Psychosis risk candidate ZNF804A localizes to synapses and regulates neurite formation and dendritic spine structure

BackgroundVariation in the gene encoding zinc finger binding protein 804A (ZNF804A) is associated with schizophrenia (SCZ) and bipolar disorder (BP). Evidence suggests that ZNF804A is a regulator of gene transcription and is present in nuclear and extranuclear compartments. However, a detailed examination of ZNF804A distribution and its neuronal functions has yet to be performed.MethodsThe localization of ZNF804A protein was examined in neurons derived from human neural progenitor cells (hNPCs), human induced pluripotent stem cells (hiPSCs) or in primary rat cortical neurons. Additionally, siRNA-mediated knockdown of ZNF804A was conducted to determine its role in neurite formation, maintenance of dendritic spine morphology and responses to activity-dependent stimulations.ResultsEndogenous ZNF804A protein localized to somato-dendritic compartments and co-localized with the putative synaptic markers in young neurons derived from hNPCs and hiPSCs. In mature rat neurons, Zfp804A, the homolog of ZNF804A, was present in a subset of dendritic spines and co-localized with synaptic proteins in specific nanodomains, as determined by superresolution microscopy. Interestingly, knockdown of ZNF804A attenuated neurite outgrowth in young neurons, an effect potentially mediated by reduced neuroligin-4 (NLGN4) expression. Furthermore, knockdown of ZNF804A in mature neurons resulted in the loss of dendritic spine density, and impaired responses to activity-dependent stimulation.ConclusionsThese data reveal a novel subcellular distribution for ZNF804A within somato-dendritic compartments and a nanoscopic organisation at excitatory synapses. Moreover, our results suggest that ZNF804A plays an active role in neurite formation, maintenance of dendritic spines and activity-dependent structural plasticity

Sequestration of Highly Expressed mRNAs in Cytoplasmic Granules, P-Bodies, and Stress Granules Enhances Cell Viability

Transcriptome analyses indicate that a core 10%–15% of the yeast genome is modulated by a variety of different stresses. However, not all the induced genes undergo translation, and null mutants of many induced genes do not show elevated sensitivity to the particular stress. Elucidation of the RNA lifecycle reveals accumulation of non-translating mRNAs in cytoplasmic granules, P-bodies, and stress granules for future regulation. P-bodies contain enzymes for mRNA degradation; under stress conditions mRNAs may be transferred to stress granules for storage and return to translation. Protein degradation by the ubiquitin-proteasome system is elevated by stress; and here we analyzed the steady state levels, decay, and subcellular localization of the mRNA of the gene encoding the F-box protein, UFO1, that is induced by stress. Using the MS2L mRNA reporter system UFO1 mRNA was observed in granules that colocalized with P-bodies and stress granules. These P-bodies stored diverse mRNAs. Granules of two mRNAs transported prior to translation, ASH1-MS2L and OXA1-MS2L, docked with P-bodies. HSP12 mRNA that gave rise to highly elevated protein levels was not observed in granules under these stress conditions. ecd3, pat1 double mutants that are defective in P-body formation were sensitive to mRNAs expressed ectopically from strong promoters. These highly expressed mRNAs showed elevated translation compared with wild-type cells, and the viability of the mutants was strongly reduced. ecd3, pat1 mutants also exhibited increased sensitivity to different stresses. Our interpretation is that sequestration of highly expressed mRNAs in P-bodies is essential for viability. Storage of mRNAs for future regulation may contribute to the discrepancy between the steady state levels of many stress-induced mRNAs and their proteins. Sorting of mRNAs for future translation or decay by individual cells could generate potentially different phenotypes in a genetically identical population and enhance its ability to withstand stress

Autistic traits and alcohol use in adolescents within the general population

It has been suggested that autistic traits are associated with less frequent alcohol use in adolescence. Our study seeks to examine the relationship between autistic traits and alcohol use in a large adolescent population. Leveraging data from the IMAGEN cohort, including 2045 14-year-old adolescents that were followed-up to age 18, we selected items on social preference/skills and rigidity from different questionnaires. We used linear regression models to (1) test the effect of the sum scores on the prevalence of alcohol use (AUDIT-C) over time, (2) explore the relationship between autistic traits and alcohol use patterns, and (3) explore the specific effect of each autistic trait on alcohol use. Higher scores on the selected items were associated with trajectories of less alcohol use from the ages between 14 and 18 (b = − 0.030; CI 95% = − 0.042, − 0.017; p < 0.001). Among adolescents who used alcohol, those who reported more autistic traits were also drinking less per occasion than their peers and were less likely to engage in binge drinking. We found significant associations between alcohol use and social preference (p < 0.001), nervousness for new situations (p = 0.001), and detail orientation (p < 0.001). Autistic traits (social impairment, detail orientation, and anxiety) may buffer against alcohol use in adolescence

Post-Exposure Prophylaxis and Methamphetamine Use among Young Sexual Minority Men: The P18 Cohort Study

Methamphetamine use is associated with increased risk of HIV infection among young sexual minority men (SMM). Post-exposure prophylaxis (PEP) is an effective strategy for individuals who are exposed to HIV, but there is limited research about PEP use among young SMM and its relationship with methamphetamine use. This study analyzes the association between ever PEP use and recent methamphetamine use among young SMM in New York City, using cross-sectional data from the P18 Cohort Study (n = 429). Multivariable logistic regression models were used to assess the association between methamphetamine use and ever PEP use. Compared with those who had not used methamphetamine in the last 6 months, young SMM who did use methamphetamine were significantly more likely to have ever used PEP (AOR = 6.07, 95% CI: 2.10&ndash;16.86). Young SMM who had ever used PrEP had 16 times higher odds of ever using PEP (AOR = 16, 95% CI: 7.41&ndash;35.95). Those who completed bachelor&rsquo;s degrees were 61% less likely to have ever used PEP (AOR = 0.39, 95% CI: 0.17&ndash;0.88). These data suggest that methamphetamine use could increase the risk of HIV infection, highlighting the critical need to target interventions for young SMM who use methamphetamine and are more likely to engage in unprotected intercourse

Police Firearm Injury Explorer (PFIE)

The Police Firearm Injury Explorer (PFIE) builds on data made available by the Gun Violence Archive (GVA) and allows for visualization and download of data on police firearm injury in the United States, 2014-2020. GVA is a non-partisan, non-profit organization that information on incidents of gun violence from over 7,500 law enforcement, media, government and commercial sources daily in an effort to provide near-real time data about the results of gun violence. For more information, visit www.gunviolencearchive.org

Chondroitin sulfate reduces the friction coefficient of articular cartilage

The objective of this study was to investigate the effect of chondroitin sulfate (CS)-C on the frictional response of bovine articular cartilage. The main hypothesis is that CS decreases the friction coefficient of articular cartilage. Corollary hypotheses are that viscosity and osmotic pressure are not the mechanisms that mediate the reduction in the friction coefficient by CS. In Experiment 1, bovine articular cartilage samples ( n=29) were tested in either phosphate buffered saline (PBS) or in PBS containing 100 mg/ml of CS following 48 h incubation in PBS or in PBS+100 mg/ml CS (control specimens were not subjected to any incubation). In Experiment 2, samples ( n=23) were tested in four different solutions: PBS, PBS+100 mg/ml CS, and PBS+polyethylene glycol (PEG) (133 or 170 mg/ml). In Experiment 3, samples ( n=18) were tested in three solutions of CS (0, 10 and 100 mg/ml). Frictional tests (cartilage-on-glass) were performed under constant stress (0.5 MPa) for 3600 s and the time-dependent friction coefficient was measured. Samples incubated or tested in a 100 mg/ml CS solution exhibited a significantly lower equilibrium friction coefficient than the respective PBS control. PEG solutions delayed the rise in the friction coefficient relative to the PBS control, but did not reduce the equilibrium value. Testing in PBS+10 mg/ml of CS did not cause any significant decrease in the friction coefficient. In conclusion, CS at a concentration of 100 mg/ml significantly reduces the friction coefficient of bovine articular cartilage and this mechanism is neither mediated by viscosity nor osmolarity. These results suggest that direct injection of CS into the joint may provide beneficial tribological effects

Study of the Fabrication Technology of Hybrid Microfluidic Biochips for Label-Free Detection of Proteins

A study of the peculiarities and a comparative analysis of the technologies used for the fabrication of elements of novel hybrid microfluidic biochips for express biomedical analysis have been carried out. The biochips were designed with an incorporated microfluidic system, which enabled an accumulation of the target compounds in a biological fluid to be achieved, thus increasing the biochip system&rsquo;s sensitivity and even implementing a label-free design of the detection unit. The multilevel process of manufacturing a microfluidic system of a given topology for label-free fluorometric detection of protein structures is presented. The technological process included the chemical modification of the working surface of glass substrates by silanization using (3-aminopropyl) trimethoxysilane (APTMS), formation of the microchannels, for which SU-8 technologies and a last generation dry film photoresist were studied and compared. The solid-state phosphor layers were deposited using three methods: drop application; airbrushing; and mechanical spraying onto the adhesive surface. The processes of sealing the system, installing input ports, and packaging using micro-assembly technologies are described. The technological process has been optimized and the biochip was implemented and tested. The presented system can be used to design novel high-performance diagnostic tools that implement the function of express detection of protein markers of diseases and create low-power multimodal, highly intelligent portable analytical decision-making systems in medicine

Variants in the Signaling Protein TSAd are Associated with Susceptibility to Ovarian Cancer in BRCA1/2 Negative High Risk Families

A substantial fraction of familial ovarian cancer cases cannot be attributed to specific genetic factors. The discovery of additional susceptibility genes will permit a more accurate assessment of hereditary cancer risk and allow for monitoring of predisposed women in order to intervene at the earliest possible stage. We focused on a population with elevated familial breast and ovarian cancer risk. In this study, we identified a SNP rs926103 whose minor allele is associated with predisposition to ovarian but not breast cancer in a Caucasian high-risk population without BRCA1 / BRCA2 mutations. We have found that the allelic variation of rs926103, which alters amino acid 52 of the encoded protein SH2D2A/TSAd, results in differences in the activity of this protein involved in multiple signal transduction pathways, including regulation of immune response, tumor vascularization, cell growth, and differentiation. Our observation provides a novel candidate genetic biomarker of elevated ovarian cancer risk in members of high-risk families without BRCA1 /2 mutations, as well as a potential therapeutic target, TSAd