The rockefeller university

Habitat transitions have shaped the evolutionary trajectory of many clades. Sea catfishes (Ariidae) have repeatedly undergone ecological transitions, including colonizing freshwaters from marine environments, leading to an adaptive radiation in Australia and New Guinea alongside non-radiating freshwater lineages elsewhere. Here, we generate and analyze one long-read reference genome and 66 short-read whole genome assemblies, in conjunction with genomic data for 54 additional species. We investigate how three major ecological transitions have shaped genomic variation among ariids over their similar to 50 million-year evolutionary history. Our results show that relatively younger freshwater lineages exhibit a higher incidence of positive selection than their more ancient marine counterparts. They also display a larger disparity in body shapes, a trend that correlates with a heightened occurrence of positive selection on genes associated with body size and elongation. Although positive selection in the Australia and New Guinea radiation does not stand out compared to non-radiating lineages overall, selection across the prolactin gene family during the marine-to-freshwater transition suggests that strong osmoregulatory adaptations may have facilitated their colonization and radiation. Our findings underscore the significant role of selection in shaping the genome and organismal traits in response to habitat shifts across macroevolutionary scales.

Protein kinase A (PKA) is a key regulator of cellular functions by selectively phosphorylating numerous substrates, including ion channels, enzymes, and transcription factors. It has long served as a model system for understanding the eukaryotic kinases. Using cryoelectron microscopy, we present complex structures of the PKA catalytic subunit (PKA-C) bound to a full- length protein substrate, the cystic fibrosis transmembrane conductance regulator (CFTR)-an ion channel vital to human health. CFTR gating requires phosphorylation of its regulatory (R) domain. Unphosphorylated CFTR engages PKA-C at two locations, establishing two "catalytic stations" near to, but not directly involving, the R domain. This configuration, coupled with the conformational flexibility of the R domain, permits transient interactions of the eleven spatially separated phosphorylation sites. Furthermore, we determined two structures of the open- pore CFTR stabilized by PKA-C, providing a molecular basis to understand how PKA-C stimulates CFTR currents even in the absence of phosphorylation.

The first search for soft unclustered energy patterns (SUEPs) is performed using an integrated luminosity of 138 fb(-1) of proton-proton collision data at root s = 13 TeV, collected in 2016-2018 by the CMS detector at the LHC. Such SUEPs are predicted by hidden valley models with a new, confining force with a large't Hooft coupling. In events with boosted topologies, selected by high-threshold hadronic triggers, the multiplicity and sphericity of clustered tracks are used to reject the background from standard model quantum chromodynamics. With no observed excess of events over the standard model expectation, limits are set on the cross section for production via gluon fusion of a scalar mediator with SUEP-like decays.

Multisystem inflammatory syndrome in children (MIS-C) is a rare condition following SARS-CoV-2 infection associated with intestinal manifestations. Genetic predisposition, including inborn errors of the OAS-RNAseL pathway, has been reported. We sequenced 154 MIS-C patients and utilized a novel statistical framework of gene burden analysis, "burdenMC," which identified an enrichment for rare predicted-deleterious variants in BTNL8 (OR = 4.2, 95% CI: 3.5-5.3, P < 10(-6)). BTNL8 encodes an intestinal epithelial regulator of V gamma 4(+)gamma delta T cells implicated in regulating gut homeostasis. Enrichment was exclusive to MIS-C, being absent in patients with COVID-19 or bacterial disease. Using an available functional test for BTNL8, rare variants from a larger cohort of MIS-C patients (n = 835) were tested which identified eight variants in 18 patients (2.2%) with impaired engagement of V gamma 4(+)gamma delta T cells. Most of these variants were in the B30.2 domain of BTNL8 implicated in sensing epithelial cell status. These findings were associated with altered intestinal permeability, suggesting a possible link between disrupted gut homeostasis and MIS-C-associated enteropathy triggered by SARS-CoV-2.

Introduction Cystic fibrosis (CF) is a hereditary autosomal recessive disease driven by deleterious variants of the CFTR gene, leading, among other symptoms, to increased lung infection susceptibility. Mucus accumulation in the CF lung is, as of yet, considered as one important factor contributing to its colonization by opportunistic pathogens such as Pseudomonas aeruginosa. However, in recent years evidence was provided that alveolar macrophages, which form the first line of defense against airborne pathogens, seem to be intrinsically defective with regard to bactericidal functionality in the CF lung. To assess the impact of CFTR deficiency in human macrophages only insufficient systems are available.Methods To address this problem and to evaluate the role of CFTR in human macrophages, we successfully differentiated human induced pluripotent stem cells (iPSC) from a CF p.Phe508del homozygous individual and a healthy donor into primitive macrophages (iMac Delta F508 and iMacWT), respectively, and compared the bactericidal functionality in the relevant cell type.Results iMac Delta F508 showed impaired P. aeruginosa clearance and intracellular killing capacity in comparison to iMacWT. Furthermore, iMac Delta F508 exhibited a less acidic lysosomal pH, and upon P. aeruginosa infection, there were signs of mitochondrial fragmentation and autophagosome formation together with a hyperinflammatory phenotype and deficient type I interferon response.Conclusion In summary, we present a defective phenotype in iMac Delta F508 upon P. aeruginosa infection, which will constitute an ideal platform to further study the role of macrophages in the context of CF.

There is a paucity of information on the prevalence, risk factors, and clinical correlates of people living with HIV (PLWH) who are co-infected with Cryptosporidium spp. in the post-combined antiretroviral therapy era in Ghana. To provide such data, in this observational study, stool samples of 640 HIV-positive and 83 HIV-negative individuals in Ghana were screened for Cryptosporidium spp. Additionally, sociodemographic parameters, clinical symptoms, medication intake, and immunological parameters were assessed. The prevalence of Cryptosporidium spp. was 11.8% (n = 73) in HIV-positive and 1.2% (n = 1) in HIV-negative participants (p < 0.001). Within the group of HIV-positive participants, the prevalence reached 26.0% in patients with CD4+ T cell counts below 200 cells/mu L and 46.2% in the subgroup with CD4+ T cell counts below 50 cells/mu L. The frequencies of the clinical manifestation of weight loss and gastrointestinal symptoms were significantly higher in patients with Cryptosporidium spp. compared to those without co-infection (45.8% vs. 21.4%, p < 0.001 and 22.2% vs. 12.2%, p = 0.031, respectively). In the modern post-cART era, the acquisition of Cryptosporidium spp. among PLWH in Ghana is driven largely by the degree of immunosuppression. Access to cART and screening for Cryptosporidium spp. as part of routine care might help control and reduce the burden of the infection.

Histone post-translational modifications play pivotal roles in eukaryotic gene expression. To date, most studies have focused on modifications in unstructured histone N-terminal tail domains and their binding proteins. However, transcriptional regulation by chromatin-effector proteins that directly recognize modifications in histone globular domains has yet to be clearly demonstrated, despite the richness of their multiple modifications. Here, we show that the ATP-dependent chromatin-remodeling BAF complex stimulates p53-dependent transcription through direct interaction with H3K56ac located on the lateral surface of the histone globular domain. Mechanistically, the BAF complex recognizes nucleosomal H3K56ac via the DPF domain in the DPF2 subunit and exhibits enhanced nucleosome-remodeling activity in the presence of H3K56ac. We further demonstrate that a defect in H3K56ac-BAF complex interaction leads to impaired p53-dependent gene expression and DNA damage responses. Our study provides direct evidence that histone globular domain modifications participate in the regulation of gene expression. The authors suggest that histone globular domain modifications participate in the regulation of gene expression. The ATP-dependent chromatin-remodeling BAF complex enhances transcription through direct interaction with H3K56ac located on the lateral surface of the histone globular domain.

Effective ocean management asks for up-to-date knowledge of marine biogeography. Here we compare eDNA and gear-based assessments of marine fish populations using an approach that focuses on the commonest species. The protocol takes advantage of the "hollow curve" of species abundance distributions, with a minority of species comprising the great majority of individuals or biomass. We analyzed new and published teleost eDNA metabarcoding surveys from three neighboring northwest Atlantic coastal locations representing sandy, rocky, or estuary habitat. Fish eDNA followed a hollow curve species abundance distribution at each location-the 10 commonest taxa accounted for more than 90% of eDNA copies. Top ten taxa were designated eDNA-dominant species (eDDS) and categorized as habitat-associated (top 10 in one study) or as shared. eDDS by category were similarly abundant in concurrent bottom trawl and seine surveys. eDDS habitat category profiles correctly classified most (94%-100%) individual eDNA and capture measurements within surveys and recognized estuarine sites in other regional eDNA and seine studies. Using a category metric like that for habitats, eDDS demonstrated strong seasonal turnover concordant with trawl catch weights. eDNA seasonal profiles applied to historical trawl and seine records highlighted known long-term trends in mid-Atlantic fish populations. This study provides evidence that eDNA-abundant fish species differ among coastal habitats and by season consistent with gear-based assessments. Grouping abundant species by category facilitated comparisons among habitats and integration with established surveys. eDNA metabarcoding of dominant fish species potentially offers a useful tool for marine biogeography and ocean monitoring.

Mate recognition systems evolve rapidly to reinforce the reproductive boundaries between species, but the underlying neural mechanisms remain enigmatic. Here we leveraged the rapid coevolution of female pheromone production and male pheromone perception in Drosophila1,2 to gain insight into how the architecture of mate recognition circuits facilitates their diversification. While in some Drosophila species females produce unique pheromones that act to arouse their conspecific males, the pheromones of most species are sexually monomorphic such that females possess no distinguishing chemosensory signatures that males can use for mate recognition3. We show that Drosophila yakuba males evolved the ability to use a sexually monomorphic pheromone, 7-tricosene, as an excitatory cue to promote courtship. By comparing key nodes in the pheromone circuits across multiple Drosophila species, we reveal that this sensory innovation arises from coordinated peripheral and central circuit adaptations: a distinct subpopulation of sensory neurons has acquired sensitivity to 7-tricosene and, in turn, selectively signals to a distinct subset of P1 neurons in the central brain to trigger courtship. Such a modular circuit organization, in which different sensory inputs can independently couple to parallel courtship control nodes, may facilitate the evolution of mate recognition systems by allowing novel sensory modalities to become linked to male arousal. Together, our findings suggest how peripheral and central circuit adaptations can be flexibly coordinated to underlie the rapid evolution of mate recognition strategies across species. Peripheral and central circuit adaptations can be flexibly coordinated in Drosophila, and such a modular circuit organization may facilitate the evolution of mate recognition systems by allowing novel sensory modalities to become linked to male arousal.

Methods rooted in chemical biology have contributed significantly to studies of integral membrane proteins. One recent key approach has been the application of genetic code expansion (GCE), which enables the site-specific incorporation of noncanonical amino acids (ncAAs) with defined chemical properties into proteins. Efficient GCE is challenging, especially for membrane proteins, which have specialized biogenesis and cell trafficking machinery and tend to be expressed at low levels in cell membranes. Many eukaryotic membrane proteins cannot be expressed functionally in E. coli and are most effectively studied in mammalian cell culture systems. Recent advances have facilitated broader applications of GCE for studies of membrane proteins. First, AARS/tRNA pairs have been engineered to function efficiently in mammalian cells. Second, bioorthogonal chemical reactions, including cell-friendly copper-free "click" chemistry, have enabled linkage of small-molecule probes such as fluorophores to membrane proteins in live cells. Finally, in concert with advances in GCE methodology, the variety of available ncAAs has increased dramatically, thus enabling the investigation of protein structure and dynamics by multidisciplinary biochemical and biophysical approaches. These developments are reviewed in the historical framework of the development of GCE technology with a focus on applications to studies of membrane proteins.