Biology subjects

Mo, F.

Publications and source records attributed to Mo, F..

9 recordsLinked to original sources

bioRxiv2026

Integrating activation-induced costimulation and cytokine signals enhance TCR-based cell therapies

TCR-based cell therapies offer broad targeting of tumor antigens with high sensitivity but often low durability due to insufficient costimulation (signal 2) and cytokine (signal 3) support. To address this, we developed a dual stimulatory receptor (DSR) consisting of the 4-1BBL ectodomain fused to the thrombopoietin receptor (cMPL) endodomain. DSR engages 4-1BB that is transiently upregulated upon TCR stimulation eliciting signal 2 and simultaneously activates cMPL-driven STAT3/5 phosphorylation providing signal 3. DSR increases the expansion of T cells, preserving their effector function and an effector-associated transcriptional profile upon repeated antigen stimulation. DSR arming significantly improves in vivo antitumor activity of T cells redirected to cancer through engineered TCRs or soluble T-cell engagers in diverse xenograft tumor models by enhancing T cell expansion and persistence post-infusion. These results demonstrate broad utility and establish DSR as a modular receptor for the effective and synchronized delivery of signals 2 and 3 to support TCR-based immunotherapies.

immunology↗

bioRxiv2026

Self-Terminating Bilayer Hydrogel Actuators via Enzyme-Programmed Mechanical Feedback

Autonomous soft materials that can actuate, perform a function, and then self-terminate without external intervention remain difficult to realize. Here, a bilayer hydrogel actuator fabricated by digital light processing-based 3D bioprinter is introduced that couples rapid thermoresponsive deformation with slower enzyme-programmed mechanical feedback to achieve self-regulated shape transformation and autonomous recovery. The system integrates a poly(N-isopropylacrylamide) actuation layer with a bovine serum albumin-poly(ethylene glycol) diacrylate enzyme-programmed layer loaded with trypsin. Above the lower critical solution temperature, deswelling of the actuation layer generates a strain mismatch across the bilayer and drives rapid closure. In parallel, proteolytic cleavage of albumin domains progressively softens the enzyme-programmed layer, reduces interlayer constraint, and acts as an intrinsic mechanical off-switch that relaxes curvature and restores the open state. This materials logic enables sustained enzyme release, time-dependent modulus loss, and autonomous shape recovery without staged external triggers. As a proof-of-concept, this platform is implemented as a gastrointestinal-retentive hydrogel gripper for localized intestinal enzyme delivery, where it exhibits thermally triggered gripping, millinewton-scale gripping force, autonomous reopening, and robust ex vivo retention on porcine small intestine under dynamic motion. These findings establish enzyme-programmed mechanical feedback as a general design strategy for self-regulated soft actuators and therapeutic materials with built-in functional lifetimes.

bioengineering↗

bioRxiv2025

Mitochondrial clone tracing within spatially intact human tissues

Understanding tissue development and intra-tissue evolution requires the ability to trace clones in intact tissues coupled with high-plex molecular profiling preserving spatial context. However, current lineage tracing tools are incompatible with spatial omics. Here, we present SUMMIT (Spatially Unveiling Mitochondrial Mutations In Tissues), a spatially-resolved lineage tracing technology that integrates gene expression profiling with mitochondrial mutation-based clone identification. Unlike synthetic lineage recording methods, SUMMIT relies only on endogenous mutations and thus can be applied to human tissues. To address the compositional mixing of cell types within spatial spots, SUMMIT includes a rigorous statistical framework to confidently assign variants to specific cell subpopulations and achieves high power for spatially localized clones by pooling information across neighboring spots. We validated SUMMIT using a controlled model in which we mixed two cancer cell lines in a mouse tumor, then demonstrated it on multiple human tissues including Barretts esophagus, gastric cardia, small bowel, and colorectal cancer. Across these samples, we distinguished between global mutations and mutations marking locally restricted clones. The coupled transcriptomic data allowed us to characterize the cell type composition within each clone and delineate their spatial configuration. This integrated approach provides a framework to understand spatially-defined clonal evolution in preserved human tissue.

genomics↗

bioRxiv2023

Adaptive Functions of Structural Variants in Human Brain Development

Quantifying the structural variants (SVs) in nonhuman primates could provide a niche to clarify the genetic backgrounds underlying human-specific traits, but such resource is largely lacking. Here, we report an accurate SV atlas in a population of 562 rhesus macaques, verified by two public SV benchmarks, an inhouse benchmark of eight macaque genomes with long-read sequencing and another inhouse benchmark of one macaque genome with whole-genome assembly. This accurate, quantitative SV map indicates stronger purifying selection on inversions, one type of poorly-clarified SVs to date, especially for those located on regulatory regions, suggesting a strategy for prioritizing inversions with the most important functions. Based on the distribution and the evolutionary features of these inversions in macaque population, we then identified 75 human-specific inversions, clarified their functional effects and prioritized them. Notably, the top-ranked inversions have substantially shaped the human transcriptome, through their dual-effects of reconfiguring the ancestral genomic architecture and introducing regional mutation hotspots at the inverted regions. As a proof-of-concept, we linked APCDD1, located on one of these inversions with the highest rank score and downregulated in human brains, to neuronal maturation. The accumulation of human-specific mutations on its promoter region, accelerated by the formation of the inversion, contributed to the decreased expression in humans. Notably, the overexpression of APCDD1 could accelerate the neuronal maturation, while its depletion in mice delays the neuronal maturation. This study thus highlights the contribution of SVs, especially the inversions, to the distinct features in human brain development.

evolutionary biology↗

bioRxiv2023

A longitudinal resource for population neuroscience of school-age children and adolescents in China

During the past decade, cognitive neuroscience has been calling for population diversity to address the challenge of validity and generalizability, ushering in a new era of population neuroscience. The developing Chinese Color Nest Project (devCCNP, 2013-2022), a ten-year pilot stage of the lifespan CCNP (2013-2032), is an ongoing project focusing on brain-mind development. The project aims to create and share a large-scale, longitudinal and multimodal dataset of typically developing children and adolescents (ages 6.0-17.9 at enrolment) in the Chinese population. The devCCNP houses not only phenotypes measured by demographic, biophysical, psychological and behavioural, cognitive, affective, and ocular-tracking assessments but also neurotypes measured with magnetic resonance imaging (MRI) of brain morphometry, resting-state function, naturalistic viewing function and diffusion structure. This Data Descriptor introduces the first data release of devCCNP including a total of 864 visits from 479 participants. Herein, we provided details of the experimental design, sampling strategies, and technical validation of the devCCNP resource. We demonstrate and discuss the potential of a multicohort longitudinal design to depict normative brain growth curves from the perspective of developmental population neuroscience. The devCCNP resource is shared as part of the "Chinese Data-sharing Warehouse for In-vivo Imaging Brain" in the Chinese Color Nest Project (CCNP) - Lifespan Brain-Mind Development Data Community (https://www.scidb.cn/en/c/ccnp) at the Science Data Bank. Design TypesO_LIAccelerated longitudinal design C_LIO_LIBrain-mind development C_LIO_LIPopulation imaging C_LIO_LIBrain chart C_LIO_LIRepeated measure C_LI MeasurementsO_LIPsychological behaviours C_LIO_LIBiophysical and physical measures C_LIO_LIIntelligence quotient measure C_LIO_LINeuroimaging C_LI Sample Characteristic - OrganismO_LIHomo sapiens C_LI Sample Characteristic - EnvironmentO_LISchool- and community-based sample C_LI Sample Characteristic - LocationO_LIChongqing and Beijing, China C_LI DurationO_LI10 years (2013-2022) C_LI

neuroscience↗

bioRxiv2023

Functional genomics identifies extension of complex N-glycans as a mechanism to evade lysis by natural killer cells

Somatic mutations can lead to the transformation of healthy cells into malignant cells and allow their evasion from immune surveillance. To uncover genes that play a role in the detection and lysis of tumor cells by natural killer (NK) cells, a B lymphoblastoid cell line was subjected to a genome-wide CRISPR screen. Among the top hits that facilitated NK evasion was SPPL3, which encodes an intramembrane protease that cleaves transmembrane glycosyltransferases in the Golgi apparatus. SPPL3-deficient cells accumulated glycosyltransferases, such as acetylglucosaminyltransferase 5 (MGAT5), and displayed increased N-glycosylation. Binding of NK receptors NKG2D and CD2 to their corresponding ligands MICB and CD58, and binding of rituximab to CD20, was disrupted by SPPL3-deletion. Inhibition of N-glycan maturation restored receptor binding and sensitivity to NK cells. To elucidate the mechanism of this resistant phenotype, a secondary CRISPR screen was performed in SPPL3-deficient cells. This screen identified glycosyltransferases that catalyze the formation of highly branched N-glycans and N-acetyl-lactosamine (LacNAc) extensions as key regulators that prevent killing. A significant enrichment of poly-LacNAc-containing tetra-antennary species was confirmed by glycoproteomic analysis. These findings provide mechanistic insight into how SPPL3 deletions have been linked to cancer.

immunology↗

bioRxiv2020

Multi-epitope vaccine design using an immunoinformatics approach for 2019 novel coronavirus in China (SARS-CoV-2)

A new coronavirus SARS-CoV-2 has caused over 9.2 million infection cases and 475758 deaths worldwide. Due to the rapid dissemination and the unavailability of specific therapy, there is a desperate need for vaccines to combat the epidemic of SARS-CoV-2. An in silico approach based on the available virus genome was applied to identify 19 high immunogenic B-cell epitopes and 499 human-leukocyte-antigen (HLA) restricted T-cell epitopes. Thirty multi-epitope peptide vaccines were designed by iNeo Suite, and manufactured by solid-phase synthesis. Docking analysis showed stable hydrogen bonds of epitopes with their corresponding HLA alleles. When four vaccine peptide candidates from the spike protein of SARS-CoV-2 were selected to immunize mice, a significantly larger amount of IgG in serum as well as an increase of CD19+ cells in ILNs was observed in peptide-immunized mice compared to the control mice. The ratio of IFN-{gamma}-secreting lymphocytes in CD4+ or CD8+ cells in the peptides-immunized mice were higher than that in the control mice. There were also a larger number of IFN-{gamma}-secreting T cells in spleen in the peptides-immunized mice. This study screened antigenic B-cell and T-cell epitopes in all encoded proteins of SARS-CoV-2, and further designed multi-epitope based peptide vaccine against viral structural proteins. The obtained vaccine peptides successfully elicited specific humoral and cellular immune responses in mice. Primate experiments and clinical trial are urgently required to validate the efficacy and safety of these vaccine peptides. ImportanceSo far, a new coronavirus SARS-CoV-2 has caused over 9.2 million infection cases and 475758 deaths worldwide. Due to the rapid dissemination and the unavailability of specific therapy, there is a desperate need for vaccines to combat the epidemic of SARS-CoV-2. Different from the development approaches for traditional vaccines, the development of our peptide vaccine is faster and simpler. In this study, we performed an in silico approach to identify the antigenic B-cell epitopes and human-leukocyte-antigen (HLA) restricted T-cell epitopes, and designed a panel of multi-epitope peptide vaccines. The resulting SARS-CoV-2 multi-epitope peptide vaccine could elicit specific humoral and cellular immune responses in mice efficiently, displaying its great potential in our fight of COVID-19.

bioinformatics↗

bioRxiv2018

Bacillus licheniformis global nitrogen homeostatic regulator TnrA is a direct repressor of pgsBCAA transcription in Poly-γ-glutamic acid synthesis

Poly-{gamma}-glutamic acid ({gamma}-PGA) is a multifunctional and naturally occurring biopolymer made from D- and L-glutamate as monomers, which is mainly produced by Bacillus. Few reports have been focused on the regulation network of {gamma}-PGA synthesis in recent years. In this study, we have demonstrated that Bacillus licheniformis global nitrogen homeostatic regulator TnrA is a direct repressor of {gamma}-PGA synthase PgsBCAA in {gamma}-PGA synthesis. First, our results confirmed that TnrA repressed {gamma}-PGA synthesis, deficiency of tnrA led to a 22.03% increase of {gamma}-PGA production, and the {gamma}-PGA yield was decreased by 19.02% in the TnrA overexpression strain. Transcriptional level assay illustrated that the {gamma}-PGA synthase gene cluster pgsBCAA transcriptional level were increased in the tnrA deficient strain WX{Delta}tnrA, indicating that {gamma}-PGA synthase PgsBCAA was negatively regulated by TnrA. Furthermore, electrophoretic mobility shift assay (EMSA) and enzyme expression assays confirmed that TnrA directly repressed pgsBCAA expression by binding to pgsBCAA promoter, and the TnrA-binding site \"CGTCGTCTTCTGTTACA\" in the pgsBCAA promoter was identified by sequence and software analysis. Finally, computer analysis confirmed that the transcription regulations of {gamma}-PGA synthase PgsBCAA by TnrA were highly conserved in other well-studied Bacillus species (B. licheniformis, Bacillus subtilis and Bacillus amyloliquefaciens). Collectively, our results implied that TnrA was a direct repressor for pgsBCAA expression in {gamma}-PGA synthesis, and this research provided a novel regulatory mechanism underlying {gamma}-PGA synthesis, and a new approach that deficiency of tnrA increases {gamma}-PGA production.\n\nImportance{gamma}-PGA is an important biopolymer with many applications, which is mainly produced by Bacillus species. Glutamic acid is the precursor for {gamma}-PGA synthesis, which is catalyzed by the {gamma}-PGA synthase PgsBCAA. Previously, the expression of PgsBCAA was reported to be regulated by ComA-ComP and DegS-DegU, DegQ and SwrA systems, however, few researches were focused on the regulation network of {gamma}-PGA synthesis in recent years. In our research, the {gamma}-PGA synthase PgsBCAA was confirmed to be negatively regulated by the nitrogen metabolism regulator TnrA, and the TnrA binding site in the pgsBCAA promoter was identified in B. licheniformis WX-02. Furthermore, computer analysis implied that TnrA-mediated regulation effect on pgsBCAA expression was highly conserved in Bacillus. Collectively, our research provided a novel regulatory mechanism underlying {gamma}-PGA synthesis, and a new approach that deficiency of tnrA increases {gamma}-PGA production.

microbiology↗

bioRxiv2018

BAP1 Loss Predicts Therapeutic Vulnerability in Malignant Peritoneal Mesothelioma

BackgroundMalignant Peritoneal Mesothelioma (PeM) is a rare but frequently fatal cancer that originates from the peritoneal lining of the abdomen. Standard treatment of PeM is limited to cytoreductive surgery and/or chemotherapy, and no effective targeted therapies for PeM yet exist. In the search for novel therapeutic target candidates in PeM, we performed a comprehensive integrative multi-omics analysis of 19 treatment-naive PeM tumors.\n\nResultsThe analysis identified PeM tumors with BAP1 loss to form a distinct molecular subtype characterized by distinct expression patterns of genes involved in chromatin remodeling, DNA repair pathway, and immune checkpoint receptor activation. This PeM subtype could potentially benefit from immune checkpoint, PARP, or HDAC inhibition therapies.\n\nConclusionsOur findings uncover BAP1 as a trackable prognostic and predictive biomarker, and refine PeM disease classification. This integrated molecular characterization provides a comprehensive foundation for developing PeM precision medicine.

cancer biology↗