Biology subjects

Tu, W.

Publications and source records attributed to Tu, W..

13 recordsLinked to original sources

bioRxiv2026

Machine Learning Gap-Fills Missing Transporter Kinetics in Biosystems Across Scales

Understanding transporter kinetics is essential for deciphering metabolite exchanges in biosystems, particularly for cells subject to substrate gradients. Nevertheless, the prediction of transporter kinetic parameters, maximum rate per gram protein (Vmax) and Michaelis-Menten constant (Km), has not yet been tackled. Here, we developed the first compound-protein interaction machine learning model of transporter Vmax and Km, MMTKPred, which achieved R2=0.553, RMSE=1.155 mmol/hr/g Protein and R2=0.330, RMSE=0.935 mM for log10-scaled Vmax and Km prediction, respectively. Moreover, we demonstrated MMTKPreds predictive power across biosystem scales, from capturing transporter kinetics modulated by point mutations and substrate changes at the molecular level, to enabling substrate-sensitive metabolic modelling of non-model yeasts at the cellular level, and rationalizing inter-species substrate competition in co-cultures. Collectively, MMTKPred effectively models metabolite transport spanning from molecular to multi- species scales, thereby offering a computational tool for rational microbial cell factory optimization. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/735998v2_ufig1.gif" ALT="Figure 1"> View larger version (62K): org.highwire.dtl.DTLVardef@18e7bb6org.highwire.dtl.DTLVardef@15bec93org.highwire.dtl.DTLVardef@8ce92org.highwire.dtl.DTLVardef@31fb44_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIMMTKPred, first transporter kinetics CPI model, reaches [~]1 log10 RMSE for Vmax and Km. C_LIO_LIMMTKPred captures the effects of point mutations and substrate changes on transporters. C_LIO_LIPredicted kinetics enables substrate sensitivity in metabolic flux modelling. C_LIO_LIPredicted kinetics explains inter-species substrate competition outcomes. C_LI

systems biology↗

bioRxiv2026

Transformation and recombination of neural information in a brain network

Mammalian brain function relies on integrated interactions among interconnected neural structures. The principles by which regional activity is transformed into projection-specific signals and then recombined at targets elsewhere in the brain are fundamental to brain processing, but remain poorly understood. Here we study these phenomena using a genetically encoded probe that provides neurophysiological readouts from virally labeled projections on a brain-wide scale via functional magnetic resonance imaging (fMRI). By analyzing outputs from thalamic and cortical somatosensory processing regions in rats, we find that projection-specific neural population activity undergoes shifts in tuning and temporal characteristics as it emanates from source regions. Patterns of neural information flow to targeted brain structures reconfigure under different conditions of stimulation and rest, contrasting with intrinsic fMRI functional connectivity profiles, which remain constant. Excitatory and inhibitory projections are coactivated during stimulation, but their relative response amplitudes change dynamically between stimulus conditions and across repeated stimuli, suggesting mechanistic roles for network-wide shifts in excitation/inhibition balance. Our results thus reveal how information flow throughout a neural system reshapes to promote stimulus selectivity and provide underpinnings of large-scale brain phenomena.

neuroscience↗

bioRxiv2026

Comprehensive 3D mapping reveals distinct spatial gradients of SST, PV, and TH interneurons across the mouse caudoputamen

In addition to spatially organized excitatory forebrain inputs along its mediolateral, dorsoventral, and anteroposterior axes, the striatum relies on cellular diversity to subserve its myriad processing functions. Distinct striatal GABAergic interneuron subtypes, including somatostatin (SST), parvalbumin (PV), and tyrosine hydroxylase (TH) interneurons likely subserve complementary computational roles. However, a detailed understanding of how these microcircuit components are distributed across striatal territories remains lacking. To address this gap, we generated a comprehensive three-dimensional atlas of SST, PV, and TH interneurons across the mouse caudoputamen using genetic labeling, brain-wide imaging, and voxel-wise quantification. We found that SST and TH interneurons were relatively enriched in the ventral caudoputamen, whereas PV interneurons were enriched dorsally. In addition, PV and TH interneurons exhibited opposing anteroposterior distribution patterns, with PV interneurons enriched posteriorly and TH interneurons showing a marked decline in density towards the striatal tail. Consequently, while the three interneuron subtypes displayed comparable densities in the functionally defined lateral striatum and anterior ventromedial striatum, PV interneurons predominated in the dorsomedial striatum and tail of striatum. We did not observe major sex differences. Together, these findings reinforce the view that the striatum is not a monolithic structure: in addition to structured excitatory inputs, inhibitory microcircuits themselves are differentially distributed across striatal territories, providing region-specific constraints on circuit computation. By integrating interneuron organization into existing anatomical frameworks, this atlas provides a foundation for linking striatal anatomy to function across behavioral domains.

neuroscience↗

bioRxiv2025

Vampire bats in Belize harbor multiple Trypanosoma cruzi genotypes: implications for parasite transmission at the wildlife-domestic-human interface

BackgroundChagas disease, caused by Trypanosoma cruzi, is a neglected tropical disease with complex sylvatic and domestic transmission cycles involving vectors, mammalian hosts, and humans. The common vampire bat (Desmodus rotundus) is an obligate blood-feeding species that frequently interacts with livestock and humans, yet their role in parasite maintenance in Central America remains poorly characterized. Methodology/Principal FindingsWe analyzed 205 blood samples from vampire bats collected at two sites in northern Belize over three years (2019, 2021, 2022). PCR screening revealed an overall T. cruzi prevalence of 41.5% and increasing infection risks over time. The amplicon-based next-generation sequencing of the parasite mini-exon locus identified 36 unique haplotypes belonging to five DTUs: TcI, TcIV, TcV, TcVI, and TcBat. TcBat was present in half of the samples sequenced. TcBat and TcVI, were detected in Belize for the first time. Belizean TcBat haplotypes clustered closely with Colombian reference sequences, and a subset formed a Belize-specific clade, indicating previously unrecognized TcBat diversity in the region; in contrast, Brazilian TcBat sequences were more distantly related. Conclusions/SignificanceVampire bats in Belize harbor diverse T. cruzi genotypes, including DTUs with established roles in human disease. Given their obligate blood diet, frequent feeding on livestock, and occasional biting of humans, vampire bats may serve as bridge hosts linking sylvatic, domestic, and human transmission cycles. Together with a recent report of an acute human Chagas disease case in northern Belize, these results underscore the need for integrated One Health surveillance of bats, vectors, livestock, and humans to better evaluate and mitigate the risk of Chagas disease in Central America. Author SummaryChagas disease, caused by the parasite Trypanosoma cruzi, is a major public health concern in the Americas but remains neglected in many regions, including Central America. The parasite is typically transmitted by kissing bugs, but wild mammals also serve as important hosts. Vampire bats (Desmodus rotundus) are unique because they feed exclusively blood and frequently bite livestock, and occasionally humans, creating opportunities for parasite transmission across different environments. In this study, we screened 205 vampire bats from northern Belize and found that over 40% were infected with T. cruzi. By sequencing parasite DNA, we discovered a surprising diversity of DTUs, including TcI, TcIV, TcV, TcVI, and TcBat. The detection of TcVI is particularly important, because this DTU, associated with human infections in South America, had not been previously reported in Belize. TcBat haplotypes were highly prevalent and genetically diverse. Our results show that vampire bats are important hosts of diverse T. cruzi genotypes in Belize and may act as bridge hosts between wildlife, livestock, human transmission cycles. Enhanced One Health surveillance across vectors, bats, domestic animals, and humans will be critical for understanding and preventing Chagas disease emergence in Central America.

molecular biology↗

bioRxiv2025

Temporally and Functionally Distinct Contributions to Value Based Choice Along the Anterior-Posterior Dorsomedial Striatal Axis

While the dorsoventral and mediolateral organization of striatum has resolved clear functional distinctions, far less is known about how the anterior-posterior striatal axis contributes to behavioral control. We explore this within the dorsomedial striatum (DMS), a key region for value-based choice, by comparing population neuronal activity and function within anterior (A-DMS) and posterior (P-DMS) subregions while mice operantly seek reward. Neural recordings show that P-DMS encoded action values and strategy information prior to choice selection while A-DMS activity represented recently selected choices and their anticipated values via a dynamic population reorganization immediately following action selection. Optogenetic perturbations were consistent with these temporally distinct coding properties as unilateral manipulation of the P-DMS prior to choice biased choice contralaterally in a value-dependent manner and unilateral inhibition of the A-DMS following choice impaired future value-based action selection. Using anterograde tracing, we found that the A-DMS and P-DMS projected to a common region within the ventromedial substantia nigra pars reticulata (vmSNr), which contained value-related signals combining aspects of upstream DMS processing. Together, our results support a model for temporally distributed influence on value-based choice across the anterior-posterior axis of the DMS.

neuroscience↗

bioRxiv2025

Generating cognate epitope sequences of T-cell receptors with a generative transformer

Single-cell TCR sequencing enables high-resolution analysis of T Cell Receptor (TCR) diversity and clonality, offering valuable insights into immune responses and disease mechanisms. However, identifying cognate epitopes for individual TCRs requires complex and costly functional assays. We address this challenge with EpitopeGen, a largescale transformer model based on the GPT-2 architecture that generates potential cognate epitope sequences directly from TCR sequences. To overcome the scarcity of TCR-epitope binding pairs ({approx} 100, 000), EpitopeGen uses a semi-supervised learning method, termed BINDSEARCH, which searches over 70 billion potential pairs and incorporates high binding affinity predictions as pseudo-labels. To incorporate CD8+ T cell biology into the model as an inductive bias, EpitopeGen employs a novel data balancing method, termed Antigen Category Filter, that carefully controls antigen category ratios in its training dataset. EpitopeGen significantly outperforms baseline approaches, generating epitopes with high binding affinity, diversity, naturalness, and biophysical stability. Notably, the epitopes generated by EpitopeGen follow biologically plausible antigen category distributions, a crucial feature not achieved by other models. Using EpitopeGen, we directly identify subsets of clonally expanded tumorinfiltrating lymphocytes that recognize tumor-associated antigens, exhibiting elevated cytotoxicity and reduced exhaustion markers. From COVID-19 patients, EpitopeGen detects T cells that recognize COVID-19 spike proteins and non-structural proteins with distinct transcriptomic characteristics. In conclusion, EpitopeGen represents the first computational method that enables direct inference of antigen recognition profiles of CD8+ T cells from plain TCR repertoires.

immunology↗

bioRxiv2024

Delivery of Peptide Coacervates to Form Stable Interaction Hubs In Cells

Cells contain membrane-bound and membraneless organelles that operate as spatially distinct biochemical niches. However, these reaction centers lose fidelity due to aging or disease. A grand challenge for biomedicine is restoring or augmenting cellular functionalities. Although commonly tackled by gene replacement therapy, an exciting new strategy is the delivery of protein-based materials that directly interact with and alter intracellular pathways. In this study, we sought to develop long-lasting materials capable of cellular uptake, akin to artificial organelles or synthetic interaction hubs. We show efficient delivery of micron-size peptide-based compartments into a variety of cell types. By loading coacervates with nanobodies and bioPROTACs, we demonstrate successful native target sequestration, and hub bioreactor function to selectively degrade targets inside human cells. These results represent an important step toward the development of synthetic organelles that can be fabricated in vitro and taken up by cells for applications in cell engineering and regenerative medicine.

synthetic biology↗

bioRxiv2023

Dissecting Multiparametric Cerebral Hemodynamics using Integrated Ultrafast Ultrasound and Multispectral Photoacoustic Imaging

Understanding brain-wide hemodynamic responses to different stimuli at high spatiotemporal resolutions can help study neuro-disorders and brain functions. However, the existing brain imaging technologies have limited resolution, sensitivity, imaging depth and provide information about only one or two hemodynamic parameters. To address this, we propose a multimodal functional ultrasound and photoacoustic (fUSPA) imaging platform, which integrates ultrafast ultrasound and multispectral photoacoustic imaging methods in a compact head-mountable device, to quantitatively map cerebral blood volume (CBV), cerebral blood flow (CBF), oxygen saturation (SO2) dynamics as well as contrast agent enhanced brain imaging with high spatiotemporal resolutions. After systematic characterization, the fUSPA system was applied to quantitatively study the changes in brain hemodynamics and vascular reactivity at single vessel resolution in response to hypercapnia stimulation. Our results show an overall increase in brain-wide CBV, CBF, and SO2, but regional differences in singular cortical veins and arteries and a reproducible anti-correlation pattern between venous and cortical hemodynamics, demonstrating the capabilities of the fUSPA system for providing multiparametric cerebrovascular information at high-resolution and sensitivity, that can bring insights into the complex mechanisms of neurodiseases.

bioengineering↗

bioRxiv2023

The longitudinal single-cell panorama of cynomolgus monkey ovary throughout lifespan revealed a conserved ovarian clock between primates

Ovarian function is critical for female fertility and impacts reproductive longevity. It is of great importance to accurately predict the aging process within the ovary for fertility assessment and disease diagnosis. However, cell metrics for evaluating the ovarian aging rate are still in urgent need, and molecular insights into ovarian development and dysfunction during the primate life course are also limited. Here, we reported large-scale ovarian cell atlas of consecutive development of cynomolgus monkeys across 22 years with 20 time points, covering the foetal, newborn, prepubertal, pubertal, adult, perimenopausal and menopausal stages. We characterized and validated distinct molecular signatures of each cluster of cells within primate ovaries, and uncovered a previously undocumented RHOXF1-positive oocyte type during primordial follicle assembly in primates. Furthermore, the constitution and developmental trajectories of primate germ cells, granulosa cells and stromal / theca cells were also elucidated, and their precursors were identified. More importantly, dynamics of cellular compositions were unravelled through the ovarian development, featured by granulosa, epithelial, stromal, and immune cells that showed strong temporal heterogeneity spanning lifetime, whilst referred to the key function during the corresponding stages. Based on the correlations of each cell type with age and stage-specific molecular dynamics, we further constructed a transcriptomic ovarian clock which could perceive an effective biological age prediction of the ovary and further applied to humans. The findings reveal granulosa, epithelial, and stromal cells as the highest performance predictors of ovarian biological age, while highlighting the crucial role of AGE-RAGE and Relaxin signaling pathways in regulating ovarian aging. Our work not only provide valuable resource for obtaining insights into the development, aging and dysfunction of key organs, but also establish a transcriptomic clock to predict biological ovarian aging thus to be potential clinical implementation in future.

developmental biology↗

bioRxiv2023

Polygenic adaptation to overnutrition reveals a role for cholinergic signaling in longevity

Overnutrition by high-sugar (HS) feeding reduces both the lifespan and healthspan across taxa. Pressuring organisms to adapt to overnutrition can highlight genes and pathways important for the healthspan in stressful environments. We used an experimental evolution approach to adapt four replicate, outbred population pairs of Drosophila melanogaster to a HS or control diet. Sexes were separated and aged on either diet until mid-life, then mated to produce the next generation, allowing enrichment for protective alleles over time. All HS-selected populations increased their lifespan and were therefore used as a platform to compare allele frequencies and gene expression. Pathways functioning in the nervous system were overrepresented in the genomic data and showed evidence for parallel evolution, although very few genes were the same across replicates. Acetylcholine-related genes, including the muscarinic receptor mAChR-A, showed significant changes in allele frequency in multiple selected populations and differential expression on a HS diet. Using genetic and pharmacological approaches, we show that cholinergic signaling affects Drosophila feeding in a sugar-specific fashion. Together, these results suggest that adaptation produces changes in allele frequencies that benefit animals under conditions of overnutrition and that it is repeatable at the pathway level.

genetics↗

bioRxiv2022

Respiration-driven brain network: neural underpinning of breathing correlates with resting-state fMRI signal

Respiration can induce motion and CO2 fluctuation during resting-state fMRI (rsfMRI) scans, which will lead to non-neural artifacts in the rsfMRI signal. In the meantime, as a crucial physiologic process, respiration that can directly drive neural activity change in the brain, and may thereby modulate the rsfMRI signal. Nonetheless, this potential neural component in the respiration-fMRI relationship is largely unexplored. To elucidate this issue, here we simultaneously recorded the electrophysiology, rsfMRI and respiration signals in rats. Our data show that respiration is indeed associated with neural activity changes, evidenced by a phase-locking relationship between slow respiration variations and the gamma-band power of the electrophysiologic signal recorded in the anterior cingulate cortex. Intriguingly, slow respiration variations are also linked to a characteristic rsfMRI network, which is mediated by gamma-band neural activity. In addition, this respiration-related brain network disappears when brain-wide neural activity is silenced at an iso-electrical state, while the respiration is maintained, further confirming the necessary role of neural activity. Taken together, this study identifies a respiration-related brain network underpinned by neural activity, which represents a novel component in the respiration-rsfMRI relationship that is distinct from respiration-related rsfMRI artifacts. It opens a new avenue for investigating the interactions between respiration, neural activity and resting-state brain networks in both healthy and diseased conditions.

neuroscience↗

bioRxiv2019

An open database of resting-state fMRI in awake rats

Rodent models are essential to translational research in health and disease. Investigation in rodent brain function and organization at the systems level using resting-state functional magnetic resonance imaging (rsfMRI) has become increasingly popular, owing to its high spatial resolution and whole-brain coverage. Due to this rapid progress, shared rodent rsfMRI databases can be of particular interest and importance to the scientific community, as inspired by human neuroscience and psychiatric research that are substantially facilitated by open human neuroimaging datasets. However, such databases in rats are still lacking. In this paper, we share an open rsfMRI database acquired in 90 rats with a well-established awake imaging paradigm that avoids anesthesia interference. Both raw and preprocessed data are made publically available. Procedures in data preprocessing to remove artefacts induced by the scanner, head motion, non-neural physiological noise are described in details. We also showcase inter-regional functional connectivity and functional networks calculated from the database.

neuroscience↗

bioRxiv2019

How brain reacts to attack at a local region

The architecture of brain networks has been extensively studied in multiple species. However, exactly how the brain network reconfigures when a local region stops functioning remains elusive. By combining chemogenetics and resting-state functional magnetic resonance imaging (rsfMRI) in awake rodents, we investigated the causal impact of acutely inactivating a hub region (i.e. dorsal anterior cingulate cortex) on brain network properties. We found that disrupting hub activity profoundly changed the function the default-mode network (DMN), and this change was associated with altered DMN-related behavior. Suppressing hub activity also impacted the topological architecture of the whole-brain network in network resilience, segregation and small worldness, but not network integration. This study has established a system that allows for mechanistically dissecting the relationship between local regions and brain network properties. Our data provide direct evidence supporting the hypothesis that acute dysfunction of a brain hub can cause large-scale network changes. This study opens an avenue of manipulating brain networks by controlling hub-node activity.

neuroscience↗