Biology subjects

Xu, M.

Publications and source records attributed to Xu, M..

At least 127 records · Page 7Linked to original sources

bioRxiv2024

VesselBoost: A Python Toolbox for Small Blood Vessel Segmentation in Human Magnetic Resonance Angiography Data

Magnetic resonance angiography (MRA) performed at ultra-high magnetic field provides a unique opportunity to study the arteries of the living human brain at the mesoscopic level. From this, we can gain new insights into the brains blood supply and vascular disease affecting small vessels. However, for quantitative characterization and precise representation of human angioarchitecture to, for example, inform blood-flow simulations, detailed segmentations of the smallest vessels are required. Given the success of deep learning-based methods in many segmentation tasks, we here explore their application to high-resolution MRA data, and address the difficulty of obtaining large data sets of correctly and comprehensively labelled data. We introduce VesselBoost, a vessel segmentation package, which utilizes deep learning and imperfect training labels for accurate vasculature segmentation. Combined with an innovative data augmentation technique, which leverages the resemblance of vascular structures, VesselBoost enables detailed vascular segmentations.

neuroscience↗

bioRxiv2024

Repression of PRMT activities sensitize homologous recombination-proficient ovarian and breast cancer cells to PARP inhibitor treatment

Therapeutic epigenetic modulation is currently being evaluated in the clinic to sensitize homologous recombination (HR)-proficient tumors to PARP inhibitors. To broaden its clinical applicability and identify more effective combination strategies, we conducted a drug screen combining PARP inhibitors with 74 well-characterized epigenetic modulators targeting five major classes of epigenetic enzymes. Notably, both type I PRMT inhibitors and PRMT5 inhibitors scored highly in combination efficacy and clinical prioritization. PRMT inhibition significantly enhanced PARP inhibitor-induced DNA damage in HR-proficient ovarian and breast cancer cells. Mechanistically, PRMT suppression downregulates DNA damage repair genes and BRCAness-associated pathways, while also modulating intrinsic innate immune responses within cancer cells. Integrative analysis of large-scale genomic and functional datasets from TCGA and DepMap further supports PRMT1, PRMT4, and PRMT5 as promising therapeutic targets in oncology. Importantly, dual inhibition of PRMT1 and PRMT5 synergistically sensitizes tumors to PARP inhibitors. Collectively, our findings provide strong rationale for the clinical development of PRMT and PARP inhibitor combinations in HR-proficient ovarian and breast cancers.

cancer biology↗

bioRxiv2024

Long-term imaging of three-dimensional hyphal development using the ePetri dish

Imaging three-dimensional microbial development and behavior over extended periods is crucial for advancing microbiological studies. Here, we introduce an upgraded ePetri dish system specifically designed for extended microbial culturing and 3D imaging, addressing the limitations of existing methods. Our approach includes a sealed growth chamber to enable long-term culturing, and a multi-step reconstruction algorithm that integrates 3D deconvolution, image filtering, ridge, and skeleton detection for detailed visualization of the hyphal network. The system effectively monitored the development of Aspergillus brasiliensis hyphae over a seven-day period, demonstrating the growth mediums stability within the chamber. The systems 3D imaging capability was validated in a volume of 5.5 mm x 4 mm x 0.5 mm, revealing a radial growth pattern of fungal hyphae. Additionally, we show that the system can identify potential filter failures that are undetectable with 2D imaging. With these capabilities, the upgraded ePetri dish represents a significant advancement in long-term 3D microbial imaging, promising new insights into microbial development and behavior across various microbiological research areas.

microbiology↗

bioRxiv2024

Neuropeptide Y co-opts neuronal ensembles for memory lability and stability

Memory engrams are formed by activity-dependent recruitment of distinct subsets of excitatory principal neurons (or neuronal ensembles) whereas inhibitory neurons pivot memory lability and stability1-5. However, the molecular logic for memory engrams to preferentially recruit specific type of interneurons over other subtypes remains enigmatic. Using activity-dependent single-cell transcriptomic profiling6-8 in mice with training of cued fear memory and extinction, we discovered that neuropeptide Y (NPY)-expressing (NPY+) GABAergic interneurons in the ventral hippocampal CA1 (vCA1) region exert fast GABAergic inhibition to facilitate the acquisition of memory, but bifurcate NPY-mediated slow peptidergic inhibition onto distinct sub-ensembles underlying the extinction of single memory trace. Genetically encoded calcium and NPY sensors revealed that both calcium dynamics of NPY+ neurons and their NPY release in vCA1 ramp up as extinction learning progresses while behavioral state switches from "fear-on" to "fear-off". Bidirectional manipulations of NPY+ neurons or NPY itself demonstrated NPY is both necessary and sufficient to control the rate and degree of memory extinction by acting on two physically non-overlapping sub-ensembles composed of NPY1R- and NPY2R-expressing neurons. CRISPR/Cas9-mediated knockout of NPY2R or NPY1R further unravels that NPY co-opts its actions on these two sub-ensembles to gate early fast and late slow stages of extinction. These findings exemplify the intricate spatiotemporal orchestration of slow peptidergic inhibitions from single subtype of GABAergic interneurons to fine-tune engram lability verse stability of memory.

neuroscience↗

bioRxiv2024

An ultra-short-acting benzodiazepine in thalamic nucleus reuniens undermines fear extinction via intermediation of hippocamposeptal circuits

Benzodiazepines, commonly used for anxiolytics, hinder conditioned fear extinction, and the underlying circuit mechanisms are unclear. Utilizing remimazolam, an ultra-short-acting benzodiazepine, we reveal its impact on the thalamic nucleus reuniens (RE) and interconnected hippocamposeptal circuits during fear extinction. Systemic or RE-specific administration of remimazolam impedes fear extinction by reducing RE activation through A type GABA receptors. Remimazolam enhances long-range GABAergic inhibition from lateral septum (LS) to RE, underlying the compromised fear extinction. RE projects to ventral hippocampus (vHPC), which in turn sends projections characterized by feed-forward inhibition to the GABAergic neurons of the LS. This is coupled with long-range GABAergic projections from the LS to RE, collectively constituting an overall positive feedback circuit construct that promotes fear extinction. RE-specific remimazolam negates the facilitation of fear extinction by disrupting this circuit. Thus, remimazolam in RE disrupts fear extinction caused by hippocamposeptal intermediation, offering mechanistic insights for the dilemma of combining anxiolytics with extinction-based exposure therapy.

neuroscience↗

bioRxiv2024

Transplantation of exogenous mitochondria mitigates myocardial dysfunction after cardiac arrest

The incidence of post-cardiac arrest myocardial dysfunction (PAMD) is high, and there is currently no effective treatment available. This study aims to investigate the protective effects of exogenous mitochondrial transplantation. Exogenous mitochondrial transplantation can enhance myocardial function and improve the survival rate. Mechanistic studies suggest that mitochondrial transplantation can limit impairment in mitochondrial morphology, augment the activity of mitochondrial complexes II and IV, and raise ATP level. As well, mitochondrial therapy ameliorated oxidative stress imbalance, reduced myocardial injury, and thus improved PAMD after cardiopulmonary resuscitation (CPR).

systems biology↗

bioRxiv2024

Regional Glymphatic Dysfunction is linked to Spinocerebellar Ataxia Type 3 pathophysiology

Spinocerebellar ataxia type 3 (SCA3) involves neuroinflammation and imbalance between production and clearance of proteins which affects the glymphatic system, the lymphatic-like, fluid-transport system in the brain. However, it is unclear whether SCA3 is related to impairments in glymphatic function. Using multimodal imaging data, 34 SCA3 patients and 36 age-, sex- and educational matched healthy controls (HCs) were compared using multiple glymphatic measurements, including choroid plexus (CP) and cerebrospinal fluid (CSF) volume, diffusion tensor imaging along the perivascular (DTI-ALPS) index, and coupling relationship between blood-oxygen-level-dependent signals and CSF flow (BOLD-CSF coupling). Then, we evaluated regional glymphatic function by dividing DTI-ALPS and BOLD-CSF coupling into anterior, middle, posterior, and cerebellum regions, thereby identifying the spatial variation of glymphatic function in the two groups. We demonstrated that compared with HCs, larger CP and CSF volumes were found in SCA3 patients. More importantly, for DTI-ALPS index and BOLD-CSF coupling, these surrogate markers for glymphatic clearance were weaker in SCA3 patients. Furthermore, altered regional glymphatic functions were most prominent in midbrain, cerebellum and middle regions. Crucially, the altered midbrain, cerebellum, middle and global glymphatic functions were accompanied by the severity of ataxia and other SCA3 symptoms. Similar to other neurodegenerative disorders, the association between multiple glymphatic indexes and SCA3 symptoms suggested that waste clearance is disrupted in SCA3 patients, which shed light on the pathogenesis of this disease from a glymphatic lens. Our findings highlighted the dysregulated glymphatic function as a novel diagnostic marker for SCA3.

neuroscience↗

bioRxiv2024

Assessment and phenotypic identification of millet germplasm (Setaria italica ) in Liaoning, China

AimsThis study evaluated millet germplasms in Liaoning Province to support the collection, preservation and innovation of millet germplasm resources. MethodsThe study was conducted from 2018 to 2020, involved the selection of 105 millet germplasm resources from the Germplasm Bank of the Liaoning Academy of Agricultural Sciences (LAAS), the observation and recording of 31 traits, and the application of multivariate analysis methods to assess phenotypic diversity. ResultsFrom the diversity analysis and correlation analysis, it was found that the tested traits had abundant diversity and complex correlations among them. principal component analysis (PCA) comprehensively analyzed all quantitative traits and extracted 7 principal components. Grey relational analysis (GRA) highlighted the varied contributions of different traits to yield. Through systematic cluster analysis, the resources were categorized into six groups at Euclidean distance of 17.09. K-mean cluster analysis determined the distribution interval and central value of each trait, then identified resources with desirable traits. ConclusionThe results revealed resources that possess characteristics such as upthrow seedling leaves, more tillers and branches, larger and well-formed ears, and lodging resistance prefer to higher grain yield. It was also discovered that the subear internode length (SIL) could be an indicator for maturity selection. Four specific resources, namely, Dungu No. 1, Xiao-li-xiang, Basen Shengu, and Yuhuanggu No. 1, were identified for further breeding and practical applications.

genetics↗

bioRxiv2024

Profiling microRNA expression during senescence and aging: mining for a diagnostic tool of senescent-cell burden

In the last decade cellular senescence, a hallmark of aging, has come into focus for pharmacologically targeting aging processes. Senolytics are one of these interventive strategies that have advanced into clinical trials, creating an unmet need for minimally invasive biomarkers of senescent cell load to identify patients at need for senotherapy. We created a landscape of miRNA and mRNA expression in five human cell types induced to senescence in-vitro and provide proof-of-principle evidence that miRNA expression can track senescence burden dynamically in-vivo using transgenic p21high senescent cell clearance in HFD fed mice. Finally, we profiled miRNA expression in seven different tissues, total plasma, and plasma derived EVs of young and 25 months old mice. In a systematic analysis, we identified 22 candidate senomiRs with potential to serve as circulating biomarkers of senescence not only in rodents, but also in upcoming human clinical senolytic trials.

molecular biology↗

bioRxiv2024

msCNVS: medium throughput single cell copy number variation sequencing with barcoded library construction free of preamplification toward clinical implementation

Single cell copy number variation sequencing (scCNV-seq) is valuable for genomic analysis of a variety of health and disease systems, yet the available methods either depend on either preamplification of the whole genome of each cell, special devices or untracable, which hinder scCNV-seq practice in clinics. Here we provide scalable multiplex scCNV-seq (msCNVS) that allows direct medium-throughput library construction for single cells, which are barcoded individually with Tn5 transposome in a microplate and immediately pooled for downstream processes, elevating the efficiency by orders of magnitude. An algorithm is developed on the distribution of segmented normalized read count density to identify the major peaks associating with integer copy numbers, further improving the accuracy for objective CNV calling. Here msCNVS faithfully distinguishes the unique CNV patterns of 5 cell lines. The individual msCNVS profiles of 70 individual K562 cells highly correlate with the profile of K562 bulk cells (R=0.90-0.98), and the triplicates of HeLa3 bulk cells correlated nearly perfect (R=0.99). The msCNVS CNV profiles of primary cell cultures of amniotic fluid are confirmed by G-banding karyotype analysis and chromosomal microarray analysis. Additionally, the coverage uniformity of msCNVS is superior to that of MDA and MALBAC and approaches what eMDA and DOP-PCR achieves. Furthermore, msCNVS detects CNV deletions in 2 stunted, abnormal blastocysts, one with CNV mosaicism, and uncovered variants of CNVs in circulated tumor cells, cancerous pleural effusion cells, and patient-derived xenograft nuclei. Thus, msCNVS promises a robust, reliable and highly efficient approach to genomic testing of precious and rare cells like those typically obtained in reproductive and cancer clinics. One-Sentence SummaryBy early pooling of multiple single cells individually barcoded with Tn5 transposome, msCNVS enables efficient CNV profiling of rare clinic samples

genomics↗

bioRxiv2024

DUAL: deep unsupervised simultaneous simulation and denoising for cryo-electron tomography

Recent biotechnological developments in cryo-electron tomography allow direct visualization of native sub-cellular structures with unprecedented details and provide essential information on protein functions/dysfunctions. Denoising can enhance the visualization of protein structures and distributions. Automatic annotation via data simulation can ameliorate the time-consuming manual labeling of large-scale datasets. Here, we combine the two major cryo-ET tasks together in DUAL, by a specific cyclic generative adversarial network with novel noise disentanglement. This enables end-to-end unsupervised learning that requires no labeled data for training. The denoising branch outperforms existing works and substantially improves downstream particle picking accuracy on benchmark datasets. The simulation branch provides learning-based cryo-ET simulation for the first time and generates synthetic tomograms indistinguishable from experimental ones. Through comprehensive evaluations, we showcase the effectiveness of DUAL in detecting macromolecular complexes across a wide range of molecular weights in experimental datasets. The versatility of DUAL is expected to empower cryo-ET researchers by improving visual interpretability, enhancing structural detection accuracy, expediting annotation processes, facilitating cross-domain model adaptability, and compensating for missing wedge artifacts. Our work represents a significant advancement in the unsupervised mining of protein structures in cryo-ET, offering a multifaceted tool that facilitates cryo-ET research.

bioinformatics↗

bioRxiv2024

SUMO Promotes DNA Repair Protein Collaboration to Support Alterative Telomere Lengthening in the Absence of PML

Alternative lengthening of telomeres (ALT) pathway maintains telomeres in a significant fraction of cancers associated with poor clinical outcomes. A better understanding of ALT mechanisms can provide a basis for developing new treatment strategies for ALT cancers. SUMO modification of telomere proteins plays a critical role in the formation of ALT telomere-associated PML bodies (APBs), where telomeres are clustered and DNA repair proteins are enriched to promote homology-directed telomere DNA synthesis in ALT. However, whether and how SUMO contributes to ALT beyond APB formation remains elusive. Here, we report that SUMO promotes collaboration among DNA repair proteins to achieve APB-independent telomere maintenance. By using ALT cancer cells with PML protein knocked out and thus devoid of APBs, we show that sumoylation is required for manifesting ALT features, including telomere clustering and telomeric DNA synthesis, independent of PML and APBs. Further, small molecule-induced telomere targeting of SUMO produces signatures of phase separation and ALT features in PML null cells in a manner depending on both sumoylation and SUMO interaction with SUMO interaction motifs (SIMs). Mechanistically, SUMO-induced effects are linked to the enrichment of DNA repair proteins, including Rad52, Rad51AP1, and BLM, to the SUMO-containing telomere foci. Finally, we find that Rad52 can undergo phase separation, enrich SUMO on telomeres, and promote telomere DNA synthesis in collaboration with the BLM helicase in a SUMO-dependent manner. Collectively, our findings suggest that, in addition to forming APBs, SUMO also promotes collaboration among DNA repair proteins to support telomere maintenance in ALT cells. Given the promising effects of sumoylation inhibitors in cancer treatment, our findings suggest their potential use in perturbing telomere maintenance in ALT cancer cells.

cell biology↗

bioRxiv2024

Myosin-I Synergizes with Arp2/3 Complex to Enhance Pushing Forces of Branched Actin Networks

Myosin-Is colocalize with Arp2/3 complex-nucleated actin networks at sites of membrane protrusion and invagination, but the mechanisms by which myosin-I motor activity coordinates with branched actin assembly to generate force are unknown. We mimicked the interplay of these proteins using the "comet tail" bead motility assay, where branched actin networks are nucleated by Arp2/3 complex on the surface of beads coated with myosin-I and the WCA domain of N-WASP. We observed that myosin-I increased bead movement efficiency by thinning actin networks without affecting growth rates. Remarkably, myosin-I triggered symmetry breaking and comet-tail formation in dense networks resistant to spontaneous fracturing. Even with arrested actin assembly, myosin-I alone could break the network. Computational modeling recapitulated these observations suggesting myosin-I acts as a repulsive force shaping the networks architecture and boosting its force-generating capacity. We propose that myosin-I leverages its power stroke to amplify the forces generated by Arp2/3 complex-nucleated actin networks.

biophysics↗

bioRxiv2024

Neurotensin-Neurotensin Receptor 2 signaling in adipocytes regulates food intake through ceramide metabolism

Neurotensin (NTS) is a secretory peptide produced by the lymphatic endothelial cells (LEC). Our previous study revealed that NTS suppressed the activity of brown adipose tissue via the interactions with NTSR2. In the current study, we found that the depletion of Ntsr2 in the white adipocytes upregulated food intake, while the local treatment of NTS suppressed the food intake. Mechanistic study revealed that the suppression of NTS-NTSR2 signaling enhanced the phosphorylation of ceramide synthetase 2 (CerS2), increased the abundance of its products ceramide C20-C24 and downregulated the production of GDF15 in the white adipose tissues, which was responsible for the elevation of food intake. With four populations of different age and ethnic background, we discovered a potential causal and positive correlation between ceramide C20-24 and food intake in human. Our study identified that NTS-NTSR2 signaling can perform the neurological regulation via controlling the production of ceramide in the white adipocytes.

physiology↗

bioRxiv2024

HDAC1/2 and HDAC3 play distinct roles in controlling adult Meibomian gland homeostasis

PurposeTo investigate the roles of HDAC1/2 and HDAC3 in adult Meibomian gland (MG) homeostasis. MethodsHDAC1/2 or HDAC3 were inducibly deleted in MG epithelial cells of adult mice. The morphology of MG was examined. Proliferation, apoptosis, and expression of MG acinus and duct marker genes, meibocyte differentiation genes, and HDAC target genes, were analyzed via immunofluorescence, TUNEL assay, and RNA in situ hybridization. ResultsCo-deletion of HDAC1/2 in MG epithelium caused gradual loss of acini and formation of cyst-like structures in the central duct. These phenotypes required homozygous deletion of both HDAC1 and HDAC2, indicating that they function redundantly in the adult MG. Short-term deletion of HDAC1/2 in MG epithelium had little effect on meibocyte maturation but caused decreased proliferation of acinar basal cells, excessive DNA damage, ectopic apoptosis, and increased p53 acetylation and p16 expression in the MG. By contrast, HDAC3 deletion in MG epithelium caused dilation of central duct, atrophy of acini, defective meibocyte maturation, increased acinar basal cell proliferation, and ectopic apoptosis and DNA damage. Levels of p53 acetylation and p21 expression were elevated in HDAC3-deficient MGs, while the expression of the differentiation regulator PPAR{gamma} and the differentiation markers PLIN2 and FASN was downregulated. ConclusionsHDAC1 and HDAC2 function redundantly in adult Meibomian gland epithelial progenitor cells and are essential for their proliferation and survival, but not for acinar differentiation, while HDAC3 is required to limit acinar progenitor cell proliferation and permit differentiation. HDAC1/2 and HDAC3 have partially overlapping roles in maintaining survival of MG cells.

molecular biology↗

bioRxiv2024

Auditory stimuli extend the temporal window of visual integration by modulating alpha-band oscillations

In multisensory environments, signals from different modalities interact to shape perception, but the underlying temporal dynamics remain unclear. We investigated how a brief auditory stimulus affects the temporal integration of successive visual events using electroencephalography (EEG). Participants viewed two consecutive flashes, with or without an auditory beep accompanying the first flash, and reported whether they perceived one or two flashes. The beep shifted the psychometric fusion threshold to longer interstimulus intervals, indicating a wider temporal integration window. This behavioural shift was accompanied by a transient reduction in poststimulus instantaneous alpha frequency, and individual differences in alpha-cycle lengthening correlated with threshold prolongation. Auditory input also weakened the relationship between prestimulus alpha frequency and perceptual report while strengthening the corresponding relationship with prestimulus alpha phase. In a follow-up transcranial alternating current stimulation (tACS) experiment, the effects of lower- versus upper-alpha stimulation on fusion thresholds differed between the visual-only and audiovisual conditions. A computational model based on phase resetting and perceptual cycles qualitatively reproduced the main findings. Together, the results suggest that a brief sound can reorganize alpha-band timing and thereby widen the temporal window of visual integration.

neuroscience↗

bioRxiv2024

NeuralTE: an accurate approach for Transposable Element superfamily classification with multi-feature fusion

MotivationClassifying Transposable Elements (TEs) at the superfamily level offers deeper insights into species variation and evolution. Recent advancements in third-generation sequencing technologies have made a large number of genomes from non-model species becoming available. However, existing TE classification methods suffer from several limitations, including the necessity to train multiple hierarchical classification models, the incapacity to perform classification at the superfamily level, and deficiencies in both accuracy and robustness. Therefore, there is an urgent need for an accurate TE classification method to improve genome annotation. ResultsIn this study, we develop NeuralTE, a deep learning method designed to classify transposons at the superfamily level. To achieve accurate TE classification, we identify various structural features of transposons, and use different combinations of k-mers for terminal repeats and internal sequences to uncover distinct patterns. Evaluation on all transposons from Repbase shows that NeuralTE outperforms existing deep learning, machine learning, and homology-based methods in classifying TEs. Testing on the transposons from novel species highlights the superior performance of NeuralTE compared to existing methods. We also conduct TE annotation experiments on rice using different classification tools, and the results show that NeuralTE achieves annotations nearly identical to the gold standard, highlighting its robustness and accuracy in classifying transposons. AvailabilityNeuralTE is publicly available at https://github.com/CSU-KangHu/NeuralTE.

bioinformatics↗

bioRxiv2024

Potent Estrogen Receptor β Agonists with Inhibitory Activity In Vitro, Fail to Suppress Xenografts of Endocrine-Resistant Cyclin-dependent Kinase 4/6 inhibitor-Resistant Breast Cancer Cells

ObjectiveSeventy percent of newly diagnosed breast cancers are estrogen receptor- positive and HER2/neu negative [1]. First-line treatments incorporate endocrine therapy and cyclin-dependent kinase 4/6 inhibitors [2]. However, therapy resistance occurs in most patients [3-5]. Hence, there is an urgent need for effective second-line treatments. We previously showed that the potent estrogen receptor-{beta} agonists, OSU-ERb-12 and LY500307, synergized with the selective estrogen receptor modulator, tamoxifen, in vitro. Furthermore, we showed that these compounds inhibited endocrine-resistant and cyclin-dependent kinase 4/6-inhibitor-resistant estrogen receptor -positive cell lines in vitro [6]. Here, we used fulvestrant- and abemaciclib-resistant T47D-derived cell line xenografts to determine the efficacy of the combination of OSU-ERb-12 and LY500307 with tamoxifen in vivo. ResultsDespite efficacy in vitro, treatments failed to reduce xenograft tumor volumes. Hence, we conclude that this treatment strategy lacks direct cancer cell-intrinsic cytotoxic efficacy in vivo.

cancer biology↗