Biology subjects

Chen, Z.

Publications and source records attributed to Chen, Z..

At least 379 records · Page 21Linked to original sources

bioRxiv2024

Joint Moment-Angle/Velocity Relations in the Hip, Knee, and Ankle: A Meta-Visualization of Datasets

Joint moment is a prominent kinetic property in biomechanical investigations, whose pattern and magnitude unravel the characteristics of musculoskeletal motion and muscle biomechanics. Nonetheless, the relations of joint moment with joint angle and velocity are complicated, and it is often unclear how the kinetic capacity of each joint varies in different configurations. With common techniques in systematic review, we collected a total of 985 passive, isometric and isokinetic joint moment datasets from literature and visualized the major joint moment-angle and moment-velocity relations in the hip, knee, and angle. The findings contribute to the understanding and analysis of musculoskeletal mechanics, as well as providing reference regarding the experimental design for future moment measurement.

biophysics↗

bioRxiv2024

Muscle Moment Arm-Joint Angle Relations in the Hip, Knee, and Ankle: A Visualization of Datasets

Muscle moment arm is a property that associates muscle force with joint moment and is crucial to biomechanical analysis. In musculoskeletal sim-ulations, the accuracy of moment arm is as important as that of muscle force, and moment arm calibration requires data from anatomical measure-ments. Nonetheless, such data are elusive, and the complex relation between moment arm and joint angle can be unclear. Using common techniques in systematic review, we collected a total of 300 moment arm datasets from literature and visualized the muscle moment arm-joint angle relations in the hip, knee, and angle. The findings contribute to the understanding and anal-ysis of musculoskeletal mechanics, as well as providing reference regarding the experimental design for future moment arm measurements.

biophysics↗

bioRxiv2024

antiCD49d Ab treatment ameliorates age-associated inflammatory response and mitigates CD8 T cell cytotoxicity after traumatic brain injury

Patients aged 65 years and older account for an increasing proportion of patients with traumatic brain injury (TBI). Older TBI patients experience increased morbidity and mortality compared to their younger counterparts. Our prior data demonstrated that by blocking 4 integrin, anti-CD49d antibody (aCD49d Ab) abrogates CD8+ T-cell infiltration into the injured brain, improves survival, and attenuates neurocognitive deficits. Here, we aimed to uncover how aCD49d Ab treatment alters local cellular responses in the aged mouse brain. Consequently, mice incur age-associated toxic cytokine and chemokine responses long-term post-TBI. aCD49d Ab attenuates this response along with a T helper (Th)1/Th17 immunological shift and remediation of overall CD8+ T cell cytotoxicity. Furthermore, aCD49d Ab reduces CD8+ T cells exhibiting higher effector status, leading to reduced clonal expansion in aged, but not young, mouse brains with chronic TBI. Together, aCD49d Ab is a promising therapeutic strategy for treating TBI in the older people. Graphic abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=88 SRC="FIGDIR/small/596673v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@97311aorg.highwire.dtl.DTLVardef@18a86borg.highwire.dtl.DTLVardef@d9162forg.highwire.dtl.DTLVardef@3f8d06_HPS_FORMAT_FIGEXP M_FIG C_FIG Aged brains after TBI comprise two pools of CD8+ T cells. The aged brain has long been resided by a population of CD8+ T cells thats exhaustive and dysfunctional. Post TBI, due to BBB impairment, functional CD8+ T cells primarily migrate into the brain parenchyma. Aged, injury-associated microglia with upregulated MHC class I molecules can present neoantigens such as neuronal and/or myelin debris in the injured brains to functional CD8+ T, resulting in downstream CD8+ T cell cytotoxicity. aCD49d Ab treatment exerts its function by blocking the migration of functional effector CD8+ T cell population, leading to less cytotoxicity and resulting in improved TBI outcomes in aged mice.

immunology↗

bioRxiv2024

Post-encoding administration of oxytocin selectively enhances memory consolidation of male faces in females

Oxytocin plays a critical role in modulating social cognition and enhancing human memory for faces. However, it remains unclear which stage of memory oxytocin affects to enhance face memory. Our study explored oxytocins potential to selectively enhance the consolidation of social memories, specifically human faces, and whether this effect varies between genders. In two preregistered, randomized, double-blind, placebo-controlled trials with heterosexual participants (total N=294, comprising 149 males and 145 females), we explored how oxytocin affects memory consolidation. We administered oxytocin immediately after encoding (i.e., Study1) and 30 minutes before retrieval in a parallel study (i.e., Study2). This design allowed us to confirm that oxytocins effects were indeed due to consolidation rather than retrieval. We found that administering oxytocin post-encoding, but not before-retrieval, significantly improved female participants ability to recognize male faces 24 hours later, with no similar enhancement observed in males recognizing opposite-gender faces. Together with our analyses of social placebo effects and approachability rating during encoding, we concluded that oxytocin enhanced consolidation of long-term social memories in humans. Our results not only advance the understanding of the neurobiological mechanisms underlying social memory consolidation but also highlight oxytocin as a pharmacological tool for selectively enhancing human memory consolidation. HighlightsO_LIOxytocin selectively enhances memory consolidation of human faces, with gender-specific effects. C_LIO_LIIn females, oxytocin after encoding improves recognition of male faces after 24 hours. C_LIO_LIOxytocin-induced enhancement of social memory is due to enhanced consolidation, not retrieval or encoding. C_LIO_LIOxytocin shows potential for selectively modulating memory consolidation in humans. C_LI

neuroscience↗

bioRxiv2024

Human tau promotes Warburg effect-like glycolytic metabolism under acute hyperglycemia conditions through modulating the homeostasis of protein-membrane association

The neurofilaments formed by hyperphosphorylated tau is a hallmark of tau-related neurodegenerative disease, including Alzheimers disease, tau related FTDP-17, Picks disease, et al. However, the biological functions of tau and the physiological significance of its phosphorylation are still not fully understood. By using human tau (441 a.a.) transgenic (hTau) mice in which murine tau has been deleted simultaneously, murine tau knockout (Tau KO) mice and C57BL/6J (C57) mice, unexpectedly, we found that under acute hyperglycemia conditions, JNK but not previously reported GSK-3{beta} mediated tau phosphorylation. Moreover, Akt, the upstream GSK-3{beta} inhibitory kinase, was activated in a tau dependent manner. By comparing the membrane-associated proteome, we found that human tau influenced the homeostasis of protein-membrane association under acute hyperglycemia conditions. Of note, with respect to WT and Tau KO mice, the membrane-association of Krts, TFAM, TRAP1, mTOR et al, were strengthened by human tau. Whereas, the membrane-association of ribosomal proteins Rpls, proteasome proteins Psmds, and mitochondrial proteins, such as COXs, Ndufa1, Mtnt4, et al, were impeded by human tau. In vitro study showed that aerobic glycolysis was promoted in the presence of human tau, which maintained NAD+/NADH ratio. On the other hand, it restricted oxidative phosphorylation level, modulated the activity of SDH, and reduced ROS production upon challenging by high glucose. Furthermore, under acute high glucose conditions, the presence of human tau significantly augmented Akt activation, but inhibited 4EBP phosphorylation simultaneously, indicating that human tau is also involved in regulating the alternative activation of mTORC1/2. In summary, the current study revealed that human tau played an important role in regulating glycolytic metabolism under acute high hyperglycemia conditions, which is similar with the Warburg-effect, through influencing the homeostasis of protein-membrane association.

molecular biology↗

bioRxiv2024

Longitudinal analysis of body weight reveals homeostatic and adaptive traits linked to lifespan in diversity outbred mice

Dense temporal measurements of physiological health using simple and consistent assays are essential to characterize biological processes associated with aging and evaluate the effectiveness of interventions on these processes. We measured body weight in 960 genetically diverse mice, every 7-10 days over the full course of their lifespan. We used a state space model to characterize the trajectories of body weight throughout life and derived 10 novel traits capturing the dynamics of body weight that are both associated with lifespan and heritable. Genetic mapping of these traits identified 12 genomic loci, none of which were previously mapped to body weight. We observed that the ability to stabilize body weight, despite fluctuations in energy intake and expenditure, is positively associated with lifespan and mapped to a genomic locus linked to energy homeostasis. Our results highlight the importance of dense longitudinal measurements of physiological traits for monitoring health and aging.

physiology↗

bioRxiv2024

Still waters run deep: Large scale genome rearrangements in the evolution of morphologically conservative Polyplacophora

BackgroundA major question in animal evolution is how genotypic and phenotypic changes are related, and whether ancient gene order is conserved in living clades. Chitons, the molluscan class Polyplacophora, retain a body plan and general morphology apparently little changed since the Palaeozoic. We present a comparative analysis of five reference quality genomes, including four de novo assemblies, covering all major chiton clades, and an updated phylogeny for the phylum. ResultsWe constructed 20 ancient molluscan linkage groups (MLGs) that are relatively conserved in bivalve karyotypes, but subject to re-ordering, rearrangement, fusion, or partial duplication among chitons, varying even between congeneric species. The largest number of novel fusions is in the most plesiomorphic clade Lepidopleurida, and the chitonid Liolophura japonica has a partial genome duplication, extending the occurrence of large-scale gene duplication within Mollusca. ConclusionsThe extreme and dynamic genome rearrangements in this class stands in contrast to most other animals, demonstrating that chitons have overcome evolutionary constraints acting on other animal groups. The apparently conservative phenome of chitons belies rapid and extensive changes in genome.

genomics↗

bioRxiv2024

Multi-parametric thrombus profiling microfluidics detects intensified biomechanical thrombogenesis associated with hypertension and aging

Arterial thrombosis, which represents a critical complication of cardiovascular diseases, is a leading cause of death and disability worldwide with no effective bioassay for clinical prediction. As a symbolic feature of arterial thrombosis, severe stenosis in the blood vessel creates a high-shear, high-gradient flow environment that effectively facilitates platelet aggregation towards vessel occlusion even with platelet amplification loops inhibited. However, no approach is currently available to comprehensively characterize the size, composition and platelet activation status of thrombi forming under this biorheological condition. Here, we present a thrombus profiling assay that monitors the multi-dimensional attributes of thrombi forming in conditions mimicking the physiological scenario of arterial thrombosis. Using this platform, we demonstrate that different receptor-ligand interactions contribute distinctively to the composition and activation status of the thrombus. Our investigation into hypertensive and older individuals reveals intensified biomechanical thrombogenesis and multi-dimensional thrombus profile abnormalities, demonstrating a direct contribution of mechanobiology to arterial thrombosis and endorsing the diagnostic potential of the assay. Furthermore, we identify the hyperactivity of GPIb-integrin IIb{beta}3 mechanosensing axis as a molecular mechanism that contributes to hypertension-associated arterial thrombosis. By studying the interactions between anti-thrombotic inhibitors and hypertension, and the inter-individual variability in personal thrombus profiles, our work reveals a critical need for personalized anti-thrombotic drug selection that accommodates each patients pathological profile.

bioengineering↗

bioRxiv2024

Myocardial infarction creates a critical time window for AAV gene therapy

Recombinant adeno-associated virus (AAV) is a major gene delivery vector for cardiac gene therapy. The factors that influence AAV-based cardiac gene transfer remain incompletely understood. This study showed that myocardial infarction (MI) enhanced cardiac AAV transduction and gene expression in mice after systemic administration, peaking at the third day post MI. These additional AAV vectors enriched at the infarcted region, correlated with the pathological permeabilization of the coronary vessels. The outcome of AAV-base gene therapy for MI, via Camk2d base editing, was significantly improved when AAV was injected at the third day post MI. Together, our findings uncovered a critical therapeutic time window after MI that facilitated AAV-based cardiac gene transfer, which could be harnessed to boost both basic and translational cardiology. MethodsAdult C57BL/6 mice were subjected to left anterior descending (LAD) coronary artery ligation. Permanent LAD ligation created the MI model while 30min ligation followed by reperfusion established the ischemia/reperfusion (I/R) model. 2x1011 AAV vectors were injected into the mice via tail vein. The AAV vectors carried transgenes that were activated by the cardiomyocyte-specific Tnnt2 promoter or the constitutively active CMV promoter. AAV expressed luciferase with the hemagglutinin (HA) tag. The amount of AAV vectors were quantified by real-time quantitative PCR (RT-qPCR) analysis of genomic DNA. Transgene expression was measured by RT-qPCR at the mRNA level or HA tag immunofluorescence imaging and western blot at the protein level. Luciferase activity was measured via bioluminescence imaging.

physiology↗

bioRxiv2024

Functional imaging of whole mouse embryonic development in utero

Despite significant advances in structural and genetic studies, investigations of early embryonic functions, such as brain activity, have long been constrained by technical challenges. Functional ultrasound (fUS) has emerged as a breakthrough modality, enabling real-time monitoring of brain activity with exceptional spatial and temporal resolution and offering unprecedented opportunities for studying functional embryonic development. In this study, we used fUS to monitor whole-embryo activity in mice from embryonic days E8.5 to E18.5, revealing patterns of neural activity throughout embryogenesis. This approach provides new opportunities to explore brain development dynamically as it unfolds. Moreover, we observed embryo responses to external stimuli, including sound, in both mice and cynomolgus macaques, offering insights into early sensory processing and neural maturation. In summary, our study establishes fUS as a powerful tool for studying embryonic brain functional development, with significant implications for scientific research, especially in non- human primate models, and clinical applications.

developmental biology↗

bioRxiv2024

PRDX6 contributes to selenocysteine metabolism and ferroptosis resistance

Selenocysteine (Sec) metabolism is crucial for cellular function and ferroptosis prevention and has traditionally been thought to begin with the uptake of the Sec carrier selenoprotein P (SELENOP). Following uptake, Sec released from SELENOP undergoes metabolisation via selenocysteine lyase (SCLY), producing selenide, a substrate used by selenophosphate synthetase 2 (SEPHS2), which provides the essential selenium donor - selenophosphate - for the biosynthesis of the selenocysteine tRNA. Here, we report the discovery of an alternative pathway mediating Sec metabolisation that is independent of SCLY and mediated by peroxiredoxin 6 (PRDX6). Mechanistically, we demonstrate that PRDX6 can readily react with selenide and interact with SEPHS2, potentially acting as a selenium delivery system. Moreover, we demonstrate the presence and functional significance of this alternative route in cancer cells where we reveal a notable association between elevated expression of PRDX6 with a highly aggressive neuroblastoma subtype. Altogether, our study sheds light on a previously unrecognized aspect of Sec metabolism and its implications in ferroptosis, offering new avenues for therapeutic exploitation.

cell biology↗

bioRxiv2024

Baikal: Unpaired Denoising of Fluorescence Microscopy Images using Diffusion Models

Fluorescence microscopy is an indispensable tool for biological discovery but image quality is constrained by desired spatial and temporal resolution, sample sensitivity, and other factors. Computational denoising methods can bypass imaging constraints and improve signal-tonoise ratio in images. However, current state of the art methods are commonly trained in a supervised manner, requiring paired noisy and clean images, limiting their application across diverse datasets. An alternative class of denoising models can be trained in a self-supervised manner, assuming independent noise across samples but are unable to generalize from available unpaired clean images. A method that can be trained without paired data and can use information from available unpaired highquality images would address both weaknesses. Here, we present Baikal, a first attempt to formulate such a framework using Denoising Diffusion Probabilistic Models (DDPM) for fluorescence microscopy images. We first train a DDPM backbone in an unconditional manner to learn generative priors over complex morphologies in microscopy images. We then apply various conditioning strategies to sample from the trained model and propose an optimal strategy to denoise the desired image. Extensive quantitative comparisons demonstrate better performance of Baikal over state of the art self-supervised methods across multiple datasets. We highlight the advantage of generative priors learnt by DDPMs in denoising complex Flywing morphologies where other methods fail. Overall, our DDPM based denoising framework presents a new class of denoising methods for fluorescence microscopy datasets that achieve good performance without collection of paired high-quality images. Github repo: https://github.com/scelesticsiva/denoising/tree/main

bioinformatics↗

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

Transcription factor binding site divergence across maize inbred lines drives transcriptional and phenotypic variation

Regulatory elements are important constituents of plant genomes that have shaped ancient and modern crops. Their identification, function, and diversity in crop genomes however are poorly characterized, thus limiting our ability to harness their power for further agricultural advances using induced or natural variation. Here, we use DNA affinity purification-sequencing (DAP-seq) to map transcription factor (TF) binding events for 200 maize TFs belonging to 30 distinct families and heterodimer pairs in two distinct inbred lines historically used for maize hybrid plant production, providing empirical binding site annotation for 5.3% of the maize genome. TF binding site comparison in B73 and Mo17 inbreds reveals widespread differences, driven largely by structural variation, that correlate with gene expression changes. TF binding site presence-absence variation helps clarify complex QTL such as vgt1, an important determinant of maize flowering time, and DICE, a distal enhancer involved in herbivore resistance. Modification of TF binding regions via CRISPR-Cas9 mediated editing alters target gene expression and phenotype. Our functional catalog of maize TF binding events enables collective and comparative TF binding analysis, and highlights its value for agricultural improvement.

plant biology↗

bioRxiv2024

Spatiotemporal transcriptomic maps of mouse intracerebral hemorrhage at single-cell resolution

Intracerebral hemorrhage (ICH) is a severe and widespread disease that results in high mortality and morbidity. Despite significant advances made in clinical and preclinical research, the prognosis of ICH remains poor due to an incomplete understanding of the complex pathological responses. To address this challenge, we generated single-cell resolution spatiotemporal transcriptomic maps of mouse brain 1, 3, 7, 14, and 28 days after ICH. Our analysis revealed the cellular constituents and their dynamic responses following ICH. We found changes in gene expression that are indicative of active phagocytosis and lipid processing in the lesion core and identified genes associated with brain repair at the lesion border. Persistent lipid accumulation culminated in the phenotypic transition of macrophages into foam cells. Furthermore, our results demonstrate that ICH could stimulate neural stem cells in the subventricular zone, thereby enhancing neurogenesis in this niche. This study provides a spatiotemporal molecular atlas of mouse ICH that advances the understanding of both local and global responses of brain cells to ICH and offers a valuable resource that can aid the development of novel therapies for this devastating condition.

neuroscience↗

bioRxiv2024

mosGraphGen: a novel tool to generate multi-omic signaling graphs to facilitate integrative and interpretable graph AI model development

Multi-omics data, i.e., genomics, epigenomics, transcriptomics, proteomics, characterize cellular complex signaling systems from multi-level and multi-view and provide a holistic view of complex cellular signaling pathways. However, it remains challenging to integrate and interpret multi-omics data for mining key disease targets and signaling pathways. Graph AI models have been widely used to analyze graph-structure datasets, and are ideal for integrative multi-omics data analysis because they can naturally integrate and represent multi-omics data as a biologically meaningful multi-level signaling graph and interpret multi-omics data via graph node and edge ranking analysis. However, it is non-trivial for graph-AI model developers to pre-analyze multi-omics data and convert the data into biologically meaningful graphs, which can be directly fed into graph-AI models. To resolve this challenge, we developed mosGraphGen (multi-omics signaling graph generator), generating Multi-omics Signaling graphs (mos-graph) of individual samples by mapping multi-omics data onto a biologically meaningful multi-level background signaling network with data normalization by aggregating measurements and aligning to the reference genome. With mosGraphGen, AI model developers can directly apply and evaluate their models using these mos-graphs. In the results, mosGraphGen was used and illustrated using two widely used multi-omics datasets of TCGA and Alzheimers disease (AD) samples. The code of mosGraphGen is open-source and publicly available via GitHub: https://github.com/FuhaiLiAiLab/mosGraphGen

systems biology↗

bioRxiv2024

Single-cell and spatial atlas of steatotic liver-related hepatocellular carcinoma

Steatotic liver disease-related hepatocellular carcinoma (SLD-HCC) poses significant challenges in liver cancer management. Our current study investigates the tumor microenvironment (TME) of SLD-HCC using single-cell transcriptomic, proteomic and spatial transcriptomic analyses. We identified altered immune-related and lipid metabolism pathways, particularly in regulatory T cells (Tregs) and cancer-associated fibroblasts (CAFs) within the SLD-HCC microenvironment, suggesting distinct cellular adaptations to a high-fat TME and general immunosuppression. Cytometry by time-of-flight revealed a cold and immunosuppressive TME depleted with CD8+ T cells and enriched with Tregs, while spatial transcriptomics uncovered a unique spatial architecture with Treg/CAF clusters specifically located at the tumor margins in SLD-HCC. Crucially, we identified Treg-CAF interactions as a key mediator associated with lack of response to immunotherapy in SLD-HCC. Our findings highlight the intricate immune dynamics of SLD-HCC, indicating potential therapeutic targets to counteract immune evasion and restore anti-tumor immunity in SLD-HCC. HighlightsO_LIThe TME of SLD-HCC exhibits altered immune and lipid pathways C_LIO_LIImmunosuppressive SLD-HCC TME is depleted with CD8+ T cells and enriched with Tregs C_LIO_LISLD-HCC has a unique spatial architecture with Treg-CAF clusters at tumor margins C_LIO_LITreg-CAF interaction via TNFSF14-TNFRSF14 axis mediates immunotherapy resistance C_LI

immunology↗

bioRxiv2024

Automated muscle path calibration with gradient-specified optimization based on moment arm

ObjectiveMuscle path modeling is more than just routing a cable that visually represents the muscle, but rather it defines how moment arms vary with different joint configurations. The muscle moment arm is the factor that translates muscle force into joint moment, and this property has an impact on the accuracy of musculoskeletal simulations. However, it is not easy to calibrate muscle paths based on a desired moment arm, because each path is configured by various parameters while the relations between moment arm and both the parameters and joint configuration are complicated. MethodsWe tackle this challenge in the simple fashion of optimization, but with an emphasis on the gradient; when specified in its analytical form, optimization speed and accuracy are improved. ResultsWe explain in detail how to differentiate the enormous cost function and how our optimization is configured, then we demonstrate the performance of this method by fast and accurate replication of muscle paths from a state-of-the-art shoulder-arm model. Conclusion and SignificanceAs long as the muscle is represented as a cable wrapping around obstacles, our method overcomes difficulties in path calibration, both for developing generic models and for customizing subject-specific models.

bioengineering↗