Biology subjects

Zhang, Z.

Publications and source records attributed to Zhang, Z..

At least 667 records · Page 37Linked to original sources

bioRxiv2024

Antimicrobial Profile from Frog Skin Peptides

This study evaluates the antimicrobial efficacy of frog skin-derived peptides Magainin 1, Magainin 2, and Bombesin against Bacillus subtilis, Escherichia coli, and Trichoderma harzianum. Experimental setups involved uniform inoculation of the microorganisms on 20 mL agar plates, treated with varying volumes (1.5 {micro}L, 5 {micro}L, and 10 {micro}L) of each peptide (10 mg/mL). For Bacillus subtilis, Magainin 2, and Bombesin demonstrated significant antibacterial activity, with inhibition zones increasing in size proportionally to the peptide volumes. Magainin 2 showed the highest efficacy, surpassing ampicillin at higher volumes. In Escherichia coli, similar dose-dependent antibacterial effects were observed, with Magainin 2 again showing superior performance, matching or exceeding the inhibition zones of ampicillin. Notably, Magainin 2, and Bombesin exhibited antifungal activity against Trichoderma harzianum with Amphotericin resistance. These antibacterial peptides show inhibitory activity on fungi, gram-positive higher than gram-negative bacteria. These findings highlight the potential of Magainin 2, and Bombesin as antimicrobial agents except of Magainin 1.

microbiology↗

bioRxiv2024

Inhibition of serine racemase prevents diabetic retinopathy

Retinal diabetic neuropathy (RDN) precedes retinal microvascular pathology in diabetic retinopathy (DR), but the therapy by antagonizing RDN to stall DR is rare. Emerging evidence including ours suggest that serine racemase (SRR) drives DR at least by promoting RDN. Thus, we explore the therapy by antagonizing SRR to stall and treat DR. We herein indicate that inhibition of SRR by oral gavage of l-aspartic acid {beta}-hydroxymate (L-ABH), a competitive inhibitor of SRR, mitigated photoreceptor dysfunction, loss of retinal ganglion cells (RGC) and retinal endothelial cell and pericyte in db/db mice, a type II diabetes model. To dissect the mechanism, intravitreal injection of L-ABH mitigates glutamate-induced neurotoxicity in the retina. In the whole body, gastrointestinal-based delivery of L-ABH maintained euglycemia and improved glucose tolerance either in db/db mice or in diet-induced obesity mice. In conclusion, inhibition of SRR prevented retinal neurovascular abnormalities in diabetic animals through executing neuroprotection in the retina and maintaining glucose homeostasis in the system. Our study reveals a novel strategy to prevent DR.

biochemistry↗

bioRxiv2024

Stochastic Gene Expression in Proliferating Cells: Differing Noise Intensity in Single-Cell and Population Perspectives

Random fluctuations (noise) in gene expression can be studied from two complementary perspectives: following expression in a single cell over time or comparing expression between cells in a proliferating population at a given time. Here, we systematically investigated scenarios where both perspectives lead to different levels of noise in a given gene product. We first consider a stable protein, whose concentration is diluted by cellular growth, and the protein inhibits growth at high concentrations, establishing a positive feedback loop. For a stochastic model with molecular bursting of gene products, we analytically predict and contrast the steady-state distributions of protein concentration in both frameworks. Although positive feedback amplifies the noise in expression, this amplification is much higher in the population framework compared to following a single cell over time. We also study other processes that lead to different noise levels even in the absence of such dilution-based feedback. When considering randomness in the partitioning of molecules between daughters during mitosis, we find that in the single-cell perspective, the noise in protein concentration is independent of noise in the cell cycle duration. In contrast, partitioning noise is amplified in the population perspective by increasing randomness in cell-cycle time. Overall, our results show that the commonly used single-cell framework that does not account for proliferating cells can, in some cases, underestimate the noise in gene product levels. These results have important implications for studying the inter-cellular variation of different stress-related expression programs across cell types that are known to inhibit cellular growth.

systems biology↗

bioRxiv2024

Genomic evolution reshapes cell type diversification in the amniote brain

Over 320 million years of evolution, amniotes have developed complex brains and cognition through largely unexplored genetic and gene expression mechanisms. We created a comprehensive single-cell atlas of over 1.3 million cells from the telencephalon and cerebellum of turtles, zebra finches, pigeons, mice, and macaques, employing single-cell resolution spatial transcriptomics to validate gene expression patterns across species. Our study revealed significant species-specific variations in cell types, highlighting their conservation and diversification in evolution. We found pronounced differences in telencephalon excitatory neurons (EX) and cerebellar cell types between birds and mammals. Birds predominantly express SLC17A6 in EX, whereas mammals expressed SLC17A7 in neocortex and SLC17A6 elsewhere, possibly due to loss of SLC17A7 function loss in birds. Additionally, we identified a novel bird-specific Purkinje cell subtype (SVIL+), implicating the LSD11/KDM1A pathway in learning and circadian rhythms, and related numerous positively selected genes in birds, suggesting an evolutionary optimization of cerebellar functions for ecological and behavioral adaptation. Our findings elucidate the complex interplay between genetic evolution and environmental adaptation, underscoring the role of genetic diversification in the development of specialized cell types across amniotes.

evolutionary biology↗

bioRxiv2024

Central nucleus of the amygdala to medial prefrontal cortex 5-HTergic neural circuit modulates the recovery of consciousness during sevoflurane anesthesia

Preoperative anxiety and depression are significant risk factors for prolonged general anesthesia emergence, raising postoperative complications and mortality. However, the neural mechanisms underlying this association remain unclear, limiting effective interventions and development of effective preventive and therapeutic strategies. Previous studies have shown that sleep-wakefulness neural circuit is closely related to neural circuitry of anesthesia recovery, with 5-Hydroxytryptamine (5-HT) playing a pivotal role of anesthesia arousal. Herein, we utilized pharmacology, optogenetics, chemogenetics, fiber photometry and retrograde tracing to demonstrate that activation of the 5-HTergic neural circuit between the central amygdala (CeA) and medial prefrontal cortex (mPFC) accelerates recovery from sevoflurane anesthesia. Particularly for individuals with anxiety- and depression-like symptoms, who exhibit more severe delayed emergence, it is necessary to enhance 5-HT neuronal activity by further optimizing parameters. To further validate the reliability of our findings and the specificity of viral tools, we successfully bred TPH2-Cre transgenic mice and repeated key experiments, which robustly confirmed all original conclusions. Pharmacological experiments further demonstrated that both 5-HTA and 5-HT2A receptors mediate the pro-arousal function of this circuit. Collectively, our study identifies a key CeA-mPFC serotonergic pathway linking emotional disorders to abnormal anesthetic emergence, providing potential targets for optimizing anesthesia management in vulnerable patients. HighlightsO_LIBoosting the 5-HTergic neural circuit between the CeA and mPFC promotes emergence from sevoflurane anesthesia, with 5-HT1A and 5-HT2A receptors playing a critical role in modulating consciousness transitions. C_LIO_LIPreoperative anxiety and depression exacerbate delayed emergence from anesthesia, highlighting the need for targeted interventions. C_LIO_LIDeciphering the aberrant neurocircuitry mechanisms underlying delayed emergence to inversely deduce the neurocircuitry principles of normal physiology represents a pathological-to-physiological research paradigm. C_LIO_LIStepwise enhancement of intervention parameters reverses delayed emergence in pathological states. C_LIO_LITailored activation of the 5-HTergic circuit offers a novel approach to mitigate complications from delayed emergence in vulnerable patient populations. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=172 SRC="FIGDIR/small/599720v3_ufig1.gif" ALT="Figure 1"> View larger version (61K): org.highwire.dtl.DTLVardef@589b26org.highwire.dtl.DTLVardef@13204fforg.highwire.dtl.DTLVardef@e6374dorg.highwire.dtl.DTLVardef@38cac0_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2024

Hepatic lipopolysaccharide binding protein partially uncouples inflammation from fibrosis in MAFLD

Non-alcoholic fatty liver disease (NAFLD), recently renamed metabolic-associated fatty liver disease (MAFLD), is the most common liver disease worldwide. The progression to fibrosis, occurring against a backdrop of hepatic steatosis and inflammation, critically determines liver-related morbidity and mortality. Inflammatory processes contribute to various stages of MAFLD and thought to instigate hepatic fibrosis. For this reason, targeting inflammation has been heavily nominated as a strategy to mitigate liver fibrosis. Lipopolysaccharide binding protein (LBP) is a secreted protein that plays an established role in innate immune responses. Here, using adoptive transfer studies and tissue-specific deletion models we show that hepatocytes are the dominant contributors to circulating LBP. In a murine model of MAFLD, hepatocyte-specific deletion of LBP restrained hepatic inflammation and improved liver function abnormalities, but not measures of fibrosis. Human studies, including genetic evidence, corroborate an important role for LBP in hepatic inflammation with minimal impact on fibrosis. Collectively, our data argues against the idea that targeting hepatic inflammation is a viable approach to reducing fibrosis.

physiology↗

bioRxiv2024

Molecular basis of Ad5-nCoV Vaccine-Induced Immunogenicity

In response to coronavirus disease 2019 (COVID-19), numerous vaccines have been developed to protect against SARS-CoV-2 infection. Ad5-nCoV (Convidecia) is a vaccine listed for emergency use by the WHO and has been administrated to millions of people globally. It comprises a series of human adenovirus 5 (Ad5) replication-incompetent vectored vaccines that transduce the spike protein (S) gene of various SARS-CoV-2 strains. Despite promising clinical data demonstrating its safety and effectiveness, the underlying molecular mechanism of its high immunogenicity and incidence of adverse reactions remains less understood. Here we combined cryo-ET, fluorescence microscopy and mass spectrometry to characterize the in situ structures, density and site-specific glycan compositions of the Ad5-nCoV_Wu and Ad5-nCoV_O vaccine-induced S antigens, which encode the unmodified SARS-CoV-2 Wuhan-Hu-1 S gene and optimized Omicron S gene, respectively. We found that the vaccine-induced S are structurally intact, antigenic and densely distributed on the cell membrane. Compared to Ad5-nCoV_Wu induced S, the Ad5-nCoV_O induced S demonstrate significantly better stability and is less likely to induce syncytia among inoculated cells. Our work demonstrated that Ad5-nCoV is a prominent platform for antigen induction and cryo-ET can be a useful technique for vaccine characterization and development.

biophysics↗

bioRxiv2024

A comparative study of the cryo-EM structures of S. cerevisiae and human anaphase-promoting complex/cyclosome (APC/C)

The anaphase-promoting complex/cyclosome (APC/C) is a large multi-subunit E3 ubiquitin ligase that controls progression through the cell cycle by orchestrating the timely proteolysis of mitotic cyclins and other cell cycle regulatory proteins. Although structures of multiple human APC/C complexes have been extensively studied over the past decade, the S. cerevisiae APC/C has been less extensively investigated. Here, we describe medium resolution structures of three S. cerevisiae APC/C complexes: unphosphorylated apo-APC/C and the ternary APC/CCDH1-substrate complex, and phosphorylated apo-APC/C. Whereas the overall architectures of human and S. cerevisiae APC/C are conserved, as well as the mechanism of CDH1 inhibition by CDK-phosphorylation, specific variations exist, including striking differences in the mechanism of coactivator-mediated stimulation of E2 binding, and the activation of APC/CCDC20 by phosphorylation. In contrast to human APC/C in which coactivator induces a conformational change of the catalytic module APC2:APC11 to allow E2 binding, in S. cerevisiae apo-APC/C the catalytic module is already positioned to bind E2. Furthermore, we find no evidence of a phospho-regulatable auto-inhibitory segment of APC1, that in the unphosphorylated human APC/C, sterically blocks the CDC20C-box binding site of APC8. Thus, although the functions of APC/C are conserved from S. cerevisiae to humans, molecular details relating to their regulatory mechanisms differ.

molecular biology↗

bioRxiv2024

Os-circANK negatively regulates resistance to bacterial blight in rice via Osa-miR398b/OsCSD1/OsCSD2 pathways

CircRNAs are widely present in plants, yet there have been no reports on the role of circRNA in the regulatory mechanisms of interactions between rice and pathogenic bacteria. As the sequence of circRNAs matches the parent gene except for the back splicing site, there is no feasible way to specifically knockdown circRNAs in plants. We identified a circRNA, named Os-circANK, derived from an ankyrin repeat protein, which was significantly downregulated post Xanthomonas oryzae pv. oryzae (Xoo) inoculation. We have created a CRISPR-Cas13d system to specifically knockdown a plant circular RNA, resulting in genetically edited rice with a targeted decrease in Os-circANK expression. Os-circANK was found to function as a sponge for Osa-miR398b, suppressing the cleavage of OsCSD1/OsCSD2 by Osa-miR398b, leading to a reduction in ROS levels following Xoo infection and a negative regulation of resistance to bacterial blight in rice. Our findings demonstrate that Os-circANK inhibits the resistance to bacterial blight in rice via the Osa-miR398b/OsCSD1/OsCSD2 pathways.

microbiology↗

bioRxiv2024

Human transcription factor combinations mapped by genome-wide footprinting with deaminase

An individuals somatic cells have the same genome but exhibit cell-type-specific transcriptome regulated by a combination of transcription factors (TFs) for each gene. Mapping of TF sites on the human genome is critically important for understanding functional genomics. Here we report a novel technique to measure human TFs binding sites genome-wide with single-base resolution by footprinting with deaminase (FOODIE). Single-molecule sequencing reads from thousands of cells after in situ deamination yielded site-specific TF binding fractions and the cooperativity among adjacent TFs. In a human lymphoblastoid cell line, we found that genes in a correlated gene module (CGM) share TF(s) in their cis-regulatory elements to participate a particular biological function. Finally, single-cell resolved experiments (scFOODIE) allow cell-type-specific TF footprinting in heterogeneous brain tissues.

genomics↗

bioRxiv2024

Single-cell analysis of ovarian myeloid cells identifies aging associated changes in macrophages and signaling dynamics

The aging of mammalian ovary is accompanied by an increase in tissue fibrosis and heightened inflammation. Myeloid cells, including macrophages, monocytes, dendritic cells, and neutrophils, play pivotal roles in shaping the ovarian tissue microenvironment and regulating inflammatory responses. However, a comprehensive understanding of the roles of these cells in the ovarian aging process is lacking. To bridge this knowledge gap, we utilized single-cell RNA sequencing (scRNAseq) and flow cytometry analysis to functionally characterize CD45+ CD11b+ myeloid cell populations in young (3 months old) and aged (14-17 months old) murine ovaries. Our dataset unveiled the presence of five ovarian macrophage subsets, including a Cx3cr1lowCd81hi subset unique to the aged murine ovary. Most notably, our data revealed significant alterations in ANNEXIN and TGF{beta} signaling within aged ovarian myeloid cells, which suggest a novel mechanism contributing to the onset and progression of aging-associated inflammation and fibrosis in the ovarian tissue.

immunology↗

bioRxiv2024

Defining cellular determinants of resistance to PD-1 pathway blockade in non-small-cell lung cancer

Despite sustained clinical responses to immune-checkpoint blockade (ICB) therapies in non-small-cell lung cancer (NSCLC), the majority of patients derive no clinical benefits, and the cellular and molecular underpinnings of such resistance remain incompletely understood. To identify cell types that may influence immunotherapy responses, we first integrated newly generated and previously published single-cell RNA sequencing data from 110 treatment-naive patients with NSCLC. Among tumor-resident cell types, we identified MMP1+ cancer-associated fibroblasts (CAFs), which were inversely correlated with the level of tumor-reactive T cells--a key determinant of response to ICB. Further single-cell analysis for newly collected 21 tumor samples from NSCLC patients treated with anti-PD-1/PD-L1 agents revealed that MMP1+ fibroblasts were indeed enriched in treatment-refractory patients, and this observation was also validated in an independent dataset of bulk RNA sequencing from 344 NSCLC patients treated with PD-L1 agents. Examination of the spatial architecture showed that MMP1+ fibroblasts were located at the tumor-stroma boundary, forming a single-cell layer that encircled the cancer cell aggregates, and we hence defined MMP1+ fibroblasts as tumor-stroma boundary (tsb)CAFs. Such tsbCAFs likely promote resistance to ICB by functioning as a physical barrier that prevents tumor-reactive T cells from recognizing and killing cancer cells. Our study provides a new framework to identify cellular underpinnings of resistance to ICB and suggests new strategies to overcome ICB resistance. Highlights{lozenge} Identification and characterization of MMP1+ fibroblasts in lung cancer. {lozenge}Single-cell meta-analysis reveals cell populations impeding the accumulation of tumor-reactive T cells. {lozenge}MMP1+ fibroblasts correlate with the low infiltration of tumor-reactive T cells and the resistance to anti-PD-1/PD-L1 treatment. {lozenge}MMP1+ fibroblasts appear to form a space barrier between malignant and T cells.

immunology↗

bioRxiv2024

Horizontally acquired CSP genes contribute to wheat adaptation and improvement

Although horizontal gene transfer (HGT) often facilitates environmental adaptation of recipient organisms, whether and how they might affect crop evolution and domestication is unclear. Here we show that three genes encoding cold shock proteins (CSPs) were transferred from bacteria to the last common ancestor of Triticeae, a tribe of the grass family that includes several major staple crops such as wheat, barley, and rye. The acquired CSP genes in wheat (TaCSPs) are functionally conserved with their bacterial homologs by encoding a nucleic acid binding protein. Experimental evidence indicates that TaCSP genes positively regulate drought response and improve photosynthetic efficiency under water deficit conditions, by directly targeting a type 1 metallothionein gene to increase ROS scavenging, which in turn contributed to the geographic expansion of wheat. We identified an elite CSP haplotype in Aegilops-tauschii, introduction of which to wheat significantly increased drought tolerance, photosynthetic efficiency and grain yields. These findings not only provide major insights into the role of HGT in crop adaptation and domestication, but also demonstrate that novel microbial genes introduced through HGT offer a stable and naturally optimized resource for transgenic crop breeding and improvement.

plant biology↗

bioRxiv2024

AARS2 ameliorates myocardial ischemia via fine-tuning PKM2-mediated metabolism

AARS2, an alanyl-tRNA synthase, is essential for protein translation, but its function in mouse hearts is not fully addressed. Here, we found that cardiomyocyte-specific deletion of mouse AARS2 exhibited evident cardiomyopathy with impaired cardiac function, notable cardiac fibrosis and cardiomyocyte apoptosis. Cardiomyocyte-specific AARS2 overexpression in mice improved cardiac function and reduced cardiac fibrosis after myocardial infarction (MI), without affecting cardiomyocyte proliferation and coronary angiogenesis. Mechanistically, AARS2 overexpression suppressed cardiomyocyte apoptosis and mitochondrial reactive oxide species production, and changed cellular metabolism from oxidative phosphorylation toward glycolysis in cardiomyocytes, thus leading to cardiomyocyte survival from ischemia and hypoxia stress. Ribo-Seq revealed that AARS2 overexpression increased pyruvate kinase M2 (PKM2) protein translation and the ratio of PKM2 dimers to tetramers that promote glycolysis. Additionally, PKM2 activator TEPP-46 reversed cardiomyocyte apoptosis and cardiac fibrosis caused by AARS2 deficiency. Thus, this study demonstrates that AARS2 plays an essential role in protecting cardiomyocytes from ischemic pressure via fine-tuning PKM2-mediated energy metabolism, and presents a novel cardiac protective AARS2-PKM2 signaling during the pathogenesis of MI.

cell biology↗

bioRxiv2024

Loopsim: Enrichment Analysis of ChromosomeConformation Capture with Fast EmpiricalDistribution Simulation

SummaryGene regulation is intricately influenced by the three-dimensional organization of the genome. In particular, chromatin can exist in loop structures that enable long-range regulatory interactions. By utilizing chromosome conformation capture techniques such as Hi-C, valuable information regarding the organization of these loop structures in 3D space can be obtained. While functional/feature enrichment has become a standard downstream analysis for different genomic data to provide biological context, tools that developed specifically for high throughput assays capturing chromosome conformation are relatively limited. Here, we present Loopsim, a command-line application that performs enrichment analysis on Hi-C loop profiles against user-defined regions. Loopsim efficiently simulates a background distribution using a distinctive sampling approach that considers loop size, intervals, loop-loop distances, and structure; it then computes loop-level statistics based on the empirical null distribution. AvailabilityLoopsim is a Python package available via PyPI (https://pypi.org/project/loopsim) and the source code is available on GitHub (https://github.com/CutaneousBioinf/Loopsim) under the MIT license.

bioinformatics↗

bioRxiv2024

Natural killer cell migration in HIV-infected individuals is inhibited by impairment of HIF-1alpha-mediated glycolysis

Natural killer (NK) cells serve as the first line of defense of the immune system and play a crucial role in fighting against HIV infection. The effective function of NK cells is closely related to their migration ability, but the status of NK cell migration in HIV-infected individuals and the regulation mechanism for NK cell migration remains unknown. Here, we found that NK cell migration was significantly impaired in HIV-infected individuals, lower in immune non-responders (INRs) compared with immune responders (IRs), and positively correlated with CD4+ T cell counts. Further investigations showed that the decreased NK cell migration in HIV infection was caused by the impairment of glycolysis. Mechanistically, we found that NK cell migration was regulated by HIF-1 pathway, and inhibitory receptor TIGIT restrained HIF-1 expression by inhibiting PI3K/AKT/mTORC1 or ERK signaling pathway, consequently weakening the glycolysis of NK cells in HIV-infected individuals, and ultimately leading to down-regulation of migration. Collectively, we uncovered a mechanism of reduced NK cell migration in HIV infection and provided a new insight for immunotherapy in HIV infection. In BriefThe effective function of NK cells is closely related to its migration ability. The authors show that impaired NK cell migration in HIV-infected individuals is caused by TIGIT inhibiting HIF-1-mediated glycolysis via PI3K/AKT/mTORC1 or ERK pathway.

immunology↗

bioRxiv2024

Respiratory mucosal administration of DNA aptamer nanomaterials protects against antigenically diverse SARS-CoV-2 variants

The ongoing COVID-19 pandemic has highlighted the need for innovative therapeutic strategies to combat rapidly evolving pathogens that challenge the efficacy of traditional vaccines and monoclonal antibody treatments. Here, we explored the potential of TMSA52, a previously described homotrimeric DNA aptamer as a universal prophylactic and therapeutic agent against SARS-CoV-2. TMSA52 demonstrates exceptional binding affinities and broad neutralization against diverse SARS-CoV-2 variant spike proteins that are further enhanced through multimerization onto lamellar iridium nanoplates. Respiratory mucosal delivery of TMSA52 nanomaterials was well-tolerated. Surprisingly, TMSA52 offered potent protection from infection with ancestral SARS-CoV-2 on-par with monoclonal antibodies, and superior protection against antigenically distant SARS-CoV-2 variants. These findings establish DNA aptamers as a promising, cost-effective, and scalable alternative to traditional monoclonal antibody therapies. This study underscores the potential of aptamer-based platforms as a next-generation strategy to enhance global pandemic preparedness and expand our arsenal of infectious disease countermeasures.

immunology↗

bioRxiv2024

Femtosecond X-ray snapshots reveal correlated displacements of specific distal atoms in a protein crystal

Protein dynamics is shaped by interactions between thermal fluctuations, external forces, and molecular structures. Thermal fluctuations have high frequencies and are hence very challenging to quantify. We were able to record femtosecond X-ray diffraction snapshots and determine atomic displacements of crystalline bovine trypsin atoms either in the native steady state or in a transient state initiated by a short THz pulse, the results of which were interpreted with numerical simulations. In the absence of THz pulses, specific distal atoms exhibited correlated movements. Under the influence of THz fields, numerical simulations demonstrated a slight enhancement of displacement correlations. The experimental results revealed a contrasting response to short THz pulses, where the measured displacements were not solely determined by the atom position, but also influenced by the atomic type. These findings call for a reinterpretation of the dynamic properties inherent in folded protein structures and the physical principles behind the formation of protein assemblies. To this end, a theoretical model was developed for lattice deformations and local excitations entraining a (squeezed) coherent steady state, explaining the emergence of atom correlations. The model accounts for the magnitudes of atomic displacements and fluctuations through a balance between harmonic and anharmonic coupling forces.

biophysics↗