Plasticity of Human Microglia and Brain Perivascular Macrophages in Aging and Alzheimer's Disease.

The complex roles of myeloid cells, including microglia and perivascular macrophages, are central to the neurobiology of Alzheimer's disease (AD), yet they remain incompletely understood. Here, we profiled 832,505 human myeloid cells from the prefrontal cortex of 1,607 unique donors covering the human lifespan and varying degrees of AD neuropathology. We delineated 13 transcriptionally distinct myeloid subtypes organized into 6 subclasses and identified AD-associated adaptive changes in myeloid cells over aging and disease progression.

Single-Cell Transcriptomics of Human Tonsils Reveals Nicotine Enhances HIV-1-Induced NLRP3 Inflammasome and Mitochondrial Activation.

Background: HIV-1 infection, even with effective antiretroviral therapy (ART), is associated with chronic inflammation and immune dysfunction, contributing to long-term health complications. Nicotine use, prevalent among people with HIV (PWH), is known to exacerbate immune activation and disease progression, but the precise biological mechanisms remain to be fully understood. This study sought to uncover the synergistic effects of HIV-1 infection and nicotine on immune cell function, focusing on beneficial insights into NLRP3 inflammasome activation, oxidative stress, and mitochondrial pathways.

Sex-specific role of high-fat diet and stress on behavior, energy metabolism, and the ventromedial hypothalamus.

Background: Scientific evidence highlights the influence of biological sex on the relationship between stress and metabolic dysfunctions. However, there is limited understanding of how diet and stress concurrently contribute to metabolic dysregulation in both males and females. Our study aimed to investigate the combined effects of high-fat diet (HFD) induced obesity and repeated stress on fear-related behaviors, metabolic, immune, and hypothalamic outcomes in male and female mice.

Single-Cell View of Tumor Microenvironment Gradients in Pleural Mesothelioma.

Immunotherapies have shown great promise in pleural mesothelioma (PM), yet most patients still do not achieve significant clinical response, highlighting the importance of improving the understanding of the tumor microenvironment (TME). Here, we utilized high-throughput, single-cell RNA sequencing (scRNA-seq) to de novo identify 54 expression programs and construct a comprehensive cellular catalog of the PM TME. We found four cancer-intrinsic programs associated with poor disease outcome and a novel fetal-like, endothelial cell population that likely responds to VEGF signaling and promotes angiogenesis.

A master regulator of opioid reward in the ventral prefrontal cortex.

In addition to their intrinsic rewarding properties, opioids can also evoke aversive reactions that protect against misuse. Cellular mechanisms that govern the interplay between opioid reward and aversion are poorly understood. We used whole-brain activity mapping in mice to show that neurons in the dorsal peduncular nucleus (DPn) are highly responsive to the opioid oxycodone.

Single-cell transcriptomic-informed deconvolution of bulk data identifies immune checkpoint blockade resistance in urothelial cancer.

Interactions within the tumor microenvironment (TME) significantly influence tumor progression and treatment responses. While single-cell RNA sequencing (scRNA-seq) and spatial genomics facilitate TME exploration, many clinical cohorts are assessed at the bulk tissue level. Integrating scRNA-seq and bulk tissue RNA-seq data through computational deconvolution is essential for obtaining clinically relevant insights.

High-Resolution Profiling of Human Vocal Fold Cellular Landscapes With Single-Nuclei RNA Sequencing.

Introduction: The function of the vocal folds (VFs) is determined by the phenotype, abundance, and distribution of differentiated cells within specific microenvironments. Identifying this histologic framework is crucial in understanding laryngeal disease. A paucity of studies investigating VF cellular heterogeneity has been undertaken.

Molecular profiling of human substantia nigra identifies diverse neuron types associated with vulnerability in Parkinson's disease.

Parkinson's disease (PD) is characterized pathologically by the loss of dopaminergic (DA) neurons in the substantia nigra (SN). Whether cell types beyond DA neurons in the SN show vulnerability in PD remains unclear. Through transcriptomic profiling of 315,867 high-quality single nuclei in the SN from individuals with and without PD, we identified cell clusters representing various neuron types, glia, endothelial cells, pericytes, fibroblasts, and T cells and investigated cell type-dependent alterations in gene expression in PD.

Sexually dimorphic role of diet and stress on behavior, energy metabolism, and the ventromedial hypothalamus.

Scientific evidence underscores the influence of biological sex on the interplay between stress and metabolic dysfunctions. However, there is limited understanding of how diet and stress jointly contribute to metabolic dysregulation in both males and females. To address this gap, our study aimed to investigate the combined effects of a high-fat diet (HFD) and repeated footshock stress on fear-related behaviors and metabolic outcomes in male and female mice.

Nuclear RNA catabolism controls endogenous retroviruses, gene expression asymmetry, and dedifferentiation.

Endogenous retroviruses (ERVs) are remnants of ancient parasitic infections and comprise sizable portions of most genomes. Although epigenetic mechanisms silence most ERVs by generating a repressive environment that prevents their expression (heterochromatin), little is known about mechanisms silencing ERVs residing in open regions of the genome (euchromatin). This is particularly important during embryonic development, where induction and repression of distinct classes of ERVs occur in short temporal windows.

Spinal cord injury regulates circular RNA expression in axons.

Introduction: Neurons transport mRNA and translational machinery to axons for local translation. After spinal cord injury (SCI), translation is assumed to enable neurorepair. Knowledge of the identity of axonal mRNAs that participate in neurorepair after SCI is limited.

MacroH2A restricts inflammatory gene expression in melanoma cancer-associated fibroblasts by coordinating chromatin looping.

MacroH2A has established tumour suppressive functions in melanoma and other cancers, but an unappreciated role in the tumour microenvironment. Using an autochthonous, immunocompetent mouse model of melanoma, we demonstrate that mice devoid of macroH2A variants exhibit increased tumour burden compared with wild-type counterparts. MacroH2A-deficient tumours accumulate immunosuppressive monocytes and are depleted of functional cytotoxic T cells, characteristics consistent with a compromised anti-tumour response.

HIV-1 activates oxidative phosphorylation in infected CD4 T cells in a human tonsil explant model.

Introduction: Human immunodeficiency virus type 1 (HIV-1) causes a chronic, incurable infection leading to immune activation and chronic inflammation in people with HIV-1 (PWH), even with virologic suppression on antiretroviral therapy (ART). The role of lymphoid structures as reservoirs for viral latency and immune activation has been implicated in chronic inflammation mechanisms. Still, the specific transcriptomic changes induced by HIV-1 infection in different cell types within lymphoid tissue remain unexplored.

A distal lung organoid model to study interstitial lung disease, viral infection and human lung development.

Organoids have been an exciting advancement in stem cell research. Here we describe a strategy for directed differentiation of human pluripotent stem cells into distal lung organoids. This protocol recapitulates lung development by sequentially specifying human pluripotent stem cells to definitive endoderm, anterior foregut endoderm, ventral anterior foregut endoderm, lung bud organoids and finally lung organoids.

Integration of Single-Cell Transcriptomics With a High Throughput Functional Screening Assay to Resolve Cell Type, Growth Kinetics, and Stemness Heterogeneity Within the Comma-1D Cell Line.

Cell lines are one of the most frequently implemented model systems in life sciences research as they provide reproducible high throughput testing. Differentiation of cell cultures varies by line and, in some cases, can result in functional modifications within a population. Although research is increasingly dependent on these model systems, the heterogeneity within cell lines has not been thoroughly investigated.

The Breast Cancer Single-Cell Atlas: Defining cellular heterogeneity within model cell lines and primary tumors to inform disease subtype, stemness, and treatment options.

Purpose: Breast Cancer (BC) is the most diagnosed cancer in women; however, through significant research, relative survival rates have significantly improved. Despite progress, there remains a gap in our understanding of BC subtypes and personalized treatments. This manuscript characterized cellular heterogeneity in BC cell lines through scRNAseq to resolve variability in subtyping, disease modeling potential, and therapeutic targeting predictions.

An atlas of late prenatal human neurodevelopment resolved by single-nucleus transcriptomics.

Late prenatal development of the human neocortex encompasses a critical period of gliogenesis and cortical expansion. However, systematic single-cell analyses to resolve cellular diversity and gliogenic lineages of the third trimester are lacking. Here, we present a comprehensive single-nucleus RNA sequencing atlas of over 200,000 nuclei derived from the proliferative germinal matrix and laminating cortical plate of 15 prenatal, non-pathological postmortem samples from 17 to 41 gestational weeks, and 3 adult controls.

Hedgehog-interacting protein acts in the habenula to regulate nicotine intake.

Hedgehog-interacting protein (HHIP) sequesters Hedgehog ligands to repress Smoothened (SMO)-mediated recruitment of the GLI family of transcription factors. Allelic variation in HHIP confers risk of chronic obstructive pulmonary disease and other smoking-related lung diseases, but underlying mechanisms are unclear. Using single-cell and cell-type-specific translational profiling, we show that HHIP expression is highly enriched in medial habenula (MHb) neurons, particularly MHb cholinergic neurons that regulate aversive behavioral responses to nicotine.

High-resolution transcriptomics informs glial pathology in human temporal lobe epilepsy.

The pathophysiology of epilepsy underlies a complex network dysfunction between neurons and glia, the molecular cell type-specific contributions of which remain poorly defined in the human disease. In this study, we validated a method that simultaneously isolates neuronal (NEUN +), astrocyte (PAX6 + NEUN-), and oligodendroglial progenitor (OPC) (OLIG2 + NEUN-) enriched nuclei populations from non-diseased, fresh-frozen human neocortex and then applied it to characterize the distinct transcriptomes of such populations isolated from electrode-mapped temporal lobe epilepsy (TLE) surgical samples. Nuclear RNA-seq confirmed cell type specificity and informed both common and distinct pathways associated with TLE in astrocytes, OPCs, and neurons.

NKG2A and HLA-E define an alternative immune checkpoint axis in bladder cancer.

Programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1)-blockade immunotherapies have limited efficacy in the treatment of bladder cancer. Here, we show that NKG2A associates with improved survival and responsiveness to PD-L1 blockade immunotherapy in bladder tumors that have high abundance of CD8 T cells. In bladder tumors, NKG2A is acquired on CD8 T cells later than PD-1 as well as other well-established immune checkpoints.