Reductions in hypothalamic Gfap expression, glial cells and α-tanycytes in lean and hypermetabolic Gnasxl-deficient mice

BACKGROUND: Neuronal and glial differentiation in the murine hypothalamus is not complete at birth, but continues over the first two weeks postnatally. Nutritional status and Leptin deficiency can influence the maturation of neuronal projections and glial patterns, and hypothalamic gliosis occurs in mouse models of obesity. Gnasxl constitutes an alternative transcript of the genomically imprinted Gnas locus and encodes a variant of the signalling protein Gαs, termed XLαs, which is expressed in defined areas of the hypothalamus. Gnasxl-deficient mice show postnatal growth retardation and undernutrition, while surviving adults remain lean and hypermetabolic with increased sympathetic nervous system (SNS) activity. Effects of this knock-out on the hypothalamic neural network have not yet been investigated. RESULTS: RNAseq analysis for gene expression changes in hypothalami of Gnasxl-deficient mice indicated Glial fibrillary acid protein (Gfap) expression to be significantly down-regulated in adult samples. Histological analysis confirmed a reduction in Gfap-positive glial cell numbers specifically in the hypothalamus. This reduction was observed in adult tissue samples, whereas no difference was found in hypothalami of postnatal stages, indicating an adaptation in adult Gnasxl-deficient mice to their earlier growth phenotype and hypermetabolism. Especially noticeable was a loss of many Gfap-positive α-tanycytes and their processes, which form part of the ependymal layer that lines the medial and dorsal regions of the 3(rd) ventricle, while β-tanycytes along the median eminence (ME) and infundibular recesses appeared unaffected. This was accompanied by local reductions in Vimentin and Nestin expression. Hypothalamic RNA levels of glial solute transporters were unchanged, indicating a potential compensatory up-regulation in the remaining astrocytes and tanycytes. CONCLUSION: Gnasxl deficiency does not directly affect glial development in the hypothalamus, since it is expressed in neurons, and Gfap-positive astrocytes and tanycytes appear normal during early postnatal stages. The loss of Gfap-expressing cells in adult hypothalami appears to be a consequence of the postnatal undernutrition, hypoglycaemia and continued hypermetabolism and leanness of Gnasxl-deficient mice, which contrasts with gliosis observed in obese mouse models. Since α-tanycytes also function as adult neural progenitor cells, these findings might indicate further developmental abnormalities in hypothalamic formations of Gnasxl-deficient mice, potentially including neuronal composition and projections

Adjustment for time-invariant and time-varying confounders in ‘unexplained residuals’ models for longitudinal data within a causal framework and associated challenges

‘Unexplained residuals’ models have been used within lifecourse epidemiology to model an exposure measured longitudinally at several time points in relation to a distal outcome. It has been claimed that these models have several advantages, including: the ability to estimate multiple total causal effects in a single model, and additional insight into the effect on the outcome of greater-than-expected increases in the exposure compared to traditional regression methods. We evaluate these properties and prove mathematically how adjustment for confounding variables must be made within this modelling framework. Importantly, we explicitly place unexplained residual models in a causal framework using directed acyclic graphs. This allows for theoretical justification of appropriate confounder adjustment and provides a framework for extending our results to more complex scenarios than those examined in this paper. We also discuss several interpretational issues relating to unexplained residual models within a causal framework. We argue that unexplained residual models offer no additional insights compared to traditional regression methods, and, in fact, are more challenging to implement; moreover, they artificially reduce estimated standard errors. Consequently, we conclude that unexplained residual models, if used, must be implemented with great care

Reconstructing Asian faunal introductions to eastern Africa from multi-proxy biomolecular and archaeological datasets

Human-mediated biological exchange has had global social and ecological impacts. In subS-aharan Africa, several domestic and commensal animals were introduced from Asia in the pre-modern period; however, the timing and nature of these introductions remain contentious. One model supports introduction to the eastern African coast after the mid-first millennium CE, while another posits introduction dating back to 3000 BCE. These distinct scenarios have implications for understanding the emergence of long-distance maritime connectivity, and the ecological and economic impacts of introduced species. Resolution of this longstanding debate requires new efforts, given the lack of well-dated fauna from high-precision excavations, and ambiguous osteomorphological identifications. We analysed faunal remains from 22 eastern African sites spanning a wide geographic and chronological range, and applied biomolecular techniques to confirm identifications of two Asian taxa: domestic chicken (Gallus gallus) and black rat (Rattus rattus). Our approach included ancient DNA (aDNA) analysis aided by BLAST-based bioinformatics, Zooarchaeology by Mass Spectrometry (ZooMS) collagen fingerprinting, and direct AMS (accelerator mass spectrometry) radiocarbon dating. Our results support a late, mid-first millennium CE introduction of these species. We discuss the implications of our findings for models of biological exchange, and emphasize the applicability of our approach to tropical areas with poor bone preservation

Childhood emotional trauma and cyberbullying perpetration among emerging adults: a multiple mediation model of the role of problematic social media use and psychopathology

Research suggests that a small minority of social media users experience problems as a result of their online use. The purpose of the present study was to examine the association of cyberbullying perpetration and problematic social media use with childhood emotional trauma, Cluster B (narcissistic, histrionic, antisocial, and borderline) personality traits, dissociative experiences (DEs), depression, and self-esteem in a nonclinical undergraduate sample. A total of 344 university students volunteered to complete a questionnaire that included measures on the aforementioned dimensions. Thirty-eight percent of the participants had emotional neglect and 27% had emotional abuse, while 44% of them demonstrated at least one cyberbullying perpetration behavior. Results indicated that cyberbullying perpetrators had higher scores on problematic social media use, dissociative experiences, Cluster B traits, depression and childhood emotional trauma, and lower on self-esteem. Path analysis demonstrated that, while adjusting for gender and age, childhood emotional trauma was directly and indirectly associated with cyberbullying perpetration via Cluster B traits. Moreover, depression and dissociation were directly associated with problematic social media use. The findings of this study emphasize the important direct role of childhood emotional trauma and pathological personality traits on cyberbullying perpetration

Linking Proteomic and Transcriptional Data through the Interactome and Epigenome Reveals a Map of Oncogene-induced Signaling

Cellular signal transduction generally involves cascades of post-translational protein modifications that rapidly catalyze changes in protein-DNA interactions and gene expression. High-throughput measurements are improving our ability to study each of these stages individually, but do not capture the connections between them. Here we present an approach for building a network of physical links among these data that can be used to prioritize targets for pharmacological intervention. Our method recovers the critical missing links between proteomic and transcriptional data by relating changes in chromatin accessibility to changes in expression and then uses these links to connect proteomic and transcriptome data. We applied our approach to integrate epigenomic, phosphoproteomic and transcriptome changes induced by the variant III mutation of the epidermal growth factor receptor (EGFRvIII) in a cell line model of glioblastoma multiforme (GBM). To test the relevance of the network, we used small molecules to target highly connected nodes implicated by the network model that were not detected by the experimental data in isolation and we found that a large fraction of these agents alter cell viability. Among these are two compounds, ICG-001, targeting CREB binding protein (CREBBP), and PKF118–310, targeting β-catenin (CTNNB1), which have not been tested previously for effectiveness against GBM. At the level of transcriptional regulation, we used chromatin immunoprecipitation sequencing (ChIP-Seq) to experimentally determine the genome-wide binding locations of p300, a transcriptional co-regulator highly connected in the network. Analysis of p300 target genes suggested its role in tumorigenesis. We propose that this general method, in which experimental measurements are used as constraints for building regulatory networks from the interactome while taking into account noise and missing data, should be applicable to a wide range of high-throughput datasets.National Science Foundation (U.S.) (DB1-0821391)National Institutes of Health (U.S.) (Grant U54-CA112967)National Institutes of Health (U.S.) (Grant R01-GM089903)National Institutes of Health (U.S.) (P30-ES002109

Design and methods of a longitudinal study investigating the impact of antiretroviral treatment on the partnerships and sexual behaviour of HIV-infected individuals in rural KwaZulu-Natal, South Africa

BACKGROUND: Diagnosed HIV-infected people form an increasingly large sub-population in South Africa, one that will continue to grow with widely promoted HIV testing and greater availability of antiretroviral therapy (ART). For HIV prevention and support, understanding the impact of long-term ART on family and sexual relationships is a health research priority. This includes improving the availability of longitudinal demographic and health data on HIV-infected individuals who have accessed ART services but who are not yet ART-eligible.DESIGN AND METHODS: The aim of the study is to investigate the impact of ART on family and partner relationships, and sexual behaviour of HIV-infected individuals accessing a public HIV treatment and care programme in rural South Africa. HIV-infected men and women aged 18 years or older attending three clinics are screened. Those people initiating ART because they meet the criteria of WHO stage 4 or CD4 ? 200 cells/?L are assigned to an 'ART initiator' group. A 'Monitoring' group is composed of people whose most recent CD4 count was >500 cells/?L and are therefore, not yet eligible for ART. During the four-year study, data on both groups is collected every 6 months during clinic visits, or where necessary by home visits or phone. Detailed information is collected on social, demographic and health characteristics including living arrangements, past and current partnerships, sexual behaviour, HIV testing and disclosure, stigma, self-efficacy, quality of family and partner relationships, fertility and fertility intentions, ART knowledge and attitudes, and gender norms. Recruitment for both groups started in January 2009. As of October 2010, 600 participants have been enrolled; 386 in the ART initiator group (141, 37% male) and 214 in the Monitoring group (31, 14% male). Recruitment remains open for the Monitoring group.DISCUSSION: The data collected in this study will provide valuable information for measuring the impact of ART on sexual behaviour, and for the planning and delivery of appropriate interventions to promote family and partner support, and safe sexual behaviour for people living with HIV in this setting and elsewhere in sub-Saharan Africa

Differential susceptibility to plasticity: a 'missing link' between gene-culture co-evolution and neuropsychiatric spectrum disorders?

Brüne's proposal that erstwhile 'vulnerability' genes need to be reconsidered as 'plasticity' genes, given the potential for certain environments to yield increased positive function in the same domain as potential dysfunction, has implications for psychiatric nosology as well as a more dynamic understanding of the relationship between genes and culture. In addition to validating neuropsychiatric spectrum disorder nosologies by calling for similar methodological shifts in gene-environment-interaction studies, Brüne's position elevates the importance of environmental contexts - inclusive of socio-cultural variables - as mechanisms that contribute to clinical presentation. We assert that when models of susceptibility to plasticity and neuropsychiatric spectrum disorders are concomitantly considered, a new line of inquiry emerges into the co-evolution and co-determination of socio-cultural contexts and endophenotypes. This presents potentially unique opportunities, benefits, challenges, and responsibilities for research and practice in psychiatry

Reconciling disparate prevalence rates of PTSD in large samples of US male Vietnam veterans and their controls

BACKGROUND: Two large independent studies funded by the US government have assessed the impact of the Vietnam War on the prevalence of PTSD in US veterans. The National Vietnam Veterans Readjustment Study (NVVRS) estimated the current PTSD prevalence to be 15.2% while the Vietnam Experience Study (VES) estimated the prevalence to be 2.2%. We compared alternative criteria for estimating the prevalence of PTSD using the NVVRS and VES public use data sets collected more than 10 years after the United States withdrew troops from Vietnam. METHODS: We applied uniform diagnostic procedures to the male veterans from the NVVRS and VES to estimate PTSD prevalences based on varying criteria including one-month and lifetime prevalence estimates, combat and non-combat prevalence estimates, and prevalence estimates using both single and multiple indicator models. RESULTS: Using a narrow and specific set of criteria, we derived current prevalence estimates for combat-related PTSD of 2.5% and 2.9% for the VES and the NVVRS, respectively. Using a more broad and sensitive set of criteria, we derived current prevalence estimates for combat-related PTSD of 12.2% and 15.8% for the VES and NVVRS, respectively. CONCLUSION: When comparable methods were applied to available data we reconciled disparate results and estimated similar current prevalences for both narrow and broad definitions of combat-related diagnoses of PTSD

Positive Psychology in Cancer Care: Bad Science, Exaggerated Claims, and Unproven Medicine

Claims of positive psychology about people with cancer enjoy great popularity because they seem to offer scientific confirmation of strongly held cultural beliefs and values. Our goal is to examine critically four widely accepted claims in the positive psychology literature regarding adaptational outcomes among individuals living with cancer. We examine: (1) the role of positive factors, such as a "fighting spirit" in extending the life of persons with cancer; (2) effects of interventions cultivating positive psychological states on immune functioning and cancer progression and mortality; and evidence concerning (3) benefit finding and (4) post-traumatic growth following serious illness such as cancer and other highly threatening experiences. Claims about these areas of research routinely made in the positive psychology literature do not fit with available evidence. We note in particular the incoherence of claims about the adaptational value of benefit finding and post-traumatic growth among cancer patients, and the implausibility of claims that interventions that enhance benefit finding improve the prognosis of cancer patients by strengthening the immune system. We urge positive psychologists to rededicate themselves to a positive psychology based on scientific evidence rather than wishful thinking

The Influence of Life History Milestones and Association Networks on Crop-Raiding Behavior in Male African Elephants

Factors that influence learning and the spread of behavior in wild animal populations are important for understanding species responses to changing environments and for species conservation. In populations of wildlife species that come into conflict with humans by raiding cultivated crops, simple models of exposure of individual animals to crops do not entirely explain the prevalence of crop raiding behavior. We investigated the influence of life history milestones using age and association patterns on the probability of being a crop raider among wild free ranging male African elephants; we focused on males because female elephants are not known to raid crops in our study population. We examined several features of an elephant association network; network density, community structure and association based on age similarity since they are known to influence the spread of behaviors in a population. We found that older males were more likely to be raiders than younger males, that males were more likely to be raiders when their closest associates were also raiders, and that males were more likely to be raiders when their second closest associates were raiders older than them. The male association network had sparse associations, a tendency for individuals similar in age and raiding status to associate, and a strong community structure. However, raiders were randomly distributed between communities. These features of the elephant association network may limit the spread of raiding behavior and likely determine the prevalence of raiding behavior in elephant populations. Our results suggest that social learning has a major influence on the acquisition of raiding behavior in younger males whereas life history factors are important drivers of raiding behavior in older males. Further, both life-history and network patterns may influence the acquisition and spread of complex behaviors in animal populations and provide insight on managing human-wildlife conflict