Biology subjects

Hu, J.

Publications and source records attributed to Hu, J..

At least 253 records · Page 14Linked to original sources

bioRxiv2024

A novel interface for cortical columnar neuromodulation with multi-point infrared neural stimulation

Cutting edge advances in electrical visual cortical prosthetics have evoked perception of shapes, motion, and letters in the blind. Here, we present an alternative optical approach using pulsed infrared neural stimulation. To interface with dense arrays of cortical columns with submillimeter spatial precision, both linear array and 100-fiber bundle array optical fiber interfaces were devised. We delivered infrared stimulation through these arrays in anesthetized cat visual cortex and monitored effects by optical imaging in contralateral visual cortex. INS modulation of response to ongoing visual oriented gratings produced enhanced responses in orientation-matched domains and suppressed responses in non-matched domains, consistent with a known higher order integration mediated by callosal inputs. Controls included dynamically applied speeds, directions and patterns of multipoint stimulation. This provides groundwork for a distinct type of prosthetic targeted to maps of visual cortical columns.

neuroscience↗

bioRxiv2024

Establishment of an Inhalation Administration Noninvasive Murine Model for Rapidly Testing Drug Activity against Mycobacterium tuberculosis

The efficacy of many compounds against Mycobacterium tuberculosis is often limited when administered via conventional oral or injection routes due to suboptimal pharmacokinetic characteristics. Inhalation delivery methods have been investigated to achieve high local therapeutic doses in the lungs. However, previous models, typically employing wild-type M. tuberculosis strains, were intricate, time-consuming, labor-intensive, and with poor repeatability. In this study, we developed an autoluminescence-based inhalation administration model to evaluate drug activity by quantifying relative light units (RLUs) emitted from live mice infected with autoluminescent M. tuberculosis. This novel approach has several improvements: it eliminates the need for anesthesia in mice during administration and simplifies the instrument manipulation; it is cost-effective by utilizing mice instead of larger animals; it shortens time from several months to 16 or 17 days for obtaining result; it is non-invasive by measuring the live RLUs of mice; up to six mice can be administrated daily and simultaneously, even 2-3 times/day; results are relatively objective and repeatable minimizing human factors. Proof-of-concept experiments demonstrated that inhalable rifampicin, isoniazid, and ethambutol showed anti-M. tuberculosis activity at concentrations as low as 0.5, 0.5, and 0.625 mg/mL, respectively, as evidenced by comparing the live RLUs of mice. Furthermore, consistency between RLUs and colony-forming units of the lungs reaffirms the reliability of RLUs as an indicator of drug efficacy, highlighting the potential of this approach for accurately assessing anti-M. tuberculosis activity in vivo. This autoluminescence-based and non-invasive inhalation model offers a substantial reduction in the time, effort, and cost required for evaluating the efficacy of screening new drugs and repurposing old drugs in vivo via inhalation administration.

microbiology↗

bioRxiv2024

EmbB and EmbC Regulate the Sensitivity of Mycobacterium abscessus to Echinomycin

Treatment of Mycobacterium abscessus (Mab) infection is a major challenge due to its intrinsic resistance to most available drugs. It is thus imperative to find new anti-Mab drugs. In this study, we investigated the activity and intrinsic resistance mechanism of echinomycin (ECH) against Mab. ECH is active against Mab (MIC: 2 {micro}g/mL). The embC gene knockout strain (Mab{Delta}embC) showed hyper-sensitive to ECH (MIC: 0.0078-0.0156 {micro}g/mL). The MICs of ECH-resistant strains screened based on the Mab{Delta}embC strain were 0.25-1 {micro}g/mL. Mutations were found in the EmbB, including Asp306Ala, Asp306Asn, Arg350Gly, Val555Ile, and Gly581Ser, which led to increased resistance to ECH when overexpressed in Mab{Delta}embC individually (0.25-0.5 {micro}g/mL). The EmbB mutants edited by the CRISPR/Cpf1 system became more resistant to ECH (MIC: 0.25-0.5 {micro}g/mL). The permeability of gene-edited and overexpressed Mab strains was reduced, as shown by the ethidium bromide accumulation assay, but it was still significantly higher than that of the parent Mab. To summarize, our study demonstrates that ECH has a strong anti-Mab activity and confirms that EmbB and EmbC are related to the sensitivity of Mab to ECH. EmbB mutation may partially compensate for the function of EmbC. Impact StatementMycobacterium abscessus (Mab) is a rapidly growing, intrinsic multidrug-resistant Mycobacterium. This study demonstrated that echinomycin (ECH) has potent antibacterial activity against Mab, and the mechanism of ECH resistance to Mab is related to EmbB and EmbC. EmbB and EmbC can alter the sensitivity of Mab to ECH by altering the permeability of its cell wall. In addition, there is a functional complementary evolution between EmbB and EmbC to regulate sensitivity to ECH. Overall, our study provides a novel anti-Mab drug candidate ECH and a scientific foundation for developing effective strategies to prevent and control Mab.

microbiology↗

bioRxiv2024

RNA Splicing Junction Landscape Reveals Abundant Tumor-Specific Transcripts in Human Cancer

RNA splicing is a critical process governing gene expression and transcriptomic diversity. Despite its importance, a detailed examination of transcript variation at the splicing junction level remains scarce. Here, we perform a thorough analysis of RNA splicing junctions in 34,775 samples across multiple sample types. We identified 29,051 tumor-specific transcripts (TSTs) in pan-cancer, with a majority of these TSTs being unannotated. Our findings show that TSTs are positively correlated with tumor stemness and linked to unfavorable outcomes in cancer patients. Additionally, TSTs display mutual exclusivity with somatic mutations and are overrepresented in transposable element-derived transcripts possessing oncogenic functions. Importantly, TSTs can generate neoepitopes that bind to MHC class I molecules for immunotherapy. Moreover, TSTs can be detected in blood extracellular vesicles from cancer patients. Our results shed light on the intricacies of RNA splicing and offer promising avenues for cancer diagnosis and therapy. In briefThis study thoroughly analyzed RNA splicing junctions in 34,775 samples and identified 29,051 tumor-specific transcripts (TSTs), which may serve as novel cancer driver genes, neoantigens, and circulating biomarkers. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=153 SRC="FIGDIR/small/579246v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@7e1db2org.highwire.dtl.DTLVardef@1cfbe81org.highwire.dtl.DTLVardef@1e427e1org.highwire.dtl.DTLVardef@1f655f5_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2024

Collective dynamical regimes predict invasion success and impacts in microbial communities

Invasions of microbial communities by species such as pathogens can have significant impacts on ecosystem services and human health1-9. Predicting the outcomes of these invasions, however, remains a challenge. Various theories propose that these outcomes depend on either characteristics of the invading species10-12 or attributes of the resident community13-16, including its composition and biodiversity3,17-19. Here we used a combination of experiments and theory to show that the interplay between dynamics, interaction strength, and diversity determine the invasion outcome in microbial communities. We found that the communities with fluctuations in species abundance are both more invasible and more diverse than stable communities, leading to a positive diversity-invasibility relationship among communities assembled in the same environment. As predicted by theory, increasing interspecies interaction strength and species pool size leads to a decrease of invasion probability in our experiment. Although diversity-invasibility relationships are qualitatively different depending upon how the diversity is changed, we provide a unified perspective on the diversity-invasibility debate by showing a universal positive correspondence between invasibility and survival fraction of resident species across all conditions. Communities composed of strongly interacting species can exhibit an emergent priority effect in which invader species are less likely to colonize than species in the original pool. However, in this regime of strong interspecies interactions, if an invasion is successful, it causes larger ecological effects on the resident community than when interactions are weak. Our results demonstrate that the invasibility and invasion effect are emergent properties of interacting species, which can be predicted by simple community-level features.

ecology↗

bioRxiv2024

Cerebra: a computationally efficient framework for accurate protein structure prediction

AO_SCPLOWBSTRACTC_SCPLOWRemarkable progress has been made in the field of protein structure prediction in the past years. State-of-the-art methods like AlphaFold2 and RoseTTAFold2 achieve prediction accuracy close to experimental structural determination, but at the cost of heavy computational consumption for model training. In this work, we propose a new protein structure prediction framework, Cerebra, for improving the computational efficiency of protein structure prediction. In this innovative network architecture, multiple sets of atomic coordinates are predicted parallelly and their mutual complementary is leveraged to rapidly improve the quality of predicted structures through a novel attention mechanism. Consequently, Cerebra markedly reduces the model training consumption, achieving a training acceleration of at least 7 folds, in comparison to OpenFold, the academic version of AlphaFold2. When evaluated on the CAMEO and CASP15 sets, the Cerebra model insufficiently trained on a single GPU only shows slight performance inferiority to the published OpenFold model.

bioinformatics↗

bioRxiv2024

Multiple Loci for Foveolar Vision in Macaque Monkey

A common tenet of neural sensory representation is that species-specific behaviors are reflected in specialized brain organizations1. In humans and nonhuman primates, the central one degree of vision is processed by the foveola2, a retinal structure which comprises a high density of photoreceptors and is crucial for primate-specific high acuity vision, color vision, and gaze-directed visual attention3,4,5. In this study, we have developed high spatial resolution ultrahigh field 7T fMRI methods for functional mapping of foveolar visual cortex in awake monkeys. We provide evidence that, in the ventral pathway (V1-V4 and TEO), viewing of a central small spot elicits a ring of multiple (at least 8) foveolar representations per hemisphere. This ring surrounds a large area called the foveolar core. This is an area populated by millimeter-scale functional domains sensitive to fine stimuli and high spatial frequencies, consistent with foveolar visual acuity, as well as color and achromatic information, and motion. The unique position of the foveolar core suggests it may be a hub subserving higher order needs of foveolar function, such as integrating different spatial scales of representation, integrating local and global features in object perception, and bringing together the four quadrants of visual space. Thus, this elaborate re-representation of central vision signifies a cortical specialization for various foveation behaviors.

neuroscience↗

bioRxiv2024

Disrupting Homologous Recombination or Single-Strand Annealing Significantly Hinders CRISPR-Cas12a-Assisted Nonhomologous End-Joining Gene Editing Efficiency in Mycobacterium abscessus

Mycobacterium abscessus, a fast-growing, non-tuberculous mycobacterium resistant to most antimicrobial drugs, causes many types of serious infections in humans, posing a significant public health challenge. Currently, effective genetic manipulation tools for M. abscessus are still being developed, which hampers research and therapeutic development. However, the clustered regularly interspaced short palindromic repeats (CRISPR) - associated protein (Cas) systems have emerged as promising methods for generating highly specific double-strand breaks (DSBs) in its genome. These DSBs can be repaired by the error-prone nonhomologous end joining (NHEJ) mechanism, facilitating targeted gene editing. Here, our study marks a pioneering application of the CRISPR-NHEJ strategy in M. abscessus. Additionally, we discovered that NrgA from Mycobacterium marinum is crucial for the repair of DSBs caused by the CRISPR-Cas system in M. abscessus. Finally, contrary to previous findings, our study also indicates that inhibiting or overexpressing homologous recombination/single-strand annealing significantly decreases the efficiency of NHEJ repair in M. abscessus. This discovery challenges established perspectives and suggests that the NHEJ repair in M. abscessus may require the involvement of components from homologous recombination and single-strand annealing, demonstrating the complex interactions among the three DSB repair pathways in M. abscessus. Impact statementThere are still very few genetic manipulation tools available for Mycobacterium abscessus. Here we report the successful application of CRISPR-Cas12a-assisted nonhomologous end joining (NHEJ) in efficient gene editing in M. abscessus. Contrary to previous research suggesting that homologous recombination (HR) inhibition may enhance such editing efficiency in other Mycobacterium species, our results showed that disruption or overexpression of either HR or single-strand annealing not only failed to enhance but also significantly reduced the gene editing efficiency in M. abscessus. This suggests that NHEJ repair in M. abscessus may require components from both HR and single-strand annealing, highlighting a complex interaction among the DSB repair pathways in M. abscessus.

microbiology↗

bioRxiv2024

Optimizing Accuracy and Efficiency in Analyzing Non-UMI Liquid Biopsy Datasets Using the Sentieon ctDNA Pipeline

Sequencing clinical liquid biopsy, especially circulating tumor DNA (ctDNA), provides a valuable method for identifying low allele frequency tumor variants, opening novel clinical applications, particularly in treatment selection for late-stage cancer patients. Despite advancements, challenges in assay development persist, primarily due to limited sample volumes and insufficiency of reads supporting low allele frequency variants. The allele frequencies of clinically significant variants often hover close to the threshold of errors introduced by PCR and sequencing processes. Therefore, more sophisticated analysis methods are crucial to further reduce base error rates, enabling accurate discrimination between background errors and genuine somatic variants. While several ctDNA analysis pipelines have been published and adopted, there is room for improvement in terms of accuracy and run efficiency. In this study, we introduce Sentieons innovative consensus-based ctDNA pipeline - a rapid and precise solution for calling small somatic variants from non-UMI ctDNA sequencing data. The pipeline comprises four core modules: alignment, consensus generation, variant calling, and variant filtering. Through benchmarking with in-vitro and real clinical datasets, we observed that the Sentieon ctDNA pipeline exhibits higher accuracy compared to alternative methods.

bioinformatics↗

bioRxiv2024

scMulan: a multitask generative pre-trained language model for single-cell analysis

Cells can be viewed as complex stories written by coordinated expression of genes. The success of AI large language models (LLMs) in mastering the human language inspired us to develop a large AI model scMulan with 368 million parameters to generate cell transcriptomics with designated attributes by learning the cell language. We defined a unified c-sentence to incorporate cell transcriptomics and meta-attributes, and pre-trained scMulan on the equivalence of 100 million human cells. Experiments showed that scMulan can generate designated pseudo transcriptomics, predict missing attributes of cells, reconstruct unobserved cells along functional gradients, and can help to identify driving regulators of cell fates. The generated data passed tests of current tools and can reflect the underlying biology.

bioinformatics↗

bioRxiv2024

The spatial structure of the tumor immune microenvironment can explain and predict patient response in high-grade serous carcinoma

Despite ovarian cancer being the deadliest gynecological malignancy, there has been little change to therapeutic options and mortality rates over the last three decades. Recent studies indicate that the composition of the tumor immune microenvironment (TIME) influences patient outcomes but are limited by a lack of spatial understanding. We performed multiplexed ion beam imaging (MIBI) on 83 human high-grade serous carcinoma tumors -- one of the largest protein-based, spatially-intact, single-cell resolution tumor datasets assembled -- and used statistical and machine learning approaches to connect features of the TIME spatial organization to patient outcomes. Along with traditional clinical/immunohistochemical attributes and indicators of TIME composition, we found that several features of TIME spatial organization had significant univariate correlations and/or high relative importance in high-dimensional predictive models. The top performing predictive model for patient progression-free survival (PFS) used a combination of TIME composition and spatial features. Results demonstrate the importance of spatial structure in understanding how the TIME contributes to treatment outcomes. Furthermore, the present study provides a generalizable roadmap for spatial analyses of the TIME in ovarian cancer research.

cancer biology↗

bioRxiv2024

Dynamic minimization of proteome reallocation explains metabolic transition in hierarchical utilization of mixed carbon sources

Cells choose between alternative pathways in metabolic networks under diverse environmental conditions, but the principles governing the choice are insufficiently understood, especially in response to dynamically changing conditions. Here we observed that a lactic acid bacterium Bacillus coagulans displayed homolactic fermentation on glucose or trehalose as the sole carbon source, but transitioned from homolactic to heterolactic fermentation during the hierarchical utilization of glucose and trehalose when growing on the mixture. We simulated the observation by dynamic minimization of reallocation of proteome (dMORP) using an enzyme-constrained genome-scale metabolic model of B. coagulans, which coincided with our omics data. Moreover, we evolved strains to co-utilize mixed carbon sources and repress the choice of heterolactic fermentation, and the dynamics after co-utilization of carbon sources could also be captured by dMORP. Altogether, the findings suggest that upon rapid environmental changes bacteria tend to minimize proteome reallocation and accordingly adjust metabolism, and dMORP would be useful in simulating and understanding cellular dynamics.

systems biology↗

bioRxiv2024

The translocation activity of Rad54 reduces crossover outcomes during homologous recombination

Homologous recombination (HR) is a template-based DNA double-strand break repair pathway that requires the selection of an appropriate DNA template for repair during the homology search stage of HR. Failure to execute the homology search quickly and efficiently can result in complex intermediates that generate genomic rearrangements, a hallmark of human cancers. Rad54 is an ATP dependent DNA motor protein that functions during the homology search by regulating the recombinase Rad51. How this regulation reduces genomic rearrangements is currently unknown. To better understand how Rad54 can prevent genomic rearrangements, we evaluated several amino acid mutations in Rad54 that were found in the COSMIC database. COSMIC is a collection of amino acid mutations identified in human cancers. These substitutions led to reduced Rad54 function and the discovery of a conserved motif in Rad54. Through genetic, biochemical, and single-molecule approaches, we show that disruption of this motif leads to failure in stabilizing early strand invasion intermediates, causing loss-of-heterozygosity rearrangements. Our study also suggests that the translocation rate of Rad54 is a determinant in balancing genetic exchange. This mechanism is likely fundamental to eukaryotic biology.

biochemistry↗

bioRxiv2024

Forced mouth opening induces post-traumatic hyperalgesia and associated peripheral sensitization after temporomandibular joints injury in mice

Temporomandibular disorder (TMD) is the most prevalent painful condition in the craniofacial area. The pathophysiology of TMD is not fully understood, and it is necessary to understand pathophysiology underlying painful TMD conditions to develop more effective treatment methods. Recent studies suggested that external or intrinsic trauma to TMJ is associated with chronic TMD in patients. Here, we investigated the effects of the TMJ trauma through forced-mouth opening (FMO) in mice to determine pain behaviors and peripheral sensitization of trigeminal nociceptors. FMO increased mechanical hyperalgesia assessed by von Frey test, spontaneous pain-like behaviors assessed by mouse grimace scale, and anxiety-like behaviors assessed by open-field test. In vivo GCaMP Ca2+ imaging of intact trigeminal ganglia (TG) showed increased spontaneous Ca2+ activity and mechanical hypersensitivity of TG neurons in the FMO compared to the sham group. Ca2+ responses evoked by cold, heat, and capsaicin stimuli were also increased. FMO-induced hyperalgesia and neuronal hyperactivities were not sex dependent. TG neurons sensitized following FMO were primarily small to medium-sized nociceptive afferents. Consistently, most TMJ afferents in the TG were small-sized peptidergic neurons expressing calcitonin gene-related peptides, whereas nonpeptidergic TMJ afferents were relatively low. FMO-induced intraneural inflammation in the surrounding tissues of the TMJ indicates potentially novel mechanisms of peripheral sensitization following TMJ injury. These results suggest that the TMJ injury leads to persistent post-traumatic hyperalgesia associated with peripheral sensitization of trigeminal nociceptors.

neuroscience↗

bioRxiv2024

A multi-scale feature fusion model based on biological knowledge graph and transformer-encoder for drug-drug interaction prediction

Drug-Drug Interaction (DDI) refers to the combined effects that occur when a patient takes multiple medications simultaneously or within the same period. This interaction can either enhance the therapeutic effects of the drugs or inhibit their efficacy, and in severe cases, it can even lead to adverse drug reactions (ADRs). Thus, it is crucial to identify potential DDIs, as this information is significant for both biological research and clinical medicine. However, most existing works only consider the information of individual drugs or focus on the local correlation between a few medical entities, thus overlooking the global performance of the entire human medical system and the potential synergistic effects of multi-scale information. Consequently, these limitations hinder the predictive ability of models. In this paper, we propose an innovative multi-scale feature fusion model called ALG-DDI, which can comprehensively incorporate attribute information, local biological information, and global semantic information. To achieve this, we first employ the Attribute Masking method to obtain the embedding vector of the molecular graph. Next, ALG-DDI leverages heterogeneous graphs to capture the local biological information between drugs and several highly related biological entities. The global semantic information is also learned from the medicine-oriented large knowledge graphs. Finally, we employ a transformer encoder to fuse the multi-scale drug representations and feed the resulting drug pair vector into a fully connected neural network for prediction. Experimental evaluations on datasets of varying sizes and different classification tasks demonstrate that ALG-DDI outperforms other state-of-the-art models.

bioinformatics↗

bioRxiv2024

Sphingolipid metabolism orchestrates the establishment of the adult hair follicle stem cell niche to control skin homeostasis

Bioactive sphingolipids serve as an essential building block of membranes, forming a selective barrier that ensures subcellular compartmentalization and facilitates cell type-specific intercellular communication through regulation of the plasma membrane receptor repertoire. How cell type-specific lipid compositions are achieved and what is their functional significance in tissue morphogenesis and maintenance has remained unclear. Here, we identify a stem-cell specific role for ceramide synthase 4 (CerS4) in orchestrating fate decisions in skin epidermis. Deletion of CerS4 in the epidermis prevents the effective development of the adult hair follicle bulge stem cell (HFSCs) niche due to altered differentiation trajectories of HFSC precursors towards upper hair follicle and inner bulge fates. Mechanistically, HFSC differentiation defects arise from an imbalance of key ceramides and their derivate sphingolipids in HFSCs associated with hyperactivity of canonical Wnt signaling. Impaired HFSC niche establishment leads to disruption of hair follicle architecture and hair follicle barrier function, ultimately triggering a T helper cell 2 - dominated immune infiltration closely resembling human atopic dermatitis. This work uncovers a fundamental role for a cell state-specific sphingolipid profile in epidermal stem cell homeostasis and the role of an intact stem cell niche in maintaining an intact skin barrier.

developmental biology↗

bioRxiv2023

Replication-driven HBV cccDNA loss in chimeric mice with humanized livers

Hepatitis B virus (HBV) infection is largely noncytopathic and requires the establishment of covalently closed circular DNA (cccDNA), which is considered stable in the nuclei of infected cells. Although challenging, approaches to directly target cccDNA molecules or kill infected cells are recommended to eliminate cccDNA. Herein, cccDNA levels were investigated in HBV-infected chimeric mice with humanized livers. HBV-infected cells support robust replication, progressively retain viral products, and head for cytopathic destruction and cccDNA loss. It is difficult for infected cells to retain cccDNA and remain noncytopathic. Replication-driven cccDNA loss is observed at both phases of spread of and persistent infection. The cccDNA replenishment is required to compensate for cccDNA loss. Blocking cccDNA replenishment pathways reduces cccDNA levels by >100-fold. These results prove an unconventional cccDNA elimination strategy that does not directly target cccDNA but aims to transform spontaneous cccDNA loss into progressive cccDNA elimination by blocking cccDNA replenishment.

microbiology↗

bioRxiv2023

Comprehensive Multi-Omic Analysis Reveals Distinct Molecular Features in Early and Advanced Stages of Hepatocellular Carcinoma

Hepatocellular Carcinoma (HCC) is a serious primary solid tumor that is prevalent worldwide. Due to its high mortality rate, it is crucial to explore both early diagnosis and advanced treatment for HCC. In recent years, multi-omic approaches have emerged as promising tools to identify biomarkers and investigate molecular mechanisms of biological processes and diseases. In this study, we performed proteomics, phosphoproteomics, metabolomics, and lipidomics to reveal the molecular features of early- and advanced-stage HCC. The data obtained from these omics were analyzed separately and then integrated to provide a comprehensive understanding of the disease. The multi-omic results unveiled intricate biological pathways and interaction networks underlying the initiation and progression of HCC. Moreover, we proposed specific potential biomarker panels for both early- and advanced-stage HCC by overlapping our data with CPTAC database, and deduced novel insights and mechanisms related to HCC origination and development.

cancer biology↗