Biology subjects

Tian, X.

Publications and source records attributed to Tian, X..

At least 91 records · Page 5Linked to original sources

bioRxiv2024

Upregulating ANKHD1 in PS19 mice reduces Tau phosphorylation and mitigates Tau-toxicity-induced cognitive deficits

Abnormal accumulation of Tau protein in the brain disrupts normal cellular function and leads to neuronal death linked with many neurodegenerative disorders such as Alzheimers disease. An attractive approach to mitigate Tau-induced neurodegeneration is to enhance the clearance of toxic Tau aggregates. We previously showed that upregulation of the fly gene mask protects against FUS- and Tau-induced photoreceptor degeneration in fly disease models. Here we have generated a transgenic mouse line carrying Cre-inducible ANKHD1, the mouse homolog of mask, to determine whether the protective role of mask is conserved from flies to mammals. Utilizing the TauP301S-PS19 mouse model for Tau-related dementia, we observed that ANKHD1 significantly reduced hyperphosphorylated human Tau in 6-month-old mice. Additionally, there was a notable trend towards reduced gliosis levels in these mice, suggesting a protective role of ANKHD1 against TauP301S-linked degeneration. Further analysis of 9-month- old mice revealed a similar trend of effects. Moreover, we found that ANKHD1 also suppresses the cognitive defect of 9-month-old PS19 female mice in novel object recognition (NOR) behavioral assay. Unlike previous therapeutic strategies that primarily focus on inhibiting Tau phosphorylation or directly clearing aggregates, this study highlights the novel role of ANKHD1 in promoting autophagy as a means to mitigate Tau pathology. This novel mechanism not only underscores ANKHD1s potential as a unique therapeutic target for tauopathies but also provides new insights into autophagy-based interventions for neurodegenerative diseases.

neuroscience↗

bioRxiv2024

Influenza Virus Enhances Bacterial Growth in the Lungs through Weakening Capsule Receptor-Mediated Bacterial Capture by Neutrophils

Certain serotypes of encapsulated bacteria are more associated with severe pneumonia than others, but the biological reason behind this association has remained largely unknown. This study has uncovered a causal relationship between capsule serotype and virulence phenotype of Streptococcus pneumoniae, a leading cause of community-acquired pneumonia, in mice using isogenic bacteria. Certain high-virulence (HV) serotypes persist in the lungs and lead to severe pneumonia, whereas the low-virulence (LV) serotypes are effectively cleared. The capsule type-dependent difference in virulence is determined by the capsule-binding receptors, which recognize the capsular polysaccharides of the LV serotypes (but not the HV serotypes) and enable pathogen capture by neutrophils through complement activation. The capsule receptor-driven immunity of lung neutrophils is significantly compromised by pre-infection of influenza virus, which enhances the survival and virulence of the LV S. pneumoniae serotypes, and recurs in the heightened pathogenicity of Haemophilus influenzae. This study not only unravels the long-sought mechanistic mystery of serotype-dependent virulence in bacterial lung infections, but also provides an explanation for the well-known pathogenesis synergism between influenza virus and respiratory bacteria. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=160 SRC="FIGDIR/small/622589v1_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@1464164org.highwire.dtl.DTLVardef@16f34e5org.highwire.dtl.DTLVardef@1f9ad46org.highwire.dtl.DTLVardef@df104d_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2024

Phase Separation to Resolve Growth-Related Circuit Failures

Fluctuations in host cell growth poses a significant challenge to synthetic gene circuits, often disrupting circuit function. Existing solutions typically rely on circuit redesign with alternative topologies or additional control elements, yet a broadly applicable approach remains elusive. Here, we introduce a new strategy based on liquid-liquid phase separation (LLPS) to stabilize circuit performance. By engineering a self-activating circuit with transcription factors (TF) fused to an intrinsically disordered region (IDR), we enable the formation of TF condensates at the promoter region, maintaining local TF concentration despite growth-mediated dilution. This condensate formation preserves bistable memory in the self-activating circuit, demonstrating that phase separation can robustly counteract growth fluctuations, offering a novel design principle for resilient synthetic circuits.

synthetic biology↗

bioRxiv2024

Motor compensations, not sensory errors, regulate serial dependence in naturalistic speech production

Motor control is essential for organisms to efficiently interact with the environment by maintaining accurate action and adjusting to future changes. Speech production, one of the most complex motor behaviors, relies on a feedback control process to detect sensory errors and trigger updates in a feedforward control process that implements compensations. However, the specific contributions of these critical processes in sensorimotor learning during continuous vocal production remain debated. Here, we used two experimental designs in five experiments to dissociate these mechanisms. First, we employed a serial-dependence design with randomized pitch perturbations, dissociating the influences of sensory errors and motor compensation on subsequent vocalizations on a trial-by-trial basis. We found that motor compensation, rather than sensory errors, predicted the compensatory responses in the subsequent trials, suggesting instantaneous serial learning mediated by updates in the feedforward process. This compensation-driven serial learning was generalized across productions of different vowel categories. Second, we further implemented a serial-dependence adaptation design in a sentential context, where auditory perturbation occurred only on a preceding syllable. Any learning effects in its subsequent syllable without pitch perturbation would reflect changes in the speech motor representation. Our results consistently revealed that compensation in the preceding syllable predicted pitch changes in the subsequent syllable, but only when the two adjacent syllables were embedded within a word boundary. Collectively, the study provides ecological-valid evidence supporting that error-based motor compensation, incorporating cognitive and linguistic constraints, directly regulates the speech motor representation and mediates the instantaneous serial learning in successive actions.

neuroscience↗

bioRxiv2024

CRB2 Depletion Induces YAP Signaling and Disrupts Mechanosensing in Podocytes

Focal Segmental Glomerulosclerosis (FSGS) is a histologic lesion caused by a variety of injurious stimuli that lead to dysfunction/loss of glomerular visceral epithelial cells (i.e. podocytes). Pathogenic mutations in CRB2, encoding the type 1 transmembrane protein Crumb 2 Homolog Protein, have been shown to cause early-onset corticosteroid-resistant nephrotic syndrome (SRNS)/FSGS. Here, we identified a 2-generation East Asian kindred (DUK40595) with biopsy-proven SRNS/FSGS caused by a compound heterozygous mutation in CRB2 comprised of the previously described truncating mutation p.Gly1036_Alafs*43 and a rare 9-bp deletion mutation p.Leu1074_Asp1076del. Because compound heterozygous mutations involving the truncating p.Gly1036_Alafs*43 variant have been associated with reduced CRB2 expression in podocytes and autosomal recessive SRNS/FSGS, we sought to define the pathogenic effects of CRB2 deficiency in podocytes. We show that CRB2 knockdown induces YAP activity and target gene expression in podocytes. It upregulates YAP-mediated mechanosignaling and increases the density of focal adhesion and F-actin. Using Elastic Resonator Interference Stress Microscopy (ERISM), we demonstrate that CRB2 knockdown also enhances podocyte contractility in a substrate stiffness-dependent manner. The knockdown effect decreases with increasing substrate stiffness, indicating impaired mechanosensing in CRB2 knockdown cells at low substrate stiffness. While the mechanical activation of CRB2 knockdown cells is associated with increased YAP activity, the enhanced cell contractility is not significantly reduced by the selective YAP inhibitors K-975 and verteporfin, suggesting that multiple pathways may be involved in mechanosignaling downstream of CRB2. Taken together, these studies provide the first evidence that CRB2 deficiency may impair podocyte mechanotransduction via disruption of YAP signaling in podocytes.

biophysics↗

bioRxiv2024

TRENDY: Gene Regulatory Network Inference Enhanced by Transformer

Gene regulatory networks (GRNs) play a crucial role in the control of cellular functions. Numerous methods have been developed to infer GRNs from gene expression data, including mechanism-based approaches, information-based approaches, and more recent deep learning techniques, the last of which often overlook the underlying gene expression mechanisms. In this work, we introduce TRENDY, a novel GRN inference method that integrates transformer models to enhance the mechanism-based WENDY approach. Through testing on both simulated and experimental datasets, TRENDY demonstrates superior performance compared to existing methods. Furthermore, we apply this transformer-based approach to three additional inference methods, showcasing its broad potential to enhance GRN inference.

genetics↗

bioRxiv2024

TvAP65 in Trichomonas vaginalis Promotes HPV Infection by Interacting with Host Molecules

Cervical cancer induced by human papillomavirus (HPV) infection poses a serious threat to womens health. Studies have shown that Trichomonas vaginalis (T. vaginalis), which is widely prevalent globally, can facilitate HPV infection. However, the underlying mechanism remains unclear. This study found that T. vaginalis significantly enhanced HPV infection in HaCaT cells and mouse vaginas through in vivo and in vitro experiments, and promoted the expression of HPV membrane receptor molecules CD151 and HSPG2. The HPV infection rate and CD151/HSPG2 expression levels were significantly decreased after reducing the expression of T. vaginalis adhesion protein 65 (TvAP65). In contrast, both HPV infection rates and CD151/HSPG2 expression were significantly increased in HaCaT cells over-expressing TvAP65. When both TvAP65 in T. vaginalis and CD151/HSPG2 in HaCaT cells were knocked down simultaneously, the infection rate of HPV in HaCaT cells was further reduced. These results suggest that TvAP65 promotes HPV infection by up-regulating the expression of CD151 and HSPG2. Furthermore, this study knocked down the 12 interacting molecules of TvAP65 in HaCaT cells one by one, and found that the HPV infection rate was significantly reduced after T. vaginalis infected HaCaT cells with low expression of FTH1, SPCS1, ATP5MC3, ITGB7, PMEPA1 or REEP5. Among them, SPCS1 played the most significant role. Simultaneous knockdown of TvAP65 and SPCS1 further significantly down-regulated the infection rate of HPV in HaCaT cells. Moreover, this molecule also down-regulated the promoting effect of T. vaginalis on HSPG2/CD151 expression. These results imply that SPCS1 plays an important role in T. vaginalis promoting HSPG2/CD151 expression and HPV infection. This study not only further proved that T. vaginalis can promote HPV infection but also explores the molecular mechanism by which TvAP65, through its interaction with SPCS1, up-regulates the expression of HSPG2 and CD151, thereby facilitating HPV infection. This provides a theoretical basis for clarifying the mechanism of co-infection between T. vaginalis and HPV.

microbiology↗

bioRxiv2024

Cortical connectivity supports motoric synchronization to both auditory and visual rhythms in a frontal-temporal network

Synchronizing motoric responses to metrical sensory rhythms is key to social activities, e.g., group singing and dancing. It remains elusive, however, whether there is a common neural network for motoric synchronization to metrical rhythms from different sensory modalities. Here, we separate sensorimotor responses from basic sensory responses by combining a metrical sensorimotor synchronization task with frequency-domain magnetoencephalography (MEG) analysis. A common frontal-temporal network, not including visual cortex, is observed during both visual- and auditory-motor synchronization, and the network remains in congenitally deaf participants during visual-motor synchronization, suggesting the network is formed by intrinsic cortical connections instead of auditory experience. Furthermore, activation of the left and right frontal-temporal areas, as well as the ipsilateral white matter connection, separately predict the precision of auditory and visual synchronization. These results reveal a common but lateralized frontal-temporal network for visual- and auditory-motor synchronization, which is generated based on intrinsic cortical connections.

neuroscience↗

bioRxiv2024

Evaluating computational approaches for comparison of protein expression across cancer indications

BackgroundThe National Cancer Institutes Clinical Proteomic Tumor Analysis Consortium (CPTAC) recently generated harmonized genomic, transcriptomic, proteomic, and clinical data for over 1,000 tumors across 10 cohorts to facilitate pan-cancer discovery research. However, protein expression comparison across CPTAC cohorts remains challenging due to non-uniform missing data and varying protein expression distribution patterns across tumor types. Here, we present our efforts to evaluate various missing data handling and normalization strategies to create a normalized pan-cancer protein expression dataset. ResultsFirst, we developed a novel algorithm to select robustly expressed proteins in tumors within any CPTAC cohort. Second, we applied a cohort hybrid imputation approach to protein abundance values from FragPipe within each cohort based on protein expression distribution patterns. Third, we calculated intensity-based absolute quantification using protein abundance values and applied both global and smooth quantile normalization methods. Our results indicate that global quantile normalization ensured identical distribution across cohorts for both tumor and normal tissues, while smooth quantile normalization preserved distribution differences between biological conditions. We assessed our method by comparing differential protein expression analysis results with and without normalization. Additionally, we examined the ranks of protein expression in the normalized CPTAC dataset for selected proteins with high protein-to-RNA expression correlation across CPTAC cohorts. We then compared these protein expression ranks with their RNA expression ranks across corresponding cohorts in The Cancer Genome Atlas (TCGA). Differential protein expression analysis revealed a high level of agreement in the fold change of tumor versus normal tissue within cohorts before and after normalization. Furthermore, our results indicate that global quantile normalization resulted in the highest cohort rank correlation between CPTAC and TCGA for selected proteins. ConclusionsIn summary, our thorough analysis demonstrates that global quantile normalization surpasses both smooth quantile normalization and no normalization, as evidenced by its higher rank correlation across cancer cohorts between CPTAC and TCGA for selected proteins. The findings suggest that combining cohort hybrid imputation with global quantile normalization is an effective method for creating a normalized CPTAC pan-cancer protein dataset, which can facilitate the study of protein expression across different cancer types.

bioinformatics↗

bioRxiv2024

PARP inhibition enhances exemestane efficacy in triple-negative breast cancer

Triple negative breast cancer (TNBC) remains the breast cancer subtype with the poorest prognosis and median survival rate. Targeting PARP1/2 with PARP inhibitors (PARPi) and achieving synthetic lethality is an effective strategy for TNBCs with BRCA1/2 mutations, however, the majority of TNBCs are BRCA1/2 wild type. Synergistic drug combinations with PARPi offers the potential to expand the use of PARPi towards BRCA-proficient cancers, including TNBC. To identify new PARPi combinations, we screened a library of 166 FDA-approved oncology drugs for synergy with the PARPi Olaparib in TNBC cells. We found that Exemestane, an aromatase inhibitor, synergised with Olaparib with a significant decrease in IC50 values and clonogenicity accompanied by elevated DNA damage and apoptosis seen in combination treatment. The mechanistic basis for synergy was rationalised by the previously unreported ability of Exemestane to induce replication stress, as evidenced by ATR pathway activation and RPA foci formation. Low impact of this combination towards normal breast epithelial cells was observed and Exemestane has no reported severe toxicity as a monotherapy. This combination was able to achieve enhanced tumor growth inhibition in a murine xenograft model, greater than either drug employed as a single-agent. GO and KEGG enrichment analysis of differential genes indicated alterations in pathways associated with cell death in response to Exemestane and Olaparib treatment.

pharmacology and toxicology↗

bioRxiv2024

Longevity or Well-being? A Dual-Dimension Structure of Neuroticism

The development of personality traits is often viewed as evolutionarily adaptive. Current neuroticism research, however, predominantly highlights its negative health impacts, neglecting its potential evolutionary advantages. We propose that neuroticisms inter-individual variability can be structured into two distinct geometric dimensions. One, named the Emotional Reactivity-Instability/Distress Spectrum (ERIS), correlates strongly with longevity and is associated with chronic diseases and risk-averse lifestyle. This dimension is underpinned by evolutionarily conserved subcortical brain regions and genes. The other, resembling the overall neuroticism score, is primarily linked to mental and stress-related disorders, as well as life satisfaction. It involves higher-order emotional brain regions and is genetically enriched in human-accelerated regions. Collectively, these dimensions represent a dual-strategy personality framework that optimizes survival and well-being, with the former being evolutionarily conservative and the latter potentially a unique human adaptation.

neuroscience↗

bioRxiv2024

Long-term NMN treatment increases lifespan and healthspan in mice in a sex dependent manner

Nicotinamide adenine dinucleotide (NAD) is essential for many enzymatic reactions, including those involved in energy metabolism, DNA repair and the activity of sirtuins, a family of defensive deacylases. During aging, levels of NAD+ can decrease by up to 50% in some tissues, the repletion of which provides a range of health benefits in both mice and humans. Whether or not the NAD+ precursor nicotinamide mononucleotide (NMN) extends lifespan in mammals is not known. Here we investigate the effect of long-term administration of NMN on the health, cancer burden, frailty and lifespan of male and female mice. Without increasing tumor counts or severity in any tissue, NMN treatment of males and females increased activity, maintained more youthful gene expression patterns, and reduced overall frailty. Reduced frailty with NMN treatment was associated with increases in levels of Anerotruncus colihominis, a gut bacterium associated with lower inflammation in mice and increased longevity in humans. NMN slowed the accumulation of adipose tissue later in life and improved metabolic health in male but not female mice, while in females but not males, NMN increased median lifespan by 8.5%, possible due to sex-specific effects of NMN on NAD+ metabolism. Together, these data show that chronic NMN treatment delays frailty, alters the microbiome, improves male metabolic health, and increases female mouse lifespan, without increasing cancer burden. These results highlight the potential of NAD+ boosters for treating age-related conditions and the importance of using both sexes for interventional lifespan studies.

pharmacology and toxicology↗

bioRxiv2024

Mapping Individual Differences in the Topological Landscape of Naturalistic Brain Dynamics

Psychiatry seeks to unravel brain dysfunction and individual differences in real-world contexts. Naturalistic stimuli, like movie watching, are increasingly recognized for eliciting complex, context-dependent neural activity with high ecological validity. Yet, current methods often rely on standard paradigms that average data across time, limiting the full potential of such stimuli. Here, we present STIM, a Topological Data Analysis-based framework designed to dynamically track how individuals integrate complex contexts in real time. Applied to large-sample fMRI data from movie watching, STIM constructs a robust low-dimensional dynamical landscape that reflects group consensus while probing individual variations at both global (spanning narratives) and local (within specific narratives) levels. At the global level, individual differences emerge along a center-periphery gradient in the dynamical landscape, which significantly predicts fluid intelligence, underscoring the importance of neural adaptability and diversity. At finer scales, local geometric features correlate with context-specific psychological traits beyond cognition. STIM also captures developmental changes in the dynamical landscape and reveals abnormalities in conditions such as autism. These findings demonstrate that STIM leverages the rich information from movie stimuli and fMRI recordings as neural probes to assess individual differences in cognition and mental health.

neuroscience↗

bioRxiv2024

Unique trajectory of gene family evolution from genomic analysis of nearly all known species in an ancient yeast lineage

Gene gains and losses are a major driver of genome evolution; their precise characterization can provide insights into the origin and diversification of major lineages. Here, we examined gene family evolution of 1,154 genomes from nearly all known species in the medically and technologically important yeast subphylum Saccharomycotina. We found that yeast gene family and genome evolution are distinct from plants, animals, and filamentous ascomycetes and are characterized by small genome sizes and smaller gene numbers but larger gene family sizes. Faster-evolving lineages (FELs) in yeasts experienced significantly higher rates of gene losses--commensurate with a narrowing of metabolic niche breadth--but higher speciation rates than their slower-evolving sister lineages (SELs). Gene families most often lost are those involved in mRNA splicing, carbohydrate metabolism, and cell division and are likely associated with intron loss, metabolic breadth, and non-canonical cell cycle processes. Our results highlight the significant role of gene family contractions in the evolution of yeast metabolism, genome function, and speciation, and suggest that gene family evolutionary trajectories have differed markedly across major eukaryotic lineages.

evolutionary biology↗

bioRxiv2024

Noise Reduction in Resource-Coupled Multi-Module Gene Circuits through Antithetic Feedback Control

Gene circuits within the same host cell often experience coupling, stemming from the competition for limited resources during transcriptional and translational processes. This resource competition introduces an additional layer of noise to gene expression. Here we present three multi-module antithetic control strategies: negatively competitive regulation (NCR) controller, alongside local and global controllers, aimed at reducing the gene expression noise within the context of resource competition. Through stochastic simulations and fluctuation-dissipation theorem (FDT) analysis, our findings highlight the superior performance of the NCR antithetic controller in reducing noise levels. Our research provides an effective control strategy for attenuating resource-driven noise and offers insight into the development of robust gene circuits.

synthetic biology↗

bioRxiv2024

Multivalent Targeting of Blood-Brain Barrier LRP1 for Neurovascular Recovery Therapy for Alzheimer s Disease

The blood-brain barrier (BBB) is a highly selective permeability barrier that safeguards the central nervous system (CNS) from potentially harmful substances while regulating the transport of essential molecules. Its dysfunction is increasingly recognized as a pivotal factor in the pathogenesis of Alzheimers disease (AD), contributing to the accumulation of amyloid-{beta} (A{beta}) plaques. We propose an AD therapeutic strategy targeting the BBB low-density lipoprotein receptor-related protein 1 (LRP1). We show that a multivalent scaffold with LRP1-specific peptide modulates the A{beta} transport at the BBB. We show via detailed experimentation on AD model mice that this intervention markedly reduces A{beta} deposits and prevents cognitive decline. This study marks a new approach to drug design, combining multivalent targeting with the regulation of membrane trafficking through advanced molecular engineering. Crucially, the therapeutic effects emerge from the multivalent nature of our proposed system. Furthermore, our findings underscore the paramount significance of the BBB in AD pathogenesis, particularly emphasizing the critical role of LRP1-mediated A{beta} clearance in mitigating disease progression.

neuroscience↗

bioRxiv2024

Protein S-glutathionylation confers cell resistance to ferroptosis

Ferroptosis is a type of cell death that is strongly associated with the cellular redox state. Glutathione is the key to buffering lipid peroxidation in ferroptosis and can also modify proteins by S-glutathionylation under oxidative stress. Here, we showed that the strong associations among glutathione pools, protein S-glutathionylation, and susceptibility to ferroptosis existed broadly in ferroptosis induced by erastin or acetaminophen. Deficiency of CHAC1, a glutathione-degrading enzyme, led to decreased glutathione pools and reduced protein S-glutathionylation, improved liver function and attenuated hepatocyte ferroptosis upon acetaminophen challenge, which could be retarded by CHAC1 overexpression. We conducted quantitative redox proteomics in primary mouse hepatocytes to identify glutathione pool-sensitive S-glutathionylated proteins and found that S-glutathionylation is required to maintain the function of ADP-ribosylation factor 6 (ARF6). Our data suggest that aberrant ARF6 S-glutathionylation increases the labile iron pool by delaying the recycling of transferrin receptors, thereby promoting ferroptosis. Our study reveals the importance of protein S-glutathionylation in conferring cell resistance to ferroptosis. O_FIG O_LINKSMALLFIG WIDTH=186 HEIGHT=200 SRC="FIGDIR/small/592374v1_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@82dbaeorg.highwire.dtl.DTLVardef@1247cc5org.highwire.dtl.DTLVardef@7b7147org.highwire.dtl.DTLVardef@49ff07_HPS_FORMAT_FIGEXP M_FIG C_FIG HIGHLIGHTSO_LIHighly upregulated CHAC1 decreases glutathione pools and protein S-glutathionylation. C_LIO_LIReduced protein S-glutathionylation associated with decreased glutathione pools promotes ferroptosis. C_LIO_LIS-glutathionylation of ARF6 at Cys90 promotes ARF6 activation. C_LIO_LIReduced S-glutathionylation of ARF6 provides a labile iron pool to drive ferroptosis. C_LI

cell biology↗

bioRxiv2024

ATP-Independent Water-Soluble Luciferins Enable Non-Invasive High-Speed Video-Rate Bioluminescence Imaging of Mice

NanoLuc luciferase and its derivatives are attractive bioluminescent reporters recognized for their efficient photon production and ATP independence. However, utilizing them for in vivo imaging poses notable challenges. Low substrate solubility has been a prominent problem, limiting in vivo brightness, while substrate instability hampers consistent results and handling. To address these issues, we developed a range of caged PEGylated luciferins with improved stability and water solubility of up to 25 mM, resulting in substantial bioluminescence increases in mouse models. This advancement has created the brightest and most sensitive luciferase-luciferin combination, enabling high-speed video-rate imaging of freely moving mice with brain-expressed luciferase. Furthermore, we developed a bioluminescent Ca2+ indicator with exceptional sensitivity to physiological Ca2+ changes and paired it with a new substrate to showcase non-invasive, video-rate imaging of Ca2+ activity in a defined brain region in awake mice. These innovative substrates and the Ca2+ indicator are poised to become invaluable resources for biological and biomedical fields.

synthetic biology↗