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Genetic and environmental components as well as their interaction contribute to the risk of schizophrenia, making it highly relevant to include environmental factors in genetic studies of schizophrenia. This study comprises genome-wide association (GWA) and follow-up analyses of all individuals born in Denmark since 1981 and diagnosed with schizophrenia as well as controls from the same birth cohort. Furthermore, we present the first genome-wide interaction survey of single nucleotide polymorphisms (SNPs) and maternal cytomegalovirus (CMV) infection. The GWA analysis included 888 cases and 882 controls, and the follow-up investigation of the top GWA results was performed in independent Danish (1396 cases and 1803 controls) and German-Dutch (1169 cases, 3714 controls) samples. The SNPs most strongly associated in the single-marker analysis of the combined Danish samples were rs4757144 in ARNTL (P=3.78 × 10(-6)) and rs8057927 in CDH13 (P=1.39 × 10(-5)). Both genes have previously been linked to schizophrenia or other psychiatric disorders. The strongest associated SNP in the combined analysis, including Danish and German-Dutch samples, was rs12922317 in RUNDC2A (P=9.04 × 10(-7)). A region-based analysis summarizing independent signals in segments of 100 kb identified a new region-based genome-wide significant locus overlapping the gene ZEB1 (P=7.0 × 10(-7)). This signal was replicated in the follow-up analysis (P=2.3 × 10(-2)). Significant interaction with maternal CMV infection was found for rs7902091 (P(SNP × CMV)=7.3 × 10(-7)) in CTNNA3, a gene not previously implicated in schizophrenia, stressing the importance of including environmental factors in genetic studies.

Investigations of improvements to the hemispherical coverage that can be achieved by augmenting a cavity-backed crossed-slot antenna with inverted-L wire structures are presented. It is found that significant improvements to the axial ratio coverage can be achieved while co-polar directivity coverage is practically unaffected. [ABSTRACT FROM AUTHOR]

Carbohydrates and glycoproteins modulate key biological functions. However, experimental structure determination of sugar polymers is notoriously difficult. Computational approaches can aid in carbohydrate structure prediction, structure determination, and design. In this work, we developed a glycan-modeling algorithm, GlycanTreeModeler, that computationally builds glycans layer-by-layer, using adaptive kernel density estimates (KDE) of common glycan conformations derived from data in the Protein Data Bank (PDB) and from quantum mechanics (QM) calculations. GlycanTreeModeler was benchmarked on a test set of glycan structures of varying lengths, or "trees". Structures predicted by GlycanTreeModeler agreed with native structures at high accuracy for both de novo modeling and experimental density-guided building. We employed these tools to design de novo glycan trees into a protein nanoparticle vaccine to shield regions of the scaffold from antibody recognition, and experimentally verified shielding. This work will inform glycoprotein model prediction, glycan masking, and further aid computational methods in experimental structure determination and refinement., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Dr. JJG is an unpaid board member of the Rosetta Commons. Under institutional participation agreements between the University of Washington, acting on behalf of the Rosetta Commons, Johns Hopkins University may be entitled to a portion of revenue received on licensing Rosetta software including methods discussed/developed in this study. As a member of the Scientific Advisory Board, JJG has a financial interest in Cyrus Biotechnology. Cyrus Biotechnology distributes the Rosetta software, which may include methods developed in this study. These arrangements have been reviewed and approved by the Johns Hopkins University in accordance with its conflict-of-interest policies. WRS is an employee of Moderna, Inc., but his contributions to this work were all conducted prior to his employment at Moderna. JAB is an employee of Johnson and Johnson Innovative Medicine, Inc., but his contributions to this work were all conducted prior to his current employment., (Copyright: © 2024 Adolf-Bryfogle et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Surgery is the third most common cause of mortality worldwide. Focused cardiac ultrasound (FOCUS) yields information on cardiac status and discloses the presence of unknown pathology. Preoperative FOCUS changes patient treatment, allowing for a patient-tailored anaesthesia. We hypothesised that preoperative FOCUS would reduce the proportion of patients who were either admitted to hospital for more than 10 days or who were dead within 30 days after high-risk, non-cardiac surgery., Methods: This was a randomised, controlled, multi-center study. Patients ≥65 years of age, admitted for urgent orthopaedic- or abdominal surgery, scheduled for general- or neuraxial anaesthesia and with ASA 3/4 were eligible for inclusion. Patients were randomised in a 1:1 ratio to preoperative FOCUS or no preoperative FOCUS performed in accordance with a predefined protocol. Primary endpoint was the proportion of patients admitted more than 10 days or who were dead within 30 days. Secondary endpoints included major complications, days of admission and changes in anaesthesia handling., Results: During the second COVID-19 wave the study monitoring committee terminated the study prematurely. We included 338 patients of which 327 were included in the final analysis. In the FOCUS group, 41/163 (25%) patients met the criteria for the primary endpoint versus 35/164 (21%) for the control group, adjusted odds ratio 1.37 (95% CI 0.86-2.30), p = .36. The proportions of patients who developed major complications did not differ significantly between groups. Length of hospital stay was 4 (3-8) days in the FOCUS group and 4 (3-7) days on the control group (adjusted p = .24)., Conclusion: The routine availability of preoperative FOCUS assessment in this cohort does not appear to reduce the risk for hospitalisation exceeding 10 days or 30-day mortality, although study enrolment was prematurely terminated., (© 2022 The Authors. Acta Anaesthesiologica Scandinavica published by John Wiley & Sons Ltd on behalf of Acta Anaesthesiologica Scandinavica Foundation.)

Monoclonal antibody therapy has played an important role against SARS-CoV-2. Strategies to deliver functional, antibody-based therapeutics with improved in vivo durability are needed to supplement current efforts and reach underserved populations. Here, we compare recombinant mAbs COV2-2196 and COV2-2130, which compromise clinical cocktail Tixagevimab/Cilgavimab, with optimized nucleic acid-launched forms. Functional profiling of in vivo-expressed, DNA-encoded monoclonal antibodies (DMAbs) demonstrated similar specificity, broad antiviral potency and equivalent protective efficacy in multiple animal challenge models of SARS-CoV-2 prophylaxis compared to protein delivery. In PK studies, DNA-delivery drove significant serum antibody titers that were better maintained compared to protein administration. Furthermore, cryo-EM studies performed on serum-derived DMAbs provide the first high-resolution visualization of in vivo-launched antibodies, revealing new interactions that may promote cooperative binding to trimeric antigen and broad activity against VoC including Omicron lineages. These data support the further study of DMAb technology in the development and delivery of valuable biologics., (© 2022. The Author(s).)

HIV Envelope (Env) is the main vaccine target for induction of neutralizing antibodies. Stabilizing Env into native-like trimer (NLT) conformations is required for recombinant protein immunogens to induce autologous neutralizing antibodies(nAbs) against difficult to neutralize HIV strains (tier-2) in rabbits and non-human primates. Immunizations of mice with NLTs have generally failed to induce tier-2 nAbs. Here, we show that DNA-encoded NLTs fold properly in vivo and induce autologous tier-2 nAbs in mice. DNA-encoded NLTs also uniquely induce both CD4 + and CD8 + T-cell responses as compared to corresponding protein immunizations. Murine neutralizing antibodies are identified with an advanced sequencing technology. The structure of an Env-Ab (C05) complex, as determined by cryo-EM, identifies a previously undescribed neutralizing Env C3/V5 epitope. Beyond potential functional immunity gains, DNA vaccines permit in vivo folding of structured antigens and provide significant cost and speed advantages for enabling rapid evaluation of new HIV vaccines., (© 2022. The Author(s).)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines may target epitopes that reduce durability or increase the potential for escape from vaccine-induced immunity. Using synthetic vaccinology, we have developed rationally immune-focused SARS-CoV-2 Spike-based vaccines. Glycans can be employed to alter antibody responses to infection and vaccines. Utilizing computational modeling and in vitro screening, we have incorporated glycans into the receptor-binding domain (RBD) and assessed antigenic profiles. We demonstrate that glycan-coated RBD immunogens elicit stronger neutralizing antibodies and have engineered seven multivalent configurations. Advanced DNA delivery of engineered nanoparticle vaccines rapidly elicits potent neutralizing antibodies in guinea pigs, hamsters, and multiple mouse models, including human ACE2 and human antibody repertoire transgenics. RBD nanoparticles induce high levels of cross-neutralizing antibodies against variants of concern with durable titers beyond 6 months. Single, low-dose immunization protects against a lethal SARS-CoV-2 challenge. Single-dose coronavirus vaccines via DNA-launched nanoparticles provide a platform for rapid clinical translation of potent and durable coronavirus vaccines., Competing Interests: Declaration of interests T.R.F.S., K.S., K.E.B., and L.M.P.F.H. are employees of Inovio Pharmaceuticals and as such receive salary and benefits, including ownership of stock and stock options, from the company. C.I. is an employee of Ligand Pharmaceuticals, Inc. and as such receives salary and benefits from the company. D.W.K. reports a patent for nanoparticle vaccine pending. D.B.W. has received grant funding, participates in industry collaborations, has received speaking honoraria, and has received fees for consulting, including serving on scientific review committees and board services. Remuneration received by D.B.W. includes direct payments or stock or stock options, and in the interest of disclosure, he notes potential conflicts associated with this work with Inovio Pharmaceuticals and possibly others. In addition, he has a patent DNA vaccine delivery pending to Inovio Pharmaceuticals. The other authors declare no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Participation in social behaviors that enhance group-level fitness may be influenced by mutations that affect patterns of social epistasis in human populations. Mutations that cause individuals to not participate in these behaviors may weaken the ability of members of a group to coordinate and regulate behavior, which may in turn negatively affect fitness. To investigate the possibility that de novo mutations degrade these adaptive social behaviors, we examine the effect of paternal age (as a well-established proxy for de novo mutation load) on one such social behavior, namely religious observance, since religiosity may be a group-level cultural adaptation facilitating enhanced social coordination. Using two large samples (Wisconsin Longitudinal Study and AddHealth), each of a different US birth cohort, paternal age was used to hierarchically predict respondent's level of church attendance after controlling for multiple covariates. The effect is absent in WLS (β = .007, ns, N = 4560); however, it is present in AddHealth (β = - .046, p < .05, N = 4873) increasing the adjusted model R 2 by .005. The WLS respondents were (mostly) born in the 1930s, whereas the AddHealth respondents were (mostly) born in the 1970s. This may indicate that social-epistatic regulation of behavior has weakened historically in the USA, which might stem from and enhance the ability for de novo mutations to influence behavior among more recently born cohorts-paralleling the secular rise in the heritability of age at sexual debut after the sexual revolution.

The schizophrenia-associated gene, BRD1, encodes an epigenetic regulator in which chromatin interactome is enriched with genes implicated in mental health. Alterations in histone modifications and epigenetic regulation contribute to brain transcriptomic changes in affective disorders and preclinical data supports a role for BRD1 in psychopathology. However, the implication of BRD1 on affective pathology remains poorly understood. In this study, we assess affective behaviors and associated neurobiology in Brd1 +/- mice along with their responses to Fluoxetine and Imipramine. This involves behavioral, neurostructural, and neurochemical characterizations along with regional cerebral gene expression profiling combined with integrative functional genomic analyses. We report behavioral changes in female Brd1 +/- mice with translational value to depressive symptomatology that can be alleviated by the administration of antidepressant medications. Behavioral changes are accompanied by altered brain morphometry and imbalances in monoaminergic systems. In accordance, gene expression changes across brain tissues reveal altered neurotransmitter signaling and cluster in functional pathways associated with depression including 'Adrenergic-, GPCR-, cAMP-, and CREB/CREM-signaling'. Integrative gene expression analysis specifically links changes in amygdaloid intracellular signaling activity to the behavioral treatment response in Brd1 +/- mice. Collectively, our study highlights the importance of BRD1 as a modulator of affective pathology and adds to our understanding of the molecular mechanisms underlying affective disorders and their treatment response.

Introduction: Perioperative mortality and morbidity remain substantial in acute surgery. Risk factors include known cardiovascular disease, but preoperative screening is insensitive to occult cardiopulmonary conditions. Focused cardiac ultrasound (FOCUS) can disclose both structural and functional cardiac disease and provides insight into the patient's haemodynamic status. This study aims to clarify whether preoperative FOCUS changes clinical outcomes in high-risk patients., Methods: This is a multi-centre, randomised, controlled, prospective study including patients ≥ 65 years of age scheduled for acute/emergency abdominal- or orthopaedic surgery. A total of 800 patients will be randomised to ± application of preoperative FOCUS. The primary endpoint is the proportion of patients admitted to hospital > 10 days or death within 30 days of surgery. The secondary endpoints include changes in the anaesthesia approach facilitated by FOCUS, biomarkers of organ function and perioperative complications., Conclusions: The knowledge generated from this study may facilitate changes in the anaesthesia evaluation and decision process and, consequently, in the entire perioperative anaesthesia clinical practice. The study has the potential to reduce the risk of perioperative cardiopulmonary complications which directly implies improved patient outcome and reduced hospital costs., Funding: The Research Fund of the Department of Anaesthesiology, Randers Regional Hospital, The Central Denmark Region's Medical Research Fund and the Hospital of Southern Jutland., Trial Registration: NCT03501927., (Articles published in the DMJ are “open access”. This means that the articles are distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits any non-commercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.)

Selective pharmacological tool compounds are invaluable for understanding the functions of the various ionotropic glutamate receptor subtypes. For the kainate receptors, these compounds are few. Here we have synthesized nine novel quinoxaline-2,3-diones with substitutions in the 7-position to investigate the structure-activity relationship at kainate and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. Compound 11 exhibited the highest binding affinity across GluK1-3 while having selectivity toward kainate vs AMPA receptors. Compound 11 potently inhibited glutamate evoked currents at homomeric GluK1 and GluK3 receptors in HEK293 cells with K b values of 65 and 39 nM, respectively. The binding mode of 11 in the ligand binding domain of GluK1 was investigated by X-ray crystallography, revealing that 11 stabilizes the receptor in an open conformation, consistent with its demonstrated antagonism. Furthermore, 11 was tested for analgesic effects in the mouse tail flick test where it significantly increased tail flick latency at doses where 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[ f ]-quinoxaline-7-sulfonamide (NBQX) was ineffective.