The RAG1 V(D)J Recombinase/Ubiquitin Ligase Promotes Ubiquitylation of Acetylated, Phosphorylated Histone 3.3

Histone variant H3.3 is associated with transcriptionally active chromatin and accumulates at loci undergoing preparation for V(D)J recombination, a DNA rearrangement required for the assembly of antigen receptors and development of B and T lymphocytes. Here we demonstrate that the RAG1 V(D)J recombinase protein promotes ubiquitylation of H3.3 that has been heavily acetylated and phosphorylated on serine 31 (acetyl-H3.3 S31p). A fragment of RAG1 promoted formation of a mono-ubiquitylated H3 product that was identified using mass spectrometry as ubiquitylated acetyl-H3.3 S31p. H3 was ubiquitylated at multiple lysine residues, and correspondingly, di-, tri- and higher-order ubiquitylated products were detected at low levels. Ubiquitylation was dependent on an intact RAG1 RING finger/ubiquitin ligase domain and required additional regions of the RAG1 amino terminus that are likely to interact with H3. Acetylated residues within the H3 amino terminal tail were also required. Purified, recombinant H3.1 and H3.3 were not good substrates, suggesting that post-translational modifications enhance recognition by RAG1. A complex including damage-DNA binding protein has also been shown to ubiquitylate H3 in response to UV treatment, suggesting the H3 ubiquitylation may be a common step in multiple DNA repair pathways

Resistance to COVID-19 vaccination has increased in Ireland and the United Kingdom during the pandemic

Objectives: Hesitance and resistance to COVID-19 vaccination poses a serious challenge to achieving adequate vaccine uptake in the general population. Cross-sectional data from the early months of the pandemic indicates that approximately one-third of adults in multiple nations are hesitant or resistant to a vaccine for COVID-19. Using longitudinal data, we tracked changes in attitudes to COVID-19 vaccination during the pandemic. Study design: This is a quantitative, longitudinal design. Method: Nationally representative samples of the adult general population of the Republic of Ireland (N ¼ 1041) and the United Kingdom (N ¼ 2025) were assessed for their attitudes towards COVID-19 vaccination at three points from March to August 2020. Results: Statistically significant increases in resistance to COVID-19 vaccination were observed in Irish (from 9.5% to 18.1%) and British (from 6.2% to 10%) adults. Conclusion: Resistance to vaccination has significantly increased in two European nations as the pandemic has progressed. Growing resistance to COVID-19 vaccination will pose a challenge to public health officials responsible for ensuring sufficient vaccine coverag

Symptoms and levels of ICD-11 Prolonged Grief Disorder in a representative community sample of UK adults.

BackgroundProlonged Grief Disorder (PGD) is a new disorder included in ICD-11 (WHO, 2018). There is a growing body of literature surrounding the prevalence and correlates of ICD-11 PGD symptoms as assessed using various measures. This study was the first to assess levels of ICD-11 PGD symptoms as measured by the International Prolonged Grief Disorder Scale (IPGDS), a self-report scale directly aligned with the ICD-11 definition of PGD, among the United Kingdom adult general population, and identify correlates.MethodParticipants included 2025 adults who participated in Wave 5 of the COVID-19 Psychological Research Consortium Study (C19PRC-UK). Prevalence rates of PGD were estimated based on two commonly used algorithms defined as 'strict' and 'moderate'. Sociodemographic, loss-related, and mental health correlates (i.e., anxiety, depression, mental health treatment seeking, loneliness) of strict and moderate PGD were then examined using multinomial logistic regressions.ResultsIt was found that 2.4% (n = 43) of participants met probable caseness for PGD using the strict criteria while 7.9% (n = 140) met probable caseness for PGD using the moderate criteria. Multinomial logistic regression analysis results showed, as predicted, that income, time since bereavement, death of a child, religiosity, and depression were associated with both moderate and strict PGD. Correlates of moderate PGD included country of residence, urbanicity, younger age of bereaved, and loneliness.ConclusionsThis study highlights that some symptoms of PGD are commonly reported in the general population, although relatively few meet the criteria for clinical significance. The routine assessment for PGD following a bereavement is discussed and the development of appropriate interventions are recommended

A Highly Conserved Program of Neuronal Microexons Is Misregulated in Autistic Brains

SummaryAlternative splicing (AS) generates vast transcriptomic and proteomic complexity. However, which of the myriad of detected AS events provide important biological functions is not well understood. Here, we define the largest program of functionally coordinated, neural-regulated AS described to date in mammals. Relative to all other types of AS within this program, 3-15 nucleotide “microexons” display the most striking evolutionary conservation and switch-like regulation. These microexons modulate the function of interaction domains of proteins involved in neurogenesis. Most neural microexons are regulated by the neuronal-specific splicing factor nSR100/SRRM4, through its binding to adjacent intronic enhancer motifs. Neural microexons are frequently misregulated in the brains of individuals with autism spectrum disorder, and this misregulation is associated with reduced levels of nSR100. The results thus reveal a highly conserved program of dynamic microexon regulation associated with the remodeling of protein-interaction networks during neurogenesis, the misregulation of which is linked to autism

Testing both affordability-availability and psychological-coping mechanisms underlying changes in alcohol use during the COVID-19 pandemic

Two theoretical perspectives have been proffered to explain changes in alcohol use during the pandemic: the 'affordability-availability' mechanism (i.e., drinking decreases due to changes in physical availability and/or reduced disposable income) and the 'psychologicalcoping' mechanism (i.e., drinking increases as adults attempt to cope with pandemic-related distress). We tested these alternative perspectives via longitudinal analyses of the COVID- 19 Psychological Consortium (C19PRC) Study data (spanning three timepoints during March to July 2020). Respondents provided data on psychological measures (e.g., anxiety, depression, posttraumatic stress, paranoia, extraversion, neuroticism, death anxiety, COVID-19 anxiety, intolerance of uncertainty, resilience), changes in socio-economic circumstances (e.g., income loss, reduced working hours), drinking motives, solitary drinking, and 'at-risk' drinking (assessed using a modified version of the AUDIT-C). Structural equation modelling was used to determine (i) whether 'at-risk' drinking during the pandemic differed from that recalled before the pandemic, (ii) dimensions of drinking motives and the psychosocial correlates of these dimensions, (iii) if increased alcohol consumption was predicted by drinking motives, solitary drinking, and socio-economic changes. The proportion of adults who recalled engaging in 'at-risk' drinking decreased significantly from 35.9% prepandemic to 32.0% during the pandemic. Drinking to cope was uniquely predicted by experiences of anxiety and/or depression and low resilience levels. Income loss or reduced working hours were not associated with coping, social enhancement, or conformity drinking motives, nor changes in drinking during lockdown. In the earliest stage of the pandemic, psychological-coping mechanisms may have been a stronger driver to changes in adults' alcohol use than 'affordability-availability' alone

Nitric oxide from inflammatory origin impairs neural stem cell proliferation by inhibiting epidermal growth factor receptor signaling

Neuroinflammation is characterized by activation of microglial cells, followed by production of nitric oxide (NO), which may have different outcomes on neurogenesis, favoring or inhibiting this process. In the present study, we investigated how the inflammatory mediator NO can affect proliferation of neural stem cells (NSCs), and explored possible mechanisms underlying this effect. We investigated which mechanisms are involved in the regulation of NSC proliferation following treatment with an inflammatory stimulus (lipopolysaccharide plus IFN-gamma), using a culture system of subventricular zone (SVZ)-derived NSCs mixed with microglia cells obtained from wild-type mice (iNOS(+/+)) or from iNOS knockout mice (iNOS(-/-)). We found an impairment of NSC cell proliferation in iNOS(+/+) mixed cultures, which was not observed in iNOS(-/-) mixed cultures. Furthermore, the increased release of NO by activated iNOS(+/+) microglial cells decreased the activation of the ERK/MAPK signaling pathway, which was concomitant with an enhanced nitration of the EGF receptor. Preventing nitrogen reactive species formation with MnTBAP, a scavenger of peroxynitrite (ONOO-), or using the ONOO- degradation catalyst FeTMPyP cell proliferation and ERK signaling were restored to basal levels in iNOS(+/+) mixed cultures. Moreover, exposure to the NO donor NOC-18 (100 mu M), for 48 h, inhibited SVZ-derived NSC proliferation. Regarding the antiproliferative effect of NO, we found that NOC-18 caused the impairment of signaling through the ERK/MAPK pathway, which may be related to increased nitration of the EGF receptor in NSC. Using MnTBAP nitration was prevented, maintaining ERK signaling, rescuing NSC proliferation. We show that NO from inflammatory origin leads to a decreased function of the EGF receptor, which compromised proliferation of NSC. We also demonstrated that NO-mediated nitration of the EGF receptor caused a decrease in its phosphorylation, thus preventing regular proliferation signaling through the ERK/MAPK pathway.Foundation for Science and Technology, (FCT, Portugal); COMPETE; FEDER [PEst-C/SAU/LA0001/2013-2014, PEst-OE/EQB/LA0023/2013-2014, PTDC/SAU-NEU/102612/2008, PTDC/NEU-OSD/0473/2012]; FCT, Portugal [SERH/BPD/78901/2011, SERH/BD/38127/2007, SFRH/BD/77903/2011, SFRH/BD/79308/2011]info:eu-repo/semantics/publishedVersio

How is loneliness related to anxiety and depression : a population-based network analysis in the early lockdown period

High risk of mental health problems is associated with loneliness resulting from social distancing measures and "lockdowns" that have been imposed globally due to the COVID-19 pandemic. This study explores the interconnectedness of loneliness, anxiety and depression on a symptom level using network analysis. A representative sample of participants (N = 1041), who were of at least 18 years of age, was recruited from the Republic of Ireland (ROI). Loneliness, anxiety and depression were assessed using validated instruments. Network analysis was used to identify the network structure of loneliness, anxiety and depression. Loneliness was found to be largely isolated from anxiety and depression nodes in the network. Anxiety and depression were largely interconnected. "Trouble relaxing," "feeling bad about oneself" and "not being able to stop or control worrying" were suggested as the most influential nodes of the network. Despite the expectation that loneliness would be implicated more robustly in the anxiety and depression network of symptoms, the results suggest loneliness as a distinct construct that is not interwoven with anxiety and depression

Mass-loading, pile-up, and mirror-mode waves at comet 67P/Churyumov-Gerasimenko

International audienceThe data from all Rosetta plasma consortium instruments and from the ROSINA COPS instrument are used to study the interaction of the solar wind with the outgassing cometary nucleus of 67P/Churyumov-Gerasimenko. During 6 and 7 June 2015, the interaction was first dominated by an increase in the solar wind dynamic pressure, caused by a higher solar wind ion density. This pressure compressed the draped magnetic field around the comet, and the increase in solar wind electrons enhanced the ionization of the outflow gas through collisional ionization. The new ions are picked up by the solar wind magnetic field, and create a ring/ring-beam distribution, which, in a high-β plasma, is unstable for mirror mode wave generation. Two different kinds of mirror modes are observed: one of small size generated by locally ionized water and one of large size generated by ionization and pickup farther away from the comet

Interleukin-6 gene (IL-6): a possible role in brain morphology in the healthy adult brain

Background: Cytokines such as interleukin 6 (IL-6) have been implicated in dual functions in neuropsychiatric disorders. Little is known about the genetic predisposition to neurodegenerative and neuroproliferative properties of cytokine genes. In this study the potential dual role of several IL-6 polymorphisms in brain morphology is investigated. Methodology: In a large sample of healthy individuals (N = 303), associations between genetic variants of IL-6 (rs1800795; rs1800796, rs2069833, rs2069840) and brain volume (gray matter volume) were analyzed using voxel-based morphometry (VBM). Selection of single nucleotide polymorphisms (SNPs) followed a tagging SNP approach (e.g., Stampa algorigthm), yielding a capture 97.08% of the variation in the IL-6 gene using four tagging SNPs. Principal findings/results: In a whole-brain analysis, the polymorphism rs1800795 (−174 C/G) showed a strong main effect of genotype (43 CC vs. 150 CG vs. 100 GG; x = 24, y = −10, z = −15; F(2,286) = 8.54, puncorrected = 0.0002; pAlphaSim-corrected = 0.002; cluster size k = 577) within the right hippocampus head. Homozygous carriers of the G-allele had significantly larger hippocampus gray matter volumes compared to heterozygous subjects. None of the other investigated SNPs showed a significant association with grey matter volume in whole-brain analyses. Conclusions/significance: These findings suggest a possible neuroprotective role of the G-allele of the SNP rs1800795 on hippocampal volumes. Studies on the role of this SNP in psychiatric populations and especially in those with an affected hippocampus (e.g., by maltreatment, stress) are warranted.Bernhard T Baune, Carsten Konrad, Dominik Grotegerd, Thomas Suslow, Eva Birosova, Patricia Ohrmann, Jochen Bauer, Volker Arolt, Walter Heindel, Katharina Domschke, Sonja Schöning, Astrid V Rauch, Christina Uhlmann, Harald Kugel and Udo Dannlowsk