Emx2 underlies the development and evolution of marsupial gliding membranes.

Phenotypic variation among species is a product of evolutionary changes to developmental programs1,2. However, how these changes generate novel morphological traits remains largely unclear. Here we studied the genomic and developmental basis of the mammalian gliding membrane, or patagium-an adaptative trait that has repeatedly evolved in different lineages, including in closely related marsupial species. Through comparative genomic analysis of 15 marsupial genomes, both from gliding and non-gliding species, we find that the Emx2 locus experienced lineage-specific patterns of accelerated cis-regulatory evolution in gliding species. By combining epigenomics, transcriptomics and in-pouch marsupial transgenics, we show that Emx2 is a critical upstream regulator of patagium development. Moreover, we identify different cis-regulatory elements that may be responsible for driving increased Emx2 expression levels in gliding species. Lastly, using mouse functional experiments, we find evidence that Emx2 expression patterns in gliders may have been modified from a pre-existing program found in all mammals. Together, our results suggest that patagia repeatedly originated through a process of convergent genomic evolution, whereby regulation of Emx2 was altered by distinct cis-regulatory elements in independently evolved species. Thus, different regulatory elements targeting the same key developmental gene may constitute an effective strategy by which natural selection has harnessed regulatory evolution in marsupial genomes to generate phenotypic novelty.

Comparative cranial biomechanics reveal that Late Cretaceous tyrannosaurids exerted relatively greater bite force than in early-diverging tyrannosauroids.

Tyrannosaurus has been an exemplar organism in feeding biomechanical analyses. An adult Tyrannosaurus could exert a bone-splintering bite force, through expanded jaw muscles and a robust skull and teeth. While feeding function of adult Tyrannosaurus has been thoroughly studied, such analyses have yet to expand to other tyrannosauroids, especially early-diverging tyrannosauroids (Dilong, Proceratosaurus, and Yutyrannus). In our analysis, we broadly assessed the cranial and feeding performance of tyrannosauroids at varying body sizes. Our sample size included small (Proceratosaurus and Dilong), medium-sized (Teratophoneus), and large (Tarbosaurus, Daspletosaurus, Gorgosaurus, and Yutyrannus) tyrannosauroids, and incorporation of tyrannosaurines at different ontogenetic stages (small juvenile Tarbosaurus, Raptorex, and mid-sized juvenile Tyrannosaurus). We used jaw muscle force calculations and finite element analysis to comprehend the cranial performance of our tyrannosauroids. Scaled subtemporal fenestrae areas and calculated jaw muscle forces show that broad-skulled tyrannosaurines (Tyrannosaurus, Daspletosaurus, juvenile Tyrannosaurus, and Raptorex) exhibited higher jaw muscle forces than other similarly sized tyrannosauroids (Gorgosaurus, Yutyrannus, and Proceratosaurus). The large proceratosaurid Yutyrannus exhibited lower cranial stress than most adult tyrannosaurids. This suggests that cranial structural adaptations of large tyrannosaurids maintained adequate safety factors at greater bite force, but their robust crania did not notably decrease bone stress. Similarly, juvenile tyrannosaurines experienced greater cranial stress than similarly-sized earlier tyrannosauroids, consistent with greater adductor muscle forces in the juveniles, and with crania no more robust than in their small adult predecessors. As adult tyrannosauroid body size increased, so too did relative jaw muscle forces manifested even in juveniles of giant adults.

Developing Cardio-Oncology Programs in the New Era: Beyond Ventricular Dysfunction Due to Cancer Treatments.

Cardiovascular disease is a common problem in cancer patients that is becoming more widely recognized. This may be a consequence of prior cardiovascular risk factors but could also be secondary to the anticancer treatments. With the goal of offering a multidisciplinary approach to guaranteeing optimal cancer therapy and the early detection of related cardiac diseases, and in light of the recent ESC Cardio-Oncology Guideline recommendations, we developed a Cardio-Oncology unit devoted to the prevention and management of these specific complications. This document brings together important aspects to consider for the development and organization of a Cardio-Oncology program through our own experience and the current evidence.

Water-soluble fluorescent chemosensor for sorbitol based on a dicationic diboronic receptor. Crystal structure and spectroscopic studies.

Selective recognition of saccharides by phenylboronic dyes capable of functioning in aqueous conditions is a central topic of modern supramolecular chemistry that impacts analytical sciences and biological chemistry. Herein, a new dicationic diboronic acid structure 11 was synthesized, structurally described by single-crystal X-ray diffraction, and studied in-depth as fluorescent receptor for six saccharides in pure water at pH = 7.4. This dicationic receptor 11 has been designed particularly to respond to sorbitol and involves two convergent and strongly acidified phenyl boronic acids, with a pKa of 6.6, that operate as binding sites. The addition of sorbitol in the micromolar concentration range to receptor 11 induces strong fluorescence change, but in the presence of fructose, mannitol, glucose, lactose and sucrose, only moderate optical changes are observed. This change in emission is attributed to a static complexation photoinduced electron transfer mechanism as evidenced by lifetime experiments and different spectroscopic tools. The diboronic receptor has a high affinity/selectivity to sorbitol (K = 31 800 M-1) over other saccharides including common interfering species such as mannitol and fructose. The results based on 1H, 11B NMR spectroscopy, high-resolution mass spectrometry and density functional theory calculations, support that sorbitol is efficiently bound to 11 in a 1 : 1 mode involving a chelating diboronate-sorbitol complexation. Since the experimental B⋯B distance (5.3 Å) in 11 is very close to the calculated distance from the DFT-optimized complex with sorbitol, the efficient binding is attributed to strong acidification and preorganization of boronic acids. These results highlight the usefulness of a new diboronic acid receptor with a strong ability for fluorescent recognition of sorbitol in physiological conditions.

Studying Hair Growth Cycle and its Effects on Mouse Skin.

Researchers should be aware that hair growth cycle drives prominent molecular, cellular, and morphological changes to the entire skin. Thus, hair growth constitutes a major experimental variable that influences the interpretation of dermatological studies. Hair growth in mice is neither asynchronous nor fully synchronized; rather, it occurs in waves that dynamically propagate across the skin. In consequence, any given area of mouse skin can contain hair follicles in different stages of the cycle in close physical proximity. Furthermore, hair growth waves in mice are initiated by probabilistic events at different time points and across stochastic locations. The consequence of such stochasticity is that precise patterns of hair growth waves differ from mouse to mouse, even in littermates of the same sex. However, such physiological stochasticity is commonly misconstrued as a significant hair growth phenotype in mutant mice or in drug-treated mice. The purpose of this article is to provide a set of guidelines for designing reliably interpretable murine studies on hair growth and to highlight key experimental caveats to be avoided. It also informs on how to account for and minimize the impact of physiological hair cycle differences when designing and interpreting nonhair growth dermatological studies in mice.

A Roadmap for a Consensus Human Skin Cell Atlas and Single-Cell Data Standardization.

Single-cell technologies have become essential to driving discovery in both basic and translational investigative dermatology. Despite the multitude of available datasets, a central reference atlas of normal human skin, which can serve as a reference resource for skin cell types, cell states, and their molecular signatures, is still lacking. For any such atlas to receive broad acceptance, participation by many investigators during atlas construction is an essential prerequisite. As part of the Human Cell Atlas project, we have assembled a Skin Biological Network to build a consensus Human Skin Cell Atlas and outline a roadmap toward that goal. We define the drivers of skin diversity to be considered when selecting sequencing datasets for the atlas and list practical hurdles during skin sampling that can result in data gaps and impede comprehensive representation and technical considerations for tissue processing and computational analysis, the accounting for which should minimize biases in cell type enrichments and exclusions and decrease batch effects. By outlining our goals for Atlas 1.0, we discuss how it will uncover new aspects of skin biology.

Dynamic interplay between IL-1 and WNT pathways in regulating dermal adipocyte lineage cells during skin development and wound regeneration.

Dermal adipocyte lineage cells are highly plastic and can undergo reversible differentiation and dedifferentiation in response to various stimuli. Using single-cell RNA sequencing of developing or wounded mouse skin, we classify dermal fibroblasts (dFBs) into distinct non-adipogenic and adipogenic cell states. Cell differentiation trajectory analyses identify IL-1-NF-κB and WNT-ß-catenin as top signaling pathways that positively and negatively associate with adipogenesis, respectively. Upon wounding, activation of adipocyte progenitors and wound-induced adipogenesis are mediated in part by neutrophils through the IL-1R-NF-κB-CREB signaling axis. In contrast, WNT activation, by WNT ligand and/or ablation of Gsk3, inhibits the adipogenic potential of dFBs but promotes lipolysis and dedifferentiation of mature adipocytes, contributing to myofibroblast formation. Finally, sustained WNT activation and inhibition of adipogenesis is seen in human keloids. These data reveal molecular mechanisms underlying the plasticity of dermal adipocyte lineage cells, defining potential therapeutic targets for defective wound healing and scar formation.

Signalling by senescent melanocytes hyperactivates hair growth.

Niche signals maintain stem cells in a prolonged quiescence or transiently activate them for proper regeneration1. Altering balanced niche signalling can lead to regenerative disorders. Melanocytic skin nevi in human often display excessive hair growth, suggesting hair stem cell hyperactivity. Here, using genetic mouse models of nevi2,3, we show that dermal clusters of senescent melanocytes drive epithelial hair stem cells to exit quiescence and change their transcriptome and composition, potently enhancing hair renewal. Nevus melanocytes activate a distinct secretome, enriched for signalling factors. Osteopontin, the leading nevus signalling factor, is both necessary and sufficient to induce hair growth. Injection of osteopontin or its genetic overexpression is sufficient to induce robust hair growth in mice, whereas germline and conditional deletions of either osteopontin or CD44, its cognate receptor on epithelial hair cells, rescue enhanced hair growth induced by dermal nevus melanocytes. Osteopontin is overexpressed in human hairy nevi, and it stimulates new growth of human hair follicles. Although broad accumulation of senescent cells, such as upon ageing or genotoxic stress, is detrimental for the regenerative capacity of tissue4, we show that signalling by senescent cell clusters can potently enhance the activity of adjacent intact stem cells and stimulate tissue renewal. This finding identifies senescent cells and their secretome as an attractive therapeutic target in regenerative disorders.

Convergent deployment of ancestral functions during the evolution of mammalian flight membranes.

Lateral flight membranes, or patagia, have evolved repeatedly in diverse mammalian lineages. While little is known about patagium development, its recurrent evolution may suggest a shared molecular basis. By combining transcriptomics, developmental experiments, and mouse transgenics, we demonstrate that lateral Wnt5a expression in the marsupial sugar glider (Petaurus breviceps) promotes the differentiation of its patagium primordium. We further show that this function of Wnt5a reprises ancestral roles in skin morphogenesis predating mammalian flight and has been convergently used during patagium evolution in eutherian bats. Moreover, we find that many genes involved in limb development have been redeployed during patagium outgrowth in both the sugar glider and bat. Together, our findings reveal that deeply conserved genetic toolkits contribute to the evolutionary transition to flight in mammals.

Screening cell-cell communication in spatial transcriptomics via collective optimal transport.

Spatial transcriptomic technologies and spatially annotated single-cell RNA sequencing datasets provide unprecedented opportunities to dissect cell-cell communication (CCC). However, incorporation of the spatial information and complex biochemical processes required in the reconstruction of CCC remains a major challenge. Here, we present COMMOT (COMMunication analysis by Optimal Transport) to infer CCC in spatial transcriptomics, which accounts for the competition between different ligand and receptor species as well as spatial distances between cells. A collective optimal transport method is developed to handle complex molecular interactions and spatial constraints. Furthermore, we introduce downstream analysis tools to infer spatial signaling directionality and genes regulated by signaling using machine learning models. We apply COMMOT to simulation data and eight spatial datasets acquired with five different technologies to show its effectiveness and robustness in identifying spatial CCC in data with varying spatial resolutions and gene coverages. Finally, COMMOT identifies new CCCs during skin morphogenesis in a case study of human epidermal development.

The hidden toll of community outreach.

Caught in a system eager for success stories, a PhD student from an underrepresented background learns how to balance his challenges in the lab with his desire to serve his community.

SDHAR-HOME: A Sensor Dataset for Human Activity Recognition at Home.

Nowadays, one of the most important objectives in health research is the improvement of the living conditions and well-being of the elderly, especially those who live alone. These people may experience undesired or dangerous situations in their daily life at home due to physical, sensorial or cognitive limitations, such as forgetting their medication or wrong eating habits. This work focuses on the development of a database in a home, through non-intrusive technology, where several users are residing by combining: a set of non-intrusive sensors which captures events that occur in the house, a positioning system through triangulation using beacons and a system for monitoring the user's state through activity wristbands. Two months of uninterrupted measurements were obtained on the daily habits of 2 people who live with a pet and receive sporadic visits, in which 18 different types of activities were labelled. In order to validate the data, a system for the real-time recognition of the activities carried out by these residents was developed using different current Deep Learning (DL) techniques based on neural networks, such as Recurrent Neural Networks (RNN), Long Short-Term Memory networks (LSTM) or Gated Recurrent Unit networks (GRU). A personalised prediction model was developed for each user, resulting in hit rates ranging from 88.29% to 90.91%. Finally, a data sharing algorithm has been developed to improve the generalisability of the model and to avoid overtraining the neural network.

Hedgehog signaling reprograms hair follicle niche fibroblasts to a hyper-activated state.

Hair follicle stem cells are regulated by dermal papilla fibroblasts, their principal signaling niche. Overactivation of Hedgehog signaling in the niche dramatically accelerates hair growth and induces follicle multiplication in mice. On single-cell RNA sequencing, dermal papilla fibroblasts increase heterogeneity to include new Wnt5ahigh states. Transcriptionally, mutant fibroblasts activate regulatory networks for Gli1, Alx3, Ebf1, Hoxc8, Sox18, and Zfp239. These networks jointly upregulate secreted factors for multiple hair morphogenesis and hair-growth-related pathways. Among these is non-conventional TGF-ß ligand Scube3. We show that in normal mouse skin, Scube3 is expressed only in dermal papillae of growing, but not in resting follicles. SCUBE3 protein microinjection is sufficient to induce new hair growth, and pharmacological TGF-ß inhibition rescues mutant hair hyper-activation phenotype. Moreover, dermal-papilla-enriched expression of SCUBE3 and its growth-activating effect are partially conserved in human scalp hair follicles. Thus, Hedgehog regulates mesenchymal niche function in the hair follicle via SCUBE3/TGF-ß mechanism.

Will climate change affect the survival of tropical and subtropical species? Predictions based on Bulwer's petrel populations in the NE Atlantic Ocean.

Climate change has repeatedly been shown to impact the demography and survival of marine top predators. However, most evidence comes from single populations of widely distributed species, limited mainly to polar and subpolar environments. Here, we aimed to evaluate the influence of environmental conditions on the survival of a tropical and migratory seabird over the course of its annual cycle. We used capture-mark-recapture data from three populations of Bulwer's petrel (Bulweria bulwerii) spread across the NE Atlantic Ocean, from the Azores, Canary, and Cabo Verde Islands (including temperate to tropical zones). We also inferred how the survival of this seabird might be affected under different climatic scenarios, defined by the Intergovernmental Panel on Climate Change. Among the environmental variables whose effect we evaluated (North Atlantic Oscillation index, Southern Oscillation Index, Sea Surface Temperature [SST] and wind speed), SST estimated for the breeding area and season was the variable with the greatest influence on adult survival. Negative effects of SST increase emerged across the three populations, most likely through indirect trophic web interactions. Unfortunately, our study also shows that the survival of Bulwer's petrel will be profoundly affected by the different scenarios of climate change, even with the most optimistic trajectory involving the lowest greenhouse gas emission. Furthermore, for the first time, our study predicts stronger impacts of climate change on tropical populations than on subtropical and temperate ones. This result highlights the devastating effect that climate change may also have on tropical areas, and the importance of considering multi-population approaches when evaluating its impacts which may differ across species distributions.

Diet-Induced Obesity Disrupts Histamine-Dependent Oleoylethanolamide Signaling in the Mouse Liver.

INTRODUCTION: Previous work suggests the existence of a paracrine signaling mechanism in which histamine released from visceral mast cells into the portal circulation contributes to fasting-induced ketogenesis by stimulating biosynthesis of the endogenous high-affinity PPAR-α agonist oleoylethanolamide (OEA). METHODS: Male C57Bl/6J mice were rendered obese by exposure to a high-fat diet (HFD; 60% fat). We measured histamine, OEA, and other fatty-acid ethanolamides by liquid-chromatography/mass spectrometry, gene transcription by RT-PCR, protein expression by ELISA, neutral lipid accumulation in the liver using Red Oil O and BODIPY staining, and collagen levels using picrosirius red staining. RESULTS: Long-term exposure to HFD suppressed both fasting-induced histamine release into portal blood and histamine-dependent OEA production in the liver. Additionally, subchronic OEA administration reduced lipid accumulation, inflammatory responses, and fibrosis in the liver of HFD-exposed mice. DISCUSSION: The results suggest that disruption of histamine-dependent OEA signaling in the liver might contribute to pathology in obesity-associated liver steatosis.

Anion Recognition by Benzoxaborole.

The binding types (H-bonding or coordinate) and stability constants for complexes of 11 mono- and di-anions with benzoxaborole (1) were determined by 1H and 11B NMR titrations in DMSO or MeCN. Compared to phenylboronic acid (PBA), 1 is a stronger Lewis acid and a poorer H-bond donor with only one B-OH group, which is expected therefore to recognize anions mostly through the coordinate bonding. This is the case however only with F-, HPO42-, and PhPO32- anions, which are coordinately bonded to 1, and partially with SO42-, which forms only the H-bonded complex with PBA, but both H-bonded and coordinate complexes with 1. The majority of tested anions (AcO-, PhPO3H-, (PhO)2PO2-, Cl-, and Br-) form H-bonded complexes with both 1 and PBA, whereas H2PO4- changes the binding mode from coordinate for PBA to H-bonded for 1. The preferable binding type for each anion is confirmed by calculations of DFT-optimized structures of the anion complexes of 1. The preferable binding type can be rationalized considering the effects of the steric hindrance, more significant for the coordinate bonding, and of increased anion basicity, which is favorable for both binding types, but enhances the strength of coordinate bonding more significantly than the strength of H-bonding.

Usefulness of telemedicine-based heart failure monitoring according to 'eHealth literacy' domains: Insights from the iCOR randomized controlled trial.

BACKGROUND: The potential positive effect of electronic health (eHealth)-based heart failure (HF) monitoring remains uncertain mainly in the 'low literacy' or 'computer or digital illiterate' patients. The aim of this study was to determine the effectiveness of a telemedicine (TM)-based managed care solution across literacy levels and information and communications technology (ICT) skills. METHODS: We performed a sub-analysis on the basis of two literacy domains encompassed in the definition of 'eHealth literacy' to the HF-patients included in the 'insuficiència Cardíaca Optimització Remota' (iCOR) randomized study comparing TM vs. usual care (UC) in HF-patients. The primary study endpoint was the incidence of a non-fatal HF event after 6 months of inclusion. The event rates of primary and secondary study endpoints were calculated for each literacy domains and its combination. Cox proportional-hazards regression models were used to evaluate the effect of 'eHealth literacy' dimensions, treatment group and the interaction term 'eHealth literacy' domains by treatment group on study endpoints. RESULTS: The beneficial effect of TM compared to UC strategy was consistent across all literacy domains (p-value for interaction 0.207 and 0.117 respectively). The risk of experiencing a primary event was significantly lower in patients that underwent allocation to the TM arm compared to UC in both clustered in the 'lower literacy' (p-value=0.001) and those allocated to the 'lower ICT skills' (p-value=0.001) subgroup. CONCLUSIONS: Non-invasive eHealth-based HF monitoring tools are effective compared to UC in preventing HF events in the early post-discharge period, regardless of two 'eHealth literacy' domains ('traditional and computer literacy').

Strong Aversive Conditioning Triggers a Long-Lasting Generalized Aversion.

Generalization is an adaptive mnemonic process in which an animal can leverage past learning experiences to navigate future scenarios, but overgeneralization is a hallmark feature of anxiety disorders. Therefore, understanding the synaptic plasticity mechanisms that govern memory generalization and its persistence is an important goal. Here, we demonstrate that strong CTA conditioning results in a long-lasting generalized aversion that persists for at least 2 weeks. Using brain slice electrophysiology and activity-dependent labeling of the conditioning-active neuronal ensemble within the gustatory cortex, we find that strong CTA conditioning induces a long-lasting increase in synaptic strengths that occurs uniformly across superficial and deep layers of GC. Repeated exposure to salt, the generalized tastant, causes a rapid attenuation of the generalized aversion that correlates with a reversal of the CTA-induced increases in synaptic strength. Unlike the uniform strengthening that happens across layers, reversal of the generalized aversion results in a more pronounced depression of synaptic strengths in superficial layers. Finally, the generalized aversion and its reversal do not impact the acquisition and maintenance of the aversion to the conditioned tastant (saccharin). The strong correlation between the generalized aversion and synaptic strengthening, and the reversal of both in superficial layers by repeated salt exposure, strongly suggests that the synaptic changes in superficial layers contribute to the formation and reversal of the generalized aversion. In contrast, the persistence of synaptic strengthening in deep layers correlates with the persistence of CTA. Taken together, our data suggest that layer-specific synaptic plasticity mechanisms separately govern the persistence and generalization of CTA memory.