Search bioRxiv⌕ Search

Biology subjects

Su, K.

Publications and source records attributed to Su, K..

18 recordsLinked to original sources

Post-infection immune response in adults with COVID-19 with and without nirmatrelvir-ritonavir treatment and virologic rebound

BackgroundNirmatrelvir-ritonavir (N-R) reduces morbidity and mortality from COVID-19 in high-risk individuals; however, N-R use has been associated with risk of SARS-CoV-2 virologic rebound. The mechanisms contributing to virologic rebound after N-R treatment are currently unknown. One plausible mechanism is that antiviral treatment may alter the development of immune responses to SARS-CoV-2 infection, thereby contributing to rebound after cessation of therapy. MethodsWe profiled immune responses in a case-ascertained, longitudinal, prospective cohort of ambulatory individuals with COVID-19. Participants were grouped according to whether virological rebound occurred and whether they had received N-R treatment. We assessed antibody, T-cell, and innate responses. ResultsWe observed no differences in the binding or neutralizing antibody, T-cell, and innate immune responses between participants with virologic rebound compared to participants without virologic rebound. N-R use was associated with slightly weaker antibody responses overall, even after adjustment for immunosuppression. ConclusionVirologic rebound after N-R treatment is likely driven by non-immune mechanisms. FundingThe project was supported by the National Institutes of Health (R01 AI 138801) and the Massachusetts Consortium on Pathogen Readiness. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.

immunology↗

Advancing ab initio genome annotation with OrionGeno

The rapid expansion of eukaryotic genome sequencing has created an urgent demand for accurate and scalable genome annotation. Existing ab initio methods often struggle to reconstruct complex gene architectures and generalize across distant lineages, limiting their use for large-scale annotation. Here we present OrionGeno, a phylogeny-aware deep learning model for end-to-end eukaryotic genome annotation. OrionGeno integrates phylogenetic context, long-range sequence modeling and joint prediction of gene structures and repetitive elements to annotate exons, introns, untranslated regions and repeats directly from genomic sequences. Applied to chromosome-level eukaryotic genomes from NCBI that lack annotations, OrionGeno generates annotations for more than 5,300 genomes, substantially expanding public annotation resources. Across diverse eukaryotic lineages, OrionGeno outperforms state-of-the-art methods at the exon, gene, protein-sequence, and protein-structural levels. It also identifies candidate protein-coding loci absent from reference protein-coding annotations in well-curated genomes. Together with a web platform and integrated annotation database, OrionGeno provides a scalable and accessible framework for translating genome assemblies into functional biological resources and supporting large-scale biodiversity initiatives such as the Earth BioGenome Project.

bioinformatics↗

Modular mRNA lipid nanoparticle platform rescues diverse genetic male infertility

Genetic male infertility arises from diverse mutations that disrupt spermatogenesis, yet therapeutic strategies capable of restoring germ-cell function remain limited. Messenger RNA (mRNA) therapeutics offer a programmable and non-integrating approach, but their functional compatibility in structured and immune-privileged tissues remains unclear. Here we identify a temporal mismatch between mRNA delivery kinetics and the progression of spermatogenesis as a key barrier to functional rescue. We show that delivery efficiency does not predict outcome: formulations with high peak expression but short duration fail to support spermiogenesis, whereas sustained expression aligned with developmental timing enables recovery. Guided by this principle, we establish a testis-targeted mRNA delivery platform that restores spermatogenesis across multiple genetic models and generates functional sperm capable of supporting embryo development and multigenerational inheritance. The approach is modular, extends to human seminiferous tubules ex vivo, and is supported by comprehensive safety analyses. Together, these findings define a design constraint for RNA therapeutics in structured tissues: functional rescue requires temporal alignment between delivery kinetics and the therapeutic window defined by tissue-specific biological programs.

bioengineering↗

SOX9 plays an essential role in myofibroblast driven hepatic granuloma integrity and parenchymal repair during schistosomiasis-induced liver damage

Schistosomiasis is a neglected, and potentially lethal, parasitic disease that affects hundreds of millions of people worldwide. As part of the schistosome lifecycle, parasite eggs accumulate within the liver where they evoke intense granulomatous pathology, typified by a dense extracellular matrix (ECM) barrier, which serves to contain toxic egg secretions. In severe cases, this progressive and irreversible egg-evoked ECM deposition can lead to pathological scarring, impaired liver function and lethality. Thus, identifying the core regulators that govern ECM deposition may aid discovery of new therapeutic targets for schistosomiasis. The transcription factor Sex determining region Y-box 9 (Sox9) is a known regulator of pathological scaring. We found that, following Schistosoma mansoni infection, SOX9 was ectopically expressed in myofibroblasts within the granuloma and in surrounding hepatocytes. In the absence of SOX9, granuloma size was significantly diminished, and mice failed to produce a robust ECM barrier around eggs, resulting in more diffuse liver injury and scattered distribution of immune cells. Immunologically, SOX9 loss in both naive and infected mice led to an increase in hepatic neutrophil and monocyte proportions, with the expansion of Ly6clo monocyte populations in infected SOX9 deficient mice only. Infected SOX9-deficient mice also displayed exaggerated Type 2 inflammation, including pronounced eosinophilia. These data highlight the importance of SOX9 for intact hepatic granuloma formation during schistosomiasis and suggest SOX9 or its related factors may provide attractive future targets for meeting the clinical need to limit and/or reverse fibrotic disease. Author SummaryMammalian infection with schistosome worms results in the deposition of parasite eggs in the liver, where they secrete organ damaging toxins. In response, the liver generates a cellular granuloma barrier rich in extracellular matrix to limit these secretions and protect the overall organ. As in other liver injuries, SOX9 becomes progressively expressed in multiple cell types during the time course of schistosome infection. To understand the role of SOX9 in the liver response to schistosomes we utilised a global SOX9 deficient mouse model. These mice show reduced and disorganised granuloma formation during schistosome infection, with disrupted hepatic immune profiles. This suggests that SOX9 is required to form a robust and coordinated granuloma barrier that limits liver damage in this important but neglected parasitic disease.

immunology↗

Extreme lead tolerance in an urban lizard

Lead (Pb) is an extremely toxic heavy metal pollutant pervasive in many environments with serious health consequences for humans and wildlife. We found that Cuban brown anole lizards (Anolis sagrei) in New Orleans, USA, have the highest mean (955{+/-}877 {micro}g/dL; N = 40) and individual (3,192 {micro}g/dL) blood lead levels of any free-living vertebrate reported to date. Unexpectedly, this extreme field lead exposure did not decrease performance in whole-organism traits commonly affected by lead (balance, sprint speed, endurance). To identify toxicity thresholds, we employed a 60-day lead-dosing experiment and found that the brown anole blood lead threshold for decreased whole-organism performance is over an order of magnitude higher than the already extreme mean field concentration (10,600 {micro}g/dL). Transcriptomic analysis of brain and liver from lizards in high and low lead sites revealed minor effects of lead exposure. However, several of the differentially expressed genes function in metal ion homeostasis and oxygen carrying capacity, pointing to cellular mechanisms that may contribute to high lead tolerance in these animals. The brown anole may be the most lead-tolerant vertebrate known to date and has the potential to serve as a powerful model system to help us understand mechanisms of lead tolerance.

ecology↗

Synthesis and Evaluation of Carmofur Analogs as Antiproliferative Agents, Inhibitors to the Main Protease (Mpro) of SARS-CoV-2, and Membrane Rupture-Inducing Agents

Initially developed as a derivatized analog of 5-fluorouracil for the treatment of colorectal cancer, carmofur has more recently demonstrated potent covalent inhibition of the main protease (Mpro) of SARS-CoV-2. Harnessing our previously described workflow for the optimized preparation of carmofur using benchtop 19F NMR spectroscopy, here, we prepared and evaluated a synthetic library of nine carmofur analogs with a selection of side chain motifs or single-atom substitution to explore the diversifiability of these compounds as Mpro inhibitors, where we discovered that a hexyl carbamate analog outperformed carmofur, and as antiproliferative agents in model human cell lines to identify differences in potency when the carbonyl electrophilicity and/or alkyl side chains are modified. Finally, we describe a novel workflow for the evaluation of membrane-rupturing small molecules through imaging of fluorescently labeled giant unilamellar vesicles (GUVs), and through this, we identified two lipophilic urethane analogs of carmofur bearing dodecyl urethane and octadecyl urethane side chains that have potent membrane-rupturing capability in the nanomolar range, providing insight into a potential mechanism for the in vitro activities of lipidated 5-fluorouracil analogs.

biochemistry↗

Neuregulin-1 Attenuates Myocardial Ischemia/Reperfusion Injury by Activating the UCP2/PINK1/LC3B-mediated Mitophagy

BACKGROUNDIschemia/reperfusion (I/R) injury may significantly affect the treatment outcomes and prognosis of patients with acute myocardial infarction following coronary artery recanalization. Available evidence suggests that neuregulin-1 (NRG-1) can provide a protection against myocardial I/R injury and is involved in various cardioprotective interventions by potential regulation of mitophagy. However, the molecular mechanisms linking NRG-1 and mitophagy remain to be clarified. This experiment aimed to determine whether NRG-1 postconditioning attenuated myocardial I/R injury through the regulation of mitophagy and to explore the underlying mechanisms. METHODBoth an in vivo myocardial I/R injury model of rats and an in vitro hypoxia/reoxygenation (H/R) model of H9C2 cardiomyocytes were applied. NRG-1 treatment was conducted immediately after I/R or H/R intervention. In the in vivo experiment, cardioprotective effects of NRG-1 were determined by infarct size, cardiac enzyme and histopathologic examinations. The potential downstream pathways and molecular targets of NRG-1 were screened by the RNA sequencing and the Protein-Protein Interaction Networks (PPI). The expression levels of mitochondrial uncoupling protein 2 (UCP2) and mitophagy-related protein in both the I/R myocardium and H/R cardiomyocytes were measured by immunofluorescence staining and Western blots. The activation of mitophagy was observed with the transmission electron microscopy (TEM) and JC-1 staining. RESULTSThe KEGG and GSEA analyses showed that the mitophagy-related pathways were enriched in the I/R myocardium treated with NRG-1, and UCP2 exhibited a significant correlation between mitophagy and interaction with PINK1. Meanwhile, the treatment with mitophagy inhibitor Mdivi-1 significant eliminated the cardioprotective effects of NRG-1 postconditioning in vivo, and the challenge with UCP2 inhibitor genipin could also attenuate the activating effect of NRG-1 postconditioning on mitophagy. Consistently, the in vitro experiment using H9C2 cardiomyocytes showd that NRG-1 treatment significantly up-regulated the expression levels of UCP2 and mitophagy-related proteins, and activated the mitophagy, whereas the challenge with small interfering RNA (siRNA)-mediated UCP2 knockdown abolished the effects of NRG-1. CONCLUSIONSNRG-1 postconditioning can produce a protection against the myocardial I/R injury by activating mitophagy through the UCP2/PINK1/LC3B signaling pathway.

molecular biology↗

Multi-View Integrative Approach For Imputing Short-Chain Fatty Acids and Identifying Key factors predicting Blood SCFA

Short-chain fatty acids (SCFAs) are the main metabolites produced by bacterial fermentation of dietary fiber within gastrointestinal tract. SCFAs produced by gut microbiotas (GMs) are absorbed by host, reach bloodstream, and are distributed to different organs, thus influencing host physiology. However, due to the limited budget or the poor sensitivity of instruments, most studies on GMs have incomplete blood SCFA data, limiting our understanding of the metabolic processes within the host. To address this gap, we developed an innovative multi-task multi-view integrative approach (M2AE, Multi-task Multi-View Attentive Encoders), to impute blood SCFA levels using gut metagenomic sequencing (MGS) data, while taking into account the intricate interplay among the gut microbiome, dietary features, and host characteristics, as well as the nuanced nature of SCFA dynamics within the body. Here, each view represents a distinct type of data input (i.e., gut microbiome compositions, dietary features, or host characteristics). Our method jointly explores both view-specific representations and cross-view correlations for effective predictions of SCFAs. We applied M2AE to two in-house datasets, which both include MGS and blood SCFAs profiles, host characteristics, and dietary features from 964 subjects and 171 subjects, respectively. Results from both of two datasets demonstrated that M2AE outperforms traditional regression-based and neural-network based approaches in imputing blood SCFAs. Furthermore, a series of gut bacterial species (e.g., Bacteroides thetaiotaomicron and Clostridium asparagiforme), host characteristics (e.g., race, gender), as well as dietary features (e.g., intake of fruits, pickles) were shown to contribute greatly to imputation of blood SCFAs. These findings demonstrated that GMs, dietary features and host characteristics might contribute to the complex biological processes involved in blood SCFA productions. These might pave the way for a deeper and more nuanced comprehension of how these factors impact human health.

bioinformatics↗

Modeling suggests SARS-CoV-2 rebound after nirmatrelvir-ritonavir treatment is driven by target cell preservation coupled with incomplete viral clearance

In a subset of SARS-CoV-2 infected individuals treated with the oral antiviral nirmatrelvir-ritonavir, the virus rebounds following treatment. The mechanisms driving this rebound are not well understood. We used a mathematical model to describe the longitudinal viral load dynamics of 51 individuals treated with nirmatrelvir-ritonavir, 20 of whom rebounded. Target cell preservation, either by a robust innate immune response or initiation of nirmatrelvir-ritonavir near the time of symptom onset, coupled with incomplete viral clearance, appear to be the main factors leading to viral rebound. Moreover, the occurrence of viral rebound is likely influenced by time of treatment initiation relative to the progression of the infection, with earlier treatments leading to a higher chance of rebound. Finally, our model demonstrates that extending the course of nirmatrelvir-ritonavir treatment, in particular to a 10-day regimen, may greatly diminish the risk for rebound in people with mild-to-moderate COVID-19 and who are at high risk of progression to severe disease. Altogether, our results suggest that in some individuals, a standard 5-day course of nirmatrelvir-ritonavir starting around the time of symptom onset may not completely eliminate the virus. Thus, after treatment ends, the virus can rebound if an effective adaptive immune response has not fully developed. These findings on the role of target cell preservation and incomplete viral clearance also offer a possible explanation for viral rebounds following other antiviral treatments for SARS-CoV-2. ImportanceNirmatrelvir-ritonavir is an effective treatment for SARS-CoV-2. In a subset of individuals treated with nirmatrelvir-ritonavir, the initial reduction in viral load is followed by viral rebound once treatment is stopped. We show the timing of treatment initiation with nirmatrelvir-ritonavir may influence the risk of viral rebound. Nirmatrelvir-ritonavir stops viral growth and preserves target cells but may not lead to full clearance of the virus. Thus, once treatment ends, if an effective adaptive immune response has not adequately developed, the remaining virus can lead to rebound. Our results provide insights into the mechanisms of rebound and can help develop better treatment strategies to minimize this possibility.

immunology↗

Generating single-cell gene expression profiles for high-resolution spatial transcriptomics based on cell boundary images

Stereo-seq is a cutting-edge technique for spatially resolved transcriptomics that combines subcellular resolution with centimeter-level field-of-view, serving as a technical foundation for analyzing large tissues at the single-cell level. Our previous work presents the first one-stop software that utilizes cell nuclei staining images and statistical methods to generate high-confidence single-cell spatial gene expression profiles for Stereo-seq data. With recent advancements in Stereo-seq technology, it is possible to acquire cell boundary information, such as cell membrane/wall staining images. To take advantage of this progress, we update our software to a new version, named STCellbin, which utilizes the cell nuclei staining images as a bridge to align cell membrane/wall staining images with spatial gene expression maps. By employing an advanced cell segmentation technique, accurate cell boundaries can be obtained, leading to more reliable single-cell spatial gene expression profiles. Experimental results verify that STCellbin can be applied on the mouse liver (cell membranes) and Arabidopsis seed (cell walls) datasets and outperforms other competitive methods. The improved capability of capturing single cell gene expression profiles by this update results in a deeper understanding of the contribution of single cell phenotypes to tissue biology. Availability & ImplementationThe source code of STCellbin is available at https://github.com/STOmics/STCellbin.

bioinformatics↗

Integrated Spatial Transcriptomic and Proteomic Analysis of Fresh Frozen Tissue Based on Stereo-seq

To simultaneously detect whole transcriptomes and protein markers on the same tissue section, we combined Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq) and Stereo-seq to develop the Stereo-CITE-seq workflow. Here, we demonstrated that Stereo-CITE-seq can co-detect mRNAs and proteins in immune organs with high spatial resolution, reproducibility and accuracy.

molecular biology↗

Spatial-temporal evolution characteristics of land use and its driving factor analysis during the period of 2000-2020 in Putian City, Fujian Province

Exploring the spatial and temporal evolution characteristics of land use and its driving force can provide scientific basis for the construction of regional ecological civilization. Based on the remote sensing cloud computing platform of Google Earth Engine (GEE), the study took the remote sensing images of the three periods of 2000, 2010 and 2020 as the basic data and interpreted them to obtain the basic land use data of Putian city and its five districts and counties. The land-use change characteristics of Putian city in those periods were systematically analyzed by using the methods of single land-use dynamics and Geo-informatic Tupu, so as to reveal the Tupu characteristics of land-use transfer and the spatial-temporal evolution pattern in the past 20 years. Then social and economic development indicators were selected to further explore the key driving force of land-use evolution in the study area by canonical correspondence analysis. The results showed that: 1) the land use structure of Putian city was mainly composed of cultivated land and forest land, and the other land types were embedded in them and the built-up land continued to expand outward. 2) The spatial distribution of Tupu units of land use transfer in Putian city was significantly different, change types of land use were diversified and the areas of cultivated land and grassland transferred out were the most obvious. Different degrees of cultivated land abandonment had occurred in various regions. Putian city was facing great challenges in ensuring food security and curbing the non-agricultural and non grain of cultivated land. 3) The macro-economic development in a specific period, especially the urban expansion and the development of the secondary industry caused by the merger of cities and counties, were the key factors driving the spatial and temporal evolution of land use and the differential distribution pattern in Putian city. The author suggested that land resources should be used efficiently in addition to optimizing the layout of land use and carrying out the renovation of abandoned land. Therefore, the study proposed to strengthen the scientific planning and effective regulation of land use, combine spatial and temporal resources of cultivated land with agriculture, culture and tourism, and build ecological barriers and ecological corridors to ensure the coordinated and sustainable development of regional ecology and economy.

ecology↗

Pairwise sequence similarity mapping with PaSiMap: reclassification of immunoglobulin domains from titin as case study

Sequence comparison is critical for the functional assignment of newly identified protein genes. As uncharacterised protein sequences accumulate, there is an increasing need for sensitive tools for their classification. Here, we present a novel multidimensional scaling pipeline, PaSiMap, which creates a map of pairwise sequence similarities. Uniquely, PaSiMap distinguishes between unique and shared features, allowing for a distinct view of protein-sequence relationships. We demonstrate PaSiMaps efficiency in detecting sequence groups and outliers using titins 169 immunoglobulin (Ig) domains. We show that Ig domain similarity is hierarchical, being firstly determined by chain location, then by the loop features of the Ig fold and, finally, by super-repeat position. The existence of a previously unidentified domain repeat in the distal, constitutive I-band is revealed. Prototypic Igs, plus notable outliers, are identified and thereby domain classification improved. This re-classification can now guide future molecular research. In summary, we demonstrate that PaSiMap is a sensitive tool for the classification of protein sequences, which adds a new perspective in the understanding of inter-protein relationships. PaSiMap is applicable to any biological system defined by a linear sequence, including nucleotides.

bioinformatics↗

NetAct: a computational platform to construct core transcription factor regulatory networks using gene activity

A major question in systems biology is how to identify the core gene regulatory circuit that governs the decision-making of a biological process. Here, we develop a computational platform, named NetAct, for constructing core transcription-factor regulatory networks using both transcriptomics data and literature-based transcription factor-target databases. NetAct robustly infers regulators activity using target expression, constructs networks based on transcriptional activity, and integrates mathematical modeling for validation. Our in-silico benchmark test shows that NetAct outperforms existing algorithms in inferring transcriptional activity and gene networks. We illustrate the application of NetAct to model networks driving TGF-{beta} induced epithelial-mesenchymal transition and macrophage polarization.

systems biology↗

Leveraging information in spatial transcriptomics to predict super-resolution gene expression from histology images in tumors

Recent developments in spatial transcriptomics (ST) technologies have enabled the profiling of transcriptome-wide gene expression while retaining the location information of measured genes within tissues. Moreover, the corresponding high-resolution hematoxylin and eosin-stained histology images are readily available for the ST tissue sections. Since histology images are easy to obtain, it is desirable to leverage information learned from ST to predict gene expression for tissue sections where only histology images are available. Here we present HisToGene, a deep learning model for gene expression prediction from histology images. To account for the spatial dependency of measured spots, HisToGene adopts Vision Transformer, a state-of-the-art method for image recognition. The well-trained HisToGene model can also predict super-resolution gene expression. Through evaluations on 32 HER2+ breast cancer samples with 9,612 spots and 785 genes, we show that HisToGene accurately predicts gene expression and outperforms ST-Net both in gene expression prediction and clustering tissue regions using the predicted expression. We further show that the predicted super-resolution gene expression also leads to higher clustering accuracy than observed gene expression. Gene expression predicted from HisToGene enables researchers to generate virtual transcriptomics data at scale and can help elucidate the molecular signatures of tissues.

bioinformatics↗

SOX9 is required for kidney fibrosis and regulates NAV3 to control renal myofibroblast function in mice and humans

Renal fibrosis is a common endpoint for many chronic kidney diseases. Extracellular matrix (ECM) from myofibroblasts causes progressive scarring and organ failure. The mechanisms underlying fibrogenesis and how it is sustained are incompletely understood. Here, we show that the transcription factor, Sex determining region Y-box 9 (SOX9), is required for kidney fibrosis. From genome-wide analysis we identify Neuron navigator 3 (NAV3) downstream of SOX9. NAV3 was upregulated in kidney disease in patients and following renal injury in mice colocalised with SOX9. By establishing an in vitro model of renal pericyte transition to myofibroblast we demonstrated that NAV3 is required for multiple aspects of fibrogenesis including actin polymerization linked to cell migration and sustaining SOX9 and active YAP1 levels. In summary, our work discovers novel SOX9-NAV3-YAP1/SOX9 circuitry as a new mechanism to explain the progression of kidney fibrosis and points to NAV3 as a novel target for pharmacological intervention.

cell biology↗

High-density genetic linkage map construction and white rot resistance QTL mapping for Vitis based on restriction site-associated DNA sequencing

Grape white rot (Coniothyrium diplodiella) is a major fungal disease affecting grape yield and quality. The present study aimed to provide a foundation to improve future grape white rot resistance breeding. To this end, interspecific hybridization was conducted between a white rot resistance cultivar Zhuosexiang (Vitus vinifera L. x Vitus labrusca L.), and a susceptible cultivar Victoria (Vitus vinifera L.), using 177 hybrid offspring and two parents for restriction site-associated DNA sequencing (RAD-seq) and high-density genetic linkage mapping. Female, male, and integrated map marker numbers were 2501, 4110, and 6249, respectively. The average genetic distance of adjacent markers was 1.25 cM, 0.77 cM, and 0.50 cM. White rot resistance identification of the two parents and 177 individuals was conducted in July and August of 2017 and 2018. Additionally, white rot resistance quantitative trait locus (QTL) mapping was conducted. In total, nine QTLs were detected and located on linkage groups LG1, LG4, LG7, LG12, LG14, and LG15, with overlapping QTLs on LG7 and LG15. Further, three candidate genes that may be responsible for grape white rot resistance were screened. The results will provide an important theoretical reference for future grape white rot resistance breeding.

genetics↗

LRRTM1 underlies synaptic convergence in visual thalamus

It has long been thought that the mammalian visual system is organized into parallel pathways, with incoming visual signals being parsed in the retina based on feature (e.g. color, contrast and motion) and then transmitted to the brain in unmixed, feature-specific channels. To faithfully convey feature-specific information from retina to cortex, thalamic relay cells must receive inputs from only a small number of functionally similar retinal ganglion cells. However, recent studies challenged this by revealing substantial levels of retinal convergence onto relay cells. Here, we sought to identify mechanisms responsible for the assembly of such convergence. Using an unbiased transcriptomics approach and targeted mutant mice, we discovered a critical role for the synaptic adhesion molecule Leucine Rich Repeat Transmembrane Neuronal 1 (LRRTM1) in the emergence of retinothalamic convergence. Importantly, LRRTM1 mutant mice display impairment in visual behaviors, suggesting a functional role of retinothalamic convergence in vision.

neuroscience↗