Despite the deep sea being the largest habitat on Earth, there are just 77 population genetic studies of invertebrates (115 species) inhabiting non‐chemosynthetic ecosystems on the deep‐sea floor ...(below 200 m depth). We review and synthesize the results of these papers. Studies reveal levels of genetic diversity comparable to shallow‐water species. Generally, populations at similar depths were well connected over 100s–1,000s km, but studies that sampled across depth ranges reveal population structure at much smaller scales (100s–1,000s m) consistent with isolation by adaptation across environmental gradients, or the existence of physical barriers to connectivity with depth. Few studies were ocean‐wide (under 4%), and 48% were Atlantic‐focused. There is strong emphasis on megafauna and commercial species with research into meiofauna, “ecosystem engineers” and other ecologically important species lacking. Only nine papers account for ~50% of the planet's surface (depths below 3,500 m). Just two species were studied below 5,000 m, a quarter of Earth's seafloor. Most studies used single‐locus mitochondrial genes revealing a common pattern of non‐neutrality, consistent with demographic instability or selective sweeps; similar to deep‐sea hydrothermal vent fauna. The absence of a clear difference between vent and non‐vent could signify that demographic instability is common in the deep sea, or that selective sweeps render single‐locus mitochondrial studies demographically uninformative. The number of population genetics studies to date is miniscule in relation to the size of the deep sea. The paucity of studies constrains meta‐analyses where broad inferences about deep‐sea ecology could be made.
Microglial homeostasis has emerged as a critical mediator of health and disease in the central nervous system. In their neuroprotective role as the predominant immune cells of the brain, microglia ...surveil the microenvironment for debris and pathogens, while also promoting neurogenesis and performing maintenance on synapses. Chronological ageing, disease onset, or traumatic injury promotes irreparable damage or deregulated signaling to reinforce neurotoxic phenotypes in microglia. These insults may include cellular senescence, a stable growth arrest often accompanied by the production of a distinctive pro‐inflammatory secretory phenotype, which may contribute to age‐ or disease‐driven decline in neuronal health and cognition and is a potential novel therapeutic target. Despite this increased scrutiny, unanswered questions remain about what distinguishes senescent microglia and non‐senescent microglia reacting to insults occurring in ageing, disease, and injury, and how central the development of senescence is in their pivot from guardian to assailant. To intelligently design future studies to untangle senescent microglia from other primed and reactionary states, specific criteria must be developed that define this population and allow for comparisons between different model systems. Comparing microglial activity seen in homeostasis, ageing, disease, and injury allows for a more coherent understanding of when and how senescent and other harmful microglial subpopulations should be targeted.
Microglia diverge from homeostasis in response to insults, transitioning from a neuroprotective role to a pro‐inflammatory state that promotes dysfunction in aging, disease, and injury. Cellular senescence in microglia plays a potentially crucial pathogenic role in these contexts, but the difficulties of distinguishing senescent microglia from those reacting to insults remain a challenge. To address this challenge, we make a set of recommendations to define microglial senescence for future studies.
The transport of energy through 1-dimensional (1D) waveguiding channels can be affected by sub-wavelength disorder, resulting in undesirable localization and backscattering phenomena. However, ...quantized disorder-resilient transport is observable in the edge currents of 2-dimensional (2D) topological band insulators with broken time-reversal symmetry. Topological pumps are able to reduce this higher-dimensional topological insulator phenomena to lower dimensionality by utilizing a pumping parameter (either space or time) as an artificial dimension. Here we demonstrate a temporal topological pump that produces on-demand, robust transport of mechanical energy using a 1D magneto-mechanical metamaterial. We experimentally demonstrate that the system is uniquely resilient to defects occurring in both space and time. Our findings open a path towards exploration of higher-dimensional topological physics with time as a synthetic dimension.
Phosphatase and tensin homolog (PTEN) is a tumor suppressor frequently mutated in diverse cancers. Germline PTEN mutations are also associated with a range of clinical outcomes, including PTEN ...hamartoma tumor syndrome (PHTS) and autism spectrum disorder (ASD). To empower new insights into PTEN function and clinically relevant genotype-phenotype relationships, we systematically evaluated the effect of PTEN mutations on lipid phosphatase activity in vivo. Using a massively parallel approach that leverages an artificial humanized yeast model, we derived high-confidence estimates of functional impact for 7,244 single amino acid PTEN variants (86% of possible). We identified 2,273 mutations with reduced cellular lipid phosphatase activity, which includes 1,789 missense mutations. These data recapitulated known functional findings but also uncovered new insights into PTEN protein structure, biochemistry, and mutation tolerance. Several residues in the catalytic pocket showed surprising mutational tolerance. We identified that the solvent exposure of wild-type residues is a critical determinant of mutational tolerance. Further, we created a comprehensive functional map by leveraging correlations between amino acid substitutions to impute functional scores for all variants, including those not present in the assay. Variant functional scores can reliably discriminate likely pathogenic from benign alleles. Further, 32% of ClinVar unclassified missense variants are phosphatase deficient in our assay, supporting their reclassification. ASD-associated mutations generally had less severe fitness scores relative to PHTS-associated mutations (p = 7.16 × 10−5) and a higher fraction of hypomorphic mutations, arguing for continued genotype-phenotype studies in larger clinical datasets that can further leverage these rich functional data.
We investigate the behavior of a topological Chern insulator in the presence of disorder, with a focus on its entanglement spectrum (EtS) constructed from the ground state. For systems with ...symmetries, the EtS was shown to contain explicit information about the topological universality class revealed by sorting the EtS against the conserved quantum numbers. In the absence of any symmetry, we demonstrate that statistical methods such as the level statistics of the EtS can be equally insightful, allowing us to distinguish when an insulator is in a topological or trivial phase and to map the boundary between the two phases. The phase diagram of a Chern insulator is explicitly computed as function of Fermi level (EF) and disorder strength using the level statistics of the EtS and energy spectrum, together with a computation of the Chern number (C) via a new, efficient real-space formula.
Accurate typing methods are required for efficient infection control. The emergence of whole-genome sequencing (WGS) technologies has enabled the development of genome-based methods applicable for ...routine typing and surveillance of bacterial pathogens. In this study, we developed the Pseudomonas aeruginosa serotyper (PAst) program, which enabled in silico serotyping of P. aeruginosa isolates using WGS data. PAst has been made publically available as a web service and aptly facilitates high-throughput serotyping analysis. The program overcomes critical issues such as the loss of in vitro typeability often associated with P. aeruginosa isolates from chronic infections and quickly determines the serogroup of an isolate based on the sequence of the O-specific antigen (OSA) gene cluster. Here, PAst analysis of 1,649 genomes resulted in successful serogroup assignments in 99.27% of the cases. This frequency is rarely achievable by conventional serotyping methods. The limited number of nontypeable isolates found using PAst was the result of either a complete absence of OSA genes in the genomes or the artifact of genomic misassembly. With PAst, P. aeruginosa serotype data can be obtained from WGS information alone. PAst is a highly efficient alternative to conventional serotyping methods in relation to outbreak surveillance of serotype O12 and other high-risk clones, while maintaining backward compatibility to historical serotype data.
Topological semimetals are gapless states of matter which have robust and unique electromagnetic responses and surface states. In this paper, we consider semimetals which have pointlike Fermi ...surfaces in various spatial dimensions D = 1, 2, 3 which naturally occur in the transition between a weak topological insulator and a trivial insulating phase. These semimetals include those of Dirac and Weyl types. We construct these phases by layering strong topological insulator phases in one dimension lower. This perspective helps us understand their effective response field theory that is generally characterized by a 1-form b which represents a source of Lorentz violation and can be read off from the location of the nodes in momentum space and the helicities/chiralities of the nodes. We derive effective response actions for the two-dimensional (2D) and 3D Dirac semimetals and extensively discuss the response of the Weyl semimetal. We also show how our work can be used to describe semimetals with Fermi surfaces with lower codimension as well as to describe the topological response of 3D topological crystalline insulators.
Drug compounds that augment the production and activity of the cystic fibrosis (CF) transmembrane regulator (CFTR) have revolutionised CF care. Many adults and some children with CF suffer advanced ...and severe lung disease or await lung transplantation. While the hope is that these drug compounds will prevent lung damage when started early in life, there is an ongoing need to care for people with advanced lung disease. The focus of this review is the accumulating data from clinical trials and case series regarding the benefits of CFTR modulator therapy in people with advanced pulmonary disease. We address the impact of treatment with ivacaftor, lumacaftor/ivacaftor, tezacaftor/ivacaftor and elexacaftor/tezacaftor/ivacaftor on lung function, pulmonary exacerbations, nutrition and quality of life. Adverse events of the different CFTR modulators, as well as the potential for drug-drug interactions, are discussed.
Coupling with inversion: Chiral diarylmethanol derivatives undergo a stereospecific nickel‐catalyzed cross‐coupling reaction with aryl Grignard reagents (see scheme). The reaction proceeds with ...inversion of configuration and high enantiospecificity. The method has been applied to the asymmetric synthesis of a triarylmethane‐based anti‐cancer compound.
The coordination‐directed assembly of metal ions and organic bridging ligands has afforded a variety of bulk‐scale hybrid materials with promising characteristics for a number of practical ...applications, such as gas storage and heterogeneous catalysis. Recently, so‐called coordination polymers have emerged as a new class of hybrid nanomaterials. Herein, we highlight advances in the syntheses of both amorphous and crystalline nanoscale coordination polymers. We also illustrate how scaling down these materials to the nano‐regime has enabled their use in a broad range of applications including catalysis, spin‐crossover, templating, biosensing, biomedical imaging, and anticancer drug delivery. These results underscore the exciting opportunities of developing next‐generation functional nanomaterials based on molecular components.
Next‐generation nanomaterials: The coordination‐directed assembly of metal ions and organic bridging ligands has afforded bulk‐scale functional hybrid materials. Their scaling‐down to the nano‐regime has led to nanoscale coordination polymers and metal–organic frameworks which have been used in a broad range of applications including catalysis, spin‐crossover, templating, biosensing, biomedical imaging, and anticancer drug delivery.
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