Biology subjects

Martin, J.

Publications and source records attributed to Martin, J..

At least 19 recordsLinked to original sources

bioRxiv2026

Genome-wide structural variants uncover strain-specific genes and evolutionary genomic determinants of a fungal maize pathogen

Genomic structural variants (SVs) are important sources of genetic diversity and contribute to the adaptation and evolution of plant-pathogenic fungi. Colletotrichum graminicola, the causal agent of maize (Zea mays L.) anthracnose, causes significant yield losses and serves as an important model for genetic studies. To investigate genomic plasticity in this pathogen, long-read genome assemblies were generated for four C. graminicola field strains collected in France, Croatia, Brazil, and Argentina and compared with the chromosome-level reference genome from the USA. Comparative analyses revealed extensive structural variation across core chromosomes, including large-scale translocations, inversions, duplications, and insertions and deletions, whereas minichromosomes showed markedly reduced collinearity among strains. Secreted proteins and predicted effectors were located significantly closer to regions affected by SVs. Approximately 174 kb of segmental duplications lacking genes were shared between core chromosome 04 and minichromosomes 11 and 13 in the reference genome but were absent from the other field strains, revealing a strain-specific structural link between core and minichromosomes. Protein clustering identified 733 candidate strain-specific genes across the reference genome. Approximately 72% of the genes annotated on the minichromosomes were strain-specific, indicating that most of their annotated genes lacked orthologous gene models in the other strains. Of the 733 candidate strain-specific genes, 492 retained homologous genomic sequences in at least one other strain and many also showed evidence of gene disruption. This pattern is consistent with lineage-specific pseudogenization and suggests that apparent gene presence-absence variation may arise through several evolutionary processes, including gene gain, gene loss and loss of gene function. Insertions and deletions in potentially regulatory flanking regions were associated with plant-pathogen interaction genes. In addition, interpretable machine learning analyses revealed a co-occurrence of duplications and LTR retrotransposons in genomic regions associated with secreted genes. This study shows that structural variation, transposable elements, and lineage-specific pseudogenization are important features of genome evolution in C. graminicola and identifies associations between genomic variation and genes involved in plant-pathogen interactions.

genomics↗

bioRxiv2026

Thermodynamic Diversity in Staphylococcal Nitrate Sensors with a Conserved Binding Pocket

Nitrate is an important oxyanion in bacterial physiology, with major roles as a nitrogen source for assimilation and as an alternative electron acceptor in anaerobic respiration. Accordingly, diverse nitrate-responsive regulatory systems sense nitrate availability and control the expression of genes involved in nitrate transport and metabolism. In the NreABC system, the soluble GAF-like domain protein NreA functions as a cellular nitrate sensor. To date, our molecular understanding of nitrate recognition by NreA has been derived primarily from studies of the Staphylococcus carnosus protein, with less known about homologues from other species. Here, we identified 736 NreA homologues through bioinformatic analysis of the GAF-like domain superfamily and selected five staphylococcal representatives for thermodynamic characterization by isothermal titration calorimetry. Despite conservation of the nitrate-binding pocket, these homologues resolved into high- and low-affinity groups with distinct thermodynamic profiles. Comparative structural modeling and chimeragenesis of a low-affinity homologue revealed that the C-terminal region is a non-coordinating determinant of nitrate-binding affinity. Together, these findings show that a conserved nitrate-binding pocket preserves recognition, while distal sequence variation shapes thermodynamics and tunes the nitrate concentration range over which NreA sensors can function.

biochemistry↗

bioRxiv2026

Extracellular protein catabolism drives regulated nitrogen handling and ammonia buffering in acute myeloid leukemia

Acute myeloid leukemia (AML) cells exhibit pronounced metabolic plasticity, yet how amino acid supply is coordinated to sustain leukemic metabolism remains poorly understood. Here, we show that AML cells catabolize extracellular proteins as a major source of amino acids through lysosomal degradation of albumin. This proteocatabolic activity supports anabolic processes and mitochondrial energy production and establishes a regulated, high-throughput regime of primary nitrogen-containing metabolites (nitrogen regimen). Sustained proteocatabolism inevitably generates ammonia, and we find elevated ammonia concentrations in bone marrow plasma from newly diagnosed AML patients that decline with effective induction therapy. Using metabolomics, isotope tracing and targeted genetic and pharmacological manipulations, we identify glutamate-ammonia ligase (GS/GLUL) as a central enzyme that buffers proteocatabolism-derived ammonia by stabilizing intracellular nitrogen homeostasis. Loss of GS function limits sustainable nitrogen handling capacity, thereby impairing leukemic proliferation and delaying disease progression in vivo. Together, our findings define extracellular protein catabolism as a regulating nitrogen management strategy in AML and reveal GS as a capacity-defining vulnerability of proteocatabolic growth.

cancer biology↗

bioRxiv2026

Colonization resistance against Clostridioides difficile is a graded, microbiota-intrinsic property of healthy human gut communities

Fecal microbiota transplantation cures approximately 90% of recurrent Clostridioides difficile infection, yet it remains unknown whether all healthy donor microbiota confer equivalent protection. We colonized germ-free C57BL/6 mice with stool microbiota from 30 healthy human donors and challenged them with C. difficile in the absence of antibiotic pretreatment. Donor microbiota conferred a spectrum of colonization resistance phenotypes: Resistant (no detectable colonization or toxin), Carrier (asymptomatic colonization with detectable toxin), Symptomatic (non-lethal diarrheal illness), and Susceptible (lethal infection). Of these, 8 conferred Resistant phenotypes, 12 Carrier, 6 mixed Resistant-Carrier outcomes, and 4 Symptomatic or Susceptible phenotypes. While 16S rRNA gene sequencing of donor stool did not distinguish phenotypes across any diversity or compositional metric tested, humanized mouse microbiomes exhibited clear phenotype-dependent differences after engraftment. Richness (observed amplicon sequence variants, Chao1) and diversity (Shannon and Faith's phylogenetic diversity) declined progressively from Resistant to Susceptible phenotypes, although substantial overlap was observed between groups. Differential abundance analysis identified taxa depleted across non-resistant phenotypes, including Lachnospiraceae taxa such as Hungatella and Sellimonas, and Bacteroides intestinalis. Shotgun metagenomics confirmed these associations and revealed coordinated depletion of biosynthetic and carbohydrate metabolism pathways in non-resistant phenotypes, consistent with broad loss of community metabolic capacity rather than loss of a single dominant function. These findings demonstrate colonization resistance is a graded, microbiota-associated ecological property, evident after host engraftment rather than being a binary trait encoded in donor stool. This has implications for donor screening in fecal microbiota transplantation and the rational design of microbiome-based therapeutics.

microbiology↗

bioRxiv2026

Next-generation insect digitization: combining phenomics and genomics by subsequent synchrotron X-ray imaging and DNA sequencing

Recent technological advances allow for the large-scale acquisition of genetic and morphological data: high-throughput sequencing has transformed the field of genomics while synchrotron X-ray microtomography enables rapid, noninvasive 3D imaging. However, integrating these approaches for the same specimens is challenging because X-rays can fragment DNA, and DNA extraction damages internal morphology, particularly relevant for small bodied organisms, such as insects. We systematically tested multiple extraction protocols and irradiation conditions across three model insect species. We irradiated more than 1,000 specimens under varying conditions and tested DNA quality through DNA barcoding and UCE sequencing. Our results demonstrate that high-quality DNA and high-resolution tomograms can be obtained from the same individuals, provided that the parameters are carefully optimized and rapid SR-CT scanning precedes DNA extraction. In this respect, our findings establish practical guidelines for combining genomics and phenomics, paving the way for comprehensive integrative digitization of biodiversity.

genetics↗

bioRxiv2026

A missing PEPC1 exaptation restricts C₄ evolution in palms (Arecaceae)

O_LIC4 and CAM photosynthesis evolved repeatedly across angiosperms, yet the four palm species examined here -- representing three of five Arecaceae subfamilies ([~]2,600 species total) -- all lack both. We hypothesized that this reflects the absence of PEPC1, a phosphoenolpyruvate carboxylase isoform required for C4 carbon fixation initiation and present in commelinids (Poaceae + Bromeliaceae) but whose distribution across monocots is unknown. C_LIO_LIWe surveyed six core C4 enzyme families by HMMER profiling across nine plant genomes -- four palms (Cocos nucifera, Elaeis guineensis, Phoenix dactylifera, Nypa fruticans), two grasses, one bromeliad, one basal monocot, and one fern. We constructed maximum-likelihood PEPC phylogenies and performed codon-based branch-site likelihood ratio tests using PAML. C_LIO_LIAll six enzyme families were present in palms. PEPC1 was detected in all commelinids (rice, maize, pineapple) but absent from all four palm species and outgroups. No palm PEPC sequence fell within the PPC-1 clade. Molecular dating indicates the Arecaceae-commelinid divergence ([~]120 Mya) predates PEPC1 origin ([~]105 Mya). Branch-site tests on the maize C4-PEPC1 branch were marginally significant (2{Delta}l = 3.03, p {approx} 0.082). C_LIO_LIThe absence of PEPC1 represents an ancestral molecular barrier that likely precluded C4 evolution in palms. This identifies a lineage-specific gene duplication as a constraint on photosynthetic pathway evolution in a major tropical plant lineage. C_LI

plant biology↗

bioRxiv2026

PEPC Gene Family Evolution Across Arecaceae: Complete Five-Subfamily Evidence for a Two-Lock Model of Irreversible C4 Exclusion

BackgroundC4 photosynthesis has evolved more than sixty times across flowering plants, but never in palms. Over 2,500 palm species have spent more than 100 million years in high-light, water-stressed habitats where C4 physiology would be advantageous, yet none have taken this path. Phosphoenolpyruvate carboxylase (PEPC) is the enzyme that gates entry into the C4 pathway. In every C4 grass, a commelinid-specific paralog called PEPC1 drives the CO2-concentrating mechanism that defines the syndrome. Until this study, one of the five palm subfamilies -- Ceroxyloideae -- had never been examined for PEPC gene content. ResultsWe present a complete PEPC census across 13 palm species spanning all five subfamilies (Calamoideae, Nypoideae, Coryphoideae, Ceroxyloideae, Arecoideae). Ceroxyloideae was characterized for the first time, using deep tBLASTn screening of ten million whole-genome shotgun reads. PEPC1 is absent from every palm species examined. Copy numbers are tightly constrained to 5-7 per genome, in stark contrast with the 6-25 copies found in grasses. A phylogenetic analysis of 337 PEPC sequences places all 55 palm loci at basal positions relative to the PEPC1 clade, consistent with the palm lineage having diverged approximately 120 million years ago -- roughly 15 million years before the PEPC1 duplication that occurred within the commelinids. Birth-death modeling reveals long-term gene family stasis in palms. Codon substitution analyses yield a genome-wide {omega} of 0.0582, indicating pervasive purifying selection and no signature of C4-specific adaptation. Coconut PEPC promoters uniformly lack the mesophyll-specific MESP-1/GT-1/DOF regulatory module that is required for C4-type gene expression. ConclusionsWe propose a Two-Lock Model of irreversible C4 exclusion in palms. The first is a Gene Lock: PEPC1 is phylogenetically absent from all five subfamilies. The second is a Regulatory Lock: the ancestral promoter architecture of palm PEPC genes lacks the cis-elements needed for mesophyll-specific expression. Together, these two locks -- one phylogenetic, one regulatory -- explain why C4 photosynthesis has never arisen in one of the largest C4-absent plant families. The model provides a testable framework for investigating other lineages that have remained closed to the C4 path.

evolutionary biology↗

bioRxiv2026

The DUF998 family protein DrmA modulates cationic glycolipid levels and the emergence of high-level daptomycin resistance in Enterococcus faecalis

Daptomycin resistance (DAP-R) in enterococci is associated with alterations in the membrane lipid composition. The membrane-bound protein MprF is responsible for the synthesis of amino acid-modified lipids in bacteria, and these modified lipids contribute to DAP-R in some Gram-positive pathogens. In enterococci, MprF synthesizes three lysine-modified lipids: the phospholipid lysyl-phosphatidylglycerol (Lys-PG), and the newly identified cationic glycolipids lysyl-diglucosyl-diacylglycerol (Lys-Glc2-DAG) and lysyl-glucosyl-diacylglycerol (Lys-Glc-DAG). Given the recent discovery of cationic glycolipids in enterococci, we re-examined a collection of laboratory-evolved DAP-R E. faecalis to investigate whether these lipids contribute to DAP-R. We found that levels of Lys-Glc2-DAG were strikingly reduced in DAP-R variants with high-level resistance. The dramatic alterations in Lys-Glc2-DAG levels were temporally coupled with the emergence of loss-of-function mutations in the gene drmA, which encodes a DUF998 family protein of unknown function. DrmA is a membrane protein with six predicted transmembrane helices and is widely distributed among Gram-positive and Gram-negative bacteria, including plant and animal pathogens. Complementation of the DAP-R strains with wild-type E. faecalis drmA significantly lowered their DAP MIC, reversing their trajectory to high-level DAP-R. Using genetic and lipidomic approaches in the natively DAP-sensitive strain OG1RF, we conclusively linked drmA loss-of-function with significantly reduced Lys-Glc2-DAG levels as well as a small but significant increase in Lys-PG levels. Yet, drmA inactivation in OG1RF did not alter its DAP MIC. We conclude that drmA loss-of-function confers elevated DAP MIC on the background of preceding mutations in the DAP-R evolutionary trajectory, most likely mutations in cls1. The recurrence of drmA mutations in multiple studies underscores its importance in DAP-R evolution. Overall, our work identifies a role for the DUF998 family in cellular lipid homeostasis and confirms its significant role in the evolution of DAP-R.

microbiology↗

bioRxiv2026

A control-validated pan-proteome deep-learning pipeline nominates GPR35 as a candidate target of the orphan bacterial metabolite ligiamycin A

Most microbial natural products with documented bioactivity lack an identified molecular target, which limits their development. We present an open, control-validated computational pipeline for natural-product target hypothesis generation. It combines a pan-proteome deep-learning drug-target interaction (DTI) model (a graph neural-network ligand encoder, an ESM-2 protein language-model encoder, and bidirectional cross-attention) with bias-corrected ranking and control-anchored molecular docking. Applying it to ligiamycin A, a 2022-described Streptomyces/Achromobacter co-culture decalin-amino-maleimide with no reported target, we find that the predicted interactions of the compound are dominated by class-A G-protein-coupled receptors. Using a drug with a known target (losartan) we identify and correct a frequent-hitter bias in the raw model; after correction the standout candidates are uniformly class-A GPCRs, led by the orphan receptor GPR35. Structure-based docking with matched positive and negative controls across three candidates corroborates GPR35 specifically: ligiamycin A scores comparably to the known GPR35 agonist zaprinast at the agonist pocket (-8.1 vs -8.3 kcal/mol; non-binder floor -5.5), whereas FFAR1 is excluded and histamine H2 is inconclusive. We propose GPR35 as a prioritized, experimentally testable target and release the workflow as a reusable tool. The result is a computational hypothesis that requires experimental validation.

bioinformatics↗

bioRxiv2026

Functional primary human 3D skeletal muscle organoids enable exercise and metabolic research

Human skeletal muscle is the principal site of insulin-stimulated glucose disposal and a major mediator of exercise-induced metabolic benefits, yet human models that preserve metabolic and exercise responsiveness remain limited. We generated primary human skeletal muscle organoids from donor-derived CD56+ myoblasts using a collagen-based extracellular matrix and serum-free IGF1-guided differentiation. The organoids formed aligned contractile tissues containing oxidative and glycolytic fiber type-like myotubes, displayed enhanced mitochondrial respiration, insulin-stimulated glucose uptake, and reproducible force generation. Electrical pulse stimulation induced AMPK activation, increased glucose utilization and lactate production, and upregulated canonical exercise-responsive genes including NR4A3 and PPARGC1A. Notably, transcriptional responses to in vitro exercise overlapped with acute exercise responses observed in skeletal muscle biopsies from the same donors. The organoids further detected functional impairments of skeletal muscle performance induced by TGF-{beta}1 and metformin and increased speed generation by testosterone treatment. These findings establish a donor-specific human skeletal muscle platform that recapitulates key features of insulin action and exercise adaptation and may enable mechanistic studies of skeletal muscle metabolism, exercise responsiveness, and therapeutic interventions relevant to diabetes.

Molecular Biology↗

bioRxiv2026

Human 3D epithelioids enable continuous long-term clonal evolution studies across multiple epithelial tissues

Modeling human epithelia in vitro remains challenging because current systems do not fully preserve the combination of architecture, heterogeneity, clonal composition, and long-term dynamics shown in vivo. While 3D approaches such as organoids and organotypic cultures capture important aspects of lineage differentiation and niche signaling, they often lose stable organization over time, limiting studies of long-lasting processes such as clonal evolution and cell competition. Here, we present human epithelioids as continuous long-term, 3D epithelial cultures efficiently derived from eight adult human epithelia, including trachea, skin, buccal mucosa, esophagus, blader, urethra, submandibular gland and endometrium. Using immunostaining, electron microscopy, single-cell RNA sequencing, functional assays and somatic mutation analyses, we deeply characterized human epithelioids and confirmed that they recapitulate native architecture and cell diversity, sustain regenerative capacity, and preserve donor-specific mutational landscapes, establishing a robust and versatile platform for longitudinal interrogation of clonal evolution, tissue dynamics and responses to clinically relevant perturbations, including radiotherapy and chemotherapy, over extended timescales.

cancer biology↗

bioRxiv2026

Effects of ERK1/2 Signaling on Cell Cycle Regulation by the Tuberin-Cyclin B1 Complex

How cells balance growth (cell size) and division (cell number) requires a complex interplay between response to external signals including growth factors, nutrient availability and metabolic cues, along with regulation of the cell cycle. The protein Tuberin (gene TSC2) is a critical regulator of these decisions. In a complex with the protein Hamartin, Tuberin functions as a negative regulator of the Target of Rapamycin (mTOR) pathway, preventing excessive growth under unfavorable conditions. However, how this growth pathway connects to decisions to progress through the G2 phase of the cell cycle and permit cell division is still unclear. In this study, we show that post-translational modification of Tuberin by the Extracellular Signal-Regulated Kinase (ERK) pathway abrogates binding between Tuberin and the mitotic cyclin, Cyclin B1. This causes an increase in mitotic cells, due to an unregulated G2/M transition, increasing the proliferation rate. Our work shows a novel role of Tuberin in cell cycle regulation by growth and mitogenic factors independent of mTOR regulation.

cell biology↗

bioRxiv2026

Developmental switch dichotomizes kidney response to NPHP3 inactivation and treatment outcome

Nephronophthisis (NPH) is n rare recessive kidney disease caused by biallelic variants in more than 25 NPHP genes encoding proteins that localize to primary cilia. It is characterized by three different forms depending on the age of onset and kidney lesions: infantile (cystic), juvenile/late onset (fibrotic). To date, the pathways linking altered primary cilia function to progressive kidney scarring in NPH remain poorly defined and therapeutic options are lacking. To address these questions, we generated two new mouse NPH models by inactivating Nphp3 specifically in kidney tubules either during embryogenesis or in adult, recapitulating the infantile and juvenile forms of the disease, respectively. Embryonic inactivation produced a rapid and severe cystic phenotype with tubular dedifferentiation, progressive interstitial fibrosis, inflammation and kidney failure, while postnatal inactivation led to a slowly progressive tubulointerstitial nephropathy characterized by tubular atrophy, fibrosis and immune cell infiltration without cyst formation. Strikingly, cilia were preserved in the early stages of both models, indicating that ciliogenesis impairment is not a primary driver of NPH3 pathogenesis. Transcriptomic profiling of the juvenile model revealed that disease initiation is driven by mitochondrial dysfunction, innate immune activation and aberrant cell cycle progression, while epithelial-to-mesenchymal transition and Wnt/{beta}-catenin remodelling emerges only at later stages of disease progression. Therapeutic intervention with the PGE1 (alprostadil) failed to rescue the cystic/infantile model but significantly attenuated fibrosis, inflammation and interstitial fibrosis in the fibrotic/juvenile model. The ability to recapitulate both disease forms through temporal modulation of gene inactivation suggests that primary cilia serve distinct, stage-specific functions in kidney tubular homeostasis, with different cellular processes being selectively vulnerable depending on the causative gene or variant. Collectively, these findings uncover early pathogenic mechanisms that may constitute tractable therapeutic targets for the treatment of nephronophthisis.

pathology↗

bioRxiv2026

In vivo base editing via single myotrophic adeno-associated viruses in dystrophic mouse muscle and satellite cells

Duchenne muscular dystrophy (DMD) is the most common, lethal X-linked neuromuscular disorder of childhood and is caused by mutations in the Dmd gene that disrupt dystrophin expression. Although adeno-associated virus-mediated gene therapies hold tremendous promise for DMD treatment, their clinical applications have been limited by dose-dependent vector and genome-level toxicities. Here, we developed and tested a single-vector adenine base editing strategy as a potentially safer genome editing approach to recode the pathogenic nonsense mutation into a benign missense mutation in mdx4cvDMD mouse model. Delivered using a muscle-tropic adeno-associated virus (MyoAAV) at a clinically-feasible dose (4E13 VG/kg), this strategy enabled detectable molecular recoding of the mdx4cv mutation in mice ranging in age from 3 days to 6 months. Yet, the overall efficiency and therapeutic impact of in vivo base editing with this system was highest in mice treated at the juvenile stage, with animals administered MyoAAV vectors at 3 weeks of age showing robust recovery of dystrophin expression and significant improvement in muscle contractile properties only one month later. Notably, introduction of adenine base editors either earlier in development, in neonatal mice, or later, in adulthood, yielded substantially lower editing efficiencies, particularly in muscle satellite cells whose editing is essential to ensure durable rescue of dystrophin expression in growing and regenerating muscle. Taken together, these results demonstrate the therapeutic potential of single-vector adenine base editing for DMD and underscore the importance of recipient age and disease stage in achieving optimal treatment outcomes for this and other genetic muscle disorders.

cell biology↗

bioRxiv2026

Sex-biased Fibroblast Subpopulations and Transcriptional Programs Reveal Mechanisms of Skin Lesion Development in Systemic Sclerosis

Systemic sclerosis (SSc) is an autoimmune connective tissue disease with pronounced sex differences: females are more frequently affected and males develop more severe skin fibrosis. The cellular mechanisms of this disparity remain unclear. Here we use single-cell transcriptomics of lesional, non-lesional, and healthy skin to define fibroblast states and sex-biased transcriptional programs during lesion development. We identify a sex-dependent divergence in SSc fibrotic regulation. Female fibroblasts exhibit heightened inflammatory signaling and canonical TGF-{beta}-driven extracellular matrix production, whereas male fibroblasts preferentially engage non-canonical TGF-{beta} pathways, mechanotransduction, and MYC-associated stress programs. We further reveal that the fibrotic lesional environment shows sex differences: SFRP2DPP4 fibroblasts predominate in females and COL11A1/COCH in males. Our findings uncover cellular mechanisms underlying sex differences in SSc fibrosis, highlight opportunities for sex-informed therapeutic strategies and underscore the necessity of integrating biological sex into precision medicine frameworks to identify divergent molecular drivers of fibrotic disease.

genomics↗

bioRxiv2026

Streamflow drought limits fish production across river ecosystems

River flows sustain biodiversity, ecosystem function, and human well-being, yet climate change and water extraction are driving frequent and severe low-flow conditions (i.e., streamflow droughts). Here, we show that declining streamflow constrains fish production by limiting juvenile recruitment, the dominant demographic pathway regulating population dynamics. Across populations, declining flows nonlinearly reduce carrying capacity and production, with severe drought reducing production by up to 90%. Flow-production relationships vary among rivers, revealing both drought-sensitive and drought-resilient responses shaped by ecological and hydrological context. In some systems, maintaining higher flows during average years yields greater ecological benefits than equivalent drought-year interventions. These results demonstrate that streamflow drought directly limits biological production and highlight how adaptive water management can be implemented to sustain freshwater ecosystems under increasing hydroclimatic variability.

ecology↗

bioRxiv2026

Dynamic dorsal body morphology encodes engineering design principles of fish propulsion and hydrodynamics

Understanding how biological shape and movement interact with surrounding fluids represents a fundamental challenge at the intersection of biology, physics, and engineering. Fish locomotion exemplifies this challenge: body morphology and swimming kinematics together determine the hydrodynamic forces and flow structures that enable efficient propulsion and maneuverability. Whereas biologists have long sought to connect morphological variation to swimming performance, traditional morphometric approaches provide limited insight into the fluid mechanical consequences of shape differences. Similarly, although computational fluid dynamics can reveal detailed flow physics, simulating hydrodynamics across diverse and dynamic morphologies remains prohibitively expensive for systematic investigation. To bridge this gap, we introduce a data-driven framework that connects fish body shape dynamics to hydro-dynamic performance through compact morphospace parameterization and reduced-order modeling. Using CFD simulations of 15 fish species from the Digital Life Project database (www.digitallife3d.org/3d-model), we generate hydrodynamic datasets capturing the shape-flow relationship. Principal Component Analysis (PCA) extracts four dominant shape parameters from dorsal body profiles, which are then integrated into an Inverse-Design with Dynamic Mode Decomposition (ID-DMD) framework to model the resulting fluid dynamics. The resulting modal analysis suggests that locomotion strategies emerge from specific shape-flow interactions. We further demonstrate the frameworks utility through single- and multi-objective shape optimization, showing how it enables efficient exploration of the morphology-hydrodynamics relationship. This approach offers a novel analysis and design tool for understanding how biological form and motion interact with fluid mechanics, with applications ranging from bio-inspired vehicle development to evolutionary biomechanics.

biophysics↗

bioRxiv2026

A cilia-dependent inflammatory programme links bacterial detection to kidney disease

The primary cilium is a microtubule-based sensory organelle projecting from the plasma membrane of most mammalian cells. Genetic defects in ciliary components cause chronic kidney disease (CKD) characterized by heightened production of inflammatory and fibrogenic mediators by tubular epithelial cells. Yet, whether this reflects a physiological role of the primary cilium remains unknown. Here, we show that primary cilia on kidney tubular cells bind uropathogenic Escherichia coli and, in response to bacterial components, initiate a fibro-inflammatory program reminiscent of CKD. Integrating single-cell transcriptomics with conditional mouse models, we observed that epithelial cilia orchestrate a similar fibro-inflammatory response in the absence of infection during CKD. This convergence reveals a shared cilia-dependent signalling axis governing both host-pathogen responses and CKD progression. Mechanistically, cilia ablation selectively impairs tubular responses to ADP-heptose, a pathogen-associated molecular pattern that activates NF-{kappa}B via the cytosolic innate immune receptor ALPK1. In human kidney organoids, ADP-heptose induces robust fibro-inflammation, and genetic or pharmacological inhibition of ALPK1 attenuates this response in a rodent CKD model. Together, these findings identify primary cilia as central orchestrators of a fibro-inflammatory program linking pathogen detection to kidney disease progression.

physiology↗