Biology subjects

Huang, Q.

Publications and source records attributed to Huang, Q..

At least 55 records · Page 3Linked to original sources

bioRxiv2025

Efficient coding in working memory is adapted to the structure of the environment

Working memory (WM) relies on efficient coding strategies to overcome its limited capacity, yet how the brain adaptively organizes WM representations to maximize coding efficiency based on environmental structure remains largely unknown. In our study, participants remembered a sequence of gratings defined in a two-dimensional feature space where we manipulated directional consistency, revealing enhanced performance for structured (consistent direction) vs non-strutured (non-consistent direction) contexts, particularly for individuals with lower WM capacity. Magnetoencephalography analyses uncovered dissociable neural bases: consistent sequences engaged anterior temporal and medial frontal cortices for abstract directional representations during maintenance, while inconsistent sequences preferentially reactivated item-specific representations in parietal regions. These neural patterns predicted behavioral performance, establishing a neural efficiency principle wherein the brain adaptively switches between relational and item-based coding strategies, mitigating WM constraints. These findings advance our understanding of how structures shape WM organization, offering insights into cognitive flexibility and neural resource allocation in complex environments.

neuroscience↗

bioRxiv2025

Antibody immunogenicity prediction and optimization with ImmunoSeq

Therapeutic antibody development faces persistent immunogenicity challenges from anti-drug antibodies (ADA). Identifying peptide fragments presented by major histocompatibility complex is the central challenge in predicting immunogenicity. Here, we presented ImmunoSeq, an interpretable and applicable method for immunogenicity prediction. ImmunoSeq addresses this by deploying complementary k-mer (k=8-12) peptide libraries: a positive library of immunologically safe peptides from fragmented human proteins/antibodies, and a negative library of murine antibody fragments capturing evolutionary-selected immunogenic triggers. For candidate antibodies, we generate all possible k-mer peptides and compute hit rate by summing positive hits (+1.0) and negative hits (-0.2 penalty) normalized against total peptide number. Higher hit rate predicts lower ADA risk, with residue-level resolution enabling precise localization of immunogenic hotspots. ImmunoSeq demonstrated superior ADA correlation and humanness classification accuracy compared to deep learning models, while accurately predicts ADA reductions in humanization, enabling sufficient sequence optimization for humanness. By leveraging dual-library discrimination principles of self/non-self-peptide, ImmunoSeq provides a robust, interpretable solution for immunogenicity prediction and sequence optimization.

immunology↗

bioRxiv2025

Identification of natural products and synthetic analogs which inhibit microsporidia spores and prevent infection

Microsporidiosis, a disease caused by microsporidia, affects many animals, with symptoms ranging from diarrhea to death, especially in immunocompromised individuals. Current treatments, such as albendazole and fumagillin, are limited in efficacy. To address this problem, we utilized Caenorhabditis elegans infected with its natural microsporidian Nematocida parisii to evaluate 4,080 structurally diverse compounds from the Boston University Center for Molecular Discovery (BU-CMD) chemical library. From this screen we identified 34 compounds that effectively inhibited N. parisii infection and restored the reproductive capacity of C. elegans. All 17 compounds we validated prevented N. parisii infection in C. elegans, and 10 were capable of suppressing microsporidia invasion by inactivating mature spores. Additionally, five of the identified compounds were also effective against Pancytospora epiphaga, a species related to human-infecting microsporidia. Together this work identifies and characterizes compounds which inhibit microsporidia infection. ImportanceMicrosporidia are a large group of microbial parasites that infect many animals, including humans. Many agriculturally important animals such as honey bees, shrimp, crabs, and fish are infected by microsporidia, and these infections often result in smaller animals, fewer offspring, and death. Only two drugs are commonly used to treat microsporidia infections; due to some species being resistant and host toxicity there is a need to identify other microsporidia inhibitors. In this study, we screened over 4000 small molecules using a model round worm infected with microsporidia. We identified several dozen inhibitors and characterized how these compounds prevented infection by determining which stage of the parasite they act upon. Together our work identified and characterized compounds that could be used as a starting point to design better microsporidia inhibitors.

microbiology↗

bioRxiv2025

Human and mouse regenerative macrophages enhance beta cell survival, function, and proliferation

Aims/hypothesisType 1 diabetes is an autoimmune disease caused by immune-mediated destruction of insulin-producing pancreatic beta cells. Interestingly, individuals with long-standing type 1 diabetes have residual beta cells, suggesting the existence of regenerative mechanisms that help maintain beta cell survival. Islet-resident macrophages have an important role in type 1 diabetes, and during disease progression can adopt a tissue-regenerating phenotype which may support beta cells. However, the specific roles of macrophages in beta cell survival, function, and proliferation remains poorly defined. This study aimed to elucidate how different macrophage subtypes influence beta cell survival, function, and proliferation. MethodsMouse and human islets were isolated from the pancreas and co-cultured in vitro with macrophages. To investigate whether macrophages enhance beta cell survival and function, beta cell apoptosis was measured using flow cytometry, and insulin secretion was assessed using a glucose-stimulated insulin secretion assay. We also examined whether macrophages further increased beta cell proliferation in the presence of harmine, a DYRK1A inhibitor. Finally, we evaluated the effect of islet co-culture on macrophage phenotype by flow cytometry and cytokine secretion analysis. ResultsWe found that regenerative, but not pro-inflammatory, macrophages enhanced beta cell survival and function through mechanisms that did not require direct cell contact. Direct contact between macrophages and islets further promoted a regenerative phenotype in macrophages, characterized by increased CD206 expression and secretion of anti-inflammatory factors. Additionally, regenerative macrophages promoted beta cell proliferation in the presence of harmine. ConclusionsOur findings demonstrate that regenerative macrophages support pancreatic beta cell survival, function, and proliferation. Harnessing the regenerative properties of macrophages could offer a novel strategy to promote beta cell survival and function, thereby improving outcomes for individuals with type 1 diabetes. Research in ContextWhat is already known about this subject? O_LIMacrophages are the predominant resident immune cells within pancreatic islets in non-diabetic individuals; they contribute to tissue homeostasis and immune surveillance. C_LIO_LIDepending on their activation state, macrophages can exert either beneficial (pro-regenerative) or harmful (pro-inflammatory) effects on beta cell function. C_LI What is the key question? O_LIHow do different macrophage subtypes regulate islet survival, regeneration, and function? C_LI What are the new findings? O_LICo-culturing mouse or human islets with regenerative macrophages enhanced beta cell survival and function. When added in the presence of a DYRK1A inhibitor (harmine), they also promoted beta cell proliferation. C_LIO_LIRegenerative macrophage-derived factors promoted mouse islet function via a contact independent mechanism. C_LIO_LIMouse islets enhanced the regenerative phenotype of macrophages. C_LI How might this impact on clinical practice in the foreseeable future? O_LILeveraging the regenerative potential of macrophages represents a novel therapeutic approach to enhance beta cells, ultimately improving outcomes for individuals with type 1 diabetes. C_LI

cell biology↗

bioRxiv2025

NAD⁺ Replenishment Mitigates Cardiomyocyte Senescence and Corrects Heart Failure with Preserved Ejection Fraction in Aged Mice

Cardiomyocyte senescence, characterized by elevated cell cycle inhibitor expression, persistent DNA damage response, and mitochondrial dysfunction, contributes to myocardial stiffness and the progression of heart failure with preserved ejection fraction (HFpEF), the most common form of heart failure affecting individuals over 65. In this study, we investigated the role of NAD metabolism in cardiomyocyte senescence and cardiac function. Aged mice exhibited reduced cardiac NAD levels, impaired NAD biosynthesis and mobilization, and increased consumption, leading to suppressed SIRT1/6 activity and accumulation of senescent cardiomyocytes. This was accompanied by diastolic dysfunction consistent with HFpEF. In senescent AC16 cardiomyocytes, NAD depletion promoted senescence, which was reversed by the NAD precursors nicotinamide riboside (NR) and dihydronicotinamide riboside (NRH). In aged mice, two months of NR or NRH treatment improved diastolic function and reduced cardiomyocyte senescence. While NR primarily activated SIRT1 to suppress cell cycle arrest markers, NRH more robustly activated both SIRT1 and SIRT6, enhancing DNA damage repair. Acetylated H2AX, a SIRT6 substrate elevated in aged hearts and senescent cells, was selectively deacetylated by NRH. These findings identify NAD availability as a critical regulator of cardiac senescence and support NAD precursors, particularly NRH, as promising senescence-reducing therapies for treating aging-associated HFpEF.

pharmacology and toxicology↗

bioRxiv2025

Desert Hedgehog mediates stem Leydig cell differentiation through Ptch2/Gli1/Sf1 signaling axis

Desert Hedgehog (Dhh) mutations cause Leydig cell dysfunction, yet the mechanisms governing Leydig lineage commitment through Dhh-mediated receptor selectivity, transcriptional effector specificity, and steroidogenic coupling remain elusive. In this study, using CRISPR/Cas9-mediated gene knockout and stem Leydig cells (SLCs) transplantation, we identified a critical Dhh/Patched 2 (Ptch2)/Glioma-associated oncogene homolog 1 (Gli1)/steroidogenic factor 1 (Sf1) signaling axis essential for SLC differentiation in Nile tilapia (Oreochromis niloticus). Dhh deficiency resulted in defective adult Leydig cells and androgen insufficiency. Rescue experiments involving 11-ketotestosterone administration and a Dhh agonist treatment, combined with SLCs transplantation, demonstrated that Dhh regulates SLC differentiation, not survival. In vitro knockout of ptch1 and ptch2 in SLCs revealed that Ptch2 likely acts as the functional receptor for Dhh. This was further supported by in vivo genetic rescue experiments, where ptch2 mutation did not impair testicular development, yet completely rescued the testicular defects in dhh mutants--consistent with Ptch2 acting as an inhibitory receptor whose loss alleviates Dhh pathway suppression. Luciferase assays in Gli-knockout SLCs demonstrated that Gli1 acts as the primary transcriptional effector, and transactivates sf1 expression. Additionally, functional transplantation assays confirmed that Sf1 is indispensable for SLCs differentiation, as Sf1-overexpressing SLCs rescued differentiation, whereas sf1-mutant SLCs failed. Overall, our work delineates the Dhh-Ptch2-Gli1-Sf1 axis and provides fundamental insights into the endocrine regulation of Leydig cell lineage development. HighlightsO_LIDhh regulates the differentiation of SLCs rather than their survival C_LIO_LIPtch2 acts as the functional receptor for Dhh signaling in SLCs C_LIO_LIGli1 is the principal transcriptional activator for Dhh signaling in SLCs C_LIO_LISf1 is the critical downstream effector of Gli1 in SLCs differentiation C_LI

developmental biology↗

bioRxiv2025

Computational nanobody design using graph neural networks and Metropolis Monte Carlo sampling

Nanobodies have emerged as promising protein therapeutics due to their high-stability, low immunogenicity, and ease of production. However, experimental screening of high-affinity nanobodies for specific antigens and their post optimization remain costly and time-consuming, mainly due to the large number of possible variants. Here, we developed a computational approach that integrates graph neural networks (GNNs) with Monte Carlo Metropolis algorithm for nanobody design. We constructed a GNN model, AiPPA, to predict the protein-protein binding free energy (BFE) without requiring the complex structure, achieving a Pearson correlation of 0.62 on benchmark. We then combined AiPPA with Metropolis importance sampling to design low-BFE nanobodies from a non-affinity template. We applied this method to the antigen TL1A, and generated two affinity nanobodies. This work establishes a physics-informed deep learning method for computational nanobody design, providing a novel development strategy for protein therapeutics.

bioinformatics↗

bioRxiv2025

De novo design of protein-binding aptamers through deep reinforcement learning assembly of nucleic acid fragments

Nucleic acid aptamers targeting proteins are becoming increasingly important in biopharmaceuticals and molecular diagnostics. Traditionally, aptamers are discovered through labor-intensive screening of nucleic acid libraries using the SELEX method. However, de novo design approaches without experimental screening remain a significant challenge. Here, we employed deep reinforcement learning to develop an artificial intelligence (AI) agent capable of de novo aptamer design, termed AiDTA (AI-driven Docking-Then-Assembling). First, nucleic acid fragments were docked to the target protein to identify target-binding fragments. Then, AiDTA automatically assembled these fragments into aptamers using the Monte Carlo tree search algorithm and a policy-value neural network to guide the agent in generating aptamers with secondary structures similar to the original constituent fragments. Experimental validation demonstrated that the AiDTA-designed DNA aptamers targeting disease-related proteins exhibited high binding affinities in the nanomolar range, achieving the de novo design of protein-binding aptamers for the first time. Our study establishes a new approach to obtaining protein-binding aptamers for potential applications in biopharmaceuticals and diagnostics.

bioinformatics↗

bioRxiv2025

Macrophages Lacking TSC2 have mTORC1-dependent GPNMB Augmentation Ameliorating Cardiac Ischemia-Reperfusion Injury

IntroductionMacrophages (M{Phi}) modulate both myocardial inflammatory and reparative phases following ischemia-reperfusion (I/R) injury. The mechanistic target of rapamycin (mTOR) is thought to play an important role in M{Phi} phenotype and functionality, but studies report conflicting net influences suggesting dependence on disease context and downstream signaling. Here, we tested the impact of M{Phi} with constitutive mTORC1 activation induced by targeted deletion of tuberous sclerosis complex 2 (TSC2) on cardiac responses to I/R injury. Methods/ResultsMyeloid TSC2 depleted (M{Phi}TSC2-/-) mice were generated by crossing Lys2Cre x TSC2flx/flx. Bone-marrow derived M{Phi}TSC2-/- vs control M{Phi} had basal increased mTORC1 and reduced mTORC2 activity. M{Phi}TSC2-/- were differentially responsive to stimulation by lipopoly- saccharide/IFN-{gamma} or IL-4 in vitro, and all disparities were prevented by rapamycin confirming the model. In vivo, M{Phi}TSC2-/- mice were strongly protected against I/R injury, with minimal change in ejection fraction, less LV dilation, hypertrophy, lung edema, or activation of stress/pro fibrotic genes. Mice pre-treated with anti-LY6G Ab to deplete neutrophils were still similarly protected, suggesting that the impact was primarily related to M{Phi}. M{Phi}TSC2-/- mice had less myocardial pro- inflammatory macrophages (CCR2+MHC-IIhi), LY6C+ monocytes, neutrophils, and CD8+ T cells 5 days post-I/R, and fewer CCR2+ but more CCR2- M{Phi} 2 weeks post I/R. Both M{Phi}TSC2-/- in vitro and in vivo post I/R phenotypes were converted to WT by rapamycin, supporting mTORC1 dependence. Lastly, synthesis of glycoprotein nonmetastatic melanoma protein B (GPNMB), a principally M{Phi} anti-inflammatory secreted protein protective against myocardial infarction was enhanced in M{Phi}TSC2-/- macrophages and hearts following I/R in an mTORC1 dependent manner. Conclusion: Constitutive macrophage-specific mTORC1 activation via TSC2 deletion reduces pro-inflammatory cell infiltration, increases GPNMB protein expression and preserves heart function following I/R injury. Rapamycin eliminates these effects. These results identify a cardioprotective mTORC1-GPNMB signaling nexus in M{Phi} in vivo.

immunology↗

bioRxiv2025

Phosphorylation of the α subunit inhibits proteasome assembly and regulates cell division in archaea

Archaea of the order Sulfolobales possess a eukaryotic-like cell division machinery and display a eukaryotic-like cell cycle, however, the cell division and cell cycle control mechanisms remain enigmatic. Here, we demonstrate that phosphorylation of the subunit by a eukaryotic-like protein kinase ePK2 affects 26S proteasome assembly and controls cell division in Saccharolobus islandicus. ePK2 exhibits cell cycle-dependent expression at both transcriptional and translational levels. Deletion or overexpression of ePK2 results in impaired cytokinesis, with the deletion cells being unable to generate single chromosome cells after synchronization and the overexpression cells exhibiting growth retardation and cell enlargement. Interestingly, overexpression of ePK2 leads to a coherent reduction in cellular proteasome activity and degradation of cell division proteins. We identify S200 and T213 of the proteasome subunit as specific target sites for ePK2 phosphorylation. Functional and structural analyses of site-directed mutants at S200 and T213 suggest that S200 phosphorylation disrupts the assembly of 20S into 26S proteasome whereas T213 phosphorylation interferes the de novo ring assembly. Collectively, our study uncovers an ingenious and efficient mechanism of proteasome phosphorylation-mediated cell division regulation, a prototype of the eukaryotic cell cycle regulation system, in Sulfolobales archaea.

microbiology↗

bioRxiv2025

Putting a lid on it: The N-terminal helix of Arf1 inhibits switching via stabilization of the overall native state

The Arf (and Arf-like) GTPases, unlike all other Ras family GTPase members, exhibit a repressed conformation in the inactive, GDP-bound form. The N-terminal helix of Arf GTPases, which is missing in the other Ras family members, caps the switch region, confining it to this repressed state. Nucleotide exchange and activation involve a massive conformational change made possible by the dissociation of the N-terminal helix from the core of the protein. Spontaneous switching in Arfs is enhanced upon deletion of this helix. While the structural and functional role of the N-terminal helix in Arf proteins is well-known, the energetic basis for its effects have not been established. Here we mapped the local stability of the Arf1{Delta}17 variant, deleted for the N-terminal helix, using high pressure biophysical approaches and compared it to that of full-length Arf1. Deletion of the N-terminal helix decreased Arf1 stability across the entire structure. Thus, rather than imposing a specific structural pathway for repression, the N-terminal helix exercises global control of Arf1 stability to repress switching. Statement of SignificanceEnergetic mapping of the N-terminal deletion mutant of Arf1 using high pressure biophysical approaches reveals that this helix maintains the protein in the repressed state unique to Arf and Arf-like GTPases via overall stabilization of the native state rather than unique allosteric communication with the switch region.

biophysics↗

bioRxiv2025

Roles and transcriptional regulation of the endogenous cellulases in association with substrate and cellular processes in a thermoacidophilic archaeon

Microbes of the order Sulfolobales are potentially next generation platforms for cellulose degradation and utilization. However, the mechanisms of cellulose degradation and utilization remain unclear. In this study, we analyzed the enzymatic activity, localization, transcriptional regulation, and interplay of three endogenous cellulases Cel1, Cel2A, and LacS, and the association of transcription with cellular processes in the model thermophilic archaeon Saccharolobus islandicus REY15A. Overexpression strains based on a vector developed in this study as well as single and double deletion mutants of the three cellulase genes were constructed and analyzed. We reveal that Cel1 and Cel2A are membrane-associated, and a higher proportion of Cel2A is secreted into the medium than Cel1. The expression of all the three cellulases is induced by carboxymethylcellulose sodium (CMC). Furthermore, we found that the transcriptional levels of cel1, cel2A, and lacS are interdependent and cel1 and cel2A levels apparently increased with lacS deletion and overexpression of an ABC transporter, suggesting of an intracellular oligosaccharide-dependent regulatory mechanism. We showed that a cell cycle transcription factor aCcr1 binds to the promoter of cel1 in vitro. Additionally, we accidentally found that the cellulase genes expression increases in the presence of uracil synthesis pathway and deletion of the cellulase genes facilitates cell growth in CMC-containing medium. This study reveals an ingenious and intricated mechanism for cellulose utilization to adapt to extreme environment in archaea and provide insights for engineering Sulfolobales archaea as biomass-degrading and utilization platforms.

microbiology↗

bioRxiv2025

A rapid and efficient red-light-activated Cre recombinase system for genome engineering in mammalian cells and transgenic mice

The Cre-loxP recombination system enables precise genome engineering; however, existing photoactivatable Cre tools suffer from several limitations, including low DNA recombination efficiency, background activation, slow activation kinetics, and poor tissue penetration. Here, we present REDMAPCre, a red-light-controlled split-Cre system based on the {Delta}PhyA/FHY1 interaction. REDMAPCre enables rapid activation (1-second illumination) and achieves an 85-fold increase in recombination efficiency. We demonstrate its efficient regulation of DNA recombination in mammalian cells and mice, as well as its compatibility with other inducible recombinase systems for Boolean logic-gated DNA recombination. Using a single-vector adeno-associated virus (AAV) delivery system, we successfully induced REDMAPCre-mediated DNA recombination in mice. Furthermore, we generated a REDMAPCre transgenic mouse line and validated its efficient, light-dependent recombination across multiple organs. To explore its functional applications, REDMAPCre transgenic mice were crossed with the relative Cre-dependent reporter mice, enabling optogenetic induction of insulin resistance and hepatic lipid accumulation via Cre-dependent overexpression of ubiquitin-like with PHD and ring finger domains 1 (UHRF1), as well as targeted cell ablation through diphtheria toxin fragment A (DTA) expression. Collectively, REDMAPCre provides a powerful tool for achieving remote control of recombination and facilitating functional genetic studies in living systems.

synthetic biology↗

bioRxiv2025

The hollow truth: ethylene-triggered ROS, PCD, senescence, and autophagy drive hollow stem formation

Hollow stems have independently evolved multiple times across the plant kingdom, and play crucial roles in plant development and various environmental adaptations. However, the mechanisms underlying stem hollowness remain poorly understood. Water spinach (Ipomoea aquatica) is one of the few hollow-stemmed plants in the Convolvulaceae family, and its hollow stems are essential for thriving in aquatic environments. Using histochemical staining and transcriptome analysis, we identified programmed cell death (PCD) is involved in cavity formation of water spinach shoot tips. Single-cell transcriptome analysis further revealed that ethylene and reactive oxygen species (ROS) drive and regulate this process by activating transcription factors IaNAC074, IaNAC087, IaNAC029, IaNTL9, and IaTGA9, which initiate PCD, senescence, and autophagy, collectively controlling cell death. These findings were validated through treatments with ethylene and ROS reagents in water spinach and transient expression in tobacco. Additionally, transcriptomic data suggest that these mechanisms may also play a role in hollow stem formation in bamboo, highlighting the conservation of PCD regulatory mechanisms in plant development. This work not only fills a major knowledge gap in the adaptive mechanisms of hollow stem formation but also opens new avenues for agricultural and ecological applications, offering strategies to enhance crop tolerance to flooding and accelerate crop growth.

plant biology↗

bioRxiv2025

Biopsychosocial Correlates of Resting and Stress-Reactive Salivary GDF15: Preliminary Findings

Growth differentiation factor 15 (GDF15) is a biomarker of energetic stress related to aging, disease, and mitochondrial defects. We recently showed that GDF15 is quantifiable in saliva and acutely inducible by psychosocial stress. To date, the associations between GDF15 and biopsychosocial factors and individual characteristics remain unknown. Here, in a sample of healthy working adults (n = 198, 70% females), we first confirmed that salivary GDF15 reacts to acute psychosocial stress, peaking 10 min following a socio-evaluative stress paradigm (+28.3%, g = 0.50, p < 0.0001). We then explored associations between i) baseline GDF15 and ii) GDF15 stress reactivity and a variety of trait- and state-level biopsychosocial factors including sex and gender characteristics; measures of mental health, stress, and burnout; physical health and health behaviors; and anthropometric and blood-based metabolic biomarkers. Baseline salivary GDF15 was higher in men than in women and was positively correlated with testosterone, while negatively correlated with estrogen and traditionally feminine gender roles. Of the psychosocial factors examined, we found that work-related stress variables were most consistently related to GDF15, with work-related cynicism, burnout, and emotional exhaustion predicting higher GDF15 reactivity, while job-related autonomy and utilization of competence predicted smaller GDF15 responses. Consistent with GDF15s induction in metabolic and renal diseases, baseline GDF15 was also positively correlated with indirect markers of metabolic disease including waist-to-hip ratio, creatinine, and albumin. Finally, participants with greater GDF15 reactivity also exhibited greater cortisol reactivity, consistent with the role of GDF15 in stress regulation and energy mobilization. Together, this exploratory analysis of salivary GDF15 suggest new biological and psychosocial correlates, calling for large-scale studies connecting human experiences with biological markers of energetic stress.

physiology↗

bioRxiv2025

Cryo-ET of IgG bivalent binding on SARS-CoV-2 provides structural basis for antibody avidity

The bivalent nature of IgG enhances its neutralization potency against enveloped viruses; however, on-virion structural details of IgG bivalent binding with antigens remain elusive. Here we used cryo-ET to investigate how two potent IgGs P17 and S309 interact with S-trimers on the SARS-CoV-2 surface. We found that these antibodies exploit the mobility of S-trimers to form diverse bivalent binding patterns. P17 stabilizes S-trimers in a one-RBD-up conformation and gathers S-trimer into linear multimers within minutes, whereas S309 primarily forms circular S-trimer assemblies that extend into lattice-like structures. Additionally, both IgGs can facilitate inter-virion coupling through bivalent binding of opposing S-trimers. These findings provide a structural basis for understanding IgG avidity and offer insights for antibody engineering and vaccine design.

biophysics↗

bioRxiv2025

Small-molecule screen in C. elegans identifies benzenesulfonamides as inhibitors of microsporidia spores

Microsporidia, a large group of fungal-related intracellular parasites, infect several economically significant animals, leading to substantial economic losses. As currently available anti-microsporidia therapies are either ineffective or come with numerous adverse effects, there is a need for alternative microsporidia inhibitors. Here we screen a subset of the ChemBridge DIVERset library, comprising 2500 diverse compounds, using Caenorhabditis elegans infected with its natural microsporidian parasite, Nematocida parisii. By testing these compounds at 60 M in 96-well assay plates, we identified 26 hits that restored the ability of C. elegans to produce progeny in the presence of N. parisii. We confirmed that out of 20 tested compounds, 18 ChemBridge compounds effectively inhibit N. parisii infection in C. elegans. Of these 18, 10 were benzenesulfonamide derivatives which inhibit microsporidia infection by inactivating spores. We screened an additional 475-compound benzenesulfonamide library, successfully identifying three compounds that are effective at a lower concentration than the initial hits. We further show that one benzenesulfonamide compound displays inhibitory activity against several species of microsporidia, inhibiting infection of species belonging to the Nematocida, Enterocytozoon, and Encephalitozoon genera. Together our results suggest that benzenesulfonamides are a potential scaffold for the development of microsporidia antiseptics.

microbiology↗

bioRxiv2025

Nonlinear Relationship Between the C-Reactive Protein to Albumin Ratio and Chronic Kidney Disease: A Cross-Sectional Analysis Using the NHANES Database

ObjectiveThe C-reactive protein to albumin ratio (CAR) has gained attention as an inflammatory biomarker with potential relevance in various diseases. However, its relationship with chronic kidney disease (CKD) remains inadequately understood. This study aims to investigate the association between CAR and CKD prevalence in a diverse, multi-ethnic U.S. cohort. MethodsThis cross-sectional analysis utilized data from the 1999-2010 National Health and Nutrition Examination Survey (NHANES). Multivariable regression and subgroup analyses were conducted to control for confounding factors and examine the link between CAR and CKD. A restrictive cubic spline model was employed to explore potential nonlinear associations. ResultsAmong 30,049 participants aged 18 years or older, 5,423 (18.05%) had CKD. Compared to the lowest quartile (Q1) of log-transformed CAR, CKD risk was higher in the second (Q2), third (Q3), and fourth (Q4) quartiles, with odds ratios of 1.28, 1.29, and 1.63, respectively. A dose-response relationship was observed, indicating that higher CAR levels were significantly associated with increased CKD risk. ConclusionElevated CAR is independently associated with a higher prevalence of CKD, suggesting its potential utility as a biomarker for CKD risk assessment in diverse populations. Further studies are needed to confirm these findings and explore underlying mechanisms.

bioinformatics↗