One's sex, sleep, and posttraumatic stress disorder

Women are approximately twice as likely as men to develop posttraumatic stress disorder (PTSD) after trauma exposure. Mechanisms underlying this difference are not well understood. Although sleep is recognized to have a critical role in PTSD and physical and psychological health more generally, research into the role of sleep in PTSD sex differences has been only recent. In this article, we review both animal and human studies relevant to sex differences in sleep and PTSD with an emphasis on the roles of sex hormones. Sleep impairment including insomnia, trauma-related nightmares, and rapid-eye-movement (REM) sleep fragmentation has been observed in individuals with chronic and developing PTSD, suggesting that sleep impairment is a characteristic of PTSD and a risk factor for its development. Preliminary findings suggested sex specific patterns of sleep alterations in developing and established PTSD. Sleep maintenance impairment in the aftermath of trauma was observed in women who subsequently developed PTSD, and greater REM sleep fragmentation soon after trauma was associated with developing PTSD in both sexes. In chronic PTSD, reduced deep sleep has been found only in men, and impaired sleep initiation and maintenance with PTSD have been found in both sexes. A limited number of studies with small samples have shown that sex hormones and their fluctuations over the menstrual cycle influenced sleep as well as fear extinction, a process hypothesized to be critical to the pathogenesis of PTSD. To further elucidate the possible relationship between the sex specific patterns of PTSD-related sleep alterations and the sexually dimorphic risk for PTSD, future studies with larger samples should comprehensively examine effects of sex hormones and the menstrual cycle on sleep responses to trauma and the risk/resilience for PTSD utilizing various methodologies including fear conditioning and extinction paradigms and animal models

Phenotypic and functional analysis of bovine peripheral blood dendritic before parturition by a novel purification methods

Dendritic cells (DCs) are specialized antigen presenting cells specializing in antigen uptake and processing, and play an important role in the innate and adaptive immune response. A subset of bovine peripheral blood DCs was identified as CD172a+/CD11c+/MHC (major histocompatibility complex) class II+ cells. Although DCs are identified at 0.1%?0.7% of peripheral blood mononuclear cells (PBMC), the phenotype and function of DCs remain poorly understood with regard to maintaining tolerance during the pregnancy. All cattle used in this study were 1 month before parturition. We have established a novel method for the purification of DCs from PBMC using magnetic?activated cell sorting, and purified the CD172a+/CD11c+ DCs, with high expression of MHC class II and CD40, at 84.8% purity. There were individual differences in the expressions of CD205 and co?stimulatory molecules CD80 and CD86 on DCs. There were positive correlations between expression of cytokine and co?stimulatory molecules in DCs, and the DCs maintained their immune tolerance, evidenced by their low expressions of the co?stimulatory molecules and cytokine production. These results suggest that before parturition a half of DCs may be immature and tend to maintain tolerance based on the low cytokine production, and the other DCs with high co?stimulatory molecules may already have the ability of modulating the T?cell linagepublishersversionPeer reviewe

Role of life events in the presence of colon polyps among African Americans

African Americans have disproportionately higher incidence and death rates of colorectal cancer among all ethnic groups in the United States. Several lifestyle factors (e.g. diet, physical activity and alcohol intake) have been suggested as risk factors for colorectal cancer. Stressful life events have also been identified as risk factors for colorectal cancer. The association between stressful life events and colon polyps, which are precursors of colorectal cancer, has yet to be determined. We aimed to evaluate the relationship between stressful life events and the presence of colon polyps and adenomas in African American men and women. In this cross-sectional study, 110 participants were recruited from a colon cancer screening program at Howard University Hospital. Participants completed an 82-item Life Events Questionnaire (Norbeck 1984), assessing major events that have occurred in the participants’ life within the past 12 months. Participants also reported whether the event had a positive or negative impact. Three scores were derived (total, positive, and negative). Total life events scores were higher (Median [M] = 29 and Interquartile range [IQR] = 18-43) in patients with one or more polyps compared to patients without polyps (M, IQR = 21,13-38; P = 0.029). Total, positive or negative Life Events scores did not differ significantly between normal and adenoma patients. Total, negative and positive Life Events scores did not differ between patients who underwent diagnostic colonoscopy (symptomatic) and patients who underwent colonoscopy for colon cancer screening (asymptomatic) and patients for surveillance colonoscopies due to a personal history of colon polyps. Linear regression analysis indicated that male gender is associated with 9.0 unit lower total Life Events score (P = 0.025). This study suggests that patients who experienced total life events may be at higher risk of having colon polyps and adenomas which indicates an association between stress and the development of colorectal polyps.https://doi.org/10.1186/1471-230X-13-10

Domain-swapped T cell receptors improve the safety of TCR gene therapy

T cells engineered to express a tumor-specific αβ T cell receptor (TCR) mediate anti-tumor immunity. However, mispairing of the therapeutic αβ chains with endogenous αβ chains reduces therapeutic TCR surface expression and generates self-reactive TCRs. We report a general strategy to prevent TCR mispairing: swapping constant domains between the α and β chains of a therapeutic TCR. When paired, domain-swapped (ds)TCRs assemble with CD3, express on the cell surface, and mediate antigen-specific T cell responses. By contrast, dsTCR chains mispaired with endogenous chains cannot properly assemble with CD3 or signal, preventing autoimmunity. We validate this approach in cell-based assays and in a mouse model of TCR gene transfer-induced graft-versus-host disease. We also validate a related approach whereby replacement of αβ TCR domains with corresponding γδ TCR domains yields a functional TCR that does not mispair. This work enables the design of safer TCR gene therapies for cancer immunotherapy

Maintaining factors of posttraumatic stress symptoms following childbirth: A population-based, two-year follow-up study

Background: Previous research has established a number of risk factors that are associated with the onset of PTSD following childbirth. However, little is known about factors that maintain PTSD symptoms. Methods: This study is part of the Akershus Birth Cohort. Questionnaire data from pregnancy week 17, 8 weeks postpartum and 2 years postpartum were used. 1473 women completed all these three questionnaires and were included in the analyses. Post-traumatic stress symptoms were measured with the Impact of Event Scale. Potential maintaining factors were personality, sleep, support and life events. The factors that were significantly correlated with post-traumatic stress symptoms were entered into regression analyses. Mediation analyses were run to test whether significant predictors would serve as mediator of post-traumatic stress symptoms at 8 weeks postpartum to post-traumatic stress symptoms at 2 years postpartum. Results: We found several low to moderate associations between maintaining factors and PTSD symptoms two years postpartum. Adjusting for the starting point – PTSD symptoms 8 weeks postpartum – only insomnia remained significantly associated. Further, insomnia mediated a small portion of the effect of PTSD symptoms 8 weeks postpartum to PTSD symptoms 2 years postpartum. Limitations: Limitations of the study include a relative homogeneous sample, modest effect sizes, low internal consistency of some of the measures and the challenge to distinguish insomnia from PTSD symptoms. Conclusions: Treatment of postpartum PTSD might benefit from addressing insomnia if present. Alleviating insomnia may itself reduce daytime symptoms of PTSD and it may also increase the efficacy of primary PTSD treatments

PEG–Polypeptide Block Copolymers as pH-Responsive Endosome-Solubilizing Drug Nanocarriers

Herein we report the potential of click chemistry-modified polypeptide-based block copolymers for the facile fabrication of pH-sensitive nanoscale drug delivery systems. PEG–polypeptide copolymers with pendant amine chains were synthesized by combining N-carboxyanhydride-based ring-opening polymerization with post-functionalization using azide–alkyne cycloaddition. The synthesized block copolymers contain a polypeptide block with amine-functional side groups and were found to self-assemble into stable polymersomes and disassemble in a pH-responsive manner under a range of biologically relevant conditions. The self-assembly of these block copolymers yields nanometer-scale vesicular structures that are able to encapsulate hydrophilic cytotoxic agents like doxorubicin at physiological pH but that fall apart spontaneously at endosomal pH levels after cellular uptake. When drug-encapsulated copolymer assemblies were delivered systemically, significant levels of tumor accumulation were achieved, with efficacy against the triple-negative breast cancer cell line, MDA-MB-468, and suppression of tumor growth in an in vivo mouse model.Novartis Institutes of Biomedical ResearchNational Institutes of Health (U.S.) (Centers for Cancer Nanotechnology Excellence Grant P30 CA14051)National Institutes of Health (U.S.) (Centers for Cancer Nanotechnology Excellence Grant 5 U54 CA151884-02)National Science Foundation (U.S.). Graduate Research FellowshipNatural Sciences and Engineering Research Council of Canada (Postdoctoral Fellowship

Engineering Nano- and Microparticles to Tune Immunity

The immune system can be a cure or cause of disease, fulfilling a protective role in attacking cancer or pathogenic microbes but also causing tissue destruction in autoimmune disorders. Thus, therapies aimed to amplify or suppress immune reactions are of great interest. However, the complex regulation of the immune system, coupled with the potential systemic side effects associated with traditional systemic drug therapies, has presented a major hurdle for the development of successful immunotherapies. Recent progress in the design of synthetic micro- and nano-particles that can target drugs, deliver imaging agents, or stimulate immune cells directly through their physical and chemical properties is leading to new approaches to deliver vaccines, promote immune responses against tumors, and suppress autoimmunity. In addition, novel strategies, such as the use of particle-laden immune cells as living targeting agents for drugs, are providing exciting new approaches for immunotherapy. This progress report describes recent advances in the design of micro- and nano-particles for immunotherapies and diagnostics.National Institutes of Health (U.S.) (AI095109)National Institutes of Health (U.S.) (CA140476)United States. Dept. of Defense (Contract W81XWH-10-1-0290)United States. Dept. of Defense (Contract W911NF-07-D-0004)Ragon Institute of MGH, MIT and Harvar

Basolateral Sorting of Syntaxin 4 Is Dependent on Its N-terminal Domain and the AP1B Clathrin Adaptor, and Required for the Epithelial Cell Polarity

Generation of epithelial cell polarity requires mechanisms to sort plasma membrane proteins to the apical and basolateral domains. Sorting involves incorporation into specific vesicular carriers and subsequent fusion to the correct target membranes mediated by specific SNARE proteins. In polarized epithelial cells, the SNARE protein syntaxin 4 localizes exclusively to the basolateral plasma membrane and plays an important role in basolateral trafficking pathways. However, the mechanism of basolateral targeting of syntaxin 4 itself has remained poorly understood. Here we show that newly synthesized syntaxin 4 is directly targeted to the basolateral plasma membrane in polarized Madin-Darby canine kidney (MDCK) cells. Basolateral targeting depends on a signal that is centered around residues 24–29 in the N-terminal domain of syntaxin 4. Furthermore, basolateral targeting of syntaxin 4 is dependent on the epithelial cell-specific clathrin adaptor AP1B. Disruption of the basolateral targeting signal of syntaxin 4 leads to non-polarized delivery to both the apical and basolateral surface, as well as partial intercellular retention in the trans-Golgi network. Importantly, disruption of the basolateral targeting signal of syntaxin 4 leads to the inability of MDCK cells to establish a polarized morphology which suggests that restriction of syntaxin 4 to the basolateral domain is required for epithelial cell polarity

Considering Trauma Exposure in the Context of Genetics Studies of Posttraumatic Stress Disorder: A Systematic Review

Background: Posttraumatic stress disorder (PTSD) is a debilitating anxiety disorder. Surveys of the general population suggest that while 50-85% of Americans will experience a traumatic event in their lifetime, only 2-50% will develop PTSD. Why some individuals develop PTSD following trauma exposure while others remain resilient is a central question in the field of trauma research. For more than half a century, the role of genetic influences on PTSD has been considered as a potential vulnerability factor. However, despite the exponential growth of molecular genetic studies over the past decade, limited progress has been made in identifying true genetic variants for PTSD. Methods: In an attempt to aid future genome wide association studies (GWAS), this paper presents a systematic review of 28 genetic association studies of PTSD. Inclusion criteria required that 1) all participants were exposed to Criterion A traumatic events, 2) polymorphisms of relevant genes were genotyped and assessed in relation to participants’ PTSD status, 3) quantitative methods were used, and 4) articles were published in English and in peer-reviewed journals. In the examination of these 28 studies, particular attention was given to variables related to trauma exposure (e.g. number of traumas, type of trauma). Results: Results indicated that most articles did not report on the GxE interaction in the context of PTSD or present data on the main effects of E despite having data available. Furthermore, some studies that did consider the GxE interaction had significant findings, underscoring the importance of examining how genotypes can modify the effect of trauma on PTSD. Additionally, results indicated that only a small number of genes continue to be studied and that there were marked differences in methodologies across studies, which subsequently limited robust conclusions. Conclusions: As trauma exposure is a necessary condition for the PTSD diagnosis, this paper identifies gaps in the current literature as well as provides recommendations for how future GWAS studies can most effectively incorporate trauma exposure data in both the design and analysis phases of studies

Identifying Individual T Cell Receptors of Optimal Avidity for Tumor Antigens.

Cytotoxic T cells recognize, via their T cell receptors (TCRs), small antigenic peptides presented by the major histocompatibility complex (pMHC) on the surface of professional antigen-presenting cells and infected or malignant cells. The efficiency of T cell triggering critically depends on TCR binding to cognate pMHC, i.e., the TCR-pMHC structural avidity. The binding and kinetic attributes of this interaction are key parameters for protective T cell-mediated immunity, with stronger TCR-pMHC interactions conferring superior T cell activation and responsiveness than weaker ones. However, high-avidity TCRs are not always available, particularly among self/tumor antigen-specific T cells, most of which are eliminated by central and peripheral deletion mechanisms. Consequently, systematic assessment of T cell avidity can greatly help distinguishing protective from non-protective T cells. Here, we review novel strategies to assess TCR-pMHC interaction kinetics, enabling the identification of the functionally most-relevant T cells. We also discuss the significance of these technologies in determining which cells within a naturally occurring polyclonal tumor-specific T cell response would offer the best clinical benefit for use in adoptive therapies, with or without T cell engineering