Biology subjects

Zhao, Z.

Publications and source records attributed to Zhao, Z..

At least 271 records · Page 15Linked to original sources

bioRxiv2024

Embryonic origins of forebrain oligodendrocytes revisited by combinatorial genetic fate mapping

Multiple embryonic origins give rise to forebrain oligodendrocytes (OLs), yet controversies and uncertainty exist regarding their differential contributions. We established intersectional and subtractional strategies to genetically fate map OLs produced by medial ganglionic eminence/preoptic area (MGE/POA), lateral/caudal ganglionic eminences (LGE/CGE) and dorsal pallium. We found that, contrary to the canonical view, LGE/CGE-derived OLs make minimum contributions to the neocortex and corpus callosum, but dominate piriform cortex and anterior commissure. Additionally, MGE/POA-derived OLs, instead of being entirely eliminated, make small but sustained contribution to cortex with a distribution pattern distinctive from those derived from the dorsal origin. Our study provides a revised and more comprehensive view of cortical and white matter OL origins, and established valuable new tools and strategies for future OL studies.

neuroscience↗

bioRxiv2024

Deciphering the co-evolutionary dynamics of L2 β-lactamases via Deep learning

L2 {beta}-lactamases, a serine-based class A {beta}-lactamases expressed by Stenotrophomonas maltophilia plays a pivotal role in antimicrobial resistance. However, limited studies have been conducted on these important enzymes. To understand the co-evolutionary dynamics of L2 {beta}-lactamase, innovative computational methodologies, including adaptive sampling molecular dynamics simulations, and deep learning methods (convolutional variational autoencoders and BindSiteS-CNN) explored conformational changes and correlations within the L2 {beta}-lactamase family together with other representative class A enzymes including SME-1 and KPC-2. This work also investigated the potential role of hydrophobic nodes and binding site residues in facilitating the functional mechanisms. The convergence of analytical approaches utilized in this effort yielded comprehensive insights into the dynamic behaviour of the {beta}-lactamases, specifically from an evolutionary standpoint. In addition, this analysis presents a promising approach for understanding how the class A {beta}-lactamases evolve in response to environmental pressure and establishes a theoretical foundation for forthcoming endeavours in drug development aimed at combating antimicrobial resistance. SynopsisDeep learning is used to reveal the dynamic co-evolutionary patterns of L2 {beta}-lactamases. O_LIAnalysis of hydrophobic nodes and binding site residues provides a detailed understanding of both local and global dynamic evolution, which explain the functional divergences. C_LIO_LIThe employment of two distinct deep learning models, the Convolutional Variational Autoencoder (CVAE) and BindSiteS-CNN, facilitates the investigation of conformational shifts, thereby depicting the dynamic evolution of L2 {beta}-lactamases. C_LIO_LIThe effectiveness of CVAE and BindSiteS-CNN in dynamic classification is corroborated with selected features. C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=96 SRC="FIGDIR/small/575584v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@1db15forg.highwire.dtl.DTLVardef@168043eorg.highwire.dtl.DTLVardef@1eebb96org.highwire.dtl.DTLVardef@5d8019_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2023

Aberrant connective tissue sheath contraction drives premature hair follicle regression by inducing progenitor cell depletion in androgenetic alopecia

Androgenetic alopecia (AGA) is characterized by progressive miniaturization of hair, forming a distinctive patterned baldness in the scalp; yet, the mechanisms for hair miniaturization in this disease remain largely unknown. Here by single-cell transcriptome analysis, we describe a concise single-cell atlas, and identify the early changes in cell subpopulations, hair follicle (HF) stem cell fate determination and cell-cell communications in AGA anagen HF units. Thereinto, apoptotic loss of HF progenitor cells is significantly increased, correlated with HF miniaturization in AGA. Mechanistically, enhanced contraction of connective tissue sheath (CTS) activates the mechanosensitive channel PIEZO1, which triggers ectopic apoptosis of progenitor cells in human anagen HFs. Continuous CTS contraction during AGA causes long-term loss of progenitor cells via inducing persistent ectopic apoptosis through PIEZO1, eventually leading to premature hair regression. Most importantly, we show that targeting CTS contraction by ML-7, a selective myosin light chain kinase (MLCK) inhibitor, can obviously improve the growth of HFs from balding scalps of AGA patients. Our study reveals the cellular hierarchies and identifies CTS with increased muscle contraction activity as a driver of premature hair regression in AGA, highlighting CTS surrounding human HF as the therapeutic target for treating this disorder.

pathology↗

bioRxiv2023

Nitric oxide mediates differential effects in mouse retinal ganglion cells

Neuromodulators have major influences on the regulation of neural circuit activity across the nervous system. Nitric oxide (NO) has been shown to be a prominent neuromodulator in many circuits and has been extensively studied in the retina. Here, it has been associated with the regulation of light adaptation, gain control, and gap junctional coupling, but its effect on the retinal output, specifically on the different types of retinal ganglion cells (RGCs), is still poorly understood. In this study, we used two-photon Ca2+imaging and multi-electrode array (MEA) recordings to measure light-evoked activity of RGCs in the ganglion cell layer in the ex vivo mouse retina. This approach allowed us to investigate the neuromodulatory effects of NO on a cell type-level. Our findings reveal that NO selectively modulates the suppression of temporal responses in a distinct subset of contrast-suppressed RGC types, increasing their activity without altering the spatial properties of their receptive fields. Given that under photopic conditions, NO release is triggered by quick changes in light levels, we propose that these RGC types signal fast contrast changes to higher visual regions. Remarkably, we found that about one-third of the RGC types, recorded using two-photon Ca2+imaging, exhibited consistent, cell type-specific adaptational response changes throughout an experiment, independent of NO. By employing a sequential-recording paradigm, we could disentangle those additional adaptational response changes from drug-induced modulations. Taken together, our research highlights the selective neuromodulatory effects of NO on RGCs and emphasizes the need of considering non-pharmacological activity changes, like adaptation, in such study designs.

neuroscience↗

bioRxiv2023

Quorum Sensing Positively Regulates CPS-dependent Autographiviridae Phages Infection in Vibrio alginolyticus

Quorum sensing (QS) orchestrates many bacterial behaviors, such as virulence and biofilm formation, across bacterial populations. Nevertheless, the underlying mechanism of QS regulating CPS-dependent phage-bacterium interactions remains unclear. In the present study, we report that QS upregulated the expression of CPS-dependent phage receptors, thus increasing phage adsorption and infection rates in V. alginolyticus. We found that QS upregulated the expression of the ugd gene, leading to increased synthesis of Autographiviridae phage receptor capsular polysaccharide (CPS) synthesis in V. alginolyticus. The signal molecule autoinducer-2 (AI-2) released by V. alginolyticus from different sources can potentially enhance CPS-dependent phage infection. Therefore, our data suggest that inhibiting quorum sensing may reduce rather than improve the therapeutic efficacy of CPS-specific phages. IMPORTANCEPhage resistance is a direct threat to phage therapy, and understanding phage-host interactions, especially bacteria block phage infection, is essential for developing successful phage therapy. In the present study, we demonstrate for the first time that V. alginolyticus uses QS to promote CPS-specific phage infection by upregulating the expression of ugd, which is necessary for the synthesis of Autographiviridae phage receptor capsular polysaccharide (CPS). Although increased CPS-specific phage susceptibility is a novel trade-off mediated by QS, it results in the upregulation of virulence factors, promoting biofilm development and enhanced capsular polysaccharide production in V. alginolyticus. This suggests that inhibiting QS may improve the effectiveness of antibiotic treatment, but it may also reduce the efficacy of phage therapy.

microbiology↗

bioRxiv2023

Detecting Features of Protein Structure through their Mediator-Accessible Redox Activities

Protein function relies on sequence, folding, and post-translational modification, and molecular measurements are commonly used to reveal these structural features. Here, we report an alternative approach that represents these molecular features as readily measurable electronic patterns and validate this experimental approach by detecting structural perturbations commonly encountered during protein biomanufacturing. Specifically, we studied a monoclonal antibody standard (NISTmAb) and focused on the electronic detection of variants that have undergone interchain-disulfide bond reduction and methionine oxidation. Electronic detection of these structural perturbations is based on mediated electrochemical probing (MEP) that discerns patterns associated with the antibodys mediator-accessible redox activity. We demonstrate that MEP can rapidly (within minutes) and quantitatively transduce the proteins structural features into robust electronic signals that can enable bioprocess monitoring and control. More broadly, the ability to transduce information of a proteins molecular structure into a more convenient electronic domain offers fundamentally new opportunities to apply the power of microelectronics and real-time data analytics to chemical and biological analysis.

bioengineering↗

bioRxiv2023

Two transcriptional cascades orchestrate cockroach leg regeneration

The mystery of appendage regeneration has fascinated humans for centuries, while the regulatory mechanisms remain unclear. In this study, a transcriptional landscape of regenerating leg was established in the American cockroach, Periplaneta americana, an ideal model for appendage regeneration with remarkable regeneration capacity. Through a large-scale in vivo screening, we identified multiple signaling pathways and transcription factors (TFs) controlling leg regeneration. Specifically, zfh-2 and bowl, which have not been previously implicated in appendage regeneration, contributes to blastema proliferation and morphogenesis in two novel transcriptional cascades BMP/JAK-STAT-zfh-2-bab1/B-H2/Lim1 and Notch-drm/bowl-bab1. Notably, zfh-2 was found working as a direct target of BMP signaling to promote cell proliferation in the blastema. These mechanisms might be conserved in the appendage regeneration of vertebrates from an evolutionary perspective. Overall, our findings reveal that two crucial transcriptional cascades orchestrate distinct cockroach leg regeneration processes, significantly advancing the comprehension of molecular mechanism in appendage regeneration.

developmental biology↗

bioRxiv2023

Reversal of pulmonary veno-occlusive disease phenotypes by inhibition of the integrated stress response

Pulmonary veno-occlusive disease (PVOD) is a rare form of pulmonary hypertension arising from EIF2AK4 gene mutations or mitomycin C (MMC) administration. The lack of effective PVOD therapies is compounded by a limited understanding of the mechanisms driving the vascular remodeling in PVOD. We show that the administration of MMC in rats mediates the activation of protein kinase R (PKR) and the integrated stress response (ISR), which lead to the release of the endothelial adhesion molecule VE-Cadherin in the complex with Rad51 to the circulation, disruption of endothelial barrier, and vascular remodeling. Pharmacological inhibition of PKR or ISR attenuates the depletion of VE-Cadherin, elevation of vascular permeability, and vascular remodeling instigated by MMC, suggesting potential clinical intervention for PVOD. Finally, the severity of PVOD phenotypes was increased by a heterozygous BMPR2 mutation that truncates the carboxyl tail of BMPR2, underscoring the role of deregulated BMP signal in the development of PVOD.

cell biology↗

bioRxiv2023

VirusImmu: a novel ensemble machine learning approach for viral immunogenicity prediction

BackgroundThe viruses threats provoke concerns regarding their sustained epidemic transmission, making the development of vaccines particularly important. In the prolonged and costly process of vaccine development, the most important initial step is to identify protective immunogens. Machine learning (ML) approaches are productive in analyzing big data such as microbial proteomes, and can remarkably reduce the cost of experimental work in developing novel vaccine candidates. ResultsWe intensively evaluated the immunogenicity prediction power of eight commonly-used ML methods by random sampling cross validation on a large dataset consisting of known viral immunogens and non-immunogens we manually curated from the public domain. XGBoost, kNN and RF showed the strongest predictive power. We then proposed a novel soft-voting based ensemble approach (VirusImmu), which demonstrated a powerful and stable capability for viral immunogenicity prediction across the test set and external test set irrespective of protein sequence length. VirusImmu was successfully applied to facilitate identifying linear B cell epitopes against African Swine Fever Virus as confirmed by indirect ELISA in vitro. ConclusionsVirusImmu exhibited tremendous potentials in predicting immunogenicity of viral protein segments. It is freely accessible at https://github.com/zhangjbig/VirusImmu.

bioinformatics↗

bioRxiv2023

Quantitative cell morphology in C. elegans embryos reveals regulations of cell volume asymmetry

The dynamics of cellular morphology throughout development are crucial for morphogenesis and organogenesis, yet their systematic characterization remains a significant challenge. By integrating both nuclear position and advanced cell membrane labeling, we develop a novel method that enables the segmentation of surfaces for over 95% of cells produced during Caenorhabditis elegans embryogenesis. With this method, we segment eight wild-type and four perturbed embryos. The output, including cell identity, shape, volume, surface and contact area, can be visualized using our custom software. We demonstrate that signaling interactions, such as Notch and Wnt, regulate not only the asymmetry of cell fate but also the asymmetry of cell volume in conjunction with mechanical compression. Furthermore, we find that the asymmetries of fate and volume are generally interconnected. ONE SENTENCE SUMMARYSystematic quantification of cell morphology with resolved cell lineage and cell fate in developing C. elegans embryo uncovers multimodal regulations of cell size. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=190 SRC="FIGDIR/small/567849v1_ufig1.gif" ALT="Figure 1"> View larger version (114K): org.highwire.dtl.DTLVardef@1b7d0fforg.highwire.dtl.DTLVardef@fa28b1org.highwire.dtl.DTLVardef@185a0deorg.highwire.dtl.DTLVardef@478a2_HPS_FORMAT_FIGEXP M_FIG C_FIG Potential Cover/Featured Image: Smiling "ghost" face of C. elegans embryo. Center: shown are skins (colored in red, dorsal view with anterior to the bottom) of a 400-celled C. elegans embryo. Cells not covered by the skins are colored in gray, green, blue, and transparent yellow, respectively. Internal and external circles: confocal fluorescence images (GFP for cell nucleus and mCherry for cell membrane) and reconstructed cell morphologies of the C. elegans embryo from the 2- to 550-cell stages respectively, connected with images of a C. elegans adult expressing the same markers.

developmental biology↗

bioRxiv2023

TIPE drives a cancer stem-like phenotype by promoting glycolysis via PKM2/HIF-1alpha axis in melanoma

TIPE (TNFAIP8) has been identified as an oncogene and participates in tumor biology. However, how its role in the metabolism of tumor cells during melanoma development remains unclear. Here, we demonstrated that TIPE promoted glycolysis by interacting with pyruvate kinase M2 (PKM2) in melanoma. We found that TIPE induced PKM2 dimerization, thereby facilitating its translocation from the cytoplasm to the nucleus. TIPE-mediated PKM2 dimerization consequently promoted HIF-1 activation and glycolysis, which contributed to melanoma progression and increased its stemness features. Notably, TIPE specifically phosphorylated PKM2 at Ser 37 in an ERK-dependent manner. Consistently, the expression of TIPE was positively correlated with the levels of PKM2 Ser37 phosphorylation and cancer stem cell markers in melanoma tissues from clinical samples and tumor bearing mice. In summary, our findings indicate that the TIPE/PKM2/HIF-1 signaling pathway plays a pivotal role in promoting cancer stem cell properties by facilitating the glycolysis, which would provide a promising therapeutic target for melanoma intervention.

cancer biology↗

bioRxiv2023

Progressively shifting patterns of co-modulation among premotor cortex neurons carry dynamically similar signals during action execution and observation

Neurons in macaque premotor cortex show firing rate modulation whether the subject performs an action or observes another individual performing a similar action. Although such mirror neurons have been thought to have highly congruent discharge during execution and observation, many if not most, show non-congruent activity. Studies of reaching movements, for which low-dimensional neural trajectories exhibit comparatively simple dynamical motifs, have shown that these prevalent patterns of co-modulation pass through subspaces which are shared in part, but in part are visited exclusively during either execution or observation. The neural dynamics of hand movements are more complex, however. We developed a novel approach to examine prevalent patterns of co-modulation during execution and observation of a task that involved reaching, grasping, and manipulation. Rather than following neural trajectories in subspaces that contain their entire time course, we identified time series of instantaneous subspaces, calculated principal angles among them, sampled trajectory segments at the times of selected behavioral events, and projected those segments into the time series of instantaneous subspaces. These instantaneous neural subspaces most often remained distinct during execution versus observation. Nevertheless, latent dynamics during execution and observation could be partially aligned with canonical correlation, indicating some similarity of the relationships among neural representations of different movements relative to one another during execution and observation. We also found that during action execution, mirror neurons showed consistent patterns of co-modulation both within and between sessions, but other non-mirror neurons that were modulated only during action execution and not during observation showed considerable variability of co-modulation.

neuroscience↗

bioRxiv2023

Quality Control for Single Cell Analysis of High-plex Tissue Profiles using CyLinter

Tumors are complex assemblies of cellular and acellular structures patterned on spatial scales from microns to centimeters. Study of these assemblies has advanced dramatically with the introduction of high-plex spatial profiling. Image-based profiling methods reveal the intensities and spatial distributions of 20-100 proteins at subcellular resolution in 103-107 cells per specimen. Despite extensive work on methods for extracting single-cell data from these images, all tissue images contain artefacts such as folds, debris, antibody aggregates, optical aberrations and image processing errors that arise from imperfections in specimen preparation, data acquisition, image assembly, and feature extraction. We show that these artefacts dramatically impact single-cell data analysis, obscuring meaningful biological interpretation. We describe an interactive quality control software tool, CyLinter, that identifies and removes data associated with imaging artefacts. CyLinter greatly improves single-cell analysis, especially for archival specimens sectioned many years prior to data collection, such as those from clinical trials.

pathology↗

bioRxiv2023

Ex vivo structures from spinach leaves

Ex vivo structure determination of macromolecules from native source is gaining increasing attention from the scientific community, as the method can be employed to dissect the function of important, multi-component molecular machines. However, the existing ex vivo procedures often require genome manipulation or availability high-affinity binders, limiting the general applicability. Here, we report simple yet robust principles for isolation of protein complexes from enriched native biological material, enabling cryoEM-facilitated high-resolution structure determination. We report the structures of ten separate membrane and soluble protein complexes determined from spinach leaves. Moreover, the developed pipeline is likely adaptable to essentially any biological system. As such, the approach may represent an attractive avenue for future structural proteomics efforts.

biochemistry↗

bioRxiv2023

Multi-omics analysis reveals novel interplays between intratumoral bacteria and glioma

Emerging evidence highlights the potential impact of intratumoral microbiota on cancer. However, the microbial composition and function in glioma remains elusive. Consequently, our study aimed to investigate the microbial community composition in glioma tissues and elucidate its role in glioma development. We parallelly performed microbial profiling, transcriptome sequencing and metabolomics detection on tumor and adjacent normal brain tissues obtained from 50 glioma patients. We employed immunohistochemistry, multicolor immunofluorescence and FISH staining to observe the presence and location of bacteria. Furthermore, an animal model was employed to validate the impact of key bacteria on glioma development. Six genera were found to be significantly enriched in glioma tissues compared to its adjacent normal brain tissues, including Fusobacterium, Longibaculum, Intestinimonas, Pasteurella, Limosilactobacillus and Arthrobacter. Both bacterial RNA and LPS were observed in glioma tissues. Multicolor immunofluorescence analysis showed higher bacterial LPS levels in tumor cells than in macrophages and in glioma tissue than in adjacent normal brain tissue. Integrated microbiomics, transcriptomics, and metabolomics revealed that genes associated with intratumoral microbes were enriched in multiple synapse-associated pathways and that metabolites associated with intratumoral microbes were (R)-N-methylsalsolinol, N-acetylaspartylglutamic acid, and N-acetyl-L-aspartic acid. Further mediation analysis suggested that intratumoral microbiome may affect the expression of neuron-related genes through bacteria-associated metabolites. In addition, a glioma mouse model suggested that Fusobacterium nucleatum promoted glioma growth by increasing the levels of N-acetylneuraminic acid and the expression levels of CCL2, CXCL1, and CXCL2. In conclusion, our findings shed light on the intricate interplays between intratumoral bacteria and glioma.

neuroscience↗

bioRxiv2023

Computational divergence analysis reveals the existence of regulatory degeneration and supports HDAC1 as a potential drug target for Alzheimer's disease

Epigenetic dysregulation has been widely reported in patients of Alzheimers disease (AD) and epigenetic drugs are gaining particular interest as a potential candidate therapy target. However, it is less clear how epigenetic dysregulation contributes to AD development. In this work, we performed regulatory divergence analysis using large-scale AD brain RNA-seq data and reported a widespread existence of regulatory degeneration among AD patients. It seems that transcription factor (TF)-mediated regulations get weakened or lost during AD development, resulting in disruption of normal neuronal function, especially including protein degradation, neuroinflammation, mitochondria and synaptic dysfunction. The regulatory degeneration burden (RDB) is well correlated with the detrimental clinical manifestations of AD patients. Studies of epigenetic marks, including histone modification, open chromatin accessibility and three TF binding sites supported the existence of regulatory degeneration. It suggested that epigenetic dysregulation contributed to regulatory degeneration, which also explained the consequence of epigenetic dysregulation. Among the epigenetic regulators, HDAC1 was proposed as a potential participator in such a process. Overall, our computational analysis suggested a novel causal mechanism of AD development and proposed HDAC1 as a drug target to treat AD.

systems biology↗

bioRxiv2023

Spatial transcriptomics of peach and nectarine elucidates the mechanism underlying fruit trichome development

Peach (Prunus persica) is an economically significant fruit-bearing tree. The trichomes of peach fruits are essential for their growth and development by playing a protective role against abiotic stresses, such as intense ultraviolet (UV) light, high temperature, cold-induced stress, and biotic stresses, such as pests and disease infestation. However, the mechanism underlying trichome development in peach fruits is unknown. Therefore, spatial transcriptome sequencing technology was used to compare the transcriptomic information seven days after flowering (DAF) of peach and nectarine fruits at an ultra-high resolution. The results revealed significant variations in how fruits at the early development stage responded to stress exposure. Comparatively, nectarine response to stress was significantly magnified than peach. Notably, a novel trichome-related marker gene, Prupe.7G196500, was identified in peach, which showed a robust function in response to jasmonic acid and wounding. Further, the Prupe.7G196500pro::GUS construct was found to specifically expressed in the trichomes of the true leaves of 10-day-old Arabidopsis thaliana (Arabidopsis) seedlings and induced by drought treatment. Finally, gain-of-function analysis showed that Prupe.7G196500 promoted trichomes development. In conclusion, this study identified the cell types and novel marker genes associated with peach fruit. The role of Prupe.7G196500 in positively regulating trichome development was also characterized, thereby laying the foundation for analyzing the mechanism involved in trichome development in peach fruits.

developmental biology↗

bioRxiv2023

Survey of white-footed mice in Connecticut, USA reveals low SARS-CoV-2 seroprevalence and infection with divergent betacoronaviruses

Diverse mammalian species display susceptibility to and infection with SARS-CoV-2. Potential SARS-CoV-2 spillback into rodents is understudied despite their host role for numerous zoonoses and human proximity. We assessed exposure and infection among white-footed mice (Peromyscus leucopus) in Connecticut, USA. We observed 1% (6/540) wild-type neutralizing antibody seroprevalence among 2020-2022 residential mice with no cross-neutralization of variants. We detected no SARS-CoV-2 infections via RT-qPCR, but identified non-SARS-CoV-2 betacoronavirus infections via pan-coronavirus PCR among 1% (5/468) of residential mice. Sequencing revealed two divergent betacoronaviruses, preliminarily named Peromyscus coronavirus-1 and -2. Both belong to the Betacoronavirus 1 species and are [~]90% identical to the closest known relative, Porcine hemagglutinating encephalomyelitis virus. Low SARS-CoV-2 seroprevalence suggests white-footed mice may not be sufficiently susceptible or exposed to SARS-CoV-2 to present a long-term human health risk. However, the discovery of divergent, non-SARS-CoV-2 betacoronaviruses expands the diversity of known rodent coronaviruses and further investigation is required to understand their transmission extent.

ecology↗