Juvenile social isolation reduces sociability in adulthood, but the underlying neural circuit mechanisms are poorly understood. We found that, in male mice, 2 weeks of social isolation immediately ...following weaning leads to a failure to activate medial prefrontal cortex neurons projecting to the posterior paraventricular thalamus (mPFC→pPVT) during social exposure in adulthood. Chemogenetic or optogenetic suppression of mPFC→pPVT activity in adulthood was sufficient to induce sociability deficits without affecting anxiety-related behaviors or preference toward rewarding food. Juvenile isolation led to both reduced excitability of mPFC→pPVT neurons and increased inhibitory input drive from low-threshold-spiking somatostatin interneurons in adulthood, suggesting a circuit mechanism underlying sociability deficits. Chemogenetic or optogenetic stimulation of mPFC→pPVT neurons in adulthood could rescue the sociability deficits caused by juvenile isolation. Our study identifies a pair of specific medial prefrontal cortex excitatory and inhibitory neuron populations required for sociability that are profoundly affected by juvenile social experience.
The preservation of hypoxic pulmonary vasoconstriction (HPV) in the denervated lung was studied in five human heart-lung transplant recipients. All five patients showed significant increases in mean ...pulmonary artery pressure and pulmonary vascular resistance during hypoxic exposure, returning toward normoxic values during recovery. Aside from PAO2 and Pao2, other factors known to influence pulmonary vascular resistance did not change significantly during the hypoxic period. There was no relation between the length of the post-transplantation period and the intensity of HPV, suggesting that reinnervation of the pulmonary vascular bed did not account for persistent HPV and that HPV persists in the human transplanted lung despite the loss of autonomic neural innervation.
The CUORE Crystal Validation Runs (CCVRs) have been carried out since the end of 2008 at the Gran Sasso National Laboratories, in order to test the performances and the radiopurity of the TeO\(_2\) ...crystals produced at SICCAS (Shanghai Institute of Ceramics, Chinese Academy of Sciences) for the CUORE experiment. In this work the results of the first 5 validation runs are presented. Results have been obtained for bulk contaminations and surface contaminations from several nuclides. An extrapolation to the CUORE background has been performed.
Neutrinoless double beta decay (\(0\nu\beta\beta\)) is a yet unobserved nuclear process which would demonstrate Lepton Number violation, a clear evidence of beyond Standard Model physics. The process ...two neutrino double beta decay (\(2\nu\beta\beta)\) is allowed by the Standard Model and has been measured in numerous experiments. In this letter, we report a measurement of \(2\nu\beta\beta\) decay half-life of \(^{100}\)Mo to the ground state of \(^{100}\)Ru of \((7.07~\pm~0.02~\text{(stat.)}~\pm~0.11~\text{(syst.)})~\times~10^{18}\)~yr by the CUPID-Mo experiment. With a relative precision of \(\pm~1.6\) \% this is the most precise measurement to date of a \(2\nu\beta\beta\) decay rate in \(^{100}\)Mo. In addition, we constrain higher-order corrections to the spectral shape which provides complementary nuclear structure information. We report a novel measurement of the shape factor \(\xi_{3,1}=0.45~\pm 0.03~\text{(stat.)} \ \pm 0.05 \ \text{(syst.)}\), which is compared to theoretical predictions for different nuclear models. We also extract the first value for the effective axial vector coupling constant obtained from a spectral shape study of \(2\nu\beta\beta\) decay.
In the Surrogate Method, the measured decay probability of a compound nucleus formed via a direct reaction is used to extract the cross section for a reaction with a different entrance channel that ...proceeds through the same compound nucleus. An extension of the Surrogate Method, the Surrogate Ratio Method (SRM), uses a ratio of measured decay probabilities to infer an unknown cross section relative to a known one. To test the SRM we compare the direct-reaction-induced fission probability ratio of {sup 234}U({alpha},{alpha}{sup '}f) to {sup 236}U({alpha},{alpha}{sup '}f) with the ratio of cross sections of {sup 233}U(n,f) to {sup 235}U(n,f). These ratios were found to be in agreement over an equivalent neutron energy range of 0.4-18 MeV.
Aims
Sodium glucose co‐transporter 2 inhibitors (SGLT2i) are indicated for treatment of type 2 diabetes mellitus (T2DM); some SGLT2i have reported cardiovascular benefit, and some have reported risk ...of below‐knee lower extremity (BKLE) amputation. This study examined the real‐world comparative effectiveness within the SGLT2i class and compared with non‐SGLT2i antihyperglycaemic agents.
Materials and methods
Data from 4 large US administrative claims databases were used to characterize risk and provide population‐level estimates of canagliflozin's effects on hospitalization for heart failure (HHF) and BKLE amputation vs other SGLT2i and non‐SGLT2i in T2DM patients. Comparative analyses using a propensity score–adjusted new‐user cohort design examined relative hazards of outcomes across all new users and a subpopulation with established cardiovascular disease.
Results
Across the 4 databases (142 800 new users of canagliflozin, 110 897 new users of other SGLT2i, 460 885 new users of non‐SGLT2i), the meta‐analytic hazard ratio estimate for HHF with canagliflozin vs non‐SGLT2i was 0.39 (95% CI, 0.26‐0.60) in the on‐treatment analysis. The estimate for BKLE amputation with canagliflozin vs non‐SGLT2i was 0.75 (95% CI, 0.40‐1.41) in the on‐treatment analysis and 1.01 (95% CI, 0.93‐1.10) in the intent‐to‐treat analysis. Effects in the subpopulation with established cardiovascular disease were similar for both outcomes. No consistent differences were observed between canagliflozin and other SGLT2i.
Conclusions
In this large comprehensive analysis, canagliflozin and other SGLT2i demonstrated HHF benefits consistent with clinical trial data, but showed no increased risk of BKLE amputation vs non‐SGLT2i. HHF and BKLE amputation results were similar in the subpopulation with established cardiovascular disease. This study helps further characterize the potential benefits and harms of SGLT2i in routine clinical practice to complement evidence from clinical trials and prior observational studies.
Multiple epidemiologic studies and some trials have linked diet with cardiovascular disease (CVD) prevention, but long-term intervention data are needed.
To test the hypothesis that a dietary ...intervention, intended to be low in fat and high in vegetables, fruits, and grains to reduce cancer, would reduce CVD risk.
Randomized controlled trial of 48,835 postmenopausal women aged 50 to 79 years, of diverse backgrounds and ethnicities, who participated in the Women's Health Initiative Dietary Modification Trial. Women were randomly assigned to an intervention (19,541 40%) or comparison group (29,294 60%) in a free-living setting. Study enrollment occurred between 1993 and 1998 in 40 US clinical centers; mean follow-up in this analysis was 8.1 years.
Intensive behavior modification in group and individual sessions designed to reduce total fat intake to 20% of calories and increase intakes of vegetables/fruits to 5 servings/d and grains to at least 6 servings/d. The comparison group received diet-related education materials.
Fatal and nonfatal coronary heart disease (CHD), fatal and nonfatal stroke, and CVD (composite of CHD and stroke).
By year 6, mean fat intake decreased by 8.2% of energy intake in the intervention vs the comparison group, with small decreases in saturated (2.9%), monounsaturated (3.3%), and polyunsaturated (1.5%) fat; increases occurred in intakes of vegetables/fruits (1.1 servings/d) and grains (0.5 serving/d). Low-density lipoprotein cholesterol levels, diastolic blood pressure, and factor VIIc levels were significantly reduced by 3.55 mg/dL, 0.31 mm Hg, and 4.29%, respectively; levels of high-density lipoprotein cholesterol, triglycerides, glucose, and insulin did not significantly differ in the intervention vs comparison groups. The numbers who developed CHD, stroke, and CVD (annualized incidence rates) were 1000 (0.63%), 434 (0.28%), and 1357 (0.86%) in the intervention and 1549 (0.65%), 642 (0.27%), and 2088 (0.88%) in the comparison group. The diet had no significant effects on incidence of CHD (hazard ratio HR, 0.97; 95% confidence interval CI, 0.90-1.06), stroke (HR, 1.02; 95% CI, 0.90-1.15), or CVD (HR, 0.98; 95% CI, 0.92-1.05). Excluding participants with baseline CVD (3.4%), the HRs (95% CIs) for CHD and stroke were 0.94 (0.86-1.02) and 1.02 (0.90-1.17), respectively. Trends toward greater reductions in CHD risk were observed in those with lower intakes of saturated fat or trans fat or higher intakes of vegetables/fruits.
Over a mean of 8.1 years, a dietary intervention that reduced total fat intake and increased intakes of vegetables, fruits, and grains did not significantly reduce the risk of CHD, stroke, or CVD in postmenopausal women and achieved only modest effects on CVD risk factors, suggesting that more focused diet and lifestyle interventions may be needed to improve risk factors and reduce CVD risk.
ClinicalTrials.gov Identifier: NCT00000611.
Understanding why some people establish and maintain effective control of HIV-1 and others do not is a priority in the effort to develop new treatments for HIV/AIDS. Using a whole-genome association ...strategy, we identified polymorphisms that explain nearly 15% of the variation among individuals in viral load during the asymptomatic set-point period of infection. One of these is found within an endogenous retroviral element and is associated with major histocompatibility allele human leukocyte antigen (HLA)-B*5701, whereas a second is located near the HLA-C gene. An additional analysis of the time to HIV disease progression implicated two genes, one of which encodes an RNA polymerase I subunit. These findings emphasize the importance of studying human genetic variation as a guide to combating infectious agents.
Taxanes remain one of the most effective medical treatments for breast cancer. Clinical trials have coupled taxanes with immune checkpoint inhibitors in patients with triple-negative breast cancer ...(TNBC) with promising results. However, the mechanism linking taxanes to immune activation is unclear. To determine if paclitaxel could elicit an antitumoral immune response, we sampled tumor tissues from patients with TNBC receiving weekly paclitaxel (80 mg/m
) and found increased stromal tumor-infiltrating lymphocytes and micronucleation over baseline in three of six samples. At clinically relevant concentrations, paclitaxel can induce chromosome missegregation on multipolar spindles during mitosis. Consequently, post-mitotic cells are multinucleated and contain micronuclei, which often activate cyclic GMP-AMP synthase (cGAS) and may induce a type I IFN response reliant on the stimulator of IFN genes (STING) pathway. Other microtubule-targeting agents, eribulin and vinorelbine, recapitulate this cGAS/STING response and increased the expression of immune checkpoint molecule, PD-L1, in TNBC cell lines. To test the possibility that microtubule-targeting agents sensitize tumors that express cGAS to immune checkpoint inhibitors, we identified 10 patients with TNBC treated with PD-L1 or PD-1, seven of whom also received microtubule-targeting agents. Elevated baseline cGAS expression significantly correlated with treatment response in patients receiving microtubule-targeting agents in combination with immune checkpoint inhibitors. Our study identifies a mechanism by which microtubule-targeting agents can potentiate an immune response in TNBC. Further, baseline cGAS expression may predict patient treatment response to therapies combining microtubule-targeting agents and immune checkpoint inhibitors.
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