The rockefeller university

This cross-sectional survey characterizes the knowledge, attitudes, and practices of international experts in the management of pain in patients with hidradenitis suppurativa.

We recognize sounds by analyzing their frequency content. Different frequency components evoke distinct mechanical waves that each travel within the hearing organ, or cochlea, to a frequency-specific place. These signals are detected by hair cells, the ear's sensory receptors, in response to vibrations of mechanically sensitive antennas termed hair bundles. An active process enhances the sensitivity, sharpens the frequency tuning, and broadens the dynamic range of hair cells through several mechanisms, including active hair-bundle motility. A dynamic interplay between negative stiffness mediated by ion channels' gating forces and delayed force feedback owing to myosin motors and channel reclosure by calcium ions brings the hair bundle to the vicinity of an oscillatory instability-a Hopf bifurcation. Operation near a Hopf bifurcation provides nonlinear generic features that are characteristic of hearing. Multiple gradients at molecular, cellular, and supercellular scales tune hair cells to characteristic frequencies that cover our auditory range.

Genetic variants underlying life-threatening diseases, being unlikely to be transmitted to the next generation, are gradually and selectively eliminated from the population through negative selection. We study the determinants of this evolutionary process in human genes underlying monogenic diseases by comparing various negative selection scores and an integrative approach, CoNeS, at 366 loci underlying inborn errors of immunity (IEI). We find that genes underlying autosomal dominant (AD) or X-linked IEI have stronger negative selection scores than those underlying autosomal recessive (AR) IEI, whose scores are not different from those of genes not known to be disease causing. Nevertheless, genes underlying AR IEI that are lethal before reproductive maturity with complete penetrance have stronger negative selection scores than other genes underlying AR IEI. We also show that genes underlying AD IEI by loss of function have stronger negative selection scores than genes underlying AD IEI by gain of function, while genes underlying AD IEI by haploinsufficiency are under stronger negative selection than other genes underlying AD IEI. These results are replicated in 1,140 genes underlying inborn errors of neurodevelopment. Finally, we propose a supervised classifier, SCoNeS, which predicts better than state-of-the-art approaches whether a gene is more likely to underlie an AD or AR disease. The clinical outcomes of monogenic inborn errors, together with their mode and mechanisms of inheritance, determine the levels of negative selection at their corresponding loci. Integrating scores of negative selection may facilitate the prioritization of candidate genes and variants in patients suspected to carry an inborn error.

Retrospective analysis of F-18-FDG PET/CT scans from over 50,000 patients reveals correlations between presence of brown adipose tissue and lower odds of having cardiometabolic conditions, such as type 2 diabetes, cardiovascular disease and hypertension. White fat stores excess energy, whereas brown and beige fat are thermogenic and dissipate energy as heat. Thermogenic adipose tissues markedly improve glucose and lipid homeostasis in mouse models, although the extent to which brown adipose tissue (BAT) influences metabolic and cardiovascular disease in humans is unclear(1,2). Here we retrospectively categorized 134,529 F-18-fluorodeoxyglucose positron emission tomography-computed tomography scans from 52,487 patients, by presence or absence of BAT, and used propensity score matching to assemble a study cohort. Scans in the study population were initially conducted for indications related to cancer diagnosis, treatment or surveillance, without previous stimulation. We report that individuals with BAT had lower prevalences of cardiometabolic diseases, and the presence of BAT was independently correlated with lower odds of type 2 diabetes, dyslipidemia, coronary artery disease, cerebrovascular disease, congestive heart failure and hypertension. These findings were supported by improved blood glucose, triglyceride and high-density lipoprotein values. The beneficial effects of BAT were more pronounced in individuals with overweight or obesity, indicating that BAT might play a role in mitigating the deleterious effects of obesity. Taken together, our findings highlight a potential role for BAT in promoting cardiometabolic health.

Environmental DNA (eDNA) technology potentially improves the monitoring of marine fish populations. Realizing this promise awaits better understanding of how eDNA relates to fish presence and abundance. Here, we evaluate performance by comparing bottom trawl catches to eDNA from concurrent water samples. In conjunction with New Jersey Ocean Trawl Survey, 1-I water samples were collected at surface and depth prior to tows at about one-fourth of Survey sites in January, June, August, and November 2019. eDNA fish diversity from 1 I was same as or higher than trawl fish diversity from 66 M litres swept by one tow. Most (70-87%) species detected by trawl in a given month were also detected by eDNA, and vice versa, including nearly all (92-100%) abundant species. Trawl and eDNA peak seasonal abundance agreed for similar to J70% of fish species. In log-scale comparisons by month, eDNA species reads correlated with species biomass, and more strongly with an allometric index calculated from biomass. In this 1-year study, eDNA reporting largely concorded with monthly trawl estimates of marine fish species richness, composition, seasonality, and relative abundance. Piggybacking eDNA onto an existing survey provided a relatively low-cost approach to better understand eDNA for marine fish stock assessment.

Eukaryotic transfer RNAs can become selectively fragmented upon various stresses, generating tRNA-derived small RNA fragments. Such fragmentation has been reported to impact a small fraction of the tRNA pool and thus presumed to not directly impact translation. We report that oxidative stress can rapidly generate tyrosine-tRNA(GUA) fragments in human cells-causing significant depletion of the precursor tRNA. Tyrosine-tRNA(GUA) depletion impaired translation of growth and metabolic genes enriched in cognate tyrosine codons. Depletion of tyrosine tRNA(GUA) or its translationally regulated targets USP3 and SCD repressed proliferation-revealing a dedicated tRNA-regulated growth-suppressive pathway for oxidative stress response. Tyrosine fragments are generated in a DIS3L2 exoribonuclease-dependent manner and inhibit hnRNPA1-mediated transcript destabilization. Moreover, tyrosine fragmentation is conserved in C. elegans. Thus, tRNA fragmentation can coordinately generate trans-acting small RNAs and functionally deplete a tRNA. Our findings reveal the existence of an underlying adaptive codon-based regulatory response inherent to the genetic code.

The delayed behavioral response to chronic antidepressants depends on dynamic changes in the hippocampus. It was suggested that the antidepressant protein p11 and the chromatin remodeling factor SMARCA3 mediate this delayed response by inducing transcriptional changes in hippocampal neurons. However, what target genes are regulated by the p11/SMARCA3 complex to mediate the behavioral response to antidepressants, and what cell type mediates these molecular changes remain unknown. Here we report that the p11/SMARCA3 complex represses Neurensin-2 transcription in hippocampal parvalbumin-expressing interneurons after chronic treatment with Selective Serotonin Reuptake Inhibitors (SSRI). The behavioral response to antidepressants requires upregulation of p11, accumulation of SMARCA3 in the cell nucleus, and a consequent repression of Neurensin-2 transcription in these interneurons. We elucidate a functional role for p11/SMARCA3/Neurensin-2 pathway in regulating AMPA-receptor signaling in parvalbumin-expressing interneurons, a function that is enhanced by chronic treatment with SSRIs. These results link SSRIs to dynamic glutamatergic changes and implicate p11/SMARCA3/Neurensin-2 pathway in the development of more specific and efficient therapeutic strategies for neuropsychiatric disorders.

Mesenteric lymph node (mLN) T cells undergo tissue adaptation upon migrating to intestinal lamina propria and epithelium, ensuring appropriate balance between tolerance and resistance. By combining mouse genetics with single-cell and chromatin analyses, we uncovered the molecular imprinting of gut epithelium on T cells. Transcriptionally, conventional and regulatory (T-reg) CD4(+) T cells from mLN, lamina propria and intestinal epithelium segregate based on the gut layer they occupy; trajectory analysis suggests a stepwise loss of CD4 programming and acquisition of an intraepithelial profile. T-reg cell fate mapping coupled with RNA sequencing and assay for transposase-accessible chromatin followed by sequencing revealed that the T-reg cell program shuts down before an intraepithelial program becomes fully accessible at the epithelium. Ablation of CD4-lineage-defining transcription factor ThPOK results in premature acquisition of an intraepithelial lymphocyte profile by mLN T-reg cells, partially recapitulating epithelium imprinting. Thus, coordinated replacement of the circulating lymphocyte program with site-specific transcriptional and chromatin changes is necessary for tissue imprinting. Mucida and colleagues examine how the gut epithelial microenvironment alters CD4(+) T cells during their conversion into intraepithelial lymphocytes. They reveal a stepwise process involving chromatin accessibility and transcription changes triggered by ThPOK downregulation.

Hidradenitis suppurativa is a chronic inflammatory disease that disproportionately affects women of childbearing age. Hidradenitis suppurativa is characterized by painful nodules, abscesses, draining dermal tunnels, and scarring with a predilection for intertriginous sites, such as the axilla, groin, and breast regions. Delay in diagnosis and treatment of hidradenitis suppurativa often results in long-term sequelae leading to significant morbidity, and rarely mortality, in these patients. This clinical opinion suggests that obstetrician-gynecologists are uniquely poised to recognize early signs of hidradenitis suppurativa during routine well-woman examinations and initiate treatment or referral to dermatology. Herein, we provide clinical pearls for obstetrician-gynecologists caring for female patients with hidradenitis suppurativa, including strategies for comprehensive management and recommendations to improve the comfort of patients with hidradenitis suppurativa during examinations.

Mechanisms for fish social behaviours involve a social brain network (SBN) which is evolutionarily conserved among vertebrates. However, considerable diversity is observed in the actual behaviour patterns amongst nearly 30000 fish species. The huge variation found in socio-sexual behaviours and strategies is likely generated by a morphologically and genetically well-conserved small forebrain system. Hence, teleost fish provide a useful model to study the fundamental mechanisms underlying social brain functions. Herein we review the foundations underlying fish social behaviours including sensory, hormonal, molecular and neuroanatomical features. Gonadotropin-releasing hormone neurons clearly play important roles, but the participation of vasotocin and isotocin is also highlighted. Genetic investigations of developing fish brain have revealed the molecular complexity of neural development of the SBN. In addition to straightforward social behaviours such as sex and aggression, new experiments have revealed higher order and unique phenomena such as social eavesdropping and social buffering in fish. Finally, observations interpreted as 'collective cognition' in fish can likely be explained by careful observation of sensory determinants and analyses using the dynamics of quantitative scaling. Understanding of the functions of the SBN in fish provide clues for understanding the origin and evolution of higher social functions in vertebrates.