Cognitive Effort Avoidance in Veterans with Suicide Attempt Histories

Suicide attempts (SA) are increasing in the United States, especially in veterans. Discovering individual cognitive features of the subset of suicide ideators who attempt suicide is critical. Cognitive theories attribute SA to facile schema-based negative interpretations of environmental events. Over-general autobiographical memory and facile solutions in problem solving tasks in SA survivors suggest that aversion to expending cognitive effort may be a neurobehavioral marker of SA risk. In veterans receiving care for mood disorder, we compared cognitive effort discounting and evidence-gathering in a beads task between veterans with (SAHx+; n = 26) versus without (SAHx-; n = 22) a history of SA. Groups did not differ in depressed mood or in a proxy metric of premorbid intelligence. Compared to SAHx- participants, SAHx+ participants self-reported significantly more severe cognitive problems in most domains, and also eschewed choice to earn higher monetary reward if earning it required a slightly increased working memory (WM) demand relative to an easy WM task. There was no group difference, however, in extent of evidence-gathering before declaring a conclusion in a beads task. These preliminary data suggest that aversion to expenditure of cognitive effort, potentially as a component of cognitive difficulties, may be a marker for SA risk

Warped dipole completed, with a tower of Higgs bosons

In the context of warped extra-dimensional models which address both the Planck-weak- and flavor-hierarchies of the Standard Model (SM), it has been argued that certain observables can be calculated within the 5D effective field theory only with the Higgs field propagating in the bulk of the extra dimension, just like other SM fields. The related studies also suggested an interesting form of decoupling of the heavy Kaluza-Klein (KK) fermion states in the warped 5D SM in the limit where the profile of the SM Higgs approaches the IR brane. We demonstrate that a similar phenomenon occurs when we include the mandatory KK excitations of the SM Higgs in loop diagrams giving dipole operators for SM fermions, where the earlier work only considered the SM Higgs (zero mode). In particular, in the limit of a quasi IR-localized SM Higgs, the effect from summing over KK Higgs modes is unsuppressed (yet finite), in contrast to the naive expectation that KK Higgs modes decouple as their masses become large. In this case, a wide range of KK Higgs modes have quasi-degenerate masses and enhanced couplings to fermions relative to those of the SM Higgs, which contribute to the above remarkable result. In addition, we find that the total contribution from KK Higgs modes in general can be comparable to that from the SM Higgs alone. It is also interesting that KK Higgs couplings to KK fermions of the same chirality as the corresponding SM modes have an unsuppressed overall contribution, in contrast to the result from the earlier studies involving the SM Higgs. Our studies suggest that KK Higgs bosons are generally an indispensable part of the warped 5D SM, and their phenomenology such as signals at the LHC are worth further investigation

Prevalence and architecture of de novo mutations in developmental disorders.

The genomes of individuals with severe, undiagnosed developmental disorders are enriched in damaging de novo mutations (DNMs) in developmentally important genes. Here we have sequenced the exomes of 4,293 families containing individuals with developmental disorders, and meta-analysed these data with data from another 3,287 individuals with similar disorders. We show that the most important factors influencing the diagnostic yield of DNMs are the sex of the affected individual, the relatedness of their parents, whether close relatives are affected and the parental ages. We identified 94 genes enriched in damaging DNMs, including 14 that previously lacked compelling evidence of involvement in developmental disorders. We have also characterized the phenotypic diversity among these disorders. We estimate that 42% of our cohort carry pathogenic DNMs in coding sequences; approximately half of these DNMs disrupt gene function and the remainder result in altered protein function. We estimate that developmental disorders caused by DNMs have an average prevalence of 1 in 213 to 1 in 448 births, depending on parental age. Given current global demographics, this equates to almost 400,000 children born per year

The contribution of X-linked coding variation to severe developmental disorders

Abstract: Over 130 X-linked genes have been robustly associated with developmental disorders, and X-linked causes have been hypothesised to underlie the higher developmental disorder rates in males. Here, we evaluate the burden of X-linked coding variation in 11,044 developmental disorder patients, and find a similar rate of X-linked causes in males and females (6.0% and 6.9%, respectively), indicating that such variants do not account for the 1.4-fold male bias. We develop an improved strategy to detect X-linked developmental disorders and identify 23 significant genes, all of which were previously known, consistent with our inference that the vast majority of the X-linked burden is in known developmental disorder-associated genes. Importantly, we estimate that, in male probands, only 13% of inherited rare missense variants in known developmental disorder-associated genes are likely to be pathogenic. Our results demonstrate that statistical analysis of large datasets can refine our understanding of modes of inheritance for individual X-linked disorders

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes

publisher: Elsevier articletitle: Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes journaltitle: Cell articlelink: https://doi.org/10.1016/j.cell.2018.05.046 content_type: article copyright: © 2018 Elsevier Inc

Clinicopathological Significance of Syndecan-1 in Cholangiocarcinoma: A Study Based on Immunohistochemistry and Public Sequencing Data

Background: Syndecan-1 (CD138; SDC1) is a heparan sulfate proteoglycan that has been attributed a key role in cancer progression in ductal adenocarcinoma of the pancreas. We therefore aimed to investigate the role of syndecan-1 in cholangiocarcinoma. Methods: We analyzed syndecan-1 expression in a large, clinicopathologically well-characterized collective of 154 intrahepatic cholangiocarcinoma, 221 extrahepatic cholangiocarcinomas, and 95 gallbladder carcinomas as well as respective normal tissues and precursor lesions by immunohistochemistry with digital image analysis and correlated with recurrence-free survival and prognostic markers. Furthermore, we conducted an analysis of cancer genes in the cholangiocarcinoma cohort of The Cancer Genome Atlas (TCGA). Results: During cholangiocarcinogenesis, syndecan-1-expression decreased when compared to normal bile ducts and biliary intraepithelial neoplasia; however, syndecan-1 levels were found to be elevated in lymph node metastases. In the TCGA cohort, high mRNA SDC1 levels were associated with poor prognosis in intrahepatic cholangiocarcinoma. However, in our large cohort, the immunohistochemical syndecan-1 expression did not significantly correlate with recurrence-free survival. Conclusions: Syndecan-1 was found to be downregulated during cholangiocarcinogenesis, yet we could not show significant effects on prognosis on protein level. Further analyses are needed to further depict its specific role

Evaluation of Proctophyllodes huitzilopochtlii on feathers from Anna's (Calypte anna) and Black-chinned (Archilochus alexandri) Hummingbirds: Prevalence assessment and imaging analysis using light and tabletop scanning electron microscopy.

Proctophyllodes huitzilopochtlii Atyeo &amp; Braasch 1966 (Acariformes: Astigmata: Proctophyllodidae), a feather mite, was found on feathers collected from five hummingbird species in California. This mite has not been previously documented on feathers from Anna's (Calypte anna [Lesson 1829]) or Black-chinned (Archilochus alexandri [Bourcier &amp; Mulsant 1846]) Hummingbirds. A total of 753 hummingbirds were evaluated for the presence of mites by species (Allen's n = 112; Anna's n = 500; Black-chinned n = 122; Rufous n = 18; Calliope n = 1), sex (males n = 421; females n = 329; 3 unidentified), and age (juvenile n = 199; after-hatch-year n = 549; 5 unidentified). Of these 753 hummingbirds evaluated, mites were present on the rectrices of 40.9% of the birds. Significantly more Anna's Hummingbirds were positive for rectricial mites (59.2%) compared with 8.2% of Black-chinned, 0.9% of Allen's, 5.6% of Rufous Hummingbirds, and 0% for Calliope (p-value &lt; 0.0001). Across all hummingbird species, male hummingbirds (44.9%) had a higher prevalence of rectricial mites compared to female hummingbirds (36.2%; p-value = 0.004), while juvenile hummingbirds (46.2%) had a non-significantly higher prevalence compared to after-hatch-year hummingbirds (39.0%; p-value = 0.089). On average, the percentage of the long axis of the rachis occupied by mites for the outer rectrices (R4 and R5) was 19%, compared to 11% for inner rectrices (R1 and R2), a significant difference (p-value = &lt;0.0001). There was a marginal lack of significance for symmetrical distribution of tail mites with the mean left side percentage of long axis of the rachis occupied by mites being 16% and very close to the mean right side score of 18% (p-value = 0.003). The identification of the feather mite species was based on light microscopic morphometry, and mite distribution on feathers was further evaluated using tabletop scanning electron microscopy (TSEM). The hummingbird-feather mite relationship is not well understood, but the specialized TSEM technique may be especially useful in examining natural positioning and developmental aspects of the mites since it allows in situ feather examination of live mites