Functional Interpretation Research Articles

Computational analysis of peripheral blood RNA sequencing data unravels disrupted immune patterns in Alzheimer's disease.

The central nervous system (CNS) and the immune system collectively coordinate cellular functionalities, sharing common developmental mechanisms. Immunity-related molecules exert an influence on brain development, challenging the conventional view of the brain as immune-privileged. Chronic inflammation emerges as a key player in the pathophysiology of Alzheimer's disease (AD), with increased stress contributing to the disease progression and potentially exacerbating existing symptoms. In this study, the most significant gene signatures from selected RNA-sequencing (RNA-seq) data from AD patients and healthy individuals were obtained and a functional analysis and biological interpretation was conducted, including network and pathway enrichment analysis. Important evidence was reported, such as enrichment in immune system responses and antigen processes, as well as positive regulation of T-cell mediated cytotoxicity and endogenous and exogenous peptide antigen, thus indicating neuroinflammation and immune response participation in disease progression. These findings suggest a disturbance in the immune infiltration of the peripheral immune environment, providing new challenges to explore key biological processes from a molecular perspective that strongly participate in AD development.

Pravne dileme u vezi s načinima zaključenja ugovora o osiguranju na daljinu - putem mobilne aplikacije i internet prezentacije

In this paper, the author states that there are two dilemmas in practice regarding the conclusion of distance insurance contracts via mobile applications and websites as a remote communication means. The first dilemma refers to the use of a double authentication as a method of concluding distance insurance contracts, while the second one concerns the permissibility of using the insurance premium payment as a method of concluding distance contracts. The author deals with both dilemmas with a functional and systemic interpretation of the provisions of the Law on the Protection of Financial Service Users in Distance Contracts and the Law of Contracts and Torts. The author concludes that a deviation from the written form of a contract is permitted, in the sense that a policyholder's double authentication is sufficient for the conclusion of a contract, and that a qualified electronic signature of the other contracting party is not required when the contract is concluded via a mobile application and a website of an insurer or a distributor. In addition, the author concludes that the insurance premium payment is an adequate method of concluding a distance contract. Finally, the author tries to provide criteria for establishing the relation between concluding a distance contract via a double authentication and the premium payment, noting that these two methods are not mutually exclusive, but complement each other.

Parallel DNA/RNA NGS Using an Identical Target Enrichment Panel in the Analysis of Hereditary Cancer Predisposition.

Germline DNA testing using the next-gene-ration sequencing (NGS) technology has become the analytical standard for the diagnostics of hereditary diseases, including cancer. Its increasing use places high demands on correct sample identification, independent confirmation of prioritized variants, and their functional and clinical interpretation. To streamline these processes, we introduced parallel DNA and RNA capture-based NGS using identical capture panel CZECANCA, which is routinely used for DNA analysis of hereditary cancer predisposition. Here, we present the analytical workflow for RNA sample processing and its analytical and diagnostic performance. Parallel DNA/RNA analysis allowed credible sample identification by calculating the kinship coefficient. The RNA capture-based approach enriched transcriptional targets for the majority of clinically relevant cancer predisposition genes to a degree that allowed analysis of the effect of identified DNA variants on mRNA processing. By comparing the panel and whole-exome RNA enrichment, we demonstrated that the tissue-specific gene expression pattern is independent of the capture panel. Moreover, technical replicates confirmed high reproducibility of the tested RNA analysis. We concluded that parallel DNA/RNA NGS using the identical gene panel is a robust and cost-effective diagnostic strategy. In our setting, it allows routine analysis of 48 DNA/RNA pairs using NextSeq 500/550 Mid Output Kit v2.5 (150 cycles) in a single run with sufficient coverage to analyse 226 cancer predisposition and candidate ge-nes. This approach can replace laborious Sanger confirmatory sequencing, increase testing turnaround, reduce analysis costs, and improve interpretation of the impact of variants by analysing their effect on mRNA processing.

Systematic profiling of mitochondria-related transcriptome in tumorigenesis, prognosis, and tumor immune microenvironment of intrahepatic cholangiocarcinoma: a multi-center cohort study.

Mitochondrial dysfunction has been shown to play a critical role in cancer biology. However, its involvement in intrahepatic cholangiocarcinoma (iCCA) remains significantly understudied. RNA sequencing data of 30 pairs of iCCA and paracancerous tissues were collected from the First Affiliated Hospital of Wenzhou Medical University (WMU). The WMU cohort (n = 30) was integrated with public TCGA (n = 30) and GSE107943 (n = 30) datasets to establish a multi-center iCCA cohort. We merged the TCGA and GSE107943 cohorts into an exploration cohort to develop a mitochondria signature for prognosis assessment, and utilized the WMU cohort for external validation. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Hallmarker analyses were used for functional interpretation of iCCA associated mitochondria-related genes (MRGs). In addition, unsupervised clustering was performed to identify mitochondria-based iCCA subtypes with the data of three institutions. Further investigations were conducted to examine the impact of mitochondrial dysfunction on drug responses, alteration of the tumor immune microenvironment, and immune responses. Two hundred and sixty-three iCCA-related MRGs were identified to be related to fatty acid metabolism, oxidative phosphorylation, and apoptosis. Through univariate and multivariate Cox, and LASSO analyses, a mitochondria signature with five optimal MRGs was established to evaluate the prognosis of iCCA patients with the AUC values ranged from 0.785 to 0.928 in the exploration cohort. The signature also exhibited satisfactory performance in the WMU cohort with AUC values of 0.817-0.871, and was identified as an independent risk predictor in both cohorts. Additionally, we found that patients with higher mitochondria score with poor prognosis presented lower infiltration levels of CD4+ T-cell, NK cells, and monocytes, and demonstrated higher sensitivity to targeted therapies, including sorafenib. Furthermore, two distant mitochondria-based subtypes were determined, and subtype 2 was associated with shorter survival time and immunosuppressive tumor microenvironment. Finally, the differential protein expression of five key MRGs was verified by Immunohistochemistry. We found mitochondrial dysfunction modulates aberrant metabolism, oxidative stress, immune responses, apoptosis, and drug sensitivity in iCCA. A mitochondria signature and two mitochondria-based iCCA subtypes were identified for clinical risk stratification and immunophenotyping.

A New Finding Relating Subatomic Particles' Mass to the Square of the Magnetic Flux Quantum Provides a Novel Interpretation of the Mass and a Novel Wave Function Interpretation

A New Finding Relating Subatomic Particles' Mass to the Square of the Magnetic Flux Quantum Provides a Novel Interpretation of the Mass and a Novel Wave Function Interpretation

Retinal microglia and ganglion cells in a cuprizone (CPZ) induced mouse model of multiple sclerosis (MS)

Aims/Purpose: Up to 90% of MS patients have ocular manifestations. Activated microglia (mg) are associated with age and diseases like MS. Mg change their activation states (ramified, hyper‐ramified, activated, amoeboid and rod) in response to stimuli, to exert either neuro‐protective or ‐toxic effects, leading to the rescue or loss of neurons. Here, we characterize retinal ganglion cell (RGC) densities and retinal mg morphotype proportions in eyes of a CPZ induced MS model and age‐matched controls.Methods: Male C57 mice were fed CPZ (0.2%w/w) mixed chow for 4 months (m) until sacrificed at 6 m (6mCPZ) or 28 m (28mCPZ) old. Age‐matched controls (6mCtrl; 28mCtrl) were fed normal chow. Enucleated eyes were fixed in 4% PFA. Whole retinas were dissected, stained (RBPMS+RGCs; iba‐1+mg), mounted and imaged. A published retinal mg morphotyping algorithm and an automated RBPMS counting script were used. Two‐way ANOVA with paired analysis (PA) was used (mg n: 6mCtrl = 15; 6mCPZ = 7; 28mCtrl = 7; 28mCPZ = 10; and RGC n: 6mCtrl = 4; 6mCPZ = 3; 28mCtrl = 3; 28mCPZ = 4).Results: There was a main effect of age for activated (p = 0.0282) and rod (p < 0.0001), and disease state for rod (p = 0.04) mg. PA showed higher activated mg in 28mCtrl versus 6mCtrl (p = 0.0485), and lower rod mg in 28mCtrl versus 6mCtrl (p = 0.0374) and in 28mCPZ versus 6mCPZ (p = 0.0007). There was a main effect of age (p = 0.0001) and disease state (p = 0.04) on RBPMS density. PA showed lower RGC density in 28mCtrl versus 6mCtrl (p = 0.0025) and in 28mCPZ versus 6mCPZ (p = 0.025).Conclusions: Our results show that there is age‐related loss of rod mg and RGCs in healthy and CPZ groups, supporting reports that rod mg are involved in protecting less damaged neurons. Age‐related increased activated mg may cause RGC loss as transcription factors like TNFα, bind to RGC receptors, inducing apoptosis. Further transcriptomic analysis may clarify functional interpretations.

HMZDupFinder: a robust computational approach for detecting intragenic homozygous duplications from exome sequencing data.

Homozygous duplications contribute to genetic disease by altering gene dosage or disrupting gene regulation and can be more deleterious to organismal biology than heterozygous duplications. Intragenic exonic duplications can result in loss-of-function (LoF) or gain-of-function (GoF) alleles that when homozygosed, i.e. brought to homozygous state at a locus by identity by descent or state, could potentially result in autosomal recessive (AR) rare disease traits. However, the detection and functional interpretation of homozygous duplications from exome sequencing data remains a challenge. We developed a framework algorithm, HMZDupFinder, that is designed to detect exonic homozygous duplications from exome sequencing (ES) data. The HMZDupFinder algorithm can efficiently process large datasets and accurately identifies small intragenic duplications, including those associated with rare disease traits. HMZDupFinder called 965 homozygous duplications with three or less exons from 8,707 ES with a recall rate of 70.9% and a precision of 16.1%. We experimentally confirmed 8/10 rare homozygous duplications. Pathogenicity assessment of these copy number variantalleles allowed clinical genomics contextualization for three homozygous duplications alleles, including two affecting known OMIM disease genes EDAR (MIM# 224900), TNNT1(MIM# 605355), and one variant in a novel candidate disease gene: PAAF1.

From art to evolution: Why functional morphology of birds matters

Here we discuss the main stages in the study of the morphology of the avian hind limbs as an example of the historical development of morphological studies in biology: from illustrations at the level of a work of art, through the collection of anatomical material and its functional interpretation to the reconstruction of hypothetical and real forms. We provide a synopsis of original studies, describing the stages in the evolution of jacanas and trogons, as well as the key locomotor adaptation of passerine birds. Reconstructions of the soft tissues and ligaments of the hind limbs of the Hesperornis, moa, and Haast’s eagle make it possible to judge the peculiarities of locomotion in extinct species.

Comparative Thematic Analysis of Social Science Research Articles by Pakistani and British Research Scholars: A Corpus-Based Study

Writers maintain the texture of the text and information with appropriate thematic choices. Previous studies have established that the problem of jumbled information existed in the academic writings of non-native English writers. Considering this, the present study aimed to analyze social science research articles written by Pakistani and British researchers keeping textual metafunction as the focal point. The objectives were to explain the functional interpretation of the thematic structures and figure out the dominant theme type in collected 160 research articles. The data was analyzed through feature coding of UAM corpus software to find out frequencies and percentages of themes and their types. The results revealed that the frequencies of themes in Pak-19 and Pak-20 were 1066 and 1252, while the frequencies in Bri-19 and Bri-20 were 1519 and 1883. Further, the findings suggested that the topical theme was frequently used as compared to textual and interpersonal themes. The second highest ratio was of textual theme as the frequencies of interpersonal theme were less as compared to textual. The topical themes functioned as noun groups, while the textual themes connected new information with previous information. Based on the findings, it was established that unmarked topical themes were prevailing in the research articles. Further, the use of finite, continuatives, and conjunctions was prevalent in textual themes.

The human brain connectome weighted by the myelin content and total intra-axonal cross-sectional area of white matter tracts.

A central goal in neuroscience is the development of a comprehensive mapping between structural and functional brain features, which facilitates mechanistic interpretation of brain function. However, the interpretability of structure-function brain models remains limited by a lack of biological detail. Here, we characterize human structural brain networks weighted by multiple white matter microstructural features including total intra-axonal cross-sectional area and myelin content. We report edge-weight-dependent spatial distributions, variance, small-worldness, rich club, hubs, as well as relationships with function, edge length, and myelin. Contrasting networks weighted by the total intra-axonal cross-sectional area and myelin content of white matter tracts, we find opposite relationships with functional connectivity, an edge-length-independent inverse relationship with each other, and the lack of a canonical rich club in myelin-weighted networks. When controlling for edge length, networks weighted by either fractional anisotropy, radial diffusivity, or neurite density show no relationship with whole-brain functional connectivity. We conclude that the co-utilization of structural networks weighted by total intra-axonal cross-sectional area and myelin content could improve our understanding of the mechanisms mediating the structure-function brain relationship.

Sorption kinetics of heavy metals from aqueous solution using Spirogyra sp.: a microcosm study

Understanding the mechanisms by which algae communities respond to disturbances in the lotic aquatic environment that is polluted by heavy metals is important, considering that algae is a biotic component of waters that acts as a producer in the aquatic food chain which has the potential to bio-magnify. This study examines the influence of time, biomass weight, heavy metal concentration, sorption capacity, and efficient removal on epilithic periphyton as a bio-accumulator of Cr, Pb, and Ni. The experiment was conducted on a laboratory scale using a canal system with a length and width of 1.2 and 1.0 meters, respectively. The canal system contains 132 L of water, has a 1.2 m2 substrate and periphyton area, a depth of 0.09 – 0.10 m, and a current flow rate of 0.04 – 0.06 m/s. The dissolved Cr6+ initial concentration in the medium was 1.64 mg/L, Pb2+ and Ni2+ concentrations were 1.4 mg/L, and the adsorption process was studied for 24 hours. Based on microscope observations and functional group interpretation utilizing infrared spectra (FTIR), the periphyton community is dominated by Spirogyra sp., which has hydroxyl (O-H), carboxyl (C-H), and carbonyl (C-C and C=O) functional groups with the ability to binding heavy metals. The remaining quantities of Cr, Pb, and Ni in water were 0.43 mg/L (removal 69.29%), 0.05 mg/L (96.43% removal), and 0.03 mg/L (97.86% removal). Periphyton has a maximal sorption capacity of 1.019 mg Cr/g, 1.97 mg Pb/g, and 1.92 mg Ni/g. The sorption kinetics of Cr, Pb, and Ni follow a pseudo-second-order model with k2 = 1.686 x 10-2 g/mg.min for Cr, 4.516 x 10-3 g/mg.min for Pb, and 2.259 x 10-2 g/mg.min for Ni, with R2 of 0.965 for Cr and 0.971 for Pb and 0.972 for Ni. Periphyton can potentially play a role as a bio-accumulator in lotic habitats, adsorbing Cr, Pb, and Ni ions, according to this study.

Insights about aliasing and spectral leakage when analyzing discrete-time finite viscoelastic functions

Material property viscoelastic inversion studies often rely on the continuous -time framework for Fourier analysis, which may not accurately represent real experimentally collected data. In this paper, we address the discrete and finite nature of viscoelastic functions obtained from experiments and discuss the impact of these characteristics on the frequency spectrum analysis. We derive equations for the Discrete-Time Fourier Transform (DTFT) of a discrete-finite stress relaxation signal corresponding to the relaxation of a generalized Maxwell model. Our analysis highlights the limitations of the traditional continuous -time framework in capturing the inherent features of real signals, which are discrete and finite in nature. This results in two phenomena: aliasing and spectral leakage. We present equations that consider these phenomena, allowing experimentalists to anticipate and account for aliasing and leakage when performing model fitting. The proposed discrete-finite approach provides a more accurate representation of real viscoelastic data, enabling researchers to make better-informed decisions in the analysis and interpretation of sample viscoelastic functions.

A review on the distribution of relaxation times analysis: A powerful tool for process identification of electrochemical systems

The Distribution of Relaxation Times (DRT) analysis gained considerable attention for its ability to reveal detailed information about complex electrochemical processes without requiring a priori knowledge. This review provides a comprehensive insight into different methods of the DRT analysis, their mathematical bases, and the latest approaches to acquiring and analyzing frequency and time domain data. The analysis is based on the deconvolution of frequency domain data into a distribution function of gains at (pre-specified) relaxation times in the time domain, which improves the spectral resolution and separability of electrochemical processes. It provides valuable information about different electrochemical processes on different time scales, making it particularly useful for the characterization of both materials and electrochemical systems. The DRT analysis can be applied to arbitrary spectra containing electromagnetic effects, resistive–capacitive processes, and solid-state diffusion. To enhance process identification, a post-processing step involving peak analysis with Gaussian or RQ-distribution peaks is presented and the assignment of peak patterns induced by distributed processes like solid-state diffusion is discussed. In addition, a step-by-step workflow for the DRT analysis is provided to guide researchers from data acquisition and validation techniques to calculation and interpretation of the distribution function.

Harnessing PROTAC technology to combat stress hormone receptor activation

Counteracting the overactivation of glucocorticoid receptors (GR) is an important therapeutic goal in stress-related psychiatry and beyond. The only clinically approved GR antagonist lacks selectivity and induces unwanted side effects. To complement existing tools of small-molecule-based inhibitors, we present a highly potent, catalytically-driven GR degrader, KH-103, based on proteolysis-targeting chimera technology. This selective degrader enables immediate and reversible GR depletion that is independent of genetic manipulation and circumvents transcriptional adaptations to inhibition. KH-103 achieves passive inhibition, preventing agonistic induction of gene expression, and significantly averts the GR’s genomic effects compared to two currently available inhibitors. Application in primary-neuron cultures revealed the dependency of a glucocorticoid-induced increase in spontaneous calcium activity on GR. Finally, we present a proof of concept for application in vivo. KH-103 opens opportunities for a more lucid interpretation of GR functions with translational potential.

Unsupervised deep frequency-channel attention factorization to non-linear feature extraction: A case study of identification and functional connectivity interpretation of Parkinson’s disease

In the realm of contemporary medical research, the extraction of pivotal attributes associated with Parkinson’s disease (PD) from intricate Magnetic Resonance Imaging (MRI) data characterized by multifaceted dimensions and non-linearity stands as a formidable challenge in the pursuit of realizing automated diagnostic support. To address this issue, an approach is introduced, denoted as the Deep Frequency-Channel Attention Factorization (Deep FCAF), designed to address the complexities inherent to the neurodegenerative ailment of Parkinson’s. The Deep FCAF amalgamates three key elements: (1) the inherent capacity for non-linear processing exhibited by neural networks, (2) the inherent capability of the attention mechanism to capture global interdependencies, and (3) the underpinning principles of tensor decomposition within the order of multi-dimensional data structures. The experiments conducted on the identification of PD underscore the efficacy of Deep FCAF in assimilating structural and non-linear factor matrices, consequently leading to an improved classification performance. Notably, the elucidation of functional connectivity based on the acquired factor matrices align with previous scholarly investigations. The mathematical formulations, derived from the MRI data, facilitate the measurement of the dynamic mechanisms inherent in the MRI data.

A proposed framework for a social-ecological traits database for studying and managing urban plants and assessing the potential of database development using Floras

Trait-based frameworks have received increased attention in biodiversity research for their capacity to streamline complex information for policy and management purposes. Such frameworks, however, are mostly developed for natural ecosystems, and social-ecological dynamics in urban ecosystems may present needs that are distinct from natural ecosystems. We proposed a framework for developing a social-ecological traits database for plant selection and spontaneous vegetation managementusing three major categories of social-ecologically relevant considerations: 1) Sustenance and maintenance effects; 2) Ecosystem service/disservice effects; and 3) Conservation and ecological-meaning effects. We further examined the potential of using the Flora of Taiwan and vascular plants of Taipei city parks as a case study for using Floras for database development, and compared the results with two global trait databases, TRY and GIFT. Issues in Flora data include: 1) systematic omission of horticultural species, 2) low species trait coverage, and 3) complexity in original data. TRY included more measurement-based traits imperative to functional interpretations; Flora had wider global coverage than TRY. GIFT was based on Floras, but included only functional traits and omitted traits of social importance identified in our framework. Information uniquely available in the Flora include information of local relevance (e.g. associated local landscapes and commonness/rarity within the region) and social aspects of ecosystem services (e.g., edibility and visual aesthetics). Maintenance considerations are lacking in all three databases. We suggest interdisciplinary collaboration to further advance the proposed social-ecological traits framework and database to enhance the functions and sustainability of urban green infrastructures.

Remains of fill and floor? contextual taphonomy in a semi-subterranean structure in the hyperarid coast of the Atacama Desert, Chile

Architectural features and shell-matrix sites are one of the most challenging records for archaeological interpretation, due to their intricate stratification and complex depositional paths. In the hyperarid coast of the Atacama Desert, hunter-gatherer-fisher developed standardized stone-built architectural features mostly built on or directly related to shell-matrix deposits during the Late Archaic period (5700 – 4000 cal. years B.P.). These structures have been usually interpreted as sedentary villages or long-term campsites. These functional interpretations are based primarily upon intrasite variability, lacking systematic site formation analysis and chronostratigraphy. As a response to concerns arising from limited interpretive approaches, we propose a detailed taphonomic study of bone assemblages from a stone-built funerary structure of the Zapatero site (∼25°S, Taltal, Chile). We recorded macroscopic taphonomic modification features on mammal and avian bone remains (n = 1776) from five stratigraphic units within the structure. Our results attest that despite some similarities between strata, key differences in overall proportions suggest different taphonomic pathways. This variability within the sample is interpreted as a re-deposition of bone refuse from previous occupations as structural filling, intentionally deposited previous to the abandonment of the structure, therefore not directly related to the occupation of the architectonic feature. Finally, we highlight the role that relatively simple zooarchaeological and taphonomical comparisons intra-site, might shed light on exceptional site formation processes on short timescales, emphasizing why we must consider this sort of data even in low relative abundances in order to interpret taphonomic history pathways and depositional practices.

Ownerless island and partial entanglement entropy in island phases

In the context of partial entanglement entropy (PEE), we study the entanglement structure of the island phases realized in several 2-dimensional holographic set-ups. From a pure quantum information perspective, the entanglement islands emerge from the self-encoding property of the system, which gives us new insights on the construction of the PEE and the physical interpretation of two-point functions of twist operators in island phases. With the contributions from the entanglement islands properly taken into account, we give a generalized prescription to construct PEE and balanced partial entanglement entropy (BPE). Here the ownerless island region, which lies inside the island \text{Is}(AB)Is(AB) of A\cup BA∪B but outside \text{Is}(A)\cup \text{Is}(B)Is(A)∪Is(B), plays a crucial role. Remarkably, we find that under different assignments for the ownerless island, we get different BPEs, which exactly correspond to different saddles of the entanglement wedge cross-section (EWCS) in the entanglement wedge of A\cup BA∪B. The assignments can be settled by choosing the one that minimizes the BPE. Furthermore, under this assignment we study the PEE and give a geometric picture for the PEE in holography, which is consistent with the geometric picture in the no-island phases.

Cerebrospinal fluid metabolome‐wide association study of Alzheimer’s disease provides insight into molecular pathways

AbstractBackgroundMany genetic risk variants have been identified for Alzheimer’s disease (AD), but their functional consequence on molecular pathways are unclear. Quantitative trait loci (QTL) studies help elucidate the functional effect of genetic variance on (neuro)biological processes. The understanding of AD mechanisms has been limited due to the relative inaccessibility of in vivo brain tissue and its surroundings. In this study, we integrated genetic and metabolomics cerebrospinal fluid (CSF) data, to understand how AD risk variants influence neurobiological processes.MethodWe performed a genome‐wide mQTL study on 5,543 CSF metabolite levels using data from 977 subjects (age 52.7±16.6 years, 63.8%female) from the Amsterdam Dementia Cohort (n = 487; 220 controls, 87 mild cognitive impairment, 180 AD‐type dementia) and the Utrecht cohort (n = 490 controls). We measured CSF metabolites with three platforms: GC‐TOF MS (primary metabolism, 393 metabolites), CSH‐QTOF MS/MS (complex lipids, 3,532 metabolites), and HILIC‐QTOF MS/MS (biogenic amines, 1,618 metabolites). Association signals between genetic variants and CSF metabolite levels were tested using linear regression, adjusted for principal components, age, sex and site (Amsterdam/Utrecht) using a Bonferroni‐corrected genome‐wide significance threshold (5.0e−8 /754 independent CSF signals = 6.0e−11). To identify metabolites with predicted CSF levels associated with AD, we integrated metabolite summary statistics with AD summary statistics (Kunkle et al., 2019; Bellenguez et al., 2022), using a metabolome‐wide association study (MWAS) approach (FUSION software).ResultWe identified 89 genome‐wide CSF mQTLs, including 89 independent loci for 62 CSF metabolite levels. Most mQTLs were biogenic amines (81), followed by mQTLs for the primary (5) metabolism and complex lipids (3) (Figure 1). MWAS results included 24 metabolite‐AD associations with P<0.05. The strongest associations included variants proximal to the CANX gene with unannotated CSF metabolite 1.09_397.32 (PBellenguez = 2.4e−6; PKunkle = 3.4e−3), and CCDC124 variants with 8.76_225.06 (PBellenguez = 2.9e−3; PKunkle = 2.8e−5) (Figure 2).ConclusionWe identified novel metabolite‐AD risk associations, including CANX and CCDC124 with unknown CSF metabolites. In future work we aim to identify these CSF metabolites using raw spectra and intensity data. This study shows that the multi‐modal integration of genetics with CSF metabolomics helps in the functional interpretation of genetic variance, and could therefore serve as useful approach for other brain‐related disorders.

Single cell multi‐omics implicates immune and vascular cells in Alzheimer’s etiology

AbstractBackgroundUnderstanding the genetic etiology of Alzheimer’s disease (AD) is critical to inform effective therapies but remains a challenge. Genetic heritability of late‐onset AD is ∼60‐80%, and genome‐wide association studies (GWAS) have uncovered dozens of noncoding single nucleotide polymorphisms (SNPs) that influence AD risk. Two challenges for the functional interpretation of AD genetic risk are (1) determining the cell types in which SNPs operate and (2) identifying the genes they dysregulate to drive AD pathogenesis. Single‐nucleus sequencing studies of human neurons, microglia, and other brain cell types have begun addressing these challenges. Yet, many AD risk SNPs remain unmapped. One possibility is that they are expressed in immunovascular brain cell types largely missed by current methods.MethodHere, we optimized Vessel Isolation and Nuclei Extraction for Sequencing (VINE‐seq) to capture multimodal gene expression and chromatin accessibility assays across all major brain cell types from 30 cognitively normal, MCI, and AD human prefrontal cortex samples.ResultWe discover early gene dysregulation in immune and vascular cell types along AD progression. We highlight the gene regulatory networks mediating this dysregulation and implicate processes associated with AD pathology and cognitive decline. Finally, we map noncoding AD risk variants to diverse immune and vascular cell types, thereby expanding our understanding of AD etiology.ConclusionDysfunction of diverse human brain immune and vascular cell types mediate the genetic risk for Alzheimer’s disease.