Biology subjects

Dai, S.

Publications and source records attributed to Dai, S..

At least 19 recordsLinked to original sources

bioRxiv2026

Engineering the NAT-ULT module increases seed number per pod in soybean

Seed number per pod is a major soybean yield-component trait, yet experimentally validated causal modules remain poorly defined. Here, we identify and functionally validate a soybean NAT-ULT regulatory module controlling ovule and seed number per pod. Through a visual screen of a fast-neutron-irradiated Glycine max cv. Williams 82 population, we isolated MO27, which increased four-seeded pod frequency from approximately 2-4% in wild type to 27-30%, without major changes in plant architecture, total pod number, or seed morphology. Comparative genome hybridization mapped the phenotype to a 46.7-kb chromosome 2 deletion containing GmNAT1 and chromosome 6 deletions encompassing GmULT-B1 and GmULT-B3. Ovule-clearing analysis showed that increased seed number originated before fertilization through elevated formation of four-ovule ovaries. CRISPR/Cas9-mediated mutagenesis of GmNAT1, GmULT-B1, and GmULT-B3 increased four-seeded pod frequency without detectable penalties in 100-seed weight, total pod number, or plant height. Tomato SlULT triple mutants also increased floral organ and locule number, supporting conserved ULT-like function in reproductive organ patterning. RNA-seq interaction analysis revealed a chromosome 6-dominant transcriptional state, accompanied by selective non-additive reprogramming of hormone/ovule-number and cell-wall-remodeling modules. Integrated genetic and transcriptomic analyses support a hierarchical model in which NAT-ULT perturbation may enhance meristematic competence and remodel reproductive developmental programs, while additional fast-neutron-background-associated transcriptional changes may further modulate the phenotype. These findings define NAT-ULT as a molecular target for engineering soybean seed number per pod.

plant biology↗

bioRxiv2026

A direct RNA sequencing workflow for simultaneous profiling of tRNA abundance and modifications in mouse liver

Transfer RNA (tRNA) is highly modified and difficult to profile using reverse-transcription-based sequencing. Here, we established a direct RNA sequencing (tRNA-DRS) workflow to simultaneously characterize tRNA abundance and modification signals in mouse liver. The workflow included small-RNA enrichment, deacylation, splint-adapter ligation, barcoding, reverse transcription, and nanopore sequencing on PromethION with modification-aware basecalling. From 1,678,666 raw reads, 1,421,279 (84.67%) reads were retained after 20-200 nt length filtering, and 17,094 uniquely mapped reads (MAPQ [≥] 10) were obtained. These reads covered 244 tRNA genes and represented all 23 tRNA isotypes. tRNA abundance was strongly skewed, with Asp, Gly, Ser, and Lys accounting for 56.6% of uniquely mapped reads. Read-body coverage indicated that most uniquely mapped reads spanned substantial portions of tRNA molecules (mean 71.1%, median 75.9%; 83.3% reads covering [≥]50% of the reference). Modification analysis identified 41,013 candidate sites, of which 711 passed stringent filtering (modification fraction [≥]50%, coverage [≥]5), spanning eight modification types and dominated by pseudouridine and m5C. Filtered sites showed position-specific clustering and isotype-dependent patterns. Together, these results support tRNA-DRS as a practical single-assay framework for simultaneous tRNA expression and epitranscriptomic profiling in mammalian tissue.

molecular biology↗

bioRxiv2026

DPCGS: a computational framework for linking GWAS to single-cell transcriptomics in complex traits and diseases

Complex traits and diseases arise from the interplay between genetic variation and cellular heterogeneity, making it essential to understand how genetic risk manifests at the cellular level. However, connecting genome-wide association studies (GWAS) to specific cell populations remains challenging due to cellular complexity and the prevalence of noncoding variants. Here, we present DPCGS, a computational framework that systematically integrates GWAS summary statistics with single-cell RNA-sequencing (scRNA-seq) data to identify trait-associated cell subpopulations, genes, and regulatory programs. Unlike existing approaches that primarily evaluate pathway enrichment or cell-type-level associations, DPCGS quantifies the enrichment of genetically prioritized genes within individual cells through a statistically calibrated gene-set scoring strategy, enabling high-resolution mapping of genetic risk to cellular states. Benchmarking across simulated and diverse human single-cell datasets demonstrates that DPCGS achieves superior accuracy, sensitivity, and robustness compared with existing methods, including scDRS and scPagwas. Applying DPCGS to Alzheimers disease and asthma reveals disease-associated cellular populations and uncovers potential molecular drivers, including CD74, FOS, and AP-1 family regulatory programs, providing insights into disease-specific immune and cellular mechanisms. By bridging genetic discoveries from GWAS with functional interpretation at single-cell resolution, DPCGS establishes a generalizable framework for dissecting the cellular architecture of complex traits and diseases. This approach enables systematic discovery of disease-relevant cell subpopulations, regulatory networks, and potential therapeutic targets, offering broad applications in human genetics, single-cell biology, and precision medicine.

bioinformatics↗

bioRxiv2026

Lamellar Normative Modelling of the Hippocampus Across the Human Lifespan

The hippocampus is a central hub of human memory and cognition and is closely associated with brain disorders. Studies have shown that it exhibits complex structural variation across the lifespan, yet the details of hippocampal morphology changes remain poorly understood. Here, we establish norms over the hippocampal geometry that resolve lamellar morphology and map lifespan trajectories across more than 27,000 individuals from 158 scanning sites. Hippocampal geometry shows spatially non-uniform developmental and ageing patterns across the lifespan, with lamellar thickness, width and length following dissociable trajectories. Across multiple brain disorders, this representation reveals localized and heterogeneous alterations beyond conventional subfield-level summaries, and uncovers a dichotomy in disease-associated patterns, with neurodegenerative conditions and schizophrenia showing predominant atrophy, whereas some other disorders exhibit focal or regionally selective hypertrophy. Transfer to a longitudinal Alzheimers Disease Neuroimaging Initiative cohort further supports out-of-sample generalization of our approach and enables individual-level tracking and conversion risk stratification. Overall, this work establishes a population-scale geometric reference for the hippocampus, extends normative brain mapping from coarse regional phenotypes to anatomically organized subcortical structure, and enables anatomically grounded characterization of disease-related alterations and individual-level deviation mapping, providing a principled basis for understanding and stratifying brain disorders across the lifespan in health and disease.

neuroscience↗

bioRxiv2026

A normative reference for large-scale human brain dynamics across the lifespan

Human brain function emerges from dynamic reconfigurations of large-scale neural networks. While population-level reference charts have transformed the study of static brain structure and connectivity, an equivalent normative framework for intrinsic brain dynamics has been lacking. This gap has limited our ability to characterize individual variability, development, ageing, and mental health conditions at scale. Here, we establish a population-level normative reference for large-scale human brain dynamics using resting-state fMRI data from more than 10,000 individuals spanning the lifespan and 91 scanning sites. We derive a compact set of recurring brain-state configurations that are reproducible across scanners and acquisition paradigms and that generalize to previously unseen cohorts. Anchoring these dynamic states to normative lifespan models enables the quantification of individual deviations relative to population reference distributions. We show that intrinsic brain dynamics undergo systematic reorganization across development and ageing, with pronounced changes before early adulthood and more gradual modulation thereafter. Applying this framework across multiple mental health conditions reveals disorder-specific and highly heterogeneous deviations in brain dynamics that are not captured by static neuroimaging measures. Robust transfer to independent cohorts and longitudinal analyses demonstrate that normative brain dynamics can be reliably assessed out of distribution. These results delineate a population-scale dynamic architecture of the human brain and extend normative brain mapping from static phenotypes to the temporal domain, providing a reference framework for studying brain function across the lifespan in health and disease.

neuroscience↗

bioRxiv2026

Evolutionary profile enhancement improves protein function annotation for remote homologs

Accurate annotation of protein function is essential for understanding biological processes, yet this remains challenging for proteins lacking characterized homologs or belonging to underrepresented functional classes. Although machine learning approaches have become the gold standard for automated function prediction, they often perform poorly on out-of-distribution samples with low sequence identity to training proteins with known annotations. We propose EPERep, an evolutionary input enhancement strategy that leverages the vast space of unannotated protein sequences to improve the prediction of the functions of underrepresented proteins. Our key insight is that, even if a query protein has insufficient similarity to annotated proteins for direct annotation transfer, a wider range of similar unannotated sequences can be identified to facilitate better representation learning. Inspired by profile-based sequence search methods, EPERep incorporates homologous sequences as contextual input to refine the representations of individual proteins from pre-trained protein language models, effectively constructing a pLM-based profile for each query protein. Across four major annotation benchmarks on EC numbers, structural domains, Pfam families, and Gene Ontology predictions, EPERep consistently outperforms strong ML and sequence-alignment baselines. Gains are most pronounced for proteins from rare functional classes, with few or no labeled homologs, and for sequences exhibiting remote homology to the training distribution. These results demonstrate that evolutionary input enhancement provides a principled and scalable strategy for improving protein function prediction, particularly in long-tail and low-identity regimes.

bioinformatics↗

bioRxiv2025

Enabling regiospecific di-halogenation in one-pot reactions using an engineered single-component flavin-dependent tryptophan halogenase

Installation of halogen atoms to organic compounds through flavin-dependent halogenases (FDHs) catalyzed reactions has emerged as an attractive strategy in organic biochemistry and synthetic biology. A cyanobacterial FDH termed AetF that contains FDH and flavin reductase in the same polypeptide chain could become a useful tool enzyme as the need of including a reductase is omitted. Notably, AetF exploits a unique substrate-interaction network to consecutively brominate tryptophan (Trp) on C5 and then C7 to generate di-brominated Trp. In this study, structure-based engineering is used to eliminate the C7 halogenation capacity of AetF. The resulting variant AetF-AIF that contains three residue substitutions mainly catalyzes bromination or iodination on C5 of Trp. We also show that combining AetF-AIF in tandem with the wild type AetF enables the generation of heterogeneously halogenated Trp in a one-pot reaction. The final products, 5-Br-7-I-Trp or 5-I-7-Br-Trp depending on the addition order of halides, account for a high ratio in the reaction mixture without additional purification step. These results display the potentials of single-component Trp-FDHs in a wide application of the halogenation reactions. Table of Content Graphic O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=105 SRC="FIGDIR/small/687318v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@101bd34org.highwire.dtl.DTLVardef@12ca797org.highwire.dtl.DTLVardef@aee280org.highwire.dtl.DTLVardef@1984907_HPS_FORMAT_FIGEXP M_FIG A single-component flavin-dependent halogenase that catalyzes di-bromination of tryptophan was engineered as a mono-halogenase and coupled in a one-pot reaction for the synthesis of heterogeneously halogenated tryptophan. C_FIG

molecular biology↗

bioRxiv2025

The gerotherapeutic drugs rapamycin, acarbose, and phenylbutyrate extend lifespan and enhance healthy aging in house crickets.

The house cricket (Acheta domesticus) is a promising preclinical geroscience model due to its short lifespan, low maintenance, age-associated functional decline, and responsiveness to geroprotective drugs. Continuous dosing with rapamycin, acarbose, and phenylbutyrate extends lifespan; whether intermittent dosing offers similar benefits remains unknown. We tested 274 sex-matched crickets given 2-week intermittent dosing of each drug starting at mid-age (8-weeks), followed by behavioral testing at 10-weeks (geriatric stage). Assays included Y-maze olfactory discrimination, open-field exploration, and treadmill performance. Locomotor gaits were identified by velocity-based K-means clustering (silhouette > 0.5). A subset was monitored for post-treatment survival using Kaplan-Meier analysis. Olfactory preference was preserved by all drugs (ds = -1.82 to -1.28, Ps < 0.01), with strongest effects in rapamycin-treated individuals. Rapamycin-treated males matched or exceeded juvenile locomotor activity; phenylbutyrate reduced male activity (d = 1.49, P < 0.05) and acarbose increased walking-to-running ratios (d = -0.75, P < 0.05). Rapamycin increased central exploration and freezing (d = -1.55, P < 0.0001), while acarbose and phenylbutyrate increased peripheral freezing (d = -0.76, P < 0.05). Rapamycin and phenylbutyrate extended maximum running time (ds = -2.30 to -1.32, Ps < 0.0001), with sex-specific jumping gains in rapamycin-treated females and acarbose-treated males. Post-treatment lifespan was prolonged by rapamycin (HR = 0.42, P < 0.001) and reduced by acarbose in females (HRs = 2.92 to 3.03, Ps < 0.05). Intermittent rapamycin preserved survival, cognition, and locomotion, while acarbose and phenylbutyrate produced selective benefits, supporting A. domesticus as a scalable model for geroprotective drug discovery.

pharmacology and toxicology↗

bioRxiv2025

Computational design of conformation-biasing mutations to alter protein functions

Most natural proteins alternate between distinct conformational states, each associated with specific functions. Intentional manipulation of conformational equilibria could lead to improved or altered protein properties. Here we develop Conformational Biasing (CB), a rapid and streamlined computational method that utilizes contrastive scoring by inverse folding models to predict variants biased towards desired conformational states. We validated CB across seven diverse deep mutational scanning datasets, successfully predicting variants of K-Ras, SARS-CoV-2 spike, {beta}2 adrenergic receptor, and Src kinase with improved conformation-specific functions including enhanced effector binding or enzymatic activity. Furthermore, applying CB to lipoic acid ligase, a conformation-switching bacterial enzyme that has been used for the development of protein labeling technologies, revealed a previously unknown mechanism for conformational gating of sequence-specificity. Variants biased toward the "open" conformation were highly promiscuous, while "closed" conformation-biased variants were even more specific than wild-type, enhancing the utility of LplA for site-specific protein labeling with fluorophores in living cells. The speed, simplicity, and versatility of CB (available at: https://github.com/alicetinglab/ConformationalBiasing/) suggest that it may be broadly applicable for understanding and engineering protein conformational dynamics, with implications for basic research, biotechnology, and medicine.

biophysics↗

bioRxiv2025

Morphological features of the domestic house cricket (Acheta domesticus) for translational aging studies

Aging alters morphology and locomotor function in diverse organisms, yet standardized model systems for studying these changes remain limited to a relatively few species. Here, we present a comprehensive analysis of age- and sex-dependent morphological variations in house crickets (Acheta domesticus), integrating refined husbandry protocols to enhance reproducibility and translational relevance. We observed progressive increases in body weight, length, and appendage dimensions with age, with pronounced sexual dimorphism emerging post-maturity. Structural adaptations, including increased femoral volume and cross-sectional area, suggest compensatory mechanisms for age-related declines in muscle efficiency, while reduced hind leg-to-body length ratios indicate potential biomechanical constraints on locomotion. Antennal growth patterns highlight prolonged sensory investment, potentially offsetting declining mobility in aging individuals. To ensure data consistency, we implemented a standardized husbandry framework incorporating self-determined photoperiods, co-housing both sexes, and controlled diet and hydration strategies. Our results underscore the necessity of harmonizing environmental conditions in gerontological research, as variations in lighting, substrate availability, and microbiome exposure may significantly impact physiological resilience and behavioral fidelity. Future work should explore the influence of microbiome diversity on lifespan and stress resilience while refining methodologies for cricket rearing from egg to adulthood. By bridging invertebrate and vertebrate aging research, this study positions house crickets as a scalable, high-throughput model for investigating age-related functional decline, behavioral plasticity, and lifespan-extending interventions. Integrating behavioral assays, biomechanical analyses, and molecular markers of aging will further elucidate the interplay between morphology, function, and longevity, advancing the utility of crickets in comparative geroscience.

animal behavior and cognition↗

bioRxiv2025

Carbon monoxide exposure stimulates growth and activity of primary producers in diverse soil ecosystems

Carbon monoxide (CO) is both a potent poison for many aerobic organisms and a desirable energy source for diverse microorganisms. Atmospheric emissions of this gas have increased since industrialization and their levels are highly elevated in many urban and natural environments; however, it is unresolved whether elevated levels of CO at environmentally relevant concentrations are primarily stimulatory or inhibitory to soil microbial communities. Here, we showed that CO exposure minimally affects microbial abundance, richness, and composition in diverse ecosystem soils, suggesting most microbes are tolerant of this gas. Genome-resolved metagenomic profiling showed that these soils harbored diverse bacteria capable of using CO an electron donor for aerobic respiration and carbon fixation. CO stimulated the growth of several of these putative CO-oxidizing bacteria in a dose-dependent manner, especially widespread proteobacterial and actinobacterial lineages. Additionally, we found a strong relationship between CO oxidation and carbon fixation and observed an enrichment of several carboxydotrophic MAGs capable of carbon fixation in most soil types. These findings highlight that environmentally relevant CO levels do not inhibit soil microbes, but instead foster the growth of distinct carboxydotrophic bacteria, suggesting a robust soil CO sink that could help mitigate anthropogenic CO emissions and contribute to carbon cycling in terrestrial ecosystems.

biochemistry↗

bioRxiv2024

Instantaneous Frequency: A New Functional Biomarker for Dynamic Brain Causal Networks

This study introduces instantaneous frequency (IF) analysis as a novel method for characterizing dynamic brain causal networks from fMRI blood-oxygen-level-dependent (BOLD) signals. Effective connectivity, estimated using dynamic causal modeling (DCM), is analyzed to derive IF sequences, with the average IF across brain regions serving as a potential biomarker for global network oscillatory behavior. Analysis of data from the Alzheimers Disease Neuroimaging Initiative (ADNI), Open Access Series of Imaging Studies (OASIS), and Human Connectome Project (HCP) demonstrates the methods efficacy in distinguishing between clinical and demographic groups, such as cognitive decline stages, sex differences, and sleep quality levels. Statistical analyses reveal significant group differences in IF metrics, highlighting its potential as a sensitive indicator for early diagnosis and monitoring of neurodegenerative and cognitive conditions. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=100 SRC="FIGDIR/small/628965v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@10da58org.highwire.dtl.DTLVardef@6eee6borg.highwire.dtl.DTLVardef@e6e756org.highwire.dtl.DTLVardef@15dff2a_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIThe study introduces instantaneous frequency (IF) as a novel biomarker derived from dynamic brain effective connectivity, capturing temporal fluctuations in brain networks. C_LIO_LIThe proposed IF biomarker effectively differentiates between various clinical stages, such as Mild Cognitive Impairment (MCI) and Alzheimers Disease (AD), and demographic factors, including sex and sleep quality. C_LIO_LIThe robustness and clinical relevance of the IF biomarker are validated using three independent datasets: ADNI, OASIS, and HCP, demonstrating its potential in cognitive and neurological research. C_LI

neuroscience↗

bioRxiv2024

Agouti and BMP signaling drive a naturally occurring fate conversion of melanophores to leucophores in zebrafish

The often-prominent pigment patterns of vertebrates are varied in form and function and depend on several types of pigment cells derived from embryonic neural crest or latent stem cells of neural crest origin. These cells and the patterns they produce have been useful for uncovering features of differentiation and morphogenesis that underlie adult phenotypes, and they offer opportunities to discover how patterns and the cell types themselves have diversified. In zebrafish, a body pattern of stripes arises by self organizing interactions among three types of pigment cells. Yet these fish also exhibit white ornamentation on their fins that depends on the transdifferentiation of black melanophores to white cells, "melanoleucophores." To identify mechanisms underlying this conversion we used ultrastructural, transcriptomic, mutational and other approaches. We show that melanophore- melanoleucophore transition depends on regional BMP signals transduced through non-canonical receptors (Rgmb-Neo1a-Lrig2) as well as BMP-dependent signaling by Agouti genes, asip1 and asip2b. These signals lead to expression of transcription factor genes including foxd3 and runx3 that are necessary to induce loss of melanin by an autophagy-like process, curtail new melanin production, and deploy a pathway for accumulating guanine crystals that, together, confer a white phenotype. These analyses uncover an important role for positional information in specifying ornamentation in zebrafish and show how tissue environmental cues and a novel gene regulatory program have allowed terminal addition of a distinct phenotype to a pre-existing cell type. SignificanceFish often have striking color patterns with important functions in behavior. In zebrafish, the familiar striped pattern forms through self-organizing interactions between pigment cells, yet the white highlights on their fins arise differently--through the transformation of black pigment cells into white ones. This study reveals how this dramatic cell transformation happens: signals from the surrounding tissue, specifically BMP and Agouti proteins, instruct black cells to change their fate. These signals trigger expression of specific genes that cause the cells to break down their black pigment while acquiring white, crystal-like structures. This work shows how local signals in tissues can drive the development of ornamental features and provides insights into how new cell types evolve.

developmental biology↗

bioRxiv2024

Capturing the Hierarchically Assorted Protein-protein Interaction Modules of Mammalian Cell

Proteins are organized into modules by both functions and physical interactions within compartments of an eukaryotic cell. The in vivo chemical crosslinking mass spectrometry (XL-MS) data collected from organelles, the whole cells and tissues are able to provide unique information about both protein-protein interaction (PPI) and the intensity of PPI. In the present study, we have retrieved 55,982 crosslinked peptides (XL-peptides) from the XL-MS databases, out of which 6,356 in vivo PPIs were identified. Introduction of the MONET software into analysis of 4,526 hetero PPIs revealed a total of 402 protein modules, including 15, 58 and 163 stable protein complex(s), condensate-forming protein module(s) and intrinsically disordered region (IDR)-containing protein module(s), respectively. The application of ChatGPT in analysis of these modules unexpectedly identified 4 vesicle-related modules. Together, these modules were assorted into 6 communities (module of modules) and 3 systems (module of communities) hierarchically. The bioinformatic analysis found that the three systems are corresponding to three compartments of eukaryotic cell: nuclei, mitochondria, endoplasmic reticulum (ER), respectively. This study presents a novel and comprehensive biomolecular modulome of a mammalian cell, which captures putative protein compositions of protein complexes, protein condensates and vesicles and provides a hierarchical protein organization and function within compartments of mammalian cell.

bioinformatics↗

bioRxiv2024

Nuclear FAK aggravates CD8+ T cell exhaustion via the SP1-IL-6 axis in colorectal cancer

Nuclear abnormalities such as nuclear deformation are hallmarks of many diseases, including cancer. Accumulating evidence suggests that the dense and mechanically stiff tumor microenvironment promotes nuclear deformation in cancer cells. However, little is known about how nuclear deformation in neoplastic cells regulates immune exhaustion in the tumor microenvironment. Here, we found that lamin A/C-mediated nuclear stiffening in neoplastic cells promotes the nuclear translocation of phosphorylated focal adhesion kinase (pFAK), which is strongly correlated with the heterogeneity and exhaustion of CD8+ T cells within the spatial context of the tumor microenvironment in human colorectal cancer. Mechanistically, we revealed that increased nuclear tension within tumor cells promotes pFAK nuclear translocation, where nuclear pFAK was found to regulate SP1/IL-6-mediated T-cell exhaustion and the transcription of proinflammatory cytokines/chemokines. Pharmacological inhibition or disruption of pFAK nuclear translocation enhanced antitumor immune responses and synergistically potentiated PD-1 and TIM-3 immunotherapy by increasing CD8+ T-cell cytotoxicity and restoring exhaustion in preclinical models of colorectal cancer. These findings highlight the pivotal role of nuclear tension-mediated pFAK translocation into the tumor cell nucleus in regulating CD8+ T-cell exhaustion, suggesting that pFAK is a promising target for advancing cancer immunotherapy.

immunology↗

bioRxiv2023

Identification of CFAP52 as a novel diagnostic target of male infertility with defects of sperm head-tail connection and flagella development

Male infertility is a worldwide population health concern. Asthenoteratozoospermia is a common cause of male infertility, but its etiology remains incompletely understood. No evidence indicates the relevance of CFAP52 mutations to human male infertility. Our whole-exome sequencing identified compound heterozygous mutations in CFAP52 recessively cosegregating with male infertility status in a non-consanguineous Chinese family. Spermatozoa of CFAP52-mutant patient mainly exhibited abnormal head-tail connection and deformed flagella. Cfap52-knockout mice resembled the human infertile phenotype, showing a mixed acephalic spermatozoa syndrome (ASS) and multiple morphological abnormalities of the sperm flagella (MMAF) phenotype. The ultrastructural analyses further revealed a failure of connecting piece formation and a serious disorder of 9+2 axoneme structure. CFAP52 interacts with a head-tail coupling regulator SPATA6 and is essential for its stability. Expression of microtubule inner proteins and radial spoke proteins were reduced after the CFAP52 deficiency. Moreover, CFAP52-associated male infertility in humans and mice could be overcome by ICSI. The study reveals a prominent role for CFAP52 in sperm development, suggesting that CFAP52 might be a novel diagnostic target for male infertility with defects of sperm head-tail connection and flagella development

genetics↗

bioRxiv2023

MiR-574-5p activates human TLR8 to promote autoimmune signaling and lupus

Endosomal single-stranded RNA-sensing Toll-like receptor-7/8 (TLR7/8) plays a pivotal role in inflammation and immune responses and autoimmune diseases. However, the mechanisms underlying the initiation of the TLR7/8-mediated autoimmune signaling remain to be fully elucidated. Here, we demonstrate that miR-574-5p is aberrantly upregulated in tissues of lupus prone mice and in the plasma of lupus patients, with its expression levels correlating with the disease activity. miR-574-5p binds to and activates human hTLR8 or its murine ortholog mTlr7 to elicit a series of MyD88-dependent immune and inflammatory responses. These responses include the overproduction of cytokines and interferons, the activation of STAT1 signaling and B lymphocytes, and the production of autoantigens. In a transgenic mouse model, the induction of miR-574-5p overexpression is associated with increased secretion of antinuclear and anti-dsDNA antibodies, increased IgG and C3 deposit in the kidney, elevated expression of inflammatory genes in the spleen. In lupus-prone mice, lentivirus-mediated silencing of miR-574-5p significantly ameliorates major symptoms associated with lupus and lupus nephritis. Collectively, these results suggest that the miR-574-5p-hTLR8/mTlr7 signaling is an important axis of immune and inflammatory responses, contributing significantly to the development of lupus and lupus nephritis.

immunology↗

bioRxiv2023

IQCH regulates spermatogenesis by interacting with CaM to promote RNA-binding proteins' expression

IQ motif-containing proteins can be recognized by calmodulin (CaM) and are essential for many biological processes. However, the role of IQ motif-containing proteins in spermatogenesis is largely unknown. In this study, we identified a loss-of-function mutation in the novel gene IQ motif-containing H (IQCH) in a Chinese family with male infertility characterized by a cracked flagellar axoneme and abnormal mitochondrial structure. To verify the function of IQCH, Iqch knockout (KO) mice were generated via CRISPR-Cas9 technology. As expected, the Iqch KO male mice exhibited impaired fertility, which was related to deficient acrosome activity and abnormal structures of the axoneme and mitochondria, mirroring the patient phenotypes. Mechanistically, IQCH can bind to CaM and subsequently regulate the expression of RNA-binding proteins (especially HNRPAB), which are indispensable for spermatogenesis. Overall, this study revealed the function of IQCH, expanded the role of IQ motif-containing proteins in reproductive processes, and provided important guidance for genetic counseling and genetic diagnosis of male infertility.

genetics↗