Dietary Restriction Enhances CD8 T Cell Ketolysis to Limit Exhaustion and Boost Anti-Tumor Immunity.

Reducing calorie intake without malnutrition limits tumor progression but the underlying mechanisms are poorly understood. Here we show that dietary restriction (DR) suppresses tumor growth by enhancing CD8 T cell-mediated anti-tumor immunity. DR reshapes CD8 T cell differentiation within the tumor microenvironment (TME), promoting the development of effector T cell subsets while limiting the accumulation of exhausted T (Tex) cells, and synergizes with anti-PD1 immunotherapy to restrict tumor growth.

Glucose-dependent glycosphingolipid biosynthesis fuels CD8 T cell function and tumor control.

Glucose is essential for T cell proliferation and function, yet its specific metabolic roles remain poorly defined. Here, we identify glycosphingolipid (GSL) biosynthesis as a key pathway fueled by glucose that enables CD8 T cell expansion and cytotoxic function . Using C-based stable isotope tracing, we demonstrate that CD8 effector T cells use glucose to synthesize uridine diphosphate-glucose (UDP-Glc), a precursor for glycogen, glycan, and GSL biosynthesis.

Non-human primate model of long-COVID identifies immune associates of hyperglycemia.

Hyperglycemia, and exacerbation of pre-existing deficits in glucose metabolism, are manifestations of the post-acute sequelae of SARS-CoV-2. Our understanding of metabolic decline after acute COVID-19 remains unclear due to the lack of animal models. Here, we report a non-human primate model of metabolic post-acute sequelae of SARS-CoV-2 using SARS-CoV-2 infected African green monkeys.

The Impact of SIV-Induced Immunodeficiency on SARS-CoV-2 Disease, Viral Dynamics, and Antiviral Immune Response in a Nonhuman Primate Model of Coinfection.

The effects of immunodeficiency associated with chronic HIV infection on COVID-19 disease and viral persistence have not been directly addressed in a controlled setting. In this pilot study, we exposed two pigtail macaques (PTMs) chronically infected with SIVmac239, exhibiting from very low to no CD4 T cells across all compartments, to SARS-CoV-2. We monitored the disease progression, viral replication, and evolution, and compared these outcomes with SIV-naïve PTMs infected with SARS-CoV-2.

Cytoplasmic binding partners of the Integrator endonuclease INTS11 and its paralog CPSF73 are required for their nuclear function.

INTS11 and CPSF73 are metal-dependent endonucleases for Integrator and pre-mRNA 3'-end processing, respectively. Here, we show that the INTS11 binding partner BRAT1/CG7044, a factor important for neuronal fitness, stabilizes INTS11 in the cytoplasm and is required for Integrator function in the nucleus. Loss of BRAT1 in neural organoids leads to transcriptomic disruption and precocious expression of neurogenesis-driving transcription factors.

A diverse proteome is present and enzymatically active in metabolite extracts.

Metabolite extraction is the critical first-step in metabolomics experiments, where it is generally regarded to inactivate and remove proteins. Here, arising from efforts to improve extraction conditions for polar metabolomics, we discover a proteomic landscape of over 1000 proteins within metabolite extracts. This is a ubiquitous feature across several common extraction and sample types.

NRF2-dependent regulation of the prostacyclin receptor PTGIR drives CD8 T cell exhaustion.

The progressive decline of CD8 T cell effector function-also known as terminal exhaustion-is a major contributor to immune evasion in cancer. Yet, the molecular mechanisms that drive CD8 T cell dysfunction remain poorly understood. Here, we report that the Kelch-like ECH-associated protein 1 (KEAP1)-Nuclear factor erythroid 2-related factor 2 (NRF2) signaling axis, which mediates cellular adaptations to oxidative stress, directly regulates CD8 T cell exhaustion.

C metabolite tracing reveals glutamine and acetate as critical in vivo fuels for CD8 T cells.

Infusion of C-labeled metabolites provides a gold standard for understanding the metabolic processes used by T cells during immune responses in vivo. Through infusion of C-labeled metabolites (glucose, glutamine, and acetate) in -infected mice, we demonstrate that CD8 T effector (Teff) cells use metabolites for specific pathways during specific phases of activation. Highly proliferative early Teff cells in vivo shunt glucose primarily toward nucleotide synthesis and leverage glutamine anaplerosis in the tricarboxylic acid (TCA) cycle to support adenosine triphosphate and de novo pyrimidine synthesis.

Impact of removing ESBL status labelling from culture reports on the use of carbapenems for non-bacteraemic patients diagnosed with ESBL-positive urinary tract infections.

Objectives: To evaluate carbapenem prescribing rates for initial definitive treatment of urinary tract infections and clinical outcomes before and after removing ESBL status labels on antibiotic susceptibility reports.

Methods: This was a retrospective cohort study of adult patients treated for at least 48 h for an ESBL-producing/ceftriaxone-resistant Enterobacterales urinary tract infection. ESBL status reporting ceased in September 2022 for a network of seven community hospitals within the USA.

Feasibility, Acceptability, and Usefulness of a Screening Tool for Caregiver Learning Differences in Early Childhood Home Visiting: Staff and Caregiver Perspectives.

Early childhood home visiting programs are well positioned to improve equity and reduce health disparities for families headed by caregivers with intellectual disabilities and other learning differences. Early identification of learning differences through screening may help home visiting staff tailor services and thus improve family engagement and outcomes. Using a mixed methods design, this study assessed potential determinants and outcomes related to implementation of a screening tool for learning differences adapted for the home visiting context.

Family planning service disruptions in the first two years of the COVID-19 pandemic: Evidence from health facilities in seven low- and middle-income countries.

Many speculated that COVID-19 would severely restrict the delivery of essential health services, including family planning (FP), but evidence of this impact is limited, partly due to data limitations. We use cross-sectional data collected from regional and national samples of health facilities (n = 2,610) offering FP across seven low- and middle-income countries (LMICs) between 2019 and 2021, with longitudinal data from four geographies, to examine reported disruptions to the FP service environment during COVID-19, assess how these disruptions varied according to health system characteristics, and evaluate how disruptions evolved throughout the first two years of the pandemic, relative to a pre-pandemic period. Findings show significant variation in the impact of COVID-19 on facility-based FP services across LMICs, with the largest disruptions to services occurring in Rajasthan, India, where COVID-19 cases were highest among geographies sampled, while in most sub-Saharan African settings there were limited disruptions impacting FP service availability, method provision, and contraceptive supplies.

Toll-like Receptor 2 Mediated Immune Regulation in Simian Immunodeficiency Virus-Infected Rhesus Macaques.

Toll-like receptors (TLRs) are crucial to the innate immune response. They regulate inflammatory reactions by initiating the production of pro-inflammatory cytokines and chemokines. TLRs also play a role in shaping the adaptive immune responses.

Ketolysis drives CD8 T cell effector function through effects on histone acetylation.

Environmental nutrient availability influences T cell metabolism, impacting T cell function and shaping immune outcomes. Here, we identified ketone bodies (KBs)-including β-hydroxybutyrate (βOHB) and acetoacetate (AcAc)-as essential fuels supporting CD8 T cell metabolism and effector function. βOHB directly increased CD8 T effector (Teff) cell cytokine production and cytolytic activity, and KB oxidation (ketolysis) was required for Teff cell responses to bacterial infection and tumor challenge.

LKB1 controls inflammatory potential through CRTC2-dependent histone acetylation.

Deregulated inflammation is a critical feature driving the progression of tumors harboring mutations in the liver kinase B1 (LKB1), yet the mechanisms linking LKB1 mutations to deregulated inflammation remain undefined. Here, we identify deregulated signaling by CREB-regulated transcription coactivator 2 (CRTC2) as an epigenetic driver of inflammatory potential downstream of LKB1 loss. We demonstrate that LKB1 mutations sensitize both transformed and non-transformed cells to diverse inflammatory stimuli, promoting heightened cytokine and chemokine production.

"You Feel a Sense of Accomplishment": Outdoor Adventure Experiences of Youths with Visual Impairments during a One-Week Sports Camp.

There are many cognitive, physical, and social-emotional benefits for youths from participating in outdoor adventure activities. However, youths with visual impairments are not given the same opportunities to participate in outdoor adventure activities as their peers without disabilities. The purpose of this study was to examine the outdoor adventure experiences of youths with visual impairments participating in a week-long sports camp.

Impact of a monthly antimicrobial stewardship quality assurance tool for elevated vancomycin levels.

Objective: We sought to determine the value of an audit-and-feedback monitoring method in facilitating meaningful practice changes to improve vancomycin dosing and monitoring.

Design: Retrospective, multicenter, before-and-after implementation observational quality assurance initiative.

Setting: The study was conducted in 7 not-for-profit, acute-care hospitals within a health system in southern Florida.

Trends in fertility intentions and contraceptive practices in the context of COVID-19 in sub-Saharan Africa: insights from four national and regional population-based cohorts.

Objectives: Studies in several sub-Saharan geographies conducted early in the COVID-19 pandemic suggested little impact on contraceptive behaviours. Initial results may mask widening disparities with rising poverty, and changes to women's pregnancy desires and contraceptive use amid prolonged health service disruptions. This study examined trends in contraceptive behaviours in four sub-Saharan African settings 1 year into the pandemic.

PYGBacking on glycogen metabolism to fuel early memory T cell recall responses.

Zhang et al. (2022) show that TCR signaling promotes the phosphorylation and activation of glycogen phosphorylase B (PYGB) in CD8 memory T (Tmem) cells. PYGB-dependent glycogen mobilization provides a carbon source to support glycolysis and early Tmem cell recall responses.

Simian Immunodeficiency Virus Infection Mediated Changes in Jejunum and Peripheral SARS-CoV-2 Receptor ACE2 and Associated Proteins or Genes in Rhesus Macaques.

Angiotensin converting enzyme-2 (ACE2) and associated proteins play a pivotal role in various physiological and pathological events, such as immune activation, inflammation, gut barrier maintenance, intestinal stem cell proliferation, and apoptosis. Although many of these clinical events are quite significant in SIV/HIV infection, expression profiling of these proteins has not been well reported. Considering the different pathological consequences in the gut after HIV infection, we hypothesized that the expression of ACE2 and associated proteins of the Renin-angiotensin system (RAS) could be compromised after SIV/HIV infection.

Interrogating in vivo T-cell metabolism in mice using stable isotope labeling metabolomics and rapid cell sorting.

T cells are integral players in the adaptive immune system that readily adapt their metabolism to meet their energetic and biosynthetic needs. A major hurdle to understand physiologic T-cell metabolism has been the differences between in vitro cell culture conditions and the complex in vivo milieu. To address this, we have developed a protocol that merges traditional immunology infection models with whole-body metabolite infusion and mass-spectrometry-based metabolomic profiling to assess T-cell metabolism in vivo.

Enhanced Intestinal TGF-β/SMAD-Dependent Signaling in Simian Immunodeficiency Virus Infected Rhesus Macaques.

Transforming growth factor-β signaling (TGF-β) maintains a balanced physiological function including cell growth, differentiation, and proliferation and regulation of immune system by modulating either SMAD2/3 and SMAD7 (SMAD-dependent) or SMAD-independent signaling pathways under normal conditions. Increased production of TGF-β promotes immunosuppression in Human Immunodeficiency Virus (HIV)/Simian Immunodeficiency Virus (SIV) infection. However, the cellular source and downstream events of increased TGF-β production that attributes to its pathological manifestations remain unknown.