Biology subjects

Su, J.

Publications and source records attributed to Su, J..

At least 73 records · Page 4Linked to original sources

bioRxiv2025

Spatial transcriptomics elucidates the central role of cerebral vasculatures in the progression of Japanese encephalitis

The cellular and molecular mechanisms underlying the neuropathology of Japanese encephalitis virus (JEV) remain obscure. Herein, we designed Stereo-seq chips to simultaneously capture the in situ transcriptomes of both the host and JEV, constructing a comprehensive spatiotemporal pathological landscape for Japanese encephalitis (JE). This study reveals the central role of the vascular system in JE pathogenesis, particularly the meninges, which displayed the strongest signal of inflammation and cell death in the JEV-infected brain. The activation of the Ackr1+ endothelial cells, disruption of the blood-brain barrier, the migration of JEV-infected monocytes, secretion of immune factors by the infected cells, and the occurrence of pyroptosis and necroptosis form a positive feedback loop, resulting in an increasing influx of immune cells and tissue damage. JEV infection leads to neurological impairments, which may be attributed to the interaction between viral proteins and host cellular factors such as Stat1, Stat3, Nfkb1, and Sp1. As the vascular system serves as a central receiver and amplifier of inflammatory signals, regulating inflammation within the vascular system is essential in mitigating JE progression.

immunology↗

bioRxiv2025

SpaIM: Single-cell Spatial Transcriptomics Imputation via Style Transfer

Spatial transcriptomics (ST) technologies have revolutionized our understanding of cellular ecosystems. However, these technologies face challenges such as sparse gene signals and limited gene detection capacities, which hinder their ability to fully capture comprehensive spatial gene expression profiles. To address these limitations, we propose leveraging single-cell RNA sequencing (scRNA-seq), which provides comprehensive gene expression data but lacks spatial context, to enrich ST profiles. Herein, we introduce SpaIM, an innovative style transfer learning model that utilizes scRNA-seq information to predict unmeasured gene expressions in ST data, thereby improving gene coverage and expressions. SpaIM segregates scRNA-seq and ST data into data-agnostic contents and data-specific styles, with the contents capture the commonalities between the two data types, while the styles highlight their unique differences. By integrating the strengths of scRNA-seq and ST, SpaIM overcomes data sparsity and limited gene coverage issues, making significant advancements over 12 existing methods. This improvement is demonstrated across 53 diverse ST datasets, spanning sequencing- and imaging-based spatial technologies in various tissue types. Additionally, SpaIM enhances downstream analyses, including the detection of ligand-receptor interactions, spatial domain characterization, and identification of differentially expressed genes. Released as open-source software, SpaIM increases accessibility for spatial transcriptomics analysis. In summary, SpaIM represents a pioneering approach to enrich spatial transcriptomics using scRNA-seq data, enabling precise gene expression imputation and advancing the field of spatial transcriptomics research.

bioinformatics↗

bioRxiv2025

The Binary Cellular Biology of Human Growth I Quantifying the Creation and Growth of the Body and its Parts

Assessing and understanding the Growth and Development of animals generally, and of human fetuses specifically, provides essential information for the management of the health of the newborn and its mother. Here we show that a consideration of the formation of the body, in units of numbers of cells, N, and the change in these numbers by the binary either/or decisions of cells to divide or not, an approach we call Binary Cellular Analysis, provides new insights and new equations for quantifying the growth and development of the body and its parts. These equations include: 1) The Binary Cellular Universal Growth Equation, which captures growth from conception to adulthood, and provides a method for biologically-based, data-driven, Growth Curves; 2) The Binary Cellular Universal Mitotic Fraction Equation, which lies within the Binary Cellular Universal Growth Equation, and captures the mechanism of growth to adult size, control of cell division; 3) The Binary Cellular Allometric Growth Equation, which captures the creation and growth of the Tissues, Organs, and Anatomical Structures of the body, and how the embryo creates each Body Part from a Single Founder Cell; and, 4) Binary Cellular Estimated Fetal Weight Equations, derived from the Binary Cellular Allometric Growth Equation, which captures the relationship between Ultrasound Measurement and the Size of the body as a whole. These equations capture the developmental process of Cellular Selection, resulting from Differential Cellular Proliferation, which molds the formation of the body from a single fertilized ovum into a multicellular animal. The parameters of these equations both capture the differences in Size and Growth between animals across the taxonomic spectrum, and between human fetuses, as well as identify the individual mechanisms of mitosis that drive Growth and Development. From the Binary Cellular Universal Growth Equation, the Growth of human fetuses can be measured, thus providing a much-needed tool for understanding the biological forces that cause a fetus to grow to Small, Average, or Large Size at birth, for providing the basis of biologically-based, data-driven, Growth Curves, and for assisting the management of the obstetric care of the fetus and its mother.

developmental biology↗

bioRxiv2025

Heterogeneity of anti-Caspr2 antibodies: specificity and pathogenicity

Maternal anti-Caspr2 (Contactin-associated protein-like 2) antibodies have been associated with increased risk for autism spectrum disorder (ASD). Previous studies have shown that in utero exposure to anti-Caspr2 antibodies results in a phenotype with ASD-like features in male mice. Here we ask whether four newly generated antibodies against Caspr2 are pathogenic to the developing fetal brain and whether they function through similar means. Our results show that the novel anti-Caspr2 antibodies recognize different epitopes of Caspr2. In utero exposure to these antibodies elicits differential ASD-like phenotypes in male offspring, tested in the social interaction, open field, and light-dark tasks. These results demonstrate variability in the antigenic specificity and pathogenicity of anti-Caspr2 antibodies which may have clinical implications.

immunology↗

bioRxiv2025

Persistent interferon signaling that causes sensory neuron plasticity and pain in arthritis

While the inflammatory processes in rheumatoid arthritis have been described, mechanisms driving pain are poorly defined. Here, we used a multitude of approaches to uncover the neural basis, mediators, intracellular signaling pathway and the mechanism of inflammatory pain. In cartilage autoantibody-induced arthritis mice, an early immune-activation and a cytokine storm were mainly driven by vascular cells and monocyte/macrophages in the dorsal root ganglion. However, persistently elevated interferons and receptor-activation of the MNK1/2-eIF4E signaling pathway at all disease phases caused sensory-motor dysfunction and pain by inducing hyperexcitability and sensitization of Gfra3+ sensory neurons. Like mice, human sensory neurons expressed interferon receptors and interferons were elevated only in individuals with painful rheumatoid arthritis. Signaling pathway inhibition in vivo reversed pain and restored limb function. The finding that joint pain before and during arthritis is caused by a defined cytokine and signaling pathway holds promise for targeted therapies for pain relief in arthritis.

neuroscience↗

bioRxiv2025

Decoding the Molecular Language of Proteins with Evola

Proteins, natures intricate molecular machines, are the products of billions of years of evolution and play fundamental roles in sustaining life. Yet, deciphering their molecular language--understanding how sequences and structures encode biological functions--remains a cornerstone challenge. Here, we introduce Evolla, an interactive protein-language model designed to transcend static classification by interpreting protein function through natural language queries. Trained on 546 million protein-text pairs and refined via Direct Preference Optimization, Evolla couples high-dimensional molecular representations with generative semantic decoding. Benchmarking establishes Evollas superiority over general large language models in functional inference, demonstrates zero-shot performance parity with the state-of-the-art supervised model, and exposes remote functional relationships invisible to conventional alignment. We validate Evolla through two distinct applications: identifying candidate eukaryotic signature proteins in Asgard archaea, with functional Vps4 homologs validated via yeast complementation; and interactively discovering a novel deep-sea polyethylene terephthalate (PET) hydrolase, PsPETase, confirmed to degrade plastic films. These results position Evolla not merely as a predictor, but as a generative engine capable of complex hypothesis formulation, shifting the paradigm from static annotation to interactive, actionable discovery. The Evolla online service is available at http://www.chat-protein.com/.

bioinformatics↗

bioRxiv2024

A genome-scale single cell CRISPRi map of trans gene regulation across human pluripotent stem cell lines

Population-scale resources of genetic, molecular, and cellular information form the basis for understanding human genomes, charting the heritable basis of disease, and tracing the effects of mutations. Pooled perturbation assays applied to cellular models, probing the effect of many perturbations coupled with an scRNA-seq readout (Perturb-seq), are especially potent references for interpreting disease-linked mutations or gene expression changes. However, the utility of existing maps has been limited by the comprehensiveness of perturbations possible, and the relevance of their cell line context. Here, we present the first genome-scale CRISPR interference (CRISPRi) perturbation map with single-cell RNA sequencing readout across many human genetic backgrounds in human pluripotent cells. To do so, we establish large-scale CRISPRi screening in human induced pluripotent stem cells from healthy donors, using over 20,000 guide RNAs to target 7,226 genes across 34 cell lines from 26 genetic backgrounds, and gather expression data from nearly 2 million cells. We comprehensively map trans expression changes induced by the target knockdowns, which complement co-expression patterns in unperturbed cells and facilitate the functional annotation of target genes to biological processes and complexes. Consistency of targeting protein complex members point to protein complexes as a nexus for aggregating transcriptional variation, revealing novel interaction partners. We characterise variation in perturbation effects across donors, with expression quantitative trait loci linked to higher genetic modulation of perturbation effects but overall low replication of trans effects due to knockdown of their corresponding cis regulators. This study pioneers population-scale CRISPR perturbations with single cell readouts that will fuel foundation models for the future of effective modulation of cellular disease phenotypes.

genetics↗

bioRxiv2024

Loss of TMEM55B modulates lipid metabolism through dysregulated lipophagy and mitochondrial function

Lipophagy is a form of selective autophagy that targets the lipid droplets for lysosomal decay and has been implicated in the onset and progression of metabolic dysfunction-associated steatotic liver disease (MASLD). Factors that augment lipophagy have been identified as targets for MASLD therapeutic development. TMEM55B is a key regulator of lysosomal positioning which is critical for the lysosome fusion with the autophagosome, but less studied. Here, we demonstrate that inhibition of TMEM55B in murine models accelerates MASLD onset and progression. In cellular models, TMEM55B deficiency enhances lipophagy, leading to increased fatty acid release from lysosomes to mitochondria but simultaneously impairs mitophagy, causing an accumulation of dysfunctional mitochondria. This imbalance leads to increased lipid accumulation and oxidative stress, worsening MASLD. These findings underscore the importance of lysosomal positioning in lipid metabolism and suggest that augmenting lipophagy may exacerbate disease in the context of mitochondrial dysfunction.

cell biology↗

bioRxiv2024

Absorbing molecules make both abdomen and back transparent in live mice

The field of tissue clearing has experienced rapid advancements in the past decades. Tissue clearing techniques primarily rely on physical or chemical approaches to match the refractive indices of cells and their surrounding medium, thereby reducing light scattering and rendering the tissue optically transparent. By doing so, it becomes possible to utilize fluorescence imaging and 3D reconstruction techniques to observe and analyze the contents and structures of tissues at a cellular level. However, effective research on in vivo tissue clearing remains limited due to the involvement of toxic substances and the removal of water or lipids. A recent article in Science reports a technique that achieves tissue transparency in live animals with absorbing molecules, marking a significant advancement in the field of in vivo tissue clearing. Although this work has great potential for imaging and light-based therapeutics, some labs found it difficult to reproduce the reported results. In this study, we report the successful reproduction of the findings, provide experimental details that we identified as key to reproducibility, present a new transparency effect observed in the back of live mice, which was not shown in the original paper, and offer insights into the future development and applications of in vivo clearing reagents.

bioengineering↗

bioRxiv2024

Endogenous Huntingtin aggregates are a huge organized scaffold and mold for Golgi apparatus impaired by mutant Huntingtin protein

Abstract Huntingtin (HTT) is a naturally aggregating protein that causes Huntington's disease (HD) when its polyglutamine (polyQ) tract exceeds 38 repeats. Despite its importance, the biology of HTT aggregates remains poorly defined. Here, using high resolution imaging of cells derived from HD families, we redefine polyQ assemblies, traditionally regarded as pathogenic aggregates, as dynamic and structurally organized intracellular compartments resembling knitted-fabric patches. These assemblies closely associate with and encircle the Golgi apparatus, integrating Golgi ribbons and stacks to form a previously unrecognized polyQ assembly-Golgi complex. Mechanistically, fragmentation of polyQ assemblies is dynamically coupled with mitotic Golgi fragmentation, whereas inhibition of ADP-ribosylation factor (ARF) function by Brefeldin A disrupts and fragments the complex, revealing an intimate structural and functional coupling between polyQ assemblies and Golgi architecture. The presence of mutant HTT (mHTT) destabilizes these assemblies and complexes, altering their response to nutrient deprivation and autophagy enhancers but not to antisense oligonucleotide (ASO) therapy. Functionally, polyQ assemblies in HD cells compromise the scaffolding capacity of the Golgi apparatus, clathrin-coated vesicles, and ARF1, impair Golgi glycosylation, and promote aberrant neuronal firing activity. Collectively, these findings establish polyQ assemblies as dynamic structural regulators of Golgi organization and function and demonstrate that mHTT disrupts the homeostatic dynamics of the polyQ assembly-Golgi complex, leading to Golgipathy.

pathology↗

bioRxiv2024

Toward De Novo Protein Design from Natural Language

Programming biological function-designing bespoke proteins to perform specified molecular tasks-is a foundational goal of molecular engineering. However, current design paradigms remain fundamentally limited: they typically require either natural proteins as starting points for optimization or manual reformulation of functional goals as geometric and sequence-level constraints to guide candidate generation. Here we introduce Pinal, a 16-billion-parameter foundation model that designs candidate proteins from natural-language descriptions of desired function. Trained on 1.7 billion synthetically annotated protein-text pairs, Pinal links functional intent to protein sequence and structure. In computational evaluations, generated candidates combined high predicted foldability with functional-description alignment and sequence diversity, providing a basis for prioritizing experimentally testable designs. We applied Pinal to four distinct design tasks-a fluorescent protein, a polyethylene terephthalate hydrolase, an alcohol dehydrogenase and a metabolic H-protein-and experimentally observed the intended function in each case, including catalytic activity for both designed enzymes. Crucially, without iterative experimental optimization, a Pinal-designed H-protein increased product titer by 1.7-fold relative to the corresponding native E. coli H-protein in a multi-enzyme CO2 fixation pathway. These findings support natural language as a high-level interface for candidate generation in protein design, enabling programmable exploration with reduced reliance on manually specified structural or sequence constraints.

bioengineering↗

bioRxiv2024

Quantitative Label-Free Single-Cell Proteomics on the Orbitrap Astral MS

Single-cell proteomics by mass spectrometry (scp-MS) holds the potential to provide unprecedented insights into molecular features directly linked to the cellular phenotype, while deconvoluting complex organisms into their basic building blocks. Tailored sample preparation that maximizes the extracted amount of material that is introduced into the mass spectrometer has rapidly propelled the field forward. However, the measured signal is still at the lower edge of detection approaching the sensitivity boundary of current instrumentation. Here, we investigate the capacity of the enhanced sensitivity of the Orbitrap Astral mass spectrometer to facilitate deeper proteome profiles from low-input to single-cell samples. We carry out a comprehensive data acquisition method survey to pinpoint which parameters provide most sensitivity. Furthermore, we explore the quantitative accuracy of the obtained measurements to ensure that the obtained abundances are in line with expected ground truth values. We culminate our technical exploration by generating small datasets from two cultured cell lines and a primary bone marrow sample, to showcase obtainable proteome coverage differences from different source materials. Finally, as a proof of concept we explore protein covariation to showcase how information on known protein complexes is captured inherently in our scp-MS data.

biochemistry↗

bioRxiv2024

Towards a new standard in genomic data privacy: a realization of owner-governance

With the rapid developments in sequencing technologies, individuals now have unprecedented access to their genomic data. However, existing data management systems or protocols are inadequate for protecting privacy, limiting individuals control over their genomic information, hindering data sharing, and posing a challenge for biomedical research. To fill the gap, an owner-governed system that fulfills owner authority, lifecycle data encryption, and verifiability at the same time is prompted. In this paper, we realized Governome, an owner-governed data management system designed to empower individuals with absolute control over their genomic data during data sharing. Governome uses a blockchain to manage all transactions and permissions, enabling data owners with dynamic permission management and to be fully informed about every data usage. It uses homomorphic encryption and zero-knowledge proofs to enable genomic data storage and computation in an encrypted and verifiable form for its whole lifecycle. Governome supports genomic analysis tasks, including individual variant query, cohort study, GWAS analysis, and forensics. Query of a variants genotype distribution among 2,504 1kGP individuals in Governome can be efficiently completed in under 18 hours on an ordinary server. Governome is an open-source project available at https://github.com/HKU-BAL/Governome.

bioinformatics↗

bioRxiv2024

Wheat TaNADPO promotes spot blotch resistance

Bipolaris sorokiniana is a common soil-borne fungal pathogen that can infect various organs of wheat (Triticum aestivum L.), causing diseases such as spot blotch, common root rot, head blight, and black point. The genetic basis of wheat resistance to B. sorokiniana is not yet fully understood. In this study, a natural population of 1,302 global common wheat germplasms was established and inoculated with B. sorokiniana at the seedling stage in a greenhouse. Resistance to spot blotch was assessed, revealing that only about 3.8% of the germplasms exhibited moderate or higher resistance levels. A genome-wide association study (GWAS) using high-density 660K single nucleotide polymorphism (SNP) data identified a region on chromosome 1BL (621.2-674.0 Mb) with 9 SNPs significantly associated (p < 10e-4) with spot blotch resistance, designated as Qsb.hebau-1BL. RNA sequencing and qRT-PCR assays showed that the gene TraesCS1B02G410300, encoding nicotinamide-adenine dinucleotide phosphate-binding oxidoreductase (TaNADPO), was significantly induced by B. sorokiniana. Five SNP variations were found in the promoter region of TaNADPO in wheat lines with or without Qsb.hebau-1BL. Transient expression of TaNADPO in Nicotiana benthamiana leaves showed a cytoplasmic subcellular localization of the fusion protein with a green fluorescent protein (GFP) tag. Wheat transgenic lines overexpressing TaNADPO exhibited significantly enhanced resistance to spot blotch compared to wildtype plants, with higher accumulation of reactive oxygen species (ROS). The knockout EMS mutant of Triticum turgidum NADPO (tdnadpo-K2561, Gln125*) showed significantly reduced resistance to spot blotch and lower ROS accumulation compared to wildtype plants. In summary, TaNADPO has been identified as a crucial gene for resistance to B. sorokiniana, providing valuable insights for developing spot blotch-resistant wheat varieties through molecular breeding techniques.

genetics↗

bioRxiv2024

ProTrek: Navigating the Protein Universe through Tri-Modal Contrastive Learning

ProTrek redefines protein exploration by seamlessly fusing sequence, structure, and natural language function (SSF) into an advanced tri-modal language model. Through contrastive learning, ProTrek bridges the gap between protein data and human understanding, enabling lightning-fast searches across nine SSF pairwise modality combinations. Trained on vastly larger datasets, ProTrek demonstrates quantum leaps in performance: (1) Elevating protein sequence-function interconversion by 30-60 fold; (2) Surpassing current alignment tools (i.e., Foldseek and MMseqs2) in both speed (100-fold acceleration) and accuracy, identifying functionally similar proteins with diverse structures; and (3) Outperforming ESM-2 in 9 of 11 downstream prediction tasks, setting new benchmarks in protein intelligence. These results suggest that ProTrek will become a core tool for protein searching, understanding, and analysis.

bioinformatics↗

bioRxiv2024

The 11β-hydroxysteroid dehydrogenase type 1 inhibitor SPI-62 prevents morbidity in a mouse model of Cushing's syndrome

11{beta}-hydroxysteroid dehydrogenase type 1 (HSD-1) inhibitors represent a potential therapeutic approach for patients with Cushings syndrome, autonomous cortisol secretion (ACS), or iatrogenic glucocorticoid (GC) excess. We assessed whether the HSD-1 inhibitor SPI-62 prevents GC-associated morbidity in a mouse Cushings syndrome model. Corticosterone (CORT) was administered to mice for 5 weeks. Animals who received CORT were randomized between vehicle and 3 SPI-62 regimens. A control group received neither CORT nor SPI-62. Body weight was measured daily to enable weight-based SPI-62 administration. Food consumption by pair-housed animals was reported weekly. Insulin sensitivity was evaluated by fasting homeostatic model assessment of insulin resistance. Adiposity and skeletal myopathy were measured using magnetic resonance imaging and post-mortem weights of fat depots and skeletal muscles. Grip strength was measured with a digital meter. Ambulation behavior in an open field maze was assessed. Post-mortem dermal thickness was quantified. Skin structure was evaluated by histology. CORT was associated with decreased insulin sensitivity, increased adiposity, skeletal myoatrophy, reduced grip strength, decreased dermal thickness, and skin structural changes. A trend of increased food consumption and an unexpected biphasic weight change were observed with CORT. SPI-62 attenuated all observed adverse effects in a dose-dependent manner. In general, results for the high SPI-62 regimen were similar as those in animals who received no CORT, suggesting that full HSD-1 inhibition should be maintained throughout a dose interval to mitigate the effects of glucocorticoid excess.

pharmacology and toxicology↗

bioRxiv2024

SaprotHub: Making Protein Modeling Accessible to All Biologists

Training and deploying large-scale protein language models typically requires deep machine learning expertise -- a barrier for researchers outside this field. SaprotHub overcomes this challenge by offering an intuitive platform that facilitates training and prediction as well as storage and sharing of models. We provide the ColabSaprot framework built on Google Colab which potentially powers hundreds of protein training and prediction applications, enabling researchers to collaboratively build and share customized models.

bioinformatics↗

bioRxiv2024

Control of Physiologic Glucose Homeostasis via the Hypothalamic Modulation of Gluconeogenic Substrate Availability

The brain augments glucose production during fasting, but the mechanisms are poorly understood. Here, we show that Cckbr-expressing neurons in the ventromedial hypothalamic nucleus (VMNCckbr cells) prevent low blood glucose during fasting through sympathetic nervous system (SNS)-mediated augmentation of adipose tissue lipolysis and substrate release. Activating VMNCckbr neurons mobilized gluconeogenic substrates without altering glycogenolysis or gluconeogenic enzyme expression. Silencing these cells (CckbrTetTox animals) reduced fasting blood glucose, impaired lipolysis, and decreased circulating glycerol (but not other gluconeogenic substrates) despite normal insulin, counterregulatory hormones, liver glycogen, and liver gluconeogenic gene expression. Furthermore, {beta}3-adrenergic adipose tissue stimulation in CckbrTetTox animals restored lipolysis and blood glucose. Hence, VMNCckbr neurons impact blood glucose not by controlling islet or liver physiology, but rather by mobilizing gluconeogenic substrates. These findings establish a central role for hypothalamic and SNS signaling during normal glucose homeostasis and highlight the importance of gluconeogenic substrate mobilization during physiologic fasting.

physiology↗