new β1A-strand of the PTB domain was discovered and new minimum structural requirement of PTB/PH domain for NPXY motif-binding was determined. Based on our data, a novel theory of structure, function and relationship of PTB, PH and FERM domains has been proposed, which extends the importance of the NPXY-PTB/PH interaction on the CSC signaling and/or other cell receptors with great potential pointing to new therapeutic strategies. The study provides new insight into the structural characteristics of PTB/PH domains, essential structural elements of PTB/PH domain required for NPXY motif-binding, and function and relationship among PTB, PH and FERM domains. Copyright © 2017 Elsevier B.V. All rights reserved.

Structure and function of POTRA domains of Omp85/TPS superfamily.

PubMed

Simmerman, Richard F; Dave, Ashita M; Bruce, Barry D

2014-01-01

The Omp85/TPS (outer-membrane protein of 85 kDa/two-partner secretion) superfamily is a ubiquitous and major class of β-barrel proteins. This superfamily is restricted to the outer membranes of gram-negative bacteria, mitochondria, and chloroplasts. The common architecture, with an N-terminus consisting of repeats of soluble polypeptide-transport-associated (POTRA) domains and a C-terminal β-barrel pore is highly conserved. The structures of multiple POTRA domains and one full-length TPS protein have been solved, yet discovering roles of individual POTRA domains has been difficult. This review focuses on similarities and differences between POTRA structures, emphasizing POTRA domains in autotrophic organisms including plants and cyanobacteria. Unique roles, specific for certain POTRA domains, are examined in the context of POTRA location with respect to their attachment to the β-barrel pore, and their degree of biological dispensability. Finally, because many POTRA domains may have the ability to interact with thousands of partner proteins, possible modes of these interactions are also explored. © 2014 Elsevier Inc. All rights reserved.

Tyrosine phosphorylation of the Lyn Src homology 2 (SH2) domain modulates its binding affinity and specificity.

PubMed

Jin, Lily L; Wybenga-Groot, Leanne E; Tong, Jiefei; Taylor, Paul; Minden, Mark D; Trudel, Suzanne; McGlade, C Jane; Moran, Michael F

2015-03-01

Src homology 2 (SH2) domains are modular protein structures that bind phosphotyrosine (pY)-containing polypeptides and regulate cellular functions through protein-protein interactions. Proteomics analysis showed that the SH2 domains of Src family kinases are themselves tyrosine phosphorylated in blood system cancers, including acute myeloid leukemia, chronic lymphocytic leukemia, and multiple myeloma. Using the Src family kinase Lyn SH2 domain as a model, we found that phosphorylation at the conserved SH2 domain residue Y(194) impacts the affinity and specificity of SH2 domain binding to pY-containing peptides and proteins. Analysis of the Lyn SH2 domain crystal structure supports a model wherein phosphorylation of Y(194) on the EF loop modulates the binding pocket that engages amino acid side chains at the pY+2/+3 position. These data indicate another level of regulation wherein SH2-mediated protein-protein interactions are modulated by SH2 kinases and phosphatases. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Incorporating molecular and functional context into the analysis and prioritization of human variants associated with cancer

PubMed Central

Peterson, Thomas A; Nehrt, Nathan L; Park, DoHwan

2012-01-01

Background and objective With recent breakthroughs in high-throughput sequencing, identifying deleterious mutations is one of the key challenges for personalized medicine. At the gene and protein level, it has proven difficult to determine the impact of previously unknown variants. A statistical method has been developed to assess the significance of disease mutation clusters on protein domains by incorporating domain functional annotations to assist in the functional characterization of novel variants. Methods Disease mutations aggregated from multiple databases were mapped to domains, and were classified as either cancer- or non-cancer-related. The statistical method for identifying significantly disease-associated domain positions was applied to both sets of mutations and to randomly generated mutation sets for comparison. To leverage the known function of protein domain regions, the method optionally distributes significant scores to associated functional feature positions. Results Most disease mutations are localized within protein domains and display a tendency to cluster at individual domain positions. The method identified significant disease mutation hotspots in both the cancer and non-cancer datasets. The domain significance scores (DS-scores) for cancer form a bimodal distribution with hotspots in oncogenes forming a second peak at higher DS-scores than non-cancer, and hotspots in tumor suppressors have scores more similar to non-cancers. In addition, on an independent mutation benchmarking set, the DS-score method identified mutations known to alter protein function with very high precision. Conclusion By aggregating mutations with known disease association at the domain level, the method was able to discover domain positions enriched with multiple occurrences of deleterious mutations while incorporating relevant functional annotations. The method can be incorporated into translational bioinformatics tools to characterize rare and novel variants within large-scale sequencing studies. PMID:22319177

TAM Receptor Tyrosine Kinases: Biologic Functions, Signaling, and Potential Therapeutic Targeting in Human Cancer

PubMed Central

Linger, Rachel M. A.; Keating, Amy K.; Earp, H. Shelton; Graham, Douglas K.

2011-01-01

Tyro-3, Axl, and Mer constitute the TAM family of receptor tyrosine kinases (RTKs) characterized by a conserved sequence within the kinase domain and adhesion molecule-like extracellular domains. This small family of RTKs regulates an intriguing mix of processes, including cell proliferation/survival, cell adhesion and migration, blood clot stabilization, and regulation of inflammatory cytokine release. Genetic or experimental alteration of TAM receptor function can contribute to a number of disease states, including coagulopathy, autoimmune disease, retinitis pigmentosa, and cancer. In this chapter, we first provide a comprehensive review of the structure, regulation, biologic functions, and down-stream signaling pathways of these receptors. In addition, we discuss recent evidence which suggests a role for TAM receptors in oncogenic mechanisms as family members are over-expressed in a spectrum of human cancers and have prognostic significance in some. Possible strategies for targeted inhibition of the TAM family in the treatment of human cancer are described. Further research will be necessary to evaluate the full clinical implications of TAM family expression and activation in cancer. PMID:18620092

Consequences of maternal morbidity on health-related functioning: a systematic scoping review

PubMed Central

Machiyama, Kazuyo; Hirose, Atsumi; Cresswell, Jenny A; Barreix, Maria; Chou, Doris; Kostanjsek, Nenad; Say, Lale; Filippi, Véronique

2017-01-01

Objectives To assess the scope of the published literature on the consequences of maternal morbidity on health-related functioning at the global level and identify key substantive findings as well as research and methodological gaps. Methods We searched for articles published between 2005 and 2014 using Medline, Embase, Popline, CINAHL Plus and three regional bibliographic databases in January 2015. Design Systematic scoping review Primary outcome Health-related functioning Results After screening 17 706 studies, 136 articles were identified for inclusion. While a substantial number of papers have documented mostly negative effects of morbidity on health-related functioning and well-being, the body of evidence is not spread evenly across conditions, domains or geographical regions. Over 60% of the studies focus on indirect conditions such as depression, diabetes and incontinence. Health-related functioning is often assessed by instruments designed for the general population including the 36-item Short Form or disease-specific tools. The functioning domains most frequently documented are physical and mental; studies that examined physical, mental, social, economic and specifically focused on marital, maternal and sexual functioning are rare. Only 16 studies were conducted in Africa. Conclusions Many assessments have not been comprehensive and have paid little attention to important functioning domains for pregnant and postpartum women. The development of a comprehensive instrument specific to maternal health would greatly advance our understanding of burden of ill health associated with maternal morbidity and help set priorities. The lack of attention to consequences on functioning associated with the main direct obstetric complications is of particular concern. Review registration CRD42015017774 PMID:28667198

The chromosomal association/dissociation of the chromatin insulator protein Cp190 of Drosophila melanogaster is mediated by the BTB/POZ domain and two acidic regions.

PubMed

Oliver, Daniel; Sheehan, Brian; South, Heather; Akbari, Omar; Pai, Chi-Yun

2010-12-31

Chromatin insulators or boundary elements are a class of functional elements in the eukaryotic genome. They regulate gene transcription by interfering with promoter-enhancer communication. The Cp190 protein of Drosophila melanogaster is essential to the function of at least three-types of chromatin insulator complexes organized by Su(Hw), CTCF and BEAF32. We mapped functional regions of Cp190 in vivo and identified three domains that are essential for the insulator function and for the viability of flies: the BTB/POZ domain, an aspartic acid-rich (D-rich) region and a C-terminal glutamic acid-rich (E-rich) region. Other domains including the centrosomal targeting domain and the zinc fingers are dispensable. The N-terminal CP190BTB-D fragment containing the BTB/POZ domain and the D-rich region is sufficient to mediate association with all three types of insulator complexes. The fragment however is not sufficient for insulator activity or viability. The Cp190 and CP190BTB-D are regulated differently in cells treated with heat-shock. The Cp190 dissociated from chromosomes during heat-shock, indicating that dissociation of Cp190 with chromosomes can be regulated. In contrast, the CP190BTB-D fragment didn't dissociate from chromosomes in the same heat-shocked condition, suggesting that the deleted C-terminal regions have a role in regulating the dissociation of Cp190 with chromosomes. The N-terminal fragment of Cp190 containing the BTB/POZ domain and the D-rich region mediates association of Cp190 with all three types of insulator complexes and that the E-rich region of Cp190 is required for dissociation of Cp190 from chromosomes during heat-shock. The heat-shock-induced dissociation is strong evidence indicating that dissociation of the essential insulator protein Cp190 from chromosomes is regulated. Our results provide a mechanism through which activities of an insulator can be modulated by internal and external cues.

Modeling Protein Domain Function

ERIC Educational Resources Information Center

Baker, William P.; Jones, Carleton "Buck"; Hull, Elizabeth

2007-01-01

This simple but effective laboratory exercise helps students understand the concept of protein domain function. They use foam beads, Styrofoam craft balls, and pipe cleaners to explore how domains within protein active sites interact to form a functional protein. The activity allows students to gain content mastery and an understanding of the…

Broadband Structural Dynamics: Understanding the Impulse-Response of Structures Across Multiple Length and Time Scales

DTIC Science & Technology

2010-08-18

Spectral domain response calculated • Time domain response obtained through inverse transform Approach 4: WASABI Wavelet Analysis of Structural Anomalies...differences at unity scale! Time Function Transform Apply Spectral Domain Transfer Function Time Function Inverse Transform Transform Transform  mtP

Functional abilities in older adults with mild cognitive impairment.

PubMed

Burton, Catherine L; Strauss, Esther; Bunce, David; Hunter, Michael A; Hultsch, David F

2009-01-01

A classification scheme and general set of criteria for diagnosing mild cognitive impairment (MCI) were recently proposed by a multidisciplinary group of experts who met at an international symposium on MCI. One of the proposed criteria included preserved basic activities of daily living and minimal impairment in complex instrumental activities of daily living (IADLs). To investigate whether older adults with MCI classified according to the subtypes identified by the Working Group (i.e. amnestic, single non-memory domain, and multiple domain with or without a memory component) differed from cognitively intact older adults on a variety of measures indexing IADLs and to examine how well measures of IADL predict concurrent MCI status. Two hundred and fifty community-dwelling older adults, ranging in age from 66 to 92, completed self-report measures of IADLs (Lawton and Brody IADL Scale, Scales of Independent Behaviour-Revised--SIB-R) and a measure of everyday problem solving indexing IADLs (Everyday Problems Test--EPT). Ratings of participants' IADL functioning were also obtained from informants (e.g. spouse, adult child and friend). Older adults with multiple-domain MCI demonstrated poorer IADL functioning than older adults with no cognitive impairment on the EPT and the SIB-R (both self- and informant-report versions). The multiple-domain MCI participants also demonstrated poorer IADLs than MCI participants with impairments in a single cognitive domain on the self-reported SIB-R and EPT. The single-domain MCI groups demonstrated poorer IADLs than older adults without cognitive impairment on the informant-reported SIB-R and EPT. No significant group differences were found on the Lawton and Brody IADL Scale. Using the EPT and SIB-R as predictors in a multinomial regression analysis, MCI group status was reliably predicted, but the classification rate was poor. Individuals with MCI demonstrated poorer IADL functioning compared to cognitively intact older adults. However, the changes in IADL functioning observed in MCI may be too subtle to be detected by certain measures, such as the Lawton and Brody IADL Scale. Copyright 2009 S. Karger AG, Basel.

The Portuguese version of the Epilepsy Surgery Inventory (ESI-55): cross-cultural adaptation and evaluation of psychometric properties.

PubMed

Alonso, Neide Barreira; Ciconelli, Rozana Mesquita; da Silva, Tatiana Indelicato; Westphal-Guitti, Ana Carolina; Azevedo, Auro Mauro; da Silva Noffs, Maria Helena; Caboclo, Luís Otávio Sales Ferreira; Sakamoto, Américo Ceiki; Targas Yacubian, Elza Márcia

2006-08-01

The purpose of this study was to develop a Portuguese version of the Epilepsy Surgery Inventory (ESI-55) and to assess its psychometric properties. Sixty patients with temporal lobe epilepsy related to unilateral mesial temporal sclerosis who underwent presurgical evaluation at the Universidade Federal de São Paulo (UNIFESP) formed the sample for this study. The psychometric properties of the ESI-55 included: reliability, validity, and responsiveness. Internal consistency was high in all domains (Cronbach's alpha ranging from 0.76 for Social Function to 0.88 for Physical Function) except Overall Quality of Life (alpha=0.45). Test-retest reliability after 1 week was good, with the intraclass correlation coefficient ranging from 0.79 (Energy/Fatigue) to 0.92 (Role Limitations due to Emotional Problems). Interrater reliability ranged from 0.84 (Cognitive Function) to 0.94 (Role Limitations due to Physical Problems). For construct validity, we verified a high correlation between the ESI-55 and Health Assessment Questionnaire-8 for the Physical Function domain (Pearson linear correlation=-0.84), and a moderate correlation for the Pain domain (P=-0.58), but for the other subscales no correlation was detected. Beck Depression Inventory and ESI-55 domains were highly statistically correlated (ANOVA: P<0.005), but there was no association of the Cognitive Function and Role Limitations due to Memory Problems subscales with neuropsychological evaluation (Pearson coefficient: P>0.05). With respect to demographic characteristics, a statistically significant correlation was observed for the variable educational level (Student t, P<0.005) and ESI-55 scores. There was a high correlation between seizure frequency and ESI-55 domains for clinical variables (ANOVA, P<0.005). Surgical treatment in this series improved health-related quality of life in the seizure-free group in three domains--Health Perception (1.24), Emotional Well-Being (1.32), and Energy/Fatigue (1.48)-as reflected by the standard response mean and the effect size of the sample. Our results support the psychometric properties of the Portuguese version of the ESI-55 as a measure of health-related quality of life.

Distribution of CpG Motifs in Upstream Gene Domains in a Reef Coral and Sea Anemone: Implications for Epigenetics in Cnidarians.

PubMed

Marsh, Adam G; Hoadley, Kenneth D; Warner, Mark E

2016-01-01

Coral reefs are under assault from stressors including global warming, ocean acidification, and urbanization. Knowing how these factors impact the future fate of reefs requires delineating stress responses across ecological, organismal and cellular scales. Recent advances in coral reef biology have integrated molecular processes with ecological fitness and have identified putative suites of temperature acclimation genes in a Scleractinian coral Acropora hyacinthus. We wondered what unique characteristics of these genes determined their coordinate expression in response to temperature acclimation, and whether or not other corals and cnidarians would likewise possess these features. Here, we focus on cytosine methylation as an epigenetic DNA modification that is responsive to environmental stressors. We identify common conserved patterns of cytosine-guanosine dinucleotide (CpG) motif frequencies in upstream promoter domains of different functional gene groups in two cnidarian genomes: a coral (Acropora digitifera) and an anemone (Nematostella vectensis). Our analyses show that CpG motif frequencies are prominent in the promoter domains of functional genes associated with environmental adaptation, particularly those identified in A. hyacinthus. Densities of CpG sites in upstream promoter domains near the transcriptional start site (TSS) are 1.38x higher than genomic background levels upstream of -2000 bp from the TSS. The increase in CpG usage suggests selection to allow for DNA methylation events to occur more frequently within 1 kb of the TSS. In addition, observed shifts in CpG densities among functional groups of genes suggests a potential role for epigenetic DNA methylation within promoter domains to impact functional gene expression responses in A. digitifera and N. vectensis. Identifying promoter epigenetic sequence motifs among genes within specific functional groups establishes an approach to describe integrated cellular responses to environmental stress in reef corals and potential roles of epigenetics on survival and fitness in the face of global climate change.

Variable-Domain Functional Regression for Modeling ICU Data.

PubMed

Gellar, Jonathan E; Colantuoni, Elizabeth; Needham, Dale M; Crainiceanu, Ciprian M

2014-12-01

We introduce a class of scalar-on-function regression models with subject-specific functional predictor domains. The fundamental idea is to consider a bivariate functional parameter that depends both on the functional argument and on the width of the functional predictor domain. Both parametric and nonparametric models are introduced to fit the functional coefficient. The nonparametric model is theoretically and practically invariant to functional support transformation, or support registration. Methods were motivated by and applied to a study of association between daily measures of the Intensive Care Unit (ICU) Sequential Organ Failure Assessment (SOFA) score and two outcomes: in-hospital mortality, and physical impairment at hospital discharge among survivors. Methods are generally applicable to a large number of new studies that record a continuous variables over unequal domains.

Transposons to toxins: the provenance, architecture and diversification of a widespread class of eukaryotic effectors

PubMed Central

Zhang, Dapeng; Burroughs, A. Maxwell; Vidal, Newton D.; Iyer, Lakshminarayan M.; Aravind, L.

2016-01-01

Enzymatic effectors targeting nucleic acids, proteins and other cellular components are the mainstay of conflicts across life forms. Using comparative genomics we identify a large class of eukaryotic proteins, which include effectors from oomycetes, fungi and other parasites. The majority of these proteins have a characteristic domain architecture with one of several N-terminal ‘Header’ domains, which are predicted to play a role in trafficking of these effectors, including a novel version of the Ubiquitin fold. The Headers are followed by one or more diverse C-terminal domains, such as restriction endonuclease (REase), protein kinase, HNH endonuclease, LK-nuclease (a RNase) and multiple distinct peptidase domains, which are predicted to carry their toxicity determinants. The most common types of these proteins appear to have originated from prokaryotic transposases (e.g. TN7 and Mu) and combine a CDC6/ORC1-STAND clade NTPase domain with a C-terminal REase domain. Other than the so-called Crinkler effectors of oomycetes and fungi, these effectors are encoded by other eukaryotic parasites such as trypanosomatids (the RHS proteins) and the rhizarian Plasmodiophora, and symbionts like Capsaspora. Remarkably, we also find these proteins in free-living eukaryotes, including several viridiplantae, fungi, amoebozoans and animals. These versions might either still be transposons or function in other poorly understood eukaryote-specific inter-organismal and inter-genomic conflicts. These include the Medea1 selfish element of Tribolium that spreads via post-zygotic killing. We present a unified mechanism for the recombination-dependent diversification and action of this widespread class of molecular weaponry deployed across diverse conflicts ranging from parasitic to free-living forms. PMID:27060143

Structural Biology of Non-Ribosomal Peptide Synthetases

PubMed Central

Miller, Bradley R.; Gulick, Andrew M.

2016-01-01

Summary The non-ribosomal peptide synthetases are modular enzymes that catalyze synthesis of important peptide products from a variety of standard and non-proteinogenic amino acid substrates. Within a single module are multiple catalytic domains that are responsible for incorporation of a single residue. After the amino acid is activated and covalently attached to an integrated carrier protein domain, the substrates and intermediates are delivered to neighboring catalytic domains for peptide bond formation or, in some modules, chemical modification. In the final module, the peptide is delivered to a terminal thioesterase domain that catalyzes release of the peptide product. This multi-domain modular architecture raises questions about the structural features that enable this assembly line synthesis in an efficient manner. The structures of the core component domains have been determined and demonstrate insights into the catalytic activity. More recently, multi-domain structures have been determined and are providing clues to the features of these enzyme systems that govern the functional interaction between multiple domains. This chapter describes the structures of NRPS proteins and the strategies that are being used to assist structural studies of these dynamic proteins, including careful consideration of domain boundaries for generation of truncated proteins and the use of mechanism-based inhibitors that trap interactions between the catalytic and carrier protein domains. PMID:26831698

The role of internal duplication in the evolution of multi-domain proteins.

PubMed

Nacher, J C; Hayashida, M; Akutsu, T

2010-08-01

Many proteins consist of several structural domains. These multi-domain proteins have likely been generated by selective genome growth dynamics during evolution to perform new functions as well as to create structures that fold on a biologically feasible time scale. Domain units frequently evolved through a variety of genetic shuffling mechanisms. Here we examine the protein domain statistics of more than 1000 organisms including eukaryotic, archaeal and bacterial species. The analysis extends earlier findings on asymmetric statistical laws for proteome to a wider variety of species. While proteins are composed of a wide range of domains, displaying a power-law decay, the computation of domain families for each protein reveals an exponential distribution, characterizing a protein universe composed of a thin number of unique families. Structural studies in proteomics have shown that domain repeats, or internal duplicated domains, represent a small but significant fraction of genome. In spite of its importance, this observation has been largely overlooked until recently. We model the evolutionary dynamics of proteome and demonstrate that these distinct distributions are in fact rooted in an internal duplication mechanism. This process generates the contemporary protein structural domain universe, determines its reduced thickness, and tames its growth. These findings have important implications, ranging from protein interaction network modeling to evolutionary studies based on fundamental mechanisms governing genome expansion.

Identification and analysis of evolutionary selection pressures acting at the molecular level in five forkhead subfamilies.

PubMed

Fetterman, Christina D; Rannala, Bruce; Walter, Michael A

2008-09-24

Members of the forkhead gene family act as transcription regulators in biological processes including development and metabolism. The evolution of forkhead genes has not been widely examined and selection pressures at the molecular level influencing subfamily evolution and differentiation have not been explored. Here, in silico methods were used to examine selection pressures acting on the coding sequence of five multi-species FOX protein subfamily clusters; FoxA, FoxD, FoxI, FoxO and FoxP. Application of site models, which estimate overall selection pressures on individual codons throughout the phylogeny, showed that the amino acid changes observed were either neutral or under negative selection. Branch-site models, which allow estimated selection pressures along specified lineages to vary as compared to the remaining phylogeny, identified positive selection along branches leading to the FoxA3 and Protostomia clades in the FoxA cluster and the branch leading to the FoxO3 clade in the FoxO cluster. Residues that may differentiate paralogs were identified in the FoxA and FoxO clusters and residues that differentiate orthologs were identified in the FoxA cluster. Neutral amino acid changes were identified in the forkhead domain of the FoxA, FoxD and FoxP clusters while positive selection was identified in the forkhead domain of the Protostomia lineage of the FoxA cluster. A series of residues under strong negative selection adjacent to the N- and C-termini of the forkhead domain were identified in all clusters analyzed suggesting a new method for refinement of domain boundaries. Extrapolation of domains among cluster members in conjunction with selection pressure information allowed prediction of residue function in the FoxA, FoxO and FoxP clusters and exclusion of known domain function in residues of the FoxA and FoxI clusters. Consideration of selection pressures observed in conjunction with known functional information allowed prediction of residue function and refinement of domain boundaries. Identification of residues that differentiate orthologs and paralogs provided insight into the development and functional consequences of paralogs and forkhead subfamily composition differences among species. Overall we found that after gene duplication of forkhead family members, rapid differentiation and subsequent fixation of amino acid changes through negative selection has occurred.

The Phe105 loop of Alix Bro1 domain plays a key role in HIV-1 release

PubMed Central

Sette, Paola; Mu, Ruiling; Dussupt, Vincent; Jiang, Jiansheng; Snyder, Greg; Smith, Patrick; Xiao, Tsan. Sam; Bouamr, Fadila

2011-01-01

Summary Alix and cellular paralogs HD-PTP and Brox contain N-terminal Bro1 domains that bind ESCRT-III CHMP4. In contrast to HD-PTP and Brox, expression of the Bro1 domain of Alix alleviates HIV-1 release defects due to interrupted access to ESCRT. In an attempt to elucidate this functional discrepancy, we solved the crystal structures of the Bro1 domains of HD-PTP and Brox. They revealed typical “boomerang” folds they share with the Bro1 Alix domain. However, they each contain unique structural features that may be relevant to their specific function(s). In particular, phenylalanine residue in position 105 (Phe105) of Alix belongs to a long loop that is unique to its Bro1 domain. Concurrently mutation of Phe105 and surrounding residues at the tip of the loop compromises the function of Alix in HIV-1 budding without affecting its interactions with Gag or CHMP4. These studies identify a new functional determinant in the Bro1 domain of Alix. PMID:21889351

Fungal-type carbohydrate binding modules from the coccolithophore Emiliania huxleyi show binding affinity to cellulose and chitin.

PubMed

Rooijakkers, Bart J M; Ikonen, Martina S; Linder, Markus B

2018-01-01

Six fungal-type cellulose binding domains were found in the genome of the coccolithophore Emiliania huxleyi and cloned and expressed in Escherichia coli. Sequence comparison indicate high similarity to fungal cellulose binding domains, raising the question of why these domains exist in coccolithophores. The proteins were tested for binding with cellulose and chitin as ligands, which resulted in the identification of two functional carbohydrate binding modules: EHUX2 and EHUX4. Compared to benchmark fungal cellulose binding domain Cel7A-CBM1 from Trichoderma reesei, these proteins showed slightly lower binding to birch and bacterial cellulose, but were more efficient chitin binders. Finally, a set of cellulose binding domains was created based on the shuffling of one well-functioning and one non-functional domain. These were characterized in order to get more information of the binding domain's sequence-function relationship, indicating characteristic differences between the molecular basis of cellulose versus chitin recognition. As previous reports have showed the presence of cellulose in coccoliths and here we find functional cellulose binding modules, a possible connection is discussed.

An Autoinhibitory Role for the Pleckstrin Homology Domain of Interleukin-2-Inducible Tyrosine Kinase and Its Interplay with Canonical Phospholipid Recognition.

PubMed

Devkota, Sujan; Joseph, Raji E; Boyken, Scott E; Fulton, D Bruce; Andreotti, Amy H

2017-06-13

Pleckstrin homology (PH) domains are well-known as phospholipid binding modules, yet evidence that PH domain function extends beyond lipid recognition is mounting. In this work, we characterize a protein binding function for the PH domain of interleukin-2-inducible tyrosine kinase (ITK), an immune cell specific signaling protein that belongs to the TEC family of nonreceptor tyrosine kinases. Its N-terminal PH domain is a well-characterized lipid binding module that localizes ITK to the membrane via phosphatidylinositol 3,4,5-trisphosphate (PIP 3 ) binding. Using a combination of nuclear magnetic resonance spectroscopy and mutagenesis, we have mapped an autoregulatory protein interaction site on the ITK PH domain that makes direct contact with the catalytic kinase domain of ITK, inhibiting the phospho-transfer reaction. Moreover, we have elucidated an important interplay between lipid binding by the ITK PH domain and the stability of the autoinhibitory complex formed by full length ITK. The ITK activation loop in the kinase domain becomes accessible to phosphorylation to the exogenous kinase LCK upon binding of the ITK PH domain to PIP 3 . By clarifying the allosteric role of the ITK PH domain in controlling ITK function, we have expanded the functional repertoire of the PH domain generally and opened the door to alternative strategies to target this specific kinase in the context of immune cell signaling.

Functional Independence and Interdependence of the Src Homology Domains of Phospholipase C-γ1 in B-Cell Receptor Signal Transduction

PubMed Central

DeBell, Karen E.; Stoica, Bogdan A.; Verí, Maria-Concetta; Di Baldassarre, Angela; Miscia, Sebastiano; Graham, Laurie J.; Rellahan, Barbara L.; Ishiai, Masamichi; Kurosaki, Tomohiro; Bonvini, Ezio

1999-01-01

B-cell receptor (BCR)-induced activation of phospholipase C-γ1 (PLCγ1) and PLCγ2 is crucial for B-cell function. While several signaling molecules have been implicated in PLCγ activation, the mechanism coupling PLCγ to the BCR remains undefined. The role of PLCγ1 SH2 and SH3 domains at different steps of BCR-induced PLCγ1 activation was examined by reconstitution in a PLCγ-negative B-cell line. PLCγ1 membrane translocation required a functional SH2 N-terminal [SH2(N)] domain, was decreased by mutation of the SH3 domain, but was unaffected by mutation of the SH2(C) domain. Tyrosine phosphorylation did not require the SH2(C) or SH3 domains but depended exclusively on a functional SH2(N) domain, which mediated the association of PLCγ1 with the adapter protein, BLNK. Forcing PLCγ1 to the membrane via a myristoylation signal did not bypass the SH2(N) domain requirement for phosphorylation, indicating that the phosphorylation mediated by this domain is not due to membrane anchoring alone. Mutation of the SH2(N) or the SH2(C) domain abrogated BCR-stimulated phosphoinositide hydrolysis and signaling events, while mutation of the SH3 domain partially decreased signaling. PLCγ1 SH domains, therefore, have interrelated but distinct roles in BCR-induced PLCγ1 activation. PMID:10523627

The cysteine-rich domain regulates ADAM protease function in vivo.

PubMed

Smith, Katherine M; Gaultier, Alban; Cousin, Helene; Alfandari, Dominique; White, Judith M; DeSimone, Douglas W

2002-12-09

ADAMs are membrane-anchored proteases that regulate cell behavior by proteolytically modifying the cell surface and ECM. Like other membrane-anchored proteases, ADAMs contain candidate "adhesive" domains downstream of their metalloprotease domains. The mechanism by which membrane-anchored cell surface proteases utilize these putative adhesive domains to regulate protease function in vivo is not well understood. We address this important question by analyzing the relative contributions of downstream extracellular domains (disintegrin, cysteine rich, and EGF-like repeat) of the ADAM13 metalloprotease during Xenopus laevis development. When expressed in embryos, ADAM13 induces hyperplasia of the cement gland, whereas ADAM10 does not. Using chimeric constructs, we find that the metalloprotease domain of ADAM10 can substitute for that of ADAM13, but that specificity for cement gland expansion requires a downstream extracellular domain of ADAM13. Analysis of finer resolution chimeras indicates an essential role for the cysteine-rich domain and a supporting role for the disintegrin domain. These and other results reveal that the cysteine-rich domain of ADAM13 cooperates intramolecularly with the ADAM13 metalloprotease domain to regulate its function in vivo. Our findings thus provide the first evidence that a downstream extracellular adhesive domain plays an active role in regulating ADAM protease function in vivo. These findings are likely relevant to other membrane-anchored cell surface proteases.

The association between sexual satisfaction and body image in women.

PubMed

Pujols, Yasisca; Seal, Brooke N; Meston, Cindy M

2010-02-01

Although sexual functioning has been linked to sexual satisfaction, it only partially explains the degree to which women report being sexually satisfied. Other factors include quality of life, relational variables, and individual factors such as body image. Of the few studies that have investigated the link between body image and sexual satisfaction, most have considered body image to be a single construct and have shown mixed results. The present study assessed multiple body image variables in order to better understand which aspects of body image influence multiple domains of sexual satisfaction, including sexual communication, compatibility, contentment, personal concern, and relational concern in a community sample of women. Women between the ages of 18 and 49 years in sexual relationships (N = 154) participated in an Internet survey that assessed sexual functioning, five domains of sexual satisfaction, and several body image variables. Body image variables included the sexual attractiveness, weight concern, and physical condition subscales of the Body Esteem Scale, the appearance-based subscale of the Cognitive Distractions During Sexual Activity Scale, and body mass index. Total score of the Sexual Satisfaction Scale for Women was the main outcome measure. Sexual functioning was measured by a modified Female Sexual Function Index. Consistent with expectations, correlations indicated significant positive relationships between sexual functioning, sexual satisfaction, and all body image variables. A multiple regression analysis revealed that sexual satisfaction was predicted by high body esteem and low frequency of appearance-based distracting thoughts during sexual activity, even after controlling for sexual functioning status. Several aspects of body image, including weight concern, physical condition, sexual attractiveness, and thoughts about the body during sexual activity predict sexual satisfaction in women. The findings suggest that women who experience low sexual satisfaction may benefit from treatments that target these specific aspects of body image.

What makes patients with fibromyalgia feel better? Correlations between Patient Global Impression of Improvement and changes in clinical symptoms and function: a pooled analysis of 4 randomized placebo-controlled trials of duloxetine.

PubMed

Hudson, James I; Arnold, Lesley M; Bradley, Laurence A; Choy, Ernest H S; Mease, Philip J; Wang, Fujun; Ahl, Jonna; Wohlreich, Madelaine M

2009-11-01

To investigate the relationship between changes in clinical rating scale items and endpoint Patient Global Impression of Improvement (PGI-I). Data were pooled from 4 randomized, double-blind, placebo-controlled studies of duloxetine in patients with fibromyalgia (FM). Variables included in the analyses were those that assessed symptoms in FM domains of pain, fatigue, sleep, cognitive difficulties, emotional well-being, physical function, and impact on daily living. The association of endpoint PGI-I with changes from baseline in individual variables was assessed using Pearson product-moment correlations (r). Stepwise linear regression was used to identify those variables for which changes from baseline were statistically significant independent predictors of the endpoint PGI-I ratings. Changes in pain variables and interference of symptoms with the ability to work were highly correlated (r >or= 0.5 or r

Function-selective domain architecture plasticity potentials in eukaryotic genome evolution

PubMed Central

Linkeviciute, Viktorija; Rackham, Owen J.L.; Gough, Julian; Oates, Matt E.; Fang, Hai

2015-01-01

To help evaluate how protein function impacts on genome evolution, we introduce a new concept of ‘architecture plasticity potential’ – the capacity to form distinct domain architectures – both for an individual domain, or more generally for a set of domains grouped by shared function. We devise a scoring metric to measure the plasticity potential for these domain sets, and evaluate how function has changed over time for different species. Applying this metric to a phylogenetic tree of eukaryotic genomes, we find that the involvement of each function is not random but highly selective. For certain lineages there is strong bias for evolution to involve domains related to certain functions. In general eukaryotic genomes, particularly animals, expand complex functional activities such as signalling and regulation, but at the cost of reducing metabolic processes. We also observe differential evolution of transcriptional regulation and a unique evolutionary role of channel regulators; crucially this is only observable in terms of the architecture plasticity potential. Our findings provide a new layer of information to understand the significance of function in eukaryotic genome evolution. A web search tool, available at http://supfam.org/Pevo, offers a wide spectrum of options for exploring functional importance in eukaryotic genome evolution. PMID:25980317

BEAUTY: an enhanced BLAST-based search tool that integrates multiple biological information resources into sequence similarity search results.

PubMed

Worley, K C; Wiese, B A; Smith, R F

1995-09-01

BEAUTY (BLAST enhanced alignment utility) is an enhanced version of the NCBI's BLAST data base search tool that facilitates identification of the functions of matched sequences. We have created new data bases of conserved regions and functional domains for protein sequences in NCBI's Entrez data base, and BEAUTY allows this information to be incorporated directly into BLAST search results. A Conserved Regions Data Base, containing the locations of conserved regions within Entrez protein sequences, was constructed by (1) clustering the entire data base into families, (2) aligning each family using our PIMA multiple sequence alignment program, and (3) scanning the multiple alignments to locate the conserved regions within each aligned sequence. A separate Annotated Domains Data Base was constructed by extracting the locations of all annotated domains and sites from sequences represented in the Entrez, PROSITE, BLOCKS, and PRINTS data bases. BEAUTY performs a BLAST search of those Entrez sequences with conserved regions and/or annotated domains. BEAUTY then uses the information from the Conserved Regions and Annotated Domains data bases to generate, for each matched sequence, a schematic display that allows one to directly compare the relative locations of (1) the conserved regions, (2) annotated domains and sites, and (3) the locally aligned regions matched in the BLAST search. In addition, BEAUTY search results include World-Wide Web hypertext links to a number of external data bases that provide a variety of additional types of information on the function of matched sequences. This convenient integration of protein families, conserved regions, annotated domains, alignment displays, and World-Wide Web resources greatly enhances the biological informativeness of sequence similarity searches. BEAUTY searches can be performed remotely on our system using the "BCM Search Launcher" World-Wide Web pages (URL is < http:/ /gc.bcm.tmc.edu:8088/ search-launcher/launcher.html > ).

Changing core beliefs with trial-based cognitive therapy may improve quality of life in social phobia: a randomized study.

PubMed

Powell, Vania Bitencourt; Oliveira, Olivia Haun de; Seixas, Camila; Almeida, Cláudia; Grangeon, Maria Conceição; Caldas, Milke; Bonfim, Thaís Delavechia; Castro, Martha; Galvão-de Almeida, Amanda; Galvão-de Almeida; Moraes, Roberta de Oliveira; Sudak, Donna; de-Oliveira, Irismar Reis

2013-01-01

To determine whether there are differences in quality of life (QoL) improvement after treatment with the trial-based thought record (TBTR) versus conventional cognitive therapy (CCT) in patients with social anxiety disorder (SAD). A randomized trial comparing TBTR with a set of CCT techniques, which included the standard 7-column dysfunctional thought record (DTR) and the positive data log (PDL) in patients with SAD, generalized type. Repeated measures analysis of variance (ANOVA) revealed a significant time effect in the general health, vitality, social functioning, and mental health domains of the Short Form 36. It also indicated significant treatment effects on the bodily pain, social functioning, role-emotional, and mental health domains, with higher scores in the TBTR group. One-way analysis of covariance (ANCOVA), using pretreatment values as covariates, showed that TBTR was associated with significantly better QoL post-treatment (bodily pain, social functioning and role-emotional) and at follow-up (role-emotional). A significant treatment effect on the role-emotional domain at 12-month follow-up denoted a sustained effect of TBTR relative to CCT. This study provided preliminary evidence that TBTR is at least as effective as CCT in improving several domains of QoL in SAD, specifically when the standard 7-column DTR and the PDL are used.

Voice Handicap Index associated with common mental disorders in elementary school teachers.

PubMed

da Rocha, Luise Marques; de Mattos Souza, Luciano Dias

2013-09-01

To verify the relationship between common mental disorders (CMDs) and the Voice Handicap Index (VHI) in elementary school teachers from municipal schools. The VHI mean scores in the group of teachers with symptoms of mental disorder were significantly higher than those in the group of teachers with no symptoms in the total scores of three subscales: disability (functional domain), handicap (emotional domain), and impairment (organic domain). An observational cross-sectional, quantitative study was conducted in the public schools of urban and rural areas of the city of Pelotas. A total of 575 teachers participated. Vocal handicap was measured using VHI, producing a total score and three subscales, including emotional, functional, and organic domains. The Self-Reporting Questionnaire, 20 items scale was used to measure mental disorder symptoms. A log transformation was used, followed by linear regression, to evaluate the relationship between the independent variables and the outcomes. Teachers with CMD symptoms and who took a sick leave from teaching because of voice problems obtained the lowest scores in VHI (P < 0.050). Emotional, functional, and organic voice handicap scores were significantly higher in teachers with CMD symptoms (P < 0.001). A close association between voice problems and mental disorders was identified based on the statistically significant association between high levels of voice handicap and the mental disorders. Copyright © 2013 The Voice Foundation. Published by Mosby, Inc. All rights reserved.

Diverse oligomeric states of CEACAM IgV domains

PubMed Central

Bonsor, Daniel A.; Günther, Sebastian; Beadenkopf, Robert; Beckett, Dorothy; Sundberg, Eric J.

2015-01-01

Carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) comprise a large family of cell surface adhesion molecules that bind to themselves and other family members to carry out numerous cellular functions, including proliferation, signaling, differentiation, tumor suppression, and survival. They also play diverse and significant roles in immunity and infection. The formation of CEACAM oligomers is caused predominantly by interactions between their N-terminal IgV domains. Although X-ray crystal structures of CEACAM IgV domain homodimers have been described, how CEACAMs form heterodimers or remain monomers is poorly understood. To address this key aspect of CEACAM function, we determined the crystal structures of IgV domains that form a homodimeric CEACAM6 complex, monomeric CEACAM8, and a heterodimeric CEACAM6–CEACAM8 complex. To confirm and quantify these interactions in solution, we used analytical ultracentrifugation to measure the dimerization constants of CEACAM homodimers and isothermal titration calorimetry to determine the thermodynamic parameters and binding affinities of CEACAM heterodimers. We found the CEACAM6–CEACAM8 heterodimeric state to be substantially favored energetically relative to the CEACAM6 homodimer. Our data provide a molecular basis for the adoption of the diverse oligomeric states known to exist for CEACAMs and suggest ways in which CEACAM6 and CEACAM8 regulate the biological functions of one another, as well as of additional CEACAMs with which they interact, both in cis and in trans. PMID:26483485

Diverse oligomeric states of CEACAM IgV domains.

PubMed

Bonsor, Daniel A; Günther, Sebastian; Beadenkopf, Robert; Beckett, Dorothy; Sundberg, Eric J

2015-11-03

Carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) comprise a large family of cell surface adhesion molecules that bind to themselves and other family members to carry out numerous cellular functions, including proliferation, signaling, differentiation, tumor suppression, and survival. They also play diverse and significant roles in immunity and infection. The formation of CEACAM oligomers is caused predominantly by interactions between their N-terminal IgV domains. Although X-ray crystal structures of CEACAM IgV domain homodimers have been described, how CEACAMs form heterodimers or remain monomers is poorly understood. To address this key aspect of CEACAM function, we determined the crystal structures of IgV domains that form a homodimeric CEACAM6 complex, monomeric CEACAM8, and a heterodimeric CEACAM6-CEACAM8 complex. To confirm and quantify these interactions in solution, we used analytical ultracentrifugation to measure the dimerization constants of CEACAM homodimers and isothermal titration calorimetry to determine the thermodynamic parameters and binding affinities of CEACAM heterodimers. We found the CEACAM6-CEACAM8 heterodimeric state to be substantially favored energetically relative to the CEACAM6 homodimer. Our data provide a molecular basis for the adoption of the diverse oligomeric states known to exist for CEACAMs and suggest ways in which CEACAM6 and CEACAM8 regulate the biological functions of one another, as well as of additional CEACAMs with which they interact, both in cis and in trans.

Ets-1 interacts through a similar binding interface with Ku70 and Poly (ADP-Ribose) Polymerase-1.

PubMed

Choul-Li, Souhaila; Legrand, Arnaud J; Vicogne, Dorothée; Villeret, Vincent; Aumercier, Marc

2018-06-18

The Ets-1 transcription factor plays an important role in various physiological and pathological processes. These diverse roles of Ets-1 are likely to depend on its interaction proteins. We have previously showed that Ets-1 interacted with DNA-dependent protein kinase (DNA-PK) complex including its regulatory subunits, Ku70 and Ku86 and with poly (ADP-ribose) polymerase-1 (PARP-1). In this study, the binding domains for the interaction between Ets-1 and these proteins were reported. We demonstrated that the interaction of Ets-1 with DNA-PK was mediated through the Ku70 subunit and was mapped to the C-terminal region of Ets-1 and the C-terminal part of Ku70 including SAP domain. The interactive domains between Ets-1 and PARP-1 have been mapped to the C-terminal region of Ets-1 and the BRCA1 carboxy-terminal (BRCT) domain of PARP-1. The results presented in this study may advance our understanding of the functional link between Ets-1 and its interaction partners, DNA-PK and PARP-1.

Antagonism of ligand-gated ion channel receptors: two domains of the glycine receptor alpha subunit form the strychnine-binding site.

PubMed Central

Vandenberg, R J; French, C R; Barry, P H; Shine, J; Schofield, P R

1992-01-01

The inhibitory glycine receptor (GlyR) is a member of the ligand-gated ion channel receptor superfamily. Glycine activation of the receptor is antagonized by the convulsant alkaloid strychnine. Using in vitro mutagenesis and functional analysis of the cDNA encoding the alpha 1 subunit of the human GlyR, we have identified several amino acid residues that form the strychnine-binding site. These residues were identified by transient expression of mutated cDNAs in mammalian (293) cells and examination of resultant [3H]strychnine binding, glycine displacement of [3H]strychnine, and electrophysiological responses to the application of glycine and strychnine. This mutational analysis revealed that residues from two separate domains within the alpha 1 subunit form the binding site for the antagonist strychnine. The first domain includes the amino acid residues Gly-160 and Tyr-161, and the second domain includes the residues Lys-200 and Tyr-202. These results, combined with analyses of other ligand-gated ion channel receptors, suggest a conserved tertiary structure and a common mechanism for antagonism in this receptor superfamily. PMID:1311851

Mouse Hepatitis Virus Strain A59 and Blocking Antireceptor Monoclonal Antibody Bind to the N-Terminal Domain of Cellular Receptor

NASA Astrophysics Data System (ADS)

Dveksler, Gabriela S.; Pensiero, Michael N.; Dieffenbach, Carl W.; Cardellichio, Christine B.; Basile, Alexis A.; Elia, Patrick E.; Holmes, Kathryn V.

1993-03-01

Mouse hepatitis virus (MHV) strain A59 uses as cellular receptors members of the carcinoembryonic antigen family in the immunoglobulin superfamily. Recombinant receptor proteins with deletions of whole or partial immunoglobulin domains were used to identify the regions of receptor glycoprotein recognized by virus and by antireceptor monoclonal antibody CC1, which blocks infection of murine cells. Monoclonal antibody CC1 and MHV-A59 virions bound only to recombinant proteins containing the entire first domain of MHV receptor. To determine which of the proteins could serve as functional virus receptors, receptor-negative hamster cells were transfected with recombinant deletion clones and then challenged with MHV-A59 virions. Receptor activity required the entire N-terminal domain with either the second or the fourth domain and the transmembrane and cytoplasmic domains. Recombinant proteins lacking the first domain or its C-terminal portion did not serve as viral receptors. Thus, like other virus receptors in the immunoglobulin superfamily, including CD4, poliovirus receptor, and intercellular adhesion molecule 1, the N-terminal domain of MHV receptor is recognized by the virus and the blocking monoclonal antibody.

A gain-of-function mutation in the M-domain of cardiac myosin-binding protein-C increases binding to actin.

PubMed

Bezold, Kristina L; Shaffer, Justin F; Khosa, Jaskiran K; Hoye, Elaine R; Harris, Samantha P

2013-07-26

The M-domain is the major regulatory subunit of cardiac myosin-binding protein-C (cMyBP-C) that modulates actin and myosin interactions to influence muscle contraction. However, the precise mechanism(s) and the specific residues involved in mediating the functional effects of the M-domain are not fully understood. Positively charged residues adjacent to phosphorylation sites in the M-domain are thought to be critical for effects of cMyBP-C on cross-bridge interactions by mediating electrostatic binding with myosin S2 and/or actin. However, recent structural studies revealed that highly conserved sequences downstream of the phosphorylation sites form a compact tri-helix bundle. Here we used site-directed mutagenesis to probe the functional significance of charged residues adjacent to the phosphorylation sites and conserved residues within the tri-helix bundle. Results confirm that charged residues adjacent to phosphorylation sites and residues within the tri-helix bundle are important for mediating effects of the M-domain on contraction. In addition, four missense variants within the tri-helix bundle that are associated with human hypertrophic cardiomyopathy caused either loss-of-function or gain-of-function effects on force. Importantly, the effects of the gain-of-function variant, L348P, increased the affinity of the M-domain for actin. Together, results demonstrate that functional effects of the M-domain are not due solely to interactions with charged residues near phosphorylatable serines and provide the first demonstration that the tri-helix bundle contributes to the functional effects of the M-domain, most likely by binding to actin.

Molecular dynamics simulations of the Bcl-2 protein to predict the structure of its unordered flexible loop domain.

PubMed

Raghav, Pawan Kumar; Verma, Yogesh Kumar; Gangenahalli, Gurudutta U

2012-05-01

B-cell lymphoma (Bcl-2) protein is an anti-apoptotic member of the Bcl-2 family. It is functionally demarcated into four Bcl-2 homology (BH) domains: BH1, BH2, BH3, BH4, one flexible loop domain (FLD), a transmembrane domain (TM), and an X domain. Bcl-2's BH domains have clearly been elucidated from a structural perspective, whereas the conformation of FLD has not yet been predicted, despite its important role in regulating apoptosis through its interactions with JNK-1, PKC, PP2A phosphatase, caspase 3, MAP kinase, ubiquitin, PS1, and FKBP38. Many important residues that regulate Bcl-2 anti-apoptotic activity are present in this domain, for example Asp34, Thr56, Thr69, Ser70, Thr74, and Ser87. The structural elucidation of the FLD would likely help in attempts to accurately predict the effect of mutating these residues on the overall structure of the protein and the interactions of other proteins in this domain. Therefore, we have generated an increased quality model of the Bcl-2 protein including the FLD through modeling. Further, molecular dynamics (MD) simulations were used for FLD optimization, to predict the flexibility, and to determine the stability of the folded FLD. In addition, essential dynamics (ED) was used to predict the collective motions and the essential subspace relevant to Bcl-2 protein function. The predicted average structure and ensemble of MD-simulated structures were submitted to the Protein Model Database (PMDB), and the Bcl-2 structures obtained exhibited enhanced quality. This study should help to elucidate the structural basis for Bcl-2 anti-apoptotic activity regulation through its binding to other proteins via the FLD.

Characterizing cognitive performance in a large longitudinal study of aging with computerized semantic indices of verbal fluency.

PubMed

Pakhomov, Serguei V S; Eberly, Lynn; Knopman, David

2016-08-01

A computational approach for estimating several indices of performance on the animal category verbal fluency task was validated, and examined in a large longitudinal study of aging. The performance indices included the traditional verbal fluency score, size of semantic clusters, density of repeated words, as well as measures of semantic and lexical diversity. Change over time in these measures was modeled using mixed effects regression in several groups of participants, including those that remained cognitively normal throughout the study (CN) and those that were diagnosed with mild cognitive impairment (MCI) or Alzheimer's disease (AD) dementia at some point subsequent to the baseline visit. The results of the study show that, with the exception of mean cluster size, the indices showed significantly greater declines in the MCI and AD dementia groups as compared to CN participants. Examination of associations between the indices and cognitive domains of memory, attention and visuospatial functioning showed that the traditional verbal fluency scores were associated with declines in all three domains, whereas semantic and lexical diversity measures were associated with declines only in the visuospatial domain. Baseline repetition density was associated with declines in memory and visuospatial domains. Examination of lexical and semantic diversity measures in subgroups with high vs. low attention scores (but normal functioning in other domains) showed that the performance of individuals with low attention was influenced more by word frequency rather than strength of semantic relatedness between words. These findings suggest that various automatically semantic indices may be used to examine various aspects of cognitive performance affected by dementia. Copyright © 2016 Elsevier Ltd. All rights reserved.

Pulse analysis of acoustic emission signals. Ph.D. Thesis

NASA Technical Reports Server (NTRS)

Houghton, J. R.

1976-01-01

A method for the signature analysis of pulses in the frequency domain and the time domain is presented. Fourier spectrum, Fourier transfer function, shock spectrum and shock spectrum ratio are examined in the frequency domain analysis, and pulse shape deconvolution is developed for use in the time domain analysis. To demonstrate the relative sensitivity of each of the methods to small changes in the pulse shape, signatures of computer modeled systems with analytical pulses are presented. Optimization techniques are developed and used to indicate the best design parameters values for deconvolution of the pulse shape. Several experiments are presented that test the pulse signature analysis methods on different acoustic emission sources. These include acoustic emissions associated with: (1) crack propagation, (2) ball dropping on a plate, (3) spark discharge and (4) defective and good ball bearings.

Structure and Function of Vps15 in the Endosomal G Protein Signaling Pathway

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

Heenan, Erin J.; Vanhooke, Janeen L.; Temple, Brenda R.

2009-09-11

G protein-coupled receptors mediate cellular responses to a wide variety of stimuli, including taste, light, and neurotransmitters. In the yeast Saccharomyces cerevisiae, activation of the pheromone pathway triggers events leading to mating. The view had long been held that the G protein-mediated signal occurs principally at the plasma membrane. Recently, it has been shown that the G protein {alpha} subunit Gpa1 can promote signaling at endosomes and requires two components of the sole phosphatidylinositol-3-kinase in yeast, Vps15 and Vps34. Vps15 contains multiple WD repeats and also binds to Gpa1 preferentially in the GDP-bound state; these observations led us to hypothesizemore » that Vps15 may function as a G protein {beta} subunit at the endosome. Here we show an X-ray crystal structure of the Vps15 WD domain that reveals a seven-bladed propeller resembling that of typical G{beta} subunits. We show further that the WD domain is sufficient to bind Gpa1 as well as to Atg14, a potential G{gamma} protein that exists in a complex with Vps15. The Vps15 kinase domain together with the intermediate domain (linking the kinase and WD domains) also contributes to Gpa1 binding and is necessary for Vps15 to sustain G protein signaling. These findings reveal that the Vps15 G{beta}-like domain serves as a scaffold to assemble Gpa1 and Atg14, whereas the kinase and intermediate domains are required for proper signaling at the endosome.« less

Recombinant expression, purification, and crystallization of the glutaminyl-tRNA synthetase from Toxoplasma gondii.

PubMed

van Rooyen, Jason M; Hakimi, Mohamed-Ali; Belrhali, Hassan

2015-06-01

Aminoacyl tRNA synthetases play a critical role in protein synthesis by providing precursor transfer-RNA molecules correctly charged with their cognate amino-acids. The essential nature of these enzymes make them attractive targets for designing new drugs against important pathogenic protozoans like Toxoplasma. Because no structural data currently exists for a protozoan glutaminyl-tRNA synthetase (QRS), an understanding of its potential as a drug target and its function in the assembly of the Toxoplasma multi-aminoacyl tRNA (MARS) complex is therefore lacking. Here we describe the optimization of expression and purification conditions that permitted the recovery and crystallization of both domains of the Toxoplasma QRS enzyme from a heterologous Escherichia coli expression system. Expression of full-length QRS was only achieved after the addition of an N-terminal histidine affinity tag and the isolated protein was active on both cellular and in vitro produced Toxoplasma tRNA. Taking advantage of the proteolytic susceptibility of QRS to cleavage into component domains, N-terminal glutathione S-transferase (GST) motif-containing domain fragments were isolated and crystallization conditions discovered. Isolation of the C-terminal catalytic domain was accomplished after subcloning the domain and optimizing expression conditions. Purified catalytic domain survived cryogenic storage and yielded large diffraction-quality crystals over-night after optimization of screening conditions. This work will form the basis of future structural studies into structural-functional relationships of both domains including potential targeted drug-design studies and investigations into the assembly of the Toxoplasma MARS complex. Copyright © 2015 Elsevier Inc. All rights reserved.

Fibromyalgia Syndrome Module at OMERACT 9

PubMed Central

Mease, Philip; Arnold, Lesley M; Choy, Ernest H; Clauw, Daniel J.; Crofford, Leslie; Glass, Jennifer M; Martin, Susan A; Morea, Jessica; Simon, Lee; Strand, Vibeke; Williams, David A

2012-01-01

Objectives (1) Establish a core domain set for fibromyalgia (FM) assessment in clinical trials and practice, (2) review outcome measures’ performance characteristics, (3) discuss development of a responder index for the assessment of FM in clinical trials, (4) review objective markers, (5) review the domain of cognitive dysfunction, (6) establish a research agenda for work regarding outcomes research. Methods (1) Results of univariate and multivariate analysis of 10 different FM clinical trials of four different drugs, mapping key domains identified in previously presented patient focus group: Delphi exercises and a clinician/researcher Delphi exercise, breakout discussions to vote on possible essential domains and reliable measures. (2) Updates presented regarding outcome measures’ status. (3) Presented update on objective markers to measure FM disease state. 4) The issue of cognitive dysfunction (dyscognition) in FM was reviewed. Results (1) Greater than 70% of OMERACT participants agreed that pain, tenderness, fatigue, patient global, multidimensional function and sleep disturbance domains should be measured in all FM clinical trials, dyscognition and depression in some trial, and domains of research interest include stiffness, anxiety, functional imaging, and cerebrospinal fluid biomarkers. (2) FM domains’ outcome measures have generally proven to be reliable, discriminative, and feasible. More sophisticated and comprehensive measures are in development, as is a responder index for FM. (3) Increasing number of objective markers are being developed for FM assessment. (4) Cognitive dysfunction assessment by self-assessed and applied outcome measures is being developed. Conclusions A multidimensional symptom core set is proposed for the evaluation of FM in clinical trials. There is ongoing research on improved measures of single domains and composite measures. PMID:19820221

Activity and Participation Characteristics of Adults with Learning Disabilities - A Systematic Review

PubMed Central

Sharfi, Kineret; Rosenblum, Sara

2014-01-01

Background ‘Learning disabilities’ (LD) refer to a wide group of neurological disorders caused by deficits in the central nervous system which influence the individual's ability to maintain-, process or convey information to others in an efficient way. A worldwide discussion about the definitions of LD continues while a conceptual framework for studying the diverse life outcomes of adults with LD is still missing. Objective The aim was to review the literature on the activity and participation of adults with LD based on the International Classification of Functioning, Disability and Health (ICF) concepts. Methods “PsychInfo”, “Eric” and “PubMed” were searched for relevant literature according to the guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). After a three-stage process, 62 articles relevant for domains of activity and participation of adults with LD were included in the review. Results Thirty-two articles focused on the domain of major life areas of education, work and employment and twelve articles focused on the domain of learning and applying knowledge. Limitations in activity and participation of the population with LD in these domains are recognized and discussed. Eighteen additional articles demonstrated that adults with LD confront difficulties in various life domains (e.g., communication, interpersonal interactions, mobility, and domestic life), however literature concerning these domains is scarce. Conclusions The ICF can be useful for further exploration of activity and participation characteristics of adults with LD in various life domains. Such exploration is required in order to gain a wider perspective of their functional characteristics and daily needs. PMID:25184315

Genome-wide identification and characterization of the apple (Malus domestica) HECT ubiquitin-protein ligase family and expression analysis of their responsiveness to abiotic stresses.

PubMed

Xu, Jianing; Xing, Shanshan; Cui, Haoran; Chen, Xuesen; Wang, Xiaoyun

2016-04-01

The ubiquitin-protein ligases (E3s) directly participate in ubiquitin (Ub) transferring to the target proteins in the ubiquitination pathway. The HECT ubiquitin-protein ligase (UPL), one type of E3s, is characterized as containing a conserved HECT domain of approximately 350 amino acids in the C terminus. Some UPLs were found to be involved in trichome development and leaf senescence in Arabidopsis. However, studies on plant UPLs, such as characteristics of the protein structure, predicted functional motifs of the HECT domain, and the regulatory expression of UPLs have all been limited. Here, we present genome-wide identification of the genes encoding UPLs (HECT gene) in apple. The 13 genes (named as MdUPL1-MdUPL13) from ten different chromosomes were divided into four groups by phylogenetic analysis. Among these groups, the encoding genes in the intron-exon structure and the included additional functional domains were quite different. Notably, the F-box domain was first found in MdUPL7 in plant UPLs. The HECT domain in different MdUPL groups also presented different spatial features and three types of conservative motifs were identified. The promoters of each MdUPL member carried multiple stress-response related elements by cis-acting element analysis. Experimental results demonstrated that the expressions of several MdUPLs were quite sensitive to cold-, drought-, and salt-stresses by qRT-PCR assay. The results of this study helped to elucidate the functions of HECT proteins, especially in Rosaceae plants.

Assessment of nutritional status in the elderly: a proposed function-driven model

PubMed Central

Engelheart, Stina; Brummer, Robert

2018-01-01

Background There is no accepted or standardized definition of ‘malnutrition’. Hence, there is also no definition of what constitutes an adequate nutritional status. In elderly people, assessment of nutritional status is complex and is complicated by multi-morbidity and disabilities combined with nutrition-related problems, such as dysphagia, decreased appetite, fatigue, and muscle weakness. Objective We propose a nutritional status model that presents nutritional status from a comprehensive functional perspective. This model visualizes the complexity of the nutritional status in elderly people. Design and results The presented model could be interpreted as the nutritional status is conditional to a person’s optimal function or situation. Another way of looking at it might be that a person’s nutritional status affects his or her optimal situation. The proposed model includes four domains: (1) physical function and capacity; (2) health and somatic disorders; (3) food and nutrition; and (4) cognitive, affective, and sensory function. Each domain has a major impact on nutritional status, which in turn has a major impact on the outcome of each domain. Conclusions Nutritional status is a multifaceted concept and there exist several knowledge gaps in the diagnosis, prevention, and optimization of treatment of inadequate nutritional status in elderly people. The nutritional status model may be useful in nutritional assessment research, as well as in the clinical setting. PMID:29720931

Parent-Reported Family Functioning Among Children With Cleft Lip/Palate.

PubMed

Crerand, Canice E; Rosenberg, Janine; Magee, Leanne; Stein, Margot B; Wilson-Genderson, Maureen; Broder, Hillary L

2015-11-01

To examine family functioning related to sociodemographic and clinical characteristics in youth with cleft lip and/or palate (CL/P). Cross-sectional, multi-site investigation. Six U.S. cleft centers. A diverse sample of 1200 children with CL/P and their parents. Parents completed the Family Environment Scale (FES), which assesses three domains of family functioning: cohesion (or closeness), expressiveness (open expression of feelings), and conflict. Demographic and clinical characteristics were also assessed including race, ethnicity, type of insurance, and surgical recommendations. The FES scores for families seeking team evaluations for their youth with CL/P (mean age = 11.6 years) fall within the average range compared with normative samples. Families receiving surgical recommendations for their youth also had FES scores in the average range, yet families of children recommended for functional surgery reported greater cohesion, expressiveness, and less conflict compared with those recommended for aesthetic surgery (P < .05). For cohesion and expressiveness, significant main effects for race (P = .012, P < .0001, respectively) and ethnicity (P = .004, P < .0001, respectively) were found but not for their interaction. No significant differences were found on the conflict domain. Families with private insurance reported significantly greater cohesion (P < .001) and expressiveness (P < .001) than did families with public insurance. Family functioning across domains was in the average range. However, observed differences by race, ethnicity, type of insurance, and surgical recommendation may warrant consideration in clinical management for patients and families.

Accurate prediction of interfacial residues in two-domain proteins using evolutionary information: implications for three-dimensional modeling.

PubMed

Bhaskara, Ramachandra M; Padhi, Amrita; Srinivasan, Narayanaswamy

2014-07-01

With the preponderance of multidomain proteins in eukaryotic genomes, it is essential to recognize the constituent domains and their functions. Often function involves communications across the domain interfaces, and the knowledge of the interacting sites is essential to our understanding of the structure-function relationship. Using evolutionary information extracted from homologous domains in at least two diverse domain architectures (single and multidomain), we predict the interface residues corresponding to domains from the two-domain proteins. We also use information from the three-dimensional structures of individual domains of two-domain proteins to train naïve Bayes classifier model to predict the interfacial residues. Our predictions are highly accurate (∼85%) and specific (∼95%) to the domain-domain interfaces. This method is specific to multidomain proteins which contain domains in at least more than one protein architectural context. Using predicted residues to constrain domain-domain interaction, rigid-body docking was able to provide us with accurate full-length protein structures with correct orientation of domains. We believe that these results can be of considerable interest toward rational protein and interaction design, apart from providing us with valuable information on the nature of interactions. © 2013 Wiley Periodicals, Inc.

Evolution of vacuolar proton pyrophosphatase domains and volutin granules: clues into the early evolutionary origin of the acidocalcisome

PubMed Central

2011-01-01

Background Volutin granules appear to be universally distributed and are morphologically and chemically identical to acidocalcisomes, which are electron-dense granular organelles rich in calcium and phosphate, whose functions include storage of phosphorus and various metal ions, metabolism of polyphosphate, maintenance of intracellular pH, osmoregulation and calcium homeostasis. Prokaryotes are thought to differ from eukaryotes in that they lack membrane-bounded organelles. However, it has been demonstrated that as in acidocalcisomes, the calcium and polyphosphate-rich intracellular "volutin granules (polyphosphate bodies)" in two bacterial species, Agrobacterium tumefaciens, and Rhodospirillum rubrum, are membrane bound and that the vacuolar proton-translocating pyrophosphatases (V-H+PPases) are present in their surrounding membranes. Volutin granules and acidocalcisomes have been found in organisms as diverse as bacteria and humans. Results Here, we show volutin granules also occur in Archaea and are, therefore, present in the three superkingdoms of life (Archaea, Bacteria and Eukarya). Molecular analyses of V-H+PPase pumps, which acidify the acidocalcisome lumen and are diagnostic proteins of the organelle, also reveal the presence of this enzyme in all three superkingdoms suggesting it is ancient and universal. Since V-H+PPase sequences contained limited phylogenetic signal to fully resolve the ancestral nodes of the tree, we investigated the divergence of protein domains in the V-H+PPase molecules. Using Protein family (Pfam) database, we found a domain in the protein, PF03030. The domain is shared by 31 species in Eukarya, 231 in Bacteria, and 17 in Archaea. The universal distribution of the V-H+PPase PF03030 domain, which is associated with the V-H+PPase function, suggests the domain and the enzyme were already present in the Last Universal Common Ancestor (LUCA). Conclusion The importance of the V-H+PPase function and the evolutionary dynamics of these domains support the early origin of the acidocalcisome organelle. In particular, the universality of volutin granules and presence of a functional V-H+PPase domain in the three superkingdoms of life reveals that the acidocalcisomes may have appeared earlier than the divergence of the superkingdoms. This result is remarkable and highlights the possibility that a high degree of cellular compartmentalization could already have been present in the LUCA. Reviewers This article was reviewed by Anthony Poole, Lakshminarayan Iyer and Daniel Kahn PMID:21974828

Breaking BAG: The Co-Chaperone BAG3 in Health and Disease.

PubMed

Behl, Christian

2016-08-01

Human BAG (Bcl-2-associated athanogene) proteins form a family of antiapoptotic proteins that currently consists of six members (BAG1-6) all sharing the BAG protein domain from which the name arises. Via this domain, BAG proteins bind to the heat shock protein 70 (Hsp70), thereby acting as a co-chaperone regulating the activity of Hsp70. In addition to their antiapoptotic activity, all human BAG proteins have distinct functions in health and disease, and BAG3 in particular is the focus of many investigations. BAG3 has a modular protein domain composition offering the possibility for manifold interactions with other proteins. Various BAG3 functions are implicated in disorders including cancer, myopathies, and neurodegeneration. The discovery of its role in selective autophagy and the description of BAG3-mediated selective macroautophagy as an adaptive mechanism to maintain cellular homeostasis, under stress as well as during aging, make BAG3 a highly interesting target for future pharmacological interventions. Copyright © 2016 Elsevier Ltd. All rights reserved.

The tetraspanin CD63 regulates ESCRT-independent and dependent endosomal sorting during melanogenesis

PubMed Central

van Niel, Guillaume; Charrin, Stéphanie; Simoes, Sabrina; Romao, Maryse; Rochin, Leila; Saftig, Paul; Marks, Michael S.; Rubinstein, Eric; Raposo, Graça

2011-01-01

Summary Cargo sorting to intraluminal vesicles (ILVs) of multivesicular endosomes is required for numerous physiological processes including lysosome-related organelle (LRO) biogenesis. PMEL – a component of melanocyte LROs (melanosomes) – is sorted to ILVs in an ESCRT-independent manner, where it is proteolytically processed and assembled into functional amyloid fibrils during melanosome maturation. Here we show that the tetraspanin CD63 directly participates in ESCRT-independent sorting of the PMEL luminal domain, but not of traditional ESCRT-dependent cargoes, to ILVs. Inactivating CD63 in cell culture or in mice impairs amyloidogenesis and downstream melanosome morphogenesis. Whereas CD63 is required for normal PMEL luminal domain sorting, the disposal of the remaining PMEL transmembrane fragment requires functional ESCRTs but not CD63. In the absence of CD63, the PMEL luminal domain follows this fragment and is targeted for ESCRT-dependent degradation. Our data thus reveal a tight interplay regulated by CD63 between two distinct endosomal ILV sorting processes for a single cargo during LRO biogenesis. PMID:21962903

Application of a Multimedia Service and Resource Management Architecture for Fault Diagnosis

PubMed Central

Castro, Alfonso; Sedano, Andrés A.; García, Fco. Javier; Villoslada, Eduardo

2017-01-01

Nowadays, the complexity of global video products has substantially increased. They are composed of several associated services whose functionalities need to adapt across heterogeneous networks with different technologies and administrative domains. Each of these domains has different operational procedures; therefore, the comprehensive management of multi-domain services presents serious challenges. This paper discusses an approach to service management linking fault diagnosis system and Business Processes for Telefónica’s global video service. The main contribution of this paper is the proposal of an extended service management architecture based on Multi Agent Systems able to integrate the fault diagnosis with other different service management functionalities. This architecture includes a distributed set of agents able to coordinate their actions under the umbrella of a Shared Knowledge Plane, inferring and sharing their knowledge with semantic techniques and three types of automatic reasoning: heterogeneous, ontology-based and Bayesian reasoning. This proposal has been deployed and validated in a real scenario in the video service offered by Telefónica Latam. PMID:29283398

Application of a Multimedia Service and Resource Management Architecture for Fault Diagnosis.

PubMed

Castro, Alfonso; Sedano, Andrés A; García, Fco Javier; Villoslada, Eduardo; Villagrá, Víctor A

2017-12-28

Nowadays, the complexity of global video products has substantially increased. They are composed of several associated services whose functionalities need to adapt across heterogeneous networks with different technologies and administrative domains. Each of these domains has different operational procedures; therefore, the comprehensive management of multi-domain services presents serious challenges. This paper discusses an approach to service management linking fault diagnosis system and Business Processes for Telefónica's global video service. The main contribution of this paper is the proposal of an extended service management architecture based on Multi Agent Systems able to integrate the fault diagnosis with other different service management functionalities. This architecture includes a distributed set of agents able to coordinate their actions under the umbrella of a Shared Knowledge Plane, inferring and sharing their knowledge with semantic techniques and three types of automatic reasoning: heterogeneous, ontology-based and Bayesian reasoning. This proposal has been deployed and validated in a real scenario in the video service offered by Telefónica Latam.

What questionnaires to use when measuring quality of life in sacral tumor patients: the updated sacral tumor survey.

PubMed

van Wulfften Palthe, Olivier D R; Janssen, Stein J; Wunder, Jay S; Ferguson, Peter C; Wei, Guo; Rose, Peter S; Yaszemski, Micheal J; Sim, Franklin H; Boland, Patrick J; Healey, John H; Hornicek, Francis J; Schwab, Joseph H

2017-05-01

Patient-reported outcomes are becoming increasingly important when investigating results of patient and disease management. In sacral tumor, the symptoms of patients can vary substantially; therefore, no single questionnaire can adequately account for the full spectrum of symptoms and disability. The purpose of this study is to analyze redundancy within the current sacral tumor survey and make a recommendation for an updated version based on the results and patient and expert opinions. A survey study from a tertiary care orthopedic oncology referral center was used. The patient sample included 70 patients with sacral tumors (78% chordoma). The following 10 questionnaires included in the current sacral tumor survey were evaluated: the Patient-Reported Outcomes Measurement Information System (PROMIS) Global Item short form, PROMIS Pain Intensity short form, PROMIS Pain Interference short form, PROMIS Neuro-QOL v1.0 Lower Extremity Function short form, PROMIS v1.0 Anxiety short form, the PROMIS v1.0 Depression short form, the International Continence Society Male short form, the Modified Obstruction-Defecation Syndrome questionnaire, the PROMIS Sexual Function Profile v1.0, and the Stoma Quality of Life tool. We performed an exploratory factor analysis to calculate the possible underlying latent traits. Spearman rank correlation coefficients were used to measure to what extent the questionnaires converged. We hypothesized the existence of six domains based on current literature: mental health, physical health, pain, gastrointestinal symptoms, sexual function, and urinary incontinence. To assess content validity, we surveyed 32 patients, 9 orthopedic oncologists, 1 medical oncologist, 1 radiation oncologist, and 1 orthopedic oncology nurse practitioner with experience in treating sacral tumor patients on the relevance of the domains. Reliability as measured by Cronbach alpha ranged from 0.65 to 0.96. Coverage measured by floor and ceiling effects ranged from 0% to 52% and from 0% to 30%, respectively. Explanatory factor analysis identified three traits to which the questionnaires that were expected to measure a similar construct correlated the most: mental health, physical function, and pain. Content validity index demonstrated low disagreement among patients (range: 0.10-0.18) and high agreement among physicians (range: 0.91-1.0) on the relevance of the proposed domains. Social health was identified by 50% of the commenting patients as an important yet missing domain. The current sacral tumor survey is incomplete and time-consuming, and not all surveys are appropriate for the sacral tumor population. Our recommended survey contains less than half the questions and includes the newly recognized social health domain. Copyright © 2016 Elsevier Inc. All rights reserved.

Electronic health record "super-users" and "under-users" in ambulatory care practices.

PubMed

Rumball-Smith, Juliet; Shekelle, Paul; Damberg, Cheryl L

2018-01-01

This study explored variation in the extent of use of electronic health record (EHR)-based health information technology (IT) functionalities across US ambulatory care practices. Use of health IT functionalities in ambulatory care is important for delivering high-quality care, including that provided in coordination with multiple practitioners. We used data from the 2014 Healthcare Information and Management Systems Society Analytics survey. The responses of 30,123 ambulatory practices with an operational EHR were analyzed to examine the extent of use of EHR-based health IT functionalities for each practice. We created a novel framework for classifying ambulatory care practices employing 7 domains of health IT functionality. Drawing from the survey responses, we created a composite "use" variable indicating the extent of health IT functionality use across these domains. "Super-user" practices were defined as having near-full employment of the 7 domains of health IT functionalities and "under-users" as those with minimal or no use of health IT functionalities. We used multivariable logistic regression to investigate how the odds of super-use and under-use varied by practice size, type, urban or rural location, and geographic region. Seventy-three percent of practices were not using EHR technologies to their full capability, and nearly 40% were classified as under-users. Under-user practices were more likely to be of smaller size, situated in the West, and located outside a metropolitan area. To achieve the broader benefits of the EHR and health IT, health systems and policy makers need to identify and address barriers to full use of health IT functionalities.

Functional health literacy and quality of life of high-school adolescents in state schools in Belo Horizonte.

PubMed

Rocha, Poliana Cristina; Rocha, Dálian Cristina; Lemos, Stela Maris Aguiar

2017-08-10

To investigate the association between functional health literacy and sociodemographic factors, quality of life, self-perception of health, and perception of contexts of violence in adolescents in state schools in Belo Horizonte. This is a cross-sectional analytical observational study with a probabilistic sample of 384 adolescents between 15 and 19 years old. Data collection was carried out in schools and included self-reporting questionnaires to assess the functional health literacy, socioeconomic classification, self-perceived health, and quality of life. The reliability of internal consistency of the functional health literacy instrument was determined by calculating Cronbach's alpha coefficient. A multivariate logistic regression analysis was performed using hierarchical data entry according to the level of determination of the theoretical model established. In order to evaluate the association, a significance level of 5% was considered, while the Odds Ratio used as a measure of the magnitude of the associations. The functional health literacy instrument presented a coefficient of 0.766, indicating adequate internal consistency. More than half of teenagers presented good functional health literacy. In the final model of multivariate analysis, the variables not practicing a religion (p = 0.006; OR = 2.108); social domain of quality of life (p = 0.004; OR = 1.022); and educational domain of quality of life (p = 0.009; OR = 1.019) remained associated with functional health literacy. Not practicing a religion and the increase in the scores of social and educational domains of quality of life increased the chances of better functional health literacy.

Domains of importance for parents, medical professionals and youth with cerebral palsy considering treatment outcomes.

PubMed

Vargus-Adams, J N; Martin, L K

2011-03-01

The aim of this study was to assess the domains of importance in therapeutic intervention for cerebral palsy (CP) using categories of the International Classification of Functioning, Disability, and Health - Children and Youth Version (ICF-CY). A total of 17 youth, 19 parents and 39 medical professionals responded to the open-ended query: 'What are the things you find most important to consider when you evaluate the effects of an intervention for yourself/your child/your patient with cerebral palsy?' Surveys were either mailed or conducted on-line. Responses were coded by two reviewers using the ICF-CY and discrepancies were resolved. Responses were distributed across the ICF-CY domains of Body Functions and Structures, Activities and Participation, and Environmental Factors, as well as non-ICF-CY concepts including quality of life. The most common responses overall were pain, motor function, mobility, community life and public services. Youth identified strength, gait pattern, hand/arm use and use of assistive technologies as priorities whereas parents were concerned with motor function, communication, mobility and provision of public services. Medical professionals listed pain, function, mobility, community life and participation most often. All surveyed groups indicate a desire to see changes in body functions and structures (pain, mental function, strength, movement), activities and participation (communication, hand/arm use, walking, school, recreation/community life) and quality of life following therapeutic interventions for CP. These results demonstrate the multiple, varied concerns regarding CP across the spectrum of functioning and health. © 2010 Blackwell Publishing Ltd.

Memory and cognitive control in an integrated theory of language processing.

PubMed

Slevc, L Robert; Novick, Jared M

2013-08-01

Pickering & Garrod's (P&G's) integrated model of production and comprehension includes no explicit role for nonlinguistic cognitive processes. Yet, how domain-general cognitive functions contribute to language processing has become clearer with well-specified theories and supporting data. We therefore believe that their account can benefit by incorporating functions like working memory and cognitive control into a unified model of language processing.

Genome-wide identification, characterization and classification of ionotropic glutamate receptor genes (iGluRs) in the malaria vector Anopheles sinensis (Diptera: Culicidae).

PubMed

Wang, Ting-Ting; Si, Feng-Ling; He, Zheng-Bo; Chen, Bin

2018-01-15

Ionotropic glutamate receptors (iGluRs) are conserved ligand-gated ion channel receptors, and ionotropic receptors (IRs) were revealed as a new family of iGluRs. Their subdivision was unsettled, and their characteristics are little known. Anopheles sinensis is a major malaria vector in eastern Asia, and its genome was recently well sequenced and annotated. We identified iGluR genes in the An. sinensis genome, analyzed their characteristics including gene structure, genome distribution, domains and specific sites by bioinformatic methods, and deduced phylogenetic relationships of all iGluRs in An. sinensis, Anopheles gambiae and Drosophila melanogaster. Based on the characteristics and phylogenetics, we generated the classification of iGluRs, and comparatively analyzed the intron number and selective pressure of three iGluRs subdivisions, iGluR group, Antenna IR and Divergent IR subfamily. A total of 56 iGluR genes were identified and named in the whole-genome of An. sinensis. These genes were located on 18 scaffolds, and 31 of them (29 being IRs) are distributed into 10 clusters that are suggested to form mainly from recent gene duplication. These iGluRs can be divided into four groups: NMDA, non-NMDA, Antenna IR and Divergent IR based on feature comparison and phylogenetic analysis. IR8a and IR25a were suggested to be monophyletic, named as Putative in the study, and moved from the Antenna subfamily in the IR family to the non-NMDA group as a sister of traditional non-NMDA. The generated iGluRs of genes (including NMDA and regenerated non-NMDA) are relatively conserved, and have a more complicated gene structure, smaller ω values and some specific functional sites. The iGluR genes in An. sinensis, An. gambiae and D. melanogaster have amino-terminal domain (ATD), ligand binding domain (LBD) and Lig_Chan domains, except for IR8a that only has the LBD and Lig_Chan domains. However, the new concept IR family of genes (including regenerated Antenna IR, and Divergent IR), especially for Divergent IR are more variable, have a simpler gene structure (intron loss phenomenon) and larger ω values, and lack specific functional sites. These IR genes have no other domains except for Antenna IRs that only have the Lig_Chan domain. This study provides a comprehensive information framework for iGluR genes in An. sinensis, and generated the classification of iGluRs by feature and bioinformatics analyses. The work lays the foundation for further functional study of these genes.

Domain-general signals in the cingulo-opercular network for visuospatial attention and episodic memory

PubMed Central

Sestieri, Carlo; Corbetta, Maurizio; Spadone, Sara; Romani, Gian Luca; Shulman, Gordon L.

2014-01-01

We investigated the functional properties of a previously described cingulo-opercular network (CON) putatively involved in cognitive control. Analyses of common fMRI task-evoked activity during perceptual and episodic memory search tasks that differently recruited the dorsal attention (DAN) and default mode network (DMN) established the generality of this network. Regions within the CON (anterior insula/frontal operculum and anterior cingulate/presupplementary cortex) displayed sustained signals during extended periods in which participants searched for behaviourally relevant information in a dynamically changing environment or from episodic memory in the absence of sensory stimulation. The CON was activated during all phases of both tasks, which involved trial initiation, target detection, decision and response, indicating its consistent involvement in a broad range of cognitive processes. Functional connectivity analyses showed that the CON flexibly linked with the DAN or DMN regions during perceptual or memory search, respectively. Aside from the CON, only a limited number of regions, including the lateral prefrontal cortex, showed evidence of domain-general, sustained activity, although in some cases the common activations may have reflected the functional-anatomical variability of domain-specific regions rather than a true domain-generality. These additional regions also showed task-dependent functional connectivity with the DMN and DAN, suggesting that this feature is not a specific marker of cognitive control. Finally, multivariate clustering analyses separated the CON from other fronto-parietal regions previously associated with cognitive control, indicating a unique fingerprint. We conclude that the CON’s functional properties and interactions with other brain regions support a broad role in cognition, consistent with its characterization as a task-control network. PMID:24144246

Relations between brain volumes, neuropsychological assessment and parental questionnaire in prematurely born children.

PubMed

Lind, Annika; Haataja, Leena; Rautava, Liisi; Väliaho, Anniina; Lehtonen, Liisa; Lapinleimu, Helena; Parkkola, Riitta; Korkman, Marit

2010-05-01

The objective of this study is to assess the relationship between brain volumes at term equivalent age and neuropsychological functions at 5 years of age in very low birth weight (VLBW) children, and to compare the results from a neuropsychological assessment and a parental questionnaire at 5 years of age. The study group included a regional cohort of 97 VLBW children and a control group of 161 children born at term. At term equivalent age, brain magnetic resonance imaging (MRI) was performed on the VLBW children, and analysed for total and regional brain volumes. At 5 years of age, a psychologist assessed the neuropsychological performance with NEPSY II, and parents completed the Five to fifteen (FTF) questionnaire on development and behaviour. The results of the control group were used to give the age-specific reference values. No significant associations were found between the brain volumes and the NEPSY II domains. As for the FTF, significant associations were found between a smaller total brain tissue volume and poorer executive functions, between a smaller cerebellar volume and both poorer executive functions and motor skills, and, surprisingly, between a larger volume of brainstem and poorer language functions. Even after adjustment for total brain tissue volume, the two associations between the cerebellar volume and the FTF domains remained borderline significant (P = 0.05). The NEPSY II domains Executive Functioning, Language and Motor Skills were significantly associated with the corresponding FTF domains. In conclusion, altered brain volumes at term equivalent age appear to affect development still at 5 years of age. The FTF seems to be a good instrument when used in combination with other neuropsychological assessment.

Domain Organization and Evolution of the Highly Divergent 5′ Coding Region of Genomes of Arteriviruses, Including the Novel Possum Nidovirus

PubMed Central

Gulyaeva, Anastasia; Hoogendoorn, Erik; Giles, Julia; Samborskiy, Dmitry

2017-01-01

ABSTRACT In five experimentally characterized arterivirus species, the 5′-end genome coding region encodes the most divergent nonstructural proteins (nsp's), nsp1 and nsp2, which include papain-like proteases (PLPs) and other poorly characterized domains. These are involved in regulation of transcription, polyprotein processing, and virus-host interaction. Here we present results of a bioinformatics analysis of this region of 14 arterivirus species, including that of the most distantly related virus, wobbly possum disease virus (WPDV), determined by a modified 5′ rapid amplification of cDNA ends (RACE) protocol. By combining profile-profile comparisons and phylogeny reconstruction, we identified an association of the four distinct domain layouts of nsp1-nsp2 with major phylogenetic lineages, implicating domain gain, including duplication, and loss in the early nsp1 evolution. Specifically, WPDV encodes highly divergent homologs of PLP1a, PLP1b, PLP1c, and PLP2, with PLP1a lacking the catalytic Cys residue, but does not encode nsp1 Zn finger (ZnF) and “nuclease” domains, which are conserved in other arteriviruses. Unexpectedly, our analysis revealed that the only catalytically active nsp1 PLP of equine arteritis virus (EAV), known as PLP1b, is most similar to PLP1c and thus is likely to be a PLP1b paralog. In all non-WPDV arteriviruses, PLP1b/c and PLP1a show contrasting patterns of conservation, with the N- and C-terminal subdomains, respectively, being enriched with conserved residues, which is indicative of different functional specializations. The least conserved domain of nsp2, the hypervariable region (HVR), has its size varied 5-fold and includes up to four copies of a novel PxPxPR motif that is potentially recognized by SH3 domain-containing proteins. Apparently, only EAV lacks the signal that directs −2 ribosomal frameshifting in the nsp2 coding region. IMPORTANCE Arteriviruses comprise a family of mammalian enveloped positive-strand RNA viruses that include some of the most economically important pathogens of swine. Most of our knowledge about this family has been obtained through characterization of viruses from five species: Equine arteritis virus, Simian hemorrhagic fever virus, Lactate dehydrogenase-elevating virus, Porcine respiratory and reproductive syndrome virus 1, and Porcine respiratory and reproductive syndrome virus 2. Here we present the results of comparative genomics analyses of viruses from all known 14 arterivirus species, including the most distantly related virus, WPDV, whose genome sequence was completed in this study. Our analysis focused on the multifunctional 5′-end genome coding region that encodes multidomain nonstructural proteins 1 and 2. Using diverse bioinformatics techniques, we identified many patterns of evolutionary conservation that are specific to members of distinct arterivirus species, both characterized and novel, or their groups. They are likely associated with structural and functional determinants important for virus replication and virus-host interaction. PMID:28053107

Spectrum response estimation for deep-water floating platforms via retardation function representation

NASA Astrophysics Data System (ADS)

Liu, Fushun; Liu, Chengcheng; Chen, Jiefeng; Wang, Bin

2017-08-01

The key concept of spectrum response estimation with commercial software, such as the SESAM software tool, typically includes two main steps: finding a suitable loading spectrum and computing the response amplitude operators (RAOs) subjected to a frequency-specified wave component. In this paper, we propose a nontraditional spectrum response estimation method that uses a numerical representation of the retardation functions. Based on estimated added mass and damping matrices of the structure, we decompose and replace the convolution terms with a series of poles and corresponding residues in the Laplace domain. Then, we estimate the power density corresponding to each frequency component using the improved periodogram method. The advantage of this approach is that the frequency-dependent motion equations in the time domain can be transformed into the Laplace domain without requiring Laplace-domain expressions for the added mass and damping. To validate the proposed method, we use a numerical semi-submerged pontoon from the SESAM. The numerical results show that the responses of the proposed method match well with those obtained from the traditional method. Furthermore, the estimated spectrum also matches well, which indicates its potential application to deep-water floating structures.

Initial constructs for patient-centered outcome measures to evaluate brain-computer interfaces

PubMed Central

Andresen, Elena M.; Fried-Oken, Melanie; Peters, Betts; Patrick, Donald L.

2016-01-01

Purpose The authors describe preliminary work toward the creation of patient-centered outcome (PCO) measures to evaluate brain-computer interface (BCI) as an assistive technology for individuals with severe speech and physical impairments (SSPI). Method In Phase 1, 591 items from 15 existing measures were mapped to the International Classification of Functioning, Disability and Health (ICF). In Phase 2, qualitative interviews were conducted with eight people with SSPI and seven caregivers. Resulting text data were coded in an iterative analysis. Results Most items (79%) mapped to the ICF environmental domain; over half (53%) mapped to more than one domain. The ICF framework was well suited for mapping items related to body functions and structures, but less so for items in other areas, including personal factors. Two constructs emerged from qualitative data: Quality of Life (QOL) and Assistive Technology. Component domains and themes were identified for each. Conclusions Preliminary constructs, domains, and themes were generated for future PCO measures relevant to BCI. Existing instruments are sufficient for initial items but do not adequately match the values of people with SSPI and their caregivers. Field methods for interviewing people with SSPI were successful, and support the inclusion of these individuals in PCO research. PMID:25806719

Resilience among abused and neglected children grown up.

PubMed

McGloin, J M; Widom, C S

2001-01-01

Although an extensive literature has accumulated documenting the maladaptive outcomes associated with childhood victimization, a limited body of knowledge addresses resilience. This paper sought to operationalize the construct of resilience across a number of domains of functioning and time periods and to determine the extent to which abused and neglected children grown up demonstrate resilience. Substantiated cases of child abuse and neglect from 1967 to 1971 were matched on gender, age, race, and approximate family social class with nonabused and nonneglected children and followed prospectively into young adulthood. Between 1989 and 1995. 1,196 participants (676 abused and neglected and 520 controls) were administered a 2-hr in-person interview, including a psychiatric assessment. Resilience requires meeting the criteria for success across six of eight domains of functioning: employment, homelessness, education, social activity, psychiatric disorder, substance abuse, and two domains assessing criminal behavior (official arrest and self-reports of violence). Results indicate that 22% of abused and neglected individuals meet the criteria for resilience. More females met the criteria for resilience and females were successful across a greater number of domains than males. We speculate on the meaning of these findings and discuss implications for the child maltreatment field. Limitations of the study are also acknowledged.

Method and apparatus to debug an integrated circuit chip via synchronous clock stop and scan

DOEpatents

Bellofatto, Ralph E [Ridgefield, CT; Ellavsky, Matthew R [Rochester, MN; Gara, Alan G [Mount Kisco, NY; Giampapa, Mark E [Irvington, NY; Gooding, Thomas M [Rochester, MN; Haring, Rudolf A [Cortlandt Manor, NY; Hehenberger, Lance G [Leander, TX; Ohmacht, Martin [Yorktown Heights, NY

2012-03-20

An apparatus and method for evaluating a state of an electronic or integrated circuit (IC), each IC including one or more processor elements for controlling operations of IC sub-units, and each the IC supporting multiple frequency clock domains. The method comprises: generating a synchronized set of enable signals in correspondence with one or more IC sub-units for starting operation of one or more IC sub-units according to a determined timing configuration; counting, in response to one signal of the synchronized set of enable signals, a number of main processor IC clock cycles; and, upon attaining a desired clock cycle number, generating a stop signal for each unique frequency clock domain to synchronously stop a functional clock for each respective frequency clock domain; and, upon synchronously stopping all on-chip functional clocks on all frequency clock domains in a deterministic fashion, scanning out data values at a desired IC chip state. The apparatus and methodology enables construction of a cycle-by-cycle view of any part of the state of a running IC chip, using a combination of on-chip circuitry and software.

Functioning of the dimeric GABAB receptor extracellular domain revealed by glycan wedge scanning

PubMed Central

Rondard, Philippe; Huang, Siluo; Monnier, Carine; Tu, Haijun; Blanchard, Bertrand; Oueslati, Nadia; Malhaire, Fanny; Li, Ying; Trinquet, Eric; Labesse, Gilles; Pin, Jean-Philippe; Liu, Jianfeng

2008-01-01

The G-protein-coupled receptor (GPCR) activated by the neurotransmitter GABA is made up of two subunits, GABAB1 and GABAB2. GABAB1 binds agonists, whereas GABAB2 is required for trafficking GABAB1 to the cell surface, increasing agonist affinity to GABAB1, and activating associated G proteins. These subunits each comprise two domains, a Venus flytrap domain (VFT) and a heptahelical transmembrane domain (7TM). How agonist binding to the GABAB1 VFT leads to GABAB2 7TM activation remains unknown. Here, we used a glycan wedge scanning approach to investigate how the GABAB VFT dimer controls receptor activity. We first identified the dimerization interface using a bioinformatics approach and then showed that introducing an N-glycan at this interface prevents the association of the two subunits and abolishes all activities of GABAB2, including agonist activation of the G protein. We also identified a second region in the VFT where insertion of an N-glycan does not prevent dimerization, but blocks agonist activation of the receptor. These data provide new insight into the function of this prototypical GPCR and demonstrate that a change in the dimerization interface is required for receptor activation. PMID:18388862

Social cognitive functioning in prodromal psychosis: A meta-analysis.

PubMed

Lee, Tae Young; Hong, Sang Bin; Shin, Na Young; Kwon, Jun Soo

2015-05-01

There is substantial evidence regarding a social cognitive deficit in schizophrenia, and it has been suggested to be a trait-marker of this disorder. However, a domain-by-domain analysis of social cognitive deficits in individuals at clinical high risk (CHR) for psychosis has not been performed. Electronic databases were searched for studies regarding social cognitive performance in individuals at CHR. The included social cognitive domains, which were classified based on the Social Cognition Psychometric Evaluation (SCOPE) initiative of the National Institute of Mental Health (NIMH), were as follows: theory of mind (ToM), social perception (SP), attributional bias (AB), and emotion processing (EP). Twenty studies that included 1229 individuals at CHR and 825 healthy controls met the inclusion criteria. The overall effect size for social cognition was medium (g=-0.477). The largest effect size was identified for AB (g=-0.708). A medium effect size was identified for EP (g=-0.446) and ToM (g=-0.425), and small effects were identified for SP (g=-0.383). This is the first quantitative domain-by-domain social cognitive meta-analysis regarding CHR individuals. The present study indicated that individuals at CHR exhibited significant impairments in all domains of social cognition compared with healthy controls, with the largest effect size identified for AB. The identification of social cognitive domains that reflect an increased risk for impending psychosis and of predictors of the conversion to psychosis via a longitudinal follow-up study is required. Copyright © 2015 Elsevier B.V. All rights reserved.

Using Common Spatial Distributions of Atoms to Relate Functionally Divergent Influenza Virus N10 and N11 Protein Structures to Functionally Characterized Neuraminidase Structures, Toxin Cell Entry Domains, and Non-Influenza Virus Cell Entry Domains

PubMed Central

Weininger, Arthur; Weininger, Susan

2015-01-01

The ability to identify the functional correlates of structural and sequence variation in proteins is a critical capability. We related structures of influenza A N10 and N11 proteins that have no established function to structures of proteins with known function by identifying spatially conserved atoms. We identified atoms with common distributed spatial occupancy in PDB structures of N10 protein, N11 protein, an influenza A neuraminidase, an influenza B neuraminidase, and a bacterial neuraminidase. By superposing these spatially conserved atoms, we aligned the structures and associated molecules. We report spatially and sequence invariant residues in the aligned structures. Spatially invariant residues in the N6 and influenza B neuraminidase active sites were found in previously unidentified spatially equivalent sites in the N10 and N11 proteins. We found the corresponding secondary and tertiary structures of the aligned proteins to be largely identical despite significant sequence divergence. We found structural precedent in known non-neuraminidase structures for residues exhibiting structural and sequence divergence in the aligned structures. In N10 protein, we identified staphylococcal enterotoxin I-like domains. In N11 protein, we identified hepatitis E E2S-like domains, SARS spike protein-like domains, and toxin components shared by alpha-bungarotoxin, staphylococcal enterotoxin I, anthrax lethal factor, clostridium botulinum neurotoxin, and clostridium tetanus toxin. The presence of active site components common to the N6, influenza B, and S. pneumoniae neuraminidases in the N10 and N11 proteins, combined with the absence of apparent neuraminidase function, suggests that the role of neuraminidases in H17N10 and H18N11 emerging influenza A viruses may have changed. The presentation of E2S-like, SARS spike protein-like, or toxin-like domains by the N10 and N11 proteins in these emerging viruses may indicate that H17N10 and H18N11 sialidase-facilitated cell entry has been supplemented or replaced by sialidase-independent receptor binding to an expanded cell population that may include neurons and T-cells. PMID:25706124

ECOD: An Evolutionary Classification of Protein Domains

PubMed Central

Kinch, Lisa N.; Pei, Jimin; Shi, Shuoyong; Kim, Bong-Hyun; Grishin, Nick V.

2014-01-01

Understanding the evolution of a protein, including both close and distant relationships, often reveals insight into its structure and function. Fast and easy access to such up-to-date information facilitates research. We have developed a hierarchical evolutionary classification of all proteins with experimentally determined spatial structures, and presented it as an interactive and updatable online database. ECOD (Evolutionary Classification of protein Domains) is distinct from other structural classifications in that it groups domains primarily by evolutionary relationships (homology), rather than topology (or “fold”). This distinction highlights cases of homology between domains of differing topology to aid in understanding of protein structure evolution. ECOD uniquely emphasizes distantly related homologs that are difficult to detect, and thus catalogs the largest number of evolutionary links among structural domain classifications. Placing distant homologs together underscores the ancestral similarities of these proteins and draws attention to the most important regions of sequence and structure, as well as conserved functional sites. ECOD also recognizes closer sequence-based relationships between protein domains. Currently, approximately 100,000 protein structures are classified in ECOD into 9,000 sequence families clustered into close to 2,000 evolutionary groups. The classification is assisted by an automated pipeline that quickly and consistently classifies weekly releases of PDB structures and allows for continual updates. This synchronization with PDB uniquely distinguishes ECOD among all protein classifications. Finally, we present several case studies of homologous proteins not recorded in other classifications, illustrating the potential of how ECOD can be used to further biological and evolutionary studies. PMID:25474468

ECOD: an evolutionary classification of protein domains.

PubMed

Cheng, Hua; Schaeffer, R Dustin; Liao, Yuxing; Kinch, Lisa N; Pei, Jimin; Shi, Shuoyong; Kim, Bong-Hyun; Grishin, Nick V

2014-12-01

Understanding the evolution of a protein, including both close and distant relationships, often reveals insight into its structure and function. Fast and easy access to such up-to-date information facilitates research. We have developed a hierarchical evolutionary classification of all proteins with experimentally determined spatial structures, and presented it as an interactive and updatable online database. ECOD (Evolutionary Classification of protein Domains) is distinct from other structural classifications in that it groups domains primarily by evolutionary relationships (homology), rather than topology (or "fold"). This distinction highlights cases of homology between domains of differing topology to aid in understanding of protein structure evolution. ECOD uniquely emphasizes distantly related homologs that are difficult to detect, and thus catalogs the largest number of evolutionary links among structural domain classifications. Placing distant homologs together underscores the ancestral similarities of these proteins and draws attention to the most important regions of sequence and structure, as well as conserved functional sites. ECOD also recognizes closer sequence-based relationships between protein domains. Currently, approximately 100,000 protein structures are classified in ECOD into 9,000 sequence families clustered into close to 2,000 evolutionary groups. The classification is assisted by an automated pipeline that quickly and consistently classifies weekly releases of PDB structures and allows for continual updates. This synchronization with PDB uniquely distinguishes ECOD among all protein classifications. Finally, we present several case studies of homologous proteins not recorded in other classifications, illustrating the potential of how ECOD can be used to further biological and evolutionary studies.

The crystal structure of the streptococcal collagen-like protein 2 globular domain from invasive M3-type group A Streptococcus shows significant similarity to immunomodulatory HIV protein gp41.

PubMed

Squeglia, Flavia; Bachert, Beth; De Simone, Alfonso; Lukomski, Slawomir; Berisio, Rita

2014-02-21

The arsenal of virulence factors deployed by streptococci includes streptococcal collagen-like (Scl) proteins. These proteins, which are characterized by a globular domain and a collagen-like domain, play key roles in host adhesion, host immune defense evasion, and biofilm formation. In this work, we demonstrate that the Scl2.3 protein is expressed on the surface of invasive M3-type strain MGAS315 of Streptococcus pyogenes. We report the crystal structure of Scl2.3 globular domain, the first of any Scl. This structure shows a novel fold among collagen trimerization domains of either bacterial or human origin. Despite there being low sequence identity, we observed that Scl2.3 globular domain structurally resembles the gp41 subunit of the envelope glycoprotein from human immunodeficiency virus type 1, an essential subunit for viral fusion to human T cells. We combined crystallographic data with modeling and molecular dynamics techniques to gather information on the entire lollipop-like Scl2.3 structure. Molecular dynamics data evidence a high flexibility of Scl2.3 with remarkable interdomain motions that are likely instrumental to the protein biological function in mediating adhesive or immune-modulatory functions in host-pathogen interactions. Altogether, our results provide molecular tools for the understanding of Scl-mediated streptococcal pathogenesis and important structural insights for the future design of small molecular inhibitors of streptococcal invasion.

A Qualitative Inquiry of the Counseling Dissertation Process

ERIC Educational Resources Information Center

Flynn, Stephen V.; Chasek, Christine L.; Harper, Irene F.; Murphy, Katherine M.; Jorgensen, Maribeth F.

2012-01-01

The authors in this consensual qualitative research study explored the dissertation experiences of 42 graduates (27 counselor educators, 13 counselors, 2 administrators) from 4 midwestern states. Identified domains included impact of environment, competing influences, personality traits, chair influence, committee function, and barriers to…

From Structure to Function: A Comprehensive Compendium of Tools to Unveil Protein Domains and Understand Their Role in Cytokinesis.

PubMed

Rincon, Sergio A; Paoletti, Anne

2016-01-01

Unveiling the function of a novel protein is a challenging task that requires careful experimental design. Yeast cytokinesis is a conserved process that involves modular structural and regulatory proteins. For such proteins, an important step is to identify their domains and structural organization. Here we briefly discuss a collection of methods commonly used for sequence alignment and prediction of protein structure that represent powerful tools for the identification homologous domains and design of structure-function approaches to test experimentally the function of multi-domain proteins such as those implicated in yeast cytokinesis.

From scenarios to domain models: processes and representations

NASA Astrophysics Data System (ADS)

Haddock, Gail; Harbison, Karan

1994-03-01

The domain specific software architectures (DSSA) community has defined a philosophy for the development of complex systems. This philosophy improves productivity and efficiency by increasing the user's role in the definition of requirements, increasing the systems engineer's role in the reuse of components, and decreasing the software engineer's role to the development of new components and component modifications only. The scenario-based engineering process (SEP), the first instantiation of the DSSA philosophy, has been adopted by the next generation controller project. It is also the chosen methodology of the trauma care information management system project, and the surrogate semi-autonomous vehicle project. SEP uses scenarios from the user to create domain models and define the system's requirements. Domain knowledge is obtained from a variety of sources including experts, documents, and videos. This knowledge is analyzed using three techniques: scenario analysis, task analysis, and object-oriented analysis. Scenario analysis results in formal representations of selected scenarios. Task analysis of the scenario representations results in descriptions of tasks necessary for object-oriented analysis and also subtasks necessary for functional system analysis. Object-oriented analysis of task descriptions produces domain models and system requirements. This paper examines the representations that support the DSSA philosophy, including reference requirements, reference architectures, and domain models. The processes used to create and use the representations are explained through use of the scenario-based engineering process. Selected examples are taken from the next generation controller project.

SPA- STATISTICAL PACKAGE FOR TIME AND FREQUENCY DOMAIN ANALYSIS

NASA Technical Reports Server (NTRS)

Brownlow, J. D.

1994-01-01

The need for statistical analysis often arises when data is in the form of a time series. This type of data is usually a collection of numerical observations made at specified time intervals. Two kinds of analysis may be performed on the data. First, the time series may be treated as a set of independent observations using a time domain analysis to derive the usual statistical properties including the mean, variance, and distribution form. Secondly, the order and time intervals of the observations may be used in a frequency domain analysis to examine the time series for periodicities. In almost all practical applications, the collected data is actually a mixture of the desired signal and a noise signal which is collected over a finite time period with a finite precision. Therefore, any statistical calculations and analyses are actually estimates. The Spectrum Analysis (SPA) program was developed to perform a wide range of statistical estimation functions. SPA can provide the data analyst with a rigorous tool for performing time and frequency domain studies. In a time domain statistical analysis the SPA program will compute the mean variance, standard deviation, mean square, and root mean square. It also lists the data maximum, data minimum, and the number of observations included in the sample. In addition, a histogram of the time domain data is generated, a normal curve is fit to the histogram, and a goodness-of-fit test is performed. These time domain calculations may be performed on both raw and filtered data. For a frequency domain statistical analysis the SPA program computes the power spectrum, cross spectrum, coherence, phase angle, amplitude ratio, and transfer function. The estimates of the frequency domain parameters may be smoothed with the use of Hann-Tukey, Hamming, Barlett, or moving average windows. Various digital filters are available to isolate data frequency components. Frequency components with periods longer than the data collection interval are removed by least-squares detrending. As many as ten channels of data may be analyzed at one time. Both tabular and plotted output may be generated by the SPA program. This program is written in FORTRAN IV and has been implemented on a CDC 6000 series computer with a central memory requirement of approximately 142K (octal) of 60 bit words. This core requirement can be reduced by segmentation of the program. The SPA program was developed in 1978.

Determination of bulk domain structure and magnetization processes in bcc ferromagnetic alloys: Analysis of magnetostriction in F e83G a17

NASA Astrophysics Data System (ADS)

He, Yangkun; Coey, J. M. D.; Schaefer, Rudolf; Jiang, Chengbao

2018-01-01

The ground state of macroscopic samples of magnetically ordered materials is a domain state because of magnetostatic energy or entropy, yet we have limited experimental means for imaging the bulk domain structure and the magnetization process directly. The common methods available reveal the domains at the surface or in electron- or x-ray transparent lamellae, not those in the bulk. The magnetization curve just reflects the vector sum of the moments of all the domains in the sample, but magnetostriction curves are more informative. They are strongly influenced by the domain structure in the unmagnetized state and its evolution during the magnetization process in an applied field. Here we report a method of determining the bulk domain structure in a cubic magnetostrictive material by combining magneto-optic Kerr microscopy with magnetostriction and magnetization measurements on single crystals as a function of applied field. We analyze the magnetostriction of F e83G a17 crystals in terms of a domain structure that is greatly influenced by sample shape and heat treatment. Saturation magnetostriction measurements are used to determine the fraction of domains orientated along the three 〈100 〉 axes in the initial state. Domain wall motion and rotation process have characteristic signatures in the magnetostriction curves, including those associated with the Δ E effect and domain rotation through a 〈110 〉 auxetic direction.

Reconstruction of the domain orientation distribution function of polycrystalline PZT ceramics using vector piezoresponse force microscopy.

PubMed

Kratzer, Markus; Lasnik, Michael; Röhrig, Sören; Teichert, Christian; Deluca, Marco

2018-01-11

Lead zirconate titanate (PZT) is one of the prominent materials used in polycrystalline piezoelectric devices. Since the ferroelectric domain orientation is the most important parameter affecting the electromechanical performance, analyzing the domain orientation distribution is of great importance for the development and understanding of improved piezoceramic devices. Here, vector piezoresponse force microscopy (vector-PFM) has been applied in order to reconstruct the ferroelectric domain orientation distribution function of polished sections of device-ready polycrystalline lead zirconate titanate (PZT) material. A measurement procedure and a computer program based on the software Mathematica have been developed to automatically evaluate the vector-PFM data for reconstructing the domain orientation function. The method is tested on differently in-plane and out-of-plane poled PZT samples, and the results reveal the expected domain patterns and allow determination of the polarization orientation distribution function at high accuracy.

On the numerical solution of the dynamically loaded hydrodynamic lubrication of the point contact problem

NASA Technical Reports Server (NTRS)

Lim, Sang G.; Brewe, David E.; Prahl, Joseph M.

1990-01-01

The transient analysis of hydrodynamic lubrication of a point-contact is presented. A body-fitted coordinate system is introduced to transform the physical domain to a rectangular computational domain, enabling the use of the Newton-Raphson method for determining pressures and locating the cavitation boundary, where the Reynolds boundary condition is specified. In order to obtain the transient solution, an explicit Euler method is used to effect a time march. The transient dynamic load is a sinusoidal function of time with frequency, fractional loading, and mean load as parameters. Results include the variation of the minimum film thickness and phase-lag with time as functions of excitation frequency. The results are compared with the analytic solution to the transient step bearing problem with the same dynamic loading function. The similarities of the results suggest an approximate model of the point contact minimum film thickness solution.

Electric-field-stimulated protein mechanics

PubMed Central

Hekstra, Doeke R.; White, K. Ian; Socolich, Michael A.; Henning, Robert W.; Šrajer, Vukica; Ranganathan, Rama

2017-01-01

The internal mechanics of proteins—the coordinated motions of amino acids and the pattern of forces constraining these motions—connects protein structure to function. Here we describe a new method combining the application of strong electric field pulses to protein crystals with time-resolved X-ray crystallography to observe conformational changes in spatial and temporal detail. Using a human PDZ domain (LNX2PDZ2) as a model system, we show that protein crystals tolerate electric field pulses strong enough to drive concerted motions on the sub-microsecond timescale. The induced motions are subtle, involve diverse physical mechanisms, and occur throughout the protein structure. The global pattern of electric-field-induced motions is consistent with both local and allosteric conformational changes naturally induced by ligand binding, including at conserved functional sites in the PDZ domain family. This work lays the foundation for comprehensive experimental study of the mechanical basis of protein function. PMID:27926732

High-precision, large-domain three-dimensional manipulation of nano-materials for fabrication nanodevices

PubMed Central

2011-01-01

Nanoscaled materials are attractive building blocks for hierarchical assembly of functional nanodevices, which exhibit diverse performances and simultaneous functions. We innovatively fabricated semiconductor nano-probes of tapered ZnS nanowires through melting and solidifying by electro-thermal process; and then, as-prepared nano-probes can manipulate nanomaterials including semiconductor/metal nanowires and nanoparticles through sufficiently electrostatic force to the desired location without structurally and functionally damage. With some advantages of high precision and large domain, we can move and position and interconnect individual nanowires for contracting nanodevices. Interestingly, by the manipulating technique, the nanodevice made of three vertically interconnecting nanowires, i.e., diode, was realized and showed an excellent electrical property. This technique may be useful to fabricate electronic devices based on the nanowires' moving, positioning, and interconnecting and may overcome fundamental limitations of conventional mechanical fabrication. PMID:21794151

Generating functions and stability study of multivariate self-excited epidemic processes

NASA Astrophysics Data System (ADS)

Saichev, A. I.; Sornette, D.

2011-09-01

We present a stability study of the class of multivariate self-excited Hawkes point processes, that can model natural and social systems, including earthquakes, epileptic seizures and the dynamics of neuron assemblies, bursts of exchanges in social communities, interactions between Internet bloggers, bank network fragility and cascading of failures, national sovereign default contagion, and so on. We present the general theory of multivariate generating functions to derive the number of events over all generations of various types that are triggered by a mother event of a given type. We obtain the stability domains of various systems, as a function of the topological structure of the mutual excitations across different event types. We find that mutual triggering tends to provide a significant extension of the stability (or subcritical) domain compared with the case where event types are decoupled, that is, when an event of a given type can only trigger events of the same type.

Comparison of structure, function and regulation of plant cold shock domain proteins to bacterial and animal cold shock domain proteins.

PubMed

Chaikam, Vijay; Karlson, Dale T

2010-01-01

The cold shock domain (CSD) is among the most ancient and well conserved nucleic acid binding domains from bacteria to higher animals and plants. The CSD facilitates binding to RNA, ssDNA and dsDNA and most functions attributed to cold shock domain proteins are mediated by this nucleic acid binding activity. In prokaryotes, cold shock domain proteins only contain a single CSD and are termed cold shock proteins (Csps). In animal model systems, various auxiliary domains are present in addition to the CSD and are commonly named Y-box proteins. Similar to animal CSPs, plant CSPs contain auxiliary C-terminal domains in addition to their N-terminal CSD. Cold shock domain proteins have been shown to play important roles in development and stress adaptation in wide variety of organisms. In this review, the structure, function and regulation of plant CSPs are compared and contrasted to the characteristics of bacterial and animal CSPs. [BMB reports 2010; 43(1): 1-8].

Quality of life as indicator of poor outcome in hemodialysis: relation with mortality in different age groups.

PubMed

van Loon, I N; Bots, M L; Boereboom, F T J; Grooteman, M P C; Blankestijn, P J; van den Dorpel, M A; Nubé, M J; Ter Wee, P M; Verhaar, M C; Hamaker, M E

2017-07-06

Physical, cognitive and psychosocial functioning are frequently impaired in dialysis patients and impairment in these domains relates to poor outcome. The aim of this analysis was to compare the prevalence of impairment as measured by the Kidney Disease Quality of Life- Short Form (KDQOL-SF) subscales between the different age categories and to assess whether the association of these subscales with mortality differs between younger and older dialysis patients. This study included data from 714 prevalent hemodialysis patients, from 26 centres, who were enrolled in the CONvective TRAnsport STudy (CONTRAST NCT00205556, 09-12-2005). Baseline HRQOL domains were evaluated for patients <65 years, 65-74 years and over 75 years. Multivariable Cox proportional hazards analyses were performed to assess the relation between the separate domains and 2-year mortality. Emotional health was higher in patients over the age of 75 compared to younger patients (mean level 71, 73 and 77 for increasing age categories respectively, p = 0.02), whilst physical functioning was significantly lower in older patients (mean level 60, 48 and 40, p < 0.01). A low level of physical functioning (Hazard Ratio (HR) 1.72 [95%Confidence Interval (CI) 1.02-2.73]), emotional health (HR 1.85 [95% 1.30-2.63]), and social functioning (HR 1.59 [95% CI 1.12-2.26]), was individually associated with an increased 2-year mortality within the whole population. The absence of effect modification suggests no evidence for different relations within the older age groups. In dialysis patients, older age is associated with lower levels of physical functioning, whilst the level of emotional health is not associated with age. KDQOL-SF domains physical functioning, emotional health and social functioning are independently associated with mortality in prevalent younger and older hemodialysis patients.

Vertebrate intersectin1 is repurposed to facilitate cortical midline connectivity and higher order cognition.

PubMed

Sengar, Ameet S; Ellegood, Jacob; Yiu, Adelaide P; Wang, Hua; Wang, Wei; Juneja, Subhash C; Lerch, Jason P; Josselyn, Sheena A; Henkelman, R Mark; Salter, Michael W; Egan, Sean E

2013-02-27

Invertebrate studies have highlighted a role for EH and SH3 domain Intersectin (Itsn) proteins in synaptic vesicle recycling and morphology. Mammals have two Itsn genes (Itsn1 and Itsn2), both of which can undergo alternative splicing to include DBL/PH and C2 domains not present in invertebrate Itsn proteins. To probe for specific and redundant functions of vertebrate Itsn genes, we generated Itsn1, Itsn2, and double mutant mice. While invertebrate mutants showed severe synaptic abnormalities, basal synaptic transmission and plasticity were unaffected at Schaffer CA1 synapses in mutant mice. Surprisingly, intercortical tracts-corpus callosum, ventral hippocampal, and anterior commissures-failed to cross the midline in mice lacking Itsn1, but not Itsn2. In contrast, tracts extending within hemispheres and those that decussate to more caudal brain segments appeared normal. Itsn1 mutant mice showed severe deficits in Morris water maze and contextual fear memory tasks, whereas mice lacking Itsn2 showed normal learning and memory. Thus, coincident with the acquisition of additional signaling domains, vertebrate Itsn1 has been functionally repurposed to also facilitate interhemispheric connectivity essential for high order cognitive functions.

Collagen fibril surface displays a constellation of sites capable of promoting fibril assembly, stability, and hemostasis

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

Orgel, J.P.; Antipova, O.; Sagi, I.

Fibrillar collagens form the structural basis of organs and tissues including the vasculature, bone, and tendon. They are also dynamic, organizational scaffolds that present binding and recognition sites for ligands, cells, and platelets. We interpret recently published X-ray diffraction findings and use atomic force microscopy data to illustrate the significance of new insights into the functional organization of the collagen fibril. These data indicate that collagen's most crucial functional domains localize primarily to the overlap region, comprising a constellation of sites we call the 'master control region.' Moreover, the collagen's most exposed aspect contains its most stable part - themore » C-terminal region that controls collagen assembly, cross-linking, and blood clotting. Hidden beneath the fibril surface exists a constellation of 'cryptic' sequences poised to promote hemostasis and cell - collagen interactions in tissue injury and regeneration. These findings begin to address several important, and previously unresolved, questions: How functional domains are organized in the fibril, which domains are accessible, and which require proteolysis or structural trauma to become exposed? Here we speculate as to how collagen fibrillar organization impacts molecular processes relating to tissue growth, development, and repair.« less

Direct Binding between Pre-S1 and TRP-like Domains in TRPP Channels Mediates Gating and Functional Regulation by PIP2.

PubMed

Zheng, Wang; Cai, Ruiqi; Hofmann, Laura; Nesin, Vasyl; Hu, Qiaolin; Long, Wentong; Fatehi, Mohammad; Liu, Xiong; Hussein, Shaimaa; Kong, Tim; Li, Jingru; Light, Peter E; Tang, Jingfeng; Flockerzi, Veit; Tsiokas, Leonidas; Chen, Xing-Zhen

2018-02-06

Transient receptor potential (TRP) channels are regulated by diverse stimuli comprising thermal, chemical, and mechanical modalities. They are also commonly regulated by phosphatidylinositol-4,5-bisphosphate (PIP2), with underlying mechanisms largely unknown. We here revealed an intramolecular interaction of the TRPP3 N and C termini (N-C) that is functionally essential. The interaction was mediated by aromatic Trp81 in pre-S1 domain and cationic Lys568 in TRP-like domain. Structure-function analyses revealed similar N-C interaction in TRPP2 as well as TRPM8/-V1/-C4 via highly conserved tryptophan and lysine/arginine residues. PIP2 bound to cationic residues in TRPP3, including K568, thereby disrupting the N-C interaction and negatively regulating TRPP3. PIP2 had similar negative effects on TRPP2. Interestingly, we found that PIP2 facilitates the N-C interaction in TRPM8/-V1, resulting in channel potentiation. The intramolecular N-C interaction might represent a shared mechanism underlying the gating and PIP2 regulation of TRP channels. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Addictions Neuroclinical Assessment: A reverse translational approach.

PubMed

Kwako, Laura E; Momenan, Reza; Grodin, Erica N; Litten, Raye Z; Koob, George F; Goldman, David

2017-08-01

Incentive salience, negative emotionality, and executive function are functional domains that are etiologic in the initiation and progression of addictive disorders, having been implicated in humans with addictive disorders and in animal models of addictions. Measures of these three neuroscience-based functional domains can capture much of the effects of inheritance and early exposures that lead to trait vulnerability shared across different addictive disorders. For specific addictive disorders, these measures can be supplemented by agent specific measures such as those that access pharmacodynamic and pharmacokinetic variation attributable to agent-specific gatekeeper molecules including receptors and drug-metabolizing enzymes. Herein, we focus on the translation and reverse translation of knowledge derived from animal models of addiction to the human condition via measures of neurobiological processes that are orthologous in animals and humans, and that are shared in addictions to different agents. Based on preclinical data and human studies, measures of these domains in a general framework of an Addictions Neuroclinical Assessment (ANA) can transform the assessment and nosology of addictive disorders, and can be informative for staging disease progression. We consider next steps and challenges for implementation of ANA in clinical care and research. This article is part of the Special Issue entitled "Alcoholism". Published by Elsevier Ltd.

Differential relations of executive functioning to borderline personality disorder presentations in adolescents.

PubMed

Kalpakci, Allison; Ha, Carolyn; Sharp, Carla

2018-05-01

Borderline personality disorder (BPD) in adolescents is highly complex and heterogeneous. Within the disorder, research has suggested the existence of at least two subgroups: one with predominantly internalizing psychopathology features and one with predominantly externalizing psychopathology features. One process that may differentiate these groups is executive functioning (EF), given that poor EF is linked to externalizing psychopathology. Against this background, the current study used a multi-informant approach to examine whether adolescent patients with predominantly externalizing BPD presentations experience greater deficits in EF than adolescent patients with predominantly internalizing presentations. The sample included inpatient adolescents ages 12-17 (M = 15.26; SD = 1.51). Analyses revealed that multiple EF domains distinguished the BPD subgroups. More specifically, adolescents with externalizing presentations exhibited greater difficulties in broad domains related to global executive functioning, metacognition and behavioural regulation and specific domains related to inhibitory control, working memory, planning/organizing, monitoring and organization of materials. While this study is the first to examine EF and adolescent BPD in the context of internalizing and externalizing psychopathology, alternative approaches to examining this question are discussed. Copyright © 2018 John Wiley & Sons, Ltd. Copyright © 2018 John Wiley & Sons, Ltd.

New insights into the roles of megalin/LRP2 and the regulation of its functional expression.

PubMed

Marzolo, María-Paz; Farfán, Pamela

2011-01-01

Since the discovery of the low-density lipoprotein receptor (LDLR) and its association with familial hypercholesterolemia in the early 1980s, a family of structurally related proteins has been discovered that has apolipoprotein E as a common ligand, and the broad functions of its members have been described. LRP2, or megalin, is a member of the LDLR family and was initially called gp330. Megalin is an endocytic receptor expressed on the apical surface of several epithelial cells that internalizes a variety of ligands including nutrients, hormones and their carrier proteins, signaling molecules, morphogens, and extracellular matrix proteins. Once internalized, these ligands are directed to the lysosomal degradation pathway or transported by transcytosis from one side of the cell to the opposite membrane. The availability of megalin at the cell surface is controlled by several regulatory mechanisms, including the phosphorylation of its cytoplasmic domain by GSK3, the proteolysis of the extracellular domain at the cell surface (shedding), the subsequent intramembrane proteolysis of the transmembrane domain by the gamma-secretase complex, and exosome secretion. Based on the important roles of its ligands and its tissue expression pattern, megalin has been recognized as an important component of many pathological conditions, including diabetic nephropathy, Lowe syndrome, Dent disease, Alzheimer's disease (AD) and gallstone disease. In addition, the expression of megalin and some of its ligands in the central and peripheral nervous system suggests a role for this receptor in neural regeneration processes. Despite its obvious importance, the regulation of megalin expression is poorly understood. In this review, we describe the functions of megalin and its association with certain pathological conditions as well as the current understanding of the mechanisms that underlie the control of megalin expression.

Site-specific chemical conjugation of human Fas ligand extracellular domain using trans-cyclooctene - methyltetrazine reactions.

PubMed

Muraki, Michiro; Hirota, Kiyonori

2017-07-03

Fas ligand plays a key role in the human immune system as a major cell death inducing protein. The extracellular domain of human Fas ligand (hFasLECD) triggers apoptosis of malignant cells, and therefore is expected to have substantial potentials in medical biotechnology. However, the current application of this protein to clinical medicine is hampered by a shortage of the benefits relative to the drawbacks including the side-effects in systemic administration. Effective procedures for the engineering of the protein by attaching useful additional functions are required to overcome the problem. A procedure for the site-specific chemical conjugation of hFasLECD with a fluorochrome and functional proteins was devised using an inverse-electron-demand Diels-Alder reaction between trans-cyclooctene group and methyltetrazine group. The conjugations in the present study were attained by using much less molar excess amounts of the compounds to be attached as compared with the conventional chemical modification reactions using maleimide derivatives in the previous study. The isolated conjugates of hFasLECD with sulfo-Cy3, avidin and rabbit IgG Fab' domain presented the functional and the structural integrities of the attached molecules without impairing the specific binding activity toward human Fas receptor extracellular domain. The present study provided a new fundamental strategy for the production of the engineered hFasLECDs with additional beneficial functions, which will lead to the developments of the improved diagnostic systems and the effective treatment methods of serious diseases by using this protein as a component of novel molecular tools.

Neuropsychological characteristics of Gulf War illness: A meta-analysis.

PubMed

Janulewicz, Patricia A; Krengel, Maxine H; Maule, Alexis; White, Roberta F; Cirillo, Joanna; Sisson, Emily; Heeren, Timothy; Sullivan, Kimberly

2017-01-01

Gulf War illness (GWI) is a disorder related to military service in the 1991 GW. Prominent symptoms include fatigue, pain and cognitive problems. These symptoms were reported by GW Veterans (GWV) immediately after the war and were eventually incorporated into case definitions of GWI. Neuropsychological function in GW veterans has been studied both among deployed GWV and in GWV diagnosed with GWI. Results have been inconsistent between and across GW populations. The purpose of the present investigation was to better characterize neuropsychological function in this veteran population. Meta-analysis techniques were applied to published studies on neuropsychological performance in GWV to identify domains of dysfunction in deployed vs. non-deployed GW-era veterans and symptomatic vs. non-symptomatic GWVs. Significantly decreased performance was found in three functional domains: attention and executive function, visuospatial skills and learning/memory. These findings document the cognitive decrements associated with GW service, validate current GWI case definitions using cognitive criteria, and identify test measures for use in GWI research assessing GWI treatment trial efficacy.

Essential roles of Gab1 tyrosine phosphorylation in growth factor-mediated signaling and angiogenesis.

PubMed

Wang, Weiye; Xu, Suowen; Yin, Meimei; Jin, Zheng Gen

2015-02-15

Growth factors and their downstream receptor tyrosine kinases (RTKs) mediate a number of biological processes controlling cell function. Adaptor (docking) proteins, which consist exclusively of domains and motifs that mediate molecular interactions, link receptor activation to downstream effectors. Recent studies have revealed that Grb2-associated-binders (Gab) family members (including Gab1, Gab2, and Gab3), when phosphorylated on tyrosine residues, provide binding sites for multiple effector proteins, such as Src homology-2 (SH2)-containing protein tyrosine phosphatase 2 (SHP2) and phosphatidylinositol 3-kinase (PI3K) regulatory subunit p85, thereby playing important roles in transducing RTKs-mediated signals into pathways with diversified biological functions. Here, we provide an up-to-date overview on the domain structure and biological functions of Gab1, the most intensively studied Gab family protein, in growth factor signaling and biological functions, with a special focus on angiogenesis. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Multimicrometer Noncovalent Monolayer Domains on Layered Materials through Thermally Controlled Langmuir-Schaefer Conversion for Noncovalent 2D Functionalization.

PubMed

Hayes, Tyler R; Bang, Jae Jin; Davis, Tyson C; Peterson, Caroline F; McMillan, David G; Claridge, Shelley A

2017-10-18

As functionalized 2D materials are incorporated into hybrid materials, ensuring large-area structural control in noncovalently adsorbed films becomes increasingly important. Noncovalent functionalization avoids disrupting electronic structure in 2D materials; however, relatively weak molecular interactions in such monolayers typically reduce stability toward solution processing and other common material handling conditions. Here, we find that controlling substrate temperature during Langmuir-Schaefer conversion of a standing phase monolayer of diynoic amphiphiles on water to a horizontally oriented monolayer on a 2D substrate routinely produces multimicrometer domains, at least an order of magnitude larger than those typically achieved through drop-casting. Following polymerization, these highly ordered monolayers retain their structures during vigorous washing with solvents including water, ethanol, tetrahydrofuran, and toluene. These findings point to a convenient and broadly applicable strategy for noncovalent functionalization of 2D materials in applications that require large-area structural control, for instance, to minimize desorption at defects during subsequent solution processing.

The CRM domain: an RNA binding module derived from an ancient ribosome-associated protein.

PubMed

Barkan, Alice; Klipcan, Larik; Ostersetzer, Oren; Kawamura, Tetsuya; Asakura, Yukari; Watkins, Kenneth P

2007-01-01

The CRS1-YhbY domain (also called the CRM domain) is represented as a stand-alone protein in Archaea and Bacteria, and in a family of single- and multidomain proteins in plants. The function of this domain is unknown, but structural data and the presence of the domain in several proteins known to interact with RNA have led to the proposal that it binds RNA. Here we describe a phylogenetic analysis of the domain, its incorporation into diverse proteins in plants, and biochemical properties of a prokaryotic and eukaryotic representative of the domain family. We show that a bacterial member of the family, Escherichia coli YhbY, is associated with pre-50S ribosomal subunits, suggesting that YhbY functions in ribosome assembly. GFP fused to a single-domain CRM protein from maize localizes to the nucleolus, suggesting that an analogous activity may have been retained in plants. We show further that an isolated maize CRM domain has RNA binding activity in vitro, and that a small motif shared with KH RNA binding domains, a conserved "GxxG" loop, contributes to its RNA binding activity. These and other results suggest that the CRM domain evolved in the context of ribosome function prior to the divergence of Archaea and Bacteria, that this function has been maintained in extant prokaryotes, and that the domain was recruited to serve as an RNA binding module during the evolution of plant genomes.

Intellectual Growth in Children as a Function of Domain Specific and Domain General Working Memory Subgroups

ERIC Educational Resources Information Center

Swanson, H. Lee

2011-01-01

This study examined whether children's growth on measures of fluid (Raven Colored Progressive Matrices) and crystallized (reading and math achievement) intelligence was attributable to domain-specific or domain-general functions of working memory (WM). A sample of 290 elementary school children was tested on measures of intelligence across three…