Biology subjects

Tong, J.

Publications and source records attributed to Tong, J..

At least 19 recordsLinked to original sources

bioRxiv2026

Xenon improves autism-like behaviors in mice through potentiation of PVT-CeA glutamatergic neurotransmission

Autism spectrum disorder (ASD) is a common neurodevelopmental disease with no currently effective treatments. In this study, Xenon (Xe), a noble gas used clinically as an anesthetic and a neuroprotectant, has been investigated for its potential therapeutic effects in ASD. Two genetic ASD mouse models (Mef2c mutant and Shank3-/- mice) were exposed to a low concentration of xenon (25%) mixed with oxygen (30%) and balanced with nitrogen for a single exposure of 30 min or for 10 min per day for 10 days. These Xe exposure paradigms rescued ASD-like behaviors in both male and female mice. The behavioral improvements persisted for up to 10 days following termination of the 10-day exposure paradigm. Mechanistically, Xe reduced glutamic acid decarboxylase expression in the inhibitory neurons (verified with RNAseq) of the paraventricular thalamic nucleus (PVT) and decreased GABA release during social interaction. Targeted infusion of the GABAA receptor agonist muscimol into the PVT abolished the Xe-mediated behavioral improvements. Reduced GABAergic transmission following Xe exposure increased PVT glutamatergic neuronal activity. Chemogenetic inhibition of these neurons eliminated the therapeutic effects of Xe, whereas chemogenetic activation mimicked the Xe-induced behavioral improvements. Furthermore, opto-inhibition of PVT glutamatergic projections to the central amygdala (CeA) blocked Xe-mediated behavioral improvement. Opto-activation of the PVT-CeA glutamatergic circuit reversed ASD-like behaviors. These findings demonstrate that Xe ameliorates ASD-like phenotypes in mouse models by modulating the PVT Glu-CeA circuit, supporting Xe as a novel potential therapy for ASD.

animal behavior and cognition↗

bioRxiv2026

Prepatterned Tissue Stiffness Gradient Controls Organ shape and size

Organ morphogenesis is orchestrated by precise coupling of mechanical and biochemical signals, yet how these two signals are integrated within tissue niche to regulate organ shape and size remains poorly understood. Here, using sweat gland as a tractable model of exocrine mini-organs, we demonstrate that dermal fibroblasts play a key role to translate prepatterned tissue stiffness gradients into spatial Wnt5a gradients via Piezo1-mediated mechanosensing. Following epidermal placode formation, progenitor cells collectively invaginate into the dermis, where spatiotemporally graded Wnt5a directs their sequential transition from ductal to glandular fate in softer distal dermis, specifying distinct exocrine compartments. Perturbation of dermal stiffness gradients and mechanosensing in vivo and ex vivo alters Wnt5a expression levels and gradient patterns and thereby changes the ductal length and glandular size, revealing a direct link between tissue mechanics and organ dimensions. To recapitulate this process in vitro, we engineer a microfluidic platform capable of generating robust and linear morphogen gradients in 3D, allowing duct-to-gland fate transitions to occur at a high resolution. Together, our finding identifies prepatterned stiffness gradients as a master upstream regulator of coupled mechanical-biochemical signaling, define a mechanistic framework for two-step sequential glandular morphogenesis, and offer new strategies for engineering glandular epithelia in regenerative medicine.

developmental biology↗

bioRxiv2026

Progranulin deficiency perturbs lipid metabolism in white matter microglia

Progranulin (PGRN) deficiency is a common hallmark in frontotemporal dementia (FTD) patients with granulin (GRN) mutations (FTD-GRN). Previous studies by our group and others have observed that reduced PGRN perturbs lysosomal function and microglial activation, which is believed to accelerate neurodegeneration in FTD-GRN patients. Lysosomal function is intrinsically linked to lipid metabolism, and evidence suggests that GRN deficiency can alter lipid profiles in the brain. Unfortunately, studies to date have focused on whole brain or cortical extracts, limiting our ability to assess cell type-dependent changes in lipid metabolism under disease conditions. Here, we employed lipidomic analysis specifically within the pontine microglia of Grn knock-out (KO) mice, a cell population that was previously linked to disease phenotypes in this model. We observed a significant reduction in the endolysosomal lipid bis(monoacylglycero)phosphate (BMP) and the lipid metabolite phosphatidylethanolamine (PE); these microglial-specific lipid alterations mirror previous whole-brain findings, suggesting that similar changes may occur across multiple cell types in the brain. We also detected a significant increase in the myelin-composing factor galactosylceramide (GalCer), which may reflect an aberrant accumulation of myelin debris within microglia that arises due to defective lysosomal clearance. Notably, lipid perturbations were exacerbated with age within Grn KO microglia, suggesting that changes in lipid metabolism are both age- and genotype-dependent in this model. Together, our results support our hypothesis that PGRN acts as a master regulator of critical microglial processes - including lysosomal function, lipid metabolism, and the regulation of myelination - in an age-dependent manner.

neuroscience↗

bioRxiv2026

Haplotype-based insights into the genetic architecture of net blotch resistance in barley

Net blotch, caused by Pyrenophora teres, is a major constraint to barley production worldwide and occurs as two epidemiologically distinct forms: net form net blotch (NFNB) and spot form net blotch (SFNB). Although numerous resistance loci have been reported in recent years, their genetic relationship remains poorly understood, and the effective deployment of resistance is constrained by the complex genetic architecture of net blotch resistance. In this study, we used a haplotype-based mapping approach to dissect the genetic basis of resistance to NFNB and SFNB in a diverse panel of 950 barley accessions from the Australian Grains Genebank (AGG). Disease responses were evaluated across 13 experiments, and a total of 40 quantitative trait loci (QTL) were identified, including 26 associated with NFNB, 29 with SFNB, and 15 common for both diseases. Most loci co-localized with previously reported QTL, while six putative novel haploblocks highlighted untapped genetic diversity within the AGG collection. Correlation analyses across phenotypic, genetic and haploblock levels revealed a partial but incomplete overlap in resistance mechanisms between NFNB and SFNB. Among the 4,497 haploblocks, approximately 60% of them showed positive local genetic correlations between the two diseases, suggesting shared genomic contributions to resistance. Haplotype composition analysis further identified a resistant haplotype group, mainly comprising accessions of Asian origin, that exhibited high levels of resistance to both forms of net blotch. Through in silico haplotype stacking, we demonstrated the cumulative genetic potential achievable by combining favourable haplotypes. When the breeding objective was to improve resistance to both NFNB and SFNB, dual-disease stacking strategies outperformed single-disease approaches, highlighting the value of prioritising haplotypes with positive pleiotropic effects. Overall, this study provides a comprehensive haplotype-level framework for understanding net blotch resistance and delivers practical insights for breeding barley cultivars with durable and broad-spectrum resistance to both NFNB and SFNB.

plant biology↗

bioRxiv2026

Comparison of localGEBV and Optimal Haplotype Stacking Fitness Functions using a Novel R Package: HapSelect

Haplotype-based breeding strategies have emerged as promising approaches to maximize long-term genetic gain by identifying complementary parental combinations while maintaining genetic diversity. However, these methods typically require phased genotypes and more intensive workflow pipelines and skillsets. We developed a novel local genomic estimated breeding value (localGEBV) fitness function with similar intent to the optimal haplotype stacking (OHS) framework fitness function and implemented both in the novel R package, HapSelect. Our aim was to evaluate whether phased haplotypes provide additional benefit over the more easily available dosage-based unphased genotypes in highly inbred crops. A subset of bread wheat nested association mapping (NAM) population comprising 444 lines genotyped with 6,054 DArT-Seq markers was analysed. Marker effects were estimated using rrBLUP, localGEBV and haplotype effects were calculated across linkage disequilibrium-defined haploblocks, and genetic algorithms (GA) were used to identify optimal sets of 30 founders using either a localGEBV derived fitness function with unphased, dosage inputs or the OHS fitness function with phased inputs. Selected parental sets were compared with conventional truncation selection (TS) through 150 generations of forward simulation. The OHS fitness function achieved a marginally greater optimized ultimate GEBV than the localGEBV fitness function during GA optimization, with only 18 of the 30 selected founders overlapped between the two methods. Despite these differences, forward simulations demonstrated nearly identical long-term genetic gain for localGEBV and OHS-selected founders, with both approaches outperforming conventional truncation selection by maintaining greater genetic diversity and delaying the genetic plateau. The minimal difference between localGEBV and OHS is likely attributable to the high homozygosity of the population, where localGEBV and haplotype effects are nearly confounded. These results demonstrate that dosage-based localGEBV provides a practical alternative to phased haplotype approaches for parent selection in inbred crops, substantially simplifying genomic workflows while maintaining long-term breeding performance. Future work should evaluate these methods in more diverse inbred populations and outbred species, where great haplotypic diversity may increase the advantage of true haplotype-based optimizations.

genetics↗

bioRxiv2026

Trait stability of diverse kabuli chickpea germplasm from delayed sowing in a rainfed environment

Structured AbstractO_ST_ABSContext and ObjectiveC_ST_ABSDelayed sowing can expose chickpea crops to stress during the critical period for yield determination, but the effect of yield components and phenology to grain yield variation is not well characterised in diverse germplasm under rainfed conditions. Identifying genetic resources for grain yield improvement requires integration of multi-environment trial and genomic analyses to disentangle direct yield effects from indirect effects of phenology. This study aimed to (1) characterise genotype by environment interaction patterns for grain yield, yield components and phenology across times of sowing and seasons, and (2) identify genomic regions associated with improved grain yield that are present in genebank accessions but absent from current Australian commercial cultivars. MethodsA diversity panel of 141 kabuli chickpea genotypes, including six commercial Australian cultivars and 135 genebank accessions, was evaluated across six rainfed trials at Narrabri, New South Wales over three seasons (2018 to 2020) under typical (MAIN) and delayed (LATE) sowing. Multi-environment trial analyses with factor analytic models partitioned genotype by environment interactions for grain yield, 100-seed weight, seed number, and thermal time to flowering, podding, and maturity. Haplotype block analysis identified high variance blocks associated with seed number, classified by their overlap with high variance thermal time to flowering blocks, to distinguish from effects mediated by phenology. Results and ConclusionsDelayed sowing reduced grain yield by up to 1.04 t ha-{superscript 1}, driven primarily by reductions in seed number rather than 100-seed weight. Accelerated phenology was a key component of adaptation among commercial cultivars. Four haploblocks with high block variance for seed number were identified across all six trials. SignificanceSeed number was the dominant driver of grain yield variation in this diverse kabuli chickpea panel. Targeted introgression of rare superior haplotypes from genebank accessions provides an opportunity to broaden the genetic base of Australian kabuli chickpea and improve yield through higher seed number, with relevance to chickpea production systems facing similar climate variability. HighlightsDelayed sowing reduced grain yield in diverse kabuli chickpea germplasm by up to 1.04 t ha-1 across three years and six trials in northern New South Wales. Seed number, not seed weight, was the dominant driver of grain yield variation, and a shorter phenological duration was associated with higher seed number. Across all six trials, haplotype block analysis identified four genomic regions in high linkage disequilibrium with high variance for seed number and low variance for flowering time. The accession FLIP 94 62C uniquely carried rare superior haplotypes at two chromosome 4 blocks, the haplotype at the 17.0 Mb block was the most superior haplotype in all trials while the haplotype at the 8.5Mb block was most superior only in the most heat stressed environment.

plant biology↗

bioRxiv2026

Dual GLP-1/FGF21 agonism suppresses voluntary alcohol consumption, alcohol choice, and nucleus accumbens dopamine modulation

Excessive alcohol consumption remains a major public health challenge with limited therapeutic options. Both glucagon-like peptide-1 (GLP-1) and fibroblast growth factor-21 (FGF21) independently regulate alcohol intake through complementary metabolic and reward pathways, but their combined potential has not been explored. Here, we report that a long-acting dual agonist, GLP1-ELP-FGF21 modulates behavioural, neurophysiological, and cognitive components of alcohol seeking in mice. A single GLP1-ELP-FGF21 dose reversibly reduces voluntary alcohol intake for at least 72 hours in male mice, has sustained effects in female mice, and markedly blunts nucleus accumbens dopamine transients aligned to the initiation and termination of lick bouts during alcohol consumption. To assess its effects on decision-making, we used a novel two-choice (alcohol versus food) decision task modelled with evidence-accumulation frameworks. Alcohol choice behaviour conformed to evidence accumulation decision models: Linear Ballistic Accumulator (LBM) and Racing diffusion models (RDM). Critically, GLP1-ELP-FGF21 selectively reduces choices for alcohol and slows the latent accumulation rate for alcohol options, without affecting food-directed choice or non-decision processes. Sensory-specific satiety devaluation confirms that reductions in reward value are explained by reductions in accumulation rates. Together, these results highlight GLP1-ELP-FGF21 as a therapeutic strategy for alcohol use disorder via modulation of central reward pathways and decision-making when confronted with alcohol reward

animal behavior and cognition↗

bioRxiv2026

ExMODE: A Multi-Omics Repository for Extremophile Adaptation and Bioprospecting

Extreme environments, though hostile to most life forms, host specialized extremophile communities that have redefined biological cognition and emerged as vital biotechnological resources, with their unique adaptive traits and bioactive molecules driving advances in multiple scientific and industrial fields. However, research on extremophiles is hindered by limitations in culture-based methods, fragmented multi-omics data with non-uniform annotation standards across repositories, the lack of cross-extreme comparative research in existing resources, and the singularity of data dimensionality that neglects key structural information, all of which restrict the functional interpretation of extremophile microbes and the exploitation of their bioprospecting potential. To tackle these challenges, we developed ExMODE (https://db.genomics.cn/exmode/), a comprehensive multi-omics database platform dedicated to extremophiles. It centrally integrates multi-omics data from diverse extreme habitats with a standardized annotation framework, resolving data fragmentation and enabling systematic cross-environment comparative analyses to elucidate extremophile adaptive mechanisms. Moreover, ExMODE aggregates multi-dimensional datasets including genes, genomes, secondary metabolite sequences and protein structures, overcoming the constraints of single-dimensional data and significantly improving the efficiency of biotechnological resource discovery from extreme microorganisms.

microbiology↗

bioRxiv2026

Single-crypt evolutionary trajectories of human sporadic and hereditary colorectal precancers

Our understanding of the earliest genomic processes and evolutionary trajectories that distinguish sporadic from hereditary human cancers remains limited, impeding early diagnosis and risk stratification. Here, we performed whole-genome sequencing of 319 single crypts dissected from normal colorectal mucosa, premalignant polyps and malignant colorectal cancers (CRCs) from five sporadic patients and three familial adenomatous polyposis (FAP) patients. We found 66% of premalignant crypts from sporadic polyps did not harbor APC mutations, but frequently accumulated non-canonical but positively selected driver mutations including KMT2C, CACNA1A and FBLN2. In contrast, most premalignant crypts (71%) in FAP indeed acquired one or more somatic APC mutations or 5q loss of heterogeneity (LOH). Sporadic polyps were dominated by clock-like mutational processes at single-crypt level. In contrast, FAP crypts evolved more diverse genomics processes, including reactive oxygen species-associated damages, APOBEC-associated mutagenesis and pks+ Escherichia coli-associated mutagenesis. Premalignant crypts in FAP also exhibited a 2-fold higher burden of LINE-1 retrotranspositions than sporadic ones, despite arising at a substantially younger age. Phylogenetic timing estimations showed that the first somatic APC mutation in FAP often occurs prenatally. Phylogeographic analysis further revealed spatial lineage segregation in early polyclonal polyps, followed by Big-Bang lineage intermixing in later monoclonal ones. Together, these data demonstrate that early colorectal tumorigenesis does not obey a universal APC-first model, where sporadic and hereditary precancers follow distinct evolutionary trajectories. Our study also highlights that polyclonal-to-monoclonal transition in premalignant stages represents the Big-Bang growth of colorectal tumors, offering crucial insight into early diagnosis and risk stratification.

cancer biology↗

bioRxiv2026

A novel fracture lattice in spiny mouse skin facilitates tissue autotomy and regeneration

Autotomy is a unique phenotype whereby an animal sheds a body part to escape predation1-3. The timing and location of autotomy are tightly regulated by preformed planes of weakness (aka fracture planes) which facilitate tissue loss. While autotomy is often followed by regeneration, these phenotypes are rarely reported in mammals4-9. A notable exception are spiny mice (Acomys) which exhibit skin autotomy and more remarkably, complete tissue regeneration10-14. Presently, mechanisms underlying autotomy and complete regeneration in Acomys skin remain elusive. Here, we report the discovery of a honeycomb-like fracture lattice in Acomys skin whose design directs tissue destruction but also facilitates regenerative healing. Unlike the single continuous surface of a fracture plane, this fracture lattice consists of a three-dimensional array of hexagonal units whose boundaries guide tissue breakage. Moreover, we identify collagen VI as the main constituent of the fracture lattice and find that it is distinctly arranged to initiate fracturing and propagation of skin tearing. By preconditioning the tissue for autotomy, the fracture lattice dampens the damage-induced inflammatory response but also upregulates a pro-regenerative gene signature, accelerating skin appendage regeneration. Lastly, we discovered the key role of spiny hairs in fracture lattice formation, as inhibiting their development leads to abnormal pattern formation and changes in skin fracture mechanics. Our results present a novel example of a uniquely evolved structural adaptation in mammalian skin that links tissue patterning, autotomy and regeneration. We expect that the application of a modular compartment structure to artificial skin and other organ engineering may enhance resilience to injury and facilitate efficient regeneration.

developmental biology↗

bioRxiv2026

The genetic repertoire of the deep sea: from sequence to structure and function

The deep sea as the largest and maybe most hostile environment on Earth is still underexplored especially regarding its genetic repertoire. Yet, previous work has revealed significant habitat-specific deep-sea biodiversity. Here, we present an integrated deep-sea genetic dataset comprising 502 million nonredundant genes from 2,138 samples and 2.4 million predicted structures, and used it to link specific protein structures with genetic variants associated with life in the deep sea and to assess their biotechnology potential. Combining global sequence analysis with biophysical and biochemical measurements revealed unprecedented sequence diversity, yet substantial structural conservation of proteins. Especially proteins involved in replication, recombination, and repair were identified to be under rapid evolution and with specialized properties. Among these, a structurally divergent helicase exhibited advantages in controlling nanopore sequencing speed. Thus, our work positions the deep sea as a unique evolutionary engine that generates and hosts genetic diversity and bridges genetic knowledge with biotechnology.

bioinformatics↗

bioRxiv2025

Crystal structure and nanobodies against domain 3 of the malaria parasite fusogen Plasmodium falciparum HAP2

Malaria parasites are transmitted to humans through a bite from an infected female Anopheles mosquito. Within the mosquito midgut, malaria parasite gametes are activated and undergo fertilisation. If parasite fertilisation is perturbed, this stops the transmission of malaria parasites from mosquito to human. One proposed target of transmission-blocking interventions is Plasmodium falciparum fusogen PfHAP2, which is essential for gamete fusion during parasite fertilisation. However, to date, no monoclonal antibodies or structures of PfHAP2 have been generated. We have identified nanobodies that bind specifically to domain 3 of PfHAP2 with nanomolar affinities, two of which show some cross-species reactivity with HAP2 of other Plasmodium species. The crystal structure of one nanobody in complex with domain 3 of PfHAP2 provides the first structural insights into this transmission-blocking target in P. falciparum.

microbiology↗

bioRxiv2025

Brain-wide Genome Editing via STEP-RNPs for Treatment of Angelman Syndrome

Brain-wide genome-editing remains a major hurdle for the treatment of neurogenetic disorders. Here, we report a non-viral, non-nanoparticle, chemical modification-based method, called Stimuli-Responsive Traceless Engineering Platform (STEP) that achieves highly efficient and brain-wide genome-editing of neurons in mice. Using cholesterol-based STEP as a lead, we show that a single administration of STEP-ribonucleoproteins (RNPs) results in functional genetic rescue with significant improvements across a battery of neurobehavioral domains in the Angelman syndrome (AS) mouse model. No significant off-target events or general toxicity effects are observed. STEP-RNPs are also highly efficient at editing human neurons and cortical brain organoids differentiated from AS patient-derived iPSCs. scRNA-seq analysis confirms functional genetic rescue via reactivation of Ube3a/UBE3A expression in human and mouse STEP-RNP-treated neuronal cells. Genome editing via STEP-RNPs has broad applications and the potential to treat many other neurogenetic disorders.

genetics↗

bioRxiv2025

Pp6-Pfkfb1 axis modulates intracellular bacterial proliferation by orchestrating host-pathogen metabolic crosstalk

Intracellular bacterial pathogens exhibit heterogeneous replication rates within host macrophages, but the mechanisms by which they manipulate host factors for survival remain incompletely understood. Using a fluorescence-dilution reporter system in Salmonella typhimurium (Salmonella)-infected macrophages, we found that Protein Phosphatase 6 (Pp6) was downregulated in macrophages harboring growing bacteria. Conditional knockout of Pp6 elevated host susceptibility to Salmonella-mediated lethality due to compromised antimicrobial defenses. MicroRNA-31 (miR-31) was identified as a negative regulator of Pp6, and its conditional ablation enhanced bacterial clearance. Yeast two-hybrid screening identified 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 1 (Pfkfb1), a metabolic regulator, as a substrate of Pp6. Pp6 deficiency resulted in significantly elevated expression of Pfkfb1, which was highly expressed in macrophages containing replicating Salmonella. Pfkfb1 deletion restricted bacterial proliferation by promoting nitric oxide (NO) production while concurrently suppressing arginase-1 (Arg-1) expression and impairing arginine metabolism in macrophages. Collectively, these results establish the Pp6-Pfkfb1 axis as a key regulator of host metabolic adaptation and intracellular bacterial survival, offering potential therapeutic targets against multidrug-resistant pathogens. Author summaryIntracellular pathogens secrete effector proteins that intercept and modify host cells to usurp host defenses and establish habitable intracellular niches, yet the host factors they manipulate for survival and virulence are not fully understood. Using a fluorescence-dilution reporter system in Salmonella typhimurium (Salmonella)-infected macrophages, we found Protein Phosphatase 6 (Pp6) was significantly decreased in macrophages harboring replicating Salmonella and its deficiency indulged bacterial growth in macrophages. However, the deletion of microRNA-31 (miR-31), a negative regulator of Pp6, enhanced Salmonella clearance. Furthermore, through yeast two- hybrid screening, we identified 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 1 (Pfkfb1) is a substrate of Pp6. And we demonstrated Pfkfb1, abundantly expressed in macrophages containing growing bacteria, is crucial for Salmonella proliferation by regulating nitric oxide (NO) levels, arginase-1 (Arg-1) expression and arginine metabolism. Overall, the molecular changes in Pp6-Pfkfb1 axis drive host metabolic adaptations that enable intracellular bacterial survival.

microbiology↗

bioRxiv2025

Assessing the Suitability of Deubiquitylases As Substrates For Targeted Protein Degradation

The development of selective inhibitors of Deubiquitylase enzymes (DUBs) is difficult due to a high level of homology in the active sites of the {approx} 100 such enzymes in the human proteome. A potential way to achieve this in a more facile manner would be to develop PROTACs or molecular glues that engage the target DUB in a less conserved region outside of the catalytic domain. However, this raises the concern that auto-deubiquitylation would make DUBs poor substrates for this modality. Here we describe a chemical genetics system to evaluate this issue. We find that some DUBs are readily degradable via the Ubiquitin-proteasome pathway and some are not. Of the latter category, some resist turnover through auto-deubiquitylation and some are simply poor proteasome substrates. SignificanceDeubiquitylases (DUBs) are a family of specialized proteases that hydrolyze the isopeptide bond between a lysine and the C-terminal carboxylate of Ubiquitin. DUBs are involved in a myriad of cellular processes and many are attractive drug targets. However, it is difficult to develop selective orthosteric inhibitors due to the high degree of homology between DUB active sites. Targeted protein degradation using a proteolysis-targeting chimera (PROTAC) that recognizes the DUB in a less conserved region outside of the catalytic domain constitutes an attractive alternative strategy for selectively inhibiting a given DUB. Such ligands may not block the catalytic activity of the enzyme, raising the concern that auto-deubiquitylation will make DUBs inherently poor substrates for PROTACs of this type. Since drug-like ligands that engage DUBs outside of the active site are extremely rare, this issue is difficult to address in a straightforward fashion. In this study we establish a generally applicable chemical genetics workflow to evaluate the degradability of DUBs by a PROTAC. The data indicate that some DUBs are readily degradable and some are not. In particular, USP11, an attractive drug target in various cancers and Alzheimers disease, is shown to be rapidly degradable, while its paralogs, USP4 and USP15 resist degradation through auto-deubiquitylation.

biochemistry↗

bioRxiv2025

Heavy Metal Exposure Disrupts Electrotactic Behavior in Caenorhabditis elegans

Environmental toxicants such as heavy metals can profoundly impact organismal physiology, yet sensitive and rapid behavioral assays to quantify such effects are limited. Here, we employed a microfluidic-based electrotaxis assay to systematically evaluate the impact of chronic exposure to metal salts on the electrotactic swimming behavior of the nematode Caenorhabditis elegans. We report that exposure to Ag, Hg, MeHg, Cu, Mn, and Pb significantly alters electrotaxis speed. Notably, Cu required higher concentrations to induce phenotypes, whereas Ag and Hg disrupted behavior at lower doses. Three other metals (Ni, Fe, and Cd) did not elicit marked electrotaxis defects. Bioaccumulation analysis of Cu, Ag, Hg, and MeHg via ICP-MS revealed that MeHg was present in highest amount in worms. Consistent with this, MeHg showed the highest toxicity. We also found dopaminergic neurodegeneration in most metal-exposed animals, correlating with behavioral impairments. Although heat shock factor-1 (HSF-1) and its downstream target hsp-16.2 were induced by some metals, their expression did not consistently correlate with electrotaxis defects. Moreover, metal-induced impairments persisted even after recovery on toxin-free media, indicating possible irreversible damage. Our findings establish electrotaxis in C. elegans as a robust, non-invasive assay to assess neurobehavioral toxicity and demonstrate its utility for detecting sub-lethal impacts of environmental metals.

animal behavior and cognition↗

bioRxiv2025

Aird-MSI: a high compression rate and decompression speed format for mass spectrometry imaging data

Mass spectrometry imaging has emerged as a pivotal tool in spatial metabolomics, yet its reliance on the imzML format poses critical challenges in data storage, transmission, and computational efficiency. While imzML ensures cross-platform compatibility, its lower compressed binary architecture results in large file sizes and high parsing overhead, hindering cloud-based analysis and real-time visualization. This study introduces an enhanced Aird compression format optimized for spatial metabolomics through two innovations: (1) a dynamic combinatorial compression algorithm for integer-based encoding of m/z and intensity data; (2) a coordinate-separation storage strategy for rapid spatial indexing. Experimental validation on 47 public datasets demonstrated significant performance gains. Compared to imzML, Aird achieved a 70% reduction in storage footprint (mean compression ratio: 30.03%) while maintaining near-lossless data precision (F1-score = 99.26% at 0.1 ppm m/z tolerance). For high-precision-controlled datasets, Aird accelerated loading speeds by 15-fold in MZmine. The Aird format overcomes crucial bottlenecks in spatial metabolomics by harmonizing storage efficiency, computational speed, and analytical precision, reducing I/O latency for large cohorts. By achieving near-native feature detection accuracy, Aird establishes a robust infrastructure for translational applications, including disease biomarker discovery and pharmacokinetic imaging.

bioinformatics↗

bioRxiv2025

Pfs48/45 nanobodies block Plasmodium falciparum transmission

Malaria parasite fertilisation occurs within the Anopheles mosquito midgut. Interventions that inhibit parasite fertilisation prevent ongoing transmission and are important for malaria elimination efforts. Pfs48/45 and Pfs230 are two leading transmission-blocking vaccine candidates. Both proteins form a complex on the surface of sexual stage parasites and are essential for male fertility. Here we have identified nanobodies against Pfs48/45 that recognise gametocytes and have strong transmission-reducing activity. The crystal structure of our most potent nanobody in complex with Pfs48/45 reveals it binds a distinct epitope to TB31F, a leading transmission-blocking monoclonal antibody. In addition, we generated bispecific nanobodies that can target both Pfs48/45 and Pfs230 simultaneously and are fused to a human Fc domain. Our results show that these bispecific nanobodies recognise both Pfs48/45 and Pfs230 and reduce malaria parasite fertilisation in Anopheles stephensi. These results demonstrate the potential of nanobodies as a versatile antibody format that can reduce malaria transmission. Author SummaryMalaria is spread when an infected Anopheles mosquito bites a human. Within the female Anopheles mosquito, malaria parasite fertilisation occurs in the mosquito midgut. If you inhibit parasite fertilisation in the mosquito, you can prevent onward transmission of the malaria parasite from mosquito to humans. Transmission blocking vaccines work by stopping parasite fertilisation and development in the mosquito and are key for malaria elimination by preventing community spread. Pfs48/45 and Pfs230 are two leading transmission-blocking vaccine candidates, and both are critical for male fertility. Here we describe the generation of nanobodies that target Pfs48/45. We show that when nanobodies against Pfs48/45 were added to infected blood meals for Anopheles mosquitoes, the nanobodies significantly reduced parasite transmission. In addition, we generated bispecific nanobodies that target both Pfs48/45 and Pfs230 and these bispecific nanobodies also significantly reduced oocyst development. Our work demonstrates the potential of nanobodies as a versatile antibody format that can reduce malaria transmission.

microbiology↗