Biology subjects

Hu, J.

Publications and source records attributed to Hu, J..

At least 343 records · Page 19Linked to original sources

bioRxiv2022

A new species of Nanhsiungchelys (Testudines: Cryptodira: Nanhsiungchelyidae) from the Upper Cretaceous of Nanxiong Basin, China, and the role of anterolateral processes on the carapace in drag reduction

Nanhsiungchelyidae are a group of large turtles that lived in Asia and North America during the Cretaceous. Here we report a new species of nanhsiungchelyid, Nanhsiungchelys yangi sp. nov., from the Upper Cretaceous of Nanxiong Basin, China. This is the second valid species of Nanhsiungchelys, and the holotype consists of a well-preserved skull and lower jaw, as well as the anterior parts of the carapace and plastron. The diagnostic features of Nanhsiungchelys include a huge estimated body size (~55.5 cm), a special network of sculptures on the surface of the skull and shell, weak cheek emargination and temporal emargination, deep nuchal emargination, and a pair of anterolateral processes on the carapace. However, Nanhsiungchelys yangi differs from the other species of Nanhsiungchelys in having a triangular-shaped snout and wide anterolateral processes. A phylogenetic analysis of nanhsiungchelyids places Nanhsiungchelys yangi and Nanhsiungchelys wuchingensis as sister taxa. Some nanhsiungchelyids bear special anterolateral processes on the carapace, which are unknown in extant turtles. Here we test the function of these processes in Nanhsiungchelys yangi using computational fluid dynamics, and the results suggest these processes could enhance locomotory performance by remarkably reducing drag force when the animal was swimming through water.

paleontology↗

bioRxiv2022

Structural insights into the elevator-type transport mechanism of a bacterial ZIP metal transporter

The Zrt-/Irt-like protein (ZIP) family consists of ubiquitously expressed divalent metal transporters critically involved in maintaining systemic and cellular homeostasis of zinc, iron, and manganese. Here, we present a study on a prokaryotic ZIP from Bordetella bronchiseptica (BbZIP) by combining structural biology, evolutionary covariance, computational modeling, and a variety of biochemical assays to tackle the issue of the transport mechanism which has not been established for the ZIP family. The apo state structure in an inward-facing conformation revealed a disassembled transport site, altered inter-helical interactions, and importantly, a rigid body movement of a 4-transmembrane helix (TM) bundle relative to the other TMs. The computationally generated and biochemically validated outward-facing conformation model revealed a slide of the 4-TM bundle, which carries the transport site(s), by approximately 8 [A] toward the extracellular side against the static TMs which mediate dimerization. These findings allowed us to conclude that BbZIP is an elevator-type transporter.

biochemistry↗

bioRxiv2022

A novel role for cystathionine gamma lyase in the control of p53: impact on endothelial senescence and metabolic reprograming

AimsAdvanced age is unequivocally linked to the development of cardiovascular disease, however, the mechanisms leading to loss of endothelial cell regenerative capacity during aging remain poorly understood. Here we aimed to investigate novel mechanisms involved in endothelial cell senescence, that impact on endothelial cell transcription and the vascular repair response upon injury Methods and resultsRNA sequencing of a unique collection of native endothelial cells from young and aged individuals, showed that aging (20 vs. 80 years) is characterized by p53- mediated reprogramming to promote the expression of senescence-associate genes. Molecular analysis revelead that p53 accumulated and acetylated in the nucleus of aged human endothelial cells to suppress glycolysis. Metabolic flux analysis identified an associated reduction in glucose uptake and ATP availability that inhibited the assembly of the telomerase complex, which was essential for proliferation. Nuclear translocation of p53 in aged endothelial cells was attributed to the loss of the vasoprotective enzyme, cystathionine {gamma}-lyase (CSE), which physically anchored p53 in the cytosol. In mice, loss of endothelial cell CSE activated p53 and arrested vascular repair upon injury, while the AAV9 mediated re-expression of an active CSE mutant retained p53 in the cytosol, maintained endothelial glucose metabolism and proliferation, and prevented endothelial cell senescence. Adenoviral overexpression of CSE in human native aged endothelial cells maintained low p53 activity and re-activated telomerase to revert endothelial cell senescence. ConclusionOur data identified the interaction between CSE and p53 as a promising target to preserve vascular regeneration during aging. Key QuestionTo identify the mechanisms that regulate endothelial cell senescence under native conditions and their impact on vascular repair in aging. Key FindingLack of a physical interaction between CSE and p53 metabolically reprogrammes endothelial cells to reduce telomerase activity and halt endothelial cell regeneration. Take home messageInterventions to increase CSE expression represent a novel therapy against p53-induced endothelial cell cycle arrest and senescense Translational perspectiveEndothelial rejuvenation strategies could serve as promising therapies against age-related cardiovascular diseases. By investigating human native endothelial cells from young and aged individuals, we identified that the age-related nuclear accumulation of p53 reprograms endothelial cell metabolism, regulates telomerase activity and inhibits endothelial cell regeneration. Nuclear localization of p53 resulted from a loss of its interaction with the cysteine catabolizing enzyme cystathionine {gamma}-lyase in the cytoplasm. Enhancing the physical interaction of p53 with CSE by gene therapy could revert endothelial cell senescence and activate endothelial reparative responses.

cell biology↗

bioRxiv2022

Ecological corridors homogenize plant root endospheric mycobiota

Ecological corridors have been shown to promote species coexistence in fragmented habitats where dispersal limits species fluxes. The corridor concept was developed and investigated mainly by focusing on macroorganisms while microorganisms, the invisible majority of biodiversity, have been disregarded. Combining an experimental corridor-mesocosm design with high-throughput amplicon sequencing, we analyzed the effect of corridors on the dynamics of endospheric fungal assemblages associated with plant roots at metric scale over two years (i.e. at five time points). We show that the plant symbiotic compartment was sensitive to corridor effects when the corridors were set up at a small spatial scale. The endospheric mycobiota of connected plants displayed higher species richness, lower beta-diversity, and a more deterministic assembly than the mycobiota of isolated plants. These effects became more pronounced with the development of host plants. Biotic corridors composed of host plants may thus play a key role in the spatial dynamics of microbial community and may influence microbial diversity and related ecological functions.

ecology↗

bioRxiv2022

Neighbourhood effect of weeds on wheat root endospheric mycobiota

O_LIMicroorganisms associated with plants provide essential functions to their hosts, and therefore affect ecosystem productivity. Agricultural intensification has modified microbial diversity in the soil reservoir and may affect plant microbial recruitment. Weeds develop spontaneously in crop fields, and could influence microorganisms associated with crop plants through a neighbourhood effect. We explore the effect of weed species on crop plant microbiota as potentially auxiliary plants that affect agricultural productivity. C_LIO_LIWe combined field and controlled laboratory studies to analyse the neighbourhood effect of weeds on wheat root endospheric mycobiota and growth. First, we analysed the effect of weed species diversity and identity recorded in the neighbourhood of individual wheat plants on soil and wheat root mycobiota in the field. Second, we used a plant-matrix design in laboratory conditions to test the effect of weed identity (9 weed treatments) and their ability to transmit root mycobiota to wheat roots, and the resulting impact on wheat growth. C_LIO_LIIn contrast to soil mycobiota, we demonstrated that wheat root endospheric mycobiota was influenced by the diversity and identity of weeds developing in their 1 m2 neighbourhood. Wheat root endospheric microbiota strongly differs in terms of richness and composition depending on the neighbouring weed plant species. Weed species transmitted from 13% to 74% of their root microbiota to wheat roots depending on weed identity in controlled conditions. C_LIO_LISynthesis. Weed neighbours modified wheat plant performance, possibly as a result of competitive interactions and changes in microbiota. Our findings suggest that crop root mycobiota was variable and was modulated by their weed neighbourhood. Synergistic effects between mycobiota of crops and weeds could therefore contribute to soil biodiversity and sustainable agriculture. C_LI

ecology↗

bioRxiv2022

Fully Desktop Fabricated Flexible Graphene Electrocorticography (ECoG) Arrays

Flexible Electrocorticography (ECoG) electrode arrays that conform to the cortical surface and record surface field potentials from multiple brain regions provide unique insights into how computations occurring in distributed brain regions mediate behavior. Current flexible ECoG devices require highly specialized microfabrication methods, precluding the ability to fabricate customizable and low-cost flexible ECoG devices easily. Here we present a fully desktop fabricated flexible graphene ECoG array. First, we synthesized a stable, conductive ink via liquid exfoliation of Graphene in Cyrene. Next, we have established a stencil-printing process for patterning the graphene ink via laser-cut stencils on flexible polyimide substrates. Benchtop tests indicate that the graphene electrodes have good conductivity of [~] 1.1 x 103 S{middle dot}cm-1, flexibility to maintain their electrical connection under static bending, and electrochemical stability in a 15-day accelerated corrosion test. Chronically implanted graphene ECoG devices remain fully functional for up to 180 days, with average in vivo impedances of 24.72 {+/-} 95.23 k {Omega} at 1 kHz. The ECoG device can measure spontaneous surface field potentials from mice under awake and anesthetized states and sensory stimulus-evoked responses. The stencil-printing fabrication process can be used to create Graphene ECoG devices with customized electrode layouts within 24 hours using commonly available laboratory equipment.

neuroscience↗

bioRxiv2022

A maximum-type microbial differential abundance test with application to high-dimensional microbiome data analyses

AO_SCPLOWBSTRACTC_SCPLOWO_ST_ABSBackgroundC_ST_ABSHigh-throughput metagenomic sequencing technologies have shown prominent advantages over traditional pathogen detection methods, bringing great potential in clinical pathogen diagnosis and treatment of infection diseases. Yet, how to accurately detect the difference of microbiome profiles between treatment or disease conditions remains computationally challenging. ResultsIn this study, we propose a novel test for identifying the difference between two high-dimensional microbiome abundance data matrices based on the centred log-ratio transformation of the microbiome compositions. The test p-value can be calculated directly with a closed-form solution from the derived asymptotic null distribution. We also investigate the asymptotic statistical power against sparse alternatives which are typically encountered in microbiome studies. The proposed Maximum-type test is Equal-Covariance-Assumption-Free (MECAF), making it widely applicable to studies that compare microbiome compositions between conditions. Our simulation studies demonstrated that the proposed MECAF test achieves desirable power than competing methods while having the type I error rate well controlled under various scenarios. The usefulness of the proposed test is further illustrated with two real microbiome data analyses. The source code of the proposed method is freely available at https://github.com/JiyuanHu. ConclusionsMECAF is a flexible differential abundance test and achieves statistical efficiency in analyzing high-throughput microbiome data. The proposed new method will allow us to efficiently discover shifts of microbiome abundances between disease and treatment conditions, broadening our understanding of the disease and ultimately improving clinical diagnosis and treatment.

bioinformatics↗

bioRxiv2022

Identification of circRNAs linked to Alzheimer's disease and related dementias

We conducted a circular-transcriptome-wide analysis and examined circRNA expression patterns associated with AD and clinical and neuropathological AD severity measures in human hippocampus and cortex brain regions. We validated prior studies of circRNA in AD cortex, and demonstrate novel patterns of expression in the AD hippocampus. We also examined circRNA expression across multiple types of dementia and show that circRNA expression differs by dementia subtype. We demonstrate robust circRNA expression in human neuronal precursor cells (NPCs). Then, using NPCs to study qPCR validated circRNA, we show that exposure to oligomeric tau elicits downregulation of circRNA similar to that observed in AD brain. These data identify circRNA that are changed with AD, and suggest that treating neuronal cells with oligomeric tau can recapitulate some of these changes.

molecular biology↗

bioRxiv2022

Impaired bone strength and bone microstructure in a novel early-onset osteoporotic rat model with a clinically relevant PLS3 mutation

Osteoporosis is a highly prevalent disorder with a strong genetic component. Recent studies identify PLS3 as a novel bone regulator of bone metabolism and PLS3 mutations lead to a rare monogenic early-onset osteoporosis. However, the mechanism of PLS3 mutation leading to osteoporosis is unknown with no animal models carrying patient-derived PLS3 mutations generated. The effective treatment strategies for PLS3-related have not been established. Here we have constructed a novel rat model with clinically relevant hemizygous E10-16del mutation of PLS3 (PLS3E10-16del/0) that recapitulate the osteoporotic phenotypes with obviously thinner cortical thickness, significant decreases in yield load, maximum load, and breaking load of femora at 3, 6, 9 months compared to WT rats. Histomorphometric analysis indicates a significantly lower mineral apposition rate in PLS3E10-16del/0rats. Treatment with alendronate (ALN, 1.0 ug/kg per day) or teriparatide (TPTD, 40ug/kg five times weekly) for 8 weeks significantly improved bone mass and bone microarchitecture, and bone strength was significantly increased after TPTD treatment (P < 0.05). Thus, our results indicate the roles of PLS3 in the regulation of bone microstructure and bone strength, providing a novel animal model for the study of early-onset osteoporosis. Alendronate and teriparatide treatment could be a potential treatment for early-onset osteoporosis induced by PLS3 mutation.

genetics↗

bioRxiv2022

An engineered xCas12i with high activity, high specificity and broad PAM range

The type-V CRISPR effector Cas12i, with its smaller size, short crRNA guiding, and self-processing features, is a potentially versatile genome editing tool. By screening Cas12i proteins from a metagenomic database, we identified a natural variant with high activity in mammalian cells, named as xCas12i. We further engineered the PAM-interacting, REC, and RuvC domains for enhanced cleavage activity and specificity. This variant, named as high-fidelity Cas12Max, exhibited robust genome editing activity and minimal off-target activity with a broad 5-TN recognition profile. With the fusion of deaminase TadA8e and further optimization of xCas12i, the base editor dCas12i-Tad8e also showed the high editing efficiency. This study provides highly efficient and specific tools for gene therapy.

bioengineering↗

bioRxiv2022

Multiplex CRISPR strategy targeting viral genome for agriculture and clinical use

African Swine Fever (ASF) is a viral disease with exceptionally high lethality in domestic pigs and wild boar worldwide1, 2, without any effective vaccine or drug to prevent its spread. In this study, we established a multiplexable CRISPR-Cas-gRNA system targeting 13 genomic loci in the ASF virus genome that could prevent viral replication by cutting its genome. Furthermore, we generated pig strains expressing the multiplexable CRISPR-Cas-gRNA via germline genome editing and demonstrated that the gene-edited pigs were more resistant to ASFV infection and less likely to spread the virus upon infection. As far as we know, our study presents the first living organism generated via germline editing to demonstrate resistance to viral infection via CRISPR-Cas. We anticipate our work to be helpful for both agricultural and biomedical applications, such as xenotransplantation.

bioengineering↗

bioRxiv2022

Microbial Risk Score for Capturing Microbial Characteristics, Integrating Multi-omics Data, and Predicting Disease Risk

BackgroundWith the rapid accumulation of microbiome-wide association studies, a great amount of microbiome data are available to study the microbiomes role in human disease and advance the microbiomes potential use for disease prediction. However, the unique features of microbiome data hinder its utility for disease prediction. MethodsMotivated from the polygenic risk score framework, we propose a microbial risk score (MRS) framework to aggregate the complicated microbial profile into a summarized risk score that can be used to measure and predict disease susceptibility. Specifically, the MRS algorithm involves two steps: 1) identifying a sub-community consisting of the signature microbial taxa associated with disease, and 2) integrating the identified microbial taxa into a continuous score. The first step is carried out using the existing sophisticated microbial association tests and pruning and thresholding method in the discovery samples. The second step constructs a community-based MRS by calculating alpha diversity on the identified sub-community in the validation samples. Moreover, we propose a multi-omics data integration method by jointly modeling the proposed MRS and other risk scores constructed from other omics data in disease prediction. ResultsThrough three comprehensive real data analyses using the NYU Langone Health COVID-19 cohort, the gut microbiome health index (GMHI) multi-study cohort, and a large type 1 diabetes cohort separately, we exhibit and evaluate the utility of the proposed MRS framework for disease prediction and multi-omics data integration. In addition, the disease-specific MRSs for colorectal adenoma, colorectal cancer, Crohns disease, and rheumatoid arthritis based on the relative abundances of 5, 6, 12, and 6 microbial taxa respectively are created and validated using the GMHI multi-study cohort. Especially, Crohns disease MRS achieves AUCs of 0.88 ([0.85-0.91]) and 0.86 ([0.78-0.95]) in the discovery and validation cohorts, respectively. ConclusionsThe proposed MRS framework sheds light on the utility of the microbiome data for disease prediction and multi-omics integration, and provides great potential in understanding the microbiomes role in disease diagnosis and prognosis.

microbiology↗

bioRxiv2022

Processing UMI Datasets at High Accuracy and Efficiency with the Sentieon ctDNA Analysis Pipeline

Liquid biopsy enables identification of low allele frequency (AF) tumor variants and novel clinical applications such as minimum residual disease (MRD) monitoring. However, challenges remain, primarily due to limited sample volume and low read count of low-AF variants. Because of the low AFs, some clinically significant variants are difficult to distinguish from errors introduced by PCR amplification and sequencing. Unique Molecular Identifiers (UMIs) have been developed to further reduce base error rates and improve the variant calling accuracy, which enables better discrimination between background errors and real somatic variants. While multiple UMI-aware ctDNA analysis pipelines have been published and adopted, their accuracy and runtime efficiency could be improved. In this study, we present the Sentieon ctDNA pipeline, a fast and accurate solution for small somatic variant calling from ctDNA sequencing data. The pipeline consists of four core modules: alignment, consensus generation, variant calling, and variant filtering. We benchmarked the ctDNA pipeline using both simulated and real datasets, and found that the Sentieon ctDNA pipeline is more accurate than alternatives.

bioinformatics↗

bioRxiv2022

A Chloroplast Protein Atlas Reveals Novel Structures and Spatial Organization of Biosynthetic Pathways

Chloroplasts are eukaryotic photosynthetic organelles that drive the global carbon cycle. Despite their importance, our understanding of their protein composition, function, and spatial organization remains limited. Here, we determined the localizations of 1,032 candidate chloroplast proteins by using fluorescent protein tagging in the model alga Chlamydomonas reinhardtii. The localizations provide insights into the functions of hundreds of poorly-characterized proteins, including identifying novel components of nucleoids, plastoglobules, and the pyrenoid. We discovered and further characterized novel organizational features, including eleven chloroplast punctate structures, cytosolic crescent structures, and diverse unexpected spatial distributions of enzymes within the chloroplast. We observed widespread protein targeting to multiple organelles, identifying proteins that likely function in multiple compartments. We also used machine learning to predict the localizations of all Chlamydomonas proteins. The strains and localization atlas developed here will serve as a resource to enable studies of chloroplast architecture and functions. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/493820v1_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@19c871eorg.highwire.dtl.DTLVardef@16ac46corg.highwire.dtl.DTLVardef@859b7dorg.highwire.dtl.DTLVardef@1a3446e_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LI1,032 candidate chloroplast proteins localized by fluorescent tagging. C_LIO_LIThis protein atlas reveals novel chloroplast structures, functional regions, and components. C_LIO_LIPrevalent dual-organelle localization suggests extensive cross-compartment coordination. C_LIO_LIAtlas-trained machine learning predicts localizations of all C. reinhardtii proteins. C_LI

plant biology↗

bioRxiv2022

A unified neural account of contextual and individual differences in altruism

Altruism is critical for cooperation and productivity in human societies, but is known to vary strongly across contexts and individuals. The origin of these differences is largely unknown, but may in principle reflect variations in different types of neurocognitive processes that temporally unfold during altruistic decision making (ranging from initial perceptual processing via value computations to final integrative choice mechanisms). Here, we address this question by examining altruistic choices in different inequality contexts with computational modeling and EEG. Our results show that across all contexts and individuals, wealth distribution choices recruit a similar late decision process evident in model-predicted evidence accumulation signals over parietal regions. Contextual and individual differences in behavior related instead to initial processing of stimulus-locked inequality-related value information in centroparietal and centrofrontal sensors, as well as to gamma-band synchronization of these value-related signals with parietal response-locked evidence-accumulation signals. Our findings suggest separable biological bases for individual and contextual differences in altruism and emphasize that these reflect differences in processing of choice-relevant information.

neuroscience↗

bioRxiv2022

DNAscope: High accuracy small variant calling using machine learning

We present DNAscope, an accurate and efficient germline small-variant caller. DNAscope combines the robust and well-established preprocessing and assembly mathematics of the GATKs HaplotypeCaller with a machine-learned genotyping model. Benchmarks of DNAscope and DNAseq (Sentieons GATK-matching germline variant calling pipeline) demonstrate that DNAscope achieves superior SNP and insertion/deletion accuracy with reduced computational cost.

bioinformatics↗

bioRxiv2022

Single-Cell RNAseq Analysis Reveals Robust Anti-PD-1-Mediated Increase of Immune Infiltrate in Metastatic Castration-Sensitive Prostate Cancer

Compared to other malignancies, the tumor microenvironment (TME) of primary and castration-resistant prostate cancer (CRPC) is relatively devoid of immune infiltrates. While androgen deprivation therapy (ADT) induces a complex immune infiltrate in localized prostate cancer, both in animal models and humans, the TME composition of metastatic, castration-sensitive prostate cancer (mCSPC) is relatively unknown and the effects of ADT and other treatments are poorly characterized in this context. To address this challenge, we analyzed metastatic sites from patients enrolled on a phase 2 clinical trial (NCT03951831), in which men were treated with standard-of-care chemo-hormonal therapy with anti-PD-1 immunotherapy, at the single cell level. Longitudinal protein activity-based analysis of TME subpopulations identified immune subpopulations conserved across multiple metastatic sites, their dynamic, treatment-mediated evolution, and associated clinical response features. Our study revealed a therapy-resistant, transcriptionally distinct tumor subpopulation, which comprises an increasing number of cells in treatment-refractory patients, and identified several druggable targets in both tumor and immune cells as candidates to advance treatment and improve outcomes for patients with mCSPC.

cancer biology↗

bioRxiv2022

Neurocomputational evidence that conflicting prosocial motives guide distributive justice

In the history of humanity, most conflicts within and between societies have originated from perceived inequality in resource distribution. How humans achieve and maintain distributive justice has therefore been an intensely studied issue. However, most research on the corresponding psychological processes has focused on inequality aversion and has been largely agnostic of other motives that may either align or oppose this behavioral tendency. Here we provide behavioral, computational, and neuroimaging evidence that distribution decisions are guided by three distinct motives - inequality aversion, harm aversion, and rank reversal aversion - that interact and in fact can also deter individuals from pursuing equality. At the neural level, we show that these three motives are encoded by separate neural systems, compete for representation in various brain areas processing equality and harm signals, and are integrated in the striatum, which functions as a crucial hub for translating the motives to behavior. Our findings provide a comprehensive framework for understanding the cognitive and biological processes by which multiple prosocial motives are coordinated in the brain to guide redistribution behaviors. This framework enhances our understanding of the brain mechanisms underlying equality-related behavior, suggests possible neural origins of individual differences in social preferences, and provides a new pathway to understand the cognitive and neural basis of clinical disorders with impaired social functions.

neuroscience↗