SEARCH · bioRxiv Science

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 Read source abstracts and check manuscript versions; preprints are not peer reviewed.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 235 records · Page 13Linked to original sources

bioRxiv2022

Cortical distribution of neurofilaments associates with pathological hallmarks and MRI measures of atrophy and diffusivity in Parkinson's disease

Increased neurofilament levels in biofluids, commonly used as a proxy for axonal degeneration in the brain, have been found in Parkinsons disease (PD), PD with dementia (PDD) and dementia with Lewy bodies (DLB), and correlate with MRI biomarkers. The aim of the current study was to unravel the regional distribution of cortical neurofilaments and their association with pathology load and MRI measures of atrophy and diffusivity in the post-mortem brain. Using a within-subject post-mortem MRI-pathology approach, we included 9 PD, 12 PDD/DLB and 18 age-matched control donors. Cortical thickness and mean diffusivity (MD) metrics were extracted respectively from 3DT1 and DTI at 3T in-situ MRI. After autopsy, pSer129 alpha-synuclein (pSer129-Syn), p-tau, and amyloid-beta, together with neurofilament light-chain (NfL) and phosphorylated neurofilament medium- and heavy-chain (p-NfM/H) immunoreactivity were quantified in 7 cortical regions, and studied in detail with confocal-laser scanning microscopy. The correlations between MRI and pathological measures were studied using linear mixed models. Compared to controls, p-NfM/H immunoreactivity was increased in all cortical regions in PD and PDD/DLB, whereas NfL immunoreactivity was mainly increased in the parahippocampal and entorhinal cortex in PDD/DLB. NfL-positive neurons showed degenerative morphological features and axonal fragmentation. Increased p-NfM/H correlated with p-tau load, and NfL correlated with pSer129-Syn but more strongly with p-tau load in PDD/DLB. Lastly, neurofilament immunoreactivity correlated with cortical thinning in PD and with increased cortical MD in PDD/DLB. Taken together, increased neurofilament immunoreactivity suggests underlying axonal injury and neurofilament accumulation in morphologically altered neurons with increasing pathological burden. Importantly, we demonstrate that such neurofilament markers at least partly explain MRI measures that are associated with the neurodegenerative process.

neuroscience↗

bioRxiv2022

Alpha-synuclein pathology and reduced neurogenesis in the olfactory system affect olfaction in a mouse model of Parkinsons disease

Parkinsons Disease (PD) is characterized by multiple symptoms including olfactory dysfunction, whose underlying mechanisms remain unclear. Here, we explored pathological changes in the olfactory pathway of transgenic (Tg) mice expressing the human A30P mutant -synuclein (-syn) (-syn-Tg mice) at 6-7 and 12-14 months of age, representing early and late-stages of motor progression, respectively. -Syn-Tg mice at late stages exhibited olfactory behavioral deficits, which correlated with severe -syn pathology in projection neurons of the olfactory pathway. In parallel, olfactory bulb (OB) neurogenesis in -syn-Tg mice was reduced in the OB granule cells at 6-7 months, and OB periglomerular cells at 12-14 months, respectively, both of which could contribute to olfactory dysfunction. Proteomic analyses showed a disruption in endo- and exocytic pathways in the OB during the early stages which appeared exacerbated at the synaptic terminals when the mice developed olfactory deficits at 12-14 months. Our data suggest that, 1) the -syn-Tg mice recapitulate the olfactory functional deficits seen in PD; 2) olfactory structures exhibit spatiotemporal disparities for vulnerability to -syn pathology; 3) -syn pathology is restricted to projection neurons in the olfactory pathway; 4) neurogenesis in adult -syn-Tg mice is reduced in the OB; and 5) synaptic endo- and exocytosis defects in the OB may further explain olfactory deficits.

neuroscience↗

bioRxiv2022

Natural and pathological aging distinctively impact the vomeronasal system and social behavior

Normal aging and many age-related disorders such as Alzheimers disease cause deficits in olfaction, however it is currently unknown how natural and pathological aging impact the detection of social odors which might contribute to the impoverishment of social behavior at old age further worsening overall health. Here, we investigated the effect of aging in the recognition of social cues and the display of social behavior. Our findings indicate that aging distinctively disrupts the processing of social olfactory cues decreasing social odor exploration, discrimination and habituation in both wild type senescent (2-year-old) mice and in 1-year-old double mutant model of Alzheimers disease (APP/PS1Het). Furthermore, social novelty was diminished in 1-year-old APP/PS1Het mice, indicating that alterations in the processing of social cues are accelerated during pathological aging. Analysis of the vomeronasal organ, the main gateway to pheromone-encoded information, indicated that natural and pathological aging distinctively reduce the neurogenic ability of the vomeronasal sensory epithelium. Cell proliferation remained majorly preserved in 1-year model of Alzheimers disease (APP/PS1Het), whereas naturally aged animals exhibited significant deficiencies in the number of mature, proliferative and progenitor cells. This study reveals fundamental differences in the cellular processes by which natural and pathological aging disrupt the exploration of social cues and social behavior.

neuroscience↗

bioRxiv2022

Dopamine depletion leads to pathological synchronization of distinct basal ganglia loops in the beta band

Motor symptoms of Parkinsons Disease (PD) are associated with dopamine deficits and pathological oscillation of basal ganglia (BG) neurons in the {beta} range ([12-30] Hz). However, how the dopamine depletion affects the oscillation dynamics of BG nuclei is still unclear. With a spiking neurons model, we here captured the features of BG nuclei interactions leading to oscillations in dopamine-depleted condition. We found that both the loop between subthalamic nucleus and Globus Pallidus pars externa (GPe) and the loop between striatal fast spiking and medium spiny neurons and GPe displayed resonances in the {beta} range, and synchronized to a common {beta} frequency through interaction. Crucially, the synchronization depends on dopamine depletion: the two loops were largely independent for high levels of dopamine, but progressively synchronized as dopamine was depleted due to the increased strength of the striatal loop. Our results highlight the role of the interplay between the GPe-STN and the GPe-striatum loop in generating sustained {beta} oscillations in PD subjects, and explain how this interplay depends on the level of dopamine. This paves the way to the design of therapies specifically addressing the onset of pathological {beta} oscillations. Author summaryParkinsons Disease is associated to the death of neurons generating a particular neurotransmitter: the dopamine. Motor symptoms of PD, on the other hand, are known to be due to dysfunctions in a particular subcortical area of the brain, the BG network. In particular, the BG network develops pathological oscillations in a specific frequency range ({beta}: [12-30] Hz). What is unclear is how dopamine depletion leads to these oscillations. In this work we developed a BG network model and we found the actual reason for these abnormal oscillations is the synchronization of two loops within the network that are individually oscillating in the {beta} range. For healthy level of dopamine the two loops are decoupled and the oscillation power is low. When dopamine is depleted (as in PD) the two loops synchronize and originate the pathological oscillations associated with motor symptoms.

neuroscience↗

bioRxiv2022

Pathway-informed deep learning model for survivalanalysis and pathological classification of gliomas

Online assessment of tumor characteristics during surgery is important and has the potential to establish an intraoperative surgeon feedback mechanism. With the availability of such feedback, surgeons could decide to be more liberal or conservative regarding the resection of the tumor. While there are methods to perform metabolomics-based online tumor pathology prediction, their model complexity and, in turn, the predictive performance is limited by the small dataset sizes. Furthermore, the information conveyed by the feedback provided on the tumor tissue could be improved both in terms of content and accuracy. In this study, we propose a metabolic pathway-informed deep learning model, PiDeeL, to perform survival analysis and pathology assessment based on metabolite concentrations. We show that incorporating pathway information into the model architecture substantially reduces parameter complexity and achieves better survival analysis and pathological classification performance. With these design decisions, we show that PiDeeL improves tumor pathology prediction performance of the state-of-the-art in terms of the Area Under the ROC Curve (AUC-ROC) by 3.38% and the Area Under the Precision-Recall Curve (AUC-PR) by 4.06%. Similarly, with respect to the time-dependent concordance index (c-index), we observe that PiDeeL achieves better survival analysis performance (improvement up to 4.3%) when compared to the state-of-the-art. Moreover, we show that importance analyses performed on input metabolite features as well as pathway-specific hidden-layer neurons of PiDeeL provide insights into tumor metabolism. We foresee that the use of this model in the surgery room will help surgeons adjust the surgery plan on the fly and will result in better prognosis estimates tailored to surgical procedures. AvailabilityThe code is released at https://github.com/ciceklab/PiDeeL. The data used in this study is released at https://zenodo.org/record/7228791. Contactcicek@cs.bilkent.edu.tr Supplementary informationSupplementary data are available at Briefings in Bioinformatics online.

bioinformatics↗

bioRxiv2022

Granulin Loss of Function in Human Mature Brain Organoids Implicates Astrocytes in TDP-43 Pathology

Loss of function (LoF) of Tar-binding protein 43 (TDP-43) and mislocalization, together with TDP-43-positive and hyperphosphorylated inclusions, are found in postmortem tissue of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients, including those carrying LoF variants in the progranulin gene (GRN). Modelling TDP-43 pathology has been challenging in vivo and in vitro. We present a 3D-induced pluripotent stem cell (iPSC)-derived paradigm - mature brain organoids (mbOrg) - composed of cortical-like-astrocytes (iA) and neurons (iN). When devoid of GRN, mbOrgs spontaneously recapitulate TDP-43 mislocalization, hyperphosphorylation and LoF phenotypes. Mixing-and-matching genotypes in mbOrgs showed that GRN-/- iA are drivers for TDP-43 pathology. Finally, we rescued TDP-43 LoF by adding exogenous progranulin, demonstrating a link between TDP-43 LoF and progranulin expression. In conclusion, we present an iPSC-derived platform that shows striking features of human TDP-43 proteinopathy and provides a tool for mechanistic modelling of TDP-43 pathology and patient-tailored therapeutic screening for FTD and ALS. HighlightsO_LIGRN-/- iPSC-derived 3D paradigm (mbOrg) composed of mature cortical-like astrocytes and neurons recapitulates features of TDP-43 proteinopathy C_LIO_LIGRN-/- cortical-like astrocytes are necessary and sufficient for the development of the TDP-43 loss of function phenotype in mbOrg. C_LIO_LIA TDP-43 phenotype can be rescued in neurons by treating neuron and astrocyte co-cultures with progranulin full length protein. C_LI eTOC blurbIn this article, de Majo and colleagues present a novel 3D iPSC-derived model to study neurodegenerative disorders such as ALS and FTD. When devoid of GRN expression, these cultures present features of ALS and FTD associated pathology hardly ever observed in vitro. These phenotypes are shown to be primarily driven by diseased astrocytes and can be rescued by progranulin supplementation.

neuroscience↗

bioRxiv2022

A 3D genome atlas of genetic variants and their pathological effects

The spatial architecture of the genome can be categorized into distinct layers. Each layer plays a critical role in transcriptional regulation and/or genomic integrity. Alterations at any level of the 3D genome can lead to an unwanted cascade of molecular events, which may ultimately drive the manifestation of disease. However, a comprehensive atlas of the mutations and structural genetic defects that affect genome organization has yet to be compiled. Moreover, we lack a centralized resource for interpretating the pathological effects of such genetic mutations. Therefore, we curated from the literature all the pathological alterations from the chromosome level on down to single nucleotide polymorphisms (SNPs) in order to investigate these diverse genetic mutations. Using a two-phase scoring algorithm, 3DFunc, we scored the transcriptomic causality of all variants in the context of 3D genome architecture from 20 cancer and 15 normal tissues. Further, 3DFunc can identify pathological variant-gene pairs in non-oncological diseases. Finally, we constructed a web-based database, 3DGeOD (https://www.csuligroup.com/3DGeOD/home), to provide all the curated variants, genomic disruptions, as well as the scoring results derived from 3DFunc. In summary, our study constructed a 3D genome atlas of genetic variants and will serve as a valuable resource for mining the putative pathological effects of any genetic mutation.

bioinformatics↗

bioRxiv2023

RGS14 is neuroprotective against seizure-induced mitochondrial oxidative stress and pathology in hippocampus

RGS14 is a complex multifunctional scaffolding protein that is highly enriched within pyramidal cells (PCs) of hippocampal area CA2. There, RGS14 suppresses glutamate-induced calcium influx and related G protein and ERK signaling in dendritic spines to restrain postsynaptic signaling and plasticity. Previous findings show that, unlike PCs of hippocampal areas CA1 and CA3, CA2 PCs are resistant to a number of neurological insults, including degeneration caused by temporal lobe epilepsy (TLE). While RGS14 is protective against peripheral injury, similar roles for RGS14 during pathological injury in hippocampus remain unexplored. Recent studies show that area CA2 modulates hippocampal excitability, generates epileptiform activity and promotes hippocampal pathology in animal models and patients with TLE. Because RGS14 suppresses CA2 excitability and signaling, we hypothesized that RGS14 would moderate seizure behavior and early hippocampal pathology following seizure activity. Using kainic acid (KA) to induce status epilepticus (KA-SE) in mice, we show loss of RGS14 (RGS14 KO) accelerated onset of limbic motor seizures and mortality compared to wild type (WT) mice, and that KA-SE upregulated RGS14 protein expression in CA2 and CA1 PCs of WT. Utilizing proteomics, we saw loss of RGS14 impacted the expression of a number of proteins at baseline and after KA-SE, many of which associated unexpectedly with mitochondrial function and oxidative stress. RGS14 was shown to localize to the mitochondria in CA2 PCs of mice and reduce mitochondrial respiration in vitro. As a readout of oxidative stress, we found RGS14 KO dramatically increased 3-nitrotyrosine levels in CA2 PCs, which was greatly exacerbated following KA-SE and correlated with a lack of superoxide dismutase 2 (SOD2) induction. Assessing for hallmarks of seizure pathology in RGS14 KO, we observed worse neuronal injury in area CA3 (but none in CA2 or CA1), and a lack of microgliosis in CA1 and CA2 compared to WT. Together, our data demonstrates a newly appreciated neuroprotective role for RGS14 against intense seizure activity in hippocampus. Our findings are consistent with a model where, after seizure, RGS14 is upregulated to support mitochondrial function and prevent oxidative stress in CA2 PCs, limit seizure onset and hippocampal neuronal injury, and promote microglial activation in hippocampus.

neuroscience↗

bioRxiv2023

Pharmacological PINK1 activation ameliorates Pathology in Parkinson's Disease models

PINK1 loss-of-function mutations and exposure to mitochondrial toxins are causative for Parkinsons disease (PD) and Parkinsonism, respectively. We demonstrate that pathological -synuclein deposition, the hallmark pathology of idiopathic PD, induces mitochondrial dysfunction and impairs mitophagy, driving accumulation of the PINK1 substrate pS65-Ubiquitin (pUb) in primary neurons and in vivo. We synthesized MTK458, a brain penetrant small molecule that binds to PINK1 and stabilizes an active heterocomplex, thereby increasing mitophagy. MTK458 mediates clearance of -synuclein pathology in PFF seeding models in vitro and in vivo and reduces pUb. We developed an ultrasensitive assay to quantify pUb levels in plasma and observed an increase in pUb in PD subjects that correlates with disease progression, paralleling our observations in PD models. Our combined findings from preclinical PD models and patient biofluids suggest that pharmacological activation of PINK1 is worthy of further study as a therapeutic strategy for disease modification in PD. HighlightsO_LIDiscovery of a plasma Parkinsons Disease biomarker candidate, pS65-Ubiquitin (pUb) C_LIO_LIPlasma pUb levels correlate with disease status and progression in PD patients. C_LIO_LIIdentification of a potent, brain penetrant PINK1 activator, MTK458 C_LIO_LIMTK458 selectively activates PINK1 by stimulating dimerization and stabilization of the PINK1/TOM complex C_LIO_LIMTK458 drives clearance of -synuclein pathology and normalizes pUb in in vivo Parkinsons models C_LI

neuroscience↗

bioRxiv2023

Post-fibrillization nitration of alpha-synuclein abolishes its seeding activity and pathology formation in primary neurons and in vivo

Increasing evidence points to post-translational modifications (PTMs) as key regulators of alpha-synuclein (-Syn) function in health and disease. However, whether these PTMs occur before or after -Syn pathology formation and their role in regulating -Syn toxicity remain unclear. In this study, we demonstrate that post-fibrillization nitration of -Syn fibrils induced their fragmentation, modified their surface and dynamic properties but not their structure, and nearly abolished their seeding activity in primary neurons and in vivo. Furthermore, we show that the dynamic and surface properties of the fibrils, rather than simply their length, are important determinants of -Syn fibril seeding activity. Altogether, our work demonstrates that post-aggregation modifications of -Syn may provide novel approaches to target a central process that contributes to pathology formation and disease progression. Finally, our results suggest that the pattern of PTMs on pathological aggregates, rather than simply their presence, could be a key determinant of their toxicity and neurodegeneration. This calls for reconsidering current approaches relying solely on quantifying and correlating the level of pathology to assess the efficacy of novel therapies, as not all -Syn aggregates in the brain are pathogenic.

neuroscience↗

bioRxiv2023

Aβ-aggregation-generated blue autofluorescence illuminates senile plaques, complex blood and vascular pathologies in the Alzheimer's disease

Senile plaque blue autofluorescence in the Alzheimers disease (AD) was discovered around 40 years ago, however, its impact on AD pathology is not fully examined. We analyzed senile plaques with immunohistochemistry and fluorescence imaging on AD brain pathological sections and also the A{beta} aggregation process in vitro in test tubes. In DAPI or Hoechst staining experiments, the data showed that the nuclear blue fluorescence could only be correctly assigned after subtracting the blue autofluorescence background. The plaque cores have very strong blue autofluorescence which is roughly 2.09 times of average DAPI nuclear staining and roughly 1.78 times of average Hoechst nuclear staining. The composite flower-like structures formed by Cathepsin D lysosomal staining wrapping dense core blue fluorescence should not be considered as central-nucleated neurons filled with defective lysosomes since there was no nuclear staining in the plaque core when the blue autofluorescence was subtracted. Furthermore, the dense cores were shown to be completely lack of nuclear signals by PI staining. The A{beta} aggregation assay indicated that both A{beta} self-oligomers and A{beta}/Hemoglobin (Hb) heterocomplexes had significant blue autofluorescence. However, the blue autofluorescence intensity was not always proportional to the intensity of A{beta} immunostaining. The majority of aggregates in the A{beta}/Hb incubations were sensitive to Proteinase K (PK) digestion while the rest were PK resistant. The blue autofluorescence of A{beta} aggregates not only labels senile plaques but also illustrates red blood cell aggregation, hemolysis, CAA, vascular amyloid plaques, vascular adhesion and microaneurysm. In summary, we conclude that A{beta}-aggregation-generated blue autofluorescence is an excellent amyloid pathology marker in the senile plaques, blood and vascular pathologies in the Alzheimers disease.

cell biology↗

bioRxiv2023

Male pathology regardless of behaviour drives transmission in an avian host-pathogen system

Host sex is an important source of heterogeneity in the severity of epidemics. Pinpointing the mechanisms causing this heterogeneity can be difficult because differences in behaviour among sexes (e.g. greater territorial aggression in males) can bias exposure risk, obfuscating the role of immune function, which can lead to differences in pathology, in driving differential susceptibility between sexes. Thus, sex-biased transmission driven by differences in immune function independent of behaviour is poorly understood, especially in non-mammalian systems. Here we examine the previously unexplored potential for male-biased pathology to affect transmission using an avian host-pathogen system. We employ a sex-dependent multistate transmission model parameterized with isolated, individual-based experimental exposures of domestic canaries and experimental transmission data of house finches. The experiment revealed that male birds have shorter incubation periods, longer recovery periods, higher pathogen burdens, and greater disease pathology, than females. Our model revealed that male-biased pathology led to epidemic size rapidly increasing with the proportion of male birds, with a nearly 16-fold increase in total epidemic size from an all-female to an all-male simulation. Our results demonstrate that female-biased resistance, independent of male behaviour, can drive sex-dependent transmission in wildlife, indicating that sex-based differences in immune function, not just differences in exposure risk, can shape epidemic dynamics.

ecology↗

bioRxiv2023

Graph attention-based fusion of pathology images and gene expression for prediction of cancer survival

Multimodal machine learning models are being developed to analyze pathology images and other modalities, such as gene expression, to gain clinical and biological in-sights. However, most frameworks for multimodal data fusion do not fully account for the interactions between different modalities. Here, we present an attention-based fusion architecture that integrates a graph representation of pathology images with gene expression data and concomitantly learns from the fused information to predict patient-specific survival. In our approach, pathology images are represented as undirected graphs, and their embeddings are combined with embeddings of gene expression signatures using an attention mechanism to stratify tumors by patient survival. We show that our framework improves the survival prediction of human non-small cell lung cancers, out-performing existing state-of-the-art approaches that lever-age multimodal data. Our framework can facilitate spatial molecular profiling to identify tumor heterogeneity using pathology images and gene expression data, complementing results obtained from more expensive spatial transcriptomic and proteomic technologies.

bioinformatics↗

bioRxiv2023

G51D mutation of the endogenous rat Snca gene disrupts synaptic localisation of α-synuclein priming for Lewy-like pathology

Point mutations in the SNCA gene, encoding -synuclein (Syn), are a known cause of familial Parkinsons disease. The G51D mutation causes early onset neurodegeneration with complex pathology. We used CRISPR/Cas9 in rats to introduce the G51D mutation into the endogenous Snca gene. Co-localisation immunostaining studies with synaptic proteins showed that SynG51D protein is no longer efficiently localised to synapses. Furthermore, biochemical isolation of synaptosomes from rat cortex demonstrated a significant depletion of Syn in SncaG51D/+ and SncaG51D/G51D rats. Unbiased proteomic investigation of the cortex identified significant synaptic dysregulation in SncaG51D/G51D animals. Finally, we compared the propensity for Lewy-like pathology of Snca+/+ and SncaG51D/G51D rats by stereotaxically delivering Syn pre-formed fibrils (PFFs) into the pre-frontal cortex. At an early time-point, 6 weeks post-injection, we observed discrete Lewy-like structures positive for phosphoserine-129-Syn (pS129-Syn) only in SncaG51D/G51D brains. At 26 weeks post-injection of PFFs SncaG51D/G51D brains exhibited intense, discrete pS129-Syn-positive structures, while Snca+/+ brains exhibited diffuse pS129-Syn immunostaining. Quantification of discrete pS129-Syn-positive structures revealed the striatum of SncaG51D/G51D rats had significantly more Lewy-like pathology than Snca+/+ rats. In summary, this novel SncaG51D rat model exhibits molecular characteristics of early synaptic dysfunction and is primed for Syn pathology.

neuroscience↗

bioRxiv2023

Investigation of microglial diversity in a mouse model of Parkinson's disease pathology

Microglia, the central nervous system resident immune cells, are now recognized to critically impact homeostasis maintenance and contribute to the outcomes of various pathological conditions including Parkinsons disease (PD). Microglia are heterogenous, with a variety of states recently identified in aging and neurodegenerative disease models, including the disease-associated microglia (DAM) which present a selective enrichment of CLEC7A encoding the CLEC7A or DECTIN1 protein, and the dark microglia (DM) displaying markers of cellular stress at the ultrastructural level. However, the roles of CLEC7A-positive microglia and DM in the pathology of PD have remained largely elusive. By applying immunofluorescence and scanning electron microscopy, we aimed to characterize 1) the CLEC7A -positive cell population, and 2) their possible relationships to DM in a mouse model harboring a G2019S pathogenic mutation of the LRRK2 gene, the most common mutation linked to PD. We examined 18-month-old mice, comparing between LRRK2 G2019S knock-in mice and wild-type controls. In the dorsal striatum, a region affected by PD pathology, extensive ultrastructural features of cellular stress (e.g., endoplasmic reticulum and Golgi apparatus dilation), as well as reduced direct cellular contacts, were observed for microglia from LRRK2 G2019S mice versus controls. CLEC7A-positive microglia exhibited extensive phagocytic ultrastructural characteristics in the LRRK2 G2019S mice. Additionally, the LRRK2 G2019S mice presented a higher proportion of DM. Lastly, immunofluorescence and biochemical analysis revealed higher number of CLEC7A-positive cells in Lrrk2 G2019S genotype versus controls both in tissues and in primary microglia cells. Of note, CLEC7A-positive cells present a selective enrichment of ameboid morphology and tend to cluster in the pathogenic animal. In summary, we provide novel insights into the involvement of recently-defined microglial states, CLEC7A-positive cells and DM, in the context of LRRK2 G2019S PD pathology.

neuroscience↗

bioRxiv2024

Smad4 Loss in the Mouse Intestinal Epithelium Alleviates the Pathological Fibrotic Response to Injury in the Colon

Mucosal healing is associated with better clinical outcomes in patients with inflammatory bowel diseases (IBDs). Unresolved injury and inflammation, on the other hand, increases pathological fibrosis and the predisposition to cancer. Loss of Smad4, a tumor suppressor, is known to increase colitis-associated cancer in mouse models of chronic IBD. Since common biological processes are involved in both injury repair and tumor growth, we sought to investigate the effect of Smad4 loss on the response to epithelial injury. To this end, Smad4 was knocked out specifically in the intestinal epithelium and transcriptomic and morphological changes compared between wild type mice and Smad4 knock out mice after DSS-induced injury. We find that Smad4 loss alleviates pathological fibrosis and enhances mucosal repair. The transcriptomic changes specific to epithelium indicate molecular changes that affect epithelial extracellular matrix (ECM) and promote enhanced mucosal repair. These findings suggest that the biological processes that promote wound healing alleviate the pathological fibrotic response to DSS. Therefore, these mucosal repair processes could be exploited to develop therapies that promote normal wound healing and prevent fibrosis. NEW AND NOTEWORTHYWe show that transcriptomic changes due to Smad4 loss in the colonic epithelium alleviates the pathological fibrotic response to DSS in an IBD mouse model of acute inflammation. Most notably, we find that collagen deposition in the epithelial ECM, as opposed to that in the lamina propria, correlates with epithelial changes that enhance wound healing. This is the first report on a mouse model providing alleviated fibrotic response in a DSS-IBD mouse model in vivo.

cell biology↗

bioRxiv2024

SN-FPN: Self-attention Nested Feature Pyramid Network for Digital Pathology Image Segmentation

Digital pathology has played a key role in replacing glass slides with digital images, enhancing various pathology workflows. Whole slide images are digitized pathological images improving the capabilities of digital pathology and contributing to the overall turnaround time for diagnoses. The digitized images have been successfully integrated with artificial intelligence algorithms assisting pathologists in many tasks, but there are still demands to develop a new algorithm for a better diagnosis process. In this paper, we propose a new deep convolutional neural network model integrating a feature pyramid network with a self-attention mechanism in three pathways: encoder, decoder, and self-attention nested for providing accurate tumor region segmentation on whole slide images. The encoder pathway adopts ResNet50 architecture for the bottom-up network. The decoder pathway adopts the feature pyramid network for the top-down network. The self-attention nested pathway forms the attention map represented by the distribution of attention scores focusing on localizing tumor regions and avoiding irrelevant information. The results of our experiment show that the proposed model outperforms the state-of-the-art deep convolutional neural network models in terms of tumor and stromal region segmentation. Moreover, various encoder networks were equipped with the proposed model and compared with each other. The results indicate that the ResNet series using the proposed model outperforms other encoder networks.

bioinformatics↗

bioRxiv2024

Nicotine Ameliorates α-synuclein Pre-formed Fibril-Induced Behavioral Deficits and Pathological Features in Mice

BackgroundEpidemiologic study suggests nicotine reduces risk of PD, could be potential treatment for Parkinsons disease. ObjectiveTo study the effect of nicotine on behavioral phenotypes and pathological characteristics of mice induced by human alpha-synuclein preformed fibers (-syn-PFF). MethodsMice were injected with 5 g of human -syn-PFF in the hippocampus while administering nicotine-containing drinking water (200g/mL). After 1 month, the motor ability, mood, spatial learning, and memory ability of the Parkinsons disease(PD)phenotype-like model were detected using open field, rotarod, Y maze, and O maze tests. The expression of pathological -syn, apoptotic proteins and the numbers of glial cells and neural stem cells in the hippocampus of mice were detected using western blotting and immunofluorescence. ResultsNicotine significantly reduced pathological -syn accumulation, -syn serine 129 phosphorylation and cell death caused by PFF injection in the hippocampus of mice, inhibited the increase of glial, microglia and apoptotic cells, decreased the expression levels of PI3K and Akt. ConclusionsNicotine may have inhibitory effects on human -syn-PFF-induced neuroinflammation and apoptosis. Thus, it reduces human -syn-PFF-induced behavioral deficits and pathological changes in mice.

animal behavior and cognition↗