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Search indexed bioRxiv preprints in genomics, neuroscience, cell biology and bioinformatics. Read source abstracts and check manuscript versions; preprints are not peer reviewed.

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bioRxiv2026

Arabidopsis Acyl-CoA Binding Protein 4, ACBP4, functions in developmentally programmed endoreduplication

Powdery mildew fungi induce localized endoreduplication, a variant of the cell cycle in which DNA is replicated but cells do not divide, in leaf mesophyll cells underlying the fungal feeding structure. Induced endoreduplication occurs concurrent with powdery mildew (PM) spore production and is associated with enhanced metabolic capacity and flux to lipids. The final ploidy of these cells is highly correlated with fungal spores produced and is the consequence of both basal (developmental) ploidy and PM-induced endoreduplication programs. Herein, we find the Arabidopsis lipid trafficking and regulatory protein ACYL-COA BINDING PROTEIN 4 (ACBP4) enhances PM spore production on Arabidopsis leaves. ACBP4 does not limit plant defense but instead supports basal mesophyll cell ploidy, with decreased final ploidy in cells underlying the fungal feeding structure in acbp4 mutants compared to wild-type (WT). Leaf epidermal cell size is decreased and stomatal density is increased in acbp4, consistent with a role for ACBP4 in developmentally programmed endoreduplication. Moreover, hypocotyl elongation in the dark, which is driven by programmed developmental endoreduplication, shows reduced hypocotyl length, cell length and ploidy in acbp4 versus WT. Together, our findings establish a novel means by which a plant ACBP promotes cell metabolism and development, with potential applications to agricultural productivity and quality.

plant biology↗

bioRxiv2026

Beyond Imbalance: An Elasticity Framework for the Distance-averaged Force-Velocity Relationship in Vertical Jump

This study aimed to (1) establish the distance-averaged F-V relationship framework and (2) develop elasticity metrics that quantify how F-V relationship variables govern jump height and inform training prescription. Theoretical derivation and experimental validation across 108 F-V relationship models derived from 1578 jumps (countermovement jump and squat jump at three knee angles; 20 well-trained subjects) yielded a standard error of 2.1% and a nearly perfect correlation (r = 0.96, p < 0.001) between measured and predicted jump height. Four elasticity metrics were formulated: force elasticity (F_{e}), the elasticity of jump height to maximal force (F_{0}); velocity elasticity (v_{e}), the elasticity of jump height to maximal velocity (v_{0}); the force-velocity elasticity norm {(\mathrm{F}-\mathrm{V}}_{\mathrm{EN}}=\sqrt{F_{e}^{2}+v_{e}^{2}}), reflecting the overall sensitivity of jump height to changes in F-V relationship variables; and the force-velocity elasticity ratio {(\mathrm{F}-\mathrm{V}}_{\mathrm{ER}}=F_{e}{\div v}_{e}), indicating which variable dominates the jump height response. Simulations and experiments revealed that F_{e} bore an inverse relationship to F_{0}, and v_{e} was inversely related to v_{0}, reflecting diminishing marginal returns. At a fixed jump height, simulations showed {\mathrm{F}-\mathrm{V}}_{\mathrm{EN}} and {\mathrm{F}-\mathrm{V}}_{\mathrm{ER}} displayed a U-shaped relationship; a balanced profile ({\mathrm{F}-\mathrm{V}}_{\mathrm{ER}}=1) did not always correspond to the lowest {\mathrm{F}-\mathrm{V}}_{\mathrm{EN}}. The distance-averaged F-V elasticity framework offers a physically grounded and quantitative tool for linking F-V relationship variables directly to jump performance, providing a basis for informing individualized training decisions.

biophysics↗

bioRxiv2026

Evolutionary origins of protein novelty across an entire yeast subphylum

Novel protein-coding sequences fuel molecular and cellular evolutionary innovations and frequently contribute to species-defining characteristics. They can originate either de novo from previously noncoding sequences or through extreme divergence of already coding ones. How frequently each mechanism occurs and how they shape the structural and functional potential of the resulting proteins remains unclear. Here, we conducted a broad computational investigation of genetic and protein novelty throughout the entire subphylum of Saccharomycotina yeasts. We detected more than 5,000 robust de novo genes across 332 species and compared them to more than 6,000 novel genes resulting from extreme sequence divergence, revealing two quantitatively similar but qualitatively distinct modes of evolution of novelty. A remarkable 40% of de novo proteins are predicted to localize to mitochondria compared to only 20% of divergent, with the latter also being substantially longer and more disordered. A detailed analysis of conservatively predicted tertiary structures of novel proteins shows that ''invention'' of new folds occurs more frequently through de novo emergence. We also illustrate cases of evolutionary ''re-invention'' of existing protein folds from noncoding sequences. Our work deepens our understanding of the origins and importance of novel proteins, opening new directions for further structural and functional characterization.

genomics↗

bioRxiv2026

Ablation of a maternal Cryptosporidium mRNA-binding protein results in sterile sporozoites

Infection with Cryptosporidium is a leading cause of diarrheal disease and early childhood mortality. This apicomplexan parasite undergoes asexual and sexual replication within the same host and recent studies have shown an intrinsic developmental program of obligate transition to male and female gametes and sex. While factors were identified that control male fate and development, how female gene expression is orchestrated remains largely unknown. Here we use the Cryptosporidium Single Cell Atlas to discover an RNA binding protein (F-RBP) as one of the earliest markers of female identity. Reporter parasites engineered based on this gene allowed us to calibrate transcriptional pseudotime against the real time of female development revealing a significant window of transcriptional fate ambiguity. While F-RBP is an early transcript, the protein persists throughout female development and into the zygote. Conditional ablation of the F-RBP gene showed it to be dispensable for sex determination and early female development in vitro. However, the gene is essential in vivo and its loss results in rapid cure. Cell biological experiments link this loss to the production of sterile oocysts which release sporozoites incapable of host cell invasion. F-RBP binds transcripts highly expressed in the female gamete enriched for a YBOX primary sequence motif and forms mRNA protein complexes in late females akin to processing or P bodies. We propose F-RBPs essential role to be in the regulation of long-term homeostasis of maternally inherited RNA required for sporozoite infectivity.

microbiology↗

bioRxiv2026

Historical squid biomass increase is not explained by rising temperature but rather by loss of top predators.

Squid abundance has been reported to increase globally between 1970 and 2010. This increase has been hypothesized to result from two primary factors: the loss of top predators due to overfishing and rising ocean temperatures. The decline in apex predators may lead to the expansion of squid populations either through reduced predation pressure or diminished competition with juvenile predators. Concurrently, increased temperatures could enhance the somatic growth rates of squid, thereby accelerating their population growth. However, empirically disentangling the impacts of predator loss and temperature on squid biomass remains challenging, especially in a food-web context. In this study, we used a size- and trait-based model of upper trophic levels that resolves the ecosystem structure -- biomass and trophic interactions of fish and squid -- for varying depth, temperature, and secondary production, to investigate two hypotheses of the historical expansion of squid, i.e., the effects of predator depletion from fishing and rising temperatures on squid biomass. Our model reveals that intensified fishing of squid predators -- specifically large demersal fish in shelf systems and large pelagic fish in open oceans -- leads to a slight increase in squid biomass. Conversely, elevated temperatures are associated with a decline in squid biomass. This temperature-driven reduction in biomass is attributed to an increased metabolism of squids beyond the available food supply. If historic overfishing on large marine predators continues to be curtailed, we expect a corresponding reduction in global squid biomass and fisheries potential, which could be further exacerbated by rising temperatures.

ecology↗

bioRxiv2026

Abundant Glomerular Neutrophil Extracellular Traps in C3 Glomerulopathy

Introduction: C3 glomerulopathy (C3G) is driven by fluid-phase alternative complement pathway dysregulation, with emerging evidence linking glomerular neutrophil infiltration to disease severity. Neutrophil extracellular traps (NETs) are implicated in other forms of glomerulonephritis. However, their participation in the pathogenesis of C3G remains undefined. Methods: Kidney biopsies from 33 patients with C3G (15 with dense deposit disease [DDD] and 18 with C3 glomerulonephritis [C3GN]) were compared with 15 anti-neutrophil cytoplasmic antibody associated vasculitis (AAV) biopsies as a neutrophil-rich disease control in this retrospective cross-sectional study. Glomerular neutrophils and NETs were identified using immunofluorescence, staining for myeloperoxidase, citrullinated histone H3, peptidyl arginine deiminase-4, and DNA. Supervised machine learning was used to quantify glomerular NET formation, and the data were correlated with kidney function at time of biopsy using linear regression. Results: Intraglomerular NETs were abundant and detected in the majority of glomeruli in C3G biopsies. Compared with AAV, C3G showed a significantly higher fraction of neutrophils forming NETs, despite similar neutrophil counts per glomerulus. NET abundance was similar in DDD and C3GN. In exploratory analyses, a greater proportion of glomeruli containing NETs was associated with lower kidney function (estimated glomerular filtration rate) at biopsy, and this association remained significant after adjustment for age, C3G subtype, and interstitial fibrosis. Conclusions: These observations demonstrate that intraglomerular NETs are a common and prominent observation in C3G and are associated with reduced kidney function at biopsy. These findings raise the possibility that NET deposition in glomeruli is a previously unrecognized driver of glomerular injury in C3G.

immunology↗

bioRxiv2026

A Biophysical Platform for Electromechanical Stimulation of Engineered Cardiac Tissues

Human engineered cardiac tissues (ECTs) provide an in vitro model for studying human cardiac physiology and drug responses, but their performance remains limited by culture systems that do not fully reproduce the heart's electrical and mechanical environment. Electrical stimulation (ES) and mechanical stimulation (MS) have each been used to improve ECT function. Their combination, referred to as electromechanical stimulation (ES+MS), can provide further benefits. However, ES+MS depends not only on the presence of both cues but also on how they are coordinated in time. Here, we developed an incubator-compatible biophysical platform that delivers ES and MS independently or in combination, with programmable control over timing, amplitude, frequency, duration, and waveform. Calibration and dynamic characterization demonstrated tissue-relevant strain delivery, rapid and repeatable motion, and minimal attenuation and timing lag at the designated frequency of 1.5 Hz. We then compared four 6 h conditioning regimens: unstimulated control, ES alone, unsynchronized ES+MS, and synchronized ES+MS. We hypothesized that the synchronized ES+MS group, in which electrical excitation was aligned with peak externally applied strain, would produce the greatest increase in contractile force. Consistent with this hypothesis, synchronized ES+MS increased normalized twitch force by approximately 44% on average, whereas the other groups showed no comparable improvement. Twitch-timing metrics did not exhibit coordinated enhancement after 6 h, suggesting that the force increase reflects an adaptive biomechanical response rather than broad tissue maturation. These findings identify ES-MS timing as an important design parameter for ECT conditioning.

bioengineering↗

bioRxiv2026

A reproducibility-audit framework for generalizable versus dataset-specific molecular transition boundaries in Alzheimer's disease

Molecular staging of Alzheimer's disease (AD) increasingly defines transition boundaries along single-cell pseudo-progression trajectories, yet whether such boundaries reproduce across brain regions, cohorts and molecular modalities is rarely tested. We present a permutation-controlled audit that combines nine boundary-detection algorithms with a fixed marker panel and four orthogonal reproducibility axes-algorithmic consensus, region, cohort and modality. On synthetic data with planted ground-truth boundaries the audit reaches 100% sensitivity and 94% specificity, rejecting four distinct artefact classes each by a different axis. Applied to the Seattle Alzheimer's Disease Brain Cell Atlas middle temporal gyrus, it localizes a transition that is robust across algorithms and recovered in most cell types but does not generalize: its leading marker is attenuated or absent in prefrontal cortex, entorhinal cortex and cerebrospinal fluid, and an apparent cross-region conservation of glial metabolic genes proves to be a global-expression offset rather than a shared program. The same audit nonetheless certifies an externally validated marker (astrocytic PTGDS) as reproducible across regions and modalities, showing that it separates generalizable anchors from dataset-specific ones rather than rejecting all signals. We provide this four-axis audit as a transferable, code-available standard to apply before a trajectory boundary is read as a biological stage, in AD and other progressive proteinopathies.

neuroscience↗

bioRxiv2026

Copulation calls indicate fertility but do not reflect female mate competition in wild Guinea baboons

Across different modalities, signals play a core role in attracting mates and influencing mating success. In several non-human primate species, females produce calls during mating that are thought to promote male competition over receptive females. The extent to which social system characteristics modulate the function of copulation calls remains less clear. We studied copulation calls in wild Guinea baboons (Papio papio), who live in a multilevel society structured around units in which females associate and mate almost exclusively with a single male. We hypothesised that females use copulation calls as an indirect form of mate competition, with competition increasing in larger units. In addition, we hypothesised that females are more likely to mate again after calling. We analysed 6116 copulations between 2014 and 2025, involving 99 reproductively active females and 78 subadult and adult males. Females produced copulation calls in 72.7% of copulations, with large inter-individual variation. Neither unit size nor its interaction with the female's swelling size or the presence of simultaneously receptive females affected the probability of calling. A survival analysis with a subset of the data (2353 copulations) revealed no effect of calling on the latency to the next mating. Our results render the hypothesis that female Guinea baboons use calls in indirect mate competition unlikely. Yet, the probability of calling varied with sexual swelling size, suggesting that calls signal female fertility. Possibly, Guinea baboon copulation calls represent an evolutionary remnant, no longer under selective pressure, and can be considered index signals of female fertility.

animal behavior and cognition↗

bioRxiv2026

Adeno-Associated Virus Mediated Expression of Bcl-xL Attenuates Apoptosis in Fuchs Endothelial Corneal Dystrophy

Fuchs Endothelial Corneal Dystrophy (FECD) is characterized by progressive corneal endothelial cell loss and the formation of corneal guttae. Currently, there is a global shortage of donor corneas and new strategies are needed to reduce the need for corneal transplantation. While adeno-associated viruses (AAVs) have the capacity to deliver anti-apoptotic genes to human corneal endothelial cells (CECs), this has not been fully explored as a therapeutic strategy for FECD. In this study, we evaluated the transduction efficiency of self-complementary (sc-) and single-stranded (ss-) AAV2 serotypes in human CECs and ex vivo tissues and assessed whether AAV-mediated expression of Bcl-xL could attenuate apoptosis in FECD. Seventeen scAAV2 serotypes were screened for transduction efficiency in normal human CECs via green fluorescent protein (GFP) expression. The top 4 AAV2 serotypes were further evaluated in FECD cell lines, healthy cadaveric donor specimens, and FECD patient specimens. FECD cell lines were transduced with anti-apoptotic ssAAV2/5-Bcl-xL (AAV2/5-CAG-eGFP-P2A-BCLXL) and treated with etoposide to induce apoptosis. We found that scAAV2/5 demonstrated high transduction efficiency across all normal and FECD cell lines and tissues. We observed that ssAAV2/5-mediated expression of Bcl-xL provided significant protection against etoposide-induced apoptosis in FECD CECs (71.68%{+/-}0.69 vs 23.96%{+/-}8.88%, p=0.018). Our findings show that AAVs have the potential for therapeutic gene delivery to the human corneal endothelium, and that targeting the Bcl-xL mediated apoptotic pathway can be further explored as a therapeutic for FECD.

cell biology↗

bioRxiv2026

The filopodial scaffold polyphosphate dictates cell adhesion-versus-invasion decisions

Inorganic polyphosphate (polyP) is an ancient polymer conserved across all life, serving cell type and location specific functions in every major compartment. Yet its role at the plasma membrane, where it accumulates to peak levels in many primary cells, is largely unknown. Here we identify polyP as a stabilizing component of filopodia, actin based membrane protrusions that govern cell adhesion, contact inhibition, and chemotaxis. Elevating cellular polyP increases filopodial stability and enhances cell adhesion, whereas reducing polyP accelerates filopodial disassembly and promotes cell migration. Mechanistically, we find that polyP acts as a structural filopodial scaffold, recruiting and organizing IRSp53, a membrane curvature inducing protein. We show that metastatic fibroblasts and breast cancer organoids carry markedly reduced and intracellularly reorganized polyP levels relative to their non transformed counterparts. Restoring endogenous polyP via lipid nanoparticle delivery suppresses their invasive phenotypes and reverses prometastatic gene expression signatures, implicating polyP as a primordial tumor suppressor.

cell biology↗

bioRxiv2026

Comparative genomics of clinical isolates of Pseudomonas aeruginosa from cystic fibrosis patients in Mexico

Pseudomonas aeruginosa (P. aeruginosa) is the primary pathogen responsible for morbidity and mortality in patients with cystic fibrosis (CF). Its genomic plasticity and constant selective pressure from antimicrobial treatments have favored the emergence of multidrug-resistant clones. This study conducted a comparative genomic analysis of 41 P. aeruginosa isolated from pediatric patients with CF in Mexico from 2015 to 2024, with the aim of characterizing their evolutionary dynamics, resistome, and virulome. Whole-genome sequencing (MGI, Illumina, and PacBio platforms) was used, with de novo assemblies performed using Unicycler v0.4.8 on the BV-BRC platform. The databases used for the resistome were CARD and NDARO, and for the virulome, VFDB. Phylogenetic reconstruction was based on core-genome alignments generated with Roary v3.13.0, with maximum likelihood reconstruction performed in IQ-TREE v2.1.2. The statistical significance of the segregation of resistance and virulence patterns was evaluated using PERMANOVA analysis. The results revealed a significant clonal prevalence of sequence types (ST) 307 and ST 167. Phylogenomic analysis grouped the isolates into three main clades; Clade 1 stood out for having the highest resistance gene load (mean of 75 genes/genome), establishing itself as the main reservoir of multidrug-resistant profiles. Genotype-phenotype concordance reached 65.5% overall, with high accuracy for aminoglycosides (87.8%) and fluoroquinolones (82.9%). Furthermore, virulome analysis identified 67 distinct patterns that were significantly segregated among the clades (PERMANOVA: R2=0.31, p=0.001). These findings demonstrate that the evolution of P. aeruginosa lineages in the pediatric clinical setting involves parallel and coordinated adaptations in both their resistance potential and their virulence arsenal. This study underscores the need to adopt a multidisciplinary approach to the clinical management of chronic P. aeruginosa infections in pediatric patients. The persistence of extensively drug-resistant (XDR) strains calls for the integration of genomic surveillance and functional diagnostics, as well as the search for therapeutic alternatives for the clinical management of patients with cystic fibrosis.

microbiology↗

bioRxiv2026

Autonomous Homeostatic Synthetic Cells via Self-Gating DNA Nanopores

Homeostasis is a fundamental hallmark of living organisms, arising from the complex interplay between biochemical reactions and regulatory feedback systems. Reconstituting such self-regulating behaviour in minimal synthetic cells enables continuous, persistent operation of biochemical reactions for extended amount of time. In this work, we demonstrate a minimal homeostatic synthetic cell capable of autonomous flux regulation using DNA nanotechnology and bottom-up synthetic biology. Our homeostatic architecture consists of Giant Unilamellar Vesicles (GUVs) equipped with gated DNA nanopores, encapsulated in vitro transcription (IVT) machinery, and an RNA degradation system. We achieve homeostasis under varying external chemical stimuli specifically varying concentrations of rNTPs by implementing a negative feedback loop between rNTP influx and RNA production. In our system, DNA nanopores facilitate the influx of rNTPs from the external environment, driving internal transcription. Crucially, the transcription process generates RNA "blockers" designed to bind and gate the DNA nanopores, thereby attenuating further rNTP influx. Our system is dynamic as encapsulated RNases slowly degrade the RNA blockers, allowing the pores to reopen as blocker concentration goes down. We first characterise the functionality and gating efficiency of the DNA nanopores using both pre-synthesised and in situ produced DNA and RNA blockers. We then demonstrate that rNTP flux through these pores is sufficient to drive IVT within the GUVs. Finally, by integrating these modules, we demonstrate robust homeostasis: the system maintains a steady-state level of RNA production for up to 16 hours. By harnessing the controllability of negative feedback loop, we demonstrate thresholding of the homeostasis level using single-stranded regulator DNA. This work establishes a versatile framework for engineering adaptive and self-sustaining responsive nanomaterials and synthetic cell chassis.

biophysics↗

bioRxiv2026

Resolving Heterogeneous Mechanical Domains via Physics-Aware Deep Clustering of Single-Molecule Force Spectroscopy Data

Many biological processes rely on mechanical forces, with protein molecules acting as key mediators. Understanding how proteins respond to mechanical stress is essential for conditions including cardiomyopathy and muscular dystrophy. Natural proteins such as dystrophin and utrophin are composed of heterogeneous folding domains with distinct mechanical properties; deciphering domain-level behavior provides insights into disease mechanisms and informs therapeutic strategies. Single-molecule force spectroscopy (SMFS) enables probing the mechanical properties of entire proteins, yet current approaches struggle to identify heterogeneous folding domains, particularly without prior knowledge. Here, we present the first automated framework to identify heterogeneous folding domains in SMFS data, applying both existing clustering methods and a novel physics-aware deep clustering architecture, LatentUnfold. LatentUnfold learns complementary latent representations from force magnitude and the force-extension physical relationship through dual autoencoders, jointly optimized for clustering assignments. We apply our framework to experimental SMFS data collected from a synthetic two-domain protein (ddFLN4-Titin I27) as well as natural protein constructs of dystrophin and utrophin, with Monte Carlo simulated datasets serving as controlled validation. For the synthetic protein, we recover mechanical properties consistent with previously reported values for each domain. For the natural proteins, we uncover two mechanically distinct domain populations - corresponding to the N-terminal domain and spectrin-like repeats - with differences in both unfolding force and contour length increase, and reveal different unfolding order between them for the first time. This work enables domain-level biological inference, overcoming prior limitations that relied on averaging and overlooked heterogeneity, thus advancing the understanding of mechanical behavior in protein unfolding.

biophysics↗

bioRxiv2026

Arterial Elastin Abundance, Rather Than Orthologue Origin, Modulates Medial Arterial Calcification in Matrix Gla Protein-Deficient Mice

Abstract Calcific deposits in the arterial media have been associated with a number of metabolic and genetic disorders including diabetes, chronic kidney disease and generalized arterial calcification of infancy. While medial calcification and physiologic hard tissue mineralization in the skeleton are both regulated by several common determinants, emerging data suggest that there might be fundamental differences in the mechanisms underlying these two processes. Objective: We previously demonstrated that elastin haploinsufficiency delays medial calcification in MGP-deficient mice. Here, using mice in which a human ELN transgene rescues mouse elastin deficiency, we investigated whether the origin and abundance of arterial elastin differentially affect the initiation and progression of medial calcification. Approach and Results: We pursued a transgenic approach to alter the arterial elastin scaffold in MGP-deficient mice. Our analyses of a humanized MGP-deficient model with 40% reduction of medial elastin content showed a complete absence of the early-stage vascular calcification. Additionally, we showed that mouse and human elastin orthologues affect vascular calcification in a comparable manner. Conclusion: Arterial elastin abundance, rather than orthologue origin, modulates the initiation and progression of medial calcification in MGP-deficient mice. A further reduction in arterial elastin beyond that achieved by elastin haploinsufficiency profoundly delays mineral deposition and maturation, whereas restoration of elastin abundance through transgenic human ELN expression restores arterial calcification.

cell biology↗

bioRxiv2026

Exploratory multi-omics analysis reveals sex-specific differences in microbial response to antibiotic exposure

Antibiotic exposure is a major driver of microbiome disruption and antimicrobial resistance gene (ARG) expansion. Yet, the role of biological sex in shaping these responses remains poorly understood. Most studies do not stratify antibiotic-induced microbiome changes by sex or integrate multi-omics datasets, limiting our understanding of how microbial, metabolic, and immune responses interact. Therefore, there remains a critical need for an integrative systems-level approach to determine how sex-specific disruptions under antibiotic pressure are paralleled across microbial, metabolic, and host immune layers. The objective of this work was to perform an exploratory study investigating how continuous antibiotic exposure reshaped the gut microbiome across sexual maturation and how these perturbations influenced downstream host responses in a sex-specific manner using an integrative multi-omics framework. Male and female mice that were exposed to continuous antibiotics were profiled over sexual maturation using shotgun metagenomics, untargeted metabolomics, and bulk RNA sequencing of the spleen to assess microbial composition, ARG dynamics, metabolic profiles, and immune responses. Overall, our results demonstrated sex-specific correlations at a systems-level that help provide valuable context to the differences observed in males and females upon antibiotic exposure.

microbiology↗

bioRxiv2026

The circadian system is affected by Alzheimers disease independently from amyloid beta deposits

Circadian disruption, notably sleep disturbances, serves as an early indicator of Alzheimers disease (AD), preceding cognitive symptoms like memory loss. The suprachiasmatic nucleus (SCN) governs biological rhythms and receives direct retinal input via melanopsin-expressing retinal ganglion cells (mRGCs) to synchronize with environmental light cycles. The anatomical and functional basis for circadian disruption in AD remains unclear. Here, we explored the multi-level relationships between gene expression, the SCN connectome, and regulations of sleep and circadian rhythms in the APP/PS1 mouse model. The sleep architecture of APP/PS1 mice displayed significantly reduced rapid eye movement sleep (REM), associated with a reduced daily core body temperature amplitude and locomotor hyperactivity. Lastly, APP/PS1 mice showed an impaired response to acute light pulse stimulation and present hyperactivity of mRGCs at a young age and hypoactivity of these cells at older ages. These physiological functions are known to be, at least in part, regulated by the SCN, the main target of mRGCs. We noted several modifications in SCN connectomics using serial blockface electron microscopy (SBEM), including a reduction of the dendro-dendritic chemical synapse (DDCS) network that receives a large part of the retinal input and is thought to be crucial for synchronicity between SCN neurons. In addition, we observed multiple signs of dystrophy, including modifications of the shape of dendrites and cell soma, accumulation of aggregated lysosomes, and swelling of axons. At the same time, we investigated the changes in gene expression using spatial transcriptomics. The SCN presents changes in the expression of genes associated with synapse formation, cell adhesion, and neurite growth. These results suggest that, despite the absence of amyloid plaques in the ventral hypothalamus, the SCN of APP/PS1 mice still undergo profound gene expression changes, impacting connectomics and physiological functions. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=157 SRC="FIGDIR/small/744599v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@ceedb0org.highwire.dtl.DTLVardef@156cfaaorg.highwire.dtl.DTLVardef@5bc262org.highwire.dtl.DTLVardef@36df4d_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2026

Salicylic acid-triggered apoplastic proteolysis releases cryptic phytocytokines with distinct immunogenic functions

Plants rely on an innate immune system to defend against pathogens through various molecular responses. In addition to classical damage- and pathogen-associated molecular patterns (DAMPs and PAMPs), plants produce endogenous signaling peptides termed phytocytokines that amplify and regulate immune responses following stress. Although most characterized phytocytokines originate from dedicated precursor proteins, the contribution of multifunctional proteins to phytocytokine generation remains poorly understood. Here, we show that salicylic acid (SA) rapidly remodels the maize apoplastic peptidome through an early, transient proteolytic program driven by apoplastic serine hydrolases. Time course peptidomics identified fourteen candidate phytocytokines, including two cryptic peptides, PC13 and PC14, released from the stress-associated zinc-finger protein ZmSAP7 and the migration inhibitory factor-like protein ZmMDL1, respectively. Both peptides activated immune-associated gene expression but triggered distinct transcriptional responses and exerted opposing effects on Ustilago maydis infection, with PC13 enhancing resistance and PC14 promoting susceptibility. Biochemical analysis demonstrated that PMSF-sensitive apoplastic serine proteases directly process ZmMDL1 to release PC14. Together, our findings uncover a SA-responsive proteolytic pathway that generates functionally distinct phytocytokines from multifunctional proteins, expanding the repertoire of immune signaling peptides and revealing an additional layer of regulation in plant defense.

plant biology↗