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Li, C.

Publications and source records attributed to Li, C..

At least 451 records · Page 25Linked to original sources

Extracellular vesicle-derived miRNA-mediated cell-cell communication inference for single-cell transcriptomic data with miRTalk

MicroRNAs are released from cells in extracellular vesicles (EVs), representing an essential mode of cell-cell communication (CCC) via an inhibitory effect on gene expression. The advent of single-cell RNA-sequencing (scRNA-seq) technologies has ushered in an era of elucidating EV-derived miRNA-mediated CCC. However, the lack of computational methods to infer such CCC poses an outstanding challenge. Herein, we present miRTalk (https://github.com/multitalk/miRTalk), a pioneering framework for inferring EV-derived miRNA-mediated CCC with a probabilistic model and a curated database, miRTalkDB, which includes EV-derived miRNA-target associations. The benchmarking against simulated and real-world datasets demonstrated the remarkable accuracy and robustness of miRTalk. Subsequently, we employed miRTalk to uncover the in-depth CCC mechanisms underlying three disease scenarios. In summary, miRTalk represents the first approach for inferring EV-derived miRNA-mediated CCC with scRNA-seq data, providing invaluable insights into the CCC dynamics underpinning biological processes.

bioinformatics↗

VirID: Beyond Virus Discovery - An Integrated Platform for Comprehensive RNA Virus Characterization

RNA viruses exhibit vast phylogenetic diversity and can significantly impact public health and agriculture. However, current bioinformatics tools for viral discovery from metagenomic data frequently generate false positive virus results, overestimate viral diversity, and misclassify virus sequences. Additionally, current tools often fail to determine virus-host associations, which hampers investigation of the potential threat posed by a newly detected virus. To address these issues we developed VirID, a software tool specifically designed for the discovery and characterization of RNA viruses from metagenomic data. The basis of VirID is a comprehensive RNA-dependent RNA polymerase (RdRP) database to enhance a workflow that includes RNA virus discovery, phylogenetic analysis, and phylogeny-based virus characterization. Benchmark tests on a simulated data set demonstrated that VirID had high accuracy in profiling viruses and estimating viral richness. In evaluations with real-world samples, VirID was able to identity RNA viruses of all type, but also provided accurate estimations of viral genetic diversity and virus classification, as well as comprehensive insights into virus associations with humans, animals, and plants. VirID therefore offers a robust tool for virus discovery and serves as a valuable resource in basic virological studies, pathogen surveillance, and early warning systems for infectious disease outbreaks.

bioinformatics↗

GeneSurfer Enables Transcriptome-wide Exploration and Functional Annotation of Gene Co-expression Modules in 3D Spatial Transcriptomics Data

Gene co-expression provides crucial insights into biological functions, however, there is a lack of exploratory analysis tools for localized gene co-expression in large-scale datasets. We present GeneSurfer, an interactive interface designed to explore localized transcriptome-wide gene co-expression patterns in the 3D spatial domain. Key features of GeneSurfer include transcriptome-wide gene filtering and gene clustering based on spatial local co-expression within transcriptomically similar cells, multi-slice 3D rendering of average expression of gene clusters, and on-the-fly Gene Ontology term annotation of co-expressed gene sets. Additionally, GeneSurfer offers multiple linked views for investigating individual genes or gene co-expression in the spatial domain at each exploration stage. Demonstrating its utility with both spatial transcriptomics and single-cell RNA sequencing data from the Allen Brain Cell Atlas, GeneSurfer effectively identifies and annotates localized transcriptome-wide co-expression, providing biological insights and facilitating hypothesis generation and validation.

bioinformatics↗

Recommendations for Population and Individual Diagnostic SNP Selection in Non-Model Species

Despite substantial reductions in the cost of sequencing over the last decade, genetic panels remain relevant due to their cost-effectiveness and flexibility across a variety of sample types. In particular, single nucleotide polymorphism (SNP) panels are increasingly favored for conservation applications. SNP panels are often used because of their adaptability, effectiveness with low-quality samples, and cost-efficiency for use in population monitoring and forensics. However, the selection of diagnostic SNPs for population assignment and individual identification can be challenging. The consequences of poor SNP selection are under-powered panels, inaccurate results, and monetary loss. Here, we develop a novel user-friendly SNP selection pipeline for population assignment and individual identification, mPCRselect. mPCRselect allows any researcher, who has sufficient SNP-level data, to design a successful and cost-effective SNP panel for species of conservation concern.

evolutionary biology↗

Forecasting trade and biosecurity risk under climate change

1.Executive summaryIt is well known that the increasing globalisation of human movement and trade has led to substantial range expansions of many taxa, and as a consequence, is increasingly exposing countries to novel biosecurity threats. This increased exposure to novel threats is expected to be exacerbated by a changing climate as trade patterns and species distributions change. In many countries biosecurity regulators are already struggling to contend with the increased exposure to pests and diseases, and as such, must shift towards a pro-active strategy of anticipating risk. However, to anticipate risk, regulators must make better use of the data they collect (e.g. border interceptions) and develop models capable of forecasting biosecurity propagule pressure and establishment exposure as a function of changing trade, human population, and species distributions. In this project, we develop a highly innovative model framework that simulates annual changes in international trade patterns (imports & exports) as a function of climate change impacts on crop productivity, labour productivity (via heat stress) and the amount of arable land. These simulated changes in global trade are then coupled with border interception data, and annual predicted changes in the geographic distributions of both human populations and threat climate suitability to estimate climate-induced changes in: 1) contamination rates for imports from different trading partners, 2) the total amount of biosecurity risk material arriving at Australias borders, and 3) its exposure to an establishment event (Figure 1.1). O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=91 SRC="FIGDIR/small/601437v1_fig1_1.gif" ALT="Figure 11"> View larger version (32K): org.highwire.dtl.DTLVardef@1755bcforg.highwire.dtl.DTLVardef@1de8225org.highwire.dtl.DTLVardef@1324d1forg.highwire.dtl.DTLVardef@16530e3_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFigure 1.1.:C_FLOATNO Conceptual diagram of innovative biosecurity forecasting model. The model is made up of two primary sub-modules: 1) The Economic submodel, which incorporates climate change damages (e.g. crop productivity & heat stress) and simulates these impacts on global import and export trade patterns; 2) The Ecological submodel that estimates threat climate suitability, country-by-commodity contamination rates, and then links these to predicted changes in both global trade flows (i.e. outputs from the Economic submodel) and human population to approximate country-specific propagule pressure and establishment exposure. C_FIG Here, we provide an in-depth description of both the trade and biosecurity risk sub-models. We then illustrate the models implementation and outputs under two different climate scenarios (RCP 4.5 and RCP 8.5) for the purposes of forecasting temporal changes in: 1) global and regional economic trade; and 2) the amount of biosecurity risk material arriving at Australias border (i.e. propagule pressure) and what it may mean for establishment exposure. In illustrating the biosecurity risk, we focused on five plant pests deemed by the Department of Agriculture, Fisheries and Forestry (DAFF) as an exemplar of different hitch-hiking functional groups. The exemplar threats examined were: O_LIOverwintering - brown marmorated stink bug (BMSB; Halyomorpha halys) C_LIO_LIEgg laying - Spongy moth (Lymantria dispar) C_LIO_LINesting - Asian honey bee (Apis cerana) C_LIO_LISheltering - Giant African snail (Lissachatina fulica) C_LIO_LIInternal storage - Khapra beetle (Trogoderma granarium). C_LI 2. Key findings & model utility2.1. Global and regional economic trade consequences of climate changeThe climate-enhanced trade model shows significant changes in trade patterns globally. Climate change impacts various countries differently, causing substantial changes in national incomes, productive capacity, and imports and exports around the world. This occurs even with relatively limited damage functions from global warming. Indeed, with limited damage functions (crop productivity losses, labour productivity losses due to heat stress, and loss of arable land from ocean inundation), the impact on national income in Australia from climate change is relatively small (e.g., damages from more substantive sea level rise and storm surge are not included). However, damages to trading partners and changes in imports to Australia, as well as the rest of the world, are considerable. To allow for easy interrogation of these predicted trade impacts, we have developed an interactive dashboard1 that allows users to examine changes in trade patterns - by country, commodity and climate change scenario - for user selected imports by country and total values. The following summarise the key findings from the select damage functions employed within this analysis: O_LIWestern African regions fare the worst in terms of overall GDP impacts, with the region at large experiencing roughly a 20% loss to GDP. The second most affected region is South Asia2 with Pakistan bearing the greatest damages. Some countries emerged relatively unscathed, prominently those located in North America, Europe, Russia, and Oceania. C_LIO_LIIn terms of climate change related damages to key Australian trading partners, we find that losses in China and Southeast Asia3 are the most consequential. Here labour productivity shocks due to heat stress lead to losses in manufacturing sector imports such as Motor vehicles and Electronic equipment. As the largest exporter of manufacturing goods and a key region affected by climate change, China sees the largest decline in exports, however most of South and Southeast Asia fares worse in terms of relative losses with India and Indonesia seeing over 10% losses. Conversely, net gains are made across several European regions, particularly Germany and the UK. C_LIO_LIThe greatest heterogeneity within macroeconomic sector was observed among agricultural imports and in particular crop sectors in large part due to the varied mix of exporters for each crop type and differential impacts experienced. The largest absolute increase among food- and agriculture-related sectors is seen within Vegetables, fruit, nuts with large increases in exports from OECD regions and China. C_LIO_LIThe climate change damage functions employed here likely vastly underestimate the true costs of climate change impacts for a number of reasons. These include the following: O_LIRecent scholarship suggests that large damages to GDP are already being experienced (Romanello et al., 2023) whereas the earlier work used here (with the exception of crop productivity) includes minimal damages at early timesteps. Further, the anticipated impacts from warming may be far larger (particularly at later timesteps) if climate sensitivities have been misestimated (leading to more extreme associated temperature paths) or tipping points are triggered. C_LIO_LIThe application of damages used within the current study is limited in terms of scope, with damages due to human health impacts and changes in tourism trends missing. In addition to the limited scope, some damages that have been implemented have not been fully allocated to all affected sectors. For example, sea level rise is understood entirely within the purview of loss of arable land while physical capital depreciation and impacts to manufacturing hubs located on coastal areas is not currently simulated. C_LIO_LISociopolitical consequences of climate change such as armed conflict and forced migration are not included. Diminished social resilience due to climate change related impacts (e.g., rising food insecurity) has the potential to feed back into the economy in myriad ways, potentially cascading into additional economic damages and/or altered trade patterns. C_LI C_LIO_LIAlthough limited climate change damages have been implemented, large changes in socioeconomic trends including economic and demographic growth are anticipated to occur within the long-term time horizon used within the current study. Such changes affect key Australian trade partners and have the potential to alter the composition of imports at a magnitude equal to or surpassing climate change impacts. Full simulation of both socioeconomic pathways as well as climate change impacts is currently a CEBRA priority. C_LI 2.2. Changes in pest propagule pressure & establishment exposure hitting Australia.While this report focuses on long-term trends in annual propagule pressure and establishment exposure hitting Australias border, the model is capable of estimating such trends for all 70 global regions and can be readily updated with new interception data. As such, to facilitate interrogation of model outputs, we have developed leaflet interactive maps for each of the five threats. Included in these maps are information4 about temporal trends in pest pressure, establishment exposure (if threat is influenced by climate suitability) and proportion of risk attributable to each infected exporters and commodity sector. The following summarise the key findings we found by running the model for the five exemplar threats: O_LIOut of the five exemplar threats, brown marmorated stink bug (BMSB; Halyomorpha halys) posed the greatest propagule pressure and established risk to Australia. This was followed by giant African snail (Lissachatina fulica), Khapra beetle (Trogoderma granarium), Asian honey bee (Apis cerana), and then spongy moth (Lymantria dispar). C_LIO_LIImports of manufacturing commodities (e.g. electronic equipment, motor vehicles and parts, plastics and metals) from infected countries posed the greatest risk of hitch-hiker contamination, with some exporting regions posing greater risk than others. C_LIO_LIWe detected marginal (albeit uncertain) positive impacts of potential area of suitable climate on the contamination rates coming from infected exporting regions for BMSB and to a lesser extent Spongy moth. This meant that in exporting regions where climate suitability is predicted to increase (e.g. Canada & United Kingdom for BMSB), contamination rates will be higher. By contrast, in regions where climate suitability is expected to decrease (e.g. Italy for BMSB), contamination rates are expected to decline. Area of suitable climate had no discernable impacts on contamination rates associated with Asian honey bee or giant African snail.5 C_LIO_LIDifferences in trends in predicted propagule pressure (i.e. number of contaminated lines) hitting Australias border between the two climate scenarios were found to be small and highly uncertain for all threats examined in this report. Multiple reasons are attributable to this: O_LIThere are compensatory effects occurring, whereby reductions (due to either decreased trade or climate-induced declines in contamination likelihoods) in contaminated items from one infected exporter is made up by increases in another. C_LIO_LIClimate impacts on exports and imports of manufactured goods - the commodity types with highest likelihoods of containing most of the modelled hitch-hikers used in this study - are likely to be severely underestimated. Recent work (Romanello et al., 2023) suggests that the existing set of damages included may severely underestimate the true impacts of climate change, especially on manufacturing sectors. Extending the trade model to include a larger set of damage functions, particularly those that encompass physical capital depreciation due to sea level rise and other disasters magnified by climate change (e.g., bushfires), is expected to result in significantly greater economic impacts within affected manufacturing and related sectors. This in turn will manifest in more significant impacts on global export and import flows, and thus, the total pest pressure expected at Australias border. C_LIO_LIThere remains significant uncertainty on how climate suitability in exporting regions impacts contamination rates. While our model detected marginal positive relationships between contamination rates and area of suitable climate for some threats (e.g. BMSB), uncertainty is partly driven by the number of infected exporting countries containing the threat and how variable climate suitability is within and among those trading partners. This uncertainty could be further reduced by including additional interception data from other countries (e.g. New Zealand) as well as incorporating additional information on other factors likely to impact contamination likelihoods such as known extent of established populations, time since establishment, or other factors that can inform population size in exporting country. C_LI C_LIO_LITrends in Australias exposure to potential BMSB or Spongy moth establishment were expected to decline overtime due to a combination of reduced propagule pressure (caused by declines in volume of trade from high risk trading partners and/or climate-induced declines contamination rates), and declines in climatic suitability at Australian locations where goods are likely to be unpacked. These declines were most pronounced under the worst-case climate scenario (RCP 8.5). By contrast, no discernable trends were found for Asian honey bee or giant African snail - mostly due to 1) minor impacts on trade volumes from infected exporters; 2) negligible impacts of climate suitability on contamination rates; and 3) climate suitability in locations import goods are most likely to be unpacked remaining relatively stable (i.e. where urban centres are predicted to remain). C_LI 2.3. Potential model utilityWe believe that this new model provides the necessary information needed for governments and industry to better anticipate - and therefore manage and adapt to - future climate change impacts on domestic and international economies, global trade, and exposure to biosecurity risk. The current work may serve as a foundation for informing policy decisions as well as a range of downstream models. For example model outputs can be used: O_LIto directly inform both short-term and long-term policies associated with border screening effort among different commodities and exporters, threat prioritisation and developing or updating Import Risk Assessments (IRAs). C_LIO_LIas inputs into other models used by DAFF such as: the post-border pest establishment likelihood model edmaps (Camac et al., 2020, 2021b)6 for informing post-border surveillance & establishment potential, the Risk Return Resource Allocation (RRRA) model, and CEBRAs value model (Dodd et al., 2021) for informing potential damages accrued over time by an exotic threat and the benefits of different mitigation strategies. C_LIO_LIto identify regions and economic sectors most susceptible to changing climate, and thus, provide governments with the necessary foresight to plan and adapt to potential impacts. C_LI

ecology↗

Rbm24 maintains survival of cochlear outer hair cells by repressing Insm1

The inactivation of Rbm24, an RNA-binding protein, results in the degeneration of cochlear outer hair cells (OHCs) during the postnatal period. However, the specific molecular mechanisms underlying this OHC death remain elusive. To address this, we conducted a comprehensive analysis comparing the gene profiles of wild-type OHCs to those lacking Rbm24 (Rbm24-/-) at postnatal day 7 (P7). Our results revealed that the overall differentiation program of OHCs is delayed in the absence of Rbm24. Furthermore, the expression of Insm1, a crucial factor for OHC development that is normally switched off by P2, remains prolonged in Rbm24-/- OHCs. Interestingly, when Insm1 is overexpressed, it also leads to OHC death. Significantly, the OHC degeneration is much less severe when both Rbm24 and Insm1 are simultaneously inactivated. These findings shed light on the important role of Rbm24 in repressing Insm1 and its impact on OHC differentiation and survival. Our study provides valuable insights into the complex genetic signaling pathways involved in OHC development.

neuroscience↗

TimiGP-Response: the pan-cancer immune landscape associated with response to immunotherapy

Accumulating evidence suggests that the tumor immune microenvironment (TIME) significantly influences the response to immunotherapy, yet this complex relationship remains elusive. To address this issue, we developed TimiGP-Response (TIME Illustration based on Gene Pairing designed for immunotherapy Response), a computational framework leveraging single-cell and bulk transcriptomic data, along with response information, to construct cell-cell interaction networks associated with responders and estimate the role of immune cells in treatment response. This framework was showcased in triple-negative breast cancer treated with immune checkpoint inhibitors targeting the PD-1:PD-L1 interaction, and orthogonally validated with imaging mass cytometry. As a result, we identified CD8+ GZMB+ T cells associated with responders and its interaction with regulatory T cells emerged as a potential feature for selecting patients who may benefit from these therapies. Subsequently, we analyzed 3,410 patients with seven cancer types (melanoma, non-small cell lung cancer, renal cell carcinoma, metastatic urothelial carcinoma, hepatocellular carcinoma, breast cancer, and esophageal cancer) treated with various immunotherapies and combination therapies, as well as several chemo- and targeted therapies as controls. Using TimiGP-Response, we depicted the pan-cancer immune landscape associated with immunotherapy response at different resolutions. At the TIME level, CD8 T cells and CD4 memory T cells were associated with responders, while anti-inflammatory (M2) macrophages and mast cells were linked to non-responders across most cancer types and datasets. Given that T cells are the primary targets of these immunotherapies and our TIME analysis highlights their importance in response to treatment, we portrayed the pan-caner landscape on 40 T cell subtypes. Notably, CD8+ and CD4+ GZMK+ effector memory T cells emerged as crucial across all cancer types and treatments, while IL-17-producing CD8+ T cells were top candidates associated with immunotherapy non-responders. In summary, this study provides a computational method to study the association between TIME and response across the pan-cancer immune landscape, offering resources and insights into immune cell interactions and their impact on treatment efficacy.

bioinformatics↗

A host enzyme reduces non-alcoholic fatty liver disease by inactivating intestinal lipopolysaccharide

The incidence of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) has been increasing world-wide. Since gut-derived bacterial lipopolysaccharides (LPS) can travel via the portal vein to the liver and play an important role in producing hepatic pathology, it seemed possible that (1) LPS stimulates hepatic cells to accumulate lipid, and (2) inactivating LPS can be preventive. Acyloxyacyl hydrolase (AOAH), the eukaryotic lipase that inactivates LPS and oxidized phospholipids, is produced in the intestine, liver, and other organs. We fed mice either normal chow or a high-fat diet for 28 weeks and found that Aoah-/- mice accumulated more hepatic lipid than did Aoah+/+ mice. In young mice, before increased hepatic fat accumulation was observed, Aoah-/-mouse livers increased their abundance of Sterol Regulatory Element-Binding Protein 1 (SREBP1) and the expression of its target genes that promote fatty acid synthesis. Aoah-/- mice also increased hepatic expression of CD36 and Fabp3, which mediate fatty acid uptake, and decreased expression of fatty acid oxidation-related genes Acot2 and Ppar-. Our results provide evidence that increasing AOAH abundance in the gut, bloodstream and/or liver may be an effective strategy for preventing or treating MASLD.

immunology↗

Insect metamorphosis is regulated differently between sexes by members of a microRNA cluster

Insects comprise the majority of all described animal species and dominate the terrestrial habitats. The evolution of insect metamorphosis played a profound role in their successful adaptation and radiation. Insect metamorphosis is dependent on hormones ecdysteroids and sesquiterpenoids such as juvenile hormone. Despite the fact there are genuine differences between sexes during insect metamorphosis which facilitate their successful mating, how such sexual dimorphism in metamorphosis is being controlled is poorly known. We first generated transcriptomic profiles of male and female flies in late larvae and early pupae stages. Using a combination of genome-wide prediction and in vitro dual-luciferase validations, members of a microRNA cluster miR-277/34 were found to potentially regulate the neuropeptide receptor (AstC-R1) that when activated inhibits the sesquiterpenoid pathway and a juvenile hormone-dependent transcription factor (Kr-h1) in fly Drosophila melanogaster. Loss-of-function mutants were created deleting either miR-277 or miR-34, and expression levels of both AstC-R1 and Kr-h1 as well as ecdysteroid and sesquiterpenoid hormone titres were altered. Further comparison of transcriptomes of the late larvae and early pupae of both sexes revealed differential gene pathways being regulated by members of miR-277/34 between sexes during metamorphosis. This study highlights how members of a microRNA cluster control hormonal and developmental gene pathways in different sexes of insects during metamorphosis.

evolutionary biology↗

Microsporidian Nosema bombycis secretes serine protease inhibitor to suppress host cell apoptosis via caspase BmICE

Microsporidia are a group of intracellular pathogens that actively manipulate host cell biological processes to facilitate their intracellular niche. Apoptosis is an important defense mechanism by which host cell control intracellular pathogens. Microsporidia modulating host cell apoptosis has been reported previously, however the molecular mechanism is not yet clear. In this report, we describe that the microsporidia Nosema bombycis inhibits apoptosis of Bombyx mori cells through a secreted protein NbSPN14, which is a serine protease inhibitor (Serpin). An immunofluorescent assay demonstrated that upon infection with N. bombycis, NbSPN14 was initially found in the B. mori cell cytoplasm and then became enriched in the host cell nucleus. Overexpression and RNA-interference (RNAi) of NbSPN14 in B. mori embryo cells confirmed that NbSPN14 inhibited host cell apoptosis. Immunofluorescent and Co-IP assays verified the co-localization and interaction of NbSPN14 with the BmICE, the caspase 3 homolog in B. mori. Knocking out of BmICE or mutating the BmICE-interacting P1 site of NbSPN14, eliminated the localization of NbSPN14 into the host nucleus and prevented the apoptosis-inhibiting effect of NbSPN14, which also proved that the interaction between BmICE and NbSPN14 occurred in host cytoplasm and the NbSPN14 translocation into host cell nucleus is dependent on BmICE. These data elucidate that N. bombycis secretory protein NbSPN14 inhibits host cell apoptosis by directly inhibiting the caspase protease BmICE, which provides an important insight for understanding pathogen-host interactions and a potential therapeutic target for N. bombycis proliferation. Author SummaryMicrosporidia constitute a class of eukaryotic pathogens that exclusively reside within host cells. The species Nosema bombycis is the first microsporidian identified as the pathogen of silkworm Pebrine disease. In our research, we discovered how N. bombycis cleverly evades the hosts defenses. It has developed a strategy to survive inside host cells by manipulating host cell apoptosis, disarming the host cells self-destruct mechanism. In this study, we discovered that the N. bombycis secretes a serine protease inhibitor named NbSPN14, which infiltrates the cytoplasm of the host cell. The NbSPN14 interacts with the executioner Caspase protease BmICE within the silkworms apoptotic pathway, effectively neutralizing its apoptoic activity and thus curbing the apoptosis of the host cells.

microbiology↗

Multiomics mapping and characterization of cellular senescence in aging human muscle uncovers novel senotherapeutics for sarcopenia

Cellular senescence is recognized as a hallmark of organismal aging but how it drives aging particularly in human tissues is not fully understood, partly due to the complex heterogeneous nature of senescence. Here in this study, we leverage single-nucleus multiomics to profile senescence in mononucleated cells of human skeletal muscle and provide the first senescence atlas. We demonstrate the intra-and inter-populational transcriptomic and epigenomic heterogeneity and dynamics of senescence in the cells. We also identify commonalities and variations in senescence-associated secretory phenotypes (SASPs) among the cells and elucidate the function of SASPs in mediating cellular interactions and niche deregulation. Furthermore, we identify targetable SASP factors and demonstrate the possibility of using Maraviroc as a pharmacological senotherapeutic for treating age-associated sarcopenia in muscle. Lastly, we define transcription factors that govern senescence state and SASP induction in aging muscle and elucidate the key function and the underlying mechanism of JUNB in regulating SASP activation in senescent cells. Altogether, our findings demonstrate the prevalence and function of cellular senescence in skeletal muscle and identify a novel pharmacological intervention for sarcopenia.

cell biology↗

TS-AI: A deep learning pipeline for multimodal subject-specific parcellation with task contrasts synthesis

Accurate mapping of brain functional subregions at an individual level is crucial. Task-based functional MRI (tfMRI) captures subject-specific activation patterns during various functions and behaviors, facilitating the individual localization of functionally distinct subregions. However, acquiring high-quality tfMRI is time-consuming and resource-intensive in both scientific and clinical settings. The present study proposes a two-stage network model, TS-AI, to individualize an atlas on cortical surfaces through the prediction of tfMRI data. TS-AI first synthesizes a battery of task contrast maps for each individual by leveraging tract-wise anatomical connectivity and resting-state networks. These synthesized maps, along with feature maps of tract-wise anatomical connectivity and resting-state networks, are then fed into an end-to-end deep neural network to individualize an atlas. TS-AI enables the synthesized task contrast maps to be used in individual parcellation without the acquisition of actual task fMRI scans. In addition, a novel feature consistency loss is designed to assign vertices with similar features to the same parcel, which increases individual specificity and mitigates overfitting risks caused by the absence of individual parcellation ground truth. The individualized parcellations were validated by assessing test-retest reliability, homogeneity, and cognitive behavior prediction using diverse reference atlases and datasets, demonstrating the superior performance and generalizability of TS-AI. Sensitivity analysis yielded insights into region-specific features influencing individual variation in functional regionalization. In addition, TS-AI identified accelerated shrinkage in the medial temporal and cingulate parcels during the progression of Alzheimers disease, suggesting its potential in clinical research and applications.

neuroscience↗

Viral diversiy within marine biofilms and their potential roles in microbially influenced corrosion

In marine environments, a wide variety of microbes exert an important influence on the corrosion of materials. Viruses are widely distributed in biofilms formed on materials and may influence the corrosion process through interactions with key corrosive microbes. However, our understanding of the viral communities within biofilms and their implications for corrosion remains notably limited. To fill this knowledge gap, we utilized 53 publicly metagenomes to investigate the ecological dynamics of viruses within biofilms on 8 different materials and their potential roles in the corrosion of materials. In biofilms, the type of materials may be the primary factor driving differences in the diversity of viral communities. Viruses within biofilms predominantly belong to Caudoviricetes, and phylogenetic analysis of Caudoviricetes and protein-sharing networks with other environments revealed the presence of numerous novel viral clades in biofilms. The presence of virus-host linkages revealed a close association between viruses and corrosive microbes in biofilms. Viruses play a key role in corrosion by modulating host corrosion-related metabolism. It was observed that viruses could enhance host resistance to metals and antibiotics via horizontal gene transfer. Furthermore, viruses can protect themselves from host antiviral systems through anti-defense systems. Overall, this work illustrates the diversity of viruses within biofilms formed on materials and the intricate interactions between viruses and corrosive microbes, revealing the potential roles of viruses in microbially influenced corrosion.

microbiology↗

MCP5, a methyl-accepting chemotaxis protein regulated by both the Hk1-Rrp1 and Rrp2-RpoN-RpoS pathways, is required for the immune evasion of Borrelia burgdorferi

Borrelia (or Borreliella) burgdorferi, the causative agent of Lyme disease, is a motile and invasive zoonotic pathogen, adept at navigating between its arthropod vector and mammalian host. While motility and chemotaxis are well established as essential for its enzootic cycle, the function of methyl-accepting chemotaxis proteins (MCPs) in the infectious cycle of B. burgdorferi remains unclear. In this study, we demonstrate that MCP5, one of the most abundant MCPs in B. burgdorferi, is differentially expressed in response to environmental signals as well as at different stages of the pathogens enzootic cycle. Specifically, the expression of mcp5 is regulated by the Hk1-Rrp1 and Rrp2-RpoN-RpoS pathways, which are critical for the spirochetes colonization of the tick vector and mammalian host, respectively. Infection experiments with an mcp5 mutant revealed that spirochetes lacking MCP5 could not establish infections in either C3H/HeN mice or Severe Combined Immunodeficiency (SCID) mice, which are defective in adaptive immunity, indicating the essential role of MCP5 in mammalian infection. However, the mcp5 mutant could establish infection and disseminate in NOD SCID Gamma (NSG) mice, which are deficient in both adaptive and most innate immune responses, suggesting a crucial role of MCP5 in evading host innate immunity. In the tick vector, the mcp5 mutants survived feeding but failed to transmit to mice, highlighting the importance of MCP5 in transmission. Our findings reveal that MCP5, regulated by the Rrp1 and Rrp2 pathways, is critical for the establishment of infection in mammalian hosts by evading host innate immunity and is important for the transmission of spirochetes from ticks to mammalian hosts, underscoring its potential as a target for intervention strategies. SUMMARYLyme disease is the most commonly reported arthropod-borne illness in the US, Europe, and Asia. The causative agent of Lyme disease, Borrelia burgdorferi, is maintained in an enzootic cycle involving arthropod vectors (Ixodes ticks) and rodent mammalian hosts. Understanding how B. burgdorferi moves within this natural cycle is crucial for developing new strategies to combat Lyme disease. The complex nature of the enzootic cycle necessitates sensory-guided movement in response to environmental stimuli. B. burgdorferi possesses a unique and intricate chemotaxis signaling system, with methyl-accepting chemotaxis proteins (MCPs) at its core. These proteins are responsible for sensing environmental signals and guiding bacterial movement toward or away from stimuli. This study found that one of the MCPs, MCP5, is highly expressed and differentially regulated during the enzootic cycle by the Hk1-Rrp1 and Rrp2-RpoN-RpoS pathways. MCP5 is crucial for mammalian infection, aiding in immune evasion and transmission from ticks to mammals, providing a foundation for further research into B. burgdorferis navigation within its hosts.

microbiology↗

Critical assessment of missense variant effect predictors on disease-relevant variant data

Regular, systematic, and independent assessment of computational tools used to predict the pathogenicity of missense variants is necessary to evaluate their clinical and research utility and suggest directions for future improvement. Here, as part of the sixth edition of the Critical Assessment of Genome Interpretation (CAGI) challenge, we assess missense variant effect predictors (or variant impact predictors) on an evaluation dataset of rare missense variants from disease-relevant databases. Our assessment evaluates predictors submitted to the CAGI6 Annotate-All-Missense challenge, predictors commonly used by the clinical genetics community, and recently developed deep learning methods for variant effect prediction. To explore a variety of settings that are relevant for different clinical and research applications, we assess performance within different subsets of the evaluation data and within high-specificity and high-sensitivity regimes. We find strong performance of many predictors across multiple settings. Meta-predictors tend to outperform their constituent individual predictors; however, several individual predictors have performance similar to that of commonly used meta-predictors. The relative performance of predictors differs in high-specificity and high-sensitivity regimes, suggesting that different methods may be best suited to different use cases. We also characterize two potential sources of bias. Predictors that incorporate allele frequency as a predictive feature tend to have reduced performance when distinguishing pathogenic variants from very rare benign variants, and predictors supervised on pathogenicity labels from curated variant databases often learn label imbalances within genes. Overall, we find notable advances over the oldest and most cited missense variant effect predictors and continued improvements among the most recently developed tools, and the CAGI Annotate-All-Missense challenge (also termed the Missense Marathon) will continue to assess state-of-the-art methods as the field progresses. Together, our results help illuminate the current clinical and research utility of missense variant effect predictors and identify potential areas for future development.

genetics↗

Potent and broadly neutralizing antibodies against sarbecoviruses elicited by single ancestral SARS-CoV-2 infection

Monoclonal antibody (mAb) therapeutics hold promise for both preventing and treating infectious diseases, especially among vulnerable populations. However, the emergence of various variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents challenges for current mAb treatments, emphasizing the need for more potent and broadly neutralizing antibodies. In this study, we employed an unbiased screening approach to discover broadly neutralizing antibodies and successfully isolated two mAbs from individuals with only exposure to ancestral SARS-CoV-2. One of these antibodies, CYFN1006-1, exhibited robust cross-neutralization against a spectrum of SARS-CoV-2 variants, including the latest JN.1 and KP.2 variants, with consistent IC50 values ranging from [~]1 to 5 ng/mL. Notably, it also displayed broad neutralization activity against SARS-CoV and related sarbecoviruses, such as WIV1, SHC014, RaTG13, and GD-Pangolin. Structural analysis revealed that these mAbs target shared hotspot but mutation-resistant epitopes, with their Fabs locking the RBD in the "down" conformation through interactions with adjacent Fabs and RBDs, and cross-linking Spike trimers into di-trimers to block viral infection. In vivo studies conducted in a JN.1-infected hamster model validated the protective efficacy of CYFN1006-1, emphasizing its therapeutic potential. These findings suggest that, through meticulous approaches, rare antibodies with cross-neutralization activities against SARS-CoV-2 and related sarbecoviruses can be identified from individuals with exclusively ancestral virus exposure.

microbiology↗

An organoid co-culture model for probing systemic anti-tumor immunity in lung cancer

Deciphering the interactions between tumor micro- and systemic immune macro-environment is essential for developing more effective cancer diagnosis and treatment strategies. Here, we established a gel-liquid interface (GLI) co-culture of lung cancer organoids (LCOs) and paired peripheral blood mononuclear cells (PBMCs), featuring with enhanced interactions of immune cells and tumor organoids, to mimic the in vivo systemic anti-tumor immunity induced by immune checkpoint inhibitors (ICI). The co-culture model recapitulates the in vivo ICI-induced T cell recruitment and subsequent tumor regression, predicting the clinical results precisely. We demonstrated that circulating tumor-reactive T cells, which are effector memory-like with high expression levels of GNLY, CD44 and CD9, can serve as an indicator of the immunotherapy efficacy. Interestingly, enhanced inflammatory signaling in blood T cells is accompanied with prompted exhaustion and compromised anti-tumor function, when encountering with organoids. Our findings suggest that the GLI co-culture can be used for developing diagnostic strategies for precision immunotherapies as well as understanding the underlying mechanisms. Summary figure O_FIG O_LINKSMALLFIG WIDTH=178 HEIGHT=200 SRC="FIGDIR/small/597327v1_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@a0829dorg.highwire.dtl.DTLVardef@1df3083org.highwire.dtl.DTLVardef@1ea1065org.highwire.dtl.DTLVardef@1da9464_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

Cell-Graph Compass: Modeling Single Cells with Graph Structure Foundation Model

Inspired by the advancements in pre-trained Large Language Models, there has been a surge of studies in the Life Sciences focusing on constructing foundation models with large scale single-cell RNA-seq data. These studies typically involve pre-training a transformer model on large-scale single-cell sequencing data, followed by fine-tuning for a variety of downstream tasks, achieving notable performance. However, these models all share a common short-coming: to utilize the transformer architecture, originally designed for textual data, they artificially impose a sequential structure on genes within cells, simplifying the complex interactions between genes. Furthermore, they focus solely on transcriptomic data, neglecting other relevant biological information. To address these issues, here we introduce Cell-Graph Compass (CGC), the first foundational model that leverages graph structures to model single cells and describes cells from multiple perspectives, including transcriptional profiles, gene text summaries, transcription factor regulatory networks, gene co-expression patterns, and gene positional relationships. By incorporating self-attention mechanisms, we pretrained the model on 50 million human single-cell sequencing data, resulting in a robust digital representation of cells. Extensive downstream experiments demonstrate that our approach can capture meaningful biological knowledge and achieve superior results in various problem scenarios, achieving the state-of-the-art (SOTA).

bioinformatics↗