ACE inhibition increases Alzheimer's disease risk by promoting tau phosphorylation.

Reportedly, over 60% of individuals in the USA aged 65 or older take antihypertensive medications, making it crucial to evaluate their potential impact on dementia. Alzheimer's disease (AD), the most prevalent form of dementia, develops insidiously over decades, effectively precluding clinical trials of antihypertensive drug effects on AD risk. Through a triangulation approach integrating large-scale human genetics, population-based study, and rigorous experimental models, we identified that angiotensin-converting enzyme (ACE) inhibitors were associated with increased AD risk, with no significant associations observed for other antihypertensive classes, including angiotensin II receptor blockers and calcium channel blockers.

Tracking clonal dynamics of CD8 T cells and immune dysregulation in progression of systemic lupus erythematosus with nephritis.

The fluctuating nature of disease activity in systemic lupus erythematosus (SLE), alternating between flares and remissions, poses substantial challenges for its effective management. The use of current biomarkers for monitoring SLE is limited in clinical settings owing to insufficient comprehension of the complex immune involvement underlying the disease course. Here, therefore, we profiled peripheral blood mononuclear cells at both stable and exacerbation states (total of n = 19) from six patients with SLE and 32 healthy donors using integrated single-cell RNA and T cell receptor (TCR) sequencing.

ATG7 in innate immune cells is required for host defense against nontuberculous mycobacterial pulmonary infections.

Infections caused by nontuberculous mycobacteria, such as Mycobacterium avium and Mycobacteroides abscessus, are becoming increasingly prevalent, and rising antibiotic resistance poses a significant clinical challenge. However, the mechanisms by which the host defense system controls these infections remain poorly understood. Here we show that the autophagy-related protein ATG7 in innate immune cells plays an essential role in controlling nontuberculous mycobacterial infection and protecting lung tissue from pathological inflammation.

Germline genetic scores associated with cancer gene expression and immune responses across multiple cancer types.

Background: Cancer is a polygenic disease that involves the dysregulation of multiple biological events, including aberrant cell proliferation and evasion of immune responses, which collectively contribute to cancer development and progression. Although the polygenic risk score (PRS) has enabled assessment of the effects of cancer risk loci, the potential impact of other genetic variants with functional relevance to cancer biology remains largely unexplored.

Methods: We conducted a large-scale analysis of UK Biobank data, including 61,249 cancer cases and 254,203 controls of European ancestry across 16 cancer types.

Integrated analysis of COVID-19 multi-omics data for eQTLs reveals genetic mechanisms underlying disease severity.

The global pandemic caused by the SARS-CoV-2 virus provided an unprecedented opportunity to investigate genetic factors influencing the disease severity of the viral infection. Despite a plethora of recent research on both SARS-CoV-2 and COVID-19, few have taken a systems biology approach to address individual-level variation, especially based on non-European populations. Accordingly, we analyzed multi-omics data generated at three timepoints from 193 Korean COVID-19 patients with mild or severe symptoms, composed of whole genome sequencing, blood-based single-cell RNA-sequencing (2.

Spatial and genomic profiling of residual breast cancer after neoadjuvant chemotherapy unveil divergent fates for each breast cancer subtype.

Residual cancer burden (RCB) is a strong prognostic marker after neoadjuvant chemotherapy (NAC) in breast cancer (BC), yet some BCs defy their predicted outcomes. Using single-cell spatial transcriptomics and genomic profiling, we investigate mechanisms underlying divergent fates of BCs with high RCB across subtypes. In triple-negative BC (TNBC), CXCL9+ macrophage-CD8 T cell interactions via chemokines and interferon-gamma signaling promote favorable outcomes, while SPP1+ macrophage-cancer cell interactions driven by hypoxia signaling correlate with poor prognosis.

Polygenic overlap between subjective well-being and psychiatric disorders and cross-ancestry validation.

Subjective well-being (SWB) is important for understanding human behaviour and health. Although the connection between SWB and psychiatric disorders has been studied, common genetic mechanisms remain unclear. This study aimed to explore the genetic relationship between SWB and psychiatric disorders.

HISSTA: a human in situ single-cell transcriptome atlas.

Motivation: Spatial transcriptomics holds great promise for revolutionizing biology and medicine by providing gene expression profiles with spatial information. Until recently, spatial resolution has been limited, but advances in high-throughput in situ imaging technologies now offer new opportunities by covering thousands of genes at a single-cell or even subcellular resolution, necessitating databases dedicated to comprehensive coverage and analysis with user-friendly intefaces.

Results: We introduce the HISSTA database, which facilitates the archival and analysis of in situ transcriptome data at single-cell resolution from various human tissues.

Unraveling the immune-activated tumor microenvironment correlated with clinical response to atezolizumab plus bevacizumab in advanced HCC.

Background & Aims: Despite atezolizumab plus bevacizumab being a standard treatment for advanced hepatocellular carcinoma (HCC), a significant proportion of patients do not achieve durable benefit. This study aimed to identify predictive biomarkers for this therapy by investigating the role of immune activation within the tumor microenvironment (TME).

Methods: We characterized the intratumoral TME of patients with advanced HCC treated with atezolizumab plus bevacizumab using single cell transcriptomics on pretreatment tumor biopsies from 12 patients.

Asian diversity in human immune cells.

The relationships of human diversity with biomedical phenotypes are pervasive yet remain understudied, particularly in a single-cell genomics context. Here, we present the Asian Immune Diversity Atlas (AIDA), a multi-national single-cell RNA sequencing (scRNA-seq) healthy reference atlas of human immune cells. AIDA comprises 1,265,624 circulating immune cells from 619 donors, spanning 7 population groups across 5 Asian countries, and 6 controls.

Paradoxical Effect of Myosteatosis on the Immune Checkpoint Inhibitor Response in Metastatic Renal Cell Carcinoma.

Background: Treatment for metastatic renal cell carcinoma (mRCC) has shifted from tyrosine kinase inhibitor (TKI) therapy to immune checkpoint inhibitor (ICI)-based therapy, improving outcomes but with variable individual responses. This study investigated the prognostic implications of pretreatment low skeletal muscle mass (LSMM) and myosteatosis in patients with mRCC undergoing first-line ICI-based therapies, comparing outcomes between PD-1 inhibitor + CTLA-4 inhibitor and PD-1 inhibitor + TKI, incorporating single-cell RNA sequencing.

Methods: A retrospective analysis was performed on 90 patients with mRCC treated with ICI-based therapies between November 2019 and March 2023.

Molecular landscape of tumor-associated tissue-resident memory T cells in tumor microenvironment of hepatocellular carcinoma.

Background: Immunotherapy for liver cancer is used to rejuvenate tumor-infiltrating lymphocytes by modulating the immune microenvironment. Thus, early protective functions of T cell subtypes with tissue-specific residency have been studied in the tumor microenvironment (TME). We identified tumor-associated tissue-resident memory T (TA-T) cells in hepatocellular carcinoma (HCC) and characterized their molecular signatures.

Precision Oncology: A Global Perspective on Implementation and Policy Development.

Despite the acknowledged merits of precision oncology (PO) and its increasing global implementation, its full potential for advancing care and prevention remains unrealized. The benefits are currently accessible to only limited patient segments because of multifaceted barriers. Successful implementation hinges on various factors-scientific complexities not limited to technical, clinical, regulatory, economic, administrative, and health care policy-related challenges.

Association between genetically predicted leisure and social activities and cardiovascular disease and other health outcomes.

Participation in leisure and social activities (LSA) is associated with better health outcomes and lower mortality. Previous observational studies demonstrated a relationship between engagement in LSA and both mental and physical health. Although several studies examined the association between LSA and health outcomes, including cardiovascular disease, their possible causal relationship has not been studied.

Single-cell RNA sequencing of peripheral blood links cell-type-specific regulation of splicing to autoimmune and inflammatory diseases.

Alternative splicing contributes to complex traits, but whether this differs in trait-relevant cell types across diverse genetic ancestries is unclear. Here we describe cell-type-specific, sex-biased and ancestry-biased alternative splicing in ~1 M peripheral blood mononuclear cells from 474 healthy donors from the Asian Immune Diversity Atlas. We identify widespread sex-biased and ancestry-biased differential splicing, most of which is cell-type-specific.

Germline functional variants contribute to somatic mutation and outcomes in neuroblastoma.

Germline genetic context may play a significant role in the development and evolution of cancer, particularly in childhood cancers such as neuroblastoma. This study investigates the role of putatively functional germline variants in neuroblastoma, even if they do not directly increase disease risk. Our whole-exome sequencing analysis of 125 patients with neuroblastoma reveals a positive correlation between germline variant burden and somatic mutations.

Therapeutic single-cell landscape: methotrexate exacerbates interstitial lung disease by compromising the stemness of alveolar epithelial cells under systemic inflammation.

Background: Interstitial lung disease (ILD) poses a serious threat in patients with rheumatoid arthritis (RA). However, the impact of cornerstone drugs, including methotrexate (MTX) and TNF inhibitor, on RA-associated ILD (RA-ILD) remains controversial.

Methods: Using an SKG mouse model and single-cell transcriptomics, we investigated the effects of MTX and TNF blockade on ILD.

Single-cell analysis of human PBMCs in healthy and type 2 diabetes populations: dysregulated immune networks in type 2 diabetes unveiled through single-cell profiling.

Abnormalities in glucose metabolism that precede the onset of type 2 diabetes (T2D) activate immune cells, leading to elevated inflammatory factors and chronic inflammation. However, no single-cell RNA sequencing (scRNA-seq) studies have characterized the properties and networks of individual immune cells in T2D. Here, we analyzed peripheral blood mononuclear cells (PBMCs) from non-diabetes and T2D patients by scRNA-seq.