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Abstract Microbial communities at the airway mucosal barrier are conserved and highly ordered, in likelihood reflecting co-evolution with human host factors. Freed of selection to digest nutrients, the airway microbiome underpins cognate management of mucosal immunity and pathogen resistance. We show here the initial results of systematic culture and whole-genome sequencing of the thoracic airway bacteria, identifying 52 novel species amongst 126 organisms that constitute 75% of commensals typically present in heathy individuals. Clinically relevant genes encode antimicrobial synthesis, adhesion and biofilm formation, immune modulation, iron utilisation, nitrous oxide (NO) metabolism and sphingolipid signalling. Using whole-genome content we identify dysbiotic features that may influence asthma and chronic obstructive pulmonary disease. We match isolate gene content to transcripts and metabolites expressed late in airway epithelial differentiation, identifying pathways to sustain host interactions with microbiota. Our results provide a systematic basis for decrypting interactions between commensals, pathogens, and mucosa in lung diseases of global significance.

Memory and learning involve activity-driven expression of proteins and cytoskeletal reorganization at new synapses, requiring posttranscriptional regulation of localized mRNA a long distance from corresponding nuclei. A key factor expressed early in synapse formation is Msp300/Nesprin-1, which organizes actin filaments around the new synapse. How Msp300 expression is regulated during synaptic plasticity is poorly understood. Here, we show that activity-dependent accumulation of Msp300 in the postsynaptic compartment of the Drosophila larval neuromuscular junction is regulated by the conserved RNA binding protein Syncrip/hnRNP Q. Syncrip (Syp) binds to msp300 transcripts and is essential for plasticity. Single-molecule imaging shows that msp300 is associated with Syp in vivo and forms ribosome-rich granules that contain the translation factor eIF4E. Elevated neural activity alters the dynamics of Syp and the number of msp300:Syp:eIF4E RNP granules at the synapse, suggesting that these particles facilitate translation. These results introduce Syp as an important early acting activity-dependent regulator of a plasticity gene that is strongly associated with human ataxias.

Plain English Summary Female genital mutilation/cutting (FGM/C) can result in short and long-term complications, which can impact physical, psychological and sexual health. Our objective was to obtain descriptive data about the most frequent health conditions and procedures associated with FGM/C among inpatients with a condition/diagnosis of FGM/C in Swiss university hospitals. We asked the Swiss university hospitals anonymized data of women and girls with a coded FGM/C diagnose who had been admitted between 2016 and 2018. Four of the five Swiss university hospitals provided the primary and secondary diagnoses coded with the International Classification of Diseases (ICD) and the interventions coded in their medical files. Only 207 inpatients had a condition/diagnosis of FGM/C. The majority was admitted either to gynaecology or obstetrics divisions. Some complications of FGM/C are probably not diagnosed. Pregnancy and childbirth represent key moments to care for and counsel a population that might not consult or be identified otherwise.

Abstract Background The real prevalence and incidence of women living with or at risk of female genital mutilation/cutting (FGM/C) is unknown in Switzerland and many parts of Europe, as there are no representative surveys similar to DHS or MICS for European countries. Indirect estimates are commonly used to estimate the number of women with FGM/C in high-income countries, but may not reflect the actual FGM/C prevalence among migrants. Direct measures may provide more accurate estimates that could guide policy- and clinical decision-making. Swiss hospital data may provide a sample of patients that can be used to describe the prevalence of FGM/C in Swiss hospitals. Our study assesses the number of inpatient women and girls in Swiss university hospitals from countries with high FGM/C prevalence, and of inpatients with a coded diagnosis of FGM/C. Methods We conducted an exploratory descriptive study in Switzerland to assess the number of women and girls admitted to Swiss university hospitals between 2016 and 2018 from 30 FGM/C practicing countries, as well as inpatients with a coded diagnosis of FGM/C using anonymized data. We calculated indirect estimates for inpatient women and girls living with or at risk of FGM/C and compared them with the number of inpatients with a coded diagnosis of FGM/C. Results 8720 women and girls from FGM/C practicing countries were admitted. 207 patients had a coded diagnosis of FGM/C, including 7 with a nationality outside the 30 targeted countries, corresponding to an overall prevalence of 2.3% (95%CI, 2.0–2.6). The number of FGM/C cases by hospital was significantly different across years (P

High numbers of COVID-19-related deaths have been reported in the United States, but estimation of the true numbers of infections is challenging. Here, the authors estimate that on 1 June 2020, 3.7% of the US population was infected with SARS-CoV-2, and 0.01% was infectious, with wide variation by state.

In the 11th version of the International Statistical Classification of Diseases and Related Health Problems (ICD-11) there has been a significant change in the placement of gender identity conditions. Gender incongruence will now be reclassified within the chapter «Conditions Relating to Sexual Health». In this paper we suggest that there are a number of potential ethical and clinical problems with this. One problem is that sexual health conditions are often assumed to have psychofunctional aetiology, so the rejected psychiatric classification may reemerge regardless of reclassification. The second problem is that reclassifying gender incongruence as a condition relating to sexual health could lead to a misguided understanding of gender identity as an issue that is necessarily or inherently related to one’s sexuality and subsequently to an imprudent focus on genital incongruence. We suggest that understanding gender incongruence as something relating to one’s sexuality and thus becoming ultimately integral to a person’s sexual health may shape the perception of what is proper medical treatment. To explain how this may happen we, in part, consider the case of intersex conditions and specifically so-called «genital-normalising» surgery. We do not want to compare intersex with gender variance, yet we argue that there is a lesson to be learnt from the way clinical nomenclature may shape the understanding of human diversity and health and disease, and therefore influence the provision of medical care, specifically genital surgery. Using the case of intersex conditions or variations of sex characteristics, pathologised as Disorders of Sex Development, we can further argue that focusing on medical anatomical or functional sexual health prognosis fails to consider gender identity in its entirety. We therefore suggest an alternative chapter entitled «Conditions Relating to Sex and Gender Identity».

Co-production has received increasing attention from managers and researchers in public services. In the health care sector, co-production has become a by-word for the meaningful engagement of patients yet there is still a lack of knowledge around what works when co-producing services. The paper sets out a set of pragmatic principles which may guide anyone embarking on co-producing health care services, and provides an illustration of a co-produced Young People’s Health Research Group in England. We conclude by outlining some learning points which are useful when establishing co-production projects.

During Drosophila and vertebrate brain development, the conserved transcription factor Prospero/Prox1 is an important regulator of the transition between proliferation and differentiation. Prospero level is low in neural stem cells and their immediate progeny, but is upregulated in larval neurons and it is unknown how this process is controlled. Here, we use single molecule fluorescent in situ hybridisation to show that larval neurons selectively transcribe a long prospero mRNA isoform containing a 15 kb 3′ untranslated region, which is bound in the brain by the conserved RNA-binding protein Syncrip/hnRNPQ. Syncrip binding increases the stability of the long prospero mRNA isoform, which allows an upregulation of Prospero protein production. Adult flies selectively lacking the long prospero isoform show abnormal behaviour that could result from impaired locomotor or neurological activity. Our findings highlight a regulatory strategy involving alternative polyadenylation followed by differential post-transcriptional regulation. This article has an associated First Person interview with the first author of the paper.

During vertebrate embryonic development, the formation of axial structures is driven by a population of stem-like cells that reside in a region of the tailbud called the chordoneural hinge (CNH). We have compared the mouse CNH transcriptome with those of surrounding tissues and shown that the CNH and tailbud mesoderm are transcriptionally similar, and distinct from the presomitic mesoderm. Amongst CNH-enriched genes are several that are required for axial elongation, including Wnt3a, Cdx2, Brachyury/T and Fgf8, and androgen/oestrogen receptor nuclear signalling components such as Greb1. We show that the pattern and duration of tailbud Greb1 expression is conserved in mouse, zebrafish and chicken embryos, and that Greb1 is required for axial elongation and somitogenesis in zebrafish embryos. The axial truncation phenotype of Greb1 morphant embryos can be explained by much reduced expression of No tail (Ntl/Brachyury), which is required for axial progenitor maintenance. Posterior segmentation defects in the morphants (including misexpression of genes such as mespb, myoD and papC) appear to result, in part, from lost expression of the segmentation clock gene, her7.

The numerous neurons and glia that form the brain originate from tightly controlled growth and division of neural stem cells, regulated systemically by important known stem cell-extrinsic signals. However, the cell-intrinsic mechanisms that control the distinctive proliferation rates of individual neural stem cells are unknown. Here, we show that the size and division rates of Drosophila neural stem cells (neuroblasts) are controlled by the highly conserved RNA binding protein Imp (IGF2BP), via one of its top binding targets in the brain, myc mRNA. We show that Imp stabilises myc mRNA leading to increased Myc protein levels, larger neuroblasts, and faster division rates. Declining Imp levels throughout development limit myc mRNA stability to restrain neuroblast growth and division, and heterogeneous Imp expression correlates with myc mRNA stability between individual neuroblasts in the brain. We propose that Imp-dependent regulation of myc mRNA stability fine-tunes individual neural stem cell proliferation rates.

Gender care for minors in England has recently been scrutinised by the courts and is currently undergoing significant transformation, shifting away from the long-standing centralised service provision model. Alongside this change, the World Professional Association for Transgender Health has recently published Version 8 of its Standard of Care, which introduces radical changes that shift away from age restrictions on medical interventions. This article considers what role judicial decision-making could, or should, play in this new era of healthcare provision for adolescent gender care, especially since Bell v. Tavistock. Despite Bell seemingly returning decision-making to clinicians, patients, and their families, we argue that the decision has left the door open in a way that threatens the autonomy and rights of gender diverse children. Through a comparative analysis with Australian case law, we demonstrate how and why uncertainties left by Bell may in fact lead to continued court involvement. Finally, we suggest several pragmatic responses that may mitigate the risk of unnecessary and time-consuming court involvement. [ABSTRACT FROM AUTHOR]

One of the many advantages of Drosophila melanogaster as a model organism is the relative ease with which gene deletions can be generated by imprecise excision of transposon insertions. Here, we describe a simple, fast, and efficient method of screening for single-gene excision events that is not biased by prior assumptions of the mutant phenotype. DNA sequence polymorphisms were used as co-dominant electrophoretic markers to identify candidate deletions in a single generation, and to delimit the breakpoints to within 0.5–1 kb, thereby rapidly identifying deficiencies that affect only the gene of interest. In addition, we used polymorphism profiling to map existing deficiencies. The method can also be applied to map the extent of deletions generated by x-rays and to identify targeted mutations generated by engineered zinc-finger nucleases in Drosophila and other polymorphic model organisms (e.g., zebrafish, mouse, Caenorhabditis elegans).

Integrin-linked kinase (ILK) is a highly evolutionarily conserved, multi-domain signaling protein that localizes to focal adhesions, myofilaments and centrosomes where it forms distinct multi-protein complexes to regulate cell adhesion, cell contraction, actin cytoskeletal organization and mitotic spindle assembly. Numerous studies have demonstrated that ILK can regulate the phosphorylation of various protein and peptide substrates in vitro, as well as the phosphorylation of potential substrates and various signaling pathways in cultured cell systems. Nevertheless, the ability of ILK to function as a protein kinase has been questioned because of its atypical kinase domain.Here, we have expressed full-length recombinant ILK, purified it to >94% homogeneity, and characterized its kinase activity. Recombinant ILK readily phosphorylates glycogen synthase kinase-3 (GSK-3) peptide and the 20-kDa regulatory light chains of myosin (LC(20)). Phosphorylation kinetics are similar to those of other active kinases, and mutation of the ATP-binding lysine (K220 within subdomain 2) causes marked reduction in enzymatic activity. We show that ILK is a Mn-dependent kinase (the K(m) for MnATP is approximately 150-fold less than that for MgATP).Taken together, our data demonstrate that ILK is a bona fide protein kinase with enzyme kinetic properties similar to other active protein kinases.

Vertebrate segmentation is regulated by the "segmentation clock", which drives cyclic expression of several genes in the caudal presomitic mesoderm (PSM). One such gene is Lunatic fringe (Lfng), which encodes a modifier of Notch signalling, and which is also expressed in a stripe at the cranial end of the PSM, adjacent to the newly forming somite border. We have investigated the functional requirements for these modes of Lfng expression during somitogenesis by generating mice in which Lfng is expressed in the cranial stripe but strongly reduced in the caudal PSM, and find that requirements for Lfng activity alter during axial growth. Formation of cervical, thoracic and lumbar somites/vertebrae, but not sacral and adjacent tail somites/vertebrae, depends on caudal, cyclic Lfng expression. Indeed, the sacral region segments normally in the complete absence of Lfng and shows a reduced requirement for another oscillating gene, Hes7, indicating that the architecture of the clock alters as segmentation progresses. We present evidence that Lfng controls dorsal-ventral axis specification in the tail, and also suggest that Lfng controls the expression or activity of a long-range signal that regulates axial extension.