Biology subjects

Zhang, L.

Publications and source records attributed to Zhang, L..

At least 685 records · Page 38Linked to original sources

bioRxiv2024

Design and optimization of novel succinate dehydrogenase inhibitors against agricultural fungi based on Transformer model

Succinate dehydrogenase inhibitors (SDHIs) are a promising class of fungicides targeting the energy production pathway of pathogenic fungi. However, overuse has led to resistance, necessitating the development of new and effective SDHIs. This study takes the Transformer model to generate a customized virtual library of potential SDHIs. These candidates were then meticulously screened based on expert knowledge and synthetic feasibility, ultimately yielding several pyrazole carboxamide derivatives as the promising leads. Subsequent synthesis, antifungal activity testing, and structural optimization further refined these leads into potent SDHI candidates. This work marks the first application of a generative model to SDHI design, establishing a robust workflow for virtual library generation, screening, activity evaluation, and structure optimization. This provides one way for the rational design of future SDHIs, not only against fungi, but potentially other agricultural pathogens as well.

biochemistry↗

bioRxiv2024

Proteolytic Cleavage of the ENaC gamma Subunit: Impact Upon Na+ and K+ Handling

The ENaC gamma subunit is essential for homeostasis of Na+, K+, and body fluid. Dual subunit cleavage before and after a short inhibitory tract allows dissociation of this tract, increasing channel open probability (PO), in vitro. Cleavage proximal to the tract occurs at a furin recognition sequence (143RKRR146 in mouse). Loss of furin-mediated cleavage prevents in vitro activation of the channel by proteolysis at distal sites. We hypothesized that 143RKRR146 mutation to 143QQQQ146 (Q4) in 129/Sv mice would reduce ENaC PO, impair flow-stimulated flux of Na+ (JNa) and K+ (JK) in perfused collecting ducts, reduce colonic amiloride-sensitive short circuit current (ISC), and impair Na+, K+, and body fluid homeostasis. Immunoblot of Q4/Q4 mouse kidney lysates confirmed loss of a band consistent in size with the furin-cleaved proteolytic fragment. However, Q4/Q4 male mice on a low Na+ diet did not exhibit altered ENaC PO or flow-induced JNa, though flow-induced JK modestly decreased. Colonic amiloride-sensitive ISC in Q4/Q4 mice was not altered. Q4/Q4 males, but not females, exhibited mildly impaired fluid volume conservation when challenged with a low Na+ diet. Blood Na+ and K+ were unchanged on a regular, low Na+, or high K+ diet. These findings suggest that biochemical evidence of gamma subunit cleavage should not be used in isolation to evaluate ENaC activity. Further, factors independent of gamma subunit cleavage modulate channel PO and the influence of ENaC on Na+, K+, and fluid volume homeostasis in 129/Sv mice, in vivo.

physiology↗

bioRxiv2024

Inferring Metabolic Objectives and Tradeoffs in Single Cells During Embryogenesis

While proliferating cells optimize their metabolism to produce biomass, the metabolic objectives of cells that perform non-proliferative tasks are unclear. The opposing requirements for optimizing each objective results in a trade-off that forces single cells to prioritize their metabolic needs and optimally allocate limited resources. To define metabolic objectives and tradeoffs in biological systems mathematically, we integrated bulk and single-cell omics data with a novel framework to infer cell objectives using metabolic modeling and machine learning. We validated this framework by identifying essential genes from CRISPR-Cas9 screens in embryonic stem cells, and by inferring the metabolic objectives of quiescent cells and during different cell-cycle phases. Applying this to embryonic cell states, we observed a decrease in metabolic entropy upon development. We further uncovered a trade-off between glutathione and biosynthetic precursors in 1-cell zygote, 2-cell embryo, and blastocyst cells, potentially representing a trade-off between pluripotency and proliferation.

systems biology↗

bioRxiv2024

The Primate-Specific Presence of Interferon Regulatory Factor-5 Pseudogene 1

Interferon regulatory factor 5 (IRF5) is a critical transcription factor, regulating the production of inflammatory cytokines and interferons. Dysregulation of IRF5 has been linked to various autoimmune and inflammatory diseases. Pseudogenes may exhibit gene regulatory functions in various mechanisms. In this study, we find the human IRF5 pseudogene 1 (IRF5P1) is a chimeric processed pseudogene containing sequences derived from multiple sources. Remarkably, IRF5P1 is specific to higher primates such as apes and humans. We propose that IRF5P1 may have originated through the ancient integration of a retroviral sequence containing IRF5 mRNA from other animals. Interestingly, IRF5P1 overlaps with another gene, triple QxxK/R motif containing (TRIQK), and the antisense strand of IRF5P1 is predominantly expressed, likely as part of the TRIQK pre-mRNA. The antisense IRF5P1 RNA may regulate IRF5 expression through complementary binding to the IRF5 mRNA, and variants in the IRF5 gene may modulate this interaction. Our analysis suggests that IRF5P1 likely had positive effects on primate evolution, making IRF5P1 a favored component to maintain in the primate lineage, and rendering the pseudogene primate specific. Further studies are essential to elucidate the potential for IRF5P1 to participate in regulatory networks governing IRF5 activity and inflammation and innate immunity.

immunology↗

bioRxiv2024

Systematic Analysis of Immune Changes after B-cell Depletion in Autoimmune Multiple Sclerosis

Multiple sclerosis (MS) is a complex genetically mediated autoimmune disease of the central nervous system where anti-CD20-mediated B cell depletion is remarkably effective in the treatment of early disease. While previous studies investigated the effect of B cell depletion on select immune cell subsets using flow cytometry-based methods, the therapeutic impact on patient immune landscape is unknown. In this study, we explored how a therapy-driven "in vivo perturbation" modulates the diverse immune landscape by measuring transcriptomic granularity with single-cell RNA sequencing (scRNAseq). We demonstrate that B cell depletion leads to cell type-specific changes in the abundance and function of CSF macrophages and peripheral blood monocytes. Specifically, a CSF-specific macrophage population with an anti-inflammatory transcriptomic signature and peripheral CD16+ monocytes increased in frequency post-B cell depletion. This was accompanied by increases in TNF messenger RNA and protein in monocytes post-B cell depletion, consistent with the finding that anti-TNF treatment exacerbates autoimmune activity in MS. In parallel, B cell depletion induced changes in peripheral CD4+ T cell populations, including increases in the frequency of TIGIT+ regulatory T cells and marked decreases in the frequency of myelin peptide loaded-tetramer binding CD4+ T cells. Collectively, this study provides an exhaustive transcriptomic map of immunological changes, revealing different mechanisms of action contributing to the high efficacy in B cell depletion treatment of MS.

immunology↗

bioRxiv2024

A mathematical framework for understanding the spontaneous emergence of complexity applicable to growing multicellular systems

In embryonic development and organogenesis, cells sharing identical genetic codes acquire diverse gene expression states in a highly reproducible spatial distribution, crucial for multicellular formation and quantifiable through positional information. To understand the spontaneous growth of complexity, we constructed a one-dimensional division-decision model, simulating the growth of cells with identical genetic networks from a single cell. Our findings highlight the pivotal role of cell division in providing positional cues, escorting the system toward states rich in information. Moreover, we pinpointed lateral inhibition as a critical mechanism translating spatial contacts into gene expression. Our model demonstrates that the spatial arrangement resulting from cell division, combined with cell lineages, imparts positional information, specifying multiple cell states with increased complexity--illustrated through examples in C.elegans. This study constitutes a foundational step in comprehending developmental intricacies, paving the way for future quantitative formulations to construct synthetic multicellular patterns.

systems biology↗

bioRxiv2024

Resistance genes are distinct in protein-protein interaction networks according to drug class and gene mobility

With growing calls for increased surveillance of antibiotic resistance as an escalating global health threat, improved bioinformatic tools are needed for tracking antibiotic resistance genes (ARGs) across One Health domains. Most studies to date profile ARGs using sequence homology, but such approaches provide limited information about the broader context or function of the ARG in bacterial genomes. Here we introduce a new pipeline for identifying ARGs in genomic data that employs machine learning analysis of Protein-Protein Interaction Networks (PPINs) as a means to improve predictions of ARGs while also providing vital information about the context, such as gene mobility. A random forest model was trained to effectively differentiate between ARGs and nonARGs and was validated using the PPINs of ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter cloacae), which represent urgent threats to human health because they tend to be multi-antibiotic resistant. The pipeline exhibited robustness in discriminating ARGs from nonARGs, achieving an average area under the precision-recall curve of 88%. We further identified that the neighbors of ARGs, i.e., genes connected to ARGs by only one edge, were disproportionately associated with mobile genetic elements, which is consistent with the understanding that ARGs tend to be mobile compared to randomly sampled genes in the PPINs. This pipeline showcases the utility of PPINs in discerning distinctive characteristics of ARGs within a broader genomic context and in differentiating ARGs from nonARGs through network-based attributes and interaction patterns. The code for running the pipeline is publicly available at https://github.com/NazifaMoumi/PPI-ARG-ESKAPE

bioinformatics↗

bioRxiv2024

Mesenchymal stem cell-derived extracellular vesicles attenuate symptoms in dextran sodium sulfate-induced ulcerative colitis mouse model

Inflammatory bowel disease (IBD) refers to a group of multifactorial and chronic inflammation affecting intestinal tract. Based on the pathogenic mechanisms, IBD mainly comprised of two categories: ulcerative colitis (UC) and Crohns disease (CD). In this study, we established a dextran sulfate sodium (DSS)-induced colitis model to mimic UC. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) as therapeutic vectors have shown regenerating effect of damaged tissues. Here, intravenous administration of MSC-EVs ameliorated IBD symptoms including gaining weight, reducing disease activity index and restoring colon length. In addition, the protective effect of MSC-EVs were demonstrated by repairing colon mucosa and reducing the infiltration of macrophages in submucosa. Collectively, MSC-EV shows a therapeutic potential for IBD.

physiology↗

bioRxiv2024

Genomic insights into photosymbiotic evolution in Tridacna squamosa

Photosymbiosis is fundamental driving force for ecological success of benthic coral reef ecosystems, and contributing to their biodiversity and resilience. As a benchmark organism indicative of reef health, the fluted giant clam (Tridacna squamosa) forms an exemplary photosymbiotic relationship with the symbiont Symbiodiniaceae dinoflagellates, whose initiation and maturation require finely coordinated interactions. However, much of the origin and dynamics of this reciprocal interplay remains unclarified. Here, we report the first complete whole genome of T. squamosa, in conjunction with integrated multi-omics data, to illuminate the key evolutionary innovations and molecular events supporting the establishment and maintenance of photosymbiotic lifestyle in the giant clam. Programmed regulation of symbiont recognition, host immune system and GPCRs signaling activation co-contributed to dinoflagellates acquisition in T. squamosa larvae. Adaptive metabolic remodeling in the host siphonal mantle, a photosymbiotic niche, is critical to maintain the robustness of phtosymbiosis. T. squamosa has expanded light sensing gene family and evolved sophisticated signaling pathways to protect against UV photo-damage. Evidence also supports significant contribution of positive selection to host DNA-repair. Overall, our study here offers fresh mechanistic insights into the parallel evolution and molecular machinery of photosymbiosis in the giant clam-dinoflagellates duet, with implications for devising solutions to sustainable conservation.

evolutionary biology↗

bioRxiv2024

Both the transcriptional activator, Bcd, and transcriptional repressor, Cic, form small mobile oligomeric clusters in early fly embryo nuclei

Transcription factors play an essential role in pattern formation during early embryo development, generating a strikingly fast and precise transcriptional response that results in sharp gene expression boundaries. To characterize the steps leading up to transcription, we performed a side-by-side comparison of the nuclear dynamics of two morphogens, a transcriptional activator, Bicoid (Bcd), and a transcriptional repressor, Capicua (Cic), both involved in body patterning along the anterior-posterior axis of the early Drosophila embryo. We used a combination of fluorescence recovery after photobleaching, fluorescence correlation spectroscopy, and single particle tracking to access a wide range of dynamical timescales. Despite their opposite effects on gene transcription, we find that Bcd and Cic have very similar nuclear dynamics, characterized by the co-existence of a freely diffusing monomer population with a number of oligomeric clusters, which range from low stoichiometry and high mobility clusters to larger, DNA-bound hubs. Our observations are consistent with the inclusion of both Bcd and Cic into transcriptional hubs or condensates, while putting constraints on the mechanism by which these form. These results fit in with the recent proposal that many transcription factors might share a common search strategy for target genes regulatory regions that makes use of their large unstructured regions, and may eventually help explain how the transcriptional response they elicit can be at the same time so fast and so precise. SIGNIFICANCEBy conducting a comparative study of the nuclear dynamics of Bicoid (a transcriptional activator) and Capicua (a transcriptional repressor) in the Drosophila embryo, we have uncovered a striking similarity in their behaviours. Despite their divergent roles in transcription, both proteins have a propensity to form oligomeric species ranging from highly mobile, low stoichiometry clusters to larger, DNA-bound hubs. Such findings impose new constraints on the existing models of gene regulation by transcription factors, particularly in aspects related to target search and oligomeric binding to gene regulatory regions needed to explain the rapid and precise transcriptional response observed in developmental processes.

biophysics↗

bioRxiv2024

Using split protein reassembly strategy to optically control PLD enzymatic activity

Phospholipase D (PLD) and phosphatidic acid (PA) play a spatio-temporal role in regulating diverse cellular activities. Although current methodologies enable optical control of the subcellular localization of PLD and by which influence local PLD enzyme activity, the overexpression of PLD elevates the basal PLD enzyme activity and further leads to increased PA levels in cells. In this study, we employed a split protein reassembly strategy and optogenetic techniques to modify superPLD (developed by Jeremy Baskin group). We splited this variants into two HKD domains and fused these domains with optogenetic and chemogenetic elements and by which we achieved control of the two HKD interaction and then restored the PLD enzymatic activity.

cell biology↗

bioRxiv2024

Discovery of orally active SARS-CoV-2 papain-like protease (PLpro) inhibitors

Vaccines and first-generation antiviral therapeutics have provided important protection against coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, there remains a need for additional therapeutic options that provide enhanced efficacy and protection against potential viral resistance. The SARS-CoV-2 papain-like protease (PLpro) is one of two essential cysteine proteases involved in viral replication. While inhibitors of the SARS-CoV-2 main protease (Mpro) have demonstrated clinical efficacy, known PLpro inhibitors have to date lacked the inhibitory potency and requisite pharmacokinetics to demonstrate that targeting PLpro translates to in vivo efficacy in a preclinical setting. Herein, we report the machine learning-driven discovery of potent, selective, and orally available SARS-CoV-2 PLpro inhibitors, with lead compound PF-07957472 (4) providing robust efficacy in a mouse-adapted model of COVID-19 infection.

microbiology↗

bioRxiv2024

Optimisation of the extraction process of naringin dihydrochalcone and its effect on reducing blood lipid levels in vitro

Response surface methodology (RSM) was used to optimize the extraction process of naringin. The central component design included three parameters of extraction, namely, temperature (X1), solid-liquid ratio (X2), and extraction time (X3). The optimum extraction temperature was 67; the ratio of material to liquid was 54:1mL/g, and the extraction time was 2.8h. According to the best extraction conditions, naringin was processed to verify the accuracy of the model. Five parallel experiments were set up, and a yield of 32.48 mg/g naringin was obtained, that was equivalent to the predicted yield of 32.56 mg/g. Naringin was purified to obtain naringin-refined products using DM101 macroporous adsorption resin. Naringin dihydrochalcone was synthesized following catalytic hydrogenation of purified naringin. The structures of naringin and naringin dihydrochalcone were determined via Fourier infrared spectrometer and nuclear magnetic resonance spectrometry. Evaluate the ability of naringin dihydrochalcone to bind with glycine bile sodium and bovine bile sodium by simulating the gastrointestinal environment in vitro. Further focusing on HepG2 cells, a high cholesterol induced high-fat HepG2 cell model was established. We measured the effects of different concentrations of naringin dihydrochalcone on intracellular lipids in denatured HepG2 cells and further validated the lipid-lowering effect of naringin at the cellular level. The results showed that naringin dihydrochalcone has potential application in functional foods for lowering blood lipids.

biochemistry↗

bioRxiv2024

Genomic features of NF1-associated peripheral nerve sheath tumors: a cohort analysis from the Johns Hopkins NF1 biospecimen repository

Neurofibromatosis type 1 (NF1) is an inherited neurocutaneous condition that predisposes to the development of peripheral nerve sheath tumors (PNST) including cutaneous neurofibromas (CNF), plexiform neurofibromas (PNF), atypical neurofibromatous neoplasms with unknown biological potential (ANNUBP), and malignant peripheral nerve sheath tumors (MPNST). The successful advancement of therapeutic development for NF1-associated PNST necessitates the systematic acquisition and analysis of human tumor specimens and their corresponding model systems. RNA sequencing (RNAseq) and whole exome sequencing (WES) data were generated from 73 and 114 primary human tumor samples, respectively. These pre-processed data, standardized for immediate computational analysis, are accessible through the NF Data Portal, allowing immediate interrogation. This analysis combines new and previously released samples, offering a comprehensive view of the entire cohort sequenced. As a dedicated effort to systematically bank tumor samples from people with NF1, in collaboration with molecular geneticists and computational biologists to advance understanding of NF1 biology, the Johns Hopkins NF1 biospecimen repository offers access to samples and genomic data to promote advancement of NF1-related therapies.

bioinformatics↗

bioRxiv2024

WRKY1 confers resistance to powdery mildew by accelerating SAR and preventing over-immunity in apple.

Powdery mildew is one of the most serious diseases in apple production. SAR has a broad-spectrum immunity in plants against pathogen. Plants activate SAR against pathogen invasion and also prevent over-immunity. The relevant mechanism is still unknown in apple. In this study, we isolated and identified powdery mildew pathogen from the field and preserved them on the apple tissue culture seedlings. We performed DAP-seq of powdery mildew-inducible WRKY40. WRKY40 positively regulates NPR3like by directly binding to the W-box element of its promoter. NPR3like represses the expression of the PR1 gene in the presence of SA by competing with TGA2 for binding to NPR1. WRKY1 positively regulates WRKY40 by directly binding to the dual W-box element of its promoter, while WRKY1 positively regulates NPR3like by directly binding to the W-box element of its promoter. The expression trends of WRKY1, WRKY40, and NPR3like were basically the same as that of PR1 within 24 h after powdery mildew and SA treatments. Besides, WRKY1 increased SA content by positively regulating EPS1. After inoculation with powdery mildew, the up-regulation of PR1 in RNAi-silenced plants of WRKY1 was more slowly compared with the wild type, and the number of spores and mycelium increased significantly. In summary, we established a new model of NPR3like inhibition of NPR1 activity positively regulated by the WRKY1-WRKY40 module and found that the WRKY1-EPS1 module accelerated the up-regulation of PR1 by increasing the SA content. Finally, we elucidated WRKY1 confers resistance to powdery mildew by accelerating SAR and preventing over-immunity in apple.

molecular biology↗

bioRxiv2024

Superagers resist typical age-related white matter structural changes

Superagers are elderly individuals with the memory ability of people 30 years younger and provide evidence that age-related cognitive decline is not inevitable. In a sample of 64 superagers (mean age 81.9; 59% women) and 55 typical older adults (mean age 82.4; 64% women) from the Vallecas Project, we studied, cross-sectionally and longitudinally over 5 years with yearly follow-ups, the global cerebral white matter status as well as region-specific white matter microstructure assessment derived from diffusivity measures. Superagers and typical older adults showed no difference in global white matter health (total white matter volume, Fazekas score, and lesions volume) cross-sectionally or longitudinally. However, analyses of diffusion parameters revealed better white matter microstructure in superagers than in typical older adults. Cross-sectional differences showed higher fractional anisotropy (FA) in superagers mostly in frontal fibres and lower mean diffusivity (MD) in most white matter tracts, expressed as an anteroposterior gradient with greater group differences in anterior tracts. FA decrease over time is slower in superagers than in typical older adults in all white matter tracts assessed, which is mirrored by MD increases over time being slower in superagers than in typical older adults in all white matter tracts except for the corticospinal tract, the uncinate fasciculus and the forceps minor. The better preservation of white matter microstructure in superagers relative to typical older adults supports resistance to age-related brain structural changes as a mechanism underpinning the remarkable memory capacity of superagers, while their regional ageing pattern is in line with the last-in-first-out hypothesis. SIGNIFICANCE STATEMENTEpisodic memory is one of the cognitive abilities most vulnerable to ageing. Although memory normally declines with age, some older people may have memory performance similar to that of people 30 years younger, and this phenomenon is often conceptualised as superageing. Understanding the superager phenotype can provide insights into mechanisms of protection against age-related memory loss and dementia. We studied the white matter structure of a large sample of 64 superagers over the age of 80 and 55 age-matched typical older adults during 5 years with yearly follow-ups showing evidence of slower age-related changes in the brains of superagers especially in protracted maturation tracts, indicating resistance to age-related changes and a regional ageing pattern in line with the last-in-first-out hypothesis.

neuroscience↗

bioRxiv2024

Identifying new cancer genes based on the integration of annotated gene sets via hypergraph neural networks

MotivationIdentifying cancer genes remains a significant challenge in cancer genomics research. Annotated gene sets encode functional associations among multiple genes, and cancer genes have been shown to cluster in hallmark signaling pathways and biological processes. The knowledge of annotated gene sets is critical for discovering cancer genes but remains to be fully exploited. ResultsHere, we present the DIsease-Specific Hypergraph neural network (DISHyper), a hypergraph-based computational method that integrates the knowledge from multiple types of annotated gene sets to predict cancer genes. First, our benchmark results demonstrate that DISHyper outperforms the existing state-of-the-art methods and highlight the advantages of employing hypergraphs for representing annotated gene sets. Second, we validate the accuracy of DISHyper-predicted cancer genes using functional validation results and multiple independent functional genomics data. Third, our model predicts 44 novel cancer genes, and subsequent analysis shows their significant associations with multiple types of cancers. Overall, our study provides a new perspective for discovering cancer genes and reveals previously undiscovered cancer genes. AvailabilityDISHyper is freely available for download at https://github.com/genemine/DISHyper. Contactjxwang@mail.csu.edu.cn

systems biology↗

bioRxiv2024

Selective attention modulates feature accumulation speed during perception and memory retrieval

Mounting evidence indicates that information processing in the visual hierarchy follows a sequential progression from low-level perceptual to high-level conceptual features during visual perception, with the reverse order during memory retrieval. However, the nature of this hierarchical processing and its modulation by selective attention remains unclear. By integrating a deep neural network with the drift-diffusion model on reaction time data, we identified parallel processing of perceptual and conceptual features during perception, rather than sequential processing. The slower reaction times observed in conceptual tasks compared to perceptual tasks were primarily driven by the larger decision boundary and longer non-decision time associated with conceptual features, which could not be compensated by their faster evidence accumulation rates. Using single-trial multivariate decoding of MEG (magnetoencephalography) data to examine the timing of neural representations of different features, we found that selective attention reversed the onset times of perceptual and conceptual features in the occipital and parietal lobes during perception. This led to earlier detection of conceptual features compared to perceptual features in the animacy and size tasks. During retrieval, the colour task exhibited earlier peak times for perceptual features compared to conceptual features in the frontal lobe, indicating that perceptual features were reconstructed with the highest fidelity before conceptual features. These findings provide novel insights into the hierarchical nature of information processing during perception and retrieval, emphasizing the crucial role of selective attention in modulating the speed of feature information accumulation.

neuroscience↗