Multimodal Feature Integration in the Angular Gyrus during Episodic and Semantic Retrieval

PubMed Central

Bonnici, Heidi M.; Richter, Franziska R.; Yazar, Yasemin

2016-01-01

Much evidence from distinct lines of investigation indicates the involvement of angular gyrus (AnG) in the retrieval of both episodic and semantic information, but the region's precise function and whether that function differs across episodic and semantic retrieval have yet to be determined. We used univariate and multivariate fMRI analysis methods to examine the role of AnG in multimodal feature integration during episodic and semantic retrieval. Human participants completed episodic and semantic memory tasks involving unimodal (auditory or visual) and multimodal (audio-visual) stimuli. Univariate analyses revealed the recruitment of functionally distinct AnG subregions during the retrieval of episodic and semantic information. Consistent with a role in multimodal feature integration during episodic retrieval, significantly greater AnG activity was observed during retrieval of integrated multimodal episodic memories compared with unimodal episodic memories. Multivariate classification analyses revealed that individual multimodal episodic memories could be differentiated in AnG, with classification accuracy tracking the vividness of participants' reported recollections, whereas distinct unimodal memories were represented in sensory association areas only. In contrast to episodic retrieval, AnG was engaged to a statistically equivalent degree during retrieval of unimodal and multimodal semantic memories, suggesting a distinct role for AnG during semantic retrieval. Modality-specific sensory association areas exhibited corresponding activity during both episodic and semantic retrieval, which mirrored the functional specialization of these regions during perception. The results offer new insights into the integrative processes subserved by AnG and its contribution to our subjective experience of remembering. SIGNIFICANCE STATEMENT Using univariate and multivariate fMRI analyses, we provide evidence that functionally distinct subregions of angular gyrus (AnG) contribute to the retrieval of episodic and semantic memories. Our multivariate pattern classifier could distinguish episodic memory representations in AnG according to whether they were multimodal (audio-visual) or unimodal (auditory or visual) in nature, whereas statistically equivalent AnG activity was observed during retrieval of unimodal and multimodal semantic memories. Classification accuracy during episodic retrieval scaled with the trial-by-trial vividness with which participants experienced their recollections. Therefore, the findings offer new insights into the integrative processes subserved by AnG and how its function may contribute to our subjective experience of remembering. PMID:27194327

Multimodal Feature Integration in the Angular Gyrus during Episodic and Semantic Retrieval.

PubMed

Bonnici, Heidi M; Richter, Franziska R; Yazar, Yasemin; Simons, Jon S

2016-05-18

Much evidence from distinct lines of investigation indicates the involvement of angular gyrus (AnG) in the retrieval of both episodic and semantic information, but the region's precise function and whether that function differs across episodic and semantic retrieval have yet to be determined. We used univariate and multivariate fMRI analysis methods to examine the role of AnG in multimodal feature integration during episodic and semantic retrieval. Human participants completed episodic and semantic memory tasks involving unimodal (auditory or visual) and multimodal (audio-visual) stimuli. Univariate analyses revealed the recruitment of functionally distinct AnG subregions during the retrieval of episodic and semantic information. Consistent with a role in multimodal feature integration during episodic retrieval, significantly greater AnG activity was observed during retrieval of integrated multimodal episodic memories compared with unimodal episodic memories. Multivariate classification analyses revealed that individual multimodal episodic memories could be differentiated in AnG, with classification accuracy tracking the vividness of participants' reported recollections, whereas distinct unimodal memories were represented in sensory association areas only. In contrast to episodic retrieval, AnG was engaged to a statistically equivalent degree during retrieval of unimodal and multimodal semantic memories, suggesting a distinct role for AnG during semantic retrieval. Modality-specific sensory association areas exhibited corresponding activity during both episodic and semantic retrieval, which mirrored the functional specialization of these regions during perception. The results offer new insights into the integrative processes subserved by AnG and its contribution to our subjective experience of remembering. Using univariate and multivariate fMRI analyses, we provide evidence that functionally distinct subregions of angular gyrus (AnG) contribute to the retrieval of episodic and semantic memories. Our multivariate pattern classifier could distinguish episodic memory representations in AnG according to whether they were multimodal (audio-visual) or unimodal (auditory or visual) in nature, whereas statistically equivalent AnG activity was observed during retrieval of unimodal and multimodal semantic memories. Classification accuracy during episodic retrieval scaled with the trial-by-trial vividness with which participants experienced their recollections. Therefore, the findings offer new insights into the integrative processes subserved by AnG and how its function may contribute to our subjective experience of remembering. Copyright © 2016 Bonnici, Richter, et al.

Rewiring the Brain: Potential Role of the Premotor Cortex in Motor Control, Learning, and Recovery of Function Following Brain Injury

PubMed Central

Kantak, Shailesh S.; Stinear, James W.; Buch, Ethan R.; Cohen, Leonardo G.

2016-01-01

The brain is a plastic organ with a capability to reorganize in response to behavior and/or injury. Following injury to the motor cortex or emergent corticospinal pathways, recovery of function depends on the capacity of surviving anatomical resources to recover and repair in response to task-specific training. One such area implicated in poststroke reorganization to promote recovery of upper extremity recovery is the premotor cortex (PMC). This study reviews the role of distinct subdivisions of PMC: dorsal (PMd) and ventral (PMv) premotor cortices as critical anatomical and physiological nodes within the neural networks for the control and learning of goal-oriented reach and grasp actions in healthy individuals and individuals with stroke. Based on evidence emerging from studies of intrinsic and extrinsic connectivity, transcranial magnetic stimulation, functional neuroimaging, and experimental studies in animals and humans, the authors propose 2 distinct patterns of reorganization that differentially engage ipsilesional and contralesional PMC. Research directions that may offer further insights into the role of PMC in motor control, learning, and poststroke recovery are also proposed. This research may facilitate neuroplasticity for maximal recovery of function following brain injury. PMID:21926382

Deconstructing the relationships between phylogenetic diversity and ecology: a case study on ecosystem functioning.

PubMed

Davies, T Jonathan; Urban, Mark C; Rayfield, Bronwyn; Cadotte, Marc W; Peres-Neto, Pedro R

2016-09-01

Recent studies have supported a link between phylogenetic diversity and various ecological properties including ecosystem function. However, such studies typically assume that phylogenetic branches of equivalent length are more or less interchangeable. Here we suggest that there is a need to consider not only branch lengths but also their placement on the phylogeny. We demonstrate how two common indices of network centrality can be used to describe the evolutionary distinctiveness of network elements (nodes and branches) on a phylogeny. If phylogenetic diversity enhances ecosystem function via complementarity and the representation of functional diversity, we would predict a correlation between evolutionary distinctiveness of network elements and their contribution to ecosystem process. In contrast, if one or a few evolutionary innovations play key roles in ecosystem function, the relationship between evolutionary distinctiveness and functional contribution may be weak or absent. We illustrate how network elements associated with high functional contribution can be identified from regressions between phylogenetic diversity and productivity using a well-known empirical data set on plant productivity from the Cedar Creek Long-Term Ecological Research. We find no association between evolutionary distinctiveness and ecosystem functioning, but we are able to identify phylogenetic elements associated with species of known high functional contribution within the Fabaceae. Our perspective provides a useful guide in the search for ecological traits linking diversity and ecosystem function, and suggests a more nuanced consideration of phylogenetic diversity is required in the conservation and biodiversity-ecosystem-function literature. © 2016 by the Ecological Society of America.

Distinct Functional Roles of β-Tubulin Isotypes in Microtubule Arrays of Tetrahymena thermophila, a Model Single-Celled Organism

PubMed Central

Pucciarelli, Sandra; Ballarini, Patrizia; Sparvoli, Daniela; Barchetta, Sabrina; Yu, Ting; Detrich, H. William; Miceli, Cristina

2012-01-01

Background The multi-tubulin hypothesis proposes that each tubulin isotype performs a unique role, or subset of roles, in the universe of microtubule function(s). To test this hypothesis, we are investigating the functions of the recently discovered, noncanonical β-like tubulins (BLTs) of the ciliate, Tetrahymena thermophila. Tetrahymena forms 17 distinct microtubular structures whose assembly had been thought to be based on single α- and β-isotypes. However, completion of the macronuclear genome sequence of Tetrahymena demonstrated that this ciliate possessed a β-tubulin multigene family: two synonymous genes (BTU1 and BTU2) encode the canonical β-tubulin, BTU2, and six genes (BLT1-6) yield five divergent β-tubulin isotypes. In this report, we examine the structural features and functions of two of the BLTs (BLT1 and BLT4) and compare them to those of BTU2. Methodology/Principal Findings With respect to BTU2, BLT1 and BLT4 had multiple sequence substitutions in their GTP-binding sites, in their interaction surfaces, and in their microtubule-targeting motifs, which together suggest that they have specialized functions. To assess the roles of these tubulins in vivo, we transformed Tetrahymena with expression vectors that direct the synthesis of GFP-tagged versions of the isotypes. We show that GFP-BLT1 and GFP-BLT4 were not detectable in somatic cilia and basal bodies, whereas GFP-BTU2 strongly labeled these structures. During cell division, GFP-BLT1 and GFP-BLT4, but not GFP-BTU2, were incorporated into the microtubule arrays of the macronucleus and into the mitotic apparatus of the micronucleus. GFP-BLT1 also participated in formation of the microtubules of the meiotic apparatus of the micronucleus during conjugation. Partitioning of the isotypes between nuclear and ciliary microtubules was confirmed biochemically. Conclusion/Significance We conclude that Tetrahymena uses a family of distinct β-tubulin isotypes to construct subsets of functionally different microtubules, a result that provides strong support for the multi-tubulin hypothesis. PMID:22745812

Diverse functions of myosin VI elucidated by an isoform-specific α-helix domain

PubMed Central

Magistrati, Elisa; Molteni, Erika; Lupia, Michela; Soffientini, Paolo; Rottner, Klemens; Cavallaro, Ugo; Pozzoli, Uberto; Mapelli, Marina; Walters, Kylie J.; Polo, Simona

2016-01-01

Myosin VI functions in endocytosis and cell motility. Alternative splicing of myosin VI mRNA generates two distinct isoform types, myosin VIshort and myosin VIlong, which differ in the C-terminal region. Their physiological and pathological role remains unknown. Here we identified an isoform-specific regulatory helix, named α2-linker that defines specific conformations and hence determines the target selectivity of human myosin VI. The presence of the α2-linker structurally defines a novel clathrin-binding domain that is unique to myosin VIlong and masks the known RRL interaction motif. This finding is relevant to ovarian cancer, where alternative myosin VI splicing is aberrantly regulated, and exon skipping dictates cell addiction to myosin VIshort for tumor cell migration. The RRL interactor optineurin contributes to this process by selectively binding myosin VIshort. Thus the α2-linker acts like a molecular switch that assigns myosin VI to distinct endocytic (myosin VIlong) or migratory (myosin VIshort) functional roles. PMID:26950368

Diverse functions of myosin VI elucidated by an isoform-specific α-helix domain.

PubMed

Wollscheid, Hans-Peter; Biancospino, Matteo; He, Fahu; Magistrati, Elisa; Molteni, Erika; Lupia, Michela; Soffientini, Paolo; Rottner, Klemens; Cavallaro, Ugo; Pozzoli, Uberto; Mapelli, Marina; Walters, Kylie J; Polo, Simona

2016-04-01

Myosin VI functions in endocytosis and cell motility. Alternative splicing of myosin VI mRNA generates two distinct isoform types, myosin VI(short) and myosin VI(long), which differ in the C-terminal region. Their physiological and pathological roles remain unknown. Here we identified an isoform-specific regulatory helix, named the α2-linker, that defines specific conformations and hence determines the target selectivity of human myosin VI. The presence of the α2-linker structurally defines a new clathrin-binding domain that is unique to myosin VI(long) and masks the known RRL interaction motif. This finding is relevant to ovarian cancer, in which alternative myosin VI splicing is aberrantly regulated, and exon skipping dictates cell addiction to myosin VI(short) in tumor-cell migration. The RRL interactor optineurin contributes to this process by selectively binding myosin VI(short). Thus, the α2-linker acts like a molecular switch that assigns myosin VI to distinct endocytic (myosin VI(long)) or migratory (myosin VI(short)) functional roles.

Generation of signaling specificity in Arabidopsis by spatially restricted buffering of ligand-receptor interactions.

PubMed

Abrash, Emily B; Davies, Kelli A; Bergmann, Dominique C

2011-08-01

Core signaling pathways function in multiple programs during multicellular development. The mechanisms that compartmentalize pathway function or confer process specificity, however, remain largely unknown. In Arabidopsis thaliana, ERECTA (ER) family receptors have major roles in many growth and cell fate decisions. The ER family acts with receptor TOO MANY MOUTHS (TMM) and several ligands of the EPIDERMAL PATTERNING FACTOR LIKE (EPFL) family, which play distinct yet overlapping roles in patterning of epidermal stomata. Here, our examination of EPFL genes EPFL6/CHALLAH (CHAL), EPFL5/CHALLAH-LIKE1, and EPFL4/CHALLAH-LIKE2 (CLL2) reveals that this family may mediate additional ER-dependent processes. chal cll2 mutants display growth phenotypes characteristic of er mutants, and genetic interactions are consistent with CHAL family molecules acting as ER family ligands. We propose that different classes of EPFL genes regulate different aspects of ER family function and introduce a TMM-based discriminatory mechanism that permits simultaneous, yet compartmentalized and distinct, function of the ER family receptors in growth and epidermal patterning.

Distinctive amygdala subregions involved in emotion-modulated Stroop interference

PubMed Central

Han, Hyun Jung; Lee, Kanghee; Kim, Hyun Taek; Kim, Hackjin

2014-01-01

Despite the well-known role of the amygdala in mediating emotional interference during tasks requiring cognitive resources, no definite conclusion has yet been reached regarding the differential roles of functionally and anatomically distinctive subcomponents of the amygdala in such processes. In this study, we examined female participants and attempted to separate the neural processes for the detection of emotional information from those for the regulation of cognitive interference from emotional distractors by adding a temporal gap between emotional stimuli and a subsequent cognitive Stroop task. Reaction time data showed a significantly increased Stroop interference effect following emotionally negative stimuli compared with neutral stimuli, and functional magnetic resonance imaging data revealed that the anterior ventral amygdala (avAMYG) showed greater responses to negative stimuli compared with neutral stimuli. In addition, individuals who scored high in neuroticism showed greater posterior dorsal amygdala (pdAMYG) responses to incongruent compared with congruent Stroop trials following negative stimuli, but not following neutral stimuli. Taken together, the findings of this study demonstrated functionally distinctive contributions of the avAMYG and pdAMYG to the emotion-modulated Stroop interference effect and suggested that the avAMYG encodes associative values of emotional stimuli whereas the pdAMYG resolves cognitive interference from emotional distractors. PMID:23543193

Structures and functions of insect arylalkylamine N-acetyltransferase (iaaNAT); a key enzyme for physiological and behavioral switch in arthropods

PubMed Central

Hiragaki, Susumu; Suzuki, Takeshi; Mohamed, Ahmed A. M.; Takeda, Makio

2015-01-01

The evolution of N-acetyltransfeases (NATs) seems complex. Vertebrate arylalkylamine N-acetyltransferase (aaNAT) has been extensively studied since it leads to the synthesis of melatonin, a multifunctional neurohormone prevalent in photoreceptor cells, and is known as a chemical token of the night. Melatonin also serves as a scavenger for reactive oxygen species. This is also true with invertebrates. NAT therefore has distinct functional implications in circadian function, as timezymes (aaNAT), and also xenobiotic reactions (arylamine NAT or simply NAT). NATs belong to a broader enzyme group, the GCN5-related N-acetyltransferase superfamily. Due to low sequence homology and a seemingly fast rate of structural differentiation, the nomenclature for NATs can be confusing. The advent of bioinformatics, however, has helped to classify this group of enzymes; vertebrates have two distinct subgroups, the timezyme type and the xenobiotic type, which has a wider substrate range including imidazolamine, pharmacological drugs, environmental toxicants and even histone. Insect aaNAT (iaaNAT) form their own clade in the phylogeny, distinct from vertebrate aaNATs. Arthropods are unique, since the phylum has exoskeleton in which quinones derived from N-acetylated monoamines function in coupling chitin and arthropodins. Monoamine oxidase (MAO) activity is limited in insects, but NAT-mediated degradation prevails. However, unexpectedly iaaNAT occurs not only among arthropods but also among basal deuterostomia, and is therefore more apomorphic. Our analyses illustrate that iaaNATs has unique physiological roles but at the same time it plays a role in a timezyme function, at least in photoperiodism. Photoperiodism has been considered as a function of circadian system but the detailed molecular mechanism is not well understood. We propose a molecular hypothesis for photoperiodism in Antheraea pernyi based on the transcription regulation of NAT interlocked by the circadian system. Therefore, the enzyme plays both unique and universal roles in insects. The unique role of iaaNATs in physiological regulation urges the targeting of this system for integrated pest management (IPM). We indeed showed a successful example of chemical compound screening with reconstituted enzyme and further attempts seem promising. PMID:25918505

Structures and functions of insect arylalkylamine N-acetyltransferase (iaaNAT); a key enzyme for physiological and behavioral switch in arthropods.

PubMed

Hiragaki, Susumu; Suzuki, Takeshi; Mohamed, Ahmed A M; Takeda, Makio

2015-01-01

The evolution of N-acetyltransfeases (NATs) seems complex. Vertebrate arylalkylamine N-acetyltransferase (aaNAT) has been extensively studied since it leads to the synthesis of melatonin, a multifunctional neurohormone prevalent in photoreceptor cells, and is known as a chemical token of the night. Melatonin also serves as a scavenger for reactive oxygen species. This is also true with invertebrates. NAT therefore has distinct functional implications in circadian function, as timezymes (aaNAT), and also xenobiotic reactions (arylamine NAT or simply NAT). NATs belong to a broader enzyme group, the GCN5-related N-acetyltransferase superfamily. Due to low sequence homology and a seemingly fast rate of structural differentiation, the nomenclature for NATs can be confusing. The advent of bioinformatics, however, has helped to classify this group of enzymes; vertebrates have two distinct subgroups, the timezyme type and the xenobiotic type, which has a wider substrate range including imidazolamine, pharmacological drugs, environmental toxicants and even histone. Insect aaNAT (iaaNAT) form their own clade in the phylogeny, distinct from vertebrate aaNATs. Arthropods are unique, since the phylum has exoskeleton in which quinones derived from N-acetylated monoamines function in coupling chitin and arthropodins. Monoamine oxidase (MAO) activity is limited in insects, but NAT-mediated degradation prevails. However, unexpectedly iaaNAT occurs not only among arthropods but also among basal deuterostomia, and is therefore more apomorphic. Our analyses illustrate that iaaNATs has unique physiological roles but at the same time it plays a role in a timezyme function, at least in photoperiodism. Photoperiodism has been considered as a function of circadian system but the detailed molecular mechanism is not well understood. We propose a molecular hypothesis for photoperiodism in Antheraea pernyi based on the transcription regulation of NAT interlocked by the circadian system. Therefore, the enzyme plays both unique and universal roles in insects. The unique role of iaaNATs in physiological regulation urges the targeting of this system for integrated pest management (IPM). We indeed showed a successful example of chemical compound screening with reconstituted enzyme and further attempts seem promising.

The Yin and Yang of YY1 in the nervous system

PubMed Central

He, Ye; Casaccia-Bonnefil, Patrizia

2008-01-01

The transcription factor Yin Yang 1 (YY1) is a multifunctional protein that can activate or repress gene expression depending on the cellular context. YY1 is ubiquitously expressed and highly conserved between species. However its role varies in diverse cell types and includes proliferation, differentiation and apoptosis. This review will focus on the function of YY1 in the nervous system including its role in neural development, neuronal function, developmental myelination and neurological disease. The multiple functions of YY1 in distinct cell types are reviewed and the possible mechanisms underlying the cell specificity for these functions are discussed. PMID:18485096

Functional characterization and cellular dynamics of the CDC-42 - RAC - CDC-24 module in Neurospora crassa.

PubMed

Araujo-Palomares, Cynthia L; Richthammer, Corinna; Seiler, Stephan; Castro-Longoria, Ernestina

2011-01-01

Rho-type GTPases are key regulators that control eukaryotic cell polarity, but their role in fungal morphogenesis is only beginning to emerge. In this study, we investigate the role of the CDC-42 - RAC - CDC-24 module in Neurospora crassa. rac and cdc-42 deletion mutants are viable, but generate highly compact colonies with severe morphological defects. Double mutants carrying conditional and loss of function alleles of rac and cdc-42 are lethal, indicating that both GTPases share at least one common essential function. The defects of the GTPase mutants are phenocopied by deletion and conditional alleles of the guanine exchange factor (GEF) cdc-24, and in vitro GDP-GTP exchange assays identify CDC-24 as specific GEF for both CDC-42 and RAC. In vivo confocal microscopy shows that this module is organized as membrane-associated cap that covers the hyphal apex. However, the specific localization patterns of the three proteins are distinct, indicating different functions of RAC and CDC-42 within the hyphal tip. CDC-42 localized as confined apical membrane-associated crescent, while RAC labeled a membrane-associated ring excluding the region labeled by CDC42. The GEF CDC-24 occupied a strategic position, localizing as broad apical membrane-associated crescent and in the apical cytosol excluding the Spitzenkörper. RAC and CDC-42 also display distinct localization patterns during branch initiation and germ tube formation, with CDC-42 accumulating at the plasma membrane before RAC. Together with the distinct cellular defects of rac and cdc-42 mutants, these localizations suggest that CDC-42 is more important for polarity establishment, while the primary function of RAC may be maintaining polarity. In summary, this study identifies CDC-24 as essential regulator for RAC and CDC-42 that have common and distinct functions during polarity establishment and maintenance of cell polarity in N. crassa.

Functional Analogy in Human Metabolism: Enzymes with Different Biological Roles or Functional Redundancy?

PubMed Central

Piergiorge, Rafael Mina; de Miranda, Antonio Basílio; Catanho, Marcos

2017-01-01

Abstract Since enzymes catalyze almost all chemical reactions that occur in living organisms, it is crucial that genes encoding such activities are correctly identified and functionally characterized. Several studies suggest that the fraction of enzymatic activities in which multiple events of independent origin have taken place during evolution is substantial. However, this topic is still poorly explored, and a comprehensive investigation of the occurrence, distribution, and implications of these events has not been done so far. Fundamental questions, such as how analogous enzymes originate, why so many events of independent origin have apparently occurred during evolution, and what are the reasons for the coexistence in the same organism of distinct enzymatic forms catalyzing the same reaction, remain unanswered. Also, several isofunctional enzymes are still not recognized as nonhomologous, even with substantial evidence indicating different evolutionary histories. In this work, we begin to investigate the biological significance of the cooccurrence of nonhomologous isofunctional enzymes in human metabolism, characterizing functional analogous enzymes identified in metabolic pathways annotated in the human genome. Our hypothesis is that the coexistence of multiple enzymatic forms might not be interpreted as functional redundancy. Instead, these enzymatic forms may be implicated in distinct (and probably relevant) biological roles. PMID:28854631

Convergent Evolution of Calcineurin Pathway Roles in Thermotolerance and Virulence in Candida glabrata

PubMed Central

Chen, Ying-Lien; Konieczka, Jay H.; Springer, Deborah J.; Bowen, Samantha E.; Zhang, Jing; Silao, Fitz Gerald S.; Bungay, Alice Alma C.; Bigol, Ursela G.; Nicolas, Marilou G.; Abraham, Soman N.; Thompson, Dawn A.; Regev, Aviv; Heitman, Joseph

2012-01-01

Candida glabrata is an emerging human fungal pathogen that is frequently drug tolerant, resulting in difficulties in treatment and a higher mortality in immunocompromised patients. The calcium-activated protein phosphatase calcineurin plays critical roles in controlling drug tolerance, hyphal growth, and virulence in diverse fungal pathogens via distinct mechanisms involving survival in serum or growth at host temperature (37° and higher). Here, we comprehensively studied the calcineurin signaling cascade in C. glabrata and found novel and uncharacterized functions of calcineurin and its downstream target Crz1 in governing thermotolerance, intracellular architecture, and pathogenesis in murine ocular, urinary tract, and systemic infections. This represents a second independent origin of a role for calcineurin in thermotolerant growth of a major human fungal pathogen, distinct from that which arose independently in Cryptococcus neoformans. Calcineurin also promotes survival of C. glabrata in serum via mechanisms distinct from C. albicans and thereby enables establishment of tissue colonization in a murine systemic infection model. To understand calcineurin signaling in detail, we performed global transcript profiling analysis and identified calcineurin- and Crz1-dependent genes in C. glabrata involved in cell wall biosynthesis, heat shock responses, and calcineurin function. Regulators of calcineurin (RCN) are a novel family of calcineurin modifiers, and two members of this family were identified in C. glabrata: Rcn1 and Rcn2. Our studies demonstrate that Rcn2 expression is controlled by calcineurin and Crz1 to function as a feedback inhibitor of calcineurin in a circuit required for calcium tolerance in C. glabrata. In contrast, the calcineurin regulator Rcn1 activates calcineurin signaling. Interestingly, neither Rcn1 nor Rcn2 is required for virulence in a murine systemic infection model. Taken together, our findings show that calcineurin signaling plays critical roles in thermotolerance and virulence, and that Rcn1 and Rcn2 have opposing functions in controlling calcineurin signaling in C. glabrata. PMID:22690377

Resolving response, decision, and strategic control: evidence for a functional topography in dorsomedial prefrontal cortex.

PubMed

Venkatraman, Vinod; Rosati, Alexandra G; Taren, Adrienne A; Huettel, Scott A

2009-10-21

The dorsomedial prefrontal cortex (DMPFC) plays a central role in aspects of cognitive control and decision making. Here, we provide evidence for an anterior-to-posterior topography within the DMPFC using tasks that evoke three distinct forms of control demands--response, decision, and strategic--each of which could be mapped onto independent behavioral data. Specifically, we identify three spatially distinct regions within the DMPFC: a posterior region associated with control demands evoked by multiple incompatible responses, a middle region associated with control demands evoked by the relative desirability of decision options, and an anterior region that predicts control demands related to deviations from an individual's preferred decision-making strategy. These results provide new insight into the functional organization of DMPFC and suggest how recent controversies about its role in complex decision making and response mapping can be reconciled.

Resolving Response, Decision, and Strategic Control: Evidence for a Functional Topography in Dorsomedial Prefrontal Cortex

PubMed Central

Venkatraman, Vinod; Rosati, Alexandra G.; Taren, Adrienne A.; Huettel, Scott A.

2009-01-01

The dorsomedial prefrontal cortex (DMPFC) plays a central role in aspects of cognitive control and decision making. Here, we provide evidence for an anterior-to-posterior topography within the DMPFC using tasks that evoke three distinct forms of control demands – response, decision, and strategic – each of which could be mapped on to independent behavioral data. Specifically, we identify three spatially distinct regions within the DMPFC: a posterior region associated with control demands evoked by multiple incompatible responses, a middle region associated with control demands evoked by the relative desirability of decision options, and an anterior region that predicts control demands related to deviations from an individual's preferred decision-making strategy. These results provide new insight into the functional organization of DMPFC, and suggest how recent controversies about its role in complex decision making and response mapping can be reconciled. PMID:19846703

PMS2 endonuclease activity has distinct biological functions and is essential for genome maintenance.

PubMed

van Oers, Johanna M M; Roa, Sergio; Werling, Uwe; Liu, Yiyong; Genschel, Jochen; Hou, Harry; Sellers, Rani S; Modrich, Paul; Scharff, Matthew D; Edelmann, Winfried

2010-07-27

The DNA mismatch repair protein PMS2 was recently found to encode a novel endonuclease activity. To determine the biological functions of this activity in mammals, we generated endonuclease-deficient Pms2E702K knock-in mice. Pms2EK/EK mice displayed increased genomic mutation rates and a strong cancer predisposition. In addition, class switch recombination, but not somatic hypermutation, was impaired in Pms2EK/EK B cells, indicating a specific role in Ig diversity. In contrast to Pms2-/- mice, Pms2EK/EK male mice were fertile, indicating that this activity is dispensable in spermatogenesis. Therefore, the PMS2 endonuclease activity has distinct biological functions and is essential for genome maintenance and tumor suppression.

'What' Is Happening in the Dorsal Visual Pathway.

PubMed

Freud, Erez; Plaut, David C; Behrmann, Marlene

2016-10-01

The cortical visual system is almost universally thought to be segregated into two anatomically and functionally distinct pathways: a ventral occipitotemporal pathway that subserves object perception, and a dorsal occipitoparietal pathway that subserves object localization and visually guided action. Accumulating evidence from both human and non-human primate studies, however, challenges this binary distinction and suggests that regions in the dorsal pathway contain object representations that are independent of those in ventral cortex and that play a functional role in object perception. We review here the evidence implicating dorsal object representations, and we propose an account of the anatomical organization, functional contributions, and origins of these representations in the service of perception. Copyright © 2016 Elsevier Ltd. All rights reserved.

A Unique Role of Endogenous Visual-Spatial Attention in Rapid Processing of Multiple Targets

ERIC Educational Resources Information Center

Guzman-Martinez, Emmanuel; Grabowecky, Marcia; Palafox, German; Suzuki, Satoru

2011-01-01

Visual spatial attention can be exogenously captured by a salient stimulus or can be endogenously allocated by voluntary effort. Whether these two attention modes serve distinctive functions is debated, but for processing of single targets the literature suggests superiority of exogenous attention (it is faster acting and serves more functions).…

Human germline and pan-cancer variomes and their distinct functional profiles

PubMed Central

Pan, Yang; Karagiannis, Konstantinos; Zhang, Haichen; Dingerdissen, Hayley; Shamsaddini, Amirhossein; Wan, Quan; Simonyan, Vahan; Mazumder, Raja

2014-01-01

Identification of non-synonymous single nucleotide variations (nsSNVs) has exponentially increased due to advances in Next-Generation Sequencing technologies. The functional impacts of these variations have been difficult to ascertain because the corresponding knowledge about sequence functional sites is quite fragmented. It is clear that mapping of variations to sequence functional features can help us better understand the pathophysiological role of variations. In this study, we investigated the effect of nsSNVs on more than 17 common types of post-translational modification (PTM) sites, active sites and binding sites. Out of 1 705 285 distinct nsSNVs on 259 216 functional sites we identified 38 549 variations that significantly affect 10 major functional sites. Furthermore, we found distinct patterns of site disruptions due to germline and somatic nsSNVs. Pan-cancer analysis across 12 different cancer types led to the identification of 51 genes with 106 nsSNV affected functional sites found in 3 or more cancer types. 13 of the 51 genes overlap with previously identified Significantly Mutated Genes (Nature. 2013 Oct 17;502(7471)). 62 mutations in these 13 genes affecting functional sites such as DNA, ATP binding and various PTM sites occur across several cancers and can be prioritized for additional validation and investigations. PMID:25232094

Cellulose synthase 'class specific regions' are intrinsically disordered and functionally undifferentiated.

PubMed

Scavuzzo-Duggan, Tess R; Chaves, Arielle M; Singh, Abhishek; Sethaphong, Latsavongsakda; Slabaugh, Erin; Yingling, Yaroslava G; Haigler, Candace H; Roberts, Alison W

2018-06-01

Cellulose synthases (CESAs) are glycosyltransferases that catalyze formation of cellulose microfibrils in plant cell walls. Seed plant CESA isoforms cluster in six phylogenetic clades, whose non-interchangeable members play distinct roles within cellulose synthesis complexes (CSCs). A 'class specific region' (CSR), with higher sequence similarity within versus between functional CESA classes, has been suggested to contribute to specific activities or interactions of different isoforms. We investigated CESA isoform specificity in the moss, Physcomitrella patens (Hedw.) B. S. G. to gain evolutionary insights into CESA structure/function relationships. Like seed plants, P. patens has oligomeric rosette-type CSCs, but the PpCESAs diverged independently and form a separate CESA clade. We showed that P. patens has two functionally distinct CESAs classes, based on the ability to complement the gametophore-negative phenotype of a ppcesa5 knockout line. Thus, non-interchangeable CESA classes evolved separately in mosses and seed plants. However, testing of chimeric moss CESA genes for complementation demonstrated that functional class-specificity is not determined by the CSR. Sequence analysis and computational modeling showed that the CSR is intrinsically disordered and contains predicted molecular recognition features, consistent with a possible role in CESA oligomerization and explaining the evolution of class-specific sequences without selection for class-specific function. © 2018 Institute of Botany, Chinese Academy of Sciences.

Genome-Wide Detection and Analysis of Multifunctional Genes

PubMed Central

Pritykin, Yuri; Ghersi, Dario; Singh, Mona

2015-01-01

Many genes can play a role in multiple biological processes or molecular functions. Identifying multifunctional genes at the genome-wide level and studying their properties can shed light upon the complexity of molecular events that underpin cellular functioning, thereby leading to a better understanding of the functional landscape of the cell. However, to date, genome-wide analysis of multifunctional genes (and the proteins they encode) has been limited. Here we introduce a computational approach that uses known functional annotations to extract genes playing a role in at least two distinct biological processes. We leverage functional genomics data sets for three organisms—H. sapiens, D. melanogaster, and S. cerevisiae—and show that, as compared to other annotated genes, genes involved in multiple biological processes possess distinct physicochemical properties, are more broadly expressed, tend to be more central in protein interaction networks, tend to be more evolutionarily conserved, and are more likely to be essential. We also find that multifunctional genes are significantly more likely to be involved in human disorders. These same features also hold when multifunctionality is defined with respect to molecular functions instead of biological processes. Our analysis uncovers key features about multifunctional genes, and is a step towards a better genome-wide understanding of gene multifunctionality. PMID:26436655

Genome-Wide Identification of Binding Sites Defines Distinct Functions for Caenorhabditis elegans PHA-4/FOXA in Development and Environmental Response

PubMed Central

Zhong, Mei; Niu, Wei; Lu, Zhi John; Sarov, Mihail; Murray, John I.; Janette, Judith; Raha, Debasish; Sheaffer, Karyn L.; Lam, Hugo Y. K.; Preston, Elicia; Slightham, Cindie; Hillier, LaDeana W.; Brock, Trisha; Agarwal, Ashish; Auerbach, Raymond; Hyman, Anthony A.; Gerstein, Mark; Mango, Susan E.; Kim, Stuart K.; Waterston, Robert H.; Reinke, Valerie; Snyder, Michael

2010-01-01

Transcription factors are key components of regulatory networks that control development, as well as the response to environmental stimuli. We have established an experimental pipeline in Caenorhabditis elegans that permits global identification of the binding sites for transcription factors using chromatin immunoprecipitation and deep sequencing. We describe and validate this strategy, and apply it to the transcription factor PHA-4, which plays critical roles in organ development and other cellular processes. We identified thousands of binding sites for PHA-4 during formation of the embryonic pharynx, and also found a role for this factor during the starvation response. Many binding sites were found to shift dramatically between embryos and starved larvae, from developmentally regulated genes to genes involved in metabolism. These results indicate distinct roles for this regulator in two different biological processes and demonstrate the versatility of transcription factors in mediating diverse biological roles. PMID:20174564

5-HT1A receptors in mood and anxiety: recent insights into autoreceptor versus heteroreceptor function

PubMed Central

Garcia-Garcia, Alvaro; Tancredi, Adrian Newman-; Leonardo, E. David

2014-01-01

Rationale Serotonin (5-HT) neurotransmission is intimately linked to anxiety and depression and a diverse body of evidence supports the involvement of the main inhibitory serotonergic receptor, the serotonin-1A (5-HT1A) subtype, in both disorders. Objectives In this review, we examine the function of 5-HT1A receptor sub-populations and re-interpret our understanding of their role in mental illness in light of new data, separating both spatial (autoreceptor vs heteroreceptor) and the temporal (developmental vs adult) roles of the endogenous 5-HT1A receptors, emphasizing their distinct actions in mediating anxiety and depression-like behaviors. Results It is difficult to unambiguously distinguish the effects of different populations of the 5-HT1A receptors with traditional genetic animal models and pharmacological approaches. However, with the advent of novel genetic systems and subpopulation-selective pharmacological agents, direct evidence for distinct roles of these populations in governing emotion related behavior are emerging. Conclusions There is strong and growing evidence for a functional dissociation between auto and heteroreceptor populations in mediating anxiety and depressive-like behaviors respectively. Furthermore, while it is well established that 5-HT1A receptors act developmentally to establish normal anxiety-like behaviors, the developmental role of 5-HT1A heteroreceptors is less clear, and the specific mechanisms underlying the developmental role of each subpopulation are likely to be key elements determining mood control in adult subjects. PMID:24337875

Natural Microbial Assemblages Reflect Distinct Organismal and Functional Partitioning

NASA Astrophysics Data System (ADS)

Wilmes, P.; Andersson, A.; Kalnejais, L. H.; Verberkmoes, N. C.; Lefsrud, M. G.; Wexler, M.; Singer, S. W.; Shah, M.; Bond, P. L.; Thelen, M. P.; Hettich, R. L.; Banfield, J. F.

2007-12-01

The ability to link microbial community structure to function has long been a primary focus of environmental microbiology. With the advent of community genomic and proteomic techniques, along with advances in microscopic imaging techniques, it is now possible to gain insights into the organismal and functional makeup of microbial communities. Biofilms growing within highly acidic solutions inside the Richmond Mine (Iron Mountain, Redding, California) exhibit distinct macro- and microscopic morphologies. They are composed of microorganisms belonging to the three domains of life, including archaea, bacteria and eukarya. The proportion of each organismal type depends on sampling location and developmental stage. For example, mature biofilms floating on top of acid mine drainage (AMD) pools exhibit layers consisting of a densely packed bottom layer of the chemoautolithotroph Leptospirillum group II, a less dense top layer composed mainly of archaea, and fungal filaments spanning across the entire biofilm. The expression of cytochrome 579 (the most highly abundant protein in the biofilm, believed to be central to iron oxidation and encoded by Leptospirillum group II) is localized at the interface of the biofilm with the AMD solution, highlighting that biofilm architecture is reflected at the functional gene expression level. Distinct functional partitioning is also apparent in a biological wastewater treatment system that selects for distinct polyphosphate accumulating organisms. Community genomic data from " Candidatus Accumulibacter phosphatis" dominated activated sludge has enabled high mass-accuracy shotgun proteomics for identification of key metabolic pathways. Comprehensive genome-wide alignment of orthologous proteins suggests distinct partitioning of protein variants involved in both core-metabolism and specific metabolic pathways among the dominant population and closely related species. In addition, strain- resolved proteogenomic analysis of the AMD biofilms also highlights the importance of strain heterogeneity for the maintenance of community structure and function. These findings explain the importance of genetic diversity in facilitating the stable performance of complex microbial processes. Furthermore, although very different in terms of habitat, both microbial communities exhibit distinct functional compartmentalization and demonstrate its role in sustaining microbial community structure.

Distinct Conformations of Ly49 Natural Killer Cell Receptors Mediate MHC Class I Recognition in Trans and Cis

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

Back, J.; Malchiodi, E; Cho, S

2009-01-01

Certain cell-surface receptors engage ligands expressed on juxtaposed cells and ligands on the same cell. The structural basis for trans versus cis binding is not known. Here, we showed that Ly49 natural killer (NK) cell receptors bound two MHC class I (MHC-I) molecules in trans when the two ligand-binding domains were backfolded onto the long stalk region. In contrast, dissociation of the ligand-binding domains from the stalk and their reorientation relative to the NK cell membrane allowed monovalent binding of MHC-I in cis. The distinct conformations (backfolded and extended) define the structural basis for cis-trans binding by Ly49 receptors andmore » explain the divergent functional consequences of cis versus trans interactions. Further analyses identified specific stalk segments that were not required for MHC-I binding in trans but were essential for inhibitory receptor function. These data identify multiple distinct roles of stalk regions for receptor function.« less

Trypanosome RNA Editing Mediator Complex proteins have distinct functions in gRNA utilization.

PubMed

Simpson, Rachel M; Bruno, Andrew E; Chen, Runpu; Lott, Kaylen; Tylec, Brianna L; Bard, Jonathan E; Sun, Yijun; Buck, Michael J; Read, Laurie K

2017-07-27

Uridine insertion/deletion RNA editing is an essential process in kinetoplastid parasites whereby mitochondrial mRNAs are modified through the specific insertion and deletion of uridines to generate functional open reading frames, many of which encode components of the mitochondrial respiratory chain. The roles of numerous non-enzymatic editing factors have remained opaque given the limitations of conventional methods to interrogate the order and mechanism by which editing progresses and thus roles of individual proteins. Here, we examined whole populations of partially edited sequences using high throughput sequencing and a novel bioinformatic platform, the Trypanosome RNA Editing Alignment Tool (TREAT), to elucidate the roles of three proteins in the RNA Editing Mediator Complex (REMC). We determined that the factors examined function in the progression of editing through a gRNA; however, they have distinct roles and REMC is likely heterogeneous in composition. We provide the first evidence that editing can proceed through numerous paths within a single gRNA and that non-linear modifications are essential, generating commonly observed junction regions. Our data support a model in which RNA editing is executed via multiple paths that necessitate successive re-modification of junction regions facilitated, in part, by the REMC variant containing TbRGG2 and MRB8180. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

Distinct roles for Ste20-like kinase SLK in muscle function and regeneration

PubMed Central

2013-01-01

Background Cell growth and terminal differentiation are controlled by complex signaling systems that regulate the tissue-specific expression of genes controlling cell fate and morphogenesis. We have previously reported that the Ste20-like kinase SLK is expressed in muscle tissue and is required for cell motility. However, the specific function of SLK in muscle tissue is still poorly understood. Methods To gain further insights into the role of SLK in differentiated muscles, we expressed a kinase-inactive SLK from the human skeletal muscle actin promoter. Transgenic muscles were surveyed for potential defects. Standard histological procedures and cardiotoxin-induced regeneration assays we used to investigate the role of SLK in myogenesis and muscle repair. Results High levels of kinase-inactive SLK in muscle tissue produced an overall decrease in SLK activity in muscle tissue, resulting in altered muscle organization, reduced litter sizes, and reduced breeding capacity. The transgenic mice did not show any differences in fiber-type distribution but displayed enhanced regeneration capacity in vivo and more robust differentiation in vitro. Conclusions Our results show that SLK activity is required for optimal muscle development in the embryo and muscle physiology in the adult. However, reduced kinase activity during muscle repair enhances regeneration and differentiation. Together, these results suggest complex and distinct roles for SLK in muscle development and function. PMID:23815977

The role of adult hippocampal neurogenesis in brain health and disease.

PubMed

Toda, Tomohisa; Parylak, Sarah L; Linker, Sara B; Gage, Fred H

2018-04-20

Adult neurogenesis in the dentate gyrus of the hippocampus is highly regulated by a number of environmental and cell-intrinsic factors to adapt to environmental changes. Accumulating evidence suggests that adult-born neurons may play distinct physiological roles in hippocampus-dependent functions, such as memory encoding and mood regulation. In addition, several brain diseases, such as neurological diseases and mood disorders, have deleterious effects on adult hippocampal neurogenesis, and some symptoms of those diseases can be partially explained by the dysregulation of adult hippocampal neurogenesis. Here we review a possible link between the physiological functions of adult-born neurons and their roles in pathological conditions.

Cycling with BRCA2 from DNA repair to mitosis

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

Lee, Hyunsook, E-mail: HL212@snu.ac.kr

Genetic integrity in proliferating cells is guaranteed by the harmony of DNA replication, appropriate DNA repair, and segregation of the duplicated genome. Breast cancer susceptibility gene BRCA2 is a unique tumor suppressor that is involved in all three processes. Hence, it is critical in genome maintenance. The functions of BRCA2 in DNA repair and homology-directed recombination (HDR) have been reviewed numerous times. Here, I will briefly go through the functions of BRCA2 in HDR and focus on the emerging roles of BRCA2 in telomere homeostasis and mitosis, then discuss how BRCA2 exerts distinct functions in a cell-cycle specific manner inmore » the maintenance of genomic integrity. - Highlights: • BRCA2 is a multifaceted tumor suppressor and is crucial in genetic integrity. • BRCA2 exerts distinct functions in cell cycle-specific manner. • Mitotic kinases regulate diverse functions of BRCA2 in mitosis and cytokinesis.« less

Cellular and Synaptic Properties of Local Inhibitory Circuits.

PubMed

Hull, Court

2017-05-01

Inhibitory interneurons play a key role in sculpting the information processed by neural circuits. Despite the wide range of physiologically and morphologically distinct types of interneurons that have been identified, common principles have emerged that have shed light on how synaptic inhibition operates, both mechanistically and functionally, across cell types and circuits. This introduction summarizes how electrophysiological approaches have been used to illuminate these key principles, including basic interneuron circuit motifs, the functional properties of inhibitory synapses, and the main roles for synaptic inhibition in regulating neural circuit function. It also highlights how some key electrophysiological methods and experiments have advanced our understanding of inhibitory synapse function. © 2017 Cold Spring Harbor Laboratory Press.

Evolutionary Algorithms for Boolean Functions in Diverse Domains of Cryptography.

PubMed

Picek, Stjepan; Carlet, Claude; Guilley, Sylvain; Miller, Julian F; Jakobovic, Domagoj

2016-01-01

The role of Boolean functions is prominent in several areas including cryptography, sequences, and coding theory. Therefore, various methods for the construction of Boolean functions with desired properties are of direct interest. New motivations on the role of Boolean functions in cryptography with attendant new properties have emerged over the years. There are still many combinations of design criteria left unexplored and in this matter evolutionary computation can play a distinct role. This article concentrates on two scenarios for the use of Boolean functions in cryptography. The first uses Boolean functions as the source of the nonlinearity in filter and combiner generators. Although relatively well explored using evolutionary algorithms, it still presents an interesting goal in terms of the practical sizes of Boolean functions. The second scenario appeared rather recently where the objective is to find Boolean functions that have various orders of the correlation immunity and minimal Hamming weight. In both these scenarios we see that evolutionary algorithms are able to find high-quality solutions where genetic programming performs the best.

Distinct roles for Arp2/3 regulators in actin assembly and endocytosis.

PubMed

Galletta, Brian J; Chuang, Dennis Y; Cooper, John A

2008-01-01

The Arp2/3 complex is essential for actin assembly and motility in many cell processes, and a large number of proteins have been found to bind and regulate it in vitro. A critical challenge is to understand the actions of these proteins in cells, especially in settings where multiple regulators are present. In a systematic study of the sequential multicomponent actin assembly processes that accompany endocytosis in yeast, we examined and compared the roles of WASp, two type-I myosins, and two other Arp2/3 activators, along with that of coronin, which is a proposed inhibitor of Arp2/3. Quantitative analysis of high-speed fluorescence imaging revealed individual functions for the regulators, manifested in part by novel phenotypes. We conclude that Arp2/3 regulators have distinct and overlapping roles in the processes of actin assembly that drive endocytosis in yeast. The formation of the endocytic actin patch, the creation of the endocytic vesicle, and the movement of the vesicle into the cytoplasm display distinct dependencies on different Arp2/3 regulators. Knowledge of these roles provides insight into the in vivo relevance of the dendritic nucleation model for actin assembly.

Unified thalamic model generates multiple distinct oscillations with state-dependent entrainment by stimulation

PubMed Central

2017-01-01

The thalamus plays a critical role in the genesis of thalamocortical oscillations, yet the underlying mechanisms remain elusive. To understand whether the isolated thalamus can generate multiple distinct oscillations, we developed a biophysical thalamic model to test the hypothesis that generation of and transition between distinct thalamic oscillations can be explained as a function of neuromodulation by acetylcholine (ACh) and norepinephrine (NE) and afferent synaptic excitation. Indeed, the model exhibited four distinct thalamic rhythms (delta, sleep spindle, alpha and gamma oscillations) that span the physiological states corresponding to different arousal levels from deep sleep to focused attention. Our simulation results indicate that generation of these distinct thalamic oscillations is a result of both intrinsic oscillatory cellular properties and specific network connectivity patterns. We then systematically varied the ACh/NE and input levels to generate a complete map of the different oscillatory states and their transitions. Lastly, we applied periodic stimulation to the thalamic network and found that entrainment of thalamic oscillations is highly state-dependent. Our results support the hypothesis that ACh/NE modulation and afferent excitation define thalamic oscillatory states and their response to brain stimulation. Our model proposes a broader and more central role of the thalamus in the genesis of multiple distinct thalamo-cortical rhythms than previously assumed. PMID:29073146

Functional dissection of the paired domain of Pax6 reveals molecular mechanisms of coordinating neurogenesis and proliferation

PubMed Central

Walcher, Tessa; Xie, Qing; Sun, Jian; Irmler, Martin; Beckers, Johannes; Öztürk, Timucin; Niessing, Dierk; Stoykova, Anastassia; Cvekl, Ales; Ninkovic, Jovica; Götz, Magdalena

2013-01-01

To achieve adequate organ development and size, cell proliferation and differentiation have to be tightly regulated and coordinated. The transcription factor Pax6 regulates patterning, neurogenesis and proliferation in forebrain development. The molecular basis of this regulation is not well understood. As the bipartite DNA-binding paired domain of Pax6 regulates forebrain development, we examined mice with point mutations in its individual DNA-binding subdomains PAI (Pax6Leca4, N50K) and RED (Pax6Leca2, R128C). This revealed distinct roles in regulating proliferation in the developing cerebral cortex, with the PAI and RED subdomain mutations reducing and increasing, respectively, the number of mitoses. Conversely, neurogenesis was affected only by the PAI subdomain mutation, phenocopying the neurogenic defects observed in full Pax6 mutants. Genome-wide expression profiling identified molecularly discrete signatures of Pax6Leca4 and Pax6Leca2 mutations. Comparison to Pax6 targets identified by chromatin immunoprecipitation led to the identification and functional characterization of distinct DNA motifs in the promoters of target genes dysregulated in the Pax6Leca2 or Pax6Leca4 mutants, further supporting the distinct regulatory functions of the DNA-binding subdomains. Thus, Pax6 achieves its key roles in the developing forebrain by utilizing particular subdomains to coordinate patterning, neurogenesis and proliferation simultaneously. PMID:23404109

Complement factor H family proteins in their non-canonical role as modulators of cellular functions.

PubMed

Józsi, Mihály; Schneider, Andrea E; Kárpáti, Éva; Sándor, Noémi

2018-01-04

Complement factor H is a major regulator of the alternative pathway of the complement system. The factor H-related proteins are less characterized, but recent data indicate that they rather promote complement activation. These proteins have some common ligands with factor H and have both overlapping and distinct functions depending on domain composition and the degree of conservation of amino acid sequence. Factor H and some of the factor H-related proteins also appear in a non-canonical function that is beyond their role in the modulation of complement activation. This review covers our current understanding on this emerging role of factor H family proteins in modulating the activation and function of various cells by binding to receptors or receptor ligands. Copyright © 2018 Elsevier Ltd. All rights reserved.

Two distinct roles of the yorkie/yap gene during homeostasis in the planarian Dugesia japonica.

PubMed

Hwang, Byulnim; An, Yang; Agata, Kiyokazu; Umesono, Yoshihiko

2015-04-01

Adult planarians possess somatic pluripotent stem cells called neoblasts that give rise to all missing cell types during regeneration and homeostasis. Recent studies revealed that the Yorkie (Yki)/Yes-associated protein (YAP) transcriptional coactivator family plays an important role in the regulation of tissue growth during development and regeneration, and therefore we investigated the role of a planarian yki-related gene (termed Djyki) during regeneration and homeostasis of the freshwater planarian Dugesia japonica. We found that knockdown of the function of Djyki by RNA interference (RNAi) downregulated neoblast proliferation and caused regeneration defects after amputation. In addition, Djyki RNAi caused edema during homeostasis. These seemingly distinct defects induced by Djyki RNAi were rescued by simultaneous RNAi of a planarian mats-related gene (termed Djmats), suggesting an important role of Djmats in the negative regulation of Djyki, in accordance with the conservation of the functional relationship of these two genes during the course of evolution. Interestingly, Djyki RNAi did not prevent normal protonephridial structure, suggesting that Djyki RNAi induced the edema phenotype without affecting the excretory system. Further analyses revealed that increased expression of the D. japonica gene DjaquaporinA (DjaqpA), which belongs to a large gene family that encodes a water channel protein for the regulation of transcellular water flow, promoted the induction of edema, but not defects in neoblast dynamics, in Djyki(RNAi) animals. Thus, we conclude that Djyki plays two distinct roles in the regulation of active proliferation of stem cells and in osmotic water transport across the body surface in D. japonica. © 2015 The Authors Development, Growth & Differentiation published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Society of Developmental Biologists.

Telomere dysfunction and cell survival: roles for distinctTIN2-containing complexes

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

Kim, Sahn-Ho; Davalos, Albert R.; Heo, Seok-Jin

Telomeres are maintained by three DNA binding proteins, TRF1, TRF2 and POT1, and several associated factors. One factor, TIN2, binds TRF1 and TRF2 directly and POT1 indirectly. These and two other proteins form a soluble complex that may be the core telomere-maintenance complex. It is not clear whether subcomplexes exist or function in vivo. Here, we provide evidence for two TIN2 subcomplexes with distinct functions in human cells. TIN2 ablation by RNA interference caused telomere uncapping and p53-independent cell death in all cells tested. However, we isolated two TIN2 complexes from cell lysates, each selectively sensitive to a TIN2 mutantmore » (TIN2-13, TIN2-15C). In cells with wild-type p53 function, TIN2-15C was more potent than TIN2-13 in causing telomere uncapping and eventual growth arrest. In cells lacking p53 function, TIN215C more than TIN2-13 caused genomic instability and cell death. Thus, TIN2 subcomplexes likely have distinct functions in telomere maintenance, and may provide selective targets for eliminating cells with mutant p53.« less

Was Hercules Happy? Some Answers from a Functional Model of Human Well-Being

ERIC Educational Resources Information Center

Vitterso, Joar; Soholt, Yngvil; Hetland, Audun; Thoresen, Irina Alekseeva; Roysamb, Espen

2010-01-01

The article proposes a functional approach as a framework for the analysis of human well-being. The model posits that the adaptive role of hedonic feelings is to regulate stability and homeostasis in human systems, and that these feelings basically are created in states of equilibrium or assimilation. To regulate change and growth, a distinct set…

Chronic stress effects on working memory: association with prefrontal cortical tyrosine hydroxylase.

PubMed

Lee, Young-A; Goto, Yukiori

2015-06-01

Chronic stress causes deficits in cognitive function including working memory, for which transmission of such catecholamines as dopamine and noradrenaline transmission in the prefrontal cortex (PFC) are crucial. Since catecholamine synthesis depends on the rate-limiting enzyme, tyrosine hydroxylase (TH), TH is thought to play an important role in PFC function. In this study, we found that two distinct population existed in Sprague-Dawley rats in terms of working memory capacity, one with higher working memory capacity, and the other with low capacity. This distinction of working memory capacity became apparent after rats were exposed to chronic stress. In addition, such working memory capacity and alterations of working memory function by chronic stress were associated with TH expression in the PFC. Copyright © 2015 Elsevier B.V. All rights reserved.

The Emerging Role of Epigenetics in Inflammation and Immunometabolism.

PubMed

Raghuraman, Sukanya; Donkin, Ida; Versteyhe, Soetkin; Barrès, Romain; Simar, David

2016-11-01

Recent research developments have shed light on the risk factors contributing to metabolic complications, implicating both genetic and environmental factors, potentially integrated by epigenetic mechanisms. Distinct epigenetic changes in immune cells are frequently observed in obesity and type 2 diabetes mellitus, and these are associated with alterations in the phenotype, function, and trafficking patterns of these cells. The first step in the development of effective therapeutic strategies is the identification of distinct epigenetic signatures associated with metabolic disorders. In this review we provide an overview of the epigenetic mechanisms influencing immune cell phenotype and function, summarize current knowledge about epigenetic changes affecting immune functions in the context of metabolic diseases, and discuss the therapeutic options currently available to counteract epigenetically driven metabolic complications. Copyright © 2016 Elsevier Ltd. All rights reserved.

PMS2 endonuclease activity has distinct biological functions and is essential for genome maintenance

PubMed Central

van Oers, Johanna M. M.; Roa, Sergio; Werling, Uwe; Liu, Yiyong; Genschel, Jochen; Sellers, Rani S.; Modrich, Paul; Scharff, Matthew D.; Edelmann, Winfried

2010-01-01

The DNA mismatch repair protein PMS2 was recently found to encode a novel endonuclease activity. To determine the biological functions of this activity in mammals, we generated endonuclease-deficient Pms2E702K knock-in mice. Pms2EK/EK mice displayed increased genomic mutation rates and a strong cancer predisposition. In addition, class switch recombination, but not somatic hypermutation, was impaired in Pms2EK/EK B cells, indicating a specific role in Ig diversity. In contrast to Pms2−/− mice, Pms2EK/EK male mice were fertile, indicating that this activity is dispensable in spermatogenesis. Therefore, the PMS2 endonuclease activity has distinct biological functions and is essential for genome maintenance and tumor suppression. PMID:20624957

Dissociable Roles of Right Inferior Frontal Cortex and Anterior Insula in Inhibitory Control: Evidence from Intrinsic and Task-Related Functional Parcellation, Connectivity, and Response Profile Analyses across Multiple Datasets

PubMed Central

Ryali, Srikanth; Chen, Tianwen; Li, Chiang-Shan R.

2014-01-01

The right inferior frontal cortex (rIFC) and the right anterior insula (rAI) have been implicated consistently in inhibitory control, but their differential roles are poorly understood. Here we use multiple quantitative techniques to dissociate the functional organization and roles of the rAI and rIFC. We first conducted a meta-analysis of 70 published inhibitory control studies to generate a commonly activated right fronto-opercular cortex volume of interest (VOI). We then segmented this VOI using two types of features: (1) intrinsic brain activity; and (2) stop-signal task-evoked hemodynamic response profiles. In both cases, segmentation algorithms identified two stable and distinct clusters encompassing the rAI and rIFC. The rAI and rIFC clusters exhibited several distinct functional characteristics. First, the rAI showed stronger intrinsic and task-evoked functional connectivity with the anterior cingulate cortex, whereas the rIFC had stronger intrinsic and task-evoked functional connectivity with dorsomedial prefrontal and lateral fronto-parietal cortices. Second, the rAI showed greater activation than the rIFC during Unsuccessful, but not Successful, Stop trials, and multivoxel response profiles in the rAI, but not the rIFC, accurately differentiated between Successful and Unsuccessful Stop trials. Third, activation in the rIFC, but not rAI, predicted individual differences in inhibitory control abilities. Crucially, these findings were replicated in two independent cohorts of human participants. Together, our findings provide novel quantitative evidence for the dissociable roles of the rAI and rIFC in inhibitory control. We suggest that the rAI is particularly important for detecting behaviorally salient events, whereas the rIFC is more involved in implementing inhibitory control. PMID:25355218

Segregated cholinergic transmission modulates dopamine neurons integrated in distinct functional circuits.

PubMed

Dautan, Daniel; Souza, Albert S; Huerta-Ocampo, Icnelia; Valencia, Miguel; Assous, Maxime; Witten, Ilana B; Deisseroth, Karl; Tepper, James M; Bolam, J Paul; Gerdjikov, Todor V; Mena-Segovia, Juan

2016-08-01

Dopamine neurons in the ventral tegmental area (VTA) receive cholinergic innervation from brainstem structures that are associated with either movement or reward. Whereas cholinergic neurons of the pedunculopontine nucleus (PPN) carry an associative/motor signal, those of the laterodorsal tegmental nucleus (LDT) convey limbic information. We used optogenetics and in vivo juxtacellular recording and labeling to examine the influence of brainstem cholinergic innervation of distinct neuronal subpopulations in the VTA. We found that LDT cholinergic axons selectively enhanced the bursting activity of mesolimbic dopamine neurons that were excited by aversive stimulation. In contrast, PPN cholinergic axons activated and changed the discharge properties of VTA neurons that were integrated in distinct functional circuits and were inhibited by aversive stimulation. Although both structures conveyed a reinforcing signal, they had opposite roles in locomotion. Our results demonstrate that two modes of cholinergic transmission operate in the VTA and segregate the neurons involved in different reward circuits.

Motoring through: the role of kinesin superfamily proteins in female meiosis.

PubMed

Camlin, Nicole J; McLaughlin, Eileen A; Holt, Janet E

2017-07-01

The kinesin motor protein family consists of 14 distinct subclasses and 45 kinesin proteins in humans. A large number of these proteins, or their orthologues, have been shown to possess essential function(s) in both the mitotic and the meiotic cell cycle. Kinesins have important roles in chromosome separation, microtubule dynamics, spindle formation, cytokinesis and cell cycle progression. This article contains a review of the literature with respect to the role of kinesin motor proteins in female meiosis in model species. Throughout, we discuss the function of each class of kinesin proteins during oocyte meiosis, and where such data are not available their role in mitosis is considered. Finally, the review highlights the potential clinical importance of this family of proteins for human oocyte quality. To examine the role of kinesin motor proteins in oocyte meiosis. A search was performed on the Pubmed database for journal articles published between January 1970 and February 2017. Search terms included 'oocyte kinesin' and 'meiosis kinesin' in addition to individual kinesin names with the terms oocyte or meiosis. Within human cells 45 kinesin motor proteins have been discovered, with the role of only 13 of these proteins, or their orthologues, investigated in female meiosis. Furthermore, of these kinesins only half have been examined in mammalian oocytes, despite alterations occurring in gene transcripts or protein expression with maternal ageing, cryopreservation or behavioral conditions, such as binge drinking, for many of them. Kinesin motor proteins have distinct and important roles throughout oocyte meiosis in many non-mammalian model species. However, the functions these proteins have in mammalian meiosis, particularly in humans, are less clear owing to lack of research. This review brings to light the need for more experimental investigation of kinesin motor proteins, particularly those associated with maternal ageing, cryopreservation or exposure to environmental toxicants. © The Author 2017. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com

Msx-1 and Msx-2 in mammary gland development.

PubMed

Satoh, Kennichi; Ginsburg, Erika; Vonderhaar, Barbara K

2004-04-01

Homeobox genes do not generally function alone to determine cell fate and morphogenesis. Rather it is the distinct combination of various members of the homeobox family of genes and their spatiotemporal patterns of expression that determine cell identity and function. Functional redundancy often makes it difficult to clearly discern the role of any one given homeobox gene. The roles that Msx1 and Msx2 play in branching morphogenesis of the mammary gland are only now becoming more evident. Many signaling pathways and transcription factors are implicated in how these homeobox genes correctly determine the morphological development of the gland. Overexpression of Msx1 and Msx2 may also be involved in tumorigenesis. Additional studies are needed to elucidate the roles of these genes in both breast development and cancer.

Distinct taxonomic and functional composition of soil microbiomes along the gradient forest-restinga-mangrove in southeastern Brazil.

PubMed

Mendes, Lucas William; Tsai, Siu Mui

2018-01-01

Soil microorganisms play crucial roles in ecosystem functioning, and the central goal in microbial ecology studies is to elucidate which factors shape community structure. A better understanding of the relationship between microbial diversity, functions and environmental parameters would increase our ability to set conservation priorities. Here, the bacterial and archaeal community structure in Atlantic Forest, restinga and mangrove soils was described and compared based on shotgun metagenomics. We hypothesized that each distinct site would harbor a distinct taxonomic and functional soil community, which is influenced by environmental parameters. Our data showed that the microbiome is shaped by soil properties, with pH, base saturation, boron and iron content significantly correlated to overall community structure. When data of specific phyla were correlated to specific soil properties, we demonstrated that parameters such as boron, copper, sulfur, potassium and aluminum presented significant correlation with the most number of bacterial groups. Mangrove soil was the most distinct site and presented the highest taxonomic and functional diversity in comparison with forest and restinga soils. From the total 34 microbial phyla identified, 14 were overrepresented in mangrove soils, including several archaeal groups. Mangrove soils hosted a high abundance of sequences related to replication, survival and adaptation; forest soils included high numbers of sequences related to the metabolism of nutrients and other composts; while restinga soils included abundant genes related to the metabolism of carbohydrates. Overall, our finds show that the microbial community structure and functional potential were clearly different across the environmental gradient, followed by functional adaptation and both were related to the soil properties.

Hsp40 function in yeast prion propagation: Amyloid diversity necessitates chaperone functional complexity.

PubMed

Sporn, Zachary A; Hines, Justin K

2015-01-01

Yeast prions are heritable protein-based elements, most of which are formed of amyloid aggregates that rely on the action of molecular chaperones for transmission to progeny. Prions can form distinct amyloid structures, known as 'strains' in mammalian systems, that dictate both pathological progression and cross-species infection barriers. In yeast these same amyloid structural polymorphisms, called 'variants', dictate the intensity of prion-associated phenotypes and stability in mitosis. We recently reported that [PSI(+)] prion variants differ in the fundamental domain requirements for one chaperone, the Hsp40/J-protein Sis1, which are mutually exclusive between 2 different yeast prions, demonstrating a functional plurality for Sis1. Here we extend that analysis to incorporate additional data that collectively support the hypothesis that Sis1 has multiple functional roles that can be accomplished by distinct sets of domains. These functions are differentially required by distinct prions and prion variants. We also present new data regarding Hsp104-mediated prion elimination and show that some Sis1 functions, but not all, are conserved in the human homolog Hdj1/DNAJB1. Importantly, of the 10 amyloid-based prions indentified to date in Saccharomyces cerevisiae, the chaperone requirements of only 4 are known, leaving a great diversity of amyloid structures, and likely modes of amyloid-chaperone interaction, largely unexplored.

Replication-coupled chromatin assembly of newly synthesized histones: distinct functions for the histone tail domains.

PubMed

Ejlassi-Lassallette, Aïda; Thiriet, Christophe

2012-02-01

The maintenance of the genome during replication requires the assembly of nucleosomes with newly synthesized histones. Achieving the deposition of newly synthesized histones in chromatin implies their transport from the cytoplasm to the nucleus at the replication sites. Several lines of evidence have revealed critical functions of the histone tail domains in these conserved cellular processes. In this review, we discuss the role of the amino termini of the nucleosome building blocks, H2A/H2B and H3/H4, in different model systems. The experimental data showed that H2A/H2B tails and H3/H4 tails display distinct functions in nuclear import and chromatin assembly. Furthermore, we describe recent studies exploiting the unique properties of the slime mold, Physarum polycephalum , that have advanced understanding of the function of the highly conserved replication-dependent diacetylation of H4.

Understanding and Communicating through Narratives

DTIC Science & Technology

2012-05-17

distinctions, and may affect the fundamental contents of personal identity . It comes as no surprise that because of these influences stories are...activists.”16 Narrative serves an inherently strategic role, it serves as living embodiment of identity and ideology at personal, organizational, and as...applied by Freeman, national level. This identity function is one of the most critical functions of narrative. The logic expressed by the identity

Comparative Oncogenomics for Peripheral Nerve Sheath Cancer Gene Discovery

DTIC Science & Technology

2015-06-01

neurofibromas and MPNSTs, establish gene signatures defining distinct tumor subtypes and functionally test the role of selected driver mutations ...allografted tumor cells, and a variety of in vitro functional assays. We will validate the relevance of these mutated mouse genes in human neurofibromas...and MPNSTs by determining whether these same genes are mutated in human tumors. 15. SUBJECT TERMS Nothing listed 16. SECURITY CLASSIFICATION OF: 17

Conceptualizing the Adventure-Sports Coach

ERIC Educational Resources Information Center

Collins, Loel; Collins, Dave

2012-01-01

As a comparatively recent development, the adventure-sports coach struggles for a clear and distinct identity. The generic term "instructor" no longer characterizes the role and function of this subgroup of outdoor professionals. Indeed, although the fields of adventure/outdoor education and leadership are comparatively well researched,…

Entorhinal Cortical Ocean Cells Encode Specific Contexts and Drive Context-Specific Fear Memory

PubMed Central

Kitamura, Takashi; Sun, Chen; Martin, Jared; Kitch, Lacey J; Schnitzer, Mark J; Tonegawa, Susumu

2016-01-01

Summary Forming distinct representations and memories of multiple contexts and episodes is thought to be a crucial function of the hippocampal-entorhinal cortical network. The hippocampal dentate gyrus (DG) and CA3 are known to contribute to these functions but the role of the entorhinal cortex (EC) is poorly understood. Here, we show that Ocean cells, excitatory stellate neurons in the medial EC layer II projecting into DG and CA3, rapidly form a distinct representation of a novel context and drive context-specific activation of downstream CA3 cells as well as context-specific fear memory. In contrast, Island cells, excitatory pyramidal neurons in the medial EC layer II projecting into CA1, are indifferent to context-specific encoding or memory. On the other hand, Ocean cells are dispensable for temporal association learning, for which Island cells are crucial. Together, the two excitatory medial EC layer II inputs to the hippocampus have complementary roles in episodic memory. PMID:26402611

dsRNA binding properties of RDE-4 and TRBP reflect their distinct roles in RNAi

PubMed Central

Parker, Greg S.; Maity, Tuhin Subhra; Bass, Brenda L.

2008-01-01

SUMMARY dsRNA binding proteins (dsRBPs) facilitate Dicer functions in RNAi. C. elegans RDE-4 facilitates cleavage of long dsRNA to siRNA, while human TRBP functions downstream to pass siRNA to RISC. We show that these distinct in vivo roles are reflected in in vitro binding properties. RDE-4 preferentially binds long dsRNA, while TRBP binds siRNA with an affinity that is independent of dsRNA length. These properties are mechanistically based in the fact that RDE-4 binds cooperatively, via contributions from multiple domains, while TRBP binds non-cooperatively. Our studies offer a paradigm for how dsRBPs, which are not sequence-specific, discern dsRNA length. Additionally, analyses of the ability of RDE-4 deletion constructs and RDE-4/TRBP chimeras to reconstitute Dicer activity suggest RDE-4 promotes activity using its dsRBM2 to bind dsRNA, its linker region to interact with Dicer, and its C-terminus for Dicer activation. PMID:18948111

A regulatory governance perspective on health technology assessment (HTA) in France: the contextual mediation of common functional pressures.

PubMed

Barron, Anthony J G; Klinger, Corinna; Shah, Sara Mehmood Birchall; Wright, John S F

2015-02-01

The new regulatory governance perspective has introduced several insights to the study of health technology assessment (HTA): it has broadened the scope for the analysis of HTA; it has provided a more sophisticated account of national diversity and the potential for cross-border policy learning; and, it has dissolved the distinction between HTA assessment and appraisal processes. In this paper, we undertake a qualitative study of the French process for HTA with a view to introducing a fourth insight: that the emergence and continuing function of national agencies for HTA follows a broadly evolutionary pattern in which contextual factors play an important mediating role. We demonstrate that the French process for HTA is characterised by distinctive institutions, processes and evidential requirements. Consistent with the mediating role of this divergent policy context, we argue that even initiatives for the harmonisation of national approaches to HTA are likely to meet with divergent national policy responses. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Taxonomic and functional distinctness of the fish assemblages in three coastal environments (bays, coastal lagoons and oceanic beaches) in Southeastern Brazil.

PubMed

Azevedo, Márcia Cristina Costa; Gomes-Gonçalves, Rafaela de Sousa; Mattos, Tailan Moretti; Uehara, Wagner; Guedes, Gustavo Henrique Soares; Araújo, Francisco Gerson

2017-08-01

Several species of marine fish use different coastal systems especially during their early development. However, these habitats are jeopardized by anthropogenic influences threatening the success of fish populations, and urgent measures are needed to priorize areas to protect their sustainability. We applied taxonomic (Δ+) and functional (X+) distinctiveness indices that represent taxonomic composition and functional roles to assess biodiversity of three different costal systems: bays, coastal lagoons and oceanic beaches. We hypothesized that difference in habitat characteristics, especially in the more dynamism and habitat homogeneity of oceanic beaches compared with more habitat diversity and sheltered conditions of bays and coastal lagoons results in differences in fish richness and taxonomic and functional diversity. The main premise is that communities phylogenetically and functionally more distinct have more interest in conservation policies. Significant differences (P < 0.004) were found in the species richness, Δ+ and X+ among the three systems according to PERMANOVA. Fish richness was higher in bays compared with the coastal lagoons and oceanic beaches. Higher Δ+ was found for the coastal lagoons compared with the bays and oceanic beaches, with the bays having some values below the confidence limit. Similar patterns were found for X+, although all values were within the confidence limits for the bays, suggesting that the absence of some taxa does not interfere in functional diversity. The hypothesis that taxonomic and functional structure of fish assemblages differ among the three systems was accepted and we suggest that coastal lagoons should be priorized in conservation programs because they support more taxonomic and functional distinctiveness. Copyright © 2017 Elsevier Ltd. All rights reserved.

Phosphorylation of Synaptojanin Differentially Regulates Endocytosis of Functionally Distinct Synaptic Vesicle Pools.

PubMed

Geng, Junhua; Wang, Liping; Lee, Joo Yeun; Chen, Chun-Kan; Chang, Karen T

2016-08-24

The rapid replenishment of synaptic vesicles through endocytosis is crucial for sustaining synaptic transmission during intense neuronal activity. Synaptojanin (Synj), a phosphoinositide phosphatase, is known to play an important role in vesicle recycling by promoting the uncoating of clathrin following synaptic vesicle uptake. Synj has been shown to be a substrate of the minibrain (Mnb) kinase, a fly homolog of the dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A); however, the functional impacts of Synj phosphorylation by Mnb are not well understood. Here we identify that Mnb phosphorylates Synj at S1029 in Drosophila We find that phosphorylation of Synj at S1029 enhances Synj phosphatase activity, alters interaction between Synj and endophilin, and promotes efficient endocytosis of the active cycling vesicle pool (also referred to as exo-endo cycling pool) at the expense of reserve pool vesicle endocytosis. Dephosphorylated Synj, on the other hand, is deficient in the endocytosis of the active recycling pool vesicles but maintains reserve pool vesicle endocytosis to restore total vesicle pool size and sustain synaptic transmission. Together, our findings reveal a novel role for Synj in modulating reserve pool vesicle endocytosis and further indicate that dynamic phosphorylation and dephosphorylation of Synj differentially maintain endocytosis of distinct functional synaptic vesicle pools. Synaptic vesicle endocytosis sustains communication between neurons during a wide range of neuronal activities by recycling used vesicle membrane and protein components. Here we identify that Synaptojanin, a protein with a known role in synaptic vesicle endocytosis, is phosphorylated at S1029 in vivo by the Minibrain kinase. We further demonstrate that the phosphorylation status of Synaptojanin at S1029 differentially regulates its participation in the recycling of distinct synaptic vesicle pools. Our results reveal a new role for Synaptojanin in maintaining synaptic vesicle pool size and in reserve vesicle endocytosis. As Synaptojanin and Minibrain perturbations are associated with various neurological disorders, such as Parkinson's, autism, and Down syndrome, understanding mechanisms modulating Synaptojanin function provides valuable insights into processes affecting neuronal communication. Copyright © 2016 the authors 0270-6474/16/368882-13$15.00/0.

Phosphorylation of Synaptojanin Differentially Regulates Endocytosis of Functionally Distinct Synaptic Vesicle Pools

PubMed Central

Geng, Junhua; Wang, Liping; Lee, Joo Yeun; Chen, Chun-Kan

2016-01-01

The rapid replenishment of synaptic vesicles through endocytosis is crucial for sustaining synaptic transmission during intense neuronal activity. Synaptojanin (Synj), a phosphoinositide phosphatase, is known to play an important role in vesicle recycling by promoting the uncoating of clathrin following synaptic vesicle uptake. Synj has been shown to be a substrate of the minibrain (Mnb) kinase, a fly homolog of the dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A); however, the functional impacts of Synj phosphorylation by Mnb are not well understood. Here we identify that Mnb phosphorylates Synj at S1029 in Drosophila. We find that phosphorylation of Synj at S1029 enhances Synj phosphatase activity, alters interaction between Synj and endophilin, and promotes efficient endocytosis of the active cycling vesicle pool (also referred to as exo-endo cycling pool) at the expense of reserve pool vesicle endocytosis. Dephosphorylated Synj, on the other hand, is deficient in the endocytosis of the active recycling pool vesicles but maintains reserve pool vesicle endocytosis to restore total vesicle pool size and sustain synaptic transmission. Together, our findings reveal a novel role for Synj in modulating reserve pool vesicle endocytosis and further indicate that dynamic phosphorylation and dephosphorylation of Synj differentially maintain endocytosis of distinct functional synaptic vesicle pools. SIGNIFICANCE STATEMENT Synaptic vesicle endocytosis sustains communication between neurons during a wide range of neuronal activities by recycling used vesicle membrane and protein components. Here we identify that Synaptojanin, a protein with a known role in synaptic vesicle endocytosis, is phosphorylated at S1029 in vivo by the Minibrain kinase. We further demonstrate that the phosphorylation status of Synaptojanin at S1029 differentially regulates its participation in the recycling of distinct synaptic vesicle pools. Our results reveal a new role for Synaptojanin in maintaining synaptic vesicle pool size and in reserve vesicle endocytosis. As Synaptojanin and Minibrain perturbations are associated with various neurological disorders, such as Parkinson's, autism, and Down syndrome, understanding mechanisms modulating Synaptojanin function provides valuable insights into processes affecting neuronal communication. PMID:27559170

The endothelin pathway: a protective or detrimental target of bardoxolone methyl on cardiac function in patients with advanced chronic kidney disease?

PubMed

Camer, Danielle; Huang, Xu-Feng

2014-01-01

Bardoxolone methyl has been reported to cause detrimental cardiovascular events in the terminated BEACON Phase III human clinical trial via modulation of the renal endothelin pathway. However, the effects of bardoxolone methyl administration on the endothelin pathway in the heart are unknown. Our purpose in this perspective is to highlight the distinctive opposing roles of the renal and heart endothelin pathway in cardiac function. Furthermore, we address the need for further investigation in order to determine if bardoxolone methyl has a protective role in cardiac function through the suppression of the endothelin pathway in the heart. © 2014 S. Karger AG, Basel.

Role of dorsolateral periaqueductal grey in the coordinated regulation of cardiovascular and respiratory function.

PubMed

Dampney, Roger A L; Furlong, Teri M; Horiuchi, Jouji; Iigaya, Kamon

2013-04-01

The midbrain periaqueductal grey (PAG) contains four longitudinal columns, referred to as the dorsomedial (dmPAG), dorsolateral (dlPAG), lateral (lPAG) and ventrolateral (vlPAG) subdivisions, which collectively have a pivotal role in integrating behavioural and physiological responses to external stressors as well as other functions. This review is focussed on the dlPAG, which is believed to be an important component of the central mechanisms that generate the defensive response to acute psychological stressors, such as the presence of a predator or other immediate threat. The anatomical connections of the dlPAG are highly specific and distinctly different from those of the other PAG subregions. The chemical properties of the dlPAG are also distinctly different from the other PAG subregions (e.g. there is a very high density of neurons that synthesize nitric oxide in the dlPAG but very few such neurons in the other PAG subregions). Recent functional studies have demonstrated that neurons in the dlPAG exert a powerful control over both sympathetic and respiratory activity, and that the pattern of the evoked respiratory changes is also distinctly different from those evoked from other PAG subregions. These studies also showed that the sympathetic and respiratory changes evoked from the dlPAG are highly correlated, suggesting the possibility that a common population of "command neurons" within this region may generate the sympathetic and respiratory changes that accompany defensive behavioural responses to acute psychological stressors. Finally, although the anatomical connections and functional properties of the dlPAG are distinctly different from the other PAG subregions, they have many similarities with adjacent parts of the superior colliculus, suggesting that the dlPAG and deep layers of the superior colliculus may be part of a common defence system in the midbrain. Copyright © 2013 Elsevier B.V. All rights reserved.

Neurotrophin signaling and visceral hypersensitivity.

PubMed

Qiao, Li-Ya

2014-06-01

Neurotrophin family are traditionally recognized for their nerve growth promoting function and are recently identified as crucial factors in regulating neuronal activity in the central and peripheral nervous systems. The family members including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3) are reported to have distinct roles in the development and maintenance of sensory phenotypes in normal states and in the modulation of sensory activity in disease. This paper highlights receptor tyrosine kinase (Trk) -mediated signal transduction by which neurotrophins regulate neuronal activity in the visceral sensory reflex pathways with emphasis on the distinct roles of NGF and BDNF signaling in physiologic and pathophysiological processes. Viscero-visceral cross-organ sensitization exists widely in human diseases. The role of neurotrophins in mediating neural cross talk and interaction in primary afferent neurons in the dorsal root ganglia (DRG) and neurotrophin signal transduction in the context of cross-organ sensitization are also discussed.

[Parietal Cortices and Body Information].

PubMed

Naito, Eiichi; Amemiya, Kaoru; Morita, Tomoyo

2016-11-01

Proprioceptive signals originating from skeletal muscles and joints contribute to the formation of both the human body schema and the body image. In this chapter, we introduce various types of bodily illusions that are elicited by proprioceptive inputs, and we discuss distinct functions implemented by different parietal cortices. First, we illustrate the primary importance of the motor network in the processing of proprioceptive (kinesthetic) signals originating from muscle spindles. Next, we argue that the right inferior parietal cortex, in concert with the inferior frontal cortex (both regions connected by the inferior branch of the superior longitudinal fasciculus-SLF III), may be involved in the conscious experience of body image. Further, we hypothesize other functions of distinct parietal regions: the association between internal hand motor representation with external object representation in the left inferior parietal cortex, visuo-kinesthetic processing in the bilateral posterior parietal cortices, and the integration of somatic signals from different body parts in the higher-order somatosensory parietal cortices. Our results indicate that a distinct parietal region, in concert with its anatomically and functionally connected frontal regions, probably plays specialized roles in the processing of body-related information.

Adipocyte Origins: Weighing the Possibilities

PubMed Central

Majka, Susan M.; Barak, Yaacov; Klemm, Dwight J.

2012-01-01

Adipose tissue is the primary energy reservoir in the body and an important endocrine organ that plays roles in energy homeostasis, feeding, insulin sensitivity and inflammation. While it was tacitly assumed that fat in different anatomical locations had a common origin and homogenous function, it is now clear that regional differences exist in adipose tissue characteristics and function. This is exemplified by the link between increased deep abdominal or visceral fat, but not peripheral adipose tissue, and the metabolic disturbances associated with obesity. Regional differences in fat function are due in large part to distinct adipocyte populations that comprise the different fat depots. Evidence accrued primarily in the last decade indicate that the distinct adipocyte populations are generated by a number of processes during and after development. These include the production of adipocytes from different germ cell layers, the formation of distinct preadipocyte populations from mesenchymal progenitors of mesodermal origin, and the production of adipocytes from hematopoietic stem cells from the bone marrow. This review will examine each of these process and their relevance to normal adipose tissue formation and contribution to obesity-related diseases. PMID:21544899

Functional diversification of hsp40: distinct j-protein functional requirements for two prions allow for chaperone-dependent prion selection.

PubMed

Harris, Julia M; Nguyen, Phil P; Patel, Milan J; Sporn, Zachary A; Hines, Justin K

2014-07-01

Yeast prions are heritable amyloid aggregates of functional yeast proteins; their propagation to subsequent cell generations is dependent upon fragmentation of prion protein aggregates by molecular chaperone proteins. Mounting evidence indicates the J-protein Sis1 may act as an amyloid specificity factor, recognizing prion and other amyloid aggregates and enabling Ssa and Hsp104 to act in prion fragmentation. Chaperone interactions with prions, however, can be affected by variations in amyloid-core structure resulting in distinct prion variants or 'strains'. Our genetic analysis revealed that Sis1 domain requirements by distinct variants of [PSI+] are strongly dependent upon overall variant stability. Notably, multiple strong [PSI+] variants can be maintained by a minimal construct of Sis1 consisting of only the J-domain and glycine/phenylalanine-rich (G/F) region that was previously shown to be sufficient for cell viability and [RNQ+] prion propagation. In contrast, weak [PSI+] variants are lost under the same conditions but maintained by the expression of an Sis1 construct that lacks only the G/F region and cannot support [RNQ+] propagation, revealing mutually exclusive requirements for Sis1 function between these two prions. Prion loss is not due to [PSI+]-dependent toxicity or dependent upon a particular yeast genetic background. These observations necessitate that Sis1 must have at least two distinct functional roles that individual prions differentially require for propagation and which are localized to the glycine-rich domains of the Sis1. Based on these distinctions, Sis1 plasmid-shuffling in a [PSI+]/[RNQ+] strain permitted J-protein-dependent prion selection for either prion. We also found that, despite an initial report to the contrary, the human homolog of Sis1, Hdj1, is capable of [PSI+] prion propagation in place of Sis1. This conservation of function is also prion-variant dependent, indicating that only one of the two Sis1-prion functions may have been maintained in eukaryotic chaperone evolution.

Functional Diversification of Hsp40: Distinct J-Protein Functional Requirements for Two Prions Allow for Chaperone-Dependent Prion Selection

PubMed Central

Patel, Milan J.; Sporn, Zachary A.; Hines, Justin K.

2014-01-01

Yeast prions are heritable amyloid aggregates of functional yeast proteins; their propagation to subsequent cell generations is dependent upon fragmentation of prion protein aggregates by molecular chaperone proteins. Mounting evidence indicates the J-protein Sis1 may act as an amyloid specificity factor, recognizing prion and other amyloid aggregates and enabling Ssa and Hsp104 to act in prion fragmentation. Chaperone interactions with prions, however, can be affected by variations in amyloid-core structure resulting in distinct prion variants or ‘strains’. Our genetic analysis revealed that Sis1 domain requirements by distinct variants of [PSI +] are strongly dependent upon overall variant stability. Notably, multiple strong [PSI +] variants can be maintained by a minimal construct of Sis1 consisting of only the J-domain and glycine/phenylalanine-rich (G/F) region that was previously shown to be sufficient for cell viability and [RNQ +] prion propagation. In contrast, weak [PSI +] variants are lost under the same conditions but maintained by the expression of an Sis1 construct that lacks only the G/F region and cannot support [RNQ +] propagation, revealing mutually exclusive requirements for Sis1 function between these two prions. Prion loss is not due to [PSI +]-dependent toxicity or dependent upon a particular yeast genetic background. These observations necessitate that Sis1 must have at least two distinct functional roles that individual prions differentially require for propagation and which are localized to the glycine-rich domains of the Sis1. Based on these distinctions, Sis1 plasmid-shuffling in a [PSI +]/[RNQ +] strain permitted J-protein-dependent prion selection for either prion. We also found that, despite an initial report to the contrary, the human homolog of Sis1, Hdj1, is capable of [PSI +] prion propagation in place of Sis1. This conservation of function is also prion-variant dependent, indicating that only one of the two Sis1-prion functions may have been maintained in eukaryotic chaperone evolution. PMID:25058638

Integration of Spectral Reflectance across the Plumage: Implications for Mating Patterns

PubMed Central

Laczi, Miklós; Török, János; Rosivall, Balázs; Hegyi, Gergely

2011-01-01

Background In complex sexual signaling systems such as plumage color, developmental or genetic links may occur among seemingly distinct traits. However, the interrelations of such traits and the functional significance of their integration rarely have been examined. Methodology/Principal Findings We investigated the parallel variation of two reflectance descriptors (brightness and UV chroma) across depigmented and melanized plumage areas of collared flycatchers (Ficedula albicollis), and the possible role of integrated color signals in mate acquisition. We found moderate integration in brightness and UV chroma across the plumage, with similar correlation structures in the two sexes despite the strong sexual dichromatism. Patterns of parallel color change across the plumage were largely unrelated to ornamental white patch sizes, but they all showed strong assortative mating between the sexes. Comparing different types of assortative mating patterns for individual spectral variables suggested a distinct role for plumage-level color axes in mate acquisition. Conclusions/Significance Our results indicate that the plumage-level, parallel variation of coloration might play a role in mate acquisition. This study underlines the importance of considering potential developmental and functional integration among apparently different ornaments in studies of sexual selection. PMID:21853088

Roles of prostaglandin E2 in the cochlea.

PubMed

Nakagawa, Takayuki

2011-06-01

Prostaglandins are one of the major groups of chemical mediators in the mammalian body. Among prostaglandins, prostaglandin E2 (PGE2) is the most abundant prostanoid in humans and involved in regulating many different fundamental biological functions. PGE2 signaling is mediated by four distinct E-prostanoid receptors (EPs) namely EP1-4. Recently, accumulating evidence indicates critical, but complex roles of EP signaling in the pathogenesis of neuronal diseases depending on the context of neuronal injury. Four distinct EPs are expressed in the stria vascularis, spiral ligament, spiral ganglion and organ of Corti, indicating an involvement of EP signaling in the cochlear function. Activation of EP4 in cochleae significantly attenuates noise-induced damage in cochleae, and activation of EP2 or EP4 induces the formation of vascular endothelial growth factor in cochleae. These findings strongly suggest that individual EP signaling may be involved in the maintenance of the cochlear sensory system similarly to the central nervous system. This review highlights recent findings on EP signaling in the central nervous system, and presents its possible roles in regulation of blood flow, protection of sensory cells and immune responses in cochleae. Copyright © 2011 Elsevier B.V. All rights reserved.

The role of mitochondria in plant development and stress tolerance

USDA-ARS?s Scientific Manuscript database

Proper cellular function requires orchestrated communication among cellular compartments and the ability of the cell to sense and respond to its environment. Plant cells contain three distinct compartments that house DNA. The nucleus contains the nuclear genome, which provides a majority of a cell's...

Conservation of Dynamics Associated with Biological Function in an Enzyme Superfamily.

PubMed

Narayanan, Chitra; Bernard, David N; Bafna, Khushboo; Gagné, Donald; Chennubhotla, Chakra S; Doucet, Nicolas; Agarwal, Pratul K

2018-03-06

Enzyme superfamily members that share common chemical and/or biological functions also share common features. While the role of structure is well characterized, the link between enzyme function and dynamics is not well understood. We present a systematic characterization of intrinsic dynamics of over 20 members of the pancreatic-type RNase superfamily, which share a common structural fold. This study is motivated by the fact that the range of chemical activity as well as molecular motions of RNase homologs spans over 10 5 folds. Dynamics was characterized using a combination of nuclear magnetic resonance experiments and computer simulations. Phylogenetic clustering led to the grouping of sequences into functionally distinct subfamilies. Detailed characterization of the diverse RNases showed conserved dynamical traits for enzymes within subfamilies. These results suggest that selective pressure for the conservation of dynamical behavior, among other factors, may be linked to the distinct chemical and biological functions in an enzyme superfamily. Copyright © 2018 Elsevier Ltd. All rights reserved.

Adapting to stress - chaperome networks in cancer.

PubMed

Joshi, Suhasini; Wang, Tai; Araujo, Thaís L S; Sharma, Sahil; Brodsky, Jeffrey L; Chiosis, Gabriela

2018-05-23

In this Opinion article, we aim to address how cells adapt to stress and the repercussions chronic stress has on cellular function. We consider acute and chronic stress-induced changes at the cellular level, with a focus on a regulator of cellular stress, the chaperome, which is a protein assembly that encompasses molecular chaperones, co-chaperones and other co-factors. We discuss how the chaperome takes on distinct functions under conditions of stress that are executed in ways that differ from the one-on-one cyclic, dynamic functions exhibited by distinct molecular chaperones. We argue that through the formation of multimeric stable chaperome complexes, a state of chaperome hyperconnectivity, or networking, is gained. The role of these chaperome networks is to act as multimolecular scaffolds, a particularly important function in cancer, where they increase the efficacy and functional diversity of several cellular processes. We predict that these concepts will change how we develop and implement drugs targeting the chaperome to treat cancer.

Distinct and overlapping fMRI activation networks for processing of novel identities and locations of objects.

PubMed

Pihlajamäki, Maija; Tanila, Heikki; Könönen, Mervi; Hänninen, Tuomo; Aronen, Hannu J; Soininen, Hilkka

2005-10-01

The ventral visual stream processes information about the identity of objects ('what'), whereas the dorsal stream processes the spatial locations of objects ('where'). There is a corresponding, although disputed, distinction for the ventrolateral and dorsolateral prefrontal areas. Furthermore, there seems to be a distinction between the anterior and posterior medial temporal lobe (MTL) structures in the processing of novel items and new spatial arrangements, respectively. Functional differentiation of the intermediary mid-line cortical and temporal neocortical structures that communicate with the occipitotemporal, occipitoparietal, prefrontal, and MTL structures, however, is unclear. Therefore, in the present functional magnetic resonance imaging (fMRI) study, we examined whether the distinction among the MTL structures extends to these closely connected cortical areas. The most striking difference in the fMRI responses during visual presentation of changes in either items or their locations was the bilateral activation of the temporal lobe and ventrolateral prefrontal cortical areas for novel object identification in contrast to wide parietal and dorsolateral prefrontal activation for the novel locations of objects. An anterior-posterior distinction of fMRI responses similar to the MTL was observed in the cingulate/retrosplenial, and superior and middle temporal cortices. In addition to the distinct areas of activation, certain frontal, parietal, and temporo-occipital areas responded to both object and spatial novelty, suggesting a common attentional network for both types of changes in the visual environment. These findings offer new insights to the functional roles and intrinsic specialization of the cingulate/retrosplenial, and lateral temporal cortical areas in visuospatial cognition.

When ignorance is no excuse: Different roles for intent across moral domains.

PubMed

Young, Liane; Saxe, Rebecca

2011-08-01

A key factor in legal and moral judgments is intent. Intent differentiates, for instance, murder from manslaughter. Is this true for all moral judgments? People deliver moral judgments of many kinds of actions, including harmful actions (e.g., assault) and purity violations (e.g., incest, consuming taboo substances). We show that intent is a key factor for moral judgments of harm, but less of a factor for purity violations. Based on the agent's innocent intent, participants judged accidental harms less morally wrong than accidental incest; based on the agent's guilty intent, participants judged failed attempts to harm more morally wrong than failed attempts to commit incest. These patterns were specific to moral judgments versus judgments of the agent's control, knowledge, or intent, the action's overall emotional salience, or participants' ratings of disgust. The current results therefore reveal distinct cognitive signatures of distinct moral domains, and may inform the distinct functional roles of moral norms. Copyright © 2011 Elsevier B.V. All rights reserved.

Expression of the Diabetes-Associated Gene TCF7L2 in Adult Mouse Brain

PubMed Central

LEE, SYANN; LEE, CHARLOTTE E.; ELIAS, CAROL F.; ELMQUIST, JOEL K.

2014-01-01

Polymorphisms of the gene TCF7L2 (transcription factor 7-like 2) are strongly associated with the development and progression of type 2 diabetes. TCF7L2 is important in the development of peripheral organs such as adipocytes, pancreas, and the intestine. However, very little is known about its expression elsewhere. In this study we used in situ hybridization histochemistry to show that TCF7L2 has a unique expression pattern in the mouse brain. TCF7L2 is expressed in two distinct populations. First, it is highly ex pressed in thalamic and tectal structures. Additionally, TCF7L2 mRNA is expressed at moderate to low levels in specific cells of the hypothalamus, preoptic nucleus, and circumventricular organs. Collectively, these patterns of expression suggest that TCF7L2 has distinct functions within the brain, with a general role in the development and maintenance of thalamic and midbrain neurons, and then a distinct role in autonomic homeostasis. PMID:19845015

The Current Status of Somatostatin-Interneurons in Inhibitory Control of Brain Function and Plasticity

PubMed Central

2016-01-01

The mammalian neocortex contains many distinct inhibitory neuronal populations to balance excitatory neurotransmission. A correct excitation/inhibition equilibrium is crucial for normal brain development, functioning, and controlling lifelong cortical plasticity. Knowledge about how the inhibitory network contributes to brain plasticity however remains incomplete. Somatostatin- (SST-) interneurons constitute a large neocortical subpopulation of interneurons, next to parvalbumin- (PV-) and vasoactive intestinal peptide- (VIP-) interneurons. Unlike the extensively studied PV-interneurons, acknowledged as key components in guiding ocular dominance plasticity, the contribution of SST-interneurons is less understood. Nevertheless, SST-interneurons are ideally situated within cortical networks to integrate unimodal or cross-modal sensory information processing and therefore likely to be important mediators of experience-dependent plasticity. The lack of knowledge on SST-interneurons partially relates to the wide variety of distinct subpopulations present in the sensory neocortex. This review informs on those SST-subpopulations hitherto described based on anatomical, molecular, or electrophysiological characteristics and whose functional roles can be attributed based on specific cortical wiring patterns. A possible role for these subpopulations in experience-dependent plasticity will be discussed, emphasizing on learning-induced plasticity and on unimodal and cross-modal plasticity upon sensory loss. This knowledge will ultimately contribute to guide brain plasticity into well-defined directions to restore sensory function and promote lifelong learning. PMID:27403348

Intestinal Mononuclear Phagocytes in Health and Disease.

PubMed

Sanders, Theodore J; Yrlid, Ulf; Maloy, Kevin J

2017-01-01

The intestine is the tissue of the body with the highest constitutive exposure to foreign antigen and is also a common entry portal for many local and systemic pathogens. Therefore, the local immune system has the unenviable task of balancing efficient responses to dangerous pathogens with tolerance toward beneficial microbiota and food antigens. As in most tissues, the decision between tolerance and immunity is critically governed by the activity of local myeloid cells. However, the unique challenges posed by the intestinal environment have necessitated the development of several specialized mononuclear phagocyte populations with distinct phenotypic and functional characteristics that have vital roles in maintaining barrier function and immune homeostasis in the intestine. Intestinal mononuclear phagocyte populations, comprising dendritic cells and macrophages, are crucial for raising appropriate active immune responses against ingested pathogens. Recent technical advances, including microsurgical approaches allowing collection of cells migrating in intestinal lymph, intravital microscopy, and novel gene-targeting approaches, have led to clearer distinctions between mononuclear phagocyte populations in intestinal tissue. In this review, we present an overview of the various subpopulations of intestinal mononuclear phagocytes and discuss their phenotypic and functional characteristics. We also outline their roles in host protection from infection and their regulatory functions in maintaining immune tolerance toward beneficial intestinal antigens.

Sorting nexin 3 mutation impairs development and neuronal function in Caenorhabditis elegans.

PubMed

Vieira, Neide; Bessa, Carlos; Rodrigues, Ana J; Marques, Paulo; Chan, Fung-Yi; de Carvalho, Ana Xavier; Correia-Neves, Margarida; Sousa, Nuno

2018-06-01

The sorting nexins family of proteins (SNXs) plays pleiotropic functions in protein trafficking and intracellular signaling and has been associated with several disorders, namely Alzheimer's disease and Down's syndrome. Despite the growing association of SNXs with neurodegeneration, not much is known about their function in the nervous system. The aim of this work was to use the nematode Caenorhabditis elegans that encodes in its genome eight SNXs orthologs, to dissect the role of distinct SNXs, particularly in the nervous system. By screening the C. elegans SNXs deletion mutants for morphological, developmental and behavioral alterations, we show here that snx-3 gene mutation leads to an array of developmental defects, such as delayed hatching, decreased brood size and life span and reduced body length. Additionally, ∆snx-3 worms present increased susceptibility to osmotic, thermo and oxidative stress and distinct behavioral deficits, namely, a chemotaxis defect which is independent of the described snx-3 role in Wnt secretion. ∆snx-3 animals also display abnormal GABAergic neuronal architecture and wiring and altered AIY interneuron structure. Pan-neuronal expression of C. elegans snx-3 cDNA in the ∆snx-3 mutant is able to rescue its locomotion defects, as well as its chemotaxis toward isoamyl alcohol. Altogether, the present work provides the first in vivo evidence of the SNX-3 role in the nervous system.

Clinical signs of pancreatitis.

PubMed

Penny, Steven M

2012-01-01

The pancreas consists of complex structures that perform vital functions. Radiologic technologists must comprehend its normal structure and function to perform functional imaging procedures in their daily practice, as well as to know how any deviation from normalcy can disrupt homeostasis. Because pancreatitis is a potentially life-threatening disease, a thorough understanding of the clinical manifestation and imaging characteristics of the various forms of the disease is crucial. This article reviews distinctive pancreatic function and discusses basic pancreas imaging. In addition, acute and chronic pancreatitis is explored, including the role of medical imaging in its diagnosis, complications, and prognosis.

Computational Identification and Analysis of Signaling Subnetworks with Distinct Functional Roles in the Regulation of TNF Production

DTIC Science & Technology

2016-01-04

extract four distinct quantitative features of response timing and intensity: the trajectory peak height, the peak time, the area under the curve, and...J., 2007, 21, 325–332. 16 S. L. Werner, J. D. Kearns, V. Zadorozhnaya, C. Lynch, E. O’Dea, M. P. Boldin , A. Ma, D. Baltimore and A. Hoffmann, Genes...Werner, J. D. Kearns, V. Zadorozhnaya, C. Lynch, E. O’Dea, M. P. Boldin , A. Ma, D. Baltimore and A. Hoffmann, Genes Dev., 2008, 22, 2093–2101. 58 J

VgrG and PAAR Proteins Define Distinct Versions of a Functional Type VI Secretion System

PubMed Central

Cianfanelli, Francesca R.; Alcoforado Diniz, Juliana; Guo, Manman; De Cesare, Virginia; Trost, Matthias; Coulthurst, Sarah J.

2016-01-01

The Type VI secretion system (T6SS) is widespread among bacterial pathogens and acts as an effective weapon against competitor bacteria and eukaryotic hosts by delivering toxic effector proteins directly into target cells. The T6SS utilises a bacteriophage-like contractile machinery to expel a puncturing device based on a tube of Hcp topped with a VgrG spike, which can be extended by a final tip from a PAAR domain-containing protein. Effector proteins are believed to be delivered by specifically associating with particular Hcp, VgrG or PAAR proteins, either covalently (‘specialised’) or non-covalently (‘cargo’ effectors). Here we used the T6SS of the opportunistic pathogen Serratia marcescens, together with integratecd genetic, proteomic and biochemical approaches, to elucidate the role of specific VgrG and PAAR homologues in T6SS function and effector specificity, revealing new aspects and unexpected subtleties in effector delivery by the T6SS. We identified effectors, both cargo and specialised, absolutely dependent on a particular VgrG for delivery to target cells, and discovered that other cargo effectors can show a preference for a particular VgrG. The presence of at least one PAAR protein was found to be essential for T6SS function, consistent with designation as a ‘core’ T6SS component. We showed that specific VgrG-PAAR combinations are required to assemble a functional T6SS and that the three distinct VgrG-PAAR assemblies in S. marcescens exhibit distinct effector specificity and efficiency. Unexpectedly, we discovered that two different PAAR-containing Rhs proteins can functionally pair with the same VgrG protein. Showing that accessory EagR proteins are involved in these interactions, native VgrG-Rhs-EagR complexes were isolated and specific interactions between EagR and cognate Rhs proteins identified. This study defines an essential yet flexible role for PAAR proteins in the T6SS and highlights the existence of distinct versions of the machinery with differential effector specificity and efficiency of target cell delivery. PMID:27352036

Finding Your Place in the Information Age Library.

ERIC Educational Resources Information Center

Rizzo, Joseph C.

2002-01-01

Discusses the role of academic libraries as campus meeting centers, highlighting the distinction between changing functional requirements that are addressed with space programming and the social and emotional needs of a community that are realized through the design of place. Offers examples of design ideas and recommendations for librarians and…

The University and Literacy. Literacy Lessons.

ERIC Educational Resources Information Center

Tohme, Georges

In order to explain the role that the university can play in the struggle against illiteracy, a distinction must be made between "social" illiterate people, who are dominated by oral tradition, and functional, or "uneducated" illiterate people, who usually know how to read and write, but without having sufficient understanding…

Different Functions of Phylogenetically Distinct Bacterial Complex I Isozymes

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

Spero, Melanie A.; Brickner, Joshua R.; Mollet, Jordan T.

NADH:quinone oxidoreductase (complex I) is a bioenergetic enzyme that transfers electrons from NADH to quinone, conserving the energy of this reaction by contributing to the proton motive force. While the importance of NADH oxidation to mitochondrial aerobic respiration is well documented, the contribution of complex I to bacterial electron transport chains has been tested in only a few species. Here, we analyze the function of two phylogenetically distinct complex I isozymes in Rhodobacter sphaeroides, an alphaproteobacterium that contains well-characterized electron transport chains. We found that R. sphaeroides complex I activity is important for aerobic respiration and required for anaerobic dimethylmore » sulfoxide (DMSO) respiration (in the absence of light), photoautotrophic growth, and photoheterotrophic growth (in the absence of an external electron acceptor). Our data also provide insight into the functions of the phylogenetically distinct R. sphaeroides complex I enzymes (complex I A and complex I E) in maintaining a cellular redox state during photoheterotrophic growth. We propose that the function of each isozyme during photoheterotrophic growth is either NADH synthesis (complex I A) or NADH oxidation (complex I E). The canonical alphaproteobacterial complex I isozyme (complex I A) was also shown to be important for routing electrons to nitrogenase-mediated H 2 production, while the horizontally acquired enzyme (complex I E) was dispensable in this process. Unlike the singular role of complex I in mitochondria, we predict that the phylogenetically distinct complex I enzymes found across bacterial species have evolved to enhance the functions of their respective electron transport chains. Cells use a proton motive force (PMF), NADH, and ATP to support numerous processes. In mitochondria, complex I uses NADH oxidation to generate a PMF, which can drive ATP synthesis. This study analyzed the function of complex I in bacteria, which contain more-diverse and more-flexible electron transport chains than mitochondria. We tested complex I function in Rhodobacter sphaeroides, a bacterium predicted to encode two phylogenetically distinct complex I isozymes. R. sphaeroides cells lacking both isozymes had growth defects during all tested modes of growth, illustrating the important function of this enzyme under diverse conditions. We conclude that the two isozymes are not functionally redundant and predict that phylogenetically distinct complex I enzymes have evolved to support the diverse lifestyles of bacteria.« less

Different Functions of Phylogenetically Distinct Bacterial Complex I Isozymes

DOE PAGES

Spero, Melanie A.; Brickner, Joshua R.; Mollet, Jordan T.; ...

2016-02-01

NADH:quinone oxidoreductase (complex I) is a bioenergetic enzyme that transfers electrons from NADH to quinone, conserving the energy of this reaction by contributing to the proton motive force. While the importance of NADH oxidation to mitochondrial aerobic respiration is well documented, the contribution of complex I to bacterial electron transport chains has been tested in only a few species. Here, we analyze the function of two phylogenetically distinct complex I isozymes in Rhodobacter sphaeroides, an alphaproteobacterium that contains well-characterized electron transport chains. We found that R. sphaeroides complex I activity is important for aerobic respiration and required for anaerobic dimethylmore » sulfoxide (DMSO) respiration (in the absence of light), photoautotrophic growth, and photoheterotrophic growth (in the absence of an external electron acceptor). Our data also provide insight into the functions of the phylogenetically distinct R. sphaeroides complex I enzymes (complex I A and complex I E) in maintaining a cellular redox state during photoheterotrophic growth. We propose that the function of each isozyme during photoheterotrophic growth is either NADH synthesis (complex I A) or NADH oxidation (complex I E). The canonical alphaproteobacterial complex I isozyme (complex I A) was also shown to be important for routing electrons to nitrogenase-mediated H 2 production, while the horizontally acquired enzyme (complex I E) was dispensable in this process. Unlike the singular role of complex I in mitochondria, we predict that the phylogenetically distinct complex I enzymes found across bacterial species have evolved to enhance the functions of their respective electron transport chains. Cells use a proton motive force (PMF), NADH, and ATP to support numerous processes. In mitochondria, complex I uses NADH oxidation to generate a PMF, which can drive ATP synthesis. This study analyzed the function of complex I in bacteria, which contain more-diverse and more-flexible electron transport chains than mitochondria. We tested complex I function in Rhodobacter sphaeroides, a bacterium predicted to encode two phylogenetically distinct complex I isozymes. R. sphaeroides cells lacking both isozymes had growth defects during all tested modes of growth, illustrating the important function of this enzyme under diverse conditions. We conclude that the two isozymes are not functionally redundant and predict that phylogenetically distinct complex I enzymes have evolved to support the diverse lifestyles of bacteria.« less

Histamine and motivation

PubMed Central

Torrealba, Fernando; Riveros, Maria E.; Contreras, Marco; Valdes, Jose L.

2012-01-01

Brain histamine may affect a variety of different behavioral and physiological functions; however, its role in promoting wakefulness has overshadowed its other important functions. Here, we review evidence indicating that brain histamine plays a central role in motivation and emphasize its differential involvement in the appetitive and consummatory phases of motivated behaviors. We discuss the inputs that control histaminergic neurons of the tuberomamillary nucleus (TMN) of the hypothalamus, which determine the distinct role of these neurons in appetitive behavior, sleep/wake cycles, and food anticipatory responses. Moreover, we review evidence supporting the dysfunction of histaminergic neurons and the cortical input of histamine in regulating specific forms of decreased motivation (apathy). In addition, we discuss the relationship between the histamine system and drug addiction in the context of motivation. PMID:22783171

Leptin protects vital organ functions after sepsis through recovering tissue myeloperoxidase activity: an anti-inflammatory role resonating with indomethacin.

PubMed

Lin, Ji; Yan, Guang-Tao; Xue, Hui; Hao, Xiu-Hua; Zhang, Kai; Wang, Lu-Huan

2007-08-01

In this research, the role of leptin on sepsis-induced organ dysfunction was evaluated. Making use of a mice sepsis model, changes of alanine transaminase and uric acid in serum, myeloperoxidase activity, leptin levels and histological alterations in heart, lung, liver and kidney were determined. Results showed that sepsis induced significantly higher levels of serum alanine transaminase and uric acid, decreased tissue myeloperoxidase activity and leptin levels, and triggered distinct histological alterations. However, leptin and indomethacin injections reversed those impairments at 6h and/or 12h after injury. These data reveal a protective role of both leptin and indomethacin on vital organ functions after sepsis by recovering tissue myeloperoxidase activity.

Structural Similarities and Differences between Two Functionally Distinct SecA Proteins, Mycobacterium tuberculosis SecA1 and SecA2

PubMed Central

Swanson, Stephanie; Ioerger, Thomas R.; Rigel, Nathan W.; Miller, Brittany K.; Braunstein, Miriam

2015-01-01

ABSTRACT While SecA is the ATPase component of the major bacterial secretory (Sec) system, mycobacteria and some Gram-positive pathogens have a second paralog, SecA2. In bacteria with two SecA paralogs, each SecA is functionally distinct, and they cannot compensate for one another. Compared to SecA1, SecA2 exports a distinct and smaller set of substrates, some of which have roles in virulence. In the mycobacterial system, some SecA2-dependent substrates lack a signal peptide, while others contain a signal peptide but possess features in the mature protein that necessitate a role for SecA2 in their export. It is unclear how SecA2 functions in protein export, and one open question is whether SecA2 works with the canonical SecYEG channel to export proteins. In this study, we report the structure of Mycobacterium tuberculosis SecA2 (MtbSecA2), which is the first structure of any SecA2 protein. A high level of structural similarity is observed between SecA2 and SecA1. The major structural difference is the absence of the helical wing domain, which is likely to play a role in how MtbSecA2 recognizes its unique substrates. Importantly, structural features critical to the interaction between SecA1 and SecYEG are preserved in SecA2. Furthermore, suppressor mutations of a dominant-negative secA2 mutant map to the surface of SecA2 and help identify functional regions of SecA2 that may promote interactions with SecYEG or the translocating polypeptide substrate. These results support a model in which the mycobacterial SecA2 works with SecYEG. IMPORTANCE SecA2 is a paralog of SecA1, which is the ATPase of the canonical bacterial Sec secretion system. SecA2 has a nonredundant function with SecA1, and SecA2 exports a distinct and smaller set of substrates than SecA1. This work reports the crystal structure of SecA2 of Mycobacterium tuberculosis (the first SecA2 structure reported for any organism). Many of the structural features of SecA1 are conserved in the SecA2 structure, including putative contacts with the SecYEG channel. Several structural differences are also identified that could relate to the unique function and selectivity of SecA2. Suppressor mutations of a secA2 mutant map to the surface of SecA2 and help identify functional regions of SecA2 that may promote interactions with SecYEG. PMID:26668263

The complex roles of space and environment in structuring functional, taxonomic and phylogenetic beta diversity of frogs in the Atlantic Forest

PubMed Central

Luiz, Amom Mendes; Sawaya, Ricardo J.

2018-01-01

Ecological communities are complex entities that can be maintained and structured by niche-based processes such as environmental conditions, and spatial processes such as dispersal. Thus, diversity patterns may be shaped simultaneously at different spatial scales by very distinct processes. Herein we assess whether and how functional, taxonomic, and phylogenetic beta diversities of frog tadpoles are explained by environmental and/or spatial predictors. We implemented a distance–based redundancy analysis to explore variation in components of beta diversity explained by pure environmental and pure spatial predictors, as well as their interactions, at both fine and broad spatial scales. Our results indicated important but complex roles of spatial and environmental predictors in structuring phylogenetic, taxonomic and functional beta diversities. The pure fine-scales spatial fraction was more important in structuring all beta diversity components, especially to functional and taxonomical spatial turnover. Environmental variables such as canopy cover and vegetation structure were important predictors of all components, but especially to functional and taxonomic beta diversity. We emphasize that distinct factors related to environment and space are affecting distinct components of beta diversity in different ways. Although weaker, phylogenetic beta diversity, which is structured more on biogeographical scales, and thus can be represented by spatially structured processes, was more related to broad spatial processes than other components. However, selected fine-scale spatial predictors denoted negative autocorrelation, which may be revealing the existence of differences in unmeasured habitat variables among samples. Although overall important, local environmental-based processes explained better functional and taxonomic beta diversity, as these diversity components carry an important ecological value. We highlight the importance of assessing different components of diversity patterns at different scales by spatially explicit models in order to improve our understanding of community structure and help to unravel the complex nature of biodiversity. PMID:29672575

Individual Distinctiveness in Call Types of Wild Western Female Gorillas

PubMed Central

Salmi, Roberta; Hammerschmidt, Kurt; Doran-Sheehy, Diane M.

2014-01-01

Individually distinct vocalizations play an important role in animal communication, allowing call recipients to respond differentially based on caller identity. However, which of the many calls in a species' repertoire should have more acoustic variability and be more recognizable is less apparent. One proposed hypothesis is that calls used over long distances should be more distinct because visual cues are not available to identify the caller. An alternative hypothesis proposes that close calls should be more recognizable because of their importance in social interactions. To examine which hypothesis garners more support, the acoustic variation and individual distinctiveness of eight call types of six wild western gorilla (Gorilla gorilla) females were investigated. Acoustic recordings of gorilla calls were collected at the Mondika Research Center (Republic of Congo). Acoustic variability was high in all gorilla calls. Similar high inter-individual variation and potential for identity coding (PIC) was found for all call types. Discriminant function analyses confirmed that all call types were individually distinct (although for call types with lowest sample size - hum, grumble and scream - this result cannot be generalized), suggesting that neither the distance at which communication occurs nor the call social function alone can explain the evolution of identity signaling in western gorilla communication. PMID:25029238

High Mitotic Activity of Polo-like Kinase 1 Is Required for Chromosome Segregation and Genomic Integrity in Human Epithelial Cells*

PubMed Central

Lera, Robert F.; Burkard, Mark E.

2012-01-01

Protein kinases play key roles in regulating human cell biology, but manifold substrates and functions make it difficult to understand mechanism. We tested whether we could dissect functions of a pleiotropic mitotic kinase, Polo-like kinase 1 (Plk1), via distinct thresholds of kinase activity. We accomplished this by titrating Plk1 activity in RPE1 human epithelial cells using chemical genetics and verifying results in additional lines. We found that distinct activity thresholds are required for known functions of Plk1 including (from low to high activity) bipolar spindle formation, timely mitotic entry, and formation of a cytokinesis cleavage furrow. Subtle losses in Plk1 activity impaired chromosome congression and produced severe anaphase dysfunction characterized by poor separation of chromosome masses. These two phenotypes were separable, suggesting that they stem from distinct phosphorylation events. Impaired chromosome segregation in anaphase was the most sensitive to modest loss in Plk1 activity. Mechanistically, it was associated with unpaired sister chromatids with stretched kinetochores, suggestive of merotelic attachments. The C-terminal Polo box domain of Plk1 was required for its anaphase function, although it was dispensable for forming a bipolar spindle. The ultimate effect of partial inhibition of Plk1 was the formation of micronuclei, an increase in tetraploid progeny, and senescence. These results demonstrate that different thresholds of Plk1 activity can elicit distinct phenotypes, illustrating a general method for separating pleiotropic functions of a protein kinase even when these are executed close in time. PMID:23105120

Microglial brain region-dependent diversity and selective regional sensitivities to ageing

PubMed Central

Grabert, Kathleen; Michoel, Tom; Karavolos, Michail H; Clohisey, Sara; Baillie, J Kenneth; Stevens, Mark P; Freeman, Tom C; Summers, Kim M; McColl, Barry W

2015-01-01

Microglia play critical roles in neural development, homeostasis and neuroinflammation and are increasingly implicated in age-related neurological dysfunction. Neurodegeneration often occurs in disease-specific spatially-restricted patterns, the origins of which are unknown. We performed the first genome-wide analysis of microglia from discrete brain regions across the adult lifespan of the mouse and reveal that microglia have distinct region-dependent transcriptional identities and age in a regionally variable manner. In the young adult brain, differences in bioenergetic and immunoregulatory pathways were the major sources of heterogeneity and suggested that cerebellar and hippocampal microglia exist in a more immune vigilant state. Immune function correlated with regional transcriptional patterns. Augmentation of the distinct cerebellar immunophenotype and a contrasting loss in distinction of the hippocampal phenotype among forebrain regions were key features during ageing. Microglial diversity may enable regionally localised homeostatic functions but could also underlie region-specific sensitivities to microglial dysregulation and involvement in age-related neurodegeneration. PMID:26780511

Self-other integration and distinction in schizophrenia: A theoretical analysis and a review of the evidence.

PubMed

van der Weiden, Anouk; Prikken, Merel; van Haren, Neeltje E M

2015-10-01

Difficulties in self-other processing lie at the core of schizophrenia and pose a problem for patients' daily social functioning. In the present selective review, we provide a framework for understanding self-other integration and distinction, and impairments herein in schizophrenia. For this purpose, we discuss classic motor prediction models in relation to mirror neuron functioning, theory of mind, mimicry, self-awareness, and self-agency phenomena. Importantly, we also discuss the role of more recent cognitive expectation models in these phenomena, and argue that these cognitive models form an essential contribution to our understanding of self-other integration and distinction. In doing so, we bring together different lines of research and connect findings from social psychology, affective neuropsychology, and psychiatry to further our understanding of when and how people integrate versus distinguish self and other, and how this goes wrong in schizophrenia patients. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

A distinct and active bacterial community in cold oxygenated fluids circulating beneath the western flank of the Mid-Atlantic ridge

PubMed Central

Meyer, Julie L.; Jaekel, Ulrike; Tully, Benjamin J.; Glazer, Brian T.; Wheat, C. Geoffrey; Lin, Huei-Ting; Hsieh, Chih-Chiang; Cowen, James P.; Hulme, Samuel M.; Girguis, Peter R.; Huber, Julie A.

2016-01-01

The rock-hosted, oceanic crustal aquifer is one of the largest ecosystems on Earth, yet little is known about its indigenous microorganisms. Here we provide the first phylogenetic and functional description of an active microbial community residing in the cold oxic crustal aquifer. Using subseafloor observatories, we recovered crustal fluids and found that the geochemical composition is similar to bottom seawater, as are cell abundances. However, based on relative abundances and functional potential of key bacterial groups, the crustal fluid microbial community is heterogeneous and markedly distinct from seawater. Potential rates of autotrophy and heterotrophy in the crust exceeded those of seawater, especially at elevated temperatures (25 °C) and deeper in the crust. Together, these results reveal an active, distinct, and diverse bacterial community engaged in both heterotrophy and autotrophy in the oxygenated crustal aquifer, providing key insight into the role of microbial communities in the ubiquitous cold dark subseafloor biosphere. PMID:26935537

The motor cortex: a network tuned to 7-14 Hz

PubMed Central

Castro-Alamancos, Manuel A.

2013-01-01

The neocortex or six layer cortex consists of at least 52 cytoarchitectonically distinct areas in humans, and similar areas can be distinguished in rodents. Each of these areas has a defining set of extrinsic connections, identifiable functional roles, a distinct laminar arrangement, etc. Thus, neocortex is extensively subdivided into areas of anatomical and functional specialization, but less is known about the specialization of cellular and network physiology across areas. The motor cortex appears to have a distinct propensity to oscillate in the 7–14 Hz frequency range. Augmenting responses, normal mu and beta oscillations, and abnormal oscillations or after discharges caused by enhancing excitation or suppressing inhibition are all expressed around this frequency range. The substrate for this activity may be an excitatory network that is unique to the motor cortex or that is more strongly suppressed in other areas, such as somatosensory cortex. Interestingly, augmenting responses are dependent on behavioral state. They are abolished during behavioral arousal. Here, I briefly review this evidence. PMID:23439785

Physiological and structural differences in spatially distinct subpopulations of cardiac mitochondria: influence of cardiac pathologies

PubMed Central

Thapa, Dharendra; Shepherd, Danielle L.

2014-01-01

Cardiac tissue contains discrete pools of mitochondria that are characterized by their subcellular spatial arrangement. Subsarcolemmal mitochondria (SSM) exist below the cell membrane, interfibrillar mitochondria (IFM) reside in rows between the myofibrils, and perinuclear mitochondria are situated at the nuclear poles. Microstructural imaging of heart tissue coupled with the development of differential isolation techniques designed to sequentially separate spatially distinct mitochondrial subpopulations have revealed differences in morphological features including shape, absolute size, and internal cristae arrangement. These findings have been complemented by functional studies indicating differences in biochemical parameters and, potentially, functional roles for the ATP generated, based upon subcellular location. Consequently, mitochondrial subpopulations appear to be influenced differently during cardiac pathologies including ischemia/reperfusion, heart failure, aging, exercise, and diabetes mellitus. These influences may be the result of specific structural and functional disparities between mitochondrial subpopulations such that the stress elicited by a given cardiac insult differentially impacts subcellular locales and the mitochondria contained within. The goal of this review is to highlight some of the inherent structural and functional differences that exist between spatially distinct cardiac mitochondrial subpopulations as well as provide an overview of the differential impact of various cardiac pathologies on spatially distinct mitochondrial subpopulations. As an outcome, we will instill a basis for incorporating subcellular spatial location when evaluating the impact of cardiac pathologies on the mitochondrion. Incorporation of subcellular spatial location may offer the greatest potential for delineating the influence of cardiac pathology on this critical organelle. PMID:24778166

The evolving neurobiology of gut feelings.

PubMed

Mayer, E A; Naliboff, B; Munakata, J

2000-01-01

The bi-directional communication between limbic regions and the viscera play a central role in the generation and expression of emotional responses and associated emotional feelings. The response of different viscera to distinct, emotion-specific patterns of autonomic output is fed back to the brain, in particular to the cingulofrontal convergence region. Even though this process unfolds largely without conscious awareness, it plays an important role in emotional function and may influence rational decision making in the healthy individual. Alterations in this bi-directional process such as peripheral pathologies within the gut or alterations at the brain level may explain the close association between certain affective disorders and functional visceral syndromes.

Cryptic diversity and ecosystem functioning: a complex tale of differential effects on decomposition.

PubMed

De Meester, N; Gingold, R; Rigaux, A; Derycke, S; Moens, T

2016-10-01

Marine ecosystems are experiencing accelerating population and species loss. Some ecosystem functions are decreasing and there is growing interest in the link between biodiversity and ecosystem functioning. The role of cryptic (morphologically identical but genetically distinct) species in this biodiversity-ecosystem functioning link is unclear and has not yet been formally tested. We tested if there is a differential effect of four cryptic species of the bacterivorous nematode Litoditis marina on the decomposition process of macroalgae. Bacterivorous nematodes can stimulate or slow down bacterial activity and modify the bacterial assemblage composition. Moreover, we tested if interspecific interactions among the four cryptic species influence the decomposition process. A laboratory experiment with both mono- and multispecific nematode cultures was conducted, and loss of organic matter and the activity of two key extracellular enzymes for the degradation of phytodetritus were assessed. L. marina mainly influenced qualitative aspects of the decomposition process rather than its overall rate: an effect of the nematodes on the enzymatic activities became manifest, although no clear nematode effect on bulk organic matter weight loss was found. We also demonstrated that species-specific effects on the decomposition process existed. Combining the four cryptic species resulted in high competition, with one dominant species, but without complete exclusion of other species. These interspecific interactions translated into different effects on the decomposition process. The species-specific differences indicated that each cryptic species may play an important and distinct role in ecosystem functioning. Functional differences may result in coexistence among very similar species.

Developmentally distinct MYB genes encode functionally equivalent proteins in Arabidopsis.

PubMed

Lee, M M; Schiefelbein, J

2001-05-01

The duplication and divergence of developmental control genes is thought to have driven morphological diversification during the evolution of multicellular organisms. To examine the molecular basis of this process, we analyzed the functional relationship between two paralogous MYB transcription factor genes, WEREWOLF (WER) and GLABROUS1 (GL1), in Arabidopsis. The WER and GL1 genes specify distinct cell types and exhibit non-overlapping expression patterns during Arabidopsis development. Nevertheless, reciprocal complementation experiments with a series of gene fusions showed that WER and GL1 encode functionally equivalent proteins, and their unique roles in plant development are entirely due to differences in their cis-regulatory sequences. Similar experiments with a distantly related MYB gene (MYB2) showed that its product cannot functionally substitute for WER or GL1. Furthermore, an analysis of the WER and GL1 proteins shows that conserved sequences correspond to specific functional domains. These results provide new insights into the evolution of the MYB gene family in Arabidopsis, and, more generally, they demonstrate that novel developmental gene function may arise solely by the modification of cis-regulatory sequences.

Membrane-Mediated Oligomerization of G Protein Coupled Receptors and Its Implications for GPCR Function

PubMed Central

Gahbauer, Stefan; Böckmann, Rainer A.

2016-01-01

The dimerization or even oligomerization of G protein coupled receptors (GPCRs) causes ongoing, controversial debates about its functional role and the coupled biophysical, biochemical or biomedical implications. A continously growing number of studies hints to a relation between oligomerization and function of GPCRs and strengthens the assumption that receptor assembly plays a key role in the regulation of protein function. Additionally, progress in the structural analysis of GPCR-G protein and GPCR-ligand interactions allows to distinguish between actively functional and non-signaling complexes. Recent findings further suggest that the surrounding membrane, i.e., its lipid composition may modulate the preferred dimerization interface and as a result the abundance of distinct dimeric conformations. In this review, the association of GPCRs and the role of the membrane in oligomerization will be discussed. An overview of the different reported oligomeric interfaces is provided and their capability for signaling discussed. The currently available data is summarized with regard to the formation of GPCR oligomers, their structures and dependency on the membrane microenvironment as well as the coupling of oligomerization to receptor function. PMID:27826255

Microglia and Beyond: Innate Immune Cells As Regulators of Brain Development and Behavioral Function.

PubMed

Lenz, Kathryn M; Nelson, Lars H

2018-01-01

Innate immune cells play a well-documented role in the etiology and disease course of many brain-based conditions, including multiple sclerosis, Alzheimer's disease, traumatic brain and spinal cord injury, and brain cancers. In contrast, it is only recently becoming clear that innate immune cells, primarily brain resident macrophages called microglia, are also key regulators of brain development. This review summarizes the current state of knowledge regarding microglia in brain development, with particular emphasis on how microglia during development are distinct from microglia later in life. We also summarize the effects of early life perturbations on microglia function in the developing brain, the role that biological sex plays in microglia function, and the potential role that microglia may play in developmental brain disorders. Finally, given how new the field of developmental neuroimmunology is, we highlight what has yet to be learned about how innate immune cells shape the development of brain and behavior.

RanBP2 modulates Cox11 and hexokinase I activities and haploinsufficiency of RanBP2 causes deficits in glucose metabolism.

PubMed

Aslanukov, Azamat; Bhowmick, Reshma; Guruju, Mallikarjuna; Oswald, John; Raz, Dorit; Bush, Ronald A; Sieving, Paul A; Lu, Xinrong; Bock, Cheryl B; Ferreira, Paulo A

2006-10-01

The Ran-binding protein 2 (RanBP2) is a large multimodular and pleiotropic protein. Several molecular partners with distinct functions interacting specifically with selective modules of RanBP2 have been identified. Yet, the significance of these interactions with RanBP2 and the genetic and physiological role(s) of RanBP2 in a whole-animal model remain elusive. Here, we report the identification of two novel partners of RanBP2 and a novel physiological role of RanBP2 in a mouse model. RanBP2 associates in vitro and in vivo and colocalizes with the mitochondrial metallochaperone, Cox11, and the pacemaker of glycolysis, hexokinase type I (HKI) via its leucine-rich domain. The leucine-rich domain of RanBP2 also exhibits strong chaperone activity toward intermediate and mature folding species of Cox11 supporting a chaperone role of RanBP2 in the cytosol during Cox11 biogenesis. Cox11 partially colocalizes with HKI, thus supporting additional and distinct roles in cell function. Cox11 is a strong inhibitor of HKI, and RanBP2 suppresses the inhibitory activity of Cox11 over HKI. To probe the physiological role of RanBP2 and its role in HKI function, a mouse model harboring a genetically disrupted RanBP2 locus was generated. RanBP2(-/-) are embryonically lethal, and haploinsufficiency of RanBP2 in an inbred strain causes a pronounced decrease of HKI and ATP levels selectively in the central nervous system. Inbred RanBP2(+/-) mice also exhibit deficits in growth rates and glucose catabolism without impairment of glucose uptake and gluconeogenesis. These phenotypes are accompanied by a decrease in the electrophysiological responses of photosensory and postreceptoral neurons. Hence, RanBP2 and its partners emerge as critical modulators of neuronal HKI, glucose catabolism, energy homeostasis, and targets for metabolic, aging disorders and allied neuropathies.

Delineation of the function of a major gamma delta T cell subset during infection.

PubMed

Andrew, Elizabeth M; Newton, Darren J; Dalton, Jane E; Egan, Charlotte E; Goodwin, Stewart J; Tramonti, Daniela; Scott, Philip; Carding, Simon R

2005-08-01

Gammadelta T cells play important but poorly defined roles in pathogen-induced immune responses and in preventing chronic inflammation and pathology. A major obstacle to defining their function is establishing the degree of functional redundancy and heterogeneity among gammadelta T cells. Using mice deficient in Vgamma1+ T cells which are a major component of the gammadelta T cell response to microbial infection, a specific immunoregulatory role for Vgamma1+ T cells in macrophage and gammadelta T cell homeostasis during infection has been established. By contrast, Vgamma1+ T cells play no significant role in pathogen containment or eradication and cannot protect mice from immune-mediated pathology. Pathogen-elicited Vgamma1+ T cells also display different functional characteristics at different stages of the host response to infection that involves unique and different populations of Vgamma1+ T cells. These findings, therefore, identify distinct and nonoverlapping roles for gammadelta T cell subsets in infection and establish the complexity and adaptability of a single population of gammadelta T cells in the host response to infection that is not predetermined, but is, instead, shaped by environmental factors.

Three regulators of G protein signaling differentially affect mating, morphology and virulence in the smut fungus Ustilago maydis.

PubMed

Moretti, Marino; Wang, Lei; Grognet, Pierre; Lanver, Daniel; Link, Hannes; Kahmann, Regine

2017-09-01

Regulators of G protein signaling (RGS) proteins modulate heterotrimeric G protein signaling negatively. To broaden an understanding of the roles of RGS proteins in fungal pathogens, we functionally characterized the three RGS protein-encoding genes (rgs1, rgs2 and rgs3) in the phytopathogenic fungus Ustilago maydis. It was found that RGS proteins played distinct roles in the regulation of development and virulence. rgs1 had a minor role in virulence when deleted in a solopathogenic strain. In crosses, rgs1 was dispensable for mating and filamentation, but was required for teliospore production. Haploid rgs2 mutants were affected in cell morphology, growth, mating and were unable to cause disease symptoms in crosses. However, virulence was unaffected when rgs2 was deleted in a solopathogenic strain, suggesting an exclusive involvement in pre-fusion events. These rgs2 phenotypes are likely connected to elevated intracellular cAMP levels. rgs3 mutants were severely attenuated in mating, in their response to pheromone, virulence and formation of mature teliospores. The mating defect could be traced back to reduced expression of the transcription factor rop1. It was speculated that the distinct roles of the three U. maydis RGS proteins were achieved by direct modulation of the Gα subunit-activated signaling pathways as well as through Gα-independent functions. © 2017 John Wiley & Sons Ltd.

Identification of discrete functional subregions of the human periaqueductal gray

PubMed Central

Satpute, Ajay B.; Wager, Tor D.; Cohen-Adad, Julien; Bianciardi, Marta; Choi, Ji-Kyung; Buhle, Jason T.; Wald, Lawrence L.; Barrett, Lisa Feldman

2013-01-01

The midbrain periaqueductal gray (PAG) region is organized into distinct subregions that coordinate survival-related responses during threat and stress [Bandler R, Keay KA, Floyd N, Price J (2000) Brain Res 53 (1):95–104]. To examine PAG function in humans, researchers have relied primarily on functional MRI (fMRI), but technological and methodological limitations have prevented researchers from localizing responses to different PAG subregions. We used high-field strength (7-T) fMRI techniques to image the PAG at high resolution (0.75 mm isotropic), which was critical for dissociating the PAG from the greater signal variability in the aqueduct. Activation while participants were exposed to emotionally aversive images segregated into subregions of the PAG along both dorsal/ventral and rostral/caudal axes. In the rostral PAG, activity was localized to lateral and dorsomedial subregions. In caudal PAG, activity was localized to the ventrolateral region. This shifting pattern of activity from dorsal to ventral PAG along the rostrocaudal axis mirrors structural and functional neurobiological observations in nonhuman animals. Activity in lateral and ventrolateral subregions also grouped with distinct emotional experiences (e.g., anger and sadness) in a factor analysis, suggesting that each subregion participates in distinct functional circuitry. This study establishes the use of high-field strength fMRI as a promising technique for revealing the functional architecture of the PAG. The techniques developed here also may be extended to investigate the functional roles of other brainstem nuclei. PMID:24082116

A Role for MORE AXILLARY GROWTH1 (MAX1) in Evolutionary Diversity in Strigolactone Signaling Upstream of MAX21[C][W][OA

PubMed Central

Challis, Richard J.; Hepworth, Jo; Mouchel, Céline; Waites, Richard; Leyser, Ottoline

2013-01-01

Strigolactones (SLs) are carotenoid-derived phytohormones with diverse roles. They are secreted from roots as attractants for arbuscular mycorrhizal fungi and have a wide range of endogenous functions, such as regulation of root and shoot system architecture. To date, six genes associated with SL synthesis and signaling have been molecularly identified using the shoot-branching mutants more axillary growth (max) of Arabidopsis (Arabidopsis thaliana) and dwarf (d) of rice (Oryza sativa). Here, we present a phylogenetic analysis of the MAX/D genes to clarify the relationships of each gene with its wider family and to allow the correlation of events in the evolution of the genes with the evolution of SL function. Our analysis suggests that the notion of a distinct SL pathway is inappropriate. Instead, there may be a diversity of SL-like compounds, the response to which requires a D14/D14-like protein. This ancestral system could have been refined toward distinct ligand-specific pathways channeled through MAX2, the most downstream known component of SL signaling. MAX2 is tightly conserved among land plants and is more diverged from its nearest sister clade than any other SL-related gene, suggesting a pivotal role in the evolution of SL signaling. By contrast, the evidence suggests much greater flexibility upstream of MAX2. The MAX1 gene is a particularly strong candidate for contributing to diversification of inputs upstream of MAX2. Our functional analysis of the MAX1 family demonstrates the early origin of its catalytic function and both redundancy and functional diversification associated with its duplication in angiosperm lineages. PMID:23424248

Probing function and structure of trehalose-6-phosphate phosphatases from pathogenic organisms suggests distinct molecular groupings.

PubMed

Cross, Megan; Lepage, Romain; Rajan, Siji; Biberacher, Sonja; Young, Neil D; Kim, Bo-Na; Coster, Mark J; Gasser, Robin B; Kim, Jeong-Sun; Hofmann, Andreas

2017-03-01

The trehalose biosynthetic pathway is of great interest for the development of novel therapeutics because trehalose is an essential disaccharide in many pathogens but is neither required nor synthesized in mammalian hosts. As such, trehalose-6-phosphate phosphatase (TPP), a key enzyme in trehalose biosynthesis, is likely an attractive target for novel chemotherapeutics. Based on a survey of genomes from a panel of parasitic nematodes and bacterial organisms and by way of a structure-based amino acid sequence alignment, we derive the topological structure of monoenzyme TPPs and classify them into 3 groups. Comparison of the functional roles of amino acid residues located in the active site for TPPs belonging to different groups reveal nuanced variations. Because current literature on this enzyme family shows a tendency to infer functional roles for individual amino acid residues, we investigated the roles of the strictly conserved aspartate tetrad in TPPs of the nematode Brugia malayi by using a conservative mutation approach. In contrast to aspartate-213, the residue inferred to carry out the nucleophilic attack on the substrate, we found that aspartate-215 and aspartate-428 of Bm TPP are involved in the chemistry steps of enzymatic hydrolysis of the substrate. Therefore, we suggest that homology-based inference of functionally important amino acids by sequence comparison for monoenzyme TPPs should only be carried out for each of the 3 groups.-Cross, M., Lepage, R., Rajan, S., Biberacher, S., Young, N. D., Kim, B.-N., Coster, M. J., Gasser, R. B., Kim, J.-S., Hofmann, A. Probing function and structure of trehalose-6-phosphate phosphatases from pathogenic organisms suggests distinct molecular groupings. © FASEB.

Synaptic transmission at functionally identified synapses in the enteric nervous system: roles for both ionotropic and metabotropic receptors.

PubMed

Gwynne, R M; Bornstein, J C

2007-03-01

Digestion and absorption of nutrients and the secretion and reabsorption of fluid in the gastrointestinal tract are regulated by neurons of the enteric nervous system (ENS), the extensive peripheral nerve network contained within the intestinal wall. The ENS is an important physiological model for the study of neural networks since it is both complex and accessible. At least 20 different neurochemically and functionally distinct classes of enteric neurons have been identified in the guinea pig ileum. These neurons express a wide range of ionotropic and metabotropic receptors. Synaptic potentials mediated by ionotropic receptors such as the nicotinic acetylcholine receptor, P2X purinoceptors and 5-HT(3) receptors are seen in many enteric neurons. However, prominent synaptic potentials mediated by metabotropic receptors, like the P2Y(1) receptor and the NK(1) receptor, are also seen in these neurons. Studies of synaptic transmission between the different neuron classes within the enteric neural pathways have shown that both ionotropic and metabotropic synaptic potentials play major roles at distinct synapses within simple reflex pathways. However, there are still functional synapses at which no known transmitter or receptor has been identified. This review describes the identified roles for both ionotropic and metabotropic neurotransmission at functionally defined synapses within the guinea pig ileum ENS. It is concluded that metabotropic synaptic potentials act as primary transmitters at some synapses. It is suggested identification of the interactions between different synaptic potentials in the production of complex behaviours will require the use of well validated computer models of the enteric neural circuitry.

The Physcomitrella patens exocyst subunit EXO70.3d has distinct roles in growth and development, and is essential for completion of the moss life cycle.

PubMed

Rawat, Anamika; Brejšková, Lucie; Hála, Michal; Cvrčková, Fatima; Žárský, Viktor

2017-10-01

The exocyst, an evolutionarily conserved secretory vesicle-tethering complex, spatially controls exocytosis and membrane turnover in fungi, metazoans and plants. The exocyst subunit EXO70 exists in multiple paralogs in land plants, forming three conserved clades with assumed distinct roles. Here we report functional analysis of the first moss exocyst subunit to be studied, Physcomitrella patens PpEXO70.3d (Pp1s97_91V6), from the, as yet, poorly characterized EXO70.3 clade. Following phylogenetic analysis to confirm the presence of three ancestral land plant EXO70 clades outside angiosperms, we prepared and phenotypically characterized loss-of-function Ppexo70.3d mutants and localized PpEXO70.3d in vivo using green fluorescent protein-tagged protein expression. Disruption of PpEXO70.3d caused pleiotropic cell elongation and differentiation defects in protonemata, altered response towards exogenous auxin, increased endogenous IAA concentrations, along with defects in bud and gametophore development. During mid-archegonia development, an abnormal egg cell is formed and subsequently collapses, resulting in mutant sterility. Mutants exhibited altered cell wall and cuticle deposition, as well as compromised cytokinesis, consistent with the protein localization to the cell plate. Despite some functional redundancy allowing survival of moss lacking PpEXO70.3d, this subunit has an essential role in the moss life cycle, indicating sub-functionalization within the moss EXO70 family. © 2017 The Authors. New Phytologist © 2017 New Phytologist Trust.

Critical Contribution of Tyr15 in the HIV-1 Integrase (IN) in Facilitating IN Assembly and Nonenzymatic Function through the IN Precursor Form with Reverse Transcriptase.

PubMed

Takahata, Tatsuro; Takeda, Eri; Tobiume, Minoru; Tokunaga, Kenzo; Yokoyama, Masaru; Huang, Yu-Lun; Hasegawa, Atsuhiko; Shioda, Tatsuo; Sato, Hironori; Kannagi, Mari; Masuda, Takao

2017-01-01

Nonenzymatic roles for HIV-1 integrase (IN) at steps prior to the enzymatic integration step have been reported. To obtain structural and functional insights into the nonenzymatic roles of IN, we performed genetic analyses of HIV-1 IN, focusing on a highly conserved Tyr15 in the N-terminal domain (NTD), which has previously been shown to regulate an equilibrium state between two NTD dimer conformations. Replacement of Tyr15 with alanine, histidine, or tryptophan prevented HIV-1 infection and caused severe impairment of reverse transcription without apparent defects in reverse transcriptase (RT) or in capsid disassembly kinetics after entry into cells. Cross-link analyses of recombinant IN proteins demonstrated that lethal mutations of Tyr15 severely impaired IN structure for assembly. Notably, replacement of Tyr15 with phenylalanine was tolerated for all IN functions, demonstrating that a benzene ring of the aromatic side chain is a key moiety for IN assembly and functions. Additional mutagenic analyses based on previously proposed tetramer models for IN assembly suggested a key role of Tyr15 in facilitating the hydrophobic interaction among IN subunits, together with other proximal residues within the subunit interface. A rescue experiment with a mutated HIV-1 with RT and IN deleted (ΔRT ΔIN) and IN and RT supplied in trans revealed that the nonenzymatic IN function might be exerted through the IN precursor conjugated with RT (RT-IN). Importantly, the lethal mutations of Tyr15 significantly reduced the RT-IN function and assembly. Taken together, Tyr15 seems to play a key role in facilitating the proper assembly of IN and RT on viral RNA through the RT-IN precursor form. Inhibitors of the IN enzymatic strand transfer function (INSTI) have been applied in combination antiretroviral therapies to treat HIV-1-infected patients. Recently, allosteric IN inhibitors (ALLINIs) that interact with HIV-1 IN residues, the locations of which are distinct from the catalytic sites targeted by INSTI, have been discovered. Importantly, ALLINIs affect the nonenzymatic role(s) of HIV-1 IN, providing a rationale for the development of next-generation IN inhibitors with a mechanism that is distinct from that of INSTI. Here, we demonstrate that Tyr15 in the HIV-1 IN NTD plays a critical role during IN assembly by facilitating the hydrophobic interaction of the NTD with the other domains of IN. Importantly, we found that the functional assembly of IN through its fusion form with RT is critical for IN to exert its nonenzymatic function. Our results provide a novel mechanistic insight into the nonenzymatic function of HIV-1 IN and its prevention. Copyright © 2016 American Society for Microbiology.

Reconsidering the roles of gratitude and indebtedness in social exchange.

PubMed

Peng, Cong; Nelissen, Rob M A; Zeelenberg, Marcel

2018-06-01

Receiving favors is often a mixed blessing and commonly triggers two emotions: the positive emotion gratitude and negative emotion indebtedness. In three studies, we examined the hypothesis that gratitude and indebtedness have distinct functions in social exchange. Contrary to current views, we believe that the function of gratitude does not primarily reside in facilitating social exchange. Instead, we propose that indebtedness motivates people to repay favours received, and thus accounts for most of the prosocial effects commonly attributed to gratitude. On the other hand consistent with current views, we believe that gratitude signals the potential for developing a relationship and fosters proximity seeking. Supporting these assumptions, in Study 1 we found that gratitude and indebtedness were associated with aspects of the favour that reflect the concern for relationship and the level of inequity. Studies 2 and 3 provided causal support for these relations, and revealed the unique associations between gratitude and the motivation of proximity seeking, and between indebtedness and the motivation to reciprocate. We argue that this functional distinction has escaped research attention as gratitude and indebtedness are naturally correlated because they stem from the same eliciting event. To appreciate this functional distinction, both emotions should be studied simultaneously in the context of social exchange.

System analysis identifies distinct and common functional networks governed by transcription factor ASCL1, in glioma and small cell lung cancer.

PubMed

Donakonda, Sainitin; Sinha, Swati; Dighe, Shrinivas Nivrutti; Rao, Manchanahalli R Satyanarayana

2017-07-25

ASCL1 is a basic Helix-Loop-Helix transcription factor (TF), which is involved in various cellular processes like neuronal development and signaling pathways. Transcriptome profiling has shown that ASCL1 overexpression plays an important role in the development of glioma and Small Cell Lung Carcinoma (SCLC), but distinct and common molecular mechanisms regulated by ASCL1 in these cancers are unknown. In order to understand how it drives the cellular functional network in these two tumors, we generated a gene expression profile in a glioma cell line (U87MG) to identify ASCL1 gene targets by an si RNA silencing approach and then compared this with a publicly available dataset of similarly silenced SCLC (NCI-H1618 cells). We constructed TF-TF and gene-gene interactions, as well as protein interaction networks of ASCL1 regulated genes in glioma and SCLC cells. Detailed network analysis uncovered various biological processes governed by ASCL1 target genes in these two tumor cell lines. We find that novel ASCL1 functions related to mitosis and signaling pathways influencing development and tumor growth are affected in both glioma and SCLC cells. In addition, we also observed ASCL1 governed functional networks that are distinct to glioma and SCLC.

Telomere dysfunction and cell survival: Roles for distinct TIN2-containing complexes

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

Kim, Sahn-ho; Davalos, Albert R.; Heo, Seok-Jin

Telomeres are maintained by three DNA binding proteins (TRF1, TRF2 and POT1), and several associated factors. One factor, TIN2, binds TRF1 and TRF2 directly and POT1 indirectly. Along with two other proteins, TPP1 and hRap1, these form a soluble complex that may be the core telomere maintenance complex. It is not clear whether sub-complexes also exist in vivo. We provide evidence for two TIN2 sub-complexes with distinct functions in human cells. We isolated these two TIN2 sub-complexes from nuclear lysates of unperturbed cells and cells expressing TIN2 mutants TIN2-13, TIN2-15C, which cannot bind TRF2 or TRF1, respectively. In cells withmore » wild-type p53 function, TIN2-15C was more potent than TIN2-13 in causing telomere uncapping and eventual growth arrest. In cells lacking p53 function, TIN2-15C was more potent than TIN2-13 in causing telomere dysfunction and cell death. Our findings suggest that distinct TIN2 complexes exist, and that TIN2-15C-sensitive subcomplexes are particularly important for cell survival in the absence of functional p53.« less

Control of B Lymphocyte Development and Functions by the mTOR Signaling Pathways

PubMed Central

Iwata, Terri N.; Ramírez-Komo, Julita A.; Park, Heon; Iritani, Brian M.

2017-01-01

Mechanistic target of rapamycin (mTOR) is a serine/threonine kinase originally discovered as the molecular target of the immunosuppressant rapamycin. mTOR forms two compositionally and functionally distinct complexes, mTORC1 and mTORC2, which are crucial for coordinating nutrient, energy, oxygen, and growth factor availability with cellular growth, proliferation, and survival. Recent studies have identified critical, non-redundant roles for mTORC1 and mTORC2 in controlling B cell development, differentiation, and functions, and have highlighted emerging roles of the Folliculin-Fnip protein complex in regulating mTOR and B cell development. In this review, we summarize the basic mechanisms of mTOR signaling; describe what is known about the roles of mTORC1, mTORC2, and the Folliculin/Fnip1 pathway in B cell development and functions; and briefly outline current clinical approaches for targeting mTOR in B cell neoplasms. We conclude by highlighting a few salient questions and future perspectives regarding mTOR in B lineage cells. PMID:28583723

Disruption of zebrafish cyclin G-associated kinase (GAK) function impairs the expression of Notch-dependent genes during neurogenesis and causes defects in neuronal development

PubMed Central

2010-01-01

Background The J-domain-containing protein auxilin, a critical regulator in clathrin-mediated transport, has been implicated in Drosophila Notch signaling. To ask if this role of auxilin is conserved and whether auxilin has additional roles in development, we have investigated the functions of auxilin orthologs in zebrafish. Results Like mammals, zebrafish has two distinct auxilin-like molecules, auxilin and cyclin G-associated kinase (GAK), differing in their domain structures and expression patterns. Both zebrafish auxilin and GAK can functionally substitute for the Drosophila auxilin, suggesting that they have overlapping molecular functions. Still, they are not completely redundant, as morpholino-mediated knockdown of the ubiquitously expressed GAK alone can increase the specification of neuronal cells, a known Notch-dependent process, and decrease the expression of Her4, a Notch target gene. Furthermore, inhibition of GAK function caused an elevated level of apoptosis in neural tissues, resulting in severe degeneration of neural structures. Conclusion In support of the notion that endocytosis plays important roles in Notch signaling, inhibition of zebrafish GAK function affects embryonic neuronal cell specification and Her4 expression. In addition, our analysis suggests that zebrafish GAK has at least two functions during the development of neural tissues: an early Notch-dependent role in neuronal patterning and a late role in maintaining the survival of neural cells. PMID:20082716

Causal Interactions between Frontalθ – Parieto-Occipitalα2 Predict Performance on a Mental Arithmetic Task

PubMed Central

Dimitriadis, Stavros I.; Sun, Yu; Thakor, Nitish V.; Bezerianos, Anastasios

2016-01-01

Many neuroimaging studies have demonstrated the different functional contributions of spatially distinct brain areas to working memory (WM) subsystems in cognitive tasks that demand both local information processing and interregional coordination. In WM cognitive task paradigms employing electroencephalography (EEG), brain rhythms such as θ and α have been linked to specific functional roles over given brain areas, but their functional coupling has not been extensively studied. Here we analyzed an arithmetic task with five cognitive workload levels (CWLs) and demonstrated functional/effective coupling between the two WM subsystems: the central executive located over frontal (F) brain areas that oscillates on the dominant θ rhythm (Frontalθ/Fθ) and the storage buffer located over parieto-occipital (PO) brain areas that operates on the α2 dominant brain rhythm (Parieto-Occipitalα2/POα2). We focused on important differences between and within WM subsystems in relation to behavioral performance. A repertoire of brain connectivity estimators was employed to elucidate the distinct roles of amplitude, phase within and between frequencies, and the hierarchical role of functionally specialized brain areas related to the task. Specifically, for each CWL, we conducted a) a conventional signal power analysis within both frequency bands at Fθ and POα2, b) the intra- and inter-frequency phase interactions between Fθ and POα2, and c) their causal phase and amplitude relationship. We found no significant statistical difference of signal power or phase interactions between correct and wrong answers. Interestingly, the study of causal interactions between Fθ and POα2 revealed frontal brain region(s) as the leader, while the strength differentiated between correct and wrong responses in every CWL with absolute accuracy. Additionally, zero time-lag between bilateral Fθ and right POa2 could serve as an indicator of mental calculation failure. Overall, our study highlights the significant role of coordinated activity between Fθ and POα2 via their causal interactions and the timing for arithmetic performance. PMID:27683547

Delineation of Roles and Functions of Respiratory Therapy Personnel. Final Report.

ERIC Educational Resources Information Center

American Association for Respiratory Therapy, Dallas, TX.

Frequently assigned tasks performed by qualified respiratory therapy personnel are delineated in the document in such a manner that proficiency examinations within the profession can be prepared from them. Four distinct proficiency levels are identified and defined. Due to the fact that proficiency examinations will be assigned for them,…

Coordinating the Cognitive Processes of Writing: The Role of the Monitor

ERIC Educational Resources Information Center

Quinlan, Thomas; Loncke, Maaike; Leijten, Marielle; Van Waes, Luuk

2012-01-01

Moment to moment, a writer faces a host of potential problems. How does the writer's mind coordinate this problem solving? In the original Hayes and Flower model, the authors posited a distinct process to manage this coordinating--that is, the "monitor." The monitor became responsible for executive function in writing. In two…

The Place of Drugs in the Management of Behavior Disorders after Traumatic Brain Injury.

ERIC Educational Resources Information Center

Rose, Martyn J.

1988-01-01

The article examines the role of drug treatment stressing the need to treat disorders of brain function rather than direct behavior control. Treatment principles concern classification, dosage, monitoring effects, timing of therapy, the distinction between passive and active disorders as well as syndromal, manipulative, ritualistic, cyclothymic,…

Professional versus Academic Values: Cultural Ambivalence in University Professional School in Australia.

ERIC Educational Resources Information Center

Harman, K. M.

1989-01-01

University staff who teach and research in professional schools are required to commit both to traditional academic norms and scholarship and to the transmission of distinctly vocational skills and attitudes. Tensions created by these two roles and the implications of these for the functioning of a university are explored. (Author/MLW)

Cultural Diversity and Anti-Poverty Policy

ERIC Educational Resources Information Center

Lamont, Michele; Small, Mario Luis

2010-01-01

This article examines how anti-poverty policy has considered the role of culture and how it ought to do so. While some have explained poverty as a function of the presumed cultural deficiency or distinctiveness of the poor, we suggest that these explanations have not been convincing and that policy requires a broader and more sophisticated…

The role of lipids in host microbe interactions.

PubMed

Lang, Roland; Mattner, Jochen

2017-06-01

Lipids are one of the major subcellular constituents and serve as signal molecules, energy sources, metabolic precursors and structural membrane components in various organisms. The function of lipids can be modified by multiple biochemical processes such as (de-)phosphorylation or (de-)glycosylation, and the organization of fatty acids into distinct cellular pools and subcellular compartments plays a pivotal role for the morphology and function of various cell populations. Thus, lipids regulate, for example, phagosome formation and maturation within host cells and thus, are critical for the elimination of microbial pathogens. Vice versa, microbial pathogens can manipulate the lipid composition of phagosomal membranes in host cells, and thus avoid their delivery to phagolysosomes. Lipids of microbial origin belong also to the strongest and most versatile inducers of mammalian immune responses upon engagement of distinct receptors on myeloid and lymphoid cells. Furthermore, microbial lipid toxins can induce membrane injuries and cell death. Thus, we will review here selected examples for mutual host-microbe interactions within the broad and divergent universe of lipids in microbial defense, tissue injury and immune evasion.

dsRNA binding properties of RDE-4 and TRBP reflect their distinct roles in RNAi.

PubMed

Parker, Greg S; Maity, Tuhin Subhra; Bass, Brenda L

2008-12-26

Double-stranded RNA (dsRNA)-binding proteins facilitate Dicer functions in RNA interference. Caenorhabditis elegans RDE-4 facilitates cleavage of long dsRNA to small interfering RNA (siRNA), while human trans-activation response RNA-binding protein (TRBP) functions downstream to pass siRNA to the RNA-induced silencing complex. We show that these distinct in vivo roles are reflected in in vitro binding properties. RDE-4 preferentially binds long dsRNA, while TRBP binds siRNA with an affinity that is independent of dsRNA length. These properties are mechanistically based on the fact that RDE-4 binds cooperatively, via contributions from multiple domains, while TRBP binds noncooperatively. Our studies offer a paradigm for how dsRNA-binding proteins, which are not sequence specific, discern dsRNA length. Additionally, analyses of the ability of RDE-4 deletion constructs and RDE-4/TRBP chimeras to reconstitute Dicer activity suggest RDE-4 promotes activity using its dsRNA-binding motif 2 to bind dsRNA, its linker region to interact with Dicer, and its C-terminus for Dicer activation.

Serotonergic Modulation Differentially Targets Distinct Network Elements within the Antennal Lobe of Drosophila melanogaster

PubMed Central

Sizemore, Tyler R.; Dacks, Andrew M.

2016-01-01

Neuromodulation confers flexibility to anatomically-restricted neural networks so that animals are able to properly respond to complex internal and external demands. However, determining the mechanisms underlying neuromodulation is challenging without knowledge of the functional class and spatial organization of neurons that express individual neuromodulatory receptors. Here, we describe the number and functional identities of neurons in the antennal lobe of Drosophila melanogaster that express each of the receptors for one such neuromodulator, serotonin (5-HT). Although 5-HT enhances odor-evoked responses of antennal lobe projection neurons (PNs) and local interneurons (LNs), the receptor basis for this enhancement is unknown. We used endogenous reporters of transcription and translation for each of the five 5-HT receptors (5-HTRs) to identify neurons, based on cell class and transmitter content, that express each receptor. We find that specific receptor types are expressed by distinct combinations of functional neuronal classes. For instance, the excitatory PNs express the excitatory 5-HTRs, while distinct classes of LNs each express different 5-HTRs. This study therefore provides a detailed atlas of 5-HT receptor expression within a well-characterized neural network, and enables future dissection of the role of serotonergic modulation of olfactory processing. PMID:27845422

The nucleolus and herpesviral usurpation.

PubMed

Ni, Liwen; Wang, Shuai; Zheng, Chunfu

2012-12-01

The nucleolus is a distinct subnuclear compartment known as the site for ribosome biogenesis in eukaryotes. Consequently, the nucleolus is also proposed to function in cell-cycle control, stress sensing and senescence, as well as in viral infection. An increasing number of viral proteins have been found to localize to the nucleolus. In this article, we review the current understanding of the functions of the nucleolus, the molecular mechanism of cellular and viral protein targeting to the nucleolus and the functional roles of the nucleolus during viral infection with a specific focus on the herpesvirus family.

A primer on caspase mechanisms.

PubMed

Ramirez, Monica L Gonzalez; Salvesen, Guy S

2018-01-12

Caspases belong to a diverse clan of proteolytic enzymes known as clan CD with highly disparate functions in cell signaling. The caspase members of this clan are only found in animals, and most of them orchestrate the demise of cells by the highly distinct regulated cell death phenotypes known as apoptosis and pyroptosis. This review looks at the mechanistic distinctions between the activity and activation mechanisms of mammalian caspases compared to other members of clan CD. We also compare and contrast the role of different caspase family members that program anti-inflammatory and pro-inflammatory cell death pathways. Copyright © 2018. Published by Elsevier Ltd.

A computational neural approach to support the discovery of gene function and classes of cancer.

PubMed

Azuaje, F

2001-03-01

Advances in molecular classification of tumours may play a central role in cancer treatment. Here, a novel approach to genome expression pattern interpretation is described and applied to the recognition of B-cell malignancies as a test set. Using cDNA microarrays data generated by a previous study, a neural network model known as simplified fuzzy ARTMAP is able to identify normal and diffuse large B-cell lymphoma (DLBCL) patients. Furthermore, it discovers the distinction between patients with molecularly distinct forms of DLBCL without previous knowledge of those subtypes.

Multiple Roles of Pitx2 in Cardiac Development and Disease

PubMed Central

2017-01-01

Cardiac development is a complex morphogenetic process initiated as bilateral cardiogenic mesoderm is specified at both sides of the gastrulating embryo. Soon thereafter, these cardiogenic cells fuse at the embryonic midline configuring a symmetrical linear cardiac tube. Left/right bilateral asymmetry is first detected in the forming heart as the cardiac tube bends to the right, and subsequently, atrial and ventricular chambers develop. Molecular signals emanating from the node confer distinct left/right signalling pathways that ultimately lead to activation of the homeobox transcription factor Pitx2 in the left side of distinct embryonic organ anlagen, including the developing heart. Asymmetric expression of Pitx2 has therefore been reported during different cardiac developmental stages, and genetic deletion of Pitx2 provided evidence of key regulatory roles of this transcription factor during cardiogenesis and thus congenital heart diseases. More recently, impaired Pitx2 function has also been linked to arrhythmogenic processes, providing novel roles in the adult heart. In this manuscript, we provide a state-of-the-art review of the fundamental roles of Pitx2 during cardiogenesis, arrhythmogenesis and its contribution to congenital heart diseases. PMID:29367545

1α,25(OH)2D3 differentially regulates miRNA expression in human bladder cancer cells

PubMed Central

Ma, Yingyu; Hu, Qiang; Luo, Wei; Pratt, Rachel N.; Glenn, Sean T.; Liu, Song; Trump, Donald L.; Johnson, Candace S.

2014-01-01

Bladder cancer is the fourth most commonly diagnosed cancer in men and eighth leading cause of cancer-related death in the US. Epidemiological and experimental studies strongly suggest a role for 1α,25(OH)2D3 in cancer prevention and treatment. The antitumor activities of 1α,25(OH)2D3 are mediated by the induction of cell cycle arrest, apoptosis, differentiation and the inhibition of angiogenesis and metastasis. MiRNAs play important regulatory roles in cancer development and progression. However, the role of 1α,25(OH)2D3 in the regulation of miRNA expression and the potential impact in bladder cancer has not been investigated. Therefore, we studied 1α,25(OH)2D3-regulated miRNA expression profiles in human bladder cancer cell line 253J and the highly tumorigenic and metastatic derivative line 253J-BV by miRNA qPCR panels. 253 J and 253J-BV cells express endogenous vitamin D receptor (VDR) which can be further induced by 1α,25(OH)2D3. VDR target gene 24-hydroxylase was induced by 1α,25(OH)2D3 in both cell lines, indicating functional 1α,25(OH)2D3 signaling. The miRNA qPCR panel assay results showed that 253J and 253J-BV cells have distinct miRNA expression profiles. Further, 1α,25(OH)2D3 differentially regulated miRNA expression profiles in 253J and 253 J-BV cells in a dynamic manner. Pathway analysis of the miRNA target genes revealed distinct patterns of contribution to the molecular functions and biological processes in the two cell lines. In conclusion, 1α,25(OH)2D3 differentially regulates the expression of miRNAs, which may contribute to distinct biological functions, in human bladder 253J and 253J-BV cells. PMID:25263658

The Splice Isoforms of the Drosophila Ecdysis Triggering Hormone Receptor Have Developmentally Distinct Roles

PubMed Central

Diao, Feici; Mena, Wilson; Shi, Jonathan; Park, Dongkook; Diao, Fengqiu; Taghert, Paul; Ewer, John; White, Benjamin H.

2016-01-01

To grow, insects must periodically shed their exoskeletons. This process, called ecdysis, is initiated by the endocrine release of Ecdysis Trigger Hormone (ETH) and has been extensively studied as a model for understanding the hormonal control of behavior. Understanding how ETH regulates ecdysis behavior, however, has been impeded by limited knowledge of the hormone’s neuronal targets. An alternatively spliced gene encoding a G-protein-coupled receptor (ETHR) that is activated by ETH has been identified, and several lines of evidence support a role in ecdysis for its A-isoform. The function of a second ETHR isoform (ETHRB) remains unknown. Here we use the recently introduced “Trojan exon” technique to simultaneously mutate the ETHR gene and gain genetic access to the neurons that express its two isoforms. We show that ETHRA and ETHRB are expressed in largely distinct subsets of neurons and that ETHRA- but not ETHRB-expressing neurons are required for ecdysis at all developmental stages. However, both genetic and neuronal manipulations indicate an essential role for ETHRB at pupal and adult, but not larval, ecdysis. We also identify several functionally important subsets of ETHR-expressing neurons including one that coexpresses the peptide Leucokinin and regulates fluid balance to facilitate ecdysis at the pupal stage. The general strategy presented here of using a receptor gene as an entry point for genetic and neuronal manipulations should be useful in establishing patterns of functional connectivity in other hormonally regulated networks. PMID:26534952

Essential role of grim-led programmed cell death for the establishment of corazonin-producing peptidergic nervous system during embryogenesis and metamorphosis in Drosophila melanogaster.

PubMed

Lee, Gyunghee; Sehgal, Ritika; Wang, Zixing; Nair, Sudershana; Kikuno, Keiko; Chen, Chun-Hong; Hay, Bruce; Park, Jae H

2013-03-15

In Drosophila melanogaster, combinatorial activities of four death genes, head involution defective (hid), reaper (rpr), grim, and sickle (skl), have been known to play crucial roles in the developmentally regulated programmed cell death (PCD) of various tissues. However, different expression patterns of the death genes also suggest distinct functions played by each. During early metamorphosis, a great number of larval neurons unfit for adult life style are removed by PCD. Among them are eight pairs of corazonin-expressing larval peptidergic neurons in the ventral nerve cord (vCrz). To reveal death genes responsible for the PCD of vCrz neurons, we examined extant and recently available mutations as well as RNA interference that disrupt functions of single or multiple death genes. We found grim as a chief proapoptotic gene and skl and rpr as minor ones. The function of grim is also required for PCD of the mitotic sibling cells of the vCrz neuronal precursors (EW3-sib) during embryonic neurogenesis. An intergenic region between grim and rpr, which, it has been suggested, may enhance expression of three death genes in embryonic neuroblasts, appears to play a role for the vCrz PCD, but not for the EW3-sib cell death. The death of vCrz neurons and EW3-sib is triggered by ecdysone and the Notch signaling pathway, respectively, suggesting distinct regulatory mechanisms of grim expression in a cell- and developmental stage-specific manner.

Cohesion, the Human Element in Combat

DTIC Science & Technology

1985-02-01

experiences based on soldiers’ sharing a com- mon religion, race, ethnic group, age, social-economic standing, or sex . These factors indicate the extent to...cultures make role distinctions between the sexes . The extent to which a cul- ture socializes its members to accept women in certain roles will affect...with army norms; o_ 3. are assigned by sex or by sex and function. 1 . ° ; v. 0- - ,-.- ’ " .’. - ," ’ ".’ "’’’ ’’.-.-’ ’ ’’, . 𔃿

A new twist in the coil: functions of the coiled-coil domain of structural maintenance of chromosome (SMC) proteins.

PubMed

Matityahu, Avi; Onn, Itay

2018-02-01

The higher-order organization of chromosomes ensures their stability and functionality. However, the molecular mechanism by which higher order structure is established is poorly understood. Dissecting the activity of the relevant proteins provides information essential for achieving a comprehensive understanding of chromosome structure. Proteins of the structural maintenance of chromosome (SMC) family of ATPases are the core of evolutionary conserved complexes. SMC complexes are involved in regulating genome dynamics and in maintaining genome stability. The structure of all SMC proteins resembles an elongated rod that contains a central coiled-coil domain, a common protein structural motif in which two α-helices twist together. In recent years, the imperative role of the coiled-coil domain to SMC protein activity and regulation has become evident. Here, we discuss recent advances in the function of the SMC coiled coils. We describe the structure of the coiled-coil domain of SMC proteins, modifications and interactions that are mediated by it. Furthermore, we assess the role of the coiled-coil domain in conformational switches of SMC proteins, and in determining the architecture of the SMC dimer. Finally, we review the interplay between mutations in the coiled-coil domain and human disorders. We suggest that distinctive properties of coiled coils of different SMC proteins contribute to their distinct functions. The discussion clarifies the mechanisms underlying the activity of SMC proteins, and advocates future studies to elucidate the function of the SMC coiled coil domain.

Bioinformatic Characterization of Glycyl Radical Enzyme-Associated Bacterial Microcompartments

PubMed Central

Zarzycki, Jan; Erbilgin, Onur

2015-01-01

Bacterial microcompartments (BMCs) are proteinaceous organelles encapsulating enzymes that catalyze sequential reactions of metabolic pathways. BMCs are phylogenetically widespread; however, only a few BMCs have been experimentally characterized. Among them are the carboxysomes and the propanediol- and ethanolamine-utilizing microcompartments, which play diverse metabolic and ecological roles. The substrate of a BMC is defined by its signature enzyme. In catabolic BMCs, this enzyme typically generates an aldehyde. Recently, it was shown that the most prevalent signature enzymes encoded by BMC loci are glycyl radical enzymes, yet little is known about the function of these BMCs. Here we characterize the glycyl radical enzyme-associated microcompartment (GRM) loci using a combination of bioinformatic analyses and active-site and structural modeling to show that the GRMs comprise five subtypes. We predict distinct functions for the GRMs, including the degradation of choline, propanediol, and fuculose phosphate. This is the first family of BMCs for which identification of the signature enzyme is insufficient for predicting function. The distinct GRM functions are also reflected in differences in shell composition and apparently different assembly pathways. The GRMs are the counterparts of the vitamin B12-dependent propanediol- and ethanolamine-utilizing BMCs, which are frequently associated with virulence. This study provides a comprehensive foundation for experimental investigations of the diverse roles of GRMs. Understanding this plasticity of function within a single BMC family, including characterization of differences in permeability and assembly, can inform approaches to BMC bioengineering and the design of therapeutics. PMID:26407889

Sme4 coiled-coil protein mediates synaptonemal complex assembly, recombinosome relocalization, and spindle pole body morphogenesis

PubMed Central

Espagne, Eric; Vasnier, Christelle; Storlazzi, Aurora; Kleckner, Nancy E.; Silar, Philippe; Zickler, Denise; Malagnac, Fabienne

2011-01-01

We identify a large coiled-coil protein, Sme4/PaMe4, that is highly conserved among the large group of Sordariales and plays central roles in two temporally and functionally distinct aspects of the fungal sexual cycle: first as a component of the meiotic synaptonemal complex (SC) and then, after disappearing and reappearing, as a component of the spindle pole body (SPB). In both cases, the protein mediates spatial juxtaposition of two major structures: linkage of homolog axes through the SC and a change in the SPB from a planar to a bent conformation. Corresponding mutants exhibit defects, respectively, in SC and SPB morphogenesis, with downstream consequences for recombination and astral-microtubule nucleation plus postmeiotic nuclear migration. Sme4 is also required for reorganization of recombination complexes in which Rad51, Mer3, and Msh4 foci relocalize from an on-axis position to a between-axis (on-SC) position concomitant with SC installation. Because involved recombinosome foci represent total recombinational interactions, these dynamics are irrespective of their designation for maturation into cross-overs or noncross-overs. The defined dual roles for Sme4 in two different structures that function at distinct phases of the sexual cycle also provide more functional links and evolutionary dynamics among the nuclear envelope, SPB, and SC. PMID:21666097

Sme4 coiled-coil protein mediates synaptonemal complex assembly, recombinosome relocalization, and spindle pole body morphogenesis.

PubMed

Espagne, Eric; Vasnier, Christelle; Storlazzi, Aurora; Kleckner, Nancy E; Silar, Philippe; Zickler, Denise; Malagnac, Fabienne

2011-06-28

We identify a large coiled-coil protein, Sme4/PaMe4, that is highly conserved among the large group of Sordariales and plays central roles in two temporally and functionally distinct aspects of the fungal sexual cycle: first as a component of the meiotic synaptonemal complex (SC) and then, after disappearing and reappearing, as a component of the spindle pole body (SPB). In both cases, the protein mediates spatial juxtaposition of two major structures: linkage of homolog axes through the SC and a change in the SPB from a planar to a bent conformation. Corresponding mutants exhibit defects, respectively, in SC and SPB morphogenesis, with downstream consequences for recombination and astral-microtubule nucleation plus postmeiotic nuclear migration. Sme4 is also required for reorganization of recombination complexes in which Rad51, Mer3, and Msh4 foci relocalize from an on-axis position to a between-axis (on-SC) position concomitant with SC installation. Because involved recombinosome foci represent total recombinational interactions, these dynamics are irrespective of their designation for maturation into cross-overs or noncross-overs. The defined dual roles for Sme4 in two different structures that function at distinct phases of the sexual cycle also provide more functional links and evolutionary dynamics among the nuclear envelope, SPB, and SC.

p39, the Primary Activator for Cyclin-dependent Kinase 5 (Cdk5) in Oligodendroglia, Is Essential for Oligodendroglia Differentiation and Myelin Repair*

PubMed Central

Bankston, Andrew N.; Li, Wenqi; Zhang, Hui; Ku, Li; Liu, Guanglu; Papa, Filomena; Zhao, Lixia; Bibb, James A.; Cambi, Franca; Tiwari-Woodruff, Seema K.; Feng, Yue

2013-01-01

Cyclin-dependent kinase 5 (Cdk5) plays key roles in normal brain development and function. Dysregulation of Cdk5 may cause neurodegeneration and cognitive impairment. Besides the well demonstrated role of Cdk5 in neurons, emerging evidence suggests the functional requirement of Cdk5 in oligodendroglia (OL) and CNS myelin development. However, whether neurons and OLs employ similar or distinct mechanisms to regulate Cdk5 activity remains elusive. We report here that in contrast to neurons that harbor high levels of two Cdk5 activators, p35 and p39, OLs express abundant p39 but negligible p35. In addition, p39 is selectively up-regulated in OLs during differentiation along with elevated Cdk5 activity, whereas p35 expression remains unaltered. Specific knockdown of p39 by siRNA significantly attenuates Cdk5 activity and OL differentiation without affecting p35. Finally, expression of p39, but not p35, is increased during myelin repair, and remyelination is impaired in p39−/− mice. Together, these results reveal that neurons and OLs harbor distinct preference of Cdk5 activators and demonstrate important functions of p39-dependent Cdk5 activation in OL differentiation during de novo myelin development and myelin repair. PMID:23645679

Ovarian phagocyte subsets and their distinct tissue distribution patterns.

PubMed

Carlock, Colin; Wu, Jean; Zhou, Cindy; Ross, April; Adams, Henry; Lou, Yahuan

2013-01-01

Ovarian macrophages, which play critical roles in various ovarian events, are probably derived from multiple lineages. Thus, a systemic classification of their subsets is a necessary first step for determination of their functions. Utilizing antibodies to five phagocyte markers, i.e. IA/IE (major histocompatibility complex class II), F4/80, CD11b (Mac-1), CD11c, and CD68, this study investigated subsets of ovarian phagocytes in mice. Three-color immunofluorescence and flow cytometry, together with morphological observation on isolated ovarian cells, demonstrated complicated phenotypes of ovarian phagocytes. Four macrophage and one dendritic cell subset, in addition to many minor phagocyte subsets, were identified. A dendritic cell-like population with a unique phenotype of CD11c(high)IA/IE⁻F4/80⁻ was also frequently observed. A preliminary age-dependent study showed dramatic increases in IA/IE⁺ macrophages and IA/IE⁺ dendritic cells after puberty. Furthermore, immunofluorescences on ovarian sections showed that each subset displayed a distinct tissue distribution pattern. The pattern for each subset may hint to their role in an ovarian function. In addition, partial isolation of ovarian macrophage subset using CD11b antibodies was attempted. Establishment of this isolation method may have provided us a tool for more precise investigation of each subset's functions at the cellular and molecular levels.

TβRIII Expression in Human Breast Cancer Stroma and the Role of Soluble TβRIII in Breast Cancer Associated Fibroblasts.

PubMed

Jovanović, Bojana; Pickup, Michael W; Chytil, Anna; Gorska, Agnieszka E; Johnson, Kimberly C; Moses, Harold L; Owens, Philip

2016-11-04

The TGF-β pathway plays a major role in tumor progression through regulation of epithelial and stromal cell signaling. Dysfunction of the pathway can lead to carcinoma progression and metastasis. To gain insight into the stromal role of the TGF-β pathway in breast cancer, we performed laser capture microdissection (LCM) from breast cancer patients and reduction mammoplasty patients. Microdissected tumor stroma and normal breast stroma were examined for gene expression. Expression of the TGF-β type III receptor ( TGFBR3 ) was greatly decreased in the tumor stroma compared to control healthy breast tissue. These results demonstrated a 44-fold decrease in TGFBR3 mRNA in tumor stroma in comparison to control tissue. We investigated publicly available databases, and have identified that TGFBR3 mRNA levels are decreased in tumor stroma. We next investigated fibroblast cell lines derived from cancerous and normal breast tissue and found that in addition to mRNA levels, TβRIII protein levels were significantly reduced. Having previously identified that cancer-associated fibroblasts secrete greater levels of tumor promoting cytokines, we investigated the consequences of soluble-TβRIII (sTβRIII) on fibroblasts. Fibroblast conditioned medium was analyzed for 102 human secreted cytokines and distinct changes in response to sTβRIII were observed. Next, we used the fibroblast-conditioned medium to stimulate human monocyte cell line THP-1. These results indicate a distinct transcriptional response depending on sTβRIII treatment and whether it was derived from normal or cancerous breast tissue. We conclude that the effect of TβRIII has distinct roles not only in cancer-associated fibroblasts but that sTβRIII has distinct paracrine functions in the tumor microenvironment.

Some lessons from the tissue transglutaminase knockout mouse.

PubMed

Sarang, Z; Tóth, B; Balajthy, Z; Köröskényi, K; Garabuczi, E; Fésüs, L; Szondy, Z

2009-04-01

Transglutaminase 2 (TG2) is an inducible transamidating acyltransferase that catalyzes Ca(2+)-dependent protein modifications. It acts as a G protein in transmembrane signaling and as a cell surface adhesion mediator, this distinguishes it from other members of the transglutaminase family. The sequence motifs and domains revealed in the TG2 structure, can each be assigned distinct cellular functions, including the regulation of cytoskeleton, cell adhesion, and cell death. Though many biological functions of the enzyme have already been described or proposed previously, studies of TG2 null mice by our laboratory during the past years revealed several novel in vivo roles of the protein. In this review we will discuss these novel roles in their biological context.

Maintaining protein composition in cilia.

PubMed

Stephen, Louise A; Elmaghloob, Yasmin; Ismail, Shehab

2017-12-20

The primary cilium is a sensory organelle that is vital in regulating several signalling pathways. Unlike most organelles cilia are open to the rest of the cell, not enclosed by membranes. The distinct protein composition is crucial to the function of cilia and many signalling proteins and receptors are specifically concentrated within distinct compartments. To maintain this composition, a mechanism is required to deliver proteins to the cilium whilst another must counter the entropic tendency of proteins to distribute throughout the cell. The combination of the two mechanisms should result in the concentration of ciliary proteins to the cilium. In this review we will look at different cellular mechanisms that play a role in maintaining the distinct composition of cilia, including regulation of ciliary access and trafficking of ciliary proteins to, from and within the cilium.

Stress Effects on Multiple Memory System Interactions

PubMed Central

Ness, Deborah; Calabrese, Pasquale

2016-01-01

Extensive behavioural, pharmacological, and neurological research reports stress effects on mammalian memory processes. While stress effects on memory quantity have been known for decades, the influence of stress on multiple memory systems and their distinct contributions to the learning process have only recently been described. In this paper, after summarizing the fundamental biological aspects of stress/emotional arousal and recapitulating functionally and anatomically distinct memory systems, we review recent animal and human studies exploring the effects of stress on multiple memory systems. Apart from discussing the interaction between distinct memory systems in stressful situations, we will also outline the fundamental role of the amygdala in mediating such stress effects. Additionally, based on the methods applied in the herein discussed studies, we will discuss how memory translates into behaviour. PMID:27034845

Functional Rarity: The Ecology of Outliers.

PubMed

Violle, Cyrille; Thuiller, Wilfried; Mouquet, Nicolas; Munoz, François; Kraft, Nathan J B; Cadotte, Marc W; Livingstone, Stuart W; Mouillot, David

2017-05-01

Rarity has been a central topic for conservation and evolutionary biologists aiming to determine the species characteristics that cause extinction risk. More recently, beyond the rarity of species, the rarity of functions or functional traits, called functional rarity, has gained momentum in helping to understand the impact of biodiversity decline on ecosystem functioning. However, a conceptual framework for defining and quantifying functional rarity is still lacking. We introduce 12 different forms of functional rarity along gradients of species scarcity and trait distinctiveness. We then highlight the potential key role of functional rarity in the long-term and large-scale maintenance of ecosystem processes, as well as the necessary linkage between functional and evolutionary rarity. Copyright © 2017 Elsevier Ltd. All rights reserved.

Effects of Dimensions of Word Knowledge and Their Accessibility on Different Levels of Reading Comprehension in Adolescent EFL Learners

ERIC Educational Resources Information Center

Choi, Yunjeong

2017-01-01

Researchers have investigated that different dimensions of word knowledge (breadth versus depth) may play distinct roles in second language (L2) reading comprehension. Yet, little research has addressed how learners' efficiency of accessing those dimensions of knowledge functions in their comprehension (i.e., the issue of knowledge availability…

Faculties of Education in Traditional Universities and Universities of the Third Age: A Partnership Model in Gerontagogy

ERIC Educational Resources Information Center

Lemieux, Andre; Boutin, Gerald; Riendeau, Jean

2007-01-01

This article discusses "Universities of the Third Age", whose function is quite distinct from established universities' traditional role in teaching, research, and community services. Consequently, there is an urgent need to develop a model of partnership between traditional universities and Universities of the Third Age, ensuring better…

Adenylyl cyclases in the digestive system.

PubMed

Sabbatini, Maria Eugenia; Gorelick, Fred; Glaser, Shannon

2014-06-01

Adenylyl cyclases (ACs) are a group of widely distributed enzymes whose functions are very diverse. There are nine known transmembrane AC isoforms activated by Gαs. Each has its own pattern of expression in the digestive system and differential regulation of function by Ca(2+) and other intracellular signals. In addition to the transmembrane isoforms, one AC is soluble and exhibits distinct regulation. In this review, the basic structure, regulation and physiological roles of ACs in the digestive system are discussed. Copyright © 2014 Elsevier Inc. All rights reserved.

Adenylyl cyclases in the digestive system

PubMed Central

Sabbatini, Maria Eugenia; Gorelick, Fred; Glaser, Shannon

2015-01-01

Adenylyl cyclases (ACs) are a group of widely distributed enzymes whose functions are very diverse. There are nine known transmembrane AC isoforms activated by Gαs. Each has its own pattern of expression in the digestive system and differential regulation of function by Ca2+ and other intracellular signals. In addition to the transmembrane isoforms, one AC is soluble and exhibits distinct regulation. In this review, the basic structure, regulation and physiological roles of ACs in the digestive system are discussed. PMID:24521753

Distinct roles for extracellular and intracellular domains in neuroligin function at inhibitory synapses.

PubMed

Nguyen, Quynh-Anh; Horn, Meryl E; Nicoll, Roger A

2016-11-02

Neuroligins (NLGNs) are postsynaptic cell adhesion molecules that interact trans-synaptically with neurexins to mediate synapse development and function. NLGN2 is only at inhibitory synapses while NLGN3 is at both excitatory and inhibitory synapses. We found that NLGN3 function at inhibitory synapses in rat CA1 depends on the presence of NLGN2 and identified a domain in the extracellular region that accounted for this functional difference between NLGN2 and 3 specifically at inhibitory synapses. We further show that the presence of a cytoplasmic tail (c-tail) is indispensible, and identified two domains in the c-tail that are necessary for NLGN function at inhibitory synapses. These domains point to a gephyrin-dependent mechanism that is disrupted by an autism-associated mutation at R705 and a gephyrin-independent mechanism reliant on a putative phosphorylation site at S714. Our work highlights unique and separate roles for the extracellular and intracellular regions in specifying and carrying out NLGN function respectively.

Protein sectors: evolutionary units of three-dimensional structure

PubMed Central

Halabi, Najeeb; Rivoire, Olivier; Leibler, Stanislas; Ranganathan, Rama

2011-01-01

Proteins display a hierarchy of structural features at primary, secondary, tertiary, and higher-order levels, an organization that guides our current understanding of their biological properties and evolutionary origins. Here, we reveal a structural organization distinct from this traditional hierarchy by statistical analysis of correlated evolution between amino acids. Applied to the S1A serine proteases, the analysis indicates a decomposition of the protein into three quasi-independent groups of correlated amino acids that we term “protein sectors”. Each sector is physically connected in the tertiary structure, has a distinct functional role, and constitutes an independent mode of sequence divergence in the protein family. Functionally relevant sectors are evident in other protein families as well, suggesting that they may be general features of proteins. We propose that sectors represent a structural organization of proteins that reflects their evolutionary histories. PMID:19703402

A Network of Genes Antagonistic to the LIN-35 Retinoblastoma Protein of Caenorhabditis elegans

PubMed Central

Polley, Stanley R. G.; Fay, David S.

2012-01-01

The Caenorhabditis elegans pRb ortholog, LIN-35, functions in a wide range of cellular and developmental processes. This includes a role of LIN-35 in nutrient utilization by the intestine, which it carries out redundantly with SLR-2, a zinc-finger protein. This and other redundant functions of LIN-35 were identified in genetic screens for mutations that display synthetic phenotypes in conjunction with loss of lin-35. To explore the intestinal role of LIN-35, we conducted a genome-wide RNA-interference-feeding screen for suppressors of lin-35; slr-2 early larval arrest. Of the 26 suppressors identified, 17 fall into three functional classes: (1) ribosome biogenesis genes, (2) mitochondrial prohibitins, and (3) chromatin regulators. Further characterization indicates that different categories of suppressors act through distinct molecular mechanisms. We also tested lin-35; slr-2 suppressors, as well as suppressors of the synthetic multivulval phenotype, to determine the spectrum of lin-35-synthetic phenotypes that could be suppressed following inhibition of these genes. We identified 19 genes, most of which are evolutionarily conserved, that can suppress multiple unrelated lin-35-synthetic phenotypes. Our study reveals a network of genes broadly antagonistic to LIN-35 as well as genes specific to the role of LIN-35 in intestinal and vulval development. Suppressors of multiple lin-35 phenotypes may be candidate targets for anticancer therapies. Moreover, screening for suppressors of phenotypically distinct synthetic interactions, which share a common altered gene, may prove to be a novel and effective approach for identifying genes whose activities are most directly relevant to the core functions of the shared gene. PMID:22542970

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.

Structural and functional dissection reveals distinct roles of Ca2+-binding sites in the giant adhesin SiiE of Salmonella enterica

PubMed Central

Klingl, Stefan; Sandmann, Achim; Taccardi, Nicola; Sticht, Heinrich; Muller, Yves A.; Hensel, Michael

2017-01-01

The giant non-fimbrial adhesin SiiE of Salmonella enterica mediates the first contact to the apical site of epithelial cells and enables subsequent invasion. SiiE is a 595 kDa protein composed of 53 repetitive bacterial immunoglobulin (BIg) domains and the only known substrate of the SPI4-encoded type 1 secretion system (T1SS). The crystal structure of BIg50-52 of SiiE revealed two distinct Ca2+-binding sites per BIg domain formed by conserved aspartate or glutamate residues. In a mutational analysis Ca2+-binding sites were disrupted by aspartate to serine exchange at various positions in the BIg domains of SiiE. Amounts of secreted SiiE diminish with a decreasing number of intact Ca2+-binding sites. BIg domains of SiiE contain distinct Ca2+-binding sites, with type I sites being similar to other T1SS-secreted proteins and type II sites newly identified in SiiE. We functionally and structurally dissected the roles of type I and type II Ca2+-binding sites in SiiE, as well as the importance of Ca2+-binding sites in various positions of SiiE. Type I Ca2+-binding sites were critical for efficient secretion of SiiE and a decreasing number of type I sites correlated with reduced secretion. Type II sites were less important for secretion, stability and surface expression of SiiE, however integrity of type II sites in the C-terminal portion was required for the function of SiiE in mediating adhesion and invasion. PMID:28558023

Evidence of Distinct Channel Conformations and Substrate Binding Affinities for the Mitochondrial Outer Membrane Protein Translocase Pore Tom40*

PubMed Central

Kuszak, Adam J.; Jacobs, Daniel; Gurnev, Philip A.; Shiota, Takuya; Louis, John M.; Lithgow, Trevor; Bezrukov, Sergey M.; Rostovtseva, Tatiana K.; Buchanan, Susan K.

2015-01-01

Nearly all mitochondrial proteins are coded by the nuclear genome and must be transported into mitochondria by the translocase of the outer membrane complex. Tom40 is the central subunit of the translocase complex and forms a pore in the mitochondrial outer membrane. To date, the mechanism it utilizes for protein transport remains unclear. Tom40 is predicted to comprise a membrane-spanning β-barrel domain with conserved α-helical domains at both the N and C termini. To investigate Tom40 function, including the role of the N- and C-terminal domains, recombinant forms of the Tom40 protein from the yeast Candida glabrata, and truncated constructs lacking the N- and/or C-terminal domains, were functionally characterized in planar lipid membranes. Our results demonstrate that each of these Tom40 constructs exhibits at least four distinct conductive levels and that full-length and truncated Tom40 constructs specifically interact with a presequence peptide in a concentration- and voltage-dependent manner. Therefore, neither the first 51 amino acids of the N terminus nor the last 13 amino acids of the C terminus are required for Tom40 channel formation or for the interaction with a presequence peptide. Unexpectedly, substrate binding affinity was dependent upon the Tom40 state corresponding to a particular conductive level. A model where two Tom40 pores act in concert as a dimeric protein complex best accounts for the observed biochemical and electrophysiological data. These results provide the first evidence for structurally distinct Tom40 conformations playing a role in substrate recognition and therefore in transport function. PMID:26336107

AINTEGUMENTA-LIKE genes have partly overlapping functions with AINTEGUMENTA but make distinct contributions to Arabidopsis thaliana flower development

PubMed Central

Krizek, Beth A.

2015-01-01

AINTEGUMENTA (ANT) is an important regulator of Arabidopsis flower development that has overlapping functions with the related AINTEGUMENTA-LIKE6 (AIL6) gene in floral organ initiation, identity specification, growth, and patterning. Two other AINTEGUMENTA-LIKE (AIL) genes, AIL5 and AIL7, are expressed in developing flowers in spatial domains that partly overlap with those of ANT. Here, it is shown that AIL5 and AIL7 also act in a partially redundant manner with ANT. The results demonstrate that AIL genes exhibit unequal genetic redundancy with roles for AIL5, AIL6, and AIL7 only revealed in the absence of ANT function. ant ail5 and ant ail7 double mutant flowers show alterations in floral organ positioning and growth, sepal fusion, and reductions in petal number. In ant ail5, petals are often replaced by filaments or dramatically reduced in size. ant ail7 double mutants produce increased numbers of carpels, which have defects in valve fusion and a loss of apical tissues. The distinct phenotypes of ant ail5, ant ail7 and the previously characterized ant ail6 indicate that AIL5, AIL6, and AIL7 make unique contributions to flower development. These distinct roles are also supported by genetic analyses of ant ail triple mutants. While ant ail5 ail6 triple mutants closely resemble ant ail6 double mutants, ant ail5 ail7 triple mutants exhibit more severe deviations from the wild type than either ant ail5 or ant ail7 double mutants. Furthermore, it is shown that AIL5, AIL6, and AIL7 act in a dose dependent manners in ant and other mutant backgrounds. PMID:25956884

Human TREX2 components PCID2 and centrin 2, but not ENY2, have distinct functions in protein export and co-localize to the centrosome.

PubMed

Cunningham, Corey N; Schmidt, Casey A; Schramm, Nathaniel J; Gaylord, Michelle R; Resendes, Karen K

2014-01-15

TREX-2 is a five protein complex, conserved from yeast to humans, involved in linking mRNA transcription and export. The centrin 2 subunit of TREX-2 is also a component of the centrosome and is additionally involved in a distinctly different process of nuclear protein export. While centrin 2 is a known multifunctional protein, the roles of other human TREX-2 complex proteins other than mRNA export are not known. In this study, we found that human TREX-2 member PCID2 but not ENY2 is involved in some of the same cellular processes as those of centrin 2 apart from the classical TREX-2 function. PCID2 is present at the centrosome in a subset of HeLa cells and this localization is centrin 2 dependent. Furthermore, the presence of PCID2 at the centrosome is prevalent throughout the cell cycle as determined by co-staining with cyclins E, A and B. PCID2 but not ENY2 is also involved in protein export. Surprisingly, siRNA knockdown of PCID2 delayed the rate of nuclear protein export, a mechanism distinct from the effects of centrin 2, which when knocked down inhibits export. Finally we showed that co-depletion of centrin 2 and PCID2 leads to blocking rather than delaying nuclear protein export, indicating the dominance of the centrin 2 phenotype. Together these results represent the first discovery of specific novel functions for PCID2 other than mRNA export and suggest that components of the TREX-2 complex serve alternative shared roles in the regulation of nuclear transport and cell cycle progression. © 2013 Published by Elsevier Inc.

MicroRNA-Target Network Inference and Local Network Enrichment Analysis Identify Two microRNA Clusters with Distinct Functions in Head and Neck Squamous Cell Carcinoma

PubMed Central

Sass, Steffen; Pitea, Adriana; Unger, Kristian; Hess, Julia; Mueller, Nikola S.; Theis, Fabian J.

2015-01-01

MicroRNAs represent ~22 nt long endogenous small RNA molecules that have been experimentally shown to regulate gene expression post-transcriptionally. One main interest in miRNA research is the investigation of their functional roles, which can typically be accomplished by identification of mi-/mRNA interactions and functional annotation of target gene sets. We here present a novel method “miRlastic”, which infers miRNA-target interactions using transcriptomic data as well as prior knowledge and performs functional annotation of target genes by exploiting the local structure of the inferred network. For the network inference, we applied linear regression modeling with elastic net regularization on matched microRNA and messenger RNA expression profiling data to perform feature selection on prior knowledge from sequence-based target prediction resources. The novelty of miRlastic inference originates in predicting data-driven intra-transcriptome regulatory relationships through feature selection. With synthetic data, we showed that miRlastic outperformed commonly used methods and was suitable even for low sample sizes. To gain insight into the functional role of miRNAs and to determine joint functional properties of miRNA clusters, we introduced a local enrichment analysis procedure. The principle of this procedure lies in identifying regions of high functional similarity by evaluating the shortest paths between genes in the network. We can finally assign functional roles to the miRNAs by taking their regulatory relationships into account. We thoroughly evaluated miRlastic on a cohort of head and neck cancer (HNSCC) patients provided by The Cancer Genome Atlas. We inferred an mi-/mRNA regulatory network for human papilloma virus (HPV)-associated miRNAs in HNSCC. The resulting network best enriched for experimentally validated miRNA-target interaction, when compared to common methods. Finally, the local enrichment step identified two functional clusters of miRNAs that were predicted to mediate HPV-associated dysregulation in HNSCC. Our novel approach was able to characterize distinct pathway regulations from matched miRNA and mRNA data. An R package of miRlastic was made available through: http://icb.helmholtz-muenchen.de/mirlastic. PMID:26694379

MicroRNA-Target Network Inference and Local Network Enrichment Analysis Identify Two microRNA Clusters with Distinct Functions in Head and Neck Squamous Cell Carcinoma.

PubMed

Sass, Steffen; Pitea, Adriana; Unger, Kristian; Hess, Julia; Mueller, Nikola S; Theis, Fabian J

2015-12-18

MicroRNAs represent ~22 nt long endogenous small RNA molecules that have been experimentally shown to regulate gene expression post-transcriptionally. One main interest in miRNA research is the investigation of their functional roles, which can typically be accomplished by identification of mi-/mRNA interactions and functional annotation of target gene sets. We here present a novel method "miRlastic", which infers miRNA-target interactions using transcriptomic data as well as prior knowledge and performs functional annotation of target genes by exploiting the local structure of the inferred network. For the network inference, we applied linear regression modeling with elastic net regularization on matched microRNA and messenger RNA expression profiling data to perform feature selection on prior knowledge from sequence-based target prediction resources. The novelty of miRlastic inference originates in predicting data-driven intra-transcriptome regulatory relationships through feature selection. With synthetic data, we showed that miRlastic outperformed commonly used methods and was suitable even for low sample sizes. To gain insight into the functional role of miRNAs and to determine joint functional properties of miRNA clusters, we introduced a local enrichment analysis procedure. The principle of this procedure lies in identifying regions of high functional similarity by evaluating the shortest paths between genes in the network. We can finally assign functional roles to the miRNAs by taking their regulatory relationships into account. We thoroughly evaluated miRlastic on a cohort of head and neck cancer (HNSCC) patients provided by The Cancer Genome Atlas. We inferred an mi-/mRNA regulatory network for human papilloma virus (HPV)-associated miRNAs in HNSCC. The resulting network best enriched for experimentally validated miRNA-target interaction, when compared to common methods. Finally, the local enrichment step identified two functional clusters of miRNAs that were predicted to mediate HPV-associated dysregulation in HNSCC. Our novel approach was able to characterize distinct pathway regulations from matched miRNA and mRNA data. An R package of miRlastic was made available through: http://icb.helmholtz-muenchen.de/mirlastic.

Projection specificity in heterogeneous locus coeruleus cell populations: implications for learning and memory

PubMed Central

Uematsu, Akira; Tan, Bao Zhen

2015-01-01

Noradrenergic neurons in the locus coeruleus (LC) play a critical role in many functions including learning and memory. This relatively small population of cells sends widespread projections throughout the brain including to a number of regions such as the amygdala which is involved in emotional associative learning and the medial prefrontal cortex which is important for facilitating flexibility when learning rules change. LC noradrenergic cells participate in both of these functions, but it is not clear how this small population of neurons modulates these partially distinct processes. Here we review anatomical, behavioral, and electrophysiological studies to assess how LC noradrenergic neurons regulate these different aspects of learning and memory. Previous work has demonstrated that subpopulations of LC noradrenergic cells innervate specific brain regions suggesting heterogeneity of function in LC neurons. Furthermore, noradrenaline in mPFC and amygdala has distinct effects on emotional learning and cognitive flexibility. Finally, neural recording data show that LC neurons respond during associative learning and when previously learned task contingencies change. Together, these studies suggest a working model in which distinct and potentially opposing subsets of LC neurons modulate particular learning functions through restricted efferent connectivity with amygdala or mPFC. This type of model may provide a general framework for understanding other neuromodulatory systems, which also exhibit cell type heterogeneity and projection specificity. PMID:26330494

Histone H3 K79 methylation states play distinct roles in UV-induced sister chromatid exchange and cell cycle checkpoint arrest in Saccharomyces cerevisiae

PubMed Central

Rossodivita, Alyssa A.; Boudoures, Anna L.; Mecoli, Jonathan P.; Steenkiste, Elizabeth M.; Karl, Andrea L.; Vines, Eudora M.; Cole, Arron M.; Ansbro, Megan R.; Thompson, Jeffrey S.

2014-01-01

Histone post-translational modifications have been shown to contribute to DNA damage repair. Prior studies have suggested that specific H3K79 methylation states play distinct roles in the response to UV-induced DNA damage. To evaluate these observations, we examined the effect of altered H3K79 methylation patterns on UV-induced G1/S checkpoint response and sister chromatid exchange (SCE). We found that the di- and trimethylated states both contribute to activation of the G1/S checkpoint to varying degrees, depending on the synchronization method, although methylation is not required for checkpoint in response to high levels of UV damage. In contrast, UV-induced SCE is largely a product of the trimethylated state, which influences the usage of gene conversion versus popout mechanisms. Regulation of H3K79 methylation by H2BK123 ubiquitylation is important for both checkpoint function and SCE. H3K79 methylation is not required for the repair of double-stranded breaks caused by transient HO endonuclease expression, but does play a modest role in survival from continuous exposure. The overall results provide evidence for the participation of H3K79 methylation in UV-induced recombination repair and checkpoint activation, and further indicate that the di- and trimethylation states play distinct roles in these DNA damage response pathways. PMID:24748660

Two distinct roles of mitogen-activated protein kinases in platelets and a novel Rac1-MAPK–dependent integrin outside-in retractile signaling pathway

PubMed Central

Flevaris, Panagiotis; Li, Zhenyu; Zhang, Guoying; Zheng, Yi; Liu, Junling

2009-01-01

Mitogen-activated protein kinases (MAPK), p38, and extracellular stimuli-responsive kinase (ERK), are acutely but transiently activated in platelets by platelet agonists, and the agonist-induced platelet MAPK activation is inhibited by ligand binding to the integrin αIIbβ3. Here we show that, although the activation of MAPK, as indicated by MAPK phosphorylation, is initially inhibited after ligand binding to integrin αIIbβ3, integrin outside-insignaling results in a late but sustained activation of MAPKs in platelets. Furthermore, we show that the early agonist-induced MAPK activation and the late integrin-mediated MAPK activation play distinct roles in different stages of platelet activation. Agonist-induced MAPK activation primarily plays an important role in stimulating secretion of platelet granules, while integrin-mediated MAPK activation is important in facilitating clot retraction. The stimulatory role of MAPK in clot retraction is mediated by stimulating myosin light chain (MLC) phosphorylation. Importantly, integrin-dependent MAPK activation, MAPK-dependent MLC phosphorylation, and clot retraction are inhibited by a Rac1 inhibitor and in Rac1 knockout platelets, indicating that integrin-induced activation of MAPK and MLC and subsequent clot retraction is Rac1-dependent. Thus, our results reveal 2 different activation mechanisms of MAPKs that are involved in distinct aspects of platelet function and a novel Rac1-MAPK–dependent cell retractile signaling pathway. PMID:18957688

Ants regulate colony spatial organization using multiple chemical road-signs

PubMed Central

Heyman, Yael; Shental, Noam; Brandis, Alexander; Hefetz, Abraham; Feinerman, Ofer

2017-01-01

Communication provides the basis for social life. In ant colonies, the prevalence of local, often chemically mediated, interactions introduces strong links between communication networks and the spatial distribution of ants. It is, however, unknown how ants identify and maintain nest chambers with distinct functions. Here, we combine individual tracking, chemical analysis and machine learning to decipher the chemical signatures present on multiple nest surfaces. We present evidence for several distinct chemical ‘road-signs' that guide the ants' movements within the dark nest. These chemical signatures can be used to classify nest chambers with different functional roles. Using behavioural manipulations, we demonstrate that at least three of these chemical signatures are functionally meaningful and allow ants from different task groups to identify their specific nest destinations, thus facilitating colony coordination and stabilization. The use of multiple chemicals that assist spatiotemporal guidance, segregation and pattern formation is abundant in multi-cellular organisms. Here, we provide a rare example for the use of these principles in the ant colony. PMID:28569746

A Synthetic DNA-Binding Domain Guides Distinct Chromatin-Modifying Small Molecules to Activate an Identical Gene Network.

PubMed

Han, Le; Pandian, Ganesh N; Chandran, Anandhakumar; Sato, Shinsuke; Taniguchi, Junichi; Kashiwazaki, Gengo; Sawatani, Yoshito; Hashiya, Kaori; Bando, Toshikazu; Xu, Yufang; Qian, Xuhong; Sugiyama, Hiroshi

2015-07-20

Synthetic dual-function ligands targeting specific DNA sequences and histone-modifying enzymes were applied to achieve regulatory control over multi-gene networks in living cells. Unlike the broad array of targeting small molecules for histone deacetylases (HDACs), few modulators are known for histone acetyltransferases (HATs), which play a central role in transcriptional control. As a novel chemical approach to induce selective HAT-regulated genes, we conjugated a DNA-binding domain (DBD) "I" to N-(4-chloro-3-trifluoromethyl-phenyl)-2-ethoxy-benzamide (CTB), an artificial HAT activator. In vitro enzyme activity assays and microarray studies were used to demonstrate that distinct functional small molecules could be transformed to have identical bioactivity when conjugated with a targeting DBD. This proof-of-concept synthetic strategy validates the switchable functions of HDACs and HATs in gene regulation and provides a molecular basis for developing versatile bioactive ligands. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Heterogeneity of Human CD4(+) T Cells Against Microbes.

PubMed

Sallusto, Federica

2016-05-20

CD4(+) T helper (Th) cells play a central role in the adaptive immune response by providing help to B cells and cytotoxic T cells and by releasing different types of cytokines in tissues to mediate protection against a wide range of pathogenic microorganisms. These functions are performed by different types of Th cells endowed with distinct migratory capacities and effector functions. Here we discuss how studies of the human T cell response to microbes have advanced our understanding of Th cell functional heterogeneity, in particular with the discovery of a distinct Th1 subset involved in the response to Mycobacteria and the characterization of two types of Th17 cells specific for extracellular bacteria or fungi. We also review new approaches to dissect at the clonal level the human CD4(+) T cell response induced by pathogens or vaccines that have revealed an unexpected degree of intraclonal diversification and propose a progressive and selective model of CD4(+) T cell differentiation.

Differential inputs to striatal cholinergic and parvalbumin interneurons imply functional distinctions

PubMed Central

Klug, Jason R; Engelhardt, Max D; Cadman, Cara N; Li, Hao; Smith, Jared B; Ayala, Sarah; Williams, Elora W; Hoffman, Hilary

2018-01-01

Striatal cholinergic (ChAT) and parvalbumin (PV) interneurons exert powerful influences on striatal function in health and disease, yet little is known about the organization of their inputs. Here using rabies tracing, electrophysiology and genetic tools, we compare the whole-brain inputs to these two types of striatal interneurons and dissect their functional connectivity in mice. ChAT interneurons receive a substantial cortical input from associative regions of cortex, such as the orbitofrontal cortex. Amongst subcortical inputs, a previously unknown inhibitory thalamic reticular nucleus input to striatal PV interneurons is identified. Additionally, the external segment of the globus pallidus targets striatal ChAT interneurons, which is sufficient to inhibit tonic ChAT interneuron firing. Finally, we describe a novel excitatory pathway from the pedunculopontine nucleus that innervates ChAT interneurons. These results establish the brain-wide direct inputs of two major types of striatal interneurons and allude to distinct roles in regulating striatal activity and controlling behavior. PMID:29714166

Ants regulate colony spatial organization using multiple chemical road-signs.

PubMed

Heyman, Yael; Shental, Noam; Brandis, Alexander; Hefetz, Abraham; Feinerman, Ofer

2017-06-01

Communication provides the basis for social life. In ant colonies, the prevalence of local, often chemically mediated, interactions introduces strong links between communication networks and the spatial distribution of ants. It is, however, unknown how ants identify and maintain nest chambers with distinct functions. Here, we combine individual tracking, chemical analysis and machine learning to decipher the chemical signatures present on multiple nest surfaces. We present evidence for several distinct chemical 'road-signs' that guide the ants' movements within the dark nest. These chemical signatures can be used to classify nest chambers with different functional roles. Using behavioural manipulations, we demonstrate that at least three of these chemical signatures are functionally meaningful and allow ants from different task groups to identify their specific nest destinations, thus facilitating colony coordination and stabilization. The use of multiple chemicals that assist spatiotemporal guidance, segregation and pattern formation is abundant in multi-cellular organisms. Here, we provide a rare example for the use of these principles in the ant colony.

LGN plays distinct roles in oral epithelial stratification, filiform papilla morphogenesis and hair follicle development

PubMed Central

Lough, Kendall J.; Patel, Jeet H.; Descovich, Carlos Patiño; Curtis, T. Anthony

2016-01-01

Oral epithelia protect against constant challenges by bacteria, viruses, toxins and injury while also contributing to the formation of ectodermal appendages such as teeth, salivary glands and lingual papillae. Despite increasing evidence that differentiation pathway genes are frequently mutated in oral cancers, comparatively little is known about the mechanisms that regulate normal oral epithelial development. Here, we characterize oral epithelial stratification and describe multiple distinct functions for the mitotic spindle orientation gene LGN (Gpsm2) in promoting differentiation and tissue patterning in the mouse oral cavity. Similar to its function in epidermis, apically localized LGN directs perpendicular divisions that promote stratification of the palatal, buccogingival and ventral tongue epithelia. Surprisingly, however, in dorsal tongue LGN is predominantly localized basally, circumferentially or bilaterally and promotes planar divisions. Loss of LGN disrupts the organization and morphogenesis of filiform papillae but appears to be dispensable for embryonic hair follicle development. Thus, LGN has crucial tissue-specific functions in patterning surface ectoderm and its appendages by controlling division orientation. PMID:27317810

Reconfiguration of parietal circuits with cognitive tutoring in elementary school children

PubMed Central

Jolles, Dietsje; Supekar, Kaustubh; Richardson, Jennifer; Tenison, Caitlin; Ashkenazi, Sarit; Rosenberg-Lee, Miriam; Fuchs, Lynn; Menon, Vinod

2016-01-01

Cognitive development is shaped by brain plasticity during childhood, yet little is known about changes in large-scale functional circuits associated with learning in academically relevant cognitive domains such as mathematics. Here, we investigate plasticity of intrinsic brain circuits associated with one-on-one math tutoring and its relation to individual differences in children’s learning. We focused on functional circuits associated with the intraparietal sulcus (IPS) and angular gyrus (AG), cytoarchitectonically distinct subdivisions of the human parietal cortex with different roles in numerical cognition. Tutoring improved performance and strengthened IPS connectivity with the lateral prefrontal cortex, ventral temporal-occipital cortex, and hippocampus. Crucially, increased IPS connectivity was associated with individual performance gains, highlighting the behavioral significance of plasticity in IPS circuits. Tutoring-related changes in IPS connectivity were distinct from those of the adjacent AG, which did not predict performance gains. Our findings provide new insights into plasticity of functional brain circuits associated with the development of specialized cognitive skills in children. PMID:27618765

Reconfiguration of parietal circuits with cognitive tutoring in elementary school children.

PubMed

Jolles, Dietsje; Supekar, Kaustubh; Richardson, Jennifer; Tenison, Caitlin; Ashkenazi, Sarit; Rosenberg-Lee, Miriam; Fuchs, Lynn; Menon, Vinod

2016-10-01

Cognitive development is shaped by brain plasticity during childhood, yet little is known about changes in large-scale functional circuits associated with learning in academically relevant cognitive domains such as mathematics. Here, we investigate plasticity of intrinsic brain circuits associated with one-on-one math tutoring and its relation to individual differences in children's learning. We focused on functional circuits associated with the intraparietal sulcus (IPS) and angular gyrus (AG), cytoarchitectonically distinct subdivisions of the human parietal cortex with different roles in numerical cognition. Tutoring improved performance and strengthened IPS connectivity with the lateral prefrontal cortex, ventral temporal-occipital cortex, and hippocampus. Crucially, increased IPS connectivity was associated with individual performance gains, highlighting the behavioral significance of plasticity in IPS circuits. Tutoring-related changes in IPS connectivity were distinct from those of the adjacent AG, which did not predict performance gains. Our findings provide new insights into plasticity of functional brain circuits associated with the development of specialized cognitive skills in children. Copyright © 2016 Elsevier Ltd. All rights reserved.

Dopamine in motivational control: rewarding, aversive, and alerting

PubMed Central

Bromberg-Martin, Ethan S.; Matsumoto, Masayuki; Hikosaka, Okihide

2010-01-01

SUMMARY Midbrain dopamine neurons are well known for their strong responses to rewards and their critical role in positive motivation. It has become increasingly clear, however, that dopamine neurons also transmit signals related to salient but non-rewarding experiences such as aversive and alerting events. Here we review recent advances in understanding the reward and non-reward functions of dopamine. Based on this data, we propose that dopamine neurons come in multiple types that are connected with distinct brain networks and have distinct roles in motivational control. Some dopamine neurons encode motivational value, supporting brain networks for seeking, evaluation, and value learning. Others encode motivational salience, supporting brain networks for orienting, cognition, and general motivation. Both types of dopamine neurons are augmented by an alerting signal involved in rapid detection of potentially important sensory cues. We hypothesize that these dopaminergic pathways for value, salience, and alerting cooperate to support adaptive behavior. PMID:21144997

Antibody-based analysis reveals “filamentous vs. non-filamentous” and “cytoplasmic vs. nuclear” crosstalk of cytoskeletal proteins

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

Kumeta, Masahiro, E-mail: kumeta@lif.kyoto-u.ac.jp; Hirai, Yuya; Yoshimura, Shige H.

2013-12-10

To uncover the molecular composition and dynamics of the functional scaffold for the nucleus, three fractions of biochemically-stable nuclear protein complexes were extracted and used as immunogens to produce a variety of monoclonal antibodies. Many helix-based cytoskeletal proteins were identified as antigens, suggesting their dynamic contribution to nuclear architecture and function. Interestingly, sets of antibodies distinguished distinct subcellular localization of a single isoform of certain cytoskeletal proteins; distinct molecular forms of keratin and actinin were found in the nucleus. Their nuclear shuttling properties were verified by the apparent nuclear accumulations under inhibition of CRM1-dependent nuclear export. Nuclear keratins do notmore » take an obvious filamentous structure, as was revealed by non-filamentous cytoplasmic keratin-specific monoclonal antibody. These results suggest the distinct roles of the helix-based cytoskeletal proteins in the nucleus. - Highlights: • A set of monoclonal antibodies were raised against nuclear scaffold proteins. • Helix-based cytoskeletal proteins were involved in nuclear scaffold. • Many cytoskeletal components shuttle into the nucleus in a CRM1-dependent manner. • Sets of antibodies distinguished distinct subcellular localization of a single isoform. • Nuclear keratin is soluble and does not form an obvious filamentous structure.« less

Distinct Roles of Cervical Epithelia and Stroma in Pregnancy and Parturition.

PubMed

Nallasamy, Shanmugasundaram; Mahendroo, Mala

2017-03-01

Through pregnancy the cervix must simultaneously remain competent for pregnancy maintenance and yet become progressively compliant to ensure on time parturition. Cervical changes precede not only term but also preterm birth. Thus, an understanding of the molecular mechanisms by which the cervix maintains the delicate balance between competence and compliance is required to prevent the potential for lifelong health complications that can result from a premature birth. Recent advances and accumulating evidence support distinct roles for the cervical epithelia and stroma in sustaining competence. Concurrently, structural reorganization of the stromal extracellular matrix allows for the gradual decline in tissue compliance. In recent years, advances in our understanding of the cervical remodeling process has resulted from the collective insights derived from biological, genomics, engineering, and mathematical modeling studies on clinical samples and animal models. This review will highlight recent literature that advances understanding of (1) the importance of barrier function in the lower female reproductive tract in protection against ascending infection, (2) cellular and extracellular matrix changes in the cervical stroma that influence the mechanical function of the cervix, (3) the potential translation of biological insights into clinical tools that impact preterm birth, and (4) the distinction between term and specific pathways of preterm birth. Finally, we present a discussion of future areas of investigation that are likely to advance understanding and lead to the development of clinical tools for accurate detection and prevention of premature birth. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

The roles of the olivocerebellar pathway in motor learning and motor control. A consensus paper

PubMed Central

Lang, Eric J.; Apps, Richard; Bengtsson, Fredrik; Cerminara, Nadia L.; De Zeeuw, Chris I.; Ebner, Timothy J.; Heck, Detlef H.; Jaeger, Dieter; Jörntell, Henrik; Kawato, Mitsuo; Otis, Thomas S.; Ozyildirim, Ozgecan; Popa, Laurentiu S.; Reeves, Alexander M.B.; Schweighofer, Nicolas; Sugihara, Izumi; Xiao, Jianqiang

2016-01-01

For many decades the predominant view in the cerebellar field has been that the olivocerebellar system's primary function is to induce plasticity in the cerebellar cortex, specifically, at the parallel fiber-Purkinje cell synapse. However, it has also long been proposed that the olivocerebellar system participates directly in motor control by helping to shape ongoing motor commands being issued by the cerebellum. Evidence consistent with both hypotheses exists; however, they are often investigated as mutually exclusive alternatives. In contrast, here we take the perspective that the olivocerebellar system can contribute to both the motor learning and motor control functions of the cerebellum, and might also play a role in development. We then consider the potential problems and benefits of its having multiple functions. Moreover, we discuss how its distinctive characteristics (e.g., low firing rates, synchronization, variable complex spike waveform) make it more or less suitable for one or the other of these functions, and why its having a dual role makes sense from an evolutionary perspective. We did not attempt to reach a consensus on the specific role(s) the olivocerebellar system plays in different types of movements, as that will ultimately be determined experimentally; however, collectively, the various contributions highlight the flexibility of the olivocerebellar system, and thereby suggest it has the potential to act in both the motor learning and motor control functions of the cerebellum. PMID:27193702

Parsing the Role of the Hippocampus in Approach-Avoidance Conflict.

PubMed

Loh, Eleanor; Kurth-Nelson, Zeb; Berron, David; Dayan, Peter; Duzel, Emrah; Dolan, Ray; Guitart-Masip, Marc

2017-01-01

The hippocampus plays a central role in the approach-avoidance conflict that is central to the genesis of anxiety. However, its exact functional contribution has yet to be identified. We designed a novel gambling task that generated approach-avoidance conflict while controlling for spatial processing. We fit subjects' behavior using a model that quantified the subjective values of choice options, and recorded neural signals using functional magnetic resonance imaging (fMRI). Distinct functional signals were observed in anterior hippocampus, with inferior hippocampus selectively recruited when subjects rejected a gamble, to a degree that covaried with individual differences in anxiety. The superior anterior hippocampus, in contrast, uniquely demonstrated value signals that were potentiated in the context of approach-avoidance conflict. These results implicate the anterior hippocampus in behavioral avoidance and choice monitoring, in a manner relevant to understanding its role in anxiety. Our findings highlight interactions between subregions of the hippocampus as an important focus for future study. © The Author 2016. Published by Oxford University Press.

Parsing the Role of the Hippocampus in Approach–Avoidance Conflict

PubMed Central

Loh, Eleanor; Kurth-Nelson, Zeb; Berron, David; Dayan, Peter; Duzel, Emrah; Dolan, Ray; Guitart-Masip, Marc

2017-01-01

Abstract The hippocampus plays a central role in the approach–avoidance conflict that is central to the genesis of anxiety. However, its exact functional contribution has yet to be identified. We designed a novel gambling task that generated approach–avoidance conflict while controlling for spatial processing. We fit subjects’ behavior using a model that quantified the subjective values of choice options, and recorded neural signals using functional magnetic resonance imaging (fMRI). Distinct functional signals were observed in anterior hippocampus, with inferior hippocampus selectively recruited when subjects rejected a gamble, to a degree that covaried with individual differences in anxiety. The superior anterior hippocampus, in contrast, uniquely demonstrated value signals that were potentiated in the context of approach–avoidance conflict. These results implicate the anterior hippocampus in behavioral avoidance and choice monitoring, in a manner relevant to understanding its role in anxiety. Our findings highlight interactions between subregions of the hippocampus as an important focus for future study. PMID:27993819

The multifaceted role of the renal mononuclear phagocyte system.

PubMed

Viehmann, Susanne F; Böhner, Alexander M C; Kurts, Christian; Brähler, Sebastian

2018-04-22

The kidney contains a large and complex network of mononuclear phagocytes, which includes dendritic cells (DCs) and macrophages (MØs). The distinction between these cell types is traditionally based on the expression of molecular markers and morphology. However, several classification systems are used in parallel to identify DCs and MØs, leading to considerable uncertainty about their identity and functional roles. The discovery that a substantial proportion of macrophages in tissues like the kidney are embryonically derived further complicates the situation. Recent studies have used newly identified transcription factors such as ZBTB46 and lineage tracing techniques for classifying mononuclear phagocytes. These approaches have shed new light on the functional specialization of these cells in health and disease, uncovered an influence of the renal microenvironment and revealed considerable cellular plasticity, especially in inflammatory situations. In this review, the current knowledge about the developmental origins and versatile functional roles of DCs and MØs in kidney homeostasis and disease is discussed. Copyright © 2018 Elsevier Inc. All rights reserved.

Non-equivalence of Wnt and R-spondin ligands during Lgr5+ intestinal stem-cell self-renewal.

PubMed

Yan, Kelley S; Janda, Claudia Y; Chang, Junlei; Zheng, Grace X Y; Larkin, Kathryn A; Luca, Vincent C; Chia, Luis A; Mah, Amanda T; Han, Arnold; Terry, Jessica M; Ootani, Akifumi; Roelf, Kelly; Lee, Mark; Yuan, Jenny; Li, Xiao; Bolen, Christopher R; Wilhelmy, Julie; Davies, Paige S; Ueno, Hiroo; von Furstenberg, Richard J; Belgrader, Phillip; Ziraldo, Solongo B; Ordonez, Heather; Henning, Susan J; Wong, Melissa H; Snyder, Michael P; Weissman, Irving L; Hsueh, Aaron J; Mikkelsen, Tarjei S; Garcia, K Christopher; Kuo, Calvin J

2017-05-11

The canonical Wnt/β-catenin signalling pathway governs diverse developmental, homeostatic and pathological processes. Palmitoylated Wnt ligands engage cell-surface frizzled (FZD) receptors and LRP5 and LRP6 co-receptors, enabling β-catenin nuclear translocation and TCF/LEF-dependent gene transactivation. Mutations in Wnt downstream signalling components have revealed diverse functions thought to be carried out by Wnt ligands themselves. However, redundancy between the 19 mammalian Wnt proteins and 10 FZD receptors and Wnt hydrophobicity have made it difficult to attribute these functions directly to Wnt ligands. For example, individual mutations in Wnt ligands have not revealed homeostatic phenotypes in the intestinal epithelium-an archetypal canonical, Wnt pathway-dependent, rapidly self-renewing tissue, the regeneration of which is fueled by proliferative crypt Lgr5 + intestinal stem cells (ISCs). R-spondin ligands (RSPO1-RSPO4) engage distinct LGR4-LGR6, RNF43 and ZNRF3 receptor classes, markedly potentiate canonical Wnt/β-catenin signalling, and induce intestinal organoid growth in vitro and Lgr5 + ISCs in vivo. However, the interchangeability, functional cooperation and relative contributions of Wnt versus RSPO ligands to in vivo canonical Wnt signalling and ISC biology remain unknown. Here we identify the functional roles of Wnt and RSPO ligands in the intestinal crypt stem-cell niche. We show that the default fate of Lgr5 + ISCs is to differentiate, unless both RSPO and Wnt ligands are present. However, gain-of-function studies using RSPO ligands and a new non-lipidated Wnt analogue reveal that these ligands have qualitatively distinct, non-interchangeable roles in ISCs. Wnt proteins are unable to induce Lgr5 + ISC self-renewal, but instead confer a basal competency by maintaining RSPO receptor expression that enables RSPO ligands to actively drive and specify the extent of stem-cell expansion. This functionally non-equivalent yet cooperative interaction between Wnt and RSPO ligands establishes a molecular precedent for regulation of mammalian stem cells by distinct priming and self-renewal factors, with broad implications for precise control of tissue regeneration.

Evolution and functional diversification of fructose bisphosphate aldolase genes in photosynthetic marine diatoms.

PubMed

Allen, Andrew E; Moustafa, Ahmed; Montsant, Anton; Eckert, Angelika; Kroth, Peter G; Bowler, Chris

2012-01-01

Diatoms and other chlorophyll-c containing, or chromalveolate, algae are among the most productive and diverse phytoplankton in the ocean. Evolutionarily, chlorophyll-c algae are linked through common, although not necessarily monophyletic, acquisition of plastid endosymbionts of red as well as most likely green algal origin. There is also strong evidence for a relatively high level of lineage-specific bacterial gene acquisition within chromalveolates. Therefore, analyses of gene content and derivation in chromalveolate taxa have indicated particularly diverse origins of their overall gene repertoire. As a single group of functionally related enzymes spanning two distinct gene families, fructose 1,6-bisphosphate aldolases (FBAs) illustrate the influence on core biochemical pathways of specific evolutionary associations among diatoms and other chromalveolates with various plastid-bearing and bacterial endosymbionts. Protein localization and activity, gene expression, and phylogenetic analyses indicate that the pennate diatom Phaeodactylum tricornutum contains five FBA genes with very little overall functional overlap. Three P. tricornutum FBAs, one class I and two class II, are plastid localized, and each appears to have a distinct evolutionary origin as well as function. Class I plastid FBA appears to have been acquired by chromalveolates from a red algal endosymbiont, whereas one copy of class II plastid FBA is likely to have originated from an ancient green algal endosymbiont. The other copy appears to be the result of a chromalveolate-specific gene duplication. Plastid FBA I and chromalveolate-specific class II plastid FBA are localized in the pyrenoid region of the chloroplast where they are associated with β-carbonic anhydrase, which is known to play a significant role in regulation of the diatom carbon concentrating mechanism. The two pyrenoid-associated FBAs are distinguished by contrasting gene expression profiles under nutrient limiting compared with optimal CO2 fixation conditions, suggestive of a distinct specialized function for each. Cytosolically localized FBAs in P. tricornutum likely play a role in glycolysis and cytoskeleton function and seem to have originated from the stramenopile host cell and from diatom-specific bacterial gene transfer, respectively.

Evolution and Functional Diversification of Fructose Bisphosphate Aldolase Genes in Photosynthetic Marine Diatoms

PubMed Central

Allen, Andrew E.; Moustafa, Ahmed; Montsant, Anton; Eckert, Angelika; Kroth, Peter G.; Bowler, Chris

2012-01-01

Diatoms and other chlorophyll-c containing, or chromalveolate, algae are among the most productive and diverse phytoplankton in the ocean. Evolutionarily, chlorophyll-c algae are linked through common, although not necessarily monophyletic, acquisition of plastid endosymbionts of red as well as most likely green algal origin. There is also strong evidence for a relatively high level of lineage-specific bacterial gene acquisition within chromalveolates. Therefore, analyses of gene content and derivation in chromalveolate taxa have indicated particularly diverse origins of their overall gene repertoire. As a single group of functionally related enzymes spanning two distinct gene families, fructose 1,6-bisphosphate aldolases (FBAs) illustrate the influence on core biochemical pathways of specific evolutionary associations among diatoms and other chromalveolates with various plastid-bearing and bacterial endosymbionts. Protein localization and activity, gene expression, and phylogenetic analyses indicate that the pennate diatom Phaeodactylum tricornutum contains five FBA genes with very little overall functional overlap. Three P. tricornutum FBAs, one class I and two class II, are plastid localized, and each appears to have a distinct evolutionary origin as well as function. Class I plastid FBA appears to have been acquired by chromalveolates from a red algal endosymbiont, whereas one copy of class II plastid FBA is likely to have originated from an ancient green algal endosymbiont. The other copy appears to be the result of a chromalveolate-specific gene duplication. Plastid FBA I and chromalveolate-specific class II plastid FBA are localized in the pyrenoid region of the chloroplast where they are associated with β-carbonic anhydrase, which is known to play a significant role in regulation of the diatom carbon concentrating mechanism. The two pyrenoid-associated FBAs are distinguished by contrasting gene expression profiles under nutrient limiting compared with optimal CO2 fixation conditions, suggestive of a distinct specialized function for each. Cytosolically localized FBAs in P. tricornutum likely play a role in glycolysis and cytoskeleton function and seem to have originated from the stramenopile host cell and from diatom-specific bacterial gene transfer, respectively. PMID:21903677

ATP-dependent chromatin assembly is functionally distinct from chromatin remodeling

PubMed Central

Torigoe, Sharon E; Patel, Ashok; Khuong, Mai T; Bowman, Gregory D; Kadonaga, James T

2013-01-01

Chromatin assembly involves the combined action of ATP-dependent motor proteins and histone chaperones. Because motor proteins in chromatin assembly also function as chromatin remodeling factors, we investigated the relationship between ATP-driven chromatin assembly and chromatin remodeling in the generation of periodic nucleosome arrays. We found that chromatin remodeling-defective Chd1 motor proteins are able to catalyze ATP-dependent chromatin assembly. The resulting nucleosomes are not, however, spaced in periodic arrays. Wild-type Chd1, but not chromatin remodeling-defective Chd1, can catalyze the conversion of randomly-distributed nucleosomes into periodic arrays. These results reveal a functional distinction between ATP-dependent nucleosome assembly and chromatin remodeling, and suggest a model for chromatin assembly in which randomly-distributed nucleosomes are formed by the nucleosome assembly function of Chd1, and then regularly-spaced nucleosome arrays are generated by the chromatin remodeling activity of Chd1. These findings uncover an unforeseen level of specificity in the role of motor proteins in chromatin assembly. DOI: http://dx.doi.org/10.7554/eLife.00863.001 PMID:23986862

Unraveling Synaptic GCaMP Signals: Differential Excitability and Clearance Mechanisms Underlying Distinct Ca2+ Dynamics in Tonic and Phasic Excitatory, and Aminergic Modulatory Motor Terminals in Drosophila

PubMed Central

Xing, Xiaomin

2018-01-01

Abstract GCaMP is an optogenetic Ca2+ sensor widely used for monitoring neuronal activities but the precise physiological implications of GCaMP signals remain to be further delineated among functionally distinct synapses. The Drosophila neuromuscular junction (NMJ), a powerful genetic system for studying synaptic function and plasticity, consists of tonic and phasic glutamatergic and modulatory aminergic motor terminals of distinct properties. We report a first simultaneous imaging and electric recording study to directly contrast the frequency characteristics of GCaMP signals of the three synapses for physiological implications. Different GCaMP variants were applied in genetic and pharmacological perturbation experiments to examine the Ca2+ influx and clearance processes underlying the GCaMP signal. Distinct mutational and drug effects on GCaMP signals indicate differential roles of Na+ and K+ channels, encoded by genes including paralytic (para), Shaker (Sh), Shab, and ether-a-go-go (eag), in excitability control of different motor terminals. Moreover, the Ca2+ handling properties reflected by the characteristic frequency dependence of the synaptic GCaMP signals were determined to a large extent by differential capacity of mitochondria-powered Ca2+ clearance mechanisms. Simultaneous focal recordings of synaptic activities further revealed that GCaMPs were ineffective in tracking the rapid dynamics of Ca2+ influx that triggers transmitter release, especially during low-frequency activities, but more adequately reflected cytosolic residual Ca2+ accumulation, a major factor governing activity-dependent synaptic plasticity. These results highlight the vast range of GCaMP response patterns in functionally distinct synaptic types and provide relevant information for establishing basic guidelines for the physiological interpretations of presynaptic GCaMP signals from in situ imaging studies. PMID:29464198

The impact of aging on epithelial barriers.

PubMed

Parrish, Alan R

2017-10-02

The epithelium has many critical roles in homeostasis, including an essential responsibility in establishing tissue barriers. In addition to the fundamental role in separating internal from external environment, epithelial barriers maintain nutrient, fluid, electrolyte and metabolic waste balance in multiple organs. While, by definition, barrier function is conserved, the structure of the epithelium varies across organs. For example, the skin barrier is a squamous layer of cells with distinct structural features, while the lung barrier is composed of a very thin single cell to minimize diffusion space. With the increased focus on age-dependent alterations in organ structure and function, there is an emerging interest in the impact of age on epithelial barriers. This review will focus on the impact of aging on the epithelial barrier of several organs, including the skin, lung, gastrointestinal tract and the kidney, at a structural and functional level.

Strain-resolved microbial community proteomics reveals simultaneous aerobic and anaerobic function during gastrointestinal tract colonization of a preterm infant

DOE PAGES

Brooks, Brandon; Mueller, R. S.; Young, Jacque C.; ...

2015-07-01

While there has been growing interest in the gut microbiome in recent years, it remains unclear whether closely related species and strains have similar or distinct functional roles and if organisms capable of both aerobic and anaerobic growth do so simultaneously. To investigate these questions, we implemented a high-throughput mass spectrometry-based proteomics approach to identify proteins in fecal samples collected on days of life 13 21 from an infant born at 28 weeks gestation. No prior studies have coupled strain-resolved community metagenomics to proteomics for such a purpose. Sequences were manually curated to resolve the genomes of two strains ofmore » Citrobacter that were present during the later stage of colonization. Proteome extracts from fecal samples were processed via a nano-2D-LC-MS/MS and peptides were identified based on information predicted from the genome sequences for the dominant organisms, Serratia and the two Citrobacter strains. These organisms are facultative anaerobes, and proteomic information indicates the utilization of both aerobic and anaerobic metabolisms throughout the time series. This may indicate growth in distinct niches within the gastrointestinal tract. We uncovered differences in the physiology of coexisting Citrobacter strains, including differences in motility and chemotaxis functions. Additionally, for both Citrobacter strains we resolved a community-essential role in vitamin metabolism and a predominant role in propionate production. Finally, in this case study we detected differences between genome abundance and activity levels for the dominant populations. This underlines the value in layering proteomic information over genetic potential.« less

Essential role of grim-led programmed cell death for the establishment of corazonin-producing peptidergic nervous system during embryogenesis and metamorphosis in Drosophila melanogaster

PubMed Central

Lee, Gyunghee; Sehgal, Ritika; Wang, Zixing; Nair, Sudershana; Kikuno, Keiko; Chen, Chun-Hong; Hay, Bruce; Park, Jae H.

2013-01-01

Summary In Drosophila melanogaster, combinatorial activities of four death genes, head involution defective (hid), reaper (rpr), grim, and sickle (skl), have been known to play crucial roles in the developmentally regulated programmed cell death (PCD) of various tissues. However, different expression patterns of the death genes also suggest distinct functions played by each. During early metamorphosis, a great number of larval neurons unfit for adult life style are removed by PCD. Among them are eight pairs of corazonin-expressing larval peptidergic neurons in the ventral nerve cord (vCrz). To reveal death genes responsible for the PCD of vCrz neurons, we examined extant and recently available mutations as well as RNA interference that disrupt functions of single or multiple death genes. We found grim as a chief proapoptotic gene and skl and rpr as minor ones. The function of grim is also required for PCD of the mitotic sibling cells of the vCrz neuronal precursors (EW3-sib) during embryonic neurogenesis. An intergenic region between grim and rpr, which, it has been suggested, may enhance expression of three death genes in embryonic neuroblasts, appears to play a role for the vCrz PCD, but not for the EW3-sib cell death. The death of vCrz neurons and EW3-sib is triggered by ecdysone and the Notch signaling pathway, respectively, suggesting distinct regulatory mechanisms of grim expression in a cell- and developmental stage-specific manner. PMID:23519152

Src family kinase expression and subcellular localization in macrophages: implications for their role in CSF-1-induced macrophage migration.

PubMed

Dwyer, Amy R; Mouchemore, Kellie A; Steer, James H; Sunderland, Andrew J; Sampaio, Natalia G; Greenland, Eloise L; Joyce, David A; Pixley, Fiona J

2016-07-01

A major role of colony-stimulating factor-1 is to stimulate the differentiation of mononuclear phagocytic lineage cells into adherent, motile, mature macrophages. The colony-stimulating factor-1 receptor transduces colony-stimulating factor-1 signaling, and we have shown previously that phosphatidylinositol 3-kinase p110δ is a critical mediator of colony-stimulating factor-1-stimulated motility through the colony-stimulating factor-1 receptor pY721 motif. Src family kinases are also implicated in the regulation of macrophage motility and in colony-stimulating factor-1 receptor signaling, although functional redundancy of the multiple SFKs expressed in macrophages makes it challenging to delineate their specific functions. We report a comprehensive analysis of individual Src family kinase expression in macrophage cell lines and primary macrophages and demonstrate colony-stimulating factor-1-induced changes in Src family kinase subcellular localization, which provides clues to their distinct and redundant functions in macrophages. Moreover, expression of individual Src family kinases is both species specific and dependent on colony-stimulating factor-1-induced macrophage differentiation. Hck associated with the activated colony-stimulating factor-1 receptor, whereas Lyn associated with the receptor in a constitutive manner. Consistent with this, inhibitor studies revealed that Src family kinases were important for both colony-stimulating factor-1 receptor activation and colony-stimulating factor-1-induced macrophage spreading, motility, and invasion. Distinct colony-stimulating factor-1-induced changes in the subcellular localization of individual SFKs suggest specific roles for these Src family kinases in the macrophage response to colony-stimulating factor-1. © Society for Leukocyte Biology.

Interference Effects Demonstrate Distinct Roles for Visual and Motor Imagery during the Mental Representation of Human Action

ERIC Educational Resources Information Center

Stevens, J.A.

2005-01-01

Four experiments were completed to characterize the utilization of visual imagery and motor imagery during the mental representation of human action. In Experiment 1, movement time functions for a motor imagery human locomotion task conformed to a speed-accuracy trade-off similar to Fitts' Law, whereas those for a visual imagery object motion task…

Disentangling Neural Sources of the Motor Interference Effect in High Functioning Autism: An EEG-Study

ERIC Educational Resources Information Center

Deschrijver, Eliane; Wiersema, Jan R.; Brass, Marcel

2017-01-01

The role of imitation in autism spectrum disorder (ASD) is controversial. Researchers have argued that deficient control of self- and other-related motor representations (self-other distinction) might explain imitation difficulties. In a recent EEG study, we showed that control of imitation relies on high-level as well as on low-level cognitive…

Role of Jumonji c-domain containing protein 6 (JMJD6) in infectivity of foot-and-mouth disease virus

USDA-ARS?s Scientific Manuscript database

Foot-and-mouth disease virus (FMDV) can utilize as many as three distinct groups of receptor molecules to attach and enter a susceptible host cell. Four integrin heterodimers (alphavBeta1, alphavBeta3, alphavBeta6, and alphavBeta8) can function as the primary receptor for FMDV field strains. FMDV ...

Are Children with "Pure" Generalized Anxiety Disorder Impaired? A Comparison with Comorbid and Healthy Children

ERIC Educational Resources Information Center

Alfano, Candice A.

2012-01-01

Despite the approach of the "Diagnostic and Statistical Manual of Mental Disorders" (5th ed.), generalized anxiety disorder (GAD) of childhood continues to face questions as to whether it should be considered a distinct clinical disorder. A potentially critical issue embedded in this debate involves the role of functional impairment which has yet…

The Molecular Pathway Regulating Bergmann Glia and Folia Generation in the Cerebellum.

PubMed

Leung, Alan W; Li, James Y H

2018-02-01

Evolution of complex behaviors in higher vertebrates and primates require the development of sophisticated neuronal circuitry and the expansion of brain surface area to accommodate the vast number of neuronal and glial populations. To achieve these goals, the neocortex in primates and the cerebellum in amniotes have developed specialized types of basal progenitors to aid the folding of their cortices. In the cerebellum, Bergmann glia constitute such a basal progenitor population, having a distinctive morphology and playing a critical role in cerebellar corticogenesis. Here, we review recent studies on the induction of Bergmann glia and their crucial role in mediating folding of the cerebellar cortex. These studies uncover a key function of FGF-ERK-ETV signaling cascade in the transformation of Bergmann glia from radial glia in the ventricular zone. Remarkably, in the neocortex, the same signaling axis operates to facilitate the transformation of ventricular radial glia into basal radial glia, a Bergmann glia-like basal progenitor population, which have been implicated in the establishment of neocortical gyri. These new findings draw a striking similarity in the function and ontogeny of the two basal progenitor populations born in distinct brain compartments.

Distinct roles of 1α and 1β heavy chains of the inner arm dynein I1 of Chlamydomonas flagella

PubMed Central

Toba, Shiori; Fox, Laura A.; Sakakibara, Hitoshi; Porter, Mary E.; Oiwa, Kazuhiro; Sale, Winfield S.

2011-01-01

The Chlamydomonas I1 dynein is a two-headed inner dynein arm important for the regulation of flagellar bending. Here we took advantage of mutant strains lacking either the 1α or 1β motor domain to distinguish the functional role of each motor domain. Single- particle electronic microscopic analysis confirmed that both the I1α and I1β complexes are single headed with similar ringlike, motor domain structures. Despite similarity in structure, however, the I1β complex has severalfold higher ATPase activity and microtubule gliding motility compared to the I1α complex. Moreover, in vivo measurement of microtubule sliding in axonemes revealed that the loss of the 1β motor results in a more severe impairment in motility and failure in regulation of microtubule sliding by the I1 dynein phosphoregulatory mechanism. The data indicate that each I1 motor domain is distinct in function: The I1β motor domain is an effective motor required for wild-type microtubule sliding, whereas the I1α motor domain may be responsible for local restraint of microtubule sliding. PMID:21148301

BMP Sustains Embryonic Stem Cell Self-Renewal through Distinct Functions of Different Krüppel-like Factors.

PubMed

Morikawa, Masato; Koinuma, Daizo; Mizutani, Anna; Kawasaki, Natsumi; Holmborn, Katarina; Sundqvist, Anders; Tsutsumi, Shuichi; Watabe, Tetsuro; Aburatani, Hiroyuki; Heldin, Carl-Henrik; Miyazono, Kohei

2016-01-12

Bone morphogenetic protein (BMP) signaling exerts paradoxical roles in pluripotent stem cells (PSCs); it sustains self-renewal of mouse embryonic stem cells (ESCs), while it induces differentiation in other PSCs, including human ESCs. Here, we revisit the roles of BMP-4 using mouse ESCs (mESCs) in naive and primed states. SMAD1 and SMAD5, which transduce BMP signals, recognize enhancer regions together with KLF4 and KLF5 in naive mESCs. KLF4 physically interacts with SMAD1 and suppresses its activity. Consistently, a subpopulation of cells with active BMP-SMAD can be ablated without disturbing the naive state of the culture. Moreover, Smad1/5 double-knockout mESCs stay in the naive state, indicating that the BMP-SMAD pathway is dispensable for it. In contrast, the MEK5-ERK5 pathway mediates BMP-4-induced self-renewal of mESCs by inducing Klf2, a critical factor for the ground state pluripotency. Our study illustrates that BMP exerts its self-renewing effect through distinct functions of different Krüppel-like factors. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Layer-specific input to distinct cell types in layer 6 of monkey primary visual cortex.

PubMed

Briggs, F; Callaway, E M

2001-05-15

Layer 6 of monkey V1 contains a physiologically and anatomically diverse population of excitatory pyramidal neurons. Distinctive arborization patterns of axons and dendrites within the functionally specialized cortical layers define eight types of layer 6 pyramidal neurons and suggest unique information processing roles for each cell type. To address how input sources contribute to cellular function, we examined the laminar sources of functional excitatory input onto individual layer 6 pyramidal neurons using scanning laser photostimulation. We find that excitatory input sources correlate with cell type. Class I neurons with axonal arbors selectively targeting magnocellular (M) recipient layer 4Calpha receive input from M-dominated layer 4B, whereas class I neurons whose axonal arbors target parvocellular (P) recipient layer 4Cbeta receive input from P-dominated layer 2/3. Surprisingly, these neuronal types do not differ significantly in the inputs they receive directly from layers 4Calpha or 4Cbeta. Class II cells, which lack dense axonal arbors within layer 4C, receive excitatory input from layers targeted by their local axons. Specifically, type IIA cells project axons to and receive input from the deep but not superficial layers. Type IIB neurons project to and receive input from the deepest and most superficial, but not middle layers. Type IIC neurons arborize throughout the cortical layers and tend to receive inputs from all cortical layers. These observations have implications for the functional roles of different layer 6 cell types in visual information processing.

Mammalian Exo1 encodes both structural and catalytic functions that play distinct roles in essential biological processes

PubMed Central

Schaetzlein, Sonja; Chahwan, Richard; Avdievich, Elena; Roa, Sergio; Wei, Kaichun; Eoff, Robert L.; Sellers, Rani S.; Clark, Alan B.; Kunkel, Thomas A.; Scharff, Matthew D.; Edelmann, Winfried

2013-01-01

Mammalian Exonuclease 1 (EXO1) is an evolutionarily conserved, multifunctional exonuclease involved in DNA damage repair, replication, immunoglobulin diversity, meiosis, and telomere maintenance. It has been assumed that EXO1 participates in these processes primarily through its exonuclease activity, but recent studies also suggest that EXO1 has a structural function in the assembly of higher-order protein complexes. To dissect the enzymatic and nonenzymatic roles of EXO1 in the different biological processes in vivo, we generated an EXO1-E109K knockin (Exo1EK) mouse expressing a stable exonuclease-deficient protein and, for comparison, a fully EXO1-deficient (Exo1null) mouse. In contrast to Exo1null/null mice, Exo1EK/EK mice retained mismatch repair activity and displayed normal class switch recombination and meiosis. However, both Exo1-mutant lines showed defects in DNA damage response including DNA double-strand break repair (DSBR) through DNA end resection, chromosomal stability, and tumor suppression, indicating that the enzymatic function is required for those processes. On a transformation-related protein 53 (Trp53)-null background, the DSBR defect caused by the E109K mutation altered the tumor spectrum but did not affect the overall survival as compared with p53-Exo1null mice, whose defects in both DSBR and mismatch repair also compromised survival. The separation of these functions demonstrates the differential requirement for the structural function and nuclease activity of mammalian EXO1 in distinct DNA repair processes and tumorigenesis in vivo. PMID:23754438

A Common Function of Basal Ganglia-Cortical Circuits Subserving Speed in Both Motor and Cognitive Domains.

PubMed

Hanakawa, Takashi; Goldfine, Andrew M; Hallett, Mark

2017-01-01

Distinct regions of the frontal cortex connect with their basal ganglia and thalamic counterparts, constituting largely segregated basal ganglia-thalamo-cortical (BTC) circuits. However, any common role of the BTC circuits in different behavioral domains remains unclear. Indeed, whether dysfunctional motor and cognitive BTC circuits are responsible for motor slowing and cognitive slowing, respectively, in Parkinson's disease (PD) is a matter of debate. Here, we used an effortful behavioral paradigm in which the effects of task rate on accuracy were tested in movement, imagery, and calculation tasks in humans. Using nonlinear fitting, we separated baseline accuracy ( A base ) and "agility" (ability to function quickly) components of performance in healthy participants and then confirmed reduced agility and preserved A base for the three tasks in PD. Using functional magnetic resonance imaging (fMRI) and diffusion tractography, we explored the neural substrates underlying speeded performance of the three tasks in healthy participants, suggesting the involvement of distinct BTC circuits in cognitive and motor agility. Language and motor BTC circuits were specifically active during speeded performance of the calculation and movement tasks, respectively, whereas premotor BTC circuits revealed activity for speeded performance of all tasks. Finally, PD showed reduced task rate-correlated activity in the language BTC circuits for speeded calculation, in the premotor BTC circuit for speeded imagery, and in the motor BTC circuits for speeded movement, as compared with controls. The present study casts light on the anatomo-functional organization of the BTC circuits and their parallel roles in invigorating movement and cognition through a function of dopamine.

Distinct Functions of CCAAT Enhancer-binding Protein Isoforms in the Regulation of Manganese Superoxide Dismutase during Interleukin-1β Stimulation*

PubMed Central

Qiu, Xiaolei; Aiken, Kimberly J.; Chokas, Ann L.; Beachy, Dawn E.; Nick, Harry S.

2008-01-01

The mitochondrial antioxidant enzyme manganese superoxide dismutase (Mn-SOD) is crucial in maintaining cellular and organismal homeostasis. Mn-SOD expression is tightly regulated in a manner that synchronizes its cytoprotective functions during inflammatory challenges. Induction of Mn-SOD gene expression by the proinflammatory cytokine IL-1β is mediated through a complex intronic enhancer element. To identify and characterize the transcription factors required for Mn-SOD enhancer function, a yeast one-hybrid assay was utilized, and two CCAAT enhancer-binding protein (C/EBP) members, C/EBP β and C/EBP δ, were identified. These two transcription factors responded to IL-1β treatment with distinct expression profiles, different temporal yet inducible interactions with the endogenous Mn-SOD enhancer, and also opposite effects on Mn-SOD transcription. C/EBP β is expressed as three isoforms, LAP* (liver-activating protein), LAP, and LIP (liver-inhibitory protein). Our functional analysis demonstrated that only the full-length C/EBP β/LAP* served as a true activator for Mn-SOD, whereas LAP, LIP, and C/EBP δ functioned as potential repressors. Finally, our systematic mutagenesis of the unique N-terminal 21 amino acids further solidified the importance of LAP* in the induction of Mn-SOD and emphasized the crucial role of this isoform. Our data demonstrating the physiological relevance of the N-terminal peptide also provide a rationale for revisiting the role of LAP* in the regulation of other genes and in pathways such as lipogenesis and development. PMID:18559338

A Common Function of Basal Ganglia-Cortical Circuits Subserving Speed in Both Motor and Cognitive Domains

PubMed Central

2017-01-01

Abstract Distinct regions of the frontal cortex connect with their basal ganglia and thalamic counterparts, constituting largely segregated basal ganglia-thalamo-cortical (BTC) circuits. However, any common role of the BTC circuits in different behavioral domains remains unclear. Indeed, whether dysfunctional motor and cognitive BTC circuits are responsible for motor slowing and cognitive slowing, respectively, in Parkinson’s disease (PD) is a matter of debate. Here, we used an effortful behavioral paradigm in which the effects of task rate on accuracy were tested in movement, imagery, and calculation tasks in humans. Using nonlinear fitting, we separated baseline accuracy (Abase) and “agility” (ability to function quickly) components of performance in healthy participants and then confirmed reduced agility and preserved Abase for the three tasks in PD. Using functional magnetic resonance imaging (fMRI) and diffusion tractography, we explored the neural substrates underlying speeded performance of the three tasks in healthy participants, suggesting the involvement of distinct BTC circuits in cognitive and motor agility. Language and motor BTC circuits were specifically active during speeded performance of the calculation and movement tasks, respectively, whereas premotor BTC circuits revealed activity for speeded performance of all tasks. Finally, PD showed reduced task rate-correlated activity in the language BTC circuits for speeded calculation, in the premotor BTC circuit for speeded imagery, and in the motor BTC circuits for speeded movement, as compared with controls. The present study casts light on the anatomo-functional organization of the BTC circuits and their parallel roles in invigorating movement and cognition through a function of dopamine. PMID:29379873

Adaptor protein complexes-1 and 3 are involved at distinct stages of flavivirus life-cycle

PubMed Central

Agrawal, Tanvi; Schu, Peter; Medigeshi, Guruprasad R.

2013-01-01

Intracellular protein trafficking pathways are hijacked by viruses at various stages of viral life-cycle. Heterotetrameric adaptor protein complexes (APs) mediate vesicular trafficking at distinct intracellular sites and are essential for maintaining the organellar homeostasis. In the present study, we studied the effect of AP-1 and AP-3 deficiency on flavivirus infection in cells functionally lacking these proteins. We show that AP-1 and AP-3 participate in flavivirus life-cycle at distinct stages. AP-3-deficient cells showed delay in initiation of Japanese encephalitis virus and dengue virus RNA replication, which resulted in reduction of infectious virus production. AP-3 was found to colocalize with RNA replication compartments in infected wild-type cells. AP-1 deficiency affected later stages of dengue virus infection where increased intracellular accumulation of infectious virus was observed. Therefore, our results propose a novel role for AP-1 and AP-3 at distinct stages of infection of some of the RNA viruses. PMID:23657274

Adaptor protein complexes-1 and 3 are involved at distinct stages of flavivirus life-cycle.

PubMed

Agrawal, Tanvi; Schu, Peter; Medigeshi, Guruprasad R

2013-01-01

Intracellular protein trafficking pathways are hijacked by viruses at various stages of viral life-cycle. Heterotetrameric adaptor protein complexes (APs) mediate vesicular trafficking at distinct intracellular sites and are essential for maintaining the organellar homeostasis. In the present study, we studied the effect of AP-1 and AP-3 deficiency on flavivirus infection in cells functionally lacking these proteins. We show that AP-1 and AP-3 participate in flavivirus life-cycle at distinct stages. AP-3-deficient cells showed delay in initiation of Japanese encephalitis virus and dengue virus RNA replication, which resulted in reduction of infectious virus production. AP-3 was found to colocalize with RNA replication compartments in infected wild-type cells. AP-1 deficiency affected later stages of dengue virus infection where increased intracellular accumulation of infectious virus was observed. Therefore, our results propose a novel role for AP-1 and AP-3 at distinct stages of infection of some of the RNA viruses.

Roles for Hedgehog signaling in adult organ homeostasis and repair

PubMed Central

Petrova, Ralitsa; Joyner, Alexandra L.

2014-01-01

The hedgehog (HH) pathway is well known for its mitogenic and morphogenic functions during development, and HH signaling continues in discrete populations of cells within many adult mammalian tissues. Growing evidence indicates that HH regulates diverse quiescent stem cell populations, but the exact roles that HH signaling plays in adult organ homeostasis and regeneration remain poorly understood. Here, we review recently identified functions of HH in modulating the behavior of tissue-specific adult stem and progenitor cells during homeostasis, regeneration and disease. We conclude that HH signaling is a key factor in the regulation of adult tissue homeostasis and repair, acting via multiple different routes to regulate distinct cellular outcomes, including maintenance of plasticity, in a context-dependent manner. PMID:25183867

Pentameric ligand-gated ion channels exhibit distinct transmembrane domain archetypes for folding/expression and function.

PubMed

Therien, J P Daniel; Baenziger, John E

2017-03-27

Although transmembrane helix-helix interactions must be strong enough to drive folding, they must still permit the inter-helix movements associated with conformational change. Interactions between the outermost M4 and adjacent M1 and M3 α-helices of pentameric ligand-gated ion channels have been implicated in folding and function. Here, we evaluate the role of different physical interactions at this interface in the function of two prokaryotic homologs, GLIC and ELIC. Strikingly, disruption of most interactions in GLIC lead to either a reduction or a complete loss of expression and/or function, while analogous disruptions in ELIC often lead to gains in function. Structural comparisons suggest that GLIC and ELIC represent distinct transmembrane domain archetypes. One archetype, exemplified by GLIC, the glycine and GABA receptors and the glutamate activated chloride channel, has extensive aromatic contacts that govern M4-M1/M3 interactions and that are essential for expression and function. The other archetype, exemplified by ELIC and both the nicotinic acetylcholine and serotonin receptors, has relatively few aromatic contacts that are detrimental to function. These archetypes likely have evolved different mechanisms to balance the need for strong M4 "binding" to M1/M3 to promote folding/expression, and the need for weaker interactions that allow for greater conformational flexibility.

Two different streams form the dorsal visual system: anatomy and functions.

PubMed

Rizzolatti, Giacomo; Matelli, Massimo

2003-11-01

There are two radically different views on the functional role of the dorsal visual stream. One considers it as a system involved in space perception. The other is of a system that codes visual information for action organization. On the basis of new anatomical data and a reconsideration of previous functional and clinical data, we propose that the dorsal stream and its recipient parietal areas form two distinct functional systems: the dorso-dorsal stream (d-d stream) and the ventro-dorsal stream (v-d stream). The d-d stream is formed by area V6 (main d-d extrastriate visual node) and areas V6A and MIP of the superior parietal lobule. Its major functional role is the control of actions "on line". Its damage leads to optic ataxia. The v-d stream is formed by area MT (main v-d extrastriate visual node) and by the visual areas of the inferior parietal lobule. As the d-d stream, v-d stream is responsible for action organization. It, however, also plays a crucial role in space perception and action understanding. The putative mechanisms linking action and perception in the v-d stream is discussed.

Complete identification of E-selectin ligands on neutrophils reveals distinct functions of PSGL-1, ESL-1, and CD44.

PubMed

Hidalgo, Andrés; Peired, Anna J; Wild, Martin; Vestweber, Dietmar; Frenette, Paul S

2007-04-01

The selectins and their ligands are required for leukocyte extravasation during inflammation. Several glycoproteins have been suggested to bind to E-selectin in vitro, but the complete identification of its physiological ligands has remained elusive. Here, we showed that E-selectin ligand-1 (ESL-1), P-selectin glycoprotein ligand-1 (PSGL-1), and CD44 encompassed all endothelial-selectin ligand activity on neutrophils by using gene- and RNA-targeted loss of function. PSGL-1 played a major role in the initial leukocyte capture, whereas ESL-1 was critical for converting initial tethers into steady slow rolling. CD44 controlled rolling velocity and mediated E-selectin-dependent redistribution of PSGL-1 and L-selectin to a major pole on slowly rolling leukocytes through p38 signaling. These results suggest distinct and dynamic contributions of these three glycoproteins in selectin-mediated neutrophil adhesion and signaling.

Complete identification of E-selectin ligand activity on neutrophils reveals a dynamic interplay and distinct functions of PSGL-1, ESL-1 and CD44

PubMed Central

Wild, Martin; Vestweber, Dietmar; Frenette, Paul S.

2014-01-01

SUMMARY The selectins and their ligands are required for leukocyte extravasation during inflammation. Several glycoproteins have been suggested to bind to E-selectin in vitro but the complete identification of its physiological ligands has remained elusive. Here, we show using gene- and RNA-targeted loss-of-function that E-selectin ligand-1 (ESL-1), PSGL-1 and CD44 encompass all endothelial selectin ligand activity on neutrophils. PSGL-1 plays a major role in the initial leukocyte capture, while ESL-1 is critical to convert initial tethers into steady slow rolling. CD44 controls rolling velocity and mediates E-selectin-dependent redistribution of PSGL-1 and L-selectin to a major pole on slowly rolling leukocytes through p38 signaling. These results suggest distinct and dynamic contributions of these three glycoproteins in selectin-mediated neutrophil adhesion and signaling. PMID:17442598

Very Long Chain Fatty Acids Are Functionally Involved in Necroptosis.

PubMed

Parisi, Laura R; Li, Nasi; Atilla-Gokcumen, G Ekin

2017-12-21

Necroptosis is a form of regulated cell death that is linked to various human diseases. Distinct membrane-related, thus lipid-dependent, alterations take place during necroptosis. However, little is known about the roles of specific lipids in this process. We used an untargeted LC-MS-based approach to reveal that distinct lipid species are regulated at the molecular level during necroptosis. We found that ceramides and very long chain fatty acids accumulate during this process. Intrigued by the specificity of very long chain fatty acid accumulation, we focused on characterizing their involvement during necroptosis. Biochemical characterizations suggested that activated fatty acid biosynthesis and elongation could be responsible for these accumulations. We further showed that inhibition of fatty acid biosynthesis and depletion of very long chain fatty acids prevented loss of plasma membrane integrity and cell death, strongly suggesting that very long chain fatty acids are functionally involved in necroptosis. Copyright © 2017 Elsevier Ltd. All rights reserved.

Macrophages: Their Emerging Roles in Bone

PubMed Central

Sinder, Benjamin P; Pettit, Allison R; McCauley, Laurie K

2016-01-01

Macrophages are present in nearly all tissues and are critical for development, homeostasis, and regeneration. Resident tissue macrophages of bone, termed osteal macrophages, are recently classified myeloid cells that are distinct from osteoclasts. Osteal macrophages are located immediately adjacent to osteoblasts, regulate bone formation, and play diverse roles in skeletal homeostasis. Genetic or pharmacological modulation of macrophages in vivo results in significant bone phenotypes, and these phenotypes depend on which macrophage subsets are altered. Macrophages are also key mediators of osseous wound healing and fracture repair, with distinct roles at various stages of the repair process. A central function of macrophages is their phagocytic ability. Each day, billions of cells die in the body and efferocytosis (phagocytosis of apoptotic cells) is a critical process in both clearing dead cells and recruitment of replacement progenitor cells to maintain homeostasis. Recent data suggest a role for efferocytosis in bone biology and these new mechanisms are outlined. Finally, although macrophages have an established role in primary tumors, emerging evidence suggests that macrophages in bone support cancers which preferentially metastasize to the skeleton. Collectively, this developing area of osteoimmunology raises new questions and promises to provide novel insights into pathophysiologic conditions as well as therapeutic and regenerative approaches vital for skeletal health. PMID:26531055

Resting state cortico-cerebellar functional connectivity networks: a comparison of anatomical and self-organizing map approaches

PubMed Central

Bernard, Jessica A.; Seidler, Rachael D.; Hassevoort, Kelsey M.; Benson, Bryan L.; Welsh, Robert C.; Wiggins, Jillian Lee; Jaeggi, Susanne M.; Buschkuehl, Martin; Monk, Christopher S.; Jonides, John; Peltier, Scott J.

2012-01-01

The cerebellum plays a role in a wide variety of complex behaviors. In order to better understand the role of the cerebellum in human behavior, it is important to know how this structure interacts with cortical and other subcortical regions of the brain. To date, several studies have investigated the cerebellum using resting-state functional connectivity magnetic resonance imaging (fcMRI; Krienen and Buckner, 2009; O'Reilly et al., 2010; Buckner et al., 2011). However, none of this work has taken an anatomically-driven lobular approach. Furthermore, though detailed maps of cerebral cortex and cerebellum networks have been proposed using different network solutions based on the cerebral cortex (Buckner et al., 2011), it remains unknown whether or not an anatomical lobular breakdown best encompasses the networks of the cerebellum. Here, we used fcMRI to create an anatomically-driven connectivity atlas of the cerebellar lobules. Timecourses were extracted from the lobules of the right hemisphere and vermis. We found distinct networks for the individual lobules with a clear division into “motor” and “non-motor” regions. We also used a self-organizing map (SOM) algorithm to parcellate the cerebellum. This allowed us to investigate redundancy and independence of the anatomically identified cerebellar networks. We found that while anatomical boundaries in the anterior cerebellum provide functional subdivisions of a larger motor grouping defined using our SOM algorithm, in the posterior cerebellum, the lobules were made up of sub-regions associated with distinct functional networks. Together, our results indicate that the lobular boundaries of the human cerebellum are not necessarily indicative of functional boundaries, though anatomical divisions can be useful. Additionally, driving the analyses from the cerebellum is key to determining the complete picture of functional connectivity within the structure. PMID:22907994

Role of the cerebellum in high stages of motor planning hierarchy

PubMed Central

Federici, Alessandra; Cesareo, Ambra; Biffi, Emilia; Valtorta, Giulia; Molteni, Massimo; Ronconi, Luca; Borgatti, Renato

2017-01-01

Motor planning is not a monolithic process, and distinct stages of motor planning are responsible for encoding different levels of abstractness. However, how these distinct components are mapped into different neural substrates remains an open question. We studied one of these high-level motor planning components, defined as second-order motor planning, in a patient (R.G.) with an extremely rare case of cerebellar agenesis but without any other cortical malformations. Second-order motor planning dictates that when two acts must be performed sequentially, planning of the second act can influence execution of the first. We used an optoelectronic system for kinematic analysis to compare R.G.’s performance with age-matched controls in a second-order motor planning task. The first act was to reach for an object, and the second was to place it into a small or large container. Our results showed that despite the expected difficulties in fine-motor skills, second-order motor planning (i.e., the ability to modulate the first act as a function of the nature of the second act) was preserved even in the patient with congenital absence of the cerebellum. These results open new intriguing speculations about the role of the cerebellum in motor planning abilities. Although prudence is imperative when suggesting conclusions made on the basis of single-case findings, this evidence suggests fascinating hypotheses about the neural circuits that support distinct stages of the motor planning hierarchy, and regarding the functional role of second-order motor planning in motor cognition and its potential dysfunction in autism. NEW & NOTEWORTHY Traditionally, the cerebellum was considered essential for motor planning. By studying an extremely rare patient with cerebellar agenesis and a group of neurotypical controls, we found that high stages of the motor planning hierarchy can be preserved even in this patient with congenital absence of the cerebellum. Our results provide interesting insights that shed light on the neural circuits supporting distinct levels of motor planning. Furthermore, the results are intriguing because of their potential clinical implications in autism. PMID:28077667

Protein kinase inhibitor peptide (PKI): a family of endogenous neuropeptides that modulate neuronal cAMP-dependent protein kinase function.

PubMed

Dalton, George D; Dewey, William L

2006-02-01

Signal transduction cascades involving cAMP-dependent protein kinase are highly conserved among a wide variety of organisms. Given the universal nature of this enzyme it is not surprising that cAMP-dependent protein kinase plays a critical role in numerous cellular processes. This is particularly evident in the nervous system where cAMP-dependent protein kinase is involved in neurotransmitter release, gene transcription, and synaptic plasticity. Protein kinase inhibitor peptide (PKI) is an endogenous thermostable peptide that modulates cAMP-dependent protein kinase function. PKI contains two distinct functional domains within its amino acid sequence that allow it to: (1) potently and specifically inhibit the activity of the free catalytic subunit of cAMP-dependent protein kinase and (2) export the free catalytic subunit of cAMP-dependent protein kinase from the nucleus. Three distinct PKI isoforms (PKIalpha, PKIbeta, PKIgamma) have been identified and each isoform is expressed in the brain. PKI modulates neuronal synaptic activity, while PKI also is involved in morphogenesis and symmetrical left-right axis formation. In addition, PKI also plays a role in regulating gene expression induced by cAMP-dependent protein kinase. Future studies should identify novel physiological functions for endogenous PKI both in the nervous system and throughout the body. Most interesting will be the determination whether functional differences exist between individual PKI isoforms which is an intriguing possibility since these isoforms exhibit: (1) cell-type specific tissue expression patterns, (2) different potencies for the inhibition of cAMP-dependent protein kinase activity, and (3) expression patterns that are hormonally, developmentally and cell-cycle regulated. Finally, synthetic peptide analogs of endogenous PKI will continue to be invaluable tools that are used to elucidate the role of cAMP-dependent protein kinase in a variety of cellular processes throughout the nervous system and the rest of the body.

Distinct Roles of PKCι/λ and PKMζ in the Initiation and Maintenance of Hippocampal Long-Term Potentiation and Memory.

PubMed

Wang, Shaoli; Sheng, Tao; Ren, Siqiang; Tian, Tian; Lu, Wei

2016-08-16

PKMζ has been proposed to be essential for maintenance of long-term potentiation (LTP) and long-term memory (LTM). However, recent data from PKMζ-knockout mice has called this role into question. Instead, the other atypical isoform, protein kinase C iota/lambda (PKCι/λ), has emerged as a potential alternative player. Therefore, the nature of the "memory molecule" maintaining learned information remains uncertain. Here, we report knockdown (KD) of PKCι/λ and PKMζ in the dorsal hippocampus and find deficits in early expression and late maintenance, respectively, during both LTP and hippocampus-dependent LTM. Sequential increases in the active form of PKCι/λ and PKMζ are detected during LTP or fear conditioning. Importantly, PKMζ, but not PKCι/λ, KD disrupts previously established LTM. Thus, PKCι/λ and PKMζ have distinct functions in LTP and memory, with PKMζ playing a specific role in memory maintenance. This relaying pattern may represent a precise molecular mechanism by which atypical PKCs regulate the different stages of memory. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Voltage-Gated Ion Channels in Cancer Cell Proliferation

PubMed Central

Rao, Vidhya R.; Perez-Neut, Mathew; Kaja, Simon; Gentile, Saverio

2015-01-01

Changes of the electrical charges across the surface cell membrane are absolutely necessary to maintain cellular homeostasis in physiological as well as in pathological conditions. The opening of ion channels alter the charge distribution across the surface membrane as they allow the diffusion of ions such as K+, Ca++, Cl−, Na+. Traditionally, voltage-gated ion channels (VGIC) are known to play fundamental roles in controlling rapid bioelectrical signaling including action potential and/or contraction. However, several investigations have revealed that these classes of proteins can also contribute significantly to cell mitotic biochemical signaling, cell cycle progression, as well as cell volume regulation. All these functions are critically important for cancer cell proliferation. Interestingly, a variety of distinct VGICs are expressed in different cancer cell types, including metastasis but not in the tissues from which these tumors were generated. Given the increasing evidence suggesting that VGIC play a major role in cancer cell biology, in this review we discuss the role of distinct VGIC in cancer cell proliferation and possible therapeutic potential of VIGC pharmacological manipulation. PMID:26010603

Moonlighting microtubule-associated proteins: regulatory functions by day and pathological functions at night.

PubMed

Oláh, J; Tőkési, N; Lehotzky, A; Orosz, F; Ovádi, J

2013-11-01

The sensing, integrating, and coordinating features of the eukaryotic cells are achieved by the complex ultrastructural arrays and multifarious functions of the cytoskeletal network. Cytoskeleton comprises fibrous protein networks of microtubules, actin, and intermediate filaments. These filamentous polymer structures are highly dynamic and undergo constant and rapid reorganization during cellular processes. The microtubular system plays a crucial role in the brain, as it is involved in an enormous number of cellular events including cell differentiation and pathological inclusion formation. These multifarious functions of microtubules can be achieved by their decoration with proteins/enzymes that exert specific effects on the dynamics and organization of the cytoskeleton and mediate distinct functions due to their moonlighting features. This mini-review focuses on two aspects of the microtubule cytoskeleton. On the one hand, we describe the heteroassociation of tubulin/microtubules with metabolic enzymes, which in addition to their catalytic activities stabilize microtubule structures via their cross-linking functions. On the other hand, we focus on the recently identified moonlighting tubulin polymerization promoting protein, TPPP/p25. TPPP/p25 is a microtubule-associated protein and it displays distinct physiological or pathological (aberrant) functions; thus it is a prototype of Neomorphic Moonlighting Proteins. The expression of TPPP/p25 is finely controlled in the human brain; this protein is indispensable for the development of projections of oligodendrocytes that are responsible for the ensheathment of axons. The nonphysiological, higher or lower TPPP/p25 level leads to distinct CNS diseases. Mechanisms contributing to the control of microtubule stability and dynamics by metabolic enzymes and TPPP/p25 will be discussed. Copyright © 2013 Wiley Periodicals, Inc.

Emergence of system roles in normative neurodevelopment

PubMed Central

Gu, Shi; Satterthwaite, Theodore D.; Medaglia, John D.; Yang, Muzhi; Gur, Raquel E.; Gur, Ruben C.; Bassett, Danielle S.

2015-01-01

Adult human cognition is supported by systems of brain regions, or modules, that are functionally coherent at rest and collectively activated by distinct task requirements. However, an understanding of how the formation of these modules supports evolving cognitive capabilities has not been delineated. Here, we quantify the formation of network modules in a sample of 780 youth (aged 8–22 y) who were studied as part of the Philadelphia Neurodevelopmental Cohort. We demonstrate that the brain’s functional network organization changes in youth through a process of modular evolution that is governed by the specific cognitive roles of each system, as defined by the balance of within- vs. between-module connectivity. Moreover, individual variability in these roles is correlated with cognitive performance. Collectively, these results suggest that dynamic maturation of network modules in youth may be a critical driver for the development of cognition. PMID:26483477

Kainate receptors coming of age: milestones of two decades of research

PubMed Central

Contractor, Anis; Mulle, Christophe; Swanson, Geoffrey T

2011-01-01

Two decades have passed since the first report of the cloning of a kainate receptor (KAR) subunit. The intervening years have seen a rapid growth in our understanding of the biophysical properties and function of kainate receptors in the brain. This research has led to an appreciation that kainate receptors play quite distinct roles at synapses relative to other members of the glutamate-gated ion channel receptor family, despite structural and functional commonalities. The surprisingly diverse and complex nature of KAR signaling underlies their unique impact on neuronal networks through their direct and indirect effects on synaptic transmission, and their prominent role in regulating cellular excitability. This review pieces together highlights from the two decades of research subsequent to the cloning of the first subunit, and provides an overview of our current understanding of the role of KARs in the CNS and their potential importance to neurological and neuropsychiatric disorders. PMID:21256604

Towards a systematic analysis of human short-chain dehydrogenases/reductases (SDR): Ligand identification and structure-activity relationships.

PubMed

Bhatia, Chitra; Oerum, Stephanie; Bray, James; Kavanagh, Kathryn L; Shafqat, Naeem; Yue, Wyatt; Oppermann, Udo

2015-06-05

Short-chain dehydrogenases/reductases (SDRs) constitute a large, functionally diverse branch of enzymes within the class of NAD(P)(H) dependent oxidoreductases. In humans, over 80 genes have been identified with distinct metabolic roles in carbohydrate, amino acid, lipid, retinoid and steroid hormone metabolism, frequently associated with inherited genetic defects. Besides metabolic functions, a subset of atypical SDR proteins appears to play critical roles in adapting to redox status or RNA processing, and thereby controlling metabolic pathways. Here we present an update on the human SDR superfamily and a ligand identification strategy using differential scanning fluorimetry (DSF) with a focused library of oxidoreductase and metabolic ligands to identify substrate classes and inhibitor chemotypes. This method is applicable to investigate structure-activity relationships of oxidoreductases and ultimately to better understand their physiological roles. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

MOR23 promotes muscle regeneration and regulates cell adhesion and migration

PubMed Central

Griffin, Christine A.; Kafadar, Kimberly A.; Pavlath, Grace K.

2009-01-01

Summary Odorant receptors (ORs) in the olfactory epithelium bind to volatile small molecules leading to the perception of smell. ORs are expressed in many tissues but their functions are largely unknown. We show multiple ORs display distinct mRNA expression patterns during myogenesis in vitro and muscle regeneration in vivo. Mouse OR23 (MOR23) expression is induced during muscle regeneration when muscle cells are extensively fusing and plays a key role in regulating migration and adhesion of muscle cells in vitro, two processes common during tissue repair. A soluble ligand for MOR23 is secreted by muscle cells in vitro and muscle tissue in vivo. MOR23 is necessary for proper skeletal muscle regeneration as loss of MOR23 leads to increased myofiber branching, commonly associated with muscular dystrophy. Together these data identify a functional role for an OR outside of the nose and suggest a larger role for ORs during tissue repair. PMID:19922870

Differential Roles for Inner Membrane Complex Proteins across Toxoplasma gondii and Sarcocystis neurona Development

PubMed Central

Dubey, Rashmi; Harrison, Brooke; Dangoudoubiyam, Sriveny; Bandini, Giulia; Cheng, Katherine; Kosber, Aziz; Agop-Nersesian, Carolina; Howe, Daniel K.; Samuelson, John; Ferguson, David J. P.

2017-01-01

ABSTRACT The inner membrane complex (IMC) of apicomplexan parasites contains a network of intermediate filament-like proteins. The 14 alveolin domain-containing IMC proteins in Toxoplasma gondii fall into different groups defined by their distinct spatiotemporal dynamics during the internal budding process of tachyzoites. Here, we analyzed representatives of different IMC protein groups across all stages of the Toxoplasma life cycle and during Sarcocystis neurona asexual development. We found that across asexually dividing Toxoplasma stages, IMC7 is present exclusively in the mother’s cytoskeleton, whereas IMC1 and IMC3 are both present in mother and daughter cytoskeletons (IMC3 is strongly enriched in daughter buds). In developing macro- and microgametocytes, IMC1 and -3 are absent, whereas IMC7 is lost in early microgametocytes but retained in macrogametocytes until late in their development. We found no roles for IMC proteins during meiosis and sporoblast formation. However, we observed that IMC1 and IMC3, but not IMC7, are present in sporozoites. Although the spatiotemporal pattern of IMC15 and IMC3 suggests orthologous functions in Sarcocystis, IMC7 may have functionally diverged in Sarcocystis merozoites. To functionally characterize IMC proteins, we knocked out IMC7, -12, -14, and -15 in Toxoplasma. IMC14 and -15 appear to be involved in switching between endodyogeny and endopolygeny. In addition, IMC7, -12, and -14, which are all recruited to the cytoskeleton outside cytokinesis, are critical for the structural integrity of extracellular tachyzoites. Altogether, stage- and development-specific roles for IMC proteins can be discerned, suggesting different niches for each IMC protein across the entire life cycle. IMPORTANCE The inner membrane complex (IMC) is a defining feature of apicomplexan parasites key to both their motility and unique cell division. To provide further insights into the IMC, we analyzed the dynamics and functions of representative alveolin domain-containing IMC proteins across developmental stages. Our work shows universal but distinct roles for IMC1, -3, and -7 during Toxoplasma asexual division but more specialized functions for these proteins during gametogenesis. In addition, we find that IMC15 is involved in daughter formation in both Toxoplasma and Sarcocystis. IMC14 and IMC15 function in limiting the number of Toxoplasma offspring per division. Furthermore, IMC7, -12, and -14, which are recruited in the G1 cell cycle stage, are required for stress resistance of extracellular tachyzoites. Thus, although the roles of the different IMC proteins appear to overlap, stage- and development-specific behaviors indicate that their functions are uniquely tailored to each life stage requirement. PMID:29062899

Differential Roles for Inner Membrane Complex Proteins across Toxoplasma gondii and Sarcocystis neurona Development.

PubMed

Dubey, Rashmi; Harrison, Brooke; Dangoudoubiyam, Sriveny; Bandini, Giulia; Cheng, Katherine; Kosber, Aziz; Agop-Nersesian, Carolina; Howe, Daniel K; Samuelson, John; Ferguson, David J P; Gubbels, Marc-Jan

2017-01-01

The inner membrane complex (IMC) of apicomplexan parasites contains a network of intermediate filament-like proteins. The 14 alveolin domain-containing IMC proteins in Toxoplasma gondii fall into different groups defined by their distinct spatiotemporal dynamics during the internal budding process of tachyzoites. Here, we analyzed representatives of different IMC protein groups across all stages of the Toxoplasma life cycle and during Sarcocystis neurona asexual development. We found that across asexually dividing Toxoplasma stages, IMC7 is present exclusively in the mother's cytoskeleton, whereas IMC1 and IMC3 are both present in mother and daughter cytoskeletons (IMC3 is strongly enriched in daughter buds). In developing macro- and microgametocytes, IMC1 and -3 are absent, whereas IMC7 is lost in early microgametocytes but retained in macrogametocytes until late in their development. We found no roles for IMC proteins during meiosis and sporoblast formation. However, we observed that IMC1 and IMC3, but not IMC7, are present in sporozoites. Although the spatiotemporal pattern of IMC15 and IMC3 suggests orthologous functions in Sarcocystis , IMC7 may have functionally diverged in Sarcocystis merozoites. To functionally characterize IMC proteins, we knocked out IMC7, -12, -14, and -15 in Toxoplasma . IMC14 and -15 appear to be involved in switching between endodyogeny and endopolygeny. In addition, IMC7, -12, and -14, which are all recruited to the cytoskeleton outside cytokinesis, are critical for the structural integrity of extracellular tachyzoites. Altogether, stage- and development-specific roles for IMC proteins can be discerned, suggesting different niches for each IMC protein across the entire life cycle. IMPORTANCE The inner membrane complex (IMC) is a defining feature of apicomplexan parasites key to both their motility and unique cell division. To provide further insights into the IMC, we analyzed the dynamics and functions of representative alveolin domain-containing IMC proteins across developmental stages. Our work shows universal but distinct roles for IMC1, -3, and -7 during Toxoplasma asexual division but more specialized functions for these proteins during gametogenesis. In addition, we find that IMC15 is involved in daughter formation in both Toxoplasma and Sarcocystis . IMC14 and IMC15 function in limiting the number of Toxoplasma offspring per division. Furthermore, IMC7, -12, and -14, which are recruited in the G 1 cell cycle stage, are required for stress resistance of extracellular tachyzoites. Thus, although the roles of the different IMC proteins appear to overlap, stage- and development-specific behaviors indicate that their functions are uniquely tailored to each life stage requirement.

Distinct 3-O-Sulfated Heparan Sulfate Modification Patterns Are Required for kal-1−Dependent Neurite Branching in a Context-Dependent Manner in Caenorhabditis elegans

PubMed Central

Tecle, Eillen; Diaz-Balzac, Carlos A.; Bülow, Hannes E.

2013-01-01

Heparan sulfate (HS) is an unbranched glycosaminoglycan exhibiting substantial molecular diversity due to multiple, nonuniformly introduced modifications, including sulfations, epimerization, and acetylation. HS modifications serve specific and instructive roles in neuronal development, leading to the hypothesis of a HS code that regulates nervous system patterning. Although the in vivo roles of many of the HS modifications have been investigated, very little is known about the function of HS 3-O-sulfation in vivo. By examining patterning of the Caenorhabditis elegans nervous system in loss of function mutants of the two 3-O-sulfotransferases, hst-3.1 and hst-3.2, we found HS 3-O-sulfation to be largely dispensable for overall neural development. However, generation of stereotypical neurite branches in hermaphroditic-specific neurons required hst-3.1, hst-3.2, as well as an extracellular cell adhesion molecule encoded by kal-1, the homolog of Kallmann Syndrome associated gene 1/anosmin-1. In contrast, kal-1−dependent neurite branching in AIY neurons required catalytic activity of hst-3.2 but not hst-3.1. The context-dependent requirement for hst-3.2 and hst-3.1 indicates that both enzymes generate distinct types of HS modification patterns in different cell types, which regulate kal-1 to promote neurite branching. We conclude that HS 3-O-sulfation does not play a general role in establishing the HS code in C. elegans but rather plays a specialized role in a context-dependent manner to establish defined aspects of neuronal circuits. PMID:23451335

The Contributions of the Amino and Carboxy Terminal Domains of Flightin to the Biomechanical Properties of Drosophila Flight Muscle Thick Filaments.

PubMed

Gasek, Nathan S; Nyland, Lori R; Vigoreaux, Jim O

2016-04-27

Flightin is a myosin binding protein present in Pancrustacea. In Drosophila, flightin is expressed in the indirect flight muscles (IFM), where it is required for the flexural rigidity, structural integrity, and length determination of thick filaments. Comparison of flightin sequences from multiple Drosophila species revealed a tripartite organization indicative of three functional domains subject to different evolutionary constraints. We use atomic force microscopy to investigate the functional roles of the N-terminal domain and the C-terminal domain that show different patterns of sequence conservation. Thick filaments containing a C-terminal domain truncated flightin (fln(ΔC44)) are significantly shorter (2.68 ± 0.06 μm; p < 0.005) than thick filaments containing a full length flightin (fln⁺; 3.21 ± 0.05 μm) and thick filaments containing an N-terminal domain truncated flightin (fln(ΔN62); 3.21 ± 0.06 μm). Persistence length was significantly reduced in fln(ΔN62) (418 ± 72 μm; p < 0.005) compared to fln⁺ (1386 ± 196μm) and fln(ΔC44)(1128 ± 193 μm). Statistical polymer chain analysis revealed that the C-terminal domain fulfills a secondary role in thick filament bending propensity. Our results indicate that the flightin amino and carboxy terminal domains make distinct contributions to thick filament biomechanics. We propose these distinct roles arise from the interplay between natural selection and sexual selection given IFM's dual role in flight and courtship behaviors.

The Contributions of the Amino and Carboxy Terminal Domains of Flightin to the Biomechanical Properties of Drosophila Flight Muscle Thick Filaments

PubMed Central

Gasek, Nathan S.; Nyland, Lori R.; Vigoreaux, Jim O.

2016-01-01

Flightin is a myosin binding protein present in Pancrustacea. In Drosophila, flightin is expressed in the indirect flight muscles (IFM), where it is required for the flexural rigidity, structural integrity, and length determination of thick filaments. Comparison of flightin sequences from multiple Drosophila species revealed a tripartite organization indicative of three functional domains subject to different evolutionary constraints. We use atomic force microscopy to investigate the functional roles of the N-terminal domain and the C-terminal domain that show different patterns of sequence conservation. Thick filaments containing a C-terminal domain truncated flightin (flnΔC44) are significantly shorter (2.68 ± 0.06 μm; p < 0.005) than thick filaments containing a full length flightin (fln+; 3.21 ± 0.05 μm) and thick filaments containing an N-terminal domain truncated flightin (flnΔN62; 3.21 ± 0.06 μm). Persistence length was significantly reduced in flnΔN62 (418 ± 72 μm; p < 0.005) compared to fln+ (1386 ± 196μm) and flnΔC44(1128 ± 193 μm). Statistical polymer chain analysis revealed that the C-terminal domain fulfills a secondary role in thick filament bending propensity. Our results indicate that the flightin amino and carboxy terminal domains make distinct contributions to thick filament biomechanics. We propose these distinct roles arise from the interplay between natural selection and sexual selection given IFM’s dual role in flight and courtship behaviors. PMID:27128952

Making the Mark: The Role of Adenosine Modifications in the Lifecycle of RNA Viruses

PubMed Central

Gonzales-van Horn, Sarah R.; Sarnow, Peter

2017-01-01

Summary Viral epitranscriptomics is a newly emerging field that has identified unique roles for RNA modifications in modulating lifecycles of RNA viruses. Despite the observation of a handful of modified viral RNAs five decades ago, very little was known about how these modifications regulate viral lifecycles, until recently. Here we review the pro- and anti-viral effects of methyl-6-adenosine in distinct viral life cycles, the role of 2′ O-methyl modifications in RNA stability and innate immune sensing, and functions of adenosine to inosine modifications in retroviral life cycles. With roles for over 100 modifications in RNA still unknown, this is a rapidly emerging field that is destined to suggest novel antiviral therapies. PMID:28618265

Theoretical investigation on functional monomer and solvent selection for molecular imprinting of tramadol

NASA Astrophysics Data System (ADS)

Fonseca, Matheus C.; Nascimento, Clebio S.; Borges, Keyller B.

2016-02-01

The purpose of this Letter was to study for the first time the interaction process of tramadol (TRM) with distinct functional monomers (FM) in the formation of molecular imprinted polymer (MIP), using density functional theory (DFT) calculations at B3LYP/6-31G(d,p). As result we were able to establish that the best MIP synthesis conditions are obtained with acrylic acid as FM in 1:3 molar ratio and with chloroform as solvent. This condition presented the lowest stabilization energy for the pre-polymerization complexes. Besides, the intermolecular hydrogen bonds found between the template molecule and functional monomers play a primary role to the complex stability.

mTOR plays critical roles in pancreatic cancer stem cells through specific and stemness-related functions

NASA Astrophysics Data System (ADS)

Matsubara, Shyuichiro; Ding, Qiang; Miyazaki, Yumi; Kuwahata, Taisaku; Tsukasa, Koichiro; Takao, Sonshin

2013-11-01

Pancreatic cancer is characterized by near-universal mutations in KRAS. The mammalian target of rapamycin (mTOR), which functions downstream of RAS, has divergent effects on stem cells. In the present study, we investigated the significance of the mTOR pathway in maintaining the properties of pancreatic cancer stem cells. The mTOR inhibitor, rapamycin, reduced the viability of CD133+ pancreatic cancer cells and sphere formation which is an index of self-renewal of stem-like cells, indicating that the mTOR pathway functions to maintain cancer stem-like cells. Further, rapamycin had different effects on CD133+ cells compared to cyclopamine which is an inhibitor of the Hedgehog pathway. Thus, the mTOR pathway has a distinct role although both pathways maintain pancreatic cancer stem cells. Therefore, mTOR might be a promising target to eliminate pancreatic cancer stem cells.

Role of Activin A in Immune Response to Breast Cancer

DTIC Science & Technology

2016-12-01

the response to radiotherapy (RT). 2 KEYWORDS Breast cancer, metastasis, transforming growth factor-beta (TGFβ) superfamily, activin- A, radiotherapy... Transforming Growth Factor-beta (TGFβ) and activin A (actA) are members of the TGFβ superfamily with overlapping as well as distinct functions in many...Vaccination C. Vanpouille-Box, S. Formenti, and S. Demaria; Weill Cornell Medical College, New York, NY Purpose/Objective(s): Transforming Growth

The Atypical Occurrence of Two Biotin Protein Ligases in Francisella novicida Is Due to Distinct Roles in Virulence and Biotin Metabolism.

PubMed

Feng, Youjun; Chin, Chui-Yoke; Chakravartty, Vandana; Gao, Rongsui; Crispell, Emily K; Weiss, David S; Cronan, John E

2015-06-09

The physiological function of biotin requires biotin protein ligase activity in order to attach the coenzyme to its cognate proteins, which are enzymes involved in central metabolism. The model intracellular pathogen Francisella novicida is unusual in that it encodes two putative biotin protein ligases rather than the usual single enzyme. F. novicida BirA has a ligase domain as well as an N-terminal DNA-binding regulatory domain, similar to the prototypical BirA protein in E. coli. However, the second ligase, which we name BplA, lacks the N-terminal DNA binding motif. It has been unclear why a bacterium would encode these two disparate biotin protein ligases, since F. novicida contains only a single biotinylated protein. In vivo complementation and enzyme assays demonstrated that BirA and BplA are both functional biotin protein ligases, but BplA is a much more efficient enzyme. BirA, but not BplA, regulated transcription of the biotin synthetic operon. Expression of bplA (but not birA) increased significantly during F. novicida infection of macrophages. BplA (but not BirA) was required for bacterial replication within macrophages as well as in mice. These data demonstrate that F. novicida has evolved two distinct enzymes with specific roles; BplA possesses the major ligase activity, whereas BirA acts to regulate and thereby likely prevent wasteful synthesis of biotin. During infection BplA seems primarily employed to maximize the efficiency of biotin utilization without limiting the expression of biotin biosynthetic genes, representing a novel adaptation strategy that may also be used by other intracellular pathogens. Our findings show that Francisella novicida has evolved two functional biotin protein ligases, BplA and BirA. BplA is a much more efficient enzyme than BirA, and its expression is significantly induced upon infection of macrophages. Only BplA is required for F. novicida pathogenicity, whereas BirA prevents wasteful biotin synthesis. These data demonstrate that the atypical occurrence of two biotin protein ligases in F. novicida is linked to distinct roles in virulence and biotin metabolism. Copyright © 2015 Feng et al.

1α,25(OH)2D3 differentially regulates miRNA expression in human bladder cancer cells.

PubMed

Ma, Yingyu; Hu, Qiang; Luo, Wei; Pratt, Rachel N; Glenn, Sean T; Liu, Song; Trump, Donald L; Johnson, Candace S

2015-04-01

Bladder cancer is the fourth most commonly diagnosed cancer in men and eighth leading cause of cancer-related death in the US. Epidemiological and experimental studies strongly suggest a role for 1α,25(OH)2D3 in cancer prevention and treatment. The antitumor activities of 1α,25(OH)2D3 are mediated by the induction of cell cycle arrest, apoptosis, differentiation and the inhibition of angiogenesis and metastasis. miRNAs play important regulatory roles in cancer development and progression. However, the role of 1α,25(OH)2D3 in the regulation of miRNA expression and the potential impact in bladder cancer has not been investigated. Therefore, we studied 1α,25(OH)2D3-regulated miRNA expression profiles in human bladder cancer cell line 253J and the highly tumorigenic and metastatic derivative line 253J-BV by miRNA qPCR panels. 253J and 253J-BV cells express endogenous vitamin D receptor (VDR), which can be further induced by 1α,25(OH)2D3. VDR target gene 24-hydroxylase was induced by 1α,25(OH)2D3 in both cell lines, indicating functional 1α,25(OH)2D3 signaling. The miRNA qPCR panel assay results showed that 253J and 253J-BV cells have distinct miRNA expression profiles. Further, 1α,25(OH)2D3 differentially regulated miRNA expression profiles in 253J and 253J-BV cells in a dynamic manner. Pathway analysis of the miRNA target genes revealed distinct patterns of contribution to the molecular functions and biological processes in the two cell lines. In conclusion, 1α,25(OH)2D3 differentially regulates the expression of miRNAs, which may contribute to distinct biological functions, in human bladder 253J and 253J-BV cells. This article is part of a Special Issue entitled '17th Vitamin D Workshop'. Copyright © 2014 Elsevier Ltd. All rights reserved.

Oculomotor learning revisited: a model of reinforcement learning in the basal ganglia incorporating an efference copy of motor actions

PubMed Central

Fee, Michale S.

2012-01-01

In its simplest formulation, reinforcement learning is based on the idea that if an action taken in a particular context is followed by a favorable outcome, then, in the same context, the tendency to produce that action should be strengthened, or reinforced. While reinforcement learning forms the basis of many current theories of basal ganglia (BG) function, these models do not incorporate distinct computational roles for signals that convey context, and those that convey what action an animal takes. Recent experiments in the songbird suggest that vocal-related BG circuitry receives two functionally distinct excitatory inputs. One input is from a cortical region that carries context information about the current “time” in the motor sequence. The other is an efference copy of motor commands from a separate cortical brain region that generates vocal variability during learning. Based on these findings, I propose here a general model of vertebrate BG function that combines context information with a distinct motor efference copy signal. The signals are integrated by a learning rule in which efference copy inputs gate the potentiation of context inputs (but not efference copy inputs) onto medium spiny neurons in response to a rewarded action. The hypothesis is described in terms of a circuit that implements the learning of visually guided saccades. The model makes testable predictions about the anatomical and functional properties of hypothesized context and efference copy inputs to the striatum from both thalamic and cortical sources. PMID:22754501

Oculomotor learning revisited: a model of reinforcement learning in the basal ganglia incorporating an efference copy of motor actions.

PubMed

Fee, Michale S

2012-01-01

In its simplest formulation, reinforcement learning is based on the idea that if an action taken in a particular context is followed by a favorable outcome, then, in the same context, the tendency to produce that action should be strengthened, or reinforced. While reinforcement learning forms the basis of many current theories of basal ganglia (BG) function, these models do not incorporate distinct computational roles for signals that convey context, and those that convey what action an animal takes. Recent experiments in the songbird suggest that vocal-related BG circuitry receives two functionally distinct excitatory inputs. One input is from a cortical region that carries context information about the current "time" in the motor sequence. The other is an efference copy of motor commands from a separate cortical brain region that generates vocal variability during learning. Based on these findings, I propose here a general model of vertebrate BG function that combines context information with a distinct motor efference copy signal. The signals are integrated by a learning rule in which efference copy inputs gate the potentiation of context inputs (but not efference copy inputs) onto medium spiny neurons in response to a rewarded action. The hypothesis is described in terms of a circuit that implements the learning of visually guided saccades. The model makes testable predictions about the anatomical and functional properties of hypothesized context and efference copy inputs to the striatum from both thalamic and cortical sources.

Mass coral bleaching causes biotic homogenization of reef fish assemblages.

PubMed

Richardson, Laura E; Graham, Nicholas A J; Pratchett, Morgan S; Eurich, Jacob G; Hoey, Andrew S

2018-04-06

Global climate change is altering community composition across many ecosystems due to nonrandom species turnover, typically characterized by the loss of specialist species and increasing similarity of biological communities across spatial scales. As anthropogenic disturbances continue to alter species composition globally, there is a growing need to identify how species responses influence the establishment of distinct assemblages, such that management actions may be appropriately assigned. Here, we use trait-based analyses to compare temporal changes in five complementary indices of reef fish assemblage structure among six taxonomically distinct coral reef habitats exposed to a system-wide thermal stress event. Our results revealed increased taxonomic and functional similarity of previously distinct reef fish assemblages following mass coral bleaching, with changes characterized by subtle, but significant, shifts toward predominance of small-bodied, algal-farming habitat generalists. Furthermore, while the taxonomic or functional richness of fish assemblages did not change across all habitats, an increase in functional originality indicated an overall loss of functional redundancy. We also found that prebleaching coral composition better predicted changes in fish assemblage structure than the magnitude of coral loss. These results emphasize how measures of alpha diversity can mask important changes in the structure and functioning of ecosystems as assemblages reorganize. Our findings also highlight the role of coral species composition in structuring communities and influencing the diversity of responses of reef fishes to disturbance. As new coral species configurations emerge, their desirability will hinge upon the composition of associated species and their capacity to maintain key ecological processes in spite of ongoing disturbances. © 2018 John Wiley & Sons Ltd.

Triple representation of language, working memory, social and emotion processing in the cerebellum: convergent evidence from task and seed-based resting-state fMRI analyses in a single large cohort.

PubMed

Guell, Xavier; Gabrieli, John D E; Schmahmann, Jeremy D

2018-05-15

Delineation of functional topography is critical to the evolving understanding of the cerebellum's role in a wide range of nervous system functions. We used data from the Human Connectome Project (n = 787) to analyze cerebellar fMRI task activation (motor, working memory, language, social and emotion processing) and resting-state functional connectivity calculated from cerebral cortical seeds corresponding to the peak Cohen's d of each task contrast. The combination of exceptional statistical power, activation from both motor and multiple non-motor tasks in the same participants, and convergent resting-state networks in the same participants revealed novel aspects of the functional topography of the human cerebellum. Consistent with prior studies there were two distinct representations of motor activation. Newly revealed were three distinct representations each for working memory, language, social, and emotional task processing that were largely separate for these four cognitive and affective domains. In most cases, the task-based activations and the corresponding resting-network correlations were congruent in identifying the two motor representations and the three non-motor representations that were unique to working memory, language, social cognition, and emotion. The definitive localization and characterization of distinct triple representations for cognition and emotion task processing in the cerebellum opens up new basic science questions as to why there are triple representations (what different functions are enabled by the different representations?) and new clinical questions (what are the differing consequences of lesions to the different representations?). Copyright © 2018 Elsevier Inc. All rights reserved.

Common and distinct brain networks underlying verbal and visual creativity.

PubMed

Zhu, Wenfeng; Chen, Qunlin; Xia, Lingxiang; Beaty, Roger E; Yang, Wenjing; Tian, Fang; Sun, Jiangzhou; Cao, Guikang; Zhang, Qinglin; Chen, Xu; Qiu, Jiang

2017-04-01

Creativity is imperative to the progression of human civilization, prosperity, and well-being. Past creative researches tends to emphasize the default mode network (DMN) or the frontoparietal network (FPN) somewhat exclusively. However, little is known about how these networks interact to contribute to creativity and whether common or distinct brain networks are responsible for visual and verbal creativity. Here, we use functional connectivity analysis of resting-state functional magnetic resonance imaging data to investigate visual and verbal creativity-related regions and networks in 282 healthy subjects. We found that functional connectivity within the bilateral superior parietal cortex of the FPN was negatively associated with visual and verbal creativity. The strength of connectivity between the DMN and FPN was positively related to both creative domains. Visual creativity was negatively correlated with functional connectivity within the precuneus of the pDMN and right middle frontal gyrus of the FPN, and verbal creativity was negatively correlated with functional connectivity within the medial prefrontal cortex of the aDMN. Critically, the FPN mediated the relationship between the aDMN and verbal creativity, and it also mediated the relationship between the pDMN and visual creativity. Taken together, decreased within-network connectivity of the FPN and DMN may allow for flexible between-network coupling in the highly creative brain. These findings provide indirect evidence for the cooperative role of the default and executive control networks in creativity, extending past research by revealing common and distinct brain systems underlying verbal and visual creative cognition. Hum Brain Mapp 38:2094-2111, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Amygdala subnuclei resting-state functional connectivity sex and estrogen differences.

PubMed

Engman, Jonas; Linnman, Clas; Van Dijk, Koene R A; Milad, Mohammed R

2016-01-01

The amygdala is a hub in emotional processing, including that of negative affect. Healthy men and women have distinct differences in amygdala responses, potentially setting the stage for the observed sex differences in the prevalence of fear, anxiety, and pain disorders. Here, we examined how amygdala subnuclei resting-state functional connectivity is affected by sex, as well as explored how the functional connectivity is related to estrogen levels. Resting-state functional connectivity was measured using functional magnetic resonance imaging (fMRI) with seeds placed in the left and right laterobasal (LB) and centromedial (CM) amygdala. Sex differences were studied in 48 healthy men and 48 healthy women, matched for age, while the association with estrogen was analyzed in a subsample of 24 women, for whom hormone levels had been assessed. For the hormone analyses, the subsample was further divided into a lower and higher estrogen levels group based on a median split. We found distinct sex differences in the LB and CM amygdala resting-state functional connectivity, as well as preliminary evidence for an association between estrogen levels and connectivity patterns. These results are potentially valuable in explaining why women are more afflicted by conditions of negative affect than are men, and could imply a mechanistic role for estrogen in modulating emotion. Copyright © 2015 Elsevier Ltd. All rights reserved.

Dok-3 and Dok-1/-2 adaptors play distinctive roles in cell fusion and proliferation during osteoclastogenesis and cooperatively protect mice from osteopenia.

PubMed

Kajikawa, Shuhei; Taguchi, Yuu; Hayata, Tadayoshi; Ezura, Yoichi; Ueta, Ryo; Arimura, Sumimasa; Inoue, Jun-Ichiro; Noda, Masaki; Yamanashi, Yuji

2018-04-15

Bone mass is determined by coordinated acts of osteoblasts and osteoclasts, which control bone formation and resorption, respectively. Osteoclasts are multinucleated, macrophage/monocyte lineage cells from bone marrow. The Dok-family adaptors Dok-1, Dok-2 and Dok-3 are expressed in the macrophage/monocyte lineage and negatively regulate many signaling pathways, implying roles in osteoclastogenesis. Indeed, mice lacking Dok-1 and Dok-2, the closest homologues with redundant functions, develop osteopenia with increased osteoclast counts compared to the wild-type controls. Here, we demonstrate that Dok-3 knockout (KO) mice also develop osteopenia. However, Dok-3 KO, but not Dok-1/-2 double-KO (DKO), mice develop larger osteoclasts within the normal cell-count range, suggesting a distinctive role for Dok-3. Indeed, Dok-3 KO, but not Dok-1/-2 DKO, bone marrow-derived cells (BMDCs) generated larger osteoclasts with more nuclei due to augmented cell-to-cell fusion in vitro. In addition, while Dok-1/-2 DKO BMDCs generated more osteoclasts, Dok-1/-2/-3 triple-KO (TKO) BMDCs generated osteoclasts increased in both number and size. Furthermore, Dok-1/-2/-3 TKO mice showed the combined effects of Dok-3 and Dok-1/-2 deficiency: severe osteopenia with more and larger osteoclasts. Together, our findings demonstrate that Dok-3 and Dok-1/-2 play distinctive but cooperative roles in osteoclastogenesis and protect mice from osteopenia, providing physiological and pathophysiological insight into bone homeostasis. Copyright © 2018 Elsevier Inc. All rights reserved.

Distinct roles for extracellular and intracellular domains in neuroligin function at inhibitory synapses

PubMed Central

Nguyen, Quynh-Anh; Horn, Meryl E; Nicoll, Roger A

2016-01-01

Neuroligins (NLGNs) are postsynaptic cell adhesion molecules that interact trans-synaptically with neurexins to mediate synapse development and function. NLGN2 is only at inhibitory synapses while NLGN3 is at both excitatory and inhibitory synapses. We found that NLGN3 function at inhibitory synapses in rat CA1 depends on the presence of NLGN2 and identified a domain in the extracellular region that accounted for this functional difference between NLGN2 and 3 specifically at inhibitory synapses. We further show that the presence of a cytoplasmic tail (c-tail) is indispensible, and identified two domains in the c-tail that are necessary for NLGN function at inhibitory synapses. These domains point to a gephyrin-dependent mechanism that is disrupted by an autism-associated mutation at R705 and a gephyrin-independent mechanism reliant on a putative phosphorylation site at S714. Our work highlights unique and separate roles for the extracellular and intracellular regions in specifying and carrying out NLGN function respectively. DOI: http://dx.doi.org/10.7554/eLife.19236.001 PMID:27805570

The provisional matrix: setting the stage for tissue repair outcomes.

PubMed

Barker, Thomas H; Engler, Adam J

2017-07-01

Since its conceptualization in the 1980s, the provisional matrix has often been characterized as a simple fibrin-containing scaffold for wound healing that supports the nascent blood clot and is functionally distinct from the basement membrane. However subsequent advances have shown that this matrix is far from passive, with distinct compositional differences as the wound matures, and providing an active role for wound remodeling. Here we review the stages of this matrix, provide an update on the state of our understanding of provisional matrix, and present some of the outstanding issues related to the provisional matrix, its components, and their assembly and use in vivo. Copyright © 2017. Published by Elsevier B.V.

Bovine brain ribonuclease is the functional homolog of human ribonuclease 1.

PubMed

Eller, Chelcie H; Lomax, Jo E; Raines, Ronald T

2014-09-19

Mounting evidence suggests that human pancreatic ribonuclease (RNase 1) plays important roles in vivo, ranging from regulating blood clotting and inflammation to directly counteracting tumorigenic cells. Understanding these putative roles has been pursued with continual comparisons of human RNase 1 to bovine RNase A, an enzyme that appears to function primarily in the ruminant gut. Our results imply a different physiology for human RNase 1. We demonstrate distinct functional differences between human RNase 1 and bovine RNase A. Moreover, we characterize another RNase 1 homolog, bovine brain ribonuclease, and find pronounced similarities between that enzyme and human RNase 1. We report that human RNase 1 and bovine brain ribonuclease share high catalytic activity against double-stranded RNA substrates, a rare quality among ribonucleases. Both human RNase 1 and bovine brain RNase are readily endocytosed by mammalian cells, aided by tight interactions with cell surface glycans. Finally, we show that both human RNase 1 and bovine brain RNase are secreted from endothelial cells in a regulated manner, implying a potential role in vascular homeostasis. Our results suggest that brain ribonuclease, not RNase A, is the true bovine homolog of human RNase 1, and provide fundamental insight into the ancestral roles and functional adaptations of RNase 1 in mammals. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

The human cerebellum: a review of physiologic neuroanatomy.

PubMed

Roostaei, Tina; Nazeri, Arash; Sahraian, Mohammad Ali; Minagar, Alireza

2014-11-01

The cerebellum resides in the posterior cranial fossa dorsal to the brainstem and has diverse connections to the cerebrum, brain stem, and spinal cord. It is anatomically and physiologically divided into distinct functional compartments and is composed of highly regular arrays of neuronal units, each sharing the same basic cerebellar microcircuitry. Its circuitry is critically involved in motor control and motor learning, and its role in nonmotor cognitive and affective functions is becoming increasingly recognized. This article describes the cerebellar gross and histologic neuroanatomy in relation to its function, and the relevance of cerebellar circuitry and firing patterns to motor learning. Copyright © 2014 Elsevier Inc. All rights reserved.

Black lesbian gender and sexual culture: celebration and resistance.

PubMed

Wilson, Bianca D M

2009-04-01

Lesbian gender expression is a persistent theme in research and writing about lesbian culture. Yet little empirical research has examined the ways lesbian gender functions within the sexual culture of lesbian communities, particularly among lesbians of colour. This study was aimed at documenting and assessing the functions of lesbian gender among African American lesbians. Particular attention was paid to identifying core characteristics of sexual discourses, such as evidence of dominant and resistant sexual scripts and contradictions between messages about sex. This study took the form of a rapid ethnography of an African American lesbian community in the USA using focus groups, individual community leader interviews and participant observations at a weekly open mic event. Findings document how lesbian gender roles translated into distinct sexual roles and expectations that appear to both parallel and radically reject heterosexual norms for sex. The deep roots of the social pressure to date within these roles were also evident within observations at the open microphone events. While data highlighted the central role that lesbian gender roles play in this community, analyses also revealed a strong resistance to the dominance of this sexual cultural system.

Parvalbumin and GAD65 Interneuron Inhibition in the Ventral Hippocampus Induces Distinct Behavioral Deficits Relevant to Schizophrenia

PubMed Central

Nguyen, Robin; Morrissey, Mark D.; Mahadevan, Vivek; Cajanding, Janine D.; Woodin, Melanie A.; Yeomans, John S.; Takehara-Nishiuchi, Kaori

2014-01-01

Hyperactivity within the ventral hippocampus (vHPC) has been linked to both psychosis in humans and behavioral deficits in animal models of schizophrenia. A local decrease in GABA-mediated inhibition, particularly involving parvalbumin (PV)-expressing GABA neurons, has been proposed as a key mechanism underlying this hyperactive state. However, direct evidence is lacking for a causal role of vHPC GABA neurons in behaviors associated with schizophrenia. Here, we probed the behavioral function of two different but overlapping populations of vHPC GABA neurons that express either PV or GAD65 by selectively inhibiting these neurons with the pharmacogenetic neuromodulator hM4D. We show that acute inhibition of vHPC GABA neurons in adult mice results in behavioral changes relevant to schizophrenia. Inhibiting either PV or GAD65 neurons produced distinct behavioral deficits. Inhibition of PV neurons, affecting ∼80% of the PV neuron population, robustly impaired prepulse inhibition of the acoustic startle reflex (PPI), startle reactivity, and spontaneous alternation, but did not affect locomotor activity. In contrast, inhibiting a heterogeneous population of GAD65 neurons, affecting ∼40% of PV neurons and 65% of cholecystokinin neurons, increased spontaneous and amphetamine-induced locomotor activity and reduced spontaneous alternation, but did not alter PPI. Inhibition of PV or GAD65 neurons also produced distinct changes in network oscillatory activity in the vHPC in vivo. Together, these findings establish a causal role for vHPC GABA neurons in controlling behaviors relevant to schizophrenia and suggest a functional dissociation between the GABAergic mechanisms involved in hippocampal modulation of sensorimotor processes. PMID:25378161

An integrated view of suppressor T cell subsets in immunoregulation

PubMed Central

Jiang, Hong; Chess, Leonard

2004-01-01

The immune system evolved to protect organisms from a virtually infinite variety of disease-causing agents but to avoid harmful responses to self. Because immune protective mechanisms include the elaboration of potent inflammatory molecules, antibodies, and killer cell activation — which together can not only destroy invading microorganisms, pathogenic autoreactive cells, and tumors, but also mortally injure normal cells — the immune system is inherently a “double-edged sword” and must be tightly regulated. Immune response regulation includes homeostatic mechanisms intrinsic to the activation and differentiation of antigen-triggered immunocompetent cells and extrinsic mechanisms mediated by suppressor cells. This review series will focus on recent advances indicating that distinct subsets of regulatory CD4+ and CD8+ T cells as well as NK T cells control the outgrowth of potentially pathogenic antigen-reactive T cells and will highlight the evidence that these suppressor T cells may play potentially important clinical roles in preventing and treating immune-mediated disease. Here we provide a historical overview of suppressor cells and the experimental basis for the existence of functionally and phenotypically distinct suppressor subsets. Finally, we will speculate on how the distinct suppressor cell subsets may function in concert to regulate immune responses. PMID:15520848

Branchial Cilia and Sperm Flagella Recruit Distinct Axonemal Components

PubMed Central

Konno, Alu; Shiba, Kogiku; Cai, Chunhua; Inaba, Kazuo

2015-01-01

Eukaryotic cilia and flagella have highly conserved 9 + 2 structures. They are functionally diverged to play cell-type-specific roles even in a multicellular organism. Although their structural components are therefore believed to be common, few studies have investigated the molecular diversity of the protein components of the cilia and flagella in a single organism. Here we carried out a proteomic analysis and compared protein components between branchial cilia and sperm flagella in a marine invertebrate chordate, Ciona intestinalis. Distinct feature of protein recruitment in branchial cilia and sperm flagella has been clarified; (1) Isoforms of α- and β-tubulins as well as those of actins are distinctly used in branchial cilia or sperm flagella. (2) Structural components, such as dynein docking complex, tektins and an outer dense fiber protein, are used differently by the cilia and flagella. (3) Sperm flagella are specialized for the cAMP- and Ca2+-dependent regulation of outer arm dynein and for energy metabolism by glycolytic enzymes. Our present study clearly demonstrates that flagellar or ciliary proteins are properly recruited according to their function and stability, despite their apparent structural resemblance and conservation. PMID:25962172

Hand2 loss-of-function in Hand1-expressing Cells Reveals Distinct Roles In Epicardial And Coronary Vessel Development

PubMed Central

Barnes, Ralston M.; Firulli, Beth A.; VanDusen, Nathan J.; Morikawa, Yuka; Conway, Simon J.; Cserjesi, Peter; Vincentz, Joshua W.; Firulli, Anthony B.

2011-01-01

Rationale The bHLH transcription factors Hand1 and Hand2 are essential for embryonic development. Given their requirement for cardiogenesis, it is imperative to determine their impact on cardiovascular function. Objective Deduce the role of Hand2 within the epicardium. Method & Results We engineered a Hand1 allele expressing Cre recombinase. Cardiac Hand1 expression is largely limited to cells of the primary heart field, overlapping little with Hand2 expression. Hand1 is expressed within the septum transversum (ST) and the Hand1-lineage marks the proepicardial organ and epicardium. To examine Hand factor functional overlap, we conditionally deleted Hand2 from Hand1-expressing cells. Hand2 mutants display defective epicardialization and fail to form coronary arteries, coincident with altered ECM deposition and Pdgfr expression. Conclusion These data demonstrate a hierarchal relationship whereby transient Hand1 ST expression defines epicardial precursors that are subsequently dependent upon Hand2 function. PMID:21350214

Parental Problem Drinking and Adolescent Externalizing Behaviors: The Mediating Role of Family Functioning

PubMed Central

Schulz, Jessica; Gordon, Mellissa S.; Ohannessian, Christine McCauley

2015-01-01

This study explored relationships among parental problem drinking, family functioning, and adolescent externalizing behaviors. The unique effects of maternal and paternal drinking were examined separately for girls and boys. The sample included 14-19 year old U.S. adolescents (Mage=16.15; SD=.75; 52.5% female) and their parents. Participants completed surveys in the spring of 2007 and 2008. Structural equation modelling was used to conduct path analysis models. Results showed the distinctive and adverse effects of parental problem drinking on adolescent alcohol use, drug use, rule breaking, and aggressive behavior over time. Findings also highlighted the indirect and mediating roles of family functioning. For both girls and boys, family cohesion mediated the relationship between parental problem drinking and adolescent externalizing behaviors. For girls, adolescent-father communication predicted increased externalizing behaviors over time. These findings draw attention to the importance of exploring adolescent and parent gender when examining parental problem drinking, family functioning, and externalizing behaviors. PMID:26073673

Pathological and therapeutic roles of innate lymphoid cells in diverse diseases.

PubMed

Kim, Jisu; Kim, Geon; Min, Hyeyoung

2017-11-01

Innate lymphoid cells (ILCs) are a recently defined type of innate-immunity cells that belong to the lymphoid lineage and have lymphoid morphology but do not express an antigen-specific B cell or T-cell receptor. ILCs regulate immune functions prior to the formation of adaptive immunity and exert effector functions through a cytokine release. ILCs have been classified into three groups according to the transcription factors that regulate their development and function and the effector cytokines they produce. Of note, ILCs resemble T helper (Th) cells, such as Th1, Th2, and Th17 cells, and show a similar dependence on transcription factors and distinct cytokine production. Despite their short history in immunology, ILCs have received much attention, and numerous studies have revealed biological functions of ILCs including host defense against pathogens, inflammation, tissue repair, and metabolic homeostasis. Here, we describe recent findings about the roles of ILCs in the pathogenesis of various diseases and potential therapeutic targets.

Volition and conflict in human medial frontal cortex.

PubMed

Nachev, Parashkev; Rees, Geraint; Parton, Andrew; Kennard, Christopher; Husain, Masud

2005-01-26

Controversy surrounds the role of human medial frontal cortex in controlling actions. Although damage to this area leads to severe difficulties in spontaneously initiating actions, the precise mechanisms underlying such "volitional" deficits remain to be established. Previous studies have implicated the medial frontal cortex in conflict monitoring and the control of voluntary action, suggesting that these key processes are functionally related or share neural substrates. Here, we combine a novel behavioral paradigm with functional imaging of the oculomotor system to reveal, for the first time, a functional subdivision of the pre-supplementary motor area (pre-SMA) into anatomically distinct areas that respond exclusively to either volition or conflict. We also demonstrate that activity in the supplementary eye field (SEF) distinguishes between success and failure in changing voluntary action plans during conflict, suggesting a role for the SEF in implementing the resolution of conflicting actions. We propose a functional architecture of human medial frontal cortex that incorporates the generation of action plans and the resolution of conflict.

Design Features for Linguistically-Mediated Meaning Construction: The Relative Roles of the Linguistic and Conceptual Systems in Subserving the Ideational Function of Language

PubMed Central

Evans, Vyvyan

2016-01-01

Recent research in language and cognitive science proposes that the linguistic system evolved to provide an “executive” control system on the evolutionarily more ancient conceptual system (e.g., Barsalou et al., 2008; Evans, 2009, 2015a,b; Bergen, 2012). In short, the claim is that embodied representations in the linguistic system interface with non-linguistic representations in the conceptual system, facilitating rich meanings, or simulations, enabling linguistically mediated communication. In this paper I build on these proposals by examining the nature of what I identify as design features for this control system. In particular, I address how the ideational function of language—our ability to deploy linguistic symbols to convey meanings of great complexity—is facilitated. The central proposal of this paper is as follows. The linguistic system of any given language user, of any given linguistic system—spoken or signed—facilitates access to knowledge representation—concepts—in the conceptual system, which subserves this ideational function. In the most general terms, the human meaning-making capacity is underpinned by two distinct, although tightly coupled representational systems: the conceptual system and the linguistic system. Each system contributes to meaning construction in qualitatively distinct ways. This leads to the first design feature: given that the two systems are representational—they are populated by semantic representations—the nature and function of the representations are qualitatively different. This proposed design feature I term the bifurcation in semantic representation. After all, it stands to reason that if a linguistic system has a different function, vis-à-vis the conceptual system, which is of far greater evolutionary antiquity, then the semantic representations will be complementary, and as such, qualitatively different, reflecting the functional distinctions of the two systems, in collectively giving rise to meaning. I consider the nature of these qualitatively distinct representations. And second, language itself is adapted to the conceptual system—the semantic potential—that it marshals in the meaning construction process. Hence, a linguistic system itself exhibits a bifurcation, in terms of the symbolic resources at its disposal. This design feature I dub the birfucation in linguistic organization. As I shall argue, this relates to two distinct reference strategies available for symbolic encoding in language: what I dub words-to-world reference and words-to-words reference. In slightly different terms, this design feature of language amounts to a distinction between a lexical subsystem, and a grammatical subsystem. PMID:26925000

Design Features for Linguistically-Mediated Meaning Construction: The Relative Roles of the Linguistic and Conceptual Systems in Subserving the Ideational Function of Language.

PubMed

Evans, Vyvyan

2016-01-01

Recent research in language and cognitive science proposes that the linguistic system evolved to provide an "executive" control system on the evolutionarily more ancient conceptual system (e.g., Barsalou et al., 2008; Evans, 2009, 2015a,b; Bergen, 2012). In short, the claim is that embodied representations in the linguistic system interface with non-linguistic representations in the conceptual system, facilitating rich meanings, or simulations, enabling linguistically mediated communication. In this paper I build on these proposals by examining the nature of what I identify as design features for this control system. In particular, I address how the ideational function of language-our ability to deploy linguistic symbols to convey meanings of great complexity-is facilitated. The central proposal of this paper is as follows. The linguistic system of any given language user, of any given linguistic system-spoken or signed-facilitates access to knowledge representation-concepts-in the conceptual system, which subserves this ideational function. In the most general terms, the human meaning-making capacity is underpinned by two distinct, although tightly coupled representational systems: the conceptual system and the linguistic system. Each system contributes to meaning construction in qualitatively distinct ways. This leads to the first design feature: given that the two systems are representational-they are populated by semantic representations-the nature and function of the representations are qualitatively different. This proposed design feature I term the bifurcation in semantic representation. After all, it stands to reason that if a linguistic system has a different function, vis-à-vis the conceptual system, which is of far greater evolutionary antiquity, then the semantic representations will be complementary, and as such, qualitatively different, reflecting the functional distinctions of the two systems, in collectively giving rise to meaning. I consider the nature of these qualitatively distinct representations. And second, language itself is adapted to the conceptual system-the semantic potential-that it marshals in the meaning construction process. Hence, a linguistic system itself exhibits a bifurcation, in terms of the symbolic resources at its disposal. This design feature I dub the birfucation in linguistic organization. As I shall argue, this relates to two distinct reference strategies available for symbolic encoding in language: what I dub words-to-world reference and words-to-words reference. In slightly different terms, this design feature of language amounts to a distinction between a lexical subsystem, and a grammatical subsystem.

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.

Integrin-linked kinase: a Scaffold protein unique among its ilk.

PubMed

Dagnino, Lina

2011-06-01

Integrin-linked kinase (ILK) is a scaffolding protein with central roles in tissue development and homeostasis. Much debate has focused on whether ILK is a bona fide or a pseudo- kinase. This aspect of ILK function has been complicated by the large volumes of conflicting observations obtained from a wide variety of experimental approaches, from in vitro models, to analyses in invertebrates and in mammals. Key findings in support or against the notion that ILK is catalytically active are summarized. The importance of ILK as an adaptor protein is well established, and defining its role as a signaling hub will be the next key step to understand its distinct biological roles across tissues and species.

Functional and phenotypic heterogeneity of group 3 innate lymphoid cells.

PubMed

Melo-Gonzalez, Felipe; Hepworth, Matthew R

2017-03-01

Group 3 innate lymphoid cells (ILC3), defined by expression of the transcription factor retinoid-related orphan receptor γt, play key roles in the regulation of inflammation and immunity in the gastrointestinal tract and associated lymphoid tissues. ILC3 consist largely of two major subsets, NCR + ILC3 and LTi-like ILC3, but also demonstrate significant plasticity and heterogeneity. Recent advances have begun to dissect the relationship between ILC3 subsets and to define distinct functional states within the intestinal tissue microenvironment. In this review we discuss the ever-expanding roles of ILC3 in the context of intestinal homeostasis, infection and inflammation - with a focus on comparing and contrasting the relative contributions of ILC3 subsets. © 2016 The Authors. Immunology published by John Wiley & Sons Ltd.

The distribution patterns of COMP and matrilin-3 in septal, alar and triangular cartilages of the human nose.

PubMed

Wiggenhauser, Paul Severin; Schwarz, Silke; Rotter, Nicole

2018-05-02

The biomechanical characteristics of septal cartilage depend strongly on the distinct extracellular matrix of cartilage tissue; therefore, it is essential that the components of this matrix are identified and understood. Cartilage oligomeric matrix protein (COMP) and matrilin-3 are localised in articular cartilage. This study was the first to examine all subtypes of mature human nasal cartilages (alar, triangular and septal) with specific attention to the distribution of COMP and matrilin-3. Three whole fresh-frozen noses from human donors were dissected, and exemplary biopsies were examined using histochemical staining (haematoxylin and eosin and Alcian blue) and immunohistochemistry (collagen II, COMP and matrilin-3). The following three zones within the nasal cartilage were identified: superficial, intermediate and central. COMP was detected as highest in the intermediate zones in all three subtypes of nasal cartilage, whereas matrilin-3 was detected with pericellular deposition mainly within septal cartilage predominantly in the superficial zones. The distinct staining patterns of COMP and matrilin-3 underscore the different functional roles of both proteins in nasal cartilage. According to the literature, COMP might be involved with collagen II in the formation of networks, whereas matrilin-3 is reported to prevent ossification or regulate mechanosensitivity. The predominant staining observed in septal cartilage suggests matrilin-3's modulatory role because of its presence in the osteochondral junctional zone and given that the biomechanical load in septal cartilage is different from that in alar or triangular cartilage. In conclusion, COMP and matrilin-3 were detected in mature human nasal cartilage but displayed different staining patterns that might be explained by the functional roles of the respective matrix protein; however, further research is necessary to identify and define the functional aspects of this morphological difference.

The Microbiota of the Human Skin.

PubMed

Egert, Markus; Simmering, Rainer

2016-01-01

The aim of this chapter is to sum up important progress in the field of human skin microbiota research that was achieved over the last years.The human skin is one of the largest and most versatile organs of the human body. Owing to its function as a protective interface between the largely sterile interior of the human body and the highly microbially contaminated outer environment, it is densely colonized with a diverse and active microbiota. This skin microbiota is of high importance for human health and well-being. It is implicated in several severe skin diseases and plays a major role in wound infections. Many less severe, but negatively perceived cosmetic skin phenomena are linked with skin microbes, too. In addition, skin microorganisms, in particular on the human hands, are crucial for the field of hygiene research. Notably, apart from being only a potential source of disease and contamination, the skin microbiota also contributes to the protective functions of the human skin in many ways. Finally, the analysis of structure and function of the human skin microbiota is interesting from a basic, evolutionary perspective on human microbe interactions.Key questions in the field of skin microbiota research deal with (a) a deeper understanding of the structure (species inventory) and function (physiology) of the healthy human skin microbiota in space and time, (b) the distinction of resident and transient skin microbiota members, (c) the distinction of beneficial skin microorganisms from microorganisms or communities with an adverse or sickening effect on their hosts, (d) factors shaping the skin microbiota and its functional role in health and disease, (e) strategies to manipulate the skin microbiota for therapeutic reasons.

Differences in the structure and functioning of two communities: Frondose and turf-forming macroalgal dominated habitats.

PubMed

M Martins, Gustavo; Hipólito, Cláudia; Parreira, Filipe; C L Prestes, Afonso; Dionísio, Maria A; N Azevedo, José M; Neto, Ana I

2016-05-01

In many coastal regions, vegetated habitats (e.g. kelps forests, seagrass beds) play a key role in the structure and functioning of shallow subtidal reef ecosystems, by modifying local environmental conditions and by providing food and habitat for a wide range of organisms. In some regions of the world, however, such idiosyncratic ecosystems are largely absent and are often replaced by less notable ecosystem formers. In the present study, we empirically compared the structure and functioning of two distinct shallow-water habitats present in the Azores: one dominated by smaller frondose brown macroalgae (Dictyotaceae and Halopteris) and one dominated by low-lying turfs. Two replicated areas of each habitat were sampled at two different times of the year, to assess spatial and temporal consistency of results. Habitats dominated by small fronds were significantly (ca. 3 times) more productive (when standardized per algal mass) compared to the turf-dominated habitats, and supported a distinct assemblage (both in terms of composition and abundance) of associated macrofauna. Unlike other well-known and studied vegetated habitats (i.e. kelp forests), however, no effects of habitat were found on the structure of benthonic fish assemblages. Results were spatially and temporally consistent suggesting that, in warmer temperate oceans, habitats dominated by species of smaller frondose brown algae can also play an important role in the structure and functioning of subtidal communities and may, to a certain extent, be considered analogous to other well-known vegetated habitats around the world (i.e. kelp forests, seagrass beds). Copyright © 2016 Elsevier Ltd. All rights reserved.

β1-adrenergic receptors activate two distinct signaling pathways in striatal neurons

PubMed Central

Meitzen, John; Luoma, Jessie I.; Stern, Christopher M.; Mermelstein, Paul G.

2010-01-01

Monoamine action in the dorsal striatum and nucleus accumbens plays essential roles in striatal physiology. Although research often focuses on dopamine and its receptors, norepinephrine and adrenergic receptors are also crucial in regulating striatal function. While noradrenergic neurotransmission has been identified in the striatum, little is known regarding the signaling pathways activated by β-adrenergic receptors in this brain region. Using cultured striatal neurons, we characterized a novel signaling pathway by which activation of β1-adrenergic receptors leads to the rapid phosphorylation of cAMP Response Element Binding Protein (CREB), a transcription-factor implicated as a molecular switch underlying long-term changes in brain function. Norepinephrine-mediated CREB phosphorylation requires β1-adrenergic receptor stimulation of a receptor tyrosine kinase, ultimately leading to the activation of a Ras/Raf/MEK/MAPK/MSK signaling pathway. Activation of β1-adrenergic receptors also induces CRE-dependent transcription and increased c-fos expression. In addition, stimulation of β1-adrenergic receptors produces cAMP production, but surprisingly, β1-adrenergic receptor activation of adenylyl cyclase was not functionally linked to rapid CREB phosphorylation. These findings demonstrate that activation of β1-adrenergic receptors on striatal neurons can stimulate two distinct signaling pathways. These adrenergic actions can produce long-term changes in gene expression, as well as rapidly modulate cellular physiology. By elucidating the mechanisms by which norepinephrine and β1-adrenergic receptor activation affects striatal physiology, we provide the means to more fully understand the role of monoamines in modulating striatal function, specifically how norepinephrine and β1-adrenergic receptors may affect striatal physiology. PMID:21143600

Distinct collective states due to trade-off between attractive and repulsive couplings

NASA Astrophysics Data System (ADS)

Sathiyadevi, K.; Chandrasekar, V. K.; Senthilkumar, D. V.; Lakshmanan, M.

2018-03-01

We investigate the effect of repulsive coupling together with an attractive coupling in a network of nonlocally coupled oscillators. To understand the complex interaction between these two couplings we introduce a control parameter in the repulsive coupling which plays a crucial role in inducing distinct complex collective patterns. In particular, we show the emergence of various cluster chimera death states through a dynamically distinct transition route, namely the oscillatory cluster state and coherent oscillation death state as a function of the repulsive coupling in the presence of the attractive coupling. In the oscillatory cluster state, the oscillators in the network are grouped into two distinct dynamical states of homogeneous and inhomogeneous oscillatory states. Further, the network of coupled oscillators follow the same transition route in the entire coupling range. Depending upon distinct coupling ranges, the system displays different number of clusters in the death state and oscillatory state. We also observe that the number of coherent domains in the oscillatory cluster state exponentially decreases with increase in coupling range and obeys a power-law decay. Additionally, we show analytical stability for observed solitary state, synchronized state, and incoherent oscillation death state.

Distinct phasic and sustained brain responses and connectivity of amygdala and bed nucleus of the stria terminalis during threat anticipation in panic disorder.

PubMed

Brinkmann, L; Buff, C; Feldker, K; Tupak, S V; Becker, M P I; Herrmann, M J; Straube, T

2017-11-01

Panic disorder (PD) patients are constantly concerned about future panic attacks and exhibit general hypersensitivity to unpredictable threat. We aimed to reveal phasic and sustained brain responses and functional connectivity of the amygdala and the bed nucleus of the stria terminalis (BNST) during threat anticipation in PD. Using functional magnetic resonance imaging (fMRI), we investigated 17 PD patients and 19 healthy controls (HC) during anticipation of temporally unpredictable aversive and neutral sounds. We used a phasic and sustained analysis model to disentangle temporally dissociable brain activations. PD patients compared with HC showed phasic amygdala and sustained BNST responses during anticipation of aversive v. neutral stimuli. Furthermore, increased phasic activation was observed in anterior cingulate cortex (ACC), insula and prefrontal cortex (PFC). Insula and PFC also showed sustained activation. Functional connectivity analyses revealed partly distinct phasic and sustained networks. We demonstrate a role for the BNST during unpredictable threat anticipation in PD and provide first evidence for dissociation between phasic amygdala and sustained BNST activation and their functional connectivity. In line with a hypersensitivity to uncertainty in PD, our results suggest time-dependent involvement of brain regions related to fear and anxiety.

Centriole assembly and the role of Mps1: defensible or dispensable?

PubMed

Pike, Amanda N; Fisk, Harold A

2011-04-14

The Mps1 protein kinase is an intriguing and controversial player in centriole assembly. Originally shown to control duplication of the budding yeast spindle pole body, Mps1 is present in eukaryotes from yeast to humans, the nematode C. elegans being a notable exception, and has also been shown to regulate the spindle checkpoint and an increasing number of cellular functions relating to genomic stability. While its function in the spindle checkpoint appears to be both universally conserved and essential in most organisms, conservation of its originally described function in spindle pole duplication has proven controversial, and it is less clear whether Mps1 is essential for centrosome duplication outside of budding yeast. Recent studies of Mps1 have identified at least two distinct functions for Mps1 in centriole assembly, while simultaneously supporting the notion that Mps1 is dispensable for the process. However, the fact that at least one centrosomal substrate of Mps1 is conserved from yeast to humans down to the phosphorylation site, combined with evidence demonstrating the exquisite control exerted over centrosomal Mps1 levels suggest that the notion of being essential may not be the most important of distinctions.

Development, regulation, metabolism and function of bone marrow adipose tissues.

PubMed

Li, Ziru; Hardij, Julie; Bagchi, Devika P; Scheller, Erica L; MacDougald, Ormond A

2018-05-01

Most adipocytes exist in discrete depots throughout the body, notably in well-defined white and brown adipose tissues. However, adipocytes also reside within specialized niches, of which the most abundant is within bone marrow. Whereas bone marrow adipose tissue (BMAT) shares many properties in common with white adipose tissue, the distinct functions of BMAT are reflected by its development, regulation, protein secretion, and lipid composition. In addition to its potential role as a local energy reservoir, BMAT also secretes proteins, including adiponectin, RANK ligand, dipeptidyl peptidase-4, and stem cell factor, which contribute to local marrow niche functions and which may also influence global metabolism. The characteristics of BMAT are also distinct depending on whether marrow adipocytes are contained within yellow or red marrow, as these can be thought of as 'constitutive' and 'regulated', respectively. The rBMAT for instance can be expanded or depleted by myriad factors, including age, nutrition, endocrine status and pharmaceuticals. Herein we review the site specificity, age-related development, regulation and metabolic characteristics of BMAT under various metabolic conditions, including the functional interactions with bone and hematopoietic cells. Copyright © 2018 Elsevier Inc. All rights reserved.

Cortical organization of inhibition-related functions and modulation by psychopathology

PubMed Central

Warren, Stacie L.; Crocker, Laura D.; Spielberg, Jeffery M.; Engels, Anna S.; Banich, Marie T.; Sutton, Bradley P.; Miller, Gregory A.; Heller, Wendy

2013-01-01

Individual differences in inhibition-related functions have been implicated as risk factors for a broad range of psychopathology, including anxiety and depression. Delineating neural mechanisms of distinct inhibition-related functions may clarify their role in the development and maintenance of psychopathology. The present study tested the hypothesis that activity in common and distinct brain regions would be associated with an ecologically sensitive, self-report measure of inhibition and a laboratory performance measure of prepotent response inhibition. Results indicated that sub-regions of DLPFC distinguished measures of inhibition, whereas left inferior frontal gyrus and bilateral inferior parietal cortex were associated with both types of inhibition. Additionally, co-occurring anxiety and depression modulated neural activity in select brain regions associated with response inhibition. Results imply that specific combinations of anxiety and depression dimensions are associated with failure to implement top-down attentional control as reflected in inefficient recruitment of posterior DLPFC and increased activation in regions associated with threat (MTG) and worry (BA10). Present findings elucidate possible neural mechanisms of interference that could help explain executive control deficits in psychopathology. PMID:23781192

Cortical organization of inhibition-related functions and modulation by psychopathology.

PubMed

Warren, Stacie L; Crocker, Laura D; Spielberg, Jeffery M; Engels, Anna S; Banich, Marie T; Sutton, Bradley P; Miller, Gregory A; Heller, Wendy

2013-01-01

Individual differences in inhibition-related functions have been implicated as risk factors for a broad range of psychopathology, including anxiety and depression. Delineating neural mechanisms of distinct inhibition-related functions may clarify their role in the development and maintenance of psychopathology. The present study tested the hypothesis that activity in common and distinct brain regions would be associated with an ecologically sensitive, self-report measure of inhibition and a laboratory performance measure of prepotent response inhibition. Results indicated that sub-regions of DLPFC distinguished measures of inhibition, whereas left inferior frontal gyrus and bilateral inferior parietal cortex were associated with both types of inhibition. Additionally, co-occurring anxiety and depression modulated neural activity in select brain regions associated with response inhibition. Results imply that specific combinations of anxiety and depression dimensions are associated with failure to implement top-down attentional control as reflected in inefficient recruitment of posterior DLPFC and increased activation in regions associated with threat (MTG) and worry (BA10). Present findings elucidate possible neural mechanisms of interference that could help explain executive control deficits in psychopathology.

Drosophila Ana1 is required for centrosome assembly and centriole elongation

PubMed Central

Saurya, Saroj; Roque, Hélio; Novak, Zsofia A.; Wainman, Alan; Aydogan, Mustafa G.; Volanakis, Adam; Sieber, Boris; Pinto, David Miguel Susano

2016-01-01

ABSTRACT Centrioles organise centrosomes and cilia, and these organelles have an important role in many cell processes. In flies, the centriole protein Ana1 is required for the assembly of functional centrosomes and cilia. It has recently been shown that Cep135 (also known as Bld10) initially recruits Ana1 to newly formed centrioles, and that Ana1 then recruits Asl (known as Cep152 in mammals) to promote the conversion of these centrioles into centrosomes. Here, we show that ana1 mutants lack detectable centrosomes in vivo, that Ana1 is irreversibly incorporated into centrioles during their assembly and appears to play a more important role in maintaining Asl at centrioles than in initially recruiting Asl to centrioles. Unexpectedly, we also find that Ana1 promotes centriole elongation in a dose-dependent manner: centrioles are shorter when Ana1 dosage is reduced and are longer when Ana1 is overexpressed. This latter function of Ana1 appears to be distinct from its role in centrosome and cilium function, as a GFP–Ana1 fusion lacking the N-terminal 639 amino acids of the protein can support centrosome assembly and cilium function but cannot promote centriole over-elongation when overexpressed. PMID:27206860

Role of Bassoon and Piccolo in Assembly and Molecular Organization of the Active Zone

PubMed Central

Gundelfinger, Eckart D.; Reissner, Carsten; Garner, Craig C.

2016-01-01

Bassoon and Piccolo are two very large scaffolding proteins of the cytomatrix assembled at the active zone (CAZ) where neurotransmitter is released. They share regions of high sequence similarity distributed along their entire length and seem to share both overlapping and distinct functions in organizing the CAZ. Here, we survey our present knowledge on protein-protein interactions and recent progress in understanding of molecular functions of these two giant proteins. These include roles in the assembly of active zones (AZ), the localization of voltage-gated Ca2+ channels (VGCCs) in the vicinity of release sites, synaptic vesicle (SV) priming and in the case of Piccolo, a role in the dynamic assembly of the actin cytoskeleton. Piccolo and Bassoon are also important for the maintenance of presynaptic structure and function, as well as for the assembly of CAZ specializations such as synaptic ribbons. Recent findings suggest that they are also involved in the regulation activity-dependent communication between presynaptic boutons and the neuronal nucleus. Together these observations suggest that Bassoon and Piccolo use their modular structure to organize super-molecular complexes essential for various aspects of presynaptic function. PMID:26793095

HNF1B variants associate with promoter methylation and regulate gene networks activated in prostate and ovarian cancer

PubMed Central

Ross-Adams, Helen; Ball, Stephen; Lawrenson, Kate; Halim, Silvia; Russell, Roslin; Wells, Claire; Strand, Siri H.; Ørntoft, Torben F.; Larson, Melissa; Armasu, Sebastian; Massie, Charles E.; Asim, Mohammad; Mortensen, Martin M.; Borre, Michael; Woodfine, Kathryn; Warren, Anne Y.; Lamb, Alastair D.; Kay, Jonathan; Whitaker, Hayley; Ramos-Montoya, Antonio; Murrell, Adele; Sørensen, Karina D.; Fridley, Brooke L.; Goode, Ellen L.; Gayther, Simon A.; Masters, John

2016-01-01

Two independent regions within HNF1B are consistently identified in prostate and ovarian cancer genome-wide association studies (GWAS); their functional roles are unclear. We link prostate cancer (PC) risk SNPs rs11649743 and rs3760511 with elevated HNF1B gene expression and allele-specific epigenetic silencing, and outline a mechanism by which common risk variants could effect functional changes that increase disease risk: functional assays suggest that HNF1B is a pro-differentiation factor that suppresses epithelial-to-mesenchymal transition (EMT) in unmethylated, healthy tissues. This tumor-suppressor activity is lost when HNF1B is silenced by promoter methylation in the progression to PC. Epigenetic inactivation of HNF1B in ovarian cancer also associates with known risk SNPs, with a similar impact on EMT. This represents one of the first comprehensive studies into the pleiotropic role of a GWAS-associated transcription factor across distinct cancer types, and is the first to describe a conserved role for a multi-cancer genetic risk factor. PMID:27732966

Hydrolase treatments help unravel the function of intervessel pits in xylem hydraulics.

PubMed

Dusotoit-Coucaud, Anaïs; Brunel, Nicole; Tixier, Aude; Cochard, Hervé; Herbette, Stéphane

2014-03-01

Intervessel pits are structures that play a key role in the efficiency and safety functions of xylem hydraulics. However, little is known about the components of the pit membrane (PM) and their role in hydraulic functions, especially in resistance to cavitation. We tested the effect of commercial chemicals including a cellulase, a hemicellulase, a pectolyase, a proteinase and DTT on xylem hydraulic properties: vulnerability to cavitation (VC) and conductance. The effects were tested on branch segments from Fagus sylvatica (where the effects on pit structure were analyzed using TEM) and Populus tremula. Cellulose hydrolysis resulted in a sharp increase in VC and a significant increase in conductance, related to complete breakdown of the PM. Pectin hydrolysis also induced a sharp increase in VC but with no effect on conductance or pit structure observable by TEM. The other treatments with hemicellulase, proteinase or DTT showed no effect. This study brings evidence that cellulose and pectins are critical components underpinning VC, and that PM components may play distinct roles in the xylem hydraulic safety and efficiency. © 2013 Scandinavian Plant Physiology Society.

An Atlas of Peroxiredoxins Created Using an Active Site Profile-Based Approach to Functionally Relevant Clustering of Proteins.

PubMed

Harper, Angela F; Leuthaeuser, Janelle B; Babbitt, Patricia C; Morris, John H; Ferrin, Thomas E; Poole, Leslie B; Fetrow, Jacquelyn S

2017-02-01

Peroxiredoxins (Prxs or Prdxs) are a large protein superfamily of antioxidant enzymes that rapidly detoxify damaging peroxides and/or affect signal transduction and, thus, have roles in proliferation, differentiation, and apoptosis. Prx superfamily members are widespread across phylogeny and multiple methods have been developed to classify them. Here we present an updated atlas of the Prx superfamily identified using a novel method called MISST (Multi-level Iterative Sequence Searching Technique). MISST is an iterative search process developed to be both agglomerative, to add sequences containing similar functional site features, and divisive, to split groups when functional site features suggest distinct functionally-relevant clusters. Superfamily members need not be identified initially-MISST begins with a minimal representative set of known structures and searches GenBank iteratively. Further, the method's novelty lies in the manner in which isofunctional groups are selected; rather than use a single or shifting threshold to identify clusters, the groups are deemed isofunctional when they pass a self-identification criterion, such that the group identifies itself and nothing else in a search of GenBank. The method was preliminarily validated on the Prxs, as the Prxs presented challenges of both agglomeration and division. For example, previous sequence analysis clustered the Prx functional families Prx1 and Prx6 into one group. Subsequent expert analysis clearly identified Prx6 as a distinct functionally relevant group. The MISST process distinguishes these two closely related, though functionally distinct, families. Through MISST search iterations, over 38,000 Prx sequences were identified, which the method divided into six isofunctional clusters, consistent with previous expert analysis. The results represent the most complete computational functional analysis of proteins comprising the Prx superfamily. The feasibility of this novel method is demonstrated by the Prx superfamily results, laying the foundation for potential functionally relevant clustering of the universe of protein sequences.

An Atlas of Peroxiredoxins Created Using an Active Site Profile-Based Approach to Functionally Relevant Clustering of Proteins

PubMed Central

Babbitt, Patricia C.; Ferrin, Thomas E.

2017-01-01

Peroxiredoxins (Prxs or Prdxs) are a large protein superfamily of antioxidant enzymes that rapidly detoxify damaging peroxides and/or affect signal transduction and, thus, have roles in proliferation, differentiation, and apoptosis. Prx superfamily members are widespread across phylogeny and multiple methods have been developed to classify them. Here we present an updated atlas of the Prx superfamily identified using a novel method called MISST (Multi-level Iterative Sequence Searching Technique). MISST is an iterative search process developed to be both agglomerative, to add sequences containing similar functional site features, and divisive, to split groups when functional site features suggest distinct functionally-relevant clusters. Superfamily members need not be identified initially—MISST begins with a minimal representative set of known structures and searches GenBank iteratively. Further, the method’s novelty lies in the manner in which isofunctional groups are selected; rather than use a single or shifting threshold to identify clusters, the groups are deemed isofunctional when they pass a self-identification criterion, such that the group identifies itself and nothing else in a search of GenBank. The method was preliminarily validated on the Prxs, as the Prxs presented challenges of both agglomeration and division. For example, previous sequence analysis clustered the Prx functional families Prx1 and Prx6 into one group. Subsequent expert analysis clearly identified Prx6 as a distinct functionally relevant group. The MISST process distinguishes these two closely related, though functionally distinct, families. Through MISST search iterations, over 38,000 Prx sequences were identified, which the method divided into six isofunctional clusters, consistent with previous expert analysis. The results represent the most complete computational functional analysis of proteins comprising the Prx superfamily. The feasibility of this novel method is demonstrated by the Prx superfamily results, laying the foundation for potential functionally relevant clustering of the universe of protein sequences. PMID:28187133

ARF6 and GASP-1 are post-endocytic sorting proteins selectively involved in the intracellular trafficking of dopamine D2 receptors mediated by GRK and PKC in transfected cells

PubMed Central

Cho, DI; Zheng, M; Min, C; Kwon, KJ; Shin, CY; Choi, HK; Kim, KM

2013-01-01

Background and Purpose GPCRs undergo both homologous and heterologous regulatory processes in which receptor phosphorylation plays a critical role. The protein kinases responsible for each pathway are well established; however, other molecular details that characterize each pathway remain unclear. In this study, the molecular mechanisms that determine the differences in the functional roles and intracellular trafficking between homologous and PKC-mediated heterologous internalization pathways for the dopamine D2 receptor were investigated. Experimental Approach All of the S/T residues located within the intracellular loops of D2 receptor were mutated, and the residues responsible for GRK- and PKC-mediated internalization were determined in HEK-293 cells and SH-SY5Y cells. The functional role of receptor internalization and the cellular components that determine the post-endocytic fate of internalized D2 receptors were investigated in the transfected cells. Key Results T134, T225/S228/S229 and S325 were involved in PKC-mediated D2 receptor desensitization. S229 and adjacent S/T residues mediated the PKC-dependent internalization of D2 receptors, which induced down-regulation and desensitization. S/T residues within the second intracellular loop and T225 were the major residues involved in GRK-mediated internalization of D2 receptors, which induced receptor resensitization. ARF6 mediated the recycling of D2 receptors internalized in response to agonist stimulation. In contrast, GASP-1 mediated the down-regulation of D2 receptors internalized in a PKC-dependent manner. Conclusions and Implications GRK- and PKC-mediated internalizations of D2 receptors occur through different intracellular trafficking pathways and mediate distinct functional roles. Distinct S/T residues within D2 receptors and different sorting proteins are involved in the dissimilar regulation of D2 receptors by GRK2 and PKC. PMID:23082996

The two-pore channel TPC1 is required for efficient protein processing through early and recycling endosomes.

PubMed

Castonguay, Jan; Orth, Joachim H C; Müller, Thomas; Sleman, Faten; Grimm, Christian; Wahl-Schott, Christian; Biel, Martin; Mallmann, Robert Theodor; Bildl, Wolfgang; Schulte, Uwe; Klugbauer, Norbert

2017-08-30

Two-pore channels (TPCs) are localized in endo-lysosomal compartments and assumed to play an important role for vesicular fusion and endosomal trafficking. Recently, it has been shown that both TPC1 and 2 were required for host cell entry and pathogenicity of Ebola viruses. Here, we investigate the cellular function of TPC1 using protein toxins as model substrates for distinct endosomal processing routes. Toxin uptake and activation through early endosomes but not processing through other compartments were reduced in TPC1 knockout cells. Detailed co-localization studies with subcellular markers confirmed predominant localization of TPC1 to early and recycling endosomes. Proteomic analysis of native TPC1 channels finally identified direct interaction with a distinct set of syntaxins involved in fusion of intracellular vesicles. Together, our results demonstrate a general role of TPC1 for uptake and processing of proteins in early and recycling endosomes, likely by providing high local Ca 2+ concentrations required for SNARE-mediated vesicle fusion.

Analysis of Microtubule Mediated Functions of Prostate Specific Membrane Antigen

DTIC Science & Technology

2006-04-01

localization of vesicles containing these markers increased to approximately 43% (38/88) when cells are incubated with tunicamycin, indicating a role...PSMA at both plasma membrane domains following nocodazole treatment. Polarity of the basolateral marker Na,K- ATPase was unaffected by nocodazole...restricted to the apical surface facing the lumen. This staining was clearly distinct from that of the endothelial cell marker CD 34 and CD31

Basolateral junctions are sufficient to suppress epithelial invasion during Drosophila oogenesis.

PubMed

Szafranski, Przemyslaw; Goode, Scott

2007-02-01

Epithelial junctions play crucial roles during metazoan evolution and development by facilitating tissue formation, maintenance, and function. Little is known about the role of distinct types of junctions in controlling epithelial transformations leading to invasion of neighboring tissues. Discovering the key junction complexes that control these processes and how they function may also provide mechanistic insight into carcinoma cell invasion. Here, using the Drosophila ovary as a model, we show that four proteins of the basolateral junction (BLJ), Fasciclin-2, Neuroglian, Discs-large, and Lethal-giant-larvae, but not proteins of other epithelial junctions, directly suppress epithelial tumorigenesis and invasion. Remarkably, the expression pattern of Fasciclin-2 predicts which cells will invade. We compared the apicobasal polarity of BLJ tumor cells to border cells (BCs), an epithelium-derived cluster that normally migrates during mid-oogenesis. Both tumor cells and BCs differentiate a lateralized membrane pattern that is necessary but not sufficient for invasion. Independent of lateralization, derepression of motility pathways is also necessary, as indicated by a strong linear correlation between faster BC migration and an increased incidence of tumor invasion. However, without membrane lateralization, derepression of motility pathways is also not sufficient for invasion. Our results demonstrate that spatiotemporal patterns of basolateral junction activity directly suppress epithelial invasion by organizing the cooperative activity of distinct polarity and motility pathways.

Human RAD50 makes a functional DNA-binding complex.

PubMed

Kinoshita, Eri; van Rossum-Fikkert, Sari; Sanchez, Humberto; Kertokalio, Aryandi; Wyman, Claire

2015-06-01

The MRE11-RAD50-NBS1 (MRN) complex has several distinct functions in DNA repair including important roles in both non-homologous end-joining (NHEJ) and homologous recombination (HR). The biochemical activities of MR(N) have been well characterized implying specific functional roles for the components. The arrangement of proteins in the complex implies interdependence of their biochemical activities making it difficult to separate specific functions. We obtained purified human RAD50 and observed that it binds ATP, undergoes ATP-dependent conformational changes as well as having ATPase activity. Scanning force microscopy analysis clearly showed that RAD50 binds DNA although not as oligomers. RAD50 alone was not functional in tethering DNA molecules. ATP increased formation of RAD50 multimers which were however globular lacking extended coiled coils, in contrast to the MR complex where ATP induced oligomers have obvious coiled coils protruding from a central domain. These results suggest that MRE11 is important in maintaining the structural arrangement of RAD50 in the protein complex and perhaps has a role in reinforcing proper alignment of the coiled coils in the ATP-bound state. Copyright © 2015 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

The Immune System and Developmental Programming of Brain and Behavior

PubMed Central

Bilbo, Staci D.; Schwarz, Jaclyn M.

2012-01-01

The brain, endocrine, and immune systems are inextricably linked. Immune molecules have a powerful impact on neuroendocrine function, including hormone-behavior interactions, during health as well as sickness. Similarly, alterations in hormones, such as during stress, can powerfully impact immune function or reactivity. These functional shifts are evolved, adaptive responses that organize changes in behavior and mobilize immune resources, but can also lead to pathology or exacerbate disease if prolonged or exaggerated. The developing brain in particular is exquisitely sensitive to both endogenous and exogenous signals, and increasing evidence suggests the immune system has a critical role in brain development and associated behavioral outcomes for the life of the individual. Indeed, there are associations between many neuropsychiatric disorders and immune dysfunction, with a distinct etiology in neurodevelopment. The goal of this review is to describe the important role of the immune system during brain development, and to discuss some of the many ways in which immune activation during early brain development can affect the later-life outcomes of neural function, immune function, mood and cognition. PMID:22982535

Guards at the gate: physiological and pathological roles of tissue-resident innate lymphoid cells in the lung.

PubMed

Cheng, Hang; Jin, Chengyan; Wu, Jing; Zhu, Shan; Liu, Yong-Jun; Chen, Jingtao

2017-12-01

The lung is an important open organ and the primary site of respiration. Many life-threatening diseases develop in the lung, e.g., pneumonia, asthma, chronic obstructive pulmonary diseases (COPDs), pulmonary fibrosis, and lung cancer. In the lung, innate immunity serves as the frontline in both anti-irritant response and anti-tumor defense and is also critical for mucosal homeostasis; thus, it plays an important role in containing these pulmonary diseases. Innate lymphoid cells (ILCs), characterized by their strict tissue residence and distinct function in the mucosa, are attracting increased attention in innate immunity. Upon sensing the danger signals from damaged epithelium, ILCs activate, proliferate, and release numerous cytokines with specific local functions; they also participate in mucosal immune-surveillance, immune-regulation, and homeostasis. However, when their functions become uncontrolled, ILCs can enhance pathological states and induce diseases. In this review, we discuss the physiological and pathological functions of ILC subsets 1 to 3 in the lung, and how the pathogenic environment affects the function and plasticity of ILCs.

Developmental and Functional Control of Natural Killer Cells by Cytokines

PubMed Central

Wu, Yang; Tian, Zhigang; Wei, Haiming

2017-01-01

Natural killer (NK) cells are effective in combating infections and tumors and as such are tempting for adoptive transfer therapy. However, they are not homogeneous but can be divided into three main subsets, including cytotoxic, tolerant, and regulatory NK cells, with disparate phenotypes and functions in diverse tissues. The development and functions of such NK cells are controlled by various cytokines, such as fms-like tyrosine kinase 3 ligand (FL), kit ligand (KL), interleukin (IL)-3, IL-10, IL-12, IL-18, transforming growth factor-β, and common-γ chain family cytokines, which operate at different stages by regulating distinct signaling pathways. Nevertheless, the specific roles of each cytokine that regulates NK cell development or that shapes different NK cell functions remain unclear. In this review, we attempt to describe the characteristics of each cytokine and the existing protocols to expand NK cells using different combinations of cytokines and feeder cells. A comprehensive understanding of the role of cytokines in NK cell development and function will aid the generation of better efficacy for adoptive NK cell treatment. PMID:28824650

Heterogeneity and phenotypic plasticity of glial cells in the mammalian enteric nervous system.

PubMed

Boesmans, Werend; Lasrado, Reena; Vanden Berghe, Pieter; Pachnis, Vassilis

2015-02-01

Enteric glial cells are vital for the autonomic control of gastrointestinal homeostasis by the enteric nervous system. Several different functions have been assigned to enteric glial cells but whether these are performed by specialized subtypes with a distinctive phenotype and function remains elusive. We used Mosaic Analysis with Double Markers and inducible lineage tracing to characterize the morphology and dynamic molecular marker expression of enteric GLIA in the myenteric plexus. Functional analysis in individually identified enteric glia was performed by Ca(2+) imaging. Our experiments have identified four morphologically distinct subpopulations of enteric glia in the gastrointestinal tract of adult mice. Marker expression analysis showed that the majority of glia in the myenteric plexus co-express glial fibrillary acidic protein (GFAP), S100β, and Sox10. However, a considerable fraction (up to 80%) of glia outside the myenteric ganglia, did not label for these markers. Lineage tracing experiments suggest that these alternative combinations of markers reflect dynamic gene regulation rather than lineage restrictions. At the functional level, the three myenteric glia subtypes can be distinguished by their differential response to adenosine triphosphate. Together, our studies reveal extensive heterogeneity and phenotypic plasticity of enteric glial cells and set a framework for further investigations aimed at deciphering their role in digestive function and disease. © 2014 Wiley Periodicals, Inc.

Making the Mark: The Role of Adenosine Modifications in the Life Cycle of RNA Viruses.

PubMed

Gonzales-van Horn, Sarah R; Sarnow, Peter

2017-06-14

Viral epitranscriptomics is a newly emerging field that has identified unique roles for RNA modifications in modulating life cycles of RNA viruses. Despite the observation of a handful of modified viral RNAs five decades ago, very little was known about how these modifications regulate viral life cycles, until recently. Here we review the pro- and anti-viral effects of methyl-6-adenosine in distinct viral life cycles, the role of 2' O-methyl modifications in RNA stability and innate immune sensing, and functions of adenosine to inosine modifications in retroviral life cycles. With roles for over 100 modifications in RNA still unknown, this is a rapidly emerging field that is destined to suggest novel antiviral therapies. Copyright © 2017 Elsevier Inc. All rights reserved.

Plakophilin-3 Is Required for Late Embryonic Amphibian Development, Exhibiting Roles in Ectodermal and Neural Tissues

PubMed Central

Munoz, William A.; Kloc, Malgorzata; Hofmann, Ilse; Sater, Amy; Vleminckx, Kris; McCrea, Pierre D.

2012-01-01

The p120-catenin family has undergone a significant expansion during the evolution of vertebrates, resulting in varied functions that have yet to be discerned or fully characterized. Likewise, members of the plakophilins, a related catenin subfamily, are found throughout the cell with little known about their functions outside the desmosomal plaque. While the plakophilin-3 (Pkp3) knockout mouse resulted in skin defects, we find larger, including lethal effects following its depletion in Xenopus. Pkp3, unlike some other characterized catenins in amphibians, does not have significant maternal deposits of mRNA. However, during embryogenesis, two Pkp3 protein products whose temporal expression is partially complimentary become expressed. Only the smaller of these products is found in adult Xenopus tissues, with an expression pattern exhibiting distinctions as well as overlaps with those observed in mammalian studies. We determined that Xenopus Pkp3 depletion causes a skin fragility phenotype in keeping with the mouse knockout, but more novel, Xenopus tailbud embryos are hyposensitive to touch even in embryos lacking outward discernable phenotypes, and we additionally resolved disruptions in certain peripheral neural structures, altered establishment and migration of neural crest, and defects in ectodermal multiciliated cells. The use of two distinct morpholinos, as well as rescue approaches, indicated the specificity of these effects. Our results point to the requirement of Pkp3 in amphibian embryogenesis, with functional roles in a number of tissue types. PMID:22496792

Diverse roles for ionotropic glutamate receptors on inhibitory interneurons in developing and adult brain.

PubMed

Akgül, Gülcan; McBain, Chris J

2016-10-01

Glutamate receptor-mediated recruitment of GABAergic inhibitory interneurons is a critical determinant of network processing. Early studies observed that many, but not all, interneuron glutamatergic synapses contain AMPA receptors that are GluA2-subunit lacking and Ca(2+) permeable, making them distinct from AMPA receptors at most principal cell synapses. Subsequent studies demonstrated considerable alignment of synaptic AMPA and NMDA receptor subunit composition within specific subtypes of interneurons, suggesting that both receptor expression profiles are developmentally and functionally linked. Indeed glutamate receptor expression profiles are largely predicted by the embryonic origins of cortical interneurons within the medial and caudal ganglionic eminences of the developing telencephalon. Distinct complements of AMPA and NMDA receptors within different interneuron subpopulations contribute to the differential recruitment of functionally divergent interneuron subtypes by common afferent inputs for appropriate feed-forward and feedback inhibitory drive and network entrainment. In contrast, the lesser-studied kainate receptors, which are often present at both pre- and postsynaptic sites, appear to follow an independent developmental expression profile. Loss of specific ionotropic glutamate receptor (iGluR) subunits during interneuron development has dramatic consequences for both cellular and network function, often precipitating circuit inhibition-excitation imbalances and in some cases lethality. Here we briefly review recent findings highlighting the roles of iGluRs in interneuron development. Published 2016. This article is a U.S. Government work and is in the public domain in the USA.

Contracting in the National Health Service (NHS): recognizing the need for co-operation.

PubMed

Joslyn, E

1997-05-01

Within the reorganized National Health Service hierarchical relationships between Health Authorities and Trusts have been replaced by functional differentiation. However, differentiation of function cannot be seen as an end in itself and management of the relationship between purchasers and providers must include managing the differentiation as well as the function. This paper suggests that collaborative and administrative activities have a distinct role to play in health service management. The paper suggests that in health service management market strategies are likely to dominate in relation to resource allocation activities. The paper also argues that administrative strategies are likely to be necessary within the internal market system--to bridge the gap resulting from the differentiation of function.

Membrane proteins bind lipids selectively to modulate their structure and function.

PubMed

Laganowsky, Arthur; Reading, Eamonn; Allison, Timothy M; Ulmschneider, Martin B; Degiacomi, Matteo T; Baldwin, Andrew J; Robinson, Carol V

2014-06-05

Previous studies have established that the folding, structure and function of membrane proteins are influenced by their lipid environments and that lipids can bind to specific sites, for example, in potassium channels. Fundamental questions remain however regarding the extent of membrane protein selectivity towards lipids. Here we report a mass spectrometry approach designed to determine the selectivity of lipid binding to membrane protein complexes. We investigate the mechanosensitive channel of large conductance (MscL) from Mycobacterium tuberculosis and aquaporin Z (AqpZ) and the ammonia channel (AmtB) from Escherichia coli, using ion mobility mass spectrometry (IM-MS), which reports gas-phase collision cross-sections. We demonstrate that folded conformations of membrane protein complexes can exist in the gas phase. By resolving lipid-bound states, we then rank bound lipids on the basis of their ability to resist gas phase unfolding and thereby stabilize membrane protein structure. Lipids bind non-selectively and with high avidity to MscL, all imparting comparable stability; however, the highest-ranking lipid is phosphatidylinositol phosphate, in line with its proposed functional role in mechanosensation. AqpZ is also stabilized by many lipids, with cardiolipin imparting the most significant resistance to unfolding. Subsequently, through functional assays we show that cardiolipin modulates AqpZ function. Similar experiments identify AmtB as being highly selective for phosphatidylglycerol, prompting us to obtain an X-ray structure in this lipid membrane-like environment. The 2.3 Å resolution structure, when compared with others obtained without lipid bound, reveals distinct conformational changes that re-position AmtB residues to interact with the lipid bilayer. Our results demonstrate that resistance to unfolding correlates with specific lipid-binding events, enabling a distinction to be made between lipids that merely bind from those that modulate membrane protein structure and/or function. We anticipate that these findings will be important not only for defining the selectivity of membrane proteins towards lipids, but also for understanding the role of lipids in modulating protein function or drug binding.

Distinct Contributions of Conserved Modules to Runt Transcription Factor Activity

PubMed Central

Walrad, Pegine B.; Hang, Saiyu; Joseph, Genevieve S.; Salas, Julia

2010-01-01

Runx proteins play vital roles in regulating transcription in numerous developmental pathways throughout the animal kingdom. Two Runx protein hallmarks are the DNA-binding Runt domain and a C-terminal VWRPY motif that mediates interaction with TLE/Gro corepressor proteins. A phylogenetic analysis of Runt, the founding Runx family member, identifies four distinct regions C-terminal to the Runt domain that are conserved in Drosophila and other insects. We used a series of previously described ectopic expression assays to investigate the functions of these different conserved regions in regulating gene expression during embryogenesis and in controlling axonal projections in the developing eye. The results indicate each conserved region is required for a different subset of activities and identify distinct regions that participate in the transcriptional activation and repression of the segmentation gene sloppy-paired-1 (slp1). Interestingly, the C-terminal VWRPY-containing region is not required for repression but instead plays a role in slp1 activation. Genetic experiments indicating that Groucho (Gro) does not participate in slp1 regulation further suggest that Runt's conserved C-terminus interacts with other factors to promote transcriptional activation. These results provide a foundation for further studies on the molecular interactions that contribute to the context-dependent properties of Runx proteins as developmental regulators. PMID:20462957

The tortuous road to an ideal CGRP function blocker for the treatment of migraine.

PubMed

Davis, Carl D; Xu, Cen

2008-01-01

The critical role of Calcitonin Gene-Related Peptide (CGRP) in migraine has been validated, with two small molecule CGRP antagonists BIBN4096BS and MK-0974 demonstrating efficacy in the reversal of acute migraine attack. Multiple approaches have been taken to find the ideal agent that most effectively inhibits CGRP's function. Here, we have summarized the progress made in recent years, including the identification and optimization of an orally bioavailable small molecule CGRP receptor antagonist. We also describe other interventions such as scavenging of CGRP itself. The advantages and disadvantages of these distinct approaches are discussed.

The two Na+ sites in the human serotonin transporter play distinct roles in the ion coupling and electrogenicity of transport.

PubMed

Felts, Bruce; Pramod, Akula Bala; Sandtner, Walter; Burbach, Nathan; Bulling, Simon; Sitte, Harald H; Henry, L Keith

2014-01-17

Neurotransmitter transporters of the SLC6 family of proteins, including the human serotonin transporter (hSERT), utilize Na(+), Cl(-), and K(+) gradients to induce conformational changes necessary for substrate translocation. Dysregulation of ion movement through monoamine transporters has been shown to impact neuronal firing potentials and could play a role in pathophysiologies, such as depression and anxiety. Despite multiple crystal structures of prokaryotic and eukaryotic SLC transporters indicating the location of both (or one) conserved Na(+)-binding sites (termed Na1 and Na2), much remains uncertain in regard to the movements and contributions of these cation-binding sites in the transport process. In this study, we utilize the unique properties of a mutation of hSERT at a single, highly conserved asparagine on TM1 (Asn-101) to provide several lines of evidence demonstrating mechanistically distinct roles for Na1 and Na2. Mutations at Asn-101 alter the cation dependence of the transporter, allowing Ca(2+) (but not other cations) to functionally replace Na(+) for driving transport and promoting 5-hydroxytryptamine (5-HT)-dependent conformational changes. Furthermore, in two-electrode voltage clamp studies in Xenopus oocytes, both Ca(2+) and Na(+) illicit 5-HT-induced currents in the Asn-101 mutants and reveal that, although Ca(2+) promotes substrate-induced current, it does not appear to be the charge carrier during 5-HT transport. These findings, in addition to functional evaluation of Na1 and Na2 site mutants, reveal separate roles for Na1 and Na2 and provide insight into initiation of the translocation process as well as a mechanism whereby the reported SERT stoichiometry can be obtained despite the presence of two putative Na(+)-binding sites.

The Two Na+ Sites in the Human Serotonin Transporter Play Distinct Roles in the Ion Coupling and Electrogenicity of Transport*

PubMed Central

Felts, Bruce; Pramod, Akula Bala; Sandtner, Walter; Burbach, Nathan; Bulling, Simon; Sitte, Harald H.; Henry, L. Keith

2014-01-01

Neurotransmitter transporters of the SLC6 family of proteins, including the human serotonin transporter (hSERT), utilize Na+, Cl−, and K+ gradients to induce conformational changes necessary for substrate translocation. Dysregulation of ion movement through monoamine transporters has been shown to impact neuronal firing potentials and could play a role in pathophysiologies, such as depression and anxiety. Despite multiple crystal structures of prokaryotic and eukaryotic SLC transporters indicating the location of both (or one) conserved Na+-binding sites (termed Na1 and Na2), much remains uncertain in regard to the movements and contributions of these cation-binding sites in the transport process. In this study, we utilize the unique properties of a mutation of hSERT at a single, highly conserved asparagine on TM1 (Asn-101) to provide several lines of evidence demonstrating mechanistically distinct roles for Na1 and Na2. Mutations at Asn-101 alter the cation dependence of the transporter, allowing Ca2+ (but not other cations) to functionally replace Na+ for driving transport and promoting 5-hydroxytryptamine (5-HT)-dependent conformational changes. Furthermore, in two-electrode voltage clamp studies in Xenopus oocytes, both Ca2+ and Na+ illicit 5-HT-induced currents in the Asn-101 mutants and reveal that, although Ca2+ promotes substrate-induced current, it does not appear to be the charge carrier during 5-HT transport. These findings, in addition to functional evaluation of Na1 and Na2 site mutants, reveal separate roles for Na1 and Na2 and provide insight into initiation of the translocation process as well as a mechanism whereby the reported SERT stoichiometry can be obtained despite the presence of two putative Na+-binding sites. PMID:24293367

Antigen presenting capacity of murine splenic myeloid cells.

PubMed

Hey, Ying-Ying; Quah, Benjamin; O'Neill, Helen C

2017-01-11

The spleen is an important site for hematopoiesis. It supports development of myeloid cells from bone marrow-derived precursors entering from blood. Myeloid subsets in spleen are not well characterised although dendritic cell (DC) subsets are clearly defined in terms of phenotype, development and functional role. Recently a novel dendritic-like cell type in spleen named 'L-DC' was distinguished from other known dendritic and myeloid cells by its distinct phenotype and developmental origin. That study also redefined splenic eosinophils as well as resident and inflammatory monocytes in spleen. L-DC are shown to be distinct from known splenic macrophages and monocyte subsets. Using a new flow cytometric procedure, it has been possible to identify and isolate L-DC in order to assess their functional competence and ability to activate T cells both in vivo and in vitro. L-DC are readily accessible to antigen given intravenously through receptor-mediated endocytosis. They are also capable of CD8 + T cell activation through antigen cross presentation, with subsequent induction of cytotoxic effector T cells. L-DC are MHCII - cells and unable to activate CD4 + T cells, a property which clearly distinguishes them from conventional DC. The myeloid subsets of resident monocytes, inflammatory monocytes, neutrophils and eosinophils, were found to have varying capacities to take up antigen, but were uniformly unable to activate either CD4 + T cells or CD8 + T cells. The results presented here demonstrate that L-DC in spleen are distinct from other myeloid cells in that they can process antigen for CD8 + T cell activation and induction of cytotoxic effector function, while both L-DC and myeloid subsets remain unable to activate CD4 + T cells. The L-DC subset in spleen is therefore distinct as an antigen presenting cell.

The moral emotions: a social-functionalist account of anger, disgust, and contempt.

PubMed

Hutcherson, Cendri A; Gross, James J

2011-04-01

Recent research has highlighted the important role of emotion in moral judgment and decision making (Greene, Sommerville, Nystrom, Darley, & Cohen, 2001; Haidt, 2001). What is less clear is whether distinctions should be drawn among specific moral emotions. Although some have argued for differences among anger, disgust, and contempt (Rozin, Lowery, Imada, & Haidt, 1999), others have suggested that these terms may describe a single undifferentiated emotional response to morally offensive behavior (Nabi, 2002). In this article, we take a social-functionalist perspective, which makes the prediction that these emotions should be differentiable both in antecedent appraisals and in consequent actions and judgments. Studies 1-3 tested and found support for our predictions concerning distinctions among antecedent appraisals, including (a) a more general role for disgust than has been previously been described, (b) an effect of self-relevance on anger but not other emotions, and (c) a role for contempt in judging incompetent actions. Studies 4 and 5 tested and found support for our specific predictions concerning functional outcomes, providing evidence that these emotions are associated with different consequences. Taken together, these studies support a social-functionalist account of anger, disgust, and contempt and lay the foundation for future research on the negative interpersonal emotions.

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

PubMed Central

Bastian, Boris C.

2016-01-01

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

Voice pedagogy-what do we need?

PubMed

Gill, Brian P; Herbst, Christian T

2016-12-01

The final keynote panel of the 10th Pan-European Voice Conference (PEVOC) was concerned with the topic 'Voice pedagogy-what do we need?' In this communication the panel discussion is summarized, and the authors provide a deepening discussion on one of the key questions, addressing the roles and tasks of people working with voice students. In particular, a distinction is made between (1) voice building (derived from the German term 'Stimmbildung'), primarily comprising the functional and physiological aspects of singing; (2) coaching, mostly concerned with performance skills; and (3) singing voice rehabilitation. Both public and private educators are encouraged to apply this distinction to their curricula, in order to arrive at more efficient singing teaching and to reduce the risk of vocal injury to the singers concerned.

Task-specific activity and connectivity within the mentalizing network during emotion and intention mentalizing.

PubMed

Atique, Bijoy; Erb, Michael; Gharabaghi, Alireza; Grodd, Wolfgang; Anders, Silke

2011-04-15

Mentalizing, i.e. the process of inferring another person's mental state, is thought to be primarily subserved by three brain regions, the VMPFC (ventromedial prefrontal cortex), precuneus and TPJ (temporo-parietal junction). However, it is still unclear what the exact roles of these regions in mentalizing are. Here, we compare activity within, and functional connectivity between, the VMPFC, precuneus and TPJ during two different mentalizing tasks. Specifically, we examine whether inferring another person's emotion ("emotion mentalizing") and inferring another person's intention ("intention mentalizing") activate similar or distinct subregions within the VMPFC, precuneus and TPJ, and whether these different kinds of mentalizing are associated with different patterns of functional connectivity between these regions. Our results indicate that emotion mentalizing and intention mentalizing activate partly distinct subregions of the right and left TPJ that can be spatially separated across participants. These subregions also showed different patterns of functional connectivity with the VMPFC: a more anterior region of the right and left TPJ, which was more strongly activated during emotion mentalizing, showed stronger functional connectivity with the VMPFC, particularly during emotion mentalizing, than a more posterior region that was more strongly activated during intention mentalizing. Critically, this double dissociation became evident only when the fine-scale distribution of activity within activated regions was analysed, and despite the fact that there was also a significant overlap of activity during the two tasks. Our findings provide first evidence that different neural modules might have evolved within the TPJ that show distinct patterns of functional connectivity and might subserve slightly different subfunctions of mentalizing. Copyright © 2010 Elsevier Inc. All rights reserved.

Eosinophils in helminth infection: defenders and dupes

PubMed Central

Huang, Lu; Appleton, Judith A.

2016-01-01

Eosinophilia is a central feature of the host response to helminth infection. Larval stages of parasitic worms are killed in vitro by eosinophils in the presence of specific antibodies or complement. These findings established host defense as the paradigm for eosinophil function. Recently, studies in eosinophil-ablated mouse strains have revealed an expanded repertoire of immunoregulatory functions for this cell. Other reports document crucial roles for eosinophils in tissue homeostasis and metabolism, processes that are central to the establishment and maintenance of parasitic worms in their hosts. In this review, we summarize current understanding of the significance of eosinophils at the host-parasite interface, highlighting their distinct functions during primary and secondary exposure. PMID:27262918

Shared and distinct contributions of rostrolateral prefrontal cortex to analogical reasoning and episodic memory retrieval.

PubMed

Westphal, Andrew J; Reggente, Nicco; Ito, Kaori L; Rissman, Jesse

2016-03-01

Rostrolateral prefrontal cortex (RLPFC) is widely appreciated to support higher cognitive functions, including analogical reasoning and episodic memory retrieval. However, these tasks have typically been studied in isolation, and thus it is unclear whether they involve common or distinct RLPFC mechanisms. Here, we introduce a novel functional magnetic resonance imaging (fMRI) task paradigm to compare brain activity during reasoning and memory tasks while holding bottom-up perceptual stimulation and response demands constant. Univariate analyses on fMRI data from twenty participants identified a large swath of left lateral prefrontal cortex, including RLPFC, that showed common engagement on reasoning trials with valid analogies and memory trials with accurately retrieved source details. Despite broadly overlapping recruitment, multi-voxel activity patterns within left RLPFC reliably differentiated these two trial types, highlighting the presence of at least partially distinct information processing modes. Functional connectivity analyses demonstrated that while left RLPFC showed consistent coupling with the fronto-parietal control network across tasks, its coupling with other cortical areas varied in a task-dependent manner. During the memory task, this region strengthened its connectivity with the default mode and memory retrieval networks, whereas during the reasoning task it coupled more strongly with a nearby left prefrontal region (BA 45) associated with semantic processing, as well as with a superior parietal region associated with visuospatial processing. Taken together, these data suggest a domain-general role for left RLPFC in monitoring and/or integrating task-relevant knowledge representations and showcase how its function cannot solely be attributed to episodic memory or analogical reasoning computations. © 2015 Wiley Periodicals, Inc.

Distinct functional contributions of primary sensory and association areas to audiovisual integration in object categorization.

PubMed

Werner, Sebastian; Noppeney, Uta

2010-02-17

Multisensory interactions have been demonstrated in a distributed neural system encompassing primary sensory and higher-order association areas. However, their distinct functional roles in multisensory integration remain unclear. This functional magnetic resonance imaging study dissociated the functional contributions of three cortical levels to multisensory integration in object categorization. Subjects actively categorized or passively perceived noisy auditory and visual signals emanating from everyday actions with objects. The experiment included two 2 x 2 factorial designs that manipulated either (1) the presence/absence or (2) the informativeness of the sensory inputs. These experimental manipulations revealed three patterns of audiovisual interactions. (1) In primary auditory cortices (PACs), a concurrent visual input increased the stimulus salience by amplifying the auditory response regardless of task-context. Effective connectivity analyses demonstrated that this automatic response amplification is mediated via both direct and indirect [via superior temporal sulcus (STS)] connectivity to visual cortices. (2) In STS and intraparietal sulcus (IPS), audiovisual interactions sustained the integration of higher-order object features and predicted subjects' audiovisual benefits in object categorization. (3) In the left ventrolateral prefrontal cortex (vlPFC), explicit semantic categorization resulted in suppressive audiovisual interactions as an index for multisensory facilitation of semantic retrieval and response selection. In conclusion, multisensory integration emerges at multiple processing stages within the cortical hierarchy. The distinct profiles of audiovisual interactions dissociate audiovisual salience effects in PACs, formation of object representations in STS/IPS and audiovisual facilitation of semantic categorization in vlPFC. Furthermore, in STS/IPS, the profiles of audiovisual interactions were behaviorally relevant and predicted subjects' multisensory benefits in performance accuracy.

Distinct Mechanisms Produce Functionally Complementary Actions of Neuropeptides that are Structurally Related but Derived from Different Precursors

PubMed Central

Vilim, F.S.; Sasaki, K.; Rybak, J.; Alexeeva, V.; Cropper, E.; Jing, J.; Orekhova, I.V.; Brezina, V.; Price, D.; Romanova, E.V.; Rubakhin, S.S.; Hatcher, N.; Sweedler, J.V.; Weiss, K.R.

2010-01-01

Many bioactive neuropeptides containing RFamide at their C-terminus have been described in both invertebrates and vertebrates. To obtain insight into the functional logic of RFamide signaling, we investigate it here in the feeding system of Aplysia. We focus on the expression, localization, and actions of two families of RFamide peptides, the FRFamides and FMRFamide, in the central neuronal circuitry and the peripheral musculature that generate the feeding movements. We describe the cloning of the FRFamide precursor protein and show that the FRFamides and FMRFamide are derived from different precursors. We map the expression of the FRFamide and FMRFamide precursors in the feeding circuitry using in-situ hybridization and immunostaining, and confirm proteolytic processing of the FRFamide precursor by mass spectrometry. We show that the two precursors are expressed in different populations of sensory neurons in the feeding system. In a representative feeding muscle, we demonstrate the presence of both FRFamides and FMRFamide and their release, probably from the processes of the sensory neurons in the muscle. Both centrally and in the periphery, the FRFamides and FMRFamide act in distinct ways, apparently through distinct mechanisms, that nevertheless, from an overall functional perspective, their actions are complementary. Together, the FRFamides and FMRFamide convert feeding motor programs from ingestive to egestive, and depress feeding muscle contractions. We conclude that these structurally related peptides, even though derived from different precursors, expressed in different neurons, and acting through different mechanisms, remain related to each other in the functional roles that they play in the system. PMID:20053896

Circulating Endothelial Progenitor Cells Present an Inflammatory Phenotype and Function in Patients With Alcoholic Liver Cirrhosis

PubMed Central

Kaur, Savneet; Sehgal, Rashi; Shastry, Saggere M.; McCaughan, Geoffrey; McGuire, Helen M.; Fazekas St de Groth, Barbara; Sarin, Shiv; Trehanpati, Nirupma; Seth, Devanshi

2018-01-01

Background and Aim: Endothelial progenitor cells (EPCs) have been implicated in liver injury and repair. However, the phenotype and potential of these heterogenous EPCs remain elusive. In particular, their involvement in the pathogenesis of alcoholic liver cirrhosis (ALC) remains unclear. The current study extensively characterized the phenotype and functions of EPCs to understand their role in ALC pathogenesis. Methods: Circulating EPCs were identified as CD34+CD133+CD31+ cells by flow cytometer in ALC patients (n = 7) and healthy controls (HC, n = 7). A comprehensive characterization of circulating EPCs using more than 30 phenotype markers was performed by mass cytometer time of flight (CyTOF) in an independent cohort of age and gender matched ALC patients (n = 4) and controls (n = 5). Ex vivo cultures of circulating EPCs from ALC patients (n = 20) and controls (n = 18) were also tested for their functions, including colony formation, LDL uptake, lectin binding and cytokine secretion (ELISA). Results: Three distinct populations of circulating EPCs (CD34+CD133+CD31+) were identified, classified on their CD45 expression (negative: CD45−; intermediate: CD45int; high: CD45hi). CD45int and CD45hi EPCs significantly increased in ALC patients compared to controls (p-val = 0.006). CyTOF data showed that CD45hi EPCs were distinct from CD45− and CD45int EPCs, with higher expression of T cell and myeloid markers, including CD3, CD4, HLA-DR, and chemokine receptors, CCR2, CCR5, CCR7, and CX3CR1. Similar to circulating EPCs, percentage of CD45hiCD34+CD31+ EPCs in ex-vivo cultures from patients, were significantly higher compared to controls (p < 0.05). Cultured EPCs from patients also showed increased LDL uptake, lectin binding and release of TNF-alpha, RANTES, FGF-2, and VEGF. Conclusions: We report the first extensive characterization of circulating human EPCs with distinct EPC subtypes. Increase in CD45hi EPC subtype in ALC patients with enhanced functions, inflammatory cytokines and angiogenic mediators in patients suggests an inflammatory role for these cells in ALC. PMID:29872403

FN400 potentials are functionally identical to N400 potentials and reflect semantic processing during recognition testing

PubMed Central

Voss, Joel L.; Federmeier, Kara D.

2010-01-01

The “F” in FN400 denotes a more frontal scalp distribution relative to the morphologically similar N400 component—a distinction consistent with the hypothesized distinct roles of FN400 in familiarity memory versus N400 in language. However, no direct comparisons have substantiated these assumed dissimilarities. To this end, we manipulated short-term semantic priming during a recognition test. Semantic priming effects on N400 were indistinguishable from memory effects at the same latency, and semantic priming strongly modulated the “FN400,” despite having no influence on familiarity memory. Thus, no evidence suggested either electrophysiological or functional differences between the N400 and FN400, and findings were contrary to the linking of the “FN400” to familiarity. Instead, it appears that semantic/conceptual priming (reflected in the N400) occurs during recognition tests, and is frequently (mis)labeled as FN400 and attributed to familiarity. PMID:20701709

Munc18-1-regulated stage-wise SNARE assembly underlying synaptic exocytosis.

PubMed

Ma, Lu; Rebane, Aleksander A; Yang, Guangcan; Xi, Zhiqun; Kang, Yuhao; Gao, Ying; Zhang, Yongli

2015-12-23

Synaptic-soluble N-ethylmaleimide-sensitive factor attachment receptor (SNARE) proteins couple their stage-wise folding/assembly to rapid exocytosis of neurotransmitters in a Munc18-1-dependent manner. The functions of the different assembly stages in exocytosis and the role of Munc18-1 in SNARE assembly are not well understood. Using optical tweezers, we observed four distinct stages of assembly in SNARE N-terminal, middle, C-terminal, and linker domains (or NTD, MD, CTD, and LD, respectively). We found that SNARE layer mutations differentially affect SNARE assembly. Comparison of their effects on SNARE assembly and on exocytosis reveals that NTD and CTD are responsible for vesicle docking and fusion, respectively, whereas MD regulates SNARE assembly and fusion. Munc18-1 initiates SNARE assembly and structures t-SNARE C-terminus independent of syntaxin N-terminal regulatory domain (NRD) and stabilizes the half-zippered SNARE complex dependent upon the NRD. Our observations demonstrate distinct functions of SNARE domains whose assembly is intimately chaperoned by Munc18-1.

Highlights on distinctive structural and functional properties of HTLV Tax proteins

PubMed Central

Romanelli, Maria Grazia; Diani, Erica; Bergamo, Elisa; Casoli, Claudio; Ciminale, Vincenzo; Bex, Françoise; Bertazzoni, Umberto

2013-01-01

Human T cell leukemia viruses (HTLVs) are complex human retroviruses of the Deltaretrovirus genus. Four types have been identified thus far, with HTLV-1 and HTLV-2 much more prevalent than HTLV-3 or HTLV-4. HTLV-1 and HTLV-2 possess strictly related genomic structures, but differ significantly in pathogenicity, as HTLV-1 is the causative agent of adult T cell leukemia and of HTLV-associated myelopathy/tropical spastic paraparesis, whereas HTLV-2 is not associated with neoplasia. HTLVs code for a protein named Tax that is responsible for enhancing viral expression and drives cell transformation. Much effort has been invested to dissect the impact of Tax on signal transduction pathways and to identify functional differences between the HTLV Tax proteins that may explain the distinct oncogenic potential of HTLV-1 and HTLV-2. This review summarizes our current knowledge of Tax-1 and Tax-2 with emphasis on their structure, role in activation of the NF-κB (nuclear factor kappa-B) pathway, and interactions with host factors. PMID:24058363

Three Types of Cortical L5 Neurons that Differ in Brain-Wide Connectivity and Function

PubMed Central

Kim, Euiseok J.; Juavinett, Ashley L.; Kyubwa, Espoir M.; Jacobs, Matthew W.; Callaway, Edward M.

2015-01-01

SUMMARY Cortical layer 5 (L5) pyramidal neurons integrate inputs from many sources and distribute outputs to cortical and subcortical structures. Previous studies demonstrate two L5 pyramid types: cortico-cortical (CC) and cortico-subcortical (CS). We characterize connectivity and function of these cell types in mouse primary visual cortex and reveal a new subtype. Unlike previously described L5 CC and CS neurons, this new subtype does not project to striatum [cortico-cortical, non-striatal (CC-NS)] and has distinct morphology, physiology and visual responses. Monosynaptic rabies tracing reveals that CC neurons preferentially receive input from higher visual areas, while CS neurons receive more input from structures implicated in top-down modulation of brain states. CS neurons are also more direction-selective and prefer faster stimuli than CC neurons. These differences suggest distinct roles as specialized output channels, with CS neurons integrating information and generating responses more relevant to movement control and CC neurons being more important in visual perception. PMID:26671462

Three Types of Cortical Layer 5 Neurons That Differ in Brain-wide Connectivity and Function.

PubMed

Kim, Euiseok J; Juavinett, Ashley L; Kyubwa, Espoir M; Jacobs, Matthew W; Callaway, Edward M

2015-12-16

Cortical layer 5 (L5) pyramidal neurons integrate inputs from many sources and distribute outputs to cortical and subcortical structures. Previous studies demonstrate two L5 pyramid types: cortico-cortical (CC) and cortico-subcortical (CS). We characterize connectivity and function of these cell types in mouse primary visual cortex and reveal a new subtype. Unlike previously described L5 CC and CS neurons, this new subtype does not project to striatum [cortico-cortical, non-striatal (CC-NS)] and has distinct morphology, physiology, and visual responses. Monosynaptic rabies tracing reveals that CC neurons preferentially receive input from higher visual areas, while CS neurons receive more input from structures implicated in top-down modulation of brain states. CS neurons are also more direction-selective and prefer faster stimuli than CC neurons. These differences suggest distinct roles as specialized output channels, with CS neurons integrating information and generating responses more relevant to movement control and CC neurons being more important in visual perception. Copyright © 2015 Elsevier Inc. All rights reserved.

Relating Worry and Executive Functioning During Childhood: The Moderating Role of Age.

PubMed

Geronimi, Elena M C; Patterson, Heather L; Woodruff-Borden, Janet

2016-06-01

The associations between worry and executive functioning across development have not been previously explored. Examining the interrelationships between these variables in childhood may further elucidate the cognitive nature of worry as well as its developmental course. Hypotheses predicted that difficulties with executive functioning would correlate with child worry; based on extant literature, age-related hypotheses were proposed for particular aspects of executive functioning. Children (N = 130) participated in the present study. Difficulties with executive functioning and child worry were assessed. Results demonstrated that each executive functioning subscale correlated with worry. The relations between worry and several facets of executive functioning were no longer significant at older ages, while the relations between worry and the facets of inhibition, shifting, and emotional control did not demonstrate age-related interaction effects. Overall, the findings suggest that worry is associated with executive functioning at young ages and that this association takes distinct forms during different childhood stages.

Major Surface Protease of Trypanosomatids: One Size Fits All? ▿

PubMed Central

Yao, Chaoqun

2010-01-01

Major surface protease (MSP or GP63) is the most abundant glycoprotein localized to the plasma membrane of Leishmania promastigotes. MSP plays several important roles in the pathogenesis of leishmaniasis, including but not limited to (i) evasion of complement-mediated lysis, (ii) facilitation of macrophage (Mø) phagocytosis of promastigotes, (iii) interaction with the extracellular matrix, (iv) inhibition of natural killer cellular functions, (v) resistance to antimicrobial peptide killing, (vi) degradation of Mø and fibroblast cytosolic proteins, and (vii) promotion of survival of intracellular amastigotes. MSP homologues have been found in all other trypanosomatids studied to date including heteroxenous members of Trypanosoma cruzi, the extracellular Trypanosoma brucei, unusual intraerythrocytic Endotrypanum spp., phytoparasitic Phytomonas spp., and numerous monoxenous species. These proteins are likely to perform roles different from those described for Leishmania spp. Multiple MSPs in individual cells may play distinct roles at some time points in trypanosomatid life cycles and collaborative or redundant roles at others. The cellular locations and the extracellular release of MSPs are also discussed in connection with MSP functions in leishmanial promastigotes. PMID:19858295

Roles of PDE1 in Pathological Cardiac Remodeling and Dysfunction.

PubMed

Chen, Si; Knight, Walter E; Yan, Chen

2018-04-23

Pathological cardiac hypertrophy and dysfunction is a response to various stress stimuli and can result in reduced cardiac output and heart failure. Cyclic nucleotide signaling regulates several cardiac functions including contractility, remodeling, and fibrosis. Cyclic nucleotide phosphodiesterases (PDEs), by catalyzing the hydrolysis of cyclic nucleotides, are critical in the homeostasis of intracellular cyclic nucleotide signaling and hold great therapeutic potential as drug targets. Recent studies have revealed that the inhibition of the PDE family member PDE1 plays a protective role in pathological cardiac remodeling and dysfunction by the modulation of distinct cyclic nucleotide signaling pathways. This review summarizes recent key findings regarding the roles of PDE1 in the cardiac system that can lead to a better understanding of its therapeutic potential.

The multifunctional nuclear pore complex: a platform for controlling gene expression

PubMed Central

Ptak, Christopher; Aitchison, John D.; Wozniak, Richard W.

2014-01-01

In addition to their established roles in nucleocytoplasmic transport, the intimate association of nuclear pore complexes (NPCs) with chromatin has long led to speculation that these structures influence peripheral chromatin structure and regulate gene expression. These ideas have their roots in morphological observations, however recent years have seen the identification of physical interactions between NPCs, chromatin, and the transcriptional machinery. Key insights into the molecular functions of specific NPC proteins have uncovered roles for these proteins in transcriptional activation and elongation, mRNA processing, as well as chromatin structure and localization. Here, we review recent studies that provide further molecular detail on the role of specific NPC components as distinct platforms for these chromatin dependent processes. PMID:24657998

Control of neuronal polarity and plasticity--a renaissance for microtubules?

PubMed

Hoogenraad, Casper C; Bradke, Frank

2009-12-01

Microtubules have been regarded as essential structures for stable neuronal morphology but new studies are highlighting their role in dynamic neuronal processes. Recent work demonstrates that the microtubule cytoskeleton has an active role during different phases of neuronal polarization - microtubules and their stability determine axon formation, they maintain the identity of axons and they regulate the dynamics of dendritic spines, the major sites of excitatory synaptic input. Although microtubules fulfill distinct cellular functions at different developmental stages, the underlying molecular mechanisms are remarkably similar. Reccurring themes are that microtubules direct specific membrane traffic and affect actin dynamics to locally organize axon growth and spine dynamics. We review the novel role of microtubules during neuronal development and discuss models for microtubule-dependent signaling in neuronal plasticity.

A Novel Role of Dickkopf-Related Protein 3 in Macropinocytosis in Human Bladder Cancer T24 Cells

PubMed Central

Tsujimura, Nonoka; Yamada, Nami O.; Kuranaga, Yuki; Kumazaki, Minami; Shinohara, Haruka; Taniguchi, Kohei; Akao, Yukihiro

2016-01-01

Dickkopf-related protein 3 (Dkk-3) is a potential tumor suppressor reported in various cancer entities. However, we found that Dkk-3 was exceptionally upregulated in bladder cancer T24 cells. To validate the biological role of Dkk-3 other than a tumor suppressor, we examined the function of Dkk-3 in T24 cells. Gene silencing of Dkk-3 inhibited cell growth through inducing G0/G1 cell-cycle arrest. Furthermore, Dkk-3 knock-down caused macropinocytosis accompanied by autophagy, which were canceled in part by their inhibitors 5-(N-ethyl-N-isopropyl) amiloride (EIPA) and 3-methyladenine (3-MA). The macropinocytosis was induced by the Dkk-3 knock-down when there were sufficient extracellular nutrients. On the other hand, when the nutritional condition was poor, the autophagy was mainly induced by the Dkk-3 knock-down. These data indicated that Dkk-3 has a role in modulating macropinocytotic and autophagic pathways, a distinct function other than a Wnt antagonist. PMID:27827955

A role for the nucleoporin Nup170p in chromatin structure and gene silencing

PubMed Central

Van de Vosse, David W.; Wan, Yakun; Lapetina, Diego L.; Chen, Wei-Ming; Chiang, Jung-Hsien; Aitchison, John D.; Wozniak, Richard W.

2013-01-01

Embedded in the nuclear envelope, nuclear pore complexes (NPCs) not only regulate nuclear transport, but also interface with transcriptionally active euchromatin, largely silenced heterochromatin, as well as the boundaries between these regions. It is unclear what functional role NPCs play in establishing or maintaining these distinct chromatin domains. We report that the yeast NPC protein Nup170p interacts with regions of the genome containing ribosomal protein and subtelomeric genes. Here, it functions in nucleosome positioning and as a repressor of transcription. We show that the role of Nup170p in subtelomeric gene silencing is linked to its association with the RSC chromatin-remodeling complex and the silencing factor Sir4p, and that the binding of Nup170p and Sir4p to subtelomeric chromatin is cooperative and necessary for the association of telomeres with the nuclear envelope. Our results establish the NPC as an active participant in silencing and the formation of peripheral heterochromatin. PMID:23452847

Essential role for SUN5 in anchoring sperm head to the tail

PubMed Central

Wang, Lina; Ouyang, Ying-Chun; Dong, Ming-Zhe; Liu, Chao; Zhao, Haichao; Cui, Xiuhong; Ma, Dongyuan; Zhang, Zhiguo; Yang, Xiaoyu; Guo, Yueshuai; Liu, Feng; Yuan, Li

2017-01-01

SUN (Sad1 and UNC84 domain containing)-domain proteins are reported to reside on the nuclear membrane playing distinct roles in nuclear dynamics. SUN5 is a new member of the SUN family, with little knowledge regarding its function. Here, we generated Sun5−/− mice and found that male mice were infertile. Most Sun5-null spermatozoa displayed a globozoospermia-like phenotype but they were actually acephalic spermatozoa. Additional studies revealed that SUN5 was located in the neck of the spermatozoa, anchoring sperm head to the tail, and without functional SUN5 the sperm head to tail coupling apparatus was detached from nucleus during spermatid elongation. Finally, we found that healthy heterozygous offspring could be obtained via intracytoplasmic injection of Sun5-mutated sperm heads for both male mice and patients. Our studies reveal the essential role of SUN5 in anchoring sperm head to the tail and provide a promising way to treat this kind of acephalic spermatozoa-associated male infertility. PMID:28945193

Roles of CONSTITUTIVE PHOTOMORPHOGENIC 10 in Arabidopsis stomata development

PubMed Central

Delgado, Dolores; Ballesteros, Isabel; Mena, Montaña; Fenoll, Carmen

2012-01-01

Stomata are epidermal bi-celled structures that differentiate within special cell lineages initiated by a subset of protodermal cells. Recently, we showed that the Arabidopsis photomorphogenic repressor COP10 controls specific cell-lineage and cell-signaling developmental mechanisms in stomatal lineages. Loss-of-function cop10-1 mutant cotyledons and leaves produced (in the light and in the dark) abundant stomatal clusters, but nonlineage epidermal cells were not affected. Here we examine COP10 role in hypocotyls, cylindrical organs displaying a distinct epidermal organization with alternate files of protruding and non-protruding cells, with the latter producing a limited number of stomata. COP10 prevents stomatal clusters and restricts stomata production in hypocotyls; these roles are specific to lineage cells as in cotyledons, since COP10 loss of function does not elicit stomatal fate in nonlineage cells; COP10 also sustains the directional cell expansion of all hypocotyl epidermal cell types, and seems necessary for the differentiation between protruding and non-protruding cell files. PMID:22836493

Laminin γ3 plays an important role in retinal lamination, photoreceptor organisation and ganglion cell differentiation.

PubMed

Dorgau, Birthe; Felemban, Majed; Sharpe, Alexander; Bauer, Roman; Hallam, Dean; Steel, David H; Lindsay, Susan; Mellough, Carla; Lako, Majlinda

2018-05-23

Laminins are heterotrimeric glycoproteins of the extracellular matrix. Eleven different laminin chains have been identified in vertebrates. They are ubiquitously expressed in the human body, with a distinct tissue distribution. Laminin expression in neural retina and their functional role during human retinogenesis is still unknown. This study investigated the laminin expression in human developing and adult retina, showing laminin α1, α5, β1, β2 and γ1 to be predominantly expressed in Bruch's membrane and the inner limiting membrane. Laminin-332 and laminin γ3 expression were mainly observed in the neural retina during retinal histogenesis. These expression patterns were largely conserved in pluripotent stem cell-derived retinal organoids. Blocking of laminin γ3 function in retinal organoids resulted in the disruption of laminar organisation and synapse formation, the loss of photoreceptor organisation and retinal ganglion cells. Our data demonstrate a unique temporal and spatial expression for laminins and reveal a novel role for laminin γ3 during human retinogenesis.

Mechanism of SOS PR-domain autoinhibition revealed by single-molecule assays on native protein from lysate

PubMed Central

Lee, Young Kwang; Low-Nam, Shalini T.; Chung, Jean K.; Hansen, Scott D.; Lam, Hiu Yue Monatrice; Alvarez, Steven; Groves, Jay T.

2017-01-01

The guanine nucleotide exchange factor (GEF) Son of Sevenless (SOS) plays a critical role in signal transduction by activating Ras. Here we introduce a single-molecule assay in which individual SOS molecules are captured from raw cell lysate using Ras-functionalized supported membrane microarrays. This enables characterization of the full-length SOS protein, which has not previously been studied in reconstitution due to difficulties in purification. Our measurements on the full-length protein reveal a distinct role of the C-terminal proline-rich (PR) domain to obstruct the engagement of allosteric Ras independently of the well-known N-terminal domain autoinhibition. This inhibitory role of the PR domain limits Grb2-independent recruitment of SOS to the membrane through binding of Ras·GTP in the SOS allosteric binding site. More generally, this assay strategy enables characterization of the functional behaviour of GEFs with single-molecule precision but without the need for purification. PMID:28452363

Mechanism of SOS PR-domain autoinhibition revealed by single-molecule assays on native protein from lysate.

PubMed

Lee, Young Kwang; Low-Nam, Shalini T; Chung, Jean K; Hansen, Scott D; Lam, Hiu Yue Monatrice; Alvarez, Steven; Groves, Jay T

2017-04-28

The guanine nucleotide exchange factor (GEF) Son of Sevenless (SOS) plays a critical role in signal transduction by activating Ras. Here we introduce a single-molecule assay in which individual SOS molecules are captured from raw cell lysate using Ras-functionalized supported membrane microarrays. This enables characterization of the full-length SOS protein, which has not previously been studied in reconstitution due to difficulties in purification. Our measurements on the full-length protein reveal a distinct role of the C-terminal proline-rich (PR) domain to obstruct the engagement of allosteric Ras independently of the well-known N-terminal domain autoinhibition. This inhibitory role of the PR domain limits Grb2-independent recruitment of SOS to the membrane through binding of Ras·GTP in the SOS allosteric binding site. More generally, this assay strategy enables characterization of the functional behaviour of GEFs with single-molecule precision but without the need for purification.

Kainate receptors coming of age: milestones of two decades of research.

PubMed

Contractor, Anis; Mulle, Christophe; Swanson, Geoffrey T

2011-03-01

Two decades have passed since the first report of the cloning of a kainate-type glutamate receptor (KAR) subunit. The intervening years have seen a rapid growth in our understanding of the biophysical properties and function of KARs in the brain. This research has led to an appreciation that KARs play very distinct roles at synapses relative to other members of the glutamate-gated ion channel receptor family, despite structural and functional commonalities. The surprisingly diverse and complex nature of KAR signaling underlies their unique impact upon neuronal networks through their direct and indirect effects on synaptic transmission, and their prominent role in regulating cell excitability. This review pieces together highlights from the two decades of research subsequent to the cloning of the first subunit, and provides an overview of our current understanding of the role of KARs in the CNS and their potential importance to neurological and neuropsychiatric disorders. Copyright © 2011 Elsevier Ltd. All rights reserved.

The Microbial Signature Provides Insight into the Mechanistic Basis of Coral Success across Reef Habitats.

PubMed

Hernandez-Agreda, Alejandra; Leggat, William; Bongaerts, Pim; Ainsworth, Tracy D

2016-07-26

For ecosystems vulnerable to environmental change, understanding the spatiotemporal stability of functionally crucial symbioses is fundamental to determining the mechanisms by which these ecosystems may persist. The coral Pachyseris speciosa is a successful environmental generalist that succeeds in diverse reef habitats. The generalist nature of this coral suggests it may have the capacity to form functionally significant microbial partnerships to facilitate access to a range of nutritional sources within different habitats. Here, we propose that coral is a metaorganism hosting three functionally distinct microbial interactions: a ubiquitous core microbiome of very few symbiotic host-selected bacteria, a microbiome of spatially and/or regionally explicit core microbes filling functional niches (<100 phylotypes), and a highly variable bacterial community that is responsive to biotic and abiotic processes across spatial and temporal scales (>100,000 phylotypes). We find that this coral hosts upwards of 170,000 distinct phylotypes and provide evidence for the persistence of a select group of bacteria in corals across environmental habitats of the Great Barrier Reef and Coral Sea. We further show that a higher number of bacteria are consistently associated with corals on mesophotic reefs than on shallow reefs. An increase in microbial diversity with depth suggests reliance by this coral on bacteria for nutrient acquisition on reefs exposed to nutrient upwelling. Understanding the complex microbial communities of host organisms across broad biotic and abiotic environments as functionally distinct microbiomes can provide insight into those interactions that are ubiquitous niche symbioses and those that provide competitive advantage within the hosts' environment. Corals have been proposed as the most diverse microbial biosphere. The high variability of microbial communities has hampered the identification of bacteria playing key functional roles that contribute to coral survival. Exploring the bacterial community in a coral with a broad environmental distribution, we found a group of bacteria present across all environments and a higher number of bacteria consistently associated with mesophotic corals (60 to 80 m). These results provide evidence of consistent and ubiquitous coral-bacterial partnerships and support the consideration of corals as metaorganisms hosting three functionally distinct microbiomes: a ubiquitous core microbiome, a microbiome filling functional niches, and a highly variable bacterial community. Copyright © 2016 Hernandez-Agreda et al.

Mediator-Dependent Transcriptional Activation by Estrogen Receptor Bound to Distal Enhancers

DTIC Science & Technology

2015-06-01

that the system was partially compromised due to the absence of suitable higher-order template structures. Indeed, very recent genome -wide studies... the human genome . Science 326(5950):289-293. 9. Malik S & Roeder RG (2003) Isolation and functional characterization of the TRAP/Mediator complex...cally distinct and essential role. A recent study in Drosophila has suggested that the MED26 require- ment is stage specific49. Thus, it remains unclear

Correlation of neural activity with behavioral kinematics reveals distinct sensory encoding and evidence accumulation processes during active tactile sensing.

PubMed

Delis, Ioannis; Dmochowski, Jacek P; Sajda, Paul; Wang, Qi

2018-07-15

Many real-world decisions rely on active sensing, a dynamic process for directing our sensors (e.g. eyes or fingers) across a stimulus to maximize information gain. Though ecologically pervasive, limited work has focused on identifying neural correlates of the active sensing process. In tactile perception, we often make decisions about an object/surface by actively exploring its shape/texture. Here we investigate the neural correlates of active tactile decision-making by simultaneously measuring electroencephalography (EEG) and finger kinematics while subjects interrogated a haptic surface to make perceptual judgments. Since sensorimotor behavior underlies decision formation in active sensing tasks, we hypothesized that the neural correlates of decision-related processes would be detectable by relating active sensing to neural activity. Novel brain-behavior correlation analysis revealed that three distinct EEG components, localizing to right-lateralized occipital cortex (LOC), middle frontal gyrus (MFG), and supplementary motor area (SMA), respectively, were coupled with active sensing as their activity significantly correlated with finger kinematics. To probe the functional role of these components, we fit their single-trial-couplings to decision-making performance using a hierarchical-drift-diffusion-model (HDDM), revealing that the LOC modulated the encoding of the tactile stimulus whereas the MFG predicted the rate of information integration towards a choice. Interestingly, the MFG disappeared from components uncovered from control subjects performing active sensing but not required to make perceptual decisions. By uncovering the neural correlates of distinct stimulus encoding and evidence accumulation processes, this study delineated, for the first time, the functional role of cortical areas in active tactile decision-making. Copyright © 2018 Elsevier Inc. All rights reserved.

Cellular Trafficking of Phospholamban and Formation of Functional Sarcoplasmic Reticulum During Myocyte DIfferentiation

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

Stenoien, David L.; Knyushko, Tatyana V.; Londono, Monica P.

2007-06-01

The sarco/endoplasmic reticulum Ca-ATPase (SERCA) family members are transmembrane proteins that play an essential role in regulating intracellular calcium levels. Phospholamban (PLB), a 52 amino acid phosphoprotein, regulates SERCA activity in adult heart and skeletal muscle. Using the C2C12 myocyte cell line, we find endogenous PLB constitutively expressed in both myoblasts and myotubes, whereas SERCA expression coincides with activation of the differentiation program. PLB has a punctuate distribution in myoblasts changing to a reticular distribution in myotubes where it colocalizes with SERCAs. To examine the distribution and dynamics of PLB and SERCA, we expressed fluorescent fusion proteins (GFP, CFP, andmore » YFP) of PLB and SERCA in myoblasts. Coexpressed PLB and SERCA localize to distinct cellular compartments in myoblasts but begin to colocalize as cells differentiate. Fluorescence Recovery After Photobleaching (FRAP) studies show different recovery patterns for each protein in myoblasts confirming their localization to distinct compartments. To extend these studies, we created stable cell lines expressing O6-alkylguanine-DNA alkyltransferase (AGT) fusions with PLB or SERCA to track their localization as myocytes differentiate. These experiments demonstrate that PLB localizes to punctate vesicles in myoblasts and adopts a reticular distribution that coincides with SERCA distribution after differentiation. Colocalization experiments indicate that a subset of PLB in myoblasts colocalizes with endosomes, Golgi, and the plasma membrane however PLB also localizes to other, as yet unidentified vesicles. Our results indicate that differentiation plays a critical role in regulating PLB distribution to ensure its colocalization within the same cellular compartment as SERCA in differentiated cells. The presence and altered distribution of PLB in undifferentiated myoblasts raises the possibility that this protein has additional functions distinct from SERCA regulation.« less

Regulation of Ras Exchange Factors and Cellular Localization of Ras Activation by Lipid Messengers in T Cells

PubMed Central

Jun, Jesse E.; Rubio, Ignacio; Roose, Jeroen P.

2013-01-01

The Ras-MAPK signaling pathway is highly conserved throughout evolution and is activated downstream of a wide range of receptor stimuli. Ras guanine nucleotide exchange factors (RasGEFs) catalyze GTP loading of Ras and play a pivotal role in regulating receptor-ligand induced Ras activity. In T cells, three families of functionally important RasGEFs are expressed: RasGRF, RasGRP, and Son of Sevenless (SOS)-family GEFs. Early on it was recognized that Ras activation is critical for T cell development and that the RasGEFs play an important role herein. More recent work has revealed that nuances in Ras activation appear to significantly impact T cell development and selection. These nuances include distinct biochemical patterns of analog versus digital Ras activation, differences in cellular localization of Ras activation, and intricate interplays between the RasGEFs during distinct T cell developmental stages as revealed by various new mouse models. In many instances, the exact nature of these nuances in Ras activation or how these may result from fine-tuning of the RasGEFs is not understood. One large group of biomolecules critically involved in the control of RasGEFs functions are lipid second messengers. Multiple, yet distinct lipid products are generated following T cell receptor (TCR) stimulation and bind to different domains in the RasGRP and SOS RasGEFs to facilitate the activation of the membrane-anchored Ras GTPases. In this review we highlight how different lipid-based elements are generated by various enzymes downstream of the TCR and other receptors and how these dynamic and interrelated lipid products may fine-tune Ras activation by RasGEFs in developing T cells. PMID:24027568

Expression and sub-cellular localization of an epigenetic regulator, co-activator arginine methyltransferase 1 (CARM1), is associated with specific breast cancer subtypes and ethnicity

PubMed Central

2013-01-01

Background Co-Activator Arginine Methyltransferase 1(CARM1) is an Estrogen Receptor (ER) cofactor that remodels chromatin for gene regulation via methylation of Histone3. We investigated CARM1 levels and localization across breast cancer tumors in a cohort of patients of either European or African ancestry. Methods We analyzed CARM1 levels using tissue microarrays with over 800 histological samples from 549 female cancer patients from the US and Nigeria, Africa. We assessed associations between CARM1 expression localized to the nucleus and cytoplasm for 11 distinct variables, including; ER status, Progesterone Receptor status, molecular subtypes, ethnicity, HER2+ status, other clinical variables and survival. Results We found that levels of cytoplasmic CARM1 are distinct among tumor sub-types and increased levels are associated with ER-negative (ER-) status. Higher nuclear CARM1 levels are associated with HER2 receptor status. EGFR expression also correlates with localization of CARM1 into the cytoplasm. This suggests there are distinct functions of CARM1 among molecular tumor types. Our data reveals a basal-like subtype association with CARM1, possibly due to expression of Epidermal Growth Factor Receptor (EGFR). Lastly, increased cytoplasmic CARM1, relative to nuclear levels, appear to be associated with self-identified African ethnicity and this result is being further investigated using quantified genetic ancestry measures. Conclusions Although it is known to be an ER cofactor in breast cancer, CARM1 expression levels are independent of ER. CARM1 has distinct functions among molecular subtypes, as is indicative of its sub-cellular localization and it may function in subtype etiology. These sub-cellular localization patterns, indicate a novel role beyond its ER cofactor function in breast cancer. Differential localization among ethnic groups may be due to ancestry-specific polymorphisms which alter the gene product. PMID:23663560

Divergent Evolutionary Patterns of NAC Transcription Factors Are Associated with Diversification and Gene Duplications in Angiosperm

PubMed Central

Jin, Xiaoli; Ren, Jing; Nevo, Eviatar; Yin, Xuegui; Sun, Dongfa; Peng, Junhua

2017-01-01

NAC (NAM/ATAF/CUC) proteins constitute one of the biggest plant-specific transcription factor (TF) families and have crucial roles in diverse developmental programs during plant growth. Phylogenetic analyses have revealed both conserved and lineage-specific NAC subfamilies, among which various origins and distinct features were observed. It is reasonable to hypothesize that there should be divergent evolutionary patterns of NAC TFs both between dicots and monocots, and among NAC subfamilies. In this study, we compared the gene duplication and loss, evolutionary rate, and selective pattern among non-lineage specific NAC subfamilies, as well as those between dicots and monocots, through genome-wide analyses of sequence and functional data in six dicot and five grass lineages. The number of genes gained in the dicot lineages was much larger than that in the grass lineages, while fewer gene losses were observed in the grass than that in the dicots. We revealed (1) uneven constitution of Clusters of Orthologous Groups (COGs) and contrasting birth/death rates among subfamilies, and (2) two distinct evolutionary scenarios of NAC TFs between dicots and grasses. Our results demonstrated that relaxed selection, resulting from concerted gene duplications, may have permitted substitutions responsible for functional divergence of NAC genes into new lineages. The underlying mechanism of distinct evolutionary fates of NAC TFs shed lights on how evolutionary divergence contributes to differences in establishing NAC gene subfamilies and thus impacts the distinct features between dicots and grasses. PMID:28713414

Distinct Domains of CheA Confer Unique Functions in Chemotaxis and Cell Length in Azospirillum brasilense Sp7.

PubMed

Gullett, Jessica M; Bible, Amber; Alexandre, Gladys

2017-07-01

Chemotaxis is the movement of cells in response to gradients of diverse chemical cues. Motile bacteria utilize a conserved chemotaxis signal transduction system to bias their motility and navigate through a gradient. A central regulator of chemotaxis is the histidine kinase CheA. This cytoplasmic protein interacts with membrane-bound receptors, which assemble into large polar arrays, to propagate the signal. In the alphaproteobacterium Azospirillum brasilense , Che1 controls transient increases in swimming speed during chemotaxis, but it also biases the cell length at division. However, the exact underlying molecular mechanisms for Che1-dependent control of multiple cellular behaviors are not known. Here, we identify specific domains of the CheA1 histidine kinase implicated in modulating each of these functions. We show that CheA1 is produced in two isoforms: a membrane-anchored isoform produced as a fusion with a conserved seven-transmembrane domain of unknown function (TMX) at the N terminus and a soluble isoform similar to prototypical CheA. Site-directed and deletion mutagenesis combined with behavioral assays confirm the role of CheA1 in chemotaxis and implicate the TMX domain in mediating changes in cell length. Fluorescence microscopy further reveals that the membrane-anchored isoform is distributed around the cell surface while the soluble isoform localizes at the cell poles. Together, the data provide a mechanism for the role of Che1 in controlling multiple unrelated cellular behaviors via acquisition of a new domain in CheA1 and production of distinct functional isoforms. IMPORTANCE Chemotaxis provides a significant competitive advantage to bacteria in the environment, and this function has been transferred laterally multiple times, with evidence of functional divergence in different genomic contexts. The molecular principles that underlie functional diversification of chemotaxis in various genomic contexts are unknown. Here, we provide a molecular mechanism by which a single CheA protein controls two unrelated functions: chemotaxis and cell length. Acquisition of this multifunctionality is seemingly a recent evolutionary event. The findings illustrate a mechanism by which chemotaxis function may be co-opted to regulate additional cellular functions. Copyright © 2017 American Society for Microbiology.

Distinct Domains of CheA Confer Unique Functions in Chemotaxis and Cell Length in Azospirillum brasilense Sp7

PubMed Central

Gullett, Jessica M.

2017-01-01

ABSTRACT Chemotaxis is the movement of cells in response to gradients of diverse chemical cues. Motile bacteria utilize a conserved chemotaxis signal transduction system to bias their motility and navigate through a gradient. A central regulator of chemotaxis is the histidine kinase CheA. This cytoplasmic protein interacts with membrane-bound receptors, which assemble into large polar arrays, to propagate the signal. In the alphaproteobacterium Azospirillum brasilense, Che1 controls transient increases in swimming speed during chemotaxis, but it also biases the cell length at division. However, the exact underlying molecular mechanisms for Che1-dependent control of multiple cellular behaviors are not known. Here, we identify specific domains of the CheA1 histidine kinase implicated in modulating each of these functions. We show that CheA1 is produced in two isoforms: a membrane-anchored isoform produced as a fusion with a conserved seven-transmembrane domain of unknown function (TMX) at the N terminus and a soluble isoform similar to prototypical CheA. Site-directed and deletion mutagenesis combined with behavioral assays confirm the role of CheA1 in chemotaxis and implicate the TMX domain in mediating changes in cell length. Fluorescence microscopy further reveals that the membrane-anchored isoform is distributed around the cell surface while the soluble isoform localizes at the cell poles. Together, the data provide a mechanism for the role of Che1 in controlling multiple unrelated cellular behaviors via acquisition of a new domain in CheA1 and production of distinct functional isoforms. IMPORTANCE Chemotaxis provides a significant competitive advantage to bacteria in the environment, and this function has been transferred laterally multiple times, with evidence of functional divergence in different genomic contexts. The molecular principles that underlie functional diversification of chemotaxis in various genomic contexts are unknown. Here, we provide a molecular mechanism by which a single CheA protein controls two unrelated functions: chemotaxis and cell length. Acquisition of this multifunctionality is seemingly a recent evolutionary event. The findings illustrate a mechanism by which chemotaxis function may be co-opted to regulate additional cellular functions. PMID:28416707

Divergent environmental filters drive functional segregation of European peatlands

NASA Astrophysics Data System (ADS)

Robroek, B.; Jassey, V.; Bragazza, L.; Buttler, A.

2015-12-01

Plant communities are largely shaped by prevailing climatic conditions. As a result, environmental change is expected to alter the (functional) composition in plant communities. Because plants, and particularly the composition of plant species, play an important role in driving ecosystem processes, it is crucial that we improve our understanding on which environmental factors are most important in shaping plant communities. Here we presnt the results for a cross-Eurpean study, were we assessed the role of environmnetal conditions on plant community composition in 56 peatlands. We show that plant species richness and diversity are relatively stable across the main environmental gradients. Nevertheless, we observe large changes in the plant community structure. In other words, species turnover increased with increasing differences in environmental viariables. Such turnover in the community composition is largely associated to gradients temperature and precipitation, whilst nutrients -often reported as major driver for changes in peatland ecosystems- were only important at the end of the gradient of current deposition levels in Europe. Using a combination of species distribution modelling and species co-occurence patterns, we identified two spatially non-exclusive groups of plant species. Species within a distinct group responded similarly to bioclimatic variables and nutrient deposition levels, whilst between group response was mirrored. These results suggest that these two groups of plants are subjected to divergent environmental filters. Additionally, European peatlands aggregate into two distinct clusters based on plant functional trait composition. Each cluster was dominated by plant species from either one of the two co-response groups. Overall, our results demonstrate that environmental change results in a gradual replacement of plant species from two divergent groups, consequently affecting the functional trait composition in peatlands.

Functional Characterization of PhapLEAFY, a FLORICAULA/LEAFY Ortholog in Phalaenopsis aphrodite.

PubMed

Jang, Seonghoe

2015-11-01

The plant-specific transcription factor LEAFY (LFY) is considered to be a master regulator of flower development in the model plant, Arabidopsis. This protein plays a dual role in plant growth, integrating signals from the floral inductive pathways and acting as a floral meristem identity gene by activating genes for floral organ development. Although LFY occupies an important position in flower development, the functional divergence of LFY homologs has been demonstrated in several plants including monocots and gymnosperms. In particular, the functional roles of LFY genes from orchid species such as Phalaenopsis that contain unique floral morphologies with distinct expression patterns of floral organ identity genes remain elusive. Here, PhapLFY, an ortholog of Arabidopsis LFY from Phalaenopsis aphrodite subsp. formosana, a Taiwanese native monopodial orchid, was isolated and characterized through analyses of expression and protein activity. PhapLFY transcripts accumulated in the floral primordia of developing inflorescences, and the PhapLFY protein had transcriptional autoactivation activity forming as a homodimer. Furthermore, PhapLFY rescues the aberrant floral phenotypes of Arabidopsis lfy mutants. Overexpression of PhapLFY alone or together with PhapFT1, a P. aphrodite subsp. formosana homolog of Arabidopsis FLOWERING LOCUS T (FT) in rice, caused precocious heading. Consistently, a higher Chl content in the sepals and morphological changes in epidermal cells were observed in the floral organs of PhapLFY knock-down orchids generated by virus-induced gene silencing. Taken together, these results suggest that PhapLFY is functionally distinct from RICE FLORICAULA/LEAFY (RFL) but similar to Arabidopsis LFY based on phenotypes of our transgenic Arabidopsis and rice plants. © The Author 2015. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please email: journals.permissions@oup.com.

TAF10 and TAF10b partially redundant roles during Drosophila melanogaster morphogenesis.

PubMed

Pahi, Z; Borsos, B N; Vedelek, B; Shidlovskii, Y V; Georgieva, S G; Boros, I M; Pankotai, T

2017-01-01

Transcription of eukaryotic genes requires the cooperative action of the RNA polymerase complex, the general transcription factors (TFIIB, TFIID, TFIIE, TFIIF and TFIIH) and chromatin modifiers. The TFIID complex contributes to transcriptional activation by several mechanisms and has a subunit with associated histone acetyltransferase (HAT) activity. The histone modifier SAGA complex has both HAT and deubiquitylase (DUB) activities. TFIID and SAGA share several TBP-associated factors (TAFs), but not their HAT subunit. Recently, several duplicated TAF proteins have been identified in higher eukaryotes, but their functional diversity has been so far poorly characterized. Here, we report the functional similarities and differences of TAF10 and TAF10b, the two TAF10 orthologs of Drosophila melanogaster. Results from in silico modeling suggest that dTAF10 and dTAF10b have similar secondary structures characterized by the presence of a histone-fold domain. Additionally, dTAF10 and dTAF10b share interaction partners and show similar expression patterns in neuronal tissues. Nonetheless, dTAF10 and dTAF10b seem to have partly distinct functions. To investigate their roles, we generated dTaf10-dTaf10b double-mutants and rescued the mutant flies with transgenes, which allowed the translation of either dTAF10 or dTAF10b protein. We found that the loss of dTAF10b resulted in pupal lethality, while animals lacking dTAF10 were able to form puparium. dTaf10 mutant adults showed distorted eye morphology. During DNA repair, dTAF10 and dTAF10b act redundantly, suggesting that these proteins have distinct but partially overlapping functions.

The catalytic region and PEST domain of PTPN18 distinctly regulate the HER2 phosphorylation and ubiquitination barcodes.

PubMed

Wang, Hong-Mei; Xu, Yun-Fei; Ning, Shang-Lei; Yang, Du-Xiao; Li, Yi; Du, Yu-Jie; Yang, Fan; Zhang, Ya; Liang, Nan; Yao, Wei; Zhang, Ling-Li; Gu, Li-Chuan; Gao, Cheng-Jiang; Pang, Qi; Chen, Yu-Xin; Xiao, Kun-Hong; Ma, Rong; Yu, Xiao; Sun, Jin-Peng

2014-09-01

The tyrosine phosphorylation barcode encoded in C-terminus of HER2 and its ubiquitination regulate diverse HER2 functions. PTPN18 was reported as a HER2 phosphatase; however, the exact mechanism by which it defines HER2 signaling is not fully understood. Here, we demonstrate that PTPN18 regulates HER2-mediated cellular functions through defining both its phosphorylation and ubiquitination barcodes. Enzymologic characterization and three crystal structures of PTPN18 in complex with HER2 phospho-peptides revealed the molecular basis for the recognition between PTPN18 and specific HER2 phosphorylation sites, which assumes two distinct conformations. Unique structural properties of PTPN18 contribute to the regulation of sub-cellular phosphorylation networks downstream of HER2, which are required for inhibition of HER2-mediated cell growth and migration. Whereas the catalytic domain of PTPN18 blocks lysosomal routing and delays the degradation of HER2 by dephosphorylation of HER2 on pY(1112), the PEST domain of PTPN18 promotes K48-linked HER2 ubiquitination and its rapid destruction via the proteasome pathway and an HER2 negative feedback loop. In agreement with the negative regulatory role of PTPN18 in HER2 signaling, the HER2/PTPN18 ratio was correlated with breast cancer stage. Taken together, our study presents a structural basis for selective HER2 dephosphorylation, a previously uncharacterized mechanism for HER2 degradation and a novel function for the PTPN18 PEST domain. The new regulatory role of the PEST domain in the ubiquitination pathway will broaden our understanding of the functions of other important PEST domain-containing phosphatases, such as LYP and PTPN12.

Structural and functional connectivity between the lateral posterior-pulvinar complex and primary visual cortex in the ferret.

PubMed

Yu, Chunxiu; Sellers, Kristin K; Radtke-Schuller, Susanne; Lu, Jinghao; Xing, Lei; Ghukasyan, Vladimir; Li, Yuhui; Shih, Yen-Yu I; Murrow, Richard; Fröhlich, Flavio

2016-01-01

The role of higher-order thalamic structures in sensory processing remains poorly understood. Here, we used the ferret (Mustela putorius furo) as a novel model species for the study of the lateral posterior (LP)-pulvinar complex and its structural and functional connectivity with area 17 [primary visual cortex (V1)]. We found reciprocal anatomical connections between the lateral part of the LP nucleus of the LP-pulvinar complex (LPl) and V1. In order to investigate the role of this feedback loop between LPl and V1 in shaping network activity, we determined the functional interactions between LPl and the supragranular, granular and infragranular layers of V1 by recording multiunit activity and local field potentials. Coherence was strongest between LPl and the supragranular V1, with the most distinct peaks in the delta and alpha frequency bands. Inter-area interaction measured by spike-phase coupling identified the delta frequency band being dominated by the infragranular V1 and multiple frequency bands that were most pronounced in the supragranular V1. This inter-area coupling was differentially modulated by full-field synthetic and naturalistic visual stimulation. We also found that visual responses in LPl were distinct from those in V1 in terms of their reliability. Together, our data support a model of multiple communication channels between LPl and the layers of V1 that are enabled by oscillations in different frequency bands. This demonstration of anatomical and functional connectivity between LPl and V1 in ferrets provides a roadmap for studying the interaction dynamics during behaviour, and a template for identifying the activity dynamics of other thalamo-cortical feedback loops. © 2015 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Cognitive impairment in Epilepsy: The Role of Network Abnormalities

PubMed Central

Holmes, Gregory L.

2015-01-01

The challenges to individuals with epilepsy extend far beyond the seizures. Co-morbidities in epilepsy are very common and are often more problematic to individuals than the seizures themselves. In this review, the pathophysiological mechanisms of cognitive impairment are discussed. While etiology of the epilepsy has a significant influence on cognition there is increasing evidence that prolonged or recurrent seizures can cause or exacerbate cognitive impairment. Alterations in signaling pathways and neuronal network function play a major role in both the pathophysiology of epilepsy and the epilepsy comorbidities. However, the biological underpinnings of cognitive impairment can be distinct from the pathophysiological processes that cause seizures. PMID:25905906

THE ROLE OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS IN CARCINOGENESIS AND CHEMOPREVENTION

PubMed Central

Peters, Jeffrey M.; Shah, Yatrik M.; Gonzalez, Frank J.

2012-01-01

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that are involved in regulating glucose and lipid homeostasis, inflammation, proliferation and differentiation. Although all of these functions might contribute to the influence of PPARs in carcinogenesis, there is a distinct need for a balanced review of the literature and additional experimentation to determine the potential for targeting PPARs for cancer therapy and cancer chemoprevention. As PPAR agonists include drugs used for the treatment of metabolic diseases, a more complete understanding of the roles of PPARs in cancer will aid in determining any increased cancer risk for patients undergoing therapy with PPAR agonists. PMID:22318237

Distinct function of estrogen receptor α in smooth muscle and fibroblast cells in prostate development.

PubMed

Vitkus, Spencer; Yeh, Chiuan-Ren; Lin, Hsiu-Hsia; Hsu, Iawen; Yu, Jiangzhou; Chen, Ming; Yeh, Shuyuan

2013-01-01

Estrogen signaling, through estrogen receptor (ER)α, has been shown to cause hypertrophy in the prostate. Our recent report has shown that epithelial ERα knockout (KO) will not affect the normal prostate development or homeostasis. However, it remains unclear whether ERα in different types of stromal cells has distinct roles in prostate development. This study proposed to elucidate how KO of ERα in the stromal smooth muscle or fibroblast cells may interrupt cross talk between prostate stromal and epithelial cells. Smooth muscle ERαKO (smERαKO) mice showed decreased glandular infolding with the proximal area exhibiting a significant decrease. Fibroblast ERαKO mouse prostates did not exhibit this phenotype but showed a decrease in the number of ductal tips. Additionally, the amount of collagen observed in the basement membrane was reduced in smERαKO prostates. Interestingly, these phenotypes were found to be mutually exclusive among smERαKO or fibroblast ERαKO mice. Compound KO of ERα in both fibroblast and smooth muscle showed combined phenotypes from each of the single KO. Further mechanistic studies showed that IGF-I and epidermal growth factor were down-regulated in prostate smooth muscle PS-1 cells lacking ERα. Together, our results indicate the distinct functions of fibroblast vs. smERα in prostate development.

Unique and shared roles of the posterior parietal and dorsolateral prefrontal cortex in cognitive functions

PubMed Central

Katsuki, Fumi; Constantinidis, Christos

2012-01-01

The dorsolateral prefrontal cortex (PFC) and posterior parietal cortex (PPC) are two parts of a broader brain network involved in the control of cognitive functions such as working-memory, spatial attention, and decision-making. The two areas share many functional properties and exhibit similar patterns of activation during the execution of mental operations. However, neurophysiological experiments in non-human primates have also documented subtle differences, revealing functional specialization within the fronto-parietal network. These differences include the ability of the PFC to influence memory performance, attention allocation, and motor responses to a greater extent, and to resist interference by distracting stimuli. In recent years, distinct cellular and anatomical differences have been identified, offering insights into how functional specialization is achieved. This article reviews the common functions and functional differences between the PFC and PPC, and their underlying mechanisms. PMID:22563310

The Centrosome and Its Duplication Cycle

PubMed Central

Fu, Jingyan; Hagan, Iain M.; Glover, David M.

2015-01-01

The centrosome was discovered in the late 19th century when mitosis was first described. Long recognized as a key organelle of the spindle pole, its core component, the centriole, was realized more than 50 or so years later also to comprise the basal body of the cilium. Here, we chart the more recent acquisition of a molecular understanding of centrosome structure and function. The strategies for gaining such knowledge were quickly developed in the yeasts to decipher the structure and function of their distinctive spindle pole bodies. Only within the past decade have studies with model eukaryotes and cultured cells brought a similar degree of sophistication to our understanding of the centrosome duplication cycle and the multiple roles of this organelle and its component parts in cell division and signaling. Now as we begin to understand these functions in the context of development, the way is being opened up for studies of the roles of centrosomes in human disease. PMID:25646378

Shugoshins function as a guardian for chromosomal stability in nuclear division.

PubMed

Yao, Yixin; Dai, Wei

2012-07-15

Accurate chromosome segregation during mitosis and meiosis is regulated and secured by several distinctly different yet intricately connected regulatory mechanisms. As chromosomal instability is a hallmark of a majority of tumors as well as a cause of infertility for germ cells, extensive research in the past has focused on the identification and characterization of molecular components that are crucial for faithful chromosome segregation during cell division. Shugoshins, including Sgo1 and Sgo2, are evolutionarily conserved proteins that function to protect sister chromatid cohesion, thus ensuring chromosomal stability during mitosis and meiosis in eukaryotes. Recent studies reveal that Shugoshins in higher animals play an essential role not only in protecting centromeric cohesion of sister chromatids and assisting bi-orientation attachment at the kinetochores, but also in safeguarding centriole cohesion/engagement during early mitosis. Many molecular components have been identified that play essential roles in modulating/mediating Sgo functions. This review primarily summarizes recent advances on the mechanisms of action of Shugoshins in suppressing chromosomal instability during nuclear division in eukaryotic organisms.

A Conserved Circular Network of Coregulated Lipids Modulates Innate Immune Responses

PubMed Central

Köberlin, Marielle S.; Snijder, Berend; Heinz, Leonhard X.; Baumann, Christoph L.; Fauster, Astrid; Vladimer, Gregory I.; Gavin, Anne-Claude; Superti-Furga, Giulio

2015-01-01

Summary Lipid composition affects the biophysical properties of membranes that provide a platform for receptor-mediated cellular signaling. To study the regulatory role of membrane lipid composition, we combined genetic perturbations of sphingolipid metabolism with the quantification of diverse steps in Toll-like receptor (TLR) signaling and mass spectrometry-based lipidomics. Membrane lipid composition was broadly affected by these perturbations, revealing a circular network of coregulated sphingolipids and glycerophospholipids. This evolutionarily conserved network architecture simultaneously reflected membrane lipid metabolism, subcellular localization, and adaptation mechanisms. Integration of the diverse TLR-induced inflammatory phenotypes with changes in lipid abundance assigned distinct functional roles to individual lipid species organized across the network. This functional annotation accurately predicted the inflammatory response of cells derived from patients suffering from lipid storage disorders, based solely on their altered membrane lipid composition. The analytical strategy described here empowers the understanding of higher-level organization of membrane lipid function in diverse biological systems. PMID:26095250

Neuron hemilineages provide the functional ground plan for the Drosophila ventral nervous system

PubMed Central

Harris, Robin M; Pfeiffer, Barret D; Rubin, Gerald M; Truman, James W

2015-01-01

Drosophila central neurons arise from neuroblasts that generate neurons in a pair-wise fashion, with the two daughters providing the basis for distinct A and B hemilineage groups. 33 postembryonically-born hemilineages contribute over 90% of the neurons in each thoracic hemisegment. We devised genetic approaches to define the anatomy of most of these hemilineages and to assessed their functional roles using the heat-sensitive channel dTRPA1. The simplest hemilineages contained local interneurons and their activation caused tonic or phasic leg movements lacking interlimb coordination. The next level was hemilineages of similar projection cells that drove intersegmentally coordinated behaviors such as walking. The highest level involved hemilineages whose activation elicited complex behaviors such as takeoff. These activation phenotypes indicate that the hemilineages vary in their behavioral roles with some contributing to local networks for sensorimotor processing and others having higher order functions of coordinating these local networks into complex behavior. DOI: http://dx.doi.org/10.7554/eLife.04493.001 PMID:26193122

Nuclear pore complex integrity requires Lnp1, a regulator of cortical endoplasmic reticulum

PubMed Central

Casey, Amanda K.; Chen, Shuliang; Novick, Peter; Ferro-Novick, Susan; Wente, Susan R.

2015-01-01

The nuclear envelope (NE) and endoplasmic reticulum (ER) are components of the same contiguous membrane system and yet have distinct cellular functions. Mounting evidence suggests roles for some ER proteins in the NE for proper nuclear pore complex (NPC) structure and function. In this study, we identify a NE role in Saccharomyces cerevisiae for Lnp1 and Sey1, proteins required for proper cortical ER formation. Both lnp1Δ and sey1Δ mutants exhibit synthetic genetic interactions with mutants in genes encoding key NPC structural components. Both Lnp1 and Sey1 physically associate with other ER components that have established NPC roles, including Rtn1, Yop1, Pom33, and Per33. Of interest, lnp1Δ rtn1Δ mutants but not rtn1Δ sey1Δ mutants exhibit defects in NPC distribution. Furthermore, the essential NPC assembly factor Ndc1 has altered interactions in the absence of Sey1. Lnp1 dimerizes in vitro via its C-terminal zinc finger motif, a property that is required for proper ER structure but not NPC integrity. These findings suggest that Lnp1's role in NPC integrity is separable from functions in the ER and is linked to Ndc1 and Rtn1 interactions. PMID:26041935

Impaired familiarity with preserved recollection after anterior temporal-lobe resection that spares the hippocampus.

PubMed

Bowles, Ben; Crupi, Carina; Mirsattari, Seyed M; Pigott, Susan E; Parrent, Andrew G; Pruessner, Jens C; Yonelinas, Andrew P; Köhler, Stefan

2007-10-09

It is well established that the medial-temporal lobe (MTL) is critical for recognition memory. The MTL is known to be composed of distinct structures that are organized in a hierarchical manner. At present, it remains controversial whether lower structures in this hierarchy, such as perirhinal cortex, support memory functions that are distinct from those of higher structures, in particular the hippocampus. Perirhinal cortex has been proposed to play a specific role in the assessment of familiarity during recognition, which can be distinguished from the selective contributions of the hippocampus to the recollection of episodic detail. Some researchers have argued, however, that the distinction between familiarity and recollection cannot capture functional specialization within the MTL and have proposed single-process accounts. Evidence supporting the dual-process view comes from demonstrations that selective hippocampal damage can produce isolated recollection impairments. It is unclear, however, whether temporal-lobe lesions that spare the hippocampus can produce selective familiarity impairments. Without this demonstration, single-process accounts cannot be ruled out. We examined recognition memory in NB, an individual who underwent surgical resection of left anterior temporal-lobe structures for treatment of intractable epilepsy. Her resection included a large portion of perirhinal cortex but spared the hippocampus. The results of four experiments based on three different experimental procedures (remember-know paradigm, receiver operating characteristics, and response-deadline procedure) indicate that NB exhibits impaired familiarity with preserved recollection. The present findings thus provide a crucial missing piece of support for functional specialization in the MTL.

Resident renal mononuclear phagocytes comprise five discrete populations with distinct phenotypes and functions

PubMed Central

Kawakami, Takahisa; Lichtnekert, Julia; Thompson, Lucas J.; Karna, Prasanthi; Bouabe, Hicham; Hohl, Tobias M.; Heinecke, Jay W.; Ziegler, Steven F.; Nelson, Peter J.; Duffield, Jeremy S.

2013-01-01

Recent reports have highlighted greater complexity, plasticity and functional diversity of mononuclear phagocytes (MPCs), including monocytes, macrophages and dendritic cells (DCs), in our organs, than previously understood. The functions and origins of MPCs resident within healthy organs, especially in the kidney, are less well understood, while studies suggest they play roles in disease states distinct from recruited monocytes. We developed an unbiased approach using flow cytometry to analyze MPCs residing in the normal mouse kidney, and identified five discrete subpopulations according to CD11b/CD11c expression as well as F4/80, CD103, CD14, CD16 and CD64 expression. In addition to distinct marker profiles, these subpopulations have different lineages and expression of genes involved in tissue homeostasis, including angiogenesis. Among them, the CD11bint CD11cint F4/80hi subpopulation notably exhibited high capacity to produce a representative anti-inflammatory cytokine, IL-10. Each subpopulation had different degrees of both macrophage (phagocytosis) and DC (antigen presentation) capacities, with a tendency to promote differentiation of regulatory T cells, while two of these showed expression of transcription factors reported to be highly expressed by classical DCs, and proclivity to exit the kidney following stimulation with LPS. In summary, resident kidney MPCs comprise discrete subpopulations, which cannot be simply classified into the conventional entities, and they produce anti-inflammatory and tissue-homeostatic factors to differing degrees. PMID:23956422

Distinguishing the roles of dorsolateral and anterior PFC in visual metacognition.

PubMed

Shekhar, Medha; Rahnev, Dobromir

2018-05-02

Visual metacognition depends on regions within the prefrontal cortex. Two areas in particular have been repeatedly implicated: the dorsolateral prefrontal cortex (DLPFC) and the anterior prefrontal cortex (aPFC). However, it is still unclear what the function of each of these areas is and how they differ from each other. To establish the specific roles of DLPFC and aPFC in metacognition, we employed online transcranial magnetic stimulation (TMS) to causally interfere with their functioning during confidence generation. Human subjects from both sexes performed a perceptual decision-making task and provided confidence ratings. We found a clear dissociation between the two areas: DLPFC TMS lowered confidence ratings, whereas aPFC TMS increased metacognitive ability but only for the second half of the experimental blocks. These results support a functional architecture where DLPFC reads out the strength of the sensory evidence and relays it to aPFC, which makes the confidence judgement by potentially incorporating additional, non-perceptual information. Indeed, simulations from a model that incorporates these putative DLPFC and aPFC functions reproduced our behavioral results. These findings establish DLPFC and aPFC as distinct nodes in a metacognitive network and suggest specific contributions from each of these regions to confidence generation. SIGNIFICANCE STATEMENT The prefrontal cortex (PFC) is known to be critical for metacognition. Two of its sub-regions - dorsolateral PFC (DLPFC) and anterior PFC (aPFC) - have specifically been implicated in confidence generation. However, it is unclear if these regions have distinct functions related to the underlying metacognitive computation. Using a causal intervention with transcranial magnetic stimulation (TMS), we demonstrate that DLPFC and aPFC have dissociable contributions: targeting DLPFC decreased average confidence ratings, while targeting aPFC specifically affected metacognitive scores. Based on these results, we postulated specific functions for DLPFC and aPFC in metacognitive computation and corroborated them using a computational model that reproduced our results. Our causal results reveal the existence of a specialized modular organization in PFC for confidence generation. Copyright © 2018 the authors.

Evidence of a robust resident bacteriophage population revealed through analysis of the human salivary virome

PubMed Central

Pride, David T; Salzman, Julia; Haynes, Matthew; Rohwer, Forest; Davis-Long, Clara; White, Richard A; Loomer, Peter; Armitage, Gary C; Relman, David A

2012-01-01

Viruses are the most abundant known infectious agents on the planet and are significant drivers of diversity in a variety of ecosystems. Although there have been numerous studies of viral communities, few have focused on viruses within the indigenous human microbiota. We analyzed 2 267 695 virome reads from viral particles and compared them with 263 516 bacterial 16S rRNA gene sequences from the saliva of five healthy human subjects over a 2- to 3-month period, in order to improve our understanding of the role viruses have in the complex oral ecosystem. Our data reveal viral communities in human saliva dominated by bacteriophages whose constituents are temporally distinct. The preponderance of shared homologs between the salivary viral communities in two unrelated subjects in the same household suggests that environmental factors are determinants of community membership. When comparing salivary viromes to those from human stool and the respiratory tract, each group was distinct, further indicating that habitat is of substantial importance in shaping human viromes. Compared with coexisting bacteria, there was concordance among certain predicted host–virus pairings such as Veillonella and Streptococcus, whereas there was discordance among others such as Actinomyces. We identified 122 728 virulence factor homologs, suggesting that salivary viruses may serve as reservoirs for pathogenic gene function in the oral environment. That the vast majority of human oral viruses are bacteriophages whose putative gene function signifies some have a prominent role in lysogeny, suggests these viruses may have an important role in helping shape the microbial diversity in the human oral cavity. PMID:22158393

Mena/VASP and αII-Spectrin complexes regulate cytoplasmic actin networks in cardiomyocytes and protect from conduction abnormalities and dilated cardiomyopathy

PubMed Central

2013-01-01

Background In the heart, cytoplasmic actin networks are thought to have important roles in mechanical support, myofibrillogenesis, and ion channel function. However, subcellular localization of cytoplasmic actin isoforms and proteins involved in the modulation of the cytoplasmic actin networks are elusive. Mena and VASP are important regulators of actin dynamics. Due to the lethal phenotype of mice with combined deficiency in Mena and VASP, however, distinct cardiac roles of the proteins remain speculative. In the present study, we analyzed the physiological functions of Mena and VASP in the heart and also investigated the role of the proteins in the organization of cytoplasmic actin networks. Results We generated a mouse model, which simultaneously lacks Mena and VASP in the heart. Mena/VASP double-deficiency induced dilated cardiomyopathy and conduction abnormalities. In wild-type mice, Mena and VASP specifically interacted with a distinct αII-Spectrin splice variant (SH3i), which is in cardiomyocytes exclusively localized at Z- and intercalated discs. At Z- and intercalated discs, Mena and β-actin localized to the edges of the sarcomeres, where the thin filaments are anchored. In Mena/VASP double-deficient mice, β-actin networks were disrupted and the integrity of Z- and intercalated discs was markedly impaired. Conclusions Together, our data suggest that Mena, VASP, and αII-Spectrin assemble cardiac multi-protein complexes, which regulate cytoplasmic actin networks. Conversely, Mena/VASP deficiency results in disrupted β-actin assembly, Z- and intercalated disc malformation, and induces dilated cardiomyopathy and conduction abnormalities. PMID:23937664

Mena/VASP and αII-Spectrin complexes regulate cytoplasmic actin networks in cardiomyocytes and protect from conduction abnormalities and dilated cardiomyopathy.

PubMed

Benz, Peter M; Merkel, Carla J; Offner, Kristin; Abeßer, Marco; Ullrich, Melanie; Fischer, Tobias; Bayer, Barbara; Wagner, Helga; Gambaryan, Stepan; Ursitti, Jeanine A; Adham, Ibrahim M; Linke, Wolfgang A; Feller, Stephan M; Fleming, Ingrid; Renné, Thomas; Frantz, Stefan; Unger, Andreas; Schuh, Kai

2013-08-12

In the heart, cytoplasmic actin networks are thought to have important roles in mechanical support, myofibrillogenesis, and ion channel function. However, subcellular localization of cytoplasmic actin isoforms and proteins involved in the modulation of the cytoplasmic actin networks are elusive. Mena and VASP are important regulators of actin dynamics. Due to the lethal phenotype of mice with combined deficiency in Mena and VASP, however, distinct cardiac roles of the proteins remain speculative. In the present study, we analyzed the physiological functions of Mena and VASP in the heart and also investigated the role of the proteins in the organization of cytoplasmic actin networks. We generated a mouse model, which simultaneously lacks Mena and VASP in the heart. Mena/VASP double-deficiency induced dilated cardiomyopathy and conduction abnormalities. In wild-type mice, Mena and VASP specifically interacted with a distinct αII-Spectrin splice variant (SH3i), which is in cardiomyocytes exclusively localized at Z- and intercalated discs. At Z- and intercalated discs, Mena and β-actin localized to the edges of the sarcomeres, where the thin filaments are anchored. In Mena/VASP double-deficient mice, β-actin networks were disrupted and the integrity of Z- and intercalated discs was markedly impaired. Together, our data suggest that Mena, VASP, and αII-Spectrin assemble cardiac multi-protein complexes, which regulate cytoplasmic actin networks. Conversely, Mena/VASP deficiency results in disrupted β-actin assembly, Z- and intercalated disc malformation, and induces dilated cardiomyopathy and conduction abnormalities.

Inverted-U shaped dopamine actions on human working memory and cognitive control

PubMed Central

Cools, R; D’Esposito, M

2011-01-01

Brain dopamine has long been implicated in cognitive control processes, including working memory. However, the precise role of dopamine in cognition is not well understood, partly because there is large variability in the response to dopaminergic drugs both across different behaviors and across different individuals. We review evidence from a series of studies with experimental animals, healthy humans and patients with Parkinson’s disease, which highlight two important factors that contribute to this large variability. First, the existence of an optimum dopamine level for cognitive function implicates the need to take into account baseline levels of dopamine when isolating dopamine’s effects. Second, cognitive control is a multi-factorial phenomenon, requiring a dynamic balance between cognitive stability and cognitive flexibility. These distinct components might implicate the prefrontal cortex and the striatum respectively. Manipulating dopamine will thus have paradoxical consequences for distinct cognitive control processes depending on distinct basal or optimal levels of dopamine in different brain regions. PMID:21531388

Distinct requirements for cranial ectoderm and mesenchyme-derived wnts in specification and differentiation of osteoblast and dermal progenitors.

PubMed

Goodnough, L Henry; Dinuoscio, Gregg J; Ferguson, James W; Williams, Trevor; Lang, Richard A; Atit, Radhika P

2014-02-01

The cranial bones and dermis differentiate from mesenchyme beneath the surface ectoderm. Fate selection in cranial mesenchyme requires the canonical Wnt effector molecule β-catenin, but the relative contribution of Wnt ligand sources in this process remains unknown. Here we show Wnt ligands are expressed in cranial surface ectoderm and underlying supraorbital mesenchyme during dermal and osteoblast fate selection. Using conditional genetics, we eliminate secretion of all Wnt ligands from cranial surface ectoderm or undifferentiated mesenchyme, to uncover distinct roles for ectoderm- and mesenchyme-derived Wnts. Ectoderm Wnt ligands induce osteoblast and dermal fibroblast progenitor specification while initiating expression of a subset of mesenchymal Wnts. Mesenchyme Wnt ligands are subsequently essential during differentiation of dermal and osteoblast progenitors. Finally, ectoderm-derived Wnt ligands provide an inductive cue to the cranial mesenchyme for the fate selection of dermal fibroblast and osteoblast lineages. Thus two sources of Wnt ligands perform distinct functions during osteoblast and dermal fibroblast formation.

Central attention is serial, but midlevel and peripheral attention are parallel-A hypothesis.

PubMed

Tamber-Rosenau, Benjamin J; Marois, René

2016-10-01

In this brief review, we argue that attention operates along a hierarchy from peripheral through central mechanisms. We further argue that these mechanisms are distinguished not just by their functional roles in cognition, but also by a distinction between serial mechanisms (associated with central attention) and parallel mechanisms (associated with midlevel and peripheral attention). In particular, we suggest that peripheral attentional deployments in distinct representational systems may be maintained simultaneously with little or no interference, but that the serial nature of central attention means that even tasks that largely rely on distinct representational systems will come into conflict when central attention is demanded. We go on to review both the behavioral and neural evidence for this prediction. We conclude that even though the existing evidence mostly favors our account of serial central and parallel noncentral attention, we know of no experiment that has conclusively borne out these claims. As such, this article offers a framework of attentional mechanisms that will aid in guiding future research on this topic.

Distinct combinations of variant ionotropic glutamate receptors mediate thermosensation and hygrosensation in Drosophila.

PubMed

Knecht, Zachary A; Silbering, Ana F; Ni, Lina; Klein, Mason; Budelli, Gonzalo; Bell, Rati; Abuin, Liliane; Ferrer, Anggie J; Samuel, Aravinthan Dt; Benton, Richard; Garrity, Paul A

2016-09-22

Ionotropic Receptors (IRs) are a large subfamily of variant ionotropic glutamate receptors present across Protostomia. While these receptors are most extensively studied for their roles in chemosensory detection, recent work has implicated two family members, IR21a and IR25a, in thermosensation in Drosophila . Here we characterize one of the most evolutionarily deeply conserved receptors, IR93a, and show that it is co-expressed and functions with IR21a and IR25a to mediate physiological and behavioral responses to cool temperatures. IR93a is also co-expressed with IR25a and a distinct receptor, IR40a, in a discrete population of sensory neurons in the sacculus, a multi-chambered pocket within the antenna. We demonstrate that this combination of receptors is required for neuronal responses to dry air and behavioral discrimination of humidity differences. Our results identify IR93a as a common component of molecularly and cellularly distinct IR pathways important for thermosensation and hygrosensation in insects.

Developmental origin of lung macrophage diversity

PubMed Central

Tan, Serena Y. S.; Krasnow, Mark A.

2016-01-01

Macrophages are specialized phagocytic cells, present in all tissues, which engulf and digest pathogens, infected and dying cells, and debris, and can recruit and regulate other immune cells and the inflammatory response and aid in tissue repair. Macrophage subpopulations play distinct roles in these processes and in disease, and are typically recognized by differences in marker expression, immune function, or tissue of residency. Although macrophage subpopulations in the brain have been found to have distinct developmental origins, the extent to which development contributes to macrophage diversity between tissues and within tissues is not well understood. Here, we investigate the development and maintenance of mouse lung macrophages by marker expression patterns, genetic lineage tracing and parabiosis. We show that macrophages populate the lung in three developmental waves, each giving rise to a distinct lineage. These lineages express different markers, reside in different locations, renew in different ways, and show little or no interconversion. Thus, development contributes significantly to lung macrophage diversity and targets each lineage to a different anatomical domain. PMID:26952982

Volition and conflict in human medial frontal cortex

PubMed Central

Nachev, Parashkev; Rees, Geraint; Parton, Andrew; Kennard, Christopher; Husain, Masud

2009-01-01

Summary Controversy surrounds the role of human medial frontal cortex in controlling actions[1-5]. Although damage to this area leads to severe difficulties in spontaneously initiating actions[6], the precise mechanisms underlying such ‘volitional’ deficits remain to be established. Previous studies have implicated the medial frontal cortex in conflict monitoring[7-10] and the control of voluntary action[11, 12], suggesting that these key processes are functionally related or share neural substrates. Here we combine a novel behavioural paradigm with functional imaging of the oculomotor system to reveal for the first time a functional subdivision of the pre-supplementary motor area (pre-SMA) into anatomically distinct areas responding exclusively to volition or to conflict. We also demonstrate that activity in the supplementary eye field (SEF) distinguishes between success and failure in changing voluntary action plans during conflict, suggesting a role for the SEF in implementing the resolution of conflicting actions. We propose a functional architecture of human medial frontal cortex that incorporates the generation of action plans and the resolution of conflict. PMID:15668167

The Role of Aquaporins in Ocular Lens Homeostasis

PubMed Central

Schey, Kevin L.; Petrova, Rosica S.; Gletten, Romell B.; Donaldson, Paul J.

2017-01-01

Aquaporins (AQPs), by playing essential roles in the maintenance of ocular lens homeostasis, contribute to the establishment and maintenance of the overall optical properties of the lens over many decades of life. Three aquaporins, AQP0, AQP1 and AQP5, each with distinctly different functional properties, are abundantly and differentially expressed in the different regions of the ocular lens. Furthermore, the diversity of AQP functionality is increased in the absence of protein turnover by age-related modifications to lens AQPs that are proposed to alter AQP function in the different regions of the lens. These regional differences in AQP functionality are proposed to contribute to the generation and directionality of the lens internal microcirculation; a system of circulating ionic and fluid fluxes that delivers nutrients to and removes wastes from the lens faster than could be achieved by passive diffusion alone. In this review, we present how regional differences in lens AQP isoforms potentially contribute to this microcirculation system by highlighting current areas of investigation and emphasizing areas where future work is required. PMID:29231874

Glucose metabolism regulates T cell activation, differentiation, and functions.

PubMed

Palmer, Clovis S; Ostrowski, Matias; Balderson, Brad; Christian, Nicole; Crowe, Suzanne M

2015-01-01

The adaptive immune system is equipped to eliminate both tumors and pathogenic microorganisms. It requires a series of complex and coordinated signals to drive the activation, proliferation, and differentiation of appropriate T cell subsets. It is now established that changes in cellular activation are coupled to profound changes in cellular metabolism. In addition, emerging evidence now suggest that specific metabolic alterations associated with distinct T cell subsets may be ancillary to their differentiation and influential in their immune functions. The "Warburg effect" originally used to describe a phenomenon in which most cancer cells relied on aerobic glycolysis for their growth is a key process that sustain T cell activation and differentiation. Here, we review how different aspects of metabolism in T cells influence their functions, focusing on the emerging role of key regulators of glucose metabolism such as HIF-1α. A thorough understanding of the role of metabolism in T cell function could provide insights into mechanisms involved in inflammatory-mediated conditions, with the potential for developing novel therapeutic approaches to treat these diseases.

Apomorphine effects on frog locomotor behavior.

PubMed

Chu, Joanne; Wilczynski, Walter

2007-05-16

The neuroanatomical pathways of the DA systems have been shown to be largely conserved across many vertebrate taxa. It is less certain whether the structural similarities seen between mammals and amphibians reflect a similar functional homology. DA is well known for its role in facilitating motor behaviors in mammals. We examined whether a similar role for DA exists in amphibians using the Northern Leopard Frog (Rana pipiens). We investigated the effects of the nonspecific DA agonist, apomorphine (APO) on a complex motor task that included two distinct components known to be differentially modulated by DA in mammals: swimming and climbing. We demonstrated that a high single dose of APO (20 mg/kg, body weight) strongly increased the amount of time spent completing the motor task. Furthermore, we showed that although APO did not significantly alter several aspects of swimming behavior, two aspects of climbing behavior were disrupted. Both climbing speed and climbing ability were impaired by APO treatment. These results increase our understanding of DA function in amphibians and add to our understanding of structure-function homologies of dopamine function across vertebrate taxa.

Drosophila Ana1 is required for centrosome assembly and centriole elongation.

PubMed

Saurya, Saroj; Roque, Hélio; Novak, Zsofia A; Wainman, Alan; Aydogan, Mustafa G; Volanakis, Adam; Sieber, Boris; Pinto, David Miguel Susano; Raff, Jordan W

2016-07-01

Centrioles organise centrosomes and cilia, and these organelles have an important role in many cell processes. In flies, the centriole protein Ana1 is required for the assembly of functional centrosomes and cilia. It has recently been shown that Cep135 (also known as Bld10) initially recruits Ana1 to newly formed centrioles, and that Ana1 then recruits Asl (known as Cep152 in mammals) to promote the conversion of these centrioles into centrosomes. Here, we show that ana1 mutants lack detectable centrosomes in vivo, that Ana1 is irreversibly incorporated into centrioles during their assembly and appears to play a more important role in maintaining Asl at centrioles than in initially recruiting Asl to centrioles. Unexpectedly, we also find that Ana1 promotes centriole elongation in a dose-dependent manner: centrioles are shorter when Ana1 dosage is reduced and are longer when Ana1 is overexpressed. This latter function of Ana1 appears to be distinct from its role in centrosome and cilium function, as a GFP-Ana1 fusion lacking the N-terminal 639 amino acids of the protein can support centrosome assembly and cilium function but cannot promote centriole over-elongation when overexpressed. © 2016. Published by The Company of Biologists Ltd.

Epithelial Sodium and Acid-Sensing Ion Channels

NASA Astrophysics Data System (ADS)

Kellenberger, Stephan

The epithelial Na+ channel (ENaC) and acid-sensing ion channels (ASICs) are non-voltage-gated Na+ channels that form their own subfamilies within the ENaC/degenerin ion channel family. ASICs are sensors of extracellular pH, and ENaC, whose main function is trans-epithelial Na+ transport, can sense extra- and intra-cellular Na+. In aldosterone-responsive epithelial cells of the kidney, ENaC plays a critical role in the control of sodium balance, blood volume and blood pressure. In airway epithelia, ENaC has a distinct role in controlling fluid reabsorption at the air-liquid interface, thereby determining the rate of mucociliary transport. In taste receptor cells of the tongue, ENaC is involved in salt taste sensation. ASICs have emerged as key sensors for extracellular protons in central and peripheral neurons. Although not all of their physiological and pathological functions are firmly established yet, there is good evidence for a role of ASICs in the brain in learning, expression of fear, and in neurodegeneration after ischaemic stroke. In sensory neurons, ASICs are involved in nociception and mechanosensation. ENaC and ASIC subunits share substantial sequence homology and the conservation of several functional domains. This chapter summarises our current understanding of the physiological functions and of the mechanisms of ion permeation, gating and regulation of ENaC and ASICs.

Small things considered: the small accessory subunits of RNA polymerase in Gram-positive bacteria

PubMed Central

Weiss, Andy; Shaw, Lindsey N.

2015-01-01

The DNA-dependent RNA polymerase core enzyme in Gram-positive bacteria consists of seven subunits. Whilst four of them (α2ββ′) are essential, three smaller subunits, δ, ε and ω (∼9–21.5 kDa), are considered accessory. Both δ and ω have been viewed as integral components of RNAP for several decades; however, ε has only recently been described. Functionally these three small subunits carry out a variety of tasks, imparting important, supportive effects on the transcriptional process of Gram-positive bacteria. While ω is thought to have a wide range of roles, reaching from maintaining structural integrity of RNAP to σ factor recruitment, the only suggested function for ε thus far is in protecting cells from phage infection. The third subunit, δ, has been shown to have distinct influences in maintaining transcriptional specificity, and thus has a key role in cellular fitness. Collectively, all three accessory subunits, although dispensable under laboratory conditions, are often thought to be crucial for proper RNAP function. Herein we provide an overview of the available literature on each subunit, summarizing landmark findings that have deepened our understanding of these proteins and their function, and outline future challenges in understanding the role of these small subunits in the transcriptional process. PMID:25878038

The Role of Adult-Born Neurons in the Constantly Changing Olfactory Bulb Network

PubMed Central

Malvaut, Sarah; Saghatelyan, Armen

2016-01-01

The adult mammalian brain is remarkably plastic and constantly undergoes structurofunctional modifications in response to environmental stimuli. In many regions plasticity is manifested by modifications in the efficacy of existing synaptic connections or synapse formation and elimination. In a few regions, however, plasticity is brought by the addition of new neurons that integrate into established neuronal networks. This type of neuronal plasticity is particularly prominent in the olfactory bulb (OB) where thousands of neuronal progenitors are produced on a daily basis in the subventricular zone (SVZ) and migrate along the rostral migratory stream (RMS) towards the OB. In the OB, these neuronal precursors differentiate into local interneurons, mature, and functionally integrate into the bulbar network by establishing output synapses with principal neurons. Despite continuous progress, it is still not well understood how normal functioning of the OB is preserved in the constantly remodelling bulbar network and what role adult-born neurons play in odor behaviour. In this review we will discuss different levels of morphofunctional plasticity effected by adult-born neurons and their functional role in the adult OB and also highlight the possibility that different subpopulations of adult-born cells may fulfill distinct functions in the OB neuronal network and odor behaviour. PMID:26839709

Axon Termination, Pruning, and Synaptogenesis in the Giant Fiber System of Drosophila melanogaster Is Promoted by Highwire.

PubMed

Borgen, Melissa; Rowland, Kimberly; Boerner, Jana; Lloyd, Brandon; Khan, Aruna; Murphey, Rodney

2017-03-01

The ubiquitin ligase Highwire has a conserved role in synapse formation. Here, we show that Highwire coordinates several facets of central synapse formation in the Drosophila melanogaster giant fiber system, including axon termination, axon pruning, and synaptic function. Despite the similarities to the fly neuromuscular junction, the role of Highwire and the underlying signaling pathways are distinct in the fly's giant fiber system. During development, branching of the giant fiber presynaptic terminal occurs and, normally, the transient branches are pruned away. However, in highwire mutants these ectopic branches persist, indicating that Highwire promotes axon pruning. highwire mutants also exhibit defects in synaptic function. Highwire promotes axon pruning and synaptic function cell-autonomously by attenuating a mitogen-activated protein kinase pathway including Wallenda, c-Jun N-terminal kinase/Basket, and the transcription factor Jun. We also show a novel role for Highwire in non-cell autonomous promotion of synaptic function from the midline glia. Highwire also regulates axon termination in the giant fibers, as highwire mutant axons exhibit severe overgrowth beyond the pruning defect. This excessive axon growth is increased by manipulating Fos expression in the cells surrounding the giant fiber terminal, suggesting that Fos regulates a trans -synaptic signal that promotes giant fiber axon growth. Copyright © 2017 by the Genetics Society of America.

Division of Labor Among the Yeast Sol Proteins Implicated in tRNA Nuclear Export and Carbohydrate Metabolism

PubMed Central

Stanford, D. R.; Whitney, M. L.; Hurto, R. L.; Eisaman, D. M.; Shen, W.-C.; Hopper, A. K.

2004-01-01

SOL1, the founding member of the S. cerevisiae SOL family, was previously identified as a multi-copy suppressor of the los1 defect in tRNA-mediated nonsense suppression. Here we report that the four-member SOL family is not essential and that individual family members appear to have distinct functions. SOL1–SOL4 are homologous to genes encoding 6-phosphogluconolactonase (6Pgl) involved in the pentose phosphate pathway. Both Sol3p and Sol4p affect this activity. However, Sol4p does not act as a los1 multi-copy suppressor. In contrast, neither Sol1p nor Sol2p, both of which correct the los1 defect in nonsense suppression, possess detectable 6Pgl activity. Rather, Sol1p and Sol2p appear to function in tRNA nuclear export as sol1 and sol2 mutants possess elevated levels of nuclear tRNA. Members of the Sol protein family appear to have different subcellular distributions. Thus, Sol3p and Sol4p likely function in carbohydrate metabolism, while Sol1p and Sol2p appear to have roles in tRNA function and nuclear export, thereby defining an unusual protein family whose individual members are biochemically distinct and spatially dispersed. PMID:15454531

Division of labor among the yeast Sol proteins implicated in tRNA nuclear export and carbohydrate metabolism.

PubMed

Stanford, D R; Whitney, M L; Hurto, R L; Eisaman, D M; Shen, W-C; Hopper, A K

2004-09-01

SOL1, the founding member of the S. cerevisiae SOL family, was previously identified as a multi-copy suppressor of the los1 defect in tRNA-mediated nonsense suppression. Here we report that the four-member SOL family is not essential and that individual family members appear to have distinct functions. SOL1-SOL4 are homologous to genes encoding 6-phosphogluconolactonase (6Pgl) involved in the pentose phosphate pathway. Both Sol3p and Sol4p affect this activity. However, Sol4p does not act as a los1 multi-copy suppressor. In contrast, neither Sol1p nor Sol2p, both of which correct the los1 defect in nonsense suppression, possess detectable 6Pgl activity. Rather, Sol1p and Sol2p appear to function in tRNA nuclear export as sol1 and sol2 mutants possess elevated levels of nuclear tRNA. Members of the Sol protein family appear to have different subcellular distributions. Thus, Sol3p and Sol4p likely function in carbohydrate metabolism, while Sol1p and Sol2p appear to have roles in tRNA function and nuclear export, thereby defining an unusual protein family whose individual members are biochemically distinct and spatially dispersed.

Microbial community composition of deep-sea corals from the Red Sea provides insight into functional adaption to a unique environment

PubMed Central

Röthig, Till; Yum, Lauren K.; Kremb, Stephan G.; Roik, Anna; Voolstra, Christian R.

2017-01-01

Microbes associated with deep-sea corals remain poorly studied. The lack of symbiotic algae suggests that associated microbes may play a fundamental role in maintaining a viable coral host via acquisition and recycling of nutrients. Here we employed 16 S rRNA gene sequencing to study bacterial communities of three deep-sea scleractinian corals from the Red Sea, Dendrophyllia sp., Eguchipsammia fistula, and Rhizotrochus typus. We found diverse, species-specific microbiomes, distinct from the surrounding seawater. Microbiomes were comprised of few abundant bacteria, which constituted the majority of sequences (up to 58% depending on the coral species). In addition, we found a high diversity of rare bacteria (taxa at <1% abundance comprised >90% of all bacteria). Interestingly, we identified anaerobic bacteria, potentially providing metabolic functions at low oxygen conditions, as well as bacteria harboring the potential to degrade crude oil components. Considering the presence of oil and gas fields in the Red Sea, these bacteria may unlock this carbon source for the coral host. In conclusion, the prevailing environmental conditions of the deep Red Sea (>20 °C, <2 mg oxygen L−1) may require distinct functional adaptations, and our data suggest that bacterial communities may contribute to coral functioning in this challenging environment. PMID:28303925

Microbial community composition of deep-sea corals from the Red Sea provides insight into functional adaption to a unique environment.

PubMed

Röthig, Till; Yum, Lauren K; Kremb, Stephan G; Roik, Anna; Voolstra, Christian R

2017-03-17

Microbes associated with deep-sea corals remain poorly studied. The lack of symbiotic algae suggests that associated microbes may play a fundamental role in maintaining a viable coral host via acquisition and recycling of nutrients. Here we employed 16 S rRNA gene sequencing to study bacterial communities of three deep-sea scleractinian corals from the Red Sea, Dendrophyllia sp., Eguchipsammia fistula, and Rhizotrochus typus. We found diverse, species-specific microbiomes, distinct from the surrounding seawater. Microbiomes were comprised of few abundant bacteria, which constituted the majority of sequences (up to 58% depending on the coral species). In addition, we found a high diversity of rare bacteria (taxa at <1% abundance comprised >90% of all bacteria). Interestingly, we identified anaerobic bacteria, potentially providing metabolic functions at low oxygen conditions, as well as bacteria harboring the potential to degrade crude oil components. Considering the presence of oil and gas fields in the Red Sea, these bacteria may unlock this carbon source for the coral host. In conclusion, the prevailing environmental conditions of the deep Red Sea (>20 °C, <2 mg oxygen L -1 ) may require distinct functional adaptations, and our data suggest that bacterial communities may contribute to coral functioning in this challenging environment.

Interactively Open Autonomy Unifies Two Approaches to Function

NASA Astrophysics Data System (ADS)

Collier, John

2004-08-01

Functionality is essential to any form of anticipation beyond simple directedness at an end. In the literature on function in biology, there are two distinct approaches. One, the etiological view, places the origin of function in selection, while the other, the organizational view, individuates function by organizational role. Both approaches have well-known advantages and disadvantages. I propose a reconciliation of the two approaches, based in an interactivist approach to the individuation and stability of organisms. The approach was suggested by Kant in the Critique of Judgment, but since it requires, on his account, the identification a new form of causation, it has not been accessible by analytical techniques. I proceed by construction of the required concept to fit certain design requirements. This construction builds on concepts introduced in my previous four talks to these meetings.

Keeping the body in mind: insula functional organization and functional connectivity integrate interoceptive, exteroceptive, and emotional awareness.

PubMed

Simmons, W Kyle; Avery, Jason A; Barcalow, Joel C; Bodurka, Jerzy; Drevets, Wayne C; Bellgowan, Patrick

2013-11-01

Relatively discrete experimental literatures have grown to support the insula's role in the domains of interoception, focal exteroceptive attention and cognitive control, and the experience of anxiety, even as theoretical accounts have asserted that the insula is a critical zone for integrating across these domains. Here we provide the first experimental demonstration that there exists a functional topography across the insula, with distinct regions in the same participants responding in a highly selective fashion for interoceptive, exteroceptive, and affective processing. Although each insular region is associated with areas of differential resting state functional connectivity relative to the other regions, overall their functional connectivity profiles are quite similar, thereby providing a map of how interoceptive, exteroceptive, and emotional awareness are integrated within the insular cortex. Copyright © 2012 Wiley Periodicals, Inc.

Specific serine-proline phosphorylation and glycogen synthase kinase 3β-directed subcellular targeting of stathmin 3/Sclip in neurons.

PubMed

Devaux, Sara; Poulain, Fabienne E; Devignot, Véronique; Lachkar, Sylvie; Irinopoulou, Theano; Sobel, André

2012-06-22

During nervous system development, neuronal growth, migration, and functional morphogenesis rely on the appropriate control of the subcellular cytoskeleton including microtubule dynamics. Stathmin family proteins play major roles during the various stages of neuronal differentiation, including axonal growth and branching, or dendritic development. We have shown previously that stathmins 2 (SCG10) and 3 (SCLIP) fulfill distinct, independent and complementary regulatory roles in axonal morphogenesis. Although the two proteins have been proposed to display the four conserved phosphorylation sites originally identified in stathmin 1, we show here that they possess distinct phosphorylation sites within their specific proline-rich domains (PRDs) that are differentially regulated by phosphorylation by proline-directed kinases involved in the control of neuronal differentiation. ERK2 or CDK5 phosphorylate the two proteins but with different site specificities. We also show for the first time that, unlike stathmin 2, stathmin 3 is a substrate for glycogen synthase kinase (GSK) 3β both in vitro and in vivo. Interestingly, stathmin 3 phosphorylated at its GSK-3β target site displays a specific subcellular localization at neuritic tips and within the actin-rich peripheral zone of the growth cone of differentiating hippocampal neurons in culture. Finally, pharmacological inhibition of GSK-3β induces a redistribution of stathmin 3, but not stathmin 2, from the periphery toward the Golgi region of neurons. Stathmin proteins can thus be either regulated locally or locally targeted by specific phosphorylation, each phosphoprotein of the stathmin family fulfilling distinct and specific roles in the control of neuronal differentiation.

The Semantic Network at Work and Rest: Differential Connectivity of Anterior Temporal Lobe Subregions.

PubMed

Jackson, Rebecca L; Hoffman, Paul; Pobric, Gorana; Lambon Ralph, Matthew A

2016-02-03

The anterior temporal lobe (ATL) makes a critical contribution to semantic cognition. However, the functional connectivity of the ATL and the functional network underlying semantic cognition has not been elucidated. In addition, subregions of the ATL have distinct functional properties and thus the potential differential connectivity between these subregions requires investigation. We explored these aims using both resting-state and active semantic task data in humans in combination with a dual-echo gradient echo planar imaging (EPI) paradigm designed to ensure signal throughout the ATL. In the resting-state analysis, the ventral ATL (vATL) and anterior middle temporal gyrus (MTG) were shown to connect to areas responsible for multimodal semantic cognition, including bilateral ATL, inferior frontal gyrus, medial prefrontal cortex, angular gyrus, posterior MTG, and medial temporal lobes. In contrast, the anterior superior temporal gyrus (STG)/superior temporal sulcus was connected to a distinct set of auditory and language-related areas, including bilateral STG, precentral and postcentral gyri, supplementary motor area, supramarginal gyrus, posterior temporal cortex, and inferior and middle frontal gyri. Complementary analyses of functional connectivity during an active semantic task were performed using a psychophysiological interaction (PPI) analysis. The PPI analysis highlighted the same semantic regions suggesting a core semantic network active during rest and task states. This supports the necessity for semantic cognition in internal processes occurring during rest. The PPI analysis showed additional connectivity of the vATL to regions of occipital and frontal cortex. These areas strongly overlap with regions found to be sensitive to executively demanding, controlled semantic processing. Previous studies have shown that semantic cognition depends on subregions of the anterior temporal lobe (ATL). However, the network of regions functionally connected to these subregions has not been demarcated. Here, we show that these ventrolateral anterior temporal subregions form part of a network responsible for semantic processing during both rest and an explicit semantic task. This demonstrates the existence of a core functional network responsible for multimodal semantic cognition regardless of state. Distinct connectivity is identified in the superior ATL, which is connected to auditory and language areas. Understanding the functional connectivity of semantic cognition allows greater understanding of how this complex process may be performed and the role of distinct subregions of the anterior temporal cortex. Copyright © 2016 Jackson et al.

The Semantic Network at Work and Rest: Differential Connectivity of Anterior Temporal Lobe Subregions

PubMed Central

Jackson, Rebecca L.; Hoffman, Paul; Pobric, Gorana

2016-01-01

The anterior temporal lobe (ATL) makes a critical contribution to semantic cognition. However, the functional connectivity of the ATL and the functional network underlying semantic cognition has not been elucidated. In addition, subregions of the ATL have distinct functional properties and thus the potential differential connectivity between these subregions requires investigation. We explored these aims using both resting-state and active semantic task data in humans in combination with a dual-echo gradient echo planar imaging (EPI) paradigm designed to ensure signal throughout the ATL. In the resting-state analysis, the ventral ATL (vATL) and anterior middle temporal gyrus (MTG) were shown to connect to areas responsible for multimodal semantic cognition, including bilateral ATL, inferior frontal gyrus, medial prefrontal cortex, angular gyrus, posterior MTG, and medial temporal lobes. In contrast, the anterior superior temporal gyrus (STG)/superior temporal sulcus was connected to a distinct set of auditory and language-related areas, including bilateral STG, precentral and postcentral gyri, supplementary motor area, supramarginal gyrus, posterior temporal cortex, and inferior and middle frontal gyri. Complementary analyses of functional connectivity during an active semantic task were performed using a psychophysiological interaction (PPI) analysis. The PPI analysis highlighted the same semantic regions suggesting a core semantic network active during rest and task states. This supports the necessity for semantic cognition in internal processes occurring during rest. The PPI analysis showed additional connectivity of the vATL to regions of occipital and frontal cortex. These areas strongly overlap with regions found to be sensitive to executively demanding, controlled semantic processing. SIGNIFICANCE STATEMENT Previous studies have shown that semantic cognition depends on subregions of the anterior temporal lobe (ATL). However, the network of regions functionally connected to these subregions has not been demarcated. Here, we show that these ventrolateral anterior temporal subregions form part of a network responsible for semantic processing during both rest and an explicit semantic task. This demonstrates the existence of a core functional network responsible for multimodal semantic cognition regardless of state. Distinct connectivity is identified in the superior ATL, which is connected to auditory and language areas. Understanding the functional connectivity of semantic cognition allows greater understanding of how this complex process may be performed and the role of distinct subregions of the anterior temporal cortex. PMID:26843633

HDAC4 as a potential therapeutic target in neurodegenerative diseases: a summary of recent achievements

PubMed Central

Mielcarek, Michal; Zielonka, Daniel; Carnemolla, Alisia; Marcinkowski, Jerzy T.; Guidez, Fabien

2015-01-01

For the past decade protein acetylation has been shown to be a crucial post-transcriptional modification involved in the regulation of protein functions. Histone acetyltransferases (HATs) mediate acetylation of histones which results in the nucleosomal relaxation associated with gene expression. The reverse reaction, histone deacetylation, is mediated by histone deacetylases (HDACs) leading to chromatin condensation followed by transcriptional repression. HDACs are divided into distinct classes: I, IIa, IIb, III, and IV, on the basis of size and sequence homology, as well as formation of distinct repressor complexes. Implications of HDACs in many diseases, such as cancer, heart failure, and neurodegeneration, have identified these molecules as unique and attractive therapeutic targets. The emergence of HDAC4 among the members of class IIa family as a major player in synaptic plasticity raises important questions about its functions in the brain. The characterization of HDAC4 specific substrates and molecular partners in the brain will not only provide a better understanding of HDAC4 biological functions but also might help to develop new therapeutic strategies to target numerous malignancies. In this review we highlight and summarize recent achievements in understanding the biological role of HDAC4 in neurodegenerative processes. PMID:25759639

A novel multi-network approach reveals tissue-specific cellular modulators of fibrosis in systemic sclerosis.

PubMed

Taroni, Jaclyn N; Greene, Casey S; Martyanov, Viktor; Wood, Tammara A; Christmann, Romy B; Farber, Harrison W; Lafyatis, Robert A; Denton, Christopher P; Hinchcliff, Monique E; Pioli, Patricia A; Mahoney, J Matthew; Whitfield, Michael L

2017-03-23

Systemic sclerosis (SSc) is a multi-organ autoimmune disease characterized by skin fibrosis. Internal organ involvement is heterogeneous. It is unknown whether disease mechanisms are common across all involved affected tissues or if each manifestation has a distinct underlying pathology. We used consensus clustering to compare gene expression profiles of biopsies from four SSc-affected tissues (skin, lung, esophagus, and peripheral blood) from patients with SSc, and the related conditions pulmonary fibrosis (PF) and pulmonary arterial hypertension, and derived a consensus disease-associate signature across all tissues. We used this signature to query tissue-specific functional genomic networks. We performed novel network analyses to contrast the skin and lung microenvironments and to assess the functional role of the inflammatory and fibrotic genes in each organ. Lastly, we tested the expression of macrophage activation state-associated gene sets for enrichment in skin and lung using a Wilcoxon rank sum test. We identified a common pathogenic gene expression signature-an immune-fibrotic axis-indicative of pro-fibrotic macrophages (MØs) in multiple tissues (skin, lung, esophagus, and peripheral blood mononuclear cells) affected by SSc. While the co-expression of these genes is common to all tissues, the functional consequences of this upregulation differ by organ. We used this disease-associated signature to query tissue-specific functional genomic networks to identify common and tissue-specific pathologies of SSc and related conditions. In contrast to skin, in the lung-specific functional network we identify a distinct lung-resident MØ signature associated with lipid stimulation and alternative activation. In keeping with our network results, we find distinct MØ alternative activation transcriptional programs in SSc-associated PF lung and in the skin of patients with an "inflammatory" SSc gene expression signature. Our results suggest that the innate immune system is central to SSc disease processes but that subtle distinctions exist between tissues. Our approach provides a framework for examining molecular signatures of disease in fibrosis and autoimmune diseases and for leveraging publicly available data to understand common and tissue-specific disease processes in complex human diseases.

Holocarboxylase Synthetase: A Moonlighting Transcriptional Coregulator of Gene Expression and a Cytosolic Regulator of Biotin Utilization.

PubMed

León-Del-Río, Alfonso; Valadez-Graham, Viviana; Gravel, Roy A

2017-08-21

The vitamin biotin is an essential nutrient for the metabolism and survival of all organisms owing to its function as a cofactor of enzymes collectively known as biotin-dependent carboxylases. These enzymes use covalently attached biotin as a vector to transfer a carboxyl group between donor and acceptor molecules during carboxylation reactions. In human cells, biotin-dependent carboxylases catalyze key reactions in gluconeogenesis, fatty acid synthesis, and amino acid catabolism. Biotin is attached to apocarboxylases by a biotin ligase: holocarboxylase synthetase (HCS) in mammalian cells and BirA in microbes. Despite their evolutionary distance, these proteins share structural and sequence similarities, underscoring their importance across all life forms. However, beyond its role in metabolism, HCS participates in the regulation of biotin utilization and acts as a nuclear transcriptional coregulator of gene expression. In this review, we discuss the function of HCS and biotin in metabolism and human disease, a putative role for the enzyme in histone biotinylation, and its participation as a nuclear factor in chromatin dynamics. We suggest that HCS be classified as a moonlighting protein, with two biotin-dependent cytosolic metabolic roles and a distinct biotin-independent nuclear coregulatory function.

LncRNA and mRNA expression profiles of glioblastoma multiforme (GBM) reveal the potential roles of lncRNAs in GBM pathogenesis.

PubMed

Li, Qi; Jia, Hongmei; Li, Haowen; Dong, Chengya; Wang, Yajie; Zou, Zhongmei

2016-11-01

Glioblastoma multiforme (GBM) is the most common brain malignancy. Long non-coding RNAs (lncRNAs) are aberrantly expressed in many cancers and are involved in their cell proliferation, apoptosis, angiogenesis, and invasion. The functional roles of lncRNAs in GBM are less known. We analyzed a cohort of exon microarray datasets from The Cancer Genome Atlas. The differently expressed lncRNAs and mRNA were subjected to construct lncRNA-mRNA co-expression network. Probable functions for lncRNAs were predicted according to lncRNA-mRNA network and genomic adjacency by GO and pathway analysis. The expression of lncRNAs and mRNAs in GBM tissues versus normal brain tissues was examined by quantitative reverse transcription polymerase chain reaction. The 398 lncRNAs and 1995 mRNAs were identified as distinctively expressed in GBM. Probable functional roles for 98 lncRNAs were involved in 30 pathways and 32 gene functions related to tumorigenesis, development, and metastasis. The identified sets of key lncRNAs specific to GBM were subsequently verified by experiment in GBM tissues. Our reports predict the biological functions of a multitude of lncRNAs in GBM that could be potential diagnostic and prognostic biomarkers as well as therapeutic targets. Moreover, our research provides a road map for the identification and analysis of lncRNAs in tumors.

Trends in Taxonomic and Functional Composition of Soil Microbiome Along a Precipitation Gradient in Israel.

PubMed

Tripathi, Binu M; Moroenyane, Itumeleng; Sherman, Chen; Lee, Yoo Kyung; Adams, Jonathan M; Steinberger, Yosef

2017-07-01

The soil microbiome is important for the functioning of terrestrial ecosystems. However, the impacts of climate on taxonomic and functional diversity of soil microbiome are not well understood. A precipitation gradient along regional scale transects may offer a model setting for understanding the effect of climate on the composition and function of the soil microbiome. Here, we compared taxonomic and functional attributes of soil microorganisms in arid, semiarid, Mediterranean, and humid Mediterranean climatic conditions of Israel using shotgun metagenomic sequencing. We hypothesized that there would be a distinct taxonomic and functional soil community for each precipitation zone, with arid environments having lower taxonomic and functional diversity, greater relative abundance of stress response and sporulation-related genes, and lower relative abundance of genes related to nutrient cycling and degradation of complex organic compounds. As hypothesized, our results showed a distinct taxonomic and functional community in each precipitation zone, revealing differences in soil taxonomic and functional selection in the different climates. Although the taxonomic diversity remained similar across all sites, the functional diversity was-as hypothesized-lower in the arid environments, suggesting that functionality is more constrained in "extreme" environments. Also, with increasing aridity, we found a significant increase in genes related to dormancy/sporulation and a decrease in those related to nutrient cycling (genes related to nitrogen, potassium, and sulfur metabolism), respectively. However, relative abundance of genes related to stress response were lower in arid soils. Overall, these results indicate that climatic conditions play an important role in shaping taxonomic and functional attributes of soil microbiome. These findings have important implications for understanding the impacts of climate change (e.g., precipitation change) on structure and function of the soil microbiome.

Cultural diversity and anti-poverty policy.

PubMed

Lamont, Michèle; Small, Mario Luis

2010-01-01

This article examines how anti-poverty policy has considered the role of culture and how it ought to do so. While some have explained poverty as a function of the presumed cultural deficiency or distinctiveness of the poor, we suggest that these explanations have not been convincing and that policy requires a broader and more sophisticated understanding of the relationship between culture and behaviour. In fact, we suggest that cultural differences may be positively employed in comprehensive anti-poverty strategies.

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

Exploring the structural basis of the selective inhibition of monoamine oxidase A by dicarbonitrile aminoheterocycles: role of Asn181 and Ile335 validated by spectroscopic and computational studies.

PubMed

Juárez-Jiménez, Jordi; Mendes, Eduarda; Galdeano, Carles; Martins, Carla; Silva, Daniel B; Marco-Contelles, José; do Carmo Carreiras, Maria; Luque, F Javier; Ramsay, Rona R

2014-02-01

Since cyanide potentiates the inhibitory activity of several monoamine oxidase (MAO) inhibitors, a series of carbonitrile-containing aminoheterocycles was examined to explore the role of nitriles in determining the inhibitory activity against MAO. Dicarbonitrile aminofurans were found to be potent, selective inhibitors against MAO A. The origin of the MAO A selectivity was identified by combining spectroscopic and computational methods. Spectroscopic changes induced in MAO A by mono- and dicarbonitrile inhibitors were different, providing experimental evidence for distinct binding modes to the enzyme. Similar differences were also found between the binding of dicarbonitrile compounds to MAO A and to MAO B. Stabilization of the flavin anionic semiquinone by monocarbonitrile compounds, but destabilization by dicarbonitriles, provided further support to the distinct binding modes of these compounds and their interaction with the flavin ring. Molecular modeling studies supported the role played by the nitrile and amino groups in anchoring the inhibitor to the binding cavity. In particular, the results highlight the role of Asn181 and Ile335 in assisting the interaction of the nitrile-containing aminofuran ring. The network of interactions afforded by the specific attachment of these functional groups provides useful guidelines for the design of selective, reversible MAO A inhibitors. Copyright © 2013 Elsevier B.V. All rights reserved.

Distinct neuronal interactions in anterior inferotemporal areas of macaque monkeys during retrieval of object association memory.

PubMed

Hirabayashi, Toshiyuki; Tamura, Keita; Takeuchi, Daigo; Takeda, Masaki; Koyano, Kenji W; Miyashita, Yasushi

2014-07-09

In macaque monkeys, the anterior inferotemporal cortex, a region crucial for object memory processing, is composed of two adjacent, hierarchically distinct areas, TE and 36, for which different functional roles and neuronal responses in object memory tasks have been characterized. However, it remains unknown how the neuronal interactions differ between these areas during memory retrieval. Here, we conducted simultaneous recordings from multiple single-units in each of these areas while monkeys performed an object association memory task and examined the inter-area differences in neuronal interactions during the delay period. Although memory neurons showing sustained activity for the presented cue stimulus, cue-holding (CH) neurons, interacted with each other in both areas, only those neurons in area 36 interacted with another type of memory neurons coding for the to-be-recalled paired associate (pair-recall neurons) during memory retrieval. Furthermore, pairs of CH neurons in area TE showed functional coupling in response to each individual object during memory retention, whereas the same class of neuron pairs in area 36 exhibited a comparable strength of coupling in response to both associated objects. These results suggest predominant neuronal interactions in area 36 during the mnemonic processing, which may underlie the pivotal role of this brain area in both storage and retrieval of object association memory. Copyright © 2014 the authors 0270-6474/14/349377-12$15.00/0.

Distinct Roles of Chromatin Insulator Proteins in Control of the Drosophila Bithorax Complex

PubMed Central

Savitsky, Mikhail; Kim, Maria; Kravchuk, Oksana; Schwartz, Yuri B.

2016-01-01

Chromatin insulators are remarkable regulatory elements that can bring distant genomic sites together and block unscheduled enhancer–promoter communications. Insulators act via associated insulator proteins of two classes: sequence-specific DNA binding factors and “bridging” proteins. The latter are required to mediate interactions between distant insulator elements. Chromatin insulators are critical for correct expression of complex loci; however, their mode of action is poorly understood. Here, we use the Drosophila bithorax complex as a model to investigate the roles of the bridging proteins Cp190 and Mod(mdg4). The bithorax complex consists of three evolutionarily conserved homeotic genes Ubx, abd-A, and Abd-B, which specify anterior–posterior identity of the last thoracic and all abdominal segments of the fly. Looking at effects of CTCF, mod(mdg4), and Cp190 mutations on expression of the bithorax complex genes, we provide the first functional evidence that Mod(mdg4) acts in concert with the DNA binding insulator protein CTCF. We find that Mod(mdg4) and Cp190 are not redundant and may have distinct functional properties. We, for the first time, demonstrate that Cp190 is critical for correct regulation of the bithorax complex and show that Cp190 is required at an exceptionally strong Fub insulator to partition the bithorax complex into two topological domains. PMID:26715665

Understanding tumor-stroma interplays for targeted therapies by armed mesenchymal stromal progenitors: the Mesenkillers

PubMed Central

Grisendi, Giulia; Bussolari, Rita; Veronesi, Elena; Piccinno, Serena; Burns, Jorge S; De Santis, Giorgio; Loschi, Pietro; Pignatti, Marco; Di Benedetto, Fabrizio; Ballarin, Roberto; Di Gregorio, Carmela; Guarneri, Valentina; Piccinini, Lino; Horwitz, Edwin M; Paolucci, Paolo; Conte, PierFranco; Dominici, Massimo

2011-01-01

A tumor represents a complex structure containing malignant cells strictly coupled with a large variety of surrounding cells constituting the tumor stroma (TS). In recent years, the importance of TS for cancer initiation, development, local invasion and metastases has become increasingly clear allowing the identification of TS as one of the possible ways to indirectly target tumors. Inside the heterogeneous stromal cell population, tumor associated fibroblasts (TAF) play a crucial role providing both functional and supportive environments. During both tumor and stroma development, several findings suggest that TAF could be recruited from different sources such as locally derived host fibroblasts, via epithelial/endothelial mesenchymal transitions or from circulating pools of fibroblasts deriving form mesenchymal progenitors, namely mesenchymal stem/stromal cells (MSC). These insights prompted scientists to identify multimodal approaches to target TS by biomolecules, monoclonal antibodies, and more recently via cell based strategies. These latter strategies appear extremely promising, although still associated with debated and unclear findings. This review discusses crosstalk between cancers and their stroma, dissecting specific tumor types, such as sarcoma, pancreatic and breast carcinoma, where stroma plays distinct paradigmatic roles. The recognition of these distinct stromal functions may help in planning effective and safer approaches aimed either to eradicate or to substitute TS by novel compounds and/or MSC having specific killing activities. PMID:22016827

Fibrinogen-Related Proteins in Tissue Repair: How a Unique Domain with a Common Structure Controls Diverse Aspects of Wound Healing.

PubMed

Zuliani-Alvarez, Lorena; Midwood, Kim S

2015-05-01

Significance: Fibrinogen-related proteins (FRePs) comprise an intriguing collection of extracellular molecules, each containing a conserved fibrinogen-like globe (FBG). This group includes the eponymous fibrinogen as well as the tenascin, angiopoietin, and ficolin families. Many of these proteins are upregulated during tissue repair and exhibit diverse roles during wound healing. Recent Advances: An increasing body of evidence highlights the specific expression of a number of FRePs following tissue injury and infection. Upon induction, each FReP uses its FBG domain to mediate quite distinct effects that contribute to different stages of tissue repair, such as driving coagulation, pathogen detection, inflammation, angiogenesis, and tissue remodeling. Critical Issues: Despite a high degree of homology among FRePs, each contains unique sequences that enable their diversification of function. Comparative analysis of the structure and function of FRePs and precise mapping of regions that interact with a variety of ligands has started to reveal the underlying molecular mechanisms by which these proteins play very different roles using their common domain. Future Directions: Fibrinogen has long been used in the clinic as a synthetic matrix serving as a scaffold or a delivery system to aid tissue repair. Novel therapeutic strategies are now emerging that harness the use of other FRePs to improve wound healing outcomes. As we learn more about the underlying mechanisms by which each FReP contributes to the repair response, specific blockade, or indeed potentiation, of their function offers real potential to enable regulation of distinct processes during pathological wound healing.

The structure and function of the pericellular matrix of articular cartilage.

PubMed

Wilusz, Rebecca E; Sanchez-Adams, Johannah; Guilak, Farshid

2014-10-01

Chondrocytes in articular cartilage are surrounded by a narrow pericellular matrix (PCM) that is both biochemically and biomechanically distinct from the extracellular matrix (ECM) of the tissue. While the PCM was first observed nearly a century ago, its role is still under investigation. In support of early hypotheses regarding its function, increasing evidence indicates that the PCM serves as a transducer of biochemical and biomechanical signals to the chondrocyte. Work over the past two decades has established that the PCM in adult tissue is defined biochemically by several molecular components, including type VI collagen and perlecan. On the other hand, the biomechanical properties of this structure have only recently been measured. Techniques such as micropipette aspiration, in situ imaging, computational modeling, and atomic force microscopy have determined that the PCM exhibits distinct mechanical properties as compared to the ECM, and that these properties are influenced by specific PCM components as well as disease state. Importantly, the unique relationships among the mechanical properties of the chondrocyte, PCM, and ECM in different zones of cartilage suggest that this region significantly influences the stress-strain environment of the chondrocyte. In this review, we discuss recent advances in the measurement of PCM mechanical properties and structure that further increase our understanding of PCM function. Taken together, these studies suggest that the PCM plays a critical role in controlling the mechanical environment and mechanobiology of cells in cartilage and other cartilaginous tissues, such as the meniscus or intervertebral disc. Copyright © 2014 International Society of Matrix Biology. Published by Elsevier B.V. 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

Mitochondrial and Chloroplast Stress Responses Are Modulated in Distinct Touch and Chemical Inhibition Phases1[OPEN

PubMed Central

Ivanova, Aneta; Millar, A. Harvey; Whelan, James

2016-01-01

Previous studies have identified a range of transcription factors that modulate retrograde regulation of mitochondrial and chloroplast functions in Arabidopsis (Arabidopsis thaliana). However, the relative importance of these regulators and whether they act downstream of separate or overlapping signaling cascades is still unclear. Here, we demonstrate that multiple stress-related signaling pathways, with distinct kinetic signatures, converge on overlapping gene sets involved in energy organelle function. The transcription factor ANAC017 is almost solely responsible for transcript induction of marker genes around 3 to 6 h after chemical inhibition of organelle function and is a key regulator of mitochondrial and specific types of chloroplast retrograde signaling. However, an independent and highly transient gene expression phase, initiated within 10 to 30 min after treatment, also targets energy organelle functions, and is related to touch and wounding responses. Metabolite analysis demonstrates that this early response is concurrent with rapid changes in tricarboxylic acid cycle intermediates and large changes in transcript abundance of genes encoding mitochondrial dicarboxylate carrier proteins. It was further demonstrated that transcription factors AtWRKY15 and AtWRKY40 have repressive regulatory roles in this touch-responsive gene expression. Together, our results show that several regulatory systems can independently affect energy organelle function in response to stress, providing different means to exert operational control. PMID:27208304

Convergence of gut microbiotas in the adaptive radiations of African cichlid fishes.

PubMed

Baldo, Laura; Pretus, Joan Lluís; Riera, Joan Lluís; Musilova, Zuzana; Bitja Nyom, Arnold Roger; Salzburger, Walter

2017-09-01

Ecoevolutionary dynamics of the gut microbiota at the macroscale level, that is, in across-species comparisons, are largely driven by ecological variables and host genotype. The repeated explosive radiations of African cichlid fishes in distinct lakes, following a dietary diversification in a context of reduced genetic diversity, provide a natural setup to explore convergence, divergence and repeatability in patterns of microbiota dynamics as a function of the host diet, phylogeny and environment. Here we characterized by 16S rRNA amplicon sequencing the gut microbiota of 29 cichlid species from two distinct lakes/radiations (Tanganyika and Barombi Mbo) and across a broad dietary and phylogenetic range. Within each lake, a significant deviation between a carnivorous and herbivorous lifestyle was found. Herbivore species were characterized by an increased bacterial taxonomic and functional diversity and converged in key compositional and functional community aspects. Despite a significant lake effect on the microbiota structure, this process has occurred with remarkable parallels in the two lakes. A metabolic signature most likely explains this trend, as indicated by a significant enrichment in herbivores/omnivores of bacterial taxa and functions associated with fiber degradation and detoxification of plant chemical compounds. Overall, compositional and functional aspects of the gut microbiota individually and altogether validate and predict main cichlid dietary habits, suggesting a fundamental role of gut bacteria in cichlid niche expansion and adaptation.

Convergence of gut microbiotas in the adaptive radiations of African cichlid fishes

PubMed Central

Baldo, Laura; Pretus, Joan Lluís; Riera, Joan Lluís; Musilova, Zuzana; Bitja Nyom, Arnold Roger; Salzburger, Walter

2017-01-01

Ecoevolutionary dynamics of the gut microbiota at the macroscale level, that is, in across-species comparisons, are largely driven by ecological variables and host genotype. The repeated explosive radiations of African cichlid fishes in distinct lakes, following a dietary diversification in a context of reduced genetic diversity, provide a natural setup to explore convergence, divergence and repeatability in patterns of microbiota dynamics as a function of the host diet, phylogeny and environment. Here we characterized by 16S rRNA amplicon sequencing the gut microbiota of 29 cichlid species from two distinct lakes/radiations (Tanganyika and Barombi Mbo) and across a broad dietary and phylogenetic range. Within each lake, a significant deviation between a carnivorous and herbivorous lifestyle was found. Herbivore species were characterized by an increased bacterial taxonomic and functional diversity and converged in key compositional and functional community aspects. Despite a significant lake effect on the microbiota structure, this process has occurred with remarkable parallels in the two lakes. A metabolic signature most likely explains this trend, as indicated by a significant enrichment in herbivores/omnivores of bacterial taxa and functions associated with fiber degradation and detoxification of plant chemical compounds. Overall, compositional and functional aspects of the gut microbiota individually and altogether validate and predict main cichlid dietary habits, suggesting a fundamental role of gut bacteria in cichlid niche expansion and adaptation. PMID:28509910

Plant Cation-Chloride Cotransporters (CCC): Evolutionary Origins and Functional Insights.

PubMed

Henderson, Sam W; Wege, Stefanie; Gilliham, Matthew

2018-02-06

Genomes of unicellular and multicellular green algae, mosses, grasses and dicots harbor genes encoding cation-chloride cotransporters (CCC). CCC proteins from the plant kingdom have been comparatively less well investigated than their animal counterparts, but proteins from both plants and animals have been shown to mediate ion fluxes, and are involved in regulation of osmotic processes. In this review, we show that CCC proteins from plants form two distinct phylogenetic clades (CCC1 and CCC2). Some lycophytes and bryophytes possess members from each clade, most land plants only have members of the CCC1 clade, and green algae possess only the CCC2 clade. It is currently unknown whether CCC1 and CCC2 proteins have similar or distinct functions, however they are both more closely related to animal KCC proteins compared to NKCCs. Existing heterologous expression systems that have been used to functionally characterize plant CCC proteins, namely yeast and Xenopus laevis oocytes, have limitations that are discussed. Studies from plants exposed to chemical inhibitors of animal CCC protein function are reviewed for their potential to discern CCC function in planta. Thus far, mutations in plant CCC genes have been evaluated only in two species of angiosperms, and such mutations cause a diverse array of phenotypes-seemingly more than could simply be explained by localized disruption of ion transport alone. We evaluate the putative roles of plant CCC proteins and suggest areas for future investigation.

Distinct spatial frequency sensitivities for processing faces and emotional expressions.

PubMed

Vuilleumier, Patrik; Armony, Jorge L; Driver, Jon; Dolan, Raymond J

2003-06-01

High and low spatial frequency information in visual images is processed by distinct neural channels. Using event-related functional magnetic resonance imaging (fMRI) in humans, we show dissociable roles of such visual channels for processing faces and emotional fearful expressions. Neural responses in fusiform cortex, and effects of repeating the same face identity upon fusiform activity, were greater with intact or high-spatial-frequency face stimuli than with low-frequency faces, regardless of emotional expression. In contrast, amygdala responses to fearful expressions were greater for intact or low-frequency faces than for high-frequency faces. An activation of pulvinar and superior colliculus by fearful expressions occurred specifically with low-frequency faces, suggesting that these subcortical pathways may provide coarse fear-related inputs to the amygdala.

Development and maintenance of intestinal regulatory T cells.

PubMed

Tanoue, Takeshi; Atarashi, Koji; Honda, Kenya

2016-05-01

Gut-resident forkhead box P3 (FOXP3)(+)CD4(+) regulatory T cells (Treg cells) are distinct from those in other organs and have gut-specific phenotypes and functions. Whereas Treg cells in other organs have T cell receptors (TCRs) specific for self antigens, intestinal Treg cells have a distinct set of TCRs that are specific for intestinal antigens, and these cells have pivotal roles in the suppression of immune responses against harmless dietary antigens and commensal microorganisms. The differentiation, migration and maintenance of intestinal Treg cells are controlled by specific signals from the local environment. In particular, certain members of the microbiota continuously provide antigens and immunoregulatory small molecules that modulate intestinal Treg cells. Understanding the development and the maintenance of intestinal Treg cells provides important insights into disease-relevant host-microorganism interactions.

Origins of adult pigmentation: diversity in pigment stem cell lineages and implications for pattern evolution

PubMed Central

Spiewak, Jessica E.

2014-01-01

Summary Teleosts comprise about half of all vertebrate species and exhibit an extraordinary diversity of adult pigment patterns that function in shoaling, camouflage and mate choice and have played important roles in speciation. Here, we review recent studies that have identified several distinct neural crest lineages, with distinct genetic requirements, that give rise to adult pigment cells in fishes. These lineages include post-embryonic, peripheral nerve associated stem cells that generate black melanophores and iridescent iridophores, cells derived directly from embryonic neural crest cells that generate yellow-orange xanthophores, and bipotent stem cells that generate both melanophores and xanthophores. This complexity in adult chromatophore lineages has implications for our understanding of adult traits, melanoma, and the evolutionary diversification of pigment cell lineages and patterns. PMID:25421288

Profiling and Quantification of Phenolics in Stevia rebaudiana Leaves.

PubMed

Karaköse, Hande; Müller, Anja; Kuhnert, Nikolai

2015-10-21

Stevia rebaudiana (Bertoni) is a plant from the Asteraceae family with significant economic value because of the steviol glycoside sweeteners in its leaves. Chlorogenic acids and flavonoid glycosides of S. rebaudiana from seven different botanical varieties cultivated over two years and harvested three times a year in eight European locations were profiled and quantified in a total of 166 samples. Compounds quantified include chlorogenic acids as well as flavonoid glycosides and aglycons. All phenolic concentration profiles show a perfect Gaussian distribution. Principal component analyses allow distinction between varieties of different geographical origin and distinction between different plant varieties. Although concentrations of all chlorogenic acids showed a positive correlation, no correlation was observed for flavonoid glycosides. Conclusions from these findings with respect to the biosynthesis and functional role of phenolics in S. rebaudiana are discussed.

Rorschach assessment of cognitive impairment from an object relations perspective.

PubMed

Lerner, P M

1996-01-01

In 1986, H. Lerner and P. Lerner proposed an object relations model of thinking that integrated Piaget's theory of early cognitive development with Mahler's theory of separation-individuation. They identified three distinct, interdigitated stages, outlined the cognitive task for each stage, detailed the necessary role and function of the stage-specific caregiving object, and suggested potential cognitive impairments associated with the object not fulfilling its function. Herein, this conceptual model is extended to the Rorschach. Rorschach indices of cognitive impairments associated with each stage were developed. The indices are then applied to the Rorschach records of children who were selected as prototypical of specific developmental disorders.

Extracellular matrix functionalized microcavities to control hematopoietic stem and progenitor cell fate.

PubMed

Kurth, Ina; Franke, Katja; Pompe, Tilo; Bornhäuser, Martin; Werner, Carsten

2011-06-14

Polymeric microcavities functionalized with extracellular matrix components were used as an experimental in vitro model to investigate principles of hematopoietic stem and progenitor cell (HSPC) fate control. Using human CD133+ HSPC we could demonstrate distinct differences in HSPC cycling and differentiation dependence on the adhesion ligand specificity (i.e., heparin, collagen I) and cytokine levels. The presented microcavity platform provides a powerful in vitro approach to explore the role of exogenous cues in HSPC fate decisions and can therefore be instrumental to progress in stem cell biology and translational research toward new therapies. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

From fish embryos to human patients: lymphangiogenesis in development and disease.

PubMed

Mauri, Cristina; Wang, Guangxia; Schulte-Merker, Stefan

2018-05-22

The lymphatic vasculature plays vital roles in immune surveillance, fluid homeostasis and fat absorption in the body. Lined by endothelial cells, the lymphatic system is functionally distinct from the blood vasculature, and fulfills different physiological functions. In recent years, insight from zebrafish, mice and human patients have improved our understanding of lymphatics, and the interplay between zebrafish genetics, studies in mice and GWAS analysis in human patients have identified genes that, when mutated, will lead to lymphedema formation. Here, we focus on components of the Vegfr3 pathway, and how they are connected to Milroy disease and Hennekam syndrome. Copyright © 2018 Elsevier Ltd. All rights reserved.

Shigeru Tsuiki: a pioneer in the research fields of complex carbohydrates and protein phosphatases.

PubMed

Miyagi, Taeko; Kikuchi, Kunimi; Tamura, Shinri

2011-11-01

Dr Tsuiki made three major contributions during his illustrious career as a biochemist. First, he developed the procedure for mucin isolation from bovine submaxillary glands. His work became the basis for mucin biochemistry. Second, he identified four distinct molecular species of mammalian sialidase. Subsequent studies based on his work led to the discovery that sialidase plays a unique role as an intracellular signalling factor involved in the regulation of a variety of cellular functions. Finally, he established the molecular basis for the diversity of mammalian protein phosphatases through protein purification and molecular cloning. His work prompted the functional studies of protein phosphatases.

Functional studies of TcRjl, a novel GTPase of Trypanosoma cruzi, reveals phenotypes related with MAPK activation during parasite differentiation and after heterologous expression in Drosophila model system

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

Reis Monteiro dos-Santos, Guilherme Rodrigo; Fontenele, Marcio Ribeiro; Dias, Felipe de Almeida

The life cycle of the protozoan parasite Trypanosoma cruzi comprises rounds of proliferative cycles and differentiation in distinct host environments. Ras GTPases are molecular switches that play pivotal regulatory functions in cell fate. Rjl is a novel GTPase with unknown function. Herein we show that TcRjl blocks in vivo cell differentiation. The forced expression of TcRjl leads to changes in the overall tyrosine protein phosphorylation profile of parasites. TcRjl expressing parasites sustained DNA synthesis regardless the external stimuli for differentiation. Heterologous expression in the Drosophila melanogaster genetic system strongly suggests a role from TcRjl protein in RTK-dependent pathways and MAPK activation.

Optical response tuning in nanorod-on-semicontinous film systems: A computational study

NASA Astrophysics Data System (ADS)

Mokkath, Junais Habeeb

2018-01-01

Strongly confined and intense optical fields within the plasmonic metal nanocavities show outstanding potential for a wide range of functionalities in nanophotonics. Using time dependent density functional theory calculations, we investigate the optical response evolution as a function of the gap separation distances in nanorod-on-film systems comprised of a nanorod (NR) made of Al or Na on top of an Al film. Huge optical field modulations emerged in the chemically distinct Na NR - Al film system in comparison to the Al NR - Al film system, indicating the vital role of metals involved. We further study the optical response modifications by placing a conducting molecule in the gap region, finding strong spectral modulations via through-molecule electron tunneling.

Distinctive Roles for Periplasmic Proteases in the Maintenance of Essential Outer Membrane Protein Assembly.

PubMed

Soltes, Garner R; Martin, Nicholas R; Park, Eunhae; Sutterlin, Holly A; Silhavy, Thomas J

2017-10-15

Outer membrane protein (OMP) biogenesis in Escherichia coli is a robust process essential to the life of the organism. It is catalyzed by the β-barrel assembly machine (Bam) complex, and a number of quality control factors, including periplasmic chaperones and proteases, maintain the integrity of this trafficking pathway. Little is known, however, about how periplasmic proteases recognize and degrade OMP substrates when assembly is compromised or whether different proteases recognize the same substrate at distinct points in the assembly pathway. In this work, we use well-defined assembly-defective mutants of LptD, the essential lipopolysaccharide assembly translocon, to show that the periplasmic protease DegP degrades substrates with assembly defects that prevent or impair initial contact with Bam, causing the mutant protein to accumulate in the periplasm. In contrast, another periplasmic protease, BepA, degrades a LptD mutant substrate that has engaged the Bam complex and formed a nearly complete barrel. Furthermore, we describe the role of the outer membrane lipoprotein YcaL, a protease of heretofore unknown function, in the degradation of a LptD substrate that has engaged the Bam complex but is stalled at an earlier step in the assembly process that is not accessible to BepA. Our results demonstrate that multiple periplasmic proteases monitor OMPs at distinct points in the assembly process. IMPORTANCE OMP assembly is catalyzed by the essential Bam complex and occurs in a cellular environment devoid of energy sources. Assembly intermediates that misfold can compromise this essential molecular machine. Here we demonstrate distinctive roles for three different periplasmic proteases that can clear OMP substrates with folding defects that compromise assembly at three different stages. These quality control factors help ensure the integrity of the permeability barrier that contributes to the intrinsic resistance of Gram-negative organisms to many antibiotics. Copyright © 2017 American Society for Microbiology.

REQUIREMENT OF ARGININOSUCCINATE LYASE FOR SYSTEMIC NITRIC OXIDE PRODUCTION

PubMed Central

Erez, Ayelet; Nagamani, Sandesh CS.; Shchelochkov, Oleg A.; Premkumar, Muralidhar H.; Campeau, Philippe M.; Chen, Yuqing; Garg, Harsha K.; Li, Li; Mian, Asad; Bertin, Terry K.; Black, Jennifer O.; Zeng, Heng; Tang, Yaoping; Reddy, Anilkumar K.; Summar, Marshall; O’Brien, William E.; Harrison, David G.; Mitch, William E.; Marini, Juan C.; Aschner, Judy L.; Bryan, Nathan S.; Lee, Brendan

2012-01-01

Nitric Oxide (NO) plays a critical role in diverse physiological and pathological processes. We show that a hypomorphic mouse model of argininosuccinate lyase (Asl) deficiency exhibits a distinct phenotype manifest by multi-organ dysfunction and NO deficiency. Loss of Asl leads to reduced NO synthesis due to decreased endogenous arginine synthesis as well as reduced utilization of extracellular arginine for NO production in both humans and mice. Hence, ASL as seen in other species through evolution has a structural function in addition to its catalytic activity. Importantly, therapy with nitrite rescued the tissue autonomous NO deficiency in hypomorphic Asl mice, while a NOS independent NO donor restored NO-dependent vascular reactivity in subjects with ASL deficiency. Our data demonstrate a previously unappreciated role for ASL in NOS function and NO homeostasis. Hence, ASL may serve as a target for manipulating NO production in experimental models, as well as treatment of NO-related diseases. PMID:22081021

ROS-mediated platelet generation: a microenvironment-dependent manner for megakaryocyte proliferation, differentiation, and maturation

PubMed Central

Chen, S; Su, Y; Wang, J

2013-01-01

Platelets have an important role in the body because of their manifold functions in haemostasis, thrombosis, and inflammation. Platelets are produced by megakaryocytes (MKs) that are differentiated from haematopoietic stem cells via several consecutive stages, including MK lineage commitment, MK progenitor proliferation, MK differentiation and maturation, cell apoptosis, and platelet release. During differentiation, the cells migrate from the osteoblastic niche to the vascular niche in the bone marrow, which is accompanied by reactive oxygen species (ROS)-dependent oxidation state changes in the microenvironment, suggesting that ROS can distinctly influence platelet generation and function in a microenvironment-dependent manner. The objective of this review is to reveal the role of ROS in regulating MK proliferation, differentiation, maturation, and platelet activation, thereby providing new insight into the mechanism of platelet generation, which may lead to the development of new therapeutic agents for thrombocytopenia and/or thrombosis. PMID:23846224

TLR10 is a B-cell Intrinsic Suppressor of Adaptive Immune Responses

PubMed Central

Hess, Nicholas J.; Jiang, Song; Li, Xinyan; Guan, Yue; Tapping, Richard I.

2016-01-01

Toll-like receptors (TLRs) play a central role in the initiation of adaptive immune responses with several TLR agonists acting as known B-cell mitogens. Despite thousands of publications on TLRs, the function of TLR10 remains unknown. We have found that antibody mediated engagement of TLR10 on primary human B-cells suppresses B-cell proliferation, cytokine production and signal transduction. When challenged with either a T-independent or T-dependent antigen, TLR10 transgenic mice exhibit diminished antibody responses. Adoptive transfer of splenic B-cells into B-cell deficient mice revealed that the suppressive effects on antigen-specific humoral immune responses are entirely B-cell intrinsic. Our results demonstrate that TLR10 has a functional role within the B-cell lineage that is distinct from that of other TLR family members and may provide a potential therapeutic target for diseases characterized by dysregulated B-cell activity. PMID:27956526

Dopamine in Drosophila: setting arousal thresholds in a miniature brain

PubMed Central

Van Swinderen, Bruno; Andretic, Rozi

2011-01-01

In mammals, the neurotransmitter dopamine (DA) modulates a variety of behaviours, although DA function is mostly associated with motor control and reward. In insects such as the fruitfly, Drosophila melanogaster, DA also modulates a wide array of behaviours, ranging from sleep and locomotion to courtship and learning. How can a single molecule play so many different roles? Adaptive changes within the DA system, anatomical specificity of action and effects on a variety of behaviours highlight the remarkable versatility of this neurotransmitter. Recent genetic and pharmacological manipulations of DA signalling in Drosophila have launched a surfeit of stories—each arguing for modulation of some aspect of the fly's waking (and sleeping) life. Although these stories often seem distinct and unrelated, there are some unifying themes underlying DA function and arousal states in this insect model. One of the central roles played by DA may involve perceptual suppression, a necessary component of both sleep and selective attention. PMID:21208962

Fungal endophytes: diversity and functional roles

USGS Publications Warehouse

Rodriguez, R.J.; White, J.F.; Arnold, A.E.; Redman, R.S.

2009-01-01

All plants in natural ecosystems appear to be symbiotic with fungal endophytes. This highly diverse group of fungi can have profound impacts on plant communities through increasing fitness by conferring abiotic and biotic stress tolerance, increasing biomass and decreasing water consumption, or decreasing fitness by altering resource allocation. Despite more than 100 yr of research resulting in thousands of journal articles, the ecological significance of these fungi remains poorly characterized. Historically, two endophytic groups (clavicipitaceous (C) and nonclavicipitaceous (NC)) have been discriminated based on phylogeny and life history traits. Here, we show that NC-endophytes represent three distinct functional groups based on host colonization and transmission, in planta biodiversity and fitness benefits conferred to hosts. Using this framework, we contrast the life histories, interactions with hosts and potential roles in plant ecophysiology of C- and NC-endophytes, and highlight several key questions for future work in endophyte biology.

Roles of microglia in brain development, tissue maintenance and repair

PubMed Central

Michell-Robinson, Mackenzie A.; Touil, Hanane; Healy, Luke M.; Owen, David R.; Durafourt, Bryce A.; Bar-Or, Amit; Antel, Jack P.

2015-01-01

The emerging roles of microglia are currently being investigated in the healthy and diseased brain with a growing interest in their diverse functions. In recent years, it has been demonstrated that microglia are not only immunocentric, but also neurobiological and can impact neural development and the maintenance of neuronal cell function in both healthy and pathological contexts. In the disease context, there is widespread consensus that microglia are dynamic cells with a potential to contribute to both central nervous system damage and repair. Indeed, a number of studies have found that microenvironmental conditions can selectively modify unique microglia phenotypes and functions. One novel mechanism that has garnered interest involves the regulation of microglial function by microRNAs, which has therapeutic implications such as enhancing microglia-mediated suppression of brain injury and promoting repair following inflammatory injury. Furthermore, recently published articles have identified molecular signatures of myeloid cells, suggesting that microglia are a distinct cell population compared to other cells of myeloid lineage that access the central nervous system under pathological conditions. Thus, new opportunities exist to help distinguish microglia in the brain and permit the study of their unique functions in health and disease. PMID:25823474

Distinct quantitative computed tomography emphysema patterns are associated with physiology and function in smokers.

PubMed

Castaldi, Peter J; San José Estépar, Raúl; Mendoza, Carlos S; Hersh, Craig P; Laird, Nan; Crapo, James D; Lynch, David A; Silverman, Edwin K; Washko, George R

2013-11-01

Emphysema occurs in distinct pathologic patterns, but little is known about the epidemiologic associations of these patterns. Standard quantitative measures of emphysema from computed tomography (CT) do not distinguish between distinct patterns of parenchymal destruction. To study the epidemiologic associations of distinct emphysema patterns with measures of lung-related physiology, function, and health care use in smokers. Using a local histogram-based assessment of lung density, we quantified distinct patterns of low attenuation in 9,313 smokers in the COPDGene Study. To determine if such patterns provide novel insights into chronic obstructive pulmonary disease epidemiology, we tested for their association with measures of physiology, function, and health care use. Compared with percentage of low-attenuation area less than -950 Hounsfield units (%LAA-950), local histogram-based measures of distinct CT low-attenuation patterns are more predictive of measures of lung function, dyspnea, quality of life, and health care use. These patterns are strongly associated with a wide array of measures of respiratory physiology and function, and most of these associations remain highly significant (P < 0.005) after adjusting for %LAA-950. In smokers without evidence of chronic obstructive pulmonary disease, the mild centrilobular disease pattern is associated with lower FEV1 and worse functional status (P < 0.005). Measures of distinct CT emphysema patterns provide novel information about the relationship between emphysema and key measures of physiology, physical function, and health care use. Measures of mild emphysema in smokers with preserved lung function can be extracted from CT scans and are significantly associated with functional measures.

The cerebellum and cognition: evidence from functional imaging studies.

PubMed

Stoodley, Catherine J

2012-06-01

Evidence for a role of the human cerebellum in cognitive functions comes from anatomical, clinical and neuroimaging data. Functional neuroimaging reveals cerebellar activation during a variety of cognitive tasks, including language, visual-spatial, executive, and working memory processes. It is important to note that overt movement is not a prerequisite for cerebellar activation: the cerebellum is engaged during conditions which either control for motor output or do not involve motor responses. Resting-state functional connectivity data reveal that, in addition to networks underlying motor control, the cerebellum is part of "cognitive" networks with prefrontal and parietal association cortices. Consistent with these findings, regional differences in activation patterns within the cerebellum are evident depending on the task demands, suggesting that the cerebellum can be broadly divided into functional regions based on the patterns of anatomical connectivity between different regions of the cerebellum and sensorimotor and association areas of the cerebral cortex. However, the distinct contribution of the cerebellum to cognitive tasks is not clear. Here, the functional neuroimaging evidence for cerebellar involvement in cognitive functions is reviewed and related to hypotheses as to why the cerebellum is active during such tasks. Identifying the precise role of the cerebellum in cognition-as well as the mechanism by which the cerebellum modulates performance during a wide range of tasks-remains a challenge for future investigations.

Functional network centrality in obesity: A resting-state and task fMRI study.

PubMed

García-García, Isabel; Jurado, María Ángeles; Garolera, Maite; Marqués-Iturria, Idoia; Horstmann, Annette; Segura, Bàrbara; Pueyo, Roser; Sender-Palacios, María José; Vernet-Vernet, Maria; Villringer, Arno; Junqué, Carme; Margulies, Daniel S; Neumann, Jane

2015-09-30

Obesity is associated with structural and functional alterations in brain areas that are often functionally distinct and anatomically distant. This suggests that obesity is associated with differences in functional connectivity of regions distributed across the brain. However, studies addressing whole brain functional connectivity in obesity remain scarce. Here, we compared voxel-wise degree centrality and eigenvector centrality between participants with obesity (n=20) and normal-weight controls (n=21). We analyzed resting state and task-related fMRI data acquired from the same individuals. Relative to normal-weight controls, participants with obesity exhibited reduced degree centrality in the right middle frontal gyrus in the resting-state condition. During the task fMRI condition, obese participants exhibited less degree centrality in the left middle frontal gyrus and the lateral occipital cortex along with reduced eigenvector centrality in the lateral occipital cortex and occipital pole. Our results highlight the central role of the middle frontal gyrus in the pathophysiology of obesity, a structure involved in several brain circuits signaling attention, executive functions and motor functions. Additionally, our analysis suggests the existence of task-dependent reduced centrality in occipital areas; regions with a role in perceptual processes and that are profoundly modulated by attention. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Transducin Duplicates in the Zebrafish Retina and Pineal Complex: Differential Specialisation after the Teleost Tetraploidisation

PubMed Central

Lagman, David; Callado-Pérez, Amalia; Franzén, Ilkin E.

2015-01-01

Gene duplications provide raw materials that can be selected for functional adaptations by evolutionary mechanisms. We describe here the results of 350 million years of evolution of three functionally related gene families: the alpha, beta and gamma subunits of transducins, the G protein involved in vision. Early vertebrate tetraploidisations resulted in separate transducin heterotrimers: gnat1/gnb1/gngt1 for rods, and gnat2/gnb3/gngt2 for cones. The teleost-specific tetraploidisation generated additional duplicates for gnb1, gnb3 and gngt2. We report here that the duplicates have undergone several types of subfunctionalisation or neofunctionalisation in the zebrafish. We have found that gnb1a and gnb1b are co-expressed at different levels in rods; gnb3a and gnb3b have undergone compartmentalisation restricting gnb3b to the dorsal and medial retina, however, gnb3a expression was detected only at very low levels in both larvae and adult retina; gngt2b expression is restricted to the dorsal and medial retina, whereas gngt2a is expressed ventrally. This dorsoventral distinction could be an adaptation to protect the lower part of the retina from intense light damage. The ontogenetic analysis shows earlier onset of expression in the pineal complex than in the retina, in accordance with its earlier maturation. Additionally, gnb1a but not gnb1b is expressed in the pineal complex, and gnb3b and gngt2b are transiently expressed in the pineal during ontogeny, thus showing partial temporal subfunctionalisation. These retina-pineal distinctions presumably reflect their distinct functional roles in vision and circadian rhythmicity. In summary, this study describes several functional differences between transducin gene duplicates resulting from the teleost-specific tetraploidisation. PMID:25806532

Genetic analysis of the cytoplasmic dynein subunit families.

PubMed

Pfister, K Kevin; Shah, Paresh R; Hummerich, Holger; Russ, Andreas; Cotton, James; Annuar, Azlina Ahmad; King, Stephen M; Fisher, Elizabeth M C

2006-01-01

Cytoplasmic dyneins, the principal microtubule minus-end-directed motor proteins of the cell, are involved in many essential cellular processes. The major form of this enzyme is a complex of at least six protein subunits, and in mammals all but one of the subunits are encoded by at least two genes. Here we review current knowledge concerning the subunits, their interactions, and their functional roles as derived from biochemical and genetic analyses. We also carried out extensive database searches to look for new genes and to clarify anomalies in the databases. Our analysis documents evolutionary relationships among the dynein subunits of mammals and other model organisms, and sheds new light on the role of this diverse group of proteins, highlighting the existence of two cytoplasmic dynein complexes with distinct cellular roles.

Genetic Analysis of the Cytoplasmic Dynein Subunit Families

PubMed Central

Pfister, K. Kevin; Shah, Paresh R; Hummerich, Holger; Russ, Andreas; Cotton, James; Annuar, Azlina Ahmad; King, Stephen M; Fisher, Elizabeth M. C

2006-01-01

Cytoplasmic dyneins, the principal microtubule minus-end-directed motor proteins of the cell, are involved in many essential cellular processes. The major form of this enzyme is a complex of at least six protein subunits, and in mammals all but one of the subunits are encoded by at least two genes. Here we review current knowledge concerning the subunits, their interactions, and their functional roles as derived from biochemical and genetic analyses. We also carried out extensive database searches to look for new genes and to clarify anomalies in the databases. Our analysis documents evolutionary relationships among the dynein subunits of mammals and other model organisms, and sheds new light on the role of this diverse group of proteins, highlighting the existence of two cytoplasmic dynein complexes with distinct cellular roles. PMID:16440056

Consenting to counter-normative sexual acts: differential effects of consent on anger and disgust as a function of transgressor or consenter.

PubMed

Russell, Pascale Sophie; Piazza, Jared

2015-01-01

Anger and disgust may have distinct roles in sexual morality; here, we tested hypotheses regarding the distinct foci, appraisals, and motivations of anger and disgust within the context of sexual offenses. We conducted four experiments in which we manipulated whether mutual consent (Studies 1-3) or desire (Study 4) was present or absent within a counter-normative sexual act. We found that anger is focused on the injustice of non-consensual sexual acts, and the transgressor of the injustice (Studies 1 and 3). Furthermore, the sexual nature of the act was not critical for the elicitation of anger--as anger also responded to unjust acts of violence (Study 3). By contrast, we hypothesised and found that disgust is focused on whether or not a person voluntarily engaged in, desired or consented to a counter-normative sexual act (Studies 2-4). Appraisals of abnormality and degradation were the primary appraisals of disgust, and the sexual nature of the act was a critical elicitor of disgust (Study 3). A final study ruled out victimisation as the mechanism of the effect of consent on disgust and indicated that the consenter's sexual desire was the mechanism (Study 4). Our results reveal that anger and disgust have differential roles in consent-related sexual offenses due to the distinct appraisals and foci of these emotions.

Acetylation within the N- and C-Terminal Domains of Src Regulates Distinct Roles of STAT3-Mediated Tumorigenesis.

PubMed

Huang, Chao; Zhang, Zhe; Chen, Lihan; Lee, Hank W; Ayrapetov, Marina K; Zhao, Ting C; Hao, Yimei; Gao, Jinsong; Yang, Chunzhang; Mehta, Gautam U; Zhuang, Zhengping; Zhang, Xiaoren; Hu, Guohong; Chin, Y Eugene

2018-06-01

Posttranslational modifications of mammalian c-Src N-terminal and C-terminal domains regulate distinct functions. Myristoylation of G 2 controls its cell membrane association and phosphorylation of Y419/Y527 controls its activation or inactivation, respectively. We provide evidence that Src-cell membrane association-dissociation and catalytic activation-inactivation are both regulated by acetylation. In EGF-treated cells, CREB binding protein (CBP) acetylates an N-terminal lysine cluster (K5, K7, and K9) of c-Src to promote dissociation from the cell membrane. CBP also acetylates the C-terminal K401, K423, and K427 of c-Src to activate intrinsic kinase activity for STAT3 recruitment and activation. N-terminal domain phosphorylation (Y14, Y45, and Y68) of STAT3 by c-Src activates transcriptionally active dimers of STAT3. Moreover, acetyl-Src translocates into nuclei, where it forms the Src-STAT3 enhanceosome for gene regulation and cancer cell proliferation. Thus, c-Src acetylation in the N-terminal and C-terminal domains play distinct roles in Src activity and regulation. Significance: CBP-mediated acetylation of lysine clusters in both the N-terminal and C-terminal regions of c-Src provides additional levels of control over STAT3 transcriptional activity. Cancer Res; 78(11); 2825-38. ©2018 AACR . ©2018 American Association for Cancer Research.

The role of the vagus nerve in the generation of cardiorespiratory interactions in a neotropical fish, the pacu, Piaractus mesopotamicus.

PubMed

Leite, Cleo Alcantara Costa; Taylor, E W; Guerra, C D R; Florindo, L H; Belão, T; Rantin, F T

2009-08-01

The role of the vagus nerve in determining heart rate (f(H)) and cardiorespiratory interactions was investigated in a neotropical fish, Piaractus mesopotamicus. During progressive hypoxia f(H) initially increased, establishing a 1:1 ratio with ventilation rate (f(R)). Subsequently there was a hypoxic bradycardia. Injection of atropine abolished a normoxic inhibitory tonus on the heart and the f(H) adjustments during progressive hypoxia, confirming that they are imposed by efferent parasympathetic inputs via the vagus nerve. Efferent activity recorded from the cardiac vagus in lightly anesthetized normoxic fish included occasional bursts of activity related to spontaneous changes in ventilation amplitude, which increased the cardiac interval. Restricting the flow of aerated water irrigating the gills resulted in increased respiratory effort and bursts of respiration-related activity in the cardiac vagus that seemed to cause f(H) to couple with f(R). Cell bodies of cardiac vagal pre-ganglionic neurons were located in two distinct groups within the dorsal vagal motor column having an overlapping distribution with respiratory motor-neurons. A small proportion of cardiac vagal pre-ganglionic neurons (2%) was in scattered positions in the ventrolateral medulla. This division of cardiac vagal pre-ganglionic neurons into distinct motor groups may relate to their functional roles in determining cardiorespiratory interactions.

Fungi Contribute Critical but Spatially Varying Roles in Nitrogen and Carbon Cycling in Acid Mine Drainage

PubMed Central

Mosier, Annika C.; Miller, Christopher S.; Frischkorn, Kyle R.; Ohm, Robin A.; Li, Zhou; LaButti, Kurt; Lapidus, Alla; Lipzen, Anna; Chen, Cindy; Johnson, Jenifer; Lindquist, Erika A.; Pan, Chongle; Hettich, Robert L.; Grigoriev, Igor V.; Singer, Steven W.; Banfield, Jillian F.

2016-01-01

The ecosystem roles of fungi have been extensively studied by targeting one organism and/or biological process at a time, but the full metabolic potential of fungi has rarely been captured in an environmental context. We hypothesized that fungal genome sequences could be assembled directly from the environment using metagenomics and that transcriptomics and proteomics could simultaneously reveal metabolic differentiation across habitats. We reconstructed the near-complete 27 Mbp genome of a filamentous fungus, Acidomyces richmondensis, and evaluated transcript and protein expression in floating and streamer biofilms from an acid mine drainage (AMD) system. A. richmondensis transcripts involved in denitrification and in the degradation of complex carbon sources (including cellulose) were up-regulated in floating biofilms, whereas central carbon metabolism and stress-related transcripts were significantly up-regulated in streamer biofilms. These findings suggest that the biofilm niches are distinguished by distinct carbon and nitrogen resource utilization, oxygen availability, and environmental challenges. An isolated A. richmondensis strain from this environment was used to validate the metagenomics-derived genome and confirm nitrous oxide production at pH 1. Overall, our analyses defined mechanisms of fungal adaptation and identified a functional shift related to different roles in carbon and nitrogen turnover for the same species of fungi growing in closely located but distinct biofilm niches. PMID:26973616

Anomalous brain functional connectivity contributing to poor adaptive behavior in Down syndrome.

PubMed

Pujol, Jesus; del Hoyo, Laura; Blanco-Hinojo, Laura; de Sola, Susana; Macià, Dídac; Martínez-Vilavella, Gerard; Amor, Marta; Deus, Joan; Rodríguez, Joan; Farré, Magí; Dierssen, Mara; de la Torre, Rafael

2015-03-01

Research in Down syndrome has substantially progressed in the understanding of the effect of gene overexpression at the molecular level, but there is a paucity of information on the ultimate consequences on overall brain functional organization. We have assessed the brain functional status in Down syndrome using functional connectivity MRI. Resting-state whole-brain connectivity degree maps were generated in 20 Down syndrome individuals and 20 control subjects to identify sites showing anomalous synchrony with other areas. A subsequent region-of-interest mapping served to detail the anomalies and to assess their potential contribution to poor adaptive behavior. Down syndrome individuals showed higher regional connectivity in a ventral brain system involving the amygdala/anterior temporal region and the ventral aspect of both the anterior cingulate and frontal cortices. By contrast, lower functional connectivity was identified in dorsal executive networks involving dorsal prefrontal and anterior cingulate cortices and posterior insula. Both functional connectivity increases and decreases contributed to account for patient scoring on adaptive behavior related to communication skills. The data overall suggest a distinctive functional organization with system-specific anomalies associated with reduced adaptive efficiency. Opposite effects were identified on distinct frontal and anterior temporal structures and relative sparing of posterior brain areas, which is generally consistent with Down syndrome cognitive profile. Relevantly, measurable connectivity changes, as a marker of the brain functional anomaly, could have a role in the development of therapeutic strategies addressed to improve the quality of life in Down syndrome individuals. Copyright © 2014 Elsevier Ltd. All rights reserved.

Synchronisation, acquisition and tracking for telemetry and data reception

NASA Astrophysics Data System (ADS)

Vandoninck, A.

1992-06-01

The important parameters of synchronization, acquisition, and tracking are addressed, and each function is highlighted separately. The following sequence is such as the functions occur in the system in time and for the type of data to be received, with distinction between telemetry and data reception, between direct carrier modulation or the use of a subcarrier, and between deep space and normal reception. For the telemetry reception the acquisition is described taking into account the difference in performances as geostationary or polar orbits, and the dependencies on the different Doppler offsets and rates are distinguished. The related functions and parameters are covered and the specifications of an average receiver are summarized. The synchronization of the valid data is described with a distinction for data directly modulated or via a subcarrier, the type of modulation and bitrate. The relevant functions and parameters of the average receiver/demodulator are summarized. The tracking of the signal in the course of the operational phase is described and relevant parameters of an actual system are presented. The reception of real data is handled and a sequence of acquisition, synchronization, and tracking is applied. Here higher bitrates and direct modulation schemes play an important role. The market equipment with the relevant parameters are discussed. The three functions in cases where deep reception is needed are covered. The high performance receiver/demodulator functions and how the acquisition, synchronization, and tracking is handled in such application, are explained.

Functional correlates of the anterolateral processing hierarchy in human auditory cortex.

PubMed

Chevillet, Mark; Riesenhuber, Maximilian; Rauschecker, Josef P

2011-06-22

Converging evidence supports the hypothesis that an anterolateral processing pathway mediates sound identification in auditory cortex, analogous to the role of the ventral cortical pathway in visual object recognition. Studies in nonhuman primates have characterized the anterolateral auditory pathway as a processing hierarchy, composed of three anatomically and physiologically distinct initial stages: core, belt, and parabelt. In humans, potential homologs of these regions have been identified anatomically, but reliable and complete functional distinctions between them have yet to be established. Because the anatomical locations of these fields vary across subjects, investigations of potential homologs between monkeys and humans require these fields to be defined in single subjects. Using functional MRI, we presented three classes of sounds (tones, band-passed noise bursts, and conspecific vocalizations), equivalent to those used in previous monkey studies. In each individual subject, three regions showing functional similarities to macaque core, belt, and parabelt were readily identified. Furthermore, the relative sizes and locations of these regions were consistent with those reported in human anatomical studies. Our results demonstrate that the functional organization of the anterolateral processing pathway in humans is largely consistent with that of nonhuman primates. Because our scanning sessions last only 15 min/subject, they can be run in conjunction with other scans. This will enable future studies to characterize functional modules in human auditory cortex at a level of detail previously possible only in visual cortex. Furthermore, the approach of using identical schemes in both humans and monkeys will aid with establishing potential homologies between them.

Burkholderia Type VI Secretion Systems Have Distinct Roles in Eukaryotic and Bacterial Cell Interactions

PubMed Central

Schwarz, Sandra; West, T. Eoin; Boyer, Frédéric; Chiang, Wen-Chi; Carl, Mike A.; Hood, Rachel D.; Rohmer, Laurence; Tolker-Nielsen, Tim; Skerrett, Shawn J.; Mougous, Joseph D.

2010-01-01

Bacteria that live in the environment have evolved pathways specialized to defend against eukaryotic organisms or other bacteria. In this manuscript, we systematically examined the role of the five type VI secretion systems (T6SSs) of Burkholderia thailandensis (B. thai) in eukaryotic and bacterial cell interactions. Consistent with phylogenetic analyses comparing the distribution of the B. thai T6SSs with well-characterized bacterial and eukaryotic cell-targeting T6SSs, we found that T6SS-5 plays a critical role in the virulence of the organism in a murine melioidosis model, while a strain lacking the other four T6SSs remained as virulent as the wild-type. The function of T6SS-5 appeared to be specialized to the host and not related to an in vivo growth defect, as ΔT6SS-5 was fully virulent in mice lacking MyD88. Next we probed the role of the five systems in interbacterial interactions. From a group of 31 diverse bacteria, we identified several organisms that competed less effectively against wild-type B. thai than a strain lacking T6SS-1 function. Inactivation of T6SS-1 renders B. thai greatly more susceptible to cell contact-induced stasis by Pseudomonas putida, Pseudomonas fluorescens and Serratia proteamaculans—leaving it 100- to 1000-fold less fit than the wild-type in competition experiments with these organisms. Flow cell biofilm assays showed that T6S-dependent interbacterial interactions are likely relevant in the environment. B. thai cells lacking T6SS-1 were rapidly displaced in mixed biofilms with P. putida, whereas wild-type cells persisted and overran the competitor. Our data show that T6SSs within a single organism can have distinct functions in eukaryotic versus bacterial cell interactions. These systems are likely to be a decisive factor in the survival of bacterial cells of one species in intimate association with those of another, such as in polymicrobial communities present both in the environment and in many infections. PMID:20865170

Myxoma Virus M064 Is a Novel Member of the Poxvirus C7L Superfamily of Host Range Factors That Controls the Kinetics of Myxomatosis in European Rabbits

PubMed Central

Liu, Jia; Wennier, Sonia; Moussatche, Nissin; Reinhard, Mary; Condit, Richard

2012-01-01

The myxoma virus (MYXV) carries three tandem C7L-like host range genes (M062R, M063R, and M064R). However, despite the fact that the sequences of these three genes are similar, they possess very distinctive functions in vivo. The role of M064 in MYXV pathogenesis was investigated and compared to the roles of M062 and M063. We report that M064 is a virulence factor that contributes to MYXV pathogenesis but lacks the host range properties associated with M062 and M063. PMID:22379095

Myxoma virus M064 is a novel member of the poxvirus C7L superfamily of host range factors that controls the kinetics of myxomatosis in European rabbits.

PubMed

Liu, Jia; Wennier, Sonia; Moussatche, Nissin; Reinhard, Mary; Condit, Richard; McFadden, Grant

2012-05-01

The myxoma virus (MYXV) carries three tandem C7L-like host range genes (M062R, M063R, and M064R). However, despite the fact that the sequences of these three genes are similar, they possess very distinctive functions in vivo. The role of M064 in MYXV pathogenesis was investigated and compared to the roles of M062 and M063. We report that M064 is a virulence factor that contributes to MYXV pathogenesis but lacks the host range properties associated with M062 and M063.

Ionic strength-dependent conformations of a ubiquitin-like small archaeal modifier protein (SAMP1) from Haloferax volcanii

PubMed Central

Ye, Kaiqin; Liao, Shanhui; Zhang, Wen; Fan, Kai; Zhang, Xuecheng; Zhang, Jiahai; Xu, Chao; Tu, Xiaoming

2013-01-01

Eukaryotic ubiquitin and ubiquitin-like systems play crucial roles in various cellular biological processes. In this work, we determined the solution structure of SAMP1 from Haloferax volcanii by NMR spectroscopy. Under low ionic conditions, SAMP1 presented two distinct conformations, one folded β-grasp and the other disordered. Interestingly, SAMP1 underwent a conformational conversion from disorder to order with ion concentration increasing, indicating that the ordered conformation is the functional form of SAMP1 under the physiological condition of H. volcanii. Furthermore, SAMP1 could interact with proteasome-activating nucleotidase B, supposing a potential role of SAMP1 in the protein degradation pathway mediated by proteasome. PMID:23818097

Distinct Quantitative Computed Tomography Emphysema Patterns Are Associated with Physiology and Function in Smokers

PubMed Central

San José Estépar, Raúl; Mendoza, Carlos S.; Hersh, Craig P.; Laird, Nan; Crapo, James D.; Lynch, David A.; Silverman, Edwin K.; Washko, George R.

2013-01-01

Rationale: Emphysema occurs in distinct pathologic patterns, but little is known about the epidemiologic associations of these patterns. Standard quantitative measures of emphysema from computed tomography (CT) do not distinguish between distinct patterns of parenchymal destruction. Objectives: To study the epidemiologic associations of distinct emphysema patterns with measures of lung-related physiology, function, and health care use in smokers. Methods: Using a local histogram-based assessment of lung density, we quantified distinct patterns of low attenuation in 9,313 smokers in the COPDGene Study. To determine if such patterns provide novel insights into chronic obstructive pulmonary disease epidemiology, we tested for their association with measures of physiology, function, and health care use. Measurements and Main Results: Compared with percentage of low-attenuation area less than −950 Hounsfield units (%LAA-950), local histogram-based measures of distinct CT low-attenuation patterns are more predictive of measures of lung function, dyspnea, quality of life, and health care use. These patterns are strongly associated with a wide array of measures of respiratory physiology and function, and most of these associations remain highly significant (P < 0.005) after adjusting for %LAA-950. In smokers without evidence of chronic obstructive pulmonary disease, the mild centrilobular disease pattern is associated with lower FEV1 and worse functional status (P < 0.005). Conclusions: Measures of distinct CT emphysema patterns provide novel information about the relationship between emphysema and key measures of physiology, physical function, and health care use. Measures of mild emphysema in smokers with preserved lung function can be extracted from CT scans and are significantly associated with functional measures. PMID:23980521

SNAP-25 IN NEUROPSYCHIATRIC DISORDERS

PubMed Central

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

2009-01-01

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

Performance Measurement and Analysis of Certain Search Algorithms

DTIC Science & Technology

1979-05-01

methodology that combines experiment and analysis in complementary and highly specialized and formalized roles, and that the richness of the domains make it ... it is difficult to determine what fraction of the observed differences between the 51 two sets is due to bias in sample set 1, and what fraction simply...given by its characteristic KMIN and KMAX functions. We posit a formal model of "knowledge" itself in which there are at least as many distinct "states

Differential Alterations in Excitatory and Inhibitory Networks Involving Dentate Granule Cells Following Chronic Treatment with Distinct Classes of NMDAR Antagonists in Hippocampal Slice Cultures

DTIC Science & Technology

2010-03-08

1992; Jung and McNaughton, 1993); (2) low incidence of recurrent excitatory synapses between granule cells (Molnar and Nadler, 1999; Okazaki et al...neurons, dentate granule cells have a relatively more negative resting membrane potential and exhibit low-frequency firing (Staley et al., 1992; Jung ...inhibition plays a dual role in brain function and possibly seizure occurrence through balancing excitation and synchronizing neuronal firing. An

Origin and Functions of Tissue Macrophages

PubMed Central

Epelman, Slava; Lavine, Kory J.; Randolph, Gwendalyn J.

2015-01-01

Macrophages are distributed in tissues throughout the body and contribute to both homeostasis and disease. Recently, it has become evident that most adult tissue macrophages originate during embryonic development and not from circulating monocytes. Each tissue has its own composition of embryonically derived and adult-derived macrophages, but it is unclear whether macrophages of distinct origins are functionally interchangeable or have unique roles at steady state. This new understanding also prompts reconsideration of the function of circulating monocytes. Classical Ly6chi monocytes patrol the extravascular space in resting organs, and Ly6clo nonclassical monocytes patrol the vasculature. Inflammation triggers monocytes to differentiate into macrophages, but whether resident and newly recruited macrophages possess similar functions during inflammation is unclear. Here, we define the tools used for identifying the complex origin of tissue macrophages and discuss the relative contributions of tissue niche versus ontological origin to the regulation of macrophage functions during steady state and inflammation. PMID:25035951

Mouse Models of Neurodevelopmental Disease of the Basal Ganglia and Associated Circuits

PubMed Central

Pappas, Samuel S.; Leventhal, Daniel K.; Albin, Roger L.; Dauer, William T.

2014-01-01

This chapter focuses on neurodevelopmental diseases that are tightly linked to abnormal function of the striatum and connected structures. We begin with an overview of three representative diseases in which striatal dysfunction plays a key role—Tourette syndrome and obsessive-compulsive disorder, Rett's syndrome, and primary dystonia. These diseases highlight distinct etiologies that disrupt striatal integrity and function during development, and showcase the varied clinical manifestations of striatal dysfunction. We then review striatal organization and function, including evidence for striatal roles in online motor control/action selection, reinforcement learning, habit formation, and action sequencing. A key barrier to progress has been the relative lack of animal models of these diseases, though recently there has been considerable progress. We review these efforts, including their relative merits providing insight into disease pathogenesis, disease symptomatology, and basal ganglia function. PMID:24947237

Predicting athletes' functional and dysfunctional emotions: The role of the motivational climate and motivation regulations.

PubMed

Ruiz, Montse C; Haapanen, Saara; Tolvanen, Asko; Robazza, Claudio; Duda, Joan L

2017-08-01

This study examined the relationships between perceptions of the motivational climate, motivation regulations, and the intensity and functionality levels of athletes' pleasant and unpleasant emotional states. Specifically, we examined the hypothesised mediational role of motivation regulations in the climate-emotion relationship. We also tested a sequence in which emotions were assumed to be predicted by the motivational climate dimensions and then served as antecedents to variability in motivation regulations. Participants (N = 494) completed a multi-section questionnaire assessing targeted variables. Structural equation modelling (SEM) revealed that a perceived task-involving climate was a positive predictor of autonomous motivation and of the impact of functional anger, and a negative predictor of the intensity of anxiety and dysfunctional anger. Autonomous motivation was a partial mediator of perceptions of a task-involving climate and the impact of functional anger. An ego-involving climate was a positive predictor of controlled motivation, and of the intensity and impact of functional anger and the intensity of dysfunctional anger. Controlled motivation partially mediated the relationship between an ego-involving climate and the intensity of dysfunctional anger. Good fit to the data also emerged for the motivational climate, emotional states, and motivation regulations sequence. Findings provide support for the consideration of hedonic tone and functionality distinctions in the assessment of athletes' emotional states.

Saliva Microbiota Carry Caries-Specific Functional Gene Signatures

PubMed Central

Chang, Xingzhi; Yuan, Xiao; Tu, Qichao; Yuan, Tong; Deng, Ye; Hemme, Christopher L.; Van Nostrand, Joy; Cui, Xinping; He, Zhili; Chen, Zhenggang; Guo, Dawei; Yu, Jiangbo; Zhang, Yue; Zhou, Jizhong; Xu, Jian

2014-01-01

Human saliva microbiota is phylogenetically divergent among host individuals yet their roles in health and disease are poorly appreciated. We employed a microbial functional gene microarray, HuMiChip 1.0, to reconstruct the global functional profiles of human saliva microbiota from ten healthy and ten caries-active adults. Saliva microbiota in the pilot population featured a vast diversity of functional genes. No significant distinction in gene number or diversity indices was observed between healthy and caries-active microbiota. However, co-presence network analysis of functional genes revealed that caries-active microbiota was more divergent in non-core genes than healthy microbiota, despite both groups exhibited a similar degree of conservation at their respective core genes. Furthermore, functional gene structure of saliva microbiota could potentially distinguish caries-active patients from healthy hosts. Microbial functions such as Diaminopimelate epimerase, Prephenate dehydrogenase, Pyruvate-formate lyase and N-acetylmuramoyl-L-alanine amidase were significantly linked to caries. Therefore, saliva microbiota carried disease-associated functional signatures, which could be potentially exploited for caries diagnosis. PMID:24533043

Saliva microbiota carry caries-specific functional gene signatures.

PubMed

Yang, Fang; Ning, Kang; Chang, Xingzhi; Yuan, Xiao; Tu, Qichao; Yuan, Tong; Deng, Ye; Hemme, Christopher L; Van Nostrand, Joy; Cui, Xinping; He, Zhili; Chen, Zhenggang; Guo, Dawei; Yu, Jiangbo; Zhang, Yue; Zhou, Jizhong; Xu, Jian

2014-01-01

Human saliva microbiota is phylogenetically divergent among host individuals yet their roles in health and disease are poorly appreciated. We employed a microbial functional gene microarray, HuMiChip 1.0, to reconstruct the global functional profiles of human saliva microbiota from ten healthy and ten caries-active adults. Saliva microbiota in the pilot population featured a vast diversity of functional genes. No significant distinction in gene number or diversity indices was observed between healthy and caries-active microbiota. However, co-presence network analysis of functional genes revealed that caries-active microbiota was more divergent in non-core genes than healthy microbiota, despite both groups exhibited a similar degree of conservation at their respective core genes. Furthermore, functional gene structure of saliva microbiota could potentially distinguish caries-active patients from healthy hosts. Microbial functions such as Diaminopimelate epimerase, Prephenate dehydrogenase, Pyruvate-formate lyase and N-acetylmuramoyl-L-alanine amidase were significantly linked to caries. Therefore, saliva microbiota carried disease-associated functional signatures, which could be potentially exploited for caries diagnosis.

Azospirillum brasilense Chemotaxis Depends on Two Signaling Pathways Regulating Distinct Motility Parameters

PubMed Central

Mukherjee, Tanmoy; Kumar, Dhivya; Burriss, Nathan; Xie, Zhihong

2016-01-01

ABSTRACT The genomes of most motile bacteria encode two or more chemotaxis (Che) systems, but their functions have been characterized in only a few model systems. Azospirillum brasilense is a motile soil alphaproteobacterium able to colonize the rhizosphere of cereals. In response to an attractant, motile A. brasilense cells transiently increase swimming speed and suppress reversals. The Che1 chemotaxis pathway was previously shown to regulate changes in the swimming speed, but it has a minor role in chemotaxis and root surface colonization. Here, we show that a second chemotaxis system, named Che4, regulates the probability of swimming reversals and is the major signaling pathway for chemotaxis and wheat root surface colonization. Experimental evidence indicates that Che1 and Che4 are functionally linked to coordinate changes in the swimming motility pattern in response to attractants. The effect of Che1 on swimming speed is shown to enhance the aerotactic response of A. brasilense in gradients, likely providing the cells with a competitive advantage in the rhizosphere. Together, the results illustrate a novel mechanism by which motile bacteria utilize two chemotaxis pathways regulating distinct motility parameters to alter movement in gradients and enhance the chemotactic advantage. IMPORTANCE Chemotaxis provides motile bacteria with a competitive advantage in the colonization of diverse niches and is a function enriched in rhizosphere bacterial communities, with most species possessing at least two chemotaxis systems. Here, we identify the mechanism by which cells may derive a significant chemotactic advantage using two chemotaxis pathways that ultimately regulate distinct motility parameters. PMID:27068592

Distinct endothelial phenotypes evoked by arterial waveforms derived from atherosclerosis-susceptible and -resistant regions of human vasculature

NASA Astrophysics Data System (ADS)

Dai, Guohao; Kaazempur-Mofrad, Mohammad R.; Natarajan, Sripriya; Zhang, Yuzhi; Vaughn, Saran; Blackman, Brett R.; Kamm, Roger D.; García-Cardeña, Guillermo; Gimbrone, Michael A., Jr.

2004-10-01

Atherosclerotic lesion localization to regions of disturbed flow within certain arterial geometries, in humans and experimental animals, suggests an important role for local hemodynamic forces in atherogenesis. To explore how endothelial cells (EC) acquire functional/dysfunctional phenotypes in response to vascular region-specific flow patterns, we have used an in vitro dynamic flow system to accurately reproduce arterial shear stress waveforms on cultured human EC and have examined the effects on EC gene expression by using a high-throughput transcriptional profiling approach. The flow patterns in the carotid artery bifurcations of several normal human subjects were characterized by using 3D flow analysis based on actual vascular geometries and blood flow profiles. Two prototypic arterial waveforms, "athero-prone" and "athero-protective," were defined as representative of the wall shear stresses in two distinct regions of the carotid artery (carotid sinus and distal internal carotid artery) that are typically "susceptible" or "resistant," respectively, to atherosclerotic lesion development. These two waveforms were applied to cultured EC, and cDNA microarrays were used to analyze the differential patterns of EC gene expression. In addition, the differential effects of athero-prone vs. athero-protective waveforms were further characterized on several parameters of EC structure and function, including actin cytoskeletal organization, expression and localization of junctional proteins, activation of the NF-B transcriptional pathway, and expression of proinflammatory cytokines and adhesion molecules. These global gene expression patterns and functional data reveal a distinct phenotypic modulation in response to the wall shear stresses present in atherosclerosis-susceptible vs. atherosclerosis-resistant human arterial geometries.

Azospirillum brasilense Chemotaxis Depends on Two Signaling Pathways Regulating Distinct Motility Parameters.

PubMed

Mukherjee, Tanmoy; Kumar, Dhivya; Burriss, Nathan; Xie, Zhihong; Alexandre, Gladys

2016-06-15

The genomes of most motile bacteria encode two or more chemotaxis (Che) systems, but their functions have been characterized in only a few model systems. Azospirillum brasilense is a motile soil alphaproteobacterium able to colonize the rhizosphere of cereals. In response to an attractant, motile A. brasilense cells transiently increase swimming speed and suppress reversals. The Che1 chemotaxis pathway was previously shown to regulate changes in the swimming speed, but it has a minor role in chemotaxis and root surface colonization. Here, we show that a second chemotaxis system, named Che4, regulates the probability of swimming reversals and is the major signaling pathway for chemotaxis and wheat root surface colonization. Experimental evidence indicates that Che1 and Che4 are functionally linked to coordinate changes in the swimming motility pattern in response to attractants. The effect of Che1 on swimming speed is shown to enhance the aerotactic response of A. brasilense in gradients, likely providing the cells with a competitive advantage in the rhizosphere. Together, the results illustrate a novel mechanism by which motile bacteria utilize two chemotaxis pathways regulating distinct motility parameters to alter movement in gradients and enhance the chemotactic advantage. Chemotaxis provides motile bacteria with a competitive advantage in the colonization of diverse niches and is a function enriched in rhizosphere bacterial communities, with most species possessing at least two chemotaxis systems. Here, we identify the mechanism by which cells may derive a significant chemotactic advantage using two chemotaxis pathways that ultimately regulate distinct motility parameters. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

The Pleiotropic MET Receptor Network: Circuit Development and the Neural-Medical Interface of Autism

PubMed Central

Eagleson, Kathie L.; Xie, Zhihui; Levitt, Pat

2016-01-01

People with autism spectrum disorder (ASD) and other neurodevelopmental disorders (NDDs) are behaviorally and medically heterogeneous. The combination of polygenicity and gene pleiotropy - the influence of one gene on distinct phenotypes - raises questions of how specific genes and their protein products interact to contribute to NDDs. A preponderance of evidence supports developmental and pathophysiological roles for the MET receptor tyrosine kinase, a multi-functional receptor that mediates distinct biological responses depending upon cell context. MET influences neuron architecture and synapse maturation in the forebrain, and regulates homeostasis in gastrointestinal and immune systems, both commonly disrupted in NDDs. Peak expression of synapse-enriched MET is conserved across rodent and primate forebrain, yet regional differences in primate neocortex are pronounced, with enrichment in circuits that participate in social information processing. A functional risk allele in the MET promoter, enriched in subgroups of children with ASD, reduces transcription and disrupts socially-relevant neural circuits structurally and functionally. In mice, circuit-specific deletion of Met causes distinct atypical behaviors. MET activation increases dendritic complexity and nascent synapse number, but synapse maturation requires reductions in MET. MET mediates its specific biological effects through different intracellular signaling pathways, and has a complex protein interactome that is enriched in ASD and other NDD candidates. The interactome is co-regulated in developing human neocortex. We suggest that a gene as pleiotropic and highly regulated as MET, together with its interactome, is biologically relevant in normal and pathophysiological contexts, impacting central and peripheral phenotypes that contribute to NDD risk and clinical symptoms. PMID:27837921

Distinct roles of autophagy-dependent and -independent functions of FIP200 revealed by generation and analysis of a mutant knock-in mouse model

PubMed Central

Chen, Song; Wang, Chenran; Yeo, Syn; Liang, Chun-Chi; Okamoto, Takako; Sun, Shaogang; Wen, Jian; Guan, Jun-Lin

2016-01-01

Autophagy is an evolutionarily conserved cellular process controlled through a set of essential autophagy genes (Atgs). However, there is increasing evidence that most, if not all, Atgs also possess functions independent of their requirement in canonical autophagy, making it difficult to distinguish the contributions of autophagy-dependent or -independent functions of a particular Atg to various biological processes. To distinguish these functions for FIP200 (FAK family-interacting protein of 200 kDa), an Atg in autophagy induction, we examined FIP200 interaction with its autophagy partner, Atg13. We found that residues 582–585 (LQFL) in FIP200 are required for interaction with Atg13, and mutation of these residues to AAAA (designated the FIP200-4A mutant) abolished its canonical autophagy function in vitro. Furthermore, we created a FIP200-4A mutant knock-in mouse model and found that specifically blocking FIP200 interaction with Atg13 abolishes autophagy in vivo, providing direct support for the essential role of the ULK1/Atg13/FIP200/Atg101 complex in the process beyond previous studies relying on the complete knockout of individual components. Analysis of the new mouse model showed that nonautophagic functions of FIP200 are sufficient to fully support embryogenesis by maintaining a protective role in TNFα-induced apoptosis. However, FIP200-mediated canonical autophagy is required to support neonatal survival and tumor cell growth. These studies provide the first genetic evidence linking an Atg's autophagy and nonautophagic functions to different biological processes in vivo. PMID:27013233

Computational modeling of heterogeneity and function of CD4+ T cells

PubMed Central

Carbo, Adria; Hontecillas, Raquel; Andrew, Tricity; Eden, Kristin; Mei, Yongguo; Hoops, Stefan; Bassaganya-Riera, Josep

2014-01-01

The immune system is composed of many different cell types and hundreds of intersecting molecular pathways and signals. This large biological complexity requires coordination between distinct pro-inflammatory and regulatory cell subsets to respond to infection while maintaining tissue homeostasis. CD4+ T cells play a central role in orchestrating immune responses and in maintaining a balance between pro- and anti- inflammatory responses. This tight balance between regulatory and effector reactions depends on the ability of CD4+ T cells to modulate distinct pathways within large molecular networks, since dysregulated CD4+ T cell responses may result in chronic inflammatory and autoimmune diseases. The CD4+ T cell differentiation process comprises an intricate interplay between cytokines, their receptors, adaptor molecules, signaling cascades and transcription factors that help delineate cell fate and function. Computational modeling can help to describe, simulate, analyze, and predict some of the behaviors in this complicated differentiation network. This review provides a comprehensive overview of existing computational immunology methods as well as novel strategies used to model immune responses with a particular focus on CD4+ T cell differentiation. PMID:25364738

Yeast silencing factor Sir4 and a subset of nucleoporins form a complex distinct from nuclear pore complexes

PubMed Central

Ptak, Christopher; Roesner, Ulyss K.

2017-01-01

Interactions occurring at the nuclear envelope (NE)–chromatin interface influence both NE structure and chromatin organization. Insights into the functions of NE–chromatin interactions have come from the study of yeast subtelomeric chromatin and its association with the NE, including the identification of various proteins necessary for tethering subtelomeric chromatin to the NE and the silencing of resident genes. Here we show that four of these proteins—the silencing factor Sir4, NE-associated Esc1, the SUMO E3 ligase Siz2, and the nuclear pore complex (NPC) protein Nup170—physically and functionally interact with one another and a subset of NPC components (nucleoporins or Nups). Importantly, this group of Nups is largely restricted to members of the inner and outer NPC rings, but it lacks numerous others including cytoplasmically and nucleoplasmically positioned Nups. We propose that this Sir4-associated Nup complex is distinct from holo-NPCs and that it plays a role in subtelomeric chromatin organization and NE tethering. PMID:28883038

Yeast silencing factor Sir4 and a subset of nucleoporins form a complex distinct from nuclear pore complexes.

PubMed

Lapetina, Diego L; Ptak, Christopher; Roesner, Ulyss K; Wozniak, Richard W

2017-10-02

Interactions occurring at the nuclear envelope (NE)-chromatin interface influence both NE structure and chromatin organization. Insights into the functions of NE-chromatin interactions have come from the study of yeast subtelomeric chromatin and its association with the NE, including the identification of various proteins necessary for tethering subtelomeric chromatin to the NE and the silencing of resident genes. Here we show that four of these proteins-the silencing factor Sir4, NE-associated Esc1, the SUMO E3 ligase Siz2, and the nuclear pore complex (NPC) protein Nup170-physically and functionally interact with one another and a subset of NPC components (nucleoporins or Nups). Importantly, this group of Nups is largely restricted to members of the inner and outer NPC rings, but it lacks numerous others including cytoplasmically and nucleoplasmically positioned Nups. We propose that this Sir4-associated Nup complex is distinct from holo-NPCs and that it plays a role in subtelomeric chromatin organization and NE tethering. © 2017 Lapetina et al.

MicroRNAs in right ventricular remodelling.

PubMed

Batkai, Sandor; Bär, Christian; Thum, Thomas

2017-10-01

Right ventricular (RV) remodelling is a lesser understood process of the chronic, progressive transformation of the RV structure leading to reduced functional capacity and subsequent failure. Besides conditions concerning whole hearts, some pathology selectively affects the RV, leading to a distinct RV-specific clinical phenotype. MicroRNAs have been identified as key regulators of biological processes that drive the progression of chronic diseases. The role of microRNAs in diseases affecting the left ventricle has been studied for many years, however there is still limited information on microRNAs specific to diseases in the right ventricle. Here, we review recently described details on the expression, regulation, and function of microRNAs in the pathological remodelling of the right heart. Recently identified strategies using microRNAs as pharmacological targets or biomarkers will be highlighted. Increasing knowledge of pathogenic microRNAs will finally help improve our understanding of underlying distinct mechanisms and help utilize novel targets or biomarkers to develop treatments for patients suffering from right heart diseases. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.

Distribution of MCH-containing fibers in the feline brainstem: Relevance for REM sleep regulation.

PubMed

Costa, Alicia; Castro-Zaballa, Santiago; Lagos, Patricia; Chase, Michael H; Torterolo, Pablo

2018-06-01

Neurons that utilize melanin-concentrating hormone (MCH) as a neuromodulator are localized in the postero-lateral hypothalamus and incerto-hypothalamic area. These neurons project diffusely throughout the central nervous system and have been implicated in critical physiological processes, such as sleep. Unlike rodents, in the order carnivora as well as in humans, MCH exerts its biological functions through two receptors: MCHR-1 and MCHR-2. Hence, the cat is an optimal animal to model MCHergic functions in humans. In the present study, we examined the distribution of MCH-positive fibers in the brainstem of the cat. MCHergic axons with distinctive varicosities and boutons were heterogeneously distributed, exhibiting different densities in distinct regions of the brainstem. High density of MCHergic fibers was found in the dorsal raphe nucleus, the laterodorsal tegmental nucleus, the periaqueductal gray, the pendunculopontine tegmental nucleus, the locus coeruleus and the prepositus hypoglossi. Because these areas are involved in the control of REM sleep, the present anatomical data support the role of this neuropeptidergic system in the control of this behavioral state. Copyright © 2018 Elsevier Inc. All rights reserved.

Evolutionary Limitation and Opportunities for Developing tRNA Synthetase Inhibitors with 5-Binding-Mode Classification

PubMed Central

Fang, Pengfei; Guo, Min

2015-01-01

Aminoacyl-tRNA synthetases (aaRSs) are enzymes that catalyze the transfer of amino acids to their cognate tRNAs as building blocks for translation. Each of the aaRS families plays a pivotal role in protein biosynthesis and is indispensable for cell growth and survival. In addition, aaRSs in higher species have evolved important non-translational functions. These translational and non-translational functions of aaRS are attractive for developing antibacterial, antifungal, and antiparasitic agents and for treating other human diseases. The interplay between amino acids, tRNA, ATP, EF-Tu and non-canonical binding partners, had shaped each family with distinct pattern of key sites for regulation, with characters varying among species across the path of evolution. These sporadic variations in the aaRSs offer great opportunity to target these essential enzymes for therapy. Up to this day, growing numbers of aaRS inhibitors have been discovered and developed. Here, we summarize the latest developments and structural studies of aaRS inhibitors, and classify them with distinct binding modes into five categories. PMID:26670257

Loss of MeCP2 in Parvalbumin-and Somatostatin-Expressing Neurons in Mice Leads to Distinct Rett Syndrome-like Phenotypes.

PubMed

Ito-Ishida, Aya; Ure, Kerstin; Chen, Hongmei; Swann, John W; Zoghbi, Huda Y

2015-11-18

Inhibitory neurons are critical for proper brain function, and their dysfunction is implicated in several disorders, including autism, schizophrenia, and Rett syndrome. These neurons are heterogeneous, and it is unclear which subtypes contribute to specific neurological phenotypes. We deleted Mecp2, the mouse homolog of the gene that causes Rett syndrome, from the two most populous subtypes, parvalbumin-positive (PV+) and somatostatin-positive (SOM+) neurons. Loss of MeCP2 partially impairs the affected neuron, allowing us to assess the function of each subtype without profound disruption of neuronal circuitry. We found that mice lacking MeCP2 in either PV+ or SOM+ neurons have distinct, non-overlapping neurological features: mice lacking MeCP2 in PV+ neurons developed motor, sensory, memory, and social deficits, whereas those lacking MeCP2 in SOM+ neurons exhibited seizures and stereotypies. Our findings indicate that PV+ and SOM+ neurons contribute complementary aspects of the Rett phenotype and may have modular roles in regulating specific behaviors. Copyright © 2015 Elsevier Inc. All rights reserved.

The multi-replication protein A (RPA) system--a new perspective.

PubMed

Sakaguchi, Kengo; Ishibashi, Toyotaka; Uchiyama, Yukinobu; Iwabata, Kazuki

2009-02-01

Replication protein A (RPA) complex has been shown, using both in vivo and in vitro approaches, to be required for most aspects of eukaryotic DNA metabolism: replication, repair, telomere maintenance and homologous recombination. Here, we review recent data concerning the function and biological importance of the multi-RPA complex. There are distinct complexes of RPA found in the biological kingdoms, although for a long time only one type of RPA complex was believed to be present in eukaryotes. Each complex probably serves a different role. In higher plants, three distinct large and medium subunits are present, but only one species of the smallest subunit. Each of these protein subunits forms stable complexes with their respective partners. They are paralogs as complex. Humans possess two paralogs and one analog of RPA. The multi-RPA system can be regarded as universal in eukaryotes. Among eukaryotic kingdoms, paralogs, orthologs, analogs and heterologs of many DNA synthesis-related factors, including RPA, are ubiquitous. Convergent evolution seems to be ubiquitous in these processes. Using recent findings, we review the composition and biological functions of RPA complexes.

E-type prostanoid receptor 4 (EP4) in disease and therapy

PubMed Central

Konya, Viktoria; Marsche, Gunther; Schuligoi, Rufina; Heinemann, Akos

2013-01-01

The large variety of biological functions governed by prostaglandin (PG) E2 is mediated by signaling through four distinct E-type prostanoid (EP) receptors. The availability of mouse strains with genetic ablation of each EP receptor subtype and the development of selective EP agonists and antagonists have tremendously advanced our understanding of PGE2 as a physiologically and clinically relevant mediator. Moreover, studies using disease models revealed numerous conditions in which distinct EP receptors might be exploited therapeutically. In this context, the EP4 receptor is currently emerging as most versatile and promising among PGE2 receptors. Anti-inflammatory, anti-thrombotic and vasoprotective effects have been proposed for the EP4 receptor, along with its recently described unfavorable tumor-promoting and pro-angiogenic roles. A possible explanation for the diverse biological functions of EP4 might be the multiple signaling pathways switched on upon EP4 activation. The present review attempts to summarize the EP4 receptor-triggered signaling modules and the possible therapeutic applications of EP4-selective agonists and antagonists. PMID:23523686

Optimization in the Face of Contradictory Criteria - the Example of Muscle

NASA Astrophysics Data System (ADS)

Davison, M.; Shiner, J. S.

2002-09-01

Biological thought suggests that organisms tend toward optimal design through evolution. This optimization should be evident in the physiology of organs and organ systems. However, a given organ often has multiple roles to play in the optimization of the organism, and sometimes the logical optimization criteria for the different roles may be contradictory. In this paper we consider the case of skeletal muscle. One of its obvious functions is movement of the organism, for which efficiency is clearly a goal. However, muscle is also important for temperature regulation through shivering. In this latter function muscle should produce heat; i.e. it should be maximally inefficient. The thermodynamic optimizations desired for these two roles appear diametrically opposed. We show a way out of this dilemma by constructing a simple, physiologically motivated model of the contraction-relaxation cycle of muscle. This model muscle can be both an efficient mover in a ‘purposeful contraction’ regime, characterized by large movements of low frequency, and a good heat producer in a distinct ‘shivering’ regime characterized by small movements of high frequency.

Cellular commitment in the developing cerebellum

PubMed Central

Marzban, Hassan; Del Bigio, Marc R.; Alizadeh, Javad; Ghavami, Saeid; Zachariah, Robby M.; Rastegar, Mojgan

2014-01-01

The mammalian cerebellum is located in the posterior cranial fossa and is critical for motor coordination and non-motor functions including cognitive and emotional processes. The anatomical structure of cerebellum is distinct with a three-layered cortex. During development, neurogenesis and fate decisions of cerebellar primordium cells are orchestrated through tightly controlled molecular events involving multiple genetic pathways. In this review, we will highlight the anatomical structure of human and mouse cerebellum, the cellular composition of developing cerebellum, and the underlying gene expression programs involved in cell fate commitments in the cerebellum. A critical evaluation of the cell death literature suggests that apoptosis occurs in ~5% of cerebellar cells, most shortly after mitosis. Apoptosis and cellular autophagy likely play significant roles in cerebellar development, we provide a comprehensive discussion of their role in cerebellar development and organization. We also address the possible function of unfolded protein response in regulation of cerebellar neurogenesis. We discuss recent advancements in understanding the epigenetic signature of cerebellar compartments and possible connections between DNA methylation, microRNAs and cerebellar neurodegeneration. Finally, we discuss genetic diseases associated with cerebellar dysfunction and their role in the aging cerebellum. PMID:25628535

SIRT3 mediates multi-tissue coupling for metabolic fuel switching.

PubMed

Dittenhafer-Reed, Kristin E; Richards, Alicia L; Fan, Jing; Smallegan, Michael J; Fotuhi Siahpirani, Alireza; Kemmerer, Zachary A; Prolla, Tomas A; Roy, Sushmita; Coon, Joshua J; Denu, John M

2015-04-07

SIRT3 is a member of the Sirtuin family of NAD(+)-dependent deacylases and plays a critical role in metabolic regulation. Organism-wide SIRT3 loss manifests in metabolic alterations; however, the coordinating role of SIRT3 among metabolically distinct tissues is unknown. Using multi-tissue quantitative proteomics comparing fasted wild-type mice to mice lacking SIRT3, innovative bioinformatic analysis, and biochemical validation, we provide a comprehensive view of mitochondrial acetylation and SIRT3 function. We find SIRT3 regulates the acetyl-proteome in core mitochondrial processes common to brain, heart, kidney, liver, and skeletal muscle, but differentially regulates metabolic pathways in fuel-producing and fuel-utilizing tissues. We propose an additional maintenance function for SIRT3 in liver and kidney where SIRT3 expression is elevated to reduce the acetate load on mitochondrial proteins. We provide evidence that SIRT3 impacts ketone body utilization in the brain and reveal a pivotal role for SIRT3 in the coordination between tissues required for metabolic homeostasis. Copyright © 2015 Elsevier Inc. All rights reserved.

Genome-wide identification of ATP-binding cassette (ABC) transporters and their roles in response to polycyclic aromatic hydrocarbons (PAHs) in the copepod Paracyclopina nana.

PubMed

Jeong, Chang-Bum; Kim, Duck-Hyun; Kang, Hye-Min; Lee, Young Hwan; Kim, Hui-Su; Kim, Il-Chan; Lee, Jae-Seong

2017-02-01

The ATP-binding cassette (ABC) protein superfamily is one of the largest gene families and is highly conserved in all domains. The ABC proteins play roles in several biological processes, including multi-xenobiotic resistance (MXR), by functioning as transporters in the cellular membrane. They also mediate the cellular efflux of a wide range of substrates against concentration gradients. In this study, 37 ABC genes belonging to eight distinct subfamilies were identified in the marine copepod Paracyclopina nana and annotated based on a phylogenetic analysis. Also, the functions of P-glycoproteins (P-gp) and multidrug resistance-associated proteins (MRPs), conferring MXR, were verified using fluorescent substrates and specific inhibitors. The activities of MXR-mediated ABC proteins and their transcriptional level were examined in response to polyaromatic hydrocarbons (PAHs), main components of the water-accommodated fraction. This study increases the understanding of the protective role of MXR in response to PAHs over the comparative evolution of ABC gene families. Copyright © 2016 Elsevier B.V. All rights reserved.

Roles of EDR1 in non-host resistance of Arabidopsis.

PubMed

Hiruma, Kei; Takano, Yoshitaka

2011-11-01

Entry control of Arabidopsis thaliana against non-adapted powdery mildews largely depends on the PEN1 secretion pathway and the PEN2-PEN3 antifungal metabolite pathway, and is critical for non-host resistance. In a recent study, we reported that ENHANCED DISEASE RESISTANCE 1 (EDR1) plays a role in entry control against a non-adapted anthracnose fungus, which exhibits an infection style distinct from that of powdery mildews. Results obtained using edr1 pen2 double mutants indicate that the contribution of EDR1 to non-host resistance is independent of that of the PEN2-mediated defence pathway. Comparative transcript profiling revealed that EDR1 is critical for expression of four plant defensin genes. The MYC2-encoded transcription factor represses defensin expression. Inactivation of MYC fully restored defensin expression in edr1 mutants, implying that EDR1 cancels MYC2 function to regulate defensin expression. These findings indicate that EDR1 exerts a critical role in non-host resistance, in part by inducing antifungal peptide expression via interference in MYC2-mediated repressor function.

Intrinsic motions in the N-terminal domain of an ionotropic glutamate receptor detected by fluorescence correlation spectroscopy.

PubMed

Jensen, Mette H; Sukumaran, Madhav; Johnson, Christopher M; Greger, Ingo H; Neuweiler, Hannes

2011-11-18

Ionotropic glutamate receptors (iGluRs) mediate excitatory neurotransmission in the central nervous system and play key roles in brain development and disease. iGluRs have two distinct extracellular domains, but the functional role of the distal N-terminal domain (NTD) is poorly understood. Crystal structures of the NTD from some non-N-methyl-d-aspartate (NMDA) iGluRs are consistent with a rigid body that facilitates receptor assembly but suggest an additional dynamic role that could modulate signaling. Here, we moved beyond spatial and temporal limitations of conventional protein single-molecule spectroscopy by employing correlation analysis of extrinsic oxazine fluorescence fluctuations. We observed nanosecond (ns)-to-microsecond (μs) motions of loop segments and helices within a region of an AMPA-type iGluR NTD, which has been identified previously to be structurally variable. Our data reveal that the AMPA receptor NTD undergoes rapid conformational fluctuations, suggesting an inherent allosteric capacity for this domain in addition to its established assembly function. Copyright © 2011 Elsevier Ltd. All rights reserved.

RNA-Sequencing Analysis Reveals a Regulatory Role for Transcription Factor Fezf2 in the Mature Motor Cortex

PubMed Central

Clare, Alison J.; Wicky, Hollie E.; Empson, Ruth M.; Hughes, Stephanie M.

2017-01-01

Forebrain embryonic zinc finger (Fezf2) encodes a transcription factor essential for the specification of layer 5 projection neurons (PNs) in the developing cerebral cortex. As with many developmental transcription factors, Fezf2 continues to be expressed into adulthood, suggesting it remains crucial to the maintenance of neuronal phenotypes. Despite the continued expression, a function has yet to be explored for Fezf2 in the PNs of the developed cortex. Here, we investigated the role of Fezf2 in mature neurons, using lentiviral-mediated delivery of a shRNA to conditionally knockdown the expression of Fezf2 in the mouse primary motor cortex (M1). RNA-sequencing analysis of Fezf2-reduced M1 revealed significant changes to the transcriptome, identifying a regulatory role for Fezf2 in the mature M1. Kyoto Encyclopedia Genes and Genomes (KEGG) pathway analyses of Fezf2-regulated genes indicated a role in neuronal signaling and plasticity, with significant enrichment of neuroactive ligand-receptor interaction, cell adhesion molecules and calcium signaling pathways. Gene Ontology analysis supported a functional role for Fezf2-regulated genes in neuronal transmission and additionally indicated an importance in the regulation of behavior. Using the mammalian phenotype ontology database, we identified a significant overrepresentation of Fezf2-regulated genes associated with specific behavior phenotypes, including associative learning, social interaction, locomotor activation and hyperactivity. These roles were distinct from that of Fezf2-regulated genes identified in development, indicating a dynamic transition in Fezf2 function. Together our findings demonstrate a regulatory role for Fezf2 in the mature brain, with Fezf2-regulated genes having functional roles in sustaining normal neuronal and behavioral phenotypes. These results support the hypothesis that developmental transcription factors are important for maintaining neuron transcriptomes and that disruption of their expression could contribute to the progression of disease phenotypes. PMID:28936162

Brain responses to social norms: Meta-analyses of fMRI studies.

PubMed

Zinchenko, Oksana; Arsalidou, Marie

2018-02-01

Social norms have a critical role in everyday decision-making, as frequent interaction with others regulates our behavior. Neuroimaging studies show that social-based and fairness-related decision-making activates an inconsistent set of areas, which sometimes includes the anterior insula, anterior cingulate cortex, and others lateral prefrontal cortices. Social-based decision-making is complex and variability in findings may be driven by socio-cognitive activities related to social norms. To distinguish among social-cognitive activities related to social norms, we identified 36 eligible articles in the functional magnetic resonance imaging (fMRI) literature, which we separate into two categories (a) social norm representation and (b) norm violations. The majority of original articles (>60%) used tasks associated with fairness norms and decision-making, such as ultimatum game, dictator game, or prisoner's dilemma; the rest used tasks associated to violation of moral norms, such as scenarios and sentences of moral depravity ratings. Using quantitative meta-analyses, we report common and distinct brain areas that show concordance as a function of category. Specifically, concordance in ventromedial prefrontal regions is distinct to social norm representation processing, whereas concordance in right insula, dorsolateral prefrontal, and dorsal cingulate cortices is distinct to norm violation processing. We propose a neurocognitive model of social norms for healthy adults, which could help guide future research in social norm compliance and mechanisms of its enforcement. © 2017 Wiley Periodicals, Inc.

Molecular Mechanisms of Stem/Progenitor Cell Maintenance in the Adrenal Cortex

PubMed Central

Lerario, Antonio Marcondes; Finco, Isabella; LaPensee, Christopher; Hammer, Gary Douglas

2017-01-01

The adrenal cortex is characterized by three histologically and functionally distinct zones: the outermost zona glomerulosa (zG), the intermediate zona fasciculata, and the innermost zona reticularis. Important aspects of the physiology and maintenance of the adrenocortical stem/progenitor cells have emerged in the last few years. Studies have shown that the adrenocortical cells descend from a pool of progenitors that are localized in the subcapsular region of the zG. These cells continually undergo a process of centripetal displacement and differentiation, which is orchestrated by several paracrine and endocrine cues, including the pituitary-derived adrenocorticotrophic hormone, and angiotensin II. However, while several roles of the endocrine axes on adrenocortical function are well established, the mechanisms coordinating the maintenance of an undifferentiated progenitor cell pool with self-renewal capacity are poorly understood. Local factors, such as the composition of the extracellular matrix (ECM) with embedded signaling molecules, and the activity of major paracrine effectors, including ligands of the sonic hedgehog and Wnt signaling pathways, are thought to play a major role. Particularly, the composition of the ECM, which exhibits substantial differences within each of the three histologically distinct concentric zones, has been shown to influence the differentiation status of adrenocortical cells. New data from other organ systems and different experimental paradigms strongly support the conclusion that the interactions of ECM components with cell-surface receptors and secreted factors are key determinants of cell fate. In this review, we summarize established and emerging data on the paracrine and autocrine regulatory loops that regulate the biology of the progenitor cell niche and propose a role for bioengineered ECM models in further elucidating this biology in the adrenal. PMID:28386245

Heterogeneity in Kv2 Channel Expression Shapes Action Potential Characteristics and Firing Patterns in CA1 versus CA2 Hippocampal Pyramidal Neurons

PubMed Central

Chevaleyre, Vivien; Murray, Karl D.; Piskorowski, Rebecca A.

2017-01-01

Abstract The CA1 region of the hippocampus plays a critical role in spatial and contextual memory, and has well-established circuitry, function and plasticity. In contrast, the properties of the flanking CA2 pyramidal neurons (PNs), important for social memory, and lacking CA1-like plasticity, remain relatively understudied. In particular, little is known regarding the expression of voltage-gated K+ (Kv) channels and the contribution of these channels to the distinct properties of intrinsic excitability, action potential (AP) waveform, firing patterns and neurotransmission between CA1 and CA2 PNs. In the present study, we used multiplex fluorescence immunolabeling of mouse brain sections, and whole-cell recordings in acute mouse brain slices, to define the role of heterogeneous expression of Kv2 family Kv channels in CA1 versus CA2 pyramidal cell excitability. Our results show that the somatodendritic delayed rectifier Kv channel subunits Kv2.1, Kv2.2, and their auxiliary subunit AMIGO-1 have region-specific differences in expression in PNs, with the highest expression levels in CA1, a sharp decrease at the CA1-CA2 boundary, and significantly reduced levels in CA2 neurons. PNs in CA1 exhibit a robust contribution of Guangxitoxin-1E-sensitive Kv2-based delayed rectifier current to AP shape and after-hyperpolarization potential (AHP) relative to that seen in CA2 PNs. Our results indicate that robust Kv2 channel expression confers a distinct pattern of intrinsic excitability to CA1 PNs, potentially contributing to their different roles in hippocampal network function. PMID:28856240

Rational site-directed mutations of the LLP-1 and LLP-2 lentivirus lytic peptide domains in the intracytoplasmic tail of human immunodeficiency virus type 1 gp41 indicate common functions in cell-cell fusion but distinct roles in virion envelope incorporation.

PubMed

Kalia, Vandana; Sarkar, Surojit; Gupta, Phalguni; Montelaro, Ronald C

2003-03-01

Two highly conserved cationic amphipathic alpha-helical motifs, designated lentivirus lytic peptides 1 and 2 (LLP-1 and LLP-2), have been characterized in the carboxyl terminus of the transmembrane (TM) envelope glycoprotein (Env) of lentiviruses. Although various properties have been attributed to these domains, their structural and functional significance is not clearly understood. To determine the specific contributions of the Env LLP domains to Env expression, processing, and incorporation and to viral replication and syncytium induction, site-directed LLP mutants of a primary dualtropic infectious human immunodeficiency virus type 1 (HIV-1) isolate (ME46) were examined. Substitutions were made for highly conserved arginine residues in either the LLP-1 or LLP-2 domain (MX1 or MX2, respectively) or in both domains (MX4). The HIV-1 mutants with altered LLP domains demonstrated distinct phenotypes. The LLP-1 mutants (MX1 and MX4) were replication defective and showed an average of 85% decrease in infectivity, which was associated with an evident decrease in gp41 incorporation into virions without a significant decrease in Env expression or processing in transfected 293T cells. In contrast, MX2 virus was replication competent and incorporated a full complement of Env into its virions, indicating a differential role for the LLP-1 domain in Env incorporation. Interestingly, the replication-competent MX2 virus was impaired in its ability to induce syncytia in T-cell lines. This defect in cell-cell fusion did not correlate with apparent defects in the levels of cell surface Env expression, oligomerization, or conformation. The lack of syncytium formation, however, correlated with a decrease of about 90% in MX2 Env fusogenicity compared to that of wild-type Env in quantitative luciferase-based cell-cell fusion assays. The LLP-1 mutant MX1 and MX4 Envs also exhibited an average of 80% decrease in fusogenicity. Altogether, these results demonstrate for the first time that the highly conserved LLP domains perform critical but distinct functions in Env incorporation and fusogenicity.

Convergent functional architecture of the superior parietal lobule unraveled with multimodal neuroimaging approaches.

PubMed

Wang, Jiaojian; Yang, Yong; Fan, Lingzhong; Xu, Jinping; Li, Changhai; Liu, Yong; Fox, Peter T; Eickhoff, Simon B; Yu, Chunshui; Jiang, Tianzi

2015-01-01

The superior parietal lobule (SPL) plays a pivotal role in many cognitive, perceptive, and motor-related processes. This implies that a mosaic of distinct functional and structural subregions may exist in this area. Recent studies have demonstrated that the ongoing spontaneous fluctuations in the brain at rest are highly structured and, like coactivation patterns, reflect the integration of cortical locations into long-distance networks. This suggests that the internal differentiation of a complex brain region may be revealed by interaction patterns that are reflected in different neuroimaging modalities. On the basis of this perspective, we aimed to identify a convergent functional organization of the SPL using multimodal neuroimaging approaches. The SPL was first parcellated based on its structural connections as well as on its resting-state connectivity and coactivation patterns. Then, post hoc functional characterizations and connectivity analyses were performed for each subregion. The three types of connectivity-based parcellations consistently identified five subregions in the SPL of each hemisphere. The two anterior subregions were found to be primarily involved in action processes and in visually guided visuomotor functions, whereas the three posterior subregions were primarily associated with visual perception, spatial cognition, reasoning, working memory, and attention. This parcellation scheme for the SPL was further supported by revealing distinct connectivity patterns for each subregion in all the used modalities. These results thus indicate a convergent functional architecture of the SPL that can be revealed based on different types of connectivity and is reflected by different functions and interactions. © 2014 Wiley Periodicals, Inc.

Functional Organization of the Parahippocampal Cortex: Dissociable Roles for Context Representations and the Perception of Visual Scenes.

PubMed

Baumann, Oliver; Mattingley, Jason B

2016-02-24

The human parahippocampal cortex has been ascribed central roles in both visuospatial and mnemonic processes. More specifically, evidence suggests that the parahippocampal cortex subserves both the perceptual analysis of scene layouts as well as the retrieval of associative contextual memories. It remains unclear, however, whether these two functional roles can be dissociated within the parahippocampal cortex anatomically. Here, we provide evidence for a dissociation between neural activation patterns associated with visuospatial analysis of scenes and contextual mnemonic processing along the parahippocampal longitudinal axis. We used fMRI to measure parahippocampal responses while participants engaged in a task that required them to judge the contextual relatedness of scene and object pairs, which were presented either as words or pictures. Results from combined factorial and conjunction analyses indicated that the posterior section of parahippocampal cortex is driven predominantly by judgments associated with pictorial scene analysis, whereas its anterior section is more active during contextual judgments regardless of stimulus category (scenes vs objects) or modality (word vs picture). Activation maxima associated with visuospatial and mnemonic processes were spatially segregated, providing support for the existence of functionally distinct subregions along the parahippocampal longitudinal axis and suggesting that, in humans, the parahippocampal cortex serves as a functional interface between perception and memory systems. Copyright © 2016 the authors 0270-6474/16/362536-07$15.00/0.

Framework for community functioning: synthesis of stress gradient and resource partitioning concepts

PubMed Central

2017-01-01

To understand how communities function and generate abundance, I develop a framework integrating elements from the stress gradient and resource partitioning concepts. The framework suggests that guild abundance depends on environmental and spatial factors but also on inter-guild interactions (competitor or facilitator richness), which can alter the fundamental niche of constituent species in negative (competition) or positive direction (facilitation). Consequently, the environmental and spatial mechanisms driving guild abundance would differ across guilds and interaction modes. Using continental data on stream diatoms and physico-chemistry, the roles of these mechanisms were tested under three interaction modes—shared preference, distinct preference, and facilitative, whereby pairs of guilds exhibited, respectively, a dominance-tolerance tradeoff along a eutrophication gradient, specialization along a pH gradient, or a donor-recipient relationship along a nitrogen gradient. Representative of the shared preference mode were the motile (dominant) and low profile (tolerant) guilds, of the distinct preference mode—the acidophilous and alkaliphilous (low profile) guilds, and of the facilitative mode—nitrogen fixers (donors) and motile species (recipients). In each mode, the influences of environment, space (latitude and longitude), and competitor or facilitator richness on guild density were assessed by variance partitioning. Pure environment constrained most strongly the density of the dominant, the acidophilous, and the recipient guild in the shared preference, distinct preference, and facilitative mode, respectively, while spatial effects were important only for the low profile guild. Higher competitor richness was associated with lower density of the tolerant guild in the shared preference mode, both guilds in the distinct preference mode, and the donor guild in the facilitative mode. Conversely, recipient density in the facilitative mode increased with donor richness in stressful nitrogen-poor environments. Thus, diatom guild abundance patterns were determined primarily by biotic and/or environmental impacts and, with the exception of the low profile guild, were insensitive to spatial effects. This framework identifies major sources of variability in diatom guild abundance with implications for the understanding of biodiversity-ecosystem functioning. PMID:29018618

Mechanistic and Evolutionary Insights from Comparative Enzymology of Phosphomonoesterases and Phosphodiesterases across the Alkaline Phosphatase Superfamily

PubMed Central

2016-01-01

Naively one might have expected an early division between phosphate monoesterases and diesterases of the alkaline phosphatase (AP) superfamily. On the contrary, prior results and our structural and biochemical analyses of phosphate monoesterase PafA, from Chryseobacterium meningosepticum, indicate similarities to a superfamily phosphate diesterase [Xanthomonas citri nucleotide pyrophosphatase/phosphodiesterase (NPP)] and distinct differences from the three metal ion AP superfamily monoesterase, from Escherichia coli AP (EcAP). We carried out a series of experiments to map out and learn from the differences and similarities between these enzymes. First, we asked why there would be independent instances of monoesterases in the AP superfamily? PafA has a much weaker product inhibition and slightly higher activity relative to EcAP, suggesting that different metabolic evolutionary pressures favored distinct active-site architectures. Next, we addressed the preferential phosphate monoester and diester catalysis of PafA and NPP, respectively. We asked whether the >80% sequence differences throughout these scaffolds provide functional specialization for each enzyme’s cognate reaction. In contrast to expectations from this model, PafA and NPP mutants with the common subset of active-site groups embedded in each native scaffold had the same monoesterase:diesterase specificities; thus, the >107-fold difference in native specificities appears to arise from distinct interactions at a single phosphoryl substituent. We also uncovered striking mechanistic similarities between the PafA and EcAP monoesterases, including evidence for ground-state destabilization and functional active-site networks that involve different active-site groups but may play analogous catalytic roles. Discovering common network functions may reveal active-site architectural connections that are critical for function, and identifying regions of functional modularity may facilitate the design of new enzymes from existing promiscuous templates. More generally, comparative enzymology and analysis of catalytic promiscuity can provide mechanistic and evolutionary insights. PMID:27670607

Transition to an Aquatic Habitat Permitted the Repeated Loss of the Pleiotropic KLK8 Gene in Mammals

PubMed Central

Hecker, Nikolai; Sharma, Virag

2017-01-01

Abstract Kallikrein related peptidase 8 (KLK8; also called neuropsin) is a serine protease that plays distinct roles in the skin and hippocampus. In the skin, KLK8 influences keratinocyte proliferation and desquamation, and activates antimicrobial peptides in sweat. In the hippocampus, KLK8 affects memory acquisition. Here, we examined the evolution of KLK8 in mammals and discovered that, out of 70 placental mammals, KLK8 is exclusively lost in three independent fully-aquatic lineages, comprising dolphin, killer whale, minke whale, and manatee. In addition, while the sperm whale has an intact KLK8 reading frame, the gene evolves neutrally in this species. We suggest that the distinct functions of KLK8 likely became obsolete in the aquatic environment, leading to the subsequent loss of KLK8 in several fully-aquatic mammalian lineages. First, the cetacean and manatee skin lacks sweat glands as an adaptation to the aquatic environment, which likely made the epidermal function of KLK8 obsolete. Second, cetaceans and manatees exhibit a proportionally small hippocampus, which may have rendered the hippocampal functions of KLK8 obsolete. Together, our results shed light on the genomic changes that correlate with skin and neuroanatomical differences of aquatic mammals, and show that even pleiotropic genes can be lost during evolution if an environmental change nullifies the need for the different functions of such genes. PMID:29145610

Identification of a functionally distinct truncated BDNF mRNA splice variant and protein in Trachemys scripta elegans.

PubMed

Ambigapathy, Ganesh; Zheng, Zhaoqing; Li, Wei; Keifer, Joyce

2013-01-01

Brain-derived neurotrophic factor (BDNF) has a diverse functional role and complex pattern of gene expression. Alternative splicing of mRNA transcripts leads to further diversity of mRNAs and protein isoforms. Here, we describe the regulation of BDNF mRNA transcripts in an in vitro model of eyeblink classical conditioning and a unique transcript that forms a functionally distinct truncated BDNF protein isoform. Nine different mRNA transcripts from the BDNF gene of the pond turtle Trachemys scripta elegans (tBDNF) are selectively regulated during classical conditioning: exon I mRNA transcripts show no change, exon II transcripts are downregulated, while exon III transcripts are upregulated. One unique transcript that codes from exon II, tBDNF2a, contains a 40 base pair deletion in the protein coding exon that generates a truncated tBDNF protein. The truncated transcript and protein are expressed in the naïve untrained state and are fully repressed during conditioning when full-length mature tBDNF is expressed, thereby having an alternate pattern of expression in conditioning. Truncated BDNF is not restricted to turtles as a truncated mRNA splice variant has been described for the human BDNF gene. Further studies are required to determine the ubiquity of truncated BDNF alternative splice variants across species and the mechanisms of regulation and function of this newly recognized BDNF protein.

Identification of a Functionally Distinct Truncated BDNF mRNA Splice Variant and Protein in Trachemys scripta elegans

PubMed Central

Ambigapathy, Ganesh; Zheng, Zhaoqing; Li, Wei; Keifer, Joyce

2013-01-01

Brain-derived neurotrophic factor (BDNF) has a diverse functional role and complex pattern of gene expression. Alternative splicing of mRNA transcripts leads to further diversity of mRNAs and protein isoforms. Here, we describe the regulation of BDNF mRNA transcripts in an in vitro model of eyeblink classical conditioning and a unique transcript that forms a functionally distinct truncated BDNF protein isoform. Nine different mRNA transcripts from the BDNF gene of the pond turtle Trachemys scripta elegans (tBDNF) are selectively regulated during classical conditioning: exon I mRNA transcripts show no change, exon II transcripts are downregulated, while exon III transcripts are upregulated. One unique transcript that codes from exon II, tBDNF2a, contains a 40 base pair deletion in the protein coding exon that generates a truncated tBDNF protein. The truncated transcript and protein are expressed in the naïve untrained state and are fully repressed during conditioning when full-length mature tBDNF is expressed, thereby having an alternate pattern of expression in conditioning. Truncated BDNF is not restricted to turtles as a truncated mRNA splice variant has been described for the human BDNF gene. Further studies are required to determine the ubiquity of truncated BDNF alternative splice variants across species and the mechanisms of regulation and function of this newly recognized BDNF protein. PMID:23825634

Contributions of volumetrics of the hippocampus and thalamus to verbal memory in temporal lobe epilepsy patients.

PubMed

Stewart, Christopher C; Griffith, H Randall; Okonkwo, Ozioma C; Martin, Roy C; Knowlton, Robert K; Richardson, Elizabeth J; Hermann, Bruce P; Seidenberg, Michael

2009-02-01

Recent theories have posited that the hippocampus and thalamus serve distinct, yet related, roles in episodic memory. Whereas the hippocampus has been implicated in long-term memory encoding and storage, the thalamus, as a whole, has been implicated in the selection of items for subsequent encoding and the use of retrieval strategies. However, dissociating the memory impairment that occurs following thalamic injury as distinguished from that following hippocampal injury has proven difficult. This study examined relationships between MRI volumetric measures of the hippocampus and thalamus and their contributions to prose and rote verbal memory functioning in 18 patients with intractable temporal lobe epilepsy (TLE). Results revealed that bilateral hippocampal and thalamic volume independently predicted delayed prose verbal memory functioning. However, bilateral hippocampal, but not thalamic, volume predicted delayed rote verbal memory functioning. Follow-up analyses indicated that bilateral thalamic volume independently predicted immediate prose, but not immediate rote, verbal recall, whereas bilateral hippocampal volume was not associated with any of these immediate memory measures. These findings underscore the cognitive significance of thalamic atrophy in chronic TLE, demonstrating that hippocampal and thalamic volume make quantitatively, and perhaps qualitatively, distinct contributions to episodic memory functioning in TLE patients. They are also consistent with theories proposing that the hippocampus supports long-term memory encoding and storage, whereas the thalamus is implicated in the executive aspects of episodic memory.

Mutations in the Arabidopsis Peroxisomal ABC Transporter COMATOSE Allow Differentiation between Multiple Functions In Planta: Insights from an Allelic Series

PubMed Central

Dietrich, Daniela; Schmuths, Heike; Lousa, Carine De Marcos; Baldwin, Jocelyn M.; Baldwin, Stephen A.; Baker, Alison; Holdsworth, Michael J.

2009-01-01

COMATOSE (CTS), the Arabidopsis homologue of human Adrenoleukodystrophy protein (ALDP), is required for import of substrates for peroxisomal β-oxidation. A new allelic series and a homology model based on the bacterial ABC transporter, Sav1866, provide novel insights into structure-function relations of ABC subfamily D proteins. In contrast to ALDP, where the majority of mutations result in protein absence from the peroxisomal membrane, all CTS mutants produced stable protein. Mutation of conserved residues in the Walker A and B motifs in CTS nucleotide-binding domain (NBD) 1 resulted in a null phenotype but had little effect in NBD2, indicating that the NBDs are functionally distinct in vivo. Two alleles containing mutations in NBD1 outside the Walker motifs (E617K and C631Y) exhibited resistance to auxin precursors 2,4-dichlorophenoxybutyric acid (2,4-DB) and indole butyric acid (IBA) but were wild type in all other tests. The homology model predicted that the transmission interfaces are domain-swapped in CTS, and the differential effects of mutations in the conserved “EAA motif” of coupling helix 2 supported this prediction, consistent with distinct roles for each NBD. Our findings demonstrate that CTS functions can be separated by mutagenesis and the structural model provides a framework for interpretation of phenotypic data. PMID:19019987

Understanding the roles of nonstructural carbohydrates in forest trees - from what we can measure to what we want to know.

PubMed

Hartmann, Henrik; Trumbore, Susan

2016-07-01

Contents 386 I. 386 II. 388 III. 392 IV. 392 V. 396 VI. 399 399 References 399 SUMMARY: Carbohydrates provide the building blocks for plant structures as well as versatile resources for metabolic processes. The nonstructural carbohydrates (NSC), mainly sugars and starch, fulfil distinct functional roles, including transport, energy metabolism and osmoregulation, and provide substrates for the synthesis of defence compounds or exchange with symbionts involved in nutrient acquisition or defence. At the whole-plant level, NSC storage buffers the asynchrony of supply and demand on diel, seasonal or decadal temporal scales and across plant organs. Despite its central role in plant function and in stand-level carbon cycling, our understanding of storage dynamics, its controls and response to environmental stresses is very limited, even after a century of research. This reflects the fact that often storage is defined by what we can measure, that is, NSC concentrations, and the interpretation of these as a proxy for a single function, storage, rather than the outcome of a range of NSC source and sink functions. New isotopic tools allow direct quantification of timescales involved in NSC dynamics, and show that NSC-C fixed years to decades previously is used to support tree functions. Here we review recent advances, with emphasis on the context of the interactions between NSC, drought and tree mortality. © 2016 The Authors. New Phytologist © 2016 New Phytologist Trust.

Heat shock protein 83 plays pleiotropic roles in embryogenesis, longevity, and fecundity of the pea aphid Acyrthosiphon pisum.

PubMed

Will, Torsten; Schmidtberg, Henrike; Skaljac, Marisa; Vilcinskas, Andreas

2017-01-01

Heat shock protein 83 (HSP83) is homologous to the chaperone HSP90. It has pleiotropic functions in Drosophila melanogaster, including the control of longevity and fecundity, and facilitates morphological evolution by buffering cryptic deleterious mutations in wild populations. In the pea aphid Acyrthosiphon pisum, HSP83 expression is moderately induced by bacterial infection but upregulated more strongly in response to heat stress and fungal infection. Stress-inducible heat shock proteins are of considerable evolutionary and ecological importance because they are known to buffer environmental variation and to influence fitness under non-optimal conditions. To investigate the functions of HSP83 in viviparous aphids, we used RNA interference to attenuate its expression and studied the impact on complex parameters. The RNA interference (RNAi)-mediated depletion of HSP83 expression in A. pisum reduced both longevity and fecundity, suggesting this chaperone has an evolutionarily conserved function in insects. Surprisingly, HSP83 depletion reduced the number of viviparous offspring while simultaneously increasing the number of premature nymphs developing in the ovaries, suggesting an unexpected role in aphid embryogenesis and eclosion. The present study indicates that reduced HSP83 expression in A. pisum reveals both functional similarities and differences compared with its reported roles in holometabolous insects. Its impact on aphid lifespan, fecundity, and embryogenesis suggests a function that determines their fitness. This could be achieved by targeting different client proteins, recruiting distinct co-chaperones or transposon activation.

The role of the oncogenic Rab35 in cancer invasion, metastasis, and immune evasion, especially in leukemia.

PubMed

Villagomez, Fabian R; Medina-Contreras, Oscar; Cerna-Cortes, Jorge Francisco; Patino-Lopez, Genaro

2018-05-28

The study of cancer has allowed researchers to describe some biological characteristics that tumor cells acquire during their development, known as the "hallmarks of cancer" but more research is needed to expand our knowledge about cancer biology and to generate new strategies of treatment. The role that RabGTPases might play in some hallmarks of cancer represents interesting areas of study since these proteins are frequently altered in cancer. However, their participation is not well known. Recently, Rab35was recognized as an oncogenic RabGTPase and and because of its association with different cellular functions, distinctly important in immune cells, a possible role of Rab35 in leukemia can be suggested. Nevertheless, the involvement of Rab35 in cancer remains poorly understood and its possible specific role in leukemia remains unknown. In this review, we analyze general aspects of the participation of RabGTPases in cancer, and especially, the plausible role of Rab35 in leukemia.

Roles of A-Kinase Anchoring Proteins and Phosphodiesterases in the Cardiovascular System

PubMed Central

Ercu, Maria; Klussmann, Enno

2018-01-01

A-kinase anchoring proteins (AKAPs) and cyclic nucleotide phosphodiesterases (PDEs) are essential enzymes in the cyclic adenosine 3′-5′ monophosphate (cAMP) signaling cascade. They establish local cAMP pools by controlling the intensity, duration and compartmentalization of cyclic nucleotide-dependent signaling. Various members of the AKAP and PDE families are expressed in the cardiovascular system and direct important processes maintaining homeostatic functioning of the heart and vasculature, e.g., the endothelial barrier function and excitation-contraction coupling. Dysregulation of AKAP and PDE function is associated with pathophysiological conditions in the cardiovascular system including heart failure, hypertension and atherosclerosis. A number of diseases, including autosomal dominant hypertension with brachydactyly (HTNB) and type I long-QT syndrome (LQT1), result from mutations in genes encoding for distinct members of the two classes of enzymes. This review provides an overview over the AKAPs and PDEs relevant for cAMP compartmentalization in the heart and vasculature and discusses their pathophysiological role as well as highlights the potential benefits of targeting these proteins and their protein-protein interactions for the treatment of cardiovascular diseases. PMID:29461511

Interactions between macrophage/Kupffer cells and hepatocytes in surgical sepsis

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

West, M.A.

Experiments were performed to investigate the role of Kupffer cell/macrophage interactions with hepatocytes in modulating liver function during infections using direct in vitro cocultivation of rat macrophages or Kupffer cells with rat hepatocytes. Protein synthesis was assayed as a sensitive indicator of integrated hepatocellular function by measuring {sup 3}H-leucine incorporation into hepatocyte protein. Septic stimuli such as lipoploysaccharide and killed bacteria were added to cocultures of hepatocytes and macrophages or Kupffer cells and the responses compared to hepatocytes alone. Information about the types of proteins synthesized by hepatocytes under various culture conditions was determined using polyacrylamide gel electrophoresis and autoradiography.more » These experiments showed that septic stimuli alter the amount and type of protein synthesized by hepatocytes and had no direct effect on hepatocytes in the absence of macrophages or Kupffer cells. The mediator(s) appears to be a heat labile, soluble monokine(s) which is distinct from interleukin-1 or tumor necrosis factor. The important role of Kupffer cells/macrophages in mediating alterations in hepatocellular function in sepsis may ultimately improve patient care.« less

PHF6 Degrees of Separation: The Multifaceted Roles of a Chromatin Adaptor Protein.

PubMed

Todd, Matthew A M; Ivanochko, Danton; Picketts, David J

2015-06-19

The importance of chromatin regulation to human disease is highlighted by the growing number of mutations identified in genes encoding chromatin remodeling proteins. While such mutations were first identified in severe developmental disorders, or in specific cancers, several genes have been implicated in both, including the plant homeodomain finger protein 6 (PHF6) gene. Indeed, germline mutations in PHF6 are the cause of the Börjeson-Forssman-Lehmann X-linked intellectual disability syndrome (BFLS), while somatic PHF6 mutations have been identified in T-cell acute lymphoblastic leukemia (T-ALL) and acute myeloid leukemia (AML). Studies from different groups over the last few years have made a significant impact towards a functional understanding of PHF6 protein function. In this review, we summarize the current knowledge of PHF6 with particular emphasis on how it interfaces with a distinct set of interacting partners and its functional roles in the nucleoplasm and nucleolus. Overall, PHF6 is emerging as a key chromatin adaptor protein critical to the regulation of neurogenesis and hematopoiesis.

Scavenger Receptors: Emerging Roles in Cancer Biology and Immunology

PubMed Central

Yu, Xiaofei; Guo, Chunqing; Fisher, Paul B.; Subjeck, John R.; Wang, Xiang-Yang

2015-01-01

Scavenger receptors constitute a large family of evolutionally conserved protein molecules that are structurally and functionally diverse. Although scavenger receptors were originally identified based on their capacity to scavenge modified lipoproteins, these molecules have been shown to recognize and bind to a broad spectrum of ligands, including modified and unmodified host-derived molecules or microbial components. As a major subset of innate pattern recognition receptors, scavenger receptors are mainly expressed on myeloid cells and function in a wide range of biological processes, such as endocytosis, adhesion, lipid transport, antigen presentation, and pathogen clearance. In addition to playing a crucial role in maintenance of host homeostasis, scavenger receptors have been implicated in the pathogenesis of a number of diseases, e.g., atherosclerosis, neurodegeneration, or metabolic disorders. Emerging evidence has begun to reveal these receptor molecules as important regulators of tumor behavior and host immune responses to cancer. This review summarizes our current understanding on the newly identified, distinct functions of scavenger receptors in cancer biology and immunology. The potential of scavenger receptors as diagnostic biomarkers and novel targets for therapeutic interventions to treat malignancies is also highlighted. PMID:26216637

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.

The Walker B motif in avian FANCM is required to limit sister chromatid exchanges but is dispensable for DNA crosslink repair

PubMed Central

Rosado, Ivan V.; Niedzwiedz, Wojciech; Alpi, Arno F.; Patel, Ketan J.

2009-01-01

FANCM, the most highly conserved component of the Fanconi Anaemia (FA) pathway can resolve recombination intermediates and remodel synthetic replication forks. However, it is not known if these activities are relevant to how this conserved protein activates the FA pathway and promotes DNA crosslink repair. Here we use chicken DT40 cells to systematically dissect the function of the helicase and nuclease domains of FANCM. Our studies reveal that these domains contribute distinct roles in the tolerance of crosslinker, UV light and camptothecin-induced DNA damage. Although the complete helicase domain is critical for crosslink repair, a predicted inactivating mutation of the Walker B box domain has no impact on FA pathway associated functions. However, this mutation does result in elevated sister chromatid exchanges (SCE). Furthermore, our genetic dissection indicates that FANCM functions with the Blm helicase to suppress spontaneous SCE events. Overall our results lead us to reappraise the role of helicase domain associated activities of FANCM with respect to the activation of the FA pathway, crosslink repair and in the resolution of recombination intermediates. PMID:19465393

Functionalism and consciousness.

PubMed

Shoemaker, S

1993-01-01

It is widely held that a mental state and the subject's introspective belief about it are always 'distinct existences' and only contingently connected. This suggests that for each sort of mental state there could be a creature that is introspectively 'blind' with respect to states of that sort, meaning that while it is capable of having such states, and of conceiving of itself as having them, it is totally without introspective access to its states of that sort. It is argued here that introspective blindness with respect to many sorts of mental states, in particular beliefs and sensory states, is not a possibility, because it is incompatible with requirements of rationality that are internal to the functional roles that are constitutive of these states. Introspective accessibility is essential to the functional roles of such mental states when the conceptual and cognitive resources of the subject of those states are sufficiently rich to make beliefs and thoughts about them a possibility. This is a version of the view that such states are necessarily self-intimating and is incompatible with the perceptual model of introspection favoured by some functionalists as well as by many non-functionalists.

Plasma and cellular fibronectin: distinct and independent functions during tissue repair

PubMed Central

2011-01-01

Fibronectin (FN) is a ubiquitous extracellular matrix (ECM) glycoprotein that plays vital roles during tissue repair. The plasma form of FN circulates in the blood, and upon tissue injury, is incorporated into fibrin clots to exert effects on platelet function and to mediate hemostasis. Cellular FN is then synthesized and assembled by cells as they migrate into the clot to reconstitute damaged tissue. The assembly of FN into a complex three-dimensional matrix during physiological repair plays a key role not only as a structural scaffold, but also as a regulator of cell function during this stage of tissue repair. FN fibrillogenesis is a complex, stepwise process that is strictly regulated by a multitude of factors. During fibrosis, there is excessive deposition of ECM, of which FN is one of the major components. Aberrant FN-matrix assembly is a major contributing factor to the switch from normal tissue repair to misregulated fibrosis. Understanding the mechanisms involved in FN assembly and how these interplay with cellular, fibrotic and immune responses may reveal targets for the future development of therapies to regulate aberrant tissue-repair processes. PMID:21923916

Temporal dynamics of retinal and extraretinal signals in the FEFsem during smooth pursuit eye movements

PubMed Central

Bakst, Leah; Fleuriet, Jérome

2017-01-01

Neurons in the smooth eye movement subregion of the frontal eye field (FEFsem) are known to play an important role in voluntary smooth pursuit eye movements. Underlying this function are projections to parietal and prefrontal visual association areas and subcortical structures, all known to play vital but differing roles in the execution of smooth pursuit. Additionally, the FEFsem has been shown to carry a diverse array of signals (e.g., eye velocity, acceleration, gain control). We hypothesized that distinct subpopulations of FEFsem neurons subserve these diverse functions and projections, and that the relative weights of retinal and extraretinal signals could form the basis for categorization of units. To investigate this, we used a step-ramp tracking task with a target blink to determine the relative contributions of retinal and extraretinal signals in individual FEFsem neurons throughout pursuit. We found that the contributions of retinal and extraretinal signals to neuronal activity and behavior change throughout the time course of pursuit. A clustering algorithm revealed three distinct neuronal subpopulations: cluster 1 was defined by a higher sensitivity to eye velocity, acceleration, and retinal image motion; cluster 2 had greater activity during blinks; and cluster 3 had significantly greater eye position sensitivity. We also performed a comparison with a sample of medial superior temporal neurons to assess similarities and differences between the two areas. Our results indicate the utility of simple tests such as the target blink for parsing the complex and multifaceted roles of cortical areas in behavior. NEW & NOTEWORTHY The frontal eye field (FEF) is known to play a critical role in volitional smooth pursuit, carrying a variety of signals that are distributed throughout the brain. This study used a novel application of a target blink task during step ramp tracking to determine, in combination with a clustering algorithm, the relative contributions of retinal and extraretinal signals to FEF activity and the extent to which these contributions could form the basis for a categorization of neurons. PMID:28202571

454 Transcriptome sequencing suggests a role for two-component signalling in cellularization and differentiation of barley endosperm transfer cells.

PubMed

Thiel, Johannes; Hollmann, Julien; Rutten, Twan; Weber, Hans; Scholz, Uwe; Weschke, Winfriede

2012-01-01

Cell specification and differentiation in the endosperm of cereals starts at the maternal-filial boundary and generates the endosperm transfer cells (ETCs). Besides the importance in assimilate transfer, ETCs are proposed to play an essential role in the regulation of endosperm differentiation by affecting development of proximate endosperm tissues. We attempted to identify signalling elements involved in early endosperm differentiation by using a combination of laser-assisted microdissection and 454 transcriptome sequencing. 454 sequencing of the differentiating ETC region from the syncytial state until functionality in transfer processes captured a high proportion of novel transcripts which are not available in existing barley EST databases. Intriguingly, the ETC-transcriptome showed a high abundance of elements of the two-component signalling (TCS) system suggesting an outstanding role in ETC differentiation. All components and subfamilies of the TCS, including distinct kinds of membrane-bound receptors, have been identified to be expressed in ETCs. The TCS system represents an ancient signal transduction system firstly discovered in bacteria and has previously been shown to be co-opted by eukaryotes, like fungi and plants, whereas in animals and humans this signalling route does not exist. Transcript profiling of TCS elements by qRT-PCR suggested pivotal roles for specific phosphorelays activated in a coordinated time flow during ETC cellularization and differentiation. ETC-specificity of transcriptionally activated TCS phosphorelays was assessed for early differentiation and cellularization contrasting to an extension of expression to other grain tissues at the beginning of ETC maturation. Features of candidate genes of distinct phosphorelays and transcriptional activation of genes putatively implicated in hormone signalling pathways hint at a crosstalk of hormonal influences, putatively ABA and ethylene, and TCS signalling. Our findings suggest an integral function for the TCS in ETC differentiation possibly coupled to sequent hormonal regulation by ABA and ethylene.

454 Transcriptome Sequencing Suggests a Role for Two-Component Signalling in Cellularization and Differentiation of Barley Endosperm Transfer Cells

PubMed Central

Thiel, Johannes; Hollmann, Julien; Rutten, Twan; Weber, Hans; Scholz, Uwe; Weschke, Winfriede

2012-01-01

Background Cell specification and differentiation in the endosperm of cereals starts at the maternal-filial boundary and generates the endosperm transfer cells (ETCs). Besides the importance in assimilate transfer, ETCs are proposed to play an essential role in the regulation of endosperm differentiation by affecting development of proximate endosperm tissues. We attempted to identify signalling elements involved in early endosperm differentiation by using a combination of laser-assisted microdissection and 454 transcriptome sequencing. Principal Findings 454 sequencing of the differentiating ETC region from the syncytial state until functionality in transfer processes captured a high proportion of novel transcripts which are not available in existing barley EST databases. Intriguingly, the ETC-transcriptome showed a high abundance of elements of the two-component signalling (TCS) system suggesting an outstanding role in ETC differentiation. All components and subfamilies of the TCS, including distinct kinds of membrane-bound receptors, have been identified to be expressed in ETCs. The TCS system represents an ancient signal transduction system firstly discovered in bacteria and has previously been shown to be co-opted by eukaryotes, like fungi and plants, whereas in animals and humans this signalling route does not exist. Transcript profiling of TCS elements by qRT-PCR suggested pivotal roles for specific phosphorelays activated in a coordinated time flow during ETC cellularization and differentiation. ETC-specificity of transcriptionally activated TCS phosphorelays was assessed for early differentiation and cellularization contrasting to an extension of expression to other grain tissues at the beginning of ETC maturation. Features of candidate genes of distinct phosphorelays and transcriptional activation of genes putatively implicated in hormone signalling pathways hint at a crosstalk of hormonal influences, putatively ABA and ethylene, and TCS signalling. Significance Our findings suggest an integral function for the TCS in ETC differentiation possibly coupled to sequent hormonal regulation by ABA and ethylene. PMID:22848641

Cognitive performance in healthy older adults relates to spontaneous switching between states of functional connectivity during rest.

PubMed

Cabral, Joana; Vidaurre, Diego; Marques, Paulo; Magalhães, Ricardo; Silva Moreira, Pedro; Miguel Soares, José; Deco, Gustavo; Sousa, Nuno; Kringelbach, Morten L

2017-07-11

Growing evidence has shown that brain activity at rest slowly wanders through a repertoire of different states, where whole-brain functional connectivity (FC) temporarily settles into distinct FC patterns. Nevertheless, the functional role of resting-state activity remains unclear. Here, we investigate how the switching behavior of resting-state FC relates with cognitive performance in healthy older adults. We analyse resting-state fMRI data from 98 healthy adults previously categorized as being among the best or among the worst performers in a cohort study of >1000 subjects aged 50+ who underwent neuropsychological assessment. We use a novel approach focusing on the dominant FC pattern captured by the leading eigenvector of dynamic FC matrices. Recurrent FC patterns - or states - are detected and characterized in terms of lifetime, probability of occurrence and switching profiles. We find that poorer cognitive performance is associated with weaker FC temporal similarity together with altered switching between FC states. These results provide new evidence linking the switching dynamics of FC during rest with cognitive performance in later life, reinforcing the functional role of resting-state activity for effective cognitive processing.

PARylation of the forkhead-associated domain protein DAWDLE regulates plant immunity.

PubMed

Feng, Baomin; Ma, Shisong; Chen, Sixue; Zhu, Ning; Zhang, Shuxin; Yu, Bin; Yu, Yu; Le, Brandon; Chen, Xuemei; Dinesh-Kumar, Savithramma P; Shan, Libo; He, Ping

2016-12-01

Protein poly(ADP-ribosyl)ation (PARylation) primarily catalyzed by poly(ADP-ribose) polymerases (PARPs) plays a crucial role in controlling various cellular responses. However, PARylation targets and their functions remain largely elusive. Here, we deployed an Arabidopsis protein microarray coupled with in vitro PARylation assays to globally identify PARylation targets in plants. Consistent with the essential role of PARylation in plant immunity, the forkhead-associated (FHA) domain protein DAWDLE (DDL), one of PARP2 targets, positively regulates plant defense to both adapted and non-adapted pathogens. Arabidopsis PARP2 interacts with and PARylates DDL, which was enhanced upon treatment of bacterial flagellin. Mass spectrometry and mutagenesis analysis identified multiple PARylation sites of DDL by PARP2. Genetic complementation assays indicate that DDL PARylation is required for its function in plant immunity. In contrast, DDL PARylation appears to be dispensable for its previously reported function in plant development partially mediated by the regulation of microRNA biogenesis. Our study uncovers many previously unknown PARylation targets and points to the distinct functions of DDL in plant immunity and development mediated by protein PARylation and small RNA biogenesis, respectively. © 2016 The Authors.

Lessons from bacterial homolog of tubulin, FtsZ for microtubule dynamics.

PubMed

Battaje, Rachana Rao; Panda, Dulal

2017-09-01

FtsZ, a homolog of tubulin, is found in almost all bacteria and archaea where it has a primary role in cytokinesis. Evidence for structural homology between FtsZ and tubulin came from their crystal structures and identification of the GTP box. Tubulin and FtsZ constitute a distinct family of GTPases and show striking similarities in many of their polymerization properties. The differences between them, more so, the complexities of microtubule dynamic behavior in comparison to that of FtsZ, indicate that the evolution to tubulin is attributable to the incorporation of the complex functionalities in higher organisms. FtsZ and microtubules function as polymers in cell division but their roles differ in the division process. The structural and partial functional homology has made the study of their dynamic properties more interesting. In this review, we focus on the application of the information derived from studies on FtsZ dynamics to study microtubule dynamics and vice versa. The structural and functional aspects that led to the establishment of the homology between the two proteins are explained to emphasize the network of FtsZ and microtubule studies and how they are connected. © 2017 Society for Endocrinology.

Kub5-Hera, the human Rtt103 homolog, plays dual functional roles in transcription termination and DNA repair

PubMed Central

Morales, Julio C.; Richard, Patricia; Rommel, Amy; Fattah, Farjana J.; Motea, Edward A.; Patidar, Praveen L.; Xiao, Ling; Leskov, Konstantin; Wu, Shwu-Yuan; Hittelman, Walter N.; Chiang, Cheng-Ming; Manley, James L.; Boothman, David A.

2014-01-01

Functions of Kub5-Hera (In Greek Mythology Hera controlled Artemis) (K-H), the human homolog of the yeast transcription termination factor Rtt103, remain undefined. Here, we show that K-H has functions in both transcription termination and DNA double-strand break (DSB) repair. K-H forms distinct protein complexes with factors that repair DSBs (e.g. Ku70, Ku86, Artemis) and terminate transcription (e.g. RNA polymerase II). K-H loss resulted in increased basal R-loop levels, DSBs, activated DNA-damage responses and enhanced genomic instability. Significantly lowered Artemis protein levels were detected in K-H knockdown cells, which were restored with specific K-H cDNA re-expression. K-H deficient cells were hypersensitive to cytotoxic agents that induce DSBs, unable to reseal complex DSB ends, and showed significantly delayed γ-H2AX and 53BP1 repair-related foci regression. Artemis re-expression in K-H-deficient cells restored DNA-repair function and resistance to DSB-inducing agents. However, R loops persisted consistent with dual roles of K-H in transcription termination and DSB repair. PMID:24589584

The role of the NG2 proteoglycan in OPC and CNS network function.

PubMed

Sakry, Dominik; Trotter, Jacqueline

2016-05-01

In the normal mammalian CNS, the NG2 proteoglycan is expressed by oligodendrocyte precursor cells (OPC) but not by any other neural cell-type. NG2 is a type-1 membrane protein, exerting multiple roles in the CNS including intracellular signaling within the OPC, with effects on migration, cytoskeleton interaction and target gene regulation. It has been recently shown that the extracellular region of NG2, in addition to an adhesive function, acts as a soluble ECM component with the capacity to alter defined neuronal network properties. This region of NG2 is thus endowed with neuromodulatory properties. In order to generate biologically active fragments yielding these properties, the sequential cleavage of the NG2 protein by α- and γ-secretases occurs. The basal level of constitutive cleavage is stimulated by neuronal network activity. This processing leads to 4 major NG2 fragments which all have been associated with distinct biological functions. Here we summarize these functions, focusing on recent discoveries and their implications for the CNS. This article is part of a Special Issue entitled SI:NG2-glia(Invited only). Copyright © 2015 Elsevier B.V. All rights reserved.

Kub5-Hera, the human Rtt103 homolog, plays dual functional roles in transcription termination and DNA repair.

PubMed

Morales, Julio C; Richard, Patricia; Rommel, Amy; Fattah, Farjana J; Motea, Edward A; Patidar, Praveen L; Xiao, Ling; Leskov, Konstantin; Wu, Shwu-Yuan; Hittelman, Walter N; Chiang, Cheng-Ming; Manley, James L; Boothman, David A

2014-04-01

Functions of Kub5-Hera (In Greek Mythology Hera controlled Artemis) (K-H), the human homolog of the yeast transcription termination factor Rtt103, remain undefined. Here, we show that K-H has functions in both transcription termination and DNA double-strand break (DSB) repair. K-H forms distinct protein complexes with factors that repair DSBs (e.g. Ku70, Ku86, Artemis) and terminate transcription (e.g. RNA polymerase II). K-H loss resulted in increased basal R-loop levels, DSBs, activated DNA-damage responses and enhanced genomic instability. Significantly lowered Artemis protein levels were detected in K-H knockdown cells, which were restored with specific K-H cDNA re-expression. K-H deficient cells were hypersensitive to cytotoxic agents that induce DSBs, unable to reseal complex DSB ends, and showed significantly delayed γ-H2AX and 53BP1 repair-related foci regression. Artemis re-expression in K-H-deficient cells restored DNA-repair function and resistance to DSB-inducing agents. However, R loops persisted consistent with dual roles of K-H in transcription termination and DSB repair.

Distinct phylogenetic relationships and biochemical properties of Arabidopsis ovarian tumor-related deubiquitinases support their functional differentiation

PubMed Central

Radjacommare, Ramalingam; Usharani, Raju; Kuo, Chih-Horng; Fu, Hongyong

2014-01-01

The reverse reaction of ubiquitylation is catalyzed by different classes of deubiquitylation enzymes (DUBs), including ovarian tumor domain (OTU)-containing DUBs; experiments using Homo sapiens proteins have demonstrated that OTU DUBs modulate various cellular processes. With the exception of OTLD1, plant OTU DUBs have not been characterized. We identified 12 Arabidopsis thaliana OTU loci and analyzed 11 of the encoded proteins in vitro to determine their preferences for the ubiquitin (UB) chains of M1, K48, and K63 linkages as well as the UB-/RUB-/SUMO-GST fusions. The A. thaliana OTU DUBs were shown to be cysteine proteases and classified into four groups with distinct linkage preferences: OTU1 (M1 = K48 > K63), OTU3/4/7/10 (K63 > K48 > M1), OTU2/9 (K48 = K63), and OTU5/11/12/OTLD1 (inactive). Five active OTU DUBs (OTU3/4/7/9/10) also cleaved RUB fusion. OTU1/3/4 cleaved M1 UB chains, suggesting a possible role for M1 chains in plant cellular signaling. The different substrate specificities of the various A. thaliana OTU DUBs indicate the involvement of distinct structural elements; for example, the OTU1 oxyanion residue D89 is essential for cleaving isopeptide bond-linked chains but dispensable for M1 chains. UB-binding activities were detected only for OTU2 and OTLD1, with distinct linkage preferences. These differences in biochemical properties support the involvement of A. thaliana OTU DUBs in different functions. Moreover, based on the established phylogenetic tree, plant- and H. sapiens-specific clades exist, which suggests that the proteins within these clades have taxa-specific functions. We also detected five OTU clades that are conserved across species, which suggests that the orthologs in different species within each clade are involved in conserved cellular processes, such as ERAD and DNA damage responses. However, different linkage preferences have been detected among potential cross-species OTU orthologs, indicating functional and mechanistic differentiation. PMID:24659992

A Discussion on Uncertainty Representation and Interpretation in Model-Based Prognostics Algorithms based on Kalman Filter Estimation Applied to Prognostics of Electronics Components

NASA Technical Reports Server (NTRS)

Celaya, Jose R.; Saxen, Abhinav; Goebel, Kai

2012-01-01

This article discusses several aspects of uncertainty representation and management for model-based prognostics methodologies based on our experience with Kalman Filters when applied to prognostics for electronics components. In particular, it explores the implications of modeling remaining useful life prediction as a stochastic process and how it relates to uncertainty representation, management, and the role of prognostics in decision-making. A distinction between the interpretations of estimated remaining useful life probability density function and the true remaining useful life probability density function is explained and a cautionary argument is provided against mixing interpretations for the two while considering prognostics in making critical decisions.