Biology subjects

Lin, Y.-C.

Publications and source records attributed to Lin, Y.-C..

At least 19 recordsLinked to original sources

bioRxiv2026

The selection for cidofovir-resistant mutant vaccinia viruses is inhibited by coinfecting cidofovir-sensitive wildtypes

Recent years have seen two outbreaks of zoonotic mpox, highlighting the need for additional therapies to treat these infections and curb the spread of the virus. However, there are only two antiviral drugs available for treating mpox, and drug resistance is a potential threat to intervention. Here we investigate how drug resistance emerges in a population of viruses where the sensitive wildtype strain vastly outnumbers the drug-resistant mutant. Using cidofovir treatment and resistance as a model system during vaccinia virus infection, we found that cidofovir-resistant poxviruses rapidly outcompete cidofovir-sensitive viruses when the two strains replicate in complete isolation. However, when the two strains infect the same cell, the drug-resistant virus lost its competitive advantage over the sensitive strain. We found that when the two viruses replicate in separate cells treated with cidofovir, the resistant strain displays faster genome replication kinetics compared to the sensitive strain. However, when the two viruses replicate in the same drug-treated cell, the strains replicated at the same rate. This showed that the drug-resistance trait was functionally shared between the two genetically-distinct strains, allowing the sensitive strain to parasitize the growth advantage of the resistant strain and preventing the rapid outgrowth of the resistant strain. These observations suggest that poxvirus coinfections negatively affect the selection for a rare trait like cidofovir-resistance. Considering that poxviruses actively prevent superinfection, we hypothesize that superinfection exclusion could maintain fitness in a population and facilitate the outgrowth of rare, advantageous traits in poxvirus populations.

microbiology↗

bioRxiv2026

Integrated Proteo-Metabolomics of Urinary Extracellular Vesicles Reveals Early Molecular Divergence and Temporal Pathogenesis of Sepsis-Associated AKI

BackgroundSepsis-associated acute kidney injury (S-AKI) is a major contributor to morbidity and mortality in critically ill patients. However, the molecular mechanisms underlying its temporal progression remain poorly understood because conventional biomarkers primarily reflect renal dysfunction rather than disease pathogenesis. Urinary extracellular vesicles (uEVs), which carry kidney-derived molecular cargo, provide a promising platform for monitoring renal-specific biological alterations during disease progression. MethodsWe conducted a longitudinal multi-omics study of uEVs collected from 81 patients with sepsis, including 48 patients with S-AKI and 33 sepsis-only controls. Patients were randomly assigned to a discovery cohort (n = 52) and an independent validation cohort (n = 29). Urine samples were collected at Day 1, Day 4, and Day 8 after AKI diagnosis. High-resolution proteomic and metabolomic profiling was performed to characterize temporal molecular alterations. Enriched pathways identified in the discovery cohort were evaluated in the validation cohort using pathway-level concordance analysis. ResultsComparative analysis between S-AKI and sepsis-only patients identified distinct stage-specific molecular alterations throughout disease progression. At the early stage (Day 1), validated pathways included complement and coagulation cascades, ferroptosis, HIF-1 signaling, sphingolipid metabolism, and arachidonic acid metabolism, highlighting coordinated inflammatory, hypoxic, and lipid metabolic responses. During the mid-stage (Day 4), persistent activation of complement and coagulation cascades, ferroptosis, and HIF-1 signaling was accompanied by metabolic reprogramming involving alanine, aspartate and glutamate metabolism and tyrosine metabolism. Although limited sample availability reduced statistical power at Day 8, phenylalanine metabolism remained validated in the metabolomic analysis, suggesting persistent metabolic dysregulation during late-stage disease progression. ConclusionsThis study provides the first longitudinal, independently validated multi-omics characterization of human uEVs in S-AKI. By integrating proteomic and metabolomic profiling, we reveal the temporal evolution of renal-specific molecular pathways from early inflammatory and hypoxic responses to subsequent metabolic reprogramming. These findings establish uEV-based multi-omics as a promising strategy for molecular phenotyping of S-AKI beyond conventional clinical biomarkers and provide a valuable resource for future biomarker discovery and therapeutic target identification.

biochemistry↗

bioRxiv2026

Electrode pooling preserves movement decoding by retaining neural population dynamics

New implantable-electrode fabrication strategies make dense, ultrafine electrode arrays with lower tissue burden increasingly feasible, shifting a key bottleneck for scalable brain-computer interfaces from electrode placement to readout capacity. Electrode pooling, in which multiple electrodes share a readout channel, could relax this bottleneck by combining extracellular signals before acquisition, but it has remained unclear whether such compression preserves the neural population structure needed for behavioral decoding. Here we evaluate this question using software-emulated electrode pooling in mouse sensorimotor cortex during a cue-guided reach-and-grasp task using a high-density microwire array coupled to a CMOS microelectrode-array platform. Pooled recordings retain forelimb kinematic information more effectively than a channel-matched control that discards electrodes. Pooling reduces the separability of electrode-specific spikes and sorted units, indicating a loss of some neuronal detail, but the mixed signals still preserve task-aligned low-dimensional latent dynamics that support decoding. When readout capacity is fixed, this trade-off allows broader electrode coverage to contribute to behaviorally informative population sampling. Together, these results define electrode pooling as a design trade-off for scalable readout, in which some electrode-specific neuronal information is lost but the population dynamics needed for movement decoding remain accessible.

neuroscience↗

bioRxiv2026

Layered social competition coordinates reproductive hierarchy formation in ants

Social interactions establish reproductive hierarchies and regulate division of labor in eusocial insect colonies. In the ant Harpegnathos saltator, queen loss induces a subset of workers to transition into reproductive pseudo-queens, known as gamergates, through a ritualized antennal-dueling tournament that can last for more than a month. Gamergate transition is associated with sustained dueling engagement, yet the interaction networks and social dynamics that shape reproductive hierarchy formation remain unclear. Here, we combine long-term automated tracking with behavioral classifiers to systematically quantify social interactions, including antennal dueling and two distinct biting behaviors: aggressive grooming and mandible locking. We find that antennal dueling is organized into two activity states, an engaged state and a disengaged state, and that persistent maintenance of the engaged state, rather than transient entry into it, predicts successful transition to gamergate fate. Early access to abundant food shapes dueling activity and biases ants toward entry into the engaged state. Moreover, engaged-state individuals exhibit a strong assortative preference for dueling with one another and cluster spatially within the colony. We further show that mandible locking precedes transitions out of the engaged state, whereas aggressive grooming reinforces the disengaged state, together consistent with a role in stabilizing worker fate. Our findings reveal how structured social interactions organize reproductive hierarchy formation by regulating stable behavioral states associated with caste fate.

neuroscience↗

bioRxiv2026

High-Speed AFM Reveals Ligand-Dependent Supramolecular Switching of Human Phosphofructokinase-1

Phosphofructokinase-1 (PFK-1) catalyzes the ATP-dependent conversion of fructose-6-phosphate (F6P) to fructose-1,6-bisphosphate (F1,6BP), the first committed step of glycolysis. Beyond classical allostery, the liver isoform PFKL forms higher-order assemblies, but how ligand binding redirects intermolecular interactions remains unclear. Here we use high-speed atomic force microscopy (HS-AFM), topology-based AFM image simulations, and molecular dynamics (MD) simulations to define ligand-dependent assembly switching of human PFKL. Wild-type PFKL (PFKL WT) forms lattice-like assemblies under APO and ATP conditions, whereas coordinated ATP and F6P loading redirects assembly toward filaments in a ligand-order-dependent manner. APO-PFKL WT also forms lattice-like assemblies on or near membrane-supported surfaces, suggesting that interfacial environments influence where assembly initiates. The filament-defective N702T mutant forms ordered double-layer lattices and preserves this geometry under APO, ATP, and ATP+F6P conditions. MD simulations suggest that lattice stabilization arises from distributed inter-tetramer contacts. These findings define a structural framework for ligand-dependent supramolecular regulation of glycolysis.

biophysics↗

bioRxiv2026

Genetic Dissection of Grain Yield and Correlated Proxy Traits Under Suboptimal Conditions

Securing sustainable crop production requires the genetic improvement of abiotic stress tolerance. Due to the broad range of environmental factors causing abiotic stress and complex genotype-by-environment interactions, it is crucial to understand the genetic basis of crop yield under suboptimal conditions. Here, we developed a dent maize Multi-parent Advanced Generation Inter-Cross (MAGIC) population comprising 388 doubled haploid (DH) lines. The population was derived from eight founders with varying stress tolerance, selected from a dent diversity panel evaluated for yield performance across a wide range of European environments. The MAGIC DH lines were genotyped via whole-genome sequencing ([~]5X coverage) and evaluated in seven testcross and 14 line per se trials, for grain dry matter yield, leaf senescence, leaf rolling, anthesis-silking interval, and six additional agronomic traits. Genetic dissection identified 22 grain yield QTL, explaining 45% of the genetic variance. Under heat and drought stress, testcross grain yield correlated significantly with leaf senescence and leaf rolling measured in line per se trials. Bivariate multi-trait analysis showed that alleles for delayed senescence and reduced rolling at detected QTL generally exhibited positive effects on grain yield, suggesting that accumulating these favorable alleles could enhance yield performance. Incorporating these proxies into multi-trait genomic prediction models improved yield prediction accuracy, although gains were constrained by modest trait correlations. Given the comprehensive data, we also provide recommendations for optimizing sequencing depth and QTL mapping strategies in experimental maize populations. Key messageThis eight-founder MAGIC population represents a powerful resource for dissecting complex traits in maize, assessing the utility of drought proxy traits, and optimizing low-coverage whole-genome sequencing approaches.

genetics↗

bioRxiv2026

Hepatitis B virus proteome analysis identifies apolipoprotein C1 facilitating particle production and virus entry

Background & AimsAntiviral therapies targeting hepatitis B virus (HBV) suppress viral replication, but rarely achieve functional cure. Understanding HBV-host cell interaction is crucial for developing novel therapeutic approaches. Here, we report host cell proteins associated with HBV virions and filamentous subviral particles (fSVPs) and characterize one of them, apolipoprotein C1 (ApoC1), mechanistically. MethodsHighly purified HBV virions and fSVPs were obtained by sequential use of several biophysical methods. Particles were analyzed by mass spectrometry and associated proteins were evaluated phenotypically using an HBV infection model. The top hit, ApoC1 was characterized in detail. ResultsAssociated with virions and fSVPs, we identified in addition to known chaperones such as HSP90AB1 and HSC70, several apolipoprotein-related factors. RNAi-based phenotypic validation identified strongest effects for ApoC1, likely due to two complementary effects. First, ApoC1 depletion reduced intracellular cholesterol level impairing HBV infection and SVP production, which was compensated by exogenous cholesterol substitution. Second, ApoC1 that is mainly enriched in high-density lipoprotein (HDL), associates with HBV virions and fSVPs and increases HBV infectivity. The same was found for hepatitis D virus (HDV), a satellite virus utilizing HBV envelopes. Supplementation of exogenous HDL enhanced infection most likely via scavenger receptor class B type 1 (SR-B1), the natural HDL receptor. Consistently, inhibition of SR-B1 suppressed HBV and HDV infection. ConclusionsWe established a method for obtaining highly purified HBV virions and fSVPs and identified the HDL component ApoC1 to associate with both particle types. ApoC1 promotes HBV and HDV infection most likely via SR-B1 facilitating viral entry.

molecular biology↗

bioRxiv2026

Real-Time Visualization of G2L4 Reverse Transcriptase in DNA Repair via Microhomology-Mediated End Joining

Double-strand break repair (DSBR) is essential for genome integrity, yet mechanistic details of error-prone microhomology-mediated end joining (MMEJ) remain unclear. A bacterial group II intron-like reverse transcriptase, G2L4 RT, has been implicated in MMEJ, but how it executes DSBR is unknown. Using high-speed atomic force microscopy (HS-AFM), we directly visualize G2L4 RT-mediated DSBR via MMEJ. We observe that G2L4 RT dimers exhibit RT3a plug protrusion upon DNA engagement and catalyze MMEJ by binding and stabilizing a 4-bp annealed microhomology and filling adjacent single-strand gaps with dNTPs. We also observe Mn2+-stimulated terminal transferase activity that generates elongated and branched DNA intermediates prior to ligation. With T4 DNA ligase, we visualize binding near nick sites and real-time nick sealing, which stabilizes the repaired products and suppresses off-pathway branching. These results reveal how G2L4 RT and ligase activities shape MMEJ intermediates and outcomes.

biophysics↗

bioRxiv2025

Scube2 Modulates Coronary Vessel Formation during Cardiac Growth and Regeneration in Zebrafish

Coronary vessel formation is essential for cardiac growth and regeneration, yet the mechanisms regulating these processes remain incompletely defined. In this study, we identified and characterized Scube2 as a novel regulator in coronary vessel formation and heart regeneration. Scube2 is expressed in the epicardium covering the coronary vasculature under homeostatic conditions in adult hearts and is strongly upregulated after cardiac injury. Zebrafish scube2 mutant exhibits reduced coronary vessel coverage during cardiac growth and pronounced myocardial defects, including abnormal vessel morphology, disorganized contractile fibers, and mitochondrial damage. Following injury, scube2 mutant hearts show impaired revascularization and persistent fibrosis, indicating defective regeneration. Mechanistically, transcriptomic profiling of scube2 mutant hearts reveals attenuated expression of angiogenic-related genes, including those mediated by vascular endothelial and platelet-derived growth factors, consistent with reduced proliferation of endothelial cells and cardiomyocytes during repair. In a gain-of-function setting, SCUBE2 enhances platelet-derived growth factor signaling by promoting receptor activation in HEK293 cells. These findings support a novel role for Scube2 in cardiac growth and regeneration by modulating coronary vessel formation. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=138 SRC="FIGDIR/small/695032v1_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@7c5b5org.highwire.dtl.DTLVardef@451c40org.highwire.dtl.DTLVardef@141c88forg.highwire.dtl.DTLVardef@1d63765_HPS_FORMAT_FIGEXP M_FIG C_FIG

developmental biology↗

bioRxiv2025

A poly(A) isoform-aware single-cell and spatial atlas defines fibroblast niches in the human bladder

Bladder function relies on coordinated interactions among epithelial, stromal, vascular, and neural compartments, but high-resolution molecular and spatial features remain undefined. We generated a publicly accessible, poly(A) isoform-aware single-nucleus and spatial reference of the adult human bladder spanning four anatomical regions and both sexes. Integrating 74,694 snRNA-seq profiles with 168,476 Xenium-resolved cells, we identified 22 cell types and 23,489 polyadenylation sites, with isoform usage improving stromal resolution beyond gene expression alone. Spatial mapping revealed layered fibroblast niches aligned with epithelial, vascular, and neural structures, supported by Visium data. This multimodal reference links isoform regulation to anatomical context and provides a reusable framework for cell-type annotation, cross-study integration, and analyses of bladder physiology and disease.

molecular biology↗

bioRxiv2025

A Covalent PFKL Activator Suppresses Tumor Growth

Glycolysis fuels vital cellular functions and its dysregulation is implicated in cancer, neurodegeneration, antibiotic resistance and diabetes. The glycolytic dependency of cancer, known as the Warburg effect, presents a key vulnerability for developing targeted anticancer agents but remains challenging due to metabolic heterogeneity and resistance. Here, we developed a first-in-class covalent phosphofructokinase-1 liver type (PFKL) activator that induces metabolic imbalance coupled to delivery of a cytotoxic payload to cancer cells in vitro and in vivo. The electrophile-drug conjugate (EDC) site-specifically and proteome-wide selectively modifies K677 in the allosteric effector site to stabilize the R-state tetramer of PFKL and destabilize cell metabolism. We introduce EDCs as a new delivery mechanism analogous to antibody-drug conjugates but differentiated by selective covalent targeting of intracellular proteins.

biochemistry↗

bioRxiv2025

Graph pangenome reveals structural variation dynamics during cucumber breeding

Structural variants (SVs) represent a significant yet underexplored component of plant genome diversity. Analyzing SV dynamics is important for understanding their contributions to phenotypic variation and their influence on genome evolution. Here, we present a graph-based pangenome for cucumber, constructed from 39 reference-level genome assemblies. The pangenome captures 171,892 high-confidence SVs and enables genotyping of these SVs across 443 cucumber accessions, representing diverse geographic origins and spanning wild progenitors, landraces, and modern cultivars. Our analyses reveal that during cucumber domestication, a substantial portion of mildly deleterious SNPs are retained, whereas SVs are consistently purged, highlighting their potentially highly deleterious nature. During the geographic expansion of cucumber, a reduction in SV burden and a younger age of SVs than SNPs were observed, suggesting stronger purifying selection acting on SVs. Additionally, notable gene flow from wild population to African and European populations was detected, resulting in an increased SV burden, potentially due to hitchhiking effects. Importantly, incorporating SV burden into genomic prediction models improved the prediction accuracy for several agronomically important traits. This study illuminates the dynamics of SVs during cucumber domestication and improvement, highlights the complex interplay between SVs and selection pressures, and underscores the extensive implications of SVs for future cucumber breeding.

plant biology↗

bioRxiv2025

Stay or Stray: Lpar1 regulates neutrophil retention and epidermal homeostasis in early zebrafish development

Neutrophils are the most abundant myeloid cells in the vertebrate innate immune system and play a crucial role in host defense. Dysregulated release from hematopoietic tissue or excessive recruitment to inflamed sites is associated with immunopathologies, including chronic inflammation and recurrent infections. Lysophosphatidic acid (LPA) is a bioactive lipid that signals through a family of G protein-coupled receptors (LPAR1-6). Among these, LPA-LPAR1 signaling is activated in inflamed tissues and is known to modulate neutrophil infiltration during inflammatory responses. However, its role in neutrophil dynamics during early development remains unclear. Here, we report a novel function of Lpar1 in regulating neutrophil behavior during early zebrafish development. In Lpar1-deficient embryos, we observed a significant increase in neutrophil dispersal from the caudal hematopoietic tissue (CHT) at 3 days post-fertilization (dpf), with most dispersed neutrophils infiltrating the skin and contributing to elevated inflammatory signaling. Prior to dispersal, Lpar1-deficient embryos exhibited increased apoptosis of superficial epidermal cells and reduced expression of cxcl12a, a key retention signal for neutrophils in the CHT. Together, these findings highlight an essential role for Lpar1 in maintaining neutrophil retention and epidermal homeostasis during early development, thereby limiting inappropriate inflammation. SUMMARY STATEMENTThis work identifies a new role for a known inflammatory receptor in coordinating immune cell retention and skin stability during early development.

developmental biology↗

bioRxiv2025

A genus-wide interaction atlas across NS4B orthologues identifies a conserved role for UFMylation in orthoflavivirus replication

Orthoflavivirus infections represent an increasing public health burden, with several members of the genus emerging or re-emerging globally. Despite the availability of few vaccines, no antiviral drugs are currently licensed for the treatment of orthoflavivirus infections. Several pre-clinical studies identified the non-structural protein 4B (NS4B), one of the least characterized viral proteins within the orthoflavivirus genus, as the most promising target for the development of potent direct-acting antivirals. However, its functional roles in viral replication are still elusive. Here, we employ an integrated proteomic approach to systematically identify cellular targets of NS4B across eight prototypic orthoflaviviruses and characterize their influence on the human proteome. Using this approach, we mapped high-confidence NS4B-interacting human proteins across the genus, underlying potentially divergent mechanisms of host adaptation across orthoflaviviruses spanning diverse pathologies and vector preferences. Among these, we unveil a novel function for UBA5, the E1-activating enzyme of the UFMylation pathway, in orthoflavivirus replication. Mechanistically, we map associations of distinct viral proteins with multiple members of the UFMylation pathway, which are selectively recruited to sites of viral replication to promote mitochondrial respiration. Finally, we demonstrate that pharmacological inhibition of UFMylation exerts potent antiviral activity in vitro and in vivo. This integrative study provides a rational framework for a system-level understanding of orthoflavivirus NS4B effector functions and sheds light on a conserved and unconventional role for UFMylation in orthoflavivirus replication.

microbiology↗

bioRxiv2025

Muscle Activation of Upper Body in Different-Angle Suspension Push-Ups: An Analysis of Angle-Specific Muscle Engagement

The aim of this study was to understand the effect on upper body muscle activation of bodily angle during push-ups performed with TRX suspension training. Nineteen men (age: 21.1 {+/-} 1.2 years; height: 174.1 {+/-} 4.9 cm; weight: 70.7 {+/-} 7.2 kg) with resistance training experience participated in this study. The participants were required to perform five push-ups on a stable surface and with TRX at five angles (+30{degrees}, +15{degrees}, 0{degrees}, -15{degrees}, and -30{degrees}, where 0{degrees} indicates that the shoulder joints were at the same height as the ankle joints when the arms were extended). The recovery period between the sets at each angle was 3-5 minutes. Stable-surface and TRX push-ups were separated by at least 48 hours. During push-ups, electromyography (EMG) data from the pectoralis major (PM), anterior deltoids (AD), triceps brachii (TRI), upper trapezius (UT), and serratus anterior (SA) were recorded. Muscle activation was indicated by the percentage of maximum voluntary isometric contraction (%MVIC). The %MVIC of each muscle group was then categorized. Repeated-measured two-way analysis of variance was used to determine differences in the muscle group activation between the push-up surface types and five angles. Statistical significance was set at p < .05. The activation of the PM, AD, and TRI during TRX push-ups was categorized as medium to extremely high. Compared with that for stable-surface push-ups, the activation of the PM during TRX push-ups was significantly higher (p < .05). Furthermore, +30{degrees}, +15{degrees}, and 0{degrees} push-ups produced greater PM activation than push-ups at lower angles (p < .05). Both TRX and stable-surface push-ups resulted in greater anterior deltoids, TRI, UT, and SA activation during -30{degrees} push-ups. This study indicates the appropriate push-up practices for different muscle groups, as determined by quantifying the muscle activation.

physiology↗

bioRxiv2025

Comparative genomic analysis of a novel heat-tolerant and euryhaline strain of unicellular marine cyanobacterium Cyanobacterium sp. DS4 from a high-temperature lagoon

BackgroundCyanobacteria have diversified through their long evolutionary history and occupy a wide range of environments on Earth. To advance our understanding of their adaption mechanisms in extreme environments, we performed stress tolerance characterizations, whole genome sequencing, and comparative genomic analyses of a novel heat-tolerant and euryhaline strain of the unicellular cyanobacterium Cyanobacterium sp. Dongsha4 (DS4). This strain was isolated from a lagoon on Dongsha Island in the South China Sea, a habitat with fluctuations in temperature, salinity, light intensity, and nutrient supply. ResultsDS4 cells can tolerate long-term high-temperature up to 50 and salinity from 0 to 6.6 %, which is similar to the results previously obtained for Cyanobacterium aponinum. In contrast, most mesophilic cyanobacteria cannot survive under these extreme conditions. Based on the 16S rRNA gene phylogeny, DS4 is most closely related to Cyanobacterium sp. NBRC 102756 isolated from Iwojima Island, Japan, and Cyanobacterium sp. MCCB114 isolated from Vypeen Island, India. For comparison with strains that have genomic information available, DS4 is most similar to Cyanobacterium aponinum strain PCC 10605 (PCC10605), sharing 81.7% of the genomic segments and 92.9% average nucleotide identity (ANI). Gene content comparisons identified multiple distinct features of DS4. Unlike related strains, DS4 possesses the genes necessary for nitrogen fixation. Other notable genes include those involved in photosynthesis, central metabolisms, cyanobacterial starch metabolisms, stress tolerances, and biosynthesis of novel secondary metabolites. ConclusionsThese findings promote our understanding of the physiology, ecology, evolution, and stress tolerance mechanisms of cyanobacteria. The information is valuable for future functional studies and biotechnology applications of heat-tolerant and euryhaline marine cyanobacteria.

genomics↗

bioRxiv2025

Mitochondrial Ca2+ flickers on endoplasmic reticulum (ER)-mitochondrial contact sites to suppress store-operated Ca2+ entry

Ca{superscript 2} homeostasis requires coordinated regulation of ER stores and mitochondrial buffering. While the ER replenishes Ca{superscript 2} via STIM1-mediated store-operated Ca{superscript 2} entry (SOCE), how mitochondria-ER contact sites (MERCs) influence this process remains unclear. Here, using fluorescent live imaging, we capture spontaneous mitochondrial Ca{superscript 2} flickering at MERCs, which is driven by the IPR-VDAC1-mediated Ca{superscript 2} transfer and exerts an inhibitory effect on SOCE. Mechanistically, MERCs establish local ER Ca{superscript 2} depletion microdomains through this Ca{superscript 2} transfer. These microdomains act as molecular traps, triggering STIM1 accumulation at MERCs via its polybasic K-domain and sequestering it away from the plasma membrane (PM) to suppress SOCE. Furthermore, acute MERC induction redistributes constitutively active, Ca{superscript 2}-insensitive STIM1 away from ER-PM junctions, demonstrating that MERCs directly outcompete the PM for STIM1 recruitment. Finally, the microtubule (EB1)-ER contacts serve as a finite-capacity reservoir that buffers excess STIM1, with its disruption unmasking the dynamic competition between MERCs and PM. Together, our findings establish a tripartite system--PM, mitochondria, and microtubules--that dictates SOCE by controlling STIM1 topography, thereby protecting cells against Ca{superscript 2} overload.

cell biology↗

bioRxiv2024

Ganoderma formosanum polysaccharides enhance antitumor immune responses by downregulating the differentiation of myeloid-derived suppressor cells and tumor-associated macrophages

Ganoderma formosanum is a native species of Ganoderma isolated in Taiwan, and our previous studies showed that a polysaccharide fraction, PS-F2, purified from the submerged culture fluid of G. formosanum ATCC 76538 exhibited immunostimulatory and antitumor property. In the current study, we investigated the immunomodulatory and antitumor effects of PS-F2 from a UV-mutated G. formosanum variant NTU-1, which produced higher yields of PS-F2 than the original strain. Oral administration of PS-F2 effectively suppressed the growth of colon 26 (CT-26) carcinoma and splenomegaly in tumor-bearing mice without adversely affecting the animals health. We found that PS-F2 treatment resulted in augmented cytotoxic T lymphocyte (CTL) while significantly reducing the accumulation of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) and regulatory T (Treg) cells in the spleen. In the tumor, PS-F2 treatment markedly enhanced CTL and Th1 responses, whereas it reduced the accumulation of tumor-associated macrophages (TAMs). Collectively, our data demonstrate that oral treatment of PS-F2 from G. formosanum NTU-1 in CT26 tumor-bearing mice activates antitumor immune responses and reduces the accumulation of immunosuppressive cells in the spleen and the tumor, leading to delayed tumor progression.

immunology↗