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The liver has a unique ability to regenerate 1 , 2 ; however, in the setting of acute liver failure (ALF), this regenerative capacity is often overwhelmed, leaving emergency liver transplantation as the only curative option 3 – 5 . Here, to advance understanding of human liver regeneration, we use paired single-nucleus RNA sequencing combined with spatial profiling of healthy and ALF explant human livers to generate a single-cell, pan-lineage atlas of human liver regeneration. We uncover a novel ANXA2 + migratory hepatocyte subpopulation, which emerges during human liver regeneration, and a corollary subpopulation in a mouse model of acetaminophen (APAP)-induced liver regeneration. Interrogation of necrotic wound closure and hepatocyte proliferation across multiple timepoints following APAP-induced liver injury in mice demonstrates that wound closure precedes hepatocyte proliferation. Four-dimensional intravital imaging of APAP-induced mouse liver injury identifies motile hepatocytes at the edge of the necrotic area, enabling collective migration of the hepatocyte sheet to effect wound closure. Depletion of hepatocyte ANXA2 reduces hepatocyte growth factor-induced human and mouse hepatocyte migration in vitro, and abrogates necrotic wound closure following APAP-induced mouse liver injury. Together, our work dissects unanticipated aspects of liver regeneration, demonstrating an uncoupling of wound closure and hepatocyte proliferation and uncovering a novel migratory hepatocyte subpopulation that mediates wound closure following liver injury. Therapies designed to promote rapid reconstitution of normal hepatic microarchitecture and reparation of the gut–liver barrier may advance new areas of therapeutic discovery in regenerative medicine. Harnessing single-nucleus RNA sequencing and spatial profiling, this work dissects unanticipated aspects of human liver regeneration to uncover a novel migratory hepatocyte subpopulation mediating wound closure following acute liver injury.

The unique metabolism of most solid tumours (aerobic glycolysis, i.e., Warburg effect) is not only the basis of diagnosing cancer with metabolic imaging but might also be associated with the resistance to apoptosis that characterises cancer. The glycolytic phenotype in cancer appears to be the common denominator of diverse molecular abnormalities in cancer and may be associated with a (potentially reversible) suppression of mitochondrial function. The generic drug dichloroacetate is an orally available small molecule that, by inhibiting the pyruvate dehydrogenase kinase, increases the flux of pyruvate into the mitochondria, promoting glucose oxidation over glycolysis. This reverses the suppressed mitochondrial apoptosis in cancer and results in suppression of tumour growth in vitro and in vivo . Here, we review the scientific and clinical rationale supporting the rapid translation of this promising metabolic modulator in early-phase cancer clinical trials.

Freshwater ecosystems are considered hotspots of biodiversity in Antarctic polar deserts. Anticipated warming is expected to change the hydrology of these systems due to increased meltwater and reduction of ice cover, with implications for environmental conditions and physical connectivity between habitats. Using 16S rRNA gene sequencing, we evaluated microbial mat and planktonic communities within a connected freshwater system in the McMurdo Wright Valley, Antarctica, to determine the roles of connectivity and habitat conditions in controlling microbial assemblage composition. We examined communities from glacial Lake Brownworth, the perennially ice-covered Lake Vanda and the Onyx River, which connects the two. In Lake Vanda, we found distinct microbial assemblages occupying sub-habitats at different lake depths, while the communities from Lake Brownworth and Onyx River were structurally similar. Despite the higher physical connectivity and dispersal opportunities between bacterial communities in the shallow parts of the system, environmental abiotic conditions dominated over dispersal in driving community structure. Functional metabolic pathway predictions suggested differences in the functional gene potential between the microbial mat communities located in shallower and deeper water depths. The findings suggest that increasing temperatures and meltwater due to future climate change will affect bacterial diversity and functioning in Antarctic freshwater ecosystems.

Orthology detection is critically important for accurate functional annotation, and has been widely used to facilitate studies on comparative and evolutionary genomics. Although various methods are now available, there has been no comprehensive analysis of performance, due to the lack of a genomic-scale 'gold standard' orthology dataset. Even in the absence of such datasets, the comparison of results from alternative methodologies contains useful information, as agreement enhances confidence and disagreement indicates possible errors. Latent Class Analysis (LCA) is a statistical technique that can exploit this information to reasonably infer sensitivities and specificities, and is applied here to evaluate the performance of various orthology detection methods on a eukaryotic dataset. Overall, we observe a trade-off between sensitivity and specificity in orthology detection, with BLAST-based methods characterized by high sensitivity, and tree-based methods by high specificity. Two algorithms exhibit the best overall balance, with both sensitivity and specificity>80%: INPARANOID identifies orthologs across two species while OrthoMCL clusters orthologs from multiple species. Among methods that permit clustering of ortholog groups spanning multiple genomes, the (automated) OrthoMCL algorithm exhibits better within-group consistency with respect to protein function and domain architecture than the (manually curated) KOG database, and the homolog clustering algorithm TribeMCL as well. By way of using LCA, we are also able to comprehensively assess similarities and statistical dependence between various strategies, and evaluate the effects of parameter settings on performance. In summary, we present a comprehensive evaluation of orthology detection on a divergent set of eukaryotic genomes, thus providing insights and guides for method selection, tuning and development for different applications. Many biological questions have been addressed by multiple tests yielding binary (yes/no) outcomes but no clear definition of truth, making LCA an attractive approach for computational biology.

Precambrian marine carbonate strata are commonly assumed to have formed in warm‐water carbonate factories due to the temperature dependence of non‐skeletal carbonate precipitation rates. However, some climate models and geological observations suggest that global climate was cool for tens of millions of years prior to the onset of Snowball Earth glaciation at ∼717 Ma, in conflict with common interpretations of pre‐glacial carbonates as warm‐water carbonate factories. We report the occurrence of guttulatic microfabric—a petrographic fingerprint of ikaite, a carbonate mineral that only forms in cold sedimentary environments—in the Beck Spring Dolomite, a carbonate succession deposited in a low‐latitude shallow marine environment between ∼780 and 730 Ma. This interpretation of pre‐glacial carbonate factories aligns cold conditions with vase‐shaped microfossils, possible algal fossils, and molecular clock dates for crown‐group metazoans. Our observations indicate that these marine ecosystems were able to thrive in cold low‐latitude environments millions of years before the Snowball glaciations. Plain Language Summary Between 717 and 635 million years ago, Earth experienced two dramatic global glacial events, known as “Snowball Earth” glaciations, during which ice covered the oceans all the way to the equator. Geoscientists are still seeking to fully understand what caused these extreme climate events and how life on Earth survived them. Although geochemists have a variety of tools to reconstruct the temperature of ancient oceans, these methods are difficult to apply in rocks this old because primary signals have been too altered. Instead, we looked for a key microscopic fingerprint (“guttulatic microfabric”) of a type of calcium carbonate mineral (“ikaite”) that only forms in cold‐water environments. Previous work had proposed that we might expect to find evidence of this cold‐water carbonate mineral associated with a specific type of sediment called “giant ooids.” We found abundant evidence of guttulatic microfabric in sedimentary rocks containing giant ooids that formed in a low‐latitude shallow marine environment millions of years before the onset of global glaciation. Our observations suggest that Earth’s climate was cold before the onset of global glaciation, which could mean that marine organisms were accustomed to cold conditions well before the Snowball glaciations. Key Points Guttulatic microfabric is a characteristic fingerprint of ikaite, a mineral that forms only in cold‐water depositional environments We report guttulatic microfabrics in grains and cements associated with giant ooids in the Tonian Beck Spring Dolomite Our findings demonstrate that global climate was cold millions of years before the onset of the Sturtian glaciation

Background The relationship between healthcare service accessibility in the community and incarceration is an important, yet not widely understood, phenomenon. Community behavioral health and the criminal legal systems are treated separately, which creates a competing demand to confront mass incarceration and expand available services. As a result, the relationship between behavioral health services, demographics and community factors, and incarceration rate has not been well addressed. Understanding potential drivers of incarceration, including access to community-based services, is necessary to reduce entry into the legal system and decrease recidivism. This study identifies county-level demographic, socioeconomic, healthcare services availability/accessibility, and criminal legal characteristics that predict per capita jail population across the U.S. More than 10 million individuals pass through U.S. jails each year, increasing the urgency of addressing this challenge. Methods The selection of variables for our model proceeded in stages. The study commenced by identifying potential descriptors and then using machine learning techniques to select non-collinear variables to predict county jail population per capita. Beta regression was then applied to nationally available data from all 3,141 U.S. counties to identify factors predicting county jail population size. Data sources include the Vera Institute’s incarceration database, Robert Wood Johnson Foundation’s County Health Rankings and Roadmaps, Uniform Crime Report, and the U.S. Census. Results Fewer per capita psychiatrists (z-score = -2.16; p  = .031), lower percent of drug treatment paid by Medicaid (-3.66; p  < .001), higher per capita healthcare costs (5.71; p  < .001), higher number of physically unhealthy days in a month (8.6; p  < .001), lower high school graduation rate (-4.05; p  < .001), smaller county size (-2.66, p  = .008; -2.71, p  = .007; medium and large versus small counties, respectively), and more police officers per capita (8.74; p  < .001) were associated with higher per capita jail population. Controlling for other factors, violent crime rate did not predict incarceration rate. Conclusions Counties with smaller populations, larger percentages of individuals that did not graduate high school, that have more health-related issues, and provide fewer community treatment services are more likely to have higher jail population per capita. Increasing access to services, including mental health providers, and improving the affordability of drug treatment and healthcare may help reduce incarceration rates.

Nucleoside analogues (NA) are essential components of AML induction therapy (cytosine arabinoside), effective treatments of lymphoproliferative disorders (fludarabine, cladribine) and are also used in the treatment of some solid tumors (gemcitabine). These important compounds share some general common characteristics, namely in terms of requiring transport by specific membrane transporters, metabolism and interaction with intracellular targets. However, these compounds differ in regard to the types of transporters that most efficiently transport a given compound, and their preferential interaction with certain targets which may explain why some compounds are more effective against rapidly proliferating tumors and others on neoplasia with a more protracted evolution. In this review, we analyze the available data concerning mechanisms of action of and resistance to NA, with particular emphasis on recent advances in the characterization of nucleoside transporters and on the potential role of activating or inactivating enzymes in the induction of clinical resistance to these compounds. We performed an extensive search of published in vitro and clinical data in which the levels of expression of nucleoside-activating or inactivating enzymes have been correlated with tumor response or patient outcome. Strategies aiming to increase the intracellular concentrations of active compounds are presented.

Clues to the evolutionary steps producing innovations in oxygenic photosynthesis may be preserved in the genomes of organisms phylogenetically placed between non-photosynthetic Vampirovibrionia (formerly Melainabacteria) and the thylakoid-containing Cyanobacteria. However, only two species with published genomes are known to occupy this phylogenetic space, both within the genus Gloeobacter . Here, we describe nearly complete, metagenome-assembled genomes (MAGs) of an uncultured organism phylogenetically placed near Gloeobacter , for which we propose the name Candidatus Aurora vandensis {Au’ro.ra. L. fem. n. aurora, the goddess of the dawn in Roman mythology; van.de’nsis. N.L. fem. adj. vandensis of Lake Vanda, Antarctica}. The MAG of A. vandensis contains homologs of most genes necessary for oxygenic photosynthesis including key reaction center proteins. Many accessory subunits associated with the photosystems in other species either are missing from the MAG or are poorly conserved. The MAG also lacks homologs of genes associated with the pigments phycocyanoerethrin, phycoeretherin and several structural parts of the phycobilisome. Additional characterization of this organism is expected to inform models of the evolution of oxygenic photosynthesis.

Background: The Combined Aerobic and Resistance Exercise Trial tested different types and doses of exercise in breast cancer patients receiving chemotherapy. Here, we explore potential moderators of the exercise training responses. Methods: Breast cancer patients initiating chemotherapy ( N =301) were randomly assigned to three times a week, supervised exercise of a standard dose of 25–30 min of aerobic exercise, a higher dose of 50–60 min of aerobic exercise, or a higher dose of 50–60 min of combined aerobic and resistance exercise. Outcomes were patient-reported symptoms and health-related fitness. Moderators were baseline demographic, exercise/fitness, and cancer variables. Results: Body mass index moderated the effects of the exercise interventions on bodily pain ( P for interaction=0.038), endocrine symptoms ( P for interaction=0.029), taxane/neuropathy symptoms ( P for interaction=0.013), aerobic fitness ( P for interaction=0.041), muscular strength ( P for interaction=0.007), and fat mass ( P for interaction=0.005). In general, healthy weight patients responded better to the higher-dose exercise interventions than overweight/obese patients. Menopausal status, age, and baseline fitness moderated the effects on patient-reported symptoms. Premenopausal, younger, and fitter patients achieved greater benefits from the higher-dose exercise interventions. Conclusions: Healthy weight, fitter, and premenopausal/younger breast cancer patients receiving chemotherapy are more likely to benefit from higher-dose exercise interventions.

Ecological theories posit that heterogeneity in environmental conditions greatly affects community structure and function. However, the degree to which ecological theory developed using plant- and animal-dominated systems applies to microbiomes is unclear. Investigating the metabolic strategies found in microbiomes are particularly informative for testing the universality of ecological theories because microorganisms have far wider metabolic capacity than plants and animals. We used metagenomic analyses to explore the relationships between the energy and physicochemical gradients in Lake Fryxell and the metabolic capacity of its benthic microbiome. Statistical analysis of the relative abundance of metabolic marker genes and gene family diversity shows that oxygenic photosynthesis, carbon fixation, and flavin-based electron bifurcation differentiate mats growing in different environmental conditions. The pattern of gene family diversity points to the likely importance of temporal environmental heterogeneity in addition to resource gradients. Overall, we found that the environmental heterogeneity of photosynthetically active radiation (PAR) and oxygen concentration ([O2]) in Lake Fryxell provide the framework by which metabolic diversity and composition of the community is structured, in accordance with its phylogenetic structure. The organization of the resulting microbial ecosystems are consistent with the maximum power principle and the species sorting model.