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Few laboratory studies permitting granular analyses of alcohol use on neurobehavioral processes in older adults have been reported. This study, reporting baseline data from an on-going longitudinal project, seeks to address this gap. Toward that end, working memory (WM) processes were targeted using the continuous recognition version of the Mnemonic Similarity Task (MST). Healthy male and female drinkers aged 65–80 years completed self-report measures of substance use, negative affect and demographics prior to testing. Drinking patterns were quantified on the basis of typical standard drinks/day (D/D). Behavioral data were obtained in a two-button forced choice paradigm. Neurophysiological data were obtained for each stimulus presentation with analyses focusing on a mid-frontal negative shift occurring ∼ 300–500 ms post stimulus (FN400) and a posterior positive shift occurring ∼ 550–800 ms after stimulus presentation (LPC). To constrain the models, for the behavioral analyses correlations between D/D, measures of negative affect, stimulus condition (“new,” “identical,” or “similar”) and performance were conducted. They indicated that only accuracy in labeling “new” items was related to D/D. Subsequent least squares regression revealed that D/D was inversely related to accuracy for new items. In a sensitivity analysis removing THC users, the D/D effect was retained. Correlations incorporating mean amplitudes for the FN400 and LPC failed to reveal identifiable patterns. Consequently, separate mixed models (e.g., stimulus condition) for FN400 and LPC were conducted. D/D was not predictive of the FN400 for any stimulus condition. It was negatively related to the LPC mean amplitude. In post-hoc analyses, the effect was most notable for “new” stimuli. After removing THC users, the magnitude and direction of the D/D effect was retained, although the p value fell short of significance. Primary models failed to reveal sex main or interaction effects. However, exploratory post-hoc analyses justify their continued study. These data lend preliminary support for the hypothesis that sustained drinking among older adults may negatively impact neurobehavioral processes. They are also consistent with expectations that alcohol effects may be modest and constrained by specific process. Importantly, these outcomes will be expanded through on-going longitudinal study, extending investigation to study of alcohol-related cognitive decline.

Research demonstrates that crime rate differences across racially segregated urban communities are primarily attributable to uneven distributions of resources between neighborhoods. Less is known about the role economic inequality within neighborhoods, what I call relative inequality, plays in maintaining ethno-racial criminal disparities. In this dissertation I explore sources of variation in the impact of relative inequality on neighborhood crime by drawing on data from the 2010-2013 National Neighborhood Crime Study Panel (NNCS2-P). I find that relative inequality effects are attenuated in higher disadvantage neighborhoods and this interaction accounts for differences in effect size by neighborhood ethno-racial composition. Results also show that relative inequality effects are weakened in cities that are more segregated, have greater minority political empowerment, and have more neighborhood development organizations. These findings suggest that initiatives to integrate and economically revitalize disadvantaged neighborhoods will not be sufficient to reduce crime and disorder so long as neighbors remain unequal.

Massive slums have become major features of cities in many low-income and middle-income countries. Here, in the first in a Series of two papers, we discuss why slums are unhealthy places with especially high risks of infection and injury. We show that children are especially vulnerable, and that the combination of malnutrition and recurrent diarrhoea leads to stunted growth and longer-term effects on cognitive development. We find that the scientific literature on slum health is underdeveloped in comparison to urban health, and poverty and health. This shortcoming is important because health is affected by factors arising from the shared physical and social environment, which have effects beyond those of poverty alone. In the second paper we will consider what can be done to improve health and make recommendations for the development of slum health as a field of study.

In the first paper in this Series we assessed theoretical and empirical evidence and concluded that the health of people living in slums is a function not only of poverty but of intimately shared physical and social environments. In this paper we extend the theory of so-called neighbourhood effects. Slums offer high returns on investment because beneficial effects are shared across many people in densely populated neighbourhoods. Neighbourhood effects also help explain how and why the benefits of interventions vary between slum and non-slum spaces and between slums. We build on this spatial concept of slums to argue that, in all low-income and-middle-income countries, census tracts should henceforth be designated slum or non-slum both to inform local policy and as the basis for research surveys that build on censuses. We argue that slum health should be promoted as a topic of enquiry alongside poverty and health.

CD4+FOXP3+ Treg cells maintain self tolerance, suppress the immune response to cancer, and protect against tissue injury during acute inflammation. Treg cells require mitochondrial metabolism to function, but how Treg cells adapt their metabolic programs to optimize their function during an immune response occurring in a metabolically stressed microenvironment remains unclear. Here, we tested whether Treg cells require the energy homeostasis-maintaining enzyme AMPK to adapt to metabolically aberrant microenvironments caused by malignancy or lung injury, finding that AMPK is dispensable for Treg cell immune-homeostatic function but is necessary for full Treg cell function in B16 melanoma tumors and during influenza virus pneumonia. AMPK-deficient Treg cells had lower mitochondrial mass and exhibited an impaired ability to maximize aerobic respiration. Mechanistically, we found that AMPK regulates DNA methyltransferase 1 to promote transcriptional programs associated with mitochondrial function in the tumor microenvironment. During viral pneumonia, we found that AMPK sustains metabolic homeostasis and mitochondrial activity. Induction of DNA hypomethylation was sufficient to rescue mitochondrial mass in AMPK-deficient Treg cells, linking AMPK function to mitochondrial metabolism via DNA methylation. These results define AMPK as a determinant of Treg cell adaptation to metabolic stress and offer potential therapeutic targets in cancer and tissue injury.

There has been considerable recent progress in designing new proteins using deep-learning methods 1 – 9 . Despite this progress, a general deep-learning framework for protein design that enables solution of a wide range of design challenges, including de novo binder design and design of higher-order symmetric architectures, has yet to be described. Diffusion models 10 , 11 have had considerable success in image and language generative modelling but limited success when applied to protein modelling, probably due to the complexity of protein backbone geometry and sequence–structure relationships. Here we show that by fine-tuning the RoseTTAFold structure prediction network on protein structure denoising tasks, we obtain a generative model of protein backbones that achieves outstanding performance on unconditional and topology-constrained protein monomer design, protein binder design, symmetric oligomer design, enzyme active site scaffolding and symmetric motif scaffolding for therapeutic and metal-binding protein design. We demonstrate the power and generality of the method, called RoseTTAFold diffusion (RFdiffusion), by experimentally characterizing the structures and functions of hundreds of designed symmetric assemblies, metal-binding proteins and protein binders. The accuracy of RFdiffusion is confirmed by the cryogenic electron microscopy structure of a designed binder in complex with influenza haemagglutinin that is nearly identical to the design model. In a manner analogous to networks that produce images from user-specified inputs, RFdiffusion enables the design of diverse functional proteins from simple molecular specifications. Fine-tuning the RoseTTAFold structure prediction network on protein structure denoising tasks yields a generative model for protein design that achieves outstanding performance on a wide range of protein structure and function design challenges.

The aim of the current study is to investigate the influence of light intensity, quality of light and alternative membrane sytems on the growth and headspace-GC/MS chemical analysis of Plectranthus amboinicus cultivated in vitro. Nodal segments were grown under light intensities (26, 51, 69, 94 and 130 µmol m−2 s−1) provided by cool-white fluorescent lamps. Apical segments were grown under light-emitting diodes blue; red; 1 blue/2.5 red; 2.5 blue/1 red; 1 blue/1 red and white fluorescent lamps. Apical and nodal segments were grown under alternative membrane and membrane-free systems. One, two or four PTFE membranes were used on the lid of the culture vessel. The membranes provided natural ventilation and worked as filters. The results have shown significant differences in the growth and carvacrol content, as well as in the content of carvacrol precursors (γ-terpinene and p-cymene) in different treatments. Among all tested light intensities, the significant increase in the dry weight and in the carvacrol content of plantlets derived from the nodal segments was recorded at 69 µmol m−2 s−1. The monochromatic red led to greater shoot length and higher dry weight in plantlets derived from the apical segments, as well as to carvacrol accumulation greater than that provided by the fluorescent lamps. The culture vessel enclosure by one and two membranes led to higher dry weight in plantlets derived from the apical and nodal segments, respectively. They also showed higher carvacrol content. Thus, it is possible optimizing the growth and carvacrol content in P. amboinicus cultivated in vitro by adjusting these environmental parameters.

Necrotizing enterocolitis (NEC) is an idiopathic, inflammatory bowel necrosis of premature infants. Clinical studies have linked NEC with antecedent red blood cell (RBC) transfusions, but the underlying mechanisms are unclear. Here we report a neonatal murine model to investigate this association. C57BL/6 mouse pups rendered anemic by timed phlebotomy and then given RBC transfusions develop NEC-like intestinal injury with prominent necrosis, inflammation, and submucosal edema/separation of the lamina propria in the ileocecal region and colon within 12–24 h. The anemic intestine is infiltrated by inflammatory macrophages, which are activated in situ by RBC transfusions via a Toll-like receptor (TLR)-4-mediated mechanism and cause bowel injury. Chelation of RBC degradation products with haptoglobin, absence of TLR4, macrophage depletion, and inhibition of macrophage activation is protective. Intestinal injury worsens with increasing severity and the duration of anemia prior to transfusion, indicating a need for the re-evaluation of current transfusion guidelines for premature infants. The development of neonatal necrotising enterocolitis has been temporally associated with red blood cell transfusions in retrospective human studies. Here, the authors develop a neonatal mouse model of necrotising enterocolitis in anaemic mice receiving red blood cell transfusion that recapitulates features of the human condition.

PurposeObesity is a major risk factor for end-stage kidney disease (ESKD) and is often a barrier to kidney transplantation. However, limited evidence exists evaluating postoperative bariatric surgery outcomes in patients with chronic kidney disease (CKD) and ESKD.Materials and MethodsWe performed a retrospective cohort study of patients who underwent bariatric surgery in 2015–2016 using the national Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program dataset. Propensity score matching was used to balance characteristics across patients with CKD and ESKD vs. those without CKD.ResultsThere were 323,034 patients without CKD, 1694 patients with CKD, and 925 patients with ESKD who underwent bariatric surgery. Patients with CKD and ESKD had a significantly increased risk of 30-day reoperation (CKD odds ratio [OR] 2.25 95% confidence interval [CI] 1.45–3.51; ESKD OR 3.10, 95% CI 1.72–5.61) and readmission (CKD OR 1.98, 95% CI 1.53–2.56; ESKD OR 2.97, 95% CI 2.05–4.31) compared to patients without CKD; mortality risk was elevated in patients with ESKD (OR 11.59, 95% CI 6.71–20.04) but not in those with CKD (OR 1.00, 95% CI 0.32–3.11). Rates of adverse outcomes were < 15% across all groups. There were 12, 50, and 172 deaths per 1000 person-years among patients without CKD, with CKD, and with ESKD, respectively.ConclusionPatients with CKD and ESKD experienced higher risk of postbariatric surgery complications compared to those without kidney disease, although absolute complication rates were low across all groups. CKD and ESKD should not be perceived as contraindications to bariatric surgery.

A wide variety of regioselectively substituted carbazole derivatives can be synthesized by the gold‐catalyzed cyclization of alkynols bearing an indol‐3‐yl and an additional group at the homopropargylic positions. The regioselectivity of the process can be controlled by both the oxidation state of the gold catalyst and the electronic nature of the substituents of the alkynol moiety. The 1,2‐alkyl migration in the spiroindoleninium intermediate, generated after indole attack to the activated alkyne, is favored with gold(I) complexes and for electron‐rich aromatic substituents at the homopropargylic position, whereas the 1,2‐alkenyl shift is preferred when using gold(III) salts and for alkyl or non‐electron‐rich aromatic groups. A gold‐catalyzed regiodivergent synthesis of carbazoles from alkynols bearing at the homopropargylic positions an indol‐3‐yl and an additional group has been described. The nature of R2 is crucial for the regiocontrol, promoting the 1,2‐alkyl migration with electron‐rich aromatics. In addition, whereas gold(III) salts favor the 1,2‐alkenyl shift, gold(I) complexes are more prone to promote 1,2‐alkyl migrations.