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Results for “Pathology”

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 Read source abstracts and check manuscript versions; preprints are not peer reviewed.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 235 records · Page 13Linked to original sources

bioRxiv2026

Aberrant accumulation of α-synuclein might be linked with the progressive motor deficits in a mouse model of Angelman syndrome

Dysfunction of maternal UBE3A leads to Angelman syndrome (AS), which is characterized by significant intellectual and motor debilities. However, the molecular underpinnings of the behavioral deficits associated with UBE3A dysfunction remain obscure. In this study, we utilized a model mouse of AS and report, for the first time, that the aberrant accumulation of -synuclein may be linked to the development of AS. Firstly, we demonstrated a progressive deterioration of various motor functions in AS mice beginning from the early adolescent phase. Subsequently, we observed an age-dependent increase in the accumulation of both soluble and insoluble -synuclein, including its pathological variant (pSer129), in the striatum and substantia nigra dopaminergic neurons of AS mice. We also found that Ube3a interacts with -synuclein and promotes its proteasome-mediated degradation, as evidenced by decreased levels of K48-linked polyubiquitinated -synuclein in the brain samples of AS mice in comparison to wild-type animals. Finally, using an RT2 Profiler PCR Array that analysed 84 genes specifically related to dopamine and serotonin pathways, we identified altered transcript level of various genes in the striatal tissues of AS mice that are commonly associated with nigrostriatal dysfunctions in Parkinson's disease. These findings highlight -synuclein as a novel target of Ube3a and suggest that -synuclein pathology may contribute to the progressive motor and other behavioral abnormalities witnessed in AS mice.

neuroscience↗

bioRxiv2026

Impaired proteostasis is an early feature of the diabetic heart in humans and mice

Diabetes and obesity increase cardiac lipid levels leading to cardiomyopathy and heart failure. We hypothesized that intermittent fasting would reduce cardiac lipid levels. Surprisingly, intermittent fasting increased myocardial triglyceride content, but rescued mortality and attenuated cardiomyopathy in mice overexpressing cardiomyocyte acyl-CoA synthetase 1 (MHC-ACSL1). Lipid overload caused cardiomyocyte accumulation of polyubiquitinated protein aggregates containing desmin, a scaffolding intermediate filament protein, which intermittent fasting prevented. Furthermore, intermittent fasting reversed elevated myocardial C16:0 ceramide content, and knockdown of ceramide synthase CerS5 and CerS6 reduced palmitate-induced protein aggregation, highlighting a role for C16:0 ceramides in this pathology. Conversely, impairing aggrephagy with cardiomyocyte-specific p62 ablation induced heart failure in mice fed a high-fat diet, with paradoxically reduced cardiac lipid content. Crucially, non-failing diabetic human hearts also exhibited protein aggregate pathology. Taken together, these results demonstrate that impaired proteostasis characterizes cardiomyopathy from cardiac lipid overload and identify a promising new therapeutic target for this condition.

molecular biology↗

bioRxiv2015

Evaluation of p53 Immunohistochemical Expression Using Open-Source Software for Digital Image Analysis: A Tissue Microarray Study of Penile Squamous Cell Carcinomas

The addition of molecular biomarkers is needed to increase the accuracy of pathologic factors as prognosticators of outcome in penile squamous cell carcinomas (SCC). Evaluation of these biomarkers is usually carried out by immunohistochemistry. Herein we assess p53 immunohistochemical expression on tissue samples of penile SCC using freely-available, open-source software packages for digital image analysis. We also compared the results of digital analysis with standard visual estimation. Percentages of p53 positive cells were higher by visual estimation than by digital analysis. However, correlation was high between both methods. Our study shows that evaluation of p53 immunohistochemical expression is feasible using open-source software packages for digital image analysis. Although our analysis was limited to penile SCC, the rationale should also hold for other tumor types in which evaluation of p53 immunohistochemical expression is required. This approach would reduce interobserver variability, and would provide a standardized method for reporting the results of immunohistochemical stains. As these diagnostic tools are freely-available online, researchers and practicing pathologists could incorporate them in their daily practice without increasing diagnostic costs.

Pathology↗

bioRxiv2016

DeepScope: Nonintrusive Whole Slide Saliency Annotation and Prediction from Pathologists at the Microscope

Modern digital pathology departments have grown to produce whole-slide image data at petabyte scale, an unprecedented treasure chest for medical machine learning tasks. Unfortunately, most digital slides are not annotated at the image level, hindering large-scale application of supervised learning. Manual labeling is prohibitive, requiring pathologists with decades of training and outstanding clinical service responsibilities. This problem is further aggravated by the United States Food and Drug Administrations ruling that primary diagnosis must come from a glass slide rather than a digital image. We present the first end-to-end framework to overcome this problem, gathering annotations in a nonintrusive manner during a pathologists routine clinical work: (i) microscope-specific 3D-printed commodity camera mounts are used to video record the glass-slide-based clinical diagnosis process; (ii) after routine scanning of the whole slide, the video frames are registered to the digital slide; (iii) motion and observation time are estimated to generate a spatial and temporal saliency map of the whole slide. Demonstrating the utility of these annotations, we train a convolutional neural network that detects diagnosis-relevant salient regions, then report accuracy of 85.15% in bladder and 91.40% in prostate, with 75.00% accuracy when training on prostate but predicting in bladder, despite different pathologists examining the different tissues. When training on one patient but testing on another, AUROC in bladder is 0.7929 0.1109 and in prostate is 0.9568{+/-}0.0374. Our tool is available at https://bitbucket.org/aschaumberg/deepscope.

pathology↗

bioRxiv2017

Changes In LXRα Phosphorylation Promote A Novel Diet-Induced Transcriptome That Alters The Transition From Fatty Liver To Steatohepatitis

Understanding the transition from fatty liver or steatosis to more advanced inflammatory and fibrotic stages of non-alcoholic fatty liver disease (steatohepatitis), is key to define strategies that alter or even reverse the progression of this pathology. The Liver X Receptor alpha (LXR) controls hepatic lipid homeostasis and inflammation. Here we show that mice carrying a mutation that abolishes phosphorylation at Ser196 (S196A) in LXR exhibit reduced hepatic inflammation and fibrosis when challenged with a high fat-high cholesterol diet, despite displaying enhanced hepatic lipid accumulation. This protective effect is associated with reduced cholesterol accumulation, a key promoter of lipid-mediated hepatic damage. Reduced steatohepatitis in S196A mice involves the reprogramming of the liver transcriptome by promoting diet-induced changes in the expression of genes involved in endoplasmic reticulum stress, extracellular matrix remodelling, inflammation and lipid metabolism. Unexpectedly, changes in LXR phosphorylation uncover novel diet-specific target genes, whose regulation does not simply mirror ligand-induced LXR activation. These unique LXR phosphorylation-sensitive, diet-responsive target genes are revealed by promoting LXR occupancy and cofactor recruitment in the context of a cholesterol-rich diet. Therefore, LXR phosphorylation at Ser196 critically acts as a novel nutritional sensor that promotes a unique diet-induced transcriptome thereby modulating metabolic, inflammatory and fibrotic responses important in the transition to steatohepatitis.

pathology↗

bioRxiv2017

Obesity/Type II Diabetes Promotes Function-Limiting Changes In Flexor Tendon Extracellular Matrix Organization That Are Not Reversed By Restoring Normal Metabolic Function

Type II Diabetes (T2DM) negatively alters baseline tendon function, including decreased range of motion and mechanical properties; however, the biological mechanisms that promote diabetic tendinopathy are unknown. To facilitate identification of therapeutic targets we developed a novel murine model of diabetic tendinopathy. Mice fed a High Fat Diet (HFD) developed diet induced obesity and T2DM. Obesity/ T2DM resulted in progressive impairments in tendon gliding function and mechanical properties, relative to mice fed a Low Fat Diet (LFD), as well as a decrease in collagen fibril diameter by transmission electron microscopy. We then determined if restoration of normal metabolic function, by switching mice from HFD to LFD, is sufficient to halt the pathological changes in tendon due to obesity/T2DM. However, switching from a HFD to LFD resulted in greater impairments in tendon gliding function than mice maintained on a HFD. Mechanistically, IR{beta} signaling is decreased in obese/T2DM murine tendons, suggesting altered IR{beta} signaling as a driver of diabetic tendinopathy. However, knock-down of IR{beta} expression in S100a4-lineage cells (IRcKOS100a4) was not sufficient to induce diabetic tendinopathy as no impairments in tendon gliding function or mechanical properties were observed in IRcKOS100a4 relative to WT. Collectively, these data define a murine model of diabetic tendinopathy, and demonstrate that tendon-specific, rather than systemic treatment approaches are needed.

pathology↗

bioRxiv2017

An improved experimental model of cystic hydatid disease in liver resembling natural infection route with stable growing dynamics and immune reaction

Cystic echinococcosis is an endemic parasitic infection in Xinjiang, China and is causing serious economic burdens and public health concerns. An experimental murine model in vivo for hepatic cystic echinococcosis was established in C57B/6 mice by injection with human protoscolices via the portal vein of three different concentrations. Mice were followed up 10 months by ultrasound, gross anatomy, pathological and immunological examinations. The protoscolice migration in portal vein, hydatid cyst growth, host immune reaction and hepatic histopathology were examed periodicly. The infection rate of the mice in the high, medium, and low concentration groups were 90%, 100%, and 63.6%, respectively. The protoscolices migrate in the portal vein with blood flow, settle in the liver and develop into orthotopic hepatic hydatid cysts, resembling the natural infection route and course. This study established an improved experimental model of low biohazard risk but stable growing dynamics and immune reaction. It is especially useful for new anti-parasite medication trials agains hydatid disease.\n\nSummary statementAn experimental murine model of cystic echinococcosis was set up. This orthotopic model resembles primary infection route and natural infectious course with low biohazard risk and high efficiency.

pathology↗

bioRxiv2017

Biological influence of extracts of cryopreserved fragments of piglets’ heart and skin

One of the new directions on which the searches used to find the methods to effectively correct the regeneration in case of different pathologies is the application of biologically active peptides and their mixtures. In the work there was investigated the biological influence of extracts of cryopreserved fragments of skin and heart of newborn piglets with the cold wound of skin and myocardial ischemia in rats respectively. For investigations the extracts were obtained from cryopreserved fragments of newborn piglets skin and heart. Cold wound of skin was modelled in rats by 10 mm copper applicator cooled in liquid nitrogen down to -196{degrees}C; the areas of wounds were determined by planimetric method, the white blood cells counts were analysed. In rats with myocardial ischemia there were studied the electrocardiograms, heart rate variability and proliferative activity of heart cells. The injection of extracts of cryopreserved fragments of skin to the animals abdominal cavity accelerates the healing of cold wound of skin and normalizes the response of immune system to an injury. After the injection during 2 months to the animals with myocardial ischemia with extracts of cryopreserved fragments of heart the normalization of electrophysiological indices of heart activity was observed that testified about the improved blood supply to a heart muscle. Being injected to healthy animals and those with myocardial ischemia the extracts of cryopreserved fragments of heart resulted in an increase in proliferative activity of heart cells. The studied extracts have a high biological effect and can be applied when designing the drugs for regenerative medicine.\n\nSummary statementThe extracts of cryopreserved fragments of piglets heart or skin were shown as stimulating reparative regeneration of heart tissues in myocardial ischemia of rats and skin in a cold wound, respectively.

pathology↗

bioRxiv2017

UV-Induced Keratin 1 Proteolysis Mediates UV-Induced Skin Damage

Keratins play critical roles in intermediate filament formation, inflammatory responses and cellular signaling in epithelium. While keratins is a major epidermal fluorophore, the mechanisms underlying the autofluorescence (AF) of keratins and its biomedical implications have remained unknown. Our study used mouse skin as a model to study these topics, showing that UV dose-dependently induced increases in green AF at the spinous layer of the epidermis of mouse within 6 hr of the UV exposures, which may be used for non-invasive prediction of UV-induced skin damage. The UV-induced AF appears to be induced by cysteine protease-mediated keratin 1 proteolysis: 1) UV rapidly induced significant keratin 1 degradation; 2) administration of keratin 1 siRNA largely decreased the UV-induced AF; and 3) administration of E-64, a cysteine protease inhibitor, significantly attenuated the UV-induced AF and keratin 1 degradation. Our study has also suggested that the UV-induced keratin 1 proteolysis may be a novel crucial pathological factor in UV-induced skin damage, which is supported by both the findings that indicate critical biological roles of keratin 1 in epithelium and our observation that prevention of UV-induced keratin 1 proteolysis can lead to decreased UV-induced skin damage. Collectively, our study has suggested that UV-induced keratin 1 proteolysis may be a novel and valuable target for diagnosis, prevention and treatment of UV-induced skin damage.

pathology↗

bioRxiv2018

Dental erosion caused by a gastrointestinal disorder in a child from the Late Holocene of Northeastern Brazil

A skeleton of an approximately 3-years-old sub-adult, in an excellent state of conservation, was found at the Pedra do Cachorro rock shelter - Buique, Pernambuco - Brazil, an archaeological site used as funerary place between 3875 and 575 cal years B.P. The skeleton has no signs of pathological bone changes, but its maxillary teeth show strong evidence of enamel and dentin wear caused by acid erosion, suggesting vomiting or gastroesophageal reflux episodes. The aim of this study was to describe the lesions and discuss the aetiology of these dental defects with the emphasis on the cause of the death of this individual.

pathology↗

bioRxiv2018

Texture Analysis of Dystrophic Muscle Biopsies

Despite the introduction of a full range of genetic diagnostic tests and sophisticated techniques in modern pathology, interpretation of histopathological images obtained from muscle biopsies remains important in the daily practice of neuropathology since it can give indications of the severity and the rate of progression of neuromuscular disease. In this paper, we propose a simple and time saving method for quantitative assessment of severity of Duchenne Muscular Dystrophy (DMD) based on computer-aided analysis of histopathological images obtained from biopsies of dystrophic muscles. Using this method, colour filtration pixel-by-pixel of the whole virtual slides (CFPP method) is adopted to semi-quantitative evaluation of morphological structure of the muscular tissue. Results demonstrate usefulness of the proposed method in neuropathological assessement of DMD severity.

pathology↗

bioRxiv2018

Clarification and confocal imaging of the non-human primate placental micro-anatomy

Placental function is essential for the development of the fetus, and is - in part - related to the 3D arrangement of the villous and vascular geometry. Recent advances in tissue clarification techniques allow for deep high-resolution imaging with confocal microscopy without altering the spatial characteristics of the tissue. These image stacks can be analyzed quantitatively to provide insights regarding the villous and vascular micro-anatomy as well as the interrelationships between the two. However, such analyses require optimization of the tissue preparation, immuno-labeling, and clarification protocol in order to provide reliable results suitable for the detection of subtle differences in pathologic pregnancies. Placental and fetal development are similar between human and non-human primate pregnancies, with the latter serving as a reliable, validated, highly-controlled, well-characterized translational model for the former.\n\nWe present a protocol for the preparation, immuno-labeling, and clarification of the non-human primate placenta optimized for confocal microscopy and subsequent quantification of the micro-anatomic structures.

pathology↗

bioRxiv2018

Segmentation of Glomeruli Within Trichrome Images Using Deep Learning

IntroductionThe number of glomeruli and glomerulosclerosis evaluated on kidney biopsy slides constitute as standard components of a renal pathology report. Prevailing methods for glomerular assessment remain manual, labor intensive and non-standardized. We developed a deep learning framework to accurately identify and segment glomeruli from digitized images of human kidney biopsies. MethodsTrichrome-stained images (n=275) from renal biopsies of 171 chronic kidney disease patients treated at the Boston Medical Center from 2009-12 were analyzed. A sliding window operation was defined to crop each original image to smaller images. Each cropped image was then evaluated by three experts into three categories: (a) No glomerulus, (b) Normal or partially sclerosed glomerulus and (c) Globally sclerosed glomerulus. This led to identification of 751 unique images representing non{-}glomerular regions, 611 images with either normal or partially sclerosed (NPS) glomeruli and 134 images with globally sclerosed (GS) glomeruli. A convolutional neural network (CNN) was trained with cropped images as inputs and corresponding labels as output. Using this model, an image processing routine was developed to scan the test data images to segment the GS glomeruli. ResultsThe CNN model was able to accurately discriminate non-glomerular images from NPS and GS images (Performance on test data - Accuracy: 92.67{+/-}2.02% and Kappa: 0.8681{+/-}0.0392). The segmentation model that was based on the CNN multi-label classifier accurately marked the GS glomeruli on the test data (Matthews correlation coefficient = 0.628). ConclusionThis work demonstrates the power of deep learning for assessing complex histologic structures from digitized human kidney biopsies.

pathology↗

bioRxiv2018

Guanabenz treatment improves Oculopharyngeal muscular dystrophy phenotype

Oculopharyngeal muscular dystrophy (OPMD) is a rare late onset genetic disease affecting most profoundly eyelid and pharyngeal muscles, leading respectively to ptosis and dysphagia, and proximal limb muscles at later stages. A short abnormal (GCG) triplet expansion in the polyA- binding protein nuclear 1 (PABPN1) gene leads to PABPN1-containing aggregates in the muscles of OPMD patients. It is commonly accepted that aggregates themselves, the aggregation process and/or the early oligomeric species of PABPN1 are toxic in OPMD. Decreasing PABPN1 aggregate load in animal models of OPMD ameliorates the muscle phenotype. In order to identify a potential therapeutic molecule that would prevent and reduce aggregates, we tested guanabenz acetate (GA), an FDA-approved antihypertensive drug, in OPMD cells as well as in the A17 OPMD mouse model. We demonstrate that treating mice with GA reduces the size and number of nuclear aggregates, improves muscle force, protects myofibres from the pathology-derived turnover and decreases fibrosis. GA is known to target various cell processes, including the unfolded protein response (UPR), which acts to attenuate endoplasmic reticulum (ER) stress. Here we used a cellular model of OPMD to demonstrate that GA increases both the phosphorylation of the eukaryotic translation initiator factor 2 subunit (eIF2) and the splicing of Xbp1, key components of the UPR. Altogether these data suggest that modulation of protein folding regulation can be beneficial for OPMD and support the further development of guanabenz or its derivatives for treatment of OPMD in humans.\n\nSignificance StatementOculopharyngeal muscular dystrophy (OPMD) is a rare late onset incurable genetic disease characterized by the formation of insoluble aggregates in skeletal muscles. It has been shown that the reduction of aggregates correlates with an improvement of the disease. Here we used a mouse model of OPMD to show that Guanabenz acetate, the active constituent of a marketed but recently discontinued drug for hypertension, decreases the number and the size of aggregates after systemic delivery and improves many aspects of the disease. We also describe experimental evidences explaining the mechanism behind the efficacy of such compound for OPMD.

pathology↗

bioRxiv2013

Embodied cognition, embodied regulation, and the Data Rate Theorem

The Data Rate Theorem carries deep implications for theories of embodied cognition, extensions providing a spectrum of necessary conditions dynamic statistical models useful in empirical studies. A large deviations argument, however, implies that the regulation and stabilization of such systems is itself an interpenetrating phenomenon necessarily convoluted with embodied cognition. For humans, the central regulatory role of culture has long been known. Although a ground-state collapse analogous to generalized anxiety appears ubiquitous to such systems, lack of cultural modulation in real-time automatons or distributed cognition man-machine cockpits makes them subject to a pathology under which all possible targets are enemies.

Neuroscience↗

bioRxiv2014

A microRNA profile in Fmr1 knockout mice reveals microRNA expression alterations with possible roles in fragile X syndrome

Fragile X syndrome (FXS), a common form of inherited mental retardation, is caused by a loss of expression of the fragile X mental retardation protein (FMRP). FMRP is involved in brain functions by interacting with mRNAs and microRNAs (miRNAs) that selectively control gene expression at translational level. However, little is known about the role of FMRP in regulating miRNA expression. Here, we found a development-dependant dynamic expression of Fmr1 mRNA (encoding FMRP) in mouse hippocampus with a small peak at postnatal day 7 (P7). MiRNA microarray analysis showed that the levels of 38 miRNAs showed a significant increase with about 15~250 folds and the levels of 26 miRNAs showed a significant decrease with only about 2~4 folds in the hippocampus of P7 Fmr1 KO mice. Q-PCR assay showed that 9 of the most increased miRNAs (>100 folds in microarrays) were increased about 40~70 folds and their pre-miRNAs were increased about 5~10 folds, but no significant difference in their pri-miRNA levels was observed, suggesting a role of FMRP in regulating miRNA processing from pri-miRNA to pre-miRNA. We further demonstrated that a set of protein-coding mRNAs, potentially targeted by the 9 miRNAs were down-regulated in the hippocampus of Fmr1 KO mice. Finally, luciferase assays demonstrated that miR-34b, miR-340, miR-148a could down-regulate the reporter gene expression by interacting with the Met 3' UTR. Taken together these findings suggest that the miRNA expression alterations resulted from the absence of FMRP might contribute to molecular pathology of FXS.

Neuroscience↗

bioRxiv2014

Metabolic free energy and deterministic-but-for-error biological codes: a ‘Data Rate Theorem’ aging model

The living state is cognitive at every scale and level of organization. Since it is possible to associate a broad class of cognitive processes with dual information sources, many pathologies can be addressed using statistical models based on the Shannon Coding, the Shannon-McMillan Source Coding, the Rate Distortion, and the Data Rate Theorems, as these impose powerful necessary condition constraints on information generation and exchange, and on system control. Deterministic-but-for-error biological codes do not directly invoke cognition, although they may be essential subcomponents within larger cognitive processes. A formal argument, however, places such codes within a similar framework, with metabolic free energy serving as a control signal stabilizing biochemical code-and-translator dynamics in the presence of noise. Demand beyond available energy supply then expresses itself in punctuated destabilization of the coding channel, affecting a spectrum of essential biological functions. Aging, normal or prematurely driven by psychosocial or environmental stressors, must eventually interfere with the routine operation of such mechanisms, triggering chronic diseases associated with senescence. Amyloid fibril formation, intrinsically disordered protein logic gates, and cell surface glycan/lectin kelp bed logic gates are reviewed from this perspective. The results, however, generalize beyond coding systems having easily recognizable symmetry modes.

Systems Biology↗

bioRxiv2014

Automatic Classification of Human Epithelial Type 2 Cell Indirect Immunofluorescence Images using Cell Pyramid Matching

This paper describes a novel system for automatic classification of images obtained from Anti-Nuclear Antibody (ANA) pathology tests on Human Epithelial type 2 (HEp-2) cells using the Indirect Immunofluorescence (IIF) protocol. The IIF protocol on HEp-2 cells has been the hallmark method to identify the presence of ANAs, due to its high sensitivity and the large range of antigens that can be detected. However, it suffers from numerous shortcomings, such as being subjective as well as time and labour intensive. Computer Aided Diagnostic (CAD) systems have been developed to address these problems, which automatically classify a HEp-2 cell image into one of its known patterns (eg. speckled, homogeneous). Most of the existing CAD systems use handpicked features to represent a HEp-2 cell image, which may only work in limited scenarios. We propose a novel automatic cell image classification method termed Cell Pyramid Matching (CPM), which is comprised of regional histograms of visual words coupled with the Multiple Kernel Learning framework. We present a study of several variations of generating histograms and show the efficacy of the system on two publicly available datasets: the ICPR HEp-2 cell classification contest dataset and the SNPHEp-2 dataset.

Bioinformatics↗