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The enteric nervous system (ENS) coordinates diverse functions in the intestine but has eluded comprehensive molecular characterization because of the rarity and diversity of cells. Here we develop two methods to profile the ENS of adult mice and humans at single-cell resolution RAISIN RNA-seq for profiling intact nuclei with ribosome-bound mRNA and MIRACL-seq for label-free enrichment of rare cell types by droplet-based profiling. The 1,187,535 nuclei in our mouse atlas include 5,068 neurons from the ileum and colon, revealing extraordinary neuron diversity. We highlight circadian expression changes in enteric neurons, show that disease-related genes are dysregulated with aging, and identify differences between the ileum and proximal/distal colon. In humans, we profile 436,202 nuclei, recovering 1,445 neurons, and identify conserved and species-specific transcriptional programs and putative neuro-epithelial, neuro-stromal, and neuro-immune interactions. The human ENS expresses risk genes for neuropathic, inflammatory, and extra-intestinal diseases, suggesting neuronal contributions to disease.Hypersensitivity reactions to drugs are often unpredictable and can be life threatening, underscoring a need for understanding their underlying mechanisms and risk factors. The extent to which germline genetic variation influences the risk of commonly reported drug allergies such as penicillin allergy remains largely unknown. We extracted data from the electronic health records of more than 600,000 participants from the UK, Estonian, and Vanderbilt University Medical Center's BioVU biobanks to study the role of genetic variation in the occurrence of self-reported penicillin hypersensitivity reactions. We used imputed SNP to HLA typing data from these cohorts to further fine map the human leukocyte antigen (HLA) association and replicated our results in 23andMe's research cohort involving a total of 1.12 million individuals. Genome-wide meta-analysis of penicillin allergy revealed two loci, including one located in the HLA region on chromosome 6. This signal was further fine-mapped to the HLA-B∗5501 allele (OR 1.41 95% CI 1.33-1.49, p value 2.04 × 10-31) and confirmed by independent replication in 23andMe's research cohort (OR 1.30 95% CI 1.25-1.34, p value 1.00 × 10-47). The lead SNP was also associated with lower lymphocyte counts and in silico follow-up suggests a potential effect on T-lymphocytes at HLA-B∗5501. We also observed a significant hit in PTPN22 and the GWAS results correlated with the genetics of rheumatoid arthritis and psoriasis. We present robust evidence for the role of an allele of the major histocompatibility complex (MHC) I gene HLA-B in the occurrence of penicillin allergy.The contribution of gene-by-environment (GxE) interactions for many human traits and diseases is poorly characterized. We propose a Bayesian whole-genome regression model for joint modeling of main genetic effects and GxE interactions in large-scale datasets, such as the UK Biobank, where many environmental variables have been measured. The method is called LEMMA (Linear Environment Mixed Model Analysis) and estimates a linear combination of environmental variables, called an environmental score (ES), that interacts with genetic markers throughout the genome. The ES provides a readily interpretable way to examine the combined effect of many environmental variables. The ES can be used both to estimate the proportion of phenotypic variance attributable to GxE effects and to test for GxE effects at genetic variants across the genome. GxE effects can induce heteroskedasticity in quantitative traits, and LEMMA accounts for this by using robust standard error estimates when testing for GxE effects. When applied to body mass index, systolic blood pressure, diastolic blood pressure, and pulse pressure in the UK Biobank, we estimate that 9.3%, 3.9%, 1.6%, and 12.5%, respectively, of phenotypic variance is explained by GxE interactions and that low-frequency variants explain most of this variance. We also identify three loci that interact with the estimated environmental scores (-log10p>7.3).Innovations in organoid-based models of human tissues have made them an exciting experimental platform for studying development and disease. However, these models require systematic benchmarking against primary tissue to establish their value. We discuss key parameters that impact the utility of organoid models, primarily focusing on cerebral organoids as examples.COVID-19 has unfortunately halted lab work, conferences, and in-person networking, which is especially detrimental to researchers just starting their labs. Through social media and our reviewer networks, we met some early-career stem cell investigators impacted by the closures. Here, they introduce themselves and their research to our readers.Lineage tracing and single-cell sequencing methods have been used independently to profile fate outcomes or molecular phenotypes, respectively. Weinreb et al. (2020) and Pei et al. Gefitinib datasheet (2020) (the latter in this issue of Cell Stem Cell) advance the shared principle that a simultaneous accounting of clonal and transcriptional trajectories provides critical new insights into organization and decision-making in hematopoiesis.In this issue of Cell Stem Cell, An et al. (2020) provide a model to study human X chromosome inactivation. They followed X chromosome activity and traced cellular heterogeneity in naive hESCS, showed that it is caused by incomplete blockade of FGF-signaling, and in doing so isolated cells resembling pre-implantation epiblasts.Large skin wounds in adult mice can heal by regenerating new hair follicles and adipocytes in their center. In this issue of Cell Stem Cell, Abbasi et al. (2020) report how typically scar-forming wound fibroblasts enter a transcriptionally distinct single-cell state of competence during regeneration of new hair follicle mesenchyme.mESCs can self-renew indefinitely in vitro. However, depending on culture conditions some strains are more unstable than others. In this issue of Cell Stem Cell, Skelly et al. (2020) and Ortmann et al. (2020) shed light into the role genetic variation plays in control of ground state pluripotency.Microfabricated and microfluidic devices enable standardized handling, precise spatiotemporal manipulation of cells and liquids, and recapitulation of cellular environments, tissues, and organ-level biology. We asked researchers how these devices can make in vitro experiments more physiologically relevant.Metabolic-associated fatty liver disease (MAFLD) represents a spectrum of disease states ranging from simple steatosis to non-alcoholic steatohepatitis (NASH). Hepatic macrophages, specifically Kupffer cells (KCs), are suggested to play important roles in the pathogenesis of MAFLD through their activation, although the exact roles played by these cells remain unclear. Here, we demonstrated that KCs were reduced in MAFLD being replaced by macrophages originating from the bone marrow. Recruited macrophages existed in two subsets with distinct activation states, either closely resembling homeostatic KCs or lipid-associated macrophages (LAMs) from obese adipose tissue. Hepatic LAMs expressed Osteopontin, a biomarker for patients with NASH, linked with the development of fibrosis. Fitting with this, LAMs were found in regions of the liver with reduced numbers of KCs, characterized by increased Desmin expression. Together, our data highlight considerable heterogeneity within the macrophage pool and suggest a need for more specific macrophage targeting strategies in MAFLD.Mother's milk contains complex microbial communities thought to be important for colonizing a preterm infant's gastrointestinal tract. However, little is known about the microbiota in the preterm mother's milk and factors influencing its composition. We characterized the temporal dynamics of microbial communities in 490 breast milk samples from 86 mothers of preterm infants (born less then 1,250g) over the first 8 weeks postpartum. Highly individualized microbial communities were identified in each mother's milk that changed temporally with notable alterations in predicted microbial functions. However, pre-pregnancy BMI, delivery mode, and antibiotics were associated with changes in these microbial dynamics. Individual classes of antibiotics and their duration of exposure during prenatal and postpartum periods showed unique relationships with microbial taxa abundance and diversity in mother's milk. These results highlight the temporal complexity of the preterm mother's milk microbiota and its relationship with maternal characteristics as well as the importance of discussing antibiotic stewardship for mothers.Planar cell polarity (PCP) organizes the orientation of cellular protrusions and migratory activity within the tissue plane. PCP establishment involves the subcellular polarization of core PCP components. It has been suggested that Wnt gradients could provide a global cue that coordinates local PCP with tissue axes. Here, we dissect the role of Wnt ligands in the orientation of hairs of Drosophila wings, an established system for the study of PCP. We found that PCP was normal in quintuple mutant wings that rely solely on the membrane-tethered Wingless for Wnt signaling, suggesting that a Wnt gradient is not required. We then used a nanobody-based approach to trap Wntless in the endoplasmic reticulum, and hence prevent all Wnt secretion, specifically during the period of PCP establishment. PCP was still established. We conclude that, even though Wnt ligands could contribute to PCP, they are not essential, and another global cue must exist for tissue-wide polarization.

Community randomised trials have had mixed success in implementing combination prevention strategies that diagnose 90% of people living with HIV, initiate and retain on antiretroviral therapy (ART) 90% of those diagnosed, and achieve viral load suppression in 90% of those on ART (90-90-90). The Bukoba Combination Prevention Evaluation (BCPE) aimed to achieve 90-90-90 in Bukoba Municipal Council, Tanzania, by scaling up new HIV testing, linkage, and retention interventions.

We did population-based, cross-sectional surveys before and after our community-wide intervention in Bukoba-a mixed urban and rural council of approximately 150 000 residents located on the western shore of Lake Victoria in Tanzania. BCPE interventions were implemented in 11 government-supported health-care facilities throughout Bukoba from Oct 1, 2014, to March 31, 2017, when national ART-eligibility guidelines expanded from CD4 counts of less than 350 cells per μL (Oct 1, 2014-Dec 31, 2015) and 500 or less cells per μL (Jan 1, 2016-Se AIDS Relief.

Despite the universal use of the two-dose trivalent measles-mumps-rubella (MMR) vaccine in the past two decades, outbreaks of these diseases still occur in countries with high vaccine uptake, giving rise to concerns about primary and secondary failure of MMR vaccine components. We aimed to provide seroconversion and waning rate estimates for the measles, mumps, and rubella components of MMR vaccines.

In this systematic review and meta-analysis we searched PubMed (including MEDLINE), Web of Science, and Embase for randomised controlled trials, cohort studies, or longitudinal studies reporting the immunogenicity and persistence of MMR vaccines, published in English from database inception to Dec 31, 2019. Studies were included if they investigated vaccine-induced immunity in healthy individuals who received a trivalent MMR vaccine, including different dosages and timepoints of vaccine administration. Studies featuring coadministration of MMR with other vaccines, maternal immunity to the MMR vaccine, or non-trivalent formulations of the vaccine were excluded.