Biology subjects

Taylor, A.

Publications and source records attributed to Taylor, A..

At least 19 recordsLinked to original sources

bioRxiv2026

Climate warming reduces the speed and predictability of polygenic adaptation to salinity decline

Climate change exposes populations to multiple stressors simultaneously, yet our understanding of how the addition of one stressor alters adaptation to another remains poor. As a result of climate change, high-latitude coastal habitats are experiencing rapid salinity decline, resulting in serious impacts on food webs and ocean circulation. Here, we examine how temperature increase impacts adaptation to salinity decline, in terms of the speed, genomic response, and repeatability of adaptation. We performed replicated Evolve-and-Resequence experiments over 20 to 25 generations in the model copepod Eurytemora carolleeae (Atlantic clade of the E. affinis species complex). Under salinity decline alone, replicate selection lines exhibited a polygenic response involving 66 selected haplotype blocks, with increasing parallelism among the replicate lines through Generation 20. Fitness (egg number) declined sharply over the first four generations but underwent full Evolutionary Rescue, recovering to ancestral levels by Generation 10. In contrast, imposing temperature increase on the salinity decline lines resulted in significantly lower parallelism among the selection lines, along with delayed and incomplete Evolutionary Rescue. Only 14% of selected SNPs were shared between the two selection regimes, and Gene Ontology analyses revealed largely distinct functional categories of genes under selection. These results show that adding warming to salinity decline can alter the genomic trajectory of salinity adaptation, slowing and impeding Evolutionary Rescue, and reducing the repeatability of polygenic responses. Our findings have direct implications for predicting evolutionary responses to realistic, multi-stressor climate change in high-latitude coastal ecosystems experiencing simultaneous ocean freshening and warming.

evolutionary biology↗

bioRxiv2026

Operationalising LLM-assisted screening of literature to support systematic reviews

Large language models (LLMs) can ease the work of screening titles and abstracts for systematic reviews, but obtaining reliable results requires researchers to make practical choices about which LLMs to use, how to combine their scores into a ranking, and how far down that ranking to read. We aimed to identify a general- purpose workflow that screens accurately, minimises human review effort, and generalises across environmental literature corpora. We ran an ensemble of five open-source LLMs across ten human-annotated systematic reviews from the field of ecology and environmental science spanning 19,155 studies. We then asked: (1) how well an ensemble of LLMs ranks relevant papers above irrelevant ones, and (2) where a human reviewer should stop working down that ranked list. A four-LLM ensemble chosen without any labels came close, on every review, to the best ranking achievable with that review's annotations (mean Average Precision 0.66 versus 0.68). We tested different rules for when to stop human review, finding that a single SAFE stopping rule chosen in advance recovered greater than 95% of relevant records on all ten reviews while requiring a human to screen 56% of the corpus on average. Against the established open-source active-learning tool ASReview, this label-free ranking reached the same recall target at lower human workload on seven of the ten reviews (39% versus 42% of the corpus on average). The paper offers a complete workflow that can be adopted for new, unlabelled reviews, using open-source LLMs small enough to run on a high-end consumer laptop, and we provide it as an open-source R package.

ecology↗

bioRxiv2026

Condition manipulation reveals an increase in sex-specific additive genetic variance, and reduced intersex genetic covariances in Drosophila prolongata, a species with sexual trait exaggeration

The between sex genetic correlation for traits has long been hypothesized as a constraint to the evolution of sexual dimorphism. Both empirical and theoretical work has suggested that this constraint is influenced by genotype-sex-environment interactions. We examine genotype-sex-environment interactions in both sexually exaggerated and non-exaggerated legs of Drosophila prolongata, to examine the role of organismal condition on evolvability of an extreme trait. We employed a nested full-sib half-sib crossing design, providing food either ad libitum, or restricting food during larval growth, to each brood. When provided food ad libitum, inter-sex genetic correlations between traits is high and positive, whereas under food restriction this correlation substantially weakens, with a modest negative sign. Similarly, comparisons of the G matrix across sexes becomes less associated under food restriction. We discuss these results in the context of the growing appreciation of the factors that facilitate sex-specific evolutionary change.

evolutionary biology↗

bioRxiv2026

Assessing the efficacy of human mesenchymal stromal cells of different tissue origins in a mouse model of kidney ischaemia reperfusion injury

Rodent models of kidney disease have been widely used to assess the efficacy, safety and mode of action of mesenchymal stromal cells (MSCs) as therapies. However, because kidney disease models, MSC type and the methods used to assess kidney injury tend to differ between research groups, it is difficult to obtain data that are sufficiently robust and reproducible to support clinical translation. We present here for the first time a side-by-side analysis of the performance of human MSCs derived from the most commonly used tissue sources, bone marrow (BM-), adipose- (A-) and umbilical cord (UC-), in a kidney ischaemia reperfusion injury (IRI) model in mice. For each animal, we performed a comprehensive assessment of kidney function and health by longitudinal transdermal measurements of sinistrin clearance, serum biomarker levels at the experimental endpoint, and histopathological scoring of sections from left and right kidneys. Furthermore, we tracked the MSCs by bioluminescence imaging in the injured mice to determine their viability over time and their capacity for homing to the damaged kidneys. Our results reveal that only modest if any beneficial effects of the MSC treatments were detectable on kidney function and histology, irrespective of cell type administered. Furthermore, all three MSC types were sequestered in the lungs without reaching the kidneys, and had completely disappeared within 7 days. Our data suggest that none of the MSC types has the capability to improve renal health following IRI to a meaningful extent, questioning their suitability as a clinical therapy. Significance StatementMSCs have been proposed as efficacious cell therapies in murine models of kidney disease, with potential for clinical translation. We compare efficacy of human MSCs of different tissue origins (adipose, bone marrow and umbilical cord) in a refined mouse model of renal IRI. Only modest if any beneficial effects on kidney function and histology were detectable for all three cell types, and cells did not reach the kidneys but sequestered in the lungs where they died.

physiology↗

bioRxiv2026

Real-time heart rate in the wild: remote collection of cardiac data in baboons using a low-power Bluetooth and LoRaWAN system

O_LICardiac rate and rhythm reveal how animals adapt physiologically to day-to-day challenges, with consequences for health and fitness. However, these data remain difficult to collect in wild animals, despite their relevance for individual health and fitness. C_LIO_LIHere, we present a system for collecting and transmitting long-term, fine-scaled physiological data in wild animals. We implanted Bluetooth-enabled cardiac and physiological monitor devices in three wild adult female baboons in the Amboseli ecosystem in Kenya and paired these devices with collars that enabled remote data downloads over long-range wide area network (LoRaWAN). C_LIO_LIThe system performed well over >10 months, providing the first long-term cardiac data in wild primates. The baboons showed strong circadian patterns in heart rate, heart rate variability, and activity. We also present data on one female who left her social group for unknown reasons; while alone she exhibited higher heart rate variability, lower activity, and evidence of disrupted sleep. C_LIO_LIIn sum, physiologgers paired with low-energy methods of remote data retrieval are powerful tools for investigating physiology in wild animals on timescales that extend over many months, with minimal disruption to their behavior. C_LI

zoology↗

bioRxiv2026

Impacts of genome architecture on the repeatability of polygenic adaptation

A central but poorly resolved question regards how genome architecture shapes the selection response and repeatability of polygenic adaptation. We addressed this question using Evolve-and-Resequence experiments under rapid salinity decline in two sibling species (clades) of the invasive copepod Eurytemora affinis complex that differ strikingly in chromosome number (15 versus 4). The 4-chromosome genome arose from chromosomal fusions of the ancestral 15-chromosome genome, bringing together coadapted alleles at fusion sites. Across 10-20 generations of selection, both clades adapted to low salinity but followed divergent evolutionary trajectories. The selection lines of the 15-chromosome clade exhibited highly parallel genomic responses, whereas the 4-chromosome clade lines showed delayed and less repeatable responses. Forward genetic simulations revealed that strong synergistic epistasis among beneficial alleles best explained elevated parallelism in the 15-chromosome clade. Additional simulations varying chromosome number and epistasis revealed that strong positive epistasis, combined with high chromosome numbers, enhances parallelism by enabling recombination to assemble coadapted allelic combinations. In contrast, the high starting frequency of beneficial alleles in the 4-chromosome clade lines indicated selection on standing variation, likely acting on alternative linked haplotypes. These findings demonstrate that genome architecture and gene-gene interactions jointly determine the dynamics and predictability of polygenic adaptation.

evolutionary biology↗

bioRxiv2026

Deep mutational scanning of recent SARS-CoV-2 variants highlights changing amino acid preferences within epistatic hotspot residues

Deep mutational scans across receptor-binding domains (RBDs) of diverging SARS-CoV-2 variants reveal ongoing changes to the effects of mutations, a phenomenon known as epistasis. Careful accounting for these altered mutational effects is important in viral surveillance and forecasting, and more broadly, for understanding the impacts of epistasis on real-world viral evolutionary trajectories. Using a yeast-display RBD deep mutational scanning (DMS) platform, we measure the impacts of virtually all single amino acid mutations and single-residue deletions in the Omicron KP.3.1.1 and LP.8.1 RBDs on folded RBD expression and binding affinity for the human ACE2 receptor. Our comprehensive maps reveal patterns of evolutionary accessibility and constraint at single-residue resolution and when compared to prior datasets, highlight sites whose amino acid preferences continue to change across viral variants. Notably, sites 455, 456, and 493 - which have exhibited repeated substitutions and epistatic dependencies across Omicron subvariants going back to BA.1 - again demonstrate altered patterns of mutational accessibility and constraint. Therefore, it appears that these hotspots of repeated RBD evolution have not yet converged on fixed amino acid solutions, but instead remain sites of ongoing epistatic reconfiguration. We compare our measurements of direct RBD:ACE2 affinity with recently published measurements of mutation impacts on ACE2 binding in the full quaternary spike context, which also integrates the effects of spike conformational dynamics; our analysis uncovers mutations like H505W that could favor adoption of the down/closed RBD conformation as a viral strategy for future antigenic evolution.

microbiology↗

bioRxiv2026

Upregulation of Genetic Markers of Poor Prognosis following Chemotherapy in Acute Myeloid Leukemia Cells

Chemoresistance, a leading cause of treatment failure in cancer, is commonly explained by Darwinian selection of treatment-resistant cell clones. However, recurring resistant tumors invariably display complex phenotypes that contribute to increased malignancy, unlikely to have been selected for by chemotherapy. The growing awareness of (non - genetic) phenotypic plasticity led to the hypothesis that chemotherapy, while reducing tumor burden, also inflicts cell stress that induces stem-like states in cells that survive treatment. Here we examined the transcriptomes of HL-60 leukemic cancer cells that survived exposure to three commonly used drugs at submaximal doses for two to four days, and compared differentially expressed genes to those associated with prognosis in public transcriptome databases of acute myeloid leukemia cohorts. While among the genes differentially upregulated in surviving cells, some reflect the therapeutic effect of chemotherapy as they were associated with favorable outcomes in cohort data, many genes upregulated were associated with poor survival, notably genes involved in stemness, epithelial-mesenchymal transition (EMT), inflammation, drug resistance, and apoptosis evasion. These findings support the idea that treatment effectiveness is the net result of an intrinsic tradeoff: Cytocidal treatment, intended to quantitatively reduce cancer cells, also qualitatively increases the malignancy of non-killed cells, which could contribute to residual disease and relapse. This result has implications for drug screening of new therapeutics, as well as in vitro profiling of patient-derived tumor cell susceptibility to existing drugs, which only assess suppression of cancer cell growth and survival. Statement of SignificanceCells surviving chemotherapy upregulate many genes that may affect prognosis. Therefore, drug screening must embrace a more holistic assessment of the biological quality of cell response beyond the rate of cell killing.

cancer biology↗

bioRxiv2026

CAR-T Targeting of Mutant Calreticulin Establishes a Potentially Curative Stem Cell-Directed Therapy for Myeloproliferative Neoplasms

Myeloproliferative neoplasms (MPNs) are sustained by mutated hematopoietic stem cells (HSCs). Existing therapies fail to eliminate this compartment, leaving allogeneic HSC transplantation as the only curative option. Recurrent MPN driver mutations in calreticulin (CALRmut) generate a C-terminal neopeptide that requires cell-surface expression for oncogenic signaling, making it an attractive immunologic target. However, it remains unknown if CALRmut is uniformly displayed on all MPN HSCs within hematopoietic microenvironments. We generated huAB2, a high-affinity CALRmut-specific humanized antibody, to use as the targeting domain for chimeric antigen receptor (CAR)-T cells. We show that CALRmut is consistently displayed on functional MPN HSCs and accessible in vivo. huAB2 CAR-T cells eradicate MPN-propagating CALRmut HSCs in patient-derived tumor xenograft models without antigen escape while preserving coexisting normal human and host hematopoiesis. These findings establish CALRmut display as an obligate feature of MPN HSC fitness and support the feasibility of curative, non-transplant immunotherapy for CALRmut MPNs. SignificanceTherapies that eradicate cancer stem cells enable cure, but their feasibility is unknown. We establish an approach to potentially cure MPNs by proving mutant calreticulin to be a MPN stem cell marker that can be targeted by CAR-T cells to selectively wipe out disease in preclinical models of human MPNs.

cancer biology↗

bioRxiv2026

NON-REDUNDANT ROLES OF COPPER TRANSPORTERS ATP7A AND ATP7B IN NORADRENERGIC SIGNALING

Menkes disease and Wilson disease are debilitating neurometabolic disorders caused by mutations in the copper (Cu) transporters ATP7A and ATP7B, respectively. In either disease, normalization of systemic Cu levels often does not eliminate neurological deficits, suggesting dysregulated Cu homeostasis within vulnerable neuronal populations. However, the specific roles of ATP7A and ATP7B and the extent of their functional redundancy in neurons remain poorly defined. Here, we selectively deleted Atp7a or Atp7b in noradrenergic neurons, which express both transporters and require Cu for catecholamine biosynthesis. ATP7A deletion reduced Cu levels in the locus coeruleus, disrupted dopamine-{beta}-hydroxylase localization, impaired norepinephrine synthesis, and induced proteomic signatures of defective vesicular trafficking and proteostasis, culminating in neurodegeneration and impaired regulation of energy balance and adaptive thermogenesis. In contrast, ATP7B deletion preserved Cu levels but altered intracellular Cu utilization, resulting in catecholamine imbalance, -synuclein upregulation, aberrant dopamine-{beta}-hydroxylase distribution, and dysregulated thermogenesis. These findings establish ATP7A and ATP7B as non-redundant regulators of noradrenergic function within neural circuits governing metabolic and energy homeostasis and provide a mechanistic framework for persistent neurological pathology independent of systemic Cu levels.

physiology↗

bioRxiv2025

Evidence for an ancient master sex determination gene in Hymenoptera

The vast majority of Hymenopterans determine sex by haplodiploidy, in which males and females develop from haploid unfertilized and diploid fertilized eggs, respectively. At the molecular level, the majority of Hymenoptera are thought to determine sex by so-called Complementary Sex Determination (CSD). Under CSD, sex is determined by the feminizing effects of one or more allele-rich loci, in which the feminizing function is imparted by the interactions of functionally distinct alleles. Because of high allelic diversity, most diploids are heterozygous and develop as females, whereas haploid individuals develop as males, as do rare homozygous diploids. Despite diverse empirical results suggesting that CSD is widespread in Hymenopterans, and substantial theoretical and empirical study of the consequences of CSD, the molecular biology of CSD has received little attention outside of the honeybee, Apis mellifera. Available evidence provides support for divergent perspectives ranging from a single (nearly) universally-conserved CSD locus or a pattern dominated by evolutionary turnover with different genes serving as the CSD gene(s) in different lineages. Recently, a novel non-coding RNA gene named ANTSR was shown to serve as a CSD gene in different ant lineages, and the authors suggested that ANTSR might serve as a more broadly-conserved CSD gene. To assess the role of ANTSR role in CSD across diverse Hymenoptera, we studied syntenic conservation and polymorphism patterns in the broad ANTSR locus, genome-wide sequence from available male and female diploid Formica ants, and data from a sibling cross for Bombus terrestris. We find evidence that ANTSR is a conserved CSD gene across diverse Aculeata, the largest group of Hymenoptera, and provide preliminary evidence that Formica may have multiple CSD loci including ANTSR.

genetics↗

bioRxiv2025

Comprehensive Lipidomic Characterization of Human Blood by High-Throughput UHPSFC/MS using Bioinert Column and Modified MTBE Extraction

Supercritical fluid chromatography is traditionally employed for nonpolar and moderately polar analytes, while the analysis of ionic compounds remains a recognized limitation of the technique. Here, we introduce a novel ultrahigh-performance supercritical fluid chromatography-mass spectrometry (UHPSFC/MS) method using a bioinert column, enabling the separation of lipids with a broad polarity range from nonpolar to ionic species. The UHPSFC/MS method was optimized using 79 lipid species across 41 lipid subclasses, achieving a total run time of 7.5 min, including the column equilibration. The comparison of the separation with conventional and bioinert columns revealed a substantial improvement in peak shapes for ionic lipid classes, such as PS, LPS, PA, LPA, CerP, and SPBP. Additionally, we introduce a combination of the modified chloroform-free extraction followed by a hexane elimination step, which reduces concentrations of nonpolar lipids allowing the injection of more concentrated extracts and minimize ion source contamination. The optimized methodology was applied for the untargeted analysis of human plasma and erythrocyte-rich fraction to achieve highly confident identification of 657 lipid species across 37 lipid subclasses in human blood. The method followed the recommendations for validation of (bio)analytical methods, and its accuracy was confirmed by quantitative analysis of the reference material NIST SRM 1950, with the determined concentrations in agreement with the consensus values from ring trials. The current methodology represents a novel high-throughput and comprehensive quantitative lipidomic method for biological samples. Moreover, the findings provide the potential for the development of bioinert components for SFC platforms.

biochemistry↗

bioRxiv2025

Suppression of non-canonical autophagy induces endothelial and cardiac dysfunction

BackgroundWhile roles for canonical autophagy in the pathophysiology of cardiovascular disease have been established, we have limited understanding of the non-canonical functions of autophagy proteins in this context. LC3-asssociated endocytosis (LANDO) is a novel non-canonical function of autophagy proteins, in which LC3 (microtubule-associated protein light chain 3) is conjugated to early endosome membranes using a portion of the canonical autophagy machinery, and functions in the endocytic recycling of several plasma membrane proteins. Here we ask whether perturbation of LANDO can promote cardiovascular pathogenesis. MethodsCardiac and endothelial functions were assessed by echocardiography and flow-mediated dilatation in mice lacking Rubicon (Rubcn-/-) or the WD domain of ATG16L1 (Atg16l1{Delta}WDki), two known effectors of LANDO. Mice with conditional depletion of Rubicon in the endothelial, myeloid and cardiomyocyte compartments were used as well. Three-dimensional murine cardiac vasculature leakiness was investigated by light sheet fluorescence microcopy. Endothelial activation induced by shear stress was characterized in vitro in primary endothelial cells isolated from murine lungs and human aortic endothelial cells. Associations between genetically predicted expression of candidate genes involved in LANDO and human cardiovascular parameters were studied in the Young Finns Study and the UK Biobank. ResultsCompared to littermate controls, young Rubcn-/- and Atg16l1{Delta}WDki mice showed a decrease in cardiac and endothelial functions, as did mice with endothelium-specific deficiency. VEGFR2 recycling to the plasma membrane and nitric oxide pathway during shear stress were disrupted in LANDO-deficient primary murine and human endothelial cells. Proteomic analysis in primary human aortic endothelial cells revealed an upregulation of intracellular hemoglobin subunit alpha (Hb-) upon shear stress, which was blunted when RUBCN was ablated. Genetic expression studies uncovered several candidate genes related to LANDO that correlated with cardiovascular parameters. These included the retromer complex subunit VPS29, disruption of which decreased Hb- expression levels in human endothelial cells. ConclusionsOur data support a pivotal role of non-canonical functions of autophagy proteins in recycling VEGFR2 upon shear stress activation in endothelial cells together with Hb- expression that may contribute to the etiology of cardiovascular diseases.

physiology↗

bioRxiv2025

BiomarkerML: A cloud-based proteomics ML workflow for biomarker discovery

BackgroundHigh-throughput affinity and mass-spectrometry-based proteomic studies of large clinical cohorts generate high-dimensional proteomic data useful for accelerated disease biomarker discovery. A powerful approach to realizing the potential of these big, complex, and non-linear data, whilst ensuring reproducible results, is to use automated machine learning (ML) and deep learning (DL) pipelines for their analysis. However, there remains a gap in comprehensive ML workflows tailored to proteomic biomarker discovery and designed for biomedical researchers who need pipelines to optimally self-configure and automatically avoid over-fitting. FindingsWe present BiomarkerML, a cloud-based workflow for automated, reproducible, and efficient ML/DL analysis of proteomic data for biomarker discovery, designed for novice-ML users and implemented in Python, R and Workflow Description Language (WDL). BiomarkerML: ingests proteomic and clinical data alongside sample labels; pre-processes data for model fitting and optionally performs dimensionality reduction and visualization; fits a catalogue of ML and DL classification and regression models; and calculates model performance metrics for model comparison. Next, the workflow applies mean SHapley Additive exPlanations (SHAP) to quantify the contribution of each protein to model predictions across all samples. Finally, proteins with high mean SHAP values, and their co-expressed protein network interactors, are identified as candidate biomarkers. Importantly, hyperparameters - configuration variables set prior to training models - are automatically fine-tuned via grid-search, and BiomarkerML employs weighted, nested cross-validation to avoid model over-fitting and data leakage. ConclusionsBiomarkerML is scalable, provides a standardized, user-friendly interface, and streamlines analyses to ensure reproducibility of results. Overall, BiomarkerML is a significant advancement, enabling novice-ML researchers to use cutting-edge ML/DL tools to identify disease biomarkers in complex proteomic data.

bioinformatics↗

bioRxiv2025

Translating Music to Touch: Exploring Tactile Perception of Pitch, Roughness, and Pleasantness

Music is a rich multisensory experience, yet individuals with hearing impairments often lack access to this important aspect of culture. As tactile technologies advance, there is growing interest in whether musical information can be conveyed through vibration. This study investigates how core dimensions of auditory music perception, pitch, roughness, and pleasantness, can be translated into the tactile domain. Participants were asked to rate these perceptual dimensions in response to sinusoidal and complex waveforms, including amplitude-modulated signals, sawtooth, and missing fundamental stimuli. Perceived pitch showed a systematic relationship with stimulus frequency for most participants, suggesting that tactile devices could at least partially convey some form of simple melodic patterns. The sawtooth waveform emerged as particularly effective for representing pitch changes, underscoring the role of rapid temporal transitions in tactile pitch encoding. Roughness ratings were negatively correlated with pleasantness, mirroring well-established findings in auditory perception. Waveforms with sudden temporal changes or rapid amplitude modulations were consistently judged as less pleasant. Taken together, these findings in normal hearing participants may inform the design of vibrotactile displays that could support access to selected music relevant perceptual dimensions, although generalization to people with hearing loss remains to be tested. Importantly, our results highlight the crucial role of the fast temporal envelope rather than the temporal fine structure, in shaping vibrotactile perception. Consistent with this interpretation, our data provide evidence for a tactile analog of the auditory missing fundamental phenomenon, reinforcing the idea that tactile pitch perception primarily relies on envelope periodicity rather than the presence of specific frequency components.

neuroscience↗

bioRxiv2025

Long-Read Sequencing of the MUC1 VNTR: Genomic Variation, Mutational Landscape, and Its Impact on ADTKD Diagnosis and Progression

BackgroundADTKD-MUC1 is caused by frameshift mutations in MUC1 gene that produce a frameshifted protein (MUC1fs) toxic to kidney cells. The genes variable number of tandem repeats (VNTR), with high GC content, makes it largely inaccessible to standard sequencing. As a result, both the reference sequence and natural variation in this region remain poorly defined, complicating mutation detection and data interpretation. Standard methods also fail to pinpoint the exact VNTR unit affected, limiting insight into mutation mechanisms and genotype-phenotype correlations. MethodsWe employed Single Molecule, Real-Time (SMRT) sequencing and characterized the genomic sequence of MUC1 in 300 individuals including 279 individuals from 143 families suspected of having ADTKD-MUC1. We compared these results to those obtained using the CLIA-approved mass spectrometry-based probe extension (PE) assay, which specifically detect the most prevalent 59dupC mutation. We correlated the structural features of the MUC1 VNTR with the rate of kidney function decline in affected individuals. ResultsWe identified MUC1 consensus sequences for 205 unique VNTR alleles, with 9 distinct types of frameshift mutations present on 52 distinct mutated VNTR alleles. MUC1 frameshift mutations were identified in 71 of 143 families (50%) with suspected ADTKD, comprising 135 genetically affected individuals (48%). The SMRT assay exhibited complete concordance and revealed that the PE assay is capable of detecting frameshift mutations in approximately 85% of affected families. The constellation of VNTR structures supports a genotype-progression model, in which fast progressors exhibit a significantly lower number of repeat units on the wild-type allele and a higher number of repeats on the mutation-bearing allele, including an increased number of frameshifted repeat units. ConclusionsSMRT sequencing outperforms current diagnostic methods for ADTKD-MUC1 and reveals the prognostic value of VNTR structures. Although their contribution to disease progression is modest ([~]6% variance explained), it remains biologically and clinically meaningful. Key Points 3O_LISingle Molecule, Real-Time (SMRT) sequencing of MUC1 outperforms existing genetic and immunohistochemical methods for ADTKD-MUC1 diagnosis. C_LIO_LICLIA-approved mass spectrometry-based genotyping assay, complemented by SMRT sequencing, can detect nearly all ADTKD-MUC1 patients. C_LIO_LIDisease progression correlates with VNTR pattern: fast progressors have fewer WT repeats and more mutant/frameshifted repeats C_LI

genetics↗

bioRxiv2025

Progressive Remodeling of Global Protein Interaction Networks in a Mouse Model of Tauopathy

Neurodegenerative disease is marked not just by loss of proteins or cells, but by dynamic rewiring of macromolecular interaction networks that precede and drive pathology. Here, we present the first temporally resolved, systems-scale map of multi-protein complex remodeling in a tauopathy model, integrating co-fractionation mass spectrometry, quantitative phosphoproteomics, and machine learning to decode phosphorylation-dependent shifts in protein interactomes across disease progression. This interactomic atlas identifies functionally validated assemblies--including MAPT-Dpysl2 and Cyfip1-actin complexes--that modulate early disease phenotypes in vivo. By revealing how phosphorylation tunes macromolecular complex architecture and function, this work reframes tauopathy as a disease of dynamic network instability, and establishes a generalizable framework for early detection and mechanistic dissection of neurodegeneration.

neuroscience↗

bioRxiv2025

Modelling Glomerular Filtration using Multispectral Optoacoustic Tomography and a Novel Near-infrared Dye

Kidney disease carries significant morbidity, mortality, and financial cost. Preclinical work exploring more accurate methods for assessing renal function is key for monitoring disease progression and the efficacy of future therapies. Measuring kidney function by dynamic contrast enhanced imaging allows us to measure left and right kidney function separately. This provides an internal control where a unilateral injury model is used. Multispectral optoacoustic tomography (MSOT) can measure the renal clearance of administered near infrared absorbers and, via the application of mathematical models, allows for the calculation of glomerular filtration rate. ABZWCY-HP{beta}CD is a cyanine dye bound to 2-hydroxylpropyl-{beta}-cyclodextrin and has shown promise as a glomerular filtration marker. Here we combine MSOT, ABZWCY-HP{beta}CD, and a modified Patlak-Rutland model to measure the glomerular filtration rate of healthy mice and following ischaemic reperfusion injury.

physiology↗