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BACKGROUNDNaive cells comprise 90% of the CD4+ T cell population in neonates and exhibit distinct age-specific capacities for proliferation and activation. We hypothesized that HIV-infected naive CD4+ T cell populations in children on long-term antiretroviral therapy (ART) would thus be distinct from infected memory cells.METHODSPeripheral blood naive and memory CD4+ T cells from 8 children with perinatal HIV on ART initiated at age 1.7-17 months were isolated by FACS. DNA was extracted from sorted cells, and HIV proviruses were counted, evaluated for intactness, and subjected to integration site analysis (ISA).RESULTSNaive CD4+ T cells containing HIV proviruses were detected in children with 95% statistical confidence. A median 4.7% of long terminal repeat-containing naive CD4+ T cells also contained HIV genetic elements consistent with intactness. Full-length proviral sequencing confirmed intactness of 1 provirus. In the participant with the greatest degree of naive cell infection, ISA revealed infected expanded cell clones in both naive and memory T cells, with no common HIV integration sites detected between subsets. Divergent integration site profiles reflected differential gene expression patterns of naive and memory T cells.CONCLUSIONThese results demonstrate that HIV persisted in both naive and memory CD4+ T cells that underwent clonal expansion and harbored intact proviruses, and suggest that infected memory T cell clones do not frequently arise from naive cell differentiation in children with perinatal HIV on long-term ART.FUNDINGCenter for Cancer Research, NCI; Office of AIDS Research; NCI FLEX; Children's and Emory Junior Faculty Focused Award.

The main barrier to HIV cure is a persistent reservoir of latently infected CD4 + T cells harboring replication-competent provirus that fuels rebound viremia upon antiretroviral therapy (ART) interruption. A leading approach to target this reservoir involves agents that reactivate latent HIV proviruses followed by direct clearance of cells expressing induced viral antigens by immune effector cells and immunotherapeutics. We previously showed that AZD5582, an antagonist of inhibitor of apoptosis proteins and mimetic of the second mitochondrial-derived activator of caspases (IAPi/SMACm), induces systemic reversal of HIV/SIV latency but with no reduction in size of the viral reservoir. In this study, we investigated the effects of AZD5582 in combination with four SIV Env-specific Rhesus monoclonal antibodies (RhmAbs) ± N-803 (an IL-15 superagonist) in SIV-infected, ART-suppressed rhesus macaques. Here we confirm the efficacy of AZD5582 in inducing SIV reactivation, demonstrate enhancement of latency reversal when AZD5582 is used in combination with N-803 and show a reduction in total and replication-competent SIV-DNA in lymph-node-derived CD4 + T cells in macaques treated with AZD5582 + RhmAbs. Further exploration of this therapeutic approach may contribute to the goal of achieving an HIV cure. Reactivation of latent SIV with an IAP antagonist, coupled with immunotherapeutic approaches, reduced replication-competent SIV in lymph node CD4 + T cells in rhesus macaques. Further exploration targeting these pathways to reduce the HIV viral reservoir is warranted.

BACKGROUND. Naive cells comprise 90% of the [CD4.sup.+] T cell population in neonates and exhibit distinct age-specific capacities for proliferation and activation. We hypothesized that HIV-infected naive [CD4.sup.+] T cell populations in children on long-term antiretroviral therapy (ART) would thus be distinct from infected memory cells. METHODS. Peripheral blood naive and memory [CD4.sup.+] T cells from 8 children with perinatal HIV on ART initiated at age 1.7-17 months were isolated by FACS. DNA was extracted from sorted cells, and HIV proviruses were counted, evaluated for intactness, and subjected to integration site analysis (ISA). RESULTS. Naive [CD4.sup.+] T cells containing HIV proviruses were detected in children with 95% statistical confidence. A median 4.7% of long terminal repeat-containing naive [CD4.sup.+] T cells also contained HIV genetic elements consistent with intactness. Full-length proviral sequencing confirmed intactness of 1 provirus. In the participant with the greatest degree of naive cell infection, ISA revealed infected expanded cell clones in both naive and memory T cells, with no common HIV integration sites detected between subsets. Divergent integration site profiles reflected differential gene expression patterns of naive and memory T cells. CONCLUSION. These results demonstrate that HIV persisted in both naive and memory [CD4.sup.+] T cells that underwent clonal expansion and harbored intact proviruses, and suggest that infected memory T cell clones do not frequently arise from naive cell differentiation in children with perinatal HIV on long-term ART. FUNDING. Center for Cancer Research, NCI; Office of AIDS Research; NCI FLEX; Children's and Emory Junior Faculty Focused Award.

In recent years, the question of whether microbial life exhibits biogeographical patterns has come under increased scrutiny. In this article, leading scientists in the field review the biogeography of microorganisms and provide a framework for assessing the impact of environmental and historical processes that contribute to microbial biodiversity. Key Points Since the eighteenth century, biologists have investigated plant and animal biogeography, but only recently have the distributions of microorganisms been examined. We consider microbial biogeography in light of habitats types (the contemporary environment) and provinces (legacies of historical events such as dispersal limitation). This framework is useful for addressing whether the distributions of microbial taxa, like those of macroorganisms, reflect the influences of both contemporary environmental conditions and past events. We review a growing body of literature that suggests that microbial assemblages are not only influenced by their current environment, but that some display a degree of provincialism — evidence that these microbial assemblages have diverged and are maintained by genetic isolation. We also find that the relative influence of historical versus environmental factors appears to be related to the scale of sampling. As a first hypothesis, we suggest that the same processes that influence macroorganism biogeography (colonization, diversification and extinction) also apply to microbial life, but that their rates scale with body size, or for single-celled organisms, cell size. Therefore, we use the idea of allometry as a structure for discussing the rates of biogeographic processes in microorganisms. We conclude that the rates of biogeographic processes probably vary more widely for microorganisms of a given size than for macroorganisms of a given size. To tackle the mechanisms generating microbial biogeographic patterns, we recommend that new microbial biogeography studies should systematically sample and record data from various distances, habitats and environmental conditions. We review the biogeography of microorganisms in light of the biogeography of macroorganisms. A large body of research supports the idea that free-living microbial taxa exhibit biogeographic patterns. Current evidence confirms that, as proposed by the Baas-Becking hypothesis, 'the environment selects' and is, in part, responsible for spatial variation in microbial diversity. However, recent studies also dispute the idea that 'everything is everywhere'. We also consider how the processes that generate and maintain biogeographic patterns in macroorganisms could operate in the microbial world.

Efforts to define serological correlates of protection against COVID-19 have been hampered by the lack of a simple, scalable, standardised assay for SARS-CoV-2 infection and antibody neutralisation. Plaque assays remain the gold standard, but are impractical for high-throughput screening. In this study, we show that expression of viral proteases may be used to quantitate infected cells. Our assays exploit the cleavage of specific oligopeptide linkers, leading to the activation of cell-based optical biosensors. First, we characterise these biosensors using recombinant SARS-CoV-2 proteases. Next, we confirm their ability to detect viral protease expression during replication of authentic virus. Finally, we generate reporter cells stably expressing an optimised luciferase-based biosensor, enabling viral infection to be measured within 24 h in a 96- or 384-well plate format, including variants of concern. We have therefore developed a luminescent SARS-CoV-2 reporter cell line, and demonstrated its utility for the relative quantitation of infectious virus and titration of neutralising antibodies.

These evidence-based guidelines are an updated version of those issued in 2008. They have been produced following a review of the published literature (2007–18) pertaining to the treatment of infections caused by MRSA. The guidelines update, where appropriate, previous recommendations, taking into account changes in the UK epidemiology of MRSA, ongoing national surveillance data and the efficacy of novel anti-staphylococcal agents licensed for use in the UK. Emerging therapies that have not been licensed for use in the UK at the time of the review have also been assessed.

The areas of the brain that encode color categorically have not yet been reliably identified. Here, we used functional MRI adaptation to identify neuronal populations that represent color categories irrespective of metric differences in color. Two colors were successively presented within a block of trials. The two colors were either from the same or different categories (e.g., \"blue 1 and blue 2\" or \"blue 1 and green 1\"), and the size of the hue difference was varied. Participants performed a target detection task unrelated to the difference in color. In the middle frontal gyrus of both hemispheres and to a lesser extent, the cerebellum, blood-oxygen level-dependent response was greater for colors from different categories relative to colors from the same category. Importantly, activation in these regions was not modulated by the size of the hue difference, suggesting that neurons in these regions represent color categorically, regardless of metric color difference. Representational similarity analyses, which investigated the similarity of the pattern of activity across local groups of voxels, identified other regions of the brain (including the visual cortex), which responded to metric but not categorical color differences. Therefore, categorical and metric hue differences appear to be coded in qualitatively different ways and in different brain regions. These findings have implications for the long-standing debate on the origin and nature of color categories, and also further our understanding of how color is processed by the brain.

Reduced appetite with ageing is a key factor that may increase risk of undernutrition. The objective of this study is to determine the impact of innovative plant protein fibre (PPF) products within a personalised optimised diet (PD), a physical activity (PA) programme, and their combination on appetite, and other nutritional, functional and clinical outcomes in community-dwelling older adults in a multi-country randomised controlled intervention trial. One hundred and eighty community-dwelling adults (approximately sixty per trial centre in Germany, Ireland and Italy) aged 65 years and over will be recruited to participate in a 12-week, parallel-group, controlled trial. Participants will be randomised into one of four groups: 1, PD (incorporating two PPF products): 2, PA; 3, PD + PA; and 4, no intervention (control). The primary outcome is appetite measured by visual analogue scales and energy intake from an ad libitum test meal. Secondary outcomes include fasting and postprandial appetite-related gut hormones, Simplified Nutritional Appetite Questionnaire score, body composition, cardiorespiratory fitness, muscle strength, physical function and PA. In addition, self-efficacy, cognitive status, dietary restraint, depressive symptoms and compliance and acceptability of the intervention will be assessed. Metabolomic profiles, RMR, muscle motor unit properties and gut microbiome will also be assessed to explore potential underlying mechanisms. This multi-centre randomised controlled trial will advance knowledge on how PD (incorporating PPF products), PA and their combination influence appetite, nutritional status and related health outcomes in community-dwelling older adults and contribute to the prevention of undernutrition. Trial registration: Clinical Trials.gov Registry NCT05608707 (registered on 2 November 2022). Protocol Version: NCT05608707 Version 4 (registered on 29 September 2023).

Neurogenesis in the adult brain gives rise to functional neurons, which integrate into neuronal circuits and modulate neural plasticity. Sustained neurogenesis throughout life occurs in the subgranular zone (SGZ) of the dentate gyrus in the hippocampus and is hypothesized to be involved in behavioral/cognitive processes such as memory and in diseases. Genomic imprinting is of critical importance to brain development and normal behavior, and exemplifies how epigenetic states regulate genome function and gene dosage. While most genes are expressed from both alleles, imprinted genes are usually expressed from either the maternally or the paternally inherited chromosome. Here, we show that in contrast to its canonical imprinting in nonneurogenic regions, Delta-like homolog 1 (Dlk1) is expressed biallelically in the SGZ, and both parental alleles are required for stem cell behavior and normal adult neurogenesis in the hippocampus. To evaluate the effects of maternally, paternally, and biallelically inherited mutations within the Dlk1 gene in specific behavioral domains, we subjected Dlk1-mutant mice to a battery of tests that dissociate and evaluate the effects of Dlk1 dosage on spatial learning ability and on anxiety traits. Importantly, reduction in Dlk1 levels triggers specific cognitive abnormalities that affect aspects of discriminating differences in environmental stimuli, emphasizing the importance of selective absence of imprinting in this neurogenic niche.

We examine co-occurrence patterns of microorganisms to evaluate community assembly \"rules.\" We use methods previously applied to macroorganisms, both to evaluate their applicability to microorganisms and to allow comparison of co-occurrence patterns observed in microorganisms to those found in macroorganisms. We use a null model analysis of 124 incidence matrices from microbial communities, including bacteria, archaea, fungi, and algae, and we compare these results to previously published findings from a meta-analysis of almost 100 macroorganism data sets. We show that assemblages of microorganisms demonstrate nonrandom patterns of co-occurrence that are broadly similar to those found in assemblages of macroorganisms. These results suggest that some taxon co-occurrence patterns may be general characteristics of communities of organisms from all domains of life. We also find that co-occurrence in microbial communities does not vary among taxonomic groups or habitat types. However, we find that the degree of co-occurrence does vary among studies that use different methods to survey microbial communities. Finally, we discuss the potential effects of the undersampling of microbial communities on our results, as well as processes that may contribute to nonrandom patterns of co-occurrence in both macrobial and microbial communities such as competition, habitat filtering, historical effects, and neutral processes.