Lack of Support for the Genes by Early Environment Interaction Hypothesis in the Pathogenesis of Schizophrenia

Ursini et al reported recently that the liability of schizophrenia explained by a polygenic risk score (PRS) derived from the variants most associated with schizophrenia was increased 5-fold in individuals who experienced complications during pregnancy or birth. Follow-up gene expression analysis showed that the genes mapping to the most associated genetic variants are highly expressed in placental tissues. If confirmed, these findings will have major implications in our understanding of the joint effect of genes and environment in the pathogenesis of schizophrenia. We examined the interplay between PRS and obstetric complications (OCs) in 5 independent samples (effective N = 2110). OCs were assessed with the full or modified Lewis-Murray scale, or with birth weight < 2.5 kg as a proxy. In a large cohort we tested whether the pathways from placenta-relevant variants in the original report were associated with case-control status. Unlike in the original study, we did not find significant effect of PRS on the presence of OCs in cases, nor a substantial difference in the association of PRS with case-control status in samples stratified by the presence of OCs. Furthermore, none of the PRS by OCs interactions were significant, nor were any of the biological pathways, examined in the Swedish cohort. Our study could not support the hypothesis of a mediating effect of placenta biology in the pathway from genes to schizophrenia. Methodology differences, in particular the different scales measuring OCs, as well as power constraints for interaction analyses in both studies, may explain this discrepancy

Evolution and Optimality of Similar Neural Mechanisms for Perception and Action during Search

A prevailing theory proposes that the brain's two visual pathways, the ventral and dorsal, lead to differing visual processing and world representations for conscious perception than those for action. Others have claimed that perception and action share much of their visual processing. But which of these two neural architectures is favored by evolution? Successful visual search is life-critical and here we investigate the evolution and optimality of neural mechanisms mediating perception and eye movement actions for visual search in natural images. We implement an approximation to the ideal Bayesian searcher with two separate processing streams, one controlling the eye movements and the other stream determining the perceptual search decisions. We virtually evolved the neural mechanisms of the searchers' two separate pathways built from linear combinations of primary visual cortex receptive fields (V1) by making the simulated individuals' probability of survival depend on the perceptual accuracy finding targets in cluttered backgrounds. We find that for a variety of targets, backgrounds, and dependence of target detectability on retinal eccentricity, the mechanisms of the searchers' two processing streams converge to similar representations showing that mismatches in the mechanisms for perception and eye movements lead to suboptimal search. Three exceptions which resulted in partial or no convergence were a case of an organism for which the targets are equally detectable across the retina, an organism with sufficient time to foveate all possible target locations, and a strict two-pathway model with no interconnections and differential pre-filtering based on parvocellular and magnocellular lateral geniculate cell properties. Thus, similar neural mechanisms for perception and eye movement actions during search are optimal and should be expected from the effects of natural selection on an organism with limited time to search for food that is not equi-detectable across its retina and interconnected perception and action neural pathways

Endogenous antigen processing drives the primary CD4+ T cell response to influenza.

By convention, CD4+ T lymphocytes recognize foreign and self peptides derived from internalized antigens in combination with major histocompatibility complex class II molecules. Alternative pathways of epitope production have been identified, but their contributions to host defense have not been established. We show here in a mouse infection model that the CD4+ T cell response to influenza, critical for durable protection from the virus, is driven principally by unconventional processing of antigen synthesized within the infected antigen-presenting cell, not by classical processing of endocytosed virions or material from infected cells. Investigation of the cellular components involved, including the H2-M molecular chaperone, the proteasome and γ-interferon-inducible lysosomal thiol reductase revealed considerable heterogeneity in the generation of individual epitopes, an arrangement that ensures peptide diversity and broad CD4+ T cell engagement. These results could fundamentally revise strategies for rational vaccine design and may lead to key insights into the induction of autoimmune and anti-tumor responses

Proteomic Analysis of Aortae from Human Lipoprotein(a) Transgenic Mice Shows an Early Metabolic Response Independent of Atherosclerosis

Background: Elevated low density lipoprotein (LDL) and lipoprotein(a) are independent risk factors for the development of atherosclerosis. Using a proteomic approach we aimed to determine early changes in arterial protein expression in transgenic mice containing both human LDL and lipoprotein(a) in circulation. Methods and Results: Plasma lipid analyses showed the lipoprotein(a) transgenic mice had significantly higher lipid levels than wildtype, including a much increased LDL and high density lipoprotein (HDL) cholesterol. Analysis of aortae from lipoprotein(a) mice showed lipoprotein(a) accumulation but no lipid accumulation or foam cells, leaving the arteries essentially atherosclerosis free. Using two-dimensional gel electrophoresis and mass spectrometry, we identified 34 arterial proteins with significantly altered abundance (P,0.05) in lipoprotein(a) transgenic mice compared to wildtype including 17 that showed a $2 fold difference. Some proteins of interest showed a similarly altered abundance at the transcript level. These changes collectively indicated an initial metabolic response that included a down regulation in energy, redox and lipid metabolism proteins and changes in structural proteins at a stage when atherosclerosis had not yet developed. Conclusions: Our study shows that human LDL and lipoprotein(a) promote changes in the expression of a unique set o

Complex problems require complex solutions: the utility of social quality theory for addressing the Social Determinants of Health

Extent: 9p.Background: In order to improve the health of the most vulnerable groups in society, the WHO Commission on Social Determinants of Health (CSDH) called for multi-sectoral action, which requires research and policy on the multiple and inter-linking factors shaping health outcomes. Most conceptual tools available to researchers tend to focus on singular and specific social determinants of health (SDH) (e.g. social capital, empowerment, social inclusion). However, a new and innovative conceptual framework, known as social quality theory, facilitates a more complex and complete understanding of the SDH, with its focus on four domains: social cohesion, social inclusion, social empowerment and socioeconomic security, all within the same conceptual framework. This paper provides both an overview of social quality theory in addition to findings from a national survey of social quality in Australia, as a means of demonstrating the operationalisation of the theory. Methods: Data were collected using a national random postal survey of 1044 respondents in September, 2009. Multivariate logistic regression analysis was conducted. Results: Statistical analysis revealed that people on lower incomes (less than $45000) experience worse social quality across all of the four domains: lower socio-economic security, lower levels of membership of organisations (lower social cohesion), higher levels of discrimination and less political action (lower social inclusion) and lower social empowerment. The findings were mixed in terms of age, with people over 65 years experiencing lower socio-economic security, but having higher levels of social cohesion, experiencing lower levels of discrimination (higher social inclusion) and engaging in more political action (higher social empowerment). In terms of gender, women had higher social cohesion than men, although also experienced more discrimination (lower social inclusion). Conclusions: Applying social quality theory allows researchers and policy makers to measure and respond to the multiple sources of oppression and advantage experienced by certain population groups, and to monitor the effectiveness of interventions over time.Paul R Ward, Samantha B Meyer, Fiona Verity, Tiffany K Gill and Tini CN Luon

Short-Term Visual Deprivation Does Not Enhance Passive Tactile Spatial Acuity

An important unresolved question in sensory neuroscience is whether, and if so with what time course, tactile perception is enhanced by visual deprivation. In three experiments involving 158 normally sighted human participants, we assessed whether tactile spatial acuity improves with short-term visual deprivation over periods ranging from under 10 to over 110 minutes. We used an automated, precisely controlled two-interval forced-choice grating orientation task to assess each participant's ability to discern the orientation of square-wave gratings pressed against the stationary index finger pad of the dominant hand. A two-down one-up staircase (Experiment 1) or a Bayesian adaptive procedure (Experiments 2 and 3) was used to determine the groove width of the grating whose orientation each participant could reliably discriminate. The experiments consistently showed that tactile grating orientation discrimination does not improve with short-term visual deprivation. In fact, we found that tactile performance degraded slightly but significantly upon a brief period of visual deprivation (Experiment 1) and did not improve over periods of up to 110 minutes of deprivation (Experiments 2 and 3). The results additionally showed that grating orientation discrimination tends to improve upon repeated testing, and confirmed that women significantly outperform men on the grating orientation task. We conclude that, contrary to two recent reports but consistent with an earlier literature, passive tactile spatial acuity is not enhanced by short-term visual deprivation. Our findings have important theoretical and practical implications. On the theoretical side, the findings set limits on the time course over which neural mechanisms such as crossmodal plasticity may operate to drive sensory changes; on the practical side, the findings suggest that researchers who compare tactile acuity of blind and sighted participants should not blindfold the sighted participants

A strong 13C chemical shift signature provides the coordination mode of histidines in zinc-binding proteins

International audienceZinc is the second most abundant metal ion incorporated in proteins, and is in many cases a crucial component of protein three-dimensional structures. Zinc ions are frequently coordinated by cysteine and histidine residues. Whereas cysteines bind to zinc via their unique Sγ atom, histidines can coordinate zinc with two different coordination modes, either Nδ1 or Nε2 is coordinating the zinc ion. The determination of this coordination mode is crucial for the accurate structure determination of a histidine-containing zinc-binding site by NMR. NMR chemical shifts contain a vast amount of information on local electronic and structural environments and surprisingly their utilization for the determination of the coordination mode of zinc-ligated histidines has been limited so far to 15N nuclei. In the present report, we observed that the 13C chemical shifts of aromatic carbons in zinc-ligated histidines represent a reliable signature of their coordination mode. Using a statistical analysis of 13C chemical shifts, we show that 13Cδ2 chemical shift is sensitive to the histidine coordination mode and that the chemical shift difference δ{13Cε1} - δ{13Cδ2} provides a reference-independent marker of this coordination mode. The present approach allows the direct determination of the coordination mode of zinc-ligated histidines even with non-isotopically enriched protein samples and without any prior structural information

Interrelationship between Dendritic Cell Trafficking and Francisella tularensis Dissemination following Airway Infection

Francisella tularensis, the etiological agent of the inhalation tularemia, multiplies in a variety of cultured mammalian cells. Nevertheless, evidence for its in vivo intracellular residence is less conclusive. Dendritic cells (DC) that are adapted for engulfing bacteria and migration towards lymphatic organs could serve as potential targets for bacterial residence and trafficking. Here, we focus on the in vivo interactions of F. tularensis with DC following airway infection of mice. Lethal airway infection of mice with the live vaccine strain (LVS) results in trafficking of a CD11bhigh/CD11cmed/autofluorescencelow DC subset from the respiratory tract to the draining mediastinal lymph node (MdLN). Simultaneously, a rapid, massive bacterial colonization of the MdLN occurs, characterized by large bacterial foci formation. Analysis of bacteria in the MdLN revealed a major population of extracellular bacteria, which co-exists with a substantial fraction of intracellular bacteria. The intracellular bacteria are viable and reside in cells sorted for DC marker expression. Moreover, in vivo vital staining experiments indicate that most of these intracellular bacteria (∼75%) reside in cells that have migrated from the airways to the MdLN after infection. The correlation between DC and bacteria accumulation in the MdLN was further demonstrated by manipulating DC migration to the MdLN through two independent pathways. Impairment of DC migration to the MdLN, either by a sphingosine-1-phosphate receptor agonist (FTY720) or by the D prostanoid receptor 1 agonist (BW245C), resulted in reduced bacterial colonization of MdLN. Moreover, BW245C treatment delayed the onset of morbidity and the time to death of the infected mice. Taken together, these results suggest that DC can serve as an inhabitation niche for F. tularensis in the early stages of infection, and that DC trafficking plays a role in pathogen dissemination. This underscores the therapeutic potential of DC migration impairing drugs in tularemia treatment

Interaction Testing and Polygenic Risk Scoring to Estimate the Association of Common Genetic Variants With Treatment Resistance in Schizophrenia

Importance: About 20% to 30% of people with schizophrenia have psychotic symptoms that do not respond adequately to first-line antipsychotic treatment. This clinical presentation, chronic and highly disabling, is known as treatment-resistant schizophrenia (TRS). The causes of treatment resistance and their relationships with causes underlying schizophrenia are largely unknown. Adequately powered genetic studies of TRS are scarce because of the difficulty in collecting data from well-characterized TRS cohorts. Objective: To examine the genetic architecture of TRS through the reassessment of genetic data from schizophrenia studies and its validation in carefully ascertained clinical samples. Design, Setting, and Participants: Two case-control genome-wide association studies (GWASs) of schizophrenia were performed in which the case samples were defined as individuals with TRS (n = 10 501) and individuals with non-TRS (n = 20 325). The differences in effect sizes for allelic associations were then determined between both studies, the reasoning being such differences reflect treatment resistance instead of schizophrenia. Genotype data were retrieved from the CLOZUK and Psychiatric Genomics Consortium (PGC) schizophrenia studies. The output was validated using polygenic risk score (PRS) profiling of 2 independent schizophrenia cohorts with TRS and non-TRS: a prevalence sample with 817 individuals (Cardiff Cognition in Schizophrenia [CardiffCOGS]) and an incidence sample with 563 individuals (Genetics Workstream of the Schizophrenia Treatment Resistance and Therapeutic Advances [STRATA-G]). Main Outcomes and Measures: GWAS of treatment resistance in schizophrenia. The results of the GWAS were compared with complex polygenic traits through a genetic correlation approach and were used for PRS analysis on the independent validation cohorts using the same TRS definition. Results: The study included a total of 85 490 participants (48 635 [56.9%] male) in its GWAS stage and 1380 participants (859 [62.2%] male) in its PRS validation stage. Treatment resistance in schizophrenia emerged as a polygenic trait with detectable heritability (1% to 4%), and several traits related to intelligence and cognition were found to be genetically correlated with it (genetic correlation, 0.41-0.69). PRS analysis in the CardiffCOGS prevalence sample showed a positive association between TRS and a history of taking clozapine (r2 = 2.03%; P = .001), which was replicated in the STRATA-G incidence sample (r2 = 1.09%; P = .04). Conclusions and Relevance: In this GWAS, common genetic variants were differentially associated with TRS, and these associations may have been obscured through the amalgamation of large GWAS samples in previous studies of broadly defined schizophrenia. Findings of this study suggest the validity of meta-analytic approaches for studies on patient outcomes, including treatment resistance

Dry Needling for Spine Related Disorders: a Scoping Review

Introduction/Background: The depth and breadth of research on dry needling (DN) has not been evaluated specifically for symptomatic spine related disorders (SRD) from myofascial trigger points (TrP), disc, nerve and articular structures not due to serious pathologies. Current literature appears to support DN for treatment of TrP. Goals of this review include identifying research published on DN treatment for SRD, sites of treatment and outcomes studied. Methods: A scoping review was conducted following Levac et al.’s five part methodological framework to determine the current state of the literature regarding DN for patients with SRD. Results: Initial and secondary search strategies yielded 55 studies in the cervical (C) region (71.43%) and 22 in the thoracolumbar-pelvic (TLP) region (28.57%). Most were randomized controlled trials (60% in C, 45.45% in TLP) and clinical trials (18.18% in C, 22.78% in TLP). The most commonly treated condition was TrP for both the C and TLP regions. In the C region, DN was provided to 23 different muscles, with the trapezius as treatment site in 41.88% of studies. DN was applied to 31 different structures in the TLP region. In the C region, there was one treatment session in 23 studies (41.82%) and 2–6 treatments in 25 (45.45%%). For the TLP region, one DN treatment was provided in 8 of the 22 total studies (36.36%) and 2–6 in 9 (40.9%). The majority of experimental designs had DN as the sole intervention. For both C and TLP regions, visual analogue scale, pressure pain threshold and range of motion were the most common outcomes. Conclusion: For SRD, DN was primarily applied to myofascial structures for pain or TrP diagnoses. Many outcomes were improved regardless of diagnosis or treatment parameters. Most studies applied just one treatment which may not reflect common clinical practice. Further research is warranted to determine optimal treatment duration and frequency. Most studies looked at DN as the sole intervention. It is unclear whether DN alone or in addition to other treatment procedures would provide superior outcomes. Functional outcome tools best suited to tracking the outcomes of DN for SRD should be explored.https://doi.org/10.1186/s12998-020-00310-