Knowledge Portal Research Articles

Data-driven nexus between malaria incidence and World Bank indicators in the Mekong River during 2000-2022.

The increase in hydro dams in the Mekong River amidst the prevalence of multidrug-resistant malaria in Cambodia has raised concerns about global public health. Political conflicts during Covid-19 pandemic led cross-border movements of malaria cases from Myanmar and caused health care burden in Thailand. While previous publications used climatic indicators for predicting mosquito-borne diseases, this research used globally recognizable World Bank indicators to find the most impactful indicators related with malaria and shed light on the predictability of mosquito-borne diseases. The World Bank datasets of the World Development Indicators and Climate Change Knowledge Portal contain 1494 time series indicators. They were stepwise screened by Pearson and Distance correlation. The sets of five and four contain respectively 19 and 149 indicators highly correlated with malaria incidence which were found similarly among five and four GMS countries. Living areas, ages, career, income, technology accessibility, infrastructural facilities, unclean fuel use, tobacco smoking, and health care deficiency have affected malaria incidence. Tonle Sap Lake, the largest freshwater lake in Southeast Asia, could contribute to the larval habitat. Seven groups of indicator topics containing 92 indicators with not-null datapoints were analyzed by regression models, including Multiple Linear, Ridge, Lasso, and Elastic Net models to choose 7 crucial features for malaria prediction via Long Short Time Memory network. The indicator of people using at least basic sanitation services and people practicing open defecation were health factors had most impacts on regression models. Malaria incidence could be predicted by one indicator to reach the optimal mean absolute error which was lower than 10 malaria cases (per 1,000 population at risk) in the Long Short Time Memory model. However, public health crises caused by political problems should be analyzed by political indexes for more precise predictions.

Loss-of-function variants in ITSN1 confer high risk of Parkinson’s disease

Parkinson’s disease (PD) is a debilitating neurodegenerative disorder and its rising global incidence highlights the need for the identification of modifiable risk factors. In a gene-based burden test of rare variants (8647 PD cases and 777,693 controls) we discovered a novel association between loss-of-function variants in ITSN1 and PD. This association was further supported with burden data from the Neurodegenerative Disease Knowledge Portal and the Accelerating Medicines Partnership Parkinson’s Disease Knowledge Platform. Our findings show that Rho GTPases and disruptions in synaptic vesicle transport may be involved in the pathogenesis of PD, pointing to the possibility of novel therapeutic approaches.

Synergism of ApoE4 and systemic infectious burden is mediated by the APOE-NLRP3 axis in Alzheimer's disease.

Systemic infections are associated with the development of AD, especially in individuals carrying the APOE4 genotype. However, the detailed mechanism through which APOE4 affects microglia inflammatory response remains unclear. We obtained human snRNA-seq data from the Synapse AD Knowledge Portal and assessed the DEGs between APOE3 and APOE4 isoforms in microglia. To verify the interaction between ApoE and infectious products, we used ApoE to stimulate in vitro and in vivo models in the presence or absence of LPS (or ATP). The NLRP3 gene knockout experiment was performed to demonstrate whether the APOE-NLRP3 axis was indispensable for microglia to regulate inflammation and mitochondrial autophagy. Results were evaluated by biochemical analyses and fluorescence imaging. Compared with APOE3, up-regulated genes in APOE4 gene carriers were involved in pro-inflammatory responses. ApoE4-stimulation significantly increased the levels of NLRP3 inflammasomes and ROS in microglia. Moreover, compared with ApoE4 alone, the co-incubation of ApoE4 with LPS (or ATP) markedly promoted pyroptosis. Both NF-κB activation and mitochondrial autophagy dysfunction were contributed by the increased level of NLRP3 inflammasomes induced by ApoE4. Furthermore, the pathological impairment induced by ApoE4 could be reversed by NLRP3 KO. Our study highlights the importance of NLRP3 inflammasomes in linking ApoE4 with microglia innate immune function. These findings not only provide a molecular basis for APOE4-mediated neuroinflammatory but also reveal the potential reason for the increased risk of AD in APOE4 gene carriers after contracting infectious diseases.

A common Alu insertion in the 3'UTR of TMEM106B is associated with risk of dementia.

Sequence variants in TMEM106B have been associated with an increased risk of developing dementia. As part of our efforts to generate a set of mouse lines in which we replaced the mouse Tmem106b gene with a human TMEM106B gene comprised of either a risk or protective haplotype, we conducted an in-depth sequence analysis of these alleles. We also analyzed transcribed TMEM106B sequences using RNA-seq data (AD Knowledge portal) and full genome sequences (1000 Genomes). We identified an AluYb8 insertion in the 3' untranslated region (3'UTR) of the TMEM106B risk haplotype. We found this AluYb8 insertion in every risk haplotype analyzed, but not in either protective haplotypes or in non-human primates. We conclude that this risk haplotype arose early in human development with a single Alu-insertion event within a unique haplotype context. This AluYb8 element may act as a functional variant in conferring an increased risk of developing dementia. We conducted an in-depth sequence analysis of (1) a risk and (2) a protective haplotype of the human TMEM106B gene. We also analyzed transcribed TMEM106B sequences using RNA-seq data (AD Knowledge Portal) and full genome sequences (1000 Genomes). We identified an AluYb8 insertion in the 3' untranslated region (3'UTR) of the TMEM106B risk haplotype. We found this AluYb8 insertion in every risk haplotype analyzed, but not in either protective haplotypes or in non-human primates. This AluYb8 element may act as a functional variant in conferring an increased risk of developing dementia.

Ансамбль онтологических моделей для обеспечения интеллектуальной поддержки лазерных аддитивных технологических процессов

Barriers hindering the use of additive manufacturing processes for metal parts production are discussed. The necessity of integrating an intelligent decision support system (DSS) into the professional activities of laser additive manufactur-ing engineers is substantiated. The advantages of the developed ontological two-level approach for forming semantic information are highlighted. This approach's peculiarity lies in separating ontological models from the databases and knowledge formed on their basis—target information. The ontology dictates the rules for the structured formation and interpretation of target information. An ensemble of ontological models, forming the foundation of the developed intel-ligent system, is presented. The composition of the ensemble, the purpose of its individual components, and possible types of connections between them are described. The ensemble includes ontologies for reference databases on equip-ment and materials for laser additive manufacturing, an archive of protocols for technological operations of laser pro-cessing, a knowledge base about settings for laser processing modes, and a database of mathematical models. The en-semble of ontological models is implemented on the IACPaaS cloud platform using its tools. Ontologies, databases, knowledge bases, and a decision support system are part of the Laser Additive Manufacturing Knowledge Portal. Ac-cumulating and using the knowledge and experience from different technologists in the portal will reduce the number of preliminary experiments needed to identify suitable technological modes and lower the qualification requirements for users of technological equipment.

The Neurodegenerative Disease Knowledge Portal: Propelling Discovery Through the Sharing of Neurodegenerative Disease Genomic Resources.

Although large-scale genetic association studies have proven opportunistic for the delineation of neurodegenerative disease processes, we still lack a full understanding of the pathological mechanisms of these diseases, resulting in few appropriate treatment options and diagnostic challenges. To mitigate these gaps, the Neurodegenerative Disease Knowledge Portal (NDKP) was created as an open-science initiative with the aim to aggregate, enable analysis, and display all available genomic datasets of neurodegenerative disease, while protecting the integrity and confidentiality of the underlying datasets. The portal contains 218 genomic datasets, including genotyping and sequencing studies, of individuals across ten different phenotypic groups, including neurological conditions such as Alzheimer's disease, amyotrophic lateral sclerosis, Lewy body dementia, and Parkinson's disease. In addition to securely hosting large genomic datasets, the NDKP provides accessible workflows and tools to effectively utilize the datasets and assist in the facilitation of customized genomic analyses. Here, we summarize the genomic datasets currently included within the portal, the bioinformatics processing of the datasets, and the variety of phenotypes captured. We also present example use-cases of the various user interfaces and integrated analytic tools to demonstrate their extensive utility in enabling the extraction of high-quality results at the source, for both genomics experts and those in other disciplines. Overall, the NDKP promotes open-science and collaboration, maximizing the potential for discovery from the large-scale datasets researchers and consortia are expending immense resources to produce and resulting in reproducible conclusions to improve diagnostic and therapeutic care for neurodegenerative disease patients.

A Detailed Examination of Türkiye's Projected Precipitation and Growth Season Trends under Climate Change Condition

This study presents a comprehensive analysis of Türkiye's changing precipitation patterns and growing season dynamics in the context of global warming, utilizing the Coupled Model Intercomparison Project Phase 5 (CMIP5) and various Representative Concentration Pathway (RCP) scenarios. In light of global warming, this study provides a thorough analysis of Türkiye's evolving precipitation patterns and growing season dynamics using multiple RCP scenarios and CMIP5. The research aims to fill a crucial gap in climate research by combining historical data and future projections to assess Türkiye's precipitation path under different greenhouse gas emission scenarios. The study employs linear regression for trend analysis and uses data from the Climate Change Knowledge Portal (CCKP), with a focus on precipitation data from 1986 to 2100. According to various RCP scenarios, this study’s findings show a considerable variation in precipitation trends over the 21st century. The RCP 8.5 scenario predicts a significant decrease in precipitation, which would present difficulties for the management of water resources and agricultural productivity. In contrast, the least severe RCP 2.6 pathway shows a fairly stable pattern of precipitation. Complex seasonal hydrological responses to climate change are revealed by monthly precipitation analysis; RCP8.5 predicts an increase in the frequency of periods of drought and heavy precipitation events. The impact of these changes in precipitation on Türkiye's agricultural growing seasons was further investigated in this study. In high-emission scenarios, there was an initial tendency towards longer growing seasons, which were subsequently followed by shorter ones. This suggests that although global warming might initially result in an extended growing season, it might ultimately cause a reduction in it, particularly in situations where mitigation efforts are minimal. The need for adaptable strategies that can respond to long-term climate trends as well as seasonal variability was highlighted by this research. It draws attention to the fact that to mitigate the effects of climate variability, informed policy decisions and integrated resource management are essential. The results highlight the need for quick action to lower the risks associated with water and highlight the potential advantages of intensive mitigation efforts in stabilizing and extending growing seasons.

Selenotranscriptome network in Alzheimer’s disease

The interplay between selenoproteins, oxidative stress, and cell death pathways holds promise in unravelling novel therapeutic targets for Alzheimer’s disease (AD) in the future. Nonetheless, further comprehensive investigations are warranted to fully comprehend the precise contributions of selenoproteins in the aetiology and potential therapeutic strategies for Alzheimer’s disease. Previous work into gene expression networks in AD has included analysis of the entire transcriptome and, as of yet, has not yielded consistent insight into pathological pathways.1 Despite the comprehensive assessment of the transcriptome enabled by current technologies, one drawback of the whole transcriptome analysis is the risk of overlooking subtle yet significant variations in metabolic pathways.2 Thus, we aimed to assess gene expression of known selenoprotein and selenium-containing pathways in two different brain regions (dorsolateral prefrontal cortex (DPC) and posterior cingulate cortex (PCC)) across the AD spectrum. We used RNA sequencing data from The Rush University’s Religious Orders Study and Memory and Aging Project (ROSMAP) cohort available in the AD Knowledge Portal (https://www.synapse.org/).3 This study included data available for a total of 889 DPC and 647 PCC samples. Four pathological phenotypes were determined based on pathology (CERAD) and clinical (CDR) status: AD ([(+) pathology, (+) clinical], prodromal disease, corresponding to donors that have not received a clinical diagnosis despite the presence of pathological alterations ([(+) pathology, (−) clinical], controls ([(−) pathology, (−) clinical] and non-AD dementia [(+) pathology, (+) clinical]. This last group was excluded from the analysis as it is assumed they may have been misdiagnosed or presented with non-AD dementia. Six selenium or AD-related pathways were assessed, accounting for 421 unique genes. Group comparisons were performed using linear mixed modelling adjusted for age, sex, APOEe4 status and batch via DESeq2 package with Benjamini-Hochberg adjustment for multiple testing. A total of 18 genes significantly differed between AD and controls in both brain areas (same direction in both brain areas; P < 0.05), including eight selenoprotein genes or genes directly associated with selenoprotein synthesis. Fifteen of them were also different (same direction) in PCC (seven selenoprotein/selenoprotein synthesis genes), and four were different in DPC (four selenoprotein/selenoprotein synthesis genes) between AD and prodromal. Only three genes significantly differed between prodromal and control samples (DPC), including the selenoprotein DIO3 and the transcription factor SP3. Our findings indicate a progressive change in gene expression across the different stages of AD. These findings shed light on critical genes involved in selenoprotein synthesis that play a role in AD pathogenesis. Restricting the analysis to a subset of pathways enabled the detection of smaller alterations between groups, which is particularly appropriate in trace element homeostasis, where small alterations may have significant downstream effects.

Climate Change Impact Assessment and Disaster Risk Financing Strategies in Mali: A Comprehensive Analysis of Drought and Flood Events

Climate change impact increasingly led to humanitarian assistance increase and needed. To better address climate change impacts mitigation, a suitable financing instrument is essential to facilitate government, humanitarian, and other stakeholders' finance mobilization. However, few studies have been done on disaster risk profiling to guide decision-makers in their choices. Disaster risk profile analysis has been conducted in Mali to facilitate financial resources mobilization and climate finance instrument choice by identifying Historical drought and flood events. To do so, published papers; and some international institution websites dealing with climate hazard events such as Reliefweb, Hazard/risk, climate information services, Relief Web; CRED- EM-DAT; World Bank Climate Knowledge Portal, World Bank- UNDRR -ThinkHazard, WFP ARC/GeoNode/VAM/DataViz addressing Mali country have been assimilated for evidence accumulation and synthesis and presented in a database. Furthermore, national statistics and national reports on hazards have been also reviewed. Before starting the reading exercise, a reading/analytical framework has been elaborated. In Mali the year 1984 to 2019, 21 flood events occurred in Mali and the most exposed regions to floods are Koulikoro, Bamako and Gao. From 1969 to 2020, 21 drought events were registered in in Mali and the most affected regions are Koulikoro, Mopti, Gao, Kayes. The time return period of drought has been estimated to 3 years while the time return of flood has been estimated to be about 2 years. Drought events are less frequent than flood events, however, drought events affect more population than floods. Also, Also, the yearly response cost for drought events is USD million 277.46 with an average US USD 204.37 cost per affected population. For the flood, even the yearly response cost is USD 11.107 million With USD 261.82 per affected population. Macro-insurance and CAT bonds are more suitable disaster risk financing instruments and are recommended to better address drought events while Anticipatory action and government contingency funds are more suitable climate disaster risk financing instruments to better address flood events in Mali.

Efectividad de las políticas públicas en los servicios de seguridad pública por vídeo digital

The objective is to analyze the effectiveness of public policies of citizen security services, in the categories of public policies and citizen security through digital video. The research is basic and qualitative, the design is phenomenological, an interview was applied, the sample is 10 workers and 30 from the population of Andahuaylas, to carry out an internal and external study. The results revealed that there is importance on the part of the municipality to address citizen security challenges with collaboration, exchange of knowledge, service channels were identified and the use of digital video is evident as a key tool, however, there is a lack of knowledge of the population.

Assessing the causal association between sleep apnea and the human gut microbiome composition: A two-sample Mendelian randomization study.

Studies have linked gut microbiota dysbiosis with sleep apnea; however, no causal relationship was found in human subjects. Finding new targets for the pathophysiology of sleep apnea might be made possible by systematically investigating the causal relationship between the human gut microbiota and sleep apnea. A two-sample Mendelian randomization analysis was conducted. The human gut microbiome composition data, spanning five taxonomic levels, were acquired from a genome-wide association study that included 18,340 participants from 24 cohorts. Genome-wide association study data for sleep apnea were obtained from the Sleep Disorder Knowledge Portal for primary analysis and the FinnGen consortium for meta-analysis. Sensitivity analyses were conducted to evaluate heterogeneity and pleiotropy. Using inverse-variance weighted analysis, eight microbial taxa were initially found to be substantially linked with the apnea-hypopnea index. Only three microbial taxa remained significant associations with sleep apnea when combined with the FinnGen consortium (the class Bacilli: B = 8.21%, 95% CI = 0.93%-15.49%; p = 0.03; the order Lactobacillales: B = 7.55%, 95% CI = 0.25%-4.85%; p = 0.04; the genus RuminococcaceaeUCG009: B = -21.63%, 95% CI = -41.47% to -1.80%; p = 0.03). Sleep apnea may lead to gut dysbiosis as significant reductions in butyrate-producing bacteria and increases in lactate-producing bacteria. By integrating genomes and metabolism, the evidence that three microbiome species are causally linked to sleep apnea may offer a fresh perspective on the underlying mechanisms of the condition.

The relationship between autoimmune disorders and intracranial aneurysms in East Asian and European populations: a bidirectional and multivariable two-sample Mendelian randomization study.

It remains unclear about the pathogenesis of intracranial aneurysms (IAs) in the setting of autoimmune disorders (ADs). However, the underlying systemic inflammatory characteristics of ADs may affect IAs through shared inflammatory pathways. Therefore, this study was conducted to explore the relationship between ADs and IAs and assess causal effects. In this study, 6 common ADs were included to explore their causal relationship with IAs. Besides, a bidirectional two-sample univariable Mendelian randomization (UVMR) analysis was performed. In addition, the primary analysis was performed by the inverse variance weighted (IVW) and Bayesian weighted Mendelian randomization (BWMR) method, and a series of sensitivity analyses were performed to assess the robustness of the results. Further, the data related to ADs and IAs were collected from open genome-wide association study studies (GWASs) and the Cerebrovascular Disease Knowledge Portal (CDKP) (including 11,084 cases and 311,458 controls), respectively. These analyses were conducted based on both the East Asian and European populations. Moreover, 6 ADs were subject to grouping according to connective tissue disease, inflammatory bowel disease, and thyroid disease. On that basis, a multivariate MR (MVMR1) analysis was further performed to explore the independent causal relationship between each AD and IAs, and an MVMR 2 analysis was conducted to investigate such potential confounders as smoking, alcohol consumption, and systolic blood pressure. Finally, these results were verified based on the data from another GWAS of IAs. The UVMR analysis results demonstrated that systemic lupus erythematosus (SLE) was associated with a high risk of IAs in the East Asian population (IVW OR, 1.06; 95%CI, 1.02-1.11; p = 0.0065, UVMR), which was supported by the results of BWMR (OR, 1.06; 95%CI, 1.02-1.11; p = 0.0067, BWMR), MVMR1 (OR, 1.06; 95%CI, 1.01-1.10; p = 0.015, MVMR1), MVMR2 (OR, 1.05; 95%CI, 1.00-1.11; p = 0.049, MVMR2), and sensitivity analyses. The results in the validation group also suggested a causal relationship between SLE and IAs (IVW OR, 1.04; 95% CI, 1.00-1.09; p = 0.046). The reverse MR analysis results did not reveal a causal relationship between IAs and ADs. In this MR study, SLE was validated to be a risk factor for IAs in the East Asian population. Therefore, the management of IAs in patients with SLE should be highlighted to avoid stroke events.

PotatoG-DKB: a potato gene-disease knowledge base mined from biological literature.

Potato is the fourth largest food crop in the world, but potato cultivation faces serious threats from various diseases and pests. Despite significant advancements in research on potato disease resistance, these findings are scattered across numerous publications. For researchers, obtaining relevant knowledge by reading and organizing a large body of literature is a time-consuming and labor-intensive process. Therefore, systematically extracting and organizing the relationships between potato genes and diseases from the literature to establish a potato gene-disease knowledge base is particularly important. Unfortunately, there is currently no such gene-disease knowledge base available. In this study, we constructed a Potato Gene-Disease Knowledge Base (PotatoG-DKB) using natural language processing techniques and large language models. We used PubMed as the data source and obtained 2,906 article abstracts related to potato biology, extracted entities and relationships between potato genes and related disease, and stored them in a Neo4j database. Using web technology, we also constructed the Potato Gene-Disease Knowledge Portal (PotatoG-DKP), an interactive visualization platform. PotatoG-DKB encompasses 22 entity types (such as genes, diseases, species, etc.) of 5,206 nodes and 9,443 edges between entities (for example, gene-disease, pathogen-disease, etc.). PotatoG-DKP can intuitively display associative relationships extracted from literature and is a powerful assistant for potato biologists and breeders to understand potato pathogenesis and disease resistance. More details about PotatoG-DKP can be obtained at https://www.potatogd.com.cn/.

SECONDARY USE OF NIH AD/ADRD DATA RESOURCES FOR BIOMEDICAL RESEARCH

Abstract People are living longer than ever before, and the world’s population aged 60 and older is expected to increase from 1 billion to 2.1 billion by 2050. As populations get older, they become more susceptible to age-related diseases such as Alzheimer’s Disease and Related Dementias (AD/ADRD), which affects more than 55 million individuals worldwide. The National Institutes of Health (NIH) aims to prevent and treat diseases such as AD/ADRD through generalist and disease-specific data resources that foster findable, interconnected, and interoperable data to accelerate biomedical innovations and medical interventions that improve human health. The goal of this assessment was to understand the value of AD/ADRD secondary data use from NIH genomic and multi-omics data resources: NIA Genetics of Alzheimer’s Disease Data Storage Site (NIAGADS), database of Genotypes and Phenotypes (dbGaP), AD Knowledge Portal (ADKP), and Gene Expression Omnibus (GEO). List of AD/ADRD datasets were retrieved through database searches or directly from repository staff (N=183). Citation frequency of data accessions were used to determine utilization of AD/ADRD genomic and multi-omics datasets in published literature. iSearch tool was used to assess secondary use drivers in resulting publications. Query of data accessions in Pubmed Central returned 284 unique publications. iSearch clustering by term showed that genomic datasets were used to study genetic risk factors of AD/ADRD while multi-omics datasets were used to functionally characterize genetic risk variants, identify gene regulatory networks, and biomarkers associated with neurodegenerative diseases. These findings indicate the usefulness of AD/ADRD secondary data to the scientific literature.

Dominant PDX1 deficiency causes highly penetrant diabetes at different ages, associated with obesity and exocrine pancreatic deficiency: Lessons for precision medicine

ObjectiveHeterozygous pathogenic or likely pathogenic (P/LP) PDX1 variants cause monogenic diabetes. We comprehensively examined the phenotypes of carriers of P/LP PDX1 variants, and delineated potential treatments that could be efficient in an objective of precision medicine. MethodsThe study primarily involved a family harboring a novel P/LP PDX1 variant. We then conducted an analysis of documented carriers of P/LP PDX1 variants, from the Human Gene Mutation Database (HGMD), RaDiO study, and Type 2 Diabetes Knowledge Portal (T2DKP) including 87 K participants. ResultsWithin the family, we identified a P/LP PDX1 variant encoding p.G232S in four relatives. All of them exhibited diabetes, albeit with very different ages of onset (10–40 years), along with caudal pancreatic agenesis and childhood-onset obesity. In the HGMD, 79 % of carriers of a P/LP PDX1 variant displayed diabetes (with differing ages of onset from eight days of life to 67 years), 63 % exhibited pancreatic insufficiency and surprisingly 40 % had obesity. The impact of P/LP PDX1 variants on increased risk of type 2 diabetes mellitus was confirmed in the T2DKP. Dipeptidyl peptidase 4 inhibitor (DPP4i) and glucagon-like peptide-1 receptor agonist (GLP1-RA), enabled good glucose control without hypoglycemia and weight management. ConclusionsThis study reveals diverse clinical presentations among the carriers of a P/LP PDX1 variant, highlighting strong variations in diabetes onset, and unexpectedly high prevalence of obesity and pancreatic development abnormalities. Clinical data suggest that DPP4i and GLP1-RA may be the best effective treatments to manage both glucose and weight controls, opening new avenue in precision diabetic medicine.

The AD Knowledge Portal: an open‐access platform for sharing data, tools, and results of aging and dementia research

AbstractBackgroundThe AD Knowledge Portal (https://adknowledgeportal.org) is a community‐driven resource developed to support transparent evaluation and broad use of resources generated within the translational research portfolio of the National Institute on Aging (NIA). This open access platform aims to accelerate Alzheimer’s disease (AD) research and maximize therapeutic discovery through sharing and re‐use of data in adherence with FAIR (Findable, Accessible, Interoperable, and Reproducible) principles. The AD Portal allows the AD research community to find curated and contextualized data, evaluate hypotheses via independent experiments, and prioritize new mechanisms for therapeutic development.MethodThe AD Portal empowers researchers to share multi‐omics human and non‐human data with appropriate attribution for re‐use, and in compliance with necessary data governance and ethical guardrails. This is accomplished through the use of the secure Synapse data sharing platform–an NIH‐supported generalist repository–and a user‐friendly data portal website.ResultThe AD Portal currently hosts resources from nine research consortia and more than 50 grants related to dementia and aging. Data from over 15,000 individuals and 30,000 specimens–encompassing central and peripheral samples from brain banks, longitudinal cohorts, and model systems–are available. While the organizing focus is aging and dementia, the provided data are generated through a broad array of modalities, including genomics, transcriptomics, epigenetics, imaging, immunoassays, mass spectrometry‐based proteomics and metabolomics, behavioral assays, and more. In addition to raw and processed data, portal users can explore open‐access experimental mouse models, computational tools, publications, and summarized evidence for putative AD targets via integrated results explorers.ConclusionThe AD Knowledge Portal offers the research community an accessible source of data, tools, and results for the study of AD and related dementias.

Single‐cell Transcriptomes Reveal Cell‐type Specific Roles of VEGF Family Genes in the Pathogenesis of Alzheimer’s Disease

AbstractBackgroundThe role of the vascular endothelial growth factors (VEGFs) in the pathogenesis of Alzheimer’s disease (AD) has been recently described, including notable changes along the VEGFB/FLT1 signaling pathway. Yet, cell‐specific alterations are not well characterized. To disentangle VEGFs’ cell‐specific effect on AD‐related traits, we performed association analyses of mRNA expression from 10 VEGF genes with cognitive performance and AD pathology in eight brain cell types using a large single nucleus RNA sequencing dataset from human brain.MethodThis project utilized recently published single‐cell transcriptomes derived from dorsolateral prefrontal cortex tissues of 424 donors collected at Rush Alzheimer’s Disease Center. Processed single cell RNA sequencing data were acquired from AD Knowledge Portal (syn2580853). Mean age at death was 89 years, 68% were females, and 37% were AD cases. Negative binomial lognormal mixed models implemented in the NEBULA R package were used to detect differential expression between AD cases and cognitively normal controls, and to analyze the associations with immunohistochemical amyloid and tangles, and finally to assess cross‐sectional and longitudinal global cognitive scores. Correction for multiple comparisons was completed using the false discovery rate procedure (Pfdr<0.05).ResultPrefrontal cortical FLT1 expression was upregulated in AD participants compared to cognitively normal controls in both endothelial (endo) and microglial (micro) cells. Higher micro‐FLT1, endo‐FLT4, and oligodendrocyte (oligo) VEGFB expression was associated with greater β‐amyloid burden in AD samples, whereas higher VEGFB expression in inhibitory neurons was associated with lower β‐amyloid burden. Higher expression of micro‐FLT1 and oligo‐VEGFB associated with worse cognitive trajectories. Higher micro‐ and endo‐ expression of FLT1 associated with lower cognition scores at the last clinic visit before death. Lastly, higher astrocyte‐expressed NRP1 was associated with lower tangle burden.ConclusionConsistent with our previously reported bulk tissue results, prefrontal cortical expression of FLT1 and FLT4 were associated with global cognition, longitudinal cognitive trajectories, and AD neuropathology, and these associations appear to be limited to endothelial and microglial cells. In contrast, VEGFB expression seems to have opposite effects on amyloid burden depending on the cell types, suggesting its more dynamic role in AD physiopathology.

Efforts toward discovering inhibitors of the SYK SH2–FCER1γ interaction as potential Alzheimer’s disease chemical probes and therapeutics

AbstractBackgroundSpleen associated tyrosine kinase (SYK) plays a potential role in several neurodegenerative conditions. To date, a few pharmacological inhibitors have been developed, targeting the ATP‐binding kinase domain, and some of these inhibitors have been reported to show beneficial effects on the pathophysiology of Alzheimer’s (PMC: 9179326).In 2015, the Accelerating Medicines Partnership: Alzheimer’s Disease (AMP‐AD) Knowledge Portal analyzed and identified SYK and the FC gamma receptor (FCεR1γ) as targets for Alzheimer’s Disease (AD), through multidimensional human “omic” (genomic, epigenomic, RNAseq, and proteomic) data (PMID: 26853544). Thus, the interaction between FCER1G p‐ITAM and SYK tandem SH2 domain was selected for further target validation and small molecule hit discovery efforts through the portfolio of novel targets to treat the Alzheimer’s disease via the Target Enablement to Accelerate Therapy Development for Alzheimer’s Disease (TREAT‐AD) program were initiated. As part of the TREAT‐AD effort, we aim to provide experimental validation of a SYK–FCεR1γ interaction inhibitor for AD and begin drug discovery campaigns to identify novel inhibitors of this interaction, with the goal of developing an in vivo chemical probe.MethodUsing purified SYK tandem‐SH2 (tSH2) domain protein, a time‐resolved fluorescence energy transfer (TR‐FRET) based assay platform was developed with a fluoroprobe‐labeled phospho‐ITAM peptide of FCεR1γ. This assay was miniaturized for ultra‐high‐throughput screening (uHTS) of 100K compounds in parallel with a DNA encoded library (DEL) screening approach (Ref: X‐Chem). The hits from these screening methods were evaluated in secondary assays in an attempt to validate the initial hits.ResultWe have previous crystallography data of the SYK tSH2 domains bound to phospho‐ITAM peptides and have established a TR‐FRET based assay to discover and characterize inhibitors of the interaction between the FCεR1γ peptide and SYK tSH2 domains. Several thio‐uric acids hit compounds have been identified from uHTS. Most of them demonstrate potency in the TR‐FRET based assay of <10 µM. Although, orthogonal experimental validation is still under process.ConclusionThrough the TREAT‐AD program, we have explored the SYK–FCεR1γ interaction and demonstrated novel screening strategies, which can be further exploited to generate novel inhibitors of this interaction.

Causal relationship between sleep traits and cognitive impairment: A Mendelian randomization study.

Observational studies had demonstrated a link between sleep disturbances and cognitive decline. Here, we aimed to investigate the causal association between genetically predicted sleep traits and cognitive impairment using Mendelian randomization (MR). Using strict criteria, we selected genetic variants from European ancestry Genome-wide association studies (GWAS) from the Sleep Disorders Knowledge Portal and UK Biobank as instrumental variables for several sleep traits, including insomnia, sleep duration, daytime sleepiness, daytime napping, and chronotype. Summary statistics related to cognitive impairment were derived from five different GWAS, including the Social Science Genetic Association Consortium. The role of self-reported sleep trait phenotypes in the etiology of cognitive impairment was explored using inverse-variance weighted (IVW) tests, MR-Egger tests, and weighted medians, and sensitivity analyses were conducted to ensure robustness. In the main IVW analysis, sleep duration (reaction time: β=-0.05, 95% CI -0.07 to -0.04, p=1.93×10-12 ), daytime sleepiness (average cortical thickness: β=-0.12, 95% CI -0.22 to -0.02, p=0.023), and daytime napping (fluid intelligence: β=-0.47, 95% CI -0.87 to -0.07, p=0.021; hippocampal volume in Alzheimer's disease: β=-0.99, 95% CI -1.64 to -0.35, p=0.002) were significantly negatively correlated with cognitive performance. However, any effects of insomnia and chronotype on cognitive impairment were not determined. Our findings highlighted that focusing on sleep behaviors or distinct sleep patterns-particularly sleep duration, daytime sleepiness, and daytime napping, was a promising approach for preventing cognitive impairment. This study also shed light on risk factors for and potential early markers of cognitive impairment risk factors.

Multimodal omics analytic framework identifies microglial immunometabolism endophenotypes underlying sex differences in Alzheimer’s disease

AbstractBackgroundAlthough Alzheimer’s disease (AD) is sexually dimorphic in prevalence, incidence, symptomology, and neuropathology, the molecular mechanisms underlying AD sex differences are incompletely understood.MethodIn this study, we investigated the interplay between cellular metabolism and immune responses (termed the “immunometabolism endophenotype”) by unique integration of single nuclei transcriptomics (snRNA‐seq) and metabolomics from the AD knowledge portal, the Alzheimer’s Disease Metabolomics Consortium, and the Cleveland Alzheimer’s Disease Research Center. We conduced pathway activity score (PAS) to investigate metabolic alteration in microglia and astrocytes from brain cortex, with PAS > 0 indicating a specific cell type with higher average gene expression within a pathway, relative to all remaining cell types.ResultWe found that female AD subjects had a reduced PAS score within the TNFR2 non‐canonical NF‐kB pathway in microglia compared to male AD subjects, indicating reduced anti‐inflammatory effects of microglia in women. In addition, women with AD also showed lower PAS score within the branched chain amino acid pathway. Integrative sc/snRNA‐seq data analysis also shows sex‐specific metabolic cell‐cell communications among microglia, astrocytes and neurons. For example, male AD subjects have higher metabolic communication between astrocytes and excitatory neurons. In particular, astrocytes show lower PAS distribution across 84 metabolic pathways in women with AD, compared to men with AD. Astrocytes in female AD subjects showed deceased PAS within creatine metabolism pathways and increased PAS within threonine catabolism pathways.ConclusionThis study demonstrates proof‐of‐concept of microglial immunometabolism underlying sex differences in AD.