Explore the vast range of titles available.

The intestine is a complex organ that promotes digestion, extracts nutrients, participates in immune surveillance, maintains critical symbiotic relationships with microbiota and affects overall health 1 . The intesting has a length of over nine metres, along which there are differences in structure and function 2 . The localization of individual cell types, cell type development trajectories and detailed cell transcriptional programs probably drive these differences in function. Here, to better understand these differences, we evaluated the organization of single cells using multiplexed imaging and single-nucleus RNA and open chromatin assays across eight different intestinal sites from nine donors. Through systematic analyses, we find cell compositions that differ substantially across regions of the intestine and demonstrate the complexity of epithelial subtypes, and find that the same cell types are organized into distinct neighbourhoods and communities, highlighting distinct immunological niches that are present in the intestine. We also map gene regulatory differences in these cells that are suggestive of a regulatory differentiation cascade, and associate intestinal disease heritability with specific cell types. These results describe the complexity of the cell composition, regulation and organization for this organ, and serve as an important reference map for understanding human biology and disease. Intestinal cell types are organized into distinct neighbourhoods and communities within the healthy human intestine, with distinct immunological niches.

Ancient Rome was the capital of an empire of ~70 million inhabitants, but little is known about the genetics of ancient Romans. Here we present 127 genomes from 29 archaeological sites in and around Rome, spanning the past 12,000 years. We observe two major prehistoric ancestry transitions: one with the introduction of farming and another prior to the Iron Age. By the founding of Rome, the genetic composition of the region approximated that of modern Mediterranean populations. During the Imperial period, Rome’s population received net immigration from the Near East, followed by an increase in genetic contributions from Europe. These ancestry shifts mirrored the geopolitical affiliations of Rome and were accompanied by marked interindividual diversity, reflecting gene flow from across the Mediterranean, Europe, and North Africa.

1. Tolerance and resistance are the two ways in which hosts can lessen the effects of infection. Tolerance aims to minimize the fitness effects resulting from incumbent pathogen populations, whereas resistance aims to reduce the pathogen population size within the host. While environmental impacts on resistance have been extensively, recorded their impacts on variation in tolerance are virtually unexplored. 2. Here, we ask how the environment, namely the host diet, influences the capacity of an organism to tolerate and resist infection, using a model host-parasite system, the burying beetle, Nicrophorus vespilloides and the entomopathogenic bacteria, Photorhabdus luminescens. 3. We first considered dose-responses and pathogen dynamics within the host, and compared our findings to responses known from other host species. We then investigated how investment in tolerance and resistance changed under different nutritional regimes. Beetles were maintained on one of five diets that varied in their ratio of protein to fat for 48 hr and then injected with P. luminescens. Survival was monitored and the phenoloxidase (PO) response and bacterial load at 24-hr postinfection were ascertained. 4. The dose required to kill 50% of individuals in this species was several magnitudes higher than in other species and the bacteria were shown to display massive decreases in population size, in contrast to patterns of proliferation found in other host species. Diet strongly modified host survival after infection, with those on the high fat/low protein diet showing 30% survival at 8 days, vs. almost 0% survival on the low-fat/high-protein diet. However, this was independent of bacterial load or variation in PO, providing evidence for diet-mediated tolerance mechanisms rather than immune-driven resistance. 5. Evolutionary ecology has long focussed on immune resistance when investigating how organisms avoid succumbing to infection. Tolerance of infection has recently become a much more prominent concept and is suggested to be influential in disease dynamics. This is one of the first studies to find diet-mediated tolerance.

Background The aim of this study was to employ high-throughput DNA sequencing to assess the incidence of bacteria with biogenic amine (BA; histamine and tyramine) producing potential from among 10 different cheeses varieties. To facilitate this, a diagnostic approach using degenerate PCR primer pairs that were previously designed to amplify segments of the histidine ( hdc ) and tyrosine ( tdc ) decarboxylase gene clusters were employed. In contrast to previous studies in which the decarboxylase genes of specific isolates were studied, in this instance amplifications were performed using total metagenomic DNA extracts. Results Amplicons were initially cloned to facilitate Sanger sequencing of individual gene fragments to ensure that a variety of hdc and tdc genes were present. Once this was established, high throughput DNA sequencing of these amplicons was performed to provide a more in-depth analysis of the histamine- and tyramine-producing bacteria present in the cheeses. High-throughput sequencing resulted in generation of a total of 1,563,764 sequencing reads and revealed that Lactobacillus curvatus , Enterococcus faecium and E. faecalis were the dominant species with tyramine producing potential, while Lb. buchneri was found to be the dominant species harbouring histaminogenic potential. Commonly used cheese starter bacteria, including Streptococcus thermophilus and Lb. delbreueckii, were also identified as having biogenic amine producing potential in the cheese studied. Molecular analysis of bacterial communities was then further complemented with HPLC quantification of histamine and tyramine in the sampled cheeses. Conclusions In this study, high-throughput DNA sequencing successfully identified populations capable of amine production in a variety of cheeses. This approach also gave an insight into the broader hdc and tdc complement within the various cheeses. This approach can be used to detect amine producing communities not only in food matrices but also in the production environment itself.

Background Air pollution is ubiquitous, yet questions remain regarding its impact on the developing brain. Large changes occur in white matter microstructure across adolescence, with notable differences by sex. Methods We investigate sex-stratified effects of annual exposure to fine particulate matter (PM 2.5 ), nitrogen dioxide (NO 2 ), and ozone (O 3 ) at ages 9–10 years on longitudinal patterns of white matter microstructure over a 2-year period. Diffusion-weighted imaging was collected on 3T MRI scanners for 8182 participants (1–2 scans per subject; 45% with two scans) from the Adolescent Brain Cognitive Development (ABCD) Study®. Restriction spectrum imaging was performed to quantify intracellular isotropic (RNI) and directional (RND) diffusion. Ensemble-based air pollution concentrations were assigned to each child’s primary residential address. Multi-pollutant, sex-stratified linear mixed-effect models assessed associations between pollutants and RNI/RND with age over time, adjusting for sociodemographic factors. Results Here we show higher PM 2.5 exposure is associated with higher RND at age 9 in both sexes, with no significant effects of PM 2.5 on RNI/RND change over time. Higher NO 2 exposure is associated with higher RNI at age 9 in both sexes, as well as attenuating RNI over time in females. Higher O 3 exposure is associated with differences in RND and RNI at age 9, as well as changes in RND and RNI over time in both sexes. Conclusions Criteria air pollutants influence patterns of white matter maturation between 9–13 years old, with some sex-specific differences in the magnitude and anatomical locations of affected tracts. This occurs at concentrations that are below current U.S. standards, suggesting exposure to low-level pollution during adolescence may have long-term consequences. Plain language summary Air pollution is known to affect health, but it is unclear whether it affects the growing human brain. We investigated whether there were differences in the development of white matter connections, which allow for faster communication between different brain regions, in children aged 9-13 years living in areas with relatively low or high air pollution in the USA. In a large group of U.S. teens, we find that polluted air is linked to differences in white matter at ages 9-10 years old and over the next two years. In some cases, males and females showed differences in the part of the brain showing changes and the amount of white matter change. Our study suggests that air pollution levels that are deemed acceptable under current regulations in the USA could have long-term effects on how a child’s brain grows. Further studies are needed to better understand the impact of these changes. Cotter et al. investigate associations between low levels of ambient pollutant exposure and white matter microstructural development during the transition from childhood to adolescence. There are sex-stratified associations, with NO 2 primarily affecting females and O 3 affecting both sexes over time.

Most patients with alcohol-associated liver disease (ALD) engage in heavy drinking defined as 4 or more drinks per day (56 g) or 8 (112 g) or more drinks per week for women and 5 or more drinks per day (70 g) or 15 (210 g) or more drinks per week for men. Although abstinence from alcohol after diagnosis of ALD improves life expectancy and reduces the risk of decompensation of liver disease, few studies have evaluated whether treatment of alcohol use disorders will reduce progression of liver disease and improve liver-related outcomes. In November 2021, the National Institute of Alcohol Abuse and Alcoholism commissioned a task force that included hepatologists, addiction medicine specialists, statisticians, clinical trialists and members of regulatory agencies to develop recommendations for the design and conduct of clinical trials to evaluate the effect of alcohol use, particularly treatment to reduce or eliminate alcohol use in patients with ALD. The task force conducted extensive reviews of relevant literature on alcohol use disorders and ALD. Findings were presented at one in-person meeting and discussed over the next 16 months to develop the final recommendations. As few clinical trials directly address this topic, the 28 recommendations approved by all members of the task force represent a consensus of expert opinions. Alcohol-associated liver disease is the main cause of liver-related morbidity and mortality globally. This Consensus Statement makes recommendations for the design, best practice and conduct of clinical trials to evaluate the effects of alcohol use in alcohol-associated liver disease and alcohol use disorder.

Air pollution is a ubiquitous neurotoxicant linked to altered structural brain connectivity. Sleep may offer neuroprotection through its roles in brain waste clearance and immune regulation. Using Fitbit-derived sleep data and multi-shell diffusion MRI from 2178 children (ages 10–13) in the ABCD Study®, we examined whether sleep moderated associations between prenatal and childhood exposure to PM 2.5 , NO 2 , and O 3 and white matter microstructure. Restriction spectrum imaging yielded restricted normalized isotropic (RNI) and directional (RND) metrics, averaged across tracts. Pollution exposure was estimated at prenatal and childhood (ages 9–10) residences. Linear mixed-effects models tested sleep-by-pollution interactions on RNI/RND. Childhood NO 2 and prenatal O 3 interacted with sleep duration and efficiency, respectively, to influence RND. Among children with similar pollutant exposure, those with longer sleep duration and higher sleep efficiency had lower RND than peers with poorer sleep. This suggests that healthy sleep may buffer adverse effects of air pollution on white matter integrity.

Runs of homozygosity (ROH) and identity-by-descent (IBD) sharing can be studied in diploid coalescent models by noting that ROH and IBD-sharing at a genomic site are predicted to be inversely related to coalescence times—which in turn can be mathematically obtained in terms of parameters describing consanguinity rates. Comparing autosomal and X-chromosomal coalescent models, we consider ROH and IBD-sharing in relation to consanguinity that proceeds via multiple forms of first-cousin mating. We predict that across populations with different levels of consanguinity, (1) in a manner that is qualitatively parallel to the increase of autosomal IBD-sharing with autosomal ROH, X-chromosomal IBD-sharing increases with X-chromosomal ROH, owing to the dependence of both quantities on consanguinity levels; (2) even in the absence of consanguinity, X-chromosomal ROH and IBD-sharing levels exceed corresponding values for the autosomes, owing to the smaller population size and lower coalescence time for the X chromosome than for autosomes; (3) with matrilateral consanguinity, the relative increase in ROH and IBD-sharing on the X chromosome compared to the autosomes is greater than in the absence of consanguinity. Examining genome-wide SNPs in human populations for which consanguinity levels have been estimated, we find that autosomal and X-chromosomal ROH and IBD-sharing levels generally accord with the predictions. We find that each 1% increase in autosomal ROH is associated with an increase of 2.1% in X-chromosomal ROH, and each 1% increase in autosomal IBD-sharing is associated with an increase of 1.6% in X-chromosomal IBD-sharing. For each calculation, particularly for ROH, the estimate is reasonably close to the increase of 2% predicted by the population-size difference between autosomes and X chromosomes. The results support the utility of coalescent models for understanding patterns of genomic sharing and their dependence on sex-biased processes.

Vaccine-serotype (VT) invasive pneumococcal disease (IPD) rates declined substantially following introduction of 7-valent pneumococcal conjugate vaccine (PCV7) into national immunization programs. Increases in non-vaccine-serotype (NVT) IPD rates occurred in some sites, presumably representing serotype replacement. We used a standardized approach to describe serotype-specific IPD changes among multiple sites after PCV7 introduction. Of 32 IPD surveillance datasets received, we identified 21 eligible databases with rate data ≥ 2 years before and ≥ 1 year after PCV7 introduction. Expected annual rates of IPD absent PCV7 introduction were estimated by extrapolation using either Poisson regression modeling of pre-PCV7 rates or averaging pre-PCV7 rates. To estimate whether changes in rates had occurred following PCV7 introduction, we calculated site specific rate ratios by dividing observed by expected IPD rates for each post-PCV7 year. We calculated summary rate ratios (RRs) using random effects meta-analysis. For children <5 years old, overall IPD decreased by year 1 post-PCV7 (RR 0.55, 95% CI 0.46-0.65) and remained relatively stable through year 7 (RR 0.49, 95% CI 0.35-0.68). Point estimates for VT IPD decreased annually through year 7 (RR 0.03, 95% CI 0.01-0.10), while NVT IPD increased (year 7 RR 2.81, 95% CI 2.12-3.71). Among adults, decreases in overall IPD also occurred but were smaller and more variable by site than among children. At year 7 after introduction, significant reductions were observed (18-49 year-olds [RR 0.52, 95% CI 0.29-0.91], 50-64 year-olds [RR 0.84, 95% CI 0.77-0.93], and ≥ 65 year-olds [RR 0.74, 95% CI 0.58-0.95]). Consistent and significant decreases in both overall and VT IPD in children occurred quickly and were sustained for 7 years after PCV7 introduction, supporting use of PCVs. Increases in NVT IPD occurred in most sites, with variable magnitude. These findings may not represent the experience in low-income countries or the effects after introduction of higher valency PCVs. High-quality, population-based surveillance of serotype-specific IPD rates is needed to monitor vaccine impact as more countries, including low-income countries, introduce PCVs and as higher valency PCVs are used. Please see later in the article for the Editors' Summary.

ObjectiveThe blood urea nitrogen-to-creatinine (BUN/creatinine) ratio has been proposed as a useful parameter in acute heart failure (AHF), but data on the normal range and the added value of the ratio compared with its separate components in patients with AHF are lacking. The aim of this study is to define the normal range of BUN/creatinine ratio and to investigate its clinical significance in patients with AHF.MethodsIn 4484 subjects from the general population without cardiovascular comorbidities, we calculated age-specific and sex-specific normal values of the BUN/creatinine ratio, deriving a higher and lower than normal range of BUN/creatinine ratio (exceeding the 95% prediction intervals). Association of abnormal range to prognosis was tested in 2033 patients with AHF for the outcome of all-cause death through 180 days, death or cardiovascular or renal rehospitalisation through 60 days and heart failure (HF) rehospitalisation within 60 days.ResultsIn a cohort of patients with AHF, 482 (24.6%) and 28 (1.4%) patients with HF were classified into higher and lower than normal range groups, respectively. In Cox regression analysis, higher than normal range of BUN/creatinine ratio group was an independent predictor for all-cause death (HR: 1.86, 95% CI 1.29 to 2.66) and death or cardiovascular or renal rehospitalisation (HR: 1.37, 95% CI 1.03 to 1.82), but not for HF rehospitalisation (HR: 1.23, 95% CI 0.81 to 1.86) after adjustment for other prognostic factors including both creatinine and BUN.ConclusionsIn patients with AHF, BUN/creatinine higher than age-specific and sex-specific normal range is associated with worse prognosis independently from both creatinine and BUN.Clinical Trialsgov identifier NCT00328692 and NCT00354458