Biology subjects

Tu, Z.

Publications and source records attributed to Tu, Z..

At least 19 recordsLinked to original sources

bioRxiv2026

A Multi-Omics Study of Cognitive Resilience to Alzheimer's Disease

Alzheimers disease (AD) is the most severe form of dementia. While significant efforts have been made to identify AD risk factors and develop therapeutics, much less attention has been given to neurobiological factors and molecular signatures associated with cognitive resilience. Substantial evidence suggests that modifiable factors, such as physical and mental activity, may contribute to cognitive reserve and resilience. To this end, we developed a resilient cohort of paired genetics, transcriptomics and proteomics data from the prefrontal cortex of 282 cognitively normal older adults. We conducted extensive preprocessing and rigorous quality control (QC), including QC on sequence metrics and sample matching across multiomics. This cohort can be leveraged for identification of molecular signatures of cognitive resilience to AD and is freely shared with the research community.

genomics↗

bioRxiv2026

A haplotype-based breeding framework for the precise pyramiding of elite QTL alleles: a lettuce case study

The efficient pyramiding of favorable alleles underlying complex traits remains a major challenge in crop breeding as most quantitative trait loci (QTLs) have not been resolved to causal genes, limiting their direct application in marker-assisted breeding. Although haplotypes provide more informative genetic units than individual markers, existing haplotype-based studies have largely focused on genetic interpretation and elite haplotype discovery, whereas computational frameworks for translating haplotypes into breeding decisions remain limited. Here, we developed HAPBDB, a haplotype-guided breeding framework that directly translates regional haplotypes into parental selection, cross design, and elite QTL pyramiding, and applied it to a lettuce genomic breeding panel. HAPBDB accurately reconstructed functional haplotypes at known loci and resolved elite haplotypes for five major QTLs controlling flowering time and yield. Integrating haplotype information across loci enabled systematic identification of accessions carrying complementary elite haplotypes and rational design of crosses that maximized favorable haplotype accumulation while minimizing segregating loci. Experimental validation using QTL-specific molecular markers demonstrated concordance between predicted and observed multi-locus genotypes across all designed F hybrids. Our results demonstrated that regional haplotypes can serve as practical breeding units even when the underlying causal genes remain unknown, thereby enabling the direct utilization of genetically mapped QTLs for precision breeding. By bridging the gap between genomic discovery and practical breeding, HAPBDB provides a practical framework for converting genomic information into breeding decisions and accelerating precision improvement of complex traits.

bioinformatics↗

bioRxiv2026

Modeling population control via tunable sex ratio distorter gene drives in Aedes aegypti

Aedes aegypti, a major vector of arboviruses, belong to subfamily Culicinae, a diverse group of mosquitoes with homomorphic sex-determining chromosomes. Males are the heterogametic sex with a dominant male-determining locus (M locus). The M locus and its counterpart m locus are embedded in a region of suppressed recombination, with a large portion of this recombination desert showing significant molecular differentiation despite homomorphy. We developed a mathematical framework to examine M-linked genome editors that specifically target the m-chromosome during spermatogenesis, mimicking the naturally occurring sex ratio distorters (SRDs) in Culicinae that produce male-biased meiotic drives. Unlike previous models for species with heteromorphic sex chromosomes (e.g., X and Y), we incorporate features stemming from the homomorphic nature of the Ae. aegypti sex chromosomes such as varied linkage to the M locus, making the degree of super-Mendelian inheritance readily tunable. We evaluated in silico SRDs with a range of M-linkage and editing efficiencies and established the theoretical foundation for developing highly efficient SRDs that outperform several methods of population suppression. These SRDs can be tuned to mitigate impact on a neighboring population. The framework developed here is suitable for exploring SRD-mediated genetic biocontrol of numerous pest species with homomorphic sex chromosomes.

genetics↗

bioRxiv2026

Coalescing nephron and ureteric bud progenitors potentiates nephrogenesis in recellularized kidney scaffolds

Bioengineered, transplantable kidney tissue using decellularized scaffolds offers a promising strategy to overcome the shortage of donor kidneys that limits organ transplantation for patients with end stage renal disease. These kidney scaffolds retain essential extracellular matrix architecture, providing a biologically active niche for recellularization. Successful generation of bioengineered kidney tissues includes enhanced patent vasculature and mature, functional nephrons with collecting ducts. Here, we report the development of engineered kidney tissue consisting of reconstituted kidney scaffolds and human pluripotent stem cell-derived nephron and ureteric bud progenitors. Structural analysis of recellularized kidney scaffolds showed advanced nephron structures that became more mature and exhibited interconnected nephron and collecting ducts. In vivo engraftment of reconstituted kidney scaffolds in mice led to vascularization, maturation, and secretory function. Notably, mouse-graft vascular anastomosis was evident with erythrocytes present in vasculature and nephron-secreted proteins detected in mouse urine, indicating functional integration. This approach demonstrates the feasibility to generate advanced bioengineered kidney tissues that offer a versatile platform for disease modeling, drug screening, and regenerative medicine. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=60 SRC="FIGDIR/small/733560v1_ufig1.gif" ALT="Figure 1"> View larger version (15K): org.highwire.dtl.DTLVardef@af021forg.highwire.dtl.DTLVardef@1b44feforg.highwire.dtl.DTLVardef@ebe73forg.highwire.dtl.DTLVardef@19b0acf_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2026

Decoding Spatial Programs in Human Glioblastoma Through Surprisal Information-Theoretical Analysis

Glioblastoma (GBM) is a highly heterogeneous and invasive brain tumor in which complex interactions among tumor cells, immune cells, and neurons shape disease progression and therapeutic resistance. Resolving spatial patterns programs in glioblastoma (GBM) requires analytical approaches that go beyond variance-driven embeddings. Here, we applied thermodynamic surprisal analysis, an information-theoretic decomposition framework, to spatial transcriptomic sequencing from human GBM specimens to identify orthogonal constraint modes that capture dominant and previously hidden spatial programs. Surprisal analysis revealed structured patterns in the data that are not highlighted by standard approaches such as PCA or cell type deconvolution, including immune-activation-associated signatures as well as spatial programs consistent with synapse remodeling. Coupling surprisal decomposition with spatial ligand-receptor interaction analysis, NICHES, along with multiplexed protein imaging connected these spatial hidden modes to reveal potential communication networks. Together, these results position surprisal analysis as a powerful, complementary strategy for interrogating spatial tumor architecture, enabling discovery of non-obvious spatial programs and interactions that are obscured by variance-based methods.

systems biology↗

bioRxiv2026

Repetition Selectively Reconfigures Offset-Defined Temporal Integration in Auditory Cortex

Auditory perception requires integrating sound over time, but whether cortical integration windows are fixed or adaptively shaped by recent sensory history remains unclear. Because auditory offset responses are shaped by the temporal structure preceding sound termination, they provide a readout of offset-defined temporal integration. Here, we recorded single-unit activity in awake rat auditory cortex while presenting 512-ms click trains with inter-click intervals of 1, 2, 4, 8 or 16 ms. Each stimulus was repeated ten times, allowing repetition number to index increasing adaptation. Across 271 offset-responsive neurons, repetition strongly compressed the maximal ICI capable of evoking a significant offset response and produced a smaller population-level shift in preferred ICI. These preferred-ICI changes were heterogeneous across neurons, with bidirectional shifts at the single-neuron level. In contrast, the effective temporal window measured with irregular-regular click trains remained stable at the population level, despite neuron-level variability. AAF and A1 further showed distinct repetition-dependent tuning profiles. These findings suggest that adaptation selectively reconfigures ICI-based offset tuning while preserving a population-level local regularity window, revealing flexible and stable components of cortical temporal integration.

neuroscience↗

bioRxiv2026

Integrative Single-Cell Epigenomic Atlas Annotates the Regulatory Genome of the Adult Mouse Brain

Histone modifications underpin the cell-type-specific gene regulatory programs that drive the remarkable cellular diversity of the mammalian brain. Here, we jointly profiled four histone modifications and the transcriptome in 2.5 million nuclei from the adult mouse brain. By integrating these data with chromatin accessibility, DNA methylation, and three-dimensional genome organization, we constructed a unified epigenomic atlas spanning over 100 brain cell subclasses, and assigned active, primed, and repressive chromatin states across 81% of the genome. Active chromatin states marked by combinatorial histone modifications better nominate candidate enhancers with functional support than chromatin accessibility alone, while H3K27me3- and H3K9me3-marked chromatin states delineate distinct modes of cell-type-specific gene repression. Finally, this multimodal resource enables deep learning models that predict cell-type-specific epigenomic features and gene expression from DNA sequence, providing a comprehensive framework for annotating the brain regulatory genome and interpreting non-coding disease risk variants. HIGHLIGHTS- A single-cell epigenome atlas of transcription and four histone modifications across 2.5M mouse brain cells - Multimodal integration maps chromatin states across [~]81% of the adult mouse brain genome - Cell-type-resolved chromatin landscapes reveal regulatory programs mediated by enhancers, Polycomb and H3K9me3 - Deep learning models predict cell-type-specific epigenomic features and gene expression from DNA sequence

genomics↗

bioRxiv2026

Temporal synchrony between human odor rhythms and mosquito olfactory preference shapes host attraction

For anthropophilic mosquitoes such as Aedes aegypti, aligning host-seeking with human availability enhances foraging efficiency and reproductive success. Although time of day modulates mosquito activity and olfactory sensitivity, it remains unknown whether human hosts display rhythmic changes in odor cues and whether mosquitoes adjust their sensory responses accordingly. Here, we combine chemical, behavioral, genetic, and transcriptomic approaches to reveal that both mosquitoes and their human hosts in this interaction are temporally synchronized. Gas chromatography-mass spectrometry showed systematic daily shifts in human body odor composition between morning and evening. Correspondingly, mosquitoes prefer host odors that match their own active phase--a time-specific preference abolished in timeless mutants and under constant darkness. Silencing the timeless gene further induced an aversion for the host scent under light-dark conditions. Transcriptomic analysis of mosquito heads and antennae uncovered rhythmic expression of sensory and neuromodulatory genes, driven by both circadian and light-dark cycles and which peaks during mosquitoes active periods, with rhythmic co-expression networks collapsing in timeless knockouts. Together, these results show that mosquito attraction to humans is temporally tuned by the interplay of host odor rhythms and mosquito sensory rhythms, revealing a previously unrecognized form of interspecific temporal synchronization in vector-host interactions.

animal behavior and cognition↗

bioRxiv2025

Echoes as Signal, Not Noise: Reverberation Sharpens Sensitivity to Temporal Structure

Sensitivity to temporal structure is fundamental to hearing, yet how natural reverberation shapes this sensitivity is unclear. Here we identify echo-facilitated temporal sensitivity (EFTS), a principle whereby the auditory system exploits echoes to selectively enhance responses to rapid temporal changes. Using transitional click trains with subtle inter-click-interval (ICI) shifts, we first show that increasing echo strength systematically enlarges the sound-level step at ICI transitions in both recorded and simulated stimuli, sharpening the physical boundary between segments of distinct temporal structure. In humans, psychophysical detection of ICI changes improves monotonically with echo level in both simulated and real free-field environments, while a late EEG change response scales with echo strength as onset responses remain comparatively stable. In awake rats, electrocorticography over auditory cortex reveals parallel echo-dependent enhancement of transition-evoked activity. Single units exhibit echo-level-dependent amplification of change-related firing and improved neurometric discriminability. Laminar local field potential and current source density analyses further show that echo-dependent divergence emerges first in granular and infragranular layers before propagating to supragranular cortex, consistent with thalamocortical drive followed by intracortical amplification. Together, these findings establish EFTS as a cross-species mechanism that reframes echoes as structured signals the brain uses to sharpen temporal integration in everyday listening.

neuroscience↗

bioRxiv2025

Brain-wide Genome Editing via STEP-RNPs for Treatment of Angelman Syndrome

Brain-wide genome-editing remains a major hurdle for the treatment of neurogenetic disorders. Here, we report a non-viral, non-nanoparticle, chemical modification-based method, called Stimuli-Responsive Traceless Engineering Platform (STEP) that achieves highly efficient and brain-wide genome-editing of neurons in mice. Using cholesterol-based STEP as a lead, we show that a single administration of STEP-ribonucleoproteins (RNPs) results in functional genetic rescue with significant improvements across a battery of neurobehavioral domains in the Angelman syndrome (AS) mouse model. No significant off-target events or general toxicity effects are observed. STEP-RNPs are also highly efficient at editing human neurons and cortical brain organoids differentiated from AS patient-derived iPSCs. scRNA-seq analysis confirms functional genetic rescue via reactivation of Ube3a/UBE3A expression in human and mouse STEP-RNP-treated neuronal cells. Genome editing via STEP-RNPs has broad applications and the potential to treat many other neurogenetic disorders.

genetics↗

bioRxiv2025

Exogenous BMP9 therapy ameliorates primary graft dysfunction post lung transplantation

Primary graft dysfunction (PGD) is a leading cause of early mortality after lung transplantation and is driven by ischemia-reperfusion injury (IRI), which destabilizes the pulmonary endothelium. Bone morphogenetic protein 9 (BMP9), a vascular quiescence factor of the TGF superfamily, maintains endothelial homeostasis through ALK-1/BMPR2-mediated signaling. Herein, this work identified a previously unrecognized suppression of BMP9 signaling during early reperfusion in a murine orthotopic lung transplant model. Allograft transcriptomic profiling revealed rapid downregulation of BMP9 pathway components, including Bmpr2, Acvrl1, Smad5, and Eng. Recombinant BMP9 administered at reperfusion enhanced Id1 expression in pulmonary endothelium, reduced neutrophil infiltration, preserved vascular barrier function, and improved oxygenation. In vitro, BMP9 attenuated proinflammatory cytokine release following simulated cold ischemia-reperfusion injury in human lung endothelial cells. Plasma from lung transplant recipients, regardless of PGD status, had impaired BMP9-induced ID1 expression in endothelial cells, with the most profound suppression observed in patients with interstitial lung disease. These findings implicate transient loss of BMP9 signaling as a key feature of transplant-induced vascular injury and support the therapeutic potential of BMP9 supplementation to restore endothelial homeostasis and improve early graft outcomes.

immunology↗

bioRxiv2025

Lineage-Specific Epigenomic Mapping of Proximal and Distal Fallopian Tube Epithelium Reveals Mesenchymal/Wnt-Driven Tumor Phenotype Diversification

High-grade serous ovarian cancer (HGSC) typically originates from the distal fallopian tube epithelium (disFTE), while the proximal epithelium (proFTE) remains less explored. Here, Using isogenic murine organoid models with common oncogenic drivers (Tp53-/-; Krasmut; Pten-/-), we show that disFTE and proFTE generate distinct tumor subtypes driven by region-specific transcriptional programs. Unlike disFTE, proFTE demonstrates continuous activation of epithelial-mesenchymal transition (EMT) across wild-type, mutant organoids, and derived tumors. Additionally, mutated proFTE organoids and their tumors exhibit persistent WNT signaling activation and grow independently of WNT signals. Chromatin profiling shows that mutant proFTE maintains a distinctive epigenetic profile with promoters associated with EMT and WNT pathways. Human proFTE with BRCAmut also shows epigenetic activation of EMT- and WNT-related genes. Tumors near the uterotubal junction (UTJ)--anatomically akin to proFTE--exhibit a pronounced EMT signature, increased Vimentin+E-cadherin+ and nuclear {beta}-catenin expression. These findings suggest proFTE-derived tumors may occupy a unique niche in gynecological malignancies, with regional identity shaping tumor phenotypes.

cancer biology↗

bioRxiv2025

CASP3-GSDME-mediated trophoblast pyroptosis contributes to systemic inflammation

Early-onset preeclampsia (EOPE) is associated with excessive apoptosis and inflammation, but the mechanistic link between these processes remains enigma. Here, we report elevated circulating pro-apoptotic proteins in EOPE patients at early pregnancy, along with concurrent CASP3 activation and GSDME cleavage in a subset of EOPE placentas. Using multiple trophoblast cell lines, we demonstrate that trophoblast cells, which highly express GSDME, undergo a shift from apoptosis to CASP3-dependent pyroptosis, driving inflammation. Notably, pyroptotic trophoblasts further induce pro-inflammatory macrophage polarization within placental villi organoids, establishing a feedback loop that amplifies both trophoblast pyroptosis and inflammatory responses in trophoblast organoids-macrophage assembloids. In vivo, CASP3-GSDME-mediated trophoblast pyroptosis contributes to systemic inflammation in wild-type pregnant mice but not in Gsdme-/- mice. Screening of EOPE prevention drugs reveals Vitamin D as a suppressor of GSDME activation and pyroptosis in trophoblast cells. These findings highlight the CASP3-GSDME axis as a promising therapeutic target for preeclampsia prevention.

cell biology↗

bioRxiv2025

Comparison and Dynamic interaction between Auditory Cortex and Prefrontal Cortex of Behaving Monkeys during Novelty Detection

The ability to detect deviations from expected sensory input is fundamental for adaptive behavior. We recorded electrocorticographic activity from the auditory (AC) and prefrontal (PFC) cortices of behaving macaques during an auditory oddball task to probe the cortical dynamics of predictive processing. Repetition of standard stimuli evoked suppression and facilitation in AC and strong low-frequency (2 Hz) enhancement in PFC, accompanied by bidirectional delta-band coupling indicative of a shared predictive state. Deviant stimuli triggered early AC responses followed by PFC activation and increased feedforward and feedback connectivity across delta, theta, and gamma bands. Behavioral engagement amplified both prediction and prediction error signals, strengthening cortical network coordination. Together, these findings reveal a hierarchical predictive network in which the AC encodes sensory regularities and violations, while the PFC integrates predictive context in a behaviorally dependent manner.

neuroscience↗

bioRxiv2025

Temporal-orbitofrontal pathway regulates choices across physical reward and visual novelty

Perceptually novel objects have profound impacts on our daily decisions. People often pay to try novel meals over familiar ones, or to see novel visual scenes at art exhibits and travel destinations. This suggests that perceptual novelty and the value of physical rewards, such as food, interact at the level of neural circuits to guide decisions, but where and how is unknown. We designed a behavioral task to study this novelty-reward interaction in animals and to uncover its neural underpinnings. Subjects chose among familiar offers associated with different expectations of novel objects and different expectations of juice rewards. Expectation of novel objects increased the preference for expected rewards. This novelty-reward interaction was reflected by neural activity in the anterior ventral temporal cortex (AVMTC) - a region previously implicated in the detection and prediction of novelty - and in the orbitofrontal cortex (OFC) - an area that receives prominent AVMTC inputs and is known for its capacity to signal subjective value of visual objects. Neural activity patterns suggested that AVMTC was upstream of OFC in the decision process. Chemogenetic disruption of the AVMTC[->]OFC circuit altered the impact of expected novelty on the valuation of physical reward. Hence, the ventral visual system impacts novelty-reward interactions during decisions through direct projections to OFC.

neuroscience↗

bioRxiv2025

TOC1 phosphorylation disproportionally enhances chromatin binding at rhythmic gene promoters

Protein phosphorylation is a key regulatory mechanism in circadian systems. TIMING OF CAB EXPRESSION 1(TOC1) is a core transcriptional repressor in the plant circadian system that is phosphorylated near its N-terminus. Phenotype testing of single and multi-phosphosite mutants shows incomplete rescue of the short period toc1 mutant. We establish that TOC1 phosphorylation (particularly at S175) is necessary for optimal interaction with FAR-RED ELONGATED HYPOCOTYL3 (FHY3) and PHYTOCHROME INTERACTING FACTOR 5 (PIF5) at the CIRCADIAN CLOCK-ASSOCIATED 1 (CCA1) promoter to downregulate CCA1 expression. At the same time, expression of the closely related LATE ELONGATED HYPOCOTYL (LHY) also requires TOC1, but is independent of the TOC1 phosphorylation state, suggesting different TOC1-dependent mechanisms in the repression of these two genes. We additionally show how phosphorylation-dependent interactions of TOC1 at specific clock gene promoters selectively regulate these circadian system components more acutely than non-rhythmic genes. Our genome-wide analysis shows that the phosphostate of TOC1 is important for optimal chromatin presence and robust rhythmic gene expression.

plant biology↗

bioRxiv2024

Temporal Configuration as a New Feature of Sound: Psychological and Neurophysiological Evidence, Cross-species Consistency and Underlying Neuronal Mechanisms

Natural sounds are defined not only by their spectral content but also by their fine temporal structure. Here we show that millisecond-scale temporal configuration--defined by the ordering of inter-click intervals (ICIs) within a click train--behaves as a distinct auditory feature, conserved across species and emerging hierarchically along the auditory pathway. Human listeners reliably discriminated click trains that shared the same average ICI but differed in temporal configuration, and these differences elicited robust mismatch negativity (MMN) responses in an oddball paradigm, indicating automatic cortical deviance detection. Awake rats showed analogous MMN-like ECoG responses to configuration changes, demonstrating cross-species generality. Neuropixels recordings along the inferior colliculus-medial geniculate body-primary auditory cortex (IC-MGB-A1) axis revealed minimal configuration sensitivity in IC, intermediate sensitivity in MGB, and strong stimulus-specific adaptation to temporal configuration in A1. Reversible cooling of auditory cortex reduced configuration sensitivity in MGB, implicating corticothalamic feedback in shaping thalamic representations. Layer-resolved analyses further showed that supragranular A1 neurons carry stronger configuration-specific adaptation than infragranular neurons. These findings identify temporal configuration as a feature-like dimension of sound and delineate a hierarchical, feedback-dependent IC-MGB-A1 circuit architecture for encoding fine temporal structure in the mammalian brain.

neuroscience↗

bioRxiv2024

A signal of temporal integration in the human auditory brain: psychological insights, EEG evidence, and clinical application

Temporal integration, the process by which the auditory system combines sound information over a curtain period to form a coherent auditory object, is essential for coherent auditory perception, yet its neural mechanisms remain underexplored. We use a "transitional click train" paradigm, which concatenates two click trains with slightly differing inter-click intervals (ICIs), to investigate temporal integration in the human cortex. Using a 64-channel electroencephalogram (EEG), we recorded responses from 42 healthy participants exposed to regular and irregular transitional click trains and conducted change detection tasks. Regular transitional click trains elicited significant change responses in the human cortex, indicative of temporal integration, whereas irregular trains did not. These neural responses were modulated by ICI length, ICI contrast, and regularity. Behavioral data mirrored EEG findings, showing enhanced detection for regular conditions compared to irregular conditions and pure tones. Furthermore, variations in change responses were associated with decision-making processes. Temporal continuity was critical, as introducing gaps between click trains diminished both behavioral and neural responses. In clinical assessments, 22 coma patients exhibited diminished or absent change responses, effectively distinguishing them from healthy individuals. Our findings identify distinct neural markers of temporal integration and highlight the potential of transitional click trains for clinical diagnostics.

neuroscience↗