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Results for “Pathology”

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bioRxiv2020

Overarching control of autophagy and DNA damage response by CHD6 revealed by modeling a rare human pathology

Members of the chromodomain-helicase-DNA binding (CHD) protein family are chromatin remodelers critically implicated in human pathologies, with CHD6 being one of its least studied members. Here, we discovered a de novo CHD6 missense mutation in a patient clinically presenting the rare Hallermann-Streiff syndrome (HSS). We used genome editing to generate isogenic iPSC lines and model HSS in relevant cell types. We show that CHD6 binds a cohort of autophagy and stress response genes across cell types. The HSS-mutation affects CHD6 protein folding and impairs its ability to recruit co-factors in response to DNA damage or autophagy stimulation. This leads to an accumulation of DNA damage burden and to senescence-like phenotypes. By combining genomics and functional assays, we describe for the first time a molecular mechanism for the chromatin control of autophagic flux and genotoxic stress surveillance that applies broadly to human cell types and explains HSS onset.

cell biology↗

bioRxiv2020

ClgR contributes to pulmonary pathology but not bacterial growth in Mycobacterium tuberculosis infection

BackgroundThe Clp proteases regulator, ClgR, is encoded in the Mycobacterium tuberculosis (Mtb) genome by Rv2745c gene (clgR). ClgR is required to clear damaged proteins, thereby preventing their accumulation in the cell. It also controls the availability of key enzymes or regulators via conditional degradation mechanism of proteolytic activity in Mtb [1,2]. MethodsIt has been previously reported that Mtb clgR gene is induced in a sigma factor SigH-dependent manner and a deletion mutant of clgR is susceptible to growth in a hypoxic environment. Whether hypoxia is indeed a restriction factor and ClgR is required for Mtb growth in that environment remains unelucidated. We began to address this hypothesis in the C57/BL6 mouse model of TB where Mtb infected lungs do not form granuloma and the lung environment is considerably non-hypoxic. ResultsOur results demonstrate that despite not having a deficit in growth in either murine lungs or primary macrophages, in comparison to wild type, the{Delta} clgR mutant failed to induce pulmonary pathology. ConclusionWe propose that ClgR is required for the pathogenesis of Mtb.

microbiology↗

bioRxiv2020

Analysis of Circulating Exosomes Reveals a Peripheral Signature of Astrocytic Pathology in Schizophrenia

BackgroundThere is considerable interest in identifying peripheral biomarkers that reflect neuropathological changes in schizophrenia. Extracellular vesicles, including exosomes can cross the blood brain barrier with their contents intact and their cargo, including lipids, proteins and genetic materials can be assayed peripherally. Circulating exosomes have been studied in other neurodegenerative disorders, but there is scarce data in schizophrenia. MethodsWe examined neuropathology relevant protein biomarkers in circulating exosomes from patients with schizophrenia and age and gender matched healthy controls using methods consistent with the recommended "Minimal information for studies of extracellular vesicles 2018" (MISEV2018) guidelines. Nanoparticle tracking analysis was used to determine the size and concentration of exosomes. Exosomal membrane marker (CD9) and specific target cargo proteins (glial fibrillary acid protein[GFAP], synaptophysin and -II-spectrin) immunopositivity was examined using Western blot analyses and band intensity quantified. ResultsNo group differences were observed between schizophrenia and control samples in plasma exosomal concentration and size or in CD9 or calnexin positivity. Exosomal GFAP concentration was significantly higher and -II-spectrin expression significantly lower in schizophrenia samples and there were no group differences observed for exosomal synaptophysin concentration. ConclusionsOur results demonstrate for the first time, a differential pattern of exosomal protein expression in schizophrenia compared to matched healthy controls, consistent with the hypothesized astro-glial pathology in this disorder. These results warrant further examination of circulating exosomes as vehicles of novel peripheral biomarkers of disease in schizophrenia and other neuropsychiatric disorders.

neuroscience↗

bioRxiv2020

TWIRLS, an automated topic-wise inference method based on massive literature, suggests a possible mechanism via ACE2 for the pathological changes in the human host after coronavirus infection

Faced with the current large-scale public health emergency, collecting, sorting, and analyzing biomedical information related to the "coronavirus" should be done as quickly as possible to gain a global perspective, which is a basic requirement for strengthening epidemic control capacity. However, for human researchers studying the viruses and the hosts, the vast amount of information available cannot be processed effectively and in a timely manner, particularly when the scientific understanding may be limited, which can further lower the information processing efficiency. We present TWIRLS, a method that can automatically acquire, organize, and classify information. Additionally, independent functional data sources can be added to build an inference system using a machine-based approach, which can provide relevant knowledge to help human researchers quickly establish subject cognition and to make more effective decisions. TWIRLS can automatically analyze more than three million words in more than 14,000 literature articles in only 4 hours. Combining with generalized gene interaction databases creates a data interface that can help researchers to further analyze the information. Using the TWIRLS system, we found that an important regulatory factor angiotensin-converting enzyme 2 (ACE2) may be involved in the host pathological changes on binding to the coronavirus after infection. After triggering functional changes in ACE2/AT2R, an imbalance in the steady-state cytokine regulatory axis involving the Renin-Angiotensin System and IP-10 leads to a cytokine storm.

bioinformatics↗

bioRxiv2020

Interpretative guides for interacting with tissue atlas and digital pathology data using the Minerva browser

The recent development of highly multiplexed tissue imaging promises to substantially accelerate research into basic biology and human disease. Concurrently, histopathology in a clinical setting is undergoing a rapid transition to digital methods. Online tissue atlases involving highly multiplexed images of research and clinical specimens will soon join genomics as a systematic source of information on the molecular basis of disease and therapeutic response. However, even with recent advances in machine learning, experience with anatomic pathology shows that there is no immediate substitute for expert visual review, annotation, and description of tissue images. In this perspective we review the ecosystem of software available for analysis of tissue images and identify a need for interactive guides or "digital docents" that allow experts to help make complex images intelligible. We illustrate this idea using Minerva software and discuss how interactive image guides are being integrated into multi-omic browsers for effective dissemination of atlas data.

scientific communication and education↗

bioRxiv2020

Induction of Alzheimer's disease pathology by early-life stress

BackgroundAlzheimers disease (AD), a progressive neurodegenerative disorder, is a serious social problem. Recently, several early-life factors have been associated with an increased risk of a clinical diagnosis of AD. MethodsWe investigated the involvement of early-life stress in AD pathogenesis using heterozygous the amyloid precursor protein (APP) mutant mice (AppNL-G-F/wt) and wild-type (Appwt/wt) mice. Maternal separation was used as an animal paradigm for early-life stress. Object location and fear conditioning tests were performed to measure cognitive functions, in addition to biochemical tests. Immunohistochemical analyses were performed after the behavioral tests. ResultsWe found that maternal-separated Appwt/wt mice showed narrowing of vessels and decreased pericyte coverage of capillaries in prefrontal cortex, while maternal-separated AppNL-G-F/wt mice additionally showed impairment of cognitive function, and earlier formation of A{beta} plaques and disruption of the blood-brain barrier. Severe activation of microglia was detected in the maternal-separated AppNL-G-F/wt mice and maternal-separated Appwt/wt mice. At the early stage, morphological changes and inflammatory responses were observed in the microglia of the maternal-separated AppNL-G-F/wt mice and maternal-separated Appwt/wt mice, as well as morphological changes in the microglia of the non-maternal-separated AppNL-G-F/wt mice. ConclusionsMicroglia activation induced by maternal separation in combination with the APP mutation may impairs the vascular system, leading to AD progression. These findings therefore suggest that maternal separation causes early induction of AD pathology via angiopathy.

neuroscience↗

bioRxiv2020

Repurposing beta3-adrenergic receptor agonists for Alzheimer's disease: Beneficial effects on recognition memory and amyloid pathology in a mouse model.

ABSTRACTOld age, the most important risk factor for Alzheimer’s disease (AD), is associated with thermoregulatory deficits. Brown adipose tissue (BAT) is the main thermogenic driver in mammals and its stimulation, through β3-adrenergic receptor (β3AR) agonists or cold acclimation, counteracts metabolic deficits in rodents and humans. Studies in animal models show that AD neuropathology leads to thermoregulatory deficits and cold-induced tau hyperphosphorylation is prevented by BAT stimulation through cold acclimation. Since metabolic disorders and AD share strong pathogenic links, we hypothesized that BAT stimulation through a β3AR agonist could exert benefits in AD as well.Here, we show that β3AR agonist administration (CL-316,243, 1 mg/kg/day i.p., from 15 to 16 months of age) decreased body weight and improved peripheral glucose metabolism and BAT thermogenesis in both non-transgenic and 3xTg-AD mice. One-month treatment with a β3AR agonist increased recognition index by 19% in 16-month-old 3xTg-AD mice compared to pre-treatment (14-month-old). Locomotion, anxiety and tau pathology were not modified. Finally, insoluble Aβ42/Aβ40 ratio was decreased by 27% in the hippocampus of CL-316,243-injected 3xTg-AD mice.Overall, our results indicate that β3AR stimulation reverses memory deficits and shifts downward the insoluble Aβ42/Aβ40 ratio in 16-month-old 3xTg-AD mice. As β3AR agonists are being clinically developed for metabolic disorders, repurposing them in AD could be a valuable therapeutic strategy.Competing Interest StatementThe authors have declared no competing interest.View Full Text

pharmacology and toxicology↗

bioRxiv2020

Lysine acetylation of TDP-43 drives phase separation and pathological aggregation

The trans-activation response DNA-binding protein TDP-43 regulates RNA processing and forms neuropathological aggregates in patients with amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Investigating TDP-43 post-translational modifications, we discovered that K84 acetylation reduced nuclear import whereas K136 acetylation impaired RNA binding and splicing capabilities of TDP-43. Such failure of RNA interaction triggered TDP-43 phase separation mediated by the C-terminal low complexity domain, leading to the formation of insoluble aggregates with pathologically phosphorylated and ubiquitinated TDP-43. Confirming the results from site-directed mutagenesis, we succeeded to introduce authentic acetyl-lysine at the identified sites via amber suppression. [AcK84]TDP-43 showed cytoplasmic mislocalization and the aggregation propensity of [acK136]TDP-43 was confirmed. With newly developed antibodies, we found that the nuclear sirtuin SIRT1 can potently deacetylate [acK136]TDP-43. Moreover, SIRT1 reduced the aggregation propensity of [acK136]TDP-43. Thus, distinct lysine acetylations modulate nuclear import, RNA binding and phase separation of TDP-43, suggesting novel regulatory mechanisms for TDP-43 pathogenesis.

cell biology↗

bioRxiv2020

Powerful Variance-Component TWAS method identifies novel and known risk genes for clinical and pathologic Alzheimer's dementia phenotypes

Transcriptome-wide association studies (TWAS) have been widely used to integrate transcriptomic and genetic data to study complex human diseases. Within a test dataset lacking transcriptomic data, existing TWAS methods first impute gene expression by creating a weighted sum that aggregates SNPs with their corresponding cis-eQTL effects on reference transcriptome. Existing TWAS methods then employ a linear regression model to assess the association between imputed gene expression and test phenotype, thereby assuming the effect of a cis-eQTL SNP on test phenotype is a linear function of the eQTLs estimated effect on reference transcriptome. To increase TWAS robustness to this assumption, we propose a novel Variance-Component TWAS procedure (VC-TWAS) that assumes the effects of cis-eQTL SNPs on phenotype are random (with variance proportional to corresponding reference cis-eQTL effects) rather than fixed. VC-TWAS is applicable to both continuous and dichotomous phenotypes, as well as individual-level and summary-level GWAS data. Using simulated data, we show VC-TWAS is more powerful than traditional TWAS especially when eQTL genetic effects on test phenotype are no longer a linear function of their eQTL genetic effects on reference transcriptome. We further applied VC-TWAS to both individual-level (N=[~]3.4K) and summary-level (N=[~]54K) GWAS data to study Alzheimers dementia (AD). With the individual-level data, we detected 13 significant risk genes including 6 known GWAS risk genes such as TOMM40 that were missed by existing TWAS methods. With the summary-level data, we detected 57 significant risk genes considering only cis-SNPs and 71 significant genes considering both cis- and trans- SNPs; these findings also validated our findings with the individual-level GWAS data. Our VC-TWAS method is implemented in the TIGAR tool for public use. Author SummaryExisting Transcriptome-wide association studies (TWAS) tools make strong assumptions about the relationships among genetic variants, transcriptome, and phenotype that may be violated in practice, thereby substantially reducing the power. Here, we propose a novel variance-component TWAS method (VC-TWAS) that relaxes these assumptions and can be implemented with both individual-level and summary-level GWAS data. Our simulation studies showed that VC-TWAS achieved higher power compared to existing TWAS methods when the underlying assumptions required by existing TWAS tools were violated. We further applied VC-TWAS to both individual-level (N=[~]3.4K) and summary-level (N=[~]54K) GWAS data to study Alzheimers dementia (AD). With individual-level data, we detected 13 significant risk genes including 6 known GWAS risk genes such as TOMM40 that were missed by existing TWAS methods. Interestingly, 5 of these genes were shown to possess significant pleiotropic effects on AD pathology phenotypes, revealing possible biological mechanisms. With summary-level data of a larger sample size, we detected 57 significant risk genes considering only cis-SNPs and 71 significant genes considering both cis- and trans- SNPs, which also validated our findings with the individual-level GWAS data. In conclusion, VC-TWAS provides an important analytic tool for identifying risk genes whose effects on phenotypes might be mediated through transcriptomes.

genetics↗

bioRxiv2020

Thiamine pyrophosphokinase deficiency induces Alzheimer's pathology

BackgroundThiamine diphosphate (TDP) reduction plays an important role in cerebral glucose hypometabolism, the neurodegenerative indicator, in Alzheimers disease (AD). The mechanism underlying TDP reduction remains elusive. Thus, it is critical to define the mechanism and its effect on neurodegeneration, the pathological basis of the disease occurrence and progression. MethodsThe mRNA levels of all known genes associated with thiamine metabolism, including thiamine pyrophosphokinase (TPK), Solute Carrier Family 19 Member 2 (SLC19A2), SLC19A3, and SLC25A19, in brain samples of patients with AD and other neurodegenerative disorders in multiple independent datasets were analyzed. TPK protein levels were further examined in the brain tissues of AD patients and control subjects. A mouse model with conditional knockout (cKO) of TPK gene in the excitatory neurons of adult brain was established. ResultsThe brain TPK mRNA level was markedly lower in AD patients, but not in other neurodegenerative disorders. The brain TPK protein level was also significantly decreased in AD patients. TPK gene knockout in the mice caused cerebral glucose hypometabolism, {beta}-amyloid deposition, Tau hyperphosphorylation, neuroinflammation, and neuronal loss and brain atrophy. Cross-species correlation analysis revealed the similar changes of gene profiling between the cKO mice and AD patients. ConclusionsThe deficiency of brain TPK, a key enzyme for TDP synthesis, is specific to AD. The cKO mice show AD-associated phenotypes and could serve as a new mouse model for AD studies. Our study provides a novel insight into the critical role of TPK in AD pathogenesis and its potential for the disease treatment.

neuroscience↗

bioRxiv2020

Loss of pH switch unique to SARS-CoV2 supports unfamiliar virus pathology

Cell surface receptor engagement is a critical aspect of viral infection. This paper compares the dynamics of virus-receptor interactions for SARS-CoV (CoV1) and CoV2. At low (endosomal) pH, the binding free energy landscape of CoV1 and CoV2 interactions with the angiotensin-converting enzyme 2 (ACE2) receptor is almost the same. However, at neutral pH the landscape is different due to the loss of a pH-switch (His445Lys) in the receptor binding domain (RBD) of CoV2 relative to CoV1. Namely, CoV1 stabilizes a transition state above the bound state. In situations where small external strains are applied by, say, shear flow in the respiratory system, the off rate of the viral particle is enhanced. As a result, CoV1 virions are expected to detach from cell surfaces in time scales that are much faster than the time needed for other receptors to reach out and stabilize virus attachment. On the other hand, the loss of this pH-switch, which sequence alignments show is unique to CoV2, eliminates the transition state and allows the virus to stay bound to the ACE2 receptor for time scales compatible with the recruitment of additional ACE2 receptors diffusing in the cell membrane. This has important implications for viral infection and its pathology. CoV1 does not trigger high infectivity in the nasal area because it either rapidly drifts down the respiratory tract or is exhaled. By contrast, this novel mutation in CoV2 should not only retain the infection in the nasal cavity until ACE2-rich cells are sufficiently depleted, but also require fewer particles for infection. This mechanism explains observed longer incubation times, extended period of viral shedding, and higher rate of transmission. These considerations governing viral entry suggest that number of ACE2-rich cells in human nasal mucosa, which should be significantly smaller for children (and females relative to males), should also correlate with onset of viral load that could be a determinant of higher virus susceptibility. Critical implications for the development of new vaccines to combat current and future pandemics that, like SARS-CoV2, export evolutionarily successful strains via higher transmission rates by viral retention in nasal epithelium are also discussed.

biophysics↗

bioRxiv2020

DiMSum: an error model and pipeline for analyzing deep mutational scanning data and diagnosing common experimental pathologies

Deep mutational scanning (DMS) enables multiplexed measurement of the effects of thousands of variants of proteins, RNAs and regulatory elements. Here, we present a customizable pipeline - DiMSum - that represents an end-to-end solution for obtaining variant fitness and error estimates from raw sequencing data. A key innovation of DiMSum is the use of an interpretable error model that captures the main sources of variability arising in DMS workflows, outperforming previous methods. DiMSum is available as an R/Bioconda package and provides summary reports to help researchers diagnose common DMS pathologies and take remedial steps in their analyses.

bioinformatics↗

bioRxiv2020

SARS-CoV-2 envelope protein causes acute respiratory distress syndrome (ARDS)-like pathological damage and constitutes an antiviral target

Cytokine storm and multi-organ failure are the main causes of SARS-CoV-2-related death. However, the origin of the virus excessively damaging abilities remains unknown. Here we show that the SARS-CoV-2 envelope (2-E) protein alone is sufficient to cause acute respiratory distress syndrome (ARDS)-like damage in vitro and in vivo. Overexpression of 2-E protein induced rapid pyroptosis-like cell death in various susceptible cells and robust secretion of cytokines and chemokines in macrophages. Intravenous administration of purified 2-E protein into mice caused ARDS-like pathological damage in lung and spleen. Overexpressed 2-E protein formed cation channels in host cell membranes, eventually leading to membrane rupture. Newly identified channel inhibitors exhibited potent anti-SARS-CoV-2 activity and excellent protective effects against the 2-E-induced damage both in vitro and in vivo. Importantly, their channel inhibition, cell protection and antiviral activities were positively correlated with each other, supporting 2-E is a promising drug target against SARS-CoV-2.

microbiology↗

bioRxiv2020

Evidence that interspecies Leishmania hybrids contribute to changes in disease pathology

BackgroundLeishmaniasis is a widespread neglected tropical disease present in over 90 countries with diverse pathologies associated with different species of Leishmania parasites transmitted by infected sand flies. Leishmania donovani causes visceral leishmaniasis, a highly virulent fatal infection of the visceral organs. Leishmania major and Leishmania tropica cause less virulent cutaneous leishmaniasis where the infection remains in the skin at the site of the sandfly bite. A major molecular epidemiological question is why some variants of L. donovani in Sri Lanka cause cutaneous disease rather than the typical visceral disease. MethodsWhole genome sequencing data for 684 L. donovani samples was used to perform sequence alignments and worldwide phylogenetic analyses to determine the source of the atypical L. donovani strains from Sri Lanka. L. donovani genome sequences originating from Sri Lanka were further analyzed for evidence of hybridization with other Leishmania species by determining the density of heterozygous alleles. Polymorphisms from potential Leishmania hybrids were used to reconstruct the parental genetic sequences to identify the potential parental species and quantify their genetic contribution through sequence comparison of the reconstructed parental sequences with all Old World Leishmania genomes. FindingsHere we show that L. donovani in Sri Lanka contains genes with widespread gene polymorphisms derived from African L. major and L. tropica genomes that were likely obtained as a result of diploid genome hybridization and recombination resulting in progeny with mosaic genomes. Furthermore, evidence is presented that multiple L. donovani hybrid parasites originating from visceral leishmaniasis endemic Africa have entered Sri Lanka yet visceral leishmaniasis remains non-existent raising the possibility that environmental factors favour the establishment of atypical L. donovani strains in Sri Lanka. InterpretationThe discovery of L. major and L. tropica genome sequences in L. donovani provides a compelling rationale how some L. donovani strains in Sri Lanka may be able to cause cutaneous rather than visceral leishmaniasis. The identification of L. donovani hybrid parasites in cutaneous leishmaniasis lesions provides a unique opportunity to investigate environmental and parasite genetic factors controlling disease epidemiology and pathogenesis. FundingCanadian Institutes of Health Research and Fonds de recherche du Quebec - Sante Research in contextO_ST_ABSEvidence before this studyC_ST_ABSDifferent Leishmania species parasites cause either benign cutaneous leishmaniasis or fatal visceral leishmaniasis. It is unknown why some variants of Leishmania donovani that typically causes visceral leishmaniasis in Asia and Africa can cause cutaneous leishmaniasis in specific geographic locations including Sri Lanka. Leishmania has a diploid genome and hybrid parasites have been identified in nature and generated experimentally. In the context of this study, hybrids are considered to be progeny derived from a single outcross event between two diverse parents. Uncertainty remains whether interspecies hybrids with visceral and cutaneous leishmaniasis causing species in nature are associated with different disease outcomes. Added value of this studyEvidence for genetic hybridization between visceral and cutaneous disease causing Leishmania species is described from Sri Lanka where cutaneous leishmaniasis is highly endemic yet there is no ongoing visceral leishmaniasis transmission. This provides a potential explanation how L. donovani can become attenuated for visceral disease and could help to identify geographic environmental factors associated with selection for parasite attenuation. Implications of all the available evidenceHybrid Leishmania parasites may be one source of atypical cutaneous leishmaniasis. Epidemiological studies are needed to determine why diverse L. donovani hybrid parasites have become ubiquitous in specific geographic locations where the incidence of cutaneous leishmaniasis is increasing. This has implications for understanding the genetic control of disease pathogenesis and for the prevention of cutaneous or visceral leishmaniasis locally and in neighboring countries.

microbiology↗

bioRxiv2020

Shear stress-induced pathological changes in endothelial cells occur through Piezo1 activation of TRPV4

Although the ion channels Piezo1 and TRPV4 have been implicated in high venous pressure- and fluid shear stress-induced vascular hyperpermeability, they have been described as working independently. Moreover, the mechanism by which Piezo1 and TRPV4 channels in endothelial cells execute the same function is poorly understood. Here we demonstrate that Piezo1 regulates TRPV4 channel activation in endothelial cells and that Piezo1-mediated TRPV4 channel opening is a function of the strength and duration of fluid shear stress. Application of the Piezo1 antagonist, GsMTx4, completely blocked the elevation in intracellular calcium ([Ca2+]i) induced by both fluid shear stress and the Piezo1 agonist, Yoda1. High and prolonged shear stress caused sustained [Ca2+]i elevation which required TRPV4 opening and was responsible for fluid shear stress- and Piezo1-mediated disruption of adherens junctions and actin remodeling. We found that Piezo1’s effects were mediated by phospholipase A2 activation. Blockade of TRPV4 channels with the selective TRPV4 blocker, HC067047, prevented the loss of endothelial cell integrity and actin disruption induced by Yoda1 or shear stress and prevented Piezo1-induced monocyte adhesion to endothelial cell monolayers. These findings demonstrate that Piezo1 activation by fluid shear stress initiates a calcium signal that causes TRPV4 opening which in turn is responsible for the sustained phase calcium elevation that triggers pathological events in endothelial cells.The abbreviations used areHUVEChuman umbilical vein endothelial cellTRPV4transient receptor potential vanilloid subfamily 4PLA2phospholipase A2AJsadherens junctions5′,6′-EET5′,6′-epoxyeicosatrienoic acidHC067HC067047GSK101GSK1016790APVPpulmonary venous pressureView Full Text

cell biology↗

bioRxiv2020

Evolutionary Action Score of TP53 Mutations: Integrated Clinico-pathologic And Protein Structural Analysis in Myelodysplastic Syndromes

ABSTRACTTo determine the impact of TP53 mutations on the phenotype and outcome of myelodysplastic syndromes, we quantified the deleterious effects of missense TP53 mutations using the computationally-derived evolutionary action score (higher score indicates worse impact), based on the phylogenetic divergence of the sequence position and amino acid change perturbation, and correlated with clinico-pathologic-genomic features in 270 newly-diagnosed TP53-mutant patients primarily treated with hypomethylating agents. Using recursive partitioning and regression trees, we identified a subset of patients with low-EAp53 mutations (≤52) with improved overall survival (OS) (n=17, 6%) compared to high-EAp53 (n=253, 94%) [median OS, 48 vs. 10 months; p=0.01]. Compared to high-EAp53, low-EAp53 patients had lower cytogenetic complexity, lower TP53 protein expression, lacked multi-allelic TP53 alterations, but had more somatic mutations in other genes. There was no difference in median TP53 variant allele frequency or distribution of R-IPSS. 3D-protein modeling showed clustering of poor-outcome mutations, indicating structural location influences outcome.Competing Interest StatementThe authors have declared no competing interest.View Full Text

cancer biology↗

bioRxiv2020

Systemic inflammation causes microglial dysfunction with a mixed AD-like pathology.

BackgroundAlzheimers disease (AD) is the primary cause of cognitive deficit in elderly humans. Late-onset AD (LOAD) is sporadic, multifactorial, non-Mendelian accounting at present for 95% of the cases in contrast to the genetic form. Risk factors for sporadic AD include Gene: Environment interactions. There is increasing evidence that lifestyle and environmental stress such as infection and chronic inflammation are underlying culprits of neurodegenerative dementia. Dementias that share or mimic pathological processes of AD include cerebrovascular diseases, Lewy body disease, TDP-43 proteinopathy. To date, very few mouse models reproduce the pathophysiological progression of mixed-vascular-AD, while the majority of studies have employed transgenic animals reproducing the familial form. MethodsWe have re-engineered the Polyinosinic:polycytidylic acid (PolyI:C) sterile infection model in wildtype C57Bl6 mice to obtain chronic low-grade systemic inflammation. We have conducted a cross-sectional analysis of aging PolyI:C and Saline control mice (3 months, 6 months, 9 months and 16 months), taking the hippocampus as a reference brain region, based on its vulnerability, and compared the brain aging phenotype to AD progression in humans with mild AD, severe AD and Controls (CTL), parallely in Vascular dementia (VaD) patient specimens. ResultsWe found that PolyI:C mice display both peripheral and central inflammation with a peak at 6 months, associated with memory deficits. The hippocampus is characterized by a pronounced and progressive tauopathy. In PolyI:C brains, microglia undergo aging-dependent morphological rearrangements progressively adopting a phagocytic phenotype. Transcriptomic analysis reveals a profound change in gene expression over the course of aging, with a peak in differential expression at 9 months. We confirm that the proinflammatory marker Lcn2 is one of the genes with the strongest upregulation in PolyI:C mice upon aging. Validation in brains from patients with increasing severity of AD and VaD shows a reproducibility of some gene targets in vascular dementia specimens rather than AD ones, in which only GFAP is strongly increased at the severe stages. ConclusionsThe PolyI:C model of sterile infection demonstrates that peripheral chronic inflammation is sufficient to cause neuropathological processes resembling a mixed-VaD-AD phenotype, with progressive tau hyperphosphorylation, changes in microglia morphology, astrogliosis and gene reprogramming reflecting increased neuroinflammation, vascular remodeling and the loss of neuronal functionality seen to some extent in humans.

neuroscience↗

bioRxiv2020

Dense, high-resolution mapping of cells and tissues from pathology images for the interpretable prediction of molecular phenotypes in cancer

While computational methods have made substantial progress in improving the accuracy and throughput of pathology workflows for diagnostic, prognostic, and genomic prediction, lack of interpretability remains a significant barrier to clinical integration. In this study, we present a novel approach for predicting clinically-relevant molecular phenotypes from histopathology whole-slide images (WSIs) using human-interpretable image features (HIFs). Our method leverages >1.6 million annotations from board-certified pathologists across >5,700 WSIs to train deep learning models for high-resolution tissue classification and cell detection across entire WSIs in five cancer types. Combining cell- and tissue-type models enables computation of 607 HIFs that comprehensively capture specific and biologically-relevant characteristics of multiple tumors. We demonstrate that these HIFs correlate with well-known markers of the tumor microenvironment (TME) and can predict diverse molecular signatures, including immune checkpoint protein expression and homologous recombination deficiency (HRD). Our HIF-based approach provides a novel, quantitative, and interpretable window into the composition and spatial architecture of the TME.

bioinformatics↗