Biology subjects

Kuang, Z.

Publications and source records attributed to Kuang, Z..

16 recordsLinked to original sources

bioRxiv2026

Depleting prion protein using splice-switching small molecules

Prion diseases are fatal neurodegenerative disorders driven by prion protein (PrP) misfolding, and lowering cellular PrP represents a promising therapeutic strategy. Here we report a small-molecule approach that reduces PrP by modulating pre-mRNA splicing of the PRNP gene. Through chemical modification of the clinically approved splicing modulator risdiplam, we generated CP3, the first class of compounds that selectively activate a cryptic exon in PRNP and routes its mRNA product for degradation, reducing PrP by [~]70% in cells. We demonstrate that CP3 activity critically depends on alternative splicing factor Luc7L, revealing a novel requirement for alternative splicing factors in small molecule splicing modulation. Strikingly, co-administration of CP3 with a Luc7L activator PTC258 significantly lowers PrP levels in the brains of transgenic mice. These results establish splicing modulation as a powerful strategy for PrP reduction and highlight the potential of small-molecule cooperativity for therapeutic RNA targeting.

biochemistry↗

bioRxiv2026

A biophysical corticostriatal model predicts learning-dependent 7T fMRI dynamics and individual reward bias in humans

Circuit-level computational models can do more than explain existing data; they can generate novel hypotheses and capture individual differences in human populations. We demonstrate this using a biophysical corticostriatal model, transforming simulated neuronal activity from local field potential (LFP) into functional magnetic resonance imaging (fMRI) signals via the balloon model, and finally generating behavioral outcomes. We then validate the results against those obtained from human subjects. The model generates a counterintuitive yet testable prediction. Although prefrontal-striatal coherence demonstrates an increase at the neural LFP scale during learning, the same circuit-- passed through the hemodynamic transform---predicts a decrease in prefrontal-striatal BOLD correlation, driven by category-selective representations that emerge in cortex but not striatum. This prediction is confirmed in fMRI data optimized for single-subject-level detection sensitivity. The model further enables single-subject fitting of a behavioral outcome, classifying individuals into those differentially responding to positive versus negative reward bias. Established biomarkers, including activation measured by the amplitude of low-frequency fluctuations and dopaminergic effects on hemodynamic latency, are also conserved across LFP and fMRI scales. These findings reposition circuit models as generative tools for human neuroscience, capable of producing mechanistically grounded hypotheses and parsing individual variation in ways inaccessible to data-driven approaches alone.

neuroscience↗

bioRxiv2025

An Interactive AI Agent for Adaptive Modeling of RNA Region-Ligand Interactions via LLM-Generated Machine Learning Workflows

Precise modeling of RNA-ligand interactions is essential for understanding RNA functionality and designing RNA-targeted therapeutics. Current computational approaches largely focus on predicting discrete binding sites, limiting their applicability to complex RNA regions that may harbor multiple or diffuse ligand binding motifs. Here, we present RLAgent, an interactive agent framework designed to predict ligand interactions at the RNA region level, enabling higher-resolution and more flexible modeling than conventional site-centric approaches. RLAgent reframes the RNA-ligand prediction workflow as a dialogue-driven process. Through a natural language interface, users can interactively configure modeling preferences without writing code. A locally hosted large language model (LLM) acts as the core orchestration agent, automating all key components of the modeling pipeline, including data validation, feature encoding, model training, evaluation, and visualization. This agent-based design lowers technical barriers and enhances reproducibility, making RNA-ligand prediction more accessible for both computational and experimental researchers.

bioinformatics↗

bioRxiv2025

The U1 snRNP protein U1C and Helix H of U1 snRNA are critical for small molecule splicing modulator function

Risdiplam and branaplam represent two classes of small-molecule splicing modulators that promote U1 snRNP recognition of weak non-canonical GA/GU-containing 5 splice sites (ss). We demonstrated that branaplam enhanced recognition of these 5 ss by reconstituted U1 snRNP in vitro, and that this effect depended on the ZnF domain of U1C and Helix H of U1 snRNA, but not U1A or U1-70K. In cells, depletion of U1C generally reduced compound-induced exon inclusion for most cassette exons. Interestingly, a subset of cassette exons became responsive to compound only upon U1C knockdown, supporting a model in which U1C stabilizes specific conformations at the 5 ss/U1 snRNA interface in a context-dependent manner that can either facilitate or hinder compound binding. Surprisingly, risdiplam shows no effect on weak 5 ss recognition in vitro, suggesting additional cellular factors are required for its activity.

biochemistry↗

bioRxiv2025

Translational control of innate barrier defense by the gut microbiota

The intestinal epithelium is protected by a mucus barrier, infused with antimicrobial proteins, that restricts microbial access to host tissue. Because assembling this barrier is energetically costly, its production must be tightly regulated. Here, we show that the microbiota regulates the translation of key mucus barrier components, including the structural glycoprotein mucin 2 and the antimicrobial enzyme lysozyme. This process is initiated by microbial induction of histone deacetylase 5 (HDAC5) in secretory epithelial cells of the intestine. HDAC5 promotes deacetylation of 14-3-3 proteins, enabling activation of the energy sensing kinase mTOR which enhances translation of mucus and antimicrobial proteins. These findings reveal a mechanism by which the microbiota controls barrier immunity at the level of protein synthesis and suggest that the HDAC5-mTOR axis integrates microbial and energetic signals to regulate intestinal defense. One sentence summaryThe gut microbiota enhances translation of innate barrier defense proteins through HDAC5-mediated activation of mTORC1 signaling.

immunology↗

bioRxiv2025

Trends Assessment of the Genetic Mutation Induced Protein-Protein Interaction Variation via Protein Large Language Driven Method

Protein-protein interaction (PPI) variations are widely observed in many principal biological processes related to various diseases, while genetic mutation is one of the most common factors resulting in those variations. Unraveling these underlying biomolecular interactions is a key challenge that hinders a profound understanding of disease mechanisms. Although current models can accurately predict quantitative binding affinity, their application in pathogenic research is limited by difficulties in defining trend types, particularly extreme "disrupting" cases, along with poor generalizability beyond single-point mutations (SNP) and insufficient biological interpretability. Here, we present TAPPI, an interpretable large language model-driven deep learning framework, to perform Trends Assessment of Protein-Protein Interaction. It categorizes PPI variations trends into four types: disrupting, decreasing, no effect, and increasing, enabling fine-grained functional assessments and bridging genetic mutation and disease mechanisms. The framework generalizes effectively across both single-point and multi-point mutations and captures complex trend outcomes relevant to diverse disease landscapes. In benchmark evaluations, TAPPI achieved the state-of-the-art prediction performance and demonstrated biological relevance through interpretable results. In external datasets from Autism Spectrum Disorder, Lennox-Gastaut syndrome, and Epileptic Encephalopathies, given the premise that TAPPIs predicted results align with pathogenic patterns, these results reveal how genetic mutations indirectly perturb disease-associated pathways and supporting our perspective of "crucial disrupting" and "bridging mutations-disease". In summary, accurate, interpretable, and pathogenically relevant prediction of PPI variations trend predicted by TAPPI provides a novel approach for mechanistic discovery.

bioinformatics↗

bioRxiv2024

Ketosis Elevates Antioxidants and Enhances Neural Function Through Improved Bioenergetics: A 1H MR Spectroscopy Study

Ketosis is known to alter the balance of neuroactive amino acids and enhance neural function when compared to a glycolytic condition. However, its influence on other metabolites, such as antioxidants and neural energy markers, and the mechanisms by which ketosis improves neural function remain unclear. Here, we measure the neurochemical effects of acute ketosis on the human brain using ultra-high-field 1H MR Spectroscopy (MRS) and investigate the subsequent impact on neural function through resting-state functional magnetic resonance imaging (rsfMRI). In a within-subjects design, N = 63 healthy adults from across the lifespan underwent 1H MRS and rsfMRI scans before and after consuming individually weight-dosed and calorically-matched ketone monoester or glucose drinks. Ketone monoester administration, but not glucose, significantly elevated cerebral antioxidants and energy markers while decreasing GABA, glutamate, and glutamine levels in the posterior cingulate cortex (PCC). Notably, increased bioenergetics, specifically an increase in total creatine, correlated with greater improvements in neural function as measured using rsfMRI. Our results integrate metabolic and functional neuroimaging findings, offering a comprehensive understanding of ketosis-induced changes in brain chemistry and functional network dynamics, yielding valuable insights into potential mechanisms by which ketosis imparts its neural benefits.

neuroscience↗

bioRxiv2023

Selected humanization of yeast U1 snRNP leads to global suppression of pre-mRNA splicing and mitochondrial dysfunction in the budding yeast

The recognition of 5 splice site (5 ss) is one of the earliest steps of pre-mRNA splicing. To better understand the mechanism and regulation of 5 ss recognition, we selectively humanized components of the yeast U1 snRNP to reveal the function of these components in 5 ss recognition and splicing. We targeted U1C and Luc7, two proteins that interact with and stabilize the yeast U1 (yU1) snRNA and the 5 ss RNA duplex. We replaced the Zinc-Finger (ZnF) domain of yU1C with its human counterpart, which resulted in cold-sensitive growth phenotype and moderate splicing defects. Next, we added an auxin-inducible degron to yLuc7 protein and found that Luc7-depleted yU1 snRNP resulted in the concomitant loss of PRP40 and Snu71 (two other essential yeast U1 snRNP proteins), and further biochemical analyses suggest a model of how these three proteins interact with each other in the U1 snRNP. The loss of these proteins resulted in a significant growth retardation accompanied by a global suppression of pre-mRNA splicing. The splicing suppression led to mitochondrial dysfunction as revealed by a release of Fe2+ into the growth medium and an induction of mitochondrial reactive oxygen species. Together, these observations indicate that the human U1C ZnF can substitute that of yeast, Luc7 is essential for the incorporation of the Luc7-Prp40-Snu71 trimer into yeast U1 snRNP, and splicing plays a major role in the regulation of mitochondria function in yeast.

biochemistry↗

bioRxiv2022

The majority of microorganisms in gas hydrate bearing subseafloor sediments ferment macromolecules

BackgroundGas hydrate-bearing subseafloor sediments harbor a large number of microorganisms. Sedimentary organic matter and upward methane fluids represent two important sources of carbon and energy for deep biosphere. However, which metabolism dominates the deep subseafloor of gas hydrate zone is poorly constrained. Here we studied the microbial communities in gas-hydrate rich sediments up to 49 meters below seafloor recovered by drilling in the South China Sea. We focused on distinct geochemical conditions, and performed metagenomic and metatranscriptomic analyses to characterize microbial diversity and their role in carbon mineralization. ResultsComparative microbial community analysis revealed that samples above and in sulfate-methane interface (SMI) zones clearly distinguish from those below the SMI. Chloroflexota, are most abundant above the SMI, whereas Caldatribacteriota dominate below the SMI. Verrucomicrobiota, Bathyarchaeia and Hadarchaeota were similarly present in both types of sediment. The genomic inventory and transcriptional activity suggest roles in fermentation of macromolecule. By contrast, sulfate reducers and methanogens, organisms that catalyze the consumption or production of commonly observed chemical compounds in sediments are rare. Methanotrophs of the ANME-1 group thrived in or slightly below the current sulfate methane interface. Rare members from Heimdallarchaeia were identified to encode the potential for anaerobic oxidation of short-chain hydrocarbons. ConclusionsThese findings indicate that fermentation of macromolecules is the predominant energy source for microorganisms in deep subseafloor sediments that are experiencing upward methane fluxes.

microbiology↗

bioRxiv2021

Miniature inverted-repeat transposable elements drive rapid microRNA diversification in angiosperms

MicroRNAs (miRNAs) are rapidly evolving endogenous small RNAs programing organism function and behavior. Although models for miRNA origination have been proposed based on sporadic cases, the genomic mechanisms driving swift diversification of the miRNA repertoires in plants remain elusive. Here, by comprehensively analyzing 20 phylogenetically representative plant species, we identified miniature inverted-repeat transposable elements (MITEs) as the predominant genomic sources for de novo miRNAs in angiosperms. Our data illustrated a transposition-transcription process whereby properly sized MITEs transposed into active genic regions could be converted into new miRNAs, termed MITE-miRNAs, in as few as 20 generations. We showed that this molecular domestication mechanism leads to a possible evolutionary arms race between the MITEs and the host genomes that rapidly and continuously changes the miRNA repertoires. We found that the MITE-miRNAs are selected for targeting genes associated with plant adaptation and habitat expansion, thereby constituting a genomic innovation potentially underlying angiosperm megadiversity.

plant biology↗

bioRxiv2021

The Copper Responsive Transcription Factor SPL7 Represses Key Abscisic Acid Biosynthetic Genes to Balance Growth and Drought Tolerance

Plants adapt to adverse environments by turning on defense against abiotic stresses, which is mainly orchestrated by the phytohormone abscisic acid (ABA). But how ABA homeostasis is modulated to balance growth and stress responses is still largely unknown. Here we report that prior treatment of Arabidopsis seedling with high copper retardates growth but enhances draught tolerance at later stages by modulating ABA accumulation. Subsequent genetic, physiological, transcriptomic, and molecular investigations revealed that the copper responsive transcription factor SQUAMOSA PROMOTER BINDING PROTEIN-LIKE 7 (SPL7) is a strong regulator of ABA accumulation. We showed that SPL7 is destabilized by high copper and consistently suppresses genes encoding three key oxygenases in the ABA biosynthetic pathway of land plants via binding to the GTAC copper response motifs in their promoters. These results revealed a new mechanism whereby copper availability, inversely reflected by SPL7 abundance, modulates de novo ABA biosynthesis to balance growth and drought tolerance. One-sentence summaryHigh copper availability represses SPL7, releasing its suppression on key ABA biosynthetic genes and leading to increased ABA accumulation that inhibits growth but enhances drought tolerance.

plant biology↗

bioRxiv2019

Mendelian Randomization with Instrumental Variable Synthesis (IVY)

Mendelian Randomization (MR) is an important causal inference method primarily used in biomedical research. This work applies contemporary techniques in machine learning to improve the robustness and power of traditional MR tools. By denoising and combining candidate genetic variants through techniques from unsupervised probabilistic graphical models, an influential latent instrumental variable is constructed for causal effect estimation. We present results on identifying relationships between biomarkers and the occurrence of coronary artery disease using individual-level real-world data from UK-BioBank via the proposed method. The approach, termed Instrumental Variable sYnthesis (IVY) is proposed as a complement to current methods, and is able to improve results based on allele scoring, particularly at moderate sample sizes.

bioinformatics↗

bioRxiv2019

The intestinal microbiota programs diurnal rhythms in host metabolism through histone deacetylase 3

Circadian rhythmicity is a defining feature of mammalian metabolism that synchronizes metabolic processes to day-night light cycles. Here, we show that the intestinal microbiota programs diurnal metabolic rhythms in the mouse small intestine through histone deacetylase 3 (HDAC3). The microbiota induced expression of intestinal epithelial HDAC3, which was recruited rhythmically to chromatin and produced synchronized diurnal oscillations in histone acetylation, metabolic gene expression, and nutrient uptake. HDAC3 also functioned non-canonically to coactivate estrogen related receptor (ERR), inducing microbiota-dependent rhythmic transcription of the lipid transporter gene Cd36 and promoting lipid absorption and diet-and jet lag-induced obesity. Our findings reveal that HDAC3 integrates microbial and circadian cues to regulate diurnal metabolic rhythms, and pinpoint a key mechanism by which the microbiota controls host metabolism. One sentence summaryThe intestinal microbiota induces daily metabolic rhythms and controls lipid uptake through the enzyme histone deacetylase 3.

microbiology↗

bioRxiv2019

Epithelial retinoid acid receptor β regulates serum amyloid A expression and vitamin A-dependent intestinal immunity

Vitamin A is a dietary component that is essential for the development of intestinal immunity. Vitamin A is absorbed and converted to its bioactive derivatives retinol and retinoic acid by the intestinal epithelium, yet little is known about how epithelial cells regulate vitamin A-dependent intestinal immunity. Here we show that epithelial cell expression of the transcription factor retinoic acid receptor {beta} (RAR{beta}) is essential for vitamin A-dependent intestinal immunity. Epithelial RAR{beta} activated vitamin A-dependent expression of serum amyloid A (SAA) proteins by binding directly to Saa promoters. In accordance with the known role of SAAs in regulating Th17 cell effector function, epithelial RAR{beta} promoted IL-17 production by intestinal Th17 cells. More broadly, epithelial RAR{beta} was required for the development of key vitamin A-dependent adaptive immune responses, including CD4+ T cell homing to the intestine and the development of immunoglobulin A-producing intestinal B cells. Our findings provide insight into how the intestinal epithelium senses dietary vitamin A status to regulate adaptive immunity and highlight the role of epithelial cells in regulating intestinal immunity in response to diet. Significance StatementVitamin A is a nutrient that is essential for the development of intestinal immunity. It is absorbed by gut epithelial cells which convert it to retinol and retinoic acid. Here we show that the transcription factor retinoic acid receptor {beta} (RAR{beta}) allows epithelial cells to sense vitamin A in the diet and regulate vitamin A-dependent immunity in the intestine. We find that epithelial RAR{beta} regulates several intestinal immune responses, including production of the immunomodulatory protein serum amyloid A, T cell homing to the intestine, and B cell production of immunoglobulin A. Our findings provide new insight into how epithelial cells sense vitamin A to regulate intestinal immunity and highlight why vitamin A is so important for immunity to infection.

immunology↗

bioRxiv2018

Relationship between Parathyroid Hormone Levels and Hazards of Fracture, Vascular Events and Death in Stage 3 and 4 Chronic Kidney Disease

Background and ObjectivesChronic kidney disease (CKD) affects [~]20% of older adults and secondary hyperparathyroidism (HPT) is a common condition in these patients. Studies have linked HPT to a greater risk of fractures, vascular events and mortality. However, the optimal parathyroid hormone (PTH) level needed to minimize these events remains uncertain.\n\nDesign, setting, participants and measurementsWe assessed relationships between baseline serum PTH levels and the subsequent 10-year probability of clinical fractures, vascular events and death in stage 3 and 4 CKD patients. We used Marshfield Clinic Health System electronic health records to analyze data from adult CKD patients spanning from 1985 to 2013. We required [≥]2 PTH measurements at baseline and used ICD-9 codes to identify medical conditions, fractures, vascular events and death. In multivariate models, we assessed relationships between serum PTH and the three clinical outcomes, controlling for age, gender, co-morbidities and osteoporosis medication.\n\nResults7594 subjects had a mean age of 68{+/-}13 years and 55% were women. Fractures, vascular events and death occurred in 19%, 60% and 29% of the cohort, respectively. In multivariate models including the whole cohort regardless of PTH assay, the probability of fracture, vascular events and death were minimized at a PTH of 23, 50 and 50 pg/mL. Below these cutpoints, the probability of fractures and death dramatically increased. When confining the analysis to patients measured using a 2nd generation PTH assay (n=5108), the hazards of fracture, vascular events and death were minimized at a PTH of zero, 60 and 58 pg/mL. Any of these clinical outcomes was minimized at a baseline PTH of 58 pg/mL.\n\nConclusionsOur study suggests that parathyroid hormone levels around 60 pg/mL might reduce the risk of fractures, vascular events and death in CKD patients. Additional epidemiologic studies and randomized clinical trials are needed to confirm these findings.

epidemiology↗

bioRxiv2017

A toolbox of immunoprecipitation-grade monoclonal antibodies against human transcription factors.

A key component to overcoming the reproducibility crisis in biomedical research is the development of readily available, rigorously validated and renewable protein affinity reagents. As part of the NIH Protein Capture Reagents Program (PCRP), we have generated a collection of 1406 highly validated, immunoprecipitation (IP) and/or immunoblotting (IB) grade, mouse monoclonal antibodies (mAbs) to 736 human transcription factors. We used HuProt human protein microarrays to identify mAbs that recognize their cognate targets with exceptional specificity. Using an integrated production and validation pipeline, we validated these mAbs in multiple experimental applications, and have distributed them to the Developmental Studies Hybridoma Bank (DSHB) and several commercial suppliers. This study allowed us to perform a meta-analysis that identified critical variables that contribute to the generation of high quality mAbs. We find that using full-length antigens for immunization, in combination with HuProt analysis, provides the highest overall success rates. The efficiencies built into this pipeline ensure substantial cost savings compared to current standard practices.

biochemistry↗