Wharton O. Y. Chan

Bats are extraordinary among mammals, having uniquely evolved powered flight and laryngeal echolocation, along with disease resistance, extended healthspans and the ability to hibernate ¹ . However, the evolutionary history of bats and the understanding of these adaptations remain unresolved. We analysed chromosome-level, long-read genome assemblies from 103 bat species, including 42 new assemblies, representing all 21 bat families. This dataset, expanded in scope and assembly quality, yielded a new bat phylogeny. We placed Myzopodidae as the earliest branch within Vespertilionoidea, and resolved yangochiropteran relationships, identifying Emballonuroidea and Vespertilionoidea as sister groups. Our analysis revealed a mosaic evolutionary history across bats and explained why previous phylogenetic studies were misled. Chromosomal ancestral-state reconstructions supported 26 ancestral bat chromosomes. We integrated a morphological dataset of 699 characters for 65 species, including 44 pre-Quaternary fossils and representatives of most living bat families, with neutrally evolving genomic sites. Fossilized birth–death and dispersal–extinction cladogenesis analyses showed that bats, and thus powered flight, probably originated in Europe in the late Palaeocene, refuting African and North American origins. Placement of the fossil † Vielasia in the oldest ‘Eochiroptera’ clade indicates that laryngeal echolocation predates crown-bat diversification. Total evidence dating, including the fossil taxa, significantly reduced unrepresented basal branch lengths compared with molecular-only divergence estimates. By integrating comprehensive genomic and morphological datasets, analysed using innovative methods, we resolve long-standing controversies in bat biology and provide new insights into the evolutionary history and trait diversification of bats.

Bats are the only mammals capable of powered flight, a physiologically demanding process requiring substantial cardiac energy expenditure. Here, we investigate how hearts of the cave nectar bat Eonycteris spelaea are adapted to meet these extreme demands. Transcriptomic profiling reveals enriched signatures of oxidative phosphorylation and fatty acid metabolism in bat hearts, distinct from mouse and human counterparts. Metabolomics analyses corroborate these findings, identifying distinct acylcarnitine profiles and elevated tricarboxylic acid cycle intermediates. Anatomically, bats have relatively larger hearts with increased mitochondrial and vascular densities along with prominent perivascular adipocytes. Echocardiography reveals superior cardiac reserve in bats, with enhanced contractile responses under dobutamine stress. Notably, isolated bat cardiomyocytes resist angiotensin II-induced hypertrophy and mitochondrial dysfunction. These integrated adaptations likely support high-energy flight while preserving cardiac function under stress. Insights from bat cardiac physiology may provide valuable information on cardioprotective mechanisms with potential application across species.

Bats as the only flying mammals incur a high metabolic cost during extended powered flight, which results in febrile-like temperatures without injury. Herein, we investigate the in vivo heat shock response (HSR) in the cave nectar bat Eonycteris spelaea. We demonstrate that E. spelaea exhibits enhanced physiological heat resistance, marked by reduced lethality, tissue damage and serum corticosterone levels in comparison to mice upon heat challenge. Additionally, E. spelaea did not exhibit an acute transcriptional response observed in heat stressed mice. Instead, bats displayed a delayed and non-canonical HSR that did not involve the activation of classical heat shock related genes and pathways. This altered response in E. spelaea is attributed to the elevated basal expression of heat shock proteins, which we demonstrate to be a common characteristic exhibited by bats from diverse sub-orders, families and diets. Taken together, we demonstrate a distinct HSR in E. spelaea relative to the conventional model organism, mouse, which may provide insights to understand novel regulatory targets and effector proteins that underlie the mammalian heat shock response.

Background: Inpatient hypoglycaemia has been well studied around the world, and more tools are being developed to understand and predict hypoglycaemic episodes. Most published data, however, focuses on patient characteristics and predictions of whether a patient would have a hypoglycaemic episode during inpatient stay. There is a paucity of data concerning the timing, as well as types of diabetic medications used, surrounding a hypoglycaemia episode. Objectives: To characterise inpatient hypoglycaemia episodes by time and associated diabetes medications, on top of baseline patient characteristics. Design: Retrospective observational study of 425 hypoglycaemia episodes, over a 2 month period from two general internal medicine wards, in a tertiary medical hospital. Methods: A discrete hypoglycaemic episode is defined as a capillary blood glucose (CBG) reading of p < 0.05) except for the basal-bolus insulin regimen ( p = 0.76). Basal insulin and sulphonylurea-associated hypoglycaemia occurred mostly in the midnight timeframe (0000–0800) at 65.6% and 47.4%, respectively, whereas premixed insulin-associated hypoglycaemia occurred mostly in the evening timeframe (1601–2359) at 51.2%. In total, there were significant differences in the distribution of hypoglycaemia across the three time frames associated with different diabetes medications ( p < 0.05). Conclusion: There are marked differences in the medications associated with inpatient hypoglycaemia at differing time points. These time points offer insight into appropriate CBG testing timings for different diabetes medications. Hence, stratified monitoring and strategic 3 a.m. testing of CBG for patients on sulphonylurea and basal insulin should be considered in tackling inpatient hypoglycaemia.

Inflammasome is linked to many inflammatory diseases, including COVID-19 and autoimmune liver diseases. While severe COVID-19 was reported to exacerbate liver failure, we report a fatal acute-on-chronic liver failure (ACLF) in a stable primary biliary cholangitis-autoimmune hepatitis overlap syndrome patient triggered by a mild COVID-19 infection. Postmortem liver biopsy showed sparse SARS-CoV-2-infected macrophages with extensive ASC (apoptosis-associated speck-like protein containing a CARD) speck-positive hepatocytes, correlating with elevated circulating ASC specks and inflammatory cytokines, and depleted blood monocyte subsets, indicating widespread liver inflammasome activation. This first report of a fatal inflammatory cascade in an autoimmune liver disease triggered by a mild remote viral infection hopes to elucidate a less-described pathophysiology of ACLF that could prompt consideration of new diagnostic and therapeutic options.

Due to the paucity of longitudinal molecular studies of COVID-19, particularly those covering the early stages of infection (Days 1-8 symptom onset), our understanding of host response over the disease course is limited. We perform longitudinal single cell RNA-seq on 286 blood samples from 108 age- and sex-matched COVID-19 patients, including 73 with early samples. We examine discrete cell subtypes and continuous cell states longitudinally, and we identify upregulation of type I IFN-stimulated genes (ISGs) as the predominant early signature of subsequent worsening of symptoms, which we validate in an independent cohort and corroborate by plasma markers. However, ISG expression is dynamic in progressors, spiking early and then rapidly receding to the level of severity-matched non-progressors. In contrast, cross-sectional analysis shows that ISG expression is deficient and IFN suppressors such as SOCS3 are upregulated in severe and critical COVID-19. We validate the latter in four independent cohorts, and SOCS3 inhibition reduces SARS-CoV-2 replication in vitro. In summary, we identify complexity in type I IFN response to COVID-19, as well as a potential avenue for host-directed therapy.

The emergence of novel betacoronaviruses has posed significant financial and human health burdens, necessitating the development of appropriate tools to combat future outbreaks. In this study, we have characterized a human cell line, IGROV-1, as a robust tool to detect, propagate, and titrate betacoronaviruses SARS-CoV-2 and HCoV-OC43. IGROV-1 cells can be used for serological assays, antiviral drug testing, and isolating SARS-CoV-2 variants from patient samples. Using time-course transcriptomics, we confirmed that IGROV-1 cells exhibit a robust innate immune response upon SARS-CoV-2 infection, recapitulating the response previously observed in primary human nasal epithelial cells. We performed genome-wide CRISPR knockout genetic screens in IGROV-1 cells and identified Aryl hydrocarbon receptor (AHR) as a critical host dependency factor for both SARS-CoV-2 and HCoV-OC43. Using DiMNF, a small molecule inhibitor of AHR, we observed that the drug selectively inhibits HCoV-OC43 infection but not SARS-CoV-2. Transcriptomic analysis in primary normal human bronchial epithelial cells revealed that DiMNF blocks HCoV-OC43 infection via basal activation of innate immune responses. Our findings highlight the potential of IGROV-1 cells as a valuable diagnostic and research tool to combat betacoronavirus diseases.