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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 Read source abstracts and check manuscript versions; preprints are not peer reviewed.

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At least 793 records · Page 44Linked to original sources

H&Enium, Applying Foundation Models to Computational Pathology and Spatial Transcriptomics to Learn an Aligned Latent Space

Bridging the gap from transcriptomic to imaging data at single-cell resolution is essential for understanding tumor biology and improving cancer diagnostics. Spatial transcriptomics enables mapping gene expression onto H&E images of segmented single cells, but remains limited by cost and throughput. We introduce H&Enium, a contrastive alignment framework that projects image and gene expression embeddings from foundation models into an aligned latent space using projection heads and a novel soft alignment target. This alignment enriches image-derived embeddings with transcriptomic context improving downstream tasks such as cell type classification and gene expression prediction. Additional evaluations on independent pathology datasets demonstrate superior generalization of our aligned representations over unaligned baselines. Our method offers a scalable path to enhance the utility of standard H&E imaging in both research and clinical settings.

pathology↗

Different kinetics of humoral response against individual antigens in the ovine model of Toxoplasma gondii infection and its pathological association

BackgroundToxoplasma gondii is a globally distributed protozoan parasite with major implications for human and animal health. In sheep, infection can cause reproductive failure and represents an important source of zoonotic transmission through contaminated meat. While cell-mediated immunity is the main protective mechanism, the contribution of humoral responses, particularly against individual recombinant antigens (rAGs), remains poorly characterized in ovine toxoplasmosis. MethodsWe analyzed the humoral response of lambs experimentally infected with two reference strains of T. gondii (RH and Me49) using different inoculation doses. Recombinant antigens rGra4Gra7, rGra8, rRop2, rCST9, and rBCLA were tested by IgG-ELISA to evaluate their kinetics during infection. Histopathological analyses of brain tissues were performed to assess lesion severity and cyst presence. Additionally, sera from naturally infected sheep were evaluated to test diagnostic performance. ResultsAn early IgG response against rGra4Gra7 and rGra8 was detected, consistent with markers of acute infections. Anti-rBCLA, rRop2, and rCST9 IgG responses were associated with the chronic phase and correlated with cyst burden. Notably, stronger anti-rGra4Gra7 IgG responses tended to associate with lower lesion scores, suggesting a potential protective role. In naturally infected sheep, IgG-ELISA against rGra4Gra7 and rGra8 demonstrated the highest diagnostic performance, outperforming total lysate antigen (TLA)-based assays. ConclusionOur findings highlight distinct kinetics of specific antibody responses against selected T. gondii antigens in sheep, suggesting their value as markers of infection stage and pathology. rGra4Gra7 and rGra8 appear particularly promising both as diagnostic candidates and for exploring mechanisms of humoral modulation in ovine toxoplasmosis.

pathology↗

PDE3A2 modRNA Fine-Tunes Nuclear cAMP Microdomains and Reverses Pathological Cardiac Hypertrophy

Pathological cardiac hypertrophy (PCH) is a precursor to heart failure, driven in part by dysregulated nuclear-localized cAMP (NLS-cAMP) signaling. Phosphodiesterase 3A2 (PDE3A2) is a key regulator of this nuclear cAMP microdomain, yet its selective modulation remains challenging. Here, we developed PDE3A2-modified RNA (PDE3A2-modRNA) to restore nuclear PDE3A2 levels and tested its efficacy in an angiotensin II-induced PCH model. Subcellular FRET imaging revealed that PCH hearts exhibit hyperactive NLS-cAMP due to PDE3A2 depletion. PDE3A2-modRNA selectively reduced NLS-cAMP without altering cytosolic cAMP, demonstrating precise microdomain regulation. In vivo, PDE3A2-modRNA improved cardiac function, attenuated hypertrophy and fibrosis, and shifted transcriptional programs toward physiological remodeling. Single-nucleus transcriptomics and immune profiling further revealed reduced oxidative stress and an improved cardiac microenvironment. These findings highlight PDE3A2-modRNA as a novel gene therapy that selectively restores nuclear cAMP homeostasis, reversing PCH-promoting transcriptional programs while preserving physiological cAMP signaling in cytosolic microdomains.

pathology↗

Long-term Locus Coeruleus Stimulation Exacerbates Tau Pathology in PS19 Mice

BackgroundAlzheimers disease (AD) is the most common form of dementia, characterized by the accumulation of amyloid-{beta} (A{beta}) plaques and hyperphosphorylated Tau tangles. The locus coeruleus (LC) is among the first brain regions to show degeneration and Tau pathology during the early stages of AD. Previous studies have demonstrated that short-term chemogenetic LC stimulation can improve memory performance in the TgF344-AD rat model, while long-term norepinephrine (NE) reuptake inhibition can worsen memory deficits in the ADLPTau mouse model. However, the effects of long-term LC stimulation in Tau mouse models on memory, synaptic plasticity, and tauopathy remain unclear. ObjectiveTo evaluate the impact of long-term locus coeruleus stimulation on memory, synaptic plasticity, and tauopathy in PS19 mice using behavioral paradigms, electrophysiological recordings, and immunohistochemical analysis. MethodsThe radial arm water maze and fear conditioning test were conducted to assess memory performance in PS19 mice with and without long-term LC stimulation. Hippocampal long-term potentiation was recorded to evaluate the effect of long-term LC stimulation on synaptic plasticity. Immunohistochemistry was employed to examine Tau phosphorylation, neurodegeneration, and neuroinflammation. ResultsLong-term LC stimulation in PS19 mice exacerbated spatial memory deficits in the water maze, impaired contextual fear memory, reduced hippocampal LTP, and increased AEP expression, Tau hyperphosphorylation, and astrocyte activation. ConclusionLong-term LC stimulation may exacerbate memory deficits in PS19 mice by impairing synaptic plasticity and increasing neural degeneration in the hippocampus. Elevated norepinephrine levels resulting from long-term LC stimulation may increase AEP expression, contributing to Tau hyperphosphorylation in the LC.

pathology↗

Interpretable classification of Alzheimer’s disease pathologies with a convolutional neural network pipeline

Neuropathologists assess vast brain areas to identify diverse and subtly-differentiated morphologies. Standard semi-quantitative scoring approaches, however, are coarse-grained and can lack precise neuroanatomic localization. We report a proof-of-concept deep learning pipeline identifying specific neuropathologies--amyloid plaques and cerebral amyloid angiopathy--in immunohistochemical-stained archival slides. Using automated segmentation of stained objects and a cloud-based interface, we annotated >70,000 plaque candidates from 43 whole slide images (WSIs) to train and evaluate convolutional neural networks. Networks achieved strong plaque classification (0.993 and 0.744 areas under the receiver operating characteristic and precision recall curve, respectively) on a 10 WSI hold-out set. Prediction confidence maps visualized morphology distributions from the full-WSI level down to 20x magnification. Resulting plaque-burden scores correlated well with established semi-quantitative scores. Finally, saliency mapping demonstrated that networks learned patterns agreeing with accepted pathologic features. This scalable means to augment a neuropathologists ability may suggest a route to neuropathologic deep phenotyping.

pathology↗

Cancer drives atherosclerotic plaque vulnerability by inducing pathological angiogenesis

Cardiovascular disease (CVD) is the leading cause of death for many cancer survivors, a phenomenon traditionally attributed to shared risk factors and cardiotoxic chemotherapies. Here, we hypothesized that cancer may also directly promote atherosclerosis. Propensity-matched analyses confirmed significantly elevated cardiovascular event rates amongst cancer patients, independent of comorbidities such as smoking. Atheroprone mice implanted with colorectal tumors demonstrated accelerated features of plaque vulnerability, driven by pathological angiogenesis and intraplaque hemorrhage. Mechanistically, tumor-secreted TNF- induced the pro-angiogenic factor LRG1 across multiple murine models and human plaques. Therapeutic interventions targeting these pathways, including with FDA-approved cytokine inhibitors or tumor resection, prevented plaque destabilization in mice and reduced coronary revascularization rates in patients. Together, these findings suggest that cancer may causally promote CVD and unveil novel translational strategies for cancer survivors.

pathology↗

The Hidden Cost of Blue Light: Multiorgan Pathology Induced by LED Exposure in Mice

Life evolved under broad-spectrum sunlight (300-3500 nm), but most modern light-emitting diodes (LEDs) emit within a restricted visible range (350-650 nm) leaving lighting environments that are short-wavelength dominant. We ask if chronic 450nm exposure dominant in LEDs alters metabolism and organ integrity in ageing mice environmentally exposed at 13 mW/cm{superscript 2} for 5 h/day over 40 weeks, at an intensity within the range of human environmental exposures. Mice exhibited progressive weight gain despite reduced food intake, with altered glucose tolerance and insulin sensitivity over time. White adipose tissue mass increased, while brown adipose tissue weight and UCP1 protein levels remained unchanged. Relative organ weights (heart, liver, kidney, testis) were each reduced by ~10%, with histopathology revealing fat deposition, hepatocellular degeneration, renal tubular damage, steatosis, and impaired testicular architecture. These findings demonstrate that chronic 450 nm light exposure is associated with metabolic alterations and multiorgan pathology in mice.

pathology↗

Visualizing micro- nanoplastics in the human brain: Early evidence for roles in microvascular pathology

Our environment has become progressively contaminated with non-biological materials, especially synthetic carbon polymers, plastics. Unsurprisingly some of these make it into the human body as detected by chemical analyses, yet it is unknown whether they cause harm or are innocent bystanders. Building on our observations of glossy deposits and unusual non-biological fluorescent particles in blood vessels, we aimed to determine whether these objects represented plastics. To do this we prepared plastics-enriched pellets from brain and subjected them to pyrolysis gas-chromatography/mass spectroscopy (py-GC/MS), electron microscopy and confocal laser scanning microscopy. Py-GC/MS confirmed the presence of 10 different plastics. Contents of pellets were examined by thin-section EM. We then used laser scanning confocal microscopy to acquire hyperspectral profiles of each type of plastic in suspensions. We found fluorescent particles in all pellets from brains. All 12 plastics in the calibration standard fluoresced. We obtained hyperspectral profiles of single species plastics from industry: Polyethylene, polypropylene and polystyrene. Controls included chemical analysis of brain storage buffer, which had no detectable plastics; and imaging water only and areas on slides lacking tissue. Abundant particles with emission profiles similar to polyethylene and polypropylene decorated the walls of both arterioles and venules. These particles were coincident with glossy deposits we first observed in white matter, suggesting that both features represent plastics. In summary our results demonstrate that synthetic polymers exhibit detectable fluorescence, and particles with similar spectral properties are visible in histologic sections. This opens the door to investigating correlations between plastics and pathology.

pathology↗

Nonsinusoidal oscillations underlie pathological phase-amplitude coupling in the motor cortex in Parkinson’s disease

Parkinsons disease (PD) is associated with abnormal beta oscillations (13-30 Hz) in the basal ganglia and motor cortex (M1). Recent reports show that M1 beta-high gamma (50-200 Hz) phase-amplitude coupling (PAC) is exaggerated in PD and is reduced following acute deep brain stimulation (DBS). Here we analyze invasive M1 electrocorticography recordings in PD patients on and off DBS, and in isolated cervical dystonia patients, and show that M1 beta oscillations are nonsinusoidal, having sharp and asymmetric features. These sharp oscillatory beta features underlie the previously reported PAC, providing an alternative to the standard interpretation of PAC as an interaction between two distinct frequency components. Specifically, the ratio between peak and trough sharpness is nearly perfectly correlated with beta-high gamma PAC (r = 0.96) and predicts PD-related motor deficit. Using a simulation of the local field potential, we demonstrate that sharp oscillatory waves can arise from synchronous synaptic activity. We propose that exaggerated beta-high gamma PAC may actually reflect such synchronous synaptic activity, manifesting as sharp beta oscillations that are \"smoothed out\" with DBS. These results support the \"desynchronization\" hypothesis of DBS wherein DBS counteracts pathological synchronization throughout the basal ganglia-thalamocortical loop. We argue that PAC can be influenced by more than one mechanism. In this case synaptic synchrony, rather than the often assumed spike-field coherence, may underlie exaggerated PAC. These often overlooked temporal features of the oscillatory waveform carry critical physiological information about neural processes and dynamics that may lead to better understanding of underlying neuropathology.

Neuroscience↗

Cellular Interplay and Cytokine Hierarchy Cause Pathological Cardiac Hypertrophy in RAF1-Mutant Noonan Syndrome

Noonan syndrome (NS) is caused by mutations in RAS/ERK pathway genes, and is characterized by craniofacial, growth, cognitive and cardiac defects. NS patients with kinase-activating RAF1 alleles typically develop pathological left ventricular hypertrophy (LVH), which is reproduced in Raf1L613V/+ knock-in mice. Here, using inducible Raf1L613V expression, we show that LVH results from the interplay of cardiac cell types. Cardiomyocyte Raf1L613V enhances Ca2+ sensitivity and cardiac contractility without causing hypertrophy. Raf1L613V expression in cardiomyocytes or activated fibroblasts exacerbates pressure overload-evoked fibrosis. Endothelial/endocardial (EC) Raf1L613V causes cardiac hypertrophy without affecting contractility. Co-culture and neutralizing antibody experiments reveal a cytokine (TNF/IL6) hierarchy in Raf1L613V-expressing ECs that drives cardiomyocyte hypertrophy in vitro. Furthermore, post-natal TNF inhibition normalizes the increased wall thickness and cardiomyocyte hypertrophy in vivo. We conclude that NS cardiomyopathy involves cardiomyocytes, ECs, and fibroblasts, TNF/IL6 signaling components represent potential therapeutic targets, and abnormal EC signaling might contribute to other forms of LVH.

cell biology↗

Tacrolimus Rescues Endothelial ALK1 Loss-Of-Function Signaling And Improves HHT Vascular Pathology

Hereditary hemorrhagic telangiectasia (HHT) is a genetic vascular disorder arising from endothelial cell (EC) proliferation and hypervascularization, for which no cure exists. Because HHT is caused by loss-of-function mutations in BMP9-ALK1-Smad1/5/8 signaling, interventions aimed at activating this pathway are of therapeutic value. By screening FDA-approved drug libraries, we identified tacrolimus (FK-506) as a potent activator of Smad1/5/8 in BMP9-challenged reporter cells. In primary ECs, tacrolimus activated Smad1/5/8 to oppose the pro-angiogenic gene expression signature associated with ALK1 loss-of-function, by notably reducing Dll4 expression. In these cells, tacrolimus also inhibited Akt and p38 stimulation by VEGF. In the BMP9/10-immunodepleted postnatal retina--a mouse model of HHT vascular pathology--tacrolimus activated endothelial Smad1/5/8 and prevented the Dll4 overexpression and hypervascularization associated with this model. Finally, tacrolimus stimulated Smad1/5/8 in cells transfected with BMP9-unresponsive ALK1 HHT mutants and in HHT patient blood outgrowth ECs. We propose that tacrolimus repurposing has therapeutic potential in HHT.

cell biology↗

Reversal of molecular pathology by RNA-targeting Cas9 in a myotonic dystrophy mouse model

The dominantly inherited, multi-systemic disease myotonic dystrophy type I (DM1) is caused by triplet repeat CTG expansions in the DMPK gene and is the most common form of adult-onset muscular dystrophy. Elimination of the toxic, repetitive CUG RNA constitutes a therapeutic for this disease. We report an RNA-targeting Cas9 (RCas9) system that supports efficient reversal of DM1 phenotypes via delivery to adult poly(CUG) DM1 mouse muscle using adeno-associated virus (AAV). We observe elimination of CUG RNA, restoration of CUG foci-associated Mbnl1 protein to wild-type subcellular localization, correction of DM1-type alternative splicing patterns in candidate genes including the voltage-gated chloride channel 1 (Clcn1) responsible for characteristic myotonia, recovery of Clcn1 staining, and reduction in centralized myonuclei. Our results establish RCas9 as a potential long-term in vivo therapeutic for DM1.\n\nOne Sentence SummaryA repurposed CRISPR system termed RNA-targeting Cas9 reverses the molecular pathology associated with the most common type of adult onset muscular dystrophy in adult mouse muscle.

molecular biology↗

Methylation-To-Expression Feature Models of Breast Cancer Accurately Predict Overall Survival, Distant-Recurrence Free Survival, And Pathologic Complete Response in Multiple Cohorts

BackgroundApproaches that capitalize on the benefits of multi-omic data integration in invasive breast carcinoma to define prognostic biomarkers for precision medicine have been slow to emerge. In this work, we examined the efficacy of our methylation-to-expression feature model (M2EFM) approach to combining molecular and clinical predictors as part of a single analysis to create prognostic risk scores for overall survival, distant metastasis, and chemosensitivity.\n\nMethodsGene expression and DNA methylation values as well as clinical variables were integrated via M2EFM to build prognostic models of overall survival using 1028 breast tumor samples and further applied to external validation cohorts of 61 and 327 samples. Data-integrated prognostic models of distant recurrence-free survival and pathologic complete response were built using 306 samples and validated on 182 samples of external validation data. Additionally, we compared the discrimination and calibration of M2EFM models to other approaches.\n\nResultsDespite different populations and assays, M2EFM models validated with good accuracy (C-index or AUC [≥] .7) for all outcomes in all validation data. M2EFM models had the most consistent performance overall and superior calibration, suggesting a greater likelihood of clinical utility. Finally, we demonstrated that M2EFM identifies functionally relevant genes, which could be useful in translating an M2EFM biomarker to the clinic.\n\nConclusionM2EFM uses multiple levels of genomic data to infer disrupted regulatory patterns, thus providing a gene signature that connects loss of regulatory control with cancer prognosis.\n\nFundingThe analyses described in this report were supported by NIH grants R01ES022222, P30CA138292, P30ES019776, and R01DE022772.\n\nConflicts of InterestThe authors declare no potential conflicts of interest.

bioinformatics↗

Deep Convolutional Neural Networks Enable Discrimination of Heterogeneous Digital Pathology Images

Pathological evaluation of tumor tissue is pivotal for diagnosis in cancer patients and automated image analysis approaches have great potential to increase precision of diagnosis and help reduce human error.\n\nIn this study, we utilize various computational methods based on convolutional neural networks (CNN) and build a stand-alone pipeline to effectively classify different histopathology images across different types of cancer. In particular, we demonstrate the utility of our pipeline to discriminate between two subtypes of lung cancer, four biomarkers of bladder cancer, and five biomarkers of breast cancer. In addition, we apply our pipeline to discriminate among four immunohistochemistry (IHC) staining scores of bladder and breast cancers.\n\nOur classification pipeline utilizes a basic architecture of CNN, Googles Inceptions within three training strategies, and an ensemble of two state-of-the-art algorithms, Inception and ResNet. These strategies include training the last layer of Googles Inceptions, training the network from scratch, and fine-tunning the parameters for our data using two pre-trained version of Googles Inception architectures, Inception-V1 and Inception-V3.\n\nWe demonstrate the power of deep learning approaches for identifying cancer subtypes, and the robustness of Googles Inceptions even in presence of extensive tumor heterogeneity. Our pipeline on average achieved accuracies of 100%, 92%, 95%, and 69% for discrimination of various cancer types, subtypes, biomarkers, and scores, respectively. Our pipeline and related documentation is freely available at https://github.com/ih-lab/CNN_Smoothie.

bioinformatics↗

Simulation of closed-loop deep brain stimulation control schemes for suppression of pathological beta oscillations in Parkinson's disease

This study presents a computational model of closed-loop control of deep brain stimulation (DBS) for Parkinsons disease (PD) to investigate clinically-viable control schemes for suppressing pathological beta-band activity. Closed-loop DBS for PD has shown promising results in preliminary clinical studies and offers the potential to achieve better control of patient symptoms and side effects with lower power consumption than conventional open-loop DBS. However, extensive testing of algorithms in patients is difficult. The model presented provides a means to explore a range of control algorithms in silico and optimize control parameters before preclinical testing. The model incorporates (i) the extracellular DBS electric field, (ii) antidromic and orthodromic activation of STN afferent fibers, (iii) the LFP detected at non-stimulating contacts on the DBS electrode and (iv) temporal variation of network beta-band activity within the thalamo-cortico-basal ganglia loop. The performance of on-off and dual-threshold controllers for suppressing beta-band activity by modulating the DBS amplitude were first verified, showing levels of beta suppression and reductions in power consumption comparable with previous clinical studies. Proportional (P) and proportional-integral (PI) closed-loop controllers for amplitude and frequency modulation were then investigated. A simple tuning rule was derived for selecting effective PI controller parameters to target long duration beta bursts while respecting clinical constraints that limit the rate of change of stimulation parameters. Of the controllers tested, PI controllers displayed superior performance for regulating network beta-band activity whilst accounting for clinical considerations. Proportional controllers resulted in undesirable rapid fluctuations of the DBS parameters which may exceed clinically tolerable rate limits. Overall, the PI controller for modulating DBS frequency performed best, reducing the mean error by 83% compared to DBS off and the mean power consumed to 25% of that utilized by open-loop DBS. The network model presented captures sufficient physiological detail to act as a surrogate for preclinical testing of closed-loop DBS algorithms using a clinically accessible biomarker, providing a first step for deriving and testing novel, clinically-suitable closed-loop DBS controllers.

bioengineering↗

GPCR-mediated clearance of tau in post-synaptic compartments attenuates tau pathology in vivo

Accumulation of pathological tau in synapses has been identified as an early pathogenic event in Alzheimers disease (AD) and correlates strongly with cognitive decline in patients with AD. Tau is a cytosolic, axonal protein. However, in the disease condition, tau accumulates in post-synaptic compartments and pre-synaptic terminals, either due to missorting within neurons, trans-synaptic transfer between neurons or due to failure of clearance systems in synapses. Using a sub-cellular fractionation assay, we show that progressive deposition of seed competent tau occurs predominantly in post-synaptic compartments in a tau transgenic mouse and in AD patient brain, making these neuronal structures particularly vulnerable to tau toxicity. Tau-mediated post-synaptic toxicity could be further exacerbated by impaired proteasome activity which we detected by measuring the levels of polyubiquitin chains that target proteins to proteasomal degradation. To combat the accumulation of tau and proteasome impairment at the subcellular level, we devised a therapeutic strategy of proteasome-mediated clearance of tau restricted to the post-synaptic compartment. Utilizing the pharmacology of GPCRs, we show that in vivo stimulation of the PAC1R receptor by its ligand can propagate intracellular PKA signaling leading to enhanced synaptic proteasome activity and reduced tau in the post-synaptic compartment. Over time, clearance of post-synaptic tau led to reduced tauopathy and cognitive decline in rTg4510 mice. Together, these results highlight a novel therapeutic strategy of targeting GPCRs that propagate cAMP/PKA signaling as a tool to activate proteolysis restricted to synapses to prevent the accumulation of tau in the early stages of AD.

neuroscience↗

Pesticides and transgenerational inheritance of pathologies: Designing, analysing and reporting rodent studies.

The evidence for transgenerational transmission of pathologies in rodents exposed to pesticides is largely based on studies with weaknesses in design and analysis and a lack of transparency in reporting the results. This paper examines these methodological and statistical issues in detail. Its particular focus is on the estimation of litter effects: the tendency for rodents within a litter to be more alike than rodents in different litters. Appropriate statistical models were fitted to published data from a series of widely reported studies carried out at Washington State University. These studies were amalgamated into a single dataset in order to estimate these litter effects and the associated treatment effects. Litter effects varied by outcome and were often substantial. Consequently, the effective sample size was often substantially less than the number of observations with implications for the power of the studies. Moreover, the reported precision of the estimates of treatment effects was too low. These problems are exacerbated by unexplained missing data across generations. Researchers in the life sciences could be more cognisant of the guidelines established in medicine for reporting randomised controlled trials, particularly cluster randomised trials. More attention should be paid to the design and analysis of multi-generational rodent studies; their imperfections have important implications for assessments of the evidence relating to the risks of pesticides for public health.

genetics↗