Impact of voluntary exercise and housing conditions on hippocampal glucocorticoid receptor, miR-124 and anxiety

Background: Lack of physical activity and increased levels of stress contribute to the development of multiple physical and mental disorders. An increasing number of studies relate voluntary exercise with greater resilience to psychological stress, a process that is highly regulated by the hypothalamic-pituitary-adrenal (HPA) axis. However, the molecular mechanisms underlying the beneficial effects of exercise on stress resilience are still poorly understood. Here we have studied the impact of long term exercise and housing conditions on: a) hippocampal expression of glucocorticoid receptor (Nr3c1), b) epigenetic regulation of Nr3c1 (DNA methylation at the Nr3c1-1F promoter and miR-124 expression), c) anxiety (elevated plus maze, EPM), and d) adrenal gland weight and adrenocorticotropic hormone receptor (Mc2r) expression. Results: Exercise increased Nr3c1 and Nr3c1-1F expression and decreased miR-124 levels in the hippocampus in single-housed mice, suggesting enhanced resilience to stress. The opposite was found for pair-housed animals. Bisulfite sequencing showed virtually no DNA methylation in the Nr3c1-1F promoter region. Single-housing increased the time spent on stretch attend postures. Exercise decreased the time spent at the open arms of the EPM, however, the mobility of the exercise groups was significantly lower. Exercise had opposite effects on the adrenal gland weight of single and pair-housed mice, while it had no effect on adrenal Mc2r expression. Conclusions: These results suggest that exercise exerts a positive impact on stress resilience in single-housed mice that could be mediated by decreasing miR-124 and increasing Nr3c1 expression in the hippocampus. However, pair-housing reverses these effects possibly due to stress from dominance disputes between pairs

An Equity-focused Assessment of the City of Richmond’s RVAgreen 2050 Planning Process

Local climate action and sustainability initiatives are often critiqued for their inattention to issues of equity and justice. In response, an increasing number of cities are now attempting to respond to this critique by making equity a more explicit goal of their climate action plans: Richmond Virginia is among those cities. The City of Richmond\u27s Office of Sustainability committed to prioritizing equity in the RVAGreen 2050 plan by recognizing how Richmond’s history of racism and structural inequalities have exacerbated climate concerns for largely Black and Latinx communities and centering historically marginalized communities of color in the engagement process. Students in URSP 637 Sustainable Community Development were asked to provide an external evaluation of the RVAGreen 2050 planning process. This report summarizes the findings of this evaluation and highlights recommendations for how to improve equity-centered engagement processed moving forward

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Mortality within 30 days of receiving checkpoint inhibitor immunotherapy: An Australian multicenter review.

e19182 Background: Mortality within 30 days of chemotherapy is recognised as an important quality assurance measure. There is limited data regarding mortality within 30 days of immunotherapy and whether the same standards should apply. In contrast to chemotherapy, immunotherapy has a favourable toxicity profile and a higher chance of durable responses. We assess 3 years of data from two regional cancer centres in Queensland, Australia. Methods: Retrospective review of patients treated with checkpoint inhibitor immunotherapy at Cairns Hospital and Gold Cold University Hospital between June 2016 and June 2019. Results: 533 patients received immunotherapy and 59 (11.1%) died within 30 days of treatment. 25 patients died within 30 days of their first treatment (4.7%). Anti-PD-L1/PD-1 was more common than anti-CTLA-4 and combination treatment (84.7% v 1.7% v 13.6%). Median age was 65 years (range 37 – 87). Most patients were treated for non-small cell lung cancer (51%) and melanoma (36%). Poor prognostic features were prevalent: ECOG 3-4 (30%), brain metastases (34%), 3 sites of metastases (59%), and raised LDH (80%). Grade 3+ toxicity was uncommon (3.4%) and there were no treatment-related mortalities. Most patients died due to progressive disease. 67% died in hospital and 25% received acute treatment within 48 hours of their death. Most patients were known to palliative care (85%). Resuscitation plans were documented in 55% before their final treatment. Discussion regarding very poor prognosis was documented in 44%. Conclusions: Thirty-day mortality rates were similar to published data relating to chemotherapy and mortality within 30 days of initiating therapy was low. While there were few significant immune-related toxicities, a quarter of patients received acute treatment within 48 hours of their death. Most patients had documented resuscitation plans and were known to palliative care. </jats:p

Genome-wide Bisulfite Sequencing in Zygotes Identifies Demethylation Targets and Maps the Contribution of TET3 Oxidation

SummaryFertilization triggers global erasure of paternal 5-methylcytosine as part of epigenetic reprogramming during the transition from gametic specialization to totipotency. This involves oxidation by TET3, but our understanding of its targets and the wider context of demethylation is limited to a small fraction of the genome. We employed an optimized bisulfite strategy to generate genome-wide methylation profiles of control and TET3-deficient zygotes, using SNPs to access paternal alleles. This revealed that in addition to pervasive removal from intergenic sequences and most retrotransposons, gene bodies constitute a major target of zygotic demethylation. Methylation loss is associated with zygotic genome activation and at gene bodies is also linked to increased transcriptional noise in early development. Our data map the primary contribution of oxidative demethylation to a subset of gene bodies and intergenic sequences and implicate redundant pathways at many loci. Unexpectedly, we demonstrate that TET3 activity also protects certain CpG islands against methylation buildup

Study of light-meson resonances decaying to KS0KπK^0_{S} K \pi in the B→(KS0Kπ)KB \to (K^0_{S} K \pi) K channels

International audienceA study is presented of $B^+ \to K^0_{\rm S} K^- \pi^+ K^-$ and $B^+ \to K^0_{\rm S} K^+ \pi^- K^+$ decays based on the analysis of proton-proton collision data collected with the LHCb detector at centre-of-mass energies of 7, 8 and 13 TeV, corresponding to an integrated luminosity of $9 fb^{-1}$. The $K^0_{\rm S} K \pi$ invariant-mass distributions of both $B^+$ decay modes show, in the $m(K^0_{\rm S} K \pi)<1.85$ GeV mass region, a rich spectrum of light-meson resonances, resolved using an amplitude analysis. A complex mixture of $J^{PC}=0^{-+}, 1^{++}$ and $1^{+-}$ resonances is observed, dominated by $\eta(1405)$, $\eta(1470)$, $\eta(1760)$, $f_1(1285)$, $f_1(1420)$ and $h_1(1405)$ resonances. The $K^0_{\rm S} K \pi$ Dalitz plots are dominated by asymmetric crossing $K^* \bar K$ bands which are different for the two $B^+$ decay modes. This is due to a different interference pattern between the $1^{++}$ and $1^{+-}$ amplitudes in the two channels. Branching fractions are measured for each resonant contribution

Study of Λ0 b and Ξ0 b decays to Λh+h ′− and evidence for CP violation in Λ0 b → ΛK+K− decays

International audienceA study of Λ 0 b and Ξ0 b decays to Λh+h ′− (h (′) = π, K) is performed using pp collision data collected by the LHCb experiment during LHC Runs 1–2, corresponding to an integrated luminosity of 9 fb−1 . The branching fractions for these decays are measured using the Λ 0 b → Λ + c (→ Λπ+)π − decay as control channel. The decays Λ 0 b → Λπ+π − and Ξ0 b → ΛK−π + are observed for the first time. For decay modes with sufficient signal yields, CP asymmetries are measured in the full and localized regions of the final-state phase space. Evidence is found for CP violation in the Λ 0 b → ΛK+K− decay, interpreted as originating primarily from an asymmetric Λ 0 b → N∗+K− decay amplitude. The measured CP asymmetries for the other decays are compatible with zero

Measurement of ϕ(1020)\phi(1020) meson production in fixed-target p\textit{p}Ne collisions at sNN\sqrt{s_{NN}} = 68.5 GeV

International audienceThe first measurement of $\phi(1020)$ meson production in fixed-target $p$Ne collisions at $\sqrt{s_{NN}}=68.5$ GeV is presented. The $\phi(1020)$ mesons are reconstructed in their $K^{+}K^{-}$ decay in a data sample consisting of proton collisions on neon nuclei at rest, corresponding to an integrated luminosity of $21.7 \pm 1.4$ nb$^{-1}$, collected by the LHCb detector at CERN. The $\phi(1020)$ production cross-section in the centre-of-mass rapidity range of $-1.8<y^*<0$ and transverse momentum range of $800<p_{T}<6500$ MeV/c is found to be $\sigma=182.7\pm2.7~\text{(stat.)}\pm14.1~\text{(syst)}~\mu$b/nucleon. A double-differential measurement of the cross-section is also provided in four regions of rapidity and six regions of transverse momentum of the $\phi(1020)$ meson and compared with the predictions from Pythia and EPOS4, which are found to underestimate the experimental values

Measurements of charmed meson and antimeson production asymmetries at s=13.6\sqrt{s} =13.6 TeV

International audienceThis article presents doubly differential measurements of the asymmetries in production rates between mesons containing a charm quark and those containing an anticharm quark in proton-proton collisions at a centre-of-mass energy of $\sqrt{s}=13.6$ TeV using data recorded by the LHCb experiment. The asymmetries of $D^0$, $D^+$ and $D_s^+$ mesons are measured for two-dimensional intervals in transverse momentum and pseudorapidity, within the range $2.5<p_T<25.0$ GeV$/c$ and $2.0<\eta<4.5$. No significant production asymmetries are observed. Comparisons to the Pythia 8 and Herwig 7 event generators are also presented, and their agreement with the data is evaluated. These measurements constitute the first measurements of production asymmetries at this centre-of-mass energy of colliding beams, and the first measurements with the LHCb Run 3 detector