The rockefeller university

Candidiasis is characterized by susceptibility to recurrent or persistent infections caused by Candida spp., typically Candida albicans, of cutaneous and mucosal surfaces. In this report, function and frequency of Th17 cells as well as genetics of patients susceptible to mucocutaneous candidiasis were studied. For patients, T-cell proliferation tests in response to Candida antigen, Th17 cell proportions, and STAT1 phosphorylation were evaluated through flow cytometry. Expression of IL17A, IL17F and IL22 genes were measured by real-time quantitative PCR. At the same time, whole exome sequencing was performed for all patients. We identified two heterozygous substitutions, one: c.821G > A (p. R274Q) was found in a multiplex family with three individuals affected, the second one: c.812A > C (p. Q271P) was found in a sporadic case. Both mutations are located in the coiled-coil domain (CCD) of STAT1. The frequency of Th17 cells, IL17A, IL17F, and IL22 gene expression in patients' peripheral blood mononuclear cells (PBMCs), and T-cell proliferation to Candida antigens were significantly reduced in the patients as compared to healthy controls. An increased STAT1 phosphorylation was observed in patients' PBMCs upon interferon (IFN)-gamma stimulation as compared to healthy controls. We report two different but neighboring heterozygous mutations, located in exon 10 of the STAT1 gene, in four Iranian patients with CMC, one of whom also had hypothyroidism. These mutations were associated with impaired T cell proliferation to Candida antigen, low Th17 cell proportions, and increased STAT1 phosphorylation upon IFN-gamma. We suggest that interfering with STAT1 phosphorylation might be a promising way for potential therapeutic measurements for such patients.

Mechanosensitive channels sense mechanical forces in cell membranes and underlie many biological sensing processes(1-3). However, how exactly they sense mechanical force remains under investigation(4). The bacterial mechanosensitive channel of small conductance, MscS, is one of the most extensively studied mechanosensitive channels(4-8), but how it is regulated by membrane tension remains unclear, even though the structures are known for its open and closed states(9-11). Here we used cryo-electron microscopy to determine the structure of MscS in different membrane environments, including one that mimics a membrane under tension. We present the structures of MscS in the subconducting and desensitized states, and demonstrate that the conformation of MscS in a lipid bilayer in the open state is dynamic. Several associated lipids have distinct roles in MscS mechanosensation. Pore lipids are necessary to prevent ion conduction in the closed state. Gatekeeper lipids stabilize the closed conformation and dissociate with membrane tension, allowing the channel to open. Pocket lipids in a solvent-exposed pocket between subunits are pulled out under sustained tension, allowing the channel to transition to the subconducting state and then to the desensitized state. Our results provide a mechanistic underpinning and expand on the 'force-from-lipids' model for MscS mechanosensation(4,11). The authors report the structural characterization of the mechanically activated channel MscS in different membrane environments and show how the mechanosensation of MscS can be visualized.

Exposures to adverse environments, both psychosocial and physicochemical, are prevalent and consequential across a broad range of childhood populations. Such adversity, especially early in life, conveys measurable risk to learning and behavior and to the foundations of both mental and physical health. Using an interactive gene-environment-time (GET) framework, we survey the independent and interactive roles of genetic variation, environmental context, and developmental timing in light of advances in the biology of adversity and resilience, as well as new discoveries in biomedical research. Drawing on this rich evidence base, we identify 4 core concepts that provide a powerful catalyst for fresh thinking about primary health care for young children: (1) all biological systems are inextricably integrated, continuously "reading" and adapting to the environment and "talking back" to the brain and each other through highly regulated channels of cross-system communication; (2) adverse environmental exposures induce alterations in developmental trajectories that can lead to persistent disruptions of organ function and structure; (3) children vary in their sensitivity to context, and this variation is influenced by interactions among genetic factors, family and community environments, and developmental timing; and (4) critical or sensitive periods provide unmatched windows of opportunity for both positive and negative influences on multiple biological systems. These rapidly moving frontiers of investigation provide a powerful framework for new, science-informed thinking about health promotion and disease prevention in the early childhood period. Advances in biology provide a platform for fresh thinking about health promotion and disease prevention in the early childhood period.

Astrocytes are a large and diverse population of morphologically complex cells that exist throughout nervous systems of multiple species. Progress over the last two decades has shown that astrocytes mediate developmental, physiological, and pathological processes. However, a long-standing open question is how astrocytes regulate neural circuits in ways that are behaviorally consequential. In this regard, we summarize recent studies using Caenorhabditis elegans, Drosophila melanogaster, Danio rerio, and Mus musculus. The data reveal diverse astrocyte mechanisms operating in seconds or much longer timescales within neural circuits and shaping multiple behavioral outputs. We also refer to human diseases that have a known primary astrocytic basis. We suggest that including astrocytes in mechanistic, theoretical, and computational studies of neural circuits provides new perspectives to understand behavior, its regulation, and its disease-related Astrocytes are a large and diverse population of morphologically complex cells that exist throughout nervous systems of multiple species. Progress over the last two decades has shown that astrocytes mediate developmental, physiological, and pathological processes. However, a long-standing open question is how astrocytes regulate neural circuits in ways that are behaviorally consequential. In this regard, we summarize recent studies using Caenorhabditis elegans, Drosophila melanogaster, Danio rerio, and Mus musculus. The data reveal diverse astrocyte mechanisms operating in seconds or much longer timescales within neural circuits and shaping multiple behavioral outputs. We also refer to human diseases that have a known primary astrocytic basis. We suggest that including astrocytes in mechanistic, theoretical, and computational studies of neural circuits provides new perspectives to understand behavior, its regulation, and its disease-related manifestations.

In humans, copy number variations in CYFIP1 appear to have sweeping physiological and structural consequences in the brain, either producing or altering the severity of intellectual disability, autism, and schizophrenia. Independently, SynGAP1 haploinsufficiency produces intellectual disability and, frequently, autism. Cyfip1 inhibits protein translation and promotes actin polymerization, and SynGAP1 is a synaptically localized Ras/Rap GAP. While these proteins are clearly distinct, studies investigating their functions in mice have shown that each regulates the maturation of synapses in the hippocampus and haploinsufficiency for either produces an exaggerated form of mGluR-dependent long-term depression, suggesting that some signaling pathways converge. In this study, we examined how Cyfip1 haploinsufficiency impacts SynGAP1 levels and localization, as well as potential sites for mechanistic interaction in mouse hippocampus. The data show that synaptic, but not total, levels of SynGAP1 in Cyfip1(+/-) mice were abnormally low during early postnatal development and in adults. This may be in response to a shift in the balance of kinases that activate SynGAP1 as levels of Cdk5 were reduced and those of activated CaMKII were maintained in Cyfip1(+/-) mice compared to wild-type mice. Alternatively, this could reflect altered actin dynamics as Rac1 activity in Cyfip1(+/-) hippocampus was boosted significantly compared to wild-type mice, and levels of synaptic F-actin were generally enhanced due in part to an increase in the activity of the WAVE regulatory complex. Decreased synaptic SynGAP1 coupled with a CaMKII-mediated bias toward Rap1 inactivation at synapses is also consistent with increased levels of synaptic GluA2, increased AMPA receptor-mediated responses to stimulation, and increased levels of synaptic mGluR1/5 compared to wild-type mice. Collectively, our data suggest that Cyfip1 regulates SynGAP1 and the two proteins work coordinately at synapses to appropriately direct actin polymerization and GAP activity.

Interoceptive signals from gut and adipose tissue and sensory cues from the environment are integrated by hubs in the brain to regulate feeding behavior and maintain homeostatic control of body weight. In vivo neural recordings have revealed that these signals control the activity of multiple layers of hunger neurons and eating is not only the result of feedback correction to a set point, but can also be under the influence of anticipatory regulations. A series of recent technical developments have revealed how peripheral and sensory signals, in particular, from the gut are conveyed to the brain to integrate neural circuits. Here, we describe the mechanisms involved in gastrointestinal stimulation by nutrients and how these signals act on the hindbrain to generate motivated behaviors. We also consider the organization of multidirectional intra- and extrahypothalamic circuits and how this has created a framework for understanding neural control of feeding.

This systematic review identifies and critically evaluates the mechanistic and clinical evidence of new promising therapeutic targets in hidradenitis suppurativa (HS). Evidence for these targets is largely based on observational data with limited ex vivo and translational data from clinical trials. A number of placebo-controlled studies have been completed or are underway utilizing IL-1, IL-23, IL-17, complement, and Jak inhibition, although there is concern regarding elevated placebo response rates and the questionable validity of clinical scores in some participant subsets. Knowledge gaps are identified suggesting a direction for future mechanistic studies in HS, including more comprehensive inflammatory endotype profiling of disease.

Serotonylation of glutamine 5 on histone H3 (H3Q5ser) was recently identified as a permissive posttranslational modification that coexists with adjacent lysine 4 trimethylation (H3K4me3). While the resulting dual modification, H3K4me3Q5ser, is enriched at regions of active gene expression in serotonergic neurons, the molecular outcome underlying H3K4me3-H3Q5ser crosstalk remains largely unexplored. Herein, we examine the impact of H3Q5ser on the readers, writers, and erasers of H3K4me3. All tested H3K4me3 readers retain binding to the H3K4me3Q5ser dual modification. Of note, the PHD finger of TAF3 favors H3K4me3Q5ser, and this binding preference is dependent on the Q5ser modification regardless of H3K4 methylation states. While the activity of the H3K4 methyltransferase, MLL1, is unaffected by H3Q5ser, the corresponding H3K4me3/2 erasers, KDM5B/C and LSD1, are profoundly inhibited by the presence of the mark. Collectively, this work suggests that adjacent H3Q5ser potentiates H3K4me3 function by either stabilizing H3K4me3 from dynamic turnover or enhancing its physical readout by downstream effectors, thereby potentially providing a mechanism for fine-tuning critical gene expression programs.

The ATP-binding cassette (ABC) transporter family contains thousands of members with diverse functions. Movement of the substrate, powered by ATP hydrolysis, can be outward (export) or inward (import). ABCA4 is a eukaryotic importer transporting retinal to the cytosol to enter the visual cycle. It also removes toxic retinoids from the disc lumen. Mutations in ABCA4 cause impaired vision or blindness. Despite decades of clinical, biochemical, and animal model studies, the molecular mechanism of ABCA4 is unknown. Here, we report the structures of human ABCA4 in two conformations. In the absence of ATP, ABCA4 adopts an outward-facing conformation, poised to recruit substrate. The presence of ATP induces large conformational changes that could lead to substrate release. These structures provide a molecular basis to understand many disease-causing mutations and a rational guide for new experiments to uncover how ABCA4 recruits, flips, and releases retinoids.

While beige adipocytes have been found to associate with dense sympathetic neurites in mouse inguinal subcutaneous white fat (iWAT), little is known about when and how this patterning is established. Here, we applied whole-tissue imaging to examine the development of sympathetic innervation in iWAT. We found that parenchymal neurites actively grow between postnatal day 6 (P6) and P28, overlapping with early postnatal beige adipogenesis. Constitutive deletion of Prdm16 in adipocytes led to a significant reduction in early postnatal beige adipocytes and sympathetic density within this window. Using an inducible, adipocyte-specific Prdm16 knockout model, we found that Prdm16 is required for guiding sympathetic growth during early development. Deleting Prdm16 in adult animals, however, did not affect sympathetic structure in iWAT. Together, these findings highlight that beige adipocyte-sympathetic neurite communication is crucial to establish sympathetic structure during the early postnatal period but may be dispensable for its maintenance in mature animals.