Functional interplay between Mediator and TFIIB in preinitiation complex assembly in relation to promoter architecture.

PubMed

Eychenne, Thomas; Novikova, Elizaveta; Barrault, Marie-Bénédicte; Alibert, Olivier; Boschiero, Claire; Peixeiro, Nuno; Cornu, David; Redeker, Virginie; Kuras, Laurent; Nicolas, Pierre; Werner, Michel; Soutourina, Julie

2016-09-15

Mediator is a large coregulator complex conserved from yeast to humans and involved in many human diseases, including cancers. Together with general transcription factors, it stimulates preinitiation complex (PIC) formation and activates RNA polymerase II (Pol II) transcription. In this study, we analyzed how Mediator acts in PIC assembly using in vivo, in vitro, and in silico approaches. We revealed an essential function of the Mediator middle module exerted through its Med10 subunit, implicating a key interaction between Mediator and TFIIB. We showed that this Mediator-TFIIB link has a global role on PIC assembly genome-wide. Moreover, the amplitude of Mediator's effect on PIC formation is gene-dependent and is related to the promoter architecture in terms of TATA elements, nucleosome occupancy, and dynamics. This study thus provides mechanistic insights into the coordinated function of Mediator and TFIIB in PIC assembly in different chromatin contexts. © 2016 Eychenne et al.; Published by Cold Spring Harbor Laboratory Press.

Neuroimaging explanations of age-related differences in task performance.

PubMed

Steffener, Jason; Barulli, Daniel; Habeck, Christian; Stern, Yaakov

2014-01-01

Advancing age affects both cognitive performance and functional brain activity and interpretation of these effects has led to a variety of conceptual research models without always explicitly linking the two effects. However, to best understand the multifaceted effects of advancing age, age differences in functional brain activity need to be explicitly tied to the cognitive task performance. This work hypothesized that age-related differences in task performance are partially explained by age-related differences in functional brain activity and formally tested these causal relationships. Functional MRI data was from groups of young and old adults engaged in an executive task-switching experiment. Analyses were voxel-wise testing of moderated-mediation and simple mediation statistical path models to determine whether age group, brain activity and their interaction explained task performance in regions demonstrating an effect of age group. Results identified brain regions whose age-related differences in functional brain activity significantly explained age-related differences in task performance. In all identified locations, significant moderated-mediation relationships resulted from increasing brain activity predicting worse (slower) task performance in older but not younger adults. Findings suggest that advancing age links task performance to the level of brain activity. The overall message of this work is that in order to understand the role of functional brain activity on cognitive performance, analysis methods should respect theoretical relationships. Namely, that age affects brain activity and brain activity is related to task performance.

Nitric oxide mediates insect cellular immunity via phospholipase A2 activation

USDA-ARS?s Scientific Manuscript database

After infection or invasion is recognized, biochemical mediators act in signaling insect immune functions. These include biogenic amines, insect cytokines, eicosanoids and nitric oxide (NO). Treating insects or isolated hemocyte populations with different mediators often leads to similar results. Se...

Parent-Reported Behavioral and Psychiatric Problems Mediate the Relationship between Sleep-Disordered Breathing and Cognitive Deficits in School-Aged Children.

PubMed

Smith, Dale L; Gozal, David; Hunter, Scott J; Kheirandish-Gozal, Leila

2017-01-01

Numerous studies over the past several decades have illustrated that children who suffer from sleep-disordered breathing (SDB) are at greater risk for cognitive, behavioral, and psychiatric problems. Although behavioral problems have been proposed as a potential mediator between SDB and cognitive functioning, these relationships have not been critically examined. This analysis is based on a community-based cohort of 1,115 children who underwent overnight polysomnography, and cognitive and behavioral phenotyping. Structural model of the relationships between SDB, behavior, and cognition, and two recently developed mediation approaches based on propensity score weighting and resampling were used to assess the mediational role of parent-reported behavior and psychiatric problems in the relationship between SDB and cognitive functioning. Multiple models utilizing two different SDB definitions further explored direct effects of SDB on cognition as well as indirect effects through behavioral pathology. All models were adjusted for age, sex, race, BMI z -score, and asthma status. Indirect effects of SDB through behavior problems were significant in all mediation models, while direct effects of SDB on cognition were not. The findings were consistent across different mediation procedures and remained essentially unaltered when different criteria for SDB, behavior, and cognition were used. Potential effects of SDB on cognitive functioning appear to occur through behavioral problems that are detectable in this pediatric population. Thus, early attentional or behavioral pathology may be implicated in the cognitive functioning deficits associated with SDB, and may present an early morbidity-related susceptibility biomarker.

Neuro-cognition and social cognition elements of social functioning and social quality of life.

PubMed

Hasson-Ohayon, Ilanit; Mashiach-Eizenberg, Michal; Arnon-Ribenfeld, Nitzan; Kravetz, Shlomo; Roe, David

2017-12-01

Previous studies have shown that deficits in social cognition mediate the association between neuro-cognition and functional outcome. Based on these findings, the current study presents an examination of the mediating role of social cognition and includes two different outcomes: social functioning assessed by objective observer and social quality of life assessed by subjective self-report. Instruments measuring different aspects of social cognition, cognitive ability, social functioning and social quality of life were administered to 131 participants who had a diagnosis of a serious mental illness. Results showed that emotion recognition and attributional bias were significant mediators such that cognitive assessment was positively related to both, which in turn, were negatively related to SQoL. While one interpretation of the data suggests that deficits in emotion recognition may serve as a possible defense mechanism, future studies should re-assess this idea. Copyright © 2017 Elsevier B.V. All rights reserved.

Plant Mediator complex and its critical functions in transcription regulation.

PubMed

Yang, Yan; Li, Ling; Qu, Li-Jia

2016-02-01

The Mediator complex is an important component of the eukaryotic transcriptional machinery. As an essential link between transcription factors and RNA polymerase II, the Mediator complex transduces diverse signals to genes involved in different pathways. The plant Mediator complex was recently purified and comprises conserved and specific subunits. It functions in concert with transcription factors to modulate various responses. In this review, we summarize the recent advances in understanding the plant Mediator complex and its diverse roles in plant growth, development, defense, non-coding RNA production, response to abiotic stresses, flowering, genomic stability and metabolic homeostasis. In addition, the transcription factors interacting with the Mediator complex are also highlighted. © 2015 Institute of Botany, Chinese Academy of Sciences.

Sources of Disconnection in Neurocognitive Aging: Cerebral White Matter Integrity, Resting-state Functional Connectivity, and White Matter Hyperintensity Volume

PubMed Central

Madden, David J.; Parks, Emily L.; Tallman, Catherine W.; Boylan, Maria A.; Hoagey, David A.; Cocjin, Sally B.; Packard, Lauren E.; Johnson, Micah A.; Chou, Ying-hui; Potter, Guy G.; Chen, Nan-kuei; Siciliano, Rachel E.; Monge, Zachary A.; Honig, Jesse A.; Diaz, Michele T.

2017-01-01

Age-related decline in fluid cognition can be characterized as a disconnection among specific brain structures, leading to a decline in functional efficiency. The potential sources of disconnection, however, are unclear. We investigated imaging measures of cerebral white matter integrity, resting-state functional connectivity, and white matter hyperintensity (WMH) volume as mediators of the relation between age and fluid cognition, in 145 healthy, community-dwelling adults 19–79 years of age. At a general level of analysis, with a single composite measure of fluid cognition and single measures of each of the three imaging modalities, age exhibited an independent influence on the cognitive and imaging measures, and the imaging variables did not mediate the age-cognition relation. At a more specific level of analysis, resting-state functional connectivity of sensorimotor networks was a significant mediator of the age-related decline in executive function. These findings suggest that different levels of analysis lead to different models of neurocognitive disconnection, and that resting-state functional connectivity, in particular, may contribute to age-related decline in executive function. PMID:28389085

Does self-efficacy mediate functional change in older adults participating in an exercise program after hip fracture? A randomized control trial

PubMed Central

Latham, Nancy K.; Ni, Pengsheng; Jette, Alan M.

2015-01-01

Objectives This study examined whether self-efficacy mediated the effect of the HIP Rehab exercise program on activity limitations in older adults after hip fracture, and whether the mediation effect was different between different gender and age groups. Design Randomized controlled trial (RCT) Setting Community Participants Two hundred and thirty two participants aged 79±9.4 years with hip fracture were randomly assigned to intervention (n=120) or attention control (n=112) groups. Interventions The 6-month intervention, the HIP Rehab, is a functionally-oriented, home-based exercise program. Data was collected at baseline, post-intervention (6 months), and follow-up (9 months). Main outcome measure Activity Measure for Post-Acute Care (AM-PAC) Results The mediation effect of the HIP Rehab exercise program on Basic Mobility function through self-efficacy for exercise was significant at 9 months (βindirect=0.21). Similarly, the mediation effect of the intervention on Daily Activity function through self-efficacy for exercise was significant at 9 months (βindirect=0.49). In subgroup analyses, the mediation effect was significant at 9 months in the younger group (≤79 years old) in comparison to the older group, and was significant in females in comparison to males. Conclusion Self-efficacy may play a partial mediating role for the effect on some longer-term functional outcomes in the HIP Rehab intervention. The results suggest that program components that target self-efficacy should be incorporated in the future hip fracture rehabilitation interventions. Age and gender of the targeted participants may also need to be considered when developing interventions. PMID:25701101

Tail and Kinase Modules Differently Regulate Core Mediator Recruitment and Function In Vivo.

PubMed

Jeronimo, Célia; Langelier, Marie-France; Bataille, Alain R; Pascal, John M; Pugh, B Franklin; Robert, François

2016-11-03

Mediator is a highly conserved transcriptional coactivator organized into four modules, namely Tail, Middle, Head, and Kinase (CKM). Previous work suggests regulatory roles for Tail and CKM, but an integrated model for these activities is lacking. Here, we analyzed the genome-wide distribution of Mediator subunits in wild-type and mutant yeast cells in which RNA polymerase II promoter escape is blocked, allowing detection of transient Mediator forms. We found that although all modules are recruited to upstream activated regions (UAS), assembly of Mediator within the pre-initiation complex is accompanied by the release of CKM. Interestingly, our data show that CKM regulates Mediator-UAS interaction rather than Mediator-promoter association. In addition, although Tail is required for Mediator recruitment to UAS, Tailless Mediator nevertheless interacts with core promoters. Collectively, our data suggest that the essential function of Mediator is mediated by Head and Middle at core promoters, while Tail and CKM play regulatory roles. Copyright © 2016 Elsevier Inc. All rights reserved.

Mediated moderation of the relation between maternal and adolescent depressive symptoms: role of adolescent physical health.

PubMed

Ferro, Mark A

2015-11-01

To examine the mediating effect of family functioning on the relation between maternal and adolescent depressive symptoms and determine whether the magnitude of the mediating effect is different for adolescents with and without chronic physical health conditions. Data come from the National Longitudinal Survey of Children and Youth. A representative survey of 11,813 adolescents and their mothers was included. Maternal and adolescent depressive symptoms were measured using the 12-item Center for Epidemiological Studies Depression Scale. Family functioning was measured using the McMaster Family Assessment Device. Multilevel multiple-group path analysis was used to examine potential mediating and moderating effects. Family functioning measured when adolescents were 14-15 years mediated the relation between maternal depressive symptoms (measured at 10-13 years) and adolescent depressive symptoms (measured at 16-19 years) for both adolescents with [αβ = 0.02 (0.02, 0.03)] and without chronic health conditions [αβ = 0.01 (0.00, 0.01)]. These findings provided evidence to suggest mediated moderation, Δαβ = 0.02 (0.01, 0.03), that is, the mediating effect of family functioning was significantly larger for adolescents with chronic health conditions. The mediating effect of family functioning in the relation between maternal and adolescent depressive symptoms is larger for adolescents with chronic health conditions. Within the framework of family-centered care, maternal depressive symptoms and family functioning are suitable targets for preventive intervention for adolescents with chronic health conditions.

Cognitive Differences in Pictorial Reasoning between High-Functioning Autism and Asperger’s Syndrome

PubMed Central

Sahyoun, Cherif P.; Soulières, Isabelle; Belliveau, John W.; Mottron, Laurent; Mody, Maria

2013-01-01

We investigated linguistic and visuospatial processing during pictorial reasoning in high-functioning autism (HFA), Asperger’s syndrome (ASP), and age and IQ-matched typically developing participants (CTRL), using three conditions designed to differentially engage linguistic mediation or visuospatial processing (Visuospatial, V; Semantic, S; Visuospatial+Semantic, V+S). The three groups did not differ in accuracy, but showed different response time profiles. ASP and CTRL participants were fastest on V+S, amenable to both linguistic and nonlinguistic mediation, whereas HFA participants were equally fast on V and V+S, where visuospatial strategies were available, and slowest on S. HFA participants appeared to favor visuospatial over linguistic mediation. The results support the use of linguistic vs. visuospatial tasks for characterizing subtypes on the autism spectrum. PMID:19267190

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

Resilience to health challenges is related to different ways of thinking: mediators of physical and emotional quality of life in a heterogeneous rare-disease cohort.

PubMed

Schwartz, Carolyn E; Michael, Wesley; Rapkin, Bruce D

2017-11-01

We sought to understand what distinguishes people who confront health challenges but still manage to thrive. This study investigated whether resilience helps to explain the impact of health challenges on quality of life (QOL) outcomes, and how resilience relates to appraisal. A web-based survey of rare-disease panel participants included the Centers for Disease Control Healthy Days Core Module, the PROMIS-10, and comorbidities. The QOL Appraisal Profile-v2 assessed cognitive processes underlying QOL. Resilience was operationalized statistically using residual modeling, and hierarchical regressions tested the mediation hypothesis that resilience accounts for a significant amount of the relationship of appraisal to QOL. The study sample (n = 3,324; mean age 50; 86% female; 90% White) represented a range of diagnostic codes, with cancer and diseases of the nervous system being the most prevalent health conditions. After adjusting for comorbidities (catalysts), resilience was associated with better physical and emotional functioning, and different appraisal processes were associated with better or worse physical or emotional functioning. After controlling for catalysts, 62% of the association of Physical Functioning and 23% of the association between Emotional Functioning and appraisal were mediated by resilience. Physical and emotional resilience comprised some of the same appraisal processes, but physically resilient people were characterized by more appraisal processes than their emotionally resilient counterparts. Resilient people employ different appraisal processes than non-resilient people, and these processes differ for physical and emotional outcomes. Resilience was a stronger mediator of the relationship between physical rather than emotional functioning and appraisal.

New aspects of grassland recovery in old-fields revealed by trait-based analyses of perennial-crop-mediated succession.

PubMed

Kelemen, András; Tóthmérész, Béla; Valkó, Orsolya; Miglécz, Tamás; Deák, Balázs; Török, Péter

2017-04-01

Classical old-field succession studies focused on vegetation changes after the abandonment of annual croplands or on succession after the elimination of cultivated crops. Perennial-crop-mediated succession, where fields are initially covered by perennial crops, reveals alternative aspects of old-field succession theories. We tested the validity of classical theories of old-field succession for perennial-crop-mediated succession. We formulated the following hypotheses: (1) functional diversity increases with increasing field age; (2) resource acquisition versus conservation trade-off shifts toward conservation at community level during the succession; (3) the importance of spatial and temporal seed dispersal decreases during the succession; and (4) competitiveness and stress-tolerance increases and ruderality decreases at community level during the succession. We studied functional diversity, trait distributions and plant strategies in differently aged old-fields using chronosequence method. We found increasing functional richness and functional divergence, but also unchanged or decreasing functional evenness. We detected a shift from resource acquisition to resource conservation strategy of communities during the succession. The role of spatial and temporal seed dispersal was found to be important not only at the initial but also at latter successional stages. We found an increasing stress-tolerance and a decreasing ruderality during succession, while the competitiveness remained unchanged at the community level. Despite the markedly different starting conditions, we found that classical and perennial-crop-mediated old-field successions have some similarities regarding the changes of functional diversity, resource acquisition versus conservation trade-off, and seed dispersal strategies. However, we revealed also the subsequent differences. The competitive character of communities remained stable during the succession; hence, the initial stages of perennial-crop-mediated succession can be similar to the middle stages of classical old-field succession. Moreover, the occupied functional niche space and differentiation were larger in the older stages, but resources were not effectively utilized within this space, suggesting that the stabilization of the vegetation requires more time.

Cumulative inequality and racial disparities in health: private insurance coverage and black/white differences in functional limitations.

PubMed

Kail, Ben Lennox; Taylor, Miles G

2014-09-01

To test different forms of private insurance coverage as mediators for racial disparities in onset, persistent level, and acceleration of functional limitations among Medicare age-eligible Americans. Data come from 7 waves of the Health and Retirement Study (1996-2008). Onset and progression latent growth models were used to estimate racial differences in onset, level, and growth of functional limitations among a sample of 5,755 people aged 65 and older in 1996. Employer-provided insurance, spousal insurance, and market insurance were next added to the model to test how differences in private insurance mediated the racial gap in physical limitations. In baseline models, African Americans had larger persistent level of limitations over time. Although employer-provided, spousal provided, and market insurances were directly associated with lower persistent levels of limitation, only differences in market insurance accounted for the racial disparities in persistent level of limitations. Results suggest private insurance is important for reducing functional limitations, but market insurance is an important mediator of the persistently larger level of limitations observed among African Americans. © The Author 2014. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Contribution of Theory of Mind, Executive Functioning, and Pragmatics to Socialization Behaviors of Children with High-Functioning Autism.

PubMed

Berenguer, Carmen; Miranda, Ana; Colomer, Carla; Baixauli, Inmaculada; Roselló, Belén

2018-02-01

Social difficulties are a key aspect of autism, but the intervening factors are still poorly understood. This study had two objectives: to compare the profile of ToM skills, executive functioning (EF), and pragmatic competence (PC) of children with high-functioning autism (HFA) and children with typical development (TD), and analyze their mediator role in social functioning. The participants were 52 children with HFA and 37 children with TD matched on age, intelligence quotient, and expressive vocabulary. Significant differences were found on measures of ToM, both explicit and applied, EF, and PC between children with HFA and TD. Multiple mediation analysis revealed that applied ToM skills and PC mediated the relations between autism symptoms and social functioning. Implications for social cognitive interventions to address these findings are discussed.

A Single-Chain Photoswitchable CRISPR-Cas9 Architecture for Light-Inducible Gene Editing and Transcription.

PubMed

Zhou, Xin X; Zou, Xinzhi; Chung, Hokyung K; Gao, Yuchen; Liu, Yanxia; Qi, Lei S; Lin, Michael Z

2018-02-16

Optical control of CRISPR-Cas9-derived proteins would be useful for restricting gene editing or transcriptional regulation to desired times and places. Optical control of Cas9 functions has been achieved with photouncageable unnatural amino acids or by using light-induced protein interactions to reconstitute Cas9-mediated functions from two polypeptides. However, these methods have only been applied to one Cas9 species and have not been used for optical control of different perturbations at two genes. Here, we use photodissociable dimeric fluorescent protein domains to engineer single-chain photoswitchable Cas9 (ps-Cas9) proteins in which the DNA-binding cleft is occluded at baseline and opened upon illumination. This design successfully controlled different species and functional variants of Cas9, mediated transcriptional activation more robustly than previous optogenetic methods, and enabled light-induced transcription of one gene and editing of another in the same cells. Thus, a single-chain photoswitchable architecture provides a general method to control a variety of Cas9-mediated functions.

Redefining the modular organization of the core Mediator complex.

PubMed

Wang, Xuejuan; Sun, Qianqian; Ding, Zhenrui; Ji, Jinhua; Wang, Jianye; Kong, Xiao; Yang, Jianghong; Cai, Gang

2014-07-01

The Mediator complex plays an essential role in the regulation of eukaryotic transcription. The Saccharomyces cerevisiae core Mediator comprises 21 subunits, which are organized into Head, Middle and Tail modules. Previously, the Head module was assigned to a distinct dense domain at the base, and the Middle and Tail modules were identified to form a tight structure above the Head module, which apparently contradicted findings from many biochemical and functional studies. Here, we compared the structures of the core Mediator and its subcomplexes, especially the first 3D structure of the Head + Middle modules, which permitted an unambiguous assignment of the three modules. Furthermore, nanogold labeling pinpointing four Mediator subunits from different modules conclusively validated the modular assignment, in which the Head and Middle modules fold back on one another and form the upper portion of the core Mediator, while the Tail module forms a distinct dense domain at the base. The new modular model of the core Mediator has reconciled the previous inconsistencies between the structurally and functionally defined Mediator modules. Collectively, these analyses completely redefine the modular organization of the core Mediator, which allow us to integrate the structural and functional information into a coherent mechanism for the Mediator's modularity and regulation in transcription initiation.

Redefining the modular organization of the core Mediator complex

PubMed Central

Wang, Xuejuan; Sun, Qianqian; Ding, Zhenrui; Ji, Jinhua; Wang, Jianye; Kong, Xiao; Yang, Jianghong; Cai, Gang

2014-01-01

The Mediator complex plays an essential role in the regulation of eukaryotic transcription. The Saccharomyces cerevisiae core Mediator comprises 21 subunits, which are organized into Head, Middle and Tail modules. Previously, the Head module was assigned to a distinct dense domain at the base, and the Middle and Tail modules were identified to form a tight structure above the Head module, which apparently contradicted findings from many biochemical and functional studies. Here, we compared the structures of the core Mediator and its subcomplexes, especially the first 3D structure of the Head + Middle modules, which permitted an unambiguous assignment of the three modules. Furthermore, nanogold labeling pinpointing four Mediator subunits from different modules conclusively validated the modular assignment, in which the Head and Middle modules fold back on one another and form the upper portion of the core Mediator, while the Tail module forms a distinct dense domain at the base. The new modular model of the core Mediator has reconciled the previous inconsistencies between the structurally and functionally defined Mediator modules. Collectively, these analyses completely redefine the modular organization of the core Mediator, which allow us to integrate the structural and functional information into a coherent mechanism for the Mediator's modularity and regulation in transcription initiation. PMID:24810298

Socioeconomic, health, and psychosocial mediators of racial disparities in cognition in early, middle, and late adulthood

PubMed Central

Zahodne, Laura B.; Manly, Jennifer J.; Smith, Jacqui; Seeman, Teresa; Lachman, Margie

2017-01-01

Racial disparities in cognitive performance exist across the life course, but it is not known whether mediators of disparities differ by age. Understanding sources of cognitive disparities at different ages can inform policies and interventions. Data were obtained for non-Hispanic Black and White respondents to The National Survey of Midlife Development in the United States (MIDUS-II) from three age groups: 28–44 (N=1210; 20% Black); 45–64 (N=2693; 15% Black), 65–85 (N=1298; 11% Black). Moderated mediation models characterized direct and indirect effects of race on episodic memory and executive function composite scores through economic, health, and psychosocial variables as a function of age group. Education, income, chronic health conditions, and external locus of control mediated cognitive disparities across the life course, though income was a stronger mediator at younger ages. Perceived discrimination was a weaker mediator among young adults due to an absence of racial differences in perceived discrimination in that group. Despite multiple indirect effects, there were still significant unexplained effects of race on cognition that were not moderated by age group. Interventional work is needed to determine whether increasing educational attainment and income, and reducing chronic health conditions and perceived constraints among Blacks, reduce cognitive disparities. Targeting income inequality and discrimination (or buffering the impact of those variables) may be differently effective at reducing cognitive disparities at different stages of the adult life course. PMID:28287782

Episodic feeling-of-knowing accuracy and cued recall in the elderly: evidence for double dissociation involving executive functioning and processing speed.

PubMed

Perrotin, Audrey; Isingrini, Michel; Souchay, Céline; Clarys, David; Taconnat, Laurence

2006-05-01

This research investigated adult age differences in a metamemory monitoring task-episodic feeling-of-knowing (FOK) and in an episodic memory task-cued recall. Executive functioning and processing speed were examined as mediators of these age differences. Young and elderly adults were administered an episodic FOK task, a cued recall task, executive tests and speed tests. Age-related decline was observed on all the measures. Correlation analyses revealed a pattern of double dissociation which indicates a specific relationship between executive score and FOK accuracy, and between speed score and cued recall. When executive functioning and processing speed were evaluated concurrently on FOK and cued recall variables, hierarchical regression analyses showed that executive score was a better mediator of age-related variance in FOK, and that speed score was the better mediator of age-related variance in cued recall.

Children's patterns of emotional reactivity to conflict as explanatory mechanisms in links between interpartner aggression and child physiological functioning.

PubMed

Davies, Patrick T; Sturge-Apple, Melissa L; Cicchetti, Dante; Manning, Liviah G; Zale, Emily

2009-11-01

This paper examined children's fearful, sad, and angry reactivity to interparental conflict as mediators of associations between their exposure to interparental aggression and physiological functioning. Participants included 200 toddlers and their mothers. Assessments of interparental aggression and children's emotional reactivity were derived from maternal surveys and a semi-structured interview. Cortisol levels and cardiac indices of sympathetic nervous system (SNS) and parasympathetic nervous system (PNS) activity were used to assess toddler physiological functioning. Results indicated that toddler exposure to interparental aggression was associated with greater cortisol levels and PNS activity and diminished SNS activity. Toddler angry emotional reactivity mediated associations between interparental aggression and cortisol and PNS functioning. Fearful emotional reactivity was a mediator of the link between interparental aggression and SNS functioning. The results are interpreted within conceptualizations of how exposure and reactivity to family risk organize individual differences in physiological functioning.

Pyroptosis: Gasdermin-Mediated Programmed Necrotic Cell Death.

PubMed

Shi, Jianjin; Gao, Wenqing; Shao, Feng

2017-04-01

Pyroptosis was long regarded as caspase-1-mediated monocyte death in response to certain bacterial insults. Caspase-1 is activated upon various infectious and immunological challenges through different inflammasomes. The discovery of caspase-11/4/5 function in sensing intracellular lipopolysaccharide expands the spectrum of pyroptosis mediators and also reveals that pyroptosis is not cell type specific. Recent studies identified the pyroptosis executioner, gasdermin D (GSDMD), a substrate of both caspase-1 and caspase-11/4/5. GSDMD represents a large gasdermin family bearing a novel membrane pore-forming activity. Thus, pyroptosis is redefined as gasdermin-mediated programmed necrosis. Gasdermins are associated with various genetic diseases, but their cellular function and mechanism of activation (except for GSDMD) are unknown. The gasdermin family suggests a new area of research on pyroptosis function in immunity, disease, and beyond. Copyright © 2016 Elsevier Ltd. All rights reserved.

Trait-mediated assembly processes predict successional changes in community diversity of tropical forests.

PubMed

Lasky, Jesse R; Uriarte, María; Boukili, Vanessa K; Chazdon, Robin L

2014-04-15

Interspecific differences in relative fitness can cause local dominance by a single species. However, stabilizing interspecific niche differences can promote local diversity. Understanding these mechanisms requires that we simultaneously quantify their effects on demography and link these effects to community dynamics. Successional forests are ideal systems for testing assembly theory because they exhibit rapid community assembly. Here, we leverage functional trait and long-term demographic data to build spatially explicit models of successional community dynamics of lowland rainforests in Costa Rica. First, we ask what the effects and relative importance of four trait-mediated community assembly processes are on tree survival, a major component of fitness. We model trait correlations with relative fitness differences that are both density-independent and -dependent in addition to trait correlations with stabilizing niche differences. Second, we ask how the relative importance of these trait-mediated processes relates to successional changes in functional diversity. Tree dynamics were more strongly influenced by trait-related interspecific variation in average survival than trait-related responses to neighbors, with wood specific gravity (WSG) positively correlated with greater survival. Our findings also suggest that competition was mediated by stabilizing niche differences associated with specific leaf area (SLA) and leaf dry matter content (LDMC). These drivers of individual-level survival were reflected in successional shifts to higher SLA and LDMC diversity but lower WSG diversity. Our study makes significant advances to identifying the links between individual tree performance, species functional traits, and mechanisms of tropical forest succession.

Adaptive functioning following pediatric traumatic brain injury: Relationship to executive function and processing speed.

PubMed

Shultz, Emily L; Hoskinson, Kristen R; Keim, Madelaine C; Dennis, Maureen; Taylor, H Gerry; Bigler, Erin D; Rubin, Kenneth H; Vannatta, Kathryn; Gerhardt, Cynthia A; Stancin, Terry; Yeates, Keith Owen

2016-10-01

Pediatric traumatic brain injury (TBI) may affect children's ability to perform everyday tasks (i.e., adaptive functioning). Guided by the American Association for Intellectual and Developmental Disabilities (AAIDD) model, we explored the association between TBI and adaptive functioning at increasing levels of specificity (global, AAIDD domains, and subscales). We also examined the contributions of executive function and processing speed as mediators of TBI's effects on adaptive functioning. Children (ages 8-13) with severe TBI (STBI; n = 19), mild-moderate TBI (MTBI; n = 50), or orthopedic injury (OI; n = 60) completed measures of executive function (TEA-Ch) and processing speed (WISC-IV) an average of 2.7 years postinjury (SD = 1.2; range: 1-5.3). Parents rated children's adaptive functioning (ABAS-II, BASC-2, CASP). STBI had lower global adaptive functioning (η2 = .04-.08) than the MTBI and OI groups, which typically did not differ. Deficits in the STBI group were particularly evident in the social domain, with specific deficits in social participation, leisure, and social adjustment (η2 = .06-.09). Jointly, executive function and processing speed were mediators of STBI's effects on global adaptive functioning and in conceptual and social domains. In the STBI group, executive function mediated social functioning, and processing speed mediated social participation. Children with STBI experience deficits in adaptive functioning, particularly in social adjustment, with less pronounced deficits in conceptual and practical skills. Executive function and processing speed may mediate the effects of STBI on adaptive functioning. Targeting adaptive functioning and associated cognitive deficits for intervention may enhance quality of life for pediatric TBI survivors. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

Adaptive functioning following pediatric traumatic brain injury: Relationship to executive function and processing speed

PubMed Central

Shultz, Emily; Robinson, Kristen E.; Keim, Madelaine; Dennis, Maureen; Taylor, H. Gerry; Bigler, Erin D.; Rubin, Kenneth H.; Vannatta, Kathryn; Gerhardt, Cynthia A.; Stancin, Terry; Yeates, Keith Owen

2016-01-01

Objective Pediatric traumatic brain injury (TBI) may affect children’s ability to perform everyday tasks (i.e., adaptive functioning). Guided by the American Association for Intellectual and Developmental Disabilities (AAIDD) model, we explored the association between TBI and adaptive functioning at increasing levels of specificity (global, AAIDD domains, and subscales). We also examined the contributions of executive function and processing speed as mediators of TBI’s effects on adaptive functioning. Method Children (ages 8–13) with severe TBI (STBI; n=19), mild-moderate TBI (MTBI; n=50), or orthopedic injury (OI; n=60) completed measures of executive function (TEA-Ch) and processing speed (WISC-IV) an average of 2.7 years post-injury (SD = 1.2; range: 1–5.3). Parents rated children’s adaptive functioning (ABAS-II, BASC-2, CASP). Results STBI had lower global adaptive functioning (η2 = .04–.08) than the MTBI and OI groups, which typically did not differ. Deficits in the STBI group were particularly evident in the social domain, with specific deficits in social participation, leisure, and social adjustment (η2 = .06–.09). Jointly, executive function and processing speed were mediators of STBI’s effects on global adaptive functioning and in conceptual and social domains. In the STBI group, executive function mediated social functioning, and processing speed mediated social participation. Conclusions Children with STBI experience deficits in adaptive functioning, particularly in social adjustment, with less pronounced deficits in conceptual and practical skills. Executive function and processing speed may mediate the effects of STBI on adaptive functioning. Targeting adaptive functioning and associated cognitive deficits for intervention may enhance quality of life for pediatric TBI survivors. PMID:27182708

Health-related quality of life in patients with hepatocellular carcinoma: the mediation effects of illness perceptions and coping.

PubMed

Fan, Sheng-Yu; Eiser, Christine; Ho, Ming-Chih; Lin, Cheng-Yao

2013-06-01

The aims of this study were to explore health-related quality of life (HRQOL) in patients with hepatocellular carcinoma (HCC). We report the following: (1) differences in HRQOL between patients with HCC and the general population; (2) significant physical and psychological predictors of HRQOL; and (3) mediation effects of illness perceptions and coping on HRQOL. Patients with HCC (n = 286) from Taiwan completed standardized measures of HRQOL, illness perception (cognitive representations, emotional representations and illness comprehensibility) and coping (emotion-oriented and problem-orientation coping). Demographic and physical variables were also collected. Patients with HCC had worse global HRQOL, physical, role, cognitive and social functioning, but better emotional functioning than the general population. Physical variables and cognitive representation were significant predictors of global HRQOL, physical functioning and emotional functioning. Cognitive representation mediated the relationships between physical variables and global HRQOL, physical functioning and emotional functioning, but coping only mediated the relationship between cognitive representation and global HRQOL. The results suggest that physical variables have direct effects on global HRQOL and physical functioning, but there were also partial mediations through cognitive representation. The effect of physical variables on emotional functioning was mediated through cognitive and emotional representations. Patients with better performance status and positive illness perceptions tended to report better HRQOL, but those with negative illness perceptions and who used more emotion-oriented coping had worse HRQOL. Limitations of the work associated with use of theory and measures developed in Europe and the US are discussed, as are the clinical implications for patients with HCC. Copyright © 2012 John Wiley & Sons, Ltd.

Organizational strategies mediate nonverbal memory impairment in obsessive-compulsive disorder.

PubMed

Savage, C R; Baer, L; Keuthen, N J; Brown, H D; Rauch, S L; Jenike, M A

1999-04-01

Previous neuropsychological studies of obsessive-compulsive disorder (OCD) have indicated impaired executive functioning and nonverbal memory. The extent to which impaired executive functioning impacts nonverbal memory has not been established. The current study investigated the mediating effects of organizational strategies used when copying a figure on subsequent nonverbal memory for that figure. We examined neuropsychological performance in 20 unmedicated subjects with OCD and 20 matched normal control subjects. Subjects were administered the Rey-Osterrieth Complex Figure Test (RCFT) and neuropsychological tests assessing various aspects of executive function. OCD subjects differed significantly from healthy control subjects in the organizational strategies used to copy the RCFT figure, and they recalled significantly less information on both immediate and delayed testing. Multiple regression analyses indicated that group differences in immediate percent recall were significantly mediated by copy organizational strategies. Further exploratory analyses indicated that organizational problems in OCD may be related to difficulties shifting mental and/or spatial set. Immediate nonverbal memory problems in OCD subjects were mediated by impaired organizational strategies used during the initial copy of the RCFT figure. Thus, the primary deficit was one affecting executive function, which then had a secondary effect on immediate memory. These findings are consistent with current theories proposing frontal-striatal system dysfunction in OCD.

Emerging functions of multi-protein complex Mediator with special emphasis on plants.

PubMed

Malik, Naveen; Agarwal, Pinky; Tyagi, Akhilesh

2017-10-01

Mediator is a multi-subunit protein complex which is involved in transcriptional regulation in yeast and other eukaryotes. As a co-activator, it connects information from transcriptional activators/repressors to transcriptional machinery including RNA polymerase II and general transcription factors. It is not only involved in transcription initiation but also has important roles to play in transcription elongation and termination. Functional attributes of different Mediator subunits have been largely defined in yeast and mammalian systems earlier, while such studies in plants have gained momentum recently. Mediator regulates various processes related to plant development and is also involved in biotic and abiotic stress response. Thus, plant Mediator, like yeast and mammalian Mediator complex, is indispensable for plant growth and survival. Interaction of its multiple subunits with other regulatory proteins and their ectopic expression or knockdown in model plant like Arabidopsis and certain crop plants are paving the way to biochemical analysis and unravel molecular mechanisms of action of Mediator in plants.

Sex differences in the neural substrates of spatial working memory during adolescence are not mediated by endogenous testosterone

PubMed Central

Alarcón, Gabriela; Cservenka, Anita; Fair, Damien A.; Nagel, Bonnie J.

2014-01-01

Adolescence is a developmental period characterized by notable changes in behavior, physical attributes, and an increase in endogenous sex steroid hormones, which may impact cognitive functioning. Moreover, sex differences in brain structure are present, leading to differences in neural function and cognition. Here, we examine sex differences in performance and blood oxygen level-dependent (BOLD) activation in a sample of adolescents during a spatial working memory (SWM) task. We also examine whether endogenous testosterone levels mediate differential brain activity between the sexes. Adolescents between ages 10 and 16 completed a SWM functional magnetic resonance imaging (fMRI) task, and serum hormone levels were assessed within seven days of scanning. While there were no sex differences in task performance (accuracy and reaction time), differences in BOLD response between girls and boys emerged, with girls deactivating brain regions in the default mode network and boys showing increased response in SWM-related brain regions of the frontal cortex. These results suggest that adolescent boys and girls adopted distinct neural strategies, while maintaining spatial cognitive strategies that facilitated comparable cognitive performance of a SWM task. A nonparametric bootstrapping procedure revealed that testosterone did not mediate sex-specific brain activity, suggesting that sex differences in BOLD activation during SWM may be better explained by other factors, such as early organizational effects of sex steroids or environmental influences. Elucidating sex differences in neural function and the influence of gonadal hormones can serve as a basis of comparison for understanding sexually dimorphic neurodevelopment and inform sex-specific psychopathology that emerges in adolescence. PMID:25312831

Splice-mediated Variants of Proteins (SpliVaP) - data and characterization of changes in signatures among protein isoforms due to alternative splicing.

PubMed

Floris, Matteo; Orsini, Massimiliano; Thanaraj, Thangavel Alphonse

2008-10-02

It is often the case that mammalian genes are alternatively spliced; the resulting alternate transcripts often encode protein isoforms that differ in amino acid sequences. Changes among the protein isoforms can alter the cellular properties of proteins. The effect can range from a subtle modulation to a complete loss of function. (i) We examined human splice-mediated protein isoforms (as extracted from a manually curated data set, and from a computationally predicted data set) for differences in the annotation for protein signatures (Pfam domains and PRINTS fingerprints) and we characterized the differences & their effects on protein functionalities. An important question addressed relates to the extent of protein isoforms that may lack any known function in the cell. (ii) We present a database that reports differences in protein signatures among human splice-mediated protein isoform sequences. (i) Characterization: The work points to distinct sets of alternatively spliced genes with varying degrees of annotation for the splice-mediated protein isoforms. Protein molecular functions seen to be often affected are those that relate to: binding, catalytic, transcription regulation, structural molecule, transporter, motor, and antioxidant; and the processes that are often affected are nucleic acid binding, signal transduction, and protein-protein interactions. Signatures are often included/excluded and truncated in length among protein isoforms; truncation is seen as the predominant type of change. Analysis points to the following novel aspects: (a) Analysis using data from the manually curated Vega indicates that one in 8.9 genes can lead to a protein isoform of no "known" function; and one in 18 expressed protein isoforms can be such an "orphan" isoform; the corresponding numbers as seen with computationally predicted ASD data set are: one in 4.9 genes and one in 9.8 isoforms. (b) When swapping of signatures occurs, it is often between those of same functional classifications. (c) Pfam domains can occur in varying lengths, and PRINTS fingerprints can occur with varying number of constituent motifs among isoforms - since such a variation is seen in large number of genes, it could be a general mechanism to modulate protein function. (ii) The reported resource (at http://www.bioinformatica.crs4.org/tools/dbs/splivap/) provides the community ability to access data on splice-mediated protein isoforms (with value-added annotation such as association with diseases) through changes in protein signatures.

Activating RNAs associate with Mediator to enhance chromatin architecture and transcription.

PubMed

Lai, Fan; Orom, Ulf A; Cesaroni, Matteo; Beringer, Malte; Taatjes, Dylan J; Blobel, Gerd A; Shiekhattar, Ramin

2013-02-28

Recent advances in genomic research have revealed the existence of a large number of transcripts devoid of protein-coding potential in multiple organisms. Although the functional role for long non-coding RNAs (lncRNAs) has been best defined in epigenetic phenomena such as X-chromosome inactivation and imprinting, different classes of lncRNAs may have varied biological functions. We and others have identified a class of lncRNAs, termed ncRNA-activating (ncRNA-a), that function to activate their neighbouring genes using a cis-mediated mechanism. To define the precise mode by which such enhancer-like RNAs function, we depleted factors with known roles in transcriptional activation and assessed their role in RNA-dependent activation. Here we report that depletion of the components of the co-activator complex, Mediator, specifically and potently diminished the ncRNA-induced activation of transcription in a heterologous reporter assay using human HEK293 cells. In vivo, Mediator is recruited to ncRNA-a target genes and regulates their expression. We show that ncRNA-a interact with Mediator to regulate its chromatin localization and kinase activity towards histone H3 serine 10. The Mediator complex harbouring disease- displays diminished ability to associate with activating ncRNAs. Chromosome conformation capture confirmed the presence of DNA looping between the ncRNA-a loci and its targets. Importantly, depletion of Mediator subunits or ncRNA-a reduced the chromatin looping between the two loci. Our results identify the human Mediator complex as the transducer of activating ncRNAs and highlight the importance of Mediator and activating ncRNA association in human disease.

Understanding the social effects of emotion regulation: the mediating role of authenticity for individual differences in suppression.

PubMed

English, Tammy; John, Oliver P

2013-04-01

Individuals differ in the strategies they use to regulate their emotions (e.g., suppression, reappraisal), and these regulatory strategies can differentially influence social outcomes. However, the mechanisms underlying these social effects remain to be specified. We examined one potential mediator that arises directly from emotion-regulatory effort (expression of positive emotion), and another mediator that does not involve emotion processes per se, but instead results from the link between regulation and self-processes (subjective inauthenticity). Across three studies, only inauthenticity mediated the link between habitual use of suppression and poor social functioning (lower relationship satisfaction, lower social support). These findings replicated across individuals socialized in Western and East Asian cultural contexts, younger and older adults, when predicting social functioning concurrently and a decade later, and even when broader adjustment was controlled. Thus, the social costs of suppression do not seem to be due to reduced positive emotion expression but rather the incongruence between inner-self and outer-behavior. Reappraisal was not consistently related to social functioning. Implications of these findings for emotion processes, self processes, and interpersonal relationships are discussed. PsycINFO Database Record (c) 2013 APA, all rights reserved.

Differences in resting corticolimbic functional connectivity in bipolar I euthymia

PubMed Central

Torrisi, Salvatore; Moody, Teena D; Vizueta, Nathalie; Thomason, Moriah E; Monti, Martin M; Townsend, Jennifer D; Bookheimer, Susan Y; Altshuler, Lori L

2012-01-01

Objective We examined resting state functional connectivity in the brain between key emotion regulation regions in bipolar I disorder to delineate differences in coupling from healthy subjects. Methods Euthymic subjects with bipolar I disorder (n = 20) and matched healthy subjects (n = 20) participated in a resting state functional magnetic resonance imaging scan. Low frequency fluctuations in blood oxygen level-dependent (BOLD) signal were correlated in the six connections between four anatomically-defined nodes: left and right amygdala and left and right ventrolateral prefrontal cortex (vlPFC). Seed-to-voxel connectivity results were probed for commonly coupled regions. Following this, an identified region was included in a mediation analysis to determine the potential of mediation. Results The bipolar I disorder group exhibited significant hyperconnectivity between right amygdala and right vlPFC relative to healthy subjects. The connectivity between these regions in the bipolar I disorder group was partially mediated by activity in the anterior cingulate cortex (ACC). Conclusions Greater coupling between right amygdala and right vlPFC and their partial mediation by the ACC were found in bipolar I disorder subjects in remission and in the absence of a psychological task. These findings have implications for a trait-related and clinically-important imaging biomarker. PMID:23347587

RNAi pathways in Mucor: A tale of proteins, small RNAs and functional diversity.

PubMed

Torres-Martínez, Santiago; Ruiz-Vázquez, Rosa M

2016-05-01

The existence of an RNA-mediated silencing mechanism in the opportunistic fungal pathogen Mucor circinelloides was first described in the early 2000. Since then, Mucor has reached an outstanding position within the fungal kingdom as a model system to achieve a deeper understanding of regulation of endogenous functions by the RNA interference (RNAi) machinery. M. circinelloides combines diverse components of its RNAi machinery to carry out functions not only limited to the defense against invasive nucleic acids, but also to regulate expression of its own genes by producing different classes of endogenous small RNA molecules (esRNAs). The recent discovery of a novel RNase that participates in a new RNA degradation pathway adds more elements to the gene silencing-mediated regulation. This review focuses on esRNAs in M. circinelloides, the different pathways involved in their biogenesis, and their roles in regulating specific physiological and developmental processes in response to environmental signals, highlighting the complexity of silencing-mediated regulation in fungi. Copyright © 2015 Elsevier Inc. All rights reserved.

Improving quality-of-life outcomes for patients with cancer through mediating effects of depressive symptoms and functional status: a three-path mediation model.

PubMed

Hsu, Mei-Chi; Tu, Chun-Hsien

2014-09-01

To test a hypothetical three-path mediation model evaluating the effects of functional status and depressive symptoms on the relationship between fatigue and quality of life in patients with cancer on the basis of the Theory of Unpleasant Symptoms. Patients with cancer often experience two or more concurrent, interrelated, mutually influential symptoms. Multiple unpleasant symptoms that have been proposed as mediating variables affecting quality of life in a model proposed in recent cancer studies are scanty. This study was a cross-sectional, descriptive, correlational design. Three hundred and twenty-six patients with cancer from oncology clinics were recruited in Taiwan between 2010-2011. Mediation models were tested and confirmed by applying structural modelling using Analysis of Moment Structures and the joint significance test. Fatigue affects patient quality of life directly or indirectly through functional status and depressive symptoms. These two mediating variables exhibited direct effects on quality of life. A path analysis approach revealed that 47·28 and 67·70% of the total effects of functional status and depressive symptoms, respectively, on the quality-of-life mediation models are attributable to 29·6 and 44·7% of the total effects between fatigue and quality of life, which mediated through two mediators, respectively. Quality of life may be enhanced by simultaneously improving physiological and psychological factors. An understanding of mediating effects is valuable in nursing care of patients with cancer, particularly in the early phase of treatment or in newly diagnosed stages I-III or recently treated patients with cancer in different disease stages. © 2013 John Wiley & Sons Ltd.

The function of the Mediator complex in plant immunity.

PubMed

An, Chuanfu; Mou, Zhonglin

2013-03-01

Upon pathogen infection, plants undergo dramatic transcriptome reprogramming to shift from normal growth and development to immune response. During this rapid process, the multiprotein Mediator complex has been recognized as an important player to fine-tune gene-specific and pathway-specific transcriptional reprogramming by acting as an adaptor/coregulator between sequence-specific transcription factor and RNA polymerase II (RNAPII). Here, we review current understanding of the role of five functionally characterized Mediator subunits (MED8, MED15, MED16, MED21 and MED25) in plant immunity. All these Mediator subunits positively regulate resistance against leaf-infecting biotrophic bacteria or necrotrophic fungi. While MED21 appears to regulate defense against fungal pathogens via relaying signals from upstream regulators and chromatin modification to RNAPII, the other four Mediator subunits locate at different positions of the defense network to convey phytohormone signal(s). Fully understanding the role of Mediator in plant immunity needs to characterize more Mediator subunits in both Arabidopsis and other plant species. Identification of interacting proteins of Mediator subunits will further help to reveal their specific regulatory mechanisms in plant immunity.

Children’s Patterns of Emotional Reactivity to Conflict as Explanatory Mechanisms in Links Between Interpartner Aggression and Child Physiological Functioning

PubMed Central

Davies, Patrick T.; Sturge-Apple, Melissa L.; Cicchetti, Dante; Manning, Liviah G.; Zale, Emily

2009-01-01

Background This paper examined children’s fearful, sad, and angry reactivity to interparental conflict as mediators of associations between their exposure to interparental aggression and physiological functioning. Methods Participants included 200 toddlers and their mothers. Assessments of interparental aggression and children’s emotional reactivity were derived from maternal surveys and a semi-structured interview. Cortisol levels and cardiac indices of sympathetic nervous system (SNS) and parasympathetic nervous system (PNS) activity were used to assess toddler physiological functioning. Results Results indicated that toddler exposure to interparental aggression was associated with greater cortisol levels and PNS activity and diminished SNS activity. Toddler angry emotional reactivity mediated associations between interparental aggression and cortisol and PNS functioning. Fearful emotional reactivity was a mediator of the link between interparental aggression and SNS functioning. Conclusions The results are interpreted within conceptualizations of how exposure and reactivity to family risk organizing individual differences in physiological functioning. PMID:19744183

Insect Responses to Linearly Polarized Reflections: Orphan Behaviors Without Neural Circuits.

PubMed

Heinloth, Tanja; Uhlhorn, Juliane; Wernet, Mathias F

2018-01-01

The e-vector orientation of linearly polarized light represents an important visual stimulus for many insects. Especially the detection of polarized skylight by many navigating insect species is known to improve their orientation skills. While great progress has been made towards describing both the anatomy and function of neural circuit elements mediating behaviors related to navigation, relatively little is known about how insects perceive non-celestial polarized light stimuli, like reflections off water, leaves, or shiny body surfaces. Work on different species suggests that these behaviors are not mediated by the "Dorsal Rim Area" (DRA), a specialized region in the dorsal periphery of the adult compound eye, where ommatidia contain highly polarization-sensitive photoreceptor cells whose receptive fields point towards the sky. So far, only few cases of polarization-sensitive photoreceptors have been described in the ventral periphery of the insect retina. Furthermore, both the structure and function of those neural circuits connecting to these photoreceptor inputs remain largely uncharacterized. Here we review the known data on non-celestial polarization vision from different insect species (dragonflies, butterflies, beetles, bugs and flies) and present three well-characterized examples for functionally specialized non-DRA detectors from different insects that seem perfectly suited for mediating such behaviors. Finally, using recent advances from circuit dissection in Drosophila melanogaster , we discuss what types of potential candidate neurons could be involved in forming the underlying neural circuitry mediating non-celestial polarization vision.

The association of ADHD and depression: Mediation by peer problems and parent-child difficulties in two complementary samples

PubMed Central

Humphreys, Kathryn L.; Katz, Shaina J.; Lee, Steve S.; Hammen, Constance L.; Brennan, Patricia A.; Najman, Jake M.

2013-01-01

Children with attention-deficit/hyperactivity disorder (ADHD) are at increased risk for the development of depression, with evidence that peer and academic difficulties mediate predictions of later depression from ADHD. The present study hypothesized that parent-child relationship difficulties may be an additional potential mediator of this association. Academic, peer, and parent-child functioning were tested as mediators of the association of attention problems and depression in two distinctly different, yet complementary samples. Study 1 was a cross-sectional sample of 230 5–10 year-old children with and without ADHD. Study 2 was a prospective longitudinal sample of 472 youth followed prospectively from birth to age 20 at risk for depression. Despite differences in age, measures, and designs, both studies implicated peer and parent-child problems as unique mediators of depressive symptoms, although academic difficulties did not uniquely mediate the ADHD-depression association. Further, inattention symptoms, but not hyperactivity, predicted depressive symptoms via the disruption of interpersonal functioning. The inclusion of oppositional defiant disorder into models impacted results, and supported its independent role in parent-child problems. Implications include support for interventions that target interpersonal competence, which may effectively reduce the risk of depression among children with ADHD. PMID:24016021

Causal Mediation Analysis for the Cox Proportional Hazards Model with a Smooth Baseline Hazard Estimator.

PubMed

Wang, Wei; Albert, Jeffrey M

2017-08-01

An important problem within the social, behavioral, and health sciences is how to partition an exposure effect (e.g. treatment or risk factor) among specific pathway effects and to quantify the importance of each pathway. Mediation analysis based on the potential outcomes framework is an important tool to address this problem and we consider the estimation of mediation effects for the proportional hazards model in this paper. We give precise definitions of the total effect, natural indirect effect, and natural direct effect in terms of the survival probability, hazard function, and restricted mean survival time within the standard two-stage mediation framework. To estimate the mediation effects on different scales, we propose a mediation formula approach in which simple parametric models (fractional polynomials or restricted cubic splines) are utilized to approximate the baseline log cumulative hazard function. Simulation study results demonstrate low bias of the mediation effect estimators and close-to-nominal coverage probability of the confidence intervals for a wide range of complex hazard shapes. We apply this method to the Jackson Heart Study data and conduct sensitivity analysis to assess the impact on the mediation effects inference when the no unmeasured mediator-outcome confounding assumption is violated.

Respiratory pathogens mediate the association between lung function and temperature in cystic fibrosis.

PubMed

Collaco, Joseph M; Raraigh, Karen S; Appel, Lawrence J; Cutting, Garry R

2016-11-01

Mean annual ambient temperature is a replicated environmental modifier of cystic fibrosis (CF) lung disease with warmer temperatures being associated with lower lung function. The mechanism of this relationship is not completely understood. However, Pseudomonas aeruginosa, a pathogen that infects the lungs of CF individuals and decreases lung function, also has a higher prevalence in individuals living in warmer climates. We therefore investigated the extent to which respiratory pathogens mediated the association between temperature and lung function. Thirteen respiratory pathogens observed on CF respiratory cultures were assessed in multistep fashion using clustered linear and logistic regression to determine if any mediated the association between temperature and lung function. Analysis was performed in the CF Twin-Sibling Study (n=1730; primary population); key findings were then evaluated in the U.S. CF Foundation Data Registry (n=15,174; replication population). In the primary population, three respiratory pathogens (P. aeruginosa, mucoid P. aeruginosa, and methicillin-resistant Staphylococcus aureus) mediated the association between temperature and lung function. P. aeruginosa accounted for 19% of the association (p=0.003), mucoid P. aeruginosa for 31% (p=0.001), and MRSA for 13% (p=0.023). The same three pathogens mediated association in the replication population (7%, p<0.001; 7%, p=0.002; and 4%, (p=0.002), respectively). Three important respiratory pathogens in CF mediate the association between lower lung function and warmer temperatures. These findings have implications for understanding regional variations in clinical outcomes, and interpreting results of epidemiologic studies and clinical trials that encompass regions with different ambient temperatures. Copyright © 2016 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

Sex differences in the neural substrates of spatial working memory during adolescence are not mediated by endogenous testosterone.

PubMed

Alarcón, Gabriela; Cservenka, Anita; Fair, Damien A; Nagel, Bonnie J

2014-12-17

Adolescence is a developmental period characterized by notable changes in behavior, physical attributes, and an increase in endogenous sex steroid hormones, which may impact cognitive functioning. Moreover, sex differences in brain structure are present, leading to differences in neural function and cognition. Here, we examine sex differences in performance and blood oxygen level-dependent (BOLD) activation in a sample of adolescents during a spatial working memory (SWM) task. We also examine whether endogenous testosterone levels mediate differential brain activity between the sexes. Adolescents between ages 10 and 16 years completed a SWM functional magnetic resonance imaging (fMRI) task, and serum hormone levels were assessed within seven days of scanning. While there were no sex differences in task performance (accuracy and reaction time), differences in BOLD response between girls and boys emerged, with girls deactivating brain regions in the default mode network and boys showing increased response in SWM-related brain regions of the frontal cortex. These results suggest that adolescent boys and girls adopted distinct neural strategies, while maintaining spatial cognitive strategies that facilitated comparable cognitive performance of a SWM task. A nonparametric bootstrapping procedure revealed that testosterone did not mediate sex-specific brain activity, suggesting that sex differences in BOLD activation during SWM may be better explained by other factors, such as early organizational effects of sex steroids or environmental influences. Elucidating sex differences in neural function and the influence of gonadal hormones can serve as a basis of comparison for understanding sexually dimorphic neurodevelopment and inform sex-specific psychopathology that emerges in adolescence. Copyright © 2014 Elsevier B.V. All rights reserved.

Mediator and Cohesin Connect Gene Expression and Chromatin Architecture

PubMed Central

Kagey, Michael H.; Newman, Jamie J.; Bilodeau, Steve; Zhan, Ye; Orlando, David A.; van Berkum, Nynke L.; Ebmeier, Christopher C.; Goossens, Jesse; Rahl, Peter B.; Levine, Stuart S.; Taatjes, Dylan J.; Dekker, Job; Young, Richard A.

2010-01-01

Summary Transcription factors control cell specific gene expression programs through interactions with diverse coactivators and the transcription apparatus. Gene activation may involve DNA loop formation between enhancer-bound transcription factors and the transcription apparatus at the core promoter, but this process is not well understood. We report here that Mediator and Cohesin physically and functionally connect the enhancers and core promoters of active genes in embryonic stem cells. Mediator, a transcriptional coactivator, forms a complex with Cohesin, which can form rings that connect two DNA segments. The Cohesin loading factor Nipbl is associated with Mediator/Cohesin complexes, providing a means to load Cohesin at promoters. DNA looping is observed between the enhancers and promoters occupied by Mediator and Cohesin. Mediator and Cohesin occupy different promoters in different cells, thus generating cell-type specific DNA loops linked to the gene expression program of each cell. PMID:20720539

Antibody-Mediated Internalization of Infectious HIV-1 Virions Differs among Antibody Isotypes and Subclasses.

PubMed

Tay, Matthew Zirui; Liu, Pinghuang; Williams, LaTonya D; McRaven, Michael D; Sawant, Sheetal; Gurley, Thaddeus C; Xu, Thomas T; Dennison, S Moses; Liao, Hua-Xin; Chenine, Agnès-Laurence; Alam, S Munir; Moody, M Anthony; Hope, Thomas J; Haynes, Barton F; Tomaras, Georgia D

2016-08-01

Emerging data support a role for antibody Fc-mediated antiviral activity in vaccine efficacy and in the control of HIV-1 replication by broadly neutralizing antibodies. Antibody-mediated virus internalization is an Fc-mediated function that may act at the portal of entry whereby effector cells may be triggered by pre-existing antibodies to prevent HIV-1 acquisition. Understanding the capacity of HIV-1 antibodies in mediating internalization of HIV-1 virions by primary monocytes is critical to understanding their full antiviral potency. Antibody isotypes/subclasses differ in functional profile, with consequences for their antiviral activity. For instance, in the RV144 vaccine trial that achieved partial efficacy, Env IgA correlated with increased risk of HIV-1 infection (i.e. decreased vaccine efficacy), whereas V1-V2 IgG3 correlated with decreased risk of HIV-1 infection (i.e. increased vaccine efficacy). Thus, understanding the different functional attributes of HIV-1 specific IgG1, IgG3 and IgA antibodies will help define the mechanisms of immune protection. Here, we utilized an in vitro flow cytometric method utilizing primary monocytes as phagocytes and infectious HIV-1 virions as targets to determine the capacity of Env IgA (IgA1, IgA2), IgG1 and IgG3 antibodies to mediate HIV-1 infectious virion internalization. Importantly, both broadly neutralizing antibodies (i.e. PG9, 2G12, CH31, VRC01 IgG) and non-broadly neutralizing antibodies (i.e. 7B2 mAb, mucosal HIV-1+ IgG) mediated internalization of HIV-1 virions. Furthermore, we found that Env IgG3 of multiple specificities (i.e. CD4bs, V1-V2 and gp41) mediated increased infectious virion internalization over Env IgG1 of the same specificity, while Env IgA mediated decreased infectious virion internalization compared to IgG1. These data demonstrate that antibody-mediated internalization of HIV-1 virions depends on antibody specificity and isotype. Evaluation of the phagocytic potency of vaccine-induced antibodies and therapeutic antibodies will enable a better understanding of their capacity to prevent and/or control HIV-1 infection in vivo.

Antibody-Mediated Internalization of Infectious HIV-1 Virions Differs among Antibody Isotypes and Subclasses

PubMed Central

McRaven, Michael D; Sawant, Sheetal; Gurley, Thaddeus C; Xu, Thomas T.; Dennison, S. Moses; Liao, Hua-Xin; Chenine, Agnès-Laurence; Alam, S. Munir; Haynes, Barton F.; Tomaras, Georgia D.

2016-01-01

Emerging data support a role for antibody Fc-mediated antiviral activity in vaccine efficacy and in the control of HIV-1 replication by broadly neutralizing antibodies. Antibody-mediated virus internalization is an Fc-mediated function that may act at the portal of entry whereby effector cells may be triggered by pre-existing antibodies to prevent HIV-1 acquisition. Understanding the capacity of HIV-1 antibodies in mediating internalization of HIV-1 virions by primary monocytes is critical to understanding their full antiviral potency. Antibody isotypes/subclasses differ in functional profile, with consequences for their antiviral activity. For instance, in the RV144 vaccine trial that achieved partial efficacy, Env IgA correlated with increased risk of HIV-1 infection (i.e. decreased vaccine efficacy), whereas V1-V2 IgG3 correlated with decreased risk of HIV-1 infection (i.e. increased vaccine efficacy). Thus, understanding the different functional attributes of HIV-1 specific IgG1, IgG3 and IgA antibodies will help define the mechanisms of immune protection. Here, we utilized an in vitro flow cytometric method utilizing primary monocytes as phagocytes and infectious HIV-1 virions as targets to determine the capacity of Env IgA (IgA1, IgA2), IgG1 and IgG3 antibodies to mediate HIV-1 infectious virion internalization. Importantly, both broadly neutralizing antibodies (i.e. PG9, 2G12, CH31, VRC01 IgG) and non-broadly neutralizing antibodies (i.e. 7B2 mAb, mucosal HIV-1+ IgG) mediated internalization of HIV-1 virions. Furthermore, we found that Env IgG3 of multiple specificities (i.e. CD4bs, V1-V2 and gp41) mediated increased infectious virion internalization over Env IgG1 of the same specificity, while Env IgA mediated decreased infectious virion internalization compared to IgG1. These data demonstrate that antibody-mediated internalization of HIV-1 virions depends on antibody specificity and isotype. Evaluation of the phagocytic potency of vaccine-induced antibodies and therapeutic antibodies will enable a better understanding of their capacity to prevent and/or control HIV-1 infection in vivo. PMID:27579713

Neuroanatomical and Cognitive Mediators of Age-Related Differences in Episodic Memory

PubMed Central

Head, Denise; Rodrigue, Karen M.; Kennedy, Kristen M.; Raz, Naftali

2009-01-01

Aging is associated with declines in episodic memory. In this study, the authors used a path analysis framework to explore the mediating role of differences in brain structure, executive functions, and processing speed in age-related differences in episodic memory. Measures of regional brain volume (prefrontal gray and white matter, caudate, hippocampus, visual cortex), executive functions (working memory, inhibitory control, task switching, temporal processing), processing speed, and episodic memory were obtained in a sample of young and older adults. As expected, age was linked to reduction in regional brain volumes and cognitive performance. Moreover, neural and cognitive factors completely mediated age differences in episodic memory. Whereas hippocampal shrinkage directly affected episodic memory, prefrontal volumetric reductions influenced episodic memory via limitations in working memory and inhibitory control. Age-related slowing predicted reduced efficiency in temporal processing, working memory, and inhibitory control. Lastly, poorer temporal processing directly affected episodic memory. No direct effects of age on episodic memory remained once these factors were taken into account. These analyses highlight the value of a multivariate approach with the understanding of complex relationships in cognitive and brain aging. PMID:18590361

Structure of the CLC-1 chloride channel from Homo sapiens.

PubMed

Park, Eunyong; MacKinnon, Roderick

2018-05-29

CLC channels mediate passive Cl - conduction, while CLC transporters mediate active Cl - transport coupled to H + transport in the opposite direction. The distinction between CLC-0/1/2 channels and CLC transporters seems undetectable by amino acid sequence. To understand why they are different functionally we determined the structure of the human CLC-1 channel. Its 'glutamate gate' residue, known to mediate proton transfer in CLC transporters, adopts a location in the structure that appears to preclude it from its transport function. Furthermore, smaller side chains produce a wider pore near the intracellular surface, potentially reducing a kinetic barrier for Cl - conduction. When the corresponding residues are mutated in a transporter, it is converted to a channel. Finally, Cl - at key sites in the pore appear to interact with reduced affinity compared to transporters. Thus, subtle differences in glutamate gate conformation, internal pore diameter and Cl - affinity distinguish CLC channels and transporters. © 2018, Park & MacKinnon.

Mediating effects of self-stigma on the relationship between perceived stigma and psychosocial outcomes among psychiatric outpatients: findings from a cross-sectional survey in Singapore

PubMed Central

Picco, Louisa; Lau, Ying Wen; Pang, Shirlene; Abdin, Edimansyah; Vaingankar, Janhavi Ajit; Chong, Siow Ann; Subramaniam, Mythily

2017-01-01

Objectives To examine whether self-stigma mediates the relationship between perceived stigma and quality of life, self-esteem and general functioning among outpatients with depression, schizophrenia, anxiety and obsessive-compulsive disorder (OCD). Design Cross-sectional survey. Setting Outpatient clinics at a tertiary psychiatric hospital in Singapore. Participants 280 outpatients with a primary clinical diagnosis of either schizophrenia, depression, anxiety or OCD. Methods Data were collected in relation to self-stigma, perceived stigma, self-esteem, functioning and quality of life. In order to examine the mediating role of self-stigma on the relationship between perceived stigma and psychosocial outcomes, bootstrapping mediation analyses were used. Results Mediation analyses revealed that the relationship between perceived stigma and psychosocial outcomes was subject to the effects of self-stigma among the overall sample. Separate mediation analyses were conducted by diagnoses and showed differences in the mediating effects of self-stigma. Among the whole sample and the subsample with OCD, self-stigma mediated the relationship between perceived stigma and all psychosocial outcomes. For those with anxiety, depression and schizophrenia, the mediating effects of self-stigma were present in all relationships except (1) perceived stigma with physical health in the anxiety sample, (2) perceived stigma with social relationships in the depression sample and (3) perceived stigma with physical health in the schizophrenia sample. Conclusions The mediating effects of self-stigma on the relationship between perceived stigma and various psychosocial outcomes are evident and differ across diagnoses. Interventions to address and reduce the effects of self-stigma along with targeted treatments and psychoeducation to assist people with mental illness overcome or better manage self-stigma while providing them the skills to counteract public stigma are needed. PMID:28851803

Quantitative sensory testing of temperature, pain, and touch in adults with Down syndrome.

PubMed

de Knegt, Nanda; Defrin, Ruth; Schuengel, Carlo; Lobbezoo, Frank; Evenhuis, Heleen; Scherder, Erik

2015-12-01

The spinothalamic pathway mediates sensations of temperature, pain, and touch. These functions seem impaired in children with Down syndrome (DS), but have not been extensively examined in adults. The objective of the present study was to compare the spinothalamic-mediated sensory functions between adults with DS and adults from the general population and to examine in the DS group the relationship between the sensory functions and level of intellectual functioning. Quantitative sensory testing (QST) was performed in 188 adults with DS (mean age 37.5 years) and 142 age-matched control participants (median age 40.5 years). Temperature, pain, and touch were evaluated with tests for cold-warm discrimination, sharp-dull discrimination (pinprick), and tactile threshold, respectively. Level of intellectual functioning was estimated with the Social Functioning Scale for Intellectual Disability (intellectual disability level) and the Wechsler Preschool and Primary Scale of Intelligence--Revised (intelligence level). Overall, the difference in spinothalamic-mediated sensory functions between the DS and control groups was not statistically significant. However, DS participants with a lower intelligence level had a statistically significant lower performance on the sharp-dull discrimination test than DS participants with higher intelligence level (adjusted p=.006) and control participants (adjusted p=.017). It was concluded that intellectual functioning level is an important factor to take into account for the assessment of spinothalamic-mediated sensory functioning in adults with DS: a lower level could coincide with impaired sensory functioning, but could also hamper QST assessment. Copyright © 2015 Elsevier Ltd. All rights reserved.

Does self-efficacy mediate functional change in older adults participating in an exercise program after hip fracture? A randomized controlled trial.

PubMed

Chang, Feng-Hang; Latham, Nancy K; Ni, Pengsheng; Jette, Alan M

2015-06-01

To examine whether self-efficacy mediated the effect of the Home-based Post-Hip Fracture Rehabilitation program on activity limitations in older adults after hip fracture and whether the mediating effect was different between sex and age groups. Randomized controlled trial. Community. Participants with hip fracture (N=232; mean age ± SD, 79±9.4y) were randomly assigned to intervention (n=120, 51.7%) and attention control (n=112, 48.3%) groups. The 6-month intervention, the Home-based Post-Hip Fracture Rehabilitation, is a functionally oriented, home-based exercise program. Data were collected at baseline, postintervention (6mo), and follow-up (9mo). Activity Measure for Post-Acute Care. The mediating effect of the Home-based Post-Hip Fracture Rehabilitation program on Basic Mobility function through self-efficacy for exercise was significant at 9 months (βindirect=.21). Similarly, the mediating effect of the intervention on Daily Activity function through self-efficacy for exercise was significant at 9 months (βindirect=.49). In subgroup analyses, the mediating effect was significant at 9 months in the younger group (age, ≤79y) in comparison to the older group and was significant in women in comparison to men. Self-efficacy may play a partial mediating role in the effect on some longer-term functional outcomes in the Home-based Post-Hip Fracture Rehabilitation intervention. The results suggest that program components that target self-efficacy should be incorporated in future hip fracture rehabilitation interventions. Age and sex of the targeted participants may also need to be considered when developing interventions. Copyright © 2015 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.

PAR-2-mediated control of barrier function and motility differs between early and late phases of postinfectious gut dysfunction in the rat.

PubMed

Fernández-Blanco, Joan Antoni; Fernández-Blanco, Juan A; Hollenberg, Morley D; Martínez, Vicente; Vergara, Patri

2013-02-15

Proteinase-activated receptor-2 (PAR-2) and mast cell (MC) mediators contribute to inflammatory and functional gastrointestinal disorders. We aimed to characterize jejunal PAR-2-mediated responses and the potential MC involvement in the early and late phases of a rat model of postinfectious gut dysfunction. Jejunal tissues of control and Trichinella spiralis-infected (14 and 30 days postinfection) rats, treated or not with the MC stabilizer, ketotifen, were used. Histopathology and immunostaining were used to characterize inflammation, PAR-2 expression, and mucosal and connective tissue MCs. Epithelial barrier function (hydroelectrolytic transport and permeability) and motility were assessed in vitro in basal conditions and after PAR-2 activation. Intestinal inflammation on day 14 postinfection (early phase) was significantly resolved by day 30 (late phase) although MC counts and epithelial permeability remained increased. PAR-2-mediated ion transport (Ussing chambers, in vitro) and epithelial surface PAR-2 expression were reduced in the early phase, with a trend toward normalization during the late phase. In control conditions, PAR-2 activation (organ bath) induced biphasic motor responses (relaxation followed by excitation). At 14 days postinfection, spontaneous contractility and PAR-2-mediated relaxations were enhanced; motor responses were normalized on day 30. Postinfectious changes in PAR-2 functions were not affected by ketotifen treatment. We concluded that, in the rat model of Trichinella spiralis infection, alterations of intestinal PAR-2 function and expression depend on the inflammatory phase considered. A lack of a ketotifen effect suggests no interplay between MCs and PAR-2-mediated motility and ion transport alterations. These observations question the role of MC mediators in PAR-2-modulating postinfectious gut dysfunction.

Sex differences in socioemotional functioning, attentional bias, and gray matter volume in maltreated children: A multilevel investigation.

PubMed

Kelly, Philip A; Viding, Essi; Puetz, Vanessa B; Palmer, Amy L; Mechelli, Andrea; Pingault, Jean-Baptiste; Samuel, Sophie; McCrory, Eamon J

2015-11-01

While maltreatment is known to impact social and emotional functioning, threat processing, and neural structure, the potentially dimorphic influence of sex on these outcomes remains relatively understudied. We investigated sex differences across these domains in a large community sample of children aged 10 to 14 years (n = 122) comprising 62 children with verified maltreatment experience and 60 well-matched nonmaltreated peers. The maltreated group relative to the nonmaltreated comparison group exhibited poorer social and emotional functioning (more peer problems and heightened emotional reactivity). Cognitively, they displayed a pattern of attentional avoidance of threat in a visual dot-probe task. Similar patterns were observed in males and females in these domains. Reduced gray matter volume was found to characterize the maltreated group in the medial orbitofrontal cortex, bilateral middle temporal lobes, and bilateral supramarginal gyrus; sex differences were observed only in the supramarginal gyrus. In addition, a disordinal interaction between maltreatment exposure and sex was found in the postcentral gyrus. Finally, attentional avoidance to threat mediated the relationship between maltreatment and emotional reactivity, and medial orbitofrontal cortex gray matter volume mediated the relationship between maltreatment and peer functioning. Similar mediation patterns were observed across sexes. This study highlights the utility of combining multiple levels of analysis when studying the "latent vulnerability" engendered by childhood maltreatment and yields tentative findings regarding a neural basis of sex differences in long-term outcomes for maltreated children.

The Puppet's Communicative Potential as a Mediating Tool in Preschool Education

ERIC Educational Resources Information Center

Ahlcrona, Mirella Forsberg

2012-01-01

This article describes a puppet as a mediating tool in early childhood education and the puppet's communicative properties, potential and use in preschool. In the empirical section, the puppet consists and functions as a starting point for children's interaction, narratives and different ways of communication. The research interest is directed…

Cyclic 3',5'-adenosine monophosphate (cAMP) signaling in the anterior pituitary gland in health and disease.

PubMed

Hernández-Ramírez, Laura C; Trivellin, Giampaolo; Stratakis, Constantine A

2018-03-05

The cyclic 3',5'-adenosine monophosphate (cAMP) was the first among the so-called "second messengers" to be described. It is conserved in most organisms and functions as a signal transducer by mediating the intracellular effects of multiple hormones and neurotransmitters. In this review, we first delineate how different members of the cAMP pathway ensure its correct compartmentalization and activity, mediate the terminal intracellular effects, and allow the crosstalk with other signaling pathways. We then focus on the pituitary gland, where cAMP exerts a crucial function by controlling the responsiveness of the cells to hypothalamic hormones, neurotransmitters and peripheral factors. We discuss the most relevant physiological functions mediated by cAMP in the different pituitary cell types, and summarize the defects affecting this pathway that have been reported in the literature. We finally discuss how a deregulated cAMP pathway is involved in the pathogenesis of pituitary disorders and how it affects the response to therapy. Copyright © 2017. Published by Elsevier B.V.

Insect Responses to Linearly Polarized Reflections: Orphan Behaviors Without Neural Circuits

PubMed Central

Heinloth, Tanja; Uhlhorn, Juliane; Wernet, Mathias F.

2018-01-01

The e-vector orientation of linearly polarized light represents an important visual stimulus for many insects. Especially the detection of polarized skylight by many navigating insect species is known to improve their orientation skills. While great progress has been made towards describing both the anatomy and function of neural circuit elements mediating behaviors related to navigation, relatively little is known about how insects perceive non-celestial polarized light stimuli, like reflections off water, leaves, or shiny body surfaces. Work on different species suggests that these behaviors are not mediated by the “Dorsal Rim Area” (DRA), a specialized region in the dorsal periphery of the adult compound eye, where ommatidia contain highly polarization-sensitive photoreceptor cells whose receptive fields point towards the sky. So far, only few cases of polarization-sensitive photoreceptors have been described in the ventral periphery of the insect retina. Furthermore, both the structure and function of those neural circuits connecting to these photoreceptor inputs remain largely uncharacterized. Here we review the known data on non-celestial polarization vision from different insect species (dragonflies, butterflies, beetles, bugs and flies) and present three well-characterized examples for functionally specialized non-DRA detectors from different insects that seem perfectly suited for mediating such behaviors. Finally, using recent advances from circuit dissection in Drosophila melanogaster, we discuss what types of potential candidate neurons could be involved in forming the underlying neural circuitry mediating non-celestial polarization vision. PMID:29615868

GPER Mediates Non-Genomic Effects of Estrogen.

PubMed

Pupo, Marco; Maggiolini, Marcello; Musti, Anna Maria

2016-01-01

Estrogens are important modulators of a broad spectrum of physiological functions in humans. However, despite their beneficial actions, a number of lines of evidence correlate the sustained exposure to exogenous estrogen with increased risk of the onset of various cancers. Mainly these steroid hormones induce their effects by binding and activating estrogen receptors (ERα and ERβ). These receptors belong to the family of ligand-regulated transcription factors, and upon activation they regulate the expression of different target genes by binding directly to specific DNA sequences. On the other hand, in recent years it has become clear that the G protein-coupled estrogen receptor 30 (GPR30/GPER) is able to mediate non-genomic action of estrogens in different cell contexts. In particular, GPER has been shown to specifically bind estrogens, and in turn to functionally cross-react with diverse cell signaling systems such as the epidermal growth factor receptor (EGFR) pathway, the Notch signaling pathway and the mitogen-activated protein kinases (MAPK) pathway. In this chapter we will present some of the different experimental techniques currently used to demonstrate the functional role of GPER in mediating non-genomic actions of estrogens, such as the dual luciferase assay, assessment of the involvement of GPER in the stimulation of cell migration in breast cancer cell lines and in cancer-associated fibroblasts, and chromatin immunoprecipitation assay. Overall, the experimental procedures described herein represent key instruments for assessing the biological role of GPER in mediating non-genomic signals of estrogen.

Diversity in GABAergic signaling.

PubMed

Vogt, Kaspar

2015-01-01

GABA(A) receptor-mediated synaptic transmission is responsible for inhibitory control of neural function in the brain. Recent progress has shown that GABA(A) receptors also provide a wide range of additional functions beyond simple inhibition. This diversity of functions is mediated by a large variety of different interneuron classes acting on a diverse population of receptor subtypes. Here, I will focus on an additional source of GABAergic signaling diversity, caused by the highly variable ion signaling mechanism of GABA(A) receptors. In concert with the other two sources of GABAergic heterogeneity, this variability in signaling allows for a wide array of GABAergic effects that are crucial for the development of the brain and its function. © 2015 Elsevier Inc. All rights reserved.

Does reflective functioning mediate the relationship between attachment and personality?

PubMed

Nazzaro, Maria Paola; Boldrini, Tommaso; Tanzilli, Annalisa; Muzi, Laura; Giovanardi, Guido; Lingiardi, Vittorio

2017-10-01

Mentalization, operationalized as reflective functioning (RF), can play a crucial role in the psychological mechanisms underlying personality functioning. This study aimed to: (a) study the association between RF, personality disorders (cluster level) and functioning; (b) investigate whether RF and personality functioning are influenced by (secure vs. insecure) attachment; and (c) explore the potential mediating effect of RF on the relationship between attachment and personality functioning. The Shedler-Westen Assessment Procedure (SWAP-200) was used to assess personality disorders and levels of psychological functioning in a clinical sample (N = 88). Attachment and RF were evaluated with the Adult Attachment Interview (AAI) and Reflective Functioning Scale (RFS). Findings showed that RF had significant negative associations with cluster A and B personality disorders, and a significant positive association with psychological functioning. Moreover, levels of RF and personality functioning were influenced by attachment patterns. Finally, RF completely mediated the relationship between (secure/insecure) attachment and adaptive psychological features, and thus accounted for differences in overall personality functioning. Lack of mentalization seemed strongly associated with vulnerabilities in personality functioning, especially in patients with cluster A and B personality disorders. These findings provide support for the development of therapeutic interventions to improve patients' RF. Copyright © 2017 Elsevier B.V. All rights reserved.

Nitroglycerin mediated dilation evaluated by ultrasound is associated with sTWEAK in hemodialysis patients.

PubMed

Rusu, Crina Claudia; Ghervan, Liviu; Racasan, Simona; Kacsa, Ina; Moldovan, Diana; Potra, Alina; Bondor, Cosmina; Anton, Florin; Patiu, Ioan Mihai; Caprioara, Mirela Gherman

2016-03-01

The main cause of death in hemodialysis (HD) patients is cardiovascular disease. Ultrasound assessment of the brachial artery dysfunction is easily achievable and can non-invasively detect atherosclerosis in various stages. In HD patients the cardiovascular risk profile is different and the determinants of brachial arterial function can be distinct comparing with general population. The aim of the study is to assess the determinants of arterial brachial function (flow-mediated and nitroglycerin-mediated dilation) evaluated by ultrasound in HD patients and their relation with tumor necrosis factor-like weak inducer of apoptosis (sTWEAK) described as atherosclerotic marker in chronic kidney disease patients. We conducted a cross-sectional observational study on 54 hemodialysis patients. We recorded clinical and biological data and we measured sTWEAK serum levels by ELISA. We evaluated the arterial brachial function by measurement of flow-mediated and nitroglycerin-mediated dilation, using B mode ultrasound. The determinants of flow-mediated dilation were: Kt/V (r=0.47, p<0.001), LDL-cholesterol (r=0.29, p=0.04), and total cholesterol (r=0.31, p=0.02). Flow-mediated dilation correlated with nitroglycerin-mediated dilation (r=0.70, p<0.001). In multivariate analysis kt/V was the only significant predictor for flow-mediated dilation (p=0.04). Nitroglycerin-mediated dilation correlates with sTWEAK (r=-0.30, p=0.03), systolic blood pressure (r=-0.28, p=0.04) and pulse pressure (r=-0.31, p=0.02). In multivariate analysis sTWEAK was the only significant predictor for nitroglycerin-mediated dilation (p=0.04). The main determinant of nitroglycerin-mediated dilation was sTWEAK. In addition, decreased nitroglycerin-mediated dilation was associated with higher systolic blood pressure and pulse pressure. The main determinant of FMD was Kt/V. Increased flow-mediated dilation was associated with better dialysis efficiency and high total cholesterol and LDL-cholesterol.

Regulation of Organic Anion Transporting Polypeptides (OATP) 1B1- and OATP1B3-Mediated Transport: An Updated Review in the Context of OATP-Mediated Drug-Drug Interactions.

PubMed

Alam, Khondoker; Crowe, Alexandra; Wang, Xueying; Zhang, Pengyue; Ding, Kai; Li, Lang; Yue, Wei

2018-03-14

Organic anion transporting polypeptides (OATP) 1B1 and OATP1B3 are important hepatic transporters that mediate the uptake of many clinically important drugs, including statins from the blood into the liver. Reduced transport function of OATP1B1 and OATP1B3 can lead to clinically relevant drug-drug interactions (DDIs). Considering the importance of OATP1B1 and OATP1B3 in hepatic drug disposition, substantial efforts have been given on evaluating OATP1B1/1B3-mediated DDIs in order to avoid unwanted adverse effects of drugs that are OATP substrates due to their altered pharmacokinetics. Growing evidences suggest that the transport function of OATP1B1 and OATP1B3 can be regulated at various levels such as genetic variation, transcriptional and post-translational regulation. The present review summarizes the up to date information on the regulation of OATP1B1 and OATP1B3 transport function at different levels with a focus on potential impact on OATP-mediated DDIs.

Regulation of Organic Anion Transporting Polypeptides (OATP) 1B1- and OATP1B3-Mediated Transport: An Updated Review in the Context of OATP-Mediated Drug-Drug Interactions

PubMed Central

Alam, Khondoker; Crowe, Alexandra; Wang, Xueying; Zhang, Pengyue; Ding, Kai; Li, Lang; Yue, Wei

2018-01-01

Organic anion transporting polypeptides (OATP) 1B1 and OATP1B3 are important hepatic transporters that mediate the uptake of many clinically important drugs, including statins from the blood into the liver. Reduced transport function of OATP1B1 and OATP1B3 can lead to clinically relevant drug-drug interactions (DDIs). Considering the importance of OATP1B1 and OATP1B3 in hepatic drug disposition, substantial efforts have been given on evaluating OATP1B1/1B3-mediated DDIs in order to avoid unwanted adverse effects of drugs that are OATP substrates due to their altered pharmacokinetics. Growing evidences suggest that the transport function of OATP1B1 and OATP1B3 can be regulated at various levels such as genetic variation, transcriptional and post-translational regulation. The present review summarizes the up to date information on the regulation of OATP1B1 and OATP1B3 transport function at different levels with a focus on potential impact on OATP-mediated DDIs. PMID:29538325

Age Differences in the Differentiation of Trait Impressions From Faces

PubMed Central

Ng, Stacey Y.; Zebrowitz, Leslie A.; Franklin, Robert G.

2016-01-01

Objectives. We investigated whether evidence that older adults (OA) show less differentiation of visual stimuli than younger adults (YA) extends to trait impressions from faces and effects of face age. We also examined whether age differences in mood, vision, or cognition-mediated differentiation differences. Finally, we investigated whether age differences in trait differentiation mediated differences in impression positivity. Method. We used a differentiation index adapted from previous work on stereotyping to assess OA and YA likelihood of assigning different faces to different levels on trait scales. We computed scores for ratings of older and younger faces’ competence, health, hostility, and untrustworthiness. Results. OA showed less differentiated trait ratings than YA. Measures of mood, vision, and cognition did not mediate these rater age differences. Hostility was differentiated more for younger than older faces, while health was differentiated more for older faces, but only by OA. Age differences in differentiation mediated age differences in impression positivity. Discussion. Less differentiation of trait impressions from faces in OA is consistent with previous evidence for less differentiation in face and emotion recognition. Results indicated that that age-related dedifferentiation does not reflect narrow changes in visual function. They also provide a novel explanation for OA positivity effects. PMID:25194140

Pupillary responses in non-proliferative diabetic retinopathy.

PubMed

Park, Jason C; Chen, Yi-Fan; Blair, Norman P; Chau, Felix Y; Lim, Jennifer I; Leiderman, Yannek I; Shahidi, Mahnaz; McAnany, J Jason

2017-03-23

The goal of this study was to determine the extent of rod-, cone-, and melanopsin-mediated pupillary light reflex (PLR) abnormalities in diabetic patients who have non-proliferative diabetic retinopathy (NPDR). Fifty diabetic subjects who have different stages of NPDR and 25 age-equivalent, non-diabetic controls participated. PLRs were measured in response to full-field, brief-flash stimuli under conditions that target the rod, cone, and intrinsically-photosensitive (melanopsin) retinal ganglion cell pathways. Pupil responses were compared among the subjects groups using age-corrected linear mixed models. Compared to control, the mean baseline pupil diameters were significantly smaller for all patient groups in the dark (all p < 0.001) and for the moderate-severe NPDR group in the light (p = 0.003). Pairwise comparisons indicated: (1) the mean melanopsin-mediated PLR was significantly reduced in the mild and moderate-severe groups (both p < 0.001); (2) the mean cone-mediated PLR was reduced significantly in the moderate-severe group (p = 0.008); (3) no significant differences in the mean rod-mediated responses. The data indicate abnormalities in NPDR patients under conditions that separately assess pupil function driven by different photoreceptor classes. The results provide evidence for compromised neural function in these patients and provide a promising approach for quantifying their neural abnormalities.

Force-Mediating Magnetic Nanoparticles to Engineer Neuronal Cell Function

PubMed Central

Gahl, Trevor J.; Kunze, Anja

2018-01-01

Cellular processes like membrane deformation, cell migration, and transport of organelles are sensitive to mechanical forces. Technically, these cellular processes can be manipulated through operating forces at a spatial precision in the range of nanometers up to a few micrometers through chaperoning force-mediating nanoparticles in electrical, magnetic, or optical field gradients. But which force-mediating tool is more suitable to manipulate cell migration, and which, to manipulate cell signaling? We review here the differences in forces sensation to control and engineer cellular processes inside and outside the cell, with a special focus on neuronal cells. In addition, we discuss technical details and limitations of different force-mediating approaches and highlight recent advancements of nanomagnetics in cell organization, communication, signaling, and intracellular trafficking. Finally, we give suggestions about how force-mediating nanoparticles can be used to our advantage in next-generation neurotherapeutic devices. PMID:29867315

Force-Mediating Magnetic Nanoparticles to Engineer Neuronal Cell Function.

PubMed

Gahl, Trevor J; Kunze, Anja

2018-01-01

Cellular processes like membrane deformation, cell migration, and transport of organelles are sensitive to mechanical forces. Technically, these cellular processes can be manipulated through operating forces at a spatial precision in the range of nanometers up to a few micrometers through chaperoning force-mediating nanoparticles in electrical, magnetic, or optical field gradients. But which force-mediating tool is more suitable to manipulate cell migration, and which, to manipulate cell signaling? We review here the differences in forces sensation to control and engineer cellular processes inside and outside the cell, with a special focus on neuronal cells. In addition, we discuss technical details and limitations of different force-mediating approaches and highlight recent advancements of nanomagnetics in cell organization, communication, signaling, and intracellular trafficking. Finally, we give suggestions about how force-mediating nanoparticles can be used to our advantage in next-generation neurotherapeutic devices.

Sputum Inflammatory Mediators Are Increased in Aspergillus fumigatus Culture-Positive Asthmatics

PubMed Central

Ghebre, Michael A; Desai, Dhananjay; Singapuri, Amisha; Woods, Joanne; Rapley, Laura; Cohen, Suzanne; Herath, Athula; Wardlaw, Andrew J; Pashley, Catherine H; May, Richard

2017-01-01

Aspergillus fumigatus sensitization and culture in asthma are associated with disease severity and lung function impairment, but their relationship with airway inflammation is poorly understood. We investigated the profile of 24 sputum inflammatory mediators in A. fumigatus culture-positive or-negative moderate-to-severe asthmatics. Fifty-two subjects were recruited from a single center. A. fumigatus was cultured from 19 asthmatics. Asthma control, symptom score, lung function, and sputum cell count were not significantly different between the asthmatics with and without a positive A. fumigatus culture. All of the sputum mediators were numerically increased in subjects with a positive versus negative sputum A. fumigatus culture. Sputum TNF-R2 was significantly elevated (P=0.03) and the mediator that best distinguished A. fumigatus culture-positive from culture-negative subjects (receiver-operator characteristic area under the curve 0.66 [95% CI: 0.51 to 0.82, P=0.045]). A. fumigates-positive culture in moderate-to-severe asthma is associated with increased inflammatory sputum mediators. PMID:28102063

Understanding large multiprotein complexes: applying a multiple allosteric networks model to explain the function of the Mediator transcription complex.

PubMed

Lewis, Brian A

2010-01-15

The regulation of transcription and of many other cellular processes involves large multi-subunit protein complexes. In the context of transcription, it is known that these complexes serve as regulatory platforms that connect activator DNA-binding proteins to a target promoter. However, there is still a lack of understanding regarding the function of these complexes. Why do multi-subunit complexes exist? What is the molecular basis of the function of their constituent subunits, and how are these subunits organized within a complex? What is the reason for physical connections between certain subunits and not others? In this article, I address these issues through a model of network allostery and its application to the eukaryotic RNA polymerase II Mediator transcription complex. The multiple allosteric networks model (MANM) suggests that protein complexes such as Mediator exist not only as physical but also as functional networks of interconnected proteins through which information is transferred from subunit to subunit by the propagation of an allosteric state known as conformational spread. Additionally, there are multiple distinct sub-networks within the Mediator complex that can be defined by their connections to different subunits; these sub-networks have discrete functions that are activated when specific subunits interact with other activator proteins.

Adult attachment, perceived social support, cultural orientation, and depressive symptoms: A moderated mediation model.

PubMed

Zhu, Wenzhen; Wang, Chiachih Dc; Chong, Chu Chian

2016-11-01

In the current study, we tested a moderated mediation model in which cultural orientation moderated the mediation model of adult attachment-perceived social support-depressive symptoms, using 2 comparable cross-cultural samples of college students recruited from China and the U.S. (n = 363 for each group). Results indicated that perceived social support mediated the effect of attachment anxiety on depressive symptoms as well as the link between attachment avoidance and depression in both samples. Moderated mediation analyses using PROCESS revealed that interdependent self-construal significantly buffered the indirect effect of attachment avoidance (via perceived social support) on depressive symptoms. The findings indicated significant differences in the mediation models between the U.S. and China groups and interdependent self-construal accounted for the between-country differences. Limitations, implications of the findings, and future research directions are discussed from the perspectives of cross-cultural variation of adult attachment functioning. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

Structural variations in prefrontal cortex mediate the relationship between early childhood stress and spatial working memory

PubMed Central

Hanson, Jamie L.; Chung, Moo K.; Avants, Brian B.; Rudolph, Karen D.; Shirtcliff, Elizabeth A.; Gee, James C.; Davidson, Richard J.; Pollak, Seth D.

2012-01-01

A large corpus of research indicates exposure to stress impairs cognitive abilities, specifically executive functioning dependent on the prefrontal cortex (PFC). We collected structural MRI scans (n=61), well-validated assessments of executive functioning, and detailed interviews assessing stress exposure in humans, to examine whether cumulative life stress affected brain morphometry and one type of executive functioning, spatial working memory, during adolescence—a critical time of brain development and reorganization. Analysis of variations in brain structure revealed that cumulative life stress and spatial working memory were related to smaller volumes in the PFC, specifically prefrontal gray and white matter between the anterior cingulate and the frontal poles. Mediation analyses revealed that individual differences in prefrontal volumes accounted for the association between cumulative life stress and spatial working memory. These results suggest that structural changes in the PFC may serve as a mediating mechanism through which greater cumulative life stress engenders decrements in cognitive functioning. PMID:22674267

Relational-interdependent self-construal as a predictor of relationship quality: the mediating roles of one's own behaviors and perceptions of the fulfillment of friendship functions.

PubMed

Morry, Marian M; Kito, Mie

2009-06-01

Relational-interdependent self-construal (RISC) is the tendency to think of oneself in terms of relationships with close others, and it influences relationship cognitions (e.g., closeness, commitment, perceived similarity). The authors expected individuals high in RISC to report more relationship supportive behaviors (RSB; e.g., higher levels of trust, more intimate disclosures), experience greater fulfillment of friendship functions (FrFu; e.g., help, emotional security, stimulating companionship), and report higher relationship quality than individuals low in RISC. The authors also hypothesized that RSB would mediate the RISC-friendship function and the RISC-relationship quality relations and that FrFu would mediate the relation between RSB and relationship quality. Structural equation modeling supported the authors' hypotheses. These effects did not differ across friendship type (same or cross sex). The authors discuss the importance of self-construal for relationship research.

Intersections between the autism spectrum and the internet: perceived benefits and preferred functions of computer-mediated communication.

PubMed

Gillespie-Lynch, Kristen; Kapp, Steven K; Shane-Simpson, Christina; Smith, David Shane; Hutman, Ted

2014-12-01

An online survey compared the perceived benefits and preferred functions of computer-mediated communication of participants with (N  =  291) and without ASD (N  =  311). Participants with autism spectrum disorder (ASD) perceived benefits of computer-mediated communication in terms of increased comprehension and control over communication, access to similar others, and the opportunity to express their true selves. They enjoyed using the Internet to meet others more, and to maintain connections with friends and family less, than did participants without ASD. People with ASD enjoyed aspects of computer-mediated communication that may be associated with special interests or advocacy, such as blogging, more than did participants without ASD. This study suggests that people with ASD may use the Internet in qualitatively different ways from those without ASD. Suggestions for interventions are discussed.

Executive functioning predicts reading, mathematics, and theory of mind during the elementary years.

PubMed

Cantin, Rachelle H; Gnaedinger, Emily K; Gallaway, Kristin C; Hesson-McInnis, Matthew S; Hund, Alycia M

2016-06-01

The goal of this study was to specify how executive functioning components predict reading, mathematics, and theory of mind performance during the elementary years. A sample of 93 7- to 10-year-old children completed measures of working memory, inhibition, flexibility, reading, mathematics, and theory of mind. Path analysis revealed that all three executive functioning components (working memory, inhibition, and flexibility) mediated age differences in reading comprehension, whereas age predicted mathematics and theory of mind directly. In addition, reading mediated the influence of executive functioning components on mathematics and theory of mind, except that flexibility also predicted mathematics directly. These findings provide important details about the development of executive functioning, reading, mathematics, and theory of mind during the elementary years. Copyright © 2016 Elsevier Inc. All rights reserved.

Executive Functioning and Processing Speed in Age-Related Differences in Memory: Contribution of a Coding Task

ERIC Educational Resources Information Center

Baudouin, Alexia; Clarys, David; Vanneste, Sandrine; Isingrini, Michel

2009-01-01

The aim of the present study was to examine executive dysfunctioning and decreased processing speed as potential mediators of age-related differences in episodic memory. We compared the performances of young and elderly adults in a free-recall task. Participants were also given tests to measure executive functions and perceptual processing speed…

Education and Physical Activity Mediate the Relationship between Ethnicity and Cognitive Function in Late Middle Aged Adults

PubMed Central

Masel, Meredith C.; Raji, Mukaila; Peek, M. Kristen

2013-01-01

Objective Minority status has been implicated as a risk factor for disparate scores on cognitive function tests in older adults. Research on ethnicity and cognitive function has yielded socioeconomic status (SES), particularly education, as a primary reason for the discrepancy. Other factors, such as physical activity may provide insight into the relationship. Despite this knowledge, few studies have thoroughly examined the mediating characteristics of education or physical activity in the relationship between ethnicity and cognitive function in younger aged groups. Most research conducted focuses only on older adults during a time when degeneration of brain tissue may complicate the exploration of the relationships among ethnicity and cognitive function. The current research will expand existing knowledge about education, physical activity, and cognitive function in minority groups. Design The study presents data from the Health and Retirement Study, a nationally representative sample of late middle aged white, black, and Hispanic adults (n=9,204, mean age +-sd=55.8+-3.1). Regression and mediation testing determined the mediating effects of education and physical activity in the relationship between ethnicity and cognitive function. Results Significant association between white ethnicity and higher scores on cognitive tests was evident as early as late middle age. The magnitude of the association significantly diminished on adjusting for education and leisure time physical activity. Conclusion Our data suggest a potential mediating role of education and physical activity on the ethnic differences in cognitive tests in late middle aged white, black, and Hispanic adults. Our findings suggest a need for studies to understand if adult education and culturally-appropriate physical activity interventions in middle age influence ethnic disparities in prevalence of cognitive impairment in old age. PMID:20401816

Age-related differences in striatal, medial temporal, and frontal involvement during value-based decision processing.

PubMed

Su, Yu-Shiang; Chen, Jheng-Ting; Tang, Yong-Jheng; Yuan, Shu-Yun; McCarrey, Anna C; Goh, Joshua Oon Soo

2018-05-21

Appropriate neural representation of value and application of decision strategies are necessary to make optimal investment choices in real life. Normative human aging alters neural selectivity and control processing in brain regions implicated in value-based decision processing including striatal, medial temporal, and frontal areas. However, the specific neural mechanisms of how these age-related functional brain changes modulate value processing in older adults remain unclear. Here, young and older adults performed a lottery-choice functional magnetic resonance imaging experiment in which probabilities of winning different magnitudes of points constituted expected values of stakes. Increasing probability of winning modulated striatal responses in young adults, but modulated medial temporal and ventromedial prefrontal areas instead in older adults. Older adults additionally engaged higher responses in dorso-medio-lateral prefrontal cortices to more unfavorable stakes. Such extrastriatal involvement mediated age-related increase in risk-taking decisions. Furthermore, lower resting-state functional connectivity between lateral prefrontal and striatal areas also predicted lottery-choice task risk-taking that was mediated by higher functional connectivity between prefrontal and medial temporal areas during the task, with this mediation relationship being stronger in older than younger adults. Overall, we report evidence of a systemic neural mechanistic change in processing of probability in mixed-lottery values with age that increases risk-taking of unfavorable stakes in older adults. Moreover, individual differences in age-related effects on baseline frontostriatal communication may be a central determinant of such subsequent age differences in value-based decision neural processing and resulting behaviors. Copyright © 2018 Elsevier Inc. All rights reserved.

Satisfaction with Life in Orofacial Pain Disorders: Associations and Theoretical Implications.

PubMed

Boggero, Ian A; Rojas-Ramirez, Marcia V; de Leeuw, Reny; Carlson, Charles R

2016-01-01

To test if patients with masticatory myofascial pain, local myalgia, centrally mediated myalgia, disc displacement, capsulitis/synovitis, or continuous neuropathic pain differed in self-reported satisfaction with life. The study also tested if satisfaction with life was similarly predicted by measures of physical, emotional, and social functioning across disorders. Satisfaction with life, fatigue, affective distress, social support, and pain data were extracted from the medical records of 343 patients seeking treatment for chronic orofacial pain. Patients were grouped by primary diagnosis assigned following their initial appointment. Satisfaction with life was compared between disorders, with and without pain intensity entered as a covariate. Disorder-specific linear regression models using physical, emotional, and social predictors of satisfaction with life were computed. Patients with centrally mediated myalgia reported significantly lower satisfaction with life than did patients with any of the other five disorders. Inclusion of pain intensity as a covariate weakened but did not eliminate the effect. Satisfaction with life was predicted by measures of physical, emotional, and social functioning, but these associations were not consistent across disorders. Results suggest that reduced satisfaction with life in patients with centrally mediated myalgia is not due only to pain intensity. There may be other factors that predispose people to both reduced satisfaction with life and centrally mediated myalgia. Furthermore, the results suggest that satisfaction with life is differentially influenced by physical, emotional, and social functioning in different orofacial pain disorders.

Living Arrangement and Life Satisfaction in Older Malaysians: The Mediating Role of Social Support Function

PubMed Central

Kooshiar, Hadi; Yahaya, Nurizan; Hamid, Tengku Aizan; Abu Samah, Asnarulkhadi; Sedaghat Jou, Vajiheh

2012-01-01

Background This cross-sectional and correlational survey examines the association between different types of living arrangements and life satisfaction in older Malaysians, while taking into account the mediating effects of social support function. Methodology and Findings A total of 1880 of older adults were selected by multistage stratified sampling. Life satisfaction and social support were measured with the Philadelphia Geriatric Center Morale Scale and Medical Outcomes Study Social Support Survey. The result shows living with children as the commonest type of living arrangement for older adults in peninsular Malaysia. Compared to living alone, living only with a spouse especially and then co-residency with children were both associated with better life satisfaction (p<.01) and social support function (p<.01). The mediating effect of social support function enhanced the relation between living arrangements and life satisfaction. Conclusion This study revealed that types of living arrangement directly, and indirectly through social support function, play an important role in predicting life satisfaction for older adults in Malaysia. This study makes remarkable contributions to the Convoy model in older Malaysians. PMID:22912806

Malleable machines in transcription regulation: the mediator complex.

PubMed

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

2008-12-01

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

Cell type-specific long-range connections of basal forebrain circuit.

PubMed

Do, Johnny Phong; Xu, Min; Lee, Seung-Hee; Chang, Wei-Cheng; Zhang, Siyu; Chung, Shinjae; Yung, Tyler J; Fan, Jiang Lan; Miyamichi, Kazunari; Luo, Liqun; Dan, Yang

2016-09-19

The basal forebrain (BF) plays key roles in multiple brain functions, including sleep-wake regulation, attention, and learning/memory, but the long-range connections mediating these functions remain poorly characterized. Here we performed whole-brain mapping of both inputs and outputs of four BF cell types - cholinergic, glutamatergic, and parvalbumin-positive (PV+) and somatostatin-positive (SOM+) GABAergic neurons - in the mouse brain. Using rabies virus -mediated monosynaptic retrograde tracing to label the inputs and adeno-associated virus to trace axonal projections, we identified numerous brain areas connected to the BF. The inputs to different cell types were qualitatively similar, but the output projections showed marked differences. The connections to glutamatergic and SOM+ neurons were strongly reciprocal, while those to cholinergic and PV+ neurons were more unidirectional. These results reveal the long-range wiring diagram of the BF circuit with highly convergent inputs and divergent outputs and point to both functional commonality and specialization of different BF cell types.

Personality compensates for impaired quality of life and social functioning in patients with psychotic disorders who experienced traumatic events.

PubMed

Boyette, Lindy-Lou; van Dam, Daniëlla; Meijer, Carin; Velthorst, Eva; Cahn, Wiepke; de Haan, Lieuwe; Kahn, René; de Haan, Lieuwe; van Os, Jim; Wiersma, Durk; Bruggeman, Richard; Cahn, Wiepke; Meijer, Carin; Myin-Germeys, Inez

2014-11-01

Patients with psychotic disorders who experienced childhood trauma show more social dysfunction than patients without traumatic experiences. However, this may not hold for all patients with traumatic experiences. Little is known about the potential compensating role of Five-Factor Model personality traits within this group, despite their strong predictive value for social functioning and well-being in the general population. Our sample consisted of 195 patients with psychotic disorders (74% diagnosed with schizophrenia) and 132 controls. Cluster analyses were conducted to identify and validate distinct personality profiles. General linear model analyses were conducted to examine whether patients with different profiles differed in social functioning and quality of life (QoL), while controlling for possible confounders. Mediation models were tested to assess potential causal links. In general, patients with higher levels of self-reported traumatic experiences (PT+) showed lower QoL and more social withdrawal compared with patients with lower traumatic experiences (PT-). Two clusters reflecting personality profiles were identified. PT+ with the first profile (lower neuroticism and higher extraversion, openness, agreeableness, and conscientiousness) presented higher levels of QoL and better social functioning in several areas, including less withdrawal, compared with both PT+ and PT- with the second profile. PT+ and PT- with the first personality profile did not differ in QoL and social functioning. Mediation analyses suggested that personality traits mediate the relation between traumatic experiences and QoL and social withdrawal. Our findings indicate that personality may "buffer" the impact of childhood traumatic experiences on functional outcome in patients with psychotic disorders. © The Author 2014. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Effect of acute moderate exercise on induced inflammation and arterial function in older adults.

PubMed

Ranadive, Sushant Mohan; Kappus, Rebecca Marie; Cook, Marc D; Yan, Huimin; Lane, Abbi Danielle; Woods, Jeffrey A; Wilund, Kenneth R; Iwamoto, Gary; Vanar, Vishwas; Tandon, Rudhir; Fernhall, Bo

2014-04-01

Acute inflammation reduces flow-mediated vasodilatation and increases arterial stiffness in young healthy individuals. However, this response has not been studied in older adults. The aim of this study, therefore, was to evaluate the effect of acute induced systemic inflammation on endothelial function and wave reflection in older adults. Furthermore, an acute bout of moderate-intensity aerobic exercise can be anti-inflammatory. Taken together, we tested the hypothesis that acute moderate-intensity endurance exercise, immediately preceding induced inflammation, would be protective against the negative effects of acute systemic inflammation on vascular function. Fifty-nine healthy volunteers between 55 and 75 years of age were randomized to an exercise or a control group. Both groups received a vaccine (induced inflammation) and sham (saline) injection in a counterbalanced crossover design. Inflammatory markers, endothelial function (flow-mediated vasodilatation) and measures of wave reflection and arterial stiffness were evaluated at baseline and at 24 and 48 h after injections. There were no significant differences in endothelial function and arterial stiffness between the exercise and control group after induced inflammation. The groups were then analysed together, and we found significant differences in the inflammatory markers 24 and 48 h after induction of acute inflammation compared with sham injection. However, flow-mediated vasodilatation, augmentation index normalized for heart rate (AIx75) and β-stiffness did not change significantly. Our results suggest that acute inflammation induced by influenza vaccination did not affect endothelial function in older adults.

Neuropsychological function in patients with anorexia nervosa or bulimia nervosa.

PubMed

Weider, Siri; Indredavik, Marit Saebø; Lydersen, Stian; Hestad, Knut

2015-05-01

This study explored the neuropsychological performance of patients diagnosed with anorexia nervosa (AN) or bulimia nervosa (BN) compared with healthy controls (HCs). An additional aim was to investigate the effect of several possible mediators on the association between eating disorders (EDs) and cognitive function. Forty patients with AN, 39 patients with BN, and 40 HCs who were comparable in age and education were consecutively recruited to complete a standardized neuropsychological test battery covering the following cognitive domains: verbal learning and memory, visual learning and memory, speed of information processing, visuospatial ability, working memory, executive function, verbal fluency, attention/vigilance, and motor function. The AN group scored significantly below the HCs on eight of the nine measured cognitive domains. The BN group also showed inferior performance on six cognitive domains. After adjusting for possible mediators, the nadir body mass index (lowest lifetime BMI) and depressive symptoms explained all findings in the BN group. Although this adjustment reduced the difference between the AN and HC groups, the AN group still performed worse than the HCs regarding verbal learning and memory, visual learning and memory, visuospatial ability, working memory, and executive functioning. Patients with EDs scored below the HCs on several cognitive function measures, this difference being most pronounced for the AN group. The nadir BMI and depressive symptoms had strong mediating effects. Longitudinal studies are needed to identify the importance of weight restoration and treatment of depressive symptoms in the prevention of a possible cognitive decline. © 2014 Wiley Periodicals, Inc.

Successful Aging and Subjective Well-Being Among Oldest-Old Adults

PubMed Central

Cho, Jinmyoung; Martin, Peter; Poon, Leonard W.

2015-01-01

Purpose of the Study: This research integrates successful aging and developmental adaptation models to empirically define the direct and indirect effects of 2 distal (i.e., education and past life experiences) and 5 proximal influences (i.e., physical functioning, cognitive functioning, physical health impairment, social resources, and perceived economic status) on subjective well-being. The proximal influences involved predictors outlined in most extant models of successful aging (e.g., Rowe & Kahn, 1998 [Rowe, J. W., & Kahn, R. L. (1998). Successful aging. New York: Pantheon Books.]). Our model extends such models by including distal impact as well as interactions between distal and proximal impacts. Design and Methods: Data were obtained from 234 centenarians and 72 octogenarians in the Georgia Centenarian Study. Structural equation modeling was conducted with Mplus 6.1. Results: Results showed significant direct effects of physical health impairment and social resources on positive aspects of subjective well-being among oldest-old adults. We also found significant indirect effects of cognitive functioning and education on positive affect among oldest-old adults. Social resources mediated the relationship between cognitive functioning and positive affect; and cognitive functioning and social resources mediated the relationship between education and positive affect. In addition, physical health impairment mediated the relationship between cognitive functioning and positive affect; and cognitive functioning and physical health impairment mediated the relationship between education and positive affect. Implications: Integrating 2 different models (i.e., successful aging and developmental adaptation) provided a comprehensive view of adaptation from a developmental perspective. PMID:25112594

Depression and reduced heart rate variability after cardiac surgery: the mediating role of emotion regulation.

PubMed

Patron, Elisabetta; Messerotti Benvenuti, Simone; Favretto, Giuseppe; Gasparotto, Renata; Palomba, Daniela

2014-02-01

Heart rate variability (HRV), as an index of autonomic nervous system (ANS) functioning, is reduced by depression after cardiac surgery, but the underlying mechanisms of this relationship are poorly understood. Poor emotion regulation as a core symptom of depression has also been associated with altered ANS functioning. The present study aimed to examine whether emotion dysregulation could be a mediator of the depression-reduced HRV relationship observed after cardiac surgery. Self-reported emotion regulation and four-minute HRV were measured in 25 depressed and 43 nondepressed patients after cardiac surgery. Mediation analysis was conducted to evaluate emotion regulation as a mediator of the depression-reduced HRV relationship. Compared to nondepressed patients, those with depression showed lower standard deviation of normal-to-normal (NN) intervals (p<.05), root mean square successive difference of NN intervals (p<.004), and number of interval differences of successive NN intervals greater than 50ms (NN50) (p<.05). Increased low frequency (LF) in normalized units (n.u.) and reduced high frequency (HF) n.u. were also found in depressed compared to nondepressed patients (p's<.01). Mediation analysis revealed that suppression of emotion-expressive behavior partially mediated the effect of depression on LF n.u. and HF n.u. Results confirmed previous findings showing that depression is associated with reduced HRV, especially a reduced vagal tone and a sympathovagal imbalance, after cardiac surgery. This study also provides preliminary evidence that increased trait levels of suppression of emotion-expressive behavior may mediate the depression-related sympathovagal imbalance after cardiac surgery. Copyright © 2013 Elsevier B.V. All rights reserved.

Age Differences in Perseveration: Cognitive and Neuroanatomical Mediators of Performance on the Wisconsin Card Sorting Test

ERIC Educational Resources Information Center

Head, Denise; Kennedy, Kristen M.; Rodrigue, Karen M.; Raz, Naftali

2009-01-01

Aging effects on the Wisconsin Card Sorting Test (WCST) are fairly well established but the mechanisms of the decline are not clearly understood. In this study, we examined the cognitive and neural mechanisms mediating age-related increases in perseveration on the WCST. MRI-based volumetry and measures of selected executive functions in…

Executive functioning and processing speed in age-related differences in time estimation: a comparison of young, old, and very old adults.

PubMed

Baudouin, Alexia; Isingrini, Michel; Vanneste, Sandrine

2018-01-25

Age-related differences in time estimation were examined by comparing the temporal performance of young, young-old, and old-old adults, in relation to two major theories of cognitive aging: executive decline and cognitive slowing. We tested the hypothesis that processing speed and executive function are differentially involved in timing depending on the temporal task used. We also tested the assumption of greater age-related effects in time estimation in old-old participants. Participants performed two standard temporal tasks: duration production and duration reproduction. They also completed tests measuring executive function and processing speed. Findings supported the view that executive function is the best mediator of reproduction performance and inversely that processing speed is the best mediator of production performance. They also showed that young-old participants provide relatively accurate temporal judgments compared to old-old participants. These findings are discussed in terms of compensation mechanisms in aging.

Cell Adhesions: Actin-Based Modules that Mediate Cell-Extracellular Matrix and Cell-Cell Interactions

PubMed Central

Bachir, Alexia; Horwitz, Alan Rick; Nelson, W. James; Bianchini, Julie M.

2018-01-01

Cell adhesions link cells to the extracellular matrix (ECM) and to each other, and depend on interactions with the actin cytoskeleton. Both cell-ECM and cell-cell adhesion sites contain discrete, yet overlapping functional modules. These modules establish physical association with the actin cytoskeleton, locally modulate actin organization and dynamics, and trigger intracellular signaling pathways. Interplay between these modules generates distinct actin architectures that underlie different stages, types, and functions of cell-ECM and cell-cell adhesions. Actomyosin contractility is required to generate mature, stable adhesions, as well as sense and translate the mechanical properties of the cellular environment to changes in cell organization and behavior. In this chapter we discuss the organization and function of different adhesion modules and how they interact with the actin cytoskeleton. We highlight the molecular mechanisms of mechanotransduction in adhesions, and how adhesion molecules mediate crosstalk between cell-ECM and cell-cell adhesion sites. PMID:28679638

Intrinsic motivation as a mediator between metacognition deficits and impaired functioning in psychosis.

PubMed

Luther, Lauren; Firmin, Ruth L; Vohs, Jenifer L; Buck, Kelly D; Rand, Kevin L; Lysaker, Paul H

2016-09-01

Poor functioning has long been observed in individuals with psychosis. Recent studies have identified metacognition - one's ability to form complex ideas about oneself and others and to use that information to respond to psychological and social challenges-as being an important determinant of functioning. However, the exact process by which deficits in metacognition lead to impaired functioning remains unclear. This study first examined whether low intrinsic motivation, or the tendency to pursue novel experiences and to engage in self-improvement, mediates the relationship between deficits in metacognition and impaired functioning. We then examined whether intrinsic motivation significantly mediated the relationship when controlling for age, education, symptoms, executive functioning, and social cognition. Mediation models were examined in a cross-sectional data set. One hundred and seventy-five individuals with a psychotic disorder completed interview-based measures of metacognition, intrinsic motivation, symptoms, and functioning and performance-based measures of executive functioning and social cognition. Analyses revealed that intrinsic motivation mediated the relationship between metacognition deficits and impaired functioning (95% CI of indirect effect [0.12-0.43]), even after controlling for the aforesaid variables (95% CI of indirect effect [0.04-0.29]). Results suggest that intrinsic motivation may be a mechanism that underlies the link between deficits in metacognition and impaired functioning and indicate that metacognition and intrinsic motivation may be important treatment targets to improve functioning in individuals with psychosis. The findings of this study suggest that deficits in metacognition may indirectly lead to impaired functioning through their effect on intrinsic motivation in individuals with psychosis. Psychological treatments that target deficits in both metacognition and intrinsic motivation may help to alleviate impaired functioning in individuals with psychosis. The cross-sectional design of this study is a limitation, and additional longitudinal studies are needed to confirm the direction of the findings and rule out rival hypotheses. Generalization of the findings may be limited by the sample composition. It may be that different relationships exist between metacognition, intrinsic motivation, and functioning in those with early psychosis or among those in an acute phase or who decline treatment. © 2016 The British Psychological Society.

Conservation and Divergence of Mediator Structure and Function: Insights from Plants.

PubMed

Dolan, Whitney L; Chapple, Clint

2017-01-01

The Mediator complex is a large, multisubunit, transcription co-regulator that is conserved across eukaryotes. Studies of the Arabidopsis Mediator complex and its subunits have shown that it functions in nearly every aspect of plant development and fitness. In addition to revealing mechanisms of regulation of plant-specific pathways, studies of plant Mediator complexes have the potential to shed light on the conservation and divergence of Mediator structure and function across Kingdoms and plant lineages. The majority of insights into plant Mediator function have come from Arabidopsis because it is the only plant from which Mediator has been purified and from which an array of Mediator mutants have been isolated by forward and reverse genetics. So far, these studies indicate that, despite low sequence similarity between many orthologous subunits, the overall structure and function of Mediator is well conserved between Kingdoms. Several studies have also expanded our knowledge of Mediator to other plant species, opening avenues of investigation into the role of Mediator in plant adaptation and fitness.

Adult males with haemophilia have a different macrovascular and microvascular endothelial function profile compared with healthy controls.

PubMed

Sun, H; Yang, M; Fung, M; Chan, S; Jawi, M; Anderson, T; Poon, M-C; Jackson, S

2017-09-01

Endothelial function has been identified as an independent predictor of cardiovascular risk in the general population. It is unclear if the haemophilia population has a different endothelial function profile compared to the healthy population. This prospective study aims to assess if there is a difference in endothelial function between haemophilia patients and healthy controls, and the impact of endothelial function on vascular outcomes in the haemophilia population. Baseline cardiovascular risk factors and endothelial function were presented. Adult males with haemophilia A or B recruited from the British Columbia and Southern Alberta haemophilia treatment centres were matched to healthy male controls by age and cardiovascular risk factors. Macrovascular endothelial function was assessed by brachial artery flow-mediated dilation (FMD) and nitroglycerin-mediated dilation (NMD), and microvascular endothelial function was assessed by hyperaemic velocity time integral (VTI). Multivariable linear regression was used to assess the association between haemophilia and endothelial function. A total of 81 patients with haemophilia and 243 controls were included. Patients with haemophilia had a similar FMD and NMD compared to controls, although haemophilia was associated with higher FMD on multivariable analysis. Haemophilia was associated with significantly lower VTI on univariate and multivariable analyses, regardless of haemophilia type and severity. Adult males with haemophilia appear to have lower microvascular endothelial function compared to healthy controls. Future studies to assess the impact of endothelial dysfunction on cardiovascular events in the haemophilia population are needed. © 2017 John Wiley & Sons Ltd.

Cognitive Differences in Pictorial Reasoning between High-Functioning Autism and Asperger's Syndrome

ERIC Educational Resources Information Center

Sahyoun, Cherif P.; Soulieres, Isabelle; Belliveau, John W.; Mottron, Laurent; Mody, Maria

2009-01-01

We investigated linguistic and visuospatial processing during pictorial reasoning in high-functioning autism (HFA), Asperger's syndrome (ASP), and age and IQ-matched typically developing participants (CTRL), using three conditions designed to differentially engage linguistic mediation or visuospatial processing (visuospatial, V; semantic, S;…

Associations of Early- and Later-Childhood Poverty With Child Cognitive Function in Indonesia: Effect Decomposition in the Presence of Exposure-Induced Mediator-Outcome Confounding.

PubMed

Maika, Amelia; Mittinty, Murthy N; Brinkman, Sally; Lynch, John

2017-05-15

The amount of family financial resources available in early life influences child health and development. Using data from the 2000 and 2007 waves of the Indonesian Family Life Survey, we estimated the associations of early-life poverty (at age <7 years) and poverty in later childhood (at age 7-14 years) with cognitive function at age 7-14 years. Our analysis provided little support for the idea that an early intervention to support household income has a larger effect than intervention later in childhood; both seemed equally important. We also decomposed the effect of poverty at age <7 years into direct and indirect effects mediated through poverty and schooling/home environment at age 7-14 years. For decomposing the effects, we used 3 approaches: 1) joint mediators, 2) path-specific, and 3) intervention analog. Being exposed to poverty before age 7 years had a larger direct effect (difference in cognitive function z score) on child cognitive function at age 7-14 years (i.e., joint mediators β = -0.07, 95% confidence interval: -0.12, -0.02) than the indirect effects mediated through later poverty at age 7-14 years (β = -0.01, 95% confidence interval: -0.04, 0.01) and school attendance/home environment at age 7-14 years. The effect of poverty on cognitive function was small; nevertheless, financial intervention may still benefit children's cognitive function. © The Author 2017. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Ability of HIV-1 Nef to downregulate CD4 and HLA class I differs among viral subtypes

PubMed Central

2013-01-01

Background The highly genetically diverse HIV-1 group M subtypes may differ in their biological properties. Nef is an important mediator of viral pathogenicity; however, to date, a comprehensive inter-subtype comparison of Nef in vitro function has not been undertaken. Here, we investigate two of Nef’s most well-characterized activities, CD4 and HLA class I downregulation, for clones obtained from 360 chronic patients infected with HIV-1 subtypes A, B, C or D. Results Single HIV-1 plasma RNA Nef clones were obtained from N=360 antiretroviral-naïve, chronically infected patients from Africa and North America: 96 (subtype A), 93 (B), 85 (C), and 86 (D). Nef clones were expressed by transfection in an immortalized CD4+ T-cell line. CD4 and HLA class I surface levels were assessed by flow cytometry. Nef expression was verified by Western blot. Subset analyses and multivariable linear regression were used to adjust for differences in age, sex and clinical parameters between cohorts. Consensus HIV-1 subtype B and C Nef sequences were synthesized and functionally assessed. Exploratory sequence analyses were performed to identify potential genotypic correlates of Nef function. Subtype B Nef clones displayed marginally greater CD4 downregulation activity (p = 0.03) and markedly greater HLA class I downregulation activity (p < 0.0001) than clones from other subtypes. Subtype C Nefs displayed the lowest in vitro functionality. Inter-subtype differences in HLA class I downregulation remained statistically significant after controlling for differences in age, sex, and clinical parameters (p < 0.0001). The synthesized consensus subtype B Nef showed higher activities compared to consensus C Nef, which was most pronounced in cells expressing lower protein levels. Nef clones exhibited substantial inter-subtype diversity: cohort consensus residues differed at 25% of codons, while a similar proportion of codons exhibited substantial inter-subtype differences in major variant frequency. These amino acids, along with others identified in intra-subtype analyses, represent candidates for mediating inter-subtype differences in Nef function. Conclusions Results support a functional hierarchy of subtype B > A/D > C for Nef-mediated CD4 and HLA class I downregulation. The mechanisms underlying these differences and their relevance to HIV-1 pathogenicity merit further investigation. PMID:24041011

Intellectual Functioning in In-Patients with Substance Use Disorders: Preliminary Results from a Clinical Mediation Study of Factors Contributing to IQ Variance.

PubMed

Braatveit, Kirsten J; Torsheim, Torbjørn; Hove, Oddbjørn

2018-01-01

To investigate the direct effect of different childhood difficulties on adult intelligence coefficient (IQ) and their possible indirect effect through the mediating pathways of education and severity substance use. Ninety in-patients aged 19-64. The participants had abstained from substance use for at least 6 weeks and had different substance use profiles. Substance use disorder (SUD) and psychiatric illnesses were diagnosed according to the International Classification of Diseases 10th edition criteria. IQ was measured with the Wechsler Adult Intelligence Scale, 4th edition. Childhood difficulties, severity of substance use and level of education were assessed through a self-report questionnaire. Mean full scale IQ for the studied population was 87.3. Learning and attention deficit/hyperactivity difficulties in childhood were directly related to adult IQ. Education had a mediating effect between childhood learning difficulties/conduct problems and the verbal comprehension index. There was no significant difference in IQ due to the specific substance used or severity of substance use. IQ variance in in-treatment individuals with SUD was related to childhood functioning alone or through the mediator of education. Substance-related factors did not contribute to IQ variance. The results fit a normal theory of IQ development with commonly known risk factors and no disturbing effect of substance use. © 2018 S. Karger AG, Basel.

Cre-mediated cell ablation contests mast cell contribution in models of antibody- and T cell-mediated autoimmunity.

PubMed

Feyerabend, Thorsten B; Weiser, Anne; Tietz, Annette; Stassen, Michael; Harris, Nicola; Kopf, Manfred; Radermacher, Peter; Möller, Peter; Benoist, Christophe; Mathis, Diane; Fehling, Hans Jörg; Rodewald, Hans-Reimer

2011-11-23

Immunological functions of mast cells remain poorly understood. Studies in Kit mutant mice suggest key roles for mast cells in certain antibody- and T cell-mediated autoimmune diseases. However, Kit mutations affect multiple cell types of both immune and nonimmune origin. Here, we show that targeted insertion of Cre-recombinase into the mast cell carboxypeptidase A3 locus deleted mast cells in connective and mucosal tissues by a genotoxic Trp53-dependent mechanism. Cre-mediated mast cell eradication (Cre-Master) mice had, with the exception of a lack of mast cells and reduced basophils, a normal immune system. Cre-Master mice were refractory to IgE-mediated anaphylaxis, and this defect was rescued by mast cell reconstitution. This mast cell-deficient strain was fully susceptible to antibody-induced autoimmune arthritis and to experimental autoimmune encephalomyelitis. Differences comparing Kit mutant mast cell deficiency models to selectively mast cell-deficient mice call for a systematic re-evaluation of immunological functions of mast cells beyond allergy. Copyright © 2011 Elsevier Inc. All rights reserved.

Socioeconomic status and oppositional defiant disorder in preschoolers: parenting practices and executive functioning as mediating variables.

PubMed

Granero, Roser; Louwaars, Leonie; Ezpeleta, Lourdes

2015-01-01

To investigate the mediating mechanisms of oppositional defiant disorder (ODD) in preschoolers through pathways analysis, considering the family socioeconomic status (SES) as the independent variable and the parenting style and the children's executive functioning (EF) as the mediating factors. The sample included 622 three-year-old children from the general population. Multi-informant reports from parents and teachers were analyzed. Structural Equation Modeling showed that the associations between SES, EF, parenting style and ODD levels differed by children's gender: (a) for girls, the association of low SES and high ODD scores was partially mediated by difficulties in EF inhibition, and parenting practices defined by corporal punishment and inconsistent discipline obtained a quasi-significant indirect effect into the association between SES and ODD; (b) for boys, SES and EF (inhibition and emotional control) had a direct effect on ODD with no mediation. SES seems a good indicator to identify children at high-risk for prevention and intervention programs for ODD. Girls with ODD in families of low SES may particularly benefit from parent training practices and training in inhibition control.

[Mediator processes in the brain structures in the late periods after external and combined exposure to ionizing radiation].

PubMed

Taĭts, M Iu; Dudina, T V; Kandybo, T S; Elkina, A I

1990-01-01

In experiments with mature Wistar male rats it was shown that X-radiation of 12.9 mCi/kg and the combined effect of X-rays and 131I of 6.5 mCi/kg changed the rate of mediator processes in the structures responsible for the hypothalamic function regulation. At remote times (6 months) following irradiation differences were observed in the discoordination of mediator interrelations associated with the peculiarities of the indirect effect of external and combined irradiation implemented via endocrine mechanism system.

Maternal Mediation in Book Reading, Home Literacy Environment, and Children's Emergent Literacy: A Comparison between Two Social Groups

ERIC Educational Resources Information Center

Korat, Ofra; Klein, Pnina; Segal-Drori, Ora

2007-01-01

The researchers addressed two questions: (1) Does maternal reading mediation and family home literacy environment (HLE) relate to children's emergent literacy (EL) level? and (2) Do the relationships among these variables differ as a function of socioeconomic strata (SES) level. A total of 94 5-6-year-old children, 47 from low SES (LSES) and 47…

Discourse Markers in Italian as L2 in Face to Face vs. Computer Mediated Settings

ERIC Educational Resources Information Center

De Marco, Anna; Leone, Paola

2013-01-01

This pilot study aims to highlight a) differences in pragmatic function and distribution of discourse markers (DMs) in computer mediated and face to face (FtF) settings and b) any correlation of DM uses and language competence. The data have been collected by video-recording and analysing three speakers of Italian L2 (language level competence:…

Cocaine-and-Amphetamine-Regulated-Transcript (CART) peptide attenuates dopamine- and cocaine-mediated locomotor activity in both male and female rats: lack of sex differences

PubMed Central

Job, Martin O.; Perry, JoAnna; Shen, Li L.; Kuhar, Michael J.

2014-01-01

Cocaine-and-Amphetamine Regulated Transcript peptide (CART peptide) is known for having an inhibitory effect on dopamine (DA)- and cocaine-mediated actions and is postulated to be a homeostatic, regulatory factor in the nucleus accumbens (NAc). Some sex differences in cocaine-mediated LMA and in the expression and function of CART peptide have been reported. However, it is not known if the inhibitory effect of CART peptide on cocaine-mediated locomotor activity (LMA) is sexually dimorphic. In this study, the effect of CART 55-102 on LMA due to intra-NAc DA and i.p. cocaine were determined in male and female Sprague-Dawley rats. The results show that CART 55-102 blunted or reduced both the DA- and cocaine-induced LMA in both males and females. In conclusion, CART peptide is effective in blunting DA- and cocaine-mediated LMA in both males and females. PMID:24630272

The Usefulness of Differential Item Functioning Methodology in Longitudinal Intervention Studies

USDA-ARS?s Scientific Manuscript database

Perceived self-efficacy (SE) for engaging in physical activity (PA) is a key variable mediating PA change in interventions. The purpose of this study is to demonstrate the usefulness of item response modeling-based (IRM) differential item functioning (DIF) in the investigation of group differences ...

Conceptual Systems Functioning as a Mediating Factor in the Development of Counseling Skills.

ERIC Educational Resources Information Center

Lutwak, Nita; Hennessy, James J.

1982-01-01

Determined the relationship between counseling systems stages and counselor effectiveness as measured by Carkhuff's accurate empathy scale. Students (N=97) were rated for stage of conceptual functioning. Counseling interviews were rated for level of empathic responding. Results indicated markedly significant differences between and among…

Dynamic synchronization of ongoing neuronal activity across spinal segments regulates sensory information flow

PubMed Central

Contreras-Hernández, E; Chávez, D; Rudomin, P

2015-01-01

Previous studies on the correlation between spontaneous cord dorsum potentials recorded in the lumbar spinal segments of anaesthetized cats suggested the operation of a population of dorsal horn neurones that modulates, in a differential manner, transmission along pathways mediating Ib non-reciprocal postsynaptic inhibition and pathways mediating primary afferent depolarization and presynaptic inhibition. In order to gain further insight into the possible neuronal mechanisms that underlie this process, we have measured changes in the correlation between the spontaneous activity of individual dorsal horn neurones and the cord dorsum potentials associated with intermittent activation of these inhibitory pathways. We found that high levels of neuronal synchronization within the dorsal horn are associated with states of incremented activity along the pathways mediating presynaptic inhibition relative to pathways mediating Ib postsynaptic inhibition. It is suggested that ongoing changes in the patterns of functional connectivity within a distributed ensemble of dorsal horn neurones play a relevant role in the state-dependent modulation of impulse transmission along inhibitory pathways, among them those involved in the central control of sensory information. This feature would allow the same neuronal network to be involved in different functional tasks. Key points We have examined, in the spinal cord of the anaesthetized cat, the relationship between ongoing correlated fluctuations of dorsal horn neuronal activity and state-dependent activation of inhibitory reflex pathways. We found that high levels of synchronization between the spontaneous activity of dorsal horn neurones occur in association with the preferential activation of spinal pathways leading to primary afferent depolarization and presynaptic inhibition relative to activation of pathways mediating Ib postsynaptic inhibition. It is suggested that changes in synchronization of ongoing activity within a distributed network of dorsal horn neurones play a relevant role in the configuration of structured (non-random) patterns of functional connectivity that shape the interaction of sensory inputs with spinal reflex pathways subserving different functional tasks. PMID:25653206

Identifying Predictors, Moderators, and Mediators of Antidepressant Response in Major Depressive Disorder: Neuroimaging Approaches

PubMed Central

Phillips, Mary L.; Chase, Henry W.; Sheline, Yvette I.; Etkin, Amit; Almeida, Jorge R.C.; Deckersbach, Thilo; Trivedi, Madhukar H.

2015-01-01

Objective Despite significant advances in neuroscience and treatment development, no widely accepted biomarkers are available to inform diagnostics or identify preferred treatments for individuals with major depressive disorder. Method In this critical review, the authors examine the extent to which multimodal neuroimaging techniques can identify biomarkers reflecting key pathophysiologic processes in depression and whether such biomarkers may act as predictors, moderators, and mediators of treatment response that might facilitate development of personalized treatments based on a better understanding of these processes. Results The authors first highlight the most consistent findings from neuroimaging studies using different techniques in depression, including structural and functional abnormalities in two parallel neural circuits: serotonergically modulated implicit emotion regulation circuitry, centered on the amygdala and different regions in the medial prefrontal cortex; and dopaminergically modulated reward neural circuitry, centered on the ventral striatum and medial prefrontal cortex. They then describe key findings from the relatively small number of studies indicating that specific measures of regional function and, to a lesser extent, structure in these neural circuits predict treatment response in depression. Conclusions Limitations of existing studies include small sample sizes, use of only one neuroimaging modality, and a focus on identifying predictors rather than moderators and mediators of differential treatment response. By addressing these limitations and, most importantly, capitalizing on the benefits of multimodal neuroimaging, future studies can yield moderators and mediators of treatment response in depression to facilitate significant improvements in shorter- and longer-term clinical and functional outcomes. PMID:25640931

Satisfaction with Life in Orofacial Pain Disorders: Associations and Theoretical Implications

PubMed Central

Boggero, Ian A.; Rojas-Ramirez, Marcia V.; de Leeuw, Reny; Carlson, Charles R.

2016-01-01

Aims To test if patients with masticatory myofascial pain, local myalgia, centrally mediated myalgia, disc displacement, capsulitis/synovitis, or continuous neuropathic pain differed in self-reported satisfaction with life. The study also tested if satisfaction with life was similarly predicted by measures of physical, emotional, and social functioning across disorders. Methods Satisfaction with life, fatigue, affective distress, social support, and pain data were extracted from the medical records of 343 patients seeking treatment for chronic orofacial pain. Patients were grouped by primary diagnosis assigned following their initial appointment. Satisfaction with life was compared between disorders, with and without pain intensity entered as a covariate. Disorder-specific linear regression models using physical, emotional, and social predictors of satisfaction with life were computed. Results Patients with centrally mediated myalgia reported significantly lower satisfaction with life than did patients with any of the other five disorders. Inclusion of pain intensity as a covariate weakened but did not eliminate the effect. Satisfaction with life was predicted by measures of physical, emotional, and social functioning, but these associations were not consistent across disorders. Conclusions Results suggest that reduced satisfaction with life in patients with centrally mediated myalgia is not due only to pain intensity. There may be other factors that predispose people to both reduced satisfaction with life and centrally mediated myalgia. Furthermore, the results suggest that satisfaction with life is differentially influenced by physical, emotional, and social functioning in different orofacial pain disorders. PMID:27128473

Effect of Intermittent Energy Restriction on Flow Mediated Dilatation, a Measure of Endothelial Function: A Short Report.

PubMed

Headland, Michelle L; Clifton, Peter M; Keogh, Jennifer B

2018-06-04

Intermittent energy restriction is a popular alternative to daily energy restriction for weight loss; however, it is unknown if endothelial function, a risk factor for cardiovascular disease, is altered by periods of severe energy restriction. The objective of the study was to determine the impact of two consecutive very low energy intake days, which is the core component of the 5:2 intermittent energy restriction diet strategy, on endothelial function compared to consecutive ad libitum eating days. The secondary objective was to explore the effects of these dietary conditions on fasting glucose concentrations. This was a 4-week randomized, single-blinded, crossover study of 35 participants. Participants consumed a very low energy diet (500 calories for women, 600 calories for men) on two consecutive days per week and 5 days of habitual eating. In weeks 3 and 4 of the trial, participants had measurements of flow mediated dilatation (FMD) and blood samples taken following either 2 habitual eating days or 2 energy restricted days in a randomized order. FMD values were not different after the two eating states (8.6% vs. 8.3%, p = 0.7). All other outcome variables were unchanged. Endothelial function, as measured by flow mediated dilatation, was not altered by two consecutive very low energy intake days. Further investigations assessing the impact in specific population groups as well as different testing conditions would be beneficial.

Coulomb Mediated Hybridization of Excitons in Coupled Quantum Dots.

PubMed

Ardelt, P-L; Gawarecki, K; Müller, K; Waeber, A M; Bechtold, A; Oberhofer, K; Daniels, J M; Klotz, F; Bichler, M; Kuhn, T; Krenner, H J; Machnikowski, P; Finley, J J

2016-02-19

We report Coulomb mediated hybridization of excitonic states in optically active InGaAs quantum dot molecules. By probing the optical response of an individual quantum dot molecule as a function of the static electric field applied along the molecular axis, we observe unexpected avoided level crossings that do not arise from the dominant single-particle tunnel coupling. We identify a new few-particle coupling mechanism stemming from Coulomb interactions between different neutral exciton states. Such Coulomb resonances hybridize the exciton wave function over four different electron and hole single-particle orbitals. Comparisons of experimental observations with microscopic eight-band k·p calculations taking into account a realistic quantum dot geometry show good agreement and reveal that the Coulomb resonances arise from broken symmetry in the artificial semiconductor molecule.

Infiltration of Macrophages Correlates with Severity of Allograft Rejection and Outcome in Human Kidney Transplantation.

PubMed

Bergler, Tobias; Jung, Bettina; Bourier, Felix; Kühne, Louisa; Banas, Miriam C; Rümmele, Petra; Wurm, Simone; Banas, Bernhard

2016-01-01

Despite substantial progress in recent years, graft survival beyond the first year still requires improvement. Since modern immunosuppression addresses mainly T-cell activation and proliferation, we studied macrophage infiltration into the allografts of 103 kidney transplant recipients during acute antibody and T-cell mediated rejection. Macrophage infiltration was correlated with both graft function and graft survival until month 36 after transplantation. Macrophage infiltration was significantly elevated in antibody-mediated and T-cell mediated rejection, but not in kidneys with established IFTA. Treatment of rejection with steroids was less successful in patients with more prominent macrophage infiltration into the allografts. Macrophage infiltration was accompanied by increased cell proliferation as well as antigen presentation. With regard to the compartmental distribution severity of T-cell-mediated rejection was correlated to the amount of CD68+ cells especially in the peritubular and perivascular compartment, whereas biopsies with ABMR showed mainly peritubular CD68 infiltration. Furthermore, severity of macrophage infiltration was a valid predictor of resulting creatinine values two weeks as well as two and three years after renal transplantation as illustrated by multivariate analysis. Additionally performed ROC curve analysis showed that magnitude of macrophage infiltration (below vs. above the median) was a valid predictor for the necessity to restart dialysis. Having additionally stratified biopsies in accordance to the magnitude of macrophage infiltration, differential CD68+ cell infiltration was reflected by striking differences in overall graft survival. The differences in acute allograft rejection have not only been reflected by different magnitudes of macrophage infiltration, but also by compartment-specific infiltration pattern and subsequent impact on resulting allograft function as well as need for dialysis initiation. There is a robust relationship between macrophage infiltration, accompanying antigen-presentation and resulting allograft function.

Infiltration of Macrophages Correlates with Severity of Allograft Rejection and Outcome in Human Kidney Transplantation

PubMed Central

Bourier, Felix; Kühne, Louisa; Banas, Miriam C.; Rümmele, Petra; Wurm, Simone; Banas, Bernhard

2016-01-01

Objective Despite substantial progress in recent years, graft survival beyond the first year still requires improvement. Since modern immunosuppression addresses mainly T-cell activation and proliferation, we studied macrophage infiltration into the allografts of 103 kidney transplant recipients during acute antibody and T-cell mediated rejection. Macrophage infiltration was correlated with both graft function and graft survival until month 36 after transplantation. Results Macrophage infiltration was significantly elevated in antibody-mediated and T-cell mediated rejection, but not in kidneys with established IFTA. Treatment of rejection with steroids was less successful in patients with more prominent macrophage infiltration into the allografts. Macrophage infiltration was accompanied by increased cell proliferation as well as antigen presentation. With regard to the compartmental distribution severity of T-cell-mediated rejection was correlated to the amount of CD68+ cells especially in the peritubular and perivascular compartment, whereas biopsies with ABMR showed mainly peritubular CD68 infiltration. Furthermore, severity of macrophage infiltration was a valid predictor of resulting creatinine values two weeks as well as two and three years after renal transplantation as illustrated by multivariate analysis. Additionally performed ROC curve analysis showed that magnitude of macrophage infiltration (below vs. above the median) was a valid predictor for the necessity to restart dialysis. Having additionally stratified biopsies in accordance to the magnitude of macrophage infiltration, differential CD68+ cell infiltration was reflected by striking differences in overall graft survival. Conclusion The differences in acute allograft rejection have not only been reflected by different magnitudes of macrophage infiltration, but also by compartment-specific infiltration pattern and subsequent impact on resulting allograft function as well as need for dialysis initiation. There is a robust relationship between macrophage infiltration, accompanying antigen-presentation and resulting allograft function. PMID:27285579

Alignment strategies for the entrainment of music and movement rhythms.

PubMed

Moens, Bart; Leman, Marc

2015-03-01

Theories of entrainment assume that spontaneous entrainment emerges from dynamic laws that operate via mediators on interactions, whereby entrainment is facilitated if certain conditions are fulfilled. In this study, we show that mediators can be built that affect the entrainment of human locomotion to music. More specifically, we built D-Jogger, a music player that functions as a mediator between music and locomotion rhythms. The D-Jogger makes it possible to manipulate the timing differences between salient moments of the rhythms (beats and footfalls) through the manipulation of the musical period and phase, which affect the condition in which entrainment functions. We conducted several experiments to explore different strategies for manipulating the entrainment of locomotion and music. The results of these experiments showed that spontaneous entrainment can be manipulated, thereby suggesting different strategies on how to embark. The findings furthermore suggest a distinction among different modalities of entrainment: finding the beat (the most difficult part of entrainment), keeping the beat (easier, as a temporal scheme has been established), and being in phase (no entrainment is needed because the music is always adapted to the human rhythm). This study points to a new avenue of research on entrainment and opens new perspectives for the neuroscience of music. © 2014 New York Academy of Sciences.

Study Protocol on Hormonal Mediation of Exercise on Cognition, Stress and Immunity (PRO-HMECSI): Effects of Different Exercise Programmes in Institutionalized Elders

PubMed Central

Teixeira, Ana Maria; Ferreira, José Pedro; Hogervorst, Eef; Braga, Margarida Ferreira; Bandelow, Stephan; Rama, Luís; Figueiredo, António; Campos, Maria João; Furtado, Guilherme Eustáquio; Chupel, Matheus Uba; Pedrosa, Filipa Martins

2016-01-01

Physical activity (PA) in elders has been shown to have positive effects on a plethora of chronic diseases and to improve immunity, mental health, and cognition. Chronic stress has also been shown to have immuno-suppressive effects and to accelerate immunosenescence. Exercise could be a significant factor in ameliorating the deleterious effects of chronic stress, but variables such as the type, intensity, and frequency of exercise that should be performed in order to effectively reduce the stress burden need to be defined clearly. PRO-HMECSI will allow us to investigate which hormonal and immunological parameters are able to mediate the effects of exercise on mucosal immunity, psychological/biological stress, and cognitive functioning in older people. Phase I consists of an observational cross-sectional study that compares elders groups (n = 223, >65 years) by functional fitness levels aiming to identify biomarkers involved in maintaining immune and mental health. Neuroendocrine and immune biomarkers of stress, psychological well-being related to mental health, neurocognitive function, functional fitness, and daily PA will be evaluated. Phase II consists of a 28-week intervention in elders with mild cognitive impairment (MCI) profile (n = 149, >65 years, divided in three groups of exercise and one control group), aiming to investigate whether the positive effect of three different types of chair-based exercise programs on physical and psychological health is mediated by an optimal endocrine environment. Primary outcomes are measures of cognitive function and global health. Secondary outcomes include the evaluation the other dimensions such as immune function, psychological health, and depression. Few studies addressed the effects of different types of exercise interventions in older population samples with MCI. We will also be able to determine which type of exercise is more effective in the immune and hormonal function of this population. PMID:27446898

Glycine Potentiates AMPA Receptor Function through Metabotropic Activation of GluN2A-Containing NMDA Receptors

PubMed Central

Li, Li-Jun; Hu, Rong; Lujan, Brendan; Chen, Juan; Zhang, Jian-Jian; Nakano, Yasuko; Cui, Tian-Yuan; Liao, Ming-Xia; Chen, Jin-Cao; Man, Heng-Ye; Feng, Hua; Wan, Qi

2016-01-01

NMDA receptors are Ca2+-permeable ion channels. The activation of NMDA receptors requires agonist glutamate and co-agonist glycine. Recent evidence indicates that NMDA receptor also has metabotropic function. Here we report that in cultured mouse hippocampal neurons, glycine increases AMPA receptor-mediated currents independent of the channel activity of NMDA receptors and the activation of glycine receptors. The potentiation of AMPA receptor function by glycine is antagonized by the inhibition of ERK1/2. In the hippocampal neurons and in the HEK293 cells transfected with different combinations of NMDA receptors, glycine preferentially acts on GluN2A-containing NMDA receptors (GluN2ARs), but not GluN2B-containing NMDA receptors (GluN2BRs), to enhance ERK1/2 phosphorylation independent of the channel activity of GluN2ARs. Without requiring the channel activity of GluN2ARs, glycine increases AMPA receptor-mediated currents through GluN2ARs. Thus, these results reveal a metabotropic function of GluN2ARs in mediating glycine-induced potentiation of AMPA receptor function via ERK1/2 activation. PMID:27807405

Development of rod function in term born and former preterm subjects.

PubMed

Fulton, Anne B; Hansen, Ronald M; Moskowitz, Anne

2009-06-01

To provide an overview of some of our electroretinographic (ERG) and psychophysical studies of normal development of rod function and their application to retinopathy of prematurity (ROP). ERG responses to full-field stimuli were recorded from dark adapted subjects. Rod photoreceptor sensitivity (SROD) was calculated by fit of a biochemical model of the activation of phototransduction to the ERG a-wave. Dark adapted psychophysical thresholds for detecting 2 degrees spots in parafoveal (10 degrees eccentric) and peripheral (30 degrees eccentric) retina were measured and the difference between the thresholds, Delta10-30, was examined as a function of age. SROD and Delta10-30 in term born and former preterm subjects were compared. In term born infants, (1) the normal developmental increase in SROD changes proportionately with the amount of rod visual pigment, rhodopsin, and (2) rod-mediated function in central retina is immature compared with that in peripheral retina. In subjects born prematurely, deficits in SROD persist long after active ROP has resolved. Maturation of rod-mediated thresholds in the central retina is prolonged by mild ROP. Characterization of the development of normal rod and rod-mediated function provides a foundation for understanding ROP.

Development of Rod Function in Term Born and Former Preterm Subjects

PubMed Central

Fulton, Anne B.; Hansen, Ronald M.; Moskowitz, Anne

2009-01-01

Purpose Provide an overview of some of our electroretinographic and psychophysical studies of normal development of rod function and their application to retinopathy of prematurity (ROP). Methods Electroretinographic (ERG) responses to full-field stimuli were recorded from dark adapted subjects. Rod photoreceptor sensitivity, SROD, was calculated by fit of a biochemical model of the activation of phototransduction to the ERG a-wave. Dark adapted psychophysical thresholds for detecting 2° spots in parafoveal (10° eccentric) and peripheral (30° eccentric) retina were measured and the difference between the thresholds, Δ10-30, was examined as a function of age. SROD and Δ10-30 in term born and former preterm subjects were compared. Results In term born infants, (1) the normal developmental increase in SROD changes proportionately with the amount of rod visual pigment, rhodopsin, and (2) rod mediated function in central retina is immature compared to that in peripheral retina. In subjects born prematurely, deficits in rod photoreceptor sensitivity persist long after active ROP has resolved. Maturation of rod mediated thresholds in the central retina is prolonged by mild ROP. Conclusions Characterization of the development of normal rod and rod mediated function provides a foundation for understanding ROP. PMID:19483509

Programming social, cognitive, and neuroendocrine development by early exposure to novelty.

PubMed

Tang, Akaysha C; Akers, Katherine G; Reeb, Bethany C; Romeo, Russell D; McEwen, Bruce S

2006-10-17

Mildly stressful early life experiences can potentially impact a broad range of social, cognitive, and physiological functions in humans, nonhuman primates, and rodents. Recent rodent studies favor a maternal-mediation hypothesis that considers maternal-care differences induced by neonatal stimulation as the cause of individual differences in offspring development. Using neonatal novelty exposure, a neonatal stimulation paradigm that dissociates maternal individual differences from a direct stimulation effect on the offspring, we investigated the effect of early exposures to novelty on a diverse range of psychological functions using several assessment paradigms. Pups that received brief neonatal novelty exposures away from the home environment showed enhancement in spatial working memory, social competition, and corticosterone response to surprise during adulthood compared with their home-staying siblings. These functional enhancements in novelty-exposed rats occurred despite evidence that maternal care was directed preferentially toward home-staying instead of novelty-exposed pups, indicating that greater maternal care is neither necessary nor sufficient for these early stimulation-induced functional enhancements. We suggest a unifying maternal-modulation hypothesis, which distinguishes itself from the maternal-mediation hypothesis in that (i) neonatal stimulation can have direct effects on pups, cumulatively leading to long-term improvement in adult offspring; and (ii) maternal behavior can attenuate or potentiate these effects, thereby decreasing or increasing this long-term functional improvement.

Comorbid psychiatric conditions as mediators to predict later social adjustment in youths with autism spectrum disorder.

PubMed

Chiang, Huey-Ling; Gau, Susan Shur-Fen

2015-08-06

Individuals with autism spectrum disorder (ASD) experience long-term social impairment and their comorbid psychiatric conditions negatively impact adaptive functioning. The aims of the study are to investigate whether comorbid psychopathologies, such as anxiety/depression, inattention, hyperactivity/impulsivity, and oppositional behaviors, mediated the link between autistic symptoms and social maladjustment. One hundred and twenty-four youths diagnosed with a clinical diagnosis of DSM-IV ASD (mean age, 10.6 ± 3.3 years) participated in this longitudinal study. They were assessed using semistructured diagnostic interviews on ASD and other psychiatric conditions at recruitment. Follow-up interviews took place approximately 3 years later (37.59 ± 15 months) while the parents reported to the Social Adjustment Inventory for Children and Adolescents on their children's social adjustment. Mediation models were used to examine the mediating effect of comorbid psychopathologies on social adjustment. Youths with ASD had worse school, peer, and home functions than controls at follow-up assessment. In general, comorbid psychiatric conditions mediated the link between autistic symptoms and different domains of social adjustment, independent of age, sex, and full-scale IQ. Additionally, we found specific mediating effects of anxiety/depression and inattention on school functions; anxiety/depression on peer relationships; and oppositional behaviors on home behaviors. Early comorbid psychopathologies may further impair later social adjustment in youths with ASD and an early identification and intervention of these comorbid conditions are suggested. © 2015 Association for Child and Adolescent Mental Health.

The moderator-mediator variable distinction in social psychological research: conceptual, strategic, and statistical considerations.

PubMed

Baron, R M; Kenny, D A

1986-12-01

In this article, we attempt to distinguish between the properties of moderator and mediator variables at a number of levels. First, we seek to make theorists and researchers aware of the importance of not using the terms moderator and mediator interchangeably by carefully elaborating, both conceptually and strategically, the many ways in which moderators and mediators differ. We then go beyond this largely pedagogical function and delineate the conceptual and strategic implications of making use of such distinctions with regard to a wide range of phenomena, including control and stress, attitudes, and personality traits. We also provide a specific compendium of analytic procedures appropriate for making the most effective use of the moderator and mediator distinction, both separately and in terms of a broader causal system that includes both moderators and mediators.

Contribution of personal and environmental factors on positive psychological functioning in adolescents.

PubMed

Fadda, Daniela; Scalas, L Francesca; Meleddu, Mauro

2015-08-01

This study examined self-esteem as mediator in the relations of personal (extraversion, neuroticism) and environmental (maternal, paternal, peer-relationships) variables with domains of positive psychological functioning (PPF) in adolescence (Satisfaction with life, Mastery, Vigor, Social Interest, Social Cheerfulness). We compared one-sided and multidimensional models using a sample of 1193 high school students (592 males and 601 females). We examined variations in adolescent PPF as a function of parenting styles via independent examination of maternal and paternal bonding. Results supported the multidimensional models, which indicated direct effects of personality traits, maternal care and peer relationships, as well as indirect effects, mediated by self-esteem, of all predictors on most PPF dimensions. Overall, our study provided a broader picture of personal and environmental predictors on different dimensions of PPF, which supported the mediating role of self-esteem and emphasized the importance of considering multidimensional models to characterize PPF in adolescents. Copyright © 2015 The Foundation for Professionals in Services for Adolescents. Published by Elsevier Ltd. All rights reserved.

Lentiviral CRISPR/Cas9 vector mediated miR-21 gene editing inhibits the epithelial to mesenchymal transition in ovarian cancer cells.

PubMed

Huo, Wenying; Zhao, Guannan; Yin, Jinggang; Ouyang, Xuan; Wang, Yinan; Yang, Chuanhe; Wang, Baojing; Dong, Peixin; Wang, Zhixiang; Watari, Hidemichi; Chaum, Edward; Pfeffer, Lawrence M; Yue, Junming

2017-01-01

CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats) mediated genome editing is a powerful approach for loss of function studies. Here we report that lentiviral CRISPR/Cas9 vectors are highly efficient in introducing mutations in the precursor miRNA sequence, thus leading to the loss of miRNA expression and function. We constructed four different lentiviral CRISPR/Cas9 vectors that target different regions of the precursor miR-21 sequence and found that these lentiviral CRISPR/Cas9 miR-21 gRNA vectors induced mutations in the precursor sequences as shown by DNA surveyor mutation assay and Sanger sequencing. Two miR-21 lentiviral CRISPR/Cas9 gRNA vectors were selected to probe miR-21 function in ovarian cancer SKOV3 and OVCAR3 cell lines. Our data demonstrate that disruption of pre-miR-21 sequences leads to reduced cell proliferation, migration and invasion. Moreover, CRISPR/Cas9-mediated miR-21 gene editing sensitizes both SKOV3 and OVCAR3 cells to chemotherapeutic drug treatment. Disruption of miR-21 leads to the inhibition of epithelial to mesenchymal transition (EMT) in both SKOV3 and OVCAR3 cells as evidenced by the upregulation of epithelial cell marker E-cadherin and downregulation of mesenchymal marker genes, vimentin and Snai2. The miR-21 target genes PDCD4 and SPRY2 were upregulated in cells transduced with miR-21gRNAs compared to controls. Our study indicates that lentiviral CRISPR/Cas9-mediated miRNA gene editing is an effective approach to address miRNA function, and disruption of miR-21 inhibits EMT in ovarian cancer cells.

Lentiviral CRISPR/Cas9 vector mediated miR-21 gene editing inhibits the epithelial to mesenchymal transition in ovarian cancer cells

PubMed Central

Huo, Wenying; Zhao, Guannan; Yin, Jinggang; Ouyang, Xuan; Wang, Yinan; Yang, Chuanhe; Wang, Baojing; Dong, Peixin; Wang, Zhixiang; Watari, Hidemichi; Chaum, Edward; Pfeffer, Lawrence M.; Yue, Junming

2017-01-01

CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats) mediated genome editing is a powerful approach for loss of function studies. Here we report that lentiviral CRISPR/Cas9 vectors are highly efficient in introducing mutations in the precursor miRNA sequence, thus leading to the loss of miRNA expression and function. We constructed four different lentiviral CRISPR/Cas9 vectors that target different regions of the precursor miR-21 sequence and found that these lentiviral CRISPR/Cas9 miR-21 gRNA vectors induced mutations in the precursor sequences as shown by DNA surveyor mutation assay and Sanger sequencing. Two miR-21 lentiviral CRISPR/Cas9 gRNA vectors were selected to probe miR-21 function in ovarian cancer SKOV3 and OVCAR3 cell lines. Our data demonstrate that disruption of pre-miR-21 sequences leads to reduced cell proliferation, migration and invasion. Moreover, CRISPR/Cas9-mediated miR-21 gene editing sensitizes both SKOV3 and OVCAR3 cells to chemotherapeutic drug treatment. Disruption of miR-21 leads to the inhibition of epithelial to mesenchymal transition (EMT) in both SKOV3 and OVCAR3 cells as evidenced by the upregulation of epithelial cell marker E-cadherin and downregulation of mesenchymal marker genes, vimentin and Snai2. The miR-21 target genes PDCD4 and SPRY2 were upregulated in cells transduced with miR-21gRNAs compared to controls. Our study indicates that lentiviral CRISPR/Cas9-mediated miRNA gene editing is an effective approach to address miRNA function, and disruption of miR-21 inhibits EMT in ovarian cancer cells. PMID:28123598

Associations among false belief understanding, counterfactual reasoning, and executive function.

PubMed

Guajardo, Nicole R; Parker, Jessica; Turley-Ames, Kandi

2009-09-01

The primary purposes of the present study were to clarify previous work on the association between counterfactual thinking and false belief performance to determine (1) whether these two variables are related and (2) if so, whether executive function skills mediate the relationship. A total of 92 3-, 4-, and 5-year-olds completed false belief, counterfactual, working memory, representational flexibility, and language measures. Counterfactual reasoning accounted for limited unique variance in false belief. Both working memory and representational flexibility partially mediated the relationship between counterfactual and false belief. Children, like adults, also generated various types of counterfactual statements to differing degrees. Results demonstrated the importance of language and executive function for both counterfactual and false belief. Implications are discussed.

The scavenger activity of the human P2X7 receptor differs from P2X7 pore function by insensitivity to antagonists, genetic variation and sodium concentration: Relevance to inflammatory brain diseases.

PubMed

Ou, Amber; Gu, Ben J; Wiley, James S

2018-04-01

Activation of P2X7 receptors is widely recognised to initiate proinflammatory responses. However P2X7 also has a dual function as a scavenger receptor which is active in the absence of ATP and plasma proteins and may be important in central nervous system (CNS) diseases. Here, we investigated both P2X7 pore formation and its phagocytic function in fresh human monocytes (as a model of microglia) by measuring ATP-induced ethidium dye uptake and fluorescent bead uptake respectively. This was studied in monocytes expressing various polymorphic variants as well as in the presence of different P2X7 antagonists and ionic media. P2X7-mediated phagocytosis was found to account for about half of Latrunculin (or Cytochalasin D)-sensitive bead engulfment by fresh human monocytes. Monocytes harbouring P2X7 Ala348Thr or Glu496Ala polymorphic variants showed increase or loss of ethidium uptake respectively, but these changes in pore formation did not always correspond to the changes in phagocytosis of YG beads. Unlike pore function, P2X7-mediated phagocytosis was not affected by three potent selective P2X7 antagonists and remained identical in Na + and K + media. Taken together, our results show that P2X7 is a scavenger receptor with important function in the CNS but its phagocytic function has features distinct from its pore function. Both P2X7 pore formation and P2X7-mediated phagocytosis should be considered in the design of new P2X7 antagonists for the treatment of CNS diseases. Copyright © 2018 Elsevier B.V. All rights reserved.

RPA-mediated unfolding of systematically varying G-quadruplex structures.

PubMed

Ray, Sujay; Qureshi, Mohammad H; Malcolm, Dominic W; Budhathoki, Jagat B; Celik, Uğur; Balci, Hamza

2013-05-21

G-quadruplex (GQ) is a noncanonical nucleic acid structure that is formed by guanine rich sequences. Unless it is destabilized by proteins such as replication protein A (RPA), GQ could interfere with DNA metabolic functions, such as replication or repair. We studied RPA-mediated GQ unfolding using single-molecule FRET on two groups of GQ structures that have different loop lengths and different numbers of G-tetrad layers. We observed a linear increase in the steady-state stability of the GQ against RPA-mediated unfolding with increasing number of layers or decreasing loop length. The stability demonstrated by different GQ structures varied by at least three orders of magnitude. Those with shorter loops (less than three nucleotides long) or a greater number of layers (more than three layers) maintained a significant folded population even at physiological RPA concentration (≈1 μM), raising the possibility of physiological viability of such GQ structures. Finally, we measured the transition time between the start and end of the RPA-mediated GQ unfolding process to be 0.35 ± 0.10 s for all GQ constructs we studied, despite significant differences in their steady-state stabilities. We propose a two-step RPA-mediated GQ unfolding mechanism that is consistent with our observations. Copyright © 2013 Biophysical Society. Published by Elsevier Inc. All rights reserved.

RPA-Mediated Unfolding of Systematically Varying G-Quadruplex Structures

PubMed Central

Ray, Sujay; Qureshi, Mohammad H.; Malcolm, Dominic W.; Budhathoki, Jagat B.; Çelik, Uğur; Balci, Hamza

2013-01-01

G-quadruplex (GQ) is a noncanonical nucleic acid structure that is formed by guanine rich sequences. Unless it is destabilized by proteins such as replication protein A (RPA), GQ could interfere with DNA metabolic functions, such as replication or repair. We studied RPA-mediated GQ unfolding using single-molecule FRET on two groups of GQ structures that have different loop lengths and different numbers of G-tetrad layers. We observed a linear increase in the steady-state stability of the GQ against RPA-mediated unfolding with increasing number of layers or decreasing loop length. The stability demonstrated by different GQ structures varied by at least three orders of magnitude. Those with shorter loops (less than three nucleotides long) or a greater number of layers (more than three layers) maintained a significant folded population even at physiological RPA concentration (≈1 μM), raising the possibility of physiological viability of such GQ structures. Finally, we measured the transition time between the start and end of the RPA-mediated GQ unfolding process to be 0.35 ± 0.10 s for all GQ constructs we studied, despite significant differences in their steady-state stabilities. We propose a two-step RPA-mediated GQ unfolding mechanism that is consistent with our observations. PMID:23708363

Calcium/calmodulin-mediated signal network in plants

NASA Technical Reports Server (NTRS)

Yang, Tianbao; Poovaiah, B. W.

2003-01-01

Various extracellular stimuli elicit specific calcium signatures that can be recognized by different calcium sensors. Calmodulin, the predominant calcium receptor, is one of the best-characterized calcium sensors in eukaryotes. In recent years, completion of the Arabidopsis genome project and advances in functional genomics have helped to identify and characterize numerous calmodulin-binding proteins in plants. There are some similarities in Ca(2+)/calmodulin-mediated signaling in plants and animals. However, plants possess multiple calmodulin genes and many calmodulin target proteins, including unique protein kinases and transcription factors. Some of these proteins are likely to act as "hubs" during calcium signal transduction. Hence, a better understanding of the function of these calmodulin target proteins should help in deciphering the Ca(2+)/calmodulin-mediated signal network and its role in plant growth, development and response to environmental stimuli.

Parental distress, parenting practices, and child adaptive outcomes following traumatic brain injury.

PubMed

Micklewright, Jackie L; King, Tricia Z; O'Toole, Kathleen; Henrich, Chris; Floyd, Frank J

2012-03-01

Moderate and severe pediatric traumatic brain injuries (TBI) are associated with significant familial distress and child adaptive sequelae. Our aim was to examine the relationship between parental psychological distress, parenting practices (authoritarian, permissive, authoritative), and child adaptive functioning 12-36 months following TBI or orthopedic injury (OI). Injury type was hypothesized to moderate the relationship between parental distress and child adaptive functioning, demonstrating a significantly stronger relationship in the TBI relative to OI group. Authoritarian parenting practices were hypothesized to mediate relationship between parental distress and child adaptive functioning across groups. Groups (TBI n = 21, OI n = 23) did not differ significantly on age at injury, time since injury, sex, race, or SES. Parents completed the Brief Symptom Inventory, Parenting Practices Questionnaire, and Vineland-II. Moderation and mediation hypotheses were tested using hierarchical multiple regression and a bootstrapping approach, respectively. Results supported moderation and revealed that higher parental psychological distress was associated with lower child adaptive functioning in the TBI group only. Mediation results indicated that higher parental distress was associated with authoritarian parenting practices and lower adaptive functioning across groups. Results suggest that parenting practices are an important area of focus for studies attempting to elucidate the relationship between parent and child functioning following TBI.

Combinatorial action of Grainyhead, Extradenticle and Notch in regulating Hox mediated apoptosis in Drosophila larval CNS

PubMed Central

Khandelwal, Risha; Govinda Rajan, Sriivatsan; Kumar, Raviranjan

2017-01-01

Hox mediated neuroblast apoptosis is a prevalent way to pattern larval central nervous system (CNS) by different Hox genes, but the mechanism of this apoptosis is not understood. Our studies with Abdominal-A (Abd-A) mediated larval neuroblast (pNB) apoptosis suggests that AbdA, its cofactor Extradenticle (Exd), a helix-loop-helix transcription factor Grainyhead (Grh), and Notch signaling transcriptionally contribute to expression of RHG family of apoptotic genes. We find that Grh, AbdA, and Exd function together at multiple motifs on the apoptotic enhancer. In vivo mutagenesis of these motifs suggest that they are important for the maintenance of the activity of the enhancer rather than its initiation. We also find that Exd function is independent of its known partner homothorax in this apoptosis. We extend some of our findings to Deformed expressing region of sub-esophageal ganglia where pNBs undergo a similar Hox dependent apoptosis. We propose a mechanism where common players like Exd-Grh-Notch work with different Hox genes through region specific enhancers to pattern respective segments of larval central nervous system. PMID:29023471

Combinatorial action of Grainyhead, Extradenticle and Notch in regulating Hox mediated apoptosis in Drosophila larval CNS.

PubMed

Khandelwal, Risha; Sipani, Rashmi; Govinda Rajan, Sriivatsan; Kumar, Raviranjan; Joshi, Rohit

2017-10-01

Hox mediated neuroblast apoptosis is a prevalent way to pattern larval central nervous system (CNS) by different Hox genes, but the mechanism of this apoptosis is not understood. Our studies with Abdominal-A (Abd-A) mediated larval neuroblast (pNB) apoptosis suggests that AbdA, its cofactor Extradenticle (Exd), a helix-loop-helix transcription factor Grainyhead (Grh), and Notch signaling transcriptionally contribute to expression of RHG family of apoptotic genes. We find that Grh, AbdA, and Exd function together at multiple motifs on the apoptotic enhancer. In vivo mutagenesis of these motifs suggest that they are important for the maintenance of the activity of the enhancer rather than its initiation. We also find that Exd function is independent of its known partner homothorax in this apoptosis. We extend some of our findings to Deformed expressing region of sub-esophageal ganglia where pNBs undergo a similar Hox dependent apoptosis. We propose a mechanism where common players like Exd-Grh-Notch work with different Hox genes through region specific enhancers to pattern respective segments of larval central nervous system.

Nonneutralizing Functional Antibodies: a New “Old” Paradigm for HIV Vaccines

PubMed Central

Ake, Julie; Robb, Merlin L.; Kim, Jerome H.; Plotkin, Stanley A.

2014-01-01

Animal and human data from various viral infections and vaccine studies suggest that nonneutralizing antibodies (nNAb) without neutralizing activity in vitro may play an important role in protection against viral infection in vivo. This was illustrated by the recent human immunodeficiency virus (HIV) RV144 vaccine efficacy trial, which demonstrated that HIV-specific IgG-mediated nNAb directed against the V2 loop of HIV type 1 envelope (Env) were inversely correlated with risk for HIV acquisition, while Env-specific plasma IgA-mediated antibodies were directly correlated with risk. However, tier 1 NAb in the subset of responders with a low level of plasma Env-specific IgA correlated with decreased risk. Nonhuman primate simian immunodeficiency virus (SIV) and simian-human immunodeficiency virus (SHIV) challenge studies suggest that Env-mediated antibodies are essential and sufficient for protection. A comparison of immune responses generated in human efficacy trials reveals subtle differences in the fine specificities of the antibody responses, in particular in HIV-specific IgG subclasses. The underlying mechanisms that may have contributed to protection against HIV acquisition in humans, although not fully understood, are possibly mediated by antibody-dependent cell-mediated cytotoxicity (ADCC) and/or other nonneutralizing humoral effector functions, such as antibody-mediated phagocytosis. The presence of such functional nNAb in mucosal tissues and cervico-vaginal and rectal secretions challenges the paradigm that NAb are the predominant immune response conferring protection, although this does not negate the desirability of evoking neutralizing antibodies through vaccination. Instead, NAb and nNAb should be looked upon as complementary or synergistic humoral effector functions. Several HIV vaccine clinical trials to study these antibody responses in various prime-boost modalities in the systemic and mucosal compartments are ongoing. The induction of high-frequency HIV-specific functional nNAb at high titers may represent an attractive hypothesis-testing strategy in future HIV vaccine efficacy trials. PMID:24920599

Resting State Functional Connectivity within the Cingulate Cortex Jointly Predicts Agreeableness and Stressor-Evoked Cardiovascular Reactivity

PubMed Central

Ryan, John P.; Sheu, Lei K.; Gianaros, Peter J.

2010-01-01

Exaggerated cardiovascular reactivity to stress confers risk for cardiovascular disease. Further, individual differences in stressor-evoked cardiovascular reactivity covary with the functionality of cortical and limbic brain areas, particularly within the cingulate cortex. What remains unclear, however, is how individual differences in personality traits interact with cingulate functionality in the prediction of stressor-evoked cardiovascular reactivity. Accordingly, we tested the associations between (i) a particular personality trait, Agreeableness, which is associated with emotional reactions to conflict, (ii) resting state functional connectivity within the cingulate cortex, and (iii) stressor-evoked blood pressure (BP) reactivity. Participants (N=39, 19 men, aged 20–37 yrs) completed a resting functional connectivity MRI protocol, followed by two standardized stressor tasks that engaged conflict processing and evoked BP reactivity. Agreeableness covaried positively with BP reactivity across individuals. Moreover, connectivity analyses demonstrated that a more positive functional connectivity between the posterior cingulate (BA31) and the perigenual anterior cingulate (BA32) covaried positively with Agreeableness and with BP reactivity. Finally, statistical mediation analyses demonstrated that BA31–BA32 connectivity mediated the covariation between Agreeableness and BP reactivity. Functional connectivity within the cingulate appears to link Agreeableness and a risk factor for cardiovascular disease, stressor-evoked BP reactivity. PMID:21130172

Pavlovian Conditioning of Rat Mucosal Mast Cells to Secrete Rat Mast Cell Protease II

NASA Astrophysics Data System (ADS)

MacQueen, Glenda; Marshall, Jean; Perdue, Mary; Siegel, Shepard; Bienenstock, John

1989-01-01

Antigen (egg albumin) injections, which stimulate mucosal mast cells to secrete mediators, were paired with an audiovisual cue. After reexposure to the audiovisual cue, a mediator (rat mast cell protease II) was measured with a sensitive and specific assay. Animals reexposed to only the audiovisual cue released a quantity of protease not significantly different from animals reexposed to both the cue and the antigen; these groups released significantly more protease than animals that had received the cue and antigen in a noncontingent manner. The results support a role for the central nervous system as a functional effector of mast cell function in the allergic state.

Dioxin Toxicity In Vivo Results from an Increase in the Dioxin-Independent Transcriptional Activity of the Aryl Hydrocarbon Receptor

PubMed Central

Céspedes, Miguel Angel; Galindo, Maximo Ibo; Couso, Juan Pablo

2010-01-01

The Aryl hydrocarbon receptor (Ahr) is the nuclear receptor mediating the toxicity of dioxins -widespread and persistent pollutants whose toxic effects include tumor promotion, teratogenesis, wasting syndrome and chloracne. Elimination of Ahr in mice eliminates dioxin toxicity but also produces adverse effects, some seemingly unrelated to dioxin. Thus the relationship between the toxic and dioxin-independent functions of Ahr is not clear, which hampers understanding and treatment of dioxin toxicity. Here we develop a Drosophila model to show that dioxin actually increases the in vivo dioxin-independent activity of Ahr. This hyperactivation resembles the effects caused by an increase in the amount of its dimerisation partner Ahr nuclear translocator (Arnt) and entails an increased transcriptional potency of Ahr, in addition to the previously described effect on nuclear translocation. Thus the two apparently different functions of Ahr, dioxin-mediated and dioxin-independent, are in fact two different levels (hyperactivated and basal, respectively) of a single function. PMID:21079739

Actin-Based Adhesion Modules Mediate Cell Interactions with the Extracellular Matrix and Neighboring Cells.

PubMed

Bachir, Alexia I; Horwitz, Alan Rick; Nelson, W James; Bianchini, Julie M

2017-07-05

Cell adhesions link cells to the extracellular matrix (ECM) and to each other and depend on interactions with the actin cytoskeleton. Both cell-ECM and cell-cell adhesion sites contain discrete, yet overlapping, functional modules. These modules establish physical associations with the actin cytoskeleton, locally modulate actin organization and dynamics, and trigger intracellular signaling pathways. Interplay between these modules generates distinct actin architectures that underlie different stages, types, and functions of cell-ECM and cell-cell adhesions. Actomyosin contractility is required to generate mature, stable adhesions, as well as to sense and translate the mechanical properties of the cellular environment into changes in cell organization and behavior. Here, we review the organization and function of different adhesion modules and how they interact with the actin cytoskeleton. We highlight the molecular mechanisms of mechanotransduction in adhesions and how adhesion molecules mediate cross talk between cell-ECM and cell-cell adhesion sites. Copyright © 2017 Cold Spring Harbor Laboratory Press; all rights reserved.

Neuronal activity determines distinct gliotransmitter release from a single astrocyte

PubMed Central

Covelo, Ana

2018-01-01

Accumulating evidence indicates that astrocytes are actively involved in brain function by regulating synaptic activity and plasticity. Different gliotransmitters, such as glutamate, ATP, GABA or D-serine, released form astrocytes have been shown to induce different forms of synaptic regulation. However, whether a single astrocyte may release different gliotransmitters is unknown. Here we show that mouse hippocampal astrocytes activated by endogenous (neuron-released endocannabinoids or GABA) or exogenous (single astrocyte Ca2+ uncaging) stimuli modulate putative single CA3-CA1 hippocampal synapses. The astrocyte-mediated synaptic modulation was biphasic and consisted of an initial glutamate-mediated potentiation followed by a purinergic-mediated depression of neurotransmitter release. The temporal dynamic properties of this biphasic synaptic regulation depended on the firing frequency and duration of the neuronal activity that stimulated astrocytes. Present results indicate that single astrocytes can decode neuronal activity and, in response, release distinct gliotransmitters to differentially regulate neurotransmission at putative single synapses. PMID:29380725

Does age of onset of risk behaviors mediate the relationship between child abuse and neglect and outcomes in middle adulthood?

PubMed

Horan, Jacqueline M; Widom, Cathy Spatz

2015-03-01

Child maltreatment has been linked with a number of risk behaviors that are associated with long-lasting maladaptive outcomes across multiple domains of functioning. This study examines whether the ages of onset of four risk behaviors-sexual intercourse, alcohol use, drug use, and criminal behavior-mediate the relationship between child maltreatment and outcomes in middle adulthood among a sample of court-documented victims of child abuse/neglect and matched controls (N = 1,196; 51.7% female; 66.2% White, 32.6% Black). Adult outcomes included employment status, welfare receipt, internalizing symptoms of anxiety and depressive symptoms, substance use problems, and criminal arrests. The results indicated gender differences in these relationships. For females, age of onset of sexual intercourse mediated the relationship between child abuse/neglect and both internalizing symptoms and substance use problems in middle adulthood. For males, age at first criminal arrest mediated the relationship between child abuse/neglect and extensive involvement in the justice system in middle adulthood. Age of onset of alcohol use and drug use did not mediate the relationship between child abuse/neglect and middle adult outcomes. This study expands current knowledge by identifying associations between early initiation of risk behavior in one domain and later, continuing problems in different domains. Thus, early initiation of specific risk behaviors may have more wide-ranging negative consequences than are typically considered during intervention or treatment and strategies may need to target multiple domains of functioning.

Does Age of Onset of Risk Behaviors Mediate the Relationship between Child Abuse and Neglect and Outcomes in Middle Adulthood?

PubMed Central

Horan, Jacqueline M.; Widom, Cathy Spatz

2014-01-01

Child maltreatment has been linked with a number of risk behaviors that are associated with long-lasting maladaptive outcomes across multiple domains of functioning. This study examines whether the ages of onset of four risk behaviors—sexual intercourse, alcohol use, drug use, and criminal behavior—mediate the relationship between child maltreatment and outcomes in middle adulthood among a sample of court-documented victims of child abuse/neglect and matched controls (N = 1,196; 51.7% female; 66.2% White, 32.6% Black). Adult outcomes included employment status, welfare receipt, internalizing symptoms of anxiety and depressive symptoms, substance use problems, and criminal arrests. The results indicated gender differences in these relationships. For females, age of onset of sexual intercourse mediated the relationship between child abuse/neglect and both internalizing symptoms and substance use problems in middle adulthood. For males, age at first criminal arrest mediated the relationship between child abuse/neglect and extensive involvement in the justice system in middle adulthood. Age of onset of alcohol use and drug use did not mediate the relationship between child abuse/neglect and middle adult outcomes. This study expands current knowledge by identifying associations between early initiation of risk behavior in one domain and later, continuing problems in different domains. Thus, early initiation of specific risk behaviors may have more wide-ranging negative consequences than are typically considered during intervention or treatment and strategies may need to target multiple domains of functioning. PMID:25104419

DOMMINO 2.0: integrating structurally resolved protein-, RNA-, and DNA-mediated macromolecular interactions

PubMed Central

Kuang, Xingyan; Dhroso, Andi; Han, Jing Ginger; Shyu, Chi-Ren; Korkin, Dmitry

2016-01-01

Macromolecular interactions are formed between proteins, DNA and RNA molecules. Being a principle building block in macromolecular assemblies and pathways, the interactions underlie most of cellular functions. Malfunctioning of macromolecular interactions is also linked to a number of diseases. Structural knowledge of the macromolecular interaction allows one to understand the interaction’s mechanism, determine its functional implications and characterize the effects of genetic variations, such as single nucleotide polymorphisms, on the interaction. Unfortunately, until now the interactions mediated by different types of macromolecules, e.g. protein–protein interactions or protein–DNA interactions, are collected into individual and unrelated structural databases. This presents a significant obstacle in the analysis of macromolecular interactions. For instance, the homogeneous structural interaction databases prevent scientists from studying structural interactions of different types but occurring in the same macromolecular complex. Here, we introduce DOMMINO 2.0, a structural Database Of Macro-Molecular INteractiOns. Compared to DOMMINO 1.0, a comprehensive database on protein-protein interactions, DOMMINO 2.0 includes the interactions between all three basic types of macromolecules extracted from PDB files. DOMMINO 2.0 is automatically updated on a weekly basis. It currently includes ∼1 040 000 interactions between two polypeptide subunits (e.g. domains, peptides, termini and interdomain linkers), ∼43 000 RNA-mediated interactions, and ∼12 000 DNA-mediated interactions. All protein structures in the database are annotated using SCOP and SUPERFAMILY family annotation. As a result, protein-mediated interactions involving protein domains, interdomain linkers, C- and N- termini, and peptides are identified. Our database provides an intuitive web interface, allowing one to investigate interactions at three different resolution levels: whole subunit network, binary interaction and interaction interface. Database URL: http://dommino.org PMID:26827237

Cancer-related marketing centrality motifs acting as pivot units in the human signaling network and mediating cross-talk between biological pathways.

PubMed

Li, Wan; Chen, Lina; Li, Xia; Jia, Xu; Feng, Chenchen; Zhang, Liangcai; He, Weiming; Lv, Junjie; He, Yuehan; Li, Weiguo; Qu, Xiaoli; Zhou, Yanyan; Shi, Yuchen

2013-12-01

Network motifs in central positions are considered to not only have more in-coming and out-going connections but are also localized in an area where more paths reach the networks. These central motifs have been extensively investigated to determine their consistent functions or associations with specific function categories. However, their functional potentials in the maintenance of cross-talk between different functional communities are unclear. In this paper, we constructed an integrated human signaling network from the Pathway Interaction Database. We identified 39 essential cancer-related motifs in central roles, which we called cancer-related marketing centrality motifs, using combined centrality indices on the system level. Our results demonstrated that these cancer-related marketing centrality motifs were pivotal units in the signaling network, and could mediate cross-talk between 61 biological pathways (25 could be mediated by one motif on average), most of which were cancer-related pathways. Further analysis showed that molecules of most marketing centrality motifs were in the same or adjacent subcellular localizations, such as the motif containing PI3K, PDK1 and AKT1 in the plasma membrane, to mediate signal transduction between 32 cancer-related pathways. Finally, we analyzed the pivotal roles of cancer genes in these marketing centrality motifs in the pathogenesis of cancers, and found that non-cancer genes were potential cancer-related genes.

Suppression of Mediator is regulated by Cdk8-dependent Grr1 turnover of the Med3 coactivator.

PubMed

Gonzalez, Deyarina; Hamidi, Nurul; Del Sol, Ricardo; Benschop, Joris J; Nancy, Thomas; Li, Chao; Francis, Lewis; Tzouros, Manuel; Krijgsveld, Jeroen; Holstege, Frank C P; Conlan, R Steven

2014-02-18

Mediator, an evolutionary conserved large multisubunit protein complex with a central role in regulating RNA polymerase II-transcribed genes, serves as a molecular switchboard at the interface between DNA binding transcription factors and the general transcription machinery. Mediator subunits include the Cdk8 module, which has both positive and negative effects on activator-dependent transcription through the activity of the cyclin-dependent kinase Cdk8, and the tail module, which is required for positive and negative regulation of transcription, correct preinitiation complex formation in basal and activated transcription, and Mediator recruitment. Currently, the molecular mechanisms governing Mediator function remain largely undefined. Here we demonstrate an autoregulatory mechanism used by Mediator to repress transcription through the activity of distinct components of different modules. We show that the function of the tail module component Med3, which is required for transcription activation, is suppressed by the kinase activity of the Cdk8 module. Med3 interacts with, and is phosphorylated by, Cdk8; site-specific phosphorylation triggers interaction with and degradation by the Grr1 ubiquitin ligase, thereby preventing transcription activation. This active repression mechanism involving Grr1-dependent ubiquitination of Med3 offers a rationale for the substoichiometric levels of the tail module that are found in purified Mediator and the corresponding increase in tail components seen in cdk8 mutants.

Impact of clinical osteoarthritis of the hip, knee and hand on self-rated health in six European countries: the European Project on OSteoArthritis.

PubMed

van Schoor, N M; Zambon, S; Castell, M V; Cooper, C; Denkinger, M; Dennison, E M; Edwards, M H; Herbolsheimer, F; Maggi, S; Sánchez-Martinez, M; Pedersen, N L; Peter, R; Schaap, L A; Rijnhart, J J M; van der Pas, S; Deeg, D J H

2016-06-01

Osteoarthritis (OA) has been shown to be associated with decreased physical function, which may impact upon a person's self-rated health (SRH). Only a few studies have examined the association between OA and SRH in the general population, but to date none have used a clinical definition of OA. The objectives are: (1) To examine the cross-sectional association between clinical OA and fair-to-poor SRH in the general population; (2) To examine whether this association differs between countries; (3) To examine whether physical function is a mediator in the association between clinical OA and SRH. Baseline data of the European Project on OSteoArthritis (EPOSA) were used, which includes pre-harmonized data from six European cohort studies (n = 2709). Clinical OA was defined according to the American College of Rheumatology criteria. SRH was assessed using one question: How is your health in general? Physical function was assessed using the Western Ontario and McMaster Universities OA Index and Australian/Canadian OA Hand Index. The prevalence of fair-to-poor SRH ranged from 19.8 % in the United Kingdom to 63.5 % in Italy. Although country differences in the strength of the associations were observed, clinical OA of the hip, knee and hand were significantly associated with fair-to-poor SRH in five out of six European countries. In most countries and at most sites, the association between clinical OA and fair-to-poor SRH was partly or fully mediated by physical function. Clinical OA at different sites was related to fair-to-poor SRH in the general population. Most associations were (partly) mediated by physical functioning, indicating that deteriorating physical function in patients with OA should be a point of attention in patient care.

Functional network mediates age-related differences in reaction time: a replication and extension study

PubMed Central

Gazes, Yunglin; Habeck, Christian; O'Shea, Deirdre; Razlighi, Qolamreza R; Steffener, Jason; Stern, Yaakov

2015-01-01

Introduction A functional activation (i.e., ordinal trend) pattern was previously identified in both young and older adults during task-switching performance, the expression of which correlated with reaction time. The current study aimed to (1) replicate this functional activation pattern in a new group of fMRI activation data, and (2) extend the previous study by specifically examining whether the effect of aging on reaction time can be explained by differences in the activation of the functional activation pattern. Method A total of 47 young and 50 older participants were included in the extension analysis. Participants performed task-switching as the activation task and were cued by the color of the stimulus for the task to be performed in each block. To test for replication, two approaches were implemented. The first approach tested the replicability of the predictive power of the previously identified functional activation pattern by forward applying the pattern to the Study II data and the second approach was rederivation of the activation pattern in the Study II data. Results Both approaches showed successful replication in the new data set. Using mediation analysis, expression of the pattern from the first approach was found to partially mediate age-related effects on reaction time such that older age was associated with greater activation of the brain pattern and longer reaction time, suggesting that brain activation efficiency (defined as “the rate of activation increase with increasing task difficulty” in Neuropsychologia 47, 2009, 2015) of the regions in the Ordinal trend pattern directly accounts for age-related differences in task performance. Discussion The successful replication of the functional activation pattern demonstrates the versatility of the Ordinal Trend Canonical Variates Analysis, and the ability to summarize each participant's brain activation map into one number provides a useful metric in multimodal analysis as well as cross-study comparisons. PMID:25874162

Dose-response relationships for environmentally mediated infectious disease transmission models

PubMed Central

Eisenberg, Joseph N. S.

2017-01-01

Environmentally mediated infectious disease transmission models provide a mechanistic approach to examining environmental interventions for outbreaks, such as water treatment or surface decontamination. The shift from the classical SIR framework to one incorporating the environment requires codifying the relationship between exposure to environmental pathogens and infection, i.e. the dose–response relationship. Much of the work characterizing the functional forms of dose–response relationships has used statistical fit to experimental data. However, there has been little research examining the consequences of the choice of functional form in the context of transmission dynamics. To this end, we identify four properties of dose–response functions that should be considered when selecting a functional form: low-dose linearity, scalability, concavity, and whether it is a single-hit model. We find that i) middle- and high-dose data do not constrain the low-dose response, and different dose–response forms that are equally plausible given the data can lead to significant differences in simulated outbreak dynamics; ii) the choice of how to aggregate continuous exposure into discrete doses can impact the modeled force of infection; iii) low-dose linear, concave functions allow the basic reproduction number to control global dynamics; and iv) identifiability analysis offers a way to manage multiple sources of uncertainty and leverage environmental monitoring to make inference about infectivity. By applying an environmentally mediated infectious disease model to the 1993 Milwaukee Cryptosporidium outbreak, we demonstrate that environmental monitoring allows for inference regarding the infectivity of the pathogen and thus improves our ability to identify outbreak characteristics such as pathogen strain. PMID:28388665

FGFR2c-mediated ERK-MAPK activity regulates coronal suture development

PubMed Central

Pfaff, Miles J.; Xue, Ke; Li, Li; Horowitz, Mark C.; Steinbacher, Derek M.; Eswarakumar, Jacob V.P.

2017-01-01

Fibroblast growth factor receptor 2 (FGFR2) signaling is critical for proper craniofacial development. A gain-of-function mutation in the 2c splice variant of the receptor’s gene is associated with Crouzon syndrome, which is characterized by craniosynostosis, the premature fusion of one or more of the cranial vault sutures, leading to craniofacial maldevelopment. Insight into the molecular mechanism of craniosynostosis has identified the ERK-MAPK signaling cascade as a critical regulator of suture patency. The aim of this study is to investigate the role of FGFR2c-induced ERK-MAPK activation in the regulation of coronal suture development. Loss-of-function and gain-of-function Fgfr2c mutant mice have overlapping phenotypes, including coronal synostosis and craniofacial dysmorphia. In vivo analysis of coronal sutures in loss-of-function and gain-of-function models demonstrated fundamentally different pathogenesis underlying coronal suture synostosis. Calvarial osteoblasts from gain-of-function mice demonstrated enhanced osteoblastic function and maturation with concomitant increase in ERK-MAPK activation. In vitro inhibition with the ERK protein inhibitor U0126 mitigated ERK protein activation levels with a concomitant reduction in alkaline phosphatase activity. This study identifies FGFR2c-mediated ERK-MAPK signaling as a key mediator of craniofacial growth and coronal suture development. Furthermore, our results solve the apparent paradox between loss-of-function and gain-of-function FGFR2c mutants with respect to coronal suture synostosis. PMID:27034231

FGFR2c-mediated ERK-MAPK activity regulates coronal suture development.

PubMed

Pfaff, Miles J; Xue, Ke; Li, Li; Horowitz, Mark C; Steinbacher, Derek M; Eswarakumar, Jacob V P

2016-07-15

Fibroblast growth factor receptor 2 (FGFR2) signaling is critical for proper craniofacial development. A gain-of-function mutation in the 2c splice variant of the receptor's gene is associated with Crouzon syndrome, which is characterized by craniosynostosis, the premature fusion of one or more of the cranial vault sutures, leading to craniofacial maldevelopment. Insight into the molecular mechanism of craniosynostosis has identified the ERK-MAPK signaling cascade as a critical regulator of suture patency. The aim of this study is to investigate the role of FGFR2c-induced ERK-MAPK activation in the regulation of coronal suture development. Loss-of-function and gain-of-function Fgfr2c mutant mice have overlapping phenotypes, including coronal synostosis and craniofacial dysmorphia. In vivo analysis of coronal sutures in loss-of-function and gain-of-function models demonstrated fundamentally different pathogenesis underlying coronal suture synostosis. Calvarial osteoblasts from gain-of-function mice demonstrated enhanced osteoblastic function and maturation with concomitant increase in ERK-MAPK activation. In vitro inhibition with the ERK protein inhibitor U0126 mitigated ERK protein activation levels with a concomitant reduction in alkaline phosphatase activity. This study identifies FGFR2c-mediated ERK-MAPK signaling as a key mediator of craniofacial growth and coronal suture development. Furthermore, our results solve the apparent paradox between loss-of-function and gain-of-function FGFR2c mutants with respect to coronal suture synostosis. Copyright © 2016 Elsevier Inc. All rights reserved.

The influence of medical burden severity and cognition on functional competence in older community-dwelling individuals with schizophrenia.

PubMed

Tsoutsoulas, Christopher; Mulsant, Benoit H; Kalache, Sawsan M; Kumar, Sanjeev; Ghazala, Zaid; Voineskos, Aristotle N; Butters, Meryl A; Menon, Mahesh; Rajji, Tarek K

2016-02-01

Cognition predicts functional competence among individuals with schizophrenia across the lifespan. However, as these individuals age, increasing levels of medical burden may also contribute to functional deficits both directly and indirectly through cognition. Thus, we assessed the relationship among, cognition, medical burden, and functional competence in older individuals with schizophrenia. We analyzed data obtained from 60 community-dwelling participants with schizophrenia and 30 control participants aged 50 or above. Cognition was assessed using the MATRICS Consensus Cognitive Battery (MCCB), functional competence was assessed using the USCD Performance-Based Skills Assessment (UPSA), and medical burden was assessed using the Cumulative Illness Rating Scale for Geriatrics (CIRS-G). Group differences were assessed using independent samples t-tests or chi-square tests. Mediation analyses using bootstrapping techniques were used to assess whether cognition mediated the effects of medical burden on functional competence. Participants with schizophrenia had higher levels of medical burden, cognitive deficits, and functional impairments. In participants with schizophrenia, cognition, but not medical burden, predicted functional competence after adjusting for age, education, gender, clinical symptoms, and anticholinergic burden of medications. In control participants, cognition and medical burden both predicted functional competence after adjusting for age, education, and gender. Further, cognition was found to fully mediate the association between medical burden and functional competence in control participants. Cognition is a robust predictor of functional competence among older individuals with schizophrenia, regardless of medical burden. Cognitive deficits associated with schizophrenia may mask any further cognitive impairment associated with medical burden and its impact on function. Copyright © 2015 Elsevier B.V. All rights reserved.

GPER mediates the effects of 17β-estradiol in cardiac mitochondrial biogenesis and function.

PubMed

Sbert-Roig, Miquel; Bauzá-Thorbrügge, Marco; Galmés-Pascual, Bel M; Capllonch-Amer, Gabriela; García-Palmer, Francisco J; Lladó, Isabel; Proenza, Ana M; Gianotti, Magdalena

2016-01-15

Considering the sexual dimorphism described in cardiac mitochondrial function and oxidative stress, we aimed to investigate the role of 17β-estradiol (E2) in these sex differences and the contribution of E2 receptors to these effects. As a model of chronic deprivation of ovarian hormones, we used ovariectomized (OVX) rats, half of which were treated with E2. Ovariectomy decreased markers of cardiac mitochondrial biogenesis and function and also increased oxidative stress, whereas E2 counteracted these effects. In H9c2 cardiomyocytes we observed that G-protein coupled estrogen receptor (GPER) agonist mimicked the effects of E2 in enhancing mitochondrial function and biogenesis, whereas GPER inhibitor neutralized them. These data suggest that E2 enhances mitochondrial function and decreases oxidative stress in cardiac muscle, thus it could be responsible for the sexual dimorphism observed in mitochondrial biogenesis and function in this tissue. These effects seem to be mediated through GPER stimulation. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

The association between family factors and child behaviour problems using dyadic data.

PubMed

Wang, Y; Pan, J; Zhang, X; Yi, C

2015-11-01

Parental psychopathology and family issues are key influence factors to child behaviour problems. This study aimed to investigate the dyadic impact of maternal and paternal depression and perceived family functioning on child behaviour problems. Both maternal and paternal depression, perceived family functioning and reported child behaviour problems were collected, respectively. Because of the interdependent characteristic of dyadic data, structural equation modelling was used to examine the relationship among all variables and the mutual influence between mother and father. Results showed that father-perceived family functioning mediated the relationship between parental depression and child behaviour problems, but mother-perceived family functioning did not show this mediation effect. Meanwhile, maternal and paternal depression influenced both of their own and their partner's perceived family functioning. The findings indicated that paternal psychopathology and family functioning should not be overlooked in child behaviour development. In addition, this study underscored the importance to investigate the different impact of father and mother on child development within a dyadic unit. © 2014 John Wiley & Sons Ltd.

Mechanisms underlying differential effectiveness of memantine and ketamine in rapid antidepressant responses

PubMed Central

Gideons, Erinn S.; Kavalali, Ege T.; Monteggia, Lisa M.

2014-01-01

Ketamine is an NMDA receptor (NMDAR) antagonist that elicits rapid antidepressant responses in patients with treatment-resistant depression. However, ketamine can also produce psychotomimetic effects that limit its utility as an antidepressant, raising the question of whether the clinically tolerated NMDAR antagonist memantine possesses antidepressant properties. Despite its similar potency to ketamine as an NMDAR antagonist, clinical data suggest that memantine does not exert rapid antidepressant actions for reasons that are poorly understood. In this study, we recapitulate the ketamine and memantine clinical findings in mice, showing that ketamine, but not memantine, has antidepressant-like effects in behavioral models. Using electrophysiology in cultured hippocampal neurons, we show that ketamine and memantine effectively block NMDAR-mediated miniature excitatory postsynaptic currents in the absence of Mg2+. However, in physiological levels of extracellular Mg2+, we identified key functional differences between ketamine and memantine in their ability to block NMDAR function at rest. This differential effect of ketamine and memantine extends to intracellular signaling coupled to NMDAR at rest, in that memantine does not inhibit the phosphorylation of eukaryotic elongation factor 2 or augment subsequent expression of BDNF, which are critical determinants of ketamine-mediated antidepressant efficacy. These results demonstrate significant differences between the efficacies of ketamine and memantine on NMDAR-mediated neurotransmission that have impacts on downstream intracellular signaling, which we hypothesize is the trigger for rapid antidepressant responses. These data provide a novel framework on the necessary functional requirements of NMDAR-mediated neurotransmission as a critical determinant necessary to elicit rapid antidepressant responses. PMID:24912158

Morningness-eveningness and daytime functioning in university students: the mediating role of sleep characteristics.

PubMed

Bakotic, Marija; Radosevic-Vidacek, Biserka; Koscec Bjelajac, Adrijana

2017-04-01

The aim of this study was to explore the mediating role of sleep characteristics in the relationship between morningness-eveningness and three different aspects of daytime functioning: daytime sleepiness, depressive mood and substance use in university students. A multiple mediator model was proposed with sleep debt, poor sleep quality and bedtime delay at weekends as parallel mediators in these relationships. We analysed the data of 1052 university students aged 18-25 years who completed a modified version of the School Sleep Habits Survey, which included questions on sleep and the Composite Scale of Morningness, Sleepiness Scale, Depressive Mood Scale and Substance Use Scale. Students with more pronounced eveningness reported greater daytime sleepiness, greater depressive mood and more frequent substance use, as well as greater sleep debt, poorer sleep quality and greater bedtime delay at weekends. Mediation analyses indicated that morningness-eveningness affected daytime sleepiness and substance use both directly and indirectly through all proposed sleep-related mediators. However, the effect of morningness-eveningness on depressive mood was entirely indirect and was accounted for more by poor sleep than by sleep debt or bedtime irregularity. In conclusion, there are multiple possible mechanisms through which morningness-eveningness affects daytime functioning in university students, and sleep characteristics are a significant mechanism. Sleep debt, poor sleep quality and bedtime irregularity can, to a significant extent, explain the feeling of daytime sleepiness and greater substance use in students with eveningness preferences. However, more depressed mood in the evening-orientated students is primarily a consequence of their poor sleep quality. © 2016 European Sleep Research Society.

The Role of Lactate-Mediated Metabolic Coupling between Astrocytes and Neurons in Long-Term Memory Formation

PubMed Central

Steinman, Michael Q.; Gao, Virginia; Alberini, Cristina M.

2016-01-01

Long-term memory formation, the ability to retain information over time about an experience, is a complex function that affects multiple behaviors, and is an integral part of an individual’s identity. In the last 50 years many scientists have focused their work on understanding the biological mechanisms underlying memory formation and processing. Molecular studies over the last three decades have mostly investigated, or given attention to, neuronal mechanisms. However, the brain is composed of different cell types that, by concerted actions, cooperate to mediate brain functions. Here, we consider some new insights that emerged from recent studies implicating astrocytic glycogen and glucose metabolisms, and particularly their coupling to neuronal functions via lactate, as an essential mechanism for long-term memory formation. PMID:26973477

Mediating pathways from central obesity to childhood asthma: a population-based longitudinal study.

PubMed

Chih, An-Hsuan; Chen, Yang-Ching; Tu, Yu-Kang; Huang, Kuo-Chin; Chiu, Tai-Yuan; Lee, Yungling Leo

2016-09-01

The mediating pathways linking obesity and asthma are largely unknown. We aimed to investigate the mediating pathways and to search for the most prominent pathological mechanism between central obesity and childhood asthma.In the Taiwan Children Health Study, we collected data on an open cohort of children aged 9-13 years. Children's respiratory outcomes, atopic conditions, obesity measures and pulmonary function were surveyed annually between 2010 and 2012. Exhaled nitric oxide fraction concentrations were recorded in 2012. Generalised estimating equations and general linear models were used to examine the associations between central obesity, possible mediators and asthma. Structural equation models were applied to investigate the pathways that mediate the link between central obesity and asthma.Central obesity (waist-to-hip ratio) most accurately predicted childhood asthma. In the active asthma model, the percentage of mediation was 28.6% for pulmonary function, 18.1% for atopy and 5.7% for airway inflammation. The percentage of mediation for pulmonary function was 40.2% in the lifetime wheeze model. Pulmonary function was responsible for the greatest percentage of mediation among the three mediators in both models.Decline in pulmonary function is the most important pathway in central obesity related asthma. Pulmonary function screening should be applied to obese children for asthma risk prediction. Copyright ©ERS 2016.

Mediator: A key regulator of plant development.

PubMed

Buendía-Monreal, Manuel; Gillmor, C Stewart

2016-11-01

Mediator is a multiprotein complex that regulates transcription at the level of RNA pol II assembly, as well as through regulation of chromatin architecture, RNA processing and recruitment of epigenetic marks. Though its modular structure is conserved in eukaryotes, its subunit composition has diverged during evolution and varies in response to environmental and tissue-specific inputs, suggesting different functions for each subunit and/or Mediator conformation. In animals, Mediator has been implicated in the control of differentiation and morphogenesis through modulation of numerous signaling pathways. In plants, studies have revealed roles for Mediator in regulation of cell division, cell fate and organogenesis, as well as developmental timing and hormone responses. We begin this review with an overview of biochemical mechanisms of yeast and animal Mediator that are likely to be conserved in all eukaryotes, as well as a brief discussion of the role of Mediator in animal development. We then present a comprehensive review of studies of the role of Mediator in plant development. Finally, we point to important questions for future research on the role of Mediator as a master coordinator of development. Copyright © 2016 Elsevier Inc. All rights reserved.

Quality of life as a mediator in the association between body mass index and negative emotionality in overweight and obese non-clinical sample.

PubMed

Pokrajac-Bulian, Alessandra; Kukić, Miljana; Bašić-Marković, Nina

2015-12-01

The present study investigates the differences in physical health-related quality of life (HRQoL) among overweight and obese people, as well as the correlates of HRQoL in this population and the association between BMI, depression, anxiety, and potential mediating effects of HRQoL. The research was conducted on a sample of overweight and obese adults who visited their primary care physician. A total of 143 women and 130 men were enrolled in the study, 43% of the subjects were overweight, and 57% of the subjects were obese. The subjects ranged in age between 21 and 60 years. Depression and anxiety were assessed using the Hospital Anxiety and Depression Scale, and HRQoL was evaluated using the Medical Outcome Study Short-Form 36. The analysis of variance results showed that women in comparison to men have lower physical HRQoL (e.g. worst physical functioning, more bodily pain), and that severely obese patients have lower physical HRQoL in comparison to overweight ones. The regression analysis results indicated that some of the aspects of physical HRQoL (e.g. physical functioning, role limitations) mediate the relationship between BMI and depression only in women. The higher level of body mass decreased the physical HRQoL, which became a potential risk factor for the development of depressive symptoms. The results from the present study show that a different pattern of functioning exists between men and women. It is important to identify the factors that can effectively motivate and stimulate obese people to change their lifestyle and to consider the differences in psychological functioning between women and men.

Enantioselective remote meta-C-H arylation and alkylation via a chiral transient mediator.

PubMed

Shi, Hang; Herron, Alastair N; Shao, Ying; Shao, Qian; Yu, Jin-Quan

2018-06-18

Enantioselective carbon-hydrogen (C-H) activation reactions by asymmetric metallation could provide new routes for the construction of chiral molecules 1,2 . However, current methods are typically limited to the formation of five- or six-membered metallacycles, thereby preventing the asymmetric functionalization of C-H bonds at positions remote to existing functional groups. Here we report enantioselective remote C-H activation using a catalytic amount of a chiral norbornene as a transient mediator, which relays initial ortho-C-H activation to the meta position. This was used in the enantioselective meta-C-H arylation of benzylamines, as well as the arylation and alkylation of homobenzylamines. The enantioselectivities obtained using the chiral transient mediator are comparable across different classes of substrates containing either neutral σ-donor or anionic coordinating groups. This relay strategy could provide an alternative means to remote chiral induction, one of the most challenging problems in asymmetric catalysis 3,4 .

Nitric oxide-mediated pathogenesis during nicotine and alcohol consumption.

PubMed

Cooper, R G; Magwere, T

2008-01-01

Nitric oxide (NO) is formed by different cell types in response to a variety of physiological and patho-physiological stimuli. The intake of nicotine and/or alcohol has patho-physiological effects on organ function, and the progression of alcohol-/tobacco-related diseases seem to be directly influenced by NO-mediated mechanisms. Nicotine has an adverse influence on blood vessel functionality, repair and maintenance. Chronic nicotine exposure augments atherosclerosis by enhancing the production of proinflammatory cytokines by macrophages which then activate atherogenic NF-kB target genes in aortic lesions. Alcohol produces NO which speeds up the apoptosis of neutrophils. Alcohol sensitizes the liver to endotoxemic shock. Nitrosative stress and increased basal levels of NO contribute to tumour growth. The progression of disease seems to be directed via a definite NO-mediated mechanism. This review gives an insight into how intake of tobacco and alcohol may affect quality of life.

Differential identity of Filopodia and Tunneling Nanotubes revealed by the opposite functions of actin regulatory complexes.

PubMed

Delage, Elise; Cervantes, Diégo Cordero; Pénard, Esthel; Schmitt, Christine; Syan, Sylvie; Disanza, Andrea; Scita, Giorgio; Zurzolo, Chiara

2016-12-23

Tunneling Nanotubes (TNTs) are actin enriched filopodia-like protrusions that play a pivotal role in long-range intercellular communication. Different pathogens use TNT-like structures as "freeways" to propagate across cells. TNTs are also implicated in cancer and neurodegenerative diseases, making them promising therapeutic targets. Understanding the mechanism of their formation, and their relation with filopodia is of fundamental importance to uncover their physiological function, particularly since filopodia, differently from TNTs, are not able to mediate transfer of cargo between distant cells. Here we studied different regulatory complexes of actin, which play a role in the formation of both these structures. We demonstrate that the filopodia-promoting CDC42/IRSp53/VASP network negatively regulates TNT formation and impairs TNT-mediated intercellular vesicle transfer. Conversely, elevation of Eps8, an actin regulatory protein that inhibits the extension of filopodia in neurons, increases TNT formation. Notably, Eps8-mediated TNT induction requires Eps8 bundling but not its capping activity. Thus, despite their structural similarities, filopodia and TNTs form through distinct molecular mechanisms. Our results further suggest that a switch in the molecular composition in common actin regulatory complexes is critical in driving the formation of either type of membrane protrusion.

The relationship of global form and motion detection to reading fluency.

PubMed

Englund, Julia A; Palomares, Melanie

2012-08-15

Visual motion processing in typical and atypical readers has suggested aspects of reading and motion processing share a common cortical network rooted in dorsal visual areas. Few studies have examined the relationship between reading performance and visual form processing, which is mediated by ventral cortical areas. We investigated whether reading fluency correlates with coherent motion detection thresholds in typically developing children using random dot kinematograms. As a comparison, we also evaluated the correlation between reading fluency and static form detection thresholds. Results show that both dorsal and ventral visual functions correlated with components of reading fluency, but that they have different developmental characteristics. Motion coherence thresholds correlated with reading rate and accuracy, which both improved with chronological age. Interestingly, when controlling for non-verbal abilities and age, reading accuracy significantly correlated with thresholds for coherent form detection but not coherent motion detection in typically developing children. Dorsal visual functions that mediate motion coherence seem to be related maturation of broad cognitive functions including non-verbal abilities and reading fluency. However, ventral visual functions that mediate form coherence seem to be specifically related to accurate reading in typically developing children. Copyright © 2012 Elsevier Ltd. All rights reserved.

Cardiovascular mechanisms of SSRI drugs and their benefits and risks in ischemic heart disease and heart failure.

PubMed

Andrade, Chittaranjan; Kumar, Chethan B; Surya, Sandarsh

2013-05-01

Depression and heart disease are commonly comorbid. Selective serotonin reuptake inhibitors (SSRIs) are commonly used to treat depression. In March 2011, we carried out a 15-year search of PubMed for preclinical and clinical publications related to SSRIs and ischemic heart disease (IHD) or congestive heart failure (CHF). We identify and discuss a number of mechanisms by which SSRIs may influence cardiovascular functioning and health outcomes in patients with heart disease; many of the mechanisms that we present have received little attention in previous reviews. We examine studies with positive, neutral, and negative outcomes in IHD and CHF patients treated with SSRIs. SSRIs influence cardiovascular functioning and health through several different mechanisms; for example, they inhibit serotonin-mediated and collagen-mediated platelet aggregation, reduce inflammatory mediator levels, and improve endothelial function. SSRIs improve indices of ventricular functioning in IHD and heart failure without adversely affecting electrocardiographic parameters. SSRIs may also be involved in favorable or unfavorable drug interactions with medications that influence cardiovascular functions. The clinical evidence suggests that, in general, SSRIs are safe in patients with IHD and may, in fact, exert a cardioprotective effect. The clinical data are less clear in patients with heart failure, and the evidence for benefits with SSRIs is weak.

Evaluating Alzheimer's disease biomarkers as mediators of age-related cognitive decline.

PubMed

Hohman, Timothy J; Tommet, Doug; Marks, Shawn; Contreras, Joey; Jones, Rich; Mungas, Dan

2017-10-01

Age-related changes in cognition are partially mediated by the presence of neuropathology and neurodegeneration. This manuscript evaluates the degree to which biomarkers of Alzheimer's disease, (AD) neuropathology and longitudinal changes in brain structure, account for age-related differences in cognition. Data from the AD Neuroimaging Initiative (n = 1012) were analyzed, including individuals with normal cognition and mild cognitive impairment. Parallel process mixed effects regression models characterized longitudinal trajectories of cognitive variables and time-varying changes in brain volumes. Baseline age was associated with both memory and executive function at baseline (p's < 0.001) and change in memory and executive function performances over time (p's < 0.05). After adjusting for clinical diagnosis, baseline, and longitudinal changes in brain volume, and baseline levels of cerebrospinal fluid biomarkers, age effects on change in episodic memory and executive function were fully attenuated, age effects on baseline memory were substantially attenuated, but an association remained between age and baseline executive function. Results support previous studies that show that age effects on cognitive decline are fully mediated by disease and neurodegeneration variables but also show domain-specific age effects on baseline cognition, specifically an age pathway to executive function that is independent of brain and disease pathways. Copyright © 2017 Elsevier Inc. All rights reserved.

Evolution of enzymes in a series is driven by dissimilar functional demands.

PubMed

Salvador, Armindo; Savageau, Michael A

2006-02-14

That distinct enzyme activities in an unbranched metabolic pathway are evolutionarily tuned to a single functional requirement is a pervasive assumption. Here we test this assumption by examining the activities of two consecutively acting enzymes in human erythrocytes with an approach to quantitative evolutionary design that avoids the above-mentioned assumption. We previously found that avoidance of NADPH depletion during the pulses of oxidative load to which erythrocytes are normally exposed is the main functional requirement mediating selection for high glucose-6-phosphate dehydrogenase activity. In the present study, we find that, in contrast, the maintenance of oxidized glutathione at low concentrations is the main functional requirement mediating selection for high glutathione reductase activity. The results in this case show that, contrary to the assumption of a single functional requirement, natural selection for the normal activities of the distinct enzymes in the pathway is mediated by different requirements. On the other hand, the results agree with the more general principles that underlie our approach. Namely, that (i) the values of biochemical parameters evolve so as to fulfill the various performance requirements that are relevant to achieve high fitness, and (ii) these performance requirements can be inferred from quantitative systems theory considerations, informed by knowledge of specific aspects of the biochemistry, physiology, genetics, and ecology of the organism.

Predictability Effects on Durations of Content and Function Words in Conversational English

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

Bell, Alan; Brenier, Jason; Gregory, Michelle L.

Content and function word duration are affected differently by their frequency and predictability. Regression analyses of conversational speech show that content words are shorter when they are more frequent, but function words are not. Repeated content words are shorter, but function words are not. Furthermore, function words have shorter pronunciations, after controlling for frequency and predictability. both content and function words are strongly affected by predictability from the word following them, and only very frequent function words show sensitivity to predictability from the preceding word. The results support the view that content and function words are accessed by different productionmore » mechanisms. We argue that words’ form differences due to frequency or repetition stem from their faster or slower lexical access, mediated by a general mechanism that coordinates the pace of higher-level planning and the execution of the articulatory plan.« less

Overlap in the functional neural systems involved in semantic and episodic memory retrieval.

PubMed

Rajah, M N; McIntosh, A R

2005-03-01

Neuroimaging and neuropsychological data suggest that episodic and semantic memory may be mediated by distinct neural systems. However, an alternative perspective is that episodic and semantic memory represent different modes of processing within a single declarative memory system. To examine whether the multiple or the unitary system view better represents the data we conducted a network analysis using multivariate partial least squares (PLS ) activation analysis followed by covariance structural equation modeling (SEM) of positron emission tomography data obtained while healthy adults performed episodic and semantic verbal retrieval tasks. It is argued that if performance of episodic and semantic retrieval tasks are mediated by different memory systems, then there should differences in both regional activations and interregional correlations related to each type of retrieval task, respectively. The PLS results identified brain regions that were differentially active during episodic retrieval versus semantic retrieval. Regions that showed maximal differences in regional activity between episodic retrieval tasks were used to construct separate functional models for episodic and semantic retrieval. Omnibus tests of these functional models failed to find a significant difference across tasks for both functional models. The pattern of path coefficients for the episodic retrieval model were not different across tasks, nor were the path coefficients for the semantic retrieval model. The SEM results suggest that the same memory network/system was engaged across tasks, given the similarities in path coefficients. Therefore, activation differences between episodic and semantic retrieval may ref lect variation along a continuum of processing during task performance within the context of a single memory system.

Social cognition as a mediator variable between neurocognition and functional outcome in schizophrenia: empirical review and new results by structural equation modeling.

PubMed

Schmidt, Stefanie J; Mueller, Daniel R; Roder, Volker

2011-09-01

Cognitive impairments are currently regarded as important determinants of functional domains and are promising treatment goals in schizophrenia. Nevertheless, the exact nature of the interdependent relationship between neurocognition and social cognition as well as the relative contribution of each of these factors to adequate functioning remains unclear. The purpose of this article is to systematically review the findings and methodology of studies that have investigated social cognition as a mediator variable between neurocognitive performance and functional outcome in schizophrenia. Moreover, we carried out a study to evaluate this mediation hypothesis by the means of structural equation modeling in a large sample of 148 schizophrenia patients. The review comprised 15 studies. All but one study provided evidence for the mediating role of social cognition both in cross-sectional and in longitudinal designs. Other variables like motivation and social competence additionally mediated the relationship between social cognition and functional outcome. The mean effect size of the indirect effect was 0.20. However, social cognitive domains were differentially effective mediators. On average, 25% of the variance in functional outcome could be explained in the mediation model. The results of our own statistical analysis are in line with these conclusions: Social cognition mediated a significant indirect relationship between neurocognition and functional outcome. These results suggest that research should focus on differential mediation pathways. Future studies should also consider the interaction with other prognostic factors, additional mediators, and moderators in order to increase the predictive power and to target those factors relevant for optimizing therapy effects.

L1CAM/Neuroglian controls the axon–axon interactions establishing layered and lobular mushroom body architecture

PubMed Central

Siegenthaler, Dominique; Enneking, Eva-Maria; Moreno, Eliza

2015-01-01

The establishment of neuronal circuits depends on the guidance of axons both along and in between axonal populations of different identity; however, the molecular principles controlling axon–axon interactions in vivo remain largely elusive. We demonstrate that the Drosophila melanogaster L1CAM homologue Neuroglian mediates adhesion between functionally distinct mushroom body axon populations to enforce and control appropriate projections into distinct axonal layers and lobes essential for olfactory learning and memory. We addressed the regulatory mechanisms controlling homophilic Neuroglian-mediated cell adhesion by analyzing targeted mutations of extra- and intracellular Neuroglian domains in combination with cell type–specific rescue assays in vivo. We demonstrate independent and cooperative domain requirements: intercalating growth depends on homophilic adhesion mediated by extracellular Ig domains. For functional cluster formation, intracellular Ankyrin2 association is sufficient on one side of the trans-axonal complex whereas Moesin association is likely required simultaneously in both interacting axonal populations. Together, our results provide novel mechanistic insights into cell adhesion molecule–mediated axon–axon interactions that enable precise assembly of complex neuronal circuits. PMID:25825519

L1CAM/Neuroglian controls the axon-axon interactions establishing layered and lobular mushroom body architecture.

PubMed

Siegenthaler, Dominique; Enneking, Eva-Maria; Moreno, Eliza; Pielage, Jan

2015-03-30

The establishment of neuronal circuits depends on the guidance of axons both along and in between axonal populations of different identity; however, the molecular principles controlling axon-axon interactions in vivo remain largely elusive. We demonstrate that the Drosophila melanogaster L1CAM homologue Neuroglian mediates adhesion between functionally distinct mushroom body axon populations to enforce and control appropriate projections into distinct axonal layers and lobes essential for olfactory learning and memory. We addressed the regulatory mechanisms controlling homophilic Neuroglian-mediated cell adhesion by analyzing targeted mutations of extra- and intracellular Neuroglian domains in combination with cell type-specific rescue assays in vivo. We demonstrate independent and cooperative domain requirements: intercalating growth depends on homophilic adhesion mediated by extracellular Ig domains. For functional cluster formation, intracellular Ankyrin2 association is sufficient on one side of the trans-axonal complex whereas Moesin association is likely required simultaneously in both interacting axonal populations. Together, our results provide novel mechanistic insights into cell adhesion molecule-mediated axon-axon interactions that enable precise assembly of complex neuronal circuits. © 2015 Siegenthaler et al.

Fasting mediated increase in p-BAD(ser155) and p-AKT(ser473) in the prefrontal cortex of mice.

PubMed

Pitchaimani, Vigneshwaran; Arumugam, Somasundaram; Thandavarayan, Rajarajan Amirthalingam; Karuppagounder, Vengadeshprabhu; Sreedhar, Remya; Afrin, Rejina; Harima, Meilei; Suzuki, Hiroshi; Miyashita, Shizuka; Nomoto, Mayumi; Sone, Hirohito; Suzuki, Kenji; Watanabe, Kenichi

2014-09-05

BAD-deficient mice and fasting have several common functional roles in seizures, beta-hydroxybutyrate (BHB) uptake in brain and alteration in counterregulatory hormonal regulation during hypoglycemia. Neuronal specific insulin receptor knockout (NIRKO) mice display impaired counterregulatory hormonal responses during hypoglycemia. In this study we investigated the fasting mediated expression of p-BAD(ser155) and p-AKT(ser473) in different regions of brain (prefrontal cortex, hippocampus, midbrain and hypothalamus). Fasting specifically increases p-BAD(ser155) and p-AKT(ser473) in prefrontal cortex and decreases in other regions of brain. Our results suggest that fasting may increase the uptake BHB by decreasing p-BAD(ser155) in the brain during hypoglycemia except prefrontal cortex and it uncovers specific functional area of p-BAD(ser155) and p-AKT(ser473) that may regulates counter regulatory hormonal response. Overall in support with previous findings, fasting mediated hypoglycemia activates prefrontal cortex insulin signaling which influences the hypothalamic paraventricular nucleus mediated activation of sympathoadrenal hormonal responses. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Secondary mediation and regression analyses of the PTClinResNet database: determining causal relationships among the International Classification of Functioning, Disability and Health levels for four physical therapy intervention trials.

PubMed

Mulroy, Sara J; Winstein, Carolee J; Kulig, Kornelia; Beneck, George J; Fowler, Eileen G; DeMuth, Sharon K; Sullivan, Katherine J; Brown, David A; Lane, Christianne J

2011-12-01

Each of the 4 randomized clinical trials (RCTs) hosted by the Physical Therapy Clinical Research Network (PTClinResNet) targeted a different disability group (low back disorder in the Muscle-Specific Strength Training Effectiveness After Lumbar Microdiskectomy [MUSSEL] trial, chronic spinal cord injury in the Strengthening and Optimal Movements for Painful Shoulders in Chronic Spinal Cord Injury [STOMPS] trial, adult stroke in the Strength Training Effectiveness Post-Stroke [STEPS] trial, and pediatric cerebral palsy in the Pediatric Endurance and Limb Strengthening [PEDALS] trial for children with spastic diplegic cerebral palsy) and tested the effectiveness of a muscle-specific or functional activity-based intervention on primary outcomes that captured pain (STOMPS, MUSSEL) or locomotor function (STEPS, PEDALS). The focus of these secondary analyses was to determine causal relationships among outcomes across levels of the International Classification of Functioning, Disability and Health (ICF) framework for the 4 RCTs. With the database from PTClinResNet, we used 2 separate secondary statistical approaches-mediation analysis for the MUSSEL and STOMPS trials and regression analysis for the STEPS and PEDALS trials-to test relationships among muscle performance, primary outcomes (pain related and locomotor related), activity and participation measures, and overall quality of life. Predictive models were stronger for the 2 studies with pain-related primary outcomes. Change in muscle performance mediated or predicted reductions in pain for the MUSSEL and STOMPS trials and, to some extent, walking speed for the STEPS trial. Changes in primary outcome variables were significantly related to changes in activity and participation variables for all 4 trials. Improvement in activity and participation outcomes mediated or predicted increases in overall quality of life for the 3 trials with adult populations. Variables included in the statistical models were limited to those measured in the 4 RCTs. It is possible that other variables also mediated or predicted the changes in outcomes. The relatively small sample size in the PEDALS trial limited statistical power for those analyses. Evaluating the mediators or predictors of change between each ICF level and for 2 fundamentally different outcome variables (pain versus walking) provided insights into the complexities inherent across 4 prevalent disability groups.

Selective Matrix (Hyaluronan) Interaction with CD44 and RhoGTPase Signaling Promotes Keratinocyte Functions and Overcomes Age-related Epidermal Dysfunction

PubMed Central

Bourguignon, Lilly Y.W.; Wong, Gabriel; Xia, Weiliang; Man, Mao-Qiang; Holleran, Walter M.; Elias, Peter M.

2013-01-01

Background Mouse epidermal chronologic aging is closely associated with aberrant matrix (hyaluronan, HA) -size distribution/production and impaired keratinocyte proliferation/differentiation, leading to a marked thinning of the epidermis with functional consequence that causes a slower recovery of permeability barrier function. Objective The goal of this study is to demonstrate mechanism-based, corrective therapeutic strategies using topical applications of small HA (HAS) and/or large HA (HAL) [or a sequential small HA (HAS) and large HA(HAL) (HAs-»HAL) treatment] as well as RhoGTPase signaling perturbation agents to regulate HA/CD44-mediated signaling, thereby restoring normal epidermal function, and permeability barrier homeostasis in aged mouse skin. Methods A number of biochemical, cell biological/molecular, pharmacological and physiological approaches were used to investigate matrix HA-CD44-mediated RhoGTPase signaling in regulating epidermal functions and skin aging. Results In this study we demonstrated that topical application of small HA (HAS) promotes keratinocyte proliferation and increases skin thickness, while it fails to upregulate keratinocyte differentiation or permeability barrier repair in aged mouse skin. In contrast, large HA (HAL) induces only minimal changes in keratinocyte proliferation and skin thickness, but restores keratinocyte differentiation and improves permeability barrier function in aged epidermis. Since neither HAS nor HAL corrects these epidermal defects in aged CD44 knock-out mice, CD44 likely mediates HA-associated epidermal functions in aged mouse skin. Finally, blockade of Rho-kinase activity with Y27632 or protein kinase-Nγ activity with Ro31-8220 significantly decreased the HA (HAS or HAL)-mediated changes in epidermal function in aged mouse skin. Conclusion The results of our study show first that HA application of different sizes regulates epidermal proliferation, differentiation and barrier function in aged mouse skin. Second, manipulation of matrix (HA) interaction with CD44 and RhoGTPase signaling could provide further novel therapeutic approaches that could be targeted for the treatment of various aging-related skin disorders. PMID:23790635

Synthesis of Strained 1,3-Diene Macrocycles via Copper-Mediated Castro-Stephens Coupling/Alkyne Reduction Tandem Reactions.

PubMed

Li, Wei; Schneider, Christopher M; Georg, Gunda I

2015-08-07

A copper-mediated macrocyclization involving the reaction of a vinyl iodide and a terminal alkyne followed by an in situ reduction of the enyne intermediate is reported. The reaction generates a conjugated Z-double bond within a strained medium-size lactone, lactam, or ether macrocycle. A variety of macrocyclic compounds bearing different ring sizes and functionalities were synthesized. A complementary stepwise procedure was also developed for less strained ring systems.

Reconstitution of active human core Mediator complex reveals a critical role of the MED14 subunit.

PubMed

Cevher, Murat A; Shi, Yi; Li, Dan; Chait, Brian T; Malik, Sohail; Roeder, Robert G

2014-12-01

The evolutionarily conserved Mediator complex is a critical coactivator for RNA polymerase II (Pol II)-mediated transcription. Here we report the reconstitution of a functional 15-subunit human core Mediator complex and its characterization by functional assays and chemical cross-linking coupled to MS (CX-MS). Whereas the reconstituted head and middle modules can stably associate, basal and coactivator functions are acquired only after incorporation of MED14 into the bimodular complex. This results from a dramatically enhanced ability of MED14-containing complexes to associate with Pol II. Altogether, our analyses identify MED14 as both an architectural and a functional backbone of the Mediator complex. We further establish a conditional requirement for metazoan-specific MED26 that becomes evident in the presence of heterologous nuclear factors. This general approach paves the way for systematic dissection of the multiple layers of functionality associated with the Mediator complex.

Gram-negative, but not Gram-positive, bacteria elicit strong PGE2 production in human monocytes.

PubMed

Hessle, Christina C; Andersson, Bengt; Wold, Agnes E

2003-12-01

Gram-positive and Gram-negative bacteria induce different cytokine patterns in human mononuclear cells. We have seen that Gram-positives preferentially induce IL-12 and TNF-alpha, whereas Gram-negatives induce more IL-10, IL-6, and IL-8. In this study, we compared the capacity of these two groups of bacteria to induce PGE2. Monocytes stimulated with Gram-negative bacterial species induced much more PGE2 than did Gram-positive bacteria (5600 +/- 330 vs. 1700 +/- 670 pg/mL, p < 0.001). Blocking of COX-2 by NS398 abolished PGE2 production, but did not alter the cytokine patterns induced by Gram-positive and Gram-negative bacteria. We suggest that Gram-positive and Gram-negative bacteria may stimulate different innate effector functions; Gram-positive bacteria promoting cell-mediated effector functions whereas Gram-negative bacteria inducing mediators inhibiting the same.

Biological Risk for the Development of Problem Behavior in Adolescence: Integrating Insights from Behavioral Genetics and Neuroscience.

PubMed

Harden, K Paige; Mann, Frank D

2015-12-01

Adolescence is a time of increasing engagement in a variety of problem behaviors, including substance use and delinquency. Genetic risk for problem behavior increases over adolescence, is mediated partially by individual differences in sensation seeking, and is exacerbated by involvement with deviant peers. In this article, we describe how findings from behavioral genetic research on problem behavior intersect with research from developmental neuroscience. In particular, the incentive-processing system, including the ventral striatum, responds increasingly to rewards in adolescence, particularly in peer contexts. This developmental shift may be influenced by hormonal changes at puberty. Individual differences in the structure and function of reward-responsive brain regions may be intermediary phenotypes that mediate adolescents' genetic risk for problem behavior. The study of problem behavior can be enriched by interdisciplinary research that integrates measures of brain structure and function into genetically informed studies.

Plant chromatin warms up in Madrid

PubMed Central

Jarillo, José A; Gaudin, Valerie; Hennig, Lars; Köhler, Claudia; Piñeiro, Manuel

2014-01-01

The 3rd European Workshop on Plant Chromatin (EWPC) was held on August 2013 in Madrid, Spain. A number of different topics on plant chromatin were presented during the meeting, including new factors mediating Polycomb Group protein function in plants, chromatin-mediated reprogramming in plant developmental transitions, the role of histone variants, and newly identified chromatin remodeling factors. The function of interactions between chromatin and transcription factors in the modulation of gene expression, the role of chromatin dynamics in the control of nuclear processes and the influence of environmental factors on chromatin organization were also reported. In this report, we highlight some of the new insights emerging in this growing area of research, presented at the 3rd EWPC. PMID:24504145

No mediating effects of glycemic control and inflammation on the association between vitamin D and lung function in the general population.

PubMed

Kaul, Anne; Gläser, Sven; Hannemann, Anke; Stubbe, Beate; Felix, Stefan B; Nauck, Matthias; Ewert, Ralf; Friedrich, Nele

2017-04-01

Vitamin D deficiency is discussed to be associated with lung health. While former studies focused on subjects suffering from pulmonary diseases, we aimed to investigate the association of 25-hydroxy vitamin D [25(OH)D] with lung function in the general population and examined whether mediating effects of inflammation, glycemic control or renal function exist. 1404 participants from the Study of Health in Pomerania with pulmonary function testing assessed by expiratory volume in 1 s (FEV 1 ), forced vital capacity (FVC), total lung capacity and Krogh index were used. Adjusted analysis of variance, linear regression models and mediation analyses were performed. Significant positive associations between 25(OH)D levels and FEV 1 , FVC and Krogh index were found. Mediator analyses revealed no mediating effect of inflammation (fibrinogen), glycemic control (HbA1c) or renal function (eGFR) on associations with FEV 1 or FVC. With respect to Krogh-Index, the association to 25(OH)D was slightly mediated by fibrinogen with a proportion mediated of 9.7%. Significant positive associations of 25(OH)D with lung function were revealed in a general population. The proposed mediating effects of inflammation, glycemic control and renal function on these relations were not confirmed. Further studies examining the causality of the association between 25(OH)D and lung function are necessary. Copyright © 2017 Elsevier Ltd. All rights reserved.

A Different Microbiome Gene Repertoire in the Airways of Cystic Fibrosis Patients with Severe Lung Disease

PubMed Central

Bacci, Giovanni; Fiscarelli, Ersilia; Taccetti, Giovanni; Dolce, Daniela; Paganin, Patrizia; Morelli, Patrizia; Tuccio, Vanessa; De Alessandri, Alessandra; Lucidi, Vincenzina

2017-01-01

In recent years, next-generation sequencing (NGS) was employed to decipher the structure and composition of the microbiota of the airways in cystic fibrosis (CF) patients. However, little is still known about the overall gene functions harbored by the resident microbial populations and which specific genes are associated with various stages of CF lung disease. In the present study, we aimed to identify the microbial gene repertoire of CF microbiota in twelve patients with severe and normal/mild lung disease by performing sputum shotgun metagenome sequencing. The abundance of metabolic pathways encoded by microbes inhabiting CF airways was reconstructed from the metagenome. We identified a set of metabolic pathways differently distributed in patients with different pulmonary function; namely, pathways related to bacterial chemotaxis and flagellar assembly, as well as genes encoding efflux-mediated antibiotic resistance mechanisms and virulence-related genes. The results indicated that the microbiome of CF patients with low pulmonary function is enriched in virulence-related genes and in genes encoding efflux-mediated antibiotic resistance mechanisms. Overall, the microbiome of severely affected adults with CF seems to encode different mechanisms for the facilitation of microbial colonization and persistence in the lung, consistent with the characteristics of multidrug-resistant microbial communities that are commonly observed in patients with severe lung disease. PMID:28758937

Function and regulation of the Mediator complex.

PubMed

Conaway, Ronald C; Conaway, Joan Weliky

2011-04-01

Over the past few years, advances in biochemical and genetic studies of the structure and function of the Mediator complex have shed new light on its subunit architecture and its mechanism of action in transcription by RNA polymerase II (pol II). The development of improved methods for reconstitution of recombinant Mediator subassemblies is enabling more in-depth analyses of basic features of the mechanisms by which Mediator interacts with and controls the activity of pol II and the general initiation factors. The discovery and characterization of multiple, functionally distinct forms of Mediator characterized by the presence or absence of the Cdk8 kinase module have led to new insights into how Mediator functions in both Pol II transcription activation and repression. Finally, progress in studies of the mechanisms by which the transcriptional activation domains (ADs) of DNA binding transcription factors target Mediator have brought to light unexpected complexities in the way Mediator participates in signal transduction. Copyright © 2011 Elsevier Ltd. All rights reserved.

Heat stress-induced nuclear transport mediated by Hikeshi confers nuclear function of Hsp70s.

PubMed

Imamoto, Naoko

2018-06-01

The prime feature of eukaryotic cells is the separation of the intracellular space into two compartments, the nucleus and the cytoplasm. Active nuclear transport is crucial for the maintenance of this separation. In this report, we focus on a nuclear transport receptor named Hikeshi, which mediates the heat stress-induced nuclear import of 70-kDa heat shock proteins (Hsp70s), and discuss how the same protein can function differently depending on the cellular compartment in which it is localized. Hsp70 is a molecular chaperone that is predominantly localized in the cytoplasm under normal conditions but is known to accumulate in the nucleus under conditions of heat stress. Although the reported function of Hsp70 is mostly attributed to its molecular function in the cytoplasm, the functions of Hsp70 may extend beyond molecular chaperone activity in the nucleus. Copyright © 2018 The Author. Published by Elsevier Ltd.. All rights reserved.

Serotonin and brain function: a tale of two receptors.

PubMed

Carhart-Harris, R L; Nutt, D J

2017-09-01

Previous attempts to identify a unified theory of brain serotonin function have largely failed to achieve consensus. In this present synthesis, we integrate previous perspectives with new and older data to create a novel bipartite model centred on the view that serotonin neurotransmission enhances two distinct adaptive responses to adversity, mediated in large part by its two most prevalent and researched brain receptors: the 5-HT1A and 5-HT2A receptors. We propose that passive coping (i.e. tolerating a source of stress) is mediated by postsynaptic 5-HT1AR signalling and characterised by stress moderation. Conversely, we argue that active coping (i.e. actively addressing a source of stress) is mediated by 5-HT2AR signalling and characterised by enhanced plasticity (defined as capacity for change). We propose that 5-HT1AR-mediated stress moderation may be the brain's default response to adversity but that an improved ability to change one's situation and/or relationship to it via 5-HT2AR-mediated plasticity may also be important - and increasingly so as the level of adversity reaches a critical point. We propose that the 5-HT1AR pathway is enhanced by conventional 5-HT reuptake blocking antidepressants such as the selective serotonin reuptake inhibitors (SSRIs), whereas the 5-HT2AR pathway is enhanced by 5-HT2AR-agonist psychedelics. This bipartite model purports to explain how different drugs (SSRIs and psychedelics) that modulate the serotonergic system in different ways, can achieve complementary adaptive and potentially therapeutic outcomes.

Serotonin and brain function: a tale of two receptors

PubMed Central

Carhart-Harris, RL; Nutt, DJ

2017-01-01

Previous attempts to identify a unified theory of brain serotonin function have largely failed to achieve consensus. In this present synthesis, we integrate previous perspectives with new and older data to create a novel bipartite model centred on the view that serotonin neurotransmission enhances two distinct adaptive responses to adversity, mediated in large part by its two most prevalent and researched brain receptors: the 5-HT1A and 5-HT2A receptors. We propose that passive coping (i.e. tolerating a source of stress) is mediated by postsynaptic 5-HT1AR signalling and characterised by stress moderation. Conversely, we argue that active coping (i.e. actively addressing a source of stress) is mediated by 5-HT2AR signalling and characterised by enhanced plasticity (defined as capacity for change). We propose that 5-HT1AR-mediated stress moderation may be the brain’s default response to adversity but that an improved ability to change one’s situation and/or relationship to it via 5-HT2AR-mediated plasticity may also be important – and increasingly so as the level of adversity reaches a critical point. We propose that the 5-HT1AR pathway is enhanced by conventional 5-HT reuptake blocking antidepressants such as the selective serotonin reuptake inhibitors (SSRIs), whereas the 5-HT2AR pathway is enhanced by 5-HT2AR-agonist psychedelics. This bipartite model purports to explain how different drugs (SSRIs and psychedelics) that modulate the serotonergic system in different ways, can achieve complementary adaptive and potentially therapeutic outcomes. PMID:28858536

On optima: the case of myoglobin-facilitated oxygen diffusion.

PubMed

Wittenberg, Jonathan B

2007-08-15

The process of myoglobin/leghemoglobin-facilitated oxygen diffusion is adapted to function in different environments in diverse organisms. We enquire how the functional parameters of the process are optimized in particular organisms. The ligand-binding properties of the proteins, myoglobin and plant symbiotic hemoglobins, we discover, suggest that they have been adapted under genetic selection pressure for optimal performance. Since carrier-mediated oxygen transport has probably evolved independantly many times, adaptation of diverse proteins for a common functionality exemplifies the process of convergent evolution. The progenitor proteins may be built on the myoglobin scaffold or may be very different.

Evidence of functional cell-mediated immune responses to nontypeable Haemophilus influenzae in otitis-prone children

PubMed Central

Seppanen, Elke; Tan, Dino; Corscadden, Karli J.; Currie, Andrew J.; Richmond, Peter C.; Thornton, Ruth B.

2018-01-01

Otitis media (OM) remains a common paediatric disease, despite advances in vaccinology. Susceptibility to recurrent acute OM (rAOM) has been postulated to involve defective cell-mediated immune responses to common otopathogenic bacteria. We compared the composition of peripheral blood mononuclear cells (PBMC) from 20 children with a history of rAOM (otitis-prone) and 20 healthy non-otitis-prone controls, and assessed innate and cell-mediated immune responses to the major otopathogen nontypeable Haemophilus influenzae (NTHi). NTHi was a potent stimulator of inflammatory cytokine secretion from PBMC within 4 hours, with no difference in cytokine levels produced between PBMC from cases or controls. In the absence of antigen stimulation, otitis-prone children had more circulating Natural Killer (NK) cells (p<0.01), particularly NKdim (CD56lo) cells (p<0.01), but fewer CD4+ T cells (p<0.01) than healthy controls. NTHi challenge significantly increased the proportion of activated (CD107a+) NK cells in otitis-prone and non-otitis-prone children (p<0.01), suggesting that NK cells from otitis-prone children are functional and respond to NTHi. CD8+ T cells and NK cells from both cases and controls produced IFNγ in response to polyclonal stimulus (Staphylococcal enterotoxin B; SEB), with more IFNγ+ CD8+ T cells present in cases than controls (p<0.05) but similar proportions of IFNγ+ NK cells. Otitis-prone children had more circulating IFNγ-producing NK cells (p<0.05) and more IFNγ-producing CD4+ (p<0.01) or CD8+ T-cells (p<0.05) than healthy controls. In response to SEB, more CD107a-expressing CD8+ T cells were present in cases than controls (p<0.01). Despite differences in PBMC composition, PBMC from otitis-prone children mounted innate and T cell-mediated responses to NTHi challenge that were comparable to healthy children. These data provide evidence that otitis-prone children do not have impaired functional cell mediated immunity. PMID:29621281

Neurophysiology of Robot-Mediated Training and Therapy: A Perspective for Future Use in Clinical Populations

PubMed Central

Turner, Duncan L.; Ramos-Murguialday, Ander; Birbaumer, Niels; Hoffmann, Ulrich; Luft, Andreas

2013-01-01

The recovery of functional movements following injury to the central nervous system (CNS) is multifaceted and is accompanied by processes occurring in the injured and non-injured hemispheres of the brain or above/below a spinal cord lesion. The changes in the CNS are the consequence of functional and structural processes collectively termed neuroplasticity and these may occur spontaneously and/or be induced by movement practice. The neurophysiological mechanisms underlying such brain plasticity may take different forms in different types of injury, for example stroke vs. spinal cord injury (SCI). Recovery of movement can be enhanced by intensive, repetitive, variable, and rewarding motor practice. To this end, robots that enable or facilitate repetitive movements have been developed to assist recovery and rehabilitation. Here, we suggest that some elements of robot-mediated training such as assistance and perturbation may have the potential to enhance neuroplasticity. Together the elemental components for developing integrated robot-mediated training protocols may form part of a neurorehabilitation framework alongside those methods already employed by therapists. Robots could thus open up a wider choice of options for delivering movement rehabilitation grounded on the principles underpinning neuroplasticity in the human CNS. PMID:24312073

29 CFR 1208.5 - Material relating to mediation function-confidential.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 29 Labor 4 2010-07-01 2010-07-01 false Material relating to mediation function-confidential. 1208.5 Section 1208.5 Labor Regulations Relating to Labor (Continued) NATIONAL MEDIATION BOARD AVAILABILITY OF INFORMATION § 1208.5 Material relating to mediation function—confidential. (a) All files...

Routes of Motivation: Stable Psychological Dispositions Are Associated with Dynamic Changes in Cortico-Cortical Functional Connectivity

PubMed Central

Viola, Vanda; Tosoni, Annalisa; Kruglanski, Arie W.; Galati, Gaspare; Mannetti, Lucia

2014-01-01

The present study provides a neurobiological framework to the theory of epistemic motivation that has been extensively studied for the last three decades in the domain of social cognition. Epistemic motivations affect the way people generate and validate hypotheses, and ultimately form and modify knowledge. Strong dispositional measures such as need for cognitive closure (NCC), the desire for a quick firm answer (any answer) to a question, show gross and stable inter-individual differences. The cognitive mechanisms and neural underpinnings of such differences, however, remain largely unexplored. Here we show that high (compared to low) levels of NCC, measured with need for cognitive closure scale, are associated with reduced online adjustment in cognitive control, as indexed by behavioral conflict adaptation. This behavioral effect is mediated by dynamic changes in cortico-cortical functional connectivity between prefrontal regions involved in conflict monitoring and implementation of cognitive control. In particular, these regions show increased functional connectivity after exposure to conflict in low but not high NCC individuals. These results demonstrate that the level of flexibility of functional cortico-cortical connections can mediate stable psychological dispositions. PMID:24892718

Parental corporal punishment in relation to children's executive function and externalizing behavior problems in China.

PubMed

Xing, Xiaopei; Wang, Meifang; Wang, Zhengyan

2018-04-01

The current study examined the relationship among paternal and maternal corporal punishment (CP), children's executive function (EF), and children's externalizing behavior problems. In total, 328 Chinese preschool-aged children and their parents and teachers participated. Paternal and maternal CP was assessed by father-reports and by mother-reports, respectively. Children's EF was assessed by the Executive Function Touch program. Children's externalizing behavior problems were assessed by mother-reports and by teacher-reports. The results of structural equation modeling generally supported working memory as a mediator linking paternal CP and children's externalizing behaviors and inhibitory control as a mediator linking maternal CP and children's externalizing behaviors. No differences by children's gender were found. The current findings highlight the importance of EF in behavioral outcomes of children who experience parental CP.

Linking and Psychological Functioning in a Chinese Sample: The Multiple Mediation of Response to Positive Affect

ERIC Educational Resources Information Center

Yang, Hongfei; Li, Juan

2016-01-01

The present study examined the associations between linking, response to positive affect, and psychological functioning in Chinese college students. The results of conducting multiple mediation analyses indicated that emotion- and self-focused positive rumination mediated the relationship between linking and psychological functioning, whereas…

The genetic locus NRC-1 within chromosome 3p12 mediates tumor suppression in renal cell carcinoma independently of histological type, tumor microenvironment, and VHL mutation.

PubMed

Lovell, M; Lott, S T; Wong, P; El-Naggar, A; Tucker, S; Killary, A M

1999-05-01

Human chromosome 3p cytogenetic abnormalities and loss of heterozygosity have been observed at high frequency in the nonpapillary form of sporadic renal cell carcinoma (RCC). The von Hippel-Lindau (VHL) gene has been identified as a tumor suppressor gene for RCC at 3p25, and functional studies as well as molecular genetic and cytogenetic analyses have suggested as many as two or three additional regions of 3p that could harbor tumor suppressor genes for sporadic RCC. We have previously functionally defined a novel genetic locus nonpapillary renal carcinoma-1 (NRC-1) within chromosome 3p12, distinct from the VHL gene, that mediates tumor suppression and rapid cell death of RCC cells in vivo. We now report the suppression of tumorigenicity of RCC cells in vivo after the transfer of a defined centric 3p fragment into different histological types of RCC. Results document the functional involvement of NRC-1 in not only different cell types of RCC (i.e., clear cell, mixed granular cell/clear cell, and sarcomatoid types) but also in papillary RCC, a less frequent histological type of RCC for which chromosome 3p LOH and genetic aberrations have only rarely been observed. We also report that the tumor suppression observed in functional genetic screens was independent of the microenvironment of the tumor, further supporting a role for NRC-1 as a more general mediator of in vivo growth control. Furthermore, this report demonstrates the first functional evidence for a VHL-independent pathway to tumorigenesis in the kidney via the genetic locus NRC-1.

Tumor-Targeting Anti-CD20 Antibodies Mediate In Vitro Expansion of Memory Natural Killer Cells: Impact of CD16 Affinity Ligation Conditions and In Vivo Priming.

PubMed

Capuano, Cristina; Battella, Simone; Pighi, Chiara; Franchitti, Lavinia; Turriziani, Ombretta; Morrone, Stefania; Santoni, Angela; Galandrini, Ricciarda; Palmieri, Gabriella

2018-01-01

Natural killer (NK) cells represent a pivotal player of innate anti-tumor immune responses. The impact of environmental factors in shaping the representativity of different NK cell subsets is increasingly appreciated. Human cytomegalovirus (HCMV) infection profoundly affects NK cell compartment, as documented by the presence of a CD94/NKG2C + FcεRIγ - long-lived "memory" NK cell subset, endowed with enhanced CD16-dependent functional capabilities, in a fraction of HCMV-seropositive subjects. However, the requirements for memory NK cell pool establishment/maintenance and activation have not been fully characterized yet. Here, we describe the capability of anti-CD20 tumor-targeting therapeutic monoclonal antibodies (mAbs) to drive the selective in vitro expansion of memory NK cells and we show the impact of donor' HCMV serostatus and CD16 affinity ligation conditions on this event. In vitro expanded memory NK cells maintain the phenotypic and functional signature of their freshly isolated counterpart; furthermore, our data demonstrate that CD16 affinity ligation conditions differently affect memory NK cell proliferation and functional activation, as rituximab-mediated low-affinity ligation represents a superior proliferative stimulus, while high-affinity aggregation mediated by glycoengineered obinutuzumab results in improved multifunctional responses. Our work also expands the molecular and functional characterization of memory NK cells, and investigates the possible impact of CD16 functional allelic variants on their in vivo and in vitro expansions. These results reveal new insights in Ab-driven memory NK cell responses in a therapeutic setting and may ultimately inspire new NK cell-based intervention strategies against cancer, in which the enhanced responsiveness to mAb-bound target could significantly impact therapeutic efficacy.

PIC Activation through Functional Interplay between Mediator and TFIIH.

PubMed

Malik, Sohail; Molina, Henrik; Xue, Zhu

2017-01-06

The multiprotein Mediator coactivator complex functions in large part by controlling the formation and function of the promoter-bound preinitiation complex (PIC), which consists of RNA polymerase II and general transcription factors. However, precisely how Mediator impacts the PIC, especially post-recruitment, has remained unclear. Here, we have studied Mediator effects on basal transcription in an in vitro transcription system reconstituted from purified components. Our results reveal a close functional interplay between Mediator and TFIIH in the early stages of PIC development. We find that under conditions when TFIIH is not normally required for transcription, Mediator actually represses transcription. TFIIH, whose recruitment to the PIC is known to be facilitated by the Mediator, then acts to relieve Mediator-induced repression to generate an active form of the PIC. Gel mobility shift analyses of PICs and characterization of TFIIH preparations carrying mutant XPB translocase subunit further indicate that this relief of repression is achieved through expending energy via ATP hydrolysis, suggesting that it is coupled to TFIIH's established promoter melting activity. Our interpretation of these results is that Mediator functions as an assembly factor that facilitates PIC maturation through its various stages. Whereas the overall effect of the Mediator is to stimulate basal transcription, its initial engagement with the PIC generates a transcriptionally inert PIC intermediate, which necessitates energy expenditure to complete the process. Copyright © 2016 Elsevier Ltd. All rights reserved.

Subjective health complaints, functional ability, fear avoidance beliefs, and days on sickness benefits after work rehabilitation - a mediation model.

PubMed

Øyeflaten, Irene; Opsahl, Jon; Eriksen, Hege R; Braathen, Tore Norendal; Lie, Stein Atle; Brage, Søren; Ihlebæk, Camilla M; Breivik, Kyrre

2016-05-23

Long-term sick leave and withdrawal from working life is a concern in western countries. In Norway, comprehensive inpatient work rehabilitation may be offered to sick listed individuals at risk of long-term absence from work. Knowledge about prognostic factors for work outcomes after long-term sick leave and work rehabilitation is still limited. The aim of this study was to test a mediation model for various hypothesized biopsychosocial predictors of continued sick leave after inpatient work rehabilitation. One thousand one hundred fifty-five participants on long-term sick leave from eight different work rehabilitation clinics answered comprehensive questionnaires at arrival to the clinic, and were followed with official register data on sickness benefits for 3 years. Structural equation models were conducted, with days on sickness benefits after work rehabilitation as the outcome. Fear avoidance beliefs for work mediated the relation between both musculoskeletal complaints and education on days on sickness benefits after work rehabilitation. The relation between musculoskeletal complaints and fear avoidance beliefs for work was furthermore fully mediated by poor physical function. Previous sick leave had a strong independent effect on continued sick leave after work rehabilitation. Fear avoidance beliefs for work did not mediate the small effect of pseudoneurological complaints on continued sick leave. Poor coping/interaction ability was neither related to continued sick leave nor fear avoidance beliefs for work. The mediation model was partly supported by the data, and provides some possible new insight into how fear avoidance beliefs for work and functional ability may intervene with subjective health complaints and days on sickness benefits after work rehabilitation.

The Mediating Role of Posttraumatic Stress Disorder with Tendency to Forgive, Social Support, and Psychosocial Functioning of Terror Survivors.

PubMed

Weinberg, Michael

2018-06-12

The study reported in this article examined the relationship between psychosocial functioning and tendency to forgive, social support, and posttraumatic stress disorder (PTSD) symptoms of terror survivors (N = 108). Structural equation modeling was used to examine whether PTSD symptoms mediated the association between tendency to forgive, social support, and psychosocial functioning. The findings demonstrated that the association between tendency to forgive and psychosocial functioning was mediated exclusively by PTSD symptoms, whereas the association between social support and psychosocial functioning was partially mediated by PTSD symptoms. The study reinforces the importance of addressing trauma survivors' psychosocial functioning as an emotional state associated with tendency to forgive, social support, and PTSD symptoms. In addition, the findings suggest that when treating trauma survivors, therapists should be aware of PTSD not only as an emotional consequence of trauma, but also as a mediator of numerous emotional and cognitive coping mechanisms.

Microbial exopolysaccharide-mediated synthesis and stabilization of metal nanoparticles.

PubMed

Sathiyanarayanan, Ganesan; Dineshkumar, Krishnamoorthy; Yang, Yung-Hun

2017-11-01

Exopolysaccharides (EPSs) are structurally and functionally valuable biopolymer secreted by different prokaryotic and eukaryotic microorganisms in response to biotic/abiotic stresses and to survive in extreme environments. Microbial EPSs are fascinating in various industrial sectors due to their excellent material properties and less toxic, highly biodegradable, and biocompatible nature. Recently, microbial EPSs have been used as a potential template for the rapid synthesis of metallic nanoparticles and EPS-mediated metal reduction processes are emerging as simple, harmless, and environmentally benign green chemistry approaches. EPS-mediated synthesis of metal nanoparticles is a distinctive metabolism-independent bio-reduction process due to the formation of interfaces between metal cations and the polyanionic functional groups (i.e. hydroxyl, carboxyl and amino groups) of the EPS. In addition, the range of physicochemical features which facilitates the EPS as an efficient stabilizing or capping agents to protect the primary structure of the metal nanoparticles with an encapsulation film in order to separate the nanoparticle core from the mixture of composites. The EPS-capping also enables the further modification of metal nanoparticles with expected material properties for multifarious applications. The present review discusses the microbial EPS-mediated green synthesis/stabilization of metal nanoparticles, possible mechanisms involved in EPS-mediated metal reduction, and application prospects of EPS-based metal nanoparticles.

Intercellular and intracellular signalling systems that globally control the expression of virulence genes in plant pathogenic bacteria.

PubMed

Ham, Jong Hyun

2013-04-01

Plant pathogenic bacteria utilize complex signalling systems to control the expression of virulence genes at the cellular level and within populations. Quorum sensing (QS), an important intercellular communication mechanism, is mediated by different types of small molecules, including N-acyl homoserine lactones (AHLs), fatty acids and small proteins. AHL-mediated signalling systems dependent on the LuxI and LuxR family proteins play critical roles in the virulence of a wide range of Gram-negative plant pathogenic bacteria belonging to the Alphaproteobacteria, Betaproteobacteria and Gammaproteobacteria. Xanthomonas spp. and Xylella fastidiosa, members of the Gammaproteobacteria, however, possess QS systems that are mediated by fatty acid-type diffusible signal factors (DSFs). Recent studies have demonstrated that Ax21, a 194-amino-acid protein in Xanthomonas oryzae pv. oryzae, plays dual functions in activating a rice innate immune pathway through binding to the rice XA21 pattern recognition receptor and in regulating bacterial virulence and biofilm formation as a QS signal molecule. In xanthomonads, DSF-mediated QS systems are connected with the signalling pathways mediated by cyclic diguanosine monophosphate (c-di-GMP), which functions as a second messenger for the control of virulence gene expression in these bacterial pathogens. © 2012 BSPP AND BLACKWELL PUBLISHING LTD.

Attachment, emotion regulation and coping in Portuguese emerging adults: a test of a mediation hypothesis.

PubMed

Cabral, Joana; Matos, Paula M; Beyers, Wim; Soenens, Bart

2012-11-01

Although the quality of parent-adolescent emotional bonds has consistently been proposed as a major influence on young adult's psycho-emotional functioning, the precise means by which these bonds either facilitate or impede adaptive coping are not well-understood. In an effort to advance this inquiry, the present study examined interrelationships among measures of parental attachment, emotion regulation processes, and preferred coping strategies within a sample of 942 college freshmen. Structural Equation Modelling was used to test whether the link between attachment to parents and the use of particular coping strategies is mediated by differences in emotion regulation mechanisms. As hypothesized, differences in attachment to parents predicted differences in the use of emotion regulation mechanisms and coping strategies. More specifically, having a close emotional bond, feeling supported in autonomy processes and having (moderately) low levels of separation anxiety toward parents predict more constructive emotion regulation mechanisms and coping strategies. Additionally emotion regulation was found to (partly or totally) mediate the association between attachment and coping.

Protective effects of flavanol-rich dark chocolate on endothelial function and wave reflection during acute hyperglycemia.

PubMed

Grassi, Davide; Desideri, Giovambattista; Necozione, Stefano; Ruggieri, Fabrizio; Blumberg, Jeffrey B; Stornello, Michele; Ferri, Claudio

2012-09-01

Nitric oxide plays a pivotal role in regulating vascular tone. Different studies show endothelial function is impaired during hyperglycemia. Dark chocolate increases flow-mediated dilation in healthy and hypertensive subjects with and without glucose intolerance; however, the effect of pretreatment with dark chocolate on endothelial function and other vascular responses to hyperglycemia has not been examined. Therefore, we aimed to investigate the effects of flavanol-rich dark chocolate administration on (1) flow-mediated dilation and wave reflections; (2) blood pressure, endothelin-1 and oxidative stress, before and after oral glucose tolerance test (OGTT). Twelve healthy volunteers (5 males, 28.2±2.7 years) randomly received either 100 g/d dark chocolate or flavanol-free white chocolate for 3 days. After 7 days washout period, volunteers were switched to the other treatment. Flow-mediated dilation, stiffness index, reflection index, peak-to-peak time, blood pressure, endothelin-1 and 8-iso-PGF(2α) were evaluated after each treatment phase and OGTT. Compared with white chocolate, dark chocolate ingestion improved flow-mediated dilation (P=0.03), wave reflections, endothelin-1 and 8-iso-PGF(2α) (P<0.05). After white chocolate ingestion, flow-mediated dilation was reduced after OGTT from 7.88±0.68 to 6.07±0.76 (P=0.027), 6.74±0.51 (P=0.046) at 1 and 2 h after the glucose load, respectively. Similarly, after white chocolate but not after dark chocolate, wave reflections, blood pressure, and endothelin-1 and 8-iso-PGF(2α) increased after OGTT. OGTT causes acute, transient impairment of endothelial function and oxidative stress, which is attenuated by flavanol-rich dark chocolate. These results suggest cocoa flavanols may contribute to vascular health by reducing the postprandial impairment of arterial function associated with the pathogenesis of atherosclerosis.

Flow-mediated dilation and peripheral arterial tonometry are disturbed in preeclampsia and reflect different aspects of endothelial function.

PubMed

Mannaerts, Dominique; Faes, Ellen; Goovaerts, Inge; Stoop, Tibor; Cornette, Jerome; Gyselaers, Wilfried; Spaanderman, Marc; Van Craenenbroeck, Emeline M; Jacquemyn, Yves

2017-11-01

Endothelial function and arterial stiffness are known to be altered in preeclamptic pregnancies. Previous studies have shown conflicting results regarding the best technique for assessing vascular function in pregnancy. In this study, we made a comprehensive evaluation of in vivo vascular function [including flow-mediated dilatation (FMD), peripheral arterial tonometry (PAT), and arterial stiffness] in preeclamptic patients and compared them with normal pregnancies. In addition, we assessed the relation between vascular function and systemic inflammation. Fourteen patients with preeclampsia (PE) and 14 healthy pregnant controls were included. Endothelial function was determined by FMD and PAT and arterial stiffness by carotid-femoral pulse-wave velocity and augmentation index. Systemic inflammation was assessed using mean platelet volume (MPV) and neutrophil-lymphocyte ratio (NLR). The reactive hyperemia index, assessed using PAT, is decreased at the third trimester compared with the first trimester in a normal, uncomplicated pregnancy ( P = 0.001). Arterial stiffness is significantly higher in PE versus normal pregnancy ( P < 0.001). Endothelial function, obtained by FMD, is deteriorated in PE versus normal pregnancy ( P = 0.015), whereas endothelial function assessment by PAT is improved in PE versus normal pregnancy ( P = 0.001). Systemic inflammation (MPV and NLR) increases during normal pregnancy. FMD and PAT are disturbed in PE. Endothelial function, assessed by FMD and PAT, shows distinct results. This may indicate that measurements with FMD and PAT reflect different aspects of endothelial function and that PAT should not be used as a substitute for FMD as a measure of endothelial function in pregnancy. Copyright © 2017 the American Physiological Society.

Role of religious involvement and spirituality in functioning among African Americans with cancer: testing a mediational model

PubMed Central

Holt, Cheryl L.; Wang, Min Qi; Caplan, Lee; Schulz, Emily; Blake, Victor; Southward, Vivian L.

2013-01-01

The present study tested a mediational model of the role of religious involvement, spirituality, and physical/emotional functioning in a sample of African American men and women with cancer. Several mediators were proposed based on theory and previous research, including sense of meaning, positive and negative affect, and positive and negative religious coping. One hundred patients were recruited through oncologist offices, key community leaders and community organizations, and interviewed by telephone. Participants completed an established measure of religious involvement, the Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being Scale (FACIT-SP-12 version 4), the Positive and Negative Affect Schedule (PANAS), the Meaning in Life Scale, the Brief RCOPE, and the SF-12, which assesses physical and emotional functioning. Positive affect completely mediated the relationship between religious behaviors and emotional functioning. Though several other constructs showed relationships with study variables, evidence of mediation was not supported. Mediational models were not significant for the physical functioning outcome, nor were there significant main effects of religious involvement or spirituality for this outcome. Implications for cancer survivorship interventions are discussed. PMID:21222026

Sex/gender differences in the brain and cognition in schizophrenia.

PubMed

Mendrek, Adrianna; Mancini-Marïe, Adham

2016-08-01

The early conceptualizations of schizophrenia have noted some sex/gender differences in epidemiology and clinical expression of the disorder. Over the past few decades, the interest in differences between male and female patients has expanded to encompass brain morphology and neurocognitive function. Despite some variability and methodological shortcomings, a few patterns emerge from the available literature. Most studies of gross neuroanatomy show more enlarged ventricles and smaller frontal lobes in men than in women with schizophrenia; finding reflecting normal sexual dimorphism. In comparison, studies of brain asymmetry and specific corticolimbic structures, suggest a disturbance in normal sexual dimorphism. The neurocognitive findings are somewhat consistent with this picture. Studies of cognitive functions mediated by the lateral frontal network tend to show sex differences in patients which are in the same direction as those observed in the general population, whereas studies of processes mediated by the corticolimbic system more frequently reveal reversal of normal sexual dimorphisms. These trends are faint and future research would need to delineate neurocognitive differences between men and women with various subtypes of schizophrenia (e.g., early versus late onset), while taking into consideration hormonal status and gender of tested participants. Copyright © 2015 Elsevier Ltd. All rights reserved.

A Bifactor Approach to Model Multifaceted Constructs in Statistical Mediation Analysis.

PubMed

Gonzalez, Oscar; MacKinnon, David P

Statistical mediation analysis allows researchers to identify the most important mediating constructs in the causal process studied. Identifying specific mediators is especially relevant when the hypothesized mediating construct consists of multiple related facets. The general definition of the construct and its facets might relate differently to an outcome. However, current methods do not allow researchers to study the relationships between general and specific aspects of a construct to an outcome simultaneously. This study proposes a bifactor measurement model for the mediating construct as a way to parse variance and represent the general aspect and specific facets of a construct simultaneously. Monte Carlo simulation results are presented to help determine the properties of mediated effect estimation when the mediator has a bifactor structure and a specific facet of a construct is the true mediator. This study also investigates the conditions when researchers can detect the mediated effect when the multidimensionality of the mediator is ignored and treated as unidimensional. Simulation results indicated that the mediation model with a bifactor mediator measurement model had unbiased and adequate power to detect the mediated effect with a sample size greater than 500 and medium a - and b -paths. Also, results indicate that parameter bias and detection of the mediated effect in both the data-generating model and the misspecified model varies as a function of the amount of facet variance represented in the mediation model. This study contributes to the largely unexplored area of measurement issues in statistical mediation analysis.

The mediating effect of psychological distress on functional dependence in stroke patients.

PubMed

Huang, Hui-Chuan; Huang, Li-Kai; Hu, Chaur-Jong; Chang, Chien-Hung; Lee, Hsin-Chien; Chi, Nai-Fang; Shyu, Meei-Ling; Chang, Hsiu-Ju

2014-12-01

To explore varied forms of psychological distress and to determine the mediating influence of psychological distress on functional outcomes in stroke patients. Previous studies attest to the influence of depression on poststroke functional recovery. While there is evidence for neuropathological deficits that occur after stroke to be associated with psychological distress, few studies have explored the effect of various types of psychological distress on functional recovery. A cross-sectional study was used. Data were collected from 178 first-time stroke patients. Study variables included demographic and disease characteristics (stroke location and stroke syndrome classification), psychological distress (the Chinese language version of the Emotional and Social Dysfunction Questionnaire) and functional outcome (Barthel index). Regression and mediation models were used to evaluate the effect of psychological distress on functional outcome. Results revealed that stroke patients experience various forms of mild psychological distress, including anger, helplessness, emotional dyscontrol, indifference, inertia and euphoria, after stroke. Regression and mediation analyses further confirmed that various forms of psychological distress significantly mediated the effect of severe stroke syndromes on functional dependence. The various forms of psychological distress after stroke might play a mediating role in functional recovery and explain how stroke severity affects functional dependence. By understanding the nature of various forms of psychological distress, healthcare professionals should adopt appropriate assessment instruments and design effective interventions to help improve mental and physical function of stroke patients. © 2014 John Wiley & Sons Ltd.

Reconstitution of active human core Mediator complex reveals a pivotal role of the MED14 subunit

PubMed Central

Cevher, Murat A.; Shi, Yi; Li, Dan; Chait, Brian T.; Malik, Sohail; Roeder, Robert G.

2014-01-01

The evolutionarily conserved Mediator complex is a critical coactivator for RNA polymerase II (Pol II)-mediated transcription. Here, we report the reconstitution of a functional 15-subunit human core Mediator complex and its characterization by functional assays and chemical cross-linking coupled to mass spectrometry (CX-MS). Whereas the reconstituted head and middle modules can stably associate, only with incorporation of MED14 into the bi-modular complex does it acquire basal and coactivator functions. This results from a dramatically enhanced ability of MED14-containing complexes to associate with Pol II. Altogether, our analyses identify MED14 as both an architectural and a functional backbone of the Mediator complex. We further establish a conditional requirement for metazoan-specific MED26 that becomes evident in the presence of heterologous nuclear factors. This general approach paves the way for systematically dissecting the multiple layers of functionalities associated with the Mediator complex. PMID:25383669

Lipoprotein lipase-dependent binding and uptake of low density lipoproteins by THP-1 monocytes and macrophages: possible involvement of lipid rafts.

PubMed

Makoveichuk, Elena; Castel, Susanna; Vilaró, Senen; Olivecrona, Gunilla

2004-11-08

Lipoprotein lipase (LPL) is produced by cells in the artery wall and can mediate binding of lipoproteins to cell surface heparan sulfate proteoglycans (HSPG), resulting in endocytosis (the bridging function). Active, dimeric LPL may dissociate to inactive monomers, the main form found in plasma. We have studied binding/internalization of human low density lipoprotein (LDL), mediated by bovine LPL, using THP-1 monocytes and macrophages. Uptake of (125)I-LDL was similar in monocytes and macrophages and was not affected by the LDL-receptor family antagonist receptor-associated protein (RAP) or by the phagocytosis inhibitor cytochalasin D. In contrast, uptake depended on HSPG and on membrane cholesterol. Incubation in the presence of dexamethasone increased the endogenous production of LPL by the cells and also increased LPL-mediated binding of LDL to the cell surfaces. Monomeric LPL was bound to the cells mostly in a heparin-resistant fashion. We conclude that the uptake of LDL mediated by LPL dimers is receptor-independent and involves cholesterol-enriched membrane areas (lipid rafts). Dimeric and monomeric LPL differ in their ability to mediate binding/uptake of LDL, probably due to different mechanisms for binding/internalization.

Automatic numerical evaluation of vacancy-mediated transport for arbitrary crystals: Onsager coefficients in the dilute limit using a Green function approach

NASA Astrophysics Data System (ADS)

Trinkle, Dallas R.

2017-10-01

A general solution for vacancy-mediated diffusion in the dilute-vacancy/dilute-solute limit for arbitrary crystal structures is derived from the master equation. A general numerical approach to the vacancy lattice Green function reduces to the sum of a few analytic functions and numerical integration of a smooth function over the Brillouin zone for arbitrary crystals. The Dyson equation solves for the Green function in the presence of a solute with arbitrary but finite interaction range to compute the transport coefficients accurately, efficiently and automatically, including cases with very large differences in solute-vacancy exchange rates. The methodology takes advantage of the space group symmetry of a crystal to reduce the complexity of the matrix inversion in the Dyson equation. An open-source implementation of the algorithm is available, and numerical results are presented for the convergence of the integration error of the bare vacancy Green function, and tracer correlation factors for a variety of crystals including wurtzite (hexagonal diamond) and garnet.

Psychological Symptoms Linking Exposure to Community Violence and Academic Functioning in African American Adolescents

PubMed Central

Busby, Danielle R.; Lambert, Sharon F.; Ialongo, Nicholas S.

2013-01-01

African American adolescents are exposed disproportionately to community violence, increasing their risk for emotional and behavioral symptoms that can detract from learning and undermine academic outcomes. The present study examined whether aggressive behavior and depressive and anxious symptoms mediated the association between exposure to community violence and academic functioning, and if the indirect effects of community violence on academic functioning differed for boys and girls, in a community sample of urban African American adolescents (N = 491; 46.6% female). Structural equation modeling was used to examine the indirect effect of exposure to community violence in grade 6 on grade 8 academic functioning. Results revealed that aggression in grade 7 mediated the association between grade 6 exposure to community violence and grade 8 academic functioning. There were no indirect effects through depressive and anxious symptoms, and gender did not moderate the indirect effect. Findings highlight the importance of targeting aggressive behavior for youth exposed to community violence to not only improve their behavioral adjustment but also their academic functioning. Implications for future research are discussed. PMID:23277294

Developmental imaging genetics: linking dopamine function to adolescent behavior.

PubMed

Padmanabhan, Aarthi; Luna, Beatriz

2014-08-01

Adolescence is a period of development characterized by numerous neurobiological changes that significantly influence behavior and brain function. Adolescence is of particular interest due to the alarming statistics indicating that mortality rates increase two to three-fold during this time compared to childhood, due largely to a peak in risk-taking behaviors resulting from increased impulsivity and sensation seeking. Furthermore, there exists large unexplained variability in these behaviors that are in part mediated by biological factors. Recent advances in molecular genetics and functional neuroimaging have provided a unique and exciting opportunity to non-invasively study the influence of genetic factors on brain function in humans. While genes do not code for specific behaviors, they do determine the structure and function of proteins that are essential to the neuronal processes that underlie behavior. Therefore, studying the interaction of genotype with measures of brain function over development could shed light on critical time points when biologically mediated individual differences in complex behaviors emerge. Here we review animal and human literature examining the neurobiological basis of adolescent development related to dopamine neurotransmission. Dopamine is of critical importance because of (1) its role in cognitive and affective behaviors, (2) its role in the pathogenesis of major psychopathology, and (3) the protracted development of dopamine signaling pathways over adolescence. We will then focus on current research examining the role of dopamine-related genes on brain function. We propose the use of imaging genetics to examine the influence of genetically mediated dopamine variability on brain function during adolescence, keeping in mind the limitations of this approach. Copyright © 2014 Elsevier Inc. All rights reserved.

Distinct phosphorylation sites on the ghrelin receptor, GHSR1a, establish a code that determines the functions of ß-arrestins

PubMed Central

Bouzo-Lorenzo, Monica; Santo-Zas, Icía; Lodeiro, Maria; Nogueiras, Rubén; Casanueva, Felipe F.; Castro, Marian; Pazos, Yolanda; Tobin, Andrew B; Butcher, Adrian J.; Camiña, Jesús P.

2016-01-01

The growth hormone secretagogue receptor, GHSR1a, mediates the biological activities of ghrelin, which includes the secretion of growth hormone, as well as the stimulation of appetite, food intake and maintenance of energy homeostasis. Mapping phosphorylation sites on GHSR1a and knowledge of how these sites control specific functional consequences unlocks new strategies for the development of therapeutic agents targeting individual functions. Herein, we have identified the phosphorylation of different sets of sites within GHSR1a which engender distinct functionality of ß-arrestins. More specifically, the Ser362, Ser363 and Thr366 residues at the carboxyl-terminal tail were primarily responsible for ß-arrestin 1 and 2 binding, internalization and ß-arrestin-mediated proliferation and adipogenesis. The Thr350 and Ser349 are not necessary for ß-arrestin recruitment, but are involved in the stabilization of the GHSR1a-ß-arrestin complex in a manner that determines the ultimate cellular consequences of ß-arrestin signaling. We further demonstrated that the mitogenic and adipogenic effect of ghrelin were mainly dependent on the ß-arrestin bound to the phosphorylated GHSR1a. In contrast, the ghrelin function on GH secretion was entirely mediated by G protein signaling. Our data is consistent with the hypothesis that the phosphorylation pattern on the C terminus of GHSR1a determines the signaling and physiological output. PMID:26935831

Soya bean Gα proteins with distinct biochemical properties exhibit differential ability to complement Saccharomyces cerevisiae gpa1 mutant.

PubMed

Roy Choudhury, Swarup; Wang, Yuqi; Pandey, Sona

2014-07-01

Signalling pathways mediated by heterotrimeric G-proteins are common to all eukaryotes. Plants have a limited number of each of the G-protein subunits, with the most elaborate G-protein network discovered so far in soya bean (Glycine max, also known as soybean) which has four Gα, four Gβ and ten Gγ proteins. Biochemical characterization of Gα proteins from plants suggests significant variation in their properties compared with the well-characterized non-plant proteins. Furthermore, the four soya bean Gα (GmGα) proteins exhibit distinct biochemical activities among themselves, but the extent to which such biochemical differences contribute to their in vivo function is also not known. We used the yeast gpa1 mutant which displays constitutive signalling and growth arrest in the pheromone-response pathway as an in vivo model to evaluate the effect of distinct biochemical activities of GmGα proteins. We showed that specific GmGα proteins can be activated during pheromone-dependent receptor-mediated signalling in yeast and they display different strengths towards complementation of yeast gpa1 phenotypes. We also identified amino acids that are responsible for differential complementation abilities of specific Gα proteins. These data establish that specific plant Gα proteins are functional in the receptor-mediated pheromone-response pathway in yeast and that the subtle biochemical differences in their activity are physiologically relevant.

The Escherichia coli Cpx envelope stress response regulates genes of diverse function that impact antibiotic resistance and membrane integrity.

PubMed

Raivio, Tracy L; Leblanc, Shannon K D; Price, Nancy L

2013-06-01

The Cpx envelope stress response mediates adaptation to stresses that cause envelope protein misfolding. Adaptation is partly conferred through increased expression of protein folding and degradation factors. The Cpx response also plays a conserved role in the regulation of virulence determinant expression and impacts antibiotic resistance. We sought to identify adaptive mechanisms that may be involved in these important functions by characterizing changes in the transcriptome of two different Escherichia coli strains when the Cpx response is induced. We show that, while there is considerable strain- and condition-specific variability in the Cpx response, the regulon is enriched for proteins and functions that are inner membrane associated under all conditions. Genes that were changed by Cpx pathway induction under all conditions were involved in a number of cellular functions and included several intergenic regions, suggesting that posttranscriptional regulation is important during Cpx-mediated adaptation. Some Cpx-regulated genes are centrally involved in energetics and play a role in antibiotic resistance. We show that a number of small, uncharacterized envelope proteins are Cpx regulated and at least two of these affect phenotypes associated with membrane integrity. Altogether, our work suggests new mechanisms of Cpx-mediated envelope stress adaptation and antibiotic resistance.

Spontaneous and natural cytotoxicity receptor-mediated cytotoxicity are effector functions of distinct natural killer subsets in hepatitis C virus-infected chimpanzees.

PubMed

Verstrepen, B E; Nieuwenhuis, I G; Mooij, P; Bogers, W M; Boonstra, A; Koopman, G

2016-07-01

In humans, CD16 and CD56 are used to identify functionally distinct natural killer (NK) subsets. Due to ubiquitous CD56 expression, this marker cannot be used to distinguish between NK cell subsets in chimpanzees. Therefore, functional analysis of distinct NK subsets during hepatitis C virus (HCV) infection has never been performed in these animals. In the present study an alternative strategy was used to identify four distinct NK subsets on the basis of the expression of CD16 and CD94. The expression of activating and inhibiting surface receptors showed that these subsets resemble human NK subsets. CD107 expression was used to determine degranulation of the different subsets in naive and HCV-infected chimpanzees. In HCV-infected chimpanzees increased spontaneous cytotoxicity was observed in CD94(high/dim) CD16(pos) and CD94(low) CD16(pos) subsets. By contrast, increased natural cytotoxicity receptor (NCR)- mediated degranulation after NKp30 and NKp44 triggering was demonstrated in the CD94(dim) CD16(neg) subset. Our findings suggest that spontaneous and NCR-mediated cytotoxicity are effector functions of distinct NK subsets in HCV-infected chimpanzees. © 2016 British Society for Immunology.

The effect of regulatory mode on procrastination: Bi-stable parahippocampus connectivity with dorsal anterior cingulate and anterior prefrontal cortex.

PubMed

Zhang, Chenyan; Ni, Yan; Feng, Tingyong

2017-06-30

Previous research has elucidated that procrastination can be influenced by regulatory mode orientations. However, the neural mechanism of regulatory modes affecting procrastination is not well understood. To address this question, we employed resting-state functional magnetic resonance imaging (RS-fMRI) to test the influence of two regulatory modes (assessment and locomotion) on procrastination. The behavioral results showed that procrastination was positively correlated with assessment orientation but negatively correlated with locomotion orientation. Neuroimaging results indicated that the functional connectivity between parahippocampal cortex (PHC) and dorsal anterior cingulate (dACC) was negatively correlated with assessment scores, while the functional connectivity between anterior prefrontal cortex (aPFC) and parahippocampal cortex (PHC) was negatively correlated with locomotion scores. Critically, mediation analysis showed that the different effects of two distinct regulatory modes on procrastination were mediated by PHC-dACC and aPFC-PHC functional connectivity respectively. These results suggested that people's procrastination could be predicted by regulatory mode orientations, which is mediated by PHC connectivity with dACC and aPFC respectively. The present study extends our knowledge on procrastination and provides neural mechanism for understanding the link between regulatory mode orientations and procrastination. Copyright © 2017. Published by Elsevier B.V.

Sleep Disturbance, Daytime Symptoms, and Functional Performance in Patients With Stable Heart Failure: A Mediation Analysis.

PubMed

Jeon, Sangchoon; Redeker, Nancy S

2016-01-01

Sleep disturbance is common among patients with heart failure (HF) who also experience symptom burden and poor functional performance. We evaluated the extent to which sleep-related, daytime symptoms (fatigue, excessive daytime sleepiness, and depressive symptoms) mediate the relationship between sleep disturbance and functional performance among patients with stable HF. We recruited patients with stable HF for this secondary analysis of data from a cross-sectional, observational study. Participants completed unattended ambulatory polysomnography from which the Respiratory Disturbance Index was calculated, along with a Six-Minute Walk Test, questionnaires to elicit sleep disturbance (Pittsburgh Sleep Quality Index, Insomnia Symptoms from the Sleep Habits Questionnaire), daytime symptoms (Center for Epidemiologic Studies Depression Scale, Global Fatigue Index, Epworth Sleepiness Scale), and self-reported functional performance (Medical Outcomes Study SF36 V2 Physical Function Scale). We used structural equation modeling with latent variables for the key analysis. Follow-up, exploratory regression analysis with bootstrapped samples was used to examine the extent to which individual daytime symptoms mediated effects of sleep disturbance on functional performance after controlling for clinical and demographic covariates. The sample included 173 New York Heart Association Class I-IV HF patients (n = 60/34.7% women; M = 60.7, SD = 16.07 years of age). Daytime symptoms mediated the relationship between sleep disturbance and functional performance. Fatigue and depression mediated the relationship between insomnia symptoms and self-reported functional performance, whereas fatigue and sleepiness mediated the relationship between sleep quality and functional performance. Sleepiness mediated the relationship between the respiratory index and self-reported functional performance only in people who did not report insomnia. Daytime symptoms explain the relationships between sleep disturbance and functional performance in stable HF.

Characterisation of an engineered trastuzumab IgE antibody and effector cell mechanisms targeting HER2/neu-positive tumour cells

PubMed Central

2010-01-01

Trastuzumab (Herceptin®), a humanized IgG1 antibody raised against the human epidermal growth factor receptor 2 (HER2/neu), is the main antibody in clinical use against breast cancer. Pre-clinical evidence and clinical studies indicate that trastuzumab employs several anti-tumour mechanisms that most likely contribute to enhanced survival of patients with HER2/neu-positive breast carcinomas. New strategies are aimed at improving antibody-based therapeutics like trastuzumab, e.g. by enhancing antibody-mediated effector function mechanisms. Based on our previous findings that a chimaeric ovarian tumour antigen-specific IgE antibody showed greater efficacy in tumour cell killing, compared to the corresponding IgG1 antibody, we have produced an IgE homologue of trastuzumab. Trastuzumab IgE was engineered with the same light- and heavy-chain variable-regions as trastuzumab, but with an epsilon in place of the gamma-1 heavy-chain constant region. We describe the physical characterisation and ligand binding properties of the trastuzumab IgE and elucidate its potential anti-tumour activities in functional assays. Both trastuzumab and trastuzumab IgE can activate monocytic cells to kill tumour cells, but they operate by different mechanisms: trastuzumab functions in antibody-dependent cell-mediated phagocytosis (ADCP), whereas trastuzumab IgE functions in antibody-dependent cell-mediated cytotoxicity (ADCC). Trastuzumab IgE, incubated with mast cells and HER2/neu-expressing tumour cells, triggers mast cell degranulation, recruiting against cancer cells a potent immune response, characteristic of allergic reactions. Finally, in viability assays both antibodies mediate comparable levels of tumour cell growth arrest. These functional characteristics of trastuzumab IgE, some distinct from those of trastuzumab, indicate its potential to complement or improve upon the existing clinical benefits of trastuzumab. PMID:18941743

Developing models of how cognitive improvements change functioning: Mediation, moderation and moderated mediation

PubMed Central

Wykes, Til; Reeder, Clare; Huddy, Vyv; Taylor, Rumina; Wood, Helen; Ghirasim, Natalia; Kontis, Dimitrios; Landau, Sabine

2012-01-01

Background Cognitive remediation (CRT) affects functioning but the extent and type of cognitive improvements necessary are unknown. Aim To develop and test models of how cognitive improvement transfers to work behaviour using the data from a current service. Method Participants (N49) with a support worker and a paid or voluntary job were offered CRT in a Phase 2 single group design with three assessments: baseline, post therapy and follow-up. Working memory, cognitive flexibility, planning and work outcomes were assessed. Results Three models were tested (mediation — cognitive improvements drive functioning improvement; moderation — post treatment cognitive level affects the impact of CRT on functioning; moderated mediation — cognition drives functioning improvements only after a certain level is achieved). There was evidence of mediation (planning improvement associated with improved work quality). There was no evidence that cognitive flexibility (total Wisconsin Card Sorting Test errors) and working memory (Wechsler Adult Intelligence Scale III digit span) mediated work functioning despite significant effects. There was some evidence of moderated mediation for planning improvement if participants had poorer memory and/or made fewer WCST errors. The total CRT effect on work quality was d = 0.55, but the indirect (planning-mediated CRT effect) was d = 0.082 Conclusion Planning improvements led to better work quality but only accounted for a small proportion of the total effect on work outcome. Other specific and non-specific effects of CRT and the work programme are likely to account for some of the remaining effect. This is the first time complex models have been tested and future Phase 3 studies need to further test mediation and moderated mediation models. PMID:22503640

Fc functional antibodies in humans with severe H7N9 and seasonal influenza

PubMed Central

Vanderven, Hillary A.; Liu, Lu; Ana-Sosa-Batiz, Fernanda; Nguyen, Thi H.O.; Wan, Yanmin; Hogarth, P. Mark; Tilmanis, Danielle; Parsons, Matthew S.; Hurt, Aeron C.; Davenport, Miles P.; Kotsimbos, Tom; Cheng, Allen C.; Kedzierska, Katherine; Zhang, Xiaoyan; Xu, Jianqing; Kent, Stephen J.

2017-01-01

BACKGROUND. Both seasonal and novel avian influenza viruses can result in severe infections requiring hospitalization. Anti-influenza antibodies (Abs) with Fc-mediated effector functions, such as Ab-dependent cellular cytotoxicity (ADCC), are of growing interest in control of influenza but have not previously been studied during severe human infections. As such, the objective of this study was to examine Fc-mediated Ab functions in humans hospitalized with influenza infection. METHODS. Serum Ab response was studied in subjects hospitalized with either pandemic H7N9 avian influenza virus in China (n = 18) or circulating seasonal influenza viruses in Melbourne, Australia (n = 16). Recombinant soluble Fc receptor dimer ELISAs, natural killer (NK) cell activation assays, and Ab-dependent killing assays with influenza-infected target cells were used to assess the Fc functionality of anti-influenza hemagglutinin (HA) Abs during severe human influenza infection. RESULTS. We found that the peak generation of Fc functional HA Abs preceded that of neutralizing Abs for both severe H7N9 and seasonal influenza infections. Subjects who succumbed to complications of H7N9 infection demonstrated reduced HA-specific Fc receptor–binding Abs (in magnitude and breadth) immediately prior to death compared with those who survived. Subjects who recovered from H7N9 and severe seasonal influenza infections demonstrated increased Fc receptor–binding Abs not only against the homologous infecting strain but against HAs from different influenza A subtypes. CONCLUSION. Collectively, survivors of severe influenza infection rapidly generate a functional Ab response capable of mediating ADCC against divergent influenza viruses. Broadly binding HA Abs with Fc-mediated functions may be a useful component of protective immunity to severe influenza infection. FUNDING. The National Health and Medical Research Council ([NHMRC] grants 1023294, 1041832, and 1071916), the Australian Department of Health, and the joint University of Melbourne/Fudan University International Research and Research Training Fund provided funding for this study. PMID:28679958

Functional analysis of a viroid RNA motif mediating cell-to-cell movement in Nicotiana benthamiana.

PubMed

Jiang, Dongmei; Wang, Meng; Li, Shifang

2017-01-01

Cell-to-cell trafficking through different cellular layers is a key process for various RNAs including those of plant viruses and viroids, but the regulatory mechanisms involved are still not fully elucidated and good model systems are important. Here, we analyse the function of a simple RNA motif (termed 'loop19') in potato spindle tuber viroid (PSTVd) which is required for trafficking in Nicotiana benthamiana leaves. Northern blotting, reverse transcriptase PCR (RT-PCR) and in situ hybridization analyses demonstrated that unlike wild-type PSTVd, which was present in the nuclei in all cell types, the trafficking-defective loop19 mutants were visible only in the nuclei of upper epidermal and palisade mesophyll cells, which shows that PSTVd loop19 plays a role in mediating RNA trafficking from palisade to spongy mesophyll cells in N.benthamiana leaves. Our findings and approaches have broad implications for studying the RNA motifs mediating trafficking of RNAs across specific cellular boundaries in other biological systems.

The V0-ATPase mediates apical secretion of exosomes containing Hedgehog-related proteins in Caenorhabditis elegans

PubMed Central

Liégeois, Samuel; Benedetto, Alexandre; Garnier, Jean-Marie; Schwab, Yannick; Labouesse, Michel

2006-01-01

Polarized intracellular trafficking in epithelia is critical in development, immunity, and physiology to deliver morphogens, defensins, or ion pumps to the appropriate membrane domain. The mechanisms that control apical trafficking remain poorly defined. Using Caenorhabditis elegans, we characterize a novel apical secretion pathway involving multivesicularbodies and the release of exosomes at the apical plasma membrane. By means of two different genetic approaches, we show that the membrane-bound V0 sector of the vacuolar H+-ATPase (V-ATPase) acts in this pathway, independent of its contribution to the V-ATPase proton pump activity. Specifically, we identified mutations in the V0 “a” subunit VHA-5 that affect either the V0-specific function or the V0+V1 function of the V-ATPase. These mutations allowed us to establish that the V0 sector mediates secretion of Hedgehog-related proteins. Our data raise the possibility that the V0 sector mediates exosome and morphogen release in mammals. PMID:16785323

HIP1 functions in clathrin-mediated endocytosis through binding to clathrin and adaptor protein 2.

PubMed

Metzler, M; Legendre-Guillemin, V; Gan, L; Chopra, V; Kwok, A; McPherson, P S; Hayden, M R

2001-10-19

Polyglutamine expansion in huntingtin is the underlying mutation leading to neurodegeneration in Huntington disease. This mutation influences the interaction of huntingtin with different proteins, including huntingtin-interacting protein 1 (HIP1), in which affinity to bind to mutant huntingtin is profoundly reduced. Here we demonstrate that HIP1 colocalizes with markers of clathrin-mediated endocytosis in neuronal cells and is highly enriched on clathrin-coated vesicles (CCVs) purified from brain homogenates. HIP1 binds to the clathrin adaptor protein 2 (AP2) and the terminal domain of the clathrin heavy chain, predominantly through a small fragment encompassing amino acids 276-335. This region, which contains consensus clathrin- and AP2-binding sites, functions in conjunction with the coiled-coil domain to target HIP1 to CCVs. Expression of various HIP1 fragments leads to a potent block of clathrin-mediated endocytosis. Our findings demonstrate that HIP1 is a novel component of the endocytic machinery.

Emotion awareness and coping in children with functional abdominal pain: a controlled study.

PubMed

van der Veek, Shelley M C; Derkx, H H F; de Haan, Else; Benninga, Marc A; Boer, Frits

2012-01-01

Literature on somatization suggests that patients suffering from medically unexplained symptoms are less aware of their emotions and use maladaptive coping strategies when coping with everyday problems. In addition, coping is hypothesized to mediate between emotion awareness and medically unexplained symptoms. Scientific evidence for the relevance of this hypothesis for children with functional abdominal pain (FAP) is, however, lacking. Therefore, the purpose of the present study was to investigate this hypothesis in Dutch children with functional abdominal pain (FAP), aged 7-18 years. Between April 2007 and April 2010, a total of 114 referred children with FAP, 235 schoolchildren without abdominal pain and 407 schoolchildren with some abdominal pain (AP) of diverse etiology filled out questionnaires concerning their pain, emotion awareness and coping. MANOVA was used to investigate group differences in emotional awareness and coping. Structural equation modeling was used to investigate the mediational role of coping. The results showed that children with FAP scored significantly lower on most aspects of emotion awareness than children without AP, although these differences were small. Contrary to expectations, children with FAP were more aware of a link between emotions and bodily sensations than children without AP. As for coping, we found that children with FAP used avoidant coping more often than children without AP. Overall, children with FAP mostly did not differ in their emotional awareness and coping compared to children with some AP. Problem focused coping had a small mediating effect for two aspects of emotion awareness. We conclude that children with FAP show only small differences in emotion awareness and coping compared to children without AP, and are practically no different from children with some AP. Contrary to common belief, it can be questioned whether emotion awareness and general coping are useful targets for psychological treatments of FAP to focus on. Copyright © 2011 Elsevier Ltd. All rights reserved.

P21 and p27: roles in carcinogenesis and drug resistance.

PubMed

Abukhdeir, Abde M; Park, Ben Ho

2008-07-01

Human cancers arise from an imbalance of cell growth and cell death. Key proteins that govern this balance are those that mediate the cell cycle. Several different molecular effectors have been identified that tightly regulate specific phases of the cell cycle, including cyclins, cyclin-dependent kinases (CDKs) and CDK inhibitors. Notably, loss of expression or function of two G1-checkpoint CDK inhibitors - p21 (CDKN1A) and p27 (CDKN1B) - has been implicated in the genesis or progression of many human malignancies. Additionally, there is a growing body of evidence suggesting that functional loss of p21 or p27 can mediate a drug-resistance phenotype. However, reports in the literature have also suggested p21 and p27 can promote tumours, indicating a paradoxical effect. Here, we review historic and recent studies of these two CDK inhibitors, including their identification, function, importance to carcinogenesis and finally their roles in drug resistance.

Facile synthesis of microporous SiO2/triangular Ag composite nanostructures for photocatalysis

NASA Astrophysics Data System (ADS)

Sirohi, Sidhharth; Singh, Anandpreet; Dagar, Chakit; Saini, Gajender; Pani, Balaram; Nain, Ratyakshi

2017-11-01

In this article, we present a novel fabrication of microporous SiO2/triangular Ag nanoparticles for dye (methylene blue) adsorption and plasmon-mediated degradation. Microporous SiO2 nanoparticles with pore size <2 nm were synthesized using cetyltrimethylammonium bromide as a structure-directing agent and functionalized with APTMS ((3-aminopropyl) trimethoxysilane) to introduce amine groups. Amine-functionalized microporous silica was used for adsorption of triangular silver (Ag) nanoparticles. The synthesized microporous SiO2 nanostructures were investigated for adsorption of different dyes including methylene blue, congo red, direct green 26 and curcumin crystalline. Amine-functionalized microporous SiO2/triangular Ag nanostructures were used for plasmon-mediated photocatalysis of methylene blue. The experimental results revealed that the large surface area of microporous silica facilitated adsorption of dye. Triangular Ag nanoparticles, due to their better charge carrier generation and enhanced surface plasmon resonance, further enhanced the photocatalysis performance.

Structural Variability within Frontoparietal Networks and Individual Differences in Attentional Functions: An Approach Using the Theory of Visual Attention.

PubMed

Chechlacz, Magdalena; Gillebert, Celine R; Vangkilde, Signe A; Petersen, Anders; Humphreys, Glyn W

2015-07-29

Visuospatial attention allows us to select and act upon a subset of behaviorally relevant visual stimuli while ignoring distraction. Bundesen's theory of visual attention (TVA) (Bundesen, 1990) offers a quantitative analysis of the different facets of attention within a unitary model and provides a powerful analytic framework for understanding individual differences in attentional functions. Visuospatial attention is contingent upon large networks, distributed across both hemispheres, consisting of several cortical areas interconnected by long-association frontoparietal pathways, including three branches of the superior longitudinal fasciculus (SLF I-III) and the inferior fronto-occipital fasciculus (IFOF). Here we examine whether structural variability within human frontoparietal networks mediates differences in attention abilities as assessed by the TVA. Structural measures were based on spherical deconvolution and tractography-derived indices of tract volume and hindrance-modulated orientational anisotropy (HMOA). Individual differences in visual short-term memory (VSTM) were linked to variability in the microstructure (HMOA) of SLF II, SLF III, and IFOF within the right hemisphere. Moreover, VSTM and speed of information processing were linked to hemispheric lateralization within the IFOF. Differences in spatial bias were mediated by both variability in microstructure and volume of the right SLF II. Our data indicate that the microstructural and macrostrucutral organization of white matter pathways differentially contributes to both the anatomical lateralization of frontoparietal attentional networks and to individual differences in attentional functions. We conclude that individual differences in VSTM capacity, processing speed, and spatial bias, as assessed by TVA, link to variability in structural organization within frontoparietal pathways. Copyright © 2015 Chechlacz et al.

Transfer function analysis of the autonomic response to respiratory activity during random interval breathing

NASA Technical Reports Server (NTRS)

Chen, M. H.; Berger, R. D.; Saul, J. P.; Stevenson, K.; Cohen, R. J.

1987-01-01

We report a new method for the noninvasive characterization of the frequency response of the autonomic nervous system (ANS) in mediating fluctuations in heart rate (HR). The approach entails computation of the transfer function magnitude and phase between instantaneous lung volume and HR. Broad band fluctuations in lung volume were initiated when subjects breathed on cue to a sequence of beeps spaced randomly in time. We studied 10 subjects in both supine and standing positions. The transfer function, averaged among all the subjects, showed systematic differences between the two postures, reflecting the differing frequency responses of the sympathetic and parasympathetic divisions of the ANS.

Regulation of metabolism by the Mediator complex.

PubMed

Youn, Dou Yeon; Xiaoli, Alus M; Pessin, Jeffrey E; Yang, Fajun

2016-01-01

The Mediator complex was originally discovered in yeast, but it is conserved in all eukaryotes. Its best-known function is to regulate RNA polymerase II-dependent gene transcription. Although the mechanisms by which the Mediator complex regulates transcription are often complicated by the context-dependent regulation, this transcription cofactor complex plays a pivotal role in numerous biological pathways. Biochemical, molecular, and physiological studies using cancer cell lines or model organisms have established the current paradigm of the Mediator functions. However, the physiological roles of the mammalian Mediator complex remain poorly defined, but have attracted a great interest in recent years. In this short review, we will summarize some of the reported functions of selective Mediator subunits in the regulation of metabolism. These intriguing findings suggest that the Mediator complex may be an important player in nutrient sensing and energy balance in mammals.

Effect of long-term fertilization on humic redox mediators in multiple microbial redox reactions.

PubMed

Guo, Peng; Zhang, Chunfang; Wang, Yi; Yu, Xinwei; Zhang, Zhichao; Zhang, Dongdong

2018-03-01

This study investigated the effects of different long-term fertilizations on humic substances (HSs), humic acids (HAs) and humins, functioning as redox mediators for various microbial redox biotransformations, including 2,2',4,4',5,5'- hexachlorobiphenyl (PCB 153 ) dechlorination, dissimilatory iron reduction, and nitrate reduction, and their electron-mediating natures. The redox activity of HSs for various microbial redox metabolisms was substantially enhanced by long-term application of organic fertilizer (pig manure). As a redox mediator, only humin extracted from soils with organic fertilizer amendment (OF-HM) maintained microbial PCB 153 dechlorination activity (1.03 μM PCB 153 removal), and corresponding HA (OF-HA) most effectively enhanced iron reduction and nitrate reduction by Shewanella putrefaciens. Electrochemical analysis confirmed the enhancement of their electron transfer capacity and redox properties. Fourier transform infrared analysis showed that C=C and C=O bonds, and carboxylic or phenolic groups in HSs might be the redox functional groups affected by fertilization. This research enhances our understanding of the influence of anthropogenic fertility on the biogeochemical cycling of elements and in situ remediation ability in agroecosystems through microorganisms' metabolisms. Copyright © 2017 Elsevier Ltd. All rights reserved.

Mitochondrial fragmentation in excitotoxicity requires ROCK activation.

PubMed

Martorell-Riera, Alejandro; Segarra-Mondejar, Marc; Reina, Manuel; Martínez-Estrada, Ofelia M; Soriano, Francesc X

2015-01-01

Mitochondria morphology constantly changes through fission and fusion processes that regulate mitochondrial function, and it therefore plays a prominent role in cellular homeostasis. Cell death progression is associated with mitochondrial fission. Fission is mediated by the mainly cytoplasmic Drp1, which is activated by different post-translational modifications and recruited to mitochondria to perform its function. Our research and other studies have shown that in the early moments of excitotoxic insult Drp1 must be nitrosylated to mediate mitochondrial fragmentation in neurons. Nonetheless, mitochondrial fission is a multistep process in which filamentous actin assembly/disassembly and myosin-mediated mitochondrial constriction play prominent roles. Here we establish that in addition to nitric oxide production, excitotoxicity-induced mitochondrial fragmentation also requires activation of the actomyosin regulator ROCK. Although ROCK1 has been shown to phosphorylate and activate Drp1, experiments using phosphor-mutant forms of Drp1 in primary cortical neurons indicate that in excitotoxic conditions, ROCK does not act directly on Drp1 to mediate fission, but may act on the actomyosin complex. Thus, these data indicate that a wider range of signaling pathways than those that target Drp1 are amenable to be inhibited to prevent mitochondrial fragmentation as therapeutic option.

Attachment insecurities and women's sexual function and satisfaction: the mediating roles of sexual self-esteem, sexual anxiety, and sexual assertiveness.

PubMed

Brassard, Audrey; Dupuy, Emmanuelle; Bergeron, Sophie; Shaver, Phillip R

2015-01-01

We examined the potential role of three mediators--sexual self-esteem, sexual anxiety, and sexual assertiveness--of the association between romantic attachment insecurities (anxiety and avoidance) and two aspects of women's sexual functioning: sexual function and sexual satisfaction. A sample of 556 women aged 18 to 30 agreed to complete an online series of validated questionnaires assessing attachment insecurities and several aspects of sexual functioning. Lower sexual self-esteem and higher sexual anxiety mediated the associations between attachment anxiety and lower sexual function and satisfaction. Lower sexual self-esteem and higher sexual anxiety also partially mediated the links between attachment-related avoidance and the two sexual functioning variables. Sexual assertiveness, however, did not mediate these associations. A significant interaction between attachment anxiety and avoidance was also found to predict sexual satisfaction, with women high in avoidance and low in anxiety being the least satisfied. Results are discussed in terms of theoretical and clinical implications.

Variability at the FCGR locus: characterization in Black South Africans and evidence for ethnic variation in and out of Africa.

PubMed

Lassaunière, R; Tiemessen, C T

2016-03-01

This study set out to comprehensively investigate all known functional FcγR variants in South African Black and Caucasian individuals. Population diversity was further assessed using data from the 1000 Genomes Project. In our cohort, Black South Africans neither possessed the haplotypes previously associated with increased surface densities of FcγRIIb and FcγRIIIa nor the FCGR2C haplotype recently associated with increased vaccine efficacy in the RV144 HIV-1 vaccine trial (despite 48.7% bearing the c.134-96T tag allele). Moreover, Africans (South Africans, Luhya Kenyans and Yoruba Nigerians) lack the FCGR2C c.798+1G splice-site allele required for the expression of functional FcγRIIc. Although the presence or absence of surface FcγRIIc did not affect natural killer cell-mediated antibody-dependent cellular cytotoxicity capability, this may be significant for other FcγRIIc-mediated functions. Overall, allele distribution and linkage disequilibrium in Africans and Caucasians differed in a manner that would suggest a differentially maintained balance of FcγR-mediated cell activation in these populations. Finally, significant variation observed among different African populations precludes the use of any one African population as a proxy for FcγR diversity in Africans. In conclusion, the findings of this study highlight further ethnic variation at the FCGR gene locus, in particular for FCGR2C, a gene with increasingly recognized clinical significance.

The effect of hepatocyte growth factor on secretory functions in human eosinophils.

PubMed

Yamauchi, Yumiko; Ueki, Shigeharu; Konno, Yasunori; Ito, Wataru; Takeda, Masahide; Nakamura, Yuka; Nishikawa, Junko; Moritoki, Yuki; Omokawa, Ayumi; Saga, Tomoo; Hirokawa, Makoto

2016-12-01

Hepatocyte growth factor (HGF), originally identified as a potent mitogen for mature hepatocytes, is now recognized as a humoral mediator in inflammatory and immune responses. Previous studies indicated that HGF negatively regulated allergic airway inflammation. In view of eosinophils playing a role in the pathogenesis of asthma, especially in airway remodeling as a rich source of pro-fibrogenic mediators, the effects of HGF on the different types of eosinophil secretory functions were examined in this study. We found that HGF significantly inhibited IL-5-induced secretion of TGF-β and VEGF from human eosinophils. The inhibitory effect is not associated with TGF-β transcription; rather, it is associated with ultrastructural granule emptying and loss of intracellular TGF-β contents, indicating HGF inhibits the process of piecemeal degranulation. The effect of HGF on extracellular trap cell death (ETosis) that mediates cytolytic degranulation was also investigated; however, immobilized IgG- or phorbol myristate acetate-induced ETosis was only minimally attenuated by HGF. These results reveal the effect of HGF on the distinct pathways of eosinophil secretory functions and also provide novel insights into the role of HGF in the pathogenesis of allergic inflammation. Copyright © 2016 Elsevier Ltd. All rights reserved.

Hierarchy of protein tyrosine kinases in interleukin-2 (IL-2) signaling: activation of syk depends on Jak3; however, neither Syk nor Lck is required for IL-2-mediated STAT activation.

PubMed

Zhou, Y J; Magnuson, K S; Cheng, T P; Gadina, M; Frucht, D M; Galon, J; Candotti, F; Geahlen, R L; Changelian, P S; O'Shea, J J

2000-06-01

Interleukin-2 (IL-2) activates several different families of tyrosine kinases, but precisely how these kinases interact is not completely understood. We therefore investigated the functional relationships among Jak3, Lck, and Syk in IL-2 signaling. We first observed that in the absence of Jak3, both Lck and Syk had the capacity to phosphorylate Stat3 and Stat5a. However, neither supported IL-2-induced STAT activation, nor did dominant negative alleles of these kinases inhibit. Moreover, pharmacological abrogation of Lck activity did not inhibit IL-2-mediated phosphorylation of Jak3 and Stat5a. Importantly, ligand-dependent Syk activation was dependent on the presence of catalytically active Jak3, whereas Lck activation was not. Interestingly, Syk functioned as a direct substrate of Jak1 but not Jak3. Additionally, Jak3 phosphorylated Jak1, whereas the reverse was not the case. Taken together, our data support a model in which Lck functions in parallel with Jak3, while Syk functions as a downstream element of Jaks in IL-2 signaling. Jak3 may regulate Syk catalytic activity indirectly via Jak1. However, IL-2-mediated Jak3/Stat activation is not dependent on Lck or Syk. While the essential roles of Jak1 and Jak3 in signaling by gammac-utilizing cytokines are clear, it will be important to dissect the exact contributions of Lck and Syk in mediating the effects of IL-2 and related cytokines.

Cultural Psychology of Differences and EMS; a New Theoretical Framework for Understanding and Reconstructing Culture.

PubMed

Yamamoto, Toshiya

2017-09-01

In this paper I introduce the outlines of our new type of theoretical framework named 'Cultural psychology of Differences' for understanding cultural others and dialogically reconstructing interactions among cultural others. In order to understand cultural others, it is necessary for us to reconstruct a new concept which enables us to analyze dynamic generation processes of culture. We propose the concept of Expanded Mediational Structure, EMS, as an elementary unit for understanding human social interactions. EMS is composed of subjects who interacts each other using objects of some kind as mediators, and a normative mediator, NM, which mediates their interactions. It is necessary to generate, share and adjust a NM to keep social interactions stable, and culture will appear when interaction malfunction is attributed to a gaps of NMs. The concept of EMS helps us to understand how culture is functionally substantialized in the plane of collective (or communal) intersubjectivity and how cultural conflicts develop and intensify. Focusing on the generation process of culture through interactions provides us with another option to understand cultural others through dialogical interactions with them.

An Overview of Electron Acceptors in Microbial Fuel Cells

PubMed Central

Ucar, Deniz; Zhang, Yifeng; Angelidaki, Irini

2017-01-01

Microbial fuel cells (MFC) have recently received increasing attention due to their promising potential in sustainable wastewater treatment and contaminant removal. In general, contaminants can be removed either as an electron donor via microbial catalyzed oxidization at the anode or removed at the cathode as electron acceptors through reduction. Some contaminants can also function as electron mediators at the anode or cathode. While previous studies have done a thorough assessment of electron donors, cathodic electron acceptors and mediators have not been as well described. Oxygen is widely used as an electron acceptor due to its high oxidation potential and ready availability. Recent studies, however, have begun to assess the use of different electron acceptors because of the (1) diversity of redox potential, (2) needs of alternative and more efficient cathode reaction, and (3) expanding of MFC based technologies in different areas. The aim of this review was to evaluate the performance and applicability of various electron acceptors and mediators used in MFCs. This review also evaluated the corresponding performance, advantages and disadvantages, and future potential applications of select electron acceptors (e.g., nitrate, iron, copper, perchlorate) and mediators. PMID:28469607

Strategies to regulate transcription factor-mediated gene positioning and interchromosomal clustering at the nuclear periphery.

PubMed

Randise-Hinchliff, Carlo; Coukos, Robert; Sood, Varun; Sumner, Michael Chas; Zdraljevic, Stefan; Meldi Sholl, Lauren; Garvey Brickner, Donna; Ahmed, Sara; Watchmaker, Lauren; Brickner, Jason H

2016-03-14

In budding yeast, targeting of active genes to the nuclear pore complex (NPC) and interchromosomal clustering is mediated by transcription factor (TF) binding sites in the gene promoters. For example, the binding sites for the TFs Put3, Ste12, and Gcn4 are necessary and sufficient to promote positioning at the nuclear periphery and interchromosomal clustering. However, in all three cases, gene positioning and interchromosomal clustering are regulated. Under uninducing conditions, local recruitment of the Rpd3(L) histone deacetylase by transcriptional repressors blocks Put3 DNA binding. This is a general function of yeast repressors: 16 of 21 repressors blocked Put3-mediated subnuclear positioning; 11 of these required Rpd3. In contrast, Ste12-mediated gene positioning is regulated independently of DNA binding by mitogen-activated protein kinase phosphorylation of the Dig2 inhibitor, and Gcn4-dependent targeting is up-regulated by increasing Gcn4 protein levels. These different regulatory strategies provide either qualitative switch-like control or quantitative control of gene positioning over different time scales. © 2016 Randise-Hinchliff et al.

Household Wealth and Neurocognitive Development Disparities among School-aged Children in Nepal

PubMed Central

Patel, Shivani A; Murray-Kolb, Laura E; LeClerq, Steven C; Khatry, Subarna K; Tielsch, James M; Katz, Joanne; Christian, Parul

2013-01-01

Background Wealth disparities in child developmental outcomes are well documented in developed countries. We sought to (1) describe the extent of wealth-based neurocognitive development disparities and (2) examine potential mediating factors of disparities among a population-based cohort of children in rural Nepal. Methods We investigated household wealth-based differences in intellectual, executive and motor function of n = 1692 children aged between 7 and 9 years in Nepal. Using linear mixed models, wealth-based differences were estimated before and after controlling for child and household demographic characteristics. We further examined wealth-based differences adjusted for three sets of mediators: child nutritional status, home environment, and schooling pattern. Results We observed a positive gradient in child neurocognitive performance by household wealth. After adjusting for child and household control factors, disparities between children in the highest and lowest wealth quintiles persisted in intellectual and motor function, but not executive function. No statistically significant wealth-based differentials in outcomes remained after accounting for nutritional status, home environment, and schooling patterns. The largest differences in neurocognitive development were associated with schooling pattern. Conclusions Household wealth patterns child neurocognitive development in rural Nepal, likely through its influence on nutritional status, the home environment, and schooling. In the current context, improving early and regular schooling in this setting is critical to addressing wealth-based disparities in outcomes. PMID:24118003

Household wealth and neurocognitive development disparities among school-aged children in Nepal.

PubMed

Patel, Shivani A; Murray-Kolb, Laura E; LeClerq, Steven C; Khatry, Subarna K; Tielsch, James M; Katz, Joanne; Christian, Parul

2013-11-01

Wealth disparities in child developmental outcomes are well documented in developed countries. We sought to (1) describe the extent of wealth-based neurocognitive development disparities and (2) examine potential mediating factors of disparities among a population-based cohort of children in rural Nepal. We investigated household wealth-based differences in intellectual, executive and motor function of n = 1692 children aged between 7 and 9 years in Nepal. Using linear mixed models, wealth-based differences were estimated before and after controlling for child and household demographic characteristics. We further examined wealth-based differences adjusted for three sets of mediators: child nutritional status, home environment, and schooling pattern. We observed a positive gradient in child neurocognitive performance by household wealth. After adjusting for child and household control factors, disparities between children in the highest and lowest wealth quintiles persisted in intellectual and motor function, but not executive function. No statistically significant wealth-based differentials in outcomes remained after accounting for nutritional status, home environment, and schooling patterns. The largest differences in neurocognitive development were associated with schooling pattern. Household wealth patterns child neurocognitive development in rural Nepal, likely through its influence on nutritional status, the home environment, and schooling. In the current context, improving early and regular schooling in this setting is critical to addressing wealth-based disparities in outcomes. © 2013 The Authors. Paediatric and Perinatal Epidemiology published by John Wiley & Sons Ltd.

Identification of key residues for protein conformational transition using elastic network model.

PubMed

Su, Ji Guo; Xu, Xian Jin; Li, Chun Hua; Chen, Wei Zu; Wang, Cun Xin

2011-11-07

Proteins usually undergo conformational transitions between structurally disparate states to fulfill their functions. The large-scale allosteric conformational transitions are believed to involve some key residues that mediate the conformational movements between different regions of the protein. In the present work, a thermodynamic method based on the elastic network model is proposed to predict the key residues involved in protein conformational transitions. In our method, the key functional sites are identified as the residues whose perturbations largely influence the free energy difference between the protein states before and after transition. Two proteins, nucleotide binding domain of the heat shock protein 70 and human/rat DNA polymerase β, are used as case studies to identify the critical residues responsible for their open-closed conformational transitions. The results show that the functionally important residues mainly locate at the following regions for these two proteins: (1) the bridging point at the interface between the subdomains that control the opening and closure of the binding cleft; (2) the hinge region between different subdomains, which mediates the cooperative motions between the corresponding subdomains; and (3) the substrate binding sites. The similarity in the positions of the key residues for these two proteins may indicate a common mechanism in their conformational transitions.

Neurological and psychiatric disorders in thyroid dysfunctions. The role of nuclear medicine: SPECT and PET imaging.

PubMed

Lass, P; Slawek, J; Derejko, M; Rubello, D

2008-06-01

Thyroid dysfunctions may be accompanied by numerous neurological and psychiatric disorders. The most known is cognitive impairment and depression in hypothyroid patients, as well as an increased risk of cerebrovascular accidents. A separate, although a rare entity, is Hashimoto's encephalopathy. In hyperthyroidism there is an increased incidence of psychiatric disorders, including apathetic hyperthyroidism and hyperthyroid dementia. Functional imaging of cerebral blood flow and metabolism helped establish both global and/or regional decrease of both cerebral blood flow and metabolism in hypothyroidism, particularly in regions mediating attention, motor speed and visuospatial processing. Hypothyroid dementia may be mediated by neurocircuitry different from that in major depression. Less is known on flow/metabolism changes in hyperthyroidism. Global blood flow may be slightly increased, with regional deficits of blood flow, particular in hyperthyroid dementia. As presented above radionuclide functional imaging showed some metabolic patterns in thyroid dysfunctions, but still many issues remain unresolved. In particular little is known about the underlying pathology of cognitive impairment and depression in hypothyroidism, which may differ from ones in euthyroid patients. Also little is known about the reversibility of changes in cerebral blood flow following thyroid replacement therapy. In hyperthyroid patients functional imaging might contribute to elucidate the background of apathetic hyperthyroidism and potential different background of psychiatric complications.

The functions of gender role traditionality, ambivalent sexism, injury, and frequency of assault on domestic violence perception: a study between Japanese and American college students.

PubMed

Yamawaki, Niwako; Ostenson, Joseph; Brown, C Ryan

2009-09-01

This study examined the mediating influence of gender-role traditionality (GRT), ambivalent sexism, and victim injury and frequency of assault on domestic violence (DV) perception differences between Japanese and American college students. As predicted, Japanese tended to minimize, blame, and excuse DV more than did Americans, and these national differences were mediated by GRT. Participants viewed the DV incident more seriously when the victim presented injury or when the incident had occurred frequently. Those high in benevolent and hostile sexism were more likely to minimize DV, whereas those high only in benevolent sexism were more likely to blame the victim.

Knee extension range of motion and self-report physical function in total knee arthroplasty: mediating effects of knee extensor strength

PubMed Central

2013-01-01

Background Knee extensor strength and knee extension range of motion (ROM) are important predictors of physical function in patients with a total knee arthroplasty (TKA). However, the relationship between the two knee measures remains unclear. The purpose of this study was to examine whether changes in knee extensor strength mediate the association between changes in knee extension ROM and self-report physical function. Methods Data from 441 patients with a TKA were collected preoperatively and 6 months postoperatively. Self-report measure of physical function was assessed by the Short Form 36 (SF-36) questionnaire. Knee extensor strength was measured by handheld dynamometry and knee extension ROM by goniometry. A bootstrapped cross product of coefficients approach was used to evaluate mediation effects. Results Mediation analyses, adjusted for clinicodemographic measures, revealed that the association between changes in knee extension ROM and SF-36 physical function was mediated by changes in knee extensor strength. Conclusions In patients with TKA, knee extensor strength mediated the influence of knee extension ROM on physical function. These results suggest that interventions to improve the range of knee extension may be useful in improving knee extensor performance. PMID:23332039

Neural networks mediating sentence reading in the deaf

PubMed Central

Hirshorn, Elizabeth A.; Dye, Matthew W. G.; Hauser, Peter C.; Supalla, Ted R.; Bavelier, Daphne

2014-01-01

The present work addresses the neural bases of sentence reading in deaf populations. To better understand the relative role of deafness and spoken language knowledge in shaping the neural networks that mediate sentence reading, three populations with different degrees of English knowledge and depth of hearing loss were included—deaf signers, oral deaf and hearing individuals. The three groups were matched for reading comprehension and scanned while reading sentences. A similar neural network of left perisylvian areas was observed, supporting the view of a shared network of areas for reading despite differences in hearing and English knowledge. However, differences were observed, in particular in the auditory cortex, with deaf signers and oral deaf showing greatest bilateral superior temporal gyrus (STG) recruitment as compared to hearing individuals. Importantly, within deaf individuals, the same STG area in the left hemisphere showed greater recruitment as hearing loss increased. To further understand the functional role of such auditory cortex re-organization after deafness, connectivity analyses were performed from the STG regions identified above. Connectivity from the left STG toward areas typically associated with semantic processing (BA45 and thalami) was greater in deaf signers and in oral deaf as compared to hearing. In contrast, connectivity from left STG toward areas identified with speech-based processing was greater in hearing and in oral deaf as compared to deaf signers. These results support the growing literature indicating recruitment of auditory areas after congenital deafness for visually-mediated language functions, and establish that both auditory deprivation and language experience shape its functional reorganization. Implications for differential reliance on semantic vs. phonological pathways during reading in the three groups is discussed. PMID:24959127

29 CFR 1425.3 - Functions of the Service under title VII of the Civil Service Reform Act.

Code of Federal Regulations, 2010 CFR

2010-07-01

... MEDIATION AND CONCILIATION SERVICE MEDIATION ASSISTANCE IN THE FEDERAL SERVICE § 1425.3 Functions of the... Service through a specific request for mediation from one or both of the parties, through notification... dispute and if, in its opinion, the need for mediation exists, the Service will use its best efforts to...

Social support mediates the relationships between extraversion, neuroticism, and cognitive function in older adults.

PubMed

McHugh Power, J E; Lawlor, B A; Kee, F

2017-06-01

We supplement existing findings on a link between social support and cognitive function in later life by considering the role of personality as an antecedent to both, and of social support as a mediator of the link between personality and cognitive function. An observational cohort study. We evaluated social support using the Lubben Social Network Scale, across 624 adults aged over 60 years, and investigated this measure as a mediator of the relationships between extraversion and neuroticism at baseline 2007-2009, and cognitive function at follow-up, 2 years later. A half-longitudinal mediation design, within a structural equation modelling framework, was used. There was a direct effect of extraversion, such that lower levels were related to higher scores of cognitive function. There was no significant direct effect of neuroticism on cognitive function at follow-up. Social support partially mediated the paths between both extraversion and neuroticism and cognitive function at follow-up. Decomposing the mediation effects by using social support subscales (measuring support from friends, relatives and neighbours) showed meaningful indirect effects for both predictors. Results suggest that social support may offer a target for interventions for cognitively at-risk older adults and add to the existing empirical evidence describing the link between personality and cognitive function. Crown Copyright © 2017. Published by Elsevier Ltd. All rights reserved.

Psychotic Symptoms and Attitudes toward Medication Mediate the Effect of Insight on Personal-Social Functions in Patients with Schizophrenia: One-Year Randomized Controlled Trial and Follow-Up.

PubMed

Zheng, Yingjun; Ning, Yuping; She, Shenglin; Deng, Yongjie; Chen, Yuwei; Yi, Wenying; Lu, Xiaodan; Chen, Xinrui; Li, Juanhua; Li, Ruikeng; Zhang, Jie; Xiao, Di; Wu, Haibo; Wu, Chao

2018-02-14

This study aimed to investigate the mediating pathway of 3 factors (psychotic symptoms, attitude toward medication, and cognitive processing speed) on the effect of insight on personal-social functioning in patients with schizophrenia. Chinese inpatients with schizophrenia (n = 168; mean age 18 ± 50 years) diagnosed according to the DSM-IV were randomly assigned to treatment with antipsychotic medication alone or combined treatment. Positive and Negative Syndrome Scale (PANSS), Drug Attitude Inventory (DAI), Assessment of Insight (SAI), and Social-Personal Performance Scale (PSPS) scores were evaluated at baseline and at 3, 6, and 12 months. Cognitive function was assessed at baseline. Multiple mediation analyses were conducted with baseline data, end point data, and changes-in-scale scores between baseline and the end point, respectively. At baseline and at 12 months, only psychotic symptoms mediated the effect of insight on personal-social functioning. For changes-in-scale scores over the 12-month follow-up, in patients receiving treatment with medication alone, the effect of improved insight on improved personal-social function was mediated by psychotic symptoms only; in patients receiving a combined treatment, the effect of improved insight on improved personal-social functioning was mediated by both psychotic symptoms and attitudes toward medication, independently. The link between insight and personal-social functions is mainly mediated by psychotic symptoms. Psychosocial intervention improves the predicting effect of insight on personal-social function by improving both the attitude toward medication and psychotic symptoms independently. © 2018 S. Karger AG, Basel.

Expression profiling and functional analysis of Toll-like receptors in primary healthy human nasal epithelial cells shows no correlation and a refractory LPS response.

PubMed

van Tongeren, J; Röschmann, K I L; Reinartz, S M; Luiten, S; Fokkens, W J; de Jong, E C; van Drunen, C M

2015-01-01

Innate immune recognition via Toll-like receptors (TLRs) on barrier cells like epithelial cells has been shown to influence the regulation of local immune responses. Here we determine expression level variations and functionality of TLRs in nasal epithelial cells from healthy donors. Expression levels of the different TLRs on primary nasal epithelial cells from healthy donors derived from inferior turbinates was determined by RT-PCR. Functionality of the TLRs was determined by stimulation with the respective ligand and evaluation of released mediators by Luminex ELISA. Primary nasal epithelial cells express different levels of TLR1-6 and TLR9. We were unable to detect mRNA of TLR7, TLR8 and TLR10. Stimulation with Poly(I:C) resulted in a significant increased secretion of IL-4, IL-6, RANTES, IP-10, MIP-1β, VEGF, FGF, IL-1RA, IL-2R and G-CSF. Stimulation with PGN only resulted in significant increased production of IL-6, VEGF and IL-1RA. Although the expression of TLR4 and co-stimulatory molecules could be confirmed, primary nasal epithelial cells appeared to be unresponsive to stimulation with LPS. Furthermore, we observed huge individual differences in TLR agonist-induced mediator release, which did not correlate with the respective expression of TLRs. Our data suggest that nasal epithelium seems to have developed a delicate system of discrimination and recognition of microbial patterns. Hypo-responsiveness to LPS could provide a mechanism to dampen the inflammatory response in the nasal mucosa in order to avoid a chronic inflammatory response. Individual, differential expression of TLRs on epithelial cells and functionality in terms of released mediators might be a crucial factor in explaining why some people develop allergies to common inhaled antigens, and others do not.

Do parent protective responses mediate the relation between parent distress and child functional disability among children with chronic pain?

PubMed

Sieberg, Christine B; Williams, Sara; Simons, Laura E

2011-10-01

To examine whether protective parent responses mediate the relation between parent distress and child functioning. At a pain clinic evaluation, 157 families participated. Parents completed measures of global distress (BSI-18), distress in the context of their child's pain (BAP-PIQ), and protective responses to their child's pain. Children completed measures of functional disability and pain. BAP-PIQ subscales were significantly associated with child functional disability, whereas BSI subscales were unrelated. Protective parent responses partially mediated the relation between parent distress and child functional disability for depression, anxiety, and catastrophizing. However, parent protective behavior fully mediated the relationship between parent helplessness and child functional disability, indicating that feelings of parent helplessness did not uniquely contribute to child functional disability. Discussion Results suggest that when treating youth with chronic pain, parental distress in the context of children's pain needs to be addressed.

The role of MAPK signal transduction pathways in the response to oxidative stress in the fungal pathogen Candida albicans: implications in virulence.

PubMed

de Dios, Carmen Herrero; Román, Elvira; Monge, Rebeca Alonso; Pla, Jesús

2010-12-01

In recent years, Mitogen-Activated Protein Kinase (MAPK) pathways have emerged as major regulators of cellular physiology. In the fungal pathogen Candida albicans, three different MAPK pathways have been characterized in the last years. The HOG pathway is mainly a stress response pathway that is activated in response to osmotic and oxidative stress and also participates regulating other pathways. The SVG pathway (or mediated by the Cek1 MAPK) is involved in cell wall formation under vegetative and filamentous growth, while the Mkc1-mediated pathway is involved in cell wall integrity. Oxidative stress is one of the types of stress that every fungal cell has to face during colonization of the host, where the cell encounters both hypoxia niches (i.e. gut) and high concentrations of reactive oxygen species (upon challenge with immune cells). Two pathways have been shown to be activated in response to oxidative stress: the HOG pathway and the MKC1-mediated pathway while the third, the Cek1 pathway is deactivated. The timing, kinetics, stimuli and functional responses generated upon oxidative stress differ among them; however, they have essential functional consequences that severely influence pathogenesis. MAPK pathways are, therefore, valuable targets to be explored in antifungal research.

Socioeconomic position and cognitive function in the Seychelles: a life course analysis.

PubMed

Kobrosly, Roni W; van Wijngaarden, Edwin; Galea, Sandro; Cory-Slechta, Deborah A; Love, Tanzy; Hong, Caroline; Shamlaye, Conrad F; Davidson, Philip W

2011-01-01

Poorer socioeconomic conditions early in life have been linked with memory, attention and learning deficits in adulthood, as well as with specific areas of educational achievement. It remains unclear, however, whether these distal associations are mediated by more current socioeconomic factors. In this study, we sought to confirm the relation between early-life socioeconomic position (SEP) and adult cognitive function, and to examine potential mediation by contemporaneous SEP. Data from 463 young adults from the Main Cohort of the Seychelles Child Development Study were analyzed using subtests of the Cambridge Neurological Test Automated Battery and the Woodcock Johnson Test of Scholastic Achievement in relation to maternal Hollingshead Social Status Index scores at study enrollment (infancy), follow-up at 107 months, and follow-up at 17 years. Findings include evidence of a link between infant-period SEP and 17-year memory, which was not mediated by childhood and 17-year SEP. Verbal and mathematical achievement at 17 years was associated with SEP at all points in the life course. SEP at different points during the young-adult life course may affect different cognitive domains later in life, which may provide targets for societal investment in ensuring adequate family resources throughout childhood and adolescence. Copyright © 2011 S. Karger AG, Basel.

Socioeconomic Position and Cognitive Function in the Seychelles: A Life Course Analysis

PubMed Central

Kobrosly, Roni W.; van Wijngaarden, Edwin; Galea, Sandro; Cory-Slechta, Deborah A.; Love, Tanzy; Hong, Caroline; Shamlaye, Conrad F.; Davidson, Philip W.

2011-01-01

Objective Poorer socioeconomic conditions early in life have been linked with memory, attention and learning deficits in adulthood, as well as with specific areas of educational achievement. It remains unclear, however, whether these distal associations are mediated by more current socioeconomic factors. In this study, we sought to confirm the relation between early-life socioeconomic position (SEP) and adult cognitive function, and to examine potential mediation by contemporaneous SEP. Methods Data from 463 young adults from the Main Cohort of the Seychelles Child Development Study were analyzed using subtests of the Cambridge Neurological Test Automated Battery and the Woodcock Johnson Test of Scholastic Achievement in relation to maternal Hollingshead Social Status Index scores at study enrollment (infancy), follow-up at 107 months, and follow-up at 17 years. Results Findings include evidence of a link between infant-period SEP and 17-year memory, which was not mediated by childhood and 17-year SEP. Verbal and mathematical achievement at 17 years was associated with SEP at all points in the life course. Conclusions SEP at different points during the young-adult life course may affect different cognitive domains later in life, which may provide targets for societal investment in ensuring adequate family resources throughout childhood and adolescence. PMID:21508650

Uncoupling of microbial community structure and function in decomposing litter across beech forest ecosystems in Central Europe.

PubMed

Purahong, Witoon; Schloter, Michael; Pecyna, Marek J; Kapturska, Danuta; Däumlich, Veronika; Mital, Sanchit; Buscot, François; Hofrichter, Martin; Gutknecht, Jessica L M; Krüger, Dirk

2014-11-12

The widespread paradigm in ecology that community structure determines function has recently been challenged by the high complexity of microbial communities. Here, we investigate the patterns of and connections between microbial community structure and microbially-mediated ecological function across different forest management practices and temporal changes in leaf litter across beech forest ecosystems in Central Europe. Our results clearly indicate distinct pattern of microbial community structure in response to forest management and time. However, those patterns were not reflected when potential enzymatic activities of microbes were measured. We postulate that in our forest ecosystems, a disconnect between microbial community structure and function may be present due to differences between the drivers of microbial growth and those of microbial function.

THE INTERACTION BETWEEN L1-TYPE PROTEINS AND ANKYRINS - A MASTER SWITCH FOR L1-TYPE CAM FUNCTION #

PubMed Central

HORTSCH, MICHAEL; NAGARAJ, KAKANAHALLI; GODENSCHWEGE, TANJA A.

2008-01-01

L1-type cell adhesion molecules (CAMs) are important mediators of neural differentiation, including axonal outgrowth and pathfinding and also of synapse formation and maintenance. In addition, their interactions with cytoskeletal components are highly conserved and regulated. How these different aspects of CAM functionality relate to each other is not well understood. Based on results from our and other laboratories we propose that Ankyrin-binding to L1-type CAMs provides a master switch. The interaction with Ankyrins directs L1-type adhesive proteins into different functional contexts, either Ankyrin-independent functions, such as neurite outgrowth and axonal pathfinding or into Ankyrin-dependent functions, such as L1’s role at axon initial segments (AIS), paranodal regions, synapses and in dendrites. PMID:18839070

Mediators in the Randomized Trial of Child- and Family-Focused Cognitive-Behavioral Therapy for Pediatric Bipolar Disorder

PubMed Central

MacPherson, Heather A.; Weinstein, Sally M.; Henry, David B.; West, Amy E.

2016-01-01

Mediation analyses can identify mechanisms of change in Cognitive-Behavioral Therapy (CBT). However, few studies have analyzed mediators of CBT for youth internalizing disorders; only one trial evaluated treatment mechanisms for youth with mixed mood diagnoses. This study evaluated mediators in the randomized trial of Child- and Family-Focused CBT (CFF-CBT) versus Treatment As Usual (TAU) for pediatric bipolar disorder (PBD), adjunctive to pharmacotherapy. Sixty-nine children ages 7-13 with PBD were randomly assigned to CFF-CBT or TAU. Primary outcomes (child mood, functioning) and candidate mediators (family functioning, parent/child coping) were assessed at baseline and 4-, 8-, 12- (post-treatment), and 39-weeks (follow-up). Compared with TAU, children receiving CFF-CBT exhibited greater improvement in mania, depression, and global functioning. Several parent and family factors significantly improved in response to CFF-CBT versus TAU, and were associated with the CFF-CBT treatment effect. Specifically, parenting skills and coping, family flexibility, and family positive reframing showed promise as mediators of child mood symptoms and global functioning. Main or mediating effects for youth coping were not significant. CFF-CBT may impact children’s mood and functioning by improving parenting skills and coping, family flexibility, and family positive reframing. Findings highlight the importance of parent coping and family functioning in the treatment of PBD. PMID:27567973

Cerebral Lateralization of Pro- and Anti-Social Tendencies

PubMed Central

2014-01-01

Mounting evidence suggest that the right-hemisphere (RH) has a relative advantage, over the left-hemisphere (LH), in mediating social intelligence - identifying social stimuli, understanding the intentions of other people, awareness of the dynamics in social relationships, and successful handling of social interactions. Furthermore, a review and synthesis of the literature suggest that pro-social attitudes and behaviors are associated with physiological activity in the RH, whereas unsocial and anti-social tendencies are mediated primarily by the LH. This hemispheric asymmetry is rooted in several neurobiological and functional differences between the two hemispheres. (I) Positive social interactions often require inhibiting one's immediate desires and considering the perspectives and needs of others. Given that self-control is mediated by the RH, pro-social emotions and behaviors are, therefore, inherently associated with the RH as it subserves the brain's self-restraint mechanisms. (II) The RH mediates experiences of vulnerability. It registers the relative clumsiness and motor weakness of the left limbs, and it is involved, more than the LH, in processing threats and mediating fear. Emotional states of vulnerability trigger the need for affiliation and sociality, therefore the RH has a greater role in mediating pro-social attitudes and behaviors. (III) The RH mediates a holistic mode of representing the world. Holistic perception emphasizes similarities rather than differences, takes a long-term perspective, is associated with divergent thinking and seeing other points-of-view, and it mediates a personal mode of relating to people. All these features of holistic perception facilitate a more empathetic attitude toward others and pro-social behaviors. PMID:24737936

Synchronous firing patterns of induced pluripotent stem cell-derived cortical neurons depend on the network structure consisting of excitatory and inhibitory neurons.

PubMed

Iida, Shoko; Shimba, Kenta; Sakai, Koji; Kotani, Kiyoshi; Jimbo, Yasuhiko

2018-06-18

The balance between glutamate-mediated excitation and GABA-mediated inhibition is critical to cortical functioning. However, the contribution of network structure consisting of the both neurons to cortical functioning has not been elucidated. We aimed to evaluate the relationship between the network structure and functional activity patterns in vitro. We used mouse induced pluripotent stem cells (iPSCs) to construct three types of neuronal populations; excitatory-rich (Exc), inhibitory-rich (Inh), and control (Cont). Then, we analyzed the activity patterns of these neuronal populations using microelectrode arrays (MEAs). Inhibitory synaptic densities differed between the three types of iPSC-derived neuronal populations, and the neurons showed spontaneously synchronized bursting activity with functional maturation for one month. Moreover, different firing patterns were observed between the three populations; Exc demonstrated the highest firing rates, including frequent, long, and dominant bursts. In contrast, Inh demonstrated the lowest firing rates and the least dominant bursts. Synchronized bursts were enhanced by disinhibition via GABA A receptor blockade. The present study, using iPSC-derived neurons and MEAs, for the first time show that synchronized bursting of cortical networks in vitro depends on the network structure consisting of excitatory and inhibitory neurons. Copyright © 2018 Elsevier Inc. All rights reserved.

Corepressors: custom tailoring and alterations while you wait

PubMed Central

Goodson, Michael; Jonas, Brian A.; Privalsky, Martin A.

2005-01-01

A diverse cadre of metazoan transcription factors mediate repression by recruiting protein complexes containing the SMRT (silencing mediator of retinoid and thyroid hormone receptor) or N-CoR (nuclear receptor corepressor) corepressors. SMRT and N-CoR nucleate the assembly of still larger corepressor complexes that perform the specific molecular incantations necessary to confer transcriptional repression. Although SMRT and N-CoR are paralogs and possess similar molecular architectures and mechanistic strategies, they nonetheless exhibit distinct molecular and biological properties. It is now clear that the functions of both SMRT and N-CoR are further diversified through alternative mRNA splicing, yielding a series of corepressor protein variants that participate in distinctive transcription factor partnerships and display distinguishable repression properties. This review will discuss what is known about the structure and actions of SMRT, N-CoR, and their splicing variants, and how alternative splicing may allow the functions of these corepressors to be adapted and tailored to different cells and to different developmental stages. PMID:16604171

Solution structure of CXCL5--a novel chemokine and adipokine implicated in inflammation and obesity.

PubMed

Sepuru, Krishna Mohan; Poluri, Krishna Mohan; Rajarathnam, Krishna

2014-01-01

The chemokine CXCL5 is selectively expressed in highly specialized cells such as epithelial type II cells in the lung and white adipose tissue macrophages in muscle, where it mediates diverse functions from combating microbial infections by regulating neutrophil trafficking to promoting obesity by inhibiting insulin signaling. Currently very little is known regarding the structural basis of how CXCL5 mediates its novel functions. Towards this missing knowledge, we have solved the solution structure of the CXCL5 dimer by NMR spectroscopy. CXCL5 is a member of a subset of seven CXCR2-activating chemokines (CAC) that are characterized by the highly conserved ELR motif in the N-terminal tail. The structure shows that CXCL5 adopts the typical chemokine fold, but also reveals several distinct differences in the 30 s loop and N-terminal residues; not surprisingly, crosstalk between N-terminal and 30 s loop residues have been implicated as a major determinant of receptor activity. CAC function also involves binding to highly sulfated glycosaminoglycans (GAG), and the CXCL5 structure reveals a distinct distribution of positively charged residues, suggesting that differences in GAG interactions also influence function. The availability of the structure should now facilitate the design of experiments to better understand the molecular basis of various CXCL5 functions, and also serve as a template for the design of inhibitors for use in a clinical setting.

Effects of change in physical activity on physical function limitations in older women: mediating roles of physical function performance and self-efficacy.

PubMed

McAuley, Edward; Morris, Katherine S; Doerksen, Shawna E; Motl, Robert W; Liang, Hu; White, Siobhan M; Wójcicki, Thomas R; Rosengren, Karl

2007-12-01

To examine the hypothesis that changes in self-efficacy and functional performance mediate, in part, the beneficial effect of physical activity on functional limitations over time. Prospective, observational study. Community-based. Two hundred forty-nine community-dwelling older women. Participants completed measures of self-reported physical activity, functional limitations, and self-efficacy. Four measures of physical function performance were also assessed. Measures were completed at baseline and 24 months. Data were analyzed using a panel model within a covariance modeling framework. Results indicated that increases in physical activity over time were associated with greater improvements in self-efficacy, which was associated in turn with improved physical function performance, both of which mediated the association between physical activity and functional limitations. Fewer functional limitations at baseline were also associated with higher levels of self-efficacy at 24 months. Age, race, and health status covariates did not significantly change these relationships. The findings support the mediating roles of self-efficacy and physical function performance in the relationship between longitudinal changes in physical activity and functional limitations in older women.

Antigen-specific and nonspecific mediators of T cell/B cell cooperation. III. Characterization of the nonspecific mediator(s) from different sources.

PubMed

Harwell, L; Kappler, J W; Marrack, P

1976-05-01

T cell-containing lymphoid populations produce a nonantigen-specific mediator(s) (NSM) which can replace T cell helper function in vitro in the response of B cells to sheep red blood cells (SRBC), but not to the hapten-protein conjugate, trinitrophenyl-keyhole limpet hemocyanin, (TNP-KLH). NSM produced under three conditions: 1) stimulation of KLH-primed cells with KLH; 2) allogeneic stimulation of normal spleen cells; and 3) stimulation of normal spleen cells with Con A (but not PHA) are indistinguishable on the basis of their biologic activity and m.w., estimated as 30 to 40,000 daltons by G-200 chromatography. Production of NSM is dependent on the presence of T cells. The action of NSM on B cells responding to SRBC in the presence of 2-mercaptoethanol is unaffected by severe macrophage depletion. Extensive absorption of NSM with SRBC failed to remove its activity, confirming its nonantigen-specific nature.

Current Research on Opioid Receptor Function

PubMed Central

Feng, Yuan; He, Xiaozhou; Yang, Yilin; Chao, Dongman; Lazarus, Lawrence H.; Xia, Ying

2012-01-01

The use of opioid analgesics has a long history in clinical settings, although the comprehensive action of opioid receptors is still less understood. Nonetheless, recent studies have generated fresh insights into opioid receptor-mediated functions and their underlying mechanisms. Three major opioid receptors (μ-opioid receptor, MOR; δ-opioid receptor, DOR; and κ-opioid receptor, KOR) have been cloned in many species. Each opioid receptor is functionally sub-classified into several pharmacological subtypes, although, specific gene corresponding each of these receptor subtypes is still unidentified as only a single gene has been isolated for each opioid receptor. In addition to pain modulation and addiction, opioid receptors are widely involved in various physiological and pathophysiological activities, including the regulation of membrane ionic homeostasis, cell proliferation, emotional response, epileptic seizures, immune function, feeding, obesity, respiratory and cardiovascular control as well as some neurodegenerative disorders. In some species, they play an essential role in hibernation. One of the most exciting findings of the past decade is the opioid-receptor, especially DOR, mediated neuroprotection and cardioprotection. The up-regulation of DOR expression and DOR activation increase the neuronal tolerance to hypoxic/ischemic stress. The DOR signal triggers (depending on stress duration and severity) different mechanisms at multiple levels to preserve neuronal survival, including the stabilization of homeostasis and increased pro-survival signaling (e.g., PKC-ERK-Bcl 2) and anti-oxidative capacity. In the heart, PKC and KATP channels are involved in the opioid receptor-mediated cardioprotection. The DOR-mediated neuroprotection and cardioprotection have the potential to significantly alter the clinical pharmacology in terms of prevention and treatment of life-threatening conditions like stroke and myocardial infarction. The main purpose of this article is to review the recent work done on opioids and their receptor functions. It shall provide an informative reference for better understanding the opioid system and further elucidation of the opioid receptor function from a physiological and pharmacological point of view. PMID:22204322

Genes of the major histocompatibility complex highlight interactions of the innate and adaptive immune system

PubMed Central

Lukasch, Barbara; Westerdahl, Helena; Strandh, Maria; Winkler, Hans; Moodley, Yoshan; Knauer, Felix

2017-01-01

Background A well-functioning immune defence is crucial for fitness, but our knowledge about the immune system and its complex interactions is still limited. Major histocompatibility complex (MHC) molecules are involved in T-cell mediated adaptive immune responses, but MHC is also highly upregulated during the initial innate immune response. The aim of our study was therefore to determine to what extent the highly polymorphic MHC is involved in interactions of the innate and adaptive immune defence and if specific functional MHC alleles (FA) or heterozygosity at the MHC are more important. Methods To do this we used captive house sparrows (Passer domesticus) to survey MHC diversity and immune function controlling for several environmental factors. MHC class I alleles were identified using parallel amplicon sequencing and to mirror immune function, several immunological tests that correspond to the innate and adaptive immunity were conducted. Results Our results reveal that MHC was linked to all immune tests, highlighting its importance for the immune defence. While all innate responses were associated with one single FA, adaptive responses (cell-mediated and humoral) were associated with several different alleles. Discussion We found that repeated injections of an antibody in nestlings and adults were linked to different FA and hence might affect different areas of the immune system. Also, individuals with a higher number of different FA produced a smaller secondary response, indicating a disadvantage of having numerous MHC alleles. These results demonstrate the complexity of the immune system in relation to the MHC and lay the foundation for other studies to further investigate this topic. PMID:28875066

Genes of the major histocompatibility complex highlight interactions of the innate and adaptive immune system.

PubMed

Lukasch, Barbara; Westerdahl, Helena; Strandh, Maria; Winkler, Hans; Moodley, Yoshan; Knauer, Felix; Hoi, Herbert

2017-01-01

A well-functioning immune defence is crucial for fitness, but our knowledge about the immune system and its complex interactions is still limited. Major histocompatibility complex (MHC) molecules are involved in T-cell mediated adaptive immune responses, but MHC is also highly upregulated during the initial innate immune response. The aim of our study was therefore to determine to what extent the highly polymorphic MHC is involved in interactions of the innate and adaptive immune defence and if specific functional MHC alleles (FA) or heterozygosity at the MHC are more important. To do this we used captive house sparrows ( Passer domesticus ) to survey MHC diversity and immune function controlling for several environmental factors. MHC class I alleles were identified using parallel amplicon sequencing and to mirror immune function, several immunological tests that correspond to the innate and adaptive immunity were conducted. Our results reveal that MHC was linked to all immune tests, highlighting its importance for the immune defence. While all innate responses were associated with one single FA, adaptive responses (cell-mediated and humoral) were associated with several different alleles. We found that repeated injections of an antibody in nestlings and adults were linked to different FA and hence might affect different areas of the immune system. Also, individuals with a higher number of different FA produced a smaller secondary response, indicating a disadvantage of having numerous MHC alleles. These results demonstrate the complexity of the immune system in relation to the MHC and lay the foundation for other studies to further investigate this topic.

Strategies to Improve Cancer Photothermal Therapy Mediated by Nanomaterials.

PubMed

de Melo-Diogo, Duarte; Pais-Silva, Cleide; Dias, Diana R; Moreira, André F; Correia, Ilídio J

2017-05-01

The deployment of hyperthermia-based treatments for cancer therapy has captured the attention of different researchers worldwide. In particular, the application of light-responsive nanomaterials to mediate hyperthermia has revealed promising results in several pre-clinical assays. Unlike conventional therapies, these nanostructures can display a preferential tumor accumulation and thus mediate, upon irradiation with near-infrared light, a selective hyperthermic effect with temporal resolution. Different types of nanomaterials such as those based on gold, carbon, copper, molybdenum, tungsten, iron, palladium and conjugated polymers have been used for this photothermal modality. This progress report summarizes the different strategies that have been applied so far for increasing the efficacy of the photothermal therapeutic effect mediated by nanomaterials, namely those that improve the accumulation of nanomaterials in tumors (e.g. by changing the corona composition or through the functionalization with targeting ligands), increase nanomaterials' intrinsic capacity to generate photoinduced heat (e.g. by synthesizing new nanomaterials or assembling nanostructures) or by optimizing the parameters related to the laser light used in the irradiation process (e.g. by modulating the radiation wavelength). Overall, the development of new strategies or the optimization and combination of the existing ones will surely give a major contribution for the application of nanomaterials in cancer PTT. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Intrinsic motivation, neurocognition and psychosocial functioning in schizophrenia: testing mediator and moderator effects.

PubMed

Nakagami, Eri; Xie, Bin; Hoe, Maanse; Brekke, John S

2008-10-01

This study examined the nature of the relationships among neurocognition, intrinsic motivation, and psychosocial functioning for persons with schizophrenia. Hypotheses concerning both mediator and moderator mechanisms were tested. 120 individuals diagnosed with schizophrenia were recruited as they entered outpatient psychosocial rehabilitation programs. Measures of psychosocial functioning and intrinsic motivation were administered at baseline. Measures of neurocognition were administered at baseline by testers blind to scores on other study variables. Data were analyzed using latent construct modeling to test for mediator and moderator effects. There were strong bivariate relationships between neurocognition, intrinsic motivation, and psychosocial functioning. The results demonstrated that intrinsic motivation strongly mediated the relationship between neurocognition and psychosocial functioning. This mediation was evidenced by: (i) the direct path from neurocognition to functional outcome no longer being statistically significant after the introduction of motivation into the model, (ii) the statistical significance of the indirect path from neurocognition through motivation to functional outcome. There was no support for the two moderation hypotheses: the level of neurocognition did not influence the relationship between intrinsic motivation and psychosocial functioning, nor did the level of intrinsic motivation influence the relationship between neurocognition and psychosocial functioning. Neurocognition influences psychosocial functioning through its relationship with intrinsic motivation. Intrinsic motivation is a critical mechanism for explaining the relationship between neurocognition and psychosocial functioning. Implications for the theoretical understanding and psychosocial treatment of intrinsic motivation in schizophrenia are discussed.

GPER Function in Breast Cancer: An Overview

PubMed Central

Lappano, Rosamaria; Pisano, Assunta; Maggiolini, Marcello

2014-01-01

The G-protein-coupled estrogen receptor-1 (GPER, formerly known as GPR30) has attracted increasing interest, considering its ability to mediate estrogenic signaling in different cell types, including the hormone-sensitive tumors like breast cancer. As observed for other GPCR-mediated responses, the activation of the epidermal growth factor receptor is a fundamental integration point in the biological action triggered by GPER. A wide number of natural and synthetic compounds, including estrogens and anti-estrogens, elicit stimulatory effects in breast cancer through GPER up-regulation and activation, suggesting that GPER function is associated with breast tumor progression and tamoxifen resistance. GPER has also been proposed as a candidate biomarker in triple-negative breast cancer, opening a novel scenario for a more comprehensive assessment of breast tumor patients. PMID:24834064

Leptin regulates bone formation via the sympathetic nervous system

NASA Technical Reports Server (NTRS)

Takeda, Shu; Elefteriou, Florent; Levasseur, Regis; Liu, Xiuyun; Zhao, Liping; Parker, Keith L.; Armstrong, Dawna; Ducy, Patricia; Karsenty, Gerard

2002-01-01

We previously showed that leptin inhibits bone formation by an undefined mechanism. Here, we show that hypothalamic leptin-dependent antiosteogenic and anorexigenic networks differ, and that the peripheral mediators of leptin antiosteogenic function appear to be neuronal. Neuropeptides mediating leptin anorexigenic function do not affect bone formation. Leptin deficiency results in low sympathetic tone, and genetic or pharmacological ablation of adrenergic signaling leads to a leptin-resistant high bone mass. beta-adrenergic receptors on osteoblasts regulate their proliferation, and a beta-adrenergic agonist decreases bone mass in leptin-deficient and wild-type mice while a beta-adrenergic antagonist increases bone mass in wild-type and ovariectomized mice. None of these manipulations affects body weight. This study demonstrates a leptin-dependent neuronal regulation of bone formation with potential therapeutic implications for osteoporosis.

FUNCTIONAL LIMITATION AND DEPRESSIVE SYMPTOMATOLOGY: CONSIDERING PERCEIVED STIGMA AND DISCRIMINATION WITHIN A STRESS AND COPING FRAMEWORK

PubMed Central

Brown, Robyn Lewis

2016-01-01

This study examines whether perceived stigma and discrimination moderate the associations between functional limitation, psychosocial coping resources, and depressive symptoms among people with physical disabilities. Using two waves of data from a large community study including a representative sample of persons with physical disabilities (N=417), an SEM-based moderated mediation analysis was performed. Mediation tests demonstrate that mastery significantly mediates the association between functional limitation and depressive symptoms over the study period. Moderated mediation tests reveal that the linkage between functional limitation and mastery varies as a function of perceived stigma and experiences of major discrimination and day-to-day discrimination, however. The implications of these findings are discussed in the context of the stress and coping literature. PMID:28497112

Investigating the neurodevelopmental mediators of aggression in children with a history of child maltreatment:An exploratory field study.

PubMed

Dileo, J F; Brewer, W; Northam, E; Yucel, M; Anderson, V

2017-08-01

Maltreatment of children is a chronic community problem that increases the risk of future aggression. Despite several decades of research highlighting this relationship, few studies have explored the potential neuropsychological deficits that are likely to mediate it. This exploratory study aimed to examine how child maltreatment may be associated with aggression via impairment in the developing prefrontal-limbic-autonomic pathways that are implicated in neuropsychological models of aggression. Furthermore, it aimed to investigate the relationship between child maltreatment and both reactive and proactive aggression subtypes. To investigate this non-invasively in an at-risk population, children with a documented protective care history (n = 20) and a community control group (n = 30), aged between 6 and 12 years, were compared on measures of cardiovascular functioning, affect regulation and cognitive functioning aligned with this neuropsychological model. Whilst no group differences were found on cardiovascular functioning (i.e., resting heart rate, heart rate reactivity, heart rate variability), the protective care group performed significantly worse on measures of affect regulation and cognitive functioning (i.e., global intelligence, executive functioning, smell identification and social cognition). The relationship between child maltreatment and aggression was mediated by executive dysfunction and affect dysregulation but not global IQ, social cognition or olfactory identification. The results suggest that interventions targeting aggression in maltreated children will benefit from clinical assessment and psychological strategies that address the executive dysfunction and affect dysregulation that has been associated with this clinical outcome.

Reorganization of functional brain networks mediates the improvement of cognitive performance following real-time neurofeedback training of working memory.

PubMed

Zhang, Gaoyan; Yao, Li; Shen, Jiahui; Yang, Yihong; Zhao, Xiaojie

2015-05-01

Working memory (WM) is essential for individuals' cognitive functions. Neuroimaging studies indicated that WM fundamentally relied on a frontoparietal working memory network (WMN) and a cinguloparietal default mode network (DMN). Behavioral training studies demonstrated that the two networks can be modulated by WM training. Different from the behavioral training, our recent study used a real-time functional MRI (rtfMRI)-based neurofeedback method to conduct WM training, demonstrating that WM performance can be significantly improved after successfully upregulating the activity of the target region of interest (ROI) in the left dorsolateral prefrontal cortex (Zhang et al., [2013]: PloS One 8:e73735); however, the neural substrate of rtfMRI-based WM training remains unclear. In this work, we assessed the intranetwork and internetwork connectivity changes of WMN and DMN during the training, and their correlations with the change of brain activity in the target ROI as well as with the improvement of post-training behavior. Our analysis revealed an "ROI-network-behavior" correlation relationship underlying the rtfMRI training. Further mediation analysis indicated that the reorganization of functional brain networks mediated the effect of self-regulation of the target brain activity on the improvement of cognitive performance following the neurofeedback training. The results of this study enhance our understanding of the neural basis of real-time neurofeedback and suggest a new direction to improve WM performance by regulating the functional connectivity in the WM related networks. © 2014 Wiley Periodicals, Inc.

Obesity and adiposity indicators, asthma, and atopy in Puerto Rican children

PubMed Central

Forno, Erick; Acosta-Pérez, Edna; Brehm, John M.; Han, Yueh-Ying; Alvarez, María; Colón-Semidey, Angel; Canino, Glorisa; Celedón, Juan C

2013-01-01

Background: Whether adiposity indicators other than body mass index should be used in studies of childhood asthma is largely unknown. The role of atopy in “obese asthma” is also unclear. Objective: To examine the relation among adiposity indicators, asthma, and atopy in Puerto Rican children, and to assess whether atopy mediates the obesity-asthma association. Methods: In a study of Puerto Rican children with (n=351) and without (n=327) asthma, we measured body mass index (BMI), percent body fat (PBF), waist circumference (WC), and waist-to-hip ratio (WHR). The outcomes studied included asthma, lung function, measures of atopy, and, among cases, indicators of asthma severity or control. We performed mediation analysis to assess the contribution of atopy to the relationship between adiposity and asthma. Results: BMI, PBF, and WC were associated with increased odds of asthma. Among cases, all three measures were generally associated with lung function, asthma severity/control, and atopy; however, there were differences depending on the adiposity indicator analyzed. Atopy considerably mediated the adiposity-asthma association in this population: allergic rhinitis accounted for 22-53% of the association with asthma, and sensitization to cockroach mediated 13-20% of the association with FVC and 29-42% of the association with emergency room visits for asthma. Conclusions: Adiposity indicators are associated with asthma, asthma severity/control, and atopy in Puerto Rican children. Atopy significantly mediates the effect of adiposity on asthma outcomes. Longitudinal studies are needed to further investigate the causal role, if any, of adiposity distribution and atopy on “obese asthma” in childhood. Clinical Implications: Assessment of adiposity rather than sole reliance on BMI may be important in studies of childhood asthma. Atopy is an important mediator of the relation between obesity and asthma in Puerto Rican children. Capsule Summary: In a cohort of Puerto Rican children, measures of adiposity were associated with asthma, asthma severity/control, and atopy; however, some differences existed depending on the adiposity indicator utilized. Atopy significantly mediated the association between adiposity indicators and asthma. PMID:24290290

Manipulating neural activity in physiologically classified neurons: triumphs and challenges

PubMed Central

Gore, Felicity; Schwartz, Edmund C.; Salzman, C. Daniel

2015-01-01

Understanding brain function requires knowing both how neural activity encodes information and how this activity generates appropriate responses. Electrophysiological, imaging and immediate early gene immunostaining studies have been instrumental in identifying and characterizing neurons that respond to different sensory stimuli, events and motor actions. Here we highlight approaches that have manipulated the activity of physiologically classified neurons to determine their role in the generation of behavioural responses. Previous experiments have often exploited the functional architecture observed in many cortical areas, where clusters of neurons share response properties. However, many brain structures do not exhibit such functional architecture. Instead, neurons with different response properties are anatomically intermingled. Emerging genetic approaches have enabled the identification and manipulation of neurons that respond to specific stimuli despite the lack of discernable anatomical organization. These approaches have advanced understanding of the circuits mediating sensory perception, learning and memory, and the generation of behavioural responses by providing causal evidence linking neural response properties to appropriate behavioural output. However, significant challenges remain for understanding cognitive processes that are probably mediated by neurons with more complex physiological response properties. Currently available strategies may prove inadequate for determining how activity in these neurons is causally related to cognitive behaviour. PMID:26240431

Transcription regulation by the Mediator complex.

PubMed

Soutourina, Julie

2018-04-01

Alterations in the regulation of gene expression are frequently associated with developmental diseases or cancer. Transcription activation is a key phenomenon in the regulation of gene expression. In all eukaryotes, mediator of RNA polymerase II transcription (Mediator), a large complex with modular organization, is generally required for transcription by RNA polymerase II, and it regulates various steps of this process. The main function of Mediator is to transduce signals from the transcription activators bound to enhancer regions to the transcription machinery, which is assembled at promoters as the preinitiation complex (PIC) to control transcription initiation. Recent functional studies of Mediator with the use of structural biology approaches and functional genomics have revealed new insights into Mediator activity and its regulation during transcription initiation, including how Mediator is recruited to transcription regulatory regions and how it interacts and cooperates with PIC components to assist in PIC assembly. Novel roles of Mediator in the control of gene expression have also been revealed by showing its connection to the nuclear pore and linking Mediator to the regulation of gene positioning in the nuclear space. Clear links between Mediator subunits and disease have also encouraged studies to explore targeting of this complex as a potential therapeutic approach in cancer and fungal infections.

Silymarin impacts on immune system as an immunomodulator: One key for many locks.

PubMed

Esmaeil, Nafiseh; Anaraki, Sima Balouchi; Gharagozloo, Marjan; Moayedi, Behjat

2017-09-01

Silymarin is a flavonoid complex extracted from the Silybum marianum plant. It acts as a strong antioxidant and free radical scavenger by different mechanisms. But in addition to antioxidant effects, silymarin/silybin reveals immunomodulatory affects with both immunostimulatory and immunosuppression activities. Different studies have shown that silymarin has the anti-inflammatory effect through the suppression of NF-κB signaling pathway and TNF-α activation. It also has different immunomodulatory activities in a dose and time-dependent manner. As an immunomodulator agent, silymarin inhibits T-lymphocyte function at low doses while stimulates inflammatory processes at high doses. Studies have shown that silymarin has attenuated autoimmune, allergic, preeclampsia, cancer, and immune-mediated liver diseases and also has suppressed oxidative and nitrosative immunotoxicity. Silymarin also has indicated dual effects on proliferation and apoptosis of different cells. In conclusion, based on the current review, silymarin has a broad spectrum of immunomodulatory functions under different conditions. Recognizing the exact mechanisms of silymarin on cellular and molecular pathways would be very valuable for treatment of immune-mediated diseases. Also further studies are needed to assess the utility of silymarin in protection against autoimmune, cancer, allergic and other diseases in human subjects. Copyright © 2017. Published by Elsevier B.V.

The secretory pathway: exploring yeast diversity.

PubMed

Delic, Marizela; Valli, Minoska; Graf, Alexandra B; Pfeffer, Martin; Mattanovich, Diethard; Gasser, Brigitte

2013-11-01

Protein secretion is an essential process for living organisms. In eukaryotes, this encompasses numerous steps mediated by several hundred cellular proteins. The core functions of translocation through the endoplasmic reticulum membrane, primary glycosylation, folding and quality control, and vesicle-mediated secretion are similar from yeasts to higher eukaryotes. However, recent research has revealed significant functional differences between yeasts and mammalian cells, and even among diverse yeast species. This review provides a current overview of the canonical protein secretion pathway in the model yeast Saccharomyces cerevisiae, highlighting differences to mammalian cells as well as currently unresolved questions, and provides a genomic comparison of the S. cerevisiae pathway to seven other yeast species where secretion has been investigated due to their attraction as protein production platforms, or for their relevance as pathogens. The analysis of Candida albicans, Candida glabrata, Kluyveromyces lactis, Pichia pastoris, Hansenula polymorpha, Yarrowia lipolytica, and Schizosaccharomyces pombe reveals that many - but not all - secretion steps are more redundant in S. cerevisiae due to duplicated genes, while some processes are even absent in this model yeast. Recent research obviates that even where homologous genes are present, small differences in protein sequence and/or differences in the regulation of gene expression may lead to quite different protein secretion phenotypes. © 2013 Federation of European Microbiological Societies. Published by John Wiley & Sons Ltd. All rights reserved.

Genome-wide scans between two honeybee populations reveal putative signatures of human-mediated selection.

PubMed

Parejo, M; Wragg, D; Henriques, D; Vignal, A; Neuditschko, M

2017-12-01

Human-mediated selection has left signatures in the genomes of many domesticated animals, including the European dark honeybee, Apis mellifera mellifera, which has been selected by apiculturists for centuries. Using whole-genome sequence information, we investigated selection signatures in spatially separated honeybee subpopulations (Switzerland, n = 39 and France, n = 17). Three different test statistics were calculated in windows of 2 kb (fixation index, cross-population extended haplotype homozygosity and cross-population composite likelihood ratio) and combined into a recently developed composite selection score. Applying a stringent false discovery rate of 0.01, we identified six significant selective sweeps distributed across five chromosomes covering eight genes. These genes are associated with multiple molecular and biological functions, including regulation of transcription, receptor binding and signal transduction. Of particular interest is a selection signature on chromosome 1, which corresponds to the WNT4 gene, the family of which is conserved across the animal kingdom with a variety of functions. In Drosophila melanogaster, WNT4 alleles have been associated with differential wing, cross vein and abdominal phenotypes. Defining phenotypic characteristics of different Apis mellifera ssp., which are typically used as selection criteria, include colour and wing venation pattern. This signal is therefore likely to be a good candidate for human mediated-selection arising from different applied breeding practices in the two managed populations. © 2017 The Authors. Animal Genetics published by John Wiley & Sons Ltd on behalf of Stichting International Foundation for Animal Genetics.

Shared elements of host-targeting pathways among apicomplexan parasites of differing lifestyles.

PubMed

Pellé, Karell G; Jiang, Rays H Y; Mantel, Pierre-Yves; Xiao, Yu-Ping; Hjelmqvist, Daisy; Gallego-Lopez, Gina M; O T Lau, Audrey; Kang, Byung-Ho; Allred, David R; Marti, Matthias

2015-11-01

Apicomplexans are a diverse group of obligate parasites occupying different intracellular niches that require modification to meet the needs of the parasite. To efficiently manipulate their environment, apicomplexans translocate numerous parasite proteins into the host cell. Whereas some parasites remain contained within a parasitophorous vacuole membrane (PVM) throughout their developmental cycle, others do not, a difference that affects the machinery needed for protein export. A signal-mediated pathway for protein export into the host cell has been characterized in Plasmodium parasites, which maintain the PVM. Here, we functionally demonstrate an analogous host-targeting pathway involving organellar staging prior to secretion in the related bovine parasite, Babesia bovis, a parasite that destroys the PVM shortly after invasion. Taking into account recent identification of a similar signal-mediated pathway in the coccidian parasite Toxoplasma gondii, we suggest a model in which this conserved pathway has evolved in multiple steps from signal-mediated trafficking to specific secretory organelles for controlled secretion to a complex protein translocation process across the PVM. © 2015 John Wiley & Sons Ltd.

Iodine, a Mild Reagent for the Aromatization of Terpenoids.

PubMed

Domingo, Victoriano; Prieto, Consuelo; Silva, Lucia; Rodilla, Jesús M L; Quílez del Moral, José F; Barrero, Alejandro F

2016-04-22

Efficient procedures based on the use of iodine for the aromatization of a series of terpenoids possessing diene and homoallylic or allylic alcohol functionalities are described. Different examples are reported as a proof-of-concept study. Furthermore, iodine also proved to mediate the dehydrogenation of testosterone.

Green tea EGCG, T-cell function, and T-cell-mediated autoimmune encephalomyelitis

USDA-ARS?s Scientific Manuscript database

Autoimmune diseases are common, disabling immune disorders affecting millions of people. Recent studies indicate that dysregulated balance of different CD4+ T-cell subpopulations plays a key role in immune pathogenesis of several major autoimmune diseases. Green tea and its active ingredient, epigal...

PCBs Alter Dopamine Mediated Function in Aging Workers

DTIC Science & Technology

2004-01-01

Do PCBs Alter Doparnine Mediated Function in Aging Workers ? Principal Investigators: Dr. Richard Seegal of the New York State Department of Health and...Award Number: DAMD17-02-1-0173 TITLE: PCBs Alter Dopamine Mediated Function in Aging Workers PRINCIPAL INVESTIGATOR: Richard F.Seegal, Ph.D...CONTRACTING ORGANIZATION: Health Research, Incorporated Rensselaer, New York 12144 REPORT DATE: January 2004 TYPE OF REPORT: Annual PREPARED FOR: U.S. Army

Same-sex attraction, social relationships, psychosocial functioning, and school performance in early adolescence.

PubMed

Bos, Henny M W; Sandfort, Theo G M; de Bruyn, Eddy H; Hakvoort, Esther M

2008-01-01

The authors examined whether 13- to 15-year-old adolescents who experience feelings of same-sex attraction (SSA) differ from those without such feelings in the quality of relationships with parents, peers, and class mentors and in psychosocial functioning (health status and school performance). The authors also assessed whether differences in psychosocial functioning resulted from differences in the quality of social relationships. Data were collected from 866 Dutch high school students (mean age 13.61 years) by means of a computer-based questionnaire. Of the participants, 74 (8.5%) reported having feelings of SSA. The participants with SSA rated the quality of their relationships with their fathers and their peers lower than did those without SSA. Participants with SSA also had poorer mental health (higher levels of depression and lower levels of self-esteem) and lower school performance. A mediation analysis revealed that differences in psychosocial functioning resulted from differences in the quality of the same-sex attracted youths' social relationships, especially with fathers and peers. Copyright (c) 2008 APA.

An update on PPAR activation by cannabinoids

PubMed Central

2016-01-01

Some cannabinoids activate the different isoforms of PPARs (α, β and γ), as shown through the use of reporter gene assays, binding studies, selective antagonists and knockout studies. Activation of all isoforms, but primarily PPARα and γ, mediates some (but not all) of the analgesic, neuroprotective, neuronal function modulation, anti‐inflammatory, metabolic, anti‐tumour, gastrointestinal and cardiovascular effects of some cannabinoids, often in conjunction with activation of the more traditional target sites of action such as the cannabinoid CB1 and CB2 receptors and the TRPV1 ion channel. PPARs also mediate some of the effects of inhibitors of endocannabinoid degradation or transport. Cannabinoids may be chaperoned to the PPARs by fatty acid binding proteins. The aims of this review are to update the evidence supporting PPAR activation by cannabinoids and to review the physiological responses to cannabinoids that are mediated, and not mediated, by PPAR activation. PMID:27077495

An update on PPAR activation by cannabinoids.

PubMed

O'Sullivan, Saoirse Elizabeth

2016-06-01

Some cannabinoids activate the different isoforms of PPARs (α, β and γ), as shown through the use of reporter gene assays, binding studies, selective antagonists and knockout studies. Activation of all isoforms, but primarily PPARα and γ, mediates some (but not all) of the analgesic, neuroprotective, neuronal function modulation, anti-inflammatory, metabolic, anti-tumour, gastrointestinal and cardiovascular effects of some cannabinoids, often in conjunction with activation of the more traditional target sites of action such as the cannabinoid CB1 and CB2 receptors and the TRPV1 ion channel. PPARs also mediate some of the effects of inhibitors of endocannabinoid degradation or transport. Cannabinoids may be chaperoned to the PPARs by fatty acid binding proteins. The aims of this review are to update the evidence supporting PPAR activation by cannabinoids and to review the physiological responses to cannabinoids that are mediated, and not mediated, by PPAR activation. © 2016 The British Pharmacological Society.

Cognitive function and competitive employment in schizophrenia: relative contribution of insight and psychopathology.

PubMed

Giugiario, Michela; Crivelli, Barbara; Mingrone, Cinzia; Montemagni, Cristiana; Scalese, Mara; Sigaudo, Monica; Rocca, Giuseppe; Rocca, Paola

2012-04-01

This study investigated the relationships among insight, psychopathology, cognitive function, and competitive employment in order to determine whether insight and/or psychopathology carried the influence of cognitive function to competitive employment. We recruited 253 outpatients with stable schizophrenia and we further divided our sample into two groups of patients (unemployed and competitive employment subjects). Clinical and neuropsychological assessments were performed. All clinical variables significantly different between the two groups of subjects were subsequently analyzed using a binary logistic regression to assess their independent contribution to competitive employment in the two patients' groups. On the basis of the regression results two mediation analyses were performed. Verbal memory, general psychopathology, and awareness of mental illness were significantly associated with competitive employment in our sample. Both awareness of mental illness and general psychopathology had a role in mediating the verbal memory-competitive employment relationship. Taken together, these findings confirmed the importance of cognitive function in obtaining competitive employment. Our results also highlighted the independent role of general psychopathology and awareness of illness on occupational functioning in schizophrenia. Thus, a greater attention must be given to the systematic investigation of insight and general psychopathology in light of an amelioration of vocational functioning in stable schizophrenia.

Quantification of mutation-derived bias for alternate mating functionalities of the Saccharomyces cerevisiae Ste2p pheromone receptor.

PubMed

Choudhary, Pooja; Loewen, Michele C

2016-01-01

Although well documented for mammalian G-protein-coupled receptors, alternate functionalities and associated alternate signalling remain to be unequivocally established for the Saccharomyces cerevisiae pheromone Ste2p receptor. Here, evidence supporting alternate functionalities for Ste2p is re-evaluated, extended and quantified. In particular, strong mating and constitutive signalling mutations, focusing on residues S254, P258 and S259 in TM6 of Ste2p, are stacked and investigated in terms of their effects on classical G-protein-mediated signal transduction associated with cell cycle arrest, and alternatively, their impact on downstream mating projection and zygote formation events. In relative dose response experiments, accounting for systemic and observational bias, mutational-derived functional differences were observed, validating the S254L-derived bias for downstream mating responses and highlighting complex relationships between TM6-mutation derived constitutive signalling and ligand-induced functionalities. Mechanistically, localization studies suggest that alterations to receptor trafficking may contribute to mutational bias, in addition to expected receptor conformational stabilization effects. Overall, these results extend previous observations and quantify the contributions of Ste2p variants to mediating cell cycle arrest versus downstream mating functionalities. © Crown copyright 2015.

Circuit resistance training attenuates acute exertion-induced reductions in arterial function but not inflammation in obese women.

PubMed

Franklin, Nina C; Robinson, Austin T; Bian, Jing-Tan; Ali, Mohamed M; Norkeviciute, Edita; McGinty, Patrick; Phillips, Shane A

2015-06-01

Cardiovascular disease (CVD) is a leading cause of preventable death among young women in the United States. Habitual resistance exercise training is known to have beneficial effects on endothelial function and CVD risk factors, including obesity; however, previous studies show that acute resistance exercise impairs endothelial function in obese adults who are sedentary, a response that may be linked to inflammation. We sought to determine if circuit-based resistance training (CRT) attenuates acute resistance exercise-induced reductions in endothelial function in a population of young, obese, sedentary women and whether or not inflammation plays a role in this response. Eighteen obese [body mass index (BMI) 30.0-40.0 kg · m(-2)] young premenopausal women were randomly assigned to either a CRT group or a no-exercise control group (CON). Conduit artery endothelial function was assessed using brachial artery flow-mediated dilation (FMD) determined by ultrasound before and after a single bout of strenuous weightlifting (SWL). In addition, circulating inflammatory mediators (tumor necrosis factor-α and C-reactive protein), blood pressure, fasting blood lipids, glucose, waist circumference, body composition, and aerobic capacity were assessed. Among participants randomized to the CRT group, 8 weeks of training led to considerable increases in FMD after SWL (P=0.001) compared to the CON group. However, no significant differences between the groups were observed in circulating inflammatory mediators, blood pressure, fasting blood lipids, or other physical and physiological characteristics. This study shows that CRT alleviates acute exertion-induced reductions in endothelial function among obese sedentary women in the absence of changes in inflammation.

Widening disparities in health between educational levels and their determinants in later life: evidence from a nine-year cohort study.

PubMed

Oshio, Takashi

2018-02-23

Education has attracted more attention as a key determinant of health in later life. In this study, the hypothesis that widened educational disparities in health can be observed in later life was investigated, and the factors that mediated the association between education and changes in health were also assessed. Using the 9-year (10-wave) longitudinal data of 20,024 individuals (9320 men and 10,704 women) aged 50-59 years at baseline, collected from a nationwide population survey in Japan (2005-2014), the changes in self-rated health, functional limitations, and psychological distress between educational levels were compared. Mediation analysis was further conducted to assess the factors that mediated the association between education and changes in health, with reference to six types of potential mediators (household spending, social participation, leisure-time physical activity, smoking, problem drinking, and regular health check-ups). The analyses were conducted separately for men and women. All three health variables rapidly deteriorated among lower-educated men and women. For men, the six potential mediators mediated 55.2%, 64.3%, and 47.3% of the associations between educational levels and changes in self-rated health, functional limitations, and psychological distress, respectively. The proportions for women were 42.0%, 49.5%, and 58.8%, respectively. Social participation was the primary mediator, followed by physical activity, regular health check-ups, and smoking. In general, no substantial or consistent differences were observed between men and women. The results suggested that policy measures that encourage social participation and promote healthy behaviors can improve educational disparities in health in later life.

Do attentional capacities and processing speed mediate the effect of age on executive functioning?

PubMed

Gilsoul, Jessica; Simon, Jessica; Hogge, Michaël; Collette, Fabienne

2018-02-06

The executive processes are well known to decline with age, and similar data also exists for attentional capacities and processing speed. Therefore, we investigated whether these two last nonexecutive variables would mediate the effect of age on executive functions (inhibition, shifting, updating, and dual-task coordination). We administered a large battery of executive, attentional and processing speed tasks to 104 young and 71 older people, and we performed mediation analyses with variables showing a significant age effect. All executive and processing speed measures showed age-related effects while only the visual scanning task performance (selective attention) was explained by age when controlled for gender and educational level. Regarding mediation analyses, visual scanning partially mediated the age effect on updating while processing speed partially mediated the age effect on shifting, updating and dual-task coordination. In a more exploratory way, inhibition was also found to partially mediate the effect of age on the three other executive functions. Attention did not greatly influence executive functioning in aging while, in agreement with the literature, processing speed seems to be a major mediator of the age effect on these processes. Interestingly, the global pattern of results seems also to indicate an influence of inhibition but further studies are needed to confirm the role of that variable as a mediator and its relative importance by comparison with processing speed.

Eukaryotic Initiation Factor eIFiso4G1 and eIFiso4G2 Are Isoforms Exhibiting Distinct Functional Differences in Supporting Translation in Arabidopsis*

PubMed Central

Gallie, Daniel R.

2016-01-01

The eukaryotic translation initiation factor (eIF) 4G is required during protein synthesis to promote the assembly of several factors involved in the recruitment of a 40S ribosomal subunit to an mRNA. Although many eukaryotes express two eIF4G isoforms that are highly similar, the eIF4G isoforms in plants, referred to as eIF4G and eIFiso4G, are highly divergent in size, sequence, and domain organization but both can interact with eIF4A, eIF4B, eIF4E isoforms, and the poly(A)-binding protein. Nevertheless, eIF4G and eIFiso4G from wheat exhibit preferences in the mRNAs they translate optimally. For example, mRNA containing the 5′-leader (called Ω) of tobacco mosaic virus preferentially uses eIF4G in wheat germ lysate. In this study, the eIF4G isoform specificity of Ω was used to examine functional differences of the eIF4G isoforms in Arabidopsis. As in wheat, Ω-mediated translation was reduced in an eif4g null mutant. Loss of the eIFiso4G1 isoform, which is similar in sequence to wheat eIFiso4G, did not substantially affect Ω-mediated translation. However, loss of the eIFiso4G2 isoform substantially reduced Ω-mediated translation. eIFiso4G2 is substantially divergent from eIFiso4G1 and is present only in the Brassicaceae, suggesting a recent evolution. eIFiso4G2 isoforms exhibit sequence-specific differences in regions representing partner protein and RNA binding sites. Loss of any eIF4G isoform also resulted in a substantial reduction in reporter transcript level. These results suggest that eIFiso4G2 appeared late in plant evolution and exhibits more functional similarity with eIF4G than with eIFiso4G1 during Ω-mediated translation. PMID:26578519

Subjective cognitive dysfunction in rehabilitation outpatients with musculoskeletal disorders or chronic pain.

PubMed

Schrier, Ernst; Geertzen, Jan H; Dijkstra, Pieter U

2017-08-01

Rehabilitation patients, without brain damage, sometimes complain about poor concentration and problems with their memory. The magnitude and associations, of this cognitive dysfunction, with different factors is unclear. To determine the magnitude of cognitive dysfunction in rehabilitation outpatient and to explore its associations with patient characteristics, diagnosis, surgery, pain, stress, anxiety and depression. Cross-sectional. Rehabilitation outpatients. Between July 2009 and January 2012, 274 rehabilitation outpatients were included and divided in 8 different groups through diagnosis. Cognitive functioning was assessed using the cognitive failure questionnaire and compared with the general Dutch population. Associations of gender, age, diagnosis, recent surgery, pain and stress coping ability with cognitive function was explored. Mediation of depression and anxiety was explored. The rehabilitation patients had a significantly higher score on the CFQ (mean 35.9±13.4) when compared to the general Dutch population (mean 31.8±11.1). Mean difference is 4.1, 95% confidence interval 2.60 to 5.60. In the stepwise linear regression analysis only gender, diagnosis and stress coping ability were significantly associated. A significant mediation effect was found of anxiety (P≤0.001) and depression (P≤0.005) between stress coping ability and cognitive function. Rehabilitation outpatients experience more cognitive problems in comparison to the general Dutch population. Reported dysfunction of cognition in rehabilitation outpatients are associated with stress coping ability and for a small amount to gender and diagnosis. The association of stress coping ability and cognitive dysfunction is mediated by depression and anxiety. Women tend to report more dysfunctional cognition compared to men. Patient characteristics, surgery and experienced pain have no significant influence on the experienced cognitive dysfunction. Cognitive problems reported by patients should be addressed by adapting the rehabilitation program, for instance write down instructions, repeat explanations and take more time for instructions. Cognitive problems in rehabilitation patients without brain damage is probably a stress coping problem and can be addressed by boosting resilience. Targeting depression or anxiety is another option of treatment cognition if those are mediating between stress coping and cognitive problems.

Identification, RNAi Knockdown and Functional Analysis of an Ejaculate Protein that Mediates a Postmating, Prezgotic Phenotype in a cricket

USDA-ARS?s Scientific Manuscript database

Male ejaculate proteins, including both sperm and seminal fluid proteins, play an important role in mediating reproductive biology. The function of ejaculate proteins can include enabling sperm-egg interactions, enhancing sperm storage, mediating female attractiveness, and even regulating female lif...

Genome-wide characterization of Mediator recruitment, function, and regulation.

PubMed

Grünberg, Sebastian; Zentner, Gabriel E

2017-05-27

Mediator is a conserved and essential coactivator complex broadly required for RNA polymerase II (RNAPII) transcription. Recent genome-wide studies of Mediator binding in budding yeast have revealed new insights into the functions of this critical complex and raised new questions about its role in the regulation of gene expression.

Mechanisms of functional improvement through cognitive rehabilitation in schizophrenia.

PubMed

Peña, J; Ibarretxe-Bilbao, N; Sánchez, P; Uriarte, J J; Elizagarate, E; Gutierrez, M; Ojeda, N

2018-06-01

Whereas the efficacy of cognitive rehabilitation in schizophrenia is widely known, studies examining mechanisms for functional improvement are still scarce. The aim of the study was to examine the mediational mechanisms through which cognitive rehabilitation improves functioning in schizophrenia. One hundred and eleven schizophrenia patients were randomly assigned to either a 4-month cognitive rehabilitation group or an active control group. Patients underwent a neurocognitive battery (including processing speed, verbal memory, working memory and executive functioning) and social cognition assessment (emotion perception, theory of mind and social perception). Functioning was assessed by the combined use of a performance-based instrument, the UCSD Performance-based Skills Assessment (UPSA) and an observer-rated instrument, the Global Assessment of Functioning (GAF). The trial was registered in clinicaltrials.gov (NCT02796417). Multiple mediational analyses revealed that the effect of cognitive rehabilitation on functional improvement was partially mediated by changes in processing speed and verbal memory, but not by the domains of social cognition and negative symptoms. More specifically, verbal memory partially mediated the treatment's effect on performance-based functioning (UPSA), whereas processing speed acted as a partial mediator for observer-rated functioning (GAF). The effect of rehabilitation on functioning did not take place through all the domains that showed significant improvement. Verbal memory and processing speed emerged as the most crucial factors. However, these complex interactions need further research. Copyright © 2018. Published by Elsevier Ltd.

The mediating role of metacognition in the relationship between executive function and self-regulated learning.

PubMed

Follmer, D Jake; Sperling, Rayne A

2016-12-01

Researchers have demonstrated significant relations among executive function, metacognition, and self-regulated learning. However, prior research emphasized the use of indirect measures of executive function and did not evaluate how specific executive functions are related to participants' self-regulated learning. The primary goals of the current study were to examine and test the relations among executive function, metacognition, and self-regulated learning as well as to examine how self-regulated learning is informed by executive function. The sample comprised 117 undergraduate students attending a large, Mid-Atlantic research university in the United States. Participants were individually administered direct and indirect measures of executive function, metacognition, and self-regulated learning. A mediation model specifying the relations among the regulatory constructs was proposed. In multiple linear regression analyses, executive function predicted metacognition and self-regulated learning. Direct measures of inhibition and shifting accounted for a significant amount of the variance in metacognition and self-regulated learning beyond an indirect measure of executive functioning. Separate mediation analyses indicated that metacognition mediated the relationship between executive functioning and self-regulated learning as well as between specific executive functions and self-regulated learning. The findings of this study are supported by previous research documenting the relations between executive function and self-regulated learning, and extend prior research by examining the manner in which executive function and self-regulated learning are linked. The findings provide initial support for executive functions as key processes, mediated by metacognition, that predict self-regulated learning. Implications for the contribution of executive functions to self-regulated learning are discussed. © 2016 The British Psychological Society.

The relative contributions of function, perceived psychological burden and partner support to cognitive distress in bladder cancer.

PubMed

Heyes, Susan M; Bond, Malcolm J; Harrington, Ann; Belan, Ingrid

2016-09-01

Bladder cancer is a genitourinary disease of increasing incidence. Despite improvements in treatment, outcomes remain equivocal with high recurrence rates. It is associated with poor psychosocial outcomes due to reduced functioning of the genitourinary system. The objective of these analyses was to query whether reported loss of function or the perception of psychological burden caused by this functional impedance was the key to understanding psychosocial outcomes. The sample comprised 119 participants with a confirmed diagnosis of bladder cancer. They completed a self-report questionnaire comprising the Bladder Cancer Index, Mini-mental Adjustment to Cancer Scale, Psychosocial Adjustment to Illness Scale and standard sociodemographic details. Simple mediation and serial mediation were used to explore the potential for psychological burden to mediate associations between loss of function and cognitive distress, and the potential additional contribution of positive partner support on these relationships. Age and duration of cancer were considered as covariates. Simple mediation demonstrated that the association between function and cognitive distress was fully mediated by perceived psychological burden. Serial mediation, which allowed for the addition of partner support, again demonstrated full mediation, with partner support being the key predictive variable. These analyses emphasise the importance of an appreciation of individuals' interpretation of the burden occasioned by bladder cancer and the role of a supportive partner. The implications for management discussions and support services in alleviating negative psychological outcomes in bladder cancer are highlighted. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

Chronic Exposure to Anabolic Androgenic Steroids Alters Neuronal Function in the Mammalian Forebrain via Androgen Receptor- and Estrogen Receptor-Mediated Mechanisms

PubMed Central

Penatti, Carlos A A; Porter, Donna M; Henderson, Leslie P

2009-01-01

Anabolic androgenic steroids (AAS) can promote detrimental effects on social behaviors for which γ-aminobutyric acid type A (GABAA) receptor-mediated circuits in the forebrain play a critical role. While all AAS bind to androgen receptors (AR), they may also be aromatized to estrogens and thus potentially impart effects via estrogen receptors (ER). Chronic exposure of wild type male mice to a combination of chemically distinct AAS increased action potential (AP) frequency, selective GABAA receptor subunit mRNAs, and GABAergic synaptic current decay in the medial preoptic area (mPOA). Experiments performed with pharmacological agents and in AR-deficient Tfm mutant mice suggest that the AAS-dependent enhancement of GABAergic transmission in wild type mice is AR-mediated. In AR-deficient mice, the AAS elicited dramatically different effects, decreasing AP frequency, sIPSC amplitude and frequency and the expression of selective GABAA receptor subunit mRNAs. Surprisingly, in the absence of AR signaling, the data indicate that the AAS do not act as ER agonists, but rather suggest a novel in vivo action in which the AAS inhibit aromatase and impair endogenous ER signaling. These results show that the AAS have the capacity to alter neuronal function in the forebrain via multiple steroid signaling mechanisms and suggest that effects of these steroids in the brain will depend not only on the balance of AR- vs. ER-mediated regulation for different target genes, but also on the ability of these drugs to alter steroid metabolism and thus the endogenous steroid milieu. PMID:19812324

Differences in problem behaviour among ethnic minority and majority preschoolers in the Netherlands and the role of family functioning and parenting factors as mediators: the Generation R Study.

PubMed

Flink, Ilse J E; Jansen, Pauline W; Beirens, Tinneke M J; Tiemeier, Henning; van IJzendoorn, Marinus H; Jaddoe, Vincent W V; Hofman, Albert; Raat, Hein

2012-12-19

Studies have shown that, compared to native counterparts, preschoolers from ethnic minorities are at an increased risk of problem behaviour. Socio-economic factors only partly explain this increased risk. This study aimed to further unravel the differences in problem behaviour among ethnic minority and native preschoolers by examining the mediating role of family functioning and parenting factors. We included 4,282 preschoolers participating in the Generation R Study, an ethnically-diverse cohort study with inclusion in early pregnancy. At child age 3 years, parents completed the Child Behavior Checklist (CBCL/1,5-5); information on demographics, socio-economic status and measures of family functioning (maternal psychopathology; general family functioning) and parenting (parenting stress; harsh parenting) were retrieved from questionnaires. CBCL Total Problems scores in each ethnic subgroup were compared with scores in the Dutch reference population. Mediation was evaluated using multivariate regression models. After adjustment for confounders, preschoolers from ethnic minorities were more likely to present problem behaviour than the Dutch subgroup (e.g. CBCL Total Problems Turkish subgroup (OR 7.0 (95% CI 4.9; 10.1)). When considering generational status, children of first generation immigrants were worse off than the second generation (P<0.01). Adjustment for socio-economic factors mediated the association between the ethnic minority status and child problem behaviour (e.g. attenuation in OR by 54.4% (P<0.05) from OR 5.1 (95% CI 2.8; 9.4) to OR 2.9 (95% CI 1.5; 5.6) in Cape Verdean subgroup). However, associations remained significant in most ethnic subgroups. A final adjustment for family functioning and parenting factors further attenuated the association (e.g. attenuation in OR by 55.5% (P<0.05) from OR 2.2 (95% CI 1.3; 4.4) to OR 1.5 (95% CI 1.0; 2.4) in European other subgroup). This study showed that preschoolers from ethnic minorities and particularly children of first generation immigrants are at an increased risk of problem behaviour compared to children born to a Dutch mother. Although socio-economic factors were found to partly explain the association between the ethnic minority status and child problem behaviour, a similar part was explained by family functioning and parenting factors. Considering these findings, it is important for health care workers to also be attentive to symptoms of parental psychopathology (e.g. depression), poor family functioning, high levels of parenting stress or harsh parenting in first and second generation immigrants with young children.

A Chinese Herbal Decoction, Shaoyao-Gancao Tang, Exerts Analgesic Effect by Down-Regulating the TRPV1 Channel in a Rat Model of Arthritic Pain.

PubMed

Sui, Feng; Zhou, Hai-Yu; Meng, Jing; Du, Xin-Liang; Sui, Yun-Peng; Zhou, Zhi-Kun; Dong, Cheng; Wang, Zhu-Ju; Wang, Wei-Hao; Dai, Li; Ma, Hai; Huo, Hai-Ru; Jiang, Ting-Liang

2016-01-01

Shaoyao-Gancao Tang (SGT) is one of the most frequently used compound formulas in the treatment of pain-related diseases in the medical practice of traditional Chinese medicine (TCM). To investigate the anti-inflammatory and antinociceptive effects, as well as to uncover the molecular mechanism of SGT, the rat pain model of arthritis was experimentally induced by single unilateral injection of rats' left hind paw with Freund's complete adjuvant (FCA). SGT was orally administered to the rats daily at three doses individually for a period of 16 days post-model induction. Swollen degrees and pain thresholds of the rats in different groups were measured for evaluation of the anti-inflammatory and anti-nociceptive effects of SGT. Furthermore, the mRNA and protein expression levels of transient receptor potential ion channel protein vanilloid receptor 1 (TRPV1) channel as well as its calcium-mediating function in the isolated DRG neurons were further detected to provide indexes for exploration of the molecular mechanisms mediating anti-arthritic activities of SGT. As a result, FCA injection induced significant allodynia, inflammation and edema, accompanied by a significant increase in both expression and calcium-mediating function of the TRPV1 channel. Pharmacologically, oral administration of SGT at a high or middle dose demonstrated a significant relief from the above-mentioned pathological conditions in a dose-dependent manner. Simultaneously the mRNA and protein expressional levels of TRPV1 channel, as well as its calcium-mediating function, were down-regulated greatly. These findings suggest that SGT possesses a significant analgesic and anti-inflammatory effect on arthritis rats; its therapeutic activities might be achieved through reversing the elevated expression and function of TRPV1 channel evoked by FCA.

Short-term exercise training improves flow-mediated dilation and circulating angiogenic cell number in older sedentary adults.

PubMed

Landers-Ramos, Rian Q; Corrigan, Kelsey J; Guth, Lisa M; Altom, Christine N; Spangenburg, Espen E; Prior, Steven J; Hagberg, James M

2016-08-01

Cardiovascular disease risk increases with age due, in part, to impaired endothelial function and decreased circulating angiogenic cell (CAC) number and function. We sought to determine if 10 days of aerobic exercise training improves endothelial function, CAC number, and intracellular redox balance in older sedentary adults. Eleven healthy subjects (4 men, 7 women), 61 ± 2 years of age participated in 60 min of aerobic exercise at 70% maximal oxygen consumption for 10 consecutive days while maintaining body weight. Before and after training, endothelial function was measured as flow-mediated dilation of the brachial artery and fasting blood was drawn to enumerate 3 CAC subtypes. Intracellular reactive oxygen species (ROS) and nitric oxide (NO) in CD34+ CACs were measured using fluorescent probes and reinforced via real-time quantitative polymerase chain reaction. Flow-mediated dilation improved significantly following training (10% ± 1.3% before vs. 16% ± 1.4% after training; P < 0.05). Likewise, CD34+/KDR+ number increased 104% and KDR+ number increased 151% (P < 0.05 for both), although CD34+ number was not significantly altered (P > 0.05). Intracellular NO and ROS levels in CD34+ CACs were not different after training (P > 0.05 for both). Messenger RNA expression of SOD1, endothelial nitric oxide synthase, and NADPH oxidase 2 and neutrophil cytosolic factor 1 in CD34+ CACs was not significantly altered with training (P > 0.05). In conclusion, 10 consecutive days of aerobic exercise increased flow-mediated dilation and CAC number in older, previously sedentary adults, but did not affect intracellular redox balance in CD34+ CACs. Overall, these data indicate that even short-term aerobic exercise training can have a significant impact on cardiovascular disease risk factors.

Clinically significant psychiatric symptoms among male carriers of the fragile X premutation, with and without FXTAS, and the mediating influence of executive functioning.

PubMed

Grigsby, Jim; Brega, Angela G; Bennett, Rachael E; Bourgeois, James A; Seritan, Andreea L; Goodrich, Glenn K; Hagerman, Randi J

2016-08-01

To clarify the neuropsychiatric phenotype of fragile X-associated tremor/ataxia syndrome (FXTAS), and assess the extent to which it is mediated by the dysexecutive syndrome that is a major feature of the disorder. We examined the prevalence of clinically meaningful psychiatric symptoms among male carriers of the fragile X premutation, with and without FXTAS, in comparison with men with a normal allele. Measures included the Neuropsychiatric Inventory (NPI), Symptom Checklist-90-R (SCL-90-R), and the Behavioral Dyscontrol Scale, a measure of executive functioning. Between-group differences were evaluated using logistic regression, followed by a mediation analysis with ordinary least squares regression to assess the contribution of dysexecutive syndrome to the observed psychiatric domains. Men with FXTAS showed higher rates of clinically significant symptoms overall and in specific domains: somatization, obsessive compulsive, depression, anxiety, psychoticism, agitation/aggression, apathy/indifference, irritability, and nighttime behavior problems. Post hoc analyses suggested that findings of psychoticism among men with FXTAS may be associated with participants' accurate acknowledgment of cognitive and physical dysfunction, rather than reflecting psychosis. Asymptomatic carriers showed no evidence of clinically significant psychiatric symptoms, but when all carriers were compared with men having a normal FMR1 allele, executive function deficits were found to mediate scores in several domains on both NPI and SCL-90-R. Building on prior research, the results provide evidence that the psychiatric phenotype for men includes clinically meaningful depression, hostility, and irritability, in association with behavioral and attentional disinhibition. It is likely that these problems reflect the effects of impaired executive functioning.

Executive functions and theory of mind as predictors of social adjustment in childhood traumatic brain injury.

PubMed

Robinson, Kristen E; Fountain-Zaragoza, Stephanie; Dennis, Maureen; Taylor, H Gerry; Bigler, Erin D; Rubin, Kenneth; Vannatta, Kathryn; Gerhardt, Cynthia A; Stancin, Terry; Yeates, Keith Owen

2014-11-15

This study examined whether executive function and theory of mind mediate the effects of pediatric traumatic brain injury (TBI) on social adjustment, relative to children with orthopedic injury (OI). Participants included 19 children with severe TBI, 41 children with complicated mild/moderate TBI, and 57 children with OI. They completed measures of executive function, as well as cognitive, affective, and conative theory of mind. Parents provided ratings of children's social adjustment. Children with severe TBI performed more poorly than children with OI on executive function and theory of mind tasks and were rated by parents as having more behavioral symptoms and worse communication and social skills. Executive function and theory of mind were positively correlated with social skills and communication skills, and negatively correlated with behavioral symptoms. In multiple mediator models, theory of mind and executive function were not significant direct predictors of any measure of social adjustment, but mediated the association between injury and adjustment for children with severe TBI. Theory of mind was a significant independent mediator when predicting social skills, but executive function was not. TBI in children, particularly severe injury, is associated with poor social adjustment. The impact of TBI on children's social adjustment is likely mediated by its effects on executive function and theory of mind.

Executive Functions and Theory of Mind as Predictors of Social Adjustment in Childhood Traumatic Brain Injury

PubMed Central

Fountain-Zaragoza, Stephanie; Dennis, Maureen; Taylor, H. Gerry; Bigler, Erin D.; Rubin, Kenneth; Vannatta, Kathryn; Gerhardt, Cynthia A.; Stancin, Terry; Yeates, Keith Owen

2014-01-01

Abstract This study examined whether executive function and theory of mind mediate the effects of pediatric traumatic brain injury (TBI) on social adjustment, relative to children with orthopedic injury (OI). Participants included 19 children with severe TBI, 41 children with complicated mild/moderate TBI, and 57 children with OI. They completed measures of executive function, as well as cognitive, affective, and conative theory of mind. Parents provided ratings of children's social adjustment. Children with severe TBI performed more poorly than children with OI on executive function and theory of mind tasks and were rated by parents as having more behavioral symptoms and worse communication and social skills. Executive function and theory of mind were positively correlated with social skills and communication skills, and negatively correlated with behavioral symptoms. In multiple mediator models, theory of mind and executive function were not significant direct predictors of any measure of social adjustment, but mediated the association between injury and adjustment for children with severe TBI. Theory of mind was a significant independent mediator when predicting social skills, but executive function was not. TBI in children, particularly severe injury, is associated with poor social adjustment. The impact of TBI on children's social adjustment is likely mediated by its effects on executive function and theory of mind. PMID:25003478

Different downstream signalling of CCK1 receptors regulates distinct functions of CCK in pancreatic beta cells.

PubMed

Ning, Shang-lei; Zheng, Wen-shuai; Su, Jing; Liang, Nan; Li, Hui; Zhang, Dao-lai; Liu, Chun-hua; Dong, Jun-hong; Zhang, Zheng-kui; Cui, Min; Hu, Qiao-Xia; Chen, Chao-chao; Liu, Chang-hong; Wang, Chuan; Pang, Qi; Chen, Yu-xin; Yu, Xiao; Sun, Jin-peng

2015-11-01

Cholecystokinin (CCK) is secreted by intestinal I cells and regulates important metabolic functions. In pancreatic islets, CCK controls beta cell functions primarily through CCK1 receptors, but the signalling pathways downstream of these receptors in pancreatic beta cells are not well defined. Apoptosis in pancreatic beta cell apoptosis was evaluated using Hoechst-33342 staining, TUNEL assays and Annexin-V-FITC/PI staining. Insulin secretion and second messenger production were monitored using ELISAs. Protein and phospho-protein levels were determined by Western blotting. A glucose tolerance test was carried out to examine the functions of CCK-8s in streptozotocin-induced diabetic mice. The sulfated carboxy-terminal octapeptide CCK26-33 amide (CCK-8s) activated CCK1 receptors and induced accumulation of both IP3 and cAMP. Whereas Gq -PLC-IP3 signalling was required for the CCK-8s-induced insulin secretion under low-glucose conditions, Gs -PKA/Epac signalling contributed more strongly to the CCK-8s-mediated insulin secretion in high-glucose conditions. CCK-8s also promoted formation of the CCK1 receptor/β-arrestin-1 complex in pancreatic beta cells. Using β-arrestin-1 knockout mice, we demonstrated that β-arrestin-1 is a key mediator of both CCK-8s-mediated insulin secretion and of its the protective effect against apoptosis in pancreatic beta cells. The anti-apoptotic effects of β-arrestin-1 occurred through cytoplasmic late-phase ERK activation, which activates the 90-kDa ribosomal S6 kinase-phospho-Bcl-2-family protein pathway. Knowledge of different CCK1 receptor-activated downstream signalling pathways in the regulation of distinct functions of pancreatic beta cells could be used to identify biased CCK1 receptor ligands for the development of new anti-diabetic drugs. © 2015 The British Pharmacological Society.

Pharmacological Enhancement of Memory and Executive Functioning in Laboratory Animals

PubMed Central

Floresco, Stan B; Jentsch, James D

2011-01-01

Investigating how different pharmacological compounds may enhance learning, memory, and higher-order cognitive functions in laboratory animals is the first critical step toward the development of cognitive enhancers that may be used to ameliorate impairments in these functions in patients suffering from neuropsychiatric disorders. Rather than focus on one aspect of cognition, or class of drug, in this review we provide a broad overview of how distinct classes of pharmacological compounds may enhance different types of memory and executive functioning, particularly those mediated by the prefrontal cortex. These include recognition memory, attention, working memory, and different components of behavioral flexibility. A key emphasis is placed on comparing and contrasting the effects of certain drugs on different cognitive and mnemonic functions, highlighting methodological issues associated with this type of research, tasks used to investigate these functions, and avenues for future research. Viewed collectively, studies of the neuropharmacological basis of cognition in rodents and non-human primates have identified targets that will hopefully open new avenues for the treatment of cognitive disabilities in persons affected by mental disorders. PMID:20844477

Differential motor and sensory functional recovery in male but not female adult rats is associated with remyelination rather than axon regeneration after sciatic nerve crush.

PubMed

Tong, Ling-Ling; Ding, You-Quan; Jing, Hong-Bo; Li, Xuan-Yang; Qi, Jian-Guo

2015-05-06

Peripheral nerve functional recovery after injuries relies on both axon regeneration and remyelination. Both axon regeneration and remyelination require intimate interactions between regenerating neurons and their accompanying Schwann cells. Previous studies have shown that motor and sensory neurons are intrinsically different in their regeneration potentials. Moreover, denervated Schwann cells accompanying myelinated motor and sensory axons have distinct gene expression profiles for regeneration-associated growth factors. However, it is unknown whether differential motor and sensory functional recovery exists. If so, the particular one among axon regeneration and remyelination responsible for this difference remains unclear. Here, we aimed to establish an adult rat sciatic nerve crush model with the nonserrated microneedle holders and measured rat motor and sensory functions during regeneration. Furthermore, axon regeneration and remyelination was evaluated by morphometric analysis of electron microscopic images on the basis of nerve fiber classification. Our results showed that Aα fiber-mediated motor function was successfully recovered in both male and female rats. Aδ fiber-mediated sensory function was partially restored in male rats, but completely recovered in female littermates. For both male and female rats, the numbers of regenerated motor and sensory axons were quite comparable. However, remyelination was diverse among myelinated motor and sensory nerve fibers. In detail, Aβ and Aδ fibers incompletely remyelinated in male, but not female rats, whereas Aα fibers fully remyelinated in both sexes. Our result indicated that differential motor and sensory functional recovery in male but not female adult rats is associated with remyelination rather than axon regeneration after sciatic nerve crush.

Sex differences in face processing are mediated by handedness and sexual orientation.

PubMed

Brewster, Paul W H; Mullin, Caitlin R; Dobrin, Roxana A; Steeves, Jennifer K E

2011-03-01

Previous research has demonstrated sex differences in face processing at both neural and behavioural levels. The present study examined the role of handedness and sexual orientation as mediators of this effect. We compared the performance of LH (left-handed) and RH (right-handed) heterosexual and homosexual male and female participants on a face recognition memory task. Our main findings were that homosexual males have better face recognition memory than both heterosexual males and homosexual women. We also demonstrate better face processing in women than in men. Finally, LH heterosexual participants had better face recognition than LH homosexual participants and also tended to be better than RH heterosexual participants. These findings are consistent with differences in the organisation and laterality of face-processing mechanisms as a function of sex, handedness, and sexual orientation.

Relationship between Anxiety and Burnout among Chinese Physicians: A Moderated Mediation Model

PubMed Central

Zhou, Jiawei; Yang, Yanjie; Qiu, Xiaohui; Yang, Xiuxian; Pan, Hui; Ban, Bo; Qiao, Zhengxue; Wang, Lin; Wang, Wenbo

2016-01-01

Objective The main goal of this research was to investigate the complex relationships among coping styles, personality, burnout, and anxiety using a moderated mediation analysis. Methods A random cluster sampling procedure was used to select a total of 1274 physicians from two tertiary grade A hospitals in Heilongjiang Province, which is located in northeast China. The Zung Self-Rating Anxiety Scale (SAS), Chinese Maslach Burnout Inventory (CMBI), Chinese version of the EPQ-revised Short Scale, and the Trait Coping Style Questionnaire (TCSQ) were used to gather data. Moderated mediation analysis was used in this study; it was executed using the PROCESS macro so that the mediators and moderator could function together in the same model. Results The prevalence of anxiety symptoms among the physicians was 31%, and there were no differences between the sexes. The results showed that positive and negative coping styles partially mediated the association between burnout and anxiety symptoms in physicians. The mediated effect of positive coping styles was moderated by Eysenck’s Psychoticism traits. Conclusions Personality traits moderate the strength of the relationships between burnout and anxiety mediated by positive coping styles; however, personality traits do not moderate the strength of the relationships between burnout and anxiety mediated by negative coping styles. PMID:27479002

The Arabidopsis mediator complex subunits MED16, MED14, and MED2 regulate mediator and RNA polymerase II recruitment to CBF-responsive cold-regulated genes.

PubMed

Hemsley, Piers A; Hurst, Charlotte H; Kaliyadasa, Ewon; Lamb, Rebecca; Knight, Marc R; De Cothi, Elizabeth A; Steele, John F; Knight, Heather

2014-01-01

The Mediator16 (MED16; formerly termed SENSITIVE TO FREEZING6 [SFR6]) subunit of the plant Mediator transcriptional coactivator complex regulates cold-responsive gene expression in Arabidopsis thaliana, acting downstream of the C-repeat binding factor (CBF) transcription factors to recruit the core Mediator complex to cold-regulated genes. Here, we use loss-of-function mutants to show that RNA polymerase II recruitment to CBF-responsive cold-regulated genes requires MED16, MED2, and MED14 subunits. Transcription of genes known to be regulated via CBFs binding to the C-repeat motif/drought-responsive element promoter motif requires all three Mediator subunits, as does cold acclimation-induced freezing tolerance. In addition, these three subunits are required for low temperature-induced expression of some other, but not all, cold-responsive genes, including genes that are not known targets of CBFs. Genes inducible by darkness also required MED16 but required a different combination of Mediator subunits for their expression than the genes induced by cold. Together, our data illustrate that plants control transcription of specific genes through the action of subsets of Mediator subunits; the specific combination defined by the nature of the stimulus but also by the identity of the gene induced.

Antigen B from Echinococcus granulosus enters mammalian cells by endocytic pathways.

PubMed

da Silva, Edileuza Danieli; Cancela, Martin; Monteiro, Karina Mariante; Ferreira, Henrique Bunselmeyer; Zaha, Arnaldo

2018-05-04

Cystic hydatid disease is a zoonosis caused by the larval stage (hydatid) of Echinococcus granulosus (Cestoda, Taeniidae). The hydatid develops in the viscera of intermediate host as a unilocular structure filled by the hydatid fluid, which contains parasitic excretory/secretory products. The lipoprotein Antigen B (AgB) is the major component of E. granulosus metacestode hydatid fluid. Functionally, AgB has been implicated in immunomodulation and lipid transport. However, the mechanisms underlying AgB functions are not completely known. In this study, we investigated AgB interactions with different mammalian cell types and the pathways involved in its internalization. AgB uptake was observed in four different cell lines, NIH-3T3, A549, J774 and RH. Inhibition of caveolae/raft-mediated endocytosis causes about 50 and 69% decrease in AgB internalization by RH and A549 cells, respectively. Interestingly, AgB colocalized with the raft endocytic marker, but also showed a partial colocalization with the clathrin endocytic marker. Finally, AgB colocalized with an endolysosomal tracker, providing evidence for a possible AgB destination after endocytosis. The results indicate that caveolae/raft-mediated endocytosis is the main route to AgB internalization, and that a clathrin-mediated entry may also occur at a lower frequency. A possible fate for AgB after endocytosis seems to be the endolysosomal system. Cellular internalization and further access to subcellular compartments could be a requirement for AgB functions as a lipid carrier and/or immunomodulatory molecule, contributing to create a more permissive microenvironment to metacestode development and survival.

Effects of hormones on platelet aggregation.

PubMed

Farré, Antonio López; Modrego, Javier; Zamorano-León, José J

2014-04-01

Platelets and their activation/inhibition mechanisms play a central role in haemostasis. It is well known agonists and antagonists of platelet activation; however, during the last years novel evidences of hormone effects on platelet activation have been reported. Platelet functionality may be modulated by the interaction between different hormones and their platelet receptors, contributing to sex differences in platelet function and even in platelet-mediated vascular damage. It has suggested aspects that apparently are well established should be reviewed. Hormones effects on platelet activity are included among them. This article tries to review knowledge about the involvement of hormones in platelet biology and activity.

Health, Wealth, and the Role of Institutions

ERIC Educational Resources Information Center

Hurd, Michael; Kapteyn, Arie

2003-01-01

A positive relationship between socioeconomic status and health has been observed over many populations and many time periods. One of the factors mediating this relation is the institutional environment in which people function. We consider longitudinal data from two countries with very different institutional environments, the United States and…

Cultures-of-Use and Morphologies of Communicative Action

ERIC Educational Resources Information Center

Thorne, Steven L.

2016-01-01

In this article I revisit the cultures-of-use conceptual framework--that technologies, as forms and processes comprising human culture, mediate and assume variable meanings, values, and conventionalized functions for different communities (Thorne, 2003). I trace the antecedent arc of investigation and serendipitous encounters that led to the 2003…

Quantifying spatial differences in metabolism in headwater streams

Treesearch

Ricardo González-Pinzón; Roy Haggerty; Alba Argerich

2014-01-01

Stream functioning includes simultaneous interaction among solute transport, nutrient processing, and metabolism. Metabolism is measured with methods that have limited spatial representativeness and are highly uncertain. These problems restrict development of methods for up-scaling biological processes that mediate nutrient processing. We used the resazurin–resorufin (...

Species Differences in Human and Rodent PEPT2-Mediated Transport of Glycylsarcosine and Cefadroxil in Pichia Pastoris Transformants

PubMed Central

Song, Feifeng; Hu, Yongjun; Jiang, Huidi

2017-01-01

The proton-coupled oligopeptide transporter PEPT2 (SLC15A2) plays an important role in the disposition of di/tripeptides and peptide-like drugs in kidney and brain. However, unlike PEPT1 (SLC15A1), there is little information about species differences in the transport of PEPT2-mediated substrates. The purpose of this study was to determine whether PEPT2 exhibited a species-dependent uptake of glycylsarcosine (GlySar) and cefadroxil using yeast Pichia pastoris cells expressing cDNA from human, mouse, and rat. In such a system, the functional activity of PEPT2 was evaluated with [3H]GlySar as a function of time, pH, substrate concentration, and specificity, and with [3H]cefadroxil as a function of concentration. We observed that the uptake of GlySar was pH-dependent with an optimal uptake at pH 6.5 for all three species. Moreover, GlySar showed saturable uptake kinetics, with Km values in human (150.6 µM) > mouse (42.8 µM) ≈ rat (36.0 µM). The PEPT2-mediated uptake of GlySar in yeast transformants was specific, being inhibited by di/tripeptides and peptide-like drugs, but not by amino acids and nonsubstrate compounds. Cefadroxil also showed a saturable uptake profile in all three species, with Km values in human (150.8 μM) > mouse (15.6 μM) ≈ rat (11.9 μM). These findings demonstrated that the PEPT2-mediated uptake of GlySar and cefadroxil was specific, species dependent, and saturable. Furthermore, based on the Km values, mice appeared similar to rats but both were less than optimal as animal models in evaluating the renal reabsorption and pharmacokinetics of peptides and peptide-like drugs in humans. PMID:27836942

The cognate coat protein is required for cell-to-cell movement of a chimeric brome mosaic virus mediated by the cucumber mosaic virus movement protein.

PubMed

Nagano, H; Mise, K; Okuno, T; Furusawa, I

1999-12-20

Cucumber mosaic cucumovirus (CMV) and brome mosaic bromovirus (BMV) have many similarities, including the three-dimensional structure of virions, genome organizations, and requirement of the coat protein (CP) for cell-to-cell movement. We have shown that a chimeric BMV with the CMV 3a movement protein (MP) gene instead of its own cannot move from cell to cell in Chenopodium quinoa, a common permissive host for both BMV and CMV. Another chimeric BMV was constructed by replacing both MP and CP genes of BMV with those of CMV (MP/CP-chimera) and tested for its infectivity in C. quinoa, to determine whether the CMV CP has some functions required for the CMV MP-mediated cell-to-cell movement and to exhibit functional difference between CPs of BMV and CMV. Cell-to-cell movement of the MP/CP-chimera occurred, and small local lesions were induced on the inoculated leaves. A frameshift mutation introduced in the CMV CP gene of the MP/CP-chimera resulted in a lack of cell-to-cell movement of the chimeric virus. These results indicate that the viral movement mediated by the CMV MP requires its cognate CP. Deletion of the amino-terminal region in CMV CP, which is not obligatory for CMV movement, also abolished cell-to-cell movement of the MP/CP-chimera. This may suggest some differences in cell-to-cell movement of the MP/CP-chimera and CMV. On the other hand, the sole replacement of BMV CP gene with that of CMV abolished viral cell-to-cell movement, suggesting a possibility that the viral movement mediated by the BMV MP may also require its cognate CP. Functional compatibility between MP and CP in viral cell-to-cell movement is discussed. Copyright 1999 Academic Press.

Nucleus Accumbens Mediates Relative Motivation for Rewards in the Absence of Choice

PubMed Central

Clithero, John A.; Reeck, Crystal; Carter, R. McKell; Smith, David V.; Huettel, Scott A.

2011-01-01

To dissociate a choice from its antecedent neural states, motivation associated with the expected outcome must be captured in the absence of choice. Yet, the neural mechanisms that mediate behavioral idiosyncrasies in motivation, particularly with regard to complex economic preferences, are rarely examined in situations without overt decisions. We employed functional magnetic resonance imaging in a large sample of participants while they anticipated earning rewards from two different modalities: monetary and candy rewards. An index for relative motivation toward different reward types was constructed using reaction times to the target for earning rewards. Activation in the nucleus accumbens (NAcc) and anterior insula (aINS) predicted individual variation in relative motivation between our reward modalities. NAcc activation, however, mediated the effects of aINS, indicating the NAcc is the likely source of this relative weighting. These results demonstrate that neural idiosyncrasies in reward efficacy exist even in the absence of explicit choices, and extend the role of NAcc as a critical brain region for such choice-free motivation. PMID:21941472

Proteolytic turnover of the Gal4 transcription factor is not required for function in vivo.

PubMed

Nalley, Kip; Johnston, Stephen Albert; Kodadek, Thomas

2006-08-31

Transactivator-promoter complexes are essential intermediates in the activation of eukaryotic gene expression. Recent studies of these complexes have shown that some are quite dynamic in living cells owing to rapid and reversible disruption of activator-promoter complexes by molecular chaperones, or a slower, ubiquitin-proteasome-pathway-mediated turnover of DNA-bound activator. These mechanisms may act to ensure continued responsiveness of activators to signalling cascades by limiting the lifetime of the active protein-DNA complex. Furthermore, the potency of some activators is compromised by proteasome inhibition, leading to the suggestion that periodic clearance of activators from a promoter is essential for high-level expression. Here we describe a variant of the chromatin immunoprecipitation assay that has allowed direct observation of the kinetic stability of native Gal4-promoter complexes in yeast. Under non-inducing conditions, the complex is dynamic, but on induction the Gal4-promoter complexes 'lock in' and exhibit long half-lives. Inhibition of proteasome-mediated proteolysis had little or no effect on Gal4-mediated gene expression. These studies, combined with earlier data, show that the lifetimes of different transactivator-promoter complexes in vivo can vary widely and that proteasome-mediated turnover is not a general requirement for transactivator function.

Multiple functions of the S-phase checkpoint mediator.

PubMed

Tanaka, Katsunori

2010-01-01

There is mounting evidence that replication defects are the major source of spontaneous genomic instability in cells, and that S-phase checkpoints are the principal defense against such instability. The S-phase checkpoint mediator protein Mrc1/Claspin mediates the checkpoint response to replication stress by facilitating phosphorylation of effector kinase by a sensor kinase. In this review, the multiple functions and the regulation of the S-phase checkpoint mediator are discussed.

Working Memory and Cognitive Flexibility Mediates Visuoconstructional Abilities in Older Adults with Heterogeneous Cognitive Ability.

PubMed

Ávila, Rafaela T; de Paula, Jonas J; Bicalho, Maria A; Moraes, Edgar N; Nicolato, Rodrigo; Malloy-Diniz, Leandro F; Diniz, Breno S

2015-05-01

Previous studies suggest that executive functions influence the performance on visuoconstructional tasks. This study aims to investigate whether the relationship between planning ability and the copy of complex figures is mediated by distinct components of executive functions (i.e., working memory, inhibitory control and cognitive flexibility). We included a 129 older adults with Alzheimer's disease (n=36, AD), mild cognitive impairment (MCI, n=67), and with no evidence of cognitive impairment (controls, n=26). We evaluated the mediation effect of planning abilities, working memory, cognitive flexibility and inhibitory control on visuoconstructional tasks using a multiple mediation models. We found a significant direct effect of planning on visuoconstructional abilities and a partial mediation effect of working memory and cognitive flexibility on visuoconstructional abilities. The present results indicate that the performance on visuoconstructional task is mediated by multiple interrelated executive functions components, in particular working memory and cognitive flexibility.

Life and death of neurons in the aging brain

NASA Technical Reports Server (NTRS)

Morrison, J. H.; Hof, P. R.; Bloom, F. E. (Principal Investigator)

1997-01-01

Neurodegenerative disorders are characterized by extensive neuron death that leads to functional decline, but the neurobiological correlates of functional decline in normal aging are less well defined. For decades, it has been a commonly held notion that widespread neuron death in the neocortex and hippocampus is an inevitable concomitant of brain aging, but recent quantitative studies suggest that neuron death is restricted in normal aging and unlikely to account for age-related impairment of neocortical and hippocampal functions. In this article, the qualitative and quantitative differences between aging and Alzheimer's disease with respect to neuron loss are discussed, and age-related changes in functional and biochemical attributes of hippocampal circuits that might mediate functional decline in the absence of neuron death are explored. When these data are viewed comprehensively, it appears that the primary neurobiological substrates for functional impairment in aging differ in important ways from those in neurodegenerative disorders such as Alzheimer's disease.

Diversity in structure and function of tethering complexes: evidence for different mechanisms in vesicular transport regulation.

PubMed

Kümmel, D; Heinemann, U

2008-04-01

The term 'tethering factor' has been coined for a heterogeneous group of proteins that all are required for protein trafficking prior to vesicle docking and SNARE-mediated membrane fusion. Two groups of tethering factors can be distinguished, long coiled-coil proteins and multi-subunit complexes. To date, eight such protein complexes have been identified in yeast, and they are required for different trafficking steps. Homologous complexes are found in all eukaryotic organisms, but conservation seems to be less strict than for other components of the trafficking machinery. In fact, for most proposed multi-subunit tethers their ability to actually bridge two membranes remains to be shown. Here we discuss recent progress in the structural and functional characterization of tethering complexes and present the emerging view that the different complexes are quite diverse in their structure and the molecular mechanisms underlying their function. TRAPP and the exocyst are the structurally best characterized tethering complexes. Their comparison fails to reveal any similarity on a struc nottural level. Furthermore, the interactions with regulatory Rab GTPases vary, with TRAPP acting as a nucleotide exchange factor and the exocyst being an effector. Considering these differences among the tethering complexes as well as between their yeast and mammalian orthologs which is apparent from recent studies, we suggest that tethering complexes do not mediate a strictly conserved process in vesicular transport but are diverse regulators acting after vesicle budding and prior to membrane fusion.

An autism-associated point mutation in the neuroligin cytoplasmic tail selectively impairs AMPA receptor-mediated synaptic transmission in hippocampus.

PubMed

Etherton, Mark R; Tabuchi, Katsuhiko; Sharma, Manu; Ko, Jaewon; Südhof, Thomas C

2011-06-03

Neuroligins are evolutionarily conserved postsynaptic cell-adhesion molecules that function, at least in part, by forming trans-synaptic complexes with presynaptic neurexins. Different neuroligin isoforms perform diverse functions and exhibit distinct intracellular localizations, but contain similar cytoplasmic sequences whose role remains largely unknown. Here, we analysed the effect of a single amino-acid substitution (R704C) that targets a conserved arginine residue in the cytoplasmic sequence of all neuroligins, and that was associated with autism in neuroligin-4. We introduced the R704C mutation into mouse neuroligin-3 by homologous recombination, and examined its effect on synapses in vitro and in vivo. Electrophysiological and morphological studies revealed that the neuroligin-3 R704C mutation did not significantly alter synapse formation, but dramatically impaired synapse function. Specifically, the R704C mutation caused a major and selective decrease in AMPA receptor-mediated synaptic transmission in pyramidal neurons of the hippocampus, without similarly changing NMDA or GABA receptor-mediated synaptic transmission, and without detectably altering presynaptic neurotransmitter release. Our results suggest that the cytoplasmic tail of neuroligin-3 has a central role in synaptic transmission by modulating the recruitment of AMPA receptors to postsynaptic sites at excitatory synapses.

Engineering of Fc Fragments with Optimized Physicochemical Properties Implying Improvement of Clinical Potentials for Fc-Based Therapeutics.

PubMed

Yang, Chunpeng; Gao, Xinyu; Gong, Rui

2017-01-01

Therapeutic monoclonal antibodies and Fc-fusion proteins are successfully used in treatment of various diseases mainly including cancer, immune disease, and viral infection, which belong to the Fc-based therapeutics. In recent years, engineered Fc-derived antibody domains have also shown potential for Fc-based therapeutics. To increase the druggability of Fc-based therapeutic candidates, many efforts have been made in optimizing physicochemical properties and functions mediated by Fc fragment. The desired result is that we can simultaneously obtain Fc variants with increased physicochemical properties in vitro and capacity of mediating appropriate functions in vivo . However, changes of physicochemical properties of Fc may result in alternation of Fc-mediated functions and vice versa , which leads to undesired outcomes for further development of Fc-based therapeutics. Therefore, whether modified Fc fragments are suitable for achievement of expected clinical results or not needs to be seriously considered. Now, this question comes to be noticed and should be figured out to make better translation from the results of laboratory into clinical applications. In this review, we summarize different strategies on engineering physicochemical properties of Fc, and preliminarily elucidate the relationships between modified Fc in vitro and the subsequent therapeutic influence in vivo .

IDO2 is a critical mediator of autoantibody production and inflammatory pathogenesis in a mouse model of autoimmune arthritis1

PubMed Central

DuHadaway, James B.; Grabler, Samantha; Metz, Richard; Prendergast, George C.; Mandik-Nayak, Laura

2014-01-01

Rheumatoid arthritis (RA) and other autoimmune disorders are associated with altered activity of the immunomodulatory enzyme indoleamine-2,3-dioxygenase (IDO). However, the precise contributions of IDO function to autoimmunity remain unclear. Here, we examine the effect of two different IDO enzymes, IDO1 and IDO2, on the development of autoimmune arthritis in the KRN preclinical model of RA. We find that IDO2, not IDO1, is critical for arthritis development, providing the first direct evidence of separate in vivo functions for IDO1 and IDO2. Mice null for Ido2 display decreased joint inflammation relative to wild-type mice due to a reduction in pathogenic autoantibodies and antibody secreting cells. Notably, IDO2 appears to specifically mediate autoreactive, but not normal B cell responses, as total serum Ig levels are not altered and IDO2 ko mice are able to mount productive antibody responses to model antigens in vitro and in vivo. Reciprocal adoptive transfer studies confirm that autoantibody production and arthritis are modulated by IDO2 expression in a cell type extrinsic to the T cell. Taken together, our results provide the first insights into IDO2 function by defining its pathogenic contributions to autoantibody-mediated autoimmunity. PMID:24489090

IDO2 is a critical mediator of autoantibody production and inflammatory pathogenesis in a mouse model of autoimmune arthritis.

PubMed

Merlo, Lauren M F; Pigott, Elizabeth; DuHadaway, James B; Grabler, Samantha; Metz, Richard; Prendergast, George C; Mandik-Nayak, Laura

2014-03-01

Rheumatoid arthritis and other autoimmune disorders are associated with altered activity of the immunomodulatory enzyme IDO. However, the precise contributions of IDO function to autoimmunity remain unclear. In this article, we examine the effect of two different IDO enzymes, IDO1 and IDO2, on the development of autoimmune arthritis in the KRN preclinical model of rheumatoid arthritis. We find that IDO2, not IDO1, is critical for arthritis development, providing direct evidence of separate in vivo functions for IDO1 and IDO2. Mice null for Ido2 display decreased joint inflammation relative to wild-type mice owing to a reduction in pathogenic autoantibodies and Ab-secreting cells. Notably, IDO2 appears to specifically mediate autoreactive responses, but not normal B cell responses, as total serum Ig levels are not altered and IDO2 knockout mice are able to mount productive Ab responses to model Ags in vitro and in vivo. Reciprocal adoptive transfer studies confirm that autoantibody production and arthritis are modulated by IDO2 expression in a cell type extrinsic to the T cell. Taken together, our results, provide important insights into IDO2 function by defining its pathogenic contributions to autoantibody-mediated autoimmunity.

Engineering of Fc Fragments with Optimized Physicochemical Properties Implying Improvement of Clinical Potentials for Fc-Based Therapeutics

PubMed Central

Yang, Chunpeng; Gao, Xinyu; Gong, Rui

2018-01-01

Therapeutic monoclonal antibodies and Fc-fusion proteins are successfully used in treatment of various diseases mainly including cancer, immune disease, and viral infection, which belong to the Fc-based therapeutics. In recent years, engineered Fc-derived antibody domains have also shown potential for Fc-based therapeutics. To increase the druggability of Fc-based therapeutic candidates, many efforts have been made in optimizing physicochemical properties and functions mediated by Fc fragment. The desired result is that we can simultaneously obtain Fc variants with increased physicochemical properties in vitro and capacity of mediating appropriate functions in vivo. However, changes of physicochemical properties of Fc may result in alternation of Fc-mediated functions and vice versa, which leads to undesired outcomes for further development of Fc-based therapeutics. Therefore, whether modified Fc fragments are suitable for achievement of expected clinical results or not needs to be seriously considered. Now, this question comes to be noticed and should be figured out to make better translation from the results of laboratory into clinical applications. In this review, we summarize different strategies on engineering physicochemical properties of Fc, and preliminarily elucidate the relationships between modified Fc in vitro and the subsequent therapeutic influence in vivo. PMID:29375551

Genetically modified mouse models to investigate thyroid development, function and growth.

PubMed

Löf, C; Patyra, K; Kero, A; Kero, J

2018-06-01

The thyroid gland produces thyroid hormones (TH), which are essential regulators for growth, development and metabolism. The thyroid is mainly controlled by the thyroid-stimulating hormone (TSH) that binds to its receptor (TSHR) on thyrocytes and mediates its action via different G protein-mediated signaling pathways. TSH primarily activates the G s -pathway, and at higher concentrations also the G q/11 -pathway, leading to an increase of intracellular cAMP and Ca 2+ , respectively. To date, the physiological importance of other G protein-mediated signaling pathways in thyrocytes is unclear. Congenital hypothyroidism (CH) is defined as the lack of TH at birth. In familial cases, high-throughput sequencing methods have facilitated the identification of novel mutations. Nevertheless, the precise etiology of CH yet remains unraveled in a proportion of cases. Genetically modified mouse models can reveal new pathophysiological mechanisms of thyroid diseases. Here, we will present an overview of genetic mouse models for thyroid diseases, which have provided crucial insights into thyroid gland development, function, and growth with a special focus on TSHR and microRNA signaling. Copyright © 2018 Elsevier Ltd. All rights reserved.

The adapter protein SLP-76 mediates "outside-in" integrin signaling and function in T cells.

PubMed

Baker, R G; Hsu, C J; Lee, D; Jordan, M S; Maltzman, J S; Hammer, D A; Baumgart, T; Koretzky, G A

2009-10-01

The adapter protein SH2 domain-containing leukocyte protein of 76 kDa (SLP-76) is an essential mediator of signaling from the T-cell antigen receptor (TCR). We report here that SLP-76 also mediates signaling downstream of integrins in T cells and that SLP-76-deficient T cells fail to support adhesion to integrin ligands. In response to both TCR and integrin stimulation, SLP-76 relocalizes to surface microclusters that colocalize with phosphorylated signaling proteins. Disruption of SLP-76 recruitment to the protein named LAT (linker for activation of T cells) inhibits SLP-76 clustering downstream of the TCR but not downstream of integrins. Conversely, an SLP-76 mutant unable to bind ADAP (adhesion and degranulation-promoting adapter protein) forms clusters following TCR but not integrin engagement and fails to support T-cell adhesion to integrin ligands. These findings demonstrate that SLP-76 relocalizes to integrin-initiated signaling complexes by a mechanism different from that employed during TCR signaling and that SLP-76 relocalization corresponds to SLP-76-dependent integrin function in T cells.

There is more to pollinator-mediated selection than pollen limitation.

PubMed

Sletvold, Nina; Agren, Jon

2014-07-01

Spatial variation in pollinator-mediated selection (Δβpoll ) is a major driver of floral diversification, but we lack a quantitative understanding of its link to pollen limitation (PL) and net selection on floral traits. For 2-5 years, we quantified Δβpoll on floral traits in two populations each of two orchid species differing in PL. In both species, spatiotemporal variation in Δβpoll explained much of the variation in net selection. Selection was consistently stronger and the proportion that was pollinator-mediated was higher in the severely pollen-limited deceptive species than in the rewarding species. Within species, variation in PL could not explain variation in Δβpoll for any trait, indicating that factors influencing the functional relationship between trait variation and pollination success govern a major part of the observed variation in Δβpoll . Separating the effects of variation in mean interaction intensity and in the functional significance of traits will be necessary to understand spatiotemporal variation in selection exerted by the biotic environment. © 2014 The Author(s). Evolution © 2014 The Society for the Study of Evolution.

Genome-wide characterization of Mediator recruitment, function, and regulation

PubMed Central

2017-01-01

ABSTRACT Mediator is a conserved and essential coactivator complex broadly required for RNA polymerase II (RNAPII) transcription. Recent genome-wide studies of Mediator binding in budding yeast have revealed new insights into the functions of this critical complex and raised new questions about its role in the regulation of gene expression. PMID:28301289

Cognitive Processing and the Functional Matching Effect in Persuasion: The Mediating Role of Subjective Perceptions of Message Quality

PubMed

Lavine; Snyder

1996-11-01

In two experiments, we examined the hypothesis that subjective perceptions of message quality mediate the functional matching effect in persuasion. In Experiment 1, participants whose attitudes and behaviors serve primarily a value-expressive function (i.e., low self-monitors) or a social-adjustive function (i.e., high self-monitors) were exposed to persuasive messages that contained value-expressive, social-adjustive, or both types of arguments in favor of voting. Functionally-relevant messages (i.e., the social-adjustive message for high self-monitors and the value-expressive message for low self-monitors) produced enhanced perceptions of message quality and persuasiveness, more positive attitudes, and more message-related behavior than functionally nonrelevant messages. Functionally mixed messages were generally more effective than messages containing only functionally nonrelevant arguments, but less effective than messages containing only functionally relevant arguments. Path analyses indicated that the influence of functional relevance on attitudes and behavior was significantly mediated by subjective perceptions of the quality of the message. In Experiment 2, we exposed participants to a functionally relevant or nonrelevant voting appeal five days before a presidential election. Results replicated those of Experiment 1; functionally relevant messages produced more favorable attitudes, and this effect was mediated by enhanced perceptions of message quality. Finally, postmessage attitudes exerted a significant influence on whether participants voted in the election, and this effect was mediated by voting intentions. Discussion focuses on the subjective nature of message evaluation and on the cognitive processes underlying the functional matching effect in persuasion.

Integrating impairments in reaction time and executive function using a diffusion model framework

PubMed Central

Karalunas, Sarah L.; Huang-Pollock, Cynthia L.

2013-01-01

Using Ratcliff’s diffusion model and ex-Gaussian decomposition, we directly evaluate the role individual differences in reaction time (RT) distribution components play in the prediction of inhibitory control and working memory (WM) capacity in children with and without ADHD. Children with (n=92, x̄ age= 10.2 years, 67% male) and without ADHD (n=62, x̄ age=10.6 years, 46% male) completed four tasks of WM and a stop signal reaction time (SSRT) task. Children with ADHD had smaller WM capacities and less efficient inhibitory control. Diffusion model analyses revealed that children with ADHD had slower drift rates (v) and faster non-decision times (Ter), but there were no group differences in boundary separations (a). Similarly, using an ex-Gaussian approach, children with ADHD had larger τ values than non-ADHD controls, but did not differ in µ or σ distribution components. Drift rate mediated the association between ADHD status and performance on both inhibitory control and WM capacity. τ also mediated the ADHD-executive function impairment associations; however, models were a poorer fit to the data. Impaired performance on RT and executive functioning tasks has long been associated with childhood ADHD. Both are believed to be important cognitive mechanisms to the disorder. We demonstrate here that drift rate, or the speed at which information accumulates towards a decision, is able to explain both. PMID:23334775

Impact of lifestyle dimensions on brain pathology and cognition

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

Schreiber, Stefanie; Vogel, Jacob; Schwimmer, Henry D.

Single lifestyle factors affect brain biomarkers and cognition. Here in this work, we addressed the covariance of various lifestyle elements and investigated their impact on positron emission tomography-based β-amyloid (Aβ), hippocampal volume, and cognitive function in aged controls. Lower Aβ burden was associated with a lifestyle comprising high cognitive engagement and low vascular risk, particularly in apolipoprotein E ε4 carriers. Although cognitive function was related to high lifetime cognitive engagement and low vascular risk, Aβ load had no relation to current cognitive function. The covariance between high adult socioeconomic status, high education, and low smoking prevalence predicted better cognitive functionmore » and this was mediated by larger hippocampal volume. Our data show that lifestyle is a complex construct composed of associated variables, some of which reflect factors operating over the life span and others which may be developmental. These factors affect brain health via different pathways, which may reinforce one another. Finally, our findings moreover support the importance of an intellectually enriched lifestyle accompanied by vascular health on both cognition and presumed cerebral mediators of cognitive function.« less

Impact of lifestyle dimensions on brain pathology and cognition

DOE PAGES

Schreiber, Stefanie; Vogel, Jacob; Schwimmer, Henry D.; ...

2016-01-30

Single lifestyle factors affect brain biomarkers and cognition. Here in this work, we addressed the covariance of various lifestyle elements and investigated their impact on positron emission tomography-based β-amyloid (Aβ), hippocampal volume, and cognitive function in aged controls. Lower Aβ burden was associated with a lifestyle comprising high cognitive engagement and low vascular risk, particularly in apolipoprotein E ε4 carriers. Although cognitive function was related to high lifetime cognitive engagement and low vascular risk, Aβ load had no relation to current cognitive function. The covariance between high adult socioeconomic status, high education, and low smoking prevalence predicted better cognitive functionmore » and this was mediated by larger hippocampal volume. Our data show that lifestyle is a complex construct composed of associated variables, some of which reflect factors operating over the life span and others which may be developmental. These factors affect brain health via different pathways, which may reinforce one another. Finally, our findings moreover support the importance of an intellectually enriched lifestyle accompanied by vascular health on both cognition and presumed cerebral mediators of cognitive function.« less

A cross-sectional study of insight and family accommodation in pediatric obsessive-compulsive disorder

PubMed Central

2013-01-01

Background Factors predicting treatment outcome in pediatric patients with obsessive-compulsive disorder (OCD) include disease severity, functional impairment, comorbid disorders, insight, and family accommodation (FA). Treatment of pediatric OCD is often only partly successful as some of these predictors are not targeted with conventional therapy. Among these, insight and FA were identified to be modifiable predictors of special relevance to pediatric OCD. Despite their clinical relevance, insight and FA remain understudied in youth with OCD. This study examined the clinical correlates of insight and FA and determined whether FA mediates the relationship between symptom severity and functional impairment in pediatric OCD. Methods This was a cross-sectional, outpatient study. Thirty-five treatment-naive children and adolescentswith DSM-IV diagnosis of OCD (mean age: 13.11 ± 3.16; 54.3% males) were included. Standard questionnaires were administered for assessing the study variables. Insight and comorbidities were assessed based on clinician’s interview. Subjects were categorized as belonging to a high insight or a low insight group, and the differences between these two groups were analyzed using ANOVA. Pearson’s correlation coefficients were calculated for the remaining variables of interest. Mediation analysis was carried out using structural equation modeling. Results Relative to those in the high insight group, subjects in the low insight group were younger, had more severe disease and symptoms, and were accommodated to a greater extent by their families. In addition, comorbid depression was more frequent in subjects belonging to the low insight group. Family accommodation was positively related to disease severity, symptom severity, and functional impairment. Family accommodation totally mediated the relationship between symptom severity and functional impairment. Conclusions Results support the differences in the diagnostic criteria between adult and pediatric patients with OCD with respect to the requirement of insight. Subjects with low insight displayed clinical characteristics of increased severity compared with their high insight counterparts, suggesting that subjects with low insight may require multimodal approach to treatment. Family accommodation was found to mediate the relationship between symptom severity and functional impairment; the use of family-based approaches to cognitive behavioral therapy, with one of the aims of reducing/mitigating FA, may provide better treatment outcomes in pediatric OCD. PMID:23786761

Everyday psychological functioning in children with unilateral cerebral palsy: does executive functioning play a role?

PubMed

Whittingham, Koa; Bodimeade, Harriet L; Lloyd, Owen; Boyd, Roslyn N

2014-06-01

To identify whether executive functioning mediates the effect of having unilateral cerebral palsy (CP) on executive functioning in everyday life, psychological functioning, and social functioning. A cross-sectional cohort of 46 children with unilateral CP (25 males, 21 females; mean age 11y 1mo, SD 2y 5mo; 24 right-sided, 22 left-sided) and 20 children with typical development (nine males, 11 females; mean age 10y 10mo, SD 2y 4mo). Cognitive executive functioning was tested using a neuropsychological battery. Executive functioning in everyday life was measured with the Behavior Rating Inventory of Executive Function (BRIEF; teacher and parent reports) and psychological and social functioning by the Strengths and Difficulties Questionnaire (SDQ). Analysis included analysis of covariance and bootstrapping. Children with unilateral CP were found to have significantly decreased functioning, compared with children with typical development, on the BRIEF Behavioral Regulation Index, the BRIEF Metacognition Index, and on the SDQ emotion, conduct, hyperactivity, and peer problems subscales. Group differences were mediated by cognitive executive functioning for the BRIEF Metacognition Index (teacher and parent report), the BRIEF Behavioral Regulation Index (parent report only), the SDQ conduct subscale, and the SDQ hyperactivity subscale. This study suggests that the increased risk of children with unilateral CP experiencing executive functioning difficulties in everyday life, conduct problems, and hyperactivity can be partly explained by decreased cognitive executive functioning abilities relative to children with typical development. © 2014 Mac Keith Press.

Does early communication mediate the relationship between motor ability and social function in children with cerebral palsy?

PubMed

Lipscombe, Belinda; Boyd, Roslyn N; Coleman, Andrea; Fahey, Michael; Rawicki, Barry; Whittingham, Koa

2016-01-01

Children diagnosed with neurodevelopmental conditions such as cerebral palsy (CP) are at risk of experiencing restrictions in social activities negatively impacting their subsequent social functioning. Research has identified motor and communication ability as being unique determinants of social function capabilities in children with CP, to date, no research has investigated whether communication is a mediator of the relationship between motor ability and social functioning. To investigate whether early communication ability at 24 months corrected age (ca.) mediates the relationship between early motor ability at 24 months ca. and later social development at 60 months ca. in a cohort of children diagnosed with cerebral palsy (CP). A cohort of 71 children (43 male) diagnosed with CP (GMFCS I=24, 33.8%, II=9, 12.7%, III=12, 16.9%, IV=10, 14.1%, V=16, 22.5%) were assessed at 24 and 60 months ca. Assessments included the Gross Motor Function Measure (GMFM), the Communication and Symbolic Behaviour Scales-Developmental Profile (CSBS-DP) Infant-Toddler Checklist and the Paediatric Evaluation of Disability Inventory (PEDI). A mediation model was examined using bootstrapping. Early communication skills mediated the relationship between early motor abilities and later social functioning, b=0.24 (95% CI=0.08-0.43 and the mediation model was significant, F (2, 68)=32.77, p<0.001, R(2)=0.49. Early communication ability partially mediates the relationship between early motor ability and later social function in children with CP. This demonstrates the important role of early communication in ongoing social development. Early identification of communication delay and enriched language exposure is crucial in this population. Copyright © 2016 Elsevier Ltd. All rights reserved.

Associations between children's social functioning and physical activity participation are not mediated by social acceptance: a cross-sectional study.

PubMed

Sebire, Simon J; Jago, Russell; Fox, Kenneth R; Page, Angie S; Brockman, Rowan; Thompson, Janice L

2011-09-30

Physical activity (PA) during childhood often occurs in social contexts. As such, children's ability to develop and maintain friendship groups may be important in understanding their PA. This paper investigates the associations among children's social functioning, and physical activity and whether perceptions of social acceptance mediate any social functioning-PA association. A cross sectional survey in which 652 10-11 year olds self-reported their peer (e.g. difficulties with friends) and conduct (e.g. anger/aggression) problems, prosocial behaviours (e.g. being kind to others) and perceptions of social acceptance. Physical activity was objectively assessed by Actigraph GT1M accelerometers to estimate counts per minute, (CPM) and minutes of moderate-to-vigorous physical activity (MVPA). Linear regression analyses were conducted to investigate associations between social functioning and PA. Indirect effects were analysed to explore mediation by social acceptance. Among boys, peer problems were negatively associated with CPM and MVPA and conduct problems were positively associated with CPM and MVPA. Prosocial behaviour was unrelated to PA in boys. Social functioning was not associated with PA among girls. Social acceptance did not mediate the social functioning-PA relationship. Boys' conduct and peer problems were associated positively and negatively respectively with their PA but this relationship was not mediated by perceptions of social acceptance. Future research should study alternative mediators to understand the processes underpinning this relationship.

Plant Enhancers: A Call for Discovery.

PubMed

Weber, Blaise; Zicola, Johan; Oka, Rurika; Stam, Maike

2016-11-01

Higher eukaryotes typically contain many different cell types, displaying different cellular functions that are influenced by biotic and abiotic cues. The different functions are characterized by specific gene expression patterns mediated by regulatory sequences such as transcriptional enhancers. Recent genome-wide approaches have identified thousands of enhancers in animals, reviving interest in enhancers in gene regulation. Although the regulatory roles of plant enhancers are as crucial as those in animals, genome-wide approaches have only very recently been applied to plants. Here we review characteristics of enhancers at the DNA and chromatin level in plants and other species, their similarities and differences, and techniques widely used for genome-wide discovery of enhancers in animal systems that can be implemented in plants. Copyright © 2016 Elsevier Ltd. All rights reserved.

Reading comprehension in adolescents with ADHD: exploring the poor comprehender profile and individual differences in vocabulary and executive functions.

PubMed

Martinussen, Rhonda; Mackenzie, Genevieve

2015-03-01

The overall objective of this study was to investigate reading comprehension in youth with and without a prior diagnosis of attention-deficit hyperactivity disorder (ADHD). The first goal was to determine whether youth with and without ADHD matched in word reading ability exhibited differences in reading comprehension proficiency. The next goal was to determine whether good and poor comprehenders within the ADHD subgroup differed from each other on language and academic achievement measures. The third objective was to examine whether word recognition or oral vocabulary knowledge mediated the effect of ADHD symptoms on reading comprehension performance. Youth with ADHD scored significantly lower than the comparison youth on a standardized measure of reading comprehension. Relative to good comprehenders with ADHD, poor comprehenders with ADHD exhibited weaknesses in expressive vocabulary, mathematical reasoning, written expression, and exhibited more executive function (EF) difficulties as reported by the teacher. Expressive vocabulary and word reading, but not teacher EF ratings, accounted for unique variance in reading comprehension performance and mediated the relationship between ADHD symptoms and reading comprehension. Implications for further research and educational practice are discussed. Copyright © 2015 Elsevier Ltd. All rights reserved.

Tetrahydroisoquinoline alkaloids mimic direct but not receptor-mediated inhibitory effects of estrogens and phytoestrogens on testicular endocrine function. Possible significance for Leydig cell insufficiency in alcohol addiction

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

Stammel, W.; Thomas, H.; Staib, W.

1991-01-01

Possible effects of various tetrahydroisoquinolines (TIQs) on rat testicular endocrine function were tested in vitro in order to prove whether these compounds may be mediators of the development of Leydig cell insufficiency. TIQ effects on different levels of regulation of testis function were compared in vitro with estrogen effects, since both classes of compounds have structural similarities. Gonadotropin-stimulated testosterone production by testicular Leydig cells was inhibited by tetrahydropapaveroline and isosalsoline, the IC{sub 50} values being comparable to those of estradiol, 2-hydroxyestradiol, and the phytoestrogens, coumestrol and genistein; salsolinol and salsoline were less effective, and salsolidine was ineffective. None of thesemore » TIQs interacted significantly with testicular estrogen receptor as analyzed by estradiol displacement. However, tetrahydropapaveroline, isosalsoline and salsolinol competitively inhibited substrate binding to cytochrome P45OXVII, with similar efficiency as the estrogens did; salsoline and salsolidine were again much less effective.« less

Orexin A/Hypocretin Modulates Leptin Receptor-Mediated Signaling by Allosteric Modulations Mediated by the Ghrelin GHS-R1A Receptor in Hypothalamic Neurons.

PubMed

Medrano, Mireia; Aguinaga, David; Reyes-Resina, Irene; Canela, Enric I; Mallol, Josefa; Navarro, Gemma; Franco, Rafael

2018-06-01

The hypothalamus is a key integrator of nutrient-seeking signals in the form of hormones and metabolites originated in both the central nervous system and the periphery. The main autocrine and paracrine target of orexinergic-related hormones such as leptin, orexin/hypocretin, and ghrelin are neuropeptide Y neurons located in the arcuate nucleus of the hypothalamus. The aim of this study was to investigate the expression and the molecular and functional relationships between leptin, orexin/hypocretin and ghrelin receptors. Biophysical studies in a heterologous system showed physical interactions between them, with potential formation of heterotrimeric complexes. Functional assays showed robust allosteric interactions particularly different when the three receptors are expressed together. Further biochemical and pharmacological assays provided evidence of heterotrimer functional expression in primary cultures of hypothalamic neurons. These findings constitute evidence of close relationships in the action of the three hormones already starting at the receptor level in hypothalamic cells.

Learning at different satiation levels reveals parallel functions for the cAMP-protein kinase A cascade in formation of long-term memory.

PubMed

Friedrich, Anke; Thomas, Ulf; Müller, Uli

2004-05-05

Learning and memory formation in intact animals is generally studied under defined parameters, including the control of feeding. We used associative olfactory conditioning of the proboscis extension response in honeybees to address effects of feeding status on processes of learning and memory formation. Comparing groups of animals with different but defined feeding status at the time of conditioning reveals new and characteristic features in memory formation. In animals fed 18 hr earlier, three-trial conditioning induces a stable memory that consists of different phases: a mid-term memory (MTM), translation-dependent early long-term memory (eLTM; 1-2 d), and a transcription-dependent late LTM (lLTM; > or =3 d). Additional feeding of a small amount of sucrose 4 hr before conditioning leads to a loss of all of these memory phases. Interestingly, the basal activity of the cAMP-dependent protein kinase A (PKA), a key player in LTM formation, differs in animals with different satiation levels. Pharmacological rescue of the low basal PKA activity in animals fed 4 hr before conditioning points to a specific function of cAMP-PKA cascade in mediating satiation-dependent memory formation. An increase in PKA activity during conditioning rescues only transcription-dependent lLTM; acquisition, MTM, and eLTM are still impaired. Thus, during conditioning, the cAMP-PKA cascade mediates the induction of the transcription-dependent lLTM, depending on the satiation level. This result provides the first evidence for a central and distinct function of the cAMP-PKA cascade connecting satiation level with learning.

Variability in nucleus accumbens activity mediates age-related suboptimal financial risk taking

PubMed Central

Samanez-Larkin, Gregory R.; Kuhnen, Camelia M.; Yoo, Daniel J.; Knutson, Brian

2010-01-01

As human life expectancy continues to rise, financial decisions of aging investors may have an increasing impact on the global economy. In this study, we examined age differences in financial decisions across the adult life span by combining functional neuroimaging with a dynamic financial investment task. During the task, older adults made more suboptimal choices than younger adults when choosing risky assets. This age-related effect was mediated by a neural measure of temporal variability in nucleus accumbens activity. These findings reveal a novel neural mechanism by which aging may disrupt rational financial choice. PMID:20107069

Childhood adversity and social functioning in psychosis: Exploring clinical and cognitive mediators.

PubMed

Palmier-Claus, Jasper; Berry, Katherine; Darrell-Berry, Hannah; Emsley, Richard; Parker, Sophie; Drake, Richard; Bucci, Sandra

2016-04-30

Childhood adversity may increase risk of impaired social functioning across the continuum of psychosis. However, the pathways by which adversity dictates functional outcome remain underexplored. This study investigated the association between childhood adversity and social functioning, and the clinical and cognitive mediators of this relationship. Fifty-four clinical (20 chronic, 20 first episode, 14 at ultra-high risk) and 120 non-clinical participants completed standardised questionnaires, semi-structured interviews and tests of theory of mind ability. The authors used multiple group structural equation modelling to fit mediation models allowing for differential relationships between the clinical and non-clinical samples. When examining each pathway separately, depression, paranoia and anxious attachment mediated the effect of childhood adversity on social functioning. In a combined model, depression was the only significant mediating variable with greater adversity predicting lower mood across groups. Childhood adversity did not significantly predict theory of mind ability in any of the models. This is the first study to indicate that childhood adversity acts on social functioning by increasing levels of depression, suggesting a common mechanism across the spectrum of psychosis. Clinical interventions should target low mood in order to improve social functioning at all stages of psychotic disorder. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Vascular risk factor burden, atherosclerosis, and functional dependence in old age: a population-based study.

PubMed

Welmer, Anna-Karin; Liang, Yajun; Angleman, Sara; Santoni, Giola; Yan, Zhongrui; Cai, Chuanzhu; Qiu, Chengxuan

2014-08-01

Vascular risk factors such as hypertension and obesity have been associated with physical limitations among older adults. The purpose of this study is to examine whether individual and aggregated vascular risk factors (VRFs) are associated with functional dependence and to what extent carotid atherosclerosis (CAS) or peripheral artery disease (PAD) may mediate the possible associations of aggregated VRFs with functional dependence. This cross-sectional study included 1,451 community-living participants aged ≥60 years in the Confucius Hometown Aging Project of China. Data on demographic features, hypertension, high total cholesterol, obesity, smoking, physical inactivity, diabetes, CAS, PAD, and cardiovascular diseases (CVDs) were collected through an interview, a clinical examination, and laboratory tests. Functional dependence was defined as being dependent in at least one activity in the personal or instrumental activities of daily living. Data were analyzed using multiple logistic models controlling for potential confounders. We used the mediation model to explore the potential mediating effect of CAS and PAD on the associations of aggregated VRFs with functional dependence. Of the 1,451 participants, 222 (15.3%) had functional dependence. The likelihood of functional dependence increased linearly with increasing number of VRFs (hypertension, high total cholesterol, abdominal obesity, and physical inactivity) (p for trend <0.002). Mediation analysis showed that controlling for demographics and CVDs up to 11% of the total association of functional dependence with clustering VRFs was mediated by CAS and PAD. Aggregation of multiple VRFs is associated with an increased likelihood of functional dependence among Chinese older adults; the association is partially mediated by carotid and peripheral artery atherosclerosis independently of CVDs.

The Mediator complex and transcription regulation

PubMed Central

Poss, Zachary C.; Ebmeier, Christopher C.

2013-01-01

The Mediator complex is a multi-subunit assembly that appears to be required for regulating expression of most RNA polymerase II (pol II) transcripts, which include protein-coding and most non-coding RNA genes. Mediator and pol II function within the pre-initiation complex (PIC), which consists of Mediator, pol II, TFIIA, TFIIB, TFIID, TFIIE, TFIIF and TFIIH and is approximately 4.0 MDa in size. Mediator serves as a central scaffold within the PIC and helps regulate pol II activity in ways that remain poorly understood. Mediator is also generally targeted by sequence-specific, DNA-binding transcription factors (TFs) that work to control gene expression programs in response to developmental or environmental cues. At a basic level, Mediator functions by relaying signals from TFs directly to the pol II enzyme, thereby facilitating TF-dependent regulation of gene expression. Thus, Mediator is essential for converting biological inputs (communicated by TFs) to physiological responses (via changes in gene expression). In this review, we summarize an expansive body of research on the Mediator complex, with an emphasis on yeast and mammalian complexes. We focus on the basics that underlie Mediator function, such as its structure and subunit composition, and describe its broad regulatory influence on gene expression, ranging from chromatin architecture to transcription initiation and elongation, to mRNA processing. We also describe factors that influence Mediator structure and activity, including TFs, non-coding RNAs and the CDK8 module. PMID:24088064

Marital Psychological and Physical Aggression and Children’s Mental and Physical Health: Direct, Mediated, and Moderated Effects

PubMed Central

El-Sheikh, Mona; Cummings, E. Mark; Kouros, Chrystyna D.; Elmore-Staton, Lori; Buckhalt, Joseph

2010-01-01

Relations between marital aggression (psychological and physical) and children’s health were examined. Children’s emotional insecurity was assessed as a mediator of these relations, with distinctions made between marital aggression against mothers and fathers and ethnicity (African American or European American), socioeconomic status, and child gender examined as moderators of effects. Participants were 251 community-recruited families, with multiple reporters of each construct. Aggression against either parent yielded similar effects for children. Children’s emotional insecurity mediated the relation between marital aggression and children’s internalizing, externalizing, and posttraumatic stress disorder symptoms. No differences were found in these pathways for African American and European American families or as a function of socioeconomic status or child gender. PMID:18229991

EGF-like peptide-enhanced cell motility in Dictyostelium functions independently of the cAMP-mediated pathway and requires active Ca2+/calmodulin signaling.

PubMed

Huber, Robert; O'Day, Danton H

2011-04-01

Current knowledge suggests that cell movement in the eukaryotic slime mold Dictyostelium discoideum is mediated by different signaling pathways involving a number of redundant components. Our previous research has identified a specific motility-enhancing function for epidermal growth factor-like (EGFL) repeats in Dictyostelium, specifically for the EGFL repeats of cyrA, a matricellular, calmodulin (CaM)-binding protein in Dictyostelium. Using mutants of cAMP signaling (carA(-), carC(-), gpaB(-), gpbA(-)), the endogenous calcium (Ca(2+)) release inhibitor TMB-8, the CaM antagonist W-7, and a radial motility bioassay, we show that DdEGFL1, a synthetic peptide whose sequence is obtained from the first EGFL repeat of cyrA, functions independently of the cAMP-mediated signaling pathways to enhance cell motility through a mechanism involving Ca(2+) signaling, CaM, and RasG. We show that DdEGFL1 increases the amounts of polymeric myosin II heavy chain and actin in the cytoskeleton by 24.1±10.7% and 25.9±2.1% respectively and demonstrate a link between Ca(2+)/CaM signaling and cytoskeletal dynamics. Finally, our findings suggest that carA and carC mediate a brake mechanism during chemotaxis since DdEGFL1 enhanced the movement of carA(-)/carC(-) cells by 844±136% compared to only 106±6% for parental DH1 cells. Based on our data, this signaling pathway also appears to involve the G-protein β subunit, RasC, RasGEFA, and protein kinase B. Together, our research provides insight into the functionality of EGFL repeats in Dictyostelium and the signaling pathways regulating cell movement in this model organism. It also identifies several mechanistic components of DdEGFL1-enhanced cell movement, which may ultimately provide a model system for understanding EGFL repeat function in higher organisms. Copyright © 2010 Elsevier Inc. All rights reserved.

The absence of Grb2-associated binder 2 (Gab2) does not disrupt NK cell development and functions.

PubMed

Zompi, Simona; Gu, Hahiua; Colucci, Francesco

2004-10-01

Scaffolding molecules bind simultaneously and link together various components of signal-transduction pathways. Grb2-associated binder 2 (Gab2) is a scaffolding protein required for FcgammaR-initiated allergic responses in mast cells and FcgammaR-mediated phagocytosis in macrophages, where it links IgE and IgG receptors to the phosphatidylinositol-3 kinase (PI-3K) pathway. The FcgammaR expressed by natural killer (NK) cells triggers antibody-dependent cellular cytotoxicity (ADCC). We show here that mouse NK cells express Gab2 and that although PI-3K was required for ADCC, this FcgammaR-mediated function was normal in Gab2-/- NK cells. Moreover, NK cell development, spontaneous cytotoxicity, and responses to and production of cytokines were not perturbed in Gab2-/- mice. Considering the striking differences between the signaling requirements of FcgammaR in macrophages and NK cells, our findings suggest that the organization of signal transduction downstream of the same FcR can be cell type-specific. Conversely, Gab family members Gab1, Gab2, and Gab3 may play specific roles in different leukocytes. As pharmacological targeting of Gab2 in mast cells is a potential strategy to treat allergy, our results suggest prudence, as NK cells may participate in IgE-mediated anaphylaxis in a Gab2-independent manner.

Rac1 and Rac3 have opposing functions in cell adhesion and differentiation of neuronal cells.

PubMed

Hajdo-Milasinović, Amra; Ellenbroek, Saskia I J; van Es, Saskia; van der Vaart, Babet; Collard, John G

2007-02-15

Rac1 and Rac3 are highly homologous members of the Rho small GTPase family. Rac1 is ubiquitously expressed and regulates cell adhesion, migration and differentiation in various cell types. Rac3 is primarily expressed in brain and may therefore have a specific function in neuronal cells. We found that depletion of Rac1 by short interference RNA leads to decreased cell-matrix adhesions and cell rounding in neuronal N1E-115 cells. By contrast, depletion of Rac3 induces stronger cell adhesions and dramatically increases the outgrowth of neurite-like protrusions, suggesting opposite functions for Rac1 and Rac3 in neuronal cells. Consistent with this, overexpression of Rac1 induces cell spreading, whereas overexpression of Rac3 results in a contractile round morphology. Rac1 is mainly found at the plasma membrane, whereas Rac3 is predominantly localized in the perinuclear region. Residues 185-187, present in the variable polybasic rich region at the carboxyl terminus are responsible for the difference in phenotype induced by Rac1 and Rac3 as well as for their different intracellular localization. The Rac1-opposing function of Rac3 is not mediated by or dependent on components of the RhoA signaling pathway. It rather seems that Rac3 exerts its function through negatively affecting integrin-mediated cell-matrix adhesions. Together, our data reveal that Rac3 opposes Rac1 in the regulation of cell adhesion and differentiation of neuronal cells.

Screening and Selection of New Antagonists of the RING-Mediated Hdm2/Hdmx Interaction

DTIC Science & Technology

2012-03-01

NUMBER (include area code) Standard Form 298 (Rev. 8-98) Prescribed by ANSI Std. Z39.18 W81XWH-10-1-0151 Screening and Selection of New ...in which individual bacteria express a different cyclotide. This comprises a new single cell-single compound approach to identify protein-protein... functionally inhibited at multiple steps to reactivate p53 function . Numbered circles indicate potential therapeutical targets for the development of Hdm2

The K-turn motif in riboswitches and other RNA species☆

PubMed Central

Lilley, David M.J.

2014-01-01

The kink turn is a widespread structure motif that introduces a tight bend into the axis of duplex RNA. This generally functions to mediate tertiary interactions, and to serve as a specific protein binding site. K-turns or closely related structures are found in at least seven different riboswitch structures, where they function as key architectural elements that help generate the ligand binding pocket. This article is part of a Special Issue entitled: Riboswitches. PMID:24798078

Childhood Cumulative Risk Exposure and Adult Amygdala Volume and Function

PubMed Central

Evans, Gary W.; Swain, James E.; King, Anthony P.; Wang, Xin; Javanbakht, Arash; Ho, S. Shaun; Angstadt, Michael; Phan, K. Luan; Xie, Hong; Liberzon, Israel

2015-01-01

Considerable work indicates that early cumulative risk exposure is aversive to human development, but very little research has examined neurological underpinnings of these robust findings. We investigated amygdala volume and reactivity to facial stimuli among adults (M = 23.7 years, n = 54) as a function of cumulative risk exposure during childhood (ages 9 and 13). In addition, we tested whether expected, cumulative risk elevations in amygdala volume would mediate functional reactivity of the amygdala during socio-emotional processing. Risks included substandard housing quality, noise, crowding, family turmoil, child separation from family, and violence. Total and left hemisphere adult amygdala volumes, respectively were positively related to cumulative risk exposure during childhood. The links between childhood cumulative risk exposure and elevated amygdala responses to emotionally neutral facial stimuli in adulthood were mediated by the respective amygdala volumes. Cumulative risk exposure in later adolescence (17 years), however, was unrelated to subsequent, adult amygdala volume or function. Physical and socioemotional risk exposures early in life appear to alter amygdala development, rendering adults more reactive to ambiguous stimuli such as neutral faces. These stress-related differences in childhood amygdala development might contribute to well-documented psychological distress as a function of early risk exposure. PMID:26469872

Intergroup contact and team functioning among nursing students: the mediation role of intergroup anxiety.

PubMed

Marletta, Giuseppe; Sarli, Leopoldo; Caricati, Luca; Mancini, Tiziana

2017-07-18

The improvement of team effectivity is one of the main concerns for healthcare organizations. Moreover, healthcare organizations must cope with increasing multicultural composition of both workforce and patients. The intergroup contact theory suggests that frequent and positive face-to-face contact among professionals or students with different cultural heritage can help to reach both increasing team effectiveness and adequate care in a multicultural setting. The aim was then to verify whether intergroup contact during practical training would decrease intergroup anxiety and then increase team functioning. A cross-sectional design was used in which a questionnaire was delivered to 83 nursing students. According to the intergroup contact theory, frequent and positive contact with non-native professionals decreased the intergroup anxiety which, in turn, increased prejudice and, more importantly, decreased team functioning. Moreover, intergroup anxiety showed a complete mediation effect on the relations between intergroup contact during practical training and both negative attitude toward immigrants and team functioning. Intergroup contact with non-native professionals or students during practical training is able to indirectly decrease prejudice and improve team functioning by lowering the anxiety that is aroused by encounter with non-native individuals.

Dynamic conformational switching in the chemokine ligand is essential for G-protein-coupled receptor activation

PubMed Central

Joseph, Prem Raj B.; Sawant, Kirti V.; Isley, Angela; Pedroza, Mesias; Garofalo, Roberto P.; Richardson, Ricardo M.; Rajarathnam, Krishna

2014-01-01

Chemokines mediate diverse functions from organogenesis to mobilizing leucocytes, and are unusual agonists for class-A GPCRs (G-protein-coupled receptors) because of their large size and multi-domain structure. The current model for receptor activation, which involves interactions between chemokine N-loop and receptor N-terminal residues (Site-I) and between chemokine N-terminal and receptor extracellular loop/transmembrane residues (Site-II), fails to describe differences in ligand/receptor selectivity and the activation of multiple signalling pathways. In the present study, we show in neutrophil-activating chemokine CXCL8 that the highly conserved GP (glycine-proline) motif located distal to both N-terminal and N-loop residues couples Site-I and Site-II interactions. Mutations in the GP motif caused various differences from native-like function to complete loss of activity that could not be correlated with the specific mutation, receptor affinity or subtype, or a specific signalling pathway. NMR studies indicated that the GP motif does not influence Site-I interactions, but molecular dynamics simulations suggested that this motif dictates substates of the CXCL8 conformational ensemble. We conclude that the GP motif enables diverse receptor functions by controlling cross-talk between Site-I and Site-II, and further propose that the repertoire of chemokine functions is best described by a conformational ensemble model in which a network of long-range coupled indirect interactions mediate receptor activity. PMID:24032673

Airway and Pulmonary β2-Adrenergic Vasodilatory Function in Current Smokers and Never Smokers.

PubMed

Hurwitz, Barry E; Mendes, Eliana S; Schmid, Andreas; Parker, Meela; Arana, Johana; Gonzalez, Alex; Wanner, Adam

2017-03-01

Cigarette smoking has been associated with diminished vasodilatory function in the airway circulation. It is possible that cigarette smoking similarly affects the pulmonary circulation before resting pulmonary circulatory abnormalities become manifested. The aim of this study was to compare the acute effect of inhaled albuterol on airway and pulmonary hemodynamic function as an index of β 2 -adrenoceptor-mediated vasodilation in smokers and never smokers. In 30 adults, airway and pulmonary vascular function was assessed before and 15 min after albuterol inhalation (270 μg). From mean systemic arterial pressure, cardiac output, airway blood flow, and mean pulmonary arterial pressure, airway vascular resistance (AVR) and pulmonary vascular resistance (PVR) were derived. Albuterol induced a substantial drop in mean (± SE) PVR (-67.2% ± 5%), with no difference between groups. In contrast, the albuterol-induced decrease in AVR was significantly greater in never smokers than in smokers (-28.6% ± 3% vs -3.1% ± 6%; P < .02). These results are consistent with a dysfunction in a β 2 -adrenergic signaling pathway mediating vasorelaxation in the airway circulation of current smokers. The vasodilatory deficit in the airway circulation but not in the pulmonary circulation could be related to local differences in the impact of cigarette smoke on the vascular endothelium. Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.

Kinetics of the iodine- and bromine-mediated transport of halide ions: demonstration of an interfacial complexation mechanism.

PubMed Central

Klotz, K H; Benz, R

1993-01-01

Stationary and kinetic experiments were performed on lipid bilayer membranes to study the mechanism of iodine- and bromine-mediated halide transport in detail. The stationary conductance data suggested that four different 1:1 complexes between I2 and Br2 and the halides I- and Br- were responsible for the observed conductance increase by iodine and bromine (I3-, I2Br-, Br2I-, and Br3-). Charge pulse experiments allowed the further elucidation of the transport mechanism. Only two of three exponential voltage relaxations predicted by the Läuger model could be resolved under all experimental conditions. This means that either the heterogeneous complexation reactions kR (association) and kD (dissociation) were too fast to be resolved or that the neutral carriers were always in equilibrium within the membrane. Experiments at different carrier and halide concentrations suggested that the translocation of the neutral carrier is much faster than the other processes involved in carrier-mediated ion transport. The model was modified accordingly. From the charge pulse data at different halide concentrations, the translocation rate constant of the complexed carriers, kAS, the dissociation constant, kD, and the total surface concentration of charged carriers, NAS, could be evaluated from one single charge pulse experiment. The association rate of the complex, kR, could be obtained in some cases from the plot of the stationary conductance data as a function of the halide concentration in the aqueous phase. The translocation rate constant, kAS, of the different complexes is a function of the image force and of the Born charging energy. It increases 5000-fold from Br3- to I3- because of an enlarged ion radius. PMID:8312500

Intersections between the Autism Spectrum and the Internet: Perceived Benefits and Preferred Functions of Computer-Mediated Communication

ERIC Educational Resources Information Center

Gillespie-Lynch, Kristen; Kapp, Steven K.; Shane-Simpson, Christina; Smith, David Shane; Hutman, Ted

2014-01-01

An online survey compared the perceived benefits and preferred functions of computer-mediated communication of participants with (N = 291) and without ASD (N = 311). Participants with autism spectrum disorder (ASD) perceived benefits of computer-mediated communication in terms of increased comprehension and control over communication, access to…

Biotic and Abiotic Properties Mediating Plant Diversity Effects on Soil Microbial Communities in an Experimental Grassland

PubMed Central

Lange, Markus; Habekost, Maike; Eisenhauer, Nico; Roscher, Christiane; Bessler, Holger; Engels, Christof; Oelmann, Yvonne; Scheu, Stefan; Wilcke, Wolfgang; Schulze, Ernst-Detlef; Gleixner, Gerd

2014-01-01

Plant diversity drives changes in the soil microbial community which may result in alterations in ecosystem functions. However, the governing factors between the composition of soil microbial communities and plant diversity are not well understood. We investigated the impact of plant diversity (plant species richness and functional group richness) and plant functional group identity on soil microbial biomass and soil microbial community structure in experimental grassland ecosystems. Total microbial biomass and community structure were determined by phospholipid fatty acid (PLFA) analysis. The diversity gradient covered 1, 2, 4, 8, 16 and 60 plant species and 1, 2, 3 and 4 plant functional groups (grasses, legumes, small herbs and tall herbs). In May 2007, soil samples were taken from experimental plots and from nearby fields and meadows. Beside soil texture, plant species richness was the main driver of soil microbial biomass. Structural equation modeling revealed that the positive plant diversity effect was mainly mediated by higher leaf area index resulting in higher soil moisture in the top soil layer. The fungal-to-bacterial biomass ratio was positively affected by plant functional group richness and negatively by the presence of legumes. Bacteria were more closely related to abiotic differences caused by plant diversity, while fungi were more affected by plant-derived organic matter inputs. We found diverse plant communities promoted faster transition of soil microbial communities typical for arable land towards grassland communities. Although some mechanisms underlying the plant diversity effect on soil microorganisms could be identified, future studies have to determine plant traits shaping soil microbial community structure. We suspect differences in root traits among different plant communities, such as root turnover rates and chemical composition of root exudates, to structure soil microbial communities. PMID:24816860

GPER Mediates Functional Endothelial Aging in Renal Arteries.

PubMed

Meyer, Matthias R; Rosemann, Thomas; Barton, Matthias; Prossnitz, Eric R

2017-01-01

Aging is associated with impaired renal artery function, which is partly characterized by arterial stiffening and a reduced vasodilatory capacity due to excessive generation of reactive oxygen species by NADPH oxidases (Nox). The abundance and activity of Nox depends on basal activity of the heptahelical transmembrane receptor GPER; however, whether GPER contributes to age-dependent functional changes in renal arteries is unknown. This study investigated the effect of aging and Nox activity on renal artery tone in wild-type and GPER-deficient (Gper-/-) mice (4 and 24 months old). In wild-type mice, aging markedly impaired endothelium-dependent, nitric oxide (NO)-mediated relaxations to acetylcholine, which were largely preserved in renal arteries of aged Gper-/- mice. The Nox inhibitor gp91ds-tat abolished this difference by greatly enhancing relaxations in wild-type mice, while having no effect in Gper-/- mice. Contractions to angiotensin II and phenylephrine in wild-type mice were partly sensitive to gp91ds-tat but unaffected by aging. Again, deletion of GPER abolished effects of Nox inhibition on contractile responses. In conclusion, basal activity of GPER is required for the age-dependent impairment of endothelium-dependent, NO-mediated relaxation in the renal artery. Restoration of relaxation by a Nox inhibitor in aged wild-type but not Gper-/- mice strongly supports a role for Nox-derived reactive oxygen species as the underlying cause. Pharmacological blockers of GPER signaling may thus be suitable to inhibit functional endothelial aging of renal arteries by reducing Nox-derived oxidative stress and, possibly, the associated age-dependent deterioration of kidney function. © 2017 S. Karger AG, Basel.

In vivo control mechanisms of motor-cargo movement on microtubules

NASA Astrophysics Data System (ADS)

Gunawardena, Shermali

2014-03-01

Within axons, molecular motors transport essential components required for neuronal growth and viability. Although many levels of regulation must exist for proper anterograde and retrograde transport of vital proteins, little is known about these mechanisms. Previous work suggested that the amyloid precursor protein (APP) functions as a kinesin-1 receptor during transport. However, how APP vesicle motility is regulated is unclear. Using genetics and in vivo imaging in Drosophila we showed that reduction of presenilin (PS) substantially increased anterograde and retrograde APP vesicle velocities. Strikingly, PS deficiency had no effect on an unrelated cargo vesicle containing synaptotagmin, which is powered by a different kinesin motor. Increased PS-mediated velocities required functional kinesin-1 and dynein motors. We also found that these PS-mediated effects on motor protein function were mediated via a pathway that involves glycogen synthase kinase-3 β (GSK-3 β) . PS genetically interacted with GSK-3 β in an activity dependent manner. Excess of active GSK-3 β perturbed transport by causing axonal blockages, which were enhanced by reduction of kinesin-1 or dynein, while excess of non-functional GSK-3 β had no effect. Strikingly, GSK-3 β-activity dependent transport defects were enhanced by reduction of PS. Collectively, our findings suggest that PS and GSK-3 β are required for normal motor protein function, and we propose a model in which PS likely regulates GSK-3 β activity during transport. These findings have important implications for our understanding of the complex regulatory machinery that must exist in vivo and how this system is coordinated during vesicle motility on microtubules.

Bcl2-associated Athanogene 3 Interactome Analysis Reveals a New Role in Modulating Proteasome Activity*

PubMed Central

Chen, Ying; Yang, Li-Na; Cheng, Li; Tu, Shun; Guo, Shu-Juan; Le, Huang-Ying; Xiong, Qian; Mo, Ran; Li, Chong-Yang; Jeong, Jun-Seop; Jiang, Lizhi; Blackshaw, Seth; Bi, Li-Jun; Zhu, Heng; Tao, Sheng-Ce; Ge, Feng

2013-01-01

Bcl2-associated athanogene 3 (BAG3), a member of the BAG family of co-chaperones, plays a critical role in regulating apoptosis, development, cell motility, autophagy, and tumor metastasis and in mediating cell adaptive responses to stressful stimuli. BAG3 carries a BAG domain, a WW domain, and a proline-rich repeat (PXXP), all of which mediate binding to different partners. To elucidate BAG3's interaction network at the molecular level, we employed quantitative immunoprecipitation combined with knockdown and human proteome microarrays to comprehensively profile the BAG3 interactome in humans. We identified a total of 382 BAG3-interacting proteins with diverse functions, including transferase activity, nucleic acid binding, transcription factors, proteases, and chaperones, suggesting that BAG3 is a critical regulator of diverse cellular functions. In addition, we characterized interactions between BAG3 and some of its newly identified partners in greater detail. In particular, bioinformatic analysis revealed that the BAG3 interactome is strongly enriched in proteins functioning within the proteasome-ubiquitination process and that compose the proteasome complex itself, suggesting that a critical biological function of BAG3 is associated with the proteasome. Functional studies demonstrated that BAG3 indeed interacts with the proteasome and modulates its activity, sustaining cell survival and underlying resistance to therapy through the down-modulation of apoptosis. Taken as a whole, this study expands our knowledge of the BAG3 interactome, provides a valuable resource for understanding how BAG3 affects different cellular functions, and demonstrates that biologically relevant data can be harvested using this kind of integrated approach. PMID:23824909

Parent-child interaction, maternal depressive symptoms and preterm infant cognitive function.

PubMed

McManus, Beth M; Poehlmann, Julie

2012-06-01

Preterm infants are at risk for cognitive difficulties due to infant neurological immaturity and family social disadvantage, and this may be exacerbated by maternal depressive symptoms. This longitudinal study of infants born preterm (<35 weeks) or low birth weight (<2500 g) (n = 137) tests if maternal depressive symptoms at 4 months is associated with preterm children's cognitive function at 16 months. Additionally, we test if this association is mediated by the quality of parent-child interaction at 9 months, and if these associations differ by levels of maternal social support. Children's cognitive function was measured using the Bayley Scales of Infant Development, 2nd edition. Maternal depressive symptoms were measured using the Center for Epidemiologic Studies Depression Scale. Perceived social support was measured using the Maternal Support scale. The quality of parent-child interaction was measured using the Parent-Child Early Relational Assessment. Linear regression and structural equation modeling were used to test the research questions. Postnatal depression at 4 months is associated with lower cognitive function (mean difference = -5.22, 95% CI: [-10.19, -0.25]) at 16 months controlling for a host of socioeconomic characteristics. For mothers with fewer depressive symptoms, bolstering effects of maternal supports on children's cognitive function were evident. We find no evidence for effect mediation by quality of parent-child interaction. Early exposure to maternal depressive symptoms appears to have a negative influence on preterm children's later cognitive function. These findings suggest important policy and programmatic implications for early detection and intervention for families of preterm infants. Copyright © 2012 Elsevier Inc. All rights reserved.

Circuit Resistance Training Attenuates Acute Exertion-Induced Reductions in Arterial Function but Not Inflammation in Obese Women

PubMed Central

Franklin, Nina C.; Robinson, Austin T.; Bian, Jing-Tan; Ali, Mohamed M.; Norkeviciute, Edita; McGinty, Patrick

2015-01-01

Abstract Background: Cardiovascular disease (CVD) is a leading cause of preventable death among young women in the United States. Habitual resistance exercise training is known to have beneficial effects on endothelial function and CVD risk factors, including obesity; however, previous studies show that acute resistance exercise impairs endothelial function in obese adults who are sedentary, a response that may be linked to inflammation. We sought to determine if circuit-based resistance training (CRT) attenuates acute resistance exercise-induced reductions in endothelial function in a population of young, obese, sedentary women and whether or not inflammation plays a role in this response. Methods: Eighteen obese [body mass index (BMI) 30.0–40.0 kg·m−2] young premenopausal women were randomly assigned to either a CRT group or a no-exercise control group (CON). Conduit artery endothelial function was assessed using brachial artery flow-mediated dilation (FMD) determined by ultrasound before and after a single bout of strenuous weightlifting (SWL). In addition, circulating inflammatory mediators (tumor necrosis factor-α and C-reactive protein), blood pressure, fasting blood lipids, glucose, waist circumference, body composition, and aerobic capacity were assessed. Results: Among participants randomized to the CRT group, 8 weeks of training led to considerable increases in FMD after SWL (P=0.001) compared to the CON group. However, no significant differences between the groups were observed in circulating inflammatory mediators, blood pressure, fasting blood lipids, or other physical and physiological characteristics. Conclusions: This study shows that CRT alleviates acute exertion-induced reductions in endothelial function among obese sedentary women in the absence of changes in inflammation. PMID:25844686

Region-specific spike frequency acceleration in Layer 5 pyramidal neurons mediated by Kv1 subunits

PubMed Central

Miller, Mark N; Okaty, Benjamin W; Nelson, Sacha B

2009-01-01

Separation of the cortical sheet into functionally distinct regions is a hallmark of neocortical organization. Cortical circuit function emerges from afferent and efferent connectivity, local connectivity within the cortical microcircuit, and the intrinsic membrane properties of neurons that comprise the circuit. While localization of functions to particular cortical areas can be partially accounted for by regional differences in both long range and local connectivity, it is unknown whether the intrinsic membrane properties of cortical cell-types differ between cortical regions. Here we report the first example of a region-specific firing type in layer 5 pyramidal neurons, and show that the intrinsic membrane and integrative properties of a discrete subtype of layer 5 pyramidal neurons differ between primary motor and somatosensory cortices due to region and cell-type-specific Kv1 subunit expression. PMID:19091962

Comparative genomics of 28 Salmonella enterica isolates: evidence for CRISPR-mediated adaptive sublineage evolution.

PubMed

Fricke, W Florian; Mammel, Mark K; McDermott, Patrick F; Tartera, Carmen; White, David G; Leclerc, J Eugene; Ravel, Jacques; Cebula, Thomas A

2011-07-01

Despite extensive surveillance, food-borne Salmonella enterica infections continue to be a significant burden on public health systems worldwide. As the S. enterica species comprises sublineages that differ greatly in antigenic representation, virulence, and antimicrobial resistance phenotypes, a better understanding of the species' evolution is critical for the prediction and prevention of future outbreaks. The roles that virulence and resistance phenotype acquisition, exchange, and loss play in the evolution of S. enterica sublineages, which to a certain extent are represented by serotypes, remains mostly uncharacterized. Here, we compare 17 newly sequenced and phenotypically characterized nontyphoidal S. enterica strains to 11 previously sequenced S. enterica genomes to carry out the most comprehensive comparative analysis of this species so far. These phenotypic and genotypic data comparisons in the phylogenetic species context suggest that the evolution of known S. enterica sublineages is mediated mostly by two mechanisms, (i) the loss of coding sequences with known metabolic functions, which leads to functional reduction, and (ii) the acquisition of horizontally transferred phage and plasmid DNA, which provides virulence and resistance functions and leads to increasing specialization. Matches between S. enterica clustered regularly interspaced short palindromic repeats (CRISPR), part of a defense mechanism against invading plasmid and phage DNA, and plasmid and prophage regions suggest that CRISPR-mediated immunity could control short-term phenotype changes and mediate long-term sublineage evolution. CRISPR analysis could therefore be critical in assessing the evolutionary potential of S. enterica sublineages and aid in the prediction and prevention of future S. enterica outbreaks.

Comparative Genomics of 28 Salmonella enterica Isolates: Evidence for CRISPR-Mediated Adaptive Sublineage Evolution ▿†

PubMed Central

Fricke, W. Florian; Mammel, Mark K.; McDermott, Patrick F.; Tartera, Carmen; White, David G.; LeClerc, J. Eugene; Ravel, Jacques; Cebula, Thomas A.

2011-01-01

Despite extensive surveillance, food-borne Salmonella enterica infections continue to be a significant burden on public health systems worldwide. As the S. enterica species comprises sublineages that differ greatly in antigenic representation, virulence, and antimicrobial resistance phenotypes, a better understanding of the species' evolution is critical for the prediction and prevention of future outbreaks. The roles that virulence and resistance phenotype acquisition, exchange, and loss play in the evolution of S. enterica sublineages, which to a certain extent are represented by serotypes, remains mostly uncharacterized. Here, we compare 17 newly sequenced and phenotypically characterized nontyphoidal S. enterica strains to 11 previously sequenced S. enterica genomes to carry out the most comprehensive comparative analysis of this species so far. These phenotypic and genotypic data comparisons in the phylogenetic species context suggest that the evolution of known S. enterica sublineages is mediated mostly by two mechanisms, (i) the loss of coding sequences with known metabolic functions, which leads to functional reduction, and (ii) the acquisition of horizontally transferred phage and plasmid DNA, which provides virulence and resistance functions and leads to increasing specialization. Matches between S. enterica clustered regularly interspaced short palindromic repeats (CRISPR), part of a defense mechanism against invading plasmid and phage DNA, and plasmid and prophage regions suggest that CRISPR-mediated immunity could control short-term phenotype changes and mediate long-term sublineage evolution. CRISPR analysis could therefore be critical in assessing the evolutionary potential of S. enterica sublineages and aid in the prediction and prevention of future S. enterica outbreaks. PMID:21602358

Susceptibility to T cell-mediated liver injury is enhanced in asialoglycoprotein receptor-deficient mice.

PubMed

McVicker, Benita L; Thiele, Geoffrey M; Casey, Carol A; Osna, Natalia A; Tuma, Dean J

2013-05-01

T cell activation and associated pro-inflammatory cytokine production is a pathological feature of inflammatory liver disease. It is also known that liver injury is associated with marked impairments in the function of many hepatic proteins including a hepatocyte-specific binding protein, the asialoglycoprotein receptor (ASGPR). Recently, it has been suggested that hepatic ASGPRs may play an important role in the physiological regulation of T lymphocytes, leading to our hypothesis that ASGPR defects correlate with inflammatory-mediated events in liver diseases. Therefore, in this study we investigated whether changes in hepatocellular ASGPR expression were related to the dysregulation of intrahepatic T lymphocytes and correlate with the development of T-cell mediated hepatitis. Mice lacking functional ASGPRs (receptor-deficient, RD), and wild-type (WT) controls were intravenously injected with T-cell mitogens, Concanavalin A (Con A) or anti-CD3 antibody. As a result of T cell mitogen treatment, RD mice lacking hepatic ASGPRs displayed enhancements in liver pathology, transaminase activities, proinflammatory cytokine expression, and caspase activation compared to that observed in normal WT mice. Furthermore, FACS analysis demonstrated that T-cell mitogen administration resulted in a significant rise in the percentage of CD8+ lymphocytes present in the livers of RD animals versus WT mice. Since these two mouse strains differ only in whether they express the hepatic ASGPR, it can be concluded that proper ASGPR function exerts a protective effect against T cell mediated hepatitis and that impairments to this hepatic receptor could be related to the accumulation of cytotoxic T cells that are observed in inflammatory liver diseases. Published by Elsevier B.V.

Effects of acidification on olfactory-mediated behaviour in freshwater and marine ecosystems: a synthesis

PubMed Central

Leduc, Antoine O. H. C.; Munday, Philip L.; Brown, Grant E.; Ferrari, Maud C. O.

2013-01-01

For many aquatic organisms, olfactory-mediated behaviour is essential to the maintenance of numerous fitness-enhancing activities, including foraging, reproduction and predator avoidance. Studies in both freshwater and marine ecosystems have demonstrated significant impacts of anthropogenic acidification on olfactory abilities of fish and macroinvertebrates, leading to impaired behavioural responses, with potentially far-reaching consequences to population dynamics and community structure. Whereas the ecological impacts of impaired olfactory-mediated behaviour may be similar between freshwater and marine ecosystems, the underlying mechanisms are quite distinct. In acidified freshwater, molecular change to chemical cues along with reduced olfaction sensitivity appear to be the primary causes of olfactory-mediated behavioural impairment. By contrast, experiments simulating future ocean acidification suggest that interference of high CO2 with brain neurotransmitter function is the primary cause for olfactory-mediated behavioural impairment in fish. Different physico-chemical characteristics between marine and freshwater systems are probably responsible for these distinct mechanisms of impairment, which, under globally rising CO2 levels, may lead to strikingly different consequences to olfaction. While fluctuations in pH may occur in both freshwater and marine ecosystems, marine habitat will remain alkaline despite future ocean acidification caused by globally rising CO2 levels. In this synthesis, we argue that ecosystem-specific mechanisms affecting olfaction need to be considered for effective management and conservation practices. PMID:23980246

Effects of acidification on olfactory-mediated behaviour in freshwater and marine ecosystems: a synthesis.

PubMed

Leduc, Antoine O H C; Munday, Philip L; Brown, Grant E; Ferrari, Maud C O

2013-01-01

For many aquatic organisms, olfactory-mediated behaviour is essential to the maintenance of numerous fitness-enhancing activities, including foraging, reproduction and predator avoidance. Studies in both freshwater and marine ecosystems have demonstrated significant impacts of anthropogenic acidification on olfactory abilities of fish and macroinvertebrates, leading to impaired behavioural responses, with potentially far-reaching consequences to population dynamics and community structure. Whereas the ecological impacts of impaired olfactory-mediated behaviour may be similar between freshwater and marine ecosystems, the underlying mechanisms are quite distinct. In acidified freshwater, molecular change to chemical cues along with reduced olfaction sensitivity appear to be the primary causes of olfactory-mediated behavioural impairment. By contrast, experiments simulating future ocean acidification suggest that interference of high CO2 with brain neurotransmitter function is the primary cause for olfactory-mediated behavioural impairment in fish. Different physico-chemical characteristics between marine and freshwater systems are probably responsible for these distinct mechanisms of impairment, which, under globally rising CO2 levels, may lead to strikingly different consequences to olfaction. While fluctuations in pH may occur in both freshwater and marine ecosystems, marine habitat will remain alkaline despite future ocean acidification caused by globally rising CO2 levels. In this synthesis, we argue that ecosystem-specific mechanisms affecting olfaction need to be considered for effective management and conservation practices.

APOC3 Loss-of-Function Mutations, Remnant Cholesterol, Low-Density Lipoprotein Cholesterol, and Cardiovascular Risk: Mediation- and Meta-Analyses of 137 895 Individuals.

PubMed

Wulff, Anders B; Nordestgaard, Børge G; Tybjærg-Hansen, Anne

2018-03-01

Loss-of-function mutations in APOC3 associate with low remnant cholesterol levels and low risk of ischemic vascular disease (IVD). Because some studies show an additional association with low levels of low-density lipoprotein cholesterol (LDL-C), low LDL-C may explain the low risk of IVD in APOC3 loss-of-function heterozygotes. We tested to what extent the low risk of IVD in APOC3 loss-of-function heterozygotes is mediated by low plasma remnant cholesterol and LDL-C. In APOC3 loss-of-function heterozygotes versus noncarriers, we first determined remnant cholesterol and LDL-C levels in meta-analyses of 137 895 individuals. Second, we determined whether the association with LDL-C was masked by lipid-lowering therapy. Finally, using mediation analysis, we determined the fraction of the low risk of IVD and ischemic heart disease mediated by remnant cholesterol and LDL-C. In meta-analyses, remnant cholesterol was 43% lower (95% confidence interval, 40%-47%), and LDL-C was 4% lower (1%-6%) in loss-of-function heterozygotes (n=776) versus noncarriers. In the general population, LDL-C was 3% lower in loss-of-function heterozygotes versus noncarriers, 4% lower when correcting for lipid-lowering therapy, and 3% lower in untreated individuals ( P values, 0.06-0.008). Remnant cholesterol mediated 37% of the observed 41% lower risk of IVD and 54% of the observed 36% lower risk of ischemic heart disease; corresponding values mediated by LDL-C were 1% and 2%. The low risk of IVD observed in APOC3 loss-of-function heterozygotes is mainly mediated by the associated low remnant cholesterol and not by low LDL-C. Furthermore, the contribution of LDL-C to IVD risk was not masked by lipid-lowering therapy. This suggests APOC3 and remnant cholesterol as important new targets for reducing cardiovascular risk. © 2018 American Heart Association, Inc.

The Role of Hyperglycemia, Insulin Resistance, and Blood Pressure in Diabetes-Associated Differences in Cognitive Performance-The Maastricht Study.

PubMed

Geijselaers, Stefan L C; Sep, Simone J S; Claessens, Danny; Schram, Miranda T; van Boxtel, Martin P J; Henry, Ronald M A; Verhey, Frans R J; Kroon, Abraham A; Dagnelie, Pieter C; Schalkwijk, Casper G; van der Kallen, Carla J H; Biessels, Geert Jan; Stehouwer, Coen D A

2017-11-01

To study to what extent differences in cognitive performance between individuals with different glucose metabolism status are potentially attributable to hyperglycemia, insulin resistance, and blood pressure-related variables. We used cross-sectional data from 2,531 participants from the Maastricht Study (mean age ± SD, 60 ± 8 years; 52% men; n = 666 with type 2 diabetes), all of whom completed a neuropsychological test battery. Hyperglycemia was assessed by a composite index of fasting glucose, postload glucose, glycated hemoglobin (HbA 1c ), and tissue advanced glycation end products; insulin resistance by the HOMA of insulin resistance index; and blood pressure-related variables included 24-h ambulatory pressures, their weighted SDs, and the use of antihypertensive medication. Linear regression analyses were used to estimate mediating effects. After adjustment for age, sex, and education, individuals with type 2 diabetes, compared with those with normal glucose metabolism, performed worse in all cognitive domains (mean differences in composite z scores for memory -0.087, processing speed -0.196, executive function and attention -0.182; P values <0.032), whereas individuals with prediabetes did not. Diabetes-associated differences in processing speed and executive function and attention were largely explained by hyperglycemia (mediating effect 79.6% [bootstrapped 95% CI 36.6; 123.4] and 50.3% [0.6; 101.2], respectively) and, for processing speed, to a lesser extent by blood pressure-related variables (17.7% [5.6; 30.1]), but not by insulin resistance. None of the factors explained the differences in memory function. Our cross-sectional data suggest that early glycemic and blood pressure control, perhaps even in the prediabetic stage, may be promising therapeutic targets for the prevention of diabetes-associated decrements in cognitive performance. © 2017 by the American Diabetes Association.

Molecular simulation of the effect of cholesterol on lipid-mediated protein-protein interactions.

PubMed

de Meyer, Frédérick J-M; Rodgers, Jocelyn M; Willems, Thomas F; Smit, Berend

2010-12-01

Experiments and molecular simulations have shown that the hydrophobic mismatch between proteins and membranes contributes significantly to lipid-mediated protein-protein interactions. In this article, we discuss the effect of cholesterol on lipid-mediated protein-protein interactions as function of hydrophobic mismatch, protein diameter and protein cluster size, lipid tail length, and temperature. To do so, we study a mesoscopic model of a hydrated bilayer containing lipids and cholesterol in which proteins are embedded, with a hybrid dissipative particle dynamics-Monte Carlo method. We propose a mechanism by which cholesterol affects protein interactions: protein-induced, cholesterol-enriched, or cholesterol-depleted lipid shells surrounding the proteins affect the lipid-mediated protein-protein interactions. Our calculations of the potential of mean force between proteins and protein clusters show that the addition of cholesterol dramatically reduces repulsive lipid-mediated interactions between proteins (protein clusters) with positive mismatch, but does not affect attractive interactions between proteins with negative mismatch. Cholesterol has only a modest effect on the repulsive interactions between proteins with different mismatch. Copyright © 2010 Biophysical Society. Published by Elsevier Inc. All rights reserved.

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

Kubo, Yoshinao; Yoshii, Hiroaki; Kamiyama, Haruka

Ezrin, radixin, and moesin (ERM) proteins supply functional linkage between integral membrane proteins and cytoskeleton in mammalian cells to regulate membrane protein dynamisms and cytoskeleton rearrangement. To assess potential role of the ERM proteins in HIV-1 lifecycle, we examined if suppression of ERM function in human cells expressing HIV-1 infection receptors influences HIV-1 envelope (Env)-mediated HIV-1-vector transduction and cell-cell fusion. Expression of an ezrin dominant negative mutant or knockdown of ezrin, radixin, or moesin with siRNA uniformly decreased transduction titers of HIV-1 vectors having X4-tropic Env. In contrast, transduction titers of R5-tropic Env HIV-1 vectors were decreased only by radixinmore » knockdown: ezrin knockdown had no detectable effects and moesin knockdown rather increased transduction titer. Each of the ERM suppressions had no detectable effects on cell surface expression of CD4, CCR5, and CXCR4 or VSV-Env-mediated HIV-1 vector transductions. Finally, the individual knockdown of ERM mRNAs uniformly decreased efficiency of cell-cell fusion mediated by X4- or R5-tropic Env and HIV-1 infection receptors. These results suggest that (i) the ERM proteins function as positive regulators of infection by X4-tropic HIV-1, (ii) moesin additionally functions as a negative regulator of R5-tropic HIV-1 virus infection at the early step(s) after the membrane fusion, and (iii) receptor protein dynamisms are regulated differently in R5- and X4-tropic HIV-1 infections.« less

Task-related functional connectivity of the caudate mediates the association between trait mindfulness and implicit learning in older adults.

PubMed

Stillman, Chelsea M; You, Xiaozhen; Seaman, Kendra L; Vaidya, Chandan J; Howard, James H; Howard, Darlene V

2016-08-01

Accumulating evidence shows a positive relationship between mindfulness and explicit cognitive functioning, i.e., that which occurs with conscious intent and awareness. However, recent evidence suggests that there may be a negative relationship between mindfulness and implicit types of learning, or those that occur without conscious awareness or intent. Here we examined the neural mechanisms underlying the recently reported negative relationship between dispositional mindfulness and implicit probabilistic sequence learning in both younger and older adults. We tested the hypothesis that the relationship is mediated by communication, or functional connectivity, of brain regions once traditionally considered to be central to dissociable learning systems: the caudate, medial temporal lobe (MTL), and prefrontal cortex (PFC). We first replicated the negative relationship between mindfulness and implicit learning in a sample of healthy older adults (60-90 years old) who completed three event-related runs of an implicit sequence learning task. Then, using a seed-based connectivity approach, we identified task-related connectivity associated with individual differences in both learning and mindfulness. The main finding was that caudate-MTL connectivity (bilaterally) was positively correlated with learning and negatively correlated with mindfulness. Further, the strength of task-related connectivity between these regions mediated the negative relationship between mindfulness and learning. This pattern of results was limited to the older adults. Thus, at least in healthy older adults, the functional communication between two interactive learning-relevant systems can account for the relationship between mindfulness and implicit probabilistic sequence learning.

Impact of serotonin 2C receptor null mutation on physiology and behavior associated with nigrostriatal dopamine pathway function.

PubMed

Abdallah, Luna; Bonasera, Stephen J; Hopf, F Woodward; O'Dell, Laura; Giorgetti, Marco; Jongsma, Minke; Carra, Scott; Pierucci, Massimo; Di Giovanni, Giuseppe; Esposito, Ennio; Parsons, Loren H; Bonci, Antonello; Tecott, Laurence H

2009-06-24

The impact of serotonergic neurotransmission on brain dopaminergic pathways has substantial relevance to many neuropsychiatric disorders. A particularly prominent role has been ascribed to the inhibitory effects of serotonin 2C receptor (5-HT(2C)R) activation on physiology and behavior mediated by the mesolimbic dopaminergic pathway, particularly in the terminal region of the nucleus accumbens. The influence of this receptor subtype on functions mediated by the nigrostriatal dopaminergic pathway is less clear. Here we report that a null mutation eliminating expression of 5-HT(2C)Rs produces marked alterations in the activity and functional output of this pathway. 5-HT(2C)R mutant mice displayed increased activity of substantia nigra pars compacta (SNc) dopaminergic neurons, elevated baseline extracellular dopamine concentrations in the dorsal striatum (DSt), alterations in grooming behavior, and enhanced sensitivity to the stereotypic behavioral effects of d-amphetamine and GBR 12909. These psychostimulant responses occurred in the absence of phenotypic differences in drug-induced extracellular dopamine concentration, suggesting a phenotypic alteration in behavioral responses to released dopamine. This was further suggested by enhanced behavioral responses of mutant mice to the D(1) receptor agonist SKF 81297. Differences in DSt D(1) or D(2) receptor expression were not found, nor were differences in medium spiny neuron firing patterns or intrinsic membrane properties following dopamine stimulation. We conclude that 5-HT(2C)Rs regulate nigrostriatal dopaminergic activity and function both at SNc dopaminergic neurons and at a locus downstream of the DSt.

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.

Repressor of Estrogen Receptor Activity (REA) Is Essential for Mammary Gland Morphogenesis and Functional Activities: Studies in Conditional Knockout Mice

PubMed Central

Park, Sunghee; Zhao, Yuechao; Yoon, Sangyeon; Xu, Jianming; Liao, Lan; Lydon, John; DeMayo, Franco; O'Malley, Bert W.

2011-01-01

Estrogen receptor (ER) is a key regulator of mammary gland development and is also implicated in breast tumorigenesis. Because ER-mediated activities depend critically on coregulator partner proteins, we have investigated the consequences of reduction or loss of function of the coregulator repressor of ER activity (REA) by conditionally deleting one allele or both alleles of the REA gene at different stages of mammary gland development. Notably, we find that heterozygosity and nullizygosity for REA result in very different mammary phenotypes and that REA has essential roles in the distinct morphogenesis and functions of the mammary gland at different stages of development, pregnancy, and lactation. During puberty, mice homozygous null for REA in the mammary gland (REAf/f PRcre/+) showed severely impaired mammary ductal elongation and morphogenesis, whereas mice heterozygous for REA (REAf/+ PRcre/+) displayed accelerated mammary ductal elongation, increased numbers of terminal end buds, and up-regulation of amphiregulin, the major paracrine mediator of estrogen-induced ductal morphogenesis. During pregnancy and lactation, mice with homozygous REA gene deletion in mammary epithelium (REAf/f whey acidic protein-Cre) showed a loss of lobuloalveolar structures and increased apoptosis of mammary alveolar epithelium, leading to impaired milk production and significant reduction in growth of their offspring, whereas body weights of the offspring nursed by females heterozygous for REA were slightly greater than those of control mice. Our findings reveal that REA is essential for mammary gland development and has a gene dosage-dependent role in the regulation of stage-specific physiological functions of the mammary gland. PMID:21862609

Equity through Assessment? Teachers' Mediation of Outcome-Focused Reforms in Socioeconomically Different Schools

ERIC Educational Resources Information Center

Strandler, Ola

2016-01-01

Despite uncertainties regarding the effects of outcome-focused reforms on teaching practices, the political confidence in the potential of such reforms to create educational change remains high. This article problematizes the assumption that two such Swedish reforms (grades and national tests in younger years) can function as an impetus for…

Control of synaptic function by endocannabinoid-mediated retrograde signaling.

PubMed

Kano, Masanobu

2014-01-01

Since the first reports in 2001, great advances have been made towards the understanding of endocannabinoid-mediated synaptic modulation. Electrophysiological studies have revealed that one of the two major endocannabinoids, 2-arachidonoylglycerol (2-AG), is produced from membrane lipids upon postsynaptic Ca(2+) elevation and/or activation of Gq/11-coupled receptors, and released from postsynaptic neurons. The released 2-AG then acts retrogradely onto presynaptic cannabinoid CB1 receptors and induces suppression of neurotransmitter release either transiently or persistently. These forms of 2-AG-mediated retrograde synaptic modulation are functional throughout the brain. The other major endocannabinoid, anandamide, mediates a certain form of endocannabinoid-mediated long-term depression (LTD). Anandamide also functions as an agonist for transient receptor potential vanilloid receptor type 1 (TRPV1) and mediates endocannabinoid-independent and TRPV1-dependent forms of LTD. It has also been demonstrated that the endocannabinoid system itself is plastic, which can be either up- or down-regulated by experimental or environmental conditions. In this review, I will make an overview of the mechanisms underlying endocannabinoid-mediated synaptic modulation.

Control of synaptic function by endocannabinoid-mediated retrograde signaling

PubMed Central

KANO, Masanobu

2014-01-01

Since the first reports in 2001, great advances have been made towards the understanding of endocannabinoid-mediated synaptic modulation. Electrophysiological studies have revealed that one of the two major endocannabinoids, 2-arachidonoylglycerol (2-AG), is produced from membrane lipids upon postsynaptic Ca2+ elevation and/or activation of Gq/11-coupled receptors, and released from postsynaptic neurons. The released 2-AG then acts retrogradely onto presynaptic cannabinoid CB1 receptors and induces suppression of neurotransmitter release either transiently or persistently. These forms of 2-AG-mediated retrograde synaptic modulation are functional throughout the brain. The other major endocannabinoid, anandamide, mediates a certain form of endocannabinoid-mediated long-term depression (LTD). Anandamide also functions as an agonist for transient receptor potential vanilloid receptor type 1 (TRPV1) and mediates endocannabinoid-independent and TRPV1-dependent forms of LTD. It has also been demonstrated that the endocannabinoid system itself is plastic, which can be either up- or down-regulated by experimental or environmental conditions. In this review, I will make an overview of the mechanisms underlying endocannabinoid-mediated synaptic modulation. PMID:25169670

Mitochondria and Mitochondrial Cascades in Alzheimer’s Disease

PubMed Central

Swerdlow, Russell H.

2017-01-01

Decades of research indicate mitochondria from Alzheimer’s disease (AD) patients differ from those of non-AD individuals. Initial studies revealed structural differences, and subsequent studies showed functional deficits. Observations of structure and function changes prompted investigators to consider the consequences, significance, and causes of AD-related mitochondrial dysfunction. Currently, extensive research argues mitochondria may mediate, drive, or contribute to a variety of AD pathologies. The perceived significance of these mitochondrial changes continues to grow, and many currently believe AD mitochondrial dysfunction represents a reasonable therapeutic target. Debate continues over the origin of AD mitochondrial changes. Some argue amyloid-β (Aβ) induces AD mitochondrial dysfunction, a view that does not challenge the amyloid cascade hypothesis and that may in fact help explain that hypothesis. Alternatively, data indicate mitochondrial dysfunction exists independent of Aβ, potentially lies upstream of Aβ deposition, and suggest a primary mitochondrial cascade hypothesis that assumes mitochondrial pathology hierarchically supersedes Aβ pathology. Mitochondria, therefore, appear at least to mediate or possibly even initiate pathologic molecular cascades in AD. This review considers studies and data that inform this area of AD research. PMID:29036828

Nociception and escape behavior in planarians

NASA Astrophysics Data System (ADS)

Schoetz Collins, Eva-Maria

2015-03-01

Planarians are famous and widely studied for their regenerative capabilities. When a moving planarian is cut through the middle, the resulting head and tail pieces instantaneously retract and exhibit a characteristic escape response that differs from normal locomotion. In asexual animals, a similar reaction is observed when the planarian undergoes fission, suggesting that reproduction through self-tearing is a rather traumatic event for the animal. Using a multiscale approach, we unravel the dynamics, mechanics, and functional aspects of the planarian escape response. This musculature-driven gait was found to be a dominating response that supersedes the urge to feed or reproduce and quantitatively differs from other modes of planarian locomotion (gliding, peristalsis). We show that this escape gait constitutes the animal's pain response mediated by TRP like receptors and the neurotransmitter histamine, and that it can be induced through adverse thermal, mechanical, electrical or chemical stimuli. Ultimately, we will examine the neuronal subpopulations involved in mediating escape reflexes in planarians and how they are functionally restored during regeneration, thereby gaining mechanistic insight into the neuronal circuits required for specific behaviors. Supported by BWF CASI and Sloan Foundation.

Molecular basis of Kar9-Bim1 complex function during mating and spindle positioning

PubMed Central

Manatschal, Cristina; Farcas, Ana-Maria; Degen, Miriam Steiner; Bayer, Mathias; Kumar, Anil; Landgraf, Christiane; Volkmer, Rudolf; Barral, Yves; Steinmetz, Michel O.

2016-01-01

The Kar9 pathway promotes nuclear fusion during mating and spindle alignment during metaphase in budding yeast. How Kar9 supports the different outcome of these two divergent processes is an open question. Here, we show that three sites in the C-terminal disordered domain of Kar9 mediate tight Kar9 interaction with the C-terminal dimerization domain of Bim1 (EB1 orthologue). Site1 and Site2 contain SxIP motifs; however, Site3 defines a novel type of EB1-binding site. Whereas Site2 and Site3 mediate Kar9 recruitment to microtubule tips, nuclear movement, and karyogamy, only Site2 functions in spindle positioning during metaphase. Site1 in turn plays an inhibitory role during mating. Additionally, the Kar9-Bim1 complex is involved in microtubule-independent activities during mating. Together, our data reveal how multiple and partially redundant EB1-binding sites provide a microtubule-associated protein with the means to modulate its biochemical properties to promote different molecular processes during cell proliferation and differentiation. PMID:27682587

Stereotype threat and executive functions: which functions mediate different threat-related outcomes?

PubMed

Rydell, Robert J; Van Loo, Katie J; Boucher, Kathryn L

2014-03-01

Stereotype threat research shows that women's math performance can be reduced by activating gender-based math stereotypes. Models of stereotype threat assert that threat reduces cognitive functioning, thereby accounting for its negative effects. This work provides a more detailed understanding of the cognitive processes through which stereotype threat leads women to underperform at math and to take risks, by examining which basic executive functions (inhibition, shifting, and updating) account for these outcomes. In Experiments 1 and 2, women under threat showed reduced inhibition, reduced updating, and reduced math performance compared with women in a control condition (or men); however, only updating accounted for women's poor math performance under threat. In Experiment 3, only updating accounted for stereotype threat's effect on women's math performance, whereas only inhibition accounted for the effect of threat on risk-taking, suggesting that distinct executive functions can account for different stereotype threat-related outcomes.

The cation transporters rOCT1 and rOCT2 interact with bicarbonate but play only a minor role for amantadine uptake into rat renal proximal tubules.

PubMed

Goralski, Kerry B; Lou, Ganlu; Prowse, Matthew T; Gorboulev, Valentin; Volk, Christopher; Koepsell, Hermann; Sitar, Daniel S

2002-12-01

In renal proximal tubules, the organic cation transporters rOCT1 and rOCT2 are supposed to mediate the first step in organic cation secretion. We investigated whether previously described differences in amantadine and tetraethylammonium (TEA) uptake into isolated renal proximal tubules could be explained by differences in their transport by rOCT1 and rOCT2. By expressing rOCT1 and rOCT2 in Xenopus oocytes and HEK 293 cells, we demonstrated that both transporters translocated amantadine. In Xenopus oocytes, the inhibitory potency of several rOCT1/2 inhibitors was similar for amantadine compared to TEA uptake and supports amantadine transport by rOCT1 and rOCT2. In proximal tubules, procainamide, quinine, cyanine(863), choline, and guanidine in concentrations that inhibit rOCT1/2-mediated TEA or amantadine uptake in Xenopus oocytes exhibited no effect on amantadine uptake. At variance, these inhibitors blocked TEA uptake into proximal tubules. Amantadine and TEA transport were sensitive to modulation by 25 mM bicarbonate. The effect of bicarbonate on organic cation transport was dependent on substrate (amantadine or TEA), cell system (oocytes, HEK 293 cells, or proximal tubules), and transporter (rOCT1 or rOCT2). In proximal tubules, only amantadine uptake was stimulated by bicarbonate. The data suggested that rat renal proximal tubules contain an organic cation transporter in addition to rOCT1 and rOCT2 that mediates amantadine uptake and requires bicarbonate for optimal function. TEA uptake by the basolateral membrane may be mediated mainly by rOCT1 and rOCT2, but these transporters may be in a different functional or regulatory state when expressed in cells or oocytes compared with expression in vivo.

Psychiatric disability as mediator of the neurocognition-functioning link in schizophrenia spectrum disorders: SEM analysis using the Evaluation of Cognitive Processes involved in Disability in Schizophrenia (ECPDS) scale.

PubMed

Roux, Paul; Urbach, Mathieu; Fonteneau, Sandrine; Berna, Fabrice; Brunel, Lore; Capdevielle, Delphine; Chereau, Isabelle; Dubreucq, Julien; Faget-Agius, Catherine; Fond, Guillaume; Leignier, Sylvain; Perier, Claire-Cécile; Richieri, Raphaëlle; Schneider, Priscille; Schürhoff, Franck; Tronche, Anne-Marie; Yazbek, Hanan; Zinetti-Bertschy, Anna; Passerieux, Christine; Brunet-Gouet, Eric

2018-06-22

The functional outcome in schizophrenia spectrum disorders is affected by multiple factors such as cognitive performance and clinical symptoms. Psychiatric disability may be another important determinant of functional outcome. The purpose of this study was to test whether schizophrenia symptoms and psychiatric disability mediated the association between cognition and functioning. Between April 2013 and July 2017, we included 108 community-dwelling adults with stable schizophrenia spectrum disorder in a multicenter study. Psychiatric disability was assessed with the Evaluation of Cognitive Processes involved in Disability in Schizophrenia (ECPDS) scale by relatives of patients. ECPDS focused on the broad array of motivational, neurocognitive, sociocognitive, and metacognitive impairments that result in activity restrictions. We used a battery of tests to assess seven cognition domains (processing speed, attention/vigilance, working, verbal and visual memory, reasoning and problem solving, and executive functioning) and cross-sectional structural equation modeling (SEM) for the mediation analyses. We estimated the one-year temporal stability of ECPDS scores in 45 participants. The model provided showed good fit and explained 43.9% of the variance in functioning. The effect of neurocognition on functioning was fully mediated by symptoms (proportion mediated: 36.5%) and psychiatric disability (proportion mediated: 31.3%). The ECPDS score had acceptable one-year temporal stability. The ECPDS scale has satisfactory psychometric properties, and shows significant convergence with neurocognition and functioning, suggesting a role for this tool in the routine evaluation of cognitive remediation needs. Our model validates psychiatric disability as a crucial step from cognitive impairment to restricted participation in life situations. Copyright © 2018 Elsevier B.V. All rights reserved.

Glutamate mediates the function of melanocortin receptor 4 on sim1 neurons in body weight regulation

USDA-ARS?s Scientific Manuscript database

The melanocortin receptor 4 (MC4R) is a well-established mediator of body weight homeostasis. However, the neurotransmitter(s) that mediate MC4R function remain largely unknown; as a result, little is known about the second-order neurons of the MC4R neural pathway. Single-minded 1 (Sim1)-expressing ...

An exponential decay model for mediation.

PubMed

Fritz, Matthew S

2014-10-01

Mediation analysis is often used to investigate mechanisms of change in prevention research. Results finding mediation are strengthened when longitudinal data are used because of the need for temporal precedence. Current longitudinal mediation models have focused mainly on linear change, but many variables in prevention change nonlinearly across time. The most common solution to nonlinearity is to add a quadratic term to the linear model, but this can lead to the use of the quadratic function to explain all nonlinearity, regardless of theory and the characteristics of the variables in the model. The current study describes the problems that arise when quadratic functions are used to describe all nonlinearity and how the use of nonlinear functions, such as exponential decay, address many of these problems. In addition, nonlinear models provide several advantages over polynomial models including usefulness of parameters, parsimony, and generalizability. The effects of using nonlinear functions for mediation analysis are then discussed and a nonlinear growth curve model for mediation is presented. An empirical example using data from a randomized intervention study is then provided to illustrate the estimation and interpretation of the model. Implications, limitations, and future directions are also discussed.

An Exponential Decay Model for Mediation

PubMed Central

Fritz, Matthew S.

2013-01-01

Mediation analysis is often used to investigate mechanisms of change in prevention research. Results finding mediation are strengthened when longitudinal data are used because of the need for temporal precedence. Current longitudinal mediation models have focused mainly on linear change, but many variables in prevention change nonlinearly across time. The most common solution to nonlinearity is to add a quadratic term to the linear model, but this can lead to the use of the quadratic function to explain all nonlinearity, regardless of theory and the characteristics of the variables in the model. The current study describes the problems that arise when quadratic functions are used to describe all nonlinearity and how the use of nonlinear functions, such as exponential decay, addresses many of these problems. In addition, nonlinear models provide several advantages over polynomial models including usefulness of parameters, parsimony, and generalizability. The effects of using nonlinear functions for mediation analysis are then discussed and a nonlinear growth curve model for mediation is presented. An empirical example using data from a randomized intervention study is then provided to illustrate the estimation and interpretation of the model. Implications, limitations, and future directions are also discussed. PMID:23625557

Depression, help-seeking perceptions, and perceived family functioning among Spanish-Dominant Hispanics and Non-Hispanic Whites.

PubMed

Keeler, Amanda R; Siegel, Jason T

2016-09-15

Guided by Beck's (1967) cognitive theory of depression, we assessed whether perceived family functioning (PFF) mediated the relationship between depressive symptomatology and help-seeking inclinations. Study 1 included 130 Spanish-Dominant Hispanics and Study 2 included 124 Non-Hispanic Whites obtained using online crowd sourcing. Participants completed measures of depressive symptomatology, PFF, and several scales measuring aspects of help seeking inclinations and self-stigma. Study 2 also included an experiment. With an eye toward potential future interventions, we assessed the malleability of PFF. Specifically, participants were randomly assigned to recall positive or negative family experiences and then PFF was measures for a second time. Both studies found PFF mediates the relationship between depressive symptomatology and the help seeking scales. Among non-depressed people, the positive manipulation improved PFF; however, among participants with elevated depressive symptomatology, writing about a positive family experience worsened PFF. With the exception of the experiment, most of the data were cross-sectional. For the experiment, it is possible that different manipulations or primes could have different effects. Whether investigating responses from Spanish-Dominant Hispanics or Non-Hispanic Whites, PFF mediates the negative relationship between heightened depressive symptomatology and familial help-seeking beliefs, as well as self-stigma. However, even though the mediation analysis offers preliminary support that increasing PFF can potentially increase help-seeking behaviors of Hispanic and Non-Hispanic White people with depression, the results of the interaction analysis, specifically the negative impact of writing about positive family memories on people with elevated depression, illustrates the challenges of persuading people with depression. Copyright © 2016 Elsevier B.V. All rights reserved.

Serum and cerebrospinal fluid immune mediators in children with autistic disorder: a longitudinal study.

PubMed

Pardo, Carlos A; Farmer, Cristan A; Thurm, Audrey; Shebl, Fatma M; Ilieva, Jorjetta; Kalra, Simran; Swedo, Susan

2017-01-01

The causes of autism likely involve genetic and environmental factors that influence neurobiological changes and the neurological and behavioral features of the disorder. Immune factors and inflammation are hypothesized pathogenic influences, but have not been examined longitudinally. In a cohort of 104 participants with autism, we performed an assessment of immune mediators such as cytokines, chemokines, or growth factors in serum and cerebrospinal fluid ( n  = 67) to determine potential influences of such mediators in autism. As compared with 54 typically developing controls, we found no evidence of differences in the blood profile of immune mediators supportive of active systemic inflammation mechanisms in participants with autism. Some modulators of immune function (e.g., EGF and soluble CD40 ligand) were increased in the autism group; however, no evidence of group differences in traditional markers of active inflammation (e.g., IL-6, TNFα, IL-1β) were observed in the serum. Further, within-subject stability (measured by estimated intraclass correlations) of most analytes was low, indicating that a single measurement is not a reliable prospective indicator of concentration for most analytes. Additionally, in participants with autism, there was little correspondence between the blood and CSF profiles of cytokines, chemokines, and growth factors, suggesting that peripheral markers may not optimally reflect the immune status of the central nervous system. Although the relatively high fraction of intrathecal production of selected chemokines involved in monocyte/microglia function may suggest a possible relationship with the homeostatic role of microglia, control data are needed for further interpretation of its relevance in autism. These longitudinal observations fail to provide support for the hypothesized role of disturbances in the expression of circulating cytokines and chemokines as an indicator of systemic inflammation in autism. ClinicalTrials.gov, NCT00298246.

Internal locus of control, health literacy and health, an Israeli cultural perspective.

PubMed

Baron-Epel, Orna; Levin-Zamir, Diane; Cohen, Vicki; Elhayany, Asher

2017-11-13

The association between health literacy (HL) and health outcomes, including self-perceived health (SPH) has been well documented. Yet the complexity of this association is not yet completely clear. Drawing on the Health Literacy Scale (HLS) study in Israel, we examined the association between HL, Internal Health Locus of Control (IHLOC) and SPH among Jews and Arabs. A face-to-face survey was conducted among 242 Arabs and 358 Jews. The questionnaire measured SPH, IHLOC and two measures of HL: a European HLScale (HLS-EU-16) and the Hebrew/Arabic Health Literacy Test (H/AHLT), based on the Short Test Of Functional Health Literacy in Adults. Analysis included multivariable logistic regressions and bootstrapping to identify mediation effects. Among Jews, IHLOC seems to be a significant mediator between HL and SPH. IHLOC was strongly associated with SPH (OR = 6.13; CI = 3.2, 11.8), while HL was not significantly associated directly with SPH. Similar results were observed when using the H/AHLT as a measure of HL. Among Arabs a different pattern emerges; IHLOC was neither associated with SPH nor was it a mediator of the association between HL and SPH. The two measures of HL seem to have different associations with SPH among Arabs, as only H/AHLT was associated significantly with SPH, and not HLS-EU-16. Thus, those with higher levels of IHLOC assess their health as better than those with low IHLOC only among Jews, and not among Arabs. IHLOC seems to be a significant mediator between HL and SPH among some cultures. Among Arabs, only functional HL seems to be positively associated with SPH. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Effect of Regular Aerobic Activity in Young Healthy Athletes on Profile of Endothelial Function and Platelet Activity.

PubMed

Podgórska, Katarzyna; Derkacz, Arkadiusz; Szahidewicz-Krupska, Ewa; Jasiczek, Jakub; Dobrowolski, Piotr; Radziwon-Balicka, Aneta; Skomro, Robert; Szuba, Andrzej; Mazur, Grzegorz; Doroszko, Adrian

2017-01-01

The aim of the study was to assess the impact of regular professional sports activity on the endothelial and platelet function in young men. The studied group were 79 young men (18-40 y, 25 athletes and 54 without any regular physical activity). The nitric oxide (NO) metabolic pathway intermediates, oxidative stress markers, mediators of inflammation, and platelet aggregation were measured. Flow mediated dilation (FMD) was studied before and after intravenous 16,0 g L-arginine infusion, which was repeated after oral administration of acetylsalicylic acid (ASA-75 mg/day) for 4 days. Both groups had similar demographic characteristics. In the athletes, there was significantly higher hsCRP level, better serum lipid profile, and lower pulse pressure. Greater baseline FMD in athletes and in response to L-arginine disappeared following ASA treatment. There were no differences in the levels of the NO pathway metabolites. The control group was characterized by higher PAI-1 following ASA treatment and sICAM-1 both at baseline and after ASA, but no differences in MDA and 6-keto-PGF-1 alpha and platelet aggregation were noted. Regular professional physical activity modulates endothelial but not platelet function and may thus exert an effect on overall cardiovascular risk.

Effect of Regular Aerobic Activity in Young Healthy Athletes on Profile of Endothelial Function and Platelet Activity

PubMed Central

Podgórska, Katarzyna; Jasiczek, Jakub; Dobrowolski, Piotr; Radziwon-Balicka, Aneta; Skomro, Robert; Szuba, Andrzej; Mazur, Grzegorz

2017-01-01

The aim of the study was to assess the impact of regular professional sports activity on the endothelial and platelet function in young men. The studied group were 79 young men (18–40 y, 25 athletes and 54 without any regular physical activity). The nitric oxide (NO) metabolic pathway intermediates, oxidative stress markers, mediators of inflammation, and platelet aggregation were measured. Flow mediated dilation (FMD) was studied before and after intravenous 16,0 g L-arginine infusion, which was repeated after oral administration of acetylsalicylic acid (ASA-75 mg/day) for 4 days. Both groups had similar demographic characteristics. In the athletes, there was significantly higher hsCRP level, better serum lipid profile, and lower pulse pressure. Greater baseline FMD in athletes and in response to L-arginine disappeared following ASA treatment. There were no differences in the levels of the NO pathway metabolites. The control group was characterized by higher PAI-1 following ASA treatment and sICAM-1 both at baseline and after ASA, but no differences in MDA and 6-keto-PGF-1 alpha and platelet aggregation were noted. Regular professional physical activity modulates endothelial but not platelet function and may thus exert an effect on overall cardiovascular risk. PMID:28630872

Visual Contrast Sensitivity Improvement by Right Frontal High-Beta Activity Is Mediated by Contrast Gain Mechanisms and Influenced by Fronto-Parietal White Matter Microstructure

PubMed Central

Quentin, Romain; Elkin Frankston, Seth; Vernet, Marine; Toba, Monica N.; Bartolomeo, Paolo; Chanes, Lorena; Valero-Cabré, Antoni

2016-01-01

Behavioral and electrophysiological studies in humans and non-human primates have correlated frontal high-beta activity with the orienting of endogenous attention and shown the ability of the latter function to modulate visual performance. We here combined rhythmic transcranial magnetic stimulation (TMS) and diffusion imaging to study the relation between frontal oscillatory activity and visual performance, and we associated these phenomena to a specific set of white matter pathways that in humans subtend attentional processes. High-beta rhythmic activity on the right frontal eye field (FEF) was induced with TMS and its causal effects on a contrast sensitivity function were recorded to explore its ability to improve visual detection performance across different stimulus contrast levels. Our results show that frequency-specific activity patterns engaged in the right FEF have the ability to induce a leftward shift of the psychometric function. This increase in visual performance across different levels of stimulus contrast is likely mediated by a contrast gain mechanism. Interestingly, microstructural measures of white matter connectivity suggest a strong implication of right fronto-parietal connectivity linking the FEF and the intraparietal sulcus in propagating high-beta rhythmic signals across brain networks and subtending top-down frontal influences on visual performance. PMID:25899709

CYCLIN-DEPENDENT KINASE8 differentially regulates plant immunity to fungal pathogens through kinase-dependent and -independent functions in Arabidopsis.

PubMed

Zhu, Yingfang; Schluttenhoffer, Craig M; Wang, Pengcheng; Fu, Fuyou; Thimmapuram, Jyothi; Zhu, Jian-Kang; Lee, Sang Yeol; Yun, Dae-Jin; Mengiste, Tesfaye

2014-10-01

CYCLIN-DEPENDENT KINASE8 (CDK8) is a widely studied component of eukaryotic Mediator complexes. However, the biological and molecular functions of plant CDK8 are not well understood. Here, we provide evidence for regulatory functions of Arabidopsis thaliana CDK8 in defense and demonstrate its functional and molecular interactions with other Mediator and non-Mediator subunits. The cdk8 mutant exhibits enhanced resistance to Botrytis cinerea but susceptibility to Alternaria brassicicola. The contributions of CDK8 to the transcriptional activation of defensin gene PDF1.2 and its interaction with MEDIATOR COMPLEX SUBUNIT25 (MED25) implicate CDK8 in jasmonate-mediated defense. Moreover, CDK8 associates with the promoter of AGMATINE COUMAROYLTRANSFERASE to promote its transcription and regulate the biosynthesis of the defense-active secondary metabolites hydroxycinnamic acid amides. CDK8 also interacts with the transcription factor WAX INDUCER1, implying its additional role in cuticle development. In addition, overlapping functions of CDK8 with MED12 and MED13 and interactions between CDK8 and C-type cyclins suggest the conserved configuration of the plant Mediator kinase module. In summary, while CDK8's positive transcriptional regulation of target genes and its phosphorylation activities underpin its defense functions, the impaired defense responses in the mutant are masked by its altered cuticle, resulting in specific resistance to B. cinerea. © 2014 American Society of Plant Biologists. All rights reserved.

Cell-Mediated Immune Function and Cytokine Regulation During Space Flight

NASA Technical Reports Server (NTRS)

Sams, Clarence F.; Pierson, Duane L.; Paloski, W. H. (Technical Monitor)

2000-01-01

The changes in immune function which occur during space flight potentially expose the crews to an increased risk for development of illness. Decreased cellular immune function has been repeatedly documented after space flight and confirmed during flight by in vivo delayed-type hypersensitivity testing. However, correlation of immune changes with a clinically significant risk factor has not yet been performed. Our hypothesis is that space flight induces a decrease in cell-mediated immune function accompanied by a shift from a type 1 cytokine pattern (favoring cell-mediated immunity) to a type 2 cytokine pattern (favoring humoral immunity). We further hypothesize that reactivation of latent viruses will occur during space flight in association with the decreased cellular immunity. To test these hypotheses, we will determine the effects of space flight on cell-mediated immunity and viral reactivation. We will utilize delayed-type hypersensitivity testing as an in vivo measure of integrated cell-mediated immune function. The production of cytokines and immunoregulatory factors by lymphocytes and monocytes will be measured to determine whether changes in cytokine patterns are associated with the space flight-induced immune dysregulation. Correlation of antigen-specific immune changes with reactivation of latent herpes viruses will be determined by measuring peripheral levels of viral (CMV, VZV, EBV) antigen-specific T cells and comparing to the levels of EBV-infected B-cells by fluorescence in situ hybridization and flow cytometry. A comparison of cell-mediated immune function, cytokine regulation and viral reactivation will provide new insights into crew member health risks during flight.

Assessing the relationships among stress, god-mediated control, and psychological distress/well-being: Does the level of education matter?

PubMed

Krause, Neal

2018-01-24

One of the primary functions of religion is to help people cope with stressful life events. The purpose of the current study is to see if God-mediated control beliefs perform this stress-buffering function. God-mediated control refers to the belief that people work together with God to reduce the effects of unwanted stressors in their lives. An effort is made to probe this relationship more deeply by seeing whether the stress moderating function of God-mediated control beliefs varies across levels of educational attainment. Findings from a recent nationwide survey suggest that strong God-mediated control beliefs reduce the magnitude of the relationship between stress and depressive symptoms, anxiety, happiness, and hope, but only among more highly educated study participants. In contrast, God-mediated control beliefs do not appear to influence the relationship between stress and distress/well-being among study participants with lower levels of educational attainment.

BET Bromodomain Inhibition Releases the Mediator Complex from Select cis-Regulatory Elements.

PubMed

Bhagwat, Anand S; Roe, Jae-Seok; Mok, Beverly Y L; Hohmann, Anja F; Shi, Junwei; Vakoc, Christopher R

2016-04-19

The bromodomain and extraterminal (BET) protein BRD4 can physically interact with the Mediator complex, but the relevance of this association to the therapeutic effects of BET inhibitors in cancer is unclear. Here, we show that BET inhibition causes a rapid release of Mediator from a subset of cis-regulatory elements in the genome of acute myeloid leukemia (AML) cells. These sites of Mediator eviction were highly correlated with transcriptional suppression of neighboring genes, which are enriched for targets of the transcription factor MYB and for functions related to leukemogenesis. A shRNA screen of Mediator in AML cells identified the MED12, MED13, MED23, and MED24 subunits as performing a similar regulatory function to BRD4 in this context, including a shared role in sustaining a block in myeloid maturation. These findings suggest that the interaction between BRD4 and Mediator has functional importance for gene-specific transcriptional activation and for AML maintenance. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Mediator-regulated transcription through the +1 nucleosome.

PubMed

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

2012-12-28

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

The Mediator Complex and Lipid Metabolism.

PubMed

Zhang, Yi; Xiaoli; Zhao, Xiaoping; Yang, Fajun

2013-03-01

The precise control of gene expression is essential for all biological processes. In addition to DNA-binding transcription factors, numerous transcription cofactors contribute another layer of regulation of gene transcription in eukaryotic cells. One of such transcription cofactors is the highly conserved Mediator complex, which has multiple subunits and is involved in various biological processes through directly interacting with relevant transcription factors. Although the current understanding on the biological functions of Mediator remains incomplete, research in the past decade has revealed an important role of Mediator in regulating lipid metabolism. Such function of Mediator is dependent on specific transcription factors, including peroxisome proliferator-activated receptor-gamma (PPARγ) and sterol regulatory element-binding proteins (SREBPs), which represent the master regulators of lipid metabolism. The medical significance of these findings is apparent, as aberrant lipid metabolism is intimately linked to major human diseases, such as type 2 diabetes and cardiovascular disease. Here, we briefly review the functions and molecular mechanisms of Mediator in regulation of lipid metabolism.

Visit-to-visit and 24-h blood pressure variability: association with endothelial and smooth muscle function in African Americans.

PubMed

Diaz, K M; Veerabhadrappa, P; Kashem, M A; Thakkar, S R; Feairheller, D L; Sturgeon, K M; Ling, C; Williamson, S T; Kretzschmar, J; Lee, H; Grimm, H; Babbitt, D M; Vin, C; Fan, X; Crabbe, D L; Brown, M D

2013-11-01

The purpose of this study was to investigate the association of visit-to-visit and 24-h blood pressure (BP) variability with markers of endothelial injury and vascular function. We recruited 72 African Americans who were non-diabetic, non-smoking and free of cardiovascular (CV) and renal disease. Office BP was measured at three visits and 24-h ambulatory BP monitoring was conducted to measure visit-to-visit and 24-h BP variability, respectively. The 5-min time-course of brachial artery flow-mediated dilation and nitroglycerin-mediated dilation were assessed as measures of endothelial and smooth muscle function. Fasted blood samples were analyzed for circulating endothelial microparticles (EMPs). Significantly lower CD31+CD42- EMPs were found in participants with high visit-to-visit systolic blood pressure (SBP) variability or high 24-h diastolic blood pressure (DBP) variability. Participants with high visit-to-visit DBP variability had significantly lower flow-mediated dilation and higher nitroglycerin-mediated dilation at multiple time-points. When analyzed as continuous variables, 24-h mean arterial pressure variability was inversely associated with CD62+ EMPs; visit-to-visit DBP variability was inversely associated with flow-mediated dilation normalized by smooth muscle function and was positively associated with nitroglycerin-mediated dilation; and 24-h DBP variability was positively associated with nitroglycerin-mediated dilation. All associations were independent of age, gender, body mass index and mean BP. In conclusion, in this cohort of African Americans visit-to-visit and 24-h BP variability were associated with measures of endothelial injury, endothelial function and smooth muscle function. These results suggest that BP variability may influence the pathogenesis of CV disease, in part, through influences on vascular health.

Is cognitive adaptation training (CAT) compensatory, restorative, or both?

PubMed

Fredrick, Megan M; Mintz, Jim; Roberts, David L; Maples, Natalie J; Sarkar, Sonali; Li, Xueying; Velligan, Dawn I

2015-08-01

Cognitive adaptation training (CAT) is a psychosocial treatment incorporating environmental supports including signs, checklists to bypass the cognitive deficits of schizophrenia. Our objective was to examine the association between CAT, functional outcomes, and cognitive test performance (cognition). The two research questions were as follows: 1) Does cognition mediate the effect of CAT intervention on functional outcome? 2) Does CAT impact cognitive test performance? A total of 120 participants with schizophrenia were randomized to one of three treatments: 1) CAT (weekly for 9months; monthly thereafter), 2) generic environmental supports (given to participants on clinic visits to promote adaptive behavior), or 3) treatment as usual (TAU). Assessments of cognition and functional outcome were conducted at baseline, 9 and 24months. Mediation analyses and mixed effects regression were conducted. Mediation analyses revealed that during the initial 9months, the direct path from treatment group to functional outcome on the primary measure was positive and highly significant. CAT significantly improved functional outcome compared to the other treatments. However, paths involving cognition were negligible. There was no evidence that cognition mediated improvement in functional outcomes. At 24months, cognition improved more in CAT compared to other treatment groups. The test for cognition mediating improvement in functional outcomes was not significant at this time point. However, improvement in functional outcome led to better performance on cognitive testing. We concluded that improvement in cognition is not a necessary condition for improvement in functional outcome and that greater engagement in functional behavior has a positive impact on cognition. Copyright © 2015 Elsevier B.V. All rights reserved.

The Arabidopsis Mediator Complex Subunits MED16, MED14, and MED2 Regulate Mediator and RNA Polymerase II Recruitment to CBF-Responsive Cold-Regulated Genes[C][W][OPEN

PubMed Central

Hemsley, Piers A.; Hurst, Charlotte H.; Kaliyadasa, Ewon; Lamb, Rebecca; Knight, Marc R.; De Cothi, Elizabeth A.; Steele, John F.; Knight, Heather

2014-01-01

The Mediator16 (MED16; formerly termed SENSITIVE TO FREEZING6 [SFR6]) subunit of the plant Mediator transcriptional coactivator complex regulates cold-responsive gene expression in Arabidopsis thaliana, acting downstream of the C-repeat binding factor (CBF) transcription factors to recruit the core Mediator complex to cold-regulated genes. Here, we use loss-of-function mutants to show that RNA polymerase II recruitment to CBF-responsive cold-regulated genes requires MED16, MED2, and MED14 subunits. Transcription of genes known to be regulated via CBFs binding to the C-repeat motif/drought-responsive element promoter motif requires all three Mediator subunits, as does cold acclimation–induced freezing tolerance. In addition, these three subunits are required for low temperature–induced expression of some other, but not all, cold-responsive genes, including genes that are not known targets of CBFs. Genes inducible by darkness also required MED16 but required a different combination of Mediator subunits for their expression than the genes induced by cold. Together, our data illustrate that plants control transcription of specific genes through the action of subsets of Mediator subunits; the specific combination defined by the nature of the stimulus but also by the identity of the gene induced. PMID:24415770

Mediated moderation or moderated mediation: relationship between length of unemployment, resilience, coping and health.

PubMed

Sojo, Víctor; Guarino, Leticia

2011-05-01

The aim of the present research was to evaluate a model of mediated moderation vs. moderated mediation that could explain the relationship between length of unemployment, dispositional resilience, coping styles and depression and social functioning of Venezuelan unemployed individuals. Self-report measures were administered to a sample of 328 unemployed residents in Caracas, Venezuela. Results indicated that emotional coping acted as a mediator in the relationship between resilience and depression. Individuals with greater resilience used more detachment coping when unemployment was longer, while individuals with poorer resilience in the same situation used less avoidance coping. Resilience acted as a protective moderating factor between longer periods of unemployment and social functioning, a process mediated by detachment coping. Overall, results supported a mediated moderation model, with resilience as the moderating factor and coping as the mediator in the relation between stress due to the length of unemployment and well-being.

Role of Caveolin-1 in Prostate Cancer Angiogenesis

DTIC Science & Technology

2008-12-01

CSD deleted rcav-1 protein (Δrcav- 1), treated EC and prostate cancer cells with different concentrations of FITC- Δrcav-1 over 1-6 h, and examined the...Months 7-24) 4. Biological function end points. (Months 25-36) We are currently investigating different siRNA transfection protocols to find...activities through auto regulatory, Akt-mediated maintanence of mRNA stabilities of cancer promoting growth factors. In preparation 6. Tahir SA

Hypoxic tumor-derived microvesicles negatively regulate NK cell function by a mechanism involving TGF-β and miR23a transfer.

PubMed

Berchem, Guy; Noman, Muhammad Zaeem; Bosseler, Manon; Paggetti, Jerome; Baconnais, Sonia; Le Cam, Eric; Nanbakhsh, Arash; Moussay, Etienne; Mami-Chouaib, Fathia; Janji, Bassam; Chouaib, Salem

2016-04-01

Tumor-derived microvesicles (TD-MVs) are key mediators which are shed by cancer cells and can sensitize neighboring cells in the tumor microenvironment. TD-MVs are extracellular vesicles composed of exosomes and MVs and promote cancer invasion and metastasis. Intratumoral hypoxia is an integral component of all solid tumors. The relationship between hypoxic tumor-shed MVs and NK-mediated cytotoxicity remains unknown. In this paper, we reported that MVs derived from hypoxic tumor cells qualitatively differ from those derived from normoxic tumor cells. Using multiple tumor models, we showed that hypoxic MVs inhibit more NK cell function as compared to normoxic MVs. Hypoxic TD-MVs package two immunosuppressive factors involved in the impairment of natural killer (NK) cell cytotoxicity against different tumor cells in vitro and in vivo . We showed that following their uptake by NK cells, hypoxic TD-MVs transfer TGF-β1 to NK cells, decreasing the cell surface expression of the activating receptor NKG2D, thereby inhibiting NK cell function. MicroRNA profiling revealed the presence of high levels of miR-210 and miR-23a in hypoxic TD-MVs. We demonstrated that miR-23a in hypoxic TD-MVs operates as an additional immunomosuppressive factor, since it directly targets the expression of CD107a in NK cells. To our knowledge, this is the first study to show that hypoxic tumor cells by secreting MVs can educate NK cells and decrease their antitumor immune response. This study highlights the existence of a novel mechanism of immune suppression mediated by hypoxic TD-MVs and further improves our understanding of the immunosuppressive mechanisms prevailing in the hypoxic tumor microenvironment.

Evidence for a causative role of N-methyl-D-aspartate receptors in an in vitro model of alcohol withdrawal hyperexcitability.

PubMed

Thomas, M P; Monaghan, D T; Morrisett, R A

1998-10-01

Synaptic mechanisms underlying hyperexcitability due to withdrawal from chronic ethanol exposure were investigated in a hippocampal explant model system using electrophysiological techniques. Whole-cell voltage clamp recordings from CA1 pyramidal cells demonstrated that acute ethanol exposure inhibited N-methyl-D-aspartate receptor (NMDAR)-mediated excitatory postsynaptic currents by over 40%. Chronic ethanol exposure for 6 to 11 days at 35 or 75 mM induced no differences from control explants in the fast component of the population synaptic response (non-NMDAR-mediated). Prolonged field potential recordings (to 10 hr) were used to monitor the withdrawal process in vitro. Ethanol-exposed explants from both 35 and 75 mM groups displayed an increase (60% and 89%, respectively) in the NMDAR-mediated component of synaptic transmission on withdrawal from chronic exposure. Prolonged tonic-clonic electrographic seizure activity was consistently observed after ethanol withdrawal only after the increase in NMDAR function. This hyperexcitability was inhibited by the NMDAR antagonist D-2-amino-5-phosphonovaleric acid and returned once the NMDAR component was reestablished after antagonist washout. In situ hybridization studies suggest that expression of NR2B subunit mRNA may be enhanced in explants after chronic ethanol exposure. No lasting differences were observed in the NMDAR component after acute in vitro ethanol exposure and withdrawal. These data suggest that the occurance of ethanol withdrawal hyperexcitability in this system may be directly dependent on alterations in NMDAR function after chronic exposure. Since this region and others that contain ethanol sensitive NMDARs may serve as epileptic foci, long term alterations in NMDAR function may be expected to generate paroxysmal depolarizing shifts underlying ictal events after withdrawal from ethanol exposure.

Disparities in Age-Associated Cognitive Decline Between African-American and Caucasian Populations: The Roles of Health Literacy and Education.

PubMed

Gupta, Vishal K; Winter, Michael; Cabral, Howard; Henault, Lori; Waite, Katherine; Hanchate, Amresh; Bickmore, Timothy W; Wolf, Michael S; Paasche-Orlow, Michael K

2016-08-01

To examine health literacy as a mediator of racial disparities in cognitive decline as measured by executive function in elderly adults. Prospective cohort study. Secondary analysis of ElderWalk trial in Boston, Massachusetts. English-speaking African-American and Caucasian individuals in a walking intervention for community-dwelling adults aged 65 and older without dementia at baseline who completed baseline and 12-month evaluations (N = 198). Health literacy was measured using the Short Test of Functional Health Literacy in Adults. Fluid and crystallized cognitive functions were measured at baseline and 12 months using the Trail-Making Test Part B minus Part B (TMT B-A) and the Controlled Oral Word Association Test (COWAT). Associations between health literacy and 12-month cognitive decline were modeled using multivariate linear regression. Participants with higher health literacy and education experienced less cognitive decline than those with limited health literacy according to the TMT B-A (P = .01). After adjusting for covariates, Caucasian participants (n = 63) experienced less decline than African-American participants (n = 135) on TMT B-A (P = .001) and COWAT (P = .001). Adjusting for health literacy led to a 25.3% decrease in the point estimate for racial difference in TMT B-A and a 19.5% decrease in COWAT. Although independently related to cognitive decline, educational attainment did not mediate racial differences. Health literacy is a partial mediator of racial disparities in cognitive decline. These results indicate the need to develop interventions to mitigate cognitive decline that individuals with low heath literacy can use and to modify the healthcare environment to better accommodate this population. © 2016, Copyright the Authors Journal compilation © 2016, The American Geriatrics Society.

Tuning the redox potential of vitamin K3 derivatives by oxidative functionalization using a Ag(i)/GO catalyst.

PubMed

El-Hout, S I; Suzuki, H; El-Sheikh, S M; Hassan, H M A; Harraz, F A; Ibrahim, I A; El-Sharkawy, E A; Tsujimura, S; Holzinger, M; Nishina, Y

2017-08-03

We propose herein initial results to develop optimum redox mediators by the combination of computational simulation and catalytic functionalization of the core structure of vitamin K 3 . We aim to correlate the calculated energy value of the LUMO of different vitamin K 3 derivatives with their actual redox potential. For this, we optimized the catalytic alkylation of 1,4-naphthoquinones with a designed Ag(i)/GO catalyst and synthesized a series of molecules.

The role of social relationships in the link between olfactory dysfunction and mortality.

PubMed

Leschak, Carrianne J; Eisenberger, Naomi I

2018-01-01

Recent work suggests that olfactory dysfunction is a strong predictor of five-year mortality in older adults. Based on past work showing: 1) that olfactory dysfunction impairs social functioning and 2) that social ties are linked with mortality, the current work explored whether impairments in social life mediated the relationship between olfactory dysfunction and mortality. Additionally, based on work showing gender differences in the social consequences of olfactory dysfunction, gender was assessed as a potential moderator of this association. Social network size mediated the olfactory-mortality link for females. To probe what feature of social networks was driving this effect, we investigated two subcomponents of social life: emotional closeness (e.g., perceived social support, loneliness) and physical closeness (e.g., physical contact, in-person socializing with others). Physical closeness significantly mediated the olfactory-mortality link for females, even after controlling for social network size. Emotional closeness did not mediate this link. Possible mechanisms underlying this relationship are discussed.

Distinct Corticostriatal and Intracortical Pathways Mediate Bilateral Sensory Responses in the Striatum.

PubMed

Reig, Ramon; Silberberg, Gilad

2016-12-01

Individual striatal neurons integrate somatosensory information from both sides of the body, however, the afferent pathways mediating these bilateral responses are unclear. Whereas ipsilateral corticostriatal projections are prevalent throughout the neocortex, contralateral projections provide sparse input from primary sensory cortices, in contrast to the dense innervation from motor and frontal regions. There is, therefore, an apparent discrepancy between the observed anatomical pathways and the recorded striatal responses. We used simultaneous in vivo whole-cell and extracellular recordings combined with focal cortical silencing, to dissect the afferent pathways underlying bilateral sensory integration in the mouse striatum. We show that unlike direct corticostriatal projections mediating responses to contralateral whisker deflection, responses to ipsilateral stimuli are mediated mainly by intracortical projections from the contralateral somatosensory cortex (S1). The dominant pathway is the callosal projection from contralateral to ipsilateral S1. Our results suggest a functional difference between the cortico-basal ganglia pathways underlying bilateral sensory and motor processes. © The Author 2016. Published by Oxford University Press.

29 CFR 1403.4 - Assignment of mediators.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 29 Labor 4 2010-07-01 2010-07-01 false Assignment of mediators. 1403.4 Section 1403.4 Labor Regulations Relating to Labor (Continued) FEDERAL MEDIATION AND CONCILIATION SERVICE FUNCTIONS AND DUTIES § 1403.4 Assignment of mediators. The Federal Service will assign one or more mediators to each labor...

Tests of Mediation: Paradoxical Decline in Statistical Power as a Function of Mediator Collinearity

ERIC Educational Resources Information Center

Beasley, T. Mark

2014-01-01

Increasing the correlation between the independent variable and the mediator ("a" coefficient) increases the effect size ("ab") for mediation analysis; however, increasing a by definition increases collinearity in mediation models. As a result, the standard error of product tests increase. The variance inflation caused by…

Surveying Parental Mediation: Connections, Challenges and Questions for Media Literacy

ERIC Educational Resources Information Center

Mendoza, Kelly

2009-01-01

This paper examines three strategies of parental mediation--coviewing, restrictive mediation, and active mediation--in order to make connections, challenge, and raise questions for media literacy. Coviewing, whether it is intentional practice, or whether it functions to promote media literacy, is explored. Restrictive mediation, how it connects to…

Same pattern, different mechanism: Locking onto the role of key species in seafloor ecosystem process

PubMed Central

Woodin, Sarah Ann; Volkenborn, Nils; Pilditch, Conrad A.; Lohrer, Andrew M.; Wethey, David S.; Hewitt, Judi E.; Thrush, Simon F.

2016-01-01

Seafloor biodiversity is a key mediator of ecosystem functioning, but its role is often excluded from global budgets or simplified to black boxes in models. New techniques allow quantification of the behavior of animals living below the sediment surface and assessment of the ecosystem consequences of complex interactions, yielding a better understanding of the role of seafloor animals in affecting key processes like primary productivity. Combining predictions based on natural history, behavior of key benthic species and environmental context allow assessment of differences in functioning and process, even when the measured ecosystem property in different systems is similar. Data from three sedimentary systems in New Zealand illustrate this. Analysis of the behaviors of the infaunal ecosystem engineers in each system revealed three very different mechanisms driving ecosystem function: density and excretion, sediment turnover and surface rugosity, and hydraulic activities and porewater bioadvection. Integrative metrics of ecosystem function in some cases differentiate among the systems (gross primary production) and in others do not (photosynthetic efficiency). Analyses based on behaviors and activities revealed important ecosystem functional differences and can dramatically improve our ability to model the impact of stressors on ecosystem and global processes. PMID:27230562

Same pattern, different mechanism: Locking onto the role of key species in seafloor ecosystem process.

PubMed

Woodin, Sarah Ann; Volkenborn, Nils; Pilditch, Conrad A; Lohrer, Andrew M; Wethey, David S; Hewitt, Judi E; Thrush, Simon F

2016-05-27

Seafloor biodiversity is a key mediator of ecosystem functioning, but its role is often excluded from global budgets or simplified to black boxes in models. New techniques allow quantification of the behavior of animals living below the sediment surface and assessment of the ecosystem consequences of complex interactions, yielding a better understanding of the role of seafloor animals in affecting key processes like primary productivity. Combining predictions based on natural history, behavior of key benthic species and environmental context allow assessment of differences in functioning and process, even when the measured ecosystem property in different systems is similar. Data from three sedimentary systems in New Zealand illustrate this. Analysis of the behaviors of the infaunal ecosystem engineers in each system revealed three very different mechanisms driving ecosystem function: density and excretion, sediment turnover and surface rugosity, and hydraulic activities and porewater bioadvection. Integrative metrics of ecosystem function in some cases differentiate among the systems (gross primary production) and in others do not (photosynthetic efficiency). Analyses based on behaviors and activities revealed important ecosystem functional differences and can dramatically improve our ability to model the impact of stressors on ecosystem and global processes.

Impulse control and underlying functions of the left DLPFC mediate age-related and age-independent individual differences in strategic social behavior.

PubMed

Steinbeis, Nikolaus; Bernhardt, Boris C; Singer, Tania

2012-03-08

Human social exchange is often characterized by conflicts of interest requiring strategic behavior for their resolution. To investigate the development of the cognitive and neural mechanisms underlying strategic behavior, we studied children's decisions while they played two types of economic exchange games with differing demands of strategic behavior. We show an increase of strategic behavior with age, which could not be explained by age-related changes in social preferences but instead by developmental differences in impulsivity and associated brain functions of the left dorsolateral prefrontal cortex (DLPFC). Furthermore, observed differences in cortical thickness of lDLPFC were predictive of differences in impulsivity and strategic behavior irrespective of age. We conclude that egoistic behavior in younger children is not caused by a lack of understanding right or wrong, but by the inability to implement behavioral control when tempted to act selfishly; a function relying on brain regions maturing only late in ontogeny. Copyright © 2012 Elsevier Inc. All rights reserved.

Influence of Cognitive Functioning on Age-Related Performance Declines in Visuospatial Sequence Learning.

PubMed

Krüger, Melanie; Hinder, Mark R; Puri, Rohan; Summers, Jeffery J

2017-01-01

Objectives: The aim of this study was to investigate how age-related performance differences in a visuospatial sequence learning task relate to age-related declines in cognitive functioning. Method: Cognitive functioning of 18 younger and 18 older participants was assessed using a standardized test battery. Participants then undertook a perceptual visuospatial sequence learning task. Various relationships between sequence learning and participants' cognitive functioning were examined through correlation and factor analysis. Results: Older participants exhibited significantly lower performance than their younger counterparts in the sequence learning task as well as in multiple cognitive functions. Factor analysis revealed two independent subsets of cognitive functions associated with performance in the sequence learning task, related to either the processing and storage of sequence information (first subset) or problem solving (second subset). Age-related declines were only found for the first subset of cognitive functions, which also explained a significant degree of the performance differences in the sequence learning task between age-groups. Discussion: The results suggest that age-related performance differences in perceptual visuospatial sequence learning can be explained by declines in the ability to process and store sequence information in older adults, while a set of cognitive functions related to problem solving mediates performance differences independent of age.

Fast and ultrafast endocytosis.

PubMed

Watanabe, Shigeki; Boucrot, Emmanuel

2017-08-01

Clathrin-mediated endocytosis (CME) is the main endocytic pathway supporting housekeeping functions in cells. However, CME may be too slow to internalize proteins from the cell surface during certain physiological processes such as reaction to stress hormones ('fight-or-flight' reaction), chemotaxis or compensatory endocytosis following exocytosis of synaptic vesicles or hormone-containing vesicles. These processes take place on a millisecond to second timescale and thus require very rapid cellular reaction to prevent overstimulation or exhaustion of the response. There are several fast endocytic processes identified so far: macropinocytosis, activity-dependent bulk endocytosis (ABDE), fast-endophilin-mediated endocytosis (FEME), kiss-and-run and ultrafast endocytosis. All are clathrin-independent and are not constitutively active but may use different molecular mechanisms to rapidly remove receptors and proteins from the cell surface. Here, we review our current understanding of fast and ultrafast endocytosis, their functions, and molecular mechanisms. Copyright © 2017 Elsevier Ltd. All rights reserved.

The relationship of autoantibodies to depression of cell-mediated immunity in infectious mononucleosis.

PubMed Central

Russell, A S; Percy, J S; Grace, M

1975-01-01

It has been postulated that autoantibody formation occurs as a consequence of a depression of function of certain thymus-derived lymphocytes (T cells). We have examined cell-mediated immunity, a T-cell function, in infectious mononucleosis, a condition in which autoantibodies are known to develop. We have shown some evidence of depressed cell-mediated immunity in patients with infectious mononucleosis but have been unable to correlate this with autoantibody production. These results do not support the hypothesis that depression of T-cell function leads to autoantibody formation. PMID:1081930

Acclimation of mechanical and hydraulic functions in trees: impact of the thigmomorphogenetic process

PubMed Central

Badel, Eric; Ewers, Frank W.; Cochard, Hervé; Telewski, Frank W.

2015-01-01

The secondary xylem (wood) of trees mediates several functions including water transport and storage, mechanical support and storage of photosynthates. The optimal structures for each of these functions will most likely differ. The complex structure and function of xylem could lead to trade-offs between conductive efficiency, resistance to embolism, and mechanical strength needed to count for mechanical loading due to gravity and wind. This has been referred to as the trade-off triangle, with the different optimal solutions to the structure/function problems depending on the environmental constraints as well as taxonomic histories. Thus, the optimisation of each function will lead to drastically different anatomical structures. Trees are able to acclimate the internal structure of their trunk and branches according to the stress they experience. These acclimations lead to specific structures that favor the efficiency or the safety of one function but can be antagonistic with other functions. Currently, there are no means to predict the way a tree will acclimate or optimize its internal structure in support of its various functions under differing environmental conditions. In this review, we will focus on the acclimation of xylem anatomy and its resulting mechanical and hydraulic functions to recurrent mechanical strain that usually result from wind-induced thigmomorphogenesis with a special focus on the construction cost and the possible trade-off between wood functions. PMID:25954292

Neighborhood, Family, and Peer Factors Associated with Early Adolescent Smoking and Alcohol Use.

PubMed

Cambron, Christopher; Kosterman, Rick; Catalano, Richard F; Guttmannova, Katarina; Hawkins, J David

2018-02-01

There is broad agreement that neighborhood contexts are important for adolescent development, but there is less consensus about their association with adolescent smoking and alcohol use. Few studies have examined associations between neighborhood socioeconomic contexts and smoking and alcohol use while also accounting for differences in family and peer risk factors for substance use. Data drawn from the Seattle Social Development Project (N = 808), a gender-balanced (female = 49%), multiethnic, theory-driven longitudinal study originating in Seattle, WA, were used to estimate trajectories of smoking and alcohol use from 5th to 9th grade. Time-varying measures of neighborhood socioeconomic, family, and peer factors were associated with smoking and alcohol use at each wave after accounting for average growth in smoking and alcohol use over time and demographic differences. Results indicated that living in more socioeconomically disadvantaged neighborhoods, lower family income, lower family general functioning, more permissive family smoking environments, and affiliation with deviant peers were independently associated with increased smoking. Lower family functioning, more permissive family alcohol use environments, and deviant peers were independently associated with increased alcohol use. The effect of neighborhood disadvantage on smoking was mediated by family income and deviant peers while the effect of neighborhood disadvantage on alcohol use was mediated by deviant peers alone. Family functioning and family substance use did not mediate associations between neighborhood disadvantage and smoking or alcohol use. The results highlight the importance of neighborhood, family, and peer factors in early adolescent smoking and alcohol use. Future studies should examine the unique association of neighborhood disadvantage with adolescent smoking net of family socioeconomics, functioning, and substance use, as well as peer affiliations. Better understanding of the role of contextual factors in early adolescent smoking and alcohol use can help bolster efforts to prevent both short and long harms from substance use.

Effectiveness of Parent-Child Mediation in Improving Family Functioning and Reducing Adolescent Problem Behavior: Results from a Pilot Randomized Controlled Trial.

PubMed

Tucker, Joan S; Edelen, Maria Orlando; Huang, Wenjing

2017-03-01

Parent-child mediation programs are intended to resolve or manage disputes and improve family functioning, but rigorous evaluations of their effectiveness are lacking. Families referred to a community-based mediation program (N = 111) were randomized to an intervention or wait-list control group, and completed three surveys over a 12-week period. With the exception of parent-reported child delinquency (which decreased more in the intervention group), this evaluation provides little support for the short-term effectiveness of parent-child mediation for improving family functioning and reducing child problem behaviors in general. Given that this is the first randomized controlled trial of a parent-child mediation program, additional evaluations involving larger samples and longer follow-ups are needed before firm conclusions can be drawn about the effectiveness of this intervention.

STAT6: its role in interleukin 4-mediated biological functions.

PubMed

Takeda, K; Kishimoto, T; Akira, S

1997-05-01

Interleukin (IL) 4 is known to be a cytokine which plays a central role in the regulation of immune response. Studies on cytokine signal transduction have clarified the mechanism by which IL4 exerts its functions. Two cytoplasmic proteins, signal transducer and activator of transcription (STAT) 6 and IL4-induced phosphotyrosine substrate/insulin receptor substrate 2 (4PS/IRS2), are activated in IL4 signal transduction. Recent studies from STAT6-deficient mice have revealed the essential role of STAT6 in IL4-mediated biological actions. In addition, STAT6 has also been demonstrated to be important for the functions mediated by IL13, which is related to IL4. IL4 and IL13 have been shown to induce the production of IgE, which is a major mediator in an allergic response. These findings indicate that STAT6 activation is involved in IL4- and IL13-mediated disorders such as allergy.

Effectiveness of Parent-Child Mediation in Improving Family Functioning and Reducing Adolescent Problem Behavior: Results from a Pilot Randomized Controlled Trial

PubMed Central

Tucker, Joan S.; Edelen, Maria Orlando; Huang, Wenjing

2016-01-01

Parent-child mediation programs are intended to resolve or manage disputes and improve family functioning, but rigorous evaluations of their effectiveness are lacking. Families referred to a community-based mediation program (N=111) were randomized to an intervention or wait-list control group, and completed three surveys over a 12-week period. With the exception of parent-reported child delinquency (which decreased more in the intervention group), this evaluation provides little support for the short-term effectiveness of parent-child mediation for improving family functioning and reducing child problem behaviors in general. Given that this is the first randomized controlled trial of a parent-child mediation program, additional evaluations involving larger samples and longer follow-ups are needed before firm conclusions can be drawn about the effectiveness of this intervention. PMID:26762375

Distinct Cellular and Subcellular Distributions of G Protein-Coupled Receptor Kinase and Arrestin Isoforms in the Striatum

PubMed Central

Bychkov, Evgeny; Zurkovsky, Lilia; Garret, Mika B.; Ahmed, Mohamed R.; Gurevich, Eugenia V.

2012-01-01

G protein-coupled receptor kinases (GRKs) and arrestins mediate desensitization of G protein-coupled receptors (GPCR). Arrestins also mediate G protein-independent signaling via GPCRs. Since GRK and arrestins demonstrate no strict receptor specificity, their functions in the brain may depend on their cellular complement, expression level, and subcellular targeting. However, cellular expression and subcellular distribution of GRKs and arrestins in the brain is largely unknown. We show that GRK isoforms GRK2 and GRK5 are similarly expressed in direct and indirect pathway neurons in the rat striatum. Arrestin-2 and arrestin-3 are also expressed in neurons of both pathways. Cholinergic interneurons are enriched in GRK2, arrestin-3, and GRK5. Parvalbumin-positive interneurons express more of GRK2 and less of arrestin-2 than medium spiny neurons. The GRK5 subcellular distribution in the human striatal neurons is altered by its phosphorylation: unphosphorylated enzyme preferentially localizes to synaptic membranes, whereas phosphorylated GRK5 is found in plasma membrane and cytosolic fractions. Both GRK isoforms are abundant in the nucleus of human striatal neurons, whereas the proportion of both arrestins in the nucleus was equally low. However, overall higher expression of arrestin-2 yields high enough concentration in the nucleus to mediate nuclear functions. These data suggest cell type- and subcellular compartment-dependent differences in GRK/arrestin-mediated desensitization and signaling. PMID:23139825

Distinct cellular and subcellular distributions of G protein-coupled receptor kinase and arrestin isoforms in the striatum.

PubMed

Bychkov, Evgeny; Zurkovsky, Lilia; Garret, Mika B; Ahmed, Mohamed R; Gurevich, Eugenia V

2012-01-01

G protein-coupled receptor kinases (GRKs) and arrestins mediate desensitization of G protein-coupled receptors (GPCR). Arrestins also mediate G protein-independent signaling via GPCRs. Since GRK and arrestins demonstrate no strict receptor specificity, their functions in the brain may depend on their cellular complement, expression level, and subcellular targeting. However, cellular expression and subcellular distribution of GRKs and arrestins in the brain is largely unknown. We show that GRK isoforms GRK2 and GRK5 are similarly expressed in direct and indirect pathway neurons in the rat striatum. Arrestin-2 and arrestin-3 are also expressed in neurons of both pathways. Cholinergic interneurons are enriched in GRK2, arrestin-3, and GRK5. Parvalbumin-positive interneurons express more of GRK2 and less of arrestin-2 than medium spiny neurons. The GRK5 subcellular distribution in the human striatal neurons is altered by its phosphorylation: unphosphorylated enzyme preferentially localizes to synaptic membranes, whereas phosphorylated GRK5 is found in plasma membrane and cytosolic fractions. Both GRK isoforms are abundant in the nucleus of human striatal neurons, whereas the proportion of both arrestins in the nucleus was equally low. However, overall higher expression of arrestin-2 yields high enough concentration in the nucleus to mediate nuclear functions. These data suggest cell type- and subcellular compartment-dependent differences in GRK/arrestin-mediated desensitization and signaling.

Plasma homocysteine and cerebral small vessel disease as possible mediators between kidney and cognitive functions in patients with diabetes mellitus.

PubMed

Sonoda, Mika; Shoji, Tetsuo; Kuwamura, Yukinobu; Okute, Yujiro; Naganuma, Toshihide; Shima, Hideaki; Motoyama, Koka; Morioka, Tomoaki; Mori, Katsuhito; Fukumoto, Shinya; Shioi, Atsushi; Shimono, Taro; Fujii, Hisako; Kabata, Daijiro; Shintani, Ayumi; Emoto, Masanori; Inaba, Masaaki

2017-06-29

Cognitive impairment is more prevalent in those with decreased kidney function. We tested a hypothesis that an increased homocysteine and/or cerebral small vessel diseases (SVDs) mediate the link between kidney and cognitive functions in a cross-sectional study in 143 type 2 diabetes patients without diagnosis of dementia or prior stroke. The exposure and outcome variables were estimated glomerular filtration rate (eGFR) and cognitive performance evaluated with Modified Mini-Mental State (3 MS) examination, respectively. The candidate mediators were plasma homocysteine concentration, and SVDs including silent cerebral infarction, cerebral microbleed, periventricular hyperintensity, and deep and subcortical white matter hyperintensity by magnetic resonance imaging. In multiple regression models adjusted for 12 potential confounders, eGFR was positively associated with 3 MS score, inversely with homocysteine, but not significantly with the presence of any type of SVD. The association of eGFR with 3 MS remained significant when each of the SVDs was added to the model, whereas it disappeared when homocysteine was included in place of SVD. Mediation analysis indicated nearly significant mediation of homocysteine (P = 0.062) but no meaningful mediations of SVDs (P = 0.842-0.930). Thus, homocysteine, not SVDs, was shown to be the possible mediator between kidney and cognitive functions in patients with type 2 diabetes mellitus.

Ran-dependent nuclear export mediators: a structural perspective

PubMed Central

Güttler, Thomas; Görlich, Dirk

2011-01-01

Nuclear export is an essential eukaryotic activity. It proceeds through nuclear pore complexes (NPCs) and is mediated by soluble receptors that shuttle between nucleus and cytoplasm. RanGTPase-dependent export mediators (exportins) constitute the largest class of these carriers and are functionally highly versatile. All of these exportins load their substrates in response to RanGTP binding in the nucleus and traverse NPCs as ternary RanGTP–exportin–cargo complexes to the cytoplasm, where GTP hydrolysis leads to export complex disassembly. The different exportins vary greatly in their substrate range. Recent structural studies of both protein- and RNA-specific exporters have illuminated how exportins bind their cargoes, how Ran triggers cargo loading and how export complexes are disassembled in the cytoplasm. Here, we review the current state of knowledge and highlight emerging principles as well as prevailing questions. PMID:21878989

Molecular mechanisms of mechanotransduction in integrin-mediated cell-matrix adhesion

PubMed Central

Li, Zhenhai; Lee, Hyunjung; Zhu, Cheng

2016-01-01

Cell-matrix adhesion complexes are multi-protein structures linking the extracellular matrix (ECM) to the cytoskeleton. They are essential to both cell motility and function by bidirectionally sensing and transmitting mechanical and biochemical stimulations. Several types of cell-matrix adhesions have been identified and they share many key molecular components, such as integrins and actin-integrin linkers. Mechanochemical coupling between ECM molecules and the actin cytoskeleton has been observed from the single cell to the single molecule level and from immune cells to neuronal cells. However, the mechanisms underlying force regulation of integrin-mediated mechanotransduction still need to be elucidated. In this review article, we focus on integrin-mediated adhesions and discuss force regulation of cell-matrix adhesions and key adaptor molecules, three different force-dependent behaviors, and molecular mechanisms for mechanochemical coupling in force regulation. PMID:27720950

Generation of an allelic series of knock-in mice using recombinase-mediated cassette exchange (RMCE).

PubMed

Roebroek, Anton J M; Van Gool, Bart

2014-01-01

Molecular genetic strategies applying embryonic stem cell (ES cell) technologies to study the function of a gene in mice or to generate a mouse model for a human disease are continuously under development. Next to (conditional) inactivation of genes the application and importance of approaches to generate knock-in mutations are increasing. In this chapter the principle and application of recombinase-mediated cassette exchange (RMCE) are discussed as being a new emerging knock-in strategy, which enables easy generation of a series of different knock-in mutations within one gene. An RMCE protocol, which was used to generate a series of different knock-in mutations in the Lrp1 gene of ES cells, is described in detail as an example of how RMCE can be used to generate highly efficiently an allelic series of differently modified ES cell clones from a parental modified ES cell clone. Subsequently the differently modified ES cell clones can be used to generate an allelic series of mutant knock-in mice.

Parental alcohol use disorders and child delinquency: the mediating effects of executive functioning and chronic family stress.

PubMed

Grekin, Emily R; Brennan, Patricia A; Hammen, Constance

2005-01-01

This study examines the relationship between parental alcohol use disorders (AUDs) and child violent and nonviolent delinquency. It also explores the mediating effects of executive functioning and chronic family stress on the parental AUD/child delinquency relationship. Participants were 816 families with children (414 boys and 402 girls) born between 1981 and 1984 at Mater Misericordiae Mother's Hospital in Brisbane, Australia. Parents and children completed semistructured interviews, questionnaires and neuropsychological tests that assessed parental alcohol use, family psychiatric history, chronic family stress, child delinquency and child executive functioning. Paternal (but not maternal) AUDs predicted child violent and nonviolent delinquency. Executive functioning mediated the relationship between paternal AUDs and violent delinquency, whereas family stress mediated the relationship between paternal AUDs and both violent and nonviolent delinquency. Results support a biosocial conceptualization of the paternal AUD/delinquency relationship. They suggest that paternal AUDs may be associated with child executive functioning and family stress, which may in turn lead to child delinquency.

Executive Functioning and School Adjustment: The Mediational Role of Pre-kindergarten Learning-related Behaviors

PubMed Central

Sasser, Tyler R.; Bierman, Karen L.; Heinrichs, Brenda

2016-01-01

164 four-year-old children (14% Latino American, 30% African American, 56% European American; 57% girls) in 22 Head Start classrooms were followed through third grade. Growth curve models were used to estimate the predictive associations between pre-kindergarten executive function (EF) skills and trajectories of academic skill development (math, literacy, overall academic functioning) and social-emotional adjustment at school (social competence, aggression), controlling for child sex, race, verbal IQ, and pre-kindergarten baseline scores. Direct developmental pathways were examined, along with indirect pathways, in which the association between preschool EF and elementary school adjustment was mediated by classroom learning behaviors. Preschool EF significantly predicted later math skills, academic functioning, and social competence, and marginally predicted later literacy skills. Preschool learning behaviors fully mediated the association between EF and later literacy skills and social competence, but did not mediate associations between EF and later math skills or academic functioning. Implications for developmental theory and early education are discussed. PMID:27231409

Thin idealization and causal attributions mediate the association between culture and obesity stereotypes: An examination of Chinese and American adolescents.

PubMed

Klaczynski, Paul A; Felmban, Wejdan S

2018-05-28

Few studies have examined age or cultural differences in the stereotypes adolescents have of persons with obesity. The present research explored the hypotheses that American adolescents have more negative obesity stereotypes than Chinese adolescents and that the effects of culture are mediated by weight attributions and thin idealization. Participants (N = 335; 181 female; M age = 14.83 years, SD = 1.57 years) completed measures of thin idealization and causal attributions and made generalizations from and attributions of stereotypical personality characteristics to obese figures. Not only did stereotypes differ between countries, but generalizations of negative characteristics from obese figures increased with age. In addition, American adolescents more firmly endorsed the 'thin ideal' and were more likely to attribute obesity to internal causes that Chinese adolescents. As anticipated, between-country differences in stereotyping were mediated by thin idealization and causal attributions. Findings are discussed in terms of the 'doctrine of the mean', social identity theory, and dual-process theories. Statement of Contribution The development of obesity stereotypes has been the subject of a number of recent studies. Although scarce, research on adolescents' obesity stereotypes indicates that the strength of these stereotypes increases with age and that these increases are mediated by thin idealization and causal attributions. The current research adds to this growing literature that differences between Chinese adolescents' and American adolescents' obesity stereotypes - in terms of the assignment of stereotypical traits to people with obesity and the generalization of negative traits from an individual person with obesity to people with obesity as a group - are mediated by thin idealization and attributions about obesity's causes. The research also indicates that (1) age differences in obesity stereotyping vary as a function of the method used to measure stereotypes, (2) Chinese adolescents are less likely than American adolescents to attribute obesity to characterological flaws, and (3) American adolescents idealize thinness more than Chinese adolescents. © 2018 The British Psychological Society.

Sex differences with aging in nutritive skeletal muscle blood flow: impact of exercise training, nitric oxide, and α-adrenergic-mediated mechanisms

PubMed Central

La Favor, Justin D.; Kraus, Raymond M.; Carrithers, Jonathan A.; Roseno, Steven L.; Gavin, Timothy P.

2014-01-01

The incidence of cardiovascular disease increases progressively with age, but aging may affect men and women differently. Age-associated changes in vascular structure and function may manifest in impaired nutritive blood flow, although the regulation of nutritive blood flow in healthy aging is not well understood. The purpose of this study was to determine if nitric oxide (NO)-mediated or α-adrenergic-mediated regulation of nutritive skeletal muscle blood flow is impaired with advanced age, and if exercise training improves age-related deficiencies. Nutritive blood flow was monitored in the vastus lateralis of healthy young and aged men and women via the microdialysis-ethanol technique prior to and following seven consecutive days of exercise training. NO-mediated and α-adrenergic-mediated regulation of nutritive blood flow was assessed by microdialysis perfusion of acetylcholine, sodium nitroprusside, NG-monomethyl-l-arginine, norepinephrine, or phentolamine. Pretraining nutritive blood flow was attenuated in aged compared with young women (7.39 ± 1.5 vs. 15.5 ± 1.9 ml·100 g−1·min−1, P = 0.018), but not aged men (aged 13.5 ± 3.7 vs. young 9.4 ± 1.3 ml·100 g−1·min−1, P = 0.747). There were no age-associated differences in NO-mediated or α-adrenergic-mediated nutritive blood flow. Exercise training increased resting nutritive blood flow only in young men (9.4 ± 1.3 vs. 19.7 ml·100 g−1·min−1, P = 0.005). The vasodilatory effect of phentolamine was significantly reduced following exercise training only in young men (12.3 ± 6.14 vs. −3.68 ± 3.26 ml·100 g−1·min−1, P = 0.048). In conclusion, the age-associated attenuation of resting nutritive skeletal muscle blood flow was specific to women, while the exercise-induced alleviation of α-adrenergic mediated vasoconstriction that was specific to young men suggests an age-associated modulation of the sympathetic response to exercise training. PMID:24951753

Sex differences with aging in nutritive skeletal muscle blood flow: impact of exercise training, nitric oxide, and α-adrenergic-mediated mechanisms.

PubMed

La Favor, Justin D; Kraus, Raymond M; Carrithers, Jonathan A; Roseno, Steven L; Gavin, Timothy P; Hickner, Robert C

2014-08-15

The incidence of cardiovascular disease increases progressively with age, but aging may affect men and women differently. Age-associated changes in vascular structure and function may manifest in impaired nutritive blood flow, although the regulation of nutritive blood flow in healthy aging is not well understood. The purpose of this study was to determine if nitric oxide (NO)-mediated or α-adrenergic-mediated regulation of nutritive skeletal muscle blood flow is impaired with advanced age, and if exercise training improves age-related deficiencies. Nutritive blood flow was monitored in the vastus lateralis of healthy young and aged men and women via the microdialysis-ethanol technique prior to and following seven consecutive days of exercise training. NO-mediated and α-adrenergic-mediated regulation of nutritive blood flow was assessed by microdialysis perfusion of acetylcholine, sodium nitroprusside, N(G)-monomethyl-L-arginine, norepinephrine, or phentolamine. Pretraining nutritive blood flow was attenuated in aged compared with young women (7.39 ± 1.5 vs. 15.5 ± 1.9 ml·100 g(−1)·min(−1), P = 0.018), but not aged men (aged 13.5 ± 3.7 vs. young 9.4 ± 1.3 ml·100 g(−1)·min(−1), P = 0.747). There were no age-associated differences in NO-mediated or α-adrenergic-mediated nutritive blood flow. Exercise training increased resting nutritive blood flow only in young men (9.4 ± 1.3 vs. 19.7 ml·100 g(−1)·min(−1), P = 0.005). The vasodilatory effect of phentolamine was significantly reduced following exercise training only in young men (12.3 ± 6.14 vs. −3.68 ± 3.26 ml·100 g(−1)·min(−1), P = 0.048). In conclusion, the age-associated attenuation of resting nutritive skeletal muscle blood flow was specific to women, while the exercise-induced alleviation of α-adrenergic mediated vasoconstriction that was specific to young men suggests an age-associated modulation of the sympathetic response to exercise training.

Social Competence and Social Support as Mediators between Comorbid Depressive and Conduct Problems and Functional Outcomes in Middle School Students

PubMed Central

Rockhill, Carol M.; Stoep, Ann Vander; McCauley, Elizabeth; Katon, Wayne J.

2009-01-01

This study examined the roles of social competence and social support as potential mediators of the association between psychopathology and functional outcomes in a middle school sample (n=521). Participants were stratified into four psychopathology risk groups (depression only, conduct problems only, comorbid depression and conduct problems, low symptoms) based on screening during early 6th grade. Functional outcomes were 6th grade point average (GPA) and parent rating of global adaptive functioning in their 7th grade student. Low levels of social competence were found to mediate the association between psychiatric symptoms and both lower grades and global functioning, for adolescents with depressive symptoms alone and with comorbid symptoms, but not for those with conduct problems alone. Lack of social support mediated the association between symptoms and lower grades for adolescents with depression alone and comorbid symptoms, but not those with conduct problems alone. These findings suggest that intervention to improve social competence and social support may enhance functional outcomes, especially for youth with depressive symptoms or comorbid depressive and conduct symptoms. PMID:18694594

Epitranscriptomic profiling across cell types reveals associations between APOBEC1-mediated RNA editing, gene expression outcomes, and cellular function.

PubMed

Rayon-Estrada, Violeta; Harjanto, Dewi; Hamilton, Claire E; Berchiche, Yamina A; Gantman, Emily Conn; Sakmar, Thomas P; Bulloch, Karen; Gagnidze, Khatuna; Harroch, Sheila; McEwen, Bruce S; Papavasiliou, F Nina

2017-12-12

Epitranscriptomics refers to posttranscriptional alterations on an mRNA sequence that are dynamic and reproducible, and affect gene expression in a similar way to epigenetic modifications. However, the functional relevance of those modifications for the transcript, the cell, and the organism remain poorly understood. Here, we focus on RNA editing and show that Apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-1 (APOBEC1), together with its cofactor RBM47, mediates robust editing in different tissues. The majority of editing events alter the sequence of the 3'UTR of targeted transcripts, and we focus on one cell type (monocytes) and on a small set of highly edited transcripts within it to show that editing alters gene expression by modulating translation (but not RNA stability or localization). We further show that specific cellular processes (phagocytosis and transendothelial migration) are enriched for transcripts that are targets of editing and that editing alters their function. Finally, we survey bone marrow progenitors and demonstrate that common monocyte progenitor cells express high levels of APOBEC1 and are susceptible to loss of the editing enzyme. Overall, APOBEC1-mediated transcriptome diversification is required for the fine-tuning of protein expression in monocytes, suggesting an epitranscriptomic mechanism for the proper maintenance of homeostasis in innate immune cells. Copyright © 2017 the Author(s). Published by PNAS.

Requirement for CDK6 in MLL-rearranged acute myeloid leukemia

PubMed Central

Placke, Theresa; Faber, Katrin; Nonami, Atsushi; Putwain, Sarah L.; Salih, Helmut R.; Heidel, Florian H.; Krämer, Alwin; Root, David E.; Barbie, David A.; Krivtsov, Andrei V.; Armstrong, Scott A.; Hahn, William C.; Huntly, Brian J.; Sykes, Stephen M.; Milsom, Michael D.; Scholl, Claudia

2014-01-01

Chromosomal rearrangements involving the H3K4 methyltransferase mixed-lineage leukemia (MLL) trigger aberrant gene expression in hematopoietic progenitors and give rise to an aggressive subtype of acute myeloid leukemia (AML). Insights into MLL fusion-mediated leukemogenesis have not yet translated into better therapies because MLL is difficult to target directly, and the identity of the genes downstream of MLL whose altered transcription mediates leukemic transformation are poorly annotated. We used a functional genetic approach to uncover that AML cells driven by MLL-AF9 are exceptionally reliant on the cell-cycle regulator CDK6, but not its functional homolog CDK4, and that the preferential growth inhibition induced by CDK6 depletion is mediated through enhanced myeloid differentiation. CDK6 essentiality is also evident in AML cells harboring alternate MLL fusions and a mouse model of MLL-AF9–driven leukemia and can be ascribed to transcriptional activation of CDK6 by mutant MLL. Importantly, the context-dependent effects of lowering CDK6 expression are closely phenocopied by a small-molecule CDK6 inhibitor currently in clinical development. These data identify CDK6 as critical effector of MLL fusions in leukemogenesis that might be targeted to overcome the differentiation block associated with MLL-rearranged AML, and underscore that cell-cycle regulators may have distinct, noncanonical, and nonredundant functions in different contexts. PMID:24764564

The impact of night-shift work on platelet function in healthy medical staff.

PubMed

Nakao, Tomoko; Yasumoto, Atsushi; Tokuoka, Suzumi; Kita, Yoshihiro; Kawahara, Takuya; Daimon, Masao; Yatomi, Yutaka

2018-04-18

Rotating shift work has been reported to increase the risk of cardiovascular diseases. Vascular endothelial dysfunction and platelet activation are among the leading causes of thrombus formation in patients with myocardial infarction or stroke. Endothelial function has been shown to be impaired immediately after night-shift work; however, it is not known whether platelets are also activated. The aim of this study was to investigate the acute impact of night-shift work on platelet function. This observational study included 11 healthy medical staff members (seven women, median age 32 years). We examined each subject's platelet aggregation rates and the serum concentrations of eicosanoid mediators after night-shift work and on day-shift work without preceding night-shift work (baseline). Platelet aggregation did not differ from baseline levels after night-shift work. However, serum cyclooxygenase (COX)-metabolized eicosanoid mediators, particularly thromboxane (Tx) B 2 (a stable metabolite of TxA 2 and the most important marker of platelet activation), were significantly higher after the night-shift than at baseline (median 65.3 vs 180.4 ng/ml). Although platelet aggregation did not increase, there was an increase in serum COX-metabolized eicosanoid mediators such as TxB 2 in healthy medical staff after night-shift work. This platelet hypersensitivity may be one of the mechanisms underlying the significant association between night-shift work and adverse cardiovascular outcomes.

Nucleolus-derived mediators in oncogenic stress response and activation of p53-dependent pathways.

PubMed

Stępiński, Dariusz

2016-08-01

Rapid growth and division of cells, including tumor ones, is correlated with intensive protein biosynthesis. The output of nucleoli, organelles where translational machineries are formed, depends on a rate of particular stages of ribosome production and on accessibility of elements crucial for their effective functioning, including substrates, enzymes as well as energy resources. Different factors that induce cellular stress also often lead to nucleolar dysfunction which results in ribosome biogenesis impairment. Such nucleolar disorders, called nucleolar or ribosomal stress, usually affect cellular functioning which in fact is a result of p53-dependent pathway activation, elicited as a response to stress. These pathways direct cells to new destinations such as cell cycle arrest, damage repair, differentiation, autophagy, programmed cell death or aging. In the case of impaired nucleolar functioning, nucleolar and ribosomal proteins mediate activation of the p53 pathways. They are also triggered as a response to oncogenic factor overexpression to protect tissues and organs against extensive proliferation of abnormal cells. Intentional impairment of any step of ribosome biosynthesis which would direct the cells to these destinations could be a strategy used in anticancer therapy. This review presents current knowledge on a nucleolus, mainly in relation to cancer biology, which is an important and extremely sensitive element of the mechanism participating in cellular stress reaction mediating activation of the p53 pathways in order to counteract stress effects, especially cancer development.

Family functioning mediates adaptation in caregivers of individuals with Rett syndrome.

PubMed

Lamb, Amanda E; Biesecker, Barbara B; Umstead, Kendall L; Muratori, Michelle; Biesecker, Leslie G; Erby, Lori H

2016-11-01

The objective of this study was to investigate factors related to family functioning and adaptation in caregivers of individuals with Rett syndrome (RS). A cross-sectional quantitative survey explored the relationships between demographics, parental self-efficacy, coping methods, family functioning and adaptation. A forward-backward, step-wise model selection procedure was used to evaluate variables associated with both family functioning and adaptation. Analyses also explored family functioning as a mediator of the relationship between other variables and adaptation. Bivariate analyses (N=400) revealed that greater parental self-efficacy, a greater proportion of problem-focused coping, and a lesser proportion of emotion-focused coping were associated with more effective family functioning. In addition, these key variables were significantly associated with greater adaptation, as was family functioning, while controlling for confounders. Finally, regression analyses suggest family functioning as a mediator of the relationships between three variables (parental self-efficacy, problem-focused coping, and emotion-focused coping) with adaptation. This study demonstrates the potentially predictive roles of expectations and coping methods and the mediator role of family functioning in adaptation among caregivers of individuals with RS, a chronic developmental disorder. A potential target for intervention is strengthening of caregiver competence in the parenting role to enhance caregiver adaptation. Published by Elsevier Ireland Ltd.

Chronic Illnesses and Depressive Symptoms Among Older People: Functional Limitations as a Mediator and Self-Perceptions of Aging as a Moderator.

PubMed

Han, Jina

2017-05-01

This research examined the mediation of functional limitations in the relationship between chronic illnesses and depressive symptoms among older Americans along with tests for the moderation of self-perceptions of aging. Data from the Health and Retirement Study (2008, 2010, and 2012) were used. Longitudinal mediation models were tested using a sample of 3,382 Americans who responded to psychosocial questions and were over 65 years old in 2008. Functional limitations mediated the linkage between chronic illnesses and depressive symptoms. Negative self-perceptions of aging exacerbated the effects of chronic illnesses on depressive symptoms. Health care professionals should be aware of depressive symptoms in older adults reporting chronic illnesses and particularly in those reporting functional limitations. To decrease the risk of depressive symptoms caused by chronic illnesses, negative self-perceptions of aging may need to be challenged.

29 CFR 1430.2 - Definitions.

Code of Federal Regulations, 2010 CFR

2010-07-01

... Relating to Labor (Continued) FEDERAL MEDIATION AND CONCILIATION SERVICE FEDERAL MEDIATION AND CONCILIATION... Mediation and Conciliation Service employee or his delegee, officially designated to perform the advisory committee management functions delineated in this part; (e) The term Service means the Federal Mediation and...

A Single Base Difference between Pit-1 Binding Sites at the hGH Promoter and Locus Control Region Specifies Distinct Pit-1 Conformations and Functions

PubMed Central

Shewchuk, Brian M.; Ho, Yugong; Liebhaber, Stephen A.; Cooke, Nancy E.

2006-01-01

Activation of the human growth hormone (hGH-N) gene in pituitary somatotropes is mediated by a locus control region (LCR). This LCR is composed of DNase I-hypersensitive sites (HS) located −14.5 kb to −32 kb relative to the hGH-N promoter. HSI, at −14.5 kb, is the dominant determinant of hGH-N expression and is essential for establishment of a 32-kb domain of histone acetylation that encompasses the active hGH locus. This activity is conferred by three binding sites for the POU domain transcription factor Pit-1. These Pit-1 elements are sufficient to activate hGH-N expression in the mouse pituitary. In contrast, Pit-1 sites at the hGH-N promoter are consistently unable to mediate similar activity. In the present study, we demonstrate that the functional difference between the promoter-proximal and the HSI Pit-1 binding sites can be attributed in part to a single base difference. This base affects the conformation of the Pit-1/DNA complex, and reciprocal exchange of the divergent bases between the two sets of Pit-1 elements results in a partial reversal of their transgenic activities. These data support a model in which the Pit-1 binding sites in the hGH LCR allosterically program the bound Pit-1 complex for chromatin activating functions. PMID:16914737

Integrating impairments in reaction time and executive function using a diffusion model framework.

PubMed

Karalunas, Sarah L; Huang-Pollock, Cynthia L

2013-07-01

Using Ratcliff's diffusion model and ex-Gaussian decomposition, we directly evaluate the role individual differences in reaction time (RT) distribution components play in the prediction of inhibitory control and working memory (WM) capacity in children with and without ADHD. Children with (n = 91, [Formula: see text] age = 10.2 years, 67 % male) and without ADHD (n = 62, [Formula: see text] age = 10.6 years, 46 % male) completed four tasks of WM and a stop signal reaction time (SSRT) task. Children with ADHD had smaller WM capacities and less efficient inhibitory control. Diffusion model analyses revealed that children with ADHD had slower drift rates (v) and faster non-decision times (Ter), but there were no group differences in boundary separations (a). Similarly, using an ex-Gaussian approach, children with ADHD had larger τ values than non-ADHD controls, but did not differ in μ or σ distribution components. Drift rate mediated the association between ADHD status and performance on both inhibitory control and WM capacity. τ also mediated the ADHD-executive function impairment associations; however, models were a poorer fit to the data. Impaired performance on RT and executive functioning tasks has long been associated with childhood ADHD. Both are believed to be important cognitive mechanisms to the disorder. We demonstrate here that drift rate, or the speed at which information accumulates towards a decision, is able to explain both.

Impact of O-glycosylation on the molecular and cellular adhesion properties of the Escherichia coli autotransporter protein Ag43.

PubMed

Reidl, Sebastian; Lehmann, Annika; Schiller, Roswitha; Salam Khan, A; Dobrindt, Ulrich

2009-08-01

Antigen 43 (Ag43) represents an entire family of closely related autotransporter proteins in Escherichia coli and has been described to confer aggregation and fluffing of cells, to promote biofilm formation, uptake and survival in macrophages as well as long-term persistence of uropathogenic E. coli in the murine urinary tract. Furthermore, it has been reported that glycosylation of the Ag43 passenger domain (alpha(43)) stabilizes its conformation and increases adhesion to Hep-2 cells. We characterized the role of Ag43 as an adhesin and the impact of O-glycosylation on the function of Ag43. To analyze whether structural variations in the alpha(43) domain correlate with different functional properties, we cloned 5 different agn43 alleles from different E. coli subtypes and tested them for autoaggregation, biofilm formation, adhesion to different eukaryotic cell lines as well as to purified components of the extracellular matrix. These experiments were performed with nonglycosylated and O-glycosylated Ag43 variants. We show for the first time that Ag43 mediates bacterial adhesion in a cell line-specific manner and that structural variations of the alpha(43) domain correlate with increased adhesive properties to proteins of the extracellular matrix such as collagen and laminin. Whereas O-glycosylation of many alpha(43) domains led to impaired autoaggregation and a significantly reduced adhesion to eukaryotic cell lines, their interaction with collagen was significantly increased. These data demonstrate that O-glycosylation is not a prerequisite for Ag43 function and that the different traits mediated by Ag43, i.e., biofilm formation, autoaggregation, adhesion to eukaryotic cells and extracellular matrix proteins, rely on distinct mechanisms.

Adolescent survivors of childhood sexual abuse: the mediating role of attachment style and coping in psychological and interpersonal functioning.

PubMed

Shapiro, D L; Levendosky, A A

1999-11-01

To examine attachment style and coping strategies as potential mediating variables between childhood sexual abuse (CSA) and psychological and interpersonal functioning in an attempt to explain variability in extent of disorder and level of functioning. Eighty adolescent females, aged 14-16 years, answered questions regarding abuse history, attachment style, coping with an interpersonal stressor, depression and trauma symptomatology, and conflict with a best friend. Structural equation modeling analyses indicated that attachment style mediates the effects of CSA and child abuse and neglect on coping and psychological distress. The indirect effects of CSA and other abuse through attachment accounted for most of the effects on coping and psychological distress. Avoidant and cognitive coping strategies also served as mediators in the models, accounting for most of the effects of the other variables on interpersonal conflict. The findings indicate that attachment style and coping strategies influence psychological and interpersonal functioning, mediating the direct effects of CSA and other types of child abuse and neglect. These results have implications for therapeutic intervention with children and adolescents who have experienced child abuse.

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

Mental and physical health-related functioning mediates between psychological job demands and sickness absence among nurses.

PubMed

Roelen, Corné; van Rhenen, Willem; Schaufeli, Wilmar; van der Klink, Jac; Magerøy, Nils; Moen, Bente; Bjorvatn, Bjørn; Pallesen, Ståle

2014-08-01

To investigate whether health-related functioning mediates the effect of psychological job demands on sickness absence in nurses. Nurses face high job demands that can have adverse health effects resulting in sickness absence. Prospective cohort study with 1-year follow-up. Data for 2964 Norwegian nurses were collected in the period 2008-2010. At baseline, psychological job demands were measured with the Demand-Control-Support Questionnaire. Health-related functioning was assessed by the Mental Composite Score and the Physical Composite Score of the SF-12 Health Survey (2nd version). Sickness absence (no = 0, yes = 1) was self-reported at 1-year follow-up. Interaction and mediation analyses were conducted stratified by tenure (<1-year, 1-2 years, 3-6 years, >6 years) as a registered nurse. A total of 2180 nurses (74%) with complete data were eligible for analysis. A significant three-way interaction between job demands, control and support was found in newly licensed nurses (tenure <1-year). Baseline psychological job demands were positively associated with sickness absence at 1-year follow-up. This association was substantially weakened when Mental Composite Score and Physical Composite Score were introduced as mediator variables, indicating a partial mediation effect that was particularly pronounced in newly licensed nurses. Psychological job demands did not modify the effect of health-related functioning on sickness absence. Both mental and physical health-related functioning mediated between psychological job demands and sickness absence. Nurse managers should pay attention to health-related functioning, because poor health-related functioning may predict sickness absence, especially in newly licensed nurses. © 2013 John Wiley & Sons Ltd.

Tea-induced improvement of endothelial function in humans: No role for epigallocatechin gallate (EGCG).

PubMed

Lorenz, Mario; Rauhut, Franziska; Hofer, Christine; Gwosc, Stefanie; Müller, Eda; Praeger, Damaris; Zimmermann, Benno F; Wernecke, Klaus-Dieter; Baumann, Gert; Stangl, Karl; Stangl, Verena

2017-05-23

Consumption of tea is inversely associated with cardiovascular diseases. However, the active compound(s) responsible for the protective effects of tea are unknown. Although many favorable cardiovascular effects in vitro are mediated by epigallocatechin gallate (EGCG), its contribution to the beneficial effects of tea in vivo remains unresolved. In a randomised crossover study, a single dose of 200 mg EGCG was applied in three different formulas (as green tea beverage, green tea extract (GTE), and isolated EGCG) to 50 healthy men. Flow-mediated dilation (FMD) and endothelial-independent nitro-mediated dilation (NMD) was measured before and two hours after ingestion. Plasma levels of tea compounds were determined after each intervention and correlated with FMD. FMD significantly improved after consumption of green tea containing 200 mg EGCG (p < 0.01). However, GTE and EGCG had no significant effect on FMD. NMD did not significantly differ between interventions. EGCG plasma levels were highest after administration of EGCG and lowest after consumption of green tea. Plasma levels of caffeine increased after green tea consumption. The results show that EGCG is most likely not involved in improvement of flow-mediated dilation by green tea. Instead, other tea compounds, metabolites or combinations thereof may play a role.

Effects of thyroxine replacement on endothelial function and carotid artery intima-media thickness in female patients with mild subclinical hypothyroidism

PubMed Central

Cabral, Monica Dias; Teixeira, Patricia; Soares, Debora; Leite, Sandra; Salles, Elizabeth; Waisman, Mario

2011-01-01

BACKGROUND: Previous studies have suggested an association between subclinical hypothyroidism and coronary artery disease that could be related to changes in serum lipids or endothelial dysfunction. METHODS: Thirty-two female subclinical hypothyroidism patients were randomly assigned to 12 months of L-thyroxine replacement or no treatment. Endothelial function was measured by the flow-mediated vasodilatation of the brachial artery, as well as mean carotid artery intima-media thickness, and lipid profiles were studied at baseline and after 12 months of follow-up. RESULTS: The mean (±SD) serum thyroid-stimulating hormone levels in the L-thyroxine replacement and control groups were 6.09±1.32 and 6.27±1.39 µUI/ml, respectively. No relationship between carotid artery intima-media thickness or brachial flow-mediated vasodilatation and free T4 and serum thyroid-stimulating hormone was found. The median L-T4 dose was 44.23±18.13 µg/day. After 12 months, there was a significant decrease in the flow-mediated vasodilatation in the subclinical hypothyroidism control group (before: 17.33±7.88 to after: 13.1±4.75%, p = 0.03), but there were no significant differences in flow-mediated vasodilatation in the L-thyroxine treated group (before: 16.81±7.0 to after: 18.52±7.44%, p = 0.39). We did not find any significant change in mean carotid intima-media thickness after 12 months of L-thyroxine treatment. CONCLUSION: Replacement therapy prevents a decline in flow-mediated vasodilatation with continuation of the subclinical hypothyroidism state. Large prospective multicenter placebo-controlled trials are necessary to investigate endothelial physiology further in subclinical hypothyroidism patients and to define the role of L-thyroxine therapy in improving endothelial function in these patients. PMID:21915478

Harvesting implementation for the GI-cat distributed catalog

NASA Astrophysics Data System (ADS)

Boldrini, Enrico; Papeschi, Fabrizio; Bigagli, Lorenzo; Mazzetti, Paolo

2010-05-01

GI-cat framework implements a distributed catalog service supporting different international standards and interoperability arrangements in use by the geoscientific community. The distribution functionality in conjunction with the mediation functionality allows to seamlessly query remote heterogeneous data sources, including OGC Web Services - e.e. OGC CSW, WCS, WFS and WMS, community standards such as UNIDATA THREDDS/OPeNDAP, SeaDataNet CDI (Common Data Index), GBIF (Global Biodiversity Information Facility) services and OpenSearch engines. In the GI-cat modular architecture a distributor component carry out the distribution functionality by query delegation to the mediator components (one for each different data source). Each of these mediator components is able to query a specific data source and convert back the results by mapping of the foreign data model to the GI-cat internal one, based on ISO 19139. In order to cope with deployment scenarios in which local data is expected, an harvesting approach has been experimented. The new strategy comes in addition to the consolidated distributed approach, allowing the user to switch between a remote and a local search at will for each federated resource; this extends GI-cat configuration possibilities. The harvesting strategy is designed in GI-cat by the use at the core of a local cache component, implemented as a native XML database and based on eXist. The different heterogeneous sources are queried for the bulk of available data; this data is then injected into the cache component after being converted to the GI-cat data model. The query and conversion steps are performed by the mediator components that were are part of the GI-cat framework. Afterward each new query can be exercised against local data that have been stored in the cache component. Considering both advantages and shortcomings that affect harvesting and query distribution approaches, it comes out that a user driven tuning is required to take the best of them. This is often related to the specific user scenarios to be implemented. GI-cat proved to be a flexible framework to address user need. The GI-cat configurator tool was updated to make such a tuning possible: each data source can be configured to enable either harvesting or query distribution approaches; in the former case an appropriate harvesting interval can be set.

Effects of Transcendental Meditation and Muscle Relaxation on Trait Anxiety, Maladjustment, Locus of Control, and Drug Use.

ERIC Educational Resources Information Center

Zuroff, David C.; Schwarz, J. Conrad

1978-01-01

Undergraduates received training in transcendental mediations (TM), training in a muscle relaxation technique, or no treatment. Measures of trait anxiety, locus of control, maladjustment, and drug use were collected before and after the treatment period. There were no differences in maladjustment, locus of control, or drug use as functions of…

School Performance and Poverty: The Mediating Role of Executive Functions

ERIC Educational Resources Information Center

Korzeniowski, C.; Cupani, M.; Ison, M.; Difabio, H.

2016-01-01

Introduction: This study aims at analyzing whether EFs may predict the SP of children from different low socioeconomic strata, having controlled the effects of age and socioeconomic status (SES). Method: The sample included 178 Argentine children of both genders (52% boys), between 6 and 10 years of age, belonging to the upper-low SES (41%),…

Central Processing Energetic Factors Mediate Impaired Motor Control in ADHD Combined Subtype but Not in ADHD Inattentive Subtype

ERIC Educational Resources Information Center

Egeland, Jens; Ueland, Torill; Johansen, Susanne

2012-01-01

Participants with attention-deficit/hyperactivity disorder (ADHD) are often impaired in visuomotor tasks. However, little is known about the contribution of modal impairment in motor function relative to central processing deficits or whether different processes underlie the impairment in ADHD combined (ADHD-C) versus ADHD inattentive (ADHD-I)…

Blood Vessels in Allotransplantation.

PubMed

Abrahimi, P; Liu, R; Pober, J S

2015-07-01

Human vascularized allografts are perfused through blood vessels composed of cells (endothelium, pericytes, and smooth muscle cells) that remain largely of graft origin and are thus subject to host alloimmune responses. Graft vessels must be healthy to maintain homeostatic functions including control of perfusion, maintenance of permselectivity, prevention of thrombosis, and participation in immune surveillance. Vascular cell injury can cause dysfunction that interferes with these processes. Graft vascular cells can be activated by mediators of innate and adaptive immunity to participate in graft inflammation contributing to both ischemia/reperfusion injury and allograft rejection. Different forms of rejection may affect graft vessels in different ways, ranging from thrombosis and neutrophilic inflammation in hyperacute rejection, to endothelialitis/intimal arteritis and fibrinoid necrosis in acute cell-mediated or antibody-mediated rejection, respectively, and to diffuse luminal stenosis in chronic rejection. While some current therapies targeting the host immune system do affect graft vascular cells, direct targeting of the graft vasculature may create new opportunities for preventing allograft injury and loss. © Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.

Immune-Mediated Mechanisms of Action of Probiotics and Synbiotics in Treating Pediatric Intestinal Diseases

PubMed Central

Gil-Campos, Mercedes

2018-01-01

The pediatric population is continually at risk of developing infectious and inflammatory diseases. The treatment for infections, particularly gastrointestinal conditions, focuses on oral or intravenous rehydration, nutritional support and, in certain case, antibiotics. Over the past decade, the probiotics and synbiotics administration for the prevention and treatment of different acute and chronic infectious diseases has dramatically increased. Probiotic microorganisms are primarily used as treatments because they can stimulate changes in the intestinal microbial ecosystem and improve the immunological status of the host. The beneficial impact of probiotics is mediated by different mechanisms. These mechanisms include the probiotics’ capacity to increase the intestinal barrier function, to prevent bacterial transferation and to modulate inflammation through immune receptor cascade signaling, as well as their ability to regulate the expression of selected host intestinal genes. Nevertheless, with respect to pediatric intestinal diseases, information pertaining to these key mechanisms of action is scarce, particularly for immune-mediated mechanisms of action. In the present work, we review the biochemical and molecular mechanisms of action of probiotics and synbiotics that affect the immune system. PMID:29303974

Memory T cells: A helpful guard for allogeneic hematopoietic stem cell transplantation without causing graft-versus-host disease.

PubMed

Huang, Wei; Chao, Nelson J

2017-12-01

Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (AHSCT) and the major cause of nonrelapse morbidity and mortality of AHSCT. In AHSCT, donor T cells facilitate hematopoietic stem cell (HSC) engraftment, contribute to anti-infection immunity, and mediate graft-versus-leukemia (GVL) responses. However, activated alloreactive T cells also attack recipient cells in vital organs, leading to GVHD. Different T-cell subsets, including naïve T (T N ) cells, memory T (T M ) cells, and regulatory T (T reg ) cells mediate different forms of GVHD and GVL; T N cells mediate severe GVHD, whereas T M cells do not cause GVHD, but preserve T-cell function including GVL. In addition, metabolic reprogramming controls T-cell differentiation and activation in these disease states. This minireview focuses on the role and the related mechanisms of T M cells in AHSCT, and the potential manipulation of T cells in AHSCT. Copyright © 2017 King Faisal Specialist Hospital & Research Centre. Published by Elsevier B.V. All rights reserved.

Personal growth initiative and identity formation in adolescence through young adulthood: mediating processes on the pathway to well-being.

PubMed

Luyckx, Koen; Robitschek, Christine

2014-10-01

Developing a personal identity is a challenging task throughout adolescence and the transition to adulthood. The present study sampling 551 14-35 year olds (54.1% female) examined personal growth initiative (PGI) as a potential predictor of core identity processes and explored whether identity functioned as a mediator on the pathway from PGI to self-esteem and depressive symptoms. Path analyses from a structural equation modeling approach indicated that all four components of PGI (i.e., planfulness, readiness for change, intentional behavior, and using resources) predicted different commitment and exploration processes, with planfulness being the most consistent predictor. Important age differences linking PGI-components to identity exploration were found. Finally, especially the degree to which individuals identified themselves with their identity commitments and the degree to which they relied on ruminative or maladaptive forms of identity exploration mediated pathways from PGI to self-esteem and depressive symptoms. Implications and suggestions for future research are discussed. Copyright © 2014 The Foundation for Professionals in Services for Adolescents. Published by Elsevier Ltd. All rights reserved.

The associations between body dissatisfaction, body figure, self-esteem, and depressed mood in adolescents in the United States and Korea: A moderated mediation analysis.

PubMed

Choi, Eunsoo; Choi, Injae

2016-12-01

The perception of one's body image becomes particularly important in adolescence. Body dissatisfaction has been associated with negative psychological functioning, such as self-esteem and depression. Previous findings showed that the decreased self-esteem due to body dissatisfaction explained the association between negative attitude toward body and psychological well-being in different cultural contexts. The present study examined adolescents from the US (N = 1002) and Korea (N = 3993) and replicated and extended the previous findings regarding body dissatisfaction and associated psychological outcomes. The results showed that body dissatisfaction predicted higher depressed mood and that self-esteem mediated this association for both American and Korean adolescents. Notably, the indirect effect of body dissatisfaction and perceived body image on depressed mood via self-esteem was greater for American adolescents than for Korean adolescents. The implications of the cultural difference in the significance of self-esteem in mediating the body dissatisfaction and depressed mood are discussed. Copyright © 2016 The Foundation for Professionals in Services for Adolescents. Published by Elsevier Ltd. All rights reserved.

No Detectable Trade-Offs Among Immune Function, Fecundity, and Survival via a Juvenile Hormone Analog in the House Cricket.

PubMed

Nava-Sánchez, A; Munguía-Steyer, R; Córdoba-Aguilar, A

2014-08-01

Hormones are key regulators of resource allocation among functions and thus play an important role in resource-based trade-offs. The juvenile hormone (JH) is an insect hormone that mediates resource allocation between immunity and life history components. Here, we have tested whether this is the case using the house cricket. We investigated whether increased levels of JH (using methoprene, a JH analog) enable an enhanced survival and fecundity (via egg number) at the cost of reduced hemocyte number (a trait that is associated with immune response in insects) in the house cricket, Acheta domesticus L. We had three groups of adult crickets of both sexes: experimental (methoprene and acetone), positive control (methoprene), and negative control (no manipulation). Prior to and after experimental treatments, we counted the number of hemocytes (for the case of both sexes) and recorded the number of eggs laid and survival of females after the manipulation. There was no difference in hemocyte number, egg number, and survival. These results do not support a JH-mediated trade-off among immune ability, survival, and fecundity. We provide arguments to explain the lack of JH-mediated trade-offs in the house cricket.

Motor dysfunction in NF1: Mediated by attention deficit or inherent to the disorder?

PubMed

Haas-Lude, Karin; Heimgärtner, Magdalena; Winter, Sarah; Mautner, Victor-Felix; Krägeloh-Mann, Ingeborg; Lidzba, Karen

2018-01-01

Attention deficit and compromised motor skills are both prevalent in Neurofibromatosis type 1 (NF1), but the relationship is unclear. We investigated motor function in children with NF1 and in children with Attention Deficit/Hyperactivity Disorder (ADHD), and explored if, in patients with NF1, attention deficit influences motor performance. Motor performance was measured using the Movement Assessment Battery for Children (M-ABC) in 71 children (26 with NF1 plus ADHD, 14 with NF1 without ADHD, and 31 with ADHD without NF1) aged 6-12 years. There was a significant effect of group on motor performance. Both NF1 groups scored below children with ADHD without NF1. Attention performance mediated motor performance in children with ADHD without NF1, but not in children with NF1. Motor function is not mediated by attention performance in children with NF1. While in ADHD, attention deficit influences motor performance, motor problems in NF1 seem to be independent from attention deficit. This argues for different pathomechanisms in these two groups of developmental disorders. Copyright © 2017 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

MARCH2 regulates autophagy by promoting CFTR ubiquitination and degradation and PIK3CA-AKT-MTOR signaling.

PubMed

Xia, Dan; Qu, Liujing; Li, Ge; Hongdu, Beiqi; Xu, Chentong; Lin, Xin; Lou, Yaxin; He, Qihua; Ma, Dalong; Chen, Yingyu

2016-09-01

MARCH2 (membrane-associated RING-CH protein 2), an E3 ubiquitin ligase, is mainly associated with the vesicle trafficking. In the present study, for the first time, we demonstrated that MARCH2 negatively regulates autophagy. Our data indicated that overexpression of MARCH2 impaired autophagy, as evidenced by attenuated levels of LC3B-II and impaired degradation of endogenous and exogenous autophagic substrates. By contrast, loss of MARCH2 expression had the opposite effects. In vivo experiments demonstrate that MARCH2 knockout mediated autophagy results in an inhibition of tumorigenicity. Further investigation revealed that the induction of autophagy by MARCH2 deficiency was mediated through the PIK3CA-AKT-MTOR signaling pathway. Additionally, we found that MARCH2 interacts with CFTR (cystic fibrosis transmembrane conductance regulator), promotes the ubiquitination and degradation of CFTR, and inhibits CFTR-mediated autophagy in tumor cells. The functional PDZ domain of MARCH2 is required for the association with CFTR. Thus, our study identified a novel negative regulator of autophagy and suggested that the physical and functional connection between the MARCH2 and CFTR in different conditions will be elucidated in the further experiments.

Sequence determinants of improved CRISPR sgRNA design.

PubMed

Xu, Han; Xiao, Tengfei; Chen, Chen-Hao; Li, Wei; Meyer, Clifford A; Wu, Qiu; Wu, Di; Cong, Le; Zhang, Feng; Liu, Jun S; Brown, Myles; Liu, X Shirley

2015-08-01

The CRISPR/Cas9 system has revolutionized mammalian somatic cell genetics. Genome-wide functional screens using CRISPR/Cas9-mediated knockout or dCas9 fusion-mediated inhibition/activation (CRISPRi/a) are powerful techniques for discovering phenotype-associated gene function. We systematically assessed the DNA sequence features that contribute to single guide RNA (sgRNA) efficiency in CRISPR-based screens. Leveraging the information from multiple designs, we derived a new sequence model for predicting sgRNA efficiency in CRISPR/Cas9 knockout experiments. Our model confirmed known features and suggested new features including a preference for cytosine at the cleavage site. The model was experimentally validated for sgRNA-mediated mutation rate and protein knockout efficiency. Tested on independent data sets, the model achieved significant results in both positive and negative selection conditions and outperformed existing models. We also found that the sequence preference for CRISPRi/a is substantially different from that for CRISPR/Cas9 knockout and propose a new model for predicting sgRNA efficiency in CRISPRi/a experiments. These results facilitate the genome-wide design of improved sgRNA for both knockout and CRISPRi/a studies. © 2015 Xu et al.; Published by Cold Spring Harbor Laboratory Press.

Validation of DSM-5 age-of-onset criterion of attention deficit/hyperactivity disorder (ADHD) in adults: Comparison of life quality, functional impairment, and family function.

PubMed

Lin, Yu-Ju; Lo, Kuan-Wu; Yang, Li-Kuang; Gau, Susan Shur-Fen

2015-12-01

The newly published Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) elevates the threshold of the ADHD age-of-onset criterion from 7 to 12 years. This study evaluated the quality of life and functional impairment of adults with ADHD who had symptoms onset by or after 7 years and examined the mediation effect of family function and anxiety/depression symptoms between ADHD diagnosis and quality of life and functional impairment. We assessed 189 adults with ADHD and 153 non-ADHD controls by psychiatric interview and self-administered reports on the Adult ADHD Quality of Life Scale, Weiss Functional Impairment Rating Scale, Family APGAR, and Adult Self Report Inventory-4. The ADHD group was divided into early-onset ADHD (onset <7 years, n=147) and late-onset ADHD (onset between 7 and 12 years, n=42). The mediation analysis was conducted to verify the mediating factors from ADHD to functional impairment and quality of life. The late-onset ADHD had more severe functional impairment at work and poorer family support than early-onset ADHD while they had comparable impairment at other domains. Less perceived family support and current anxiety/depressive symptoms partially mediated the link between ADHD diagnosis and quality of life/functional impairment both in early- and late-onset ADHD. Our data support decreased quality of life and increased functional impairment in adult ADHD, regardless of age of onset, and these adverse outcomes may be mediated by family support and anxiety/depression at adulthood. Our findings also imply that the new DSM-5 ADHD criteria do not over-include individuals without impairment. Copyright © 2015 Elsevier Ltd. All rights reserved.

Differential activation of an identified motor neuron and neuromodulation provide Aplysia's retractor muscle an additional function.

PubMed

McManus, Jeffrey M; Lu, Hui; Cullins, Miranda J; Chiel, Hillel J

2014-08-15

To survive, animals must use the same peripheral structures to perform a variety of tasks. How does a nervous system employ one muscle to perform multiple functions? We addressed this question through work on the I3 jaw muscle of the marine mollusk Aplysia californica's feeding system. This muscle mediates retraction of Aplysia's food grasper in multiple feeding responses and is innervated by a pool of identified neurons that activate different muscle regions. One I3 motor neuron, B38, is active in the protraction phase, rather than the retraction phase, suggesting the muscle has an additional function. We used intracellular, extracellular, and muscle force recordings in several in vitro preparations as well as recordings of nerve and muscle activity from intact, behaving animals to characterize B38's activation of the muscle and its activity in different behavior types. We show that B38 specifically activates the anterior region of I3 and is specifically recruited during one behavior, swallowing. The function of this protraction-phase jaw muscle contraction is to hold food; thus the I3 muscle has an additional function beyond mediating retraction. We additionally show that B38's typical activity during in vivo swallowing is insufficient to generate force in an unmodulated muscle and that intrinsic and extrinsic modulation shift the force-frequency relationship to allow contraction. Using methods that traverse levels from individual neuron to muscle to intact animal, we show how regional muscle activation, differential motor neuron recruitment, and neuromodulation are key components in Aplysia's generation of multifunctionality. Copyright © 2014 the American Physiological Society.

Adolescent Cannabis Use: What is the Evidence for Functional Brain Alteration?

PubMed

Lorenzetti, Valentina; Alonso-Lana, Silvia; Youssef, George J; Verdejo-Garcia, Antonio; Suo, Chao; Cousijn, Janna; Takagi, Michael; Yücel, Murat; Solowij, Nadia

2016-01-01

Cannabis use typically commences during adolescence, a period during which the brain undergoes profound remodeling in areas that are high in cannabinoid receptors and that mediate cognitive control and emotion regulation. It is therefore important to determine the impact of adolescent cannabis use on brain function. We investigate the impact of adolescent cannabis use on brain function by reviewing the functional magnetic resonance imaging studies in adolescent samples. We systematically reviewed the literature and identified 13 functional neuroimaging studies in adolescent cannabis users (aged 13 to 18 years) performing working memory, inhibition and reward processing tasks. The majority of the studies found altered brain function, but intact behavioural task performance in adolescent cannabis users versus controls. The most consistently reported differences were in the frontal-parietal network, which mediates cognitive control. Heavier use was associated with abnormal brain function in most samples. A minority of studies controlled for the influence of confounders that can also undermine brain function, such as tobacco and alcohol use, psychopathology symptoms, family history of psychiatric disorders and substance use. Emerging evidence shows abnormal frontal-parietal network activity in adolescent cannabis users, particularly in heavier users. Brain functional alterations may reflect a compensatory neural mechanism that enables normal behavioural performance. It remains unclear if cannabis exposure drives these alterations, as substance use and mental health confounders have not been systematically examined. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Optimized Replicating Renilla Luciferase Reporter HIV-1 Utilizing Novel Internal Ribosome Entry Site Elements for Native Nef Expression and Function.

PubMed

Alberti, Michael O; Jones, Jennifer J; Miglietta, Riccardo; Ding, Haitao; Bakshi, Rakesh K; Edmonds, Tara G; Kappes, John C; Ochsenbauer, Christina

2015-12-01

We previously developed replication-competent reporter HIV-1 (referred to herein as LucR.T2A reporter viruses), utilizing a "ribosome skipping" T2A peptide strategy to link Renilla luciferase (LucR) with Nef expression. The demonstrated utility for HIV-1 vaccine and transmission study applications included measurement of neutralizing antibody (NAb) activity in vaccine sera, improved cell-mediated virus inhibition assays, such as T cell-mediated virus inhibition and antibody-dependent cell-mediated cytotoxicity (ADCC) assays, and humanized mouse models. Herein, we extend our prior work and introduce reporter virus technology for applications that require fully functional Nef. We demonstrate that in CD4(+) T cells productively infected with LucR.T2A reporter viruses, T2A peptide-driven Nef expression and function, such as down-regulation of surface CD4 and MHC-I, were impaired. We overcame this limitation of LucR.T2A reporter viruses and achieved physiological Nef expression and function by engineering novel LucR reporter HIV-1 comprising 11 different internal ribosome entry site (IRES) elements chosen for size and relative activity. A range of Nef expression was observed in 293T cells transfected with the different LucR.IRES reporter virus constructs. Iteratively, we identified IRES reporter genomes that expressed Nef closest to physiological levels and produced virus with infectivity, titers, and replication kinetics similar to nonreporter viruses. Our results demonstrated that LucR reporter activity was stable over multiple replication cycles in peripheral blood mononuclear cells (PBMCs). Furthermore, we analyzed Nef functionality, i.e., down-modulation of MHC-I and CD4, following infection of T cell lines and PBMCs. Unlike LucR.T2A reporter virus, one of the redesigned LucR.IRES reporter viruses [containing the modified encephalomyocarditis virus (EMCV) 6ATR IRES element, "6ATRi"] demonstrated Nef expression and function similar to parental "nonreporter" virus. In a previously validated (nef-independent) T cell-based NAb neutralization assay, LucR.6ATRi reporter virus performed indistinguishably from LucR.T2A reporter virus. In summary, reporter viruses comprising the "6ATRi" element promise to augment HIV-1 vaccine and transmission research approaches requiring a sensitive reporter readout combined with wild-type Nef function.

Optimized Replicating Renilla Luciferase Reporter HIV-1 Utilizing Novel Internal Ribosome Entry Site Elements for Native Nef Expression and Function

PubMed Central

Alberti, Michael O.; Jones, Jennifer J.; Miglietta, Riccardo; Ding, Haitao; Bakshi, Rakesh K.; Edmonds, Tara G.; Kappes, John C.

2015-01-01

Abstract We previously developed replication-competent reporter HIV-1 (referred to herein as LucR.T2A reporter viruses), utilizing a “ribosome skipping” T2A peptide strategy to link Renilla luciferase (LucR) with Nef expression. The demonstrated utility for HIV-1 vaccine and transmission study applications included measurement of neutralizing antibody (NAb) activity in vaccine sera, improved cell-mediated virus inhibition assays, such as T cell-mediated virus inhibition and antibody-dependent cell-mediated cytotoxicity (ADCC) assays, and humanized mouse models. Herein, we extend our prior work and introduce reporter virus technology for applications that require fully functional Nef. We demonstrate that in CD4+ T cells productively infected with LucR.T2A reporter viruses, T2A peptide-driven Nef expression and function, such as down-regulation of surface CD4 and MHC-I, were impaired. We overcame this limitation of LucR.T2A reporter viruses and achieved physiological Nef expression and function by engineering novel LucR reporter HIV-1 comprising 11 different internal ribosome entry site (IRES) elements chosen for size and relative activity. A range of Nef expression was observed in 293T cells transfected with the different LucR.IRES reporter virus constructs. Iteratively, we identified IRES reporter genomes that expressed Nef closest to physiological levels and produced virus with infectivity, titers, and replication kinetics similar to nonreporter viruses. Our results demonstrated that LucR reporter activity was stable over multiple replication cycles in peripheral blood mononuclear cells (PBMCs). Furthermore, we analyzed Nef functionality, i.e., down-modulation of MHC-I and CD4, following infection of T cell lines and PBMCs. Unlike LucR.T2A reporter virus, one of the redesigned LucR.IRES reporter viruses [containing the modified encephalomyocarditis virus (EMCV) 6ATR IRES element, “6ATRi”] demonstrated Nef expression and function similar to parental “nonreporter” virus. In a previously validated (nef-independent) T cell-based NAb neutralization assay, LucR.6ATRi reporter virus performed indistinguishably from LucR.T2A reporter virus. In summary, reporter viruses comprising the “6ATRi” element promise to augment HIV-1 vaccine and transmission research approaches requiring a sensitive reporter readout combined with wild-type Nef function. PMID:26101895

Dissociable Genetic Contributions to Error Processing: A Multimodal Neuroimaging Study

PubMed Central

Agam, Yigal; Vangel, Mark; Roffman, Joshua L.; Gallagher, Patience J.; Chaponis, Jonathan; Haddad, Stephen; Goff, Donald C.; Greenberg, Jennifer L.; Wilhelm, Sabine; Smoller, Jordan W.; Manoach, Dara S.

2014-01-01

Background Neuroimaging studies reliably identify two markers of error commission: the error-related negativity (ERN), an event-related potential, and functional MRI activation of the dorsal anterior cingulate cortex (dACC). While theorized to reflect the same neural process, recent evidence suggests that the ERN arises from the posterior cingulate cortex not the dACC. Here, we tested the hypothesis that these two error markers also have different genetic mediation. Methods We measured both error markers in a sample of 92 comprised of healthy individuals and those with diagnoses of schizophrenia, obsessive-compulsive disorder or autism spectrum disorder. Participants performed the same task during functional MRI and simultaneously acquired magnetoencephalography and electroencephalography. We examined the mediation of the error markers by two single nucleotide polymorphisms: dopamine D4 receptor (DRD4) C-521T (rs1800955), which has been associated with the ERN and methylenetetrahydrofolate reductase (MTHFR) C677T (rs1801133), which has been associated with error-related dACC activation. We then compared the effects of each polymorphism on the two error markers modeled as a bivariate response. Results We replicated our previous report of a posterior cingulate source of the ERN in healthy participants in the schizophrenia and obsessive-compulsive disorder groups. The effect of genotype on error markers did not differ significantly by diagnostic group. DRD4 C-521T allele load had a significant linear effect on ERN amplitude, but not on dACC activation, and this difference was significant. MTHFR C677T allele load had a significant linear effect on dACC activation but not ERN amplitude, but the difference in effects on the two error markers was not significant. Conclusions DRD4 C-521T, but not MTHFR C677T, had a significant differential effect on two canonical error markers. Together with the anatomical dissociation between the ERN and error-related dACC activation, these findings suggest that these error markers have different neural and genetic mediation. PMID:25010186

Longitudinal Pathways from Cumulative Contextual Risk at Birth to School Functioning in Adolescence: Analysis of Mediation Effects and Gender Moderation.

PubMed

January, Stacy-Ann A; Mason, W Alex; Savolainen, Jukka; Solomon, Starr; Chmelka, Mary B; Miettunen, Jouko; Veijola, Juha; Moilanen, Irma; Taanila, Anja; Järvelin, Marjo-Riitta

2017-01-01

Children and adolescents exposed to multiple contextual risks are more likely to have academic difficulties and externalizing behavior problems than those who experience fewer risks. This study used data from the Northern Finland Birth Cohort 1986 (a population-based study; N = 6961; 51 % female) to investigate (a) the impact of cumulative contextual risk at birth on adolescents' academic performance and misbehavior in school, (b) learning difficulties and/or externalizing behavior problems in childhood as intervening mechanisms in the association of cumulative contextual risk with functioning in adolescence, and (c) potential gender differences in the predictive associations of cumulative contextual risk at birth with functioning in childhood or adolescence. The results of the structural equation modeling analysis suggested that exposure to cumulative contextual risk at birth had negative associations with functioning 16 years later, and academic difficulties and externalizing behavior problems in childhood mediated some of the predictive relations. Gender, however, did not moderate any of the associations. Therefore, the findings of this study have implications for the prevention of learning and conduct problems in youth and future research on the impact of cumulative risk exposure.

A low K+ signal is required for functional high-affinity K+ uptake through HAK5 transporters.

PubMed

Rubio, Francisco; Fon, Mario; Ródenas, Reyes; Nieves-Cordones, Manuel; Alemán, Fernando; Rivero, Rosa M; Martínez, Vicente

2014-11-01

The high-affinity K(+) transporter HAK5 is a key system for root K(+) uptake and, under very low external K(+), the only one capable of supplying K(+) to the plant. Functional HAK5-mediated K(+) uptake should be tightly regulated for plant adaptation to different environmental conditions. Thus, it has been described that the gene encoding the transporter is transcriptionally regulated, being highly induced under K(+) limitation. Here we show that environmental conditions, such as the lack of K(+), NO(3)(-) or P, that induced a hyperpolarization of the plasma membrane of root cells, induce HAK5 transcription. However, only the deprivation of K(+) produces functional HAK5-mediated K(+) uptake in the root. These results suggest on the one hand the existence of a posttranscriptional regulation of HAK5 elicited by the low K(+) signal and on the other that HAK5 may be involved in yet-unknown functions related to NO(3)(-) and P deficiencies. These results have been obtained here with Solanum lycopersicum (cv. Micro-Tom) as well as Arabidopsis thaliana plants, suggesting that the posttranscriptional regulation of high-affinity HAK transporters take place in all plant species. © 2014 Scandinavian Plant Physiology Society.

Longitudinal Pathways from Cumulative Contextual Risk at Birth to School Functioning in Adolescence: Analysis of Mediation Effects and Gender Moderation

PubMed Central

January, Stacy-Ann A.; Mason, W. Alex; Savolainen, Jukka; Solomon, Starr; Chmelka, Mary B.; Miettunen, Jouko; Veijola, Juha; Moilanen, Irma; Taanila, Anja; Järvelin, Marjo-Riitta

2016-01-01

Children and adolescents exposed to multiple contextual risks are more likely to have academic difficulties and externalizing behavior problems than those who experience fewer risks. This study used data from the Northern Finland Birth Cohort 1986 (a population-based study; N = 6,961; 51% female) to investigate (a) the impact of cumulative contextual risk at birth on adolescents’ academic performance and misbehavior in school, (b) learning difficulties and/or externalizing behavior problems in childhood as intervening mechanisms in the association of cumulative contextual risk with functioning in adolescence, and (c) potential gender differences in the predictive associations of cumulative contextual risk at birth with functioning in childhood or adolescence. The results of the structural equation modeling analysis suggested that exposure to cumulative contextual risk at birth had negative associations with functioning 16 years later, and academic difficulties and externalizing behavior problems in childhood mediated some of the predictive relations. Gender, however, did not moderate any of the associations. Therefore, the findings of this study have implications for the prevention of learning and conduct problems in youth and future research on the impact of cumulative risk exposure. PMID:27665276

The Mediator Complex: At the Nexus of RNA Polymerase II Transcription.

PubMed

Jeronimo, Célia; Robert, François

2017-10-01

Mediator is an essential, large, multisubunit, transcriptional co-activator highly conserved across eukaryotes. Mediator interacts with gene-specific transcription factors at enhancers as well as with the RNA polymerase II (RNAPII) transcription machinery bound at promoters. It also interacts with several other factors involved in various aspects of transcription, chromatin regulation, and mRNA processing. Hence, Mediator is at the nexus of RNAPII transcription, regulating its many steps and connecting transcription with co-transcriptional events. To achieve this flexible role, Mediator, which is divided into several functional modules, reorganizes its conformation and composition while making transient contacts with other components. Here, we review the mechanisms of action of Mediator and propose a unifying model for its function. Copyright © 2017 Elsevier Ltd. All rights reserved.

Interactions among aging, gender, and gonadectomy effects upon naloxone hypophagia in rats.

PubMed

Islam, A K; Beczkowska, I W; Bodnar, R J

1993-11-01

The present study examined the dose-dependent (0.25-5 mg/kg) effects of systemic naloxone upon deprivation-induced intake and high-fat intake as functions of age (4, 8, 14, and 20 months), gender, and gonadectomy in rats. Significant increases in body weight were observed as functions of age and gonadectomy. Whereas aging significantly reduced basal deprivation-induced intake, it generally failed to alter basal high-fat intake. Whereas age, gender, and gonadectomy failed to alter the decreases in deprivation-induced intake following low (0.25-2.5 mg/kg) naloxone doses, sham males displayed significantly greater age-related and gender-related inhibition following the 5 mg/kg dose of naloxone. Young gonadectomized rats displayed significant increases in naloxone's inhibition of deprivation-induced intake as well. More dramatic changes occurred in naloxone's inhibition of high-fat intake. Naloxone's potency increased in sham female rats as a function of age, and decreased in sham males and ovariectomized females as a function of age. Whereas sham males and ovariectomized females were most sensitive to naloxone's inhibition of high-fat intake at young ages, sham females were most sensitive at older ages. These data indicate that effects of age, gender, and gonadectomy upon naloxone-induced hypophagia dissociate as a function of the type of intake. Because selective opioid antagonist studies demonstrate that deprivation-induced intake is mediated by the mu1 receptor and high-fat intake is mediated by kappa and mu2 receptors, it is postulated that the differential effects of aging, gender, and gonadectomy variables upon opioid mediation of the two forms of intake may reflect their interaction with different opioid receptor subtypes.

Malondialdehyde-Acetaldehyde (MAA) Adducted Surfactant Protein Alters Macrophage Functions through Scavenger Receptor A

PubMed Central

Sapkota, Muna; Kharbanda, Kusum K.; Wyatt, Todd A.

2016-01-01

Background Reactive aldehydes like acetaldehyde and malondialdehyde generated as a result of alcohol metabolism and cigarette smoke exposure lead to the formation of malondialdehyde-acetaldehyde-adducted proteins (MAA adducts). These aldehydes can adduct to different proteins such as bovine serum album (BSA) and surfactant proteins A or D (SPA, SPD). Macrophages play an important role in innate immunity, but the effect of MAA adducts on macrophage function has not yet been examined. Because macrophage scavenger receptor A (SRA; CD204) mediates the uptake of modified proteins, we hypothesized that the effects of MAA modified proteins on macrophage function are primarily mediated through SRA. Methods and Results We tested this hypothesis by exposing SPD-MAA to macrophages and measuring functions. SPD-MAA treatment significantly stimulated pro-inflammatory cytokine TNF-α release in the macrophage cell line, RAW 264.7. A significant reduction in phagocytosis of zymosan particles was also observed. SPD-MAA stimulated a significant dose-dependent increase in TNF-α and IL-6 release from peritoneal macrophages of WT mice. But a significantly less TNF-α and IL-6 were released from peritoneal macrophages of SRA−/− mice. We observed a significant reduction in phagocytosis of zymosan particles in peritoneal macrophages from WT mice treated with SPD-MAA. No further SPD-MAA-induced reduction was seen in peritoneal macrophages form SRA−/− mice. SPD-MAA treatment significantly increased SRA mRNA expression, but had no effect on surface receptor protein expression. Protein kinase C alpha inhibitor and NF-κB inhibitor significantly reduced pro-inflammatory cytokine release in response to SPD-MAA. Conclusion In conclusion, our data demonstrate that SRA is important for MAA-adducted protein-mediated effect on macrophage functions. PMID:27783409

Childhood Conduct Problems and Young Adult Outcomes Among Women with Childhood ADHD

PubMed Central

Owens, Elizabeth B.; Hinshaw, Stephen P.

2015-01-01

We tested whether conduct problems predicted young adult functioning and psychiatric symptoms among women diagnosed with ADHD during childhood, in the context of three potential adolescent mediators: internalizing problems, peer rejection, and school failure and disciplinary problems. We controlled for childhood ADHD severity, IQ, and demographic factors, and in the mediational tests, for adolescent conduct problems. Data emanated from 140 participants in the Berkeley Girls with ADHD Longitudinal Study. We used bootstrapping methods to assess indirect effects (mediators). Both childhood (F1,118 change = 9.00, p = .003, R2 change = .069) and adolescent (F1,109 change = 10.41, p = .002, R2 change = .083) conduct problems were associated with worse overall functioning during young adulthood, controlling for initial ADHD severity, child IQ, and demographics. Results were similar when predicting psychiatric symptoms. Adolescent school failure and disciplinary problems mediated the relations between childhood conduct problems and both young-adult functioning and externalizing problems; adolescent internalizing problems and peer conflict mediated the relation between childhood conduct problems and young-adult internalizing problems. As is true for boys, childhood and adolescent conduct problems are associated with poor adult outcomes among girls with ADHD, with school failure and disciplinary problems, internalizing problems, and peer conflict functioning as mediators of these relations. PMID:26854507

Parental palliative cancer: psychosocial adjustment and health-related quality of life in adolescents participating in a German family counselling service

PubMed Central

2012-01-01

Background Parental palliative disease is a family affair, however adolescent's well-being and coping are still rarely considered. The objectives of this paper were a) to identify differences in psychosocial adjustment and health-related quality of life (HRQoL) among adolescents and young adults with parents suffering from palliative cancer or cancers in other disease stages, b) to relate psychosocial adjustment and health-related quality of life to adolescent coping, and c) to explore significant mediator and predictor variables. Methods Cross-sectional data were derived from a multi-site research study of families before child-centered counselling. N=86 adolescents and young adults were included, their mean age 13.78 years (sd 2.45), 56% being female. Performed analyses included ANCOVA, multiple linear regression, and mediation analysis. Results Adolescents with parents suffering from palliative cancers reported significantly less total psychosocial problems, and better overall HRQoL. There were no significant group differences regarding coping frequency and efficacy. Our set of coping items significantly mediated the effect of parental disease stage on psychosocial problems and HRQoL. Further, parental disease status and general family functioning predicted psychosocial problems (R2adj =.390) and HRQoL (R2adj =.239) best. Conclusion The study indicates distress among adolescents throughout the entire parental disease process. Our analysis suggests that counselling services could offer supportive interventions which focus particularly on adolescent coping as well as family functioning. PMID:23110440

The olfactory pathway mediates sheltering behavior of Caribbean spiny lobsters, Panulirus argus, to conspecific urine signals.

PubMed

Horner, Amy J; Weissburg, Marc J; Derby, Charles D

2008-03-01

The "noses" of diverse taxa are organized into different subsystems whose functions are often not well understood. The "nose" of decapod crustaceans is organized into two parallel pathways that originate in different populations of antennular sensilla and project to specific neuropils in the brain-the aesthetasc/olfactory lobe pathway and the non-aesthetasc/lateral antennular neuropil pathway. In this study, we investigated the role of these pathways in mediating shelter selection of Caribbean spiny lobsters, Panulirus argus, in response to conspecific urine signals. We compared the behavior of ablated animals and intact controls. Our results show that control and non-aesthetasc ablated lobsters have a significant overall preference for shelters emanating urine over control shelters. Thus the non-aesthetasc pathway does not play a critical role in shelter selection. In contrast, spiny lobsters with aesthetascs ablated did not show a preference for either shelter, suggesting that the aesthetasc/olfactory pathway is important for processing social odors. Our results show a difference in the function of these dual chemosensory pathways in responding to social cues, with the aesthetasc/olfactory lobe pathway playing a major role. We discuss our results in the context of why the noses of many animals contain multiple parallel chemosensory systems.