Biology subjects

Zhang, Q.

Publications and source records attributed to Zhang, Q..

At least 217 records · Page 12Linked to original sources

bioRxiv2025

A spatiotemporal cancer cell trajectory underlies glioblastoma heterogeneity

Cancer cells display highly heterogeneous and plastic states in glioblastoma, an incurable brain tumour. However, how these malignant states arise and whether they follow defined cellular trajectories across tumours is poorly understood. Here, we generated a deep single cell and spatial multi-omic atlas of human glioblastoma that pairs transcriptomic, epigenomic and genomic profiling of 12 tumours across multiple regions. We identify that glioblastoma heterogeneity is driven by spatially-patterned transitions of cancer cells from developmental-like states towards those defined by a glial injury response and hypoxia. This cellular trajectory regionalises tumours into distinct tissue niches and manifests in a molecularly conserved manner across tumours as well as genetically distinct tumour subclones. Moreover, using a new deep learning framework to map cancer cell states jointly with clones in situ, we show that tumour subclones are finely spatially intermixed through glioblastoma tissue niches. Finally, we show that this cancer cell trajectory is intimately linked to myeloid heterogeneity and unfolds across regionalised myeloid signalling environments. Our findings define a stereotyped trajectory of cancer cells in glioblastoma and unify glioblastoma tumour heterogeneity into a tractable cellular and tissue framework.

cancer biology↗

bioRxiv2025

An intercellular signaling pathway in the mouse retina connects Kv2.1, GLT-1, and nitric oxide synthase 1 to optic nerve regeneration

We report here that a multicellular signaling pathway in the mouse retina targeting glutamate homeostasis and nitric oxide production is activated upon optic nerve injury and modulates reti-nal ganglion cells (RGCs) ability to mount a robust regenerative response. A novel highly sen-sitive and specific NO sensor (FL2) revealed that optic nerve injury leads to a rapid, prolonged elevation of NO in the inner retina. Amacrine cell-specific genetic deletion of the neuron-specific isoform of nitric oxide synthase (NOS1, nNOS) or the NOS1 inhibitor N(w)-propyl-L-arginine (L-NPA) suppressed optic nerve regeneration. Steps leading to NOS1 activation are shown to in-clude Kv2.1 phosphorylation and activation, reversal of glutamate uptake by the glutamate transporter GLT-1 (EAAT2), and subsequent NMDA receptor activation. Conditional knockout of the glutamate transporter GLT-1 in bipolar cells, intraocular injection of the GLT-1 blockers dihydrokainate (DHK) or WAY213613, the N-methyl-D-aspartate (NMDA) receptor antagonist D-2-amino-5-phosphonovalerate (D-AP5), or the Kv2.1 blockers RY796 or stromatoxin all sup-pressed NO generation and strongly diminished RGCs ability to respond to Pten deletion and other factors. Thus, optic nerve injury activates a sequence of pathophysiological changes in retinal interneurons that gates RGCs ability to regenerate injured axons. Significance StatementCells use extracellular signals to coordinate responses to injury and to promote repair and re-generation. The NMDA receptor, which has a high affinity for glutamate and is functionally cou-pled to nitric oxide synthase, has the potential to mediate such responses by responding to changes in extracellular glutamate. In the mouse retina after optic nerve injury, potassium channels in retinal ganglion cells, glutamate transporters in neighboring cells, and NMDA recep-tors in amacrine cells, are all involved in a pathway that regulates the generation of nitric oxide, which we show promotes axon regeneration after injury.

neuroscience↗

bioRxiv2025

Synaptic Toxicity of OGA Inhibitors and the Failure of Ceperognastat

O-GlcNAcase inhibitors (OGAi) have been proposed as therapeutics for Alzheimers disease due to their ability to increase O-GlcNAcylation of tau and reduce its aggregation. However, the recent failure of ceperognastat in a Phase II trial--marked by accelerated cognitive decline in the treatment arm--has raised concerns about the safety of this therapeutic class. Here, we evaluated the acute synaptic effects of three structurally distinct OGAi (ceperognastat, ASN90, and MK8719) in mouse hippocampal slices. Electrophysiological recordings revealed that all three compounds impaired both short- and long-term synaptic plasticity, as evidenced by reduced paired-pulse facilitation/depression and suppressed long-term potentiation. Immunohistochemistry showed altered synaptic protein levels, with increased PSD-95 and reduced Synaptophysin 1 in neurons, alongside a biphasic shift in Tau phosphorylation. These findings indicate that OGAi produce rapid and convergent synaptotoxic effects across pre- and postsynaptic compartments, likely reflecting a class-wide mechanism. We argue that electrophysiological screening should be standard in CNS drug development and caution against targeting essential synaptic processes in chronic neurodegenerative conditions.

pharmacology and toxicology↗

bioRxiv2025

Hidden in plain sight: Bacterial genomes reveal thousands of lytic phages with therapeutic potential

Phages are typically classified as temperate, integrating into host genomes, or lytic, replicating and killing bacteria. Lytic phages are not expected in bacterial genome sequences, yet our analysis of 3.6 million bacterial assemblies from 1,226 species revealed >100,000 complete lytic phage genomes, which we term Bacterial Assembly-associated Phage Sequences (BAPS). This represents a [~]five-fold increase in the number of phages with known hosts and fundamentally reshapes our understanding of phage biology. Identifying BAPS has enabled the discovery of entirely novel phage clusters, including clusters distantly related to Salmonella Goslarviruses in E. coli, and Shigella, while significantly expanding known genera such as Seoulvirus (from 16 to >300 members). Notably, close relatives of therapeutic lytic phages were also detected, suggesting clinical isolate sequencing unknowingly archives viable phage candidates. The discovery of complete, lytic phage genomes within bacterial assemblies challenges long-standing assumptions and reveals a vast, untapped reservoir of phages.

microbiology↗

bioRxiv2025

Uev1A counteracts oncogenic Ras stimuli in both polyploid and diploid cells

Oncogenic Ras is known to induce DNA replication stress, leading to cellular senescence or death. In contrast, we found that it can also trigger polyploid Drosophila ovarian nurse cells to die by inducing aberrant division stress. To explore intrinsic protective mechanisms against this specific form of cellular stress, here we conducted a genome-wide genetic screen and identified the E2 enzyme Uev1A as a key protector. Reducing its expression levels exacerbates the nurse cell death induced by oncogenic Ras, while overexpressing it or its human homologs, UBE2V1 and UBE2V2, mitigates this effect. Although Uev1A is primarily known for its non-proteolytic functions, our studies demonstrate that it collaborates with the E3 APC/C complex to mediate the proteasomal degradation of Cyclin A, a key cyclin that drives cell division. Furthermore, Uev1A and UBE2V1/2 also counteract oncogenic Ras-driven tumorigenesis in diploid cells, suppressing the overgrowth of germline tumors in Drosophila and human colorectal tumor xenografts in nude mice, respectively. Remarkably, elevated expression levels of UBE2V1/2 correlate with improved survival rates in human colorectal cancer patients harboring oncogenic KRAS mutations, indicating that their upregulation could represent a promising therapeutic strategy.

cell biology↗

bioRxiv2025

Two telomere-to-telomere, gap-free genome assemblies and comparisons revealed the conserved key genes associated with sugar accumulation in Rubus genus

For the first time, we assembled two highly continuous, completely gap-free reference genomes of the Rubus subgenus: Rubus hirsutus Thunb. Penglei (XMM) and Rubus eustephanos Focke ex Diels Dahongpao (DHP), which are widely distributed in southern China with similar phenotypic traits (Figures 1A, 1B, and Figure S1), yet ripe fruits display distinct sugar accumulation levels (Table S1), making them ideal candidates for investigating the mechanisms underlying sugar accumulation in the Rubus genus. The XMM (213.53 Mb, 28,204 genes) and DHP (218.26 Mb, 28,569 genes) genomes exhibit close evolutionary relationships, diverging approximately 3.21 Mya. Comparative genomics identified extensive synteny, interspecific structural variations (translocations, inversions, segmental duplications), and presence/absence variation (PAV). Using Hi-C interaction heatmaps and Sanger sequencing, we validated interspecific structural inversions. Additionally, we identified a sugar transporter gene (MFS1), which is present in XMM but absent in DHP. Combined analysis of the gene family expansion/contraction and transcriptome identified two conserved key genes (RhSTP13 and RhSTP7) associated with sugar accumulation in Rubus genus and displayed distinct roles through transient expression assay. To facilitate functional genomics study, we also established a comprehensive Rubus database, RubusDB, a freely accessible repository consolidating all genomic, transcriptomic and phenotypic data of Rubus genus. These findings provide a foundational framework for elucidating the genetic basis of sugar accumulation, genome diversification, and trait improvement in Rubus species. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=170 SRC="FIGDIR/small/646780v2_fig1.gif" ALT="Figure 1"> View larger version (72K): org.highwire.dtl.DTLVardef@1baca20org.highwire.dtl.DTLVardef@2c01eaorg.highwire.dtl.DTLVardef@131dc00org.highwire.dtl.DTLVardef@62a04f_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFIGURE 1.C_FLOATNO Phenotypic characterization, de novo genome assemblies, variation, and evolution of Rubus hirsutus Thunb. Penglei (XMM) and Rubus eustephanos Focke ex Diels Dahongpao (DHP). (A) Illustration of XMM whole plants, stem, flower bud and flower, respectively. (B) Illustration of DHP whole plants, stem, flower bud and flower, respectively. (C) The chromosome karyotype analysis of XMM. Bar = 10 {micro}m. (D) Circular diagram of XMM and DHP reference genomes. (a) Chromosomes are represented by centromeres (dark red) and telomeres (blue); (b) CEN18 density; (c) CEN17 density; (d) Gene density; (e) TE density; (f) PAV density; (g) SNP density; (h) Collinear lines at the center of diagram highlight homoeologous chromosomes relationships and non-homoeologous regions. (E) Genomic alignments between XMM and DHP. Inversions, duplications and translocations are marked with orange, blue and green ribbons, respectively. (F) Identification of large inversions in chromosome 7 between XMM and DHP. The three heatmaps show the chromatin interaction matrix, including mapping Hi-C data of DHP against DHP genome (left), mapping Hi-C data of DHP against XMM genome (middle) and mapping Hi-C data of XMM against XMM genome (right). The lower panel illustrates gene alignments between XMM and DHP. (G) Synteny, structural rearrangements, monomer, and identity distribution in the 16-20 Mbp region of chromosome 6 between XMM and DHP. (H) Local genome synteny of chromosome 5, with a structural variation that is present only in XMM. The PAV region includes a gene related to sugar transporter (MFS1, XMM05G025540). (I) Gene-level matchings of MFS genes in the PAVs region between XMM and DHP. (J) Phylogenetic relationships and divergence times between raspberries and other Rosaceae species. The black numbers close to the divergence nodes indicate the divergence times and the red bars represent the 95% confidence intervals. The red and black numbers indicate expanded and contracted ortholog groups at the corresponding node. Scale bar corresponds to 10 Mya. C_FIG

genomics↗

bioRxiv2025

Spatial Transcriptomics Unveils the Blueprint of Mammalian Lung Development

Mammalian lung development is a complex, highly orchestrated process involving the precise coordination of diverse cell types. Despite significant advances, the spatial gene expression patterns and regulatory mechanisms within the developmental niches of different lung structures remain incompletely understood. In this study, we present a comprehensive spatial transcriptomic atlas of mouse lung development, spanning from the early pseudoglandular to the alveolar stage. We further uncover transcription factor (TF) regulation landscapes by integrating spatial epigenome, including novel TF-eRegulons critical for epithelial progenitors during early lung development. Our analysis also identifies hundreds of spatiotemporally dynamic cell-cell communications, such as BMP8B-mediated ligand-receptor signaling enriched in airway branching. Notably, we delineate the distinct developmental trajectories of alveolar AT1 and AT2 cells and reveal that collagen pathways facilitate their spatial convergence, forming primary alveoli during the canalicular-saccular transition. Together, this spatial transcriptomic atlas provides a foundational resource for understanding the complex cellular and molecular orchestration underlying mammalian lung development.

developmental biology↗

bioRxiv2025

A heart releasing neuropeptide that synchronizes brain-heart regulation during courtship behavior

Distinct internal states drive varied animal behaviors, yet the mechanisms by which non-neuronal factors encode these states remain largely unknown. Here, we show that cardiac activity regulates internal mating states through a conserved brain-heart axis in male flies and mice. In Drosophila, a ppk23-P1 pathway triggers heart rate acceleration upon female perception via crustacean cardioactive peptide, while the heart secretes ion transport peptide that feeds back onto P1 neurons to enhance courtship. Ejaculation rapidly decreases heart rate via Corazonin, mitigating prolonged tachycardia. In mice, a conserved Substance P-TacR1 pathway modulates courtship. Finally, we developed a computational framework to decode internal mating states from cardiac physiology, revealing distinct cardiac signatures. Our findings unveil a novel role for heart-derived neuropeptides in internal state regulation, elucidate a positive feedback loop between the heart and brain, and demonstrate the evolutionary conservation of the brain-heart axis in orchestrating dynamic behavioral and physiological states.

neuroscience↗

bioRxiv2025

Glycolysis-enhancing alpha 1-adrenergic antagonists are neuroprotective in Alzheimers disease

Terazosin (TZ) is an 1-adrenergic receptor antagonist that enhances glycolysis by activating the enzyme phosphoglycerate kinase 1 (PGK1). Epidemiological data suggest that TZ may be neuroprotective in Parkinsons disease and in dementia with Lewy bodies and that glycolysis-enhancing drugs might be protective in other neurodegenerative diseases involving protein aggregation, such as Alzheimers disease (AD). We investigated TZ in AD and report four main results. First, we found that TZ increased ATP levels in a Saccharomyces cerevisiae mutant with impaired energy homeostasis and reduced the aggregation of the AD-associated protein, amyloid beta (A{beta}) 42. Second, in an AD transgenic mouse model (5xFAD) we found that TZ attenuated amyloid pathology in the hippocampus and rescued cognitive impairments in spatial memory and interval timing behavioral assays. Third, using the Alzheimers Disease Neuroimaging Initiative (ADNI) database, we found that AD patients newly started on TZ or related glycolysis-enhancing drugs had a slower progression of both cognitive dysfunction and neuroimaging biomarkers, such as 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), a measure of brain metabolism. Finally, in a large human administrative dataset, we found that patients taking TZ or related glycolysis-enhancing drugs had a lower hazard of being diagnosed with AD compared to those taking tamsulosin or 5-alpha reductase inhibitors. These data further implicate metabolism in neurodegenerative diseases and suggest that glycolysis-enhancing drugs may be neuroprotective in AD.

neuroscience↗

bioRxiv2025

A differentiated and durable allogeneic strategy applicable to cell therapies

Autologous T cell therapies have shown profound clinical responses; however, their widespread use has been limited primarily due to their individualized manufacturing requirements. To develop a persistent "off-the-shelf" allogeneic (Allo) approach, a multiplex Nme2Cas9-based cytosine base editor was deployed to knockout select HLA Class I and II alleles (HLA-A, HLA-B, and the class II transactivator (CIITA)), while retaining HLA-C to protect from NK cell rejection. Matching the residual HLA-C allele from homozygous donors to the host prevented rejection of the donor T cells by allogeneic host T and NK cells. Site-specific integration of a tumor-specific CAR or TCR into the TRAC locus using SpyCas9 nuclease and an adeno-associated virus (AAV) template allowed for high localized insertion rate while simultaneously removing the endogenous TCR and preventing GvHD. Using a lipid nanoparticle (LNP)-based delivery system of the editing components enabled a robust cell engineering process, achieving high editing rates and cell expansion. These allogeneic T cells demonstrated comparable functional activity to their autologous counterparts in preclinical assays. Moreover, this gene editing approach generated cells with minimal chromosomal aberrations. The Allo strategy has also been applied to induced pluripotent stem cells (iPSCs), suggesting potential applications in regenerative medicine applications.

bioengineering↗

bioRxiv2025

Computational Modeling of the Biphasic Depletion of Ovarian Follicle Reserve and the Chemical Effects on Ovarian Aging

IntroductionHuman ovaries begin development in utero. Through oogenesis, the numbers of oocytes and primordial follicles peak to a few million during fetal development, then decline to hundreds of thousands per ovary at birth. These primordial follicles do not regenerate and are thus regarded as the ovarian reserve. Over the life course, the reserve continues to deplete, due to atresia and activation, until menopause when about 1000 primordial follicles remain. Exposure to chemotherapy drugs and environmental pollutants can accelerate follicular depletion potentially leading to a greater risk of early menopause, primary ovarian insufficiency (POI), and infertility. Physiologically, the ovarian reserve is depleted in a seemingly biphasic pattern - a slow steady decline from birth to mid-30s, followed by a faster decline to menopause which typically occurs around age 50 years. While this depletion pattern has been described with empirical mathematical formulations, rarely is it modeled mechanistically. A mechanic model that can characterize the dynamics of follicular depletion throughout the life course will help researchers better understand and predict the impact of chemical exposures on ovarian aging. MethodsHere we propose a minimal mechanistic model, which includes (1) a zero-order feedforward inhibition of primordial follicle activation by a local autocrine/paracrine inhibitory factor secreted by the primordial follicles, and (2) a high-gain feedback inhibition of primordial follicle activation by the anti-Mullerian hormone (AMH) secreted by the growing (primary, secondary, and early antral) follicles. The model is configured such that the two regulatory processes prevent primordial follicles from premature overactivation in early and late reproductive life stages, respectively. Two exposure scenarios - chemo-drugs/radiation and tobacco smoke - are presented to demonstrate predictive robustness and biological plausibility of chemically induced increases in cellular atresia. ResultsOur model recapitulates the biphasic depletion curve and predicts a constant supply of growing follicles through most of the active reproductive lifespan. This model predicts that the size of the initial primordial follicle pool plays the most significant role in determining menopausal age and suggests that unilateral ovariectomy may have a more attenuated effect than expected. Simulations of transient exposure to chemotherapy drugs provide an exposure example for promoting atresia of primordial and/or growing follicles and suggest exposure at earlier ages have greater impact on ovarian reserve and menopausal timing than exposure at later ages. Also, simulations of chronic chemical exposures suggest that chemicals which directly promote primordial follicle atresia are more damaging than chemicals directly promoting growing follicle atresia or inhibiting AMH, potentially leading to earlier age at menopause. A specific scenario of chronic exposure to cigarette smoke of various intensities was simulated to validate the prediction power of the model. ConclusionsThe ovary may have compensatory factors to extend reproductive age as long as possible amid insults that reduce the primordial follicle pool. The timing of these insults are likely an important variable. Future elaborations of such mechanistically based computational modeling with integration of in vitro toxicity testing data may help scaling efforts in predicting the implications of reproductive toxicants on ovarian aging.

systems biology↗

bioRxiv2025

Relative contributions of the ERG11VF125AL and MRR1AN647T mutations to fluconazole resistance in Clade III Candidozyma (Candida) auris clinical isolates

ObjectivesCandidozyma (Candida) auris is an emerging fungal pathogen of global concern that often exhibits multi-drug resistance. Over 90% of isolates are resistant to fluconazole. Of the six described clades of C. auris, Clade III has been found to be nearly universally fluconazole resistant and almost every Clade III isolate described carries a mutation in the gene encoding the fluconazole target sterol demethylase (ERG11) leading to a VF125AL substitution and a mutation leading to a N647T substitution in the gene encoding Mrr1a, a transcriptional regulator of the Mdr1 transporter. Both mutations have been shown to contribute to fluconazole resistance in C. auris. MethodsIn the present study we introduced the Clade III MRR1A mutation into a Clade I background using CRISPR-Cas9 gene editing. In two Clade III clinical isolates we corrected the native MRR1A and ERG11 mutations to their wild-type sequences as well as disrupted MDR1. Triazole susceptibilities and MDR1 gene expression were measured in all strains. ResultsIntroduction of the N647T substitution in a Clade I background confers a modest reduction in fluconazole and voriconazole susceptibility. Similarly, correction of MRR1A or disruption of MDR1 in each Clade III background resulted in a one-dilution decrease in fluconazole and voriconazole MIC while the ERG11 correction resulted in a three-dilution decrease in fluconazole and voriconazole MIC. ConclusionsOur findings show that while the MRR1A mutation makes a modest contribution, the ERG11 mutation is responsible for most of the fluconazole resistance observed in Clade III isolates. We also show that while these mutations likewise affect voriconazole susceptibility, they have no effect on susceptibility to itraconazole, isavuconazole, or posaconazole suggesting the potential therapeutic utility of these antifungals for infections due to Clade III isolates of C. auris.

microbiology↗

bioRxiv2025

Construction of Complete Telomere-to-Telomere Genome Assembly of the Rabbit Using Haploid Embryonic Stem Cells

The rabbit owns commercial importance in meat and fur production, and also has long served as a valuable animal model in biomedical research. Yet, the complete assembly of a high-quality rabbit reference genome has not been established. Here, we present a telomere-to-telomere (T2T) genome assembly of the New Zealand White (NZW) rabbit, the most complete and accurate rabbit genome to date. Using a haploid embryonic stem cells (haESCs) to overcame the challenges of homologous sequence interference and structural variation, we generate a genome with a contig N50 of 137.71 Mb, anchoring all chromosomes with only three gaps, through integrating long-read sequencing (PacBio HiFi, Oxford Nanopore), Hi-C, and Illumina data. Quality assessments reveal near-complete coverage of the BUSCO mammalian gene set, with 99.61% completeness. Notably, this complete assembly allowed for the first comprehensive annotation of the rabbit immunoglobulin loci and major histocompatibility complex region, which were previously unresolved in earlier genome versions. The NZW-T2T assembly based on haESCs not only provides a critical resource for advancing rabbit-based research, but also set a new benchmark for de novo genome assembly for other animals with complex genome.

genomics↗

bioRxiv2025

Deletion of Nrf1α promotes glutamine addiction of HepG2 cells and thus enhances its apoptosis caused by glutamine deprivation

Glutamine metabolism plays a central role in regulating uncontrolled growth of tumor (exhibiting glutamine addiction) by modulating bioenergetics and redox homeostasis, as well as serving as a precursor for biomass synthesis. Thus, limiting its availability is becoming a potential therapeutic strategy. Since Nrf1 is an indispensable determinant of mitochondrial homeostasis through the integration of a multilevel regulatory network for redox balance, no reports on the regulatory role of Nrf1 in glutamine addiction emerged hitherto. In this study, we found that glutamine deprivation leads to mitochondrial morphological and functional damage, reduced GSH levels, increased ROS, and rapid death of Nrf1-knockout HepG2 cells. A series of further experiments revealed that such rapid death of Nrf1-deficient cells from glutamine deprivation is caused by different ways. Loss of Nrf1 results in an obvious enhancement of glycolysis and fatty acid synthesis, leading to extensive catabolism of glutamine into -KG within mitochondria; the -KG reverses TCA cycles to generate citrate, which exits to the cytosol for fatty acid synthesis. Simultaneously, increased expression of xCT together with decreased expression of GLUL leads to elevated extracellular efflux of glutamate and reduced capacity for glutamine synthesis. These factors intensify glutamine addiction of Nrf1-null cells, with reducing GSH synthesis and increasing ROS levels due to dysfunctional mitochondria, ultimately leading to enhanced cell death upon glutamine deprivation. Overall, such insights into Nrf1s role in cancer glutamine metabolism are conducive to developing much specific preventive and therapeutic strategies by precision Nrf1-targeting anti-tumorigenesis.

biochemistry↗

bioRxiv2025

FACED 2.0 enables large-scale voltage and calcium imaging in vivo

Monitoring neuronal activity at large scale and high spatiotemporal resolution is crucial for understanding information processing within the brain. We optimized a kilohertz-frame-rate two-photon fluorescence microscope with all-optical megahertz line-scan rate to achieve ultrafast imaging across large areas and volumes at subcellular resolution. Applying this technique to voltage and calcium imaging in vivo, we demonstrated simultaneous recording of voltage activity over 200 neurons and calcium activity over 14,000 neurons.

neuroscience↗

bioRxiv2025

Protein Secretion From Liver Ex Vivo Reveals Regulation of Hepatokines by Sex and Circadian Rhythm

Here, we use an ex vivo approach compatible with the circadian timescale to interrogate protein secretion from liver, revealing several findings. Proteomic analyses in male and female mice identify hundreds of proteins that exhibit time-of-day-dependent or clock-dependent secretion involved in extracellular matrix, immune, redox, xenobiotic, and fatty acid functions. Among these, the liver secretes more endostatin, a cleavage product of collagen type XVIII alpha 1 (COL18A1), during the inactive, fasting phase of the diurnal cycle. Temporal regulation of COL18A1/endostatin is dysregulated upon loss of Bmal1 through combined effects on Col18a1 transcriptional repression and proteolytic processing. Functional experiments in vivo and in vitro reveal that endostatin suppresses mitochondrial gene expression in white adipose tissue in a time-dependent manner and reduces mitochondrial respiration in adipocytes, while enhancing lipolysis. These results support a mechanism of inter-organ crosstalk whereby hepatically derived, temporally-restricted endostatin tunes adipocytes toward metabolic activities required during the fasting phase.

molecular biology↗

bioRxiv2025

Discovery of The Clinical Candidate S-892216: A Second-Generation of SARS-CoV-2 3CL Protease Inhibitor for Treating COVID-19

The coronavirus disease 2019 (COVID-19) pandemic crisis has been mitigated by worldwide efforts to develop vaccines and therapeutic drugs. However, there remains concern regarding public health and an unmet need for therapeutic options. Herein, we report the discovery of S-892216, a second-generation SARS-CoV-2 3C-like protease (3CLpro) inhibitor, to treat COVID-19. S-892216 is a reversible covalent 3CLpro inhibitor with highly potent antiviral activity and an EC50 value of 2.48 nM against SARS-CoV-2 infected cells. Structure-based design of a covalent modifier for compound 1 revealed that introducing a nitrile warhead increased 3CLpro inhibition activity by 180-fold. Subsequent optimization efforts yielded S-892216, which combined a favorable pharmacokinetic profile and high off-target selectivity. S-892216 exhibited antiviral activity against diverse SARS-CoV-2 variants, with no cross-resistance to major mutations reducing antiviral activities of nirmatrelvir and ensitrelvir. In SARS-CoV-2-infected mice, S-892216 inhibited viral replication in the lungs similar to ensitrelvir, although at a 30-fold lower dose.

biochemistry↗

bioRxiv2025

Interactive effect of Moringa oleifera mediated green nanoparticles and arbuscular mycorrhizal fungi on growth, root system architecture, and nutrient uptake in maize (Zea mays L.)

The synergistic interaction between green nanoparticles (NPs) and mycorrhizal fungi promotes plant growth by improving nutrient absorption, optimizing root function, and stress resistance. In this study, we explored the impact of arbuscular mycorrhizal fungus (AMF) Funnaliformis mosseae and Moringa oleifera mediated green NPs viz; iron oxide (FeO), zinc oxide (ZnO), and Zn doped FeO (Zn/Fe) NPs, both individually and in combination, on maize growth, root system architecture, organic acids production, mycorrhizal colonization, and nutrients uptake. Prior to NP synthesis, metabolomic analysis of Moringa oleifera leaves was conducted to characterize its bioactive compounds. The structural properties of green synthesized NPs confirmed by characterization using scanning electron microscopy (SEM), Fourier transform infrared (FTIR) spectroscopy, UV-Vis spectrophotometry, and X-ray diffraction (XRD). The results showed that all individual and combined treatments of AMF and green NPs significantly enhanced maize growth compared to the control. Among the single NP treatments, Zn/Fe NPs exhibited superior performance over FeO and ZnO. However, when combined with AMF, ZnO and Zn/Fe NPs induced the highest growth responses than FeO NPs. The ZnO NPs proved most compatibility with AMF for improving colonization in maize roots, whereas FeO and Zn/Fe NPs reduced colonization efficiency. Furthermore, combination of AMF and ZnO NPs (AMF+ ZnO) noted as most prominent treatment for improvement of maize growth compared to other all treatments, highlighting the potential of AMF+ ZnO NPs for sustainable agricultural applications.

plant biology↗