Biology subjects

Fujita, M.

Publications and source records attributed to Fujita, M..

At least 37 records · Page 2Linked to original sources

bioRxiv2024

Relation of CMV and brain atrophy to trajectories of immunosenescence in diverse populations

Immunosenescence (ISC), the aging of the immune system, has largely been studied in populations of European descent. Here, circulating immune cell cytometric data from African-American, Hispanic, and non-Hispanic White participants were generated. Known and novel age effects were identified using either a meta-analysis approach or a parallel genetic approach. Most results are consistent across the three populations, but some cell populations display evidence of heterogeneity, such as a PD-L1+CD56+ NK cell subset. The study estimated "Immunological Age" (IA) during physiologic aging. While we found no relation of IA to Multiple Sclerosis, IA is associated with entorhinal cortex atrophy, a presymptomatic feature of Alzheimers disease, linking neurodegeneration and peripheral immunity. ISC trajectories were also inferred, highlighting age, CMV status, and genetic ancestry as key influences. Our assessment offers reference ISC trajectories for personalization of assessments of immune function over the life course in diverse populations.

immunology↗

bioRxiv2024

CqHKT1 and CqSOS1 mediate genotype-dependent Na+ exclusion under high salt stress in quinoa

Salinity threatens crop production worldwide, and salinized areas are steadily increasing. As most crops are sensitive to salt, there is a need to improve the salt tolerance of major crops and promote the cultivation of under-utilized salt-tolerant crops. Quinoa, a pseudocereal and leafy vegetable from the Andean region of South America, is highly salt-tolerant, thrives in marginal environments, and has excellent nutritional properties. Research has often focused on epidermal bladder cells, a feature of quinoa thought to contribute to salt tolerance; however recent evidence suggests that these cells are not directly involved. The salt tolerance mechanism in quinoa remains unclear. Here, we show genotype-dependent differences in Na+ and K+ accumulation mechanisms using representative 18 lines of three genotypes by focusing on young quinoa seedlings at a stage without epidermal bladder cells. High salinity (600 mM NaCl) did not affect the early growth of all three quinoa genotypes. Under high salinity, lowland quinoa lines accumulated the most Na+ in the aerial parts, whereas southern highland lines accumulated the least. By contrast, K+ accumulation was slightly reduced in the aerial parts but significantly decreased in roots of all the genotypes. Resequencing of 18 quinoa lines supports the notion that genotype determines aboveground Na+ uptake and gene expression in response to salt stress. Using virus-induced gene silencing, we further demonstrated that CqHKT1 and CqSOS1 mediate Na+ exclusion in quinoa. These findings provide insight into salt tolerance mechanisms, serving as a basis for improving crop production under salt stress.

plant biology↗

bioRxiv2024

Contributions of genetic variation in astrocytes to cell and molecular mechanisms of risk and resilience to late onset Alzheimer's disease

Reactive astrocytes are associated with Alzheimers disease (AD), and several AD genetic risk variants are associated with genes highly expressed in astrocytes. However, the contribution of genetic risk within astrocytes to cellular processes relevant to the pathogenesis of AD remains ill-defined. Here we present a resource for studying AD genetic risk in astrocytes using a large collection of induced pluripotent stem cell (iPSC) lines from deeply phenotyped individuals with a range of neuropathological and cognitive outcomes. IPSC lines from forty-four individuals were differentiated into astrocytes followed by unbiased molecular profiling using RNA sequencing and tandem mass tag-mass spectrometry. We demonstrate the utility of this resource in examining gene- and pathway-level associations with clinical and neuropathological traits, as well as in analyzing genetic risk and resilience factors through parallel analyses of iPSC-astrocytes and brain tissue from the same individuals. Our analyses reveal that genes and pathways altered in iPSC-derived astrocytes from AD individuals are concordantly dysregulated in AD brain tissue. This includes increased prefoldin proteins, extracellular matrix factors, COPI-mediated trafficking components and reduced proteins involved in cellular respiration and fatty acid oxidation. Additionally, iPSC-derived astrocytes from individuals resilient to high AD neuropathology show elevated basal levels of interferon response proteins and increased secretion of interferon gamma. Correspondingly, higher polygenic risk scores for AD are associated with lower levels of interferon response proteins. This study establishes an experimental system that integrates genetic information with a heterogeneous set of iPSCs to identify genetic contributions to molecular pathways affecting AD risk and resilience.

neuroscience↗

bioRxiv2024

A heterocyclic compound inhibits viral release by inducing cell surface BST2/Tetherin/CD317/HM1.24

The introduction of combined antiretroviral therapy (cART) has greatly improved the quality of life of human immunodeficiency virus type 1 (HIV-1)-infected individuals. Nonetheless, the ever-present desire to seek out a full remedy for HIV-1 infections makes the discovery of novel antiviral medication compelling. Owing to this, a new late-stage inhibitor, Lenacapavir/Sunlenca, an HIV multi-phase suppressor, was clinically authorized in 2022. Besides unveiling cutting-edge antivirals inhibiting late-stage proteins or processes, newer therapeutics targeting host restriction factors hold promise for the curative care of HIV-1 infections. Notwithstanding, bone marrow stromal antigen 2 (BST2)/Tetherin/CD317/HM1.24, which entraps progeny virions is an appealing HIV-1 therapeutic candidate. In this study, a novel drug screening system was established, using the Jurkat/Vpr-HiBiT T cells, to identify drugs that could obstruct HIV-1 release; the candidate compounds were selected from the Ono Pharmaceutical compound library. Jurkat T cells expressing Vpr-HiBiT were infected with NL4-3, and the amount of virus release was quantified indirectly by the amount of Vpr-HiBiT incorporated into the progeny virions. Subsequently, the candidate compounds that suppressed viral release were used to synthesize the heterocyclic compound, HT-7, which reduces HIV-1 release with less cellular toxicity. Notably, HT-7 increased cell surface BST2 coupled with HIV-1 release reduction in Jurkat cells but not Jurkat/KO-BST2 cells. Seemingly, HT-7 impeded simian immunodeficiency virus (SIV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) release. Concisely, these results suggest that the reduction in viral release, following HT-7 treatment, resulted from the modulation of cell surface expression of BST2 by HT-7. ImportanceA collection of scientific strategies has been revealed to find long-term cure for HIV-1 infection. One of these techniques, the therapeutic approach, involves harnessing late events that are not targeted by current medication. The regulator of HIV-1 assembly and release, the HIV-1 Gag protein, has emerged as a prospective inhibitor. We set up a high-efficiency, economically viable, and facile screening system for the identification of late-stage inhibitors. Herein, we discovered a heterocyclic compound that inhibits HIV-1 release. This newly high- performance testing technique can be employed in virological research for investigating HIV- 1 late-stage processes.

microbiology↗

bioRxiv2024

Regulation of angiogenesis by endocytic trafficking mediated by cytoplasmic dynein 1 light intermediate chain 1

Dynein cytoplasmic 1 light intermediate chain 1 (LIC1, DYNC1LI1) is a core subunit of the dynein motor complex. The LIC1 subunit also interacts with various cargo adaptors to regulate Rab-mediated endosomal recycling and lysosomal degradation. Defects in this gene are predicted to alter dynein motor function, Rab binding capabilities, and cytoplasmic cargo trafficking. Here, we have identified a dync1li1 zebrafish mutant, harboring a premature stop codon at the exon 12/13 splice acceptor site, that displays increased angiogenesis. In vitro, LIC1-deficient human endothelial cells display increases in cell surface levels of the pro-angiogenic receptor VEGFR2, SRC phosphorylation, and Rab11-mediated endosomal recycling. In vivo, endothelial-specific expression of constitutively active Rab11a leads to excessive angiogenesis, similar to the dync1li1 mutants. Increased angiogenesis is also evident in zebrafish harboring mutations in rilpl1/2, the adaptor proteins that promote Rab docking to Lic1 to mediate lysosomal targeting. These findings suggest that LIC1 and the Rab-adaptor proteins RILPL1 and 2 restrict angiogenesis by promoting degradation of VEGFR2-containing recycling endosomes. Disruption of LIC1- and RILPL1/2-mediated lysosomal targeting increases Rab11-mediated recycling endosome activity, promoting excessive SRC signaling and angiogenesis.

cell biology↗

bioRxiv2024

A Human Brain Map of Mitochondrial Respiratory Capacity and Diversity

Mitochondrial oxidative phosphorylation (OxPhos) powers brain activity1,2, and mitochondrial defects are linked to neurodegenerative and neuropsychiatric disorders3,4, underscoring the need to define the brains molecular energetic landscape5-10. To bridge the cognitive neuroscience and cell biology scale gap, we developed a physical voxelization approach to partition a frozen human coronal hemisphere section into 703 voxels comparable to neuroimaging resolution (3x3x3 mm). In each cortical and subcortical brain voxel, we profiled mitochondrial phenotypes including OxPhos enzyme activities, mitochondrial DNA and volume density, and mitochondria-specific respiratory capacity. We show that the human brain contains a diversity of mitochondrial phenotypes driven by both topology and cell types. Compared to white matter, grey matter contains >50% more mitochondria. We show that the more abundant grey matter mitochondria also are biochemically optimized for energy transformation, particularly among recently evolved cortical brain regions. Scaling these data to the whole brain, we created a backward linear regression model integrating several neuroimaging modalities11, thereby generating a brain-wide map of mitochondrial distribution and specialization that predicts mitochondrial characteristics in an independent brain region of the same donor brain. This new approach and the resulting MitoBrainMap of mitochondrial phenotypes provide a foundation for exploring the molecular energetic landscape that enables normal brain functions, relating it to neuroimaging data, and defining the subcellular basis for regionalized brain processes relevant to neuropsychiatric and neurodegenerative disorders.

neuroscience↗

bioRxiv2024

A pharmacological toolkit for human microglia identifies Topoisomerase I inhibitors as immunomodulators for Alzheimer's disease

AbstractWhile efforts to identify microglial subtypes have recently accelerated, the relation of transcriptomically defined states to function has been largely limited to in silico annotations. Here, we characterize a set of pharmacological compounds that have been proposed to polarize human microglia towards two distinct states - one enriched for AD and MS genes and another characterized by increased expression of antigen presentation genes. Using different model systems including HMC3 cells, iPSC-derived microglia and cerebral organoids, we characterize the effect of these compounds in mimicking human microglial subtypes in vitro. We show that the Topoisomerase I inhibitor Camptothecin induces a CD74high/MHChigh microglial subtype which is specialized in amyloid beta phagocytosis. Camptothecin suppressed amyloid toxicity and restored microglia back to their homeostatic state in a zebrafish amyloid model. Our work provides avenues to recapitulate human microglial subtypes in vitro, enabling functional characterization and providing a foundation for modulating human microglia in vivo.

neuroscience↗

bioRxiv2023

Human disease-specific cell signatures in non-lesional tissue in Multiple Sclerosis detected by single-cell and spatial transcriptomics

Recent investigations of cell type changes in Multiple Sclerosis (MS) using single-cell profiling methods have focused on active lesional and peri-lesional brain tissue, and have implicated a number of peripheral and central nervous system cell types. However, an important question is the extent to which so-called "normal-appearing" non-lesional tissue in individuals with MS accumulate changes over the lifespan. Here, we compared post-mortem non-lesional brain tissue from donors with a pathological or clinical diagnosis of MS from the Religious Orders Study or Rush Memory and Aging Project (ROSMAP) cohorts to age- and sex-matched brains from persons without MS (controls). We profiled three brain regions using single-nucleus RNA-seq: dorsolateral prefrontal cortex (DLPFC), normal appearing white matter (NAWM) and the pulvinar in thalamus (PULV), from 15 control individuals, 8 individuals with MS, and 5 individuals with other detrimental pathologies accompanied by demyelination, resulting in a total of 78 samples. We identified region- and cell type-specific differences in non-lesional samples from individuals diagnosed with MS and/or exhibiting secondary demyelination with other neurological conditions, as compared to control donors. These differences included lower proportions of oligodendrocytes with expression of myelination related genes MOBP, MBP, PLP1, as well as higher proportions of CRYAB+ oligodendrocytes in all three brain regions. Among microglial signatures, we identified subgroups that were higher in both demyelination (TMEM163+/ERC2+), as well as those that were specifically higher in MS donors (HIF1A+/SPP1+) and specifically in donors with secondary demyelination (SOCS6+/MYO1E+), in both white and grey matter. To validate our findings, we generated Visium spatial transcriptomics data on matched tissue from 13 donors, and recapitulated our observations of gene expression differences in oligodendrocytes and microglia. Finally, we show that some of the differences observed between control and MS donors in NAWM mirror those previously reported between control WM and active lesions in MS donors. Overall, our investigation sheds additional light on cell type- and disease-specific differences present even in non-lesional white and grey matter tissue, highlighting widespread cellular signatures that may be associated with downstream pathological changes.

neuroscience↗

bioRxiv2023

The heparin-binding domain of VEGF165 directly binds to integrin αvβ3 and plays a critical role in signaling.

VEGF-A is a key cytokine in tumor angiogenesis and a major therapeutic target for cancer. VEGF165 is the predominant isoform and is the most potent angiogenesis stimulant. VEGFR2/KDR domains 2 and 3 (D2D3) bind to the N-terminal domain (NTD, residues 1-110) of VEGF165. Since removal of the heparin-binding domain (HBD, residues 111-165) markedly reduced the mitogenic activity of VEGF165, it has been proposed that the HBD plays a critical role in the mitogenicity of VEGF165. Integrin v{beta}3 has been shown to bind to VEGF165, but the role of integrin v{beta}3 in VEGF165 signaling are unclear. Here we describe that v{beta}3 specifically bound to the isolated HBD, but not to the NTD. We identified several critical amino acid residues in HBD for integrin binding (Arg-123, Arg-124, Lys-125, Lys-140, Arg-145, and Arg-149) by docking simulation and mutagenesis, and generated full-length VEGF165 that is defective in integrin binding by including mutations in the HBD. The full-length VEGF165 mutant defective in integrin binding (R123A/R124A/K125A/K140A/R145A/R149A) was defective in ERK1/2 phosphorylation, integrin {beta}3 phosphorylation, and KDR phosphorylation, although the mutation did not affect KDR binding to VEGF165. We propose a model in which VEGF165 induces KDR (through NTD)-VEGF165 (through HBD)-integrin v{beta}3 ternary complex formation on the cell surface and this process is critically involved in potent mitogenicity of VEGF165.

biochemistry↗

bioRxiv2023

Psychosocial experiences are associated with human brain mitochondrial biology

Psychosocial experiences affect brain health and aging trajectories, but the molecular pathways underlying these associations remain unclear. Normal brain function relies heavily on energy transformation by mitochondria oxidative phosphorylation (OxPhos), and two main lines of evidence bi-directionally link mitochondria as both targets and drivers of psychosocial experiences. On the one hand, chronic stress exposure and possibly mood states alter multiple aspects of mitochondrial biology; and on the other hand, functional variations in mitochondrial OxPhos capacity alter social behavior, stress reactivity, and mood. However, knowledge on whether positive or negative psychosocial exposures and experiences are linked to mitochondrial biology in the human brain is currently unknown. By combining longitudinal antemortem assessments of psychosocial factors with postmortem brain (dorsolateral prefrontal cortex) proteomics in older adults, we found that positive experiences (e.g. higher well-being) are linked to greater abundance of the mitochondrial OxPhos machinery, whereas negative experiences (e.g. higher negative mood) are linked to lower OxPhos protein content. Combined, psychosocial factors explained 18% of the variance in the abundance of OxPhos complex I, the primary biochemical entry point that energizes brain mitochondria. To increase the sensitivity of our approach, we next interrogated mitochondrial psychobiological associations in specific neuronal and non-neuronal brain cells with single-nucleus RNA sequencing. These results revealed strong cell type specific associations, particularly between positive psychosocial experiences and molecular mitochondrial phenotypes in glial cells, whereas neurons tended to show opposite associations. Accordingly, in bulk transcriptomic analyses where all cells are pooled, these RNA-based associations were masked. Thus, our results highlight the likely underestimation of effect sizes in bulk brain tissues, and document novel cell type specific mitochondrial psychobiological associations in the human brain. Cell type specific mitochondrial recalibrations represent a potential psychobiological pathway linking positive and negative psychosocial experiences to human brain biology. Significance statementPsychosocial experiences predict health trajectories, but the underlying mechanism remains unclear. We found that positive psychosocial experiences are linked to greater abundance of the mitochondrial energy transformation machinery, whereas negative experiences are linked to lower abundance. Overall, we found that psychosocial experiences explain 18% of the variance in abundance of complex I proteins, the main entry point of the mitochondrial oxidative phosphorylation (OxPhos) system. At single-cell resolution using single nucleus transcriptomics, positive psychosocial experiences were particularly related to glial cell mitochondrial phenotypes. Opposite associations between glial cells and neurons were naturally masked in bulk transcriptomic analyses. Our results suggest that mitochondrial recalibrations in specific brain cell types may represent a potential psychobiological pathway linking psychosocial experiences to human brain health.

cell biology↗

bioRxiv2023

Evolution of wheat blast resistance gene Rmg8 accompanied by differentiation of variants recognizing the powdery mildew fungus

Wheat blast, a devastating disease having spread recently from South America to Asia and Africa, is caused by Pyricularia oryzae pathotype Triticum which emerged in 1985. Rmg8 and Rmg7, genes for resistance to wheat blast found in common wheat and tetraploid wheat, respectively, recognize the same avirulence gene, AVR-Rmg8. Here, we show an evolutionary process in which resistance gene(s), which had obtained an ability to recognize AVR-Rmg8 before the differentiation of Triticum and Aegilops, has expanded its target pathogens. Molecular cloning revealed that Rmg7 was one of alleles of Pm4 (Pm4a), a gene for resistance to wheat powdery mildew on 2AL, whereas Rmg8 was its homoeolog on 2BL ineffective against wheat powdery mildew. Rmg8 variants with the ability to recognize AVR-Rmg8 were distributed not only in Triticum spp. but also in Aegilops speltoides, Ae. umbellulata, and Ae. comosa. This result suggests that the origin of resistance gene(s) recognizing AVR-Rmg8 dates back to the time before differentiation of A, B, S, U, and M genomes, that is, [~]5 million years before the emergence of its current target, the wheat blast fungus. Phylogenetic analyses suggested that, in the evolutionary process thereafter, some of their variants gained the ability to recognize the wheat powdery mildew fungus and evolved into genes for resistance to wheat powdery mildew.

plant biology↗

bioRxiv2023

Breeding of a near-isogenic wheat line resistant to wheat blast at both seedling and heading stages through incorporation of Rmg8

Wheat blast caused by Pyricularia oryzae Triticum pathotype (MoT) has been transmitted from South America to Bangladesh and Zambia and is now spreading in these countries. To prepare against its further spread to Asian countries, we introduced Rmg8, a gene for resistance to wheat blast, into a Japanese elite cultivar, Chikugoizumi (ChI), through recurrent backcrosses, and established ChI near-isogenic lines, #2-1-10 with the Rmg8/Rmg8 genotype and #4-2-10 with the rmg8/rmg8 genotype. A molecular analysis suggested that at least 96.6% of the #2-1-10 genome was derived from the recurrent parent ChI. The #2-1-10 line was resistant to MoT not only in primary leaves at the seedling stage but also in spikes and flag leaves at the heading stage. The strength of the resistance in spikes of this Rmg8 carrier was comparable to that of a carrier of the 2NS segment which has been the only one genetic resource released to farmers field for wheat blast resistance. On the other hand, the 2NS resistance was not expressed on leaves at the seedling stage nor flag leaves at the heading stage. Considering that leaf blast has been increasingly reported and regarded as an important inoculum source for spike blast, Rmg8 expressed at both the seedling and heading stages, or more strictly in both leaves and spikes, is suggested to be useful to prevent the spread of MoT in Asia and Africa.

plant biology↗

bioRxiv2023

The Crucial Role of CTCF in Mitotic Progression during Early Development of Sea Urchin.

CCCTC-binding factor (CTCF), an insulator protein with 11 zinc fingers, is enriched at the boundaries of topologically associated domains (TADs) in eukaryotic genomes. In this study, we isolated and analyzed the cDNAs encoding HpCTCF, the CTCF homolog in the sea urchin Hemicentrotus pulcherrimus, to investigate its expression patterns and functions during early development of sea urchin. HpCTCF contains nine zinc fingers corresponding to fingers 2-10 of the vertebrate CTCF. The expression pattern analysis revealed that HpCTCF mRNA was detected at all developmental stages and in the entire embryo. Upon expressing the HpCTCF-GFP fusion protein in early embryos, we observed its uniform distribution within interphase nuclei. However, during mitosis, it disappeared from the chromosomes and subsequently reassembled on the chromosome during telophase. Moreover, the morpholino-mediated knockdown of HpCTCF resulted in mitotic arrest during the morula-to-blastula stage. Most of the arrested chromosomes were not phospholylated at serine 10 of histone H3, indicating that mitosis was arrested at the telophase by HpCTCF depletion. Furthermore, impaired sister chromatid segregation was observed using time-lapse imaging of HpCTCF-knockdown embryos. Thus, HpCTCF is essential for mitotic progression during the early development of sea urchins, especially during the telophase-to-interphase transition. However, the normal development of pluteus larvae in CRISPR-mediated HpCTCF knockout embryos suggests that disruption of zygotic HpCTCF expression has little effect on embryonic and larval development.

developmental biology↗

bioRxiv2023

Cellular dynamics across aged human brains uncover a multicellular cascade leading to Alzheimer's disease

Alzheimers Disease (AD) is a progressive neurodegenerative disease seen with advancing age. Recent studies have revealed diverse AD-associated cell states, yet when and how they impact the causal chain leading to AD remains unknown. To reconstruct the dynamics of the brains cellular environment along the disease cascade and to distinguish between AD and aging effects, we built a comprehensive cell atlas of the aged prefrontal cortex from 1.64 million single-nucleus RNA-seq profiles. We associated glial, vascular and neuronal subpopulations with AD-related traits for 424 aging individuals, and aligned them along the disease cascade using causal modeling. We identified two distinct lipid-associated microglial subpopulations, one contributed to amyloid-{beta} proteinopathy while the other mediated the effect of amyloid-{beta} in accelerating tau proteinopathy, as well as an astrocyte subpopulation that mediated the effect of tau on cognitive decline. To model the coordinated dynamics of the entire cellular environment we devised the BEYOND methodology which uncovered two distinct trajectories of brain aging that are defined by distinct sequences of changes in cellular communities. Older individuals are engaged in one of two possible trajectories, each associated with progressive changes in specific cellular communities that end with: (1) AD dementia or (2) alternative brain aging. Thus, we provide a cellular foundation for a new perspective of AD pathophysiology that could inform the development of new therapeutic interventions targeting cellular communities, while designing a different clinical management for those individuals on the path to AD or to alternative brain aging.

neuroscience↗

bioRxiv2023

Structural Characterization of TRAF6 N-terminal for Therapeutic Uses

Tumor Necrosis Factor Receptor Associated Factors (TRAFs) are a protein family with a wide variety of roles and binding partners. Among them, TRAF6, a ubiquitin ligase, possesses unique receptor binding specificity and shows diverse functions in immune system regulation, cellular signaling, central nervous system (CNS), and tumor formation. TRAF6 consists of an N-terminal Really Interesting New Gene (RING) domain, multiple zinc fingers, and a C-terminal TRAF domain. RING domain and zinc fingers mediate the activation of nuclear factor kappa B (NF-{kappa}B), which has essential roles in the regulation of inflammatory responses, proliferation, differentiation, migration, cell adhesion, and apoptosis. Therefore, it has been found that TRAF6 is overexpressed in various types of cancer including pancreatic, liver, lung, head and neck, breast, colorectal cancers, and melanoma along with inflammatory, autoimmune and neurodegenerative disorders. Furthermore, TRAF6 is an important therapeutic target for numerous disorders and structural studies of this protein are crucial for the development of next-generation therapeutics. Here, we present a TRAF6 N-terminal structure determined at the Turkish Light Source "Turkish DeLight" to 2.6 [A] resolution at cryogenic temperature. This structure offers insight into the domain organization and zinc-binding, which are critical for protein function. Since the RING domain and the zinc fingers are key targets for TRAF6 therapeutics, structural insights are crucial for future research.

molecular biology↗

bioRxiv2022

Cell-subtype specific effects of genetic variation in the aging and Alzheimer cortex

The relationship between genetic variation and gene expression in individual brain cell types and subtypes has remained elusive. Here, we generated single-nucleus RNA sequencing data from the dorsolateral prefrontal cortex of 424 individuals of advanced age; analyzing 1.5 million nuclear transcriptomes, we assessed the effect of genetic variants on RNA expression in cis (cis-eQTL) for 7 cell types and 81 cell subtypes. This effort identified 10,004 eGenes at the cell type level and 8,138 eGenes at the cell subtype level. Many eGenes are only detected within cell subtypes. A new variant influences APOE expression only in microglia and is associated with greater cerebral amyloid angiopathy but not Alzheimer pathology, accounting for the effect of APOE{varepsilon}4, providing mechanistic insights into both pathologies. While eQTLs are readily detected, only a TMEM106B variant robustly affects the proportion of cell subtypes. Integration of these results with GWAS highlighted the targeted cell type and likely causal gene within susceptibility loci for Alzheimers, Parkinsons, schizophrenia, and educational attainment.

genomics↗

bioRxiv2022

A pan-cancer PDX histology image repository with genomic and pathological annotations for deep learning analysis

Patient-derived xenografts (PDXs) model human intra-tumoral heterogeneity in the context of the intact tissue of immunocompromised mice. Histological imaging via hematoxylin and eosin (H&E) staining is performed on PDX samples for routine assessment and, in principle, captures the complex interplay between tumor and stromal cells. Deep learning (DL)-based analysis of large human H&E image repositories has extracted inter-cellular and morphological signals correlated with disease phenotype and therapeutic response. Here, we present an extensive, pan-cancer repository of nearly 1,000 PDX and paired human progenitor H&E images. These images, curated from the PDXNet consortium, are associated with genomic and transcriptomic data, clinical metadata, pathological assessment of cell composition, and, in several cases, detailed pathological annotation of tumor, stroma, and necrotic regions. We demonstrate that DL can be applied to these images to classify tumor regions and to predict xenograft-transplant lymphoproliferative disorder, the unintended outgrowth of human lymphocytes at the transplantation site. This repository enables PDX-specific, investigations of cancer biology through histopathological analysis and contributes important model system data that expand on existing human histology repositories. We expect the PDXNet Image Repository to be valuable for controlled digital pathology analysis, both for the evaluation of technical issues such as stain normalization and for development of novel computational methods based on spatial behaviors within cancer tissues.

bioinformatics↗

bioRxiv2022

COOBoostR: an extreme gradient boosting-based tool for robust tissue or cell-of-origin prediction of tumors

We here present COOBoostR (https://github.com/SWJ9385/COOBoostR), a computational method designed for the putative prediction of tissue-or cell-of-origin of various cancer types. COOBoostR leverages regional somatic mutation density information and chromatin mark features to be applied to an extreme gradient boosting-based machine-learning algorithm. COOBoostR ranks chromatin marks from various tissue and cell types which best explain the somatic mutation density landscape of any sample of interest. Through integrating either ChIP-seq based chromatin data or bulk/single cell chromatin accessibility data along with regional somatic mutation density data derived from normal cells/tissue, precancerous lesions, and cancer types, we show that COOBoostR outperforms existing random forest-based methods in prediction speed with comparable or better tissue or cell-of-origin prediction performance. In addition, our results suggest a dynamic somatic mutation accumulation at the normal tissue or cell stage which could be intertwined with the changes in open chromatin marks and enhancer sites. These results further represent chromatin marks shaping the somatic mutation landscape at the early stage of mutation accumulation, possibly even before the initiation of precancerous lesions or neoplasia.

bioinformatics↗