Biology subjects

Zhu, C.

Publications and source records attributed to Zhu, C..

At least 91 records · Page 5Linked to original sources

bioRxiv2025

A humanized 16A antibody conjugated with DNA topoisomerase I inhibitors, targeting a GSTA glycosite-signature epitope.

BackgroundWe previously reported the 16A antibody, which binds to the abnormally glycosylated tandem repeat region of the MUC1 glycoprotein, and developed 16A-MMAE as an antibody-drug conjugate. However, its antitumor efficacy as an antibody-drug conjugate with DNA topoisomerase Iinhibitors remains unknown. MethodsWe humanized the 16A antibody and conjugated it to DXd and MF6, two DNA topoisomerase I inhibitors. The antitumor efficacy of the conjugates was evaluated in vitro and in vivo. ResultsThe humanized 16A-DXd conjugate showed potent antitumoral efficacy, with an IC50 in the nM range against CFPAC1 cells. In vivo, h16A-DXd and h16A-MF6 inhibited tumor growth in asubcutaneous mouse tumor transplantation model using CT26-COSMC KO-hMUC1 cells, administered at a dose of 10 mg/kg. ConclusionsThe high antitumor efficacy of h16A-conjugated DNA topoisomerase I inhibitors supports further clinical development. The relatively low toxicity of h16A-DXd and h16A-MF6 may enable a higher therapeutic window, since MUC1-positive cells internalize the antibody-drug conjugate more efficiently.

pharmacology and toxicology↗

bioRxiv2025

The Global Wheat Full Semantic Organ Segmentation (GWFSS) dataset

Computer vision is increasingly used in farmers fields and agricultural experiments to quantify important traits. Imaging setups with a sub-millimetre ground sampling distance enable the detection and tracking of plant features, including size, shape, and colour. Although todays AI-driven foundation models segment almost any object in an image, they still fail for complex plant canopies. To improve model performance, the global wheat dataset consortium assembled a diverse set of images from experiments around the globe. After the head detection dataset (GWHD), the new dataset targets a full semantic segmentation (GWFSS) of wheat organs (leaves, stems and spikes) covering all developmental stages. Images were collected by 11 institutions using a wide range of imaging setups. Two datasets are provided: i) a set of 1096 diverse images in which all organs were labelled at the pixel level, and (ii) a dataset of 52,078 images without annotations available for additional training. The labelled set was used to train segmentation models based on DeepLabV3Plus and Segformer. Our Segformer model performed slightly better than DeepLabV3Plus with a mIOU for leaves and spikes of ca. 90%. However, the precision for stems with 54% was rather lower. The major advantages over published models are: i) the exclusion of weeds from the wheat canopy, ii) the detection of all wheat features including necrotic and senescent tissues and its separation from crop residues. This facilitates further development in classifying healthy vs. unhealthy tissue to address the increasing need for accurate quantification of senescence and diseases in wheat canopies.

plant biology↗

bioRxiv2025

Sex Differences in the Cancer Proteome

Proteins play a central role in cancer biology: they are the most common drug targets and biomarkers. Sex influences the proteome in many diseases, ranging from neurological to cardiovascular. In cancer, sex is associated with incidence, progression and therapeutic response, as well as characteristics of the tumour genome and transcriptome. The extent to which sex differences impact the cancer proteome remains largely unknown. To fill this gap, we quantified sex differences across 1,590 proteomes from eight cancer types, identifying 901 genes with sex-differential proteins abundance in adenocarcinomas of the lung, and 20 genes across five other tumour types: squamous cell carcinoma of the lung, hepatocellular carcinomas, clear cell cancers of the kidney, adenocarcinomas of the pancreas and glioblastoma. A subset of these protein differences could be rationalized by sex-differential copy number aberrations. Pathway analysis showed that male-biased proteins in lung adenocarcinoma were enriched in MYC and E2F target pathways. These findings highlight the modest impact of sex on the cancer proteome, but the very limited power of existing proteomics cohorts for these analyses.

cancer biology↗

bioRxiv2025

HighPlay：Cyclic Peptide Sequence Design Based on Reinforcement Learning and Protein Structure Prediction

The structural diversity and good biocompatibility of cyclic peptides has led to their emergence as potential therapeutic agents. Traditional cyclic peptide design relies on natural template modification and combinatorial chemical library screening, but suffers from bottlenecks such as limited molecular diversity, high cost, and time-consuming.AI technologies have improved design efficiency by predicting target binding patterns and generating scaffold structures, but they still require extensive laboratory screening. In this study, we propose HighPlay, which integrates reinforcement learning (Monte Carlo Tree Search) with the HighFold structure prediction model to design cyclic peptide sequences for protein targets, dynamically exploring the sequence space without the need of predefined target information. The model was applied to the design of cyclic peptide sequences for three different targets, which were screened and verified by molecular dynamics simulation, and showed good binding affinity. Specifically, the cyclic peptide sequences designed for TEAD4 target showed micromolar-level affinity in further experimental validation.

bioinformatics↗

bioRxiv2025

DMBT1 promotes SARS-CoV-2 infection and its SRCR-derived peptide inhibits SARS-CoV-2 infection

DMBT1 is a large scavenger receptor cysteine rich (SRCR) B protein that has been reported as a tumor suppressor gene and a co-receptor for HIV-1 infection. Here we found DMBT1 is a major mucosal protein bound to SARS-CoV-2. Overexpression of DMBT1 in 293T cells enhanced infection by SARS-CoV-2 in ACE2 dependent manner. Blocking experiments using overlapping peptide library of SRCR domain of DMBT1 showed that CQGRVEVLYRGSWGTV peptide, which contains bacteria-binding VEVLXXXXW motif, could inhibit SARS-CoV-2 infection. High concentration of the peptide can significantly inhibit the replication of SARS-CoV-2 in hamsters. Single cell sequencing analysis showed the highest expression abundance of DMBT1 at airway submucosal glands. These results demonstrate that membrane DMBT1 can promote SARS-CoV-2 infection, and serve as a candidate target for antiviral development. Author SummaryWe discovered that a protein named as DMBT1, which is found in our mucous membranes, plays a significant role in SARS-CoV-2 infection. DMBT1 is a large glycoprotein that has previously reported linked to tumor suppression and HIV-1 infection. Our single-cell sequencing analysis revealed that DMBT1 is most abundant in the airway submucosal glands. In our study, we found that when DMBT1 is overexpressed in cells, it enhances SARS-CoV-2 infection. Using a peptide library from DMBT1, we pinpointed a specific peptide, CQGRVEVLYRGSWGTV, which can inhibit SARS-CoV-2 infection. At high concentrations, it significantly reduces the viruss ability to replicate in hamsters. These findings suggest that DMBT1 on the cell membrane can promote SARS-CoV-2 infection and highlight DMBT1 as a potential target for developing antiviral treatments.

microbiology↗

bioRxiv2025

Microglia Adopt Temporally Specific Subtypes after Irradiation, Correlating with Neuronal Asynchrony

Cranial radiotherapy causes progressive neurocognitive impairments in cancer survivors. Neuroinflammation is a key contributor, but its dynamics and consequences for brain function remain poorly understood. Here, we performed comprehensive longitudinal profiling from 6 hours to 1 year after irradiation (IR) of the mouse hippocampus, using transcriptomic, protein, and histological analyses. We identified delayed microglial responses initiated by mitotic progression coupled interferon signaling. IR rewired the parenchymal phagocyte profiles, triggered by progressive microglial loss, failure of repopulation through self-renewal, and compensatory generation of microglia-like cells derived from peripheral monocytes. These findings were also observed in autopsied human brain. Finally, we demonstrate two phases of neuronal asynchrony, an early one associated with inflammation and a late one associated with aberrant synaptic regulation. These results provide comprehensive, longitudinal insights into microglia responses that can aid in tailoring therapies to preserve cognition in cancer survivors.

neuroscience↗

bioRxiv2025

Sex Differences in Cancer Functional Genomics: Gene Dependency and Drug Sensitivity

Patient sex influences a wide range of cancer phenotypes, including prevalence, response to therapy and survival endpoints. Molecular sex differences across the central dogma have been identified that may drive these phenotypic differences. Despite a growing catalog of specific genomic, transcriptomic and proteomic sex differences in a range of cancer types, their functional consequences remain unclear. To assess how patient sex impacts cancer cell function, we evaluated 1,209 cell lines subjected to CRISPR knockout, RNAi knockdown or drug exposures. Despite limited statistical power, we identified pan- and per-cancer sex differences in gene essentiality in six sex-linked and fourteen autosomal genes, and in drug sensitivity for two compounds. These data expand our understanding of the propagation of sex-differing molecular features to functional outcomes, and their role in influencing patient phenotypes. They highlight the importance of considering sex-specific effects in mechanistic and functional studies.

cancer biology↗

bioRxiv2025

In Silico Discovery of Small Molecule Modulators Targeting Ebola Virus VP 35 and VP 40 protein

Ebola virus (EBoV) proteins VP35 and VP40 are acknowledged as significant pharmacological targets for disrupting viral replication, virion assembly, and the budding process from host cells. We employed molecular docking based throughput virtual screening (HTVS), standard precision (SP), and extra precision (XP) docking to discover candidate compounds. Subsequently, molecular dynamics simulations, and ADMET analyses to identify potential small molecular compounds that could inhibit the Ebola virus. Among 210,590 compounds from the SPECS database, we found the compounds AO-022/43452438, AN-465/43369333, and AN-465/43369198 were optimal candidates for the EBOV-VP35 protein, while AN-465/43369160, AN-465/4341136, and AN-465/43369952 also emerged as optimal compounds for the EBOV-VP40 protein. Furthermore, we employed the energy decomposition technique, MM-GB/SA, to identify the top ten amino acids that significantly contribute to the binding interactions. ADMET result implicated that the six compounds have potential druggability, but special attention should be given to AN-465/43369333 due to potential cardiac toxicity. In conclusions, the six compounds and their key interacting amino acid sites identified in this study may serve as a valuable platform for the future development of novel therapeutics targeting the Ebola virus.

bioinformatics↗

bioRxiv2025

A unique two-excipient heat stable tablet formulation of oral insulin: preliminary results

We report a novel formulation approach for development of a thermostable oral insulin tablet. Using freeze drying to form a heat stable tablet in a single-step process, we demonstrate hydroxypropyl beta cyclodextrin (HP-{beta}-CD) encapsulated lipophilic ion-pair complex of insulin using bile salt achieves intestinal absorption and sustained glucose levels. The tablets produced using this simple approach with only two excipients offer protection from enzymatic and stomach acid degradation and facilitate insulin uptake, without any need for specialized drug manufacturing or enteric coating. Insulin in this innovative formulation is thermotolerant, capable of maintaining stability even under heat stress at 30-40{degrees}C/65-75% RH. The convenient presentation of insulin as a thermostable oral tablet presents a low-cost scalable manufacturing method that simplifies the logistics of storage, transport, and distribution in any setting, including areas where cold storage maybe limited or unavailable. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=141 SRC="FIGDIR/small/635377v1_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@16b4b64org.highwire.dtl.DTLVardef@122c11forg.highwire.dtl.DTLVardef@b50c0borg.highwire.dtl.DTLVardef@29bf28_HPS_FORMAT_FIGEXP M_FIG Our unique formulation approach protects insulin from stomach and temperature induced degradation, improves intestinal permeability providing a sustained release of insulin for glycemic control. The freeze dried tablet product format is easily scalable and flexible, increasing accessibility across all populations. C_FIG

biochemistry↗

bioRxiv2025

Predicting the structures of cyclic peptides containing unnatural amino acids by HighFold2

Cyclic peptides containing unnatural amino acids possess many excellent properties and have become promising candidates in drug discovery. Therefore, accurately predicting the three-dimensional structures of cyclic peptides containing unnatural residues will significantly advance the development of cyclic peptide-based therapeutics. Although deep learning-based structural prediction models have made tremendous progress, these models still cannot predict the structures of cyclic peptides containing unnatural amino acids. To address this gap, we introduce a novel model, HighFold2, built upon the AlphaFold-Multimer framework. HighFold2 first extends the pre-defined rigid groups and their initial atomic coordinates from natural amino acids to unnatural amino acids, thus enabling structural prediction for these residues. Then, it incorporates an additional neural network to characterize the atom-level features of peptides, allowing for multi-scale modeling of peptide molecules while enabling the distinction between various unnatural amino acids. Besides, HighFold2 constructs a relative position encoding matrix for cyclic peptides based on different cyclization constraints. Except for training using spatial structures with unnatural amino acids, HighFold2 also parameterizes the unnatural amino acids to relax the predicted structure by energy minimization for clash elimination. Extensive empirical experiments demonstrate that HighFold2 can accurately predict the three-dimensional structures of cyclic peptide monomers containing unnatural amino acids and their complexes with proteins, with the median RMSD for C reaching 1.891 [A]. All these results indicate the effectiveness of HighFold2, representing a significant advancement in cyclic peptide-based drug discovery.

bioinformatics↗

bioRxiv2024

Dissociable neurofunctional and molecular characterizations of reward and punishment sensitivity

While the hyper-and hypo-reward or punishment sensitivities (RS, PS) have received considerable attention as prominent transdiagnostic features of psychopathology, the lack of an overarching neurobiological characterization currently limits their early identifications and neuromodulations. Here we combined microarray data from the Allen Human Brain Atlas with a multimodal fMRI approach to uncover the neurobiological signatures of RS and PS in a discovery-replication design (N=655 participants). Both RS and PS were mapped separately in the brain, with the intrinsic functional connectome in the fronto-striatal network encoding reward responsiveness, while the fronto-insular system was particularly engaged in punishment sensitivity. This dissociable functional connectome patterns related to RS and PS were also specific in differentiating decisions driven by social or monetary reward and punishment motivations. Further imaging transcriptomic analyses revealed that functional connectome variations for RS and PS were associated with topography of specific gene sets enriched in ontological pathways, including synaptic transmission, dopaminergic metabolism, immune response and stress adaptation. On the neurotransmitter level, the serotonin neuromodulator was identified as a pivotal hub regulating the intrinsic functional connectome patterns of RS and PS, with this process critically dependent on its interactions with dopaminergic, opioid and GABAergic systems. Overall, these findings indicate dissociable neural connectome mapping of RS and PS and highlight their linkage with transcriptomic profiles, which may offer valuable insights into the treatment evaluation for symptomatology relevant to reward/punishment processing deficits.

neuroscience↗

bioRxiv2024

Radiation damage behavior of soft matter in ultrafast cryo-electron microscopy (cryo-UEM)

Whether time-modulated pulsed-electron imaging in ultrafast electron microscopy (UEM) can mitigate the electron radiation damage that occurs to samples, is still controversial. The effectiveness of such mitigation effect and relevant potential application in cryo-EM remain to be explored. Herein, we built an ultrafast cryo-EM (cryo-UEM) device based on an ultrafast laser system. Using such equipment and the saturated aliphatic hydrocarbon compounds (C44H90), the fading curves of diffraction intensity and corresponding critical electron doses (Ne) of the samples were carefully measured under different imaging modes, temperatures, imaging dose rates and pulsed repetition rates. Our experimental results show that, the fading curves and Ne values of the C44H90 crystals are uncorrelated with the imaging electron dose rates and do not show dependence on the dose-rate effect. As the temperature decreased, the Ne values of the sample increased, indicating the cryoprotective effect on radiation damage to the samples. Surprisingly, at a constant temperature, the fading curves and Ne values of the sample in multi-electrons-packet and near-single-electron-packet pulsed modes are all approximately the same as those in conventional continuous electron-beam mode, even when the results are obtained at different pulsed repetition rates. These results show that the time-modulated pulsed electron beam does not seem to mitigate the electron radiation damage that occurs on samples. Our findings offer new insights and experimental basis for the radiation damage behavior of samples under electron beams, and provide guidance and inspiration for elucidating the fundamental principles of radiation damage.

biophysics↗

bioRxiv2024

TurboID-based proximity labeling identifies novel germline proteins that maintain E granule integrity and small RNA homeostasis in C. elegans

Germ granules are biomolecular condensates composed of RNA and proteins that play crucial roles in RNA metabolism and posttranscriptional gene regulation. C. elegans germ granules consist of at least seven distinct subcompartments, including P granules, Z granules, Mutator foci, SIMR foci, P-bodies, D granules and E granules. Among these condensates, the E granule, which is nonrandomly positioned within the germ granule, is required for the production of a specialized class of small interfering RNAs (siRNAs). However, the mechanisms underlying E granule formation and its functional significance remain largely unexplored. In this study, via the use of TurboID- based proximity labeling technology combined with an RNAi-based reverse genetic screen, we identified two novel components of the E granule, EGC-2/C27B7.5 and EGC-3/F59G1.8, which initiate E granule assembly. The depletion of EGC-2 or EGC- 3 disrupts the perinuclear localization of the EGO and PICS complexes, both of which are enriched in E granules and are required for E-class siRNA and piRNA biogenesis, respectively. Small RNAomic analyses revealed that both EGC-2 and EGC-3 promote the production of 5 E-class siRNA, whereas prohibiting piRNA maturation. Taken together, our results elucidate the roles of EGC-2 and EGC-3 in maintaining E granule integrity and small RNA homeostasis, and suggest that intracellular condensation may exert distinct regulatory effects on different biological processes. Additionally, the combination of proximity labeling technology and reverse genetic screening provides a robust strategy for studying the assembly of biomolecular condensates.

genetics↗

bioRxiv2024

Serum and Tear Autoantibodies from NOD and NOR Mice as Potential Diagnostic Indicators of Local and Systemic Inflammation in Sjögren's Disease

BackgroundSjogrens Disease (SjD) is an autoimmune disease characterized by lymphocytic infiltration of salivary and lacrimal glands (LG). The LG produces the protein-rich aqueous component of tears, and SjD-associated autoimmune dacryoadenitis (AD) may thus alter tear autoantibody composition. MethodsThe presence of tertiary lymphoid structures (TLS) in LG from two murine models of SjD-associated AD, male NOD and male NOR mice, were evaluated using immunofluorescence. IgG and IgA reactivity in serum and tears from these models were probed in three studies against a panel of 80-120 autoantigens using autoantibody microarrays relative to serum and tears from healthy male BALB/c mice. Data were analyzed by R package Limma. ResultsAnalysis of immunofluorescence in LG sections from both SjD models showed TLS. Only one autoantibody was significantly elevated in tears and serum in both SjD models across all studies. Three autoantibodies were significantly elevated in serum but not in tears in both SjD models across all studies. Conversely, six IgG and thirteen IgA autoantibodies (6 sharing the same autoantigen) were significantly elevated in tears but not serum in both SjD models. ConclusionNOD and NOR mice with SjD-associated AD have distinct autoantibody profiles in tears and serum. Tear IgA isotype autoantibodies showed a greater diversity than tear IgG autoantibodies. TLS observed in LG are a likely source of the tear autoantibodies.

immunology↗

bioRxiv2024

Unraveling transposable element-mediated regulatory landscape in diverse human immune cells

Transposable elements (TEs) are key contributors to genetic novelty. Despite increasing evidence of their importance, their roles in shaping the regulatory landscape of diverse immune cell populations remain largely unclear. Using single-cell multiome data from human peripheral blood mononuclear cells, we annotated the cell-specific cis-regulatory elements for major immune cell populations and identified a highly cell-specific signature of the overrepresented TE families. Focusing on monocytes that bear fast-evolving transcriptomes, we found that high proportions of their enhancers are TE-derived and bound by multiple pioneer transcription factors. Among them, we confirmed that the core myeloid regulator SPI1 can bind and regulate hundreds of TE-derived enhancers, which further affect the expression of adjacent immune genes. Additionally, interspecies comparison reveals that non-conserved monocyte enhancers are frequently generated by lineage-specific TE insertions, and correlate with the evolved gene expression between human and mouse. Overall, our study supports the importance of TEs in shaping the regulatory landscape of diverse immune cell populations.

genomics↗

bioRxiv2024

DNA topoisomerase I acts as supercoiling sensor for transcription elongation in E. coli

When DNA is transcribed to RNA, the DNA double helix is constantly unwound and rewound to provide access for RNA polymerase (RNAP). This induces DNA supercoiling as a function of transcript length due to over- and under-twisting of the DNA downstream and upstream of RNAP, respectively. Using single-particle cryo-EM and in vivo assays we investigated the relationship between bacterial RNAP and DNA Topoisomerase I (TopoI), which removes negative supercoils accumulating upstream of RNAP. TopoI binds to relaxed DNA upstream of RNAP in a manner suggesting a sensory role awaiting the formation of negative supercoils and involving a conformational switch in the functional domains of TopoI. On DNA substrates mimicking negatively supercoiled DNA, TopoI threads one strand into the active site for cleavage while binding the complementary strand with an auxiliary domain. We propose a comprehensive model for DNA relaxation in the context of a transcribing RNAP.

molecular biology↗

bioRxiv2024

Red sandstone surface microbiota: functional convergence despite taxonomic divergence under dispersal limitation and hetero selection

Understanding the role of microbiota on stone surface is essential for developing effective grottoes conservation strategies. However, ecological feature of microbial communities on stone surface have been rarely investigated systematically. In this study, we explored diversity, assembly, and functional profiles of microbial communities on the red sandstone surface of the Leshan Giant Buddha from microbial ecology perspective. The results show that Proteobacteria, Actinobacteria, Cyanobacteria, and Ascomycota are the dominant phyla. Fundamental metabolic pathways are maintained during the formation of visually distinguishable microbial communities, but gene profiles vary across microbial communities of different colors. Ecological modelling suggests that selective pressure from the harsh stone surface environment fostered the interplay of dispersal limitation and heterogeneous selection during community assembly. The assembly of visually distinct microbial communities is linked to a narrower ecological niche, higher proportion of habitat specialists, and sparser network structure. Microbial-mediated ammonium assimilation and nitrogen mineralization might be the two prominent processes that contribute to stone biodeterioration. This study deepens our understanding of the assembly mechanisms and functional potentials of microbial communities on stone cultural heritage surfaces, provides microbial ecological insights for the conservation of these cultural treasures. ImportanceMinimal systematically research on the ecological interpretation of stone biodeterioration. This study reports dispersal limitation and heterogeneous selection shape the microbial community assembly responsible for the biodeterioration of red sandstone. Furthermore, fundamental metabolic processes of microbial communities, such as ammonium assimilation and nitrogen mineralization, are identified as contributors to stone biodeterioration. This study improves our understanding of microbial community assembly and their functional roles, providing a microbial ecological basis for developing effective strategies for the conservation of stone cultural heritage.

ecology↗

bioRxiv2024

Evaluation of scalp-based targeting methods of DLPFC for TMS therapy: EEG cap F3, Beam F3, CPC F3, and adjusted Beam F3

BackgroundRepetitive transcranial magnetic stimulation targeting the left dorsolateral prefrontal cortex (DLPFC) offers a promising approach for treating depression. Scalp-based targeting methods, including EEG Cap, Beam F3, CPC F3, and adjusted Beam F3, have evolved to improve clinical application. ObejectivesTo evaluate and compare the accuracy, reliability, speed, and training efficacy of these four methods. MethodsThree trained technicians conducted repeated DLPFC targeting measurements on 10 3D-printed head models. Accuracy was assessed by calculating targeting error and electric field strength at the subgenual anterior cingulate cortex anti-correlated peak. Reliability was evaluated through inter- and intra-rater variability, and training efficacy was examined by comparing targeting errors between trained technicians and novices. ResultsCPC F3, Beam F3, and adjusted Beam F3 demonstrated comparable accuracy in terms of electric field strength, but CPC F3 had the lowest targeting error (4.2 mm). CPC F3 also exhibited the highest reliability (inter-rater variability at 3.3 mm, intra-rater variability at 2.3 mm). The EEG cap was the fastest method (80 seconds), while CPC F3 was faster than Beam F3 but slower than EEG Cap. No significant differences in targeting error between trained technicians and novices were noted with CPC F3 and adjusted Beam F3. ConclusionThe comparative analysis of four scalp-based targeting methods provides insights that can enhance clinical decision-making and the practical application. While accuracy among CPC F3, Beam F3, and adjusted Beam F3 was comparable, CPC F3 emerges as highly practical due to its significantly better reliability, training efficacy, moderate speed, and straightforward implementation.

neuroscience↗