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Human prenatal skin is populated by innate immune cells, including macrophages, but whether they act solely in immunity or have additional functions in morphogenesis is unclear. Here we assembled a comprehensive multi-omics reference atlas of prenatal human skin (7–17 post-conception weeks), combining single-cell and spatial transcriptomics data, to characterize the microanatomical tissue niches of the skin. This atlas revealed that crosstalk between non-immune and immune cells underpins the formation of hair follicles, is implicated in scarless wound healing and is crucial for skin angiogenesis. We systematically compared a hair-bearing skin organoid (SkO) model derived from human embryonic stem cells and induced pluripotent stem cells to prenatal and adult skin 1 . The SkO model closely recapitulated in vivo skin epidermal and dermal cell types during hair follicle development and expression of genes implicated in the pathogenesis of genetic hair and skin disorders. However, the SkO model lacked immune cells and had markedly reduced endothelial cell heterogeneity and quantity. Our in vivo prenatal skin cell atlas indicated that macrophages and macrophage-derived growth factors have a role in driving endothelial development. Indeed, vascular network remodelling was enhanced following transfer of autologous macrophages derived from induced pluripotent stem cells into SkO cultures. Innate immune cells are therefore key players in skin morphogenesis beyond their conventional role in immunity, a function they achieve through crosstalk with non-immune cells. A comprehensive multi-omics reference atlas of prenatal human skin shows that innate immune cells crosstalk with non-immune cells to perform pivotal roles in skin morphogenesis, including the formation of hair follicles.

Herbicides are a valuable tool in agricultural ecosystems to manage nuisance species. Due to the reliance on herbicides for weed control, herbicide resistance is a growing concern. Herbicides are also used extensively in aquatic and natural systems, but the genetics and evolutionary dynamics of resistance are not as frequently incorporated into management plans in these systems. In Eurasian watermilfoil, a widespread and heavily managed invasive aquatic weed in the United States, clonal lineages have been characterized as resistant to fluridone, a commonly used phytoene desaturase (PDS)‐inhibitor herbicide. In order to locate genomic loci associated with herbicide resistance, we created an F2 mapping population segregating for fluridone resistance. Using this population, we examined the pds gene for amino acid alterations in resistant individuals and performed bulk segregant analysis between the highly resistant and susceptible F2 individuals. Additionally, we compared pds gene expression between resistant and susceptible strains in control and treated environments using RT‐qPCR. We found no evidence of amino acid alterations to the pds gene in fluridone resistant individuals or increased pds expression in the resistant strain, either in the presence or absence of fluridone. Our QTL mapping identified a putative QTL on chromosome seven, while the gene encoding fluridone's target molecule, phytoene desaturase (PDS) is located on chromosomes 10–12. Our results indicate that fluridone resistance in the Eurasian watermilfoil strain isolated from Lake Lansing, MI, is due to at least one non‐target site mechanism. Characterizing mechanisms of herbicide resistance within invasive plants enables effective and thoughtful herbicide usage, as well as the development of diagnostic biomarkers for resistance in unknown populations.

The World Health Organization has identified excessive COVID-19 pandemic–related information as a public health crisis, calling it an “infodemic.” Social media allows misinformation to spread quickly and outcompete scientifically grounded information delivered via other methods. Dear Pandemic is an innovative, multidisciplinary, social media–based science communication project whose mission is to educate and empower individuals to successfully navigate the overwhelming amount of information circulating during the pandemic. This mission has 2 primary objectives: (1) to disseminate trustworthy, comprehensive, and timely scientific content about the pandemic to lay audiences via social media and (2) to promote media literacy and information-hygiene practices, equipping readers to better manage the COVID-19 infodemic within their own networks. The volunteer team of scientists publishes 8-16 posts per week on pandemic-relevant topics. Nearly 2 years after it launched in March 2020, the project has a combined monthly reach of more than 4 million unique views across 4 social media channels, an email newsletter, and a website. We describe the project’s guiding principles, lessons learned, challenges, and opportunities. Dear Pandemic has emerged as an example of a promising new paradigm for public health communication and intervention. The contributors deliver content in ways that are personal, practical, actionable, responsive, and native to social media platforms. The project’s guiding principles are a model for public health communication targeting future infodemics and can bridge the chasm between the scientific community and the practical daily decision-making needs of the general public.

ABSTRACTBackgroundObesity is a complex, chronic, stigmatized disease whereby abnormal or excess body fat may impair health or increase the risk of medical complications, and can reduce quality of life and shorten lifespan in children and families. We developed this guideline to provide evidence-based recommendations on options for managing pediatric obesity that support shared decision-making among children living with obesity, their families, and their health care providers. MethodsWe followed the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. We used the Guidelines International Network principles to manage competing interests. Caregivers, health care providers, and people living with obesity participated throughout the guideline development process, which optimized relevance. We surveyed end users (caregivers, health care providers) to prioritize health outcomes, completed 3 scoping reviews (2 on minimal important difference estimates; 1 on clinical assessment), performed 1 systematic review to characterize families’ values and preferences, and conducted 3 systematic reviews and meta-analyses to examine the benefits and harms of behavioural and psychological, pharmacologic, and surgical interventions for managing obesity in children. Guideline panellists developed recommendations focused on an individualized approach to care by using the GRADE evidence-to-decision framework, incorporating values and preferences of children living with obesity and their caregivers. RecommendationsOur guideline includes 10 recommendations and 9 good practice statements for managing obesity in children. Managing pediatric obesity should be guided by a comprehensive child and family assessment based on our good practice statements. Behavioural and psychological interventions, particularly multicomponent interventions (strong recommendation, very low to moderate certainty), should form the foundation of care, with tailored therapy and support using shared decision-making based on the potential benefits, harms, certainty of evidence, and values and preferences of children and families. Pharmacologic and surgical interventions should be considered (conditional recommendation, low to moderate certainty) as therapeutic options based on availability, feasibility, and acceptability, and guided by shared decision-making between health care providers and families. InterpretationThis guideline will support children, families, and health care providers to have informed discussions about the balance of benefits and harms for available obesity management interventions to support value- and preference-sensitive decision-making.

The interferon-inducible transmembrane (IFITM) family of proteins has been shown to restrict a broad range of viruses in vitro and in vivo by halting progress through the late endosomal pathway. Further, single nucleotide polymorphisms (SNPs) in its sequence have been linked with risk of developing severe influenza virus infections in humans. The number of viruses restricted by this host protein has continued to grow since it was first demonstrated as playing an antiviral role; all of which enter cells via the endosomal pathway. We therefore sought to test the limits of antimicrobial restriction by Ifitm3 using a knockout mouse model. We showed that Ifitm3 does not impact on the restriction or pathogenesis of bacterial (Salmonella typhimurium, Citrobacter rodentium, Mycobacterium tuberculosis) or protozoan (Plasmodium berghei) pathogens, despite in vitro evidence. However, Ifitm3 is capable of restricting respiratory syncytial virus (RSV) in vivo either through directly restricting RSV cell infection, or by exerting a previously uncharacterised function controlling disease pathogenesis. This represents the first demonstration of a virus that enters directly through the plasma membrane, without the need for the endosomal pathway, being restricted by the IFITM family; therefore further defining the role of these antiviral proteins.

Hyperhaploid clones (24–34 chromosomes) were identified in 33 patients with multiple myeloma (MM), demonstrating a novel numerical cytogenetic subgroup. Strikingly, all hyperhaploid karyotypes were found to harbor monosomy 17p, the single most important risk stratification lesion in MM. A catastrophic loss of nearly a haploid set of chromosomes results in disomies of chromosomes 3, 5, 7, 9, 11, 15, 18, 19 and 21, the same basic set of odd-numbered chromosomes found in trisomy in hyperdiploid myeloma. All other autosomes are found in monosomy, resulting in additional clinically relevant monosomies of 1p, 6q, 13q and 16q. Hypotriploid subclones (58–68 chromosomes) were also identified in 11 of the 33 patients and represent a duplication of the hyperhaploid clone. Analysis of clones utilizing interphase fluorescence in situ hybridization (iFISH), metaphase FISH and spectral karyotyping identified either monosomy 17 or del17p in all patients. Amplification of 1q21 was identified in eight patients, demonstrating an additional high-risk marker. Importantly, our findings indicate that current iFISH strategies may be uninformative or ambiguous in the detection of these clones, suggesting this patient subgroup maybe underreported. Overall survival for patients with hyperhaploid clones was poor, with a 5-year survival rate of 23.1%. These findings identify a distinct numerical subgroup with cytogenetically defined high-risk disease.

Panton-Valentine leukocidin (PVL) is a pore-forming toxin secreted by Staphylococcus aureus strains that cause severe infections. Bicomponent PVL kills phagocytes depending on cell surface receptors, such as complement 5a receptor 1 (C5aR1). How the PVL-receptor interaction enables assembly of the leukocidin complex, targeting of membranes, and insertion of a pore channel remains incompletely understood. Here, we demonstrate that PVL binds the anionic phospholipids, phosphatidic acid, and cardiolipin, under acidic conditions and targets lipid bilayers that mimic lysosomal and mitochondrial membranes, but not the plasma membrane. The PVL–lipid interaction was sufficient to enable leukocidin complex formation as determined by neutron reflectometry and the rupture of model membranes, independent of protein receptors. In phagocytes, PVL and its C5aR1 receptor were internalized depending on sphingomyelin and cholesterol, which were dispensable for the interaction of the toxin with the plasma membrane. Internalized PVL compromised the integrity of lysosomes and mitochondria before plasma membrane rupture. Preventing the acidification of organelles or the genetic loss of PVL impaired the escape of intracellular S. aureus from macrophages. Together, the findings advance our understanding of how an S. aureus toxin kills host cells and provide key insights into how leukocidins target membranes.

Technology is transforming societies worldwide. A major innovation is the emergence of robotics and autonomous systems (RAS), which have the potential to revolutionize cities for both people and nature. Nonetheless, the opportunities and challenges associated with RAS for urban ecosystems have yet to be considered systematically. Here, we report the findings of an online horizon scan involving 170 expert participants from 35 countries. We conclude that RAS are likely to transform land use, transport systems and human–nature interactions. The prioritized opportunities were primarily centred on the deployment of RAS for the monitoring and management of biodiversity and ecosystems. Fewer challenges were prioritized. Those that were emphasized concerns surrounding waste from unrecovered RAS, and the quality and interpretation of RAS-collected data. Although the future impacts of RAS for urban ecosystems are difficult to predict, examining potentially important developments early is essential if we are to avoid detrimental consequences but fully realize the benefits. The future challenges and potential opportunities of robotics and autonomous systems in urban ecosystems, and how they may impact biodiversity, are explored and prioritized via a global horizon scan of 170 experts.

Renal allograft recipients generally need to take several immunosuppressive agents for life. Calcineurin inhibitors and glucocorticosteroids are the mainstays of most regimens but have undesirable chronic effects. We postulated that aggressive T-cell depletion combined with the newer immunosuppressant sirolimus would permit transplantation without multidrug treatment. We therefore tested T-cell depletion with rabbit antithymocyte globulin followed by sirolimus monotherapy in 12 patients in an open-label study. This approach was tolerated well, and all patients achieved excellent renal function, and most did not need chronic steroid treatment or calcineurin inhibitors. Rejection was typically correlated with low concentrations of sirolimus, indicating continued dependence on maintenance immunosuppression.

L’obésité est une maladie chronique complexe et stigmatisante caractérisée par une accumulation anormale ou excessive de graisse corporelle susceptible de nuire à la santé, d’accroître le risque de complications médicales et de réduire l’espérance de vie des enfants, leur qualité de vie ainsi que celle de leur famille. Ce guide de pratique clinique a donc été élaboré afin de proposer des recommandations fondées sur des données probantes quant aux options de prise en charge de l’obésité pédiatrique et ce, afin de soutenir une prise de décision partagée entre les enfants concernés, leur famille et les professionnels de la santé. Nous avons utilisé le système GRADE (Grading of Recommendations, Assessment, Development and Evaluation) d’évaluation des données probantes pour l’élaboration et la classification des recommandations. Nous avons également appliqué les principes du Guidelines International Network pour gérer les conflits d’intérêts. Pour optimiser la pertinence et l’applicabilité des recommandations, des parents/tutrices ou tuteurs, des prestataires de soins de santé et des personnes vivant avec l’obésité ont été impliqués tout au long du processus d’élaboration du guide de pratique clinique. Nous avons réalisé un sondage auprès d’utilisatrices et d’utilisateurs primaires (parents/tutrices ou tuteurs et prestataires de soins de santé) pour hiérarchiser les indicateurs de santé. Nous avons effectué 3 études de portée (2 sur les estimations des différences minimales importantes et 1 sur l’évaluation clinique). Nous avons réalisé 1 revue systématique pour caractériser les valeurs et les préférences des familles. Nous avons effectué 3 revues systématiques et méta-analyses pour examiner les effets bénéfiques et indésirables des interventions comportementales et psychologiques, pharmacologiques et chirurgicales dans la prise en charge de l’obésité chez les enfants. Les membres du panel ont formulé des recommandations axées sur une approche individualisée des soins, en utilisant le système GRADE pour la prise de décision fondée sur les données probantes. Ils ont aussi tenu compte des valeurs et des préférences des enfants vivant avec l’obésité et de leur famille. Notre guide de pratique clinique comporte 10 recommandations et 9 énoncés de bonnes pratiques pour la prise en charge de l’obésité chez l’enfant. La prise en charge de l’obésité pédiatrique doit être guidée par une évaluation exhaustive de l’enfant et de sa famille, en fonction de nos énoncés de bonnes pratiques. Les interventions comportementales et psychologiques, et en particulier les interventions multimodales (forte recommandation, certitude très faible à modérée), doivent constituer la base des soins, avec des traitements et du soutien sur mesure sélectionnés de manière conjointe en fonction des effets bénéfiques et indésirables potentiels, du degré de certitude à l’égard des données probantes et des valeurs et préférences de l’enfant et de sa famille. Les interventions pharmacologiques et chirurgicales doivent être considérées (recommandation conditionnelle, certitude faible à modérée) comme des options thérapeutiques selon leur accessibilité, faisabilité et acceptabilité, et guidées par une prise de décision partagée entre les prestataires de soins de santé et les familles. Ce guide de pratique clinique aidera les enfants, les familles et les professionnels de la santé à avoir des discussions éclairées sur l’équilibre entre les bénéfices et les risques des interventions disponibles pour la prise en charge de l’obésité, afin de soutenir une prise de décision fondée sur les valeurs et les préférences des enfants et leur famille.