Biology subjects

Shrivastava, A.

Publications and source records attributed to Shrivastava, A..

At least 19 recordsLinked to original sources

bioRxiv2026

Glial Mutant Huntingtin Expression Initiates a Progressive Pathological Cascade Toward Neuronal Involvement in Drosophila

The mechanisms of involvement of glial cells in the progression of Huntingtons disease remain sparingly elucidated. Using the Drosophila melanogaster model, we investigated the temporal course of the disease pathogenesis induced by pan-glial expression of HTTex1pQ93 in comparison to the temporal course of pathology induced by pan-neuronal expression. Our behavioural data were supported by quantitative confocal microscopy, quantification of aggregate formation and its morphometry, Manders M2 colocalization index, and correlative holotomography. Expression of mHTT in glial cells led to developmental defects and subsequent delayed onset of motor dysfunction and death with increasing amounts of HTT and changes in the immunoreactivity of glial cells. In spite of the progressive increase in HTT accumulation, glial aggregates showed stability after their initial formation, while neuronal mHTT revealed distinct age-dependent remodelling of its aggregates. Importantly, there was an initial preference of glial mHTT for glial compartments followed by a progressively increasing number of HTT in the neurons with aging. Correlative holotomography provided spatial evidence of the neuronal association of HTT. Together, these findings demonstrate that glial mHTT establishes a distinct progressive pathological trajectory characterised by evolving glial pathology, increasing neuronal involvement, and delayed functional decline, highlighting glia as an active component of HD-like disease progression.

neuroscience↗

bioRxiv2026

Food perception alone stimulates oviposition through serotonin signaling in Drosophila

Reproduction is strongly shaped by nutrient availability, but whether sensory information about food can regulate reproductive output before nutrients are consumed remains unclear. Here, using Drosophila melanogaster, we show that sensory perception of dietary yeast, a protein-rich food source widely used to stimulate fecundity in the fruit fly, is sufficient to rapidly promote egg laying. Specifically, we found that yeast odor exposure increased the rate of oviposition and the number of eggs laid within hours, independent of yeast intake, and that this response was mediated by olfactory signaling through the odorant receptor co-receptor Orco. We further identified serotonin receptor 2A (5-HT2A), but not 5-HT2B, as necessary for yeast odor-induced egg laying. We then asked whether yeast odor also elicits broader life-history changes and whether its reproductive and longevity effects depend on a shared mechanism. Consistent with previous observations, yeast odor also shortened lifespan. However, this lifespan effect was independent of 5-HT2A signaling, indicating that the reproductive and longevity responses to food perception are separable. Finally, our brain connectomic analyses revealed that yeast-responsive olfactory neurons preferentially influence oviposition descending neurons (OviDNs) compared with other olfactory neurons. OviDNs further connect with endocrine-related circuitry in the corpora allata (CA), and, most interestingly, the interneurons linking OviDNs to CA neurons are enriched for serotonergic and dopaminergic modulation. Taken together, our observations indicate that nutrient acquisition is not a prerequisite for animals to adjust their reproduction to the nutritional environment. Sensory information predicting food availability itself can elicit changes in neural state, likely through olfactory-reproductive circuits, that acutely alter reproductive physiology.

physiology↗

bioRxiv2026

neissflow: Streamlining Genomic Epidemiology of Neisseria gonorrhoeae with Nextflow

Antimicrobial-resistant Neisseria gonorrhoeae (Ng) poses a growing global public health threat. Existing tools available for Ng genome analysis carry notable limitations, including incomplete resistance marker coverage, absence of species identification, and lack of phylogenetic capability. We developed neiss-flow, a highly parallelized Nextflow pipeline for Ng genome analysis that integrates five subworkflows: read preprocessing, species identification, de novo assembly, antimicrobial resistance (AMR) profiling, and recombination-aware phylogenetic analysis with outbreak detection. neissflow performs extensive quality control on reads, assemblies, variant calls, and phylogenetic results. Validation was performed on two datasets: a mixed-species dataset (n=158; 105 Ng and 53 non-gonococcal species) for sensitivity/specificity assessment, and a reproducibility dataset (n=283 replicate sequences from 17 reference strains) for consistency and phylogenetic validation. neissflow achieved 100% sensitivity and specificity for Ng species identification compared with MALDI-TOF and PubMLST methods. All nine AMR and typing analytes demonstrated [≥]98.1% concordance with PubMLST genotype calls. Genotype-phenotype validation confirmed perfect concordance for key resistance determinants including gyrA mutations with ciprofloxacin resistance, 23S rRNA mutations with high-level azithromycin resistance, and tetM plasmid gene with high-level tetracycline resistance. Reproducibility analysis demonstrated 99.97% concordance across 3,093 analyte calls. Phylogenetic validation demonstrated 100% accuracy for both strain-level and intra-MLST clustering. neissflow is a robust, accessible, and standardized pipeline, positioning it as a valuable tool for public health laboratories engaged in Ng AMR monitoring and outbreak investigations. ImportanceNeisseria gonorrhoeae (Ng) is the second most common reported bacterial sexually transmitted infection and has developed resistance to all clinically relevant antibiotics. Surveillance of Ng resistance informs clinical recommendations for treatment of gonococcal infections. Whole genome sequencing (WGS) offers powerful insights into resistance mechanisms and transmission dynamics. However, many public health laboratories lack the resources needed to analyze these data effectively. We developed neissflow as an end-to-end, accessible Ng WGS analysis pipeline. neissflow demonstrated exceptional accuracy and reproducibility across diverse reference datasets. neissflow enables broader adoption of whole-genome sequencing-based surveillance and supports timely public health responses to emerging antimicrobial resistance in Ng by lowering technical barriers.

bioinformatics↗

bioRxiv2026

A Sensory Pathway Controls Motile Microcolony Formation and Spatial Organization in Gliding Bacteria

How cells transition between distinct modes of collective organization is a fundamental question in biology. We uncover the regulatory landscape governing the choice between bacterial swarming and zorbing. In Flavobacterium johnsoniae, zorbs are spherical, biofilm-like microcolonies that migrate collectively, whereas swarms are multilayered and ordered populations that expand planarly. We identify RgzAB, an unorthodox sensor kinase-response regulator pair governing this transition; suppressor and knockout mutants establish the importance of RgzA phosphorelay and RgzB as a downstream component. Transcriptomic and perturbation analyses link this switch to iron availability, connecting environmental sensing to collective behavior. Remarkably, RgzA activity also governs spatial organization within mixed populations: activated cells encapsulate wildtype neighbors into segregated co-zorbs, within which wildtype cells assemble into networks undergoing an abundance-dependent, percolation-like transition. Together, these findings reveal that one sensory circuit governs bacterial collectives at nested scales, from motility choice to the internal architecture of the collective.

microbiology↗

bioRxiv2026

Redox-modulated bacterial deubiquitinase ElaD: Target recognition and suppression of K63-linked polyubiquitin accumulation in yeast.

Bacterial deubiquitinases (DUBs) are important virulence effectors that manipulate host ubiquitin signaling during infection. ElaD, a CE-clan DUB expressed by enterohemorrhagic Escherichia coli, preferentially cleaves K63-linked ubiquitin chains, yet its effects on conserved cellular stress responses remain poorly understood. We demonstrate that ElaD exhibits redox-dependent DUB activity in vitro. In addition, we identified the molecular basis underlying the selective recognition of substrate proteins, ubiquitin and NEDD8 by ElaD. Structural and mutational analyses reveal that, beyond the conserved catalytic site, ElaD engages ubiquitin through a combination of electrostatic and hydrophobic interactions. Using Saccharomyces cerevisiae as a heterologous model system, we show that wild-type ElaD rescues the proteotoxic stress phenotype of ubp2{Delta} yeast cells, whereas specific ElaD mutants fail to confer a similar response. Furthermore, expression of ElaD suppresses oxidative stress-induced accumulation of K63-linked polyubiquitin and may perturb stress-associated translational regulation linked to K63 ubiquitin signaling. Consequently, cells expressing ElaD exhibit altered stress adaptation and diminished fitness during prolonged oxidative stress. Collectively, these findings indicate that ElaD perturbs ubiquitin-mediated stress signaling by counteracting K63-linked ubiquitination events that support adaptive cellular responses. Our study highlights how a bacterial DUB can reprogram conserved ubiquitin-dependent pathways and exploit host ubiquitin signaling networks to modulate cellular stress responses and protein homeostasis. These findings further suggest potential host targets of bacterial DUBs during infection.

biophysics↗

bioRxiv2026

Non-enzymatic RNA Glycation is a Metabolic Sensor of Cellular Stress

Non-enzymatic RNA modifications expand the epitranscriptome, encoding a rapid and chemistry-driven response to cellular stress. While methylglyoxal, a reactive glycolytic byproduct of metabolic stress, has been shown to modify proteins and DNA, its impact on RNA has remained unexplored. Here, we identify mRNA as a dynamic substrate of MGO, whose modification is actively regulated by DJ-1 and the glyoxalase detoxification system. We show that mRNA glycation impairs translation and engages both the integrated stress response and the ribotoxic stress pathway, culminating in compromised pancreatic {beta}-cell function and reduced insulin secretion. Notably, this phenotype is alleviated by the frontline antihyperglycemic agent metformin. Together, our findings position mRNA as a direct sensor of metabolic stress and establish RNA glycation as a mechanistic link between glycolytic imbalance, translational stress and disease.

molecular biology↗

bioRxiv2026

Systematic Screening of a Glycolysis-targeting Small-molecule Library Identifies Novel Inhibitors of Fungal Morphogenesis in Candida albicans

Fungal infections are an increasing global health concern, with Candida albicans emerging as a leading cause of mucosal and life-threatening systemic infections. C. albicans relies on yeast-to-hyphae transition, to establish systemic infections in the host. Our recent work demonstrated that glycolysis is a key regulator of hyphal differentiation in C. albicans. Leveraging this knowledge, we screened a small-molecule compound library containing glycolysis inhibitors for their ability to block fungal morphogenesis and identified multiple inhibitors of glycolysis that robustly block hyphal differentiation without compromising overall growth. While early glycolysis pathway inhibitors showed moderate effects, two compounds (NPD10084 and PKM2-IN-6) targeting pyruvate kinase activity emerged as the most potent inhibitors of fungal morphogenesis, completely blocking hyphal differentiation, in multiple filamentation-inducing conditions. Comparative RNA-Seq analysis revealed that pyruvate kinase inhibition using PKM2-IN-6 resulted in the repression of multiple genes associated with fungal morphogenesis, biofilm formation, and virulence. These transcriptional changes were accompanied by a significant reduction in biofilm formation and increased sensitivity to conventional antifungal drugs, including amphotericin B and fluconazole, in the presence of PKM2-IN-6. Furthermore, administration of PKM2-IN-6 significantly improved the survival of mice in a systemic model of murine candidiasis underscoring the in vivo efficacy of this compound. Molecular docking analysis showed stable binding of both compounds to the ATP-binding pocket of pyruvate kinase, suggesting ATP-competitive inhibition as the mode of action. Collectively, our study has identified novel inhibitors of fungal morphogenesis in C. albicans that target pyruvate kinase activity to increase antifungal susceptibility and attenuate the virulence of C. albicans. ImportanceCandida albicans is a major fungal pathogen that causes fatal infections, particularly in immunocompromised individuals. The increasing prevalence of antifungal resistance and the limited availability of effective antifungal therapies underscore the need for new treatment strategies. In this study, we identify pyruvate kinase, a key glycolytic enzyme, as an important regulator of fungal morphogenesis and virulence. Pharmacological inhibition of pyruvate kinase blocked hyphal differentiation without affecting fungal growth, impaired biofilm formation, and enhanced the activity of clinically relevant antifungal drugs. Transcriptomic analysis further revealed broad repression of genes involved in filamentation, biofilm formation, cell adhesion, antifungal resistance, and virulence, providing a molecular basis for these phenotypes. Importantly, pyruvate kinase inhibition also improved host survival in a murine model of systemic candidiasis. Together, our findings identify pyruvate kinase as a promising therapeutic target and demonstrate the potential of targeting fungal metabolism to effectively combat C. albicans infections.

microbiology↗

bioRxiv2025

Spontaneous cancer regression as inversion of spontaneous cancer progression: Malignant melanoma remission as a case-study towards clinical applicability

The spontaneous cancer regression process (SCR) a rather rare paradoxical natural phenomenon, shows that malignant tumors can episodically undergo complete permanent elimination without treatment, and thus may be used for gaining clues to incisive therapeutic innovations. SCR of malignant breast tumors occurs subclinically across human populations ([~]22% rate), according to Scandinavian and Wisconsin Screening Registries (monitoring 0.33million and 2.95million population respectively). SCR occurs in discoid melanomas ([~]12% rate). SCR process has high novelty with no toxicity nor recurrence, and duplicating SCR process is indeed clinically desirable. We aim to probe SCR using melanoma as illustrative pilot-study, and identify candidate leads that may mimic SCR on the tumor. We investigated molecular biological of melanoma, finding two reciprocal phases: spontaneous-progression and spontaneous-regression, and showed driver genes for melanoma SCR. Then, we pursued network pharmaco-informatics analysis. We found that spontaneous melanoma eradication shows an unexpected finding, in distinct contrast to the prevalent view that immunological processes and immunotherapy are critical for melanoma regression, than targeting DNA. We found that in contradistinction, it is DNA interference process that is primary route for melanoma regression, while anti-tumor immune activation is only secondarily needed. We observed that targeting two pathways (kinase-system, inositide-system) by inhibiting two genes, arrested melanoma-progression phase, and activated the reverse phase, melanoma-regression. We investigated the interactions of possible candidate leads, indicating significant therapeutic potency. Our findings underscore the high impact possibility for leveraging the anomalous phenomenon of spontaneous cancer regression as a general oncological principle for probing targeted therapeutic interventions, with substantial clinical potentials.

cancer biology↗

bioRxiv2025

Shared neural geometries for bilingual semantic representations

The human brain has the remarkable ability to comprehend and express similar concepts in multiple languages. To understand how it does so, we examined responses of hippocampal neurons during passive listening, directed speaking, and spontaneous conversation, in both English and Spanish, in a small group of balanced bilinguals. We find a small number of putative cross-language neurons, whose responses to equivalent words (e.g., "tierra" and "earth") are correlated. However, neurons semantic tunings differed substantially by language, suggesting language-specific neural implementations. Instead, the crucial driver of translation was a preserved geometric organization of neural responses between the two languages, one that did not depend on neuron level functional overlap. Indeed, that geometry was implemented by a common set of neurons along distinct readout axes; this difference in readout may help prevent cross-language interference. Together, these results suggest that hippocampus encodes a language-independent internal model for meaning.

neuroscience↗

bioRxiv2025

Sulbactam-Durlobactam Plus Ceftriaxone Dosing and Novel Treatment Regimens for Mycobacterium abscessus Lung Disease

BackgroundIDSA guideline-based therapy achieves sputum culture conversion rates in 20-34% of patients with Mycobacterium abscessus (MAB) lung disease (LD). Double-{beta}-lactam combinations have been proposed to improve cure, based on time-kill curves. MethodsWe performed minimum inhibitory concentrations (MICs) experiments followed by hollow fiber system model of MAB-LD (HFS-MAB) exposure-effect studies with sulbactam-durlobactam administered every 8h (q8h), q12h, and q24h, to identify target exposures. Next, the sulbactam-durlobactam target exposure plus ceftriaxone was administered in the HFS-MAB inoculated with three different MAB isolates, as was the sulbactam-durlobactam-ceftriaxone combination with epetraborole and omadacycline (SDCEO).{gamma} -slopes (kill-speed) were calculated for all regimens. The minimal sulbactam-durlobactam clinical doses that achieved target exposure were identified using Monte Carlo experiments. ResultsCeftriaxone reduced sulbactam-durlobactam MICs by 8-tube dilutions. In the HFS-MAB, sulbactam-durlobactam microbial kill and antimicrobial resistance were linked to % time concentration persists above MIC (%TMIC), with target exposure of 50%. Sulbactam-durlobactam killed 3.85 log10 CFU/mL below day 0 burden (B0) with regrowth. Sulbactam-durlobactam plus ceftriaxone killed without regrowth and demonstrated Bliss additivity.{gamma} of bacterial population in >95% of virtual subjects were 2.28 (0.97-4.80) log10 CFU/mL/day for sulbactam-durlobactam-ceftriaxone and 2.91 (1.65-4.93) log10 CFU/mL/day for SDCEO. The optimal sulbactam-durlobactam dose co-administered with ceftriaxone was 2G q8h for creatinine clearance >90 mL/min, 2G q12h for 60-90 mL/min, 1G q12h for [≥]30 to <60 mL/min, and 1G q24h for <30 mL/min. ConclusionSulbactam-durlobactam-ceftriaxone achieved the highest microbial kill encountered so far in the HFS-MAB. Sulbactam-durlobactam-ceftriaxone should be tested as the backbone for novel treatment shortening regimens.

pharmacology and toxicology↗

bioRxiv2025

Regulatory Plasticity and Metabolic Trade-offs Drive Adaptive Evolution of Alternative Flagellar Configurations in Pseudomonas aeruginosa

Evolutionary constraints governing flagellar number in bacterial pathogens remain poorly understood. While related Pseudomonas species are hyperflagellated, P. aeruginosa maintains strict monoflagellation through the FleQ-FleN regulatory circuit. Here, we demonstrate that FleN dosage is essential for maintaining monoflagellation and bacterial fitness. Wild-type P. aeruginosa consistently displayed unipolar monoflagellation, while {Delta}fleN mutants developed over two-to-five flagella per cell in uni- or bipolar arrangements. Hyperflagellated {Delta}fleN cells exhibited severe fitness defects including reduced growth rates, attenuated virulence in nematode infection models, and competitive disadvantages in co-culture experiments. Remarkably, {Delta}fleN cells rapidly evolved suppressor mutations in fleQ that partially restored growth and motility without always restoring monoflagellation. Five independent suppressor alleles mapped to critical FleQ functional domains (four in the AAA+ ATPase domain, one in the DNA-binding domain), suggesting reduced protein activity that rebalances the disrupted regulatory circuit. Single-cell motility analysis revealed that suppressor strains exhibit heterogeneous swimming dynamics, with subpopulations achieving wild-type speeds despite carrying multiple flagella. Proteomic analysis demonstrated that hyperflagellation triggers extensive cellular reprogramming beyond flagellar components, affecting metabolic pathways, stress responses, and signaling networks. While hyperflagellated cells suffered complete loss of pathogenicity in animal infection models, environmental selection under viscous conditions could drive wild-type cells to evolve enhanced motility through specific fleN mutations. These findings suggest that bacterial flagellar regulatory circuits function as evolutionary capacitors, normally constraining phenotypic variation but enabling rapid adaptation to alternative motility configurations when environmental pressures exceed the performance limits of standard monotrichous flagellation. SIGNIFICANCE STATEMENTBacterial flagella are extracellular appendages that rotate to propel the cell and enable swimming motility. While some bacteria have multiple flagella, many pathogenic species like Pseudomonas aeruginosa have just one. Surprisingly, mutants of P. aeruginosa with multiple flagella performed worse, i.e., they grew more slowly, were less infectious in laboratory animals, and were outcompeted by wild-type bacteria. Even when some mutant bacteria evolved compensatory changes, they still struggled compared to single-flagellum bacteria. This reveals an important evolutionary trade-off: while multiple flagella might seem advantageous for movement, having just one flagellum allows bacteria to grow faster and cause more severe infections. This plasticity likely explains why P. aeruginosa is so successful both in the environment and as a human pathogen.

microbiology↗

bioRxiv2025

Expansion of OSMR expression and signaling in the human dorsal root ganglion links OSM to neuropathic pain

RNA sequencing studies on human dorsal root ganglion (hDRG) from patients suffering from neuropathic pain show upregulation of OSM, linking this IL-6 family cytokine to pain disorders. In mice, however, OSM signaling causes itch behaviors through a direct effect on its cognate receptor expressed uniquely by pruriceptive sensory neurons. We hypothesized that an expansion in function of OSM-OSM receptor (OSMR) in sensory disorders in humans could be explained by species differences in receptor expression and signaling. Our in situ hybridization and immunohistochemical findings demonstrate broad expression of OSMR in DRG nociceptors and afferent fibers innervating the superficial and deep skin of humans. In patch-clamp electrophysiology, OSM directly activates human sensory neurons engaging MAPK signaling to promote action potential firing. Using CRISPR editing we show that OSM activation of MAPK signaling is dependent on OSMR and not LIFR in hDRG. Bulk, single-nuclei, and single-cell RNA-seq of OSM-treated hDRG cultures reveal expansive similarities in the transcriptomic signature observed in pain DRGs from neuropathic patients, indicating that OSM alone can orchestrate transcriptomic signatures associated with pain. We conclude that OSM-OSMR signaling via MAPKs is a critical signaling factor for DRG plasticity that may underlie neuropathic pain in patients.

neuroscience↗

bioRxiv2025

Substrate viscoelasticity regulates fibroblast adhesion and migration

Mechanical properties of the extracellular matrix (ECM) modulate cell-substrate interactions and influence cellular behaviors such as contractility, migrations, and proliferation. Although the effects of substrate stiffness on mechanobiology have been well studied, the role of ECM viscoelasticity in fibrotic progression remains less understood. To examine how viscoelasticity affects the biophysical properties and regulates the signaling of human mammary fibroblasts, we engineered elastic (E) and viscoelastic (VE) polyacrylamide hydrogels with comparable storage moduli ([~]14.52 {+/-} 1.03 kPa) but distinctly different loss moduli. Fibroblasts cultured on E hydrogels spread extensively (2428.93 {+/-} 864.71 m{superscript 2}), developed prominent stress fibers with higher zyxin intensity, and generated higher traction stresses (2931.57 {+/-} 1732.61 Pa). In contrast, fibroblasts on VE substrates formed smaller focal adhesion areas (54.2% reduction), exhibited lower critical adhesion strengths (51.8%), and generated 21% lower traction stresses (p < 0.001), indicating weaker adhesions. These substrates also promoted migrations and showed enhanced proliferation accompanied by reduced YAP activity, suggesting a mechanotransduction shift that may involve alternative signaling pathways. In contrast, E substrates showed YAP nuclear translocation, consistent with greater cytoskeletal tension and contractility. These findings highlight the importance of energy dissipation mechanisms in regulating fibroblast function on substrates mimicking the fibrotic milieu. Our results demonstrate that tuning the ECM viscoelasticity is a useful strategy to regulate cell behaviors in tissue engineered scaffolds, and develop better disease modeling for regenerative medicine.

bioengineering↗

bioRxiv2024

Ionic Liquid-Induced Modulation of Ubiquitin Stability: The Dominant Role of Hydrophobic Interactions

Despite the widespread use of imidazolium-based ionic liquids (ILs) in biotechnology, pharmaceuticals, and green chemistry, their detailed interactions with proteins, particularly affecting structural stability, remain poorly understood. This study examines the effects of ILs on ubiquitin, a thermodynamically robust protein with a {beta}-grasp structure. We found that IL-induced destabilisation follows a consistent order with previous findings: [BF4]- > [MeSO4]- > [Cl]- for anions and [BMIM]+ > [BMPyr]+ > [EMIM]+ for cations. Through pH and ionic strength-dependent studies, we observed that hydrophobic interactions predominantly influence the stability of positively charged ubiquitin, with electrostatic interactions playing a secondary role. NMR studies identified residues impacted by [BMIM][BF4]; however, mutagenesis of these residues showed minimal changes in destabilisation, suggesting a global effect. This led us to conduct a broader empirical analysis, incorporating solvent-accessible surface area evaluations, which confirmed that hydrophobic residues are the primary drivers of stability alterations in ubiquitin, with charged residues playing a minimal role. Additionally, single-molecule force spectroscopy results indicate that imidazolium ILs decrease the unfolding barrier without altering transition state structures, offering insights into protein folding dynamics. ILs appear to modulate the stability landscape of proteins by energetically and kinetically favouring the unfolded state over the folded state. These insights offer potential strategies for the selective tuning of protein stability, which could be exploited to modulate protein-protein or protein-substrate interactions in various applications of ILs.

biophysics↗

bioRxiv2024

Potassium ferric oxalate nanoparticles prevent human blood clotting and thrombosis in a mouse model

Blood clot creates occlusion in the veins and arteries, which leads to pernicious effects. Here, the anticoagulation properties of potassium ferric oxalate nanoparticles (KFeOx-NPs) in human blood were demonstrated for blood clot management. The mechanism involves the chelation of calcium ions from the blood by the oxalate present in the KFeOx-NPs. Various commercial assays were used to determine the clotting time for the KFeOx-NPs and identified the hindrance in activating factor XII in the intrinsic pathway. We used animal models to show toxicity and biodistribution profiles and determined the safety and efficacy. Intravenously injected KFeOx-NPs increased clotting time and thrombosis prevention in a mouse model confirmed by ultrasound and the power Doppler images. Coating catheters with KFeOx-NPs prevents clot formation with reduced protein attachment when incubated with blood, enhancing blood flow properties. In biological applications, KFeOx-NPs may improve the long-term prevention of blood clot formation and enhance the efficiency of medical devices. TOC O_FIG O_LINKSMALLFIG WIDTH=188 HEIGHT=200 SRC="FIGDIR/small/621820v1_ufig1.gif" ALT="Figure 1"> View larger version (68K): org.highwire.dtl.DTLVardef@1292afeorg.highwire.dtl.DTLVardef@1c5ba81org.highwire.dtl.DTLVardef@576f23org.highwire.dtl.DTLVardef@4186e9_HPS_FORMAT_FIGEXP M_FIG C_FIG PVP-stabilized novel potassium ferric oxalate nanoparticles were synthesized for the application of blood clot management and thrombosis prevention.

pathology↗

bioRxiv2024

Swarming bacteria exhibit developmental phase transitions to establish scattered colonies in new regions

The bacterial Type 9 Secretion System (T9SS) is essential for the development of periodontal diseases and Bacteroidetes gliding motility. T9SS-driven motile bacteria, abundant within the human oral microbiota, transport non-motile oral microbes and bacteriophages as cargo, shaping the spatial structure of polymicrobial communities. However, the physical rules governing the dispersal of T9SS-driven bacterial swarms are barely understood. Here, we collected time-lapse images, under anaerobic conditions, of developing swarms of a T9SS-driven microbe common to the human oral microbiota. Tracking of swarms revealed that small peripheral flares emerging from a colony develop structures that resemble fireworks displaying a chrysanthemum effect and flower-like patterns that convert to wave-like patterns and which further evolve into scattered microcolonies. Particle-image velocimetry showed density-dependent phase transitions and initial vorticity within these emerging patterns. Numerical simulations demonstrate that these patterns arise due to changes in swarm speed and alignment strength. Our data reveal a strategy used by an anaerobic swarming bacterium to control swarm behavior, resulting in scattered microcolonies distant from the mother colony, thus reducing competition for resources among colony members. This might ensure species survival even if conditions change drastically in one location of the human oral cavity.

microbiology↗

bioRxiv2024

A membrane-associated conveyor belt controls the rotational direction of the bacterial type 9 secretion system

Many bacteria utilize the type 9 secretion system (T9SS) for gliding motility, surface colonization, and pathogenesis. This dual-function motor supports both gliding motility and protein secretion, where rotation of the T9SS plays a central role. Fueled by the energy of the stored proton motive force and transmitted through the torque of membrane-anchored stator units, the rotary T9SS propels an adhesin-coated conveyor belt along the bacterial outer membrane like a molecular snowmobile, thereby enabling gliding motion. However, the mechanisms controlling the rotational direction and gliding motility of T9SS remain elusive. Shedding light on this mechanism, we find that in the gliding bacterium Flavobacterium johnsoniae, deletion of the C-terminus of a conveyor belt protein GldJ controls, and in fact, reverses the rotational direction of T9SS from counterclockwise to clockwise thus suggesting that the interface between the conveyor belt protein GldJ and the T9SS ring protein GldK plays an important role in controlling the directionality of T9SS. Combined with MD simulation of the T9SS stator units GldLM, we suggest a tri-component gearset model where the conveyor belt controls the rotational direction of its driver, the T9SS, thus providing adaptive sensory feedback to influence the motility of the gliding bacterium.

microbiology↗

bioRxiv2024

Mitochondrial calcium uniporter regulates human fibroblast-like synoviocytes invasion via altering mitochondrial dynamics and dictates rheumatoid arthritis pathogenesis

Rheumatoid arthritis (RA) is characterized by the aggressive migration and invasion of fibroblast-like synoviocytes (FLS) into cartilage and bone, a process that is significantly influenced by mitochondrial calcium uptake. This study highlights the critical role of mitochondrial calcium uniporter (MCU) in regulating FLS migration and mitochondrial dynamics, and its potential as a therapeutic target in RA. Notably, RA-FLS exhibited increased MCU expression and mitochondrial dysfunction compared to controls. Treatment with Ru360, a potent MCU inhibitor significantly reduced RA-FLS migration, calcium influx, and mitochondrial reactive oxygen species (ROS) levels, while restoring mitochondrial morphology and enhancing ATP production. Further analysis of MCU complex expression revealed elevated levels of MCU and other regulatory subunits (EMRE, MICU1, MICU2) in RA-FLS compared to controls, indicating mitochondrial dysfunction in RA. Mechanistically, MCU inhibition altered gene expression related to cytoskeletal dynamics, focal adhesion, and metabolic pathways. In human RA-FLS, MCU inhibition suppressed migration and invasion both in vitro and in vivo. The interaction between MCU and Miro1, essential for mitochondrial transport, was validated, and its disruption impaired FLS migration. Our findings highlight MCU as a promising therapeutic target to inhibit FLS migration and ameliorate RA progression.

immunology↗