Biology subjects

Ma, M.

Publications and source records attributed to Ma, M..

At least 55 records · Page 3Linked to original sources

bioRxiv2025

Functionally-Coupled Ion Channels Begin Co-assembling at the Start of Their Synthesis

Calcium binding to BK channels lowers BK activation threshold, substantiating functional coupling with calcium-permeable channels. This coupling requires close proximity between different channel types, and the formation of BK-CaV1.3 hetero-clusters at nanometer distances exemplifies this unique organization. To investigate the structural basis of this interaction, we tested the hypothesis that BK and CaV1.3 channels assemble before their insertion into the plasma membrane. Our approach incorporated four strategies: (1) detecting interactions between BK and CaV1.3 proteins inside the cell, (2) identifying membrane compartments where intracellular hetero-clusters reside, (3) measuring the proximity of their mRNAs, and (4) assessing protein interactions at the plasma membrane during early translation. These analyses revealed that a subset of BK and CaV1.3 transcripts are spatially close in micro-translational complexes, and their newly synthesized proteins associate within the endoplasmic reticulum (ER) and Golgi. Comparisons with other proteins, transcripts, and randomized localization models support the conclusion that BK and CaV1.3 hetero-clusters form before their insertion at the plasma membrane. Significance statementThis work examines the proximity between BK and CaV1.3 molecules at the level of their mRNAs and newly synthesized proteins to reveal that these channels interact early in their biogenesis. Two cell models were used: a heterologous expression system to investigate the steps of protein trafficking and a pancreatic beta cell line to study the localization of endogenous channel mRNAs. Our findings show that BK and CaV1.3 channels begin assembling intracellularly before reaching the plasma membrane, revealing new aspects of their spatial organization. This intracellular assembly suggests a coordinated process that contributes to functional coupling.

biophysics↗

bioRxiv2025

SpatialAgent: An Autonomous AI Agent for Spatial Biology

Advances in AI are transforming scientific discovery, yet spatial biology, a field that deciphers the molecular organization within tissues, remains constrained by labor-intensive workflows. Here, we present SpatialAgent, an autonomous AI agent for spatial biology research. SpatialAgent couples large language models with a Plan-Act-Conclude architecture, dynamic tool and skill retrieval, multimodal interpretation, and verification modules that audit generated claims. It supports the full discovery loop, from gene-panel design and multimodal annotation to trajectory inference, cell-cell communication analysis, imputation, and hypothesis generation. Across human and mouse brain, heart, tonsil, colon, and prostate datasets, SpatialAgent outperformed established computational baselines and matched or surpassed expert scientists in key tasks. In open-ended case studies, it recovered known tissue organization and generated spatially grounded hypotheses. In a prospective mouse prostate cancer Xenium study, it designed a compact 100-gene add-on panel that profiled 4.2 million cells across 21 samples, improved cell-type and malignant-state prediction, and captured spatially structured tumor and microenvironment programs. SpatialAgent establishes a framework for autonomous and collaborative discovery in spatial biology.

bioinformatics↗

bioRxiv2025

Characterizing the Microbiome of 'Sterile' Organs in Experimental Mice

Recent studies have shown that microorganisms can be present in organs or blood traditionally considered sterile, both in healthy and diseased individuals. In this study, we investigated the presence of microorganisms in the "sterile" organs (brain, heart, kidney, liver, lung, and spleen) of commercially available experimental mice using culturomics and metagenomics. To avoid potential environmental contamination, strict disinfection assays were performed. Among 104 mice of the C57BL/6J, BALB/c, and ICR strains purchased from three major experimental animal suppliers in China, 23 mice (22.1%) exhibited a high microbial burden (>1 x 104 CFU/g tissue) in at least one organ, and 42 mice (40.4%) exhibited >1 x 103 CFU/g tissue in at least one organ. In total, 216 microbial species were identified through culturomics. Of them, 56 microbial species were found in the organs of at least three mice of the 42 mice (>1 x 103 CFU/g tissue in at least one organ). Metagenomics analysis of 10 high-burden mice verified the existence of microbes in the mouse organs and identified 262 species. Several species, including Acinetobacter sp., Alcaligenes faecalis, and Ligilactobacillus murinus, were identified as the most abundant microbes across both culturomics and metagenomics assays. 16S FISH staining assays verify the presence of microbes in the mouse organs. Feces Metagenomics analysis and detection of the wide distribution of L. murinus in the mouse mesenteric lymph nodes (MLNs) imply that microbial cells could be translocated from the gut to the MLNs and then to the remote tissues. Together, these findings reveal the presence of non-pathogenic microorganisms in the "sterile" tissues of experimental mice, raising concerns about potential variability in experimental outcomes when using such animals in research.

microbiology↗

bioRxiv2025

The conserved nature of nitrogen recycling within the bacterial pouch of Tetraponera ants

Microbial symbioses are fundamental to the nutrition of many animal groups, yet the mechanisms of nutrient provisioning remain poorly understood -- even in social insects, a diverse clade whose global ecological dominance and sophisticated caste systems make them disproportionately well-studied models for symbiosis research. Here, we investigate the functional significance of a specialized and unusual symbiotic organ-- the bacterial pouch--in four ant species within the Tetraponera nigra-group, focusing on the symbionts roles in nitrogen recycling and colony fitness. Bacterial pouch houses a microbial community consistently dominated by the core bacterial symbiont Tokpelaia. Metagenomic sequencing and targeted {superscript 1}N-labeled urea feeding experiments demonstrate that these symbionts assimilate nitrogen from urea into amino acids, transferring them to adult workers and developing larvae that incorporate recycled nitrogen into their tissues. Disruption of this nitrogen-recycling symbiosis severely impairs larval growth and overall colony fitness. Our study highlights the critical role of the bacterial pouch in sustaining colony fitness in nitrogen-limited environments, providing new insights into the pivotal role of microbial symbioses in the ecological success of social insects.

ecology↗

bioRxiv2025

A Hyperbolic Discrete Diffusion 3D RNA Inverse Folding Model for functional RNA design

Generative design of functional RNAs presents revolutionary opportunities for diverse RNA-based biotechnologies and biomedical applications. To this end, RNA inverse folding is a promising strategy for generatively designing new RNA sequences that can fold into desired topological structures. However, three-dimensional (3D) RNA inverse folding remains highly challenging due to limited availability of experimentally derived 3D structural data and unique characteristics of RNA 3D structures. In this study, we propose RIdiffusion, a hyperbolic denoising diffusion generative RNA inverse folding model, for 3D RNA design tasks. By embedding geometric features of RNA 3D structures and topological properties into hyperbolic space, RIdiffusion efficiently recovers the distribution of nucleotides for targeted RNA 3D structures based on limited training samples using a discrete diffusion model. We perform extensive evaluations on RIdiffusion using different datasets and strict data-splitting strategies and the results demonstrate that RIdiffusion consistently outperforms baseline generative models for RNA inverse folding. This study introduces RIdiffusion as a powerful tool for the generative design of functional RNAs, even in structure-data-scarce scenarios. By leveraging geometric deep learning, RIdiffusion enhances performance and holds promise for diverse downstream applications.

bioinformatics↗

bioRxiv2025

Metabolic heterogeneity coupled with a resistance gene generates antibiotic heteroresistance

Heteroresistance is a form of antibiotic resistance in which a phenotypically unstable subpopulation of resistant cells exists within a majority population of susceptible cells. The impact of the extracellular environment on mechanisms of heteroresistance is unclear. Studying fosfomycin heteroresistance in an Enterobacter cloacae complex isolate, we observed that glucose availability greatly increased the frequency of the resistant subpopulation. Glucose downregulated the glycerol and fosfomycin importer GlpT, whose expression was heterogenous at the single cell level. This heterogeneous expression of GlpT, in combination with the expression of the fosfomycin resistance gene fosA, which acted as a resistance enhancer, led to the generation of heteroresistance. Correspondingly, the frequency of the fosfomycin resistant subpopulation was increased in murine models of hyperglycemia/diabetes. These data demonstrate how metabolic heterogeneity and carbon source availability can impact antibiotic resistance phenotypes in the infection environment.

microbiology↗

bioRxiv2025

Changes in the health-related ecosystem services and disservices provided by urban trees over multiple decades in a small city

The effects of urban trees on public health should change over decades due to shifts in tree composition and abundance, environmental conditions, human demography, and disease incidence. However, there are few case studies documenting changes in the health-related ecosystem services and disservices provided by trees over time. Here we use seven tree censuses to quantify changes in the effects of city-owned trees on air pollution, allergenic pollen, hydrology, and heat due to shifts in tree abundance and environmental conditions in Ithaca, New York, a small city in the Northeastern United States. We also review how shifts in disease incidence have affected these trees health consequences. From 2005 to 2021, trees removed 20% more ozone and 268% more PM2.5; they also removed substantially more runoff and had higher cooling capacity. In contrast, the amount of certain air pollutants removed by trees dropped from 2005 to 2021 for sulfur dioxide (361 kg/yr to 8 kg/yr), carbon monoxide (65 kg/yr to 32 kg/yr), and nitrogen dioxide (380 kg/yr to 298 kg/yr) as their ambient concentrations dropped. Pollen production by street trees from 1947 to 2021 initially dropped due to Dutch elm disease but has quadrupled since the 1980s due to increases in several high-pollen producing genera. Overall, this study illustrates how the public health effects of trees vary over decades due to changes in tree composition and abundance, environmental conditions, and changes in disease incidence and human demography, emphasizing the importance of incorporating long-term perspectives into contemporary tree management decisions. Highlights[bullet] Urban trees health-related ecosystem services changed over decades in a case study [bullet]The removal of SO2, NO2, and CO by urban trees is diminishing due to cleaner air [bullet]Shifts in tree composition have had large effects on allergenic pollen production [bullet]Changes in human disease incidence over decades mediate trees health effects

ecology↗

bioRxiv2025

Generating cognate epitope sequences of T-cell receptors with a generative transformer

Single-cell TCR sequencing enables high-resolution analysis of T Cell Receptor (TCR) diversity and clonality, offering valuable insights into immune responses and disease mechanisms. However, identifying cognate epitopes for individual TCRs requires complex and costly functional assays. We address this challenge with EpitopeGen, a largescale transformer model based on the GPT-2 architecture that generates potential cognate epitope sequences directly from TCR sequences. To overcome the scarcity of TCR-epitope binding pairs ({approx} 100, 000), EpitopeGen uses a semi-supervised learning method, termed BINDSEARCH, which searches over 70 billion potential pairs and incorporates high binding affinity predictions as pseudo-labels. To incorporate CD8+ T cell biology into the model as an inductive bias, EpitopeGen employs a novel data balancing method, termed Antigen Category Filter, that carefully controls antigen category ratios in its training dataset. EpitopeGen significantly outperforms baseline approaches, generating epitopes with high binding affinity, diversity, naturalness, and biophysical stability. Notably, the epitopes generated by EpitopeGen follow biologically plausible antigen category distributions, a crucial feature not achieved by other models. Using EpitopeGen, we directly identify subsets of clonally expanded tumorinfiltrating lymphocytes that recognize tumor-associated antigens, exhibiting elevated cytotoxicity and reduced exhaustion markers. From COVID-19 patients, EpitopeGen detects T cells that recognize COVID-19 spike proteins and non-structural proteins with distinct transcriptomic characteristics. In conclusion, EpitopeGen represents the first computational method that enables direct inference of antigen recognition profiles of CD8+ T cells from plain TCR repertoires.

immunology↗

bioRxiv2024

Enantioselective photoenzymatic C(sp3)-H functionalization via single-electron oxidation of carbanions

Established strategies for enantioselective hydroalkylation for C(sp3)-C(sp3) bond formation usually require pre-functionalized substrates as radical precursors in both transition-metal and photoenzymatic catalysis. Based on a sequential proton transfer/electron transfer (PT/ET) strategy, here we show a cooperative photoenzymatic system consisting of a flavin-dependent ene-reductase (ER) and an organophotoredox catalyst fluorescein (FI) to achieve atom-economic enantiodivergent hydroalkylation of electron-deficient C(sp3)-H with olefins. Mechanistic studies revealed a pathway for radical intermediate formation via excited-state FI*-induced single-electron oxidation of carbanions under alkaline conditions. The overall catalytic efficiency is enhanced by the electron transfer (ET) between FMNox and FI-*, while the stereoselectivity is controlled by ERs through enantioselective hydrogen atom transfer (HAT). We anticipate that this mode of photoenzymatic catalysis will inspire new pathways for generating free radical intermediates and foster innovative strategies for achieving photoenzymatic new-to-nature reactions. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=95 SRC="FIGDIR/small/627421v2_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@11b6c1eorg.highwire.dtl.DTLVardef@1575346org.highwire.dtl.DTLVardef@1c24a2org.highwire.dtl.DTLVardef@1a93c0d_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2024

Reduction of DNA Topoisomerase Top2 reprograms the epigenetic landscape and extends health and life span across species

DNA topoisomerases are essential molecular machines that manage DNA topology in the cell and play important roles in DNA replication and transcription. We find that knocking down the enzyme Topoisomerase Top2 or its mammalian homolog Top2b increases the life span of S. cerevisiae, C. elegans, and mice. Top2b reduction also extends the health span of mice and alleviates the pathologies of aging in multiple tissues. At the cellular/molecular level, Top2b reduction attenuates the major hallmarks of aging, such as cellular senescence, de-regulated nutrient sensing, epigenetic alteration, and lysosomal biogenesis. We observed that Top2b reduction significantly changes the epigenetic landscape in various mouse tissues toward those of the young animals, and differentially down-regulates genes with active promoter and high expression. Our observations suggest that Top2 reduction confers longevity effect across species via a conserved mechanism, and may be used as a novel therapeutic strategy for countering aging.

biochemistry↗

bioRxiv2024

Post-translational modifications orchestrate the intrinsic signaling bias of orphan receptor GPR52

Despite recent advances in GPCR structure and pharmacology, the regulation of GPCR activation, signaling, and functioning by diverse post-translational modifications (PTMs) has been largely unexplored. Furthermore, for a special category of self-activating orphan GPCRs, it is completely unknown whether and how specific PTMs control their unique signaling profiles and cellular functions. In this study of GPR52, an orphan GPCR with exceedingly high constitutive G protein signaling activity and emerging as a neurotherapeutic target, we discovered its disproportionately low arrestin recruitment activity. Through profiling the N-glycosylation and phosphorylation patterns of the receptor and clarifying their roles in G protein versus arrestin coupling, we found these two types of PTMs in specific motifs differentially shape the intrinsic signaling bias of GPR52. While N-terminal N-glycosylation promotes constitutive Gs signaling possibly through favoring the self-activating conformation, phosphorylation in helix 8, to our great surprise, suppresses arrestin recruitment and thus attenuates receptor internalization. In addition, we uncovered the counteracting roles of N-glycosylation and phosphorylation in modulating GPR52-dependent accumulation of the huntingtin protein (HTT) in brain striatal cells. Thus, our study provides novel insights into the regulation of intrinsic signaling bias and cellular function of an orphan GPCR via distinct PTMs in different motifs.

cell biology↗

bioRxiv2024

Social Experience Shapes Fighting Strategies for Reproductive Success

Social isolation generally increases aggression but decreases mating competition, resulting in an intricate and ambiguous relationship between social experience, aggression, and reproductive success. In male Drosophila, aggression is often characterized by lunging, a frequent and comparatively low-intensity combat behavior. Here, we provide a behavioral paradigm for studying a less frequent but more vigorous fighting form known as tussling. While social enrichment decreases lunging, aligning with past observations, it heightens the more forceful tussling behavior. These two forms of aggression rely on different olfactory receptor neurons, specifically Or67d for lunging and Or47b for tussling. We further identify three pairs of central pC1 neurons that specifically promote tussling. Moreover, shifting from lunging to tussling in socially enriched males is accompanied with better territory control and mating success. Our findings identify distinct sensory and central neurons for two fighting forms and suggest that social experience may shape fighting strategies to optimize reproductive success.

neuroscience↗

bioRxiv2024

A low-cost, open-source 3D printer for multimaterial and high-throughput direct ink writing of soft and living materials

Direct ink writing is a 3D printing method that is compatible with a wide range of structural, elastomeric, electronic, and living materials, and it continues to expand its uses into physics, engineering, and biology laboratories. However, the large footprint, closed hardware and software ecosystems, and expense of commercial systems often hamper widespread adoption. Here, we present a compact, simple-to-build, low-cost, multimaterial, and high-throughput direct ink writing 3D printer platform with detailed assembly files and instructions provided freely online. In contrast to existing low-cost 3D printers and bioprinters, which typically modify off-the-shelf plastic 3D printers, this system is built from scratch, offering a lower cost and full customizability. Despite its low cost, we demonstrate advanced active mixing and multimaterial multinozzle 3D (MM3D) printing methods, which previously have relied on expensive and custom motion control platforms. We finally introduce embedded multinozzle and 3D gradient nozzle designs that offer high throughput and graded 3D parts. This powerful, easy-to-build, and customizable printing platform can help stimulate a vibrant biomaker community of engineers, biologists, and educators.

bioengineering↗

bioRxiv2024

Cav3.1 is a leucine sensor in POMC neurons mediating appetite suppression and weight loss

Hypothalamic leucine sensing promotes satiety and weight loss but an understanding of how leucine regulates neuronal activity is lacking. Here we show that Cacna1g, encoding the T-type voltage-gated calcium channel Cav3.1, is enriched in hypothalamic leucine-sensing neurons and mediates leucine sensing. Pharmacological inhibition of Cav3.1 blunts leucine-induced activation of POMC neurons as well as the anorectic response to leucine in vivo. In addition, genetic deletion of Cacna1g in POMC neurons abolishes the appetite- and weight-suppressive effects of high-protein feeding. Mechanistically, we show that leucine binds to the voltage-sensing segment of Cav3.1, thereby reducing its threshold for voltage-dependent activation. Last, pharmacological activation of hypothalamic Cav3.1 promotes weight loss in diet-induced obese mice and potentiates the weight loss response to GLP-1 receptor agonism. These results reveal that Cav3.1 is a neuronal leucine sensor and a relevant weight loss target.

neuroscience↗

bioRxiv2024

Tracing neurodiverse disruptions underlying emotional episodic memory to diagnosis-specific network of emotional regulation in psychiatric disorders

BackgroundAffective symptoms are a prevalent psychopathological feature in various psychiatric disorders. However, the underlying neurobiological mechanisms are complex and not yet fully understood. MethodsWe used normative modelling to establish a reference for neurofunctional activation of functional magnetic resonance imaging based on an emotional episodic memory task, which is frequently used to study affective symptoms in psychiatric disorders. This normative reference was derived from a large dataset of healthy individuals (n = 409), and used to evaluate individualized functional alterations by calculating deviations from this reference in a clinical dataset of 328 participants, which included 168 healthy controls and patients with major depressive disorder (MDD, n = 56), bipolar disorder (BD, n = 31), and schizophrenia (SZ, n = 73). The neurofunctional deviations were mapped to emotional networks with specific emotional functions and used to predict affective symptoms in different mental disorders. The microscale cellular signatures underlying macroscale variations were identified using imaging transcriptomic analysis, and associated with affective symptoms. ResultsWe observed distinct patterns of cross-scale neural alterations linked to affective symptoms in three psychiatric disorders. Macroscale neural dysfunctions in distinct disorders were embedded into non-overlapping emotional networks and significantly associated with affective symptoms. The oligodendrocytes may mediate the network-specific impairments, and microglia for MDD, astrocytes for BD, and excitatory neurons for SZ as replicable cell-type correlates of affective symptoms. ConclusionsThese findings have potential implications for the understanding of unique neuropathological patterns of affective symptoms in distinct psychiatric disorders and improving individualized treatment response.

neuroscience↗

bioRxiv2024

Transcriptomic study of testicular hypoxia adaptation in Tibetan sheep

The Tibetan sheep is a typical hypoxia-tolerant mammal, which lives on the plateau, an altitude of between 2,500 and 5,000 meters above sea level, the study of its hypoxic adaptation mechanism provides reference for exploring the hypoxic adaptation mechanism of other animals. To grope for the genetic mechanism of adaptation to hypoxic environment at the transcriptional level in Tibetan sheep testicular tissue, and to identify candidate genes and key pathways related to sheep adaptation. Histological observation of testicular tissues from two sheep breeds was carried out using hematoxylin-eosin (HE) conventional staining. A total of 277 differentially expressed genes (DEGs) were authenticated at high altitude Tibetan sheep (ZYH) and low altitude Tibetan sheep (ZYM) by RNA sequencing technology (RNA-Seq), which included 165 up-regulated genes and 112 down-regulated genes. Functional analyses revealed several terms and pathways, such as were closely related with testis adaptation to plateau. Several genes (including GGT5, AGTR2, EDN1, LPAR3, CYP2C19, IGFBP3, APOC3 and PKC1) were remarkably enriched in several pathways and terms, which may impact the Plateau adaptability of sheep by adjusting its reproductive activity and sexual maturation, and protecting Sertoli cells, various spermatocytes and spermatogenesis processes. The results make a reasonable case for a better understanding of the molecular mechanisms of adaptation to altitude in sheep.

genomics↗

bioRxiv2024

Bidirectional modulation of negative emotional states by parallel genetically-distinct basolateral amygdala pathways to ventral striatum subregions

Distinct basolateral amygdala (BLA) cell populations influence emotional responses in manners thought important for anxiety and anxiety disorders. The BLA contains numerous cell types which can broadcast information into structures that may elicit changes in emotional states and behaviors. BLA excitatory neurons can be divided into two main classes, one of which expresses Ppp1r1b (encoding protein phosphatase 1 regulatory inhibitor subunit 1B) which is downstream of the genes encoding the D1 and D2 dopamine receptors (drd1 and drd2 respectively). The role of drd1+ or drd2+ BLA neurons in learned and unlearned emotional responses is unknown. Here, we identified that the drd1+ and drd2+ BLA neuron populations form two parallel pathways for communication with the ventral striatum. These neurons arise from the basal nucleus of the BLA, innervate the entire space of the ventral striatum, and are capable of exciting ventral striatum neurons. Further, through three separate behavioral assays, we found that the drd1+ and drd2+ parallel pathways bidirectionally influence both learned and unlearned emotional states when they are activated or suppressed, and do so depending upon where they synapse in the ventral striatum - with unique contributions of drd1+ and drd2+ circuitry on negative emotional states. Overall, these results contribute to a model whereby parallel, genetically-distinct BLA to ventral striatum circuits inform emotional states in a projection-specific manner.

neuroscience↗

bioRxiv2024

Miniscope Recording Calcium Signals at Hippocampus of Mice Navigating an Odor Plume

Mice navigate an odor plume with a complex spatiotemporal structure in the dark to find the source of odorants. This article describes a protocol to monitor behavior and record Ca2+ transients in dorsal CA1 stratum pyramidale neurons in hippocampus (dCA1) in mice navigating an odor plume in a 50 cm x 50 cm x 25 cm odor arena. An epifluorescence miniscope focused through a GRIN lens imaged Ca2+ transients in dCA1 neurons expressing the calcium sensor GCaMP6f in Thy1-GCaMP6f mice. The paper describes the behavioral protocol to train the mice to perform this odor plume navigation task in an automated odor arena. The methods include a step-by-step procedure for the surgery for GRIN lens implantation and baseplate placement for imaging GCaMP6f in CA1. The article provides information on real-time tracking of the mouse position to automate the start of the trials and delivery of a sugar water reward. In addition, the protocol includes information on using of an interface board to synchronize metadata describing the automation of the odor navigation task and frame times for the miniscope and a digital camera tracking mouse position. Moreover, the methods delineate the pipeline used to process GCaMP6f fluorescence movies by motion correction using NorMCorre followed by identification of regions of interest with EXTRACT. Finally, the paper describes an artificial neural network approach to decode spatial paths from CA1 neural ensemble activity to predict mouse navigation of the odor plume. SUMMARYThis protocol describes how to investigate the brain-behavior relationship in hippocampal CA1 in mice navigating an odor plume. This article provides a step-by-step protocol, including the surgery to access imaging of the hippocampus, behavioral training, miniscope GCaMP6f recording and processing of the brain and behavioral data to decode the mouse position from ROI neural activity.

neuroscience↗