T-cell development

Chronically elevated levels of glucose are deleterious to pancreatic β cells and contribute to β cell dysfunction, which is characterized by decreased insulin production and a loss of β cell identity. The Krüppel-like transcription factor, Glis3 has previously been shown to positively regulate insulin transcription and mutations within the Glis3 locus have been associated with the development of several pathologies including type 2 diabetes mellitus. In this report, we show that Glis3 is significantly downregulated at the transcriptional level in INS1 832/13 cells within hours of being subjected to high glucose concentrations and that diminished expression of Glis3 is at least partly attributable to increased oxidative stress...

While dysfunction and death of light-detecting photoreceptor cells underlie most inherited retinal dystrophies, knowledge of the species-specific details of human rod and cone photoreceptor cell development remains limited. Here, we generate retinal organoids carrying retinal disease-causing variants in NR2E3, as well as isogenic and unrelated controls. Organoids were sampled using single-cell RNA sequencing across the developmental window encompassing photoreceptor specification, emergence, and maturation...

Dry eye disease (DED) can arise from a variety of factors, including inflammation, meibomian gland dysfunction (MGD), and neurosensory abnormalities. Individuals with DED may exhibit a range of clinical signs, including tear instability, reduced tear production, and epithelial disruption, that are driven by different pathophysiological contributors. Those affected often report a spectrum of pain and visual symptoms that can impact physical and mental aspects of health, placing an overall burden on an individual's well-being...

Liver hepatocellular carcinoma (LIHC) is a significant global health issue with limited treatment options. In this study, single-cell RNA sequencing (scRNA-seq) data were used to explore the molecular mechanisms of LIHC development and identify potential targets for therapy. The expression of peroxisome proliferator-activated receptors (PPAR)-related genes was analysed in LIHC samples, and primary cell populations, including natural killer cells, T cells, B cells, myeloid cells, endothelial cells, fibroblasts and hepatocytes, were identified...

PURPOSE: ARO-HIF2 is an siRNA drug designed to selectively target hypoxia-inducible factor-2α (HIF2α) interrupting downstream pro-oncogenic signaling in clear cell renal cell carcinoma (ccRCC). The aims of this Phase 1 study (AROHIF21001) were to evaluate safety, tolerability, pharmacokinetics, and establish a recommended Phase 2 dose. PATIENTS AND METHODS: Subjects with ccRCC and progressive disease after at least 2 prior therapies that included VEGF and immune checkpoint inhibitors were progressively enrolled into dose-escalation cohorts of ARO-HIF2 administered intravenously at 225, 525, or 1,050 mg weekly...

UNLABELLED: Angiotensin converting enzyme 2 (ACE2), the host receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, is differentially expressed in a wide variety of tissues and cell types. The expression of ACE2 is under tight regulation, but the mechanisms regulating ACE2 expression have not yet been well defined. Through a genome-wide CRISPR knockout screen, we discovered that host factors TRAF3, DYRK1A, and RAD54L2 (TDR) form a complex to regulate the expression of ACE2...

Vogt-Koyanagi-Harada (VKH) disease is a multisystem disorder characterized by bilateral granulomatous panuveitis resulting in serous retinal detachments, disk edema, and a sunset glow fundus development. Furthermore, it is associated with various extraocular findings, such as tinnitus, hearing loss, vertigo, poliosis, and vitiligo (1). VKH is considered to be an autoimmune disease mediated by T-cells targeting melanocyte antigen tyrosinase peptide (2). Moreover, VKH more often occurs in individuals with a genetic predisposition to the disease, including those of Asian and Hispanic heritage (3)...

Mycosis fugnoides (MF) is an indolent cutaneous T-cell lymphoma (CTLC) and is the most common of all cutaneous lymphomas. An increased risk for developing a second primary malignancy in patients with CTCL has been described in several studies, with a range from 1.04 to 2.4 (1-4). Caucasian males are at higher risk for MF development. MF is often diagnosed at ages between 55 and 67 years, and second malignancy usually occurs 5 or 6 years after the diagnosis of MF was established (5). The most common second primary malignancies include non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), lung carcinoma, bladder carcinoma, and melanoma...

PURPOSE: Gene therapy using adeno-associated virus (AAV) vector-mediated gene delivery has undergone substantial growth in recent years with promising results in both preclinical and clinical studies, as well as emerging regulatory approval. However, the inability to quantify the efficacy of gene therapy from cellular delivery of gene-editing technology to specific functional outcomes is an obstacle for efficient development of gene therapy treatments. Building on prior works that used the CEST reporter gene lysine rich protein, we hypothesized that AAV viral capsids may generate endogenous CEST contrast from an abundance of surface lysine residues...

Inhibition of hypoxanthine-guanine-xanthine phosphoribosyltransferase activity decreases the pool of 6-oxo and 6-amino purine nucleoside monophosphates required for DNA and RNA synthesis, resulting in a reduction in cell growth. Therefore, inhibitors of this enzyme have potential to control infections, caused by Plasmodium falciparum and Plasmodium vivax , Trypanosoma brucei , Mycobacterium tuberculosis , and Helicobacter pylori . Five compounds synthesized here that contain a purine base covalently linked by a prolinol group to one or two phosphonate groups have K i values ranging from 3 nM to >10 μM, depending on the structure of the inhibitor and the biological origin of the enzyme...

Aqueous rechargeable zinc-ion batteries (ARZIBs) are considered as an emerging energy storage technology owing to their low cost, inherent safety, and reasonable energy density. However, significant challenges associated with electrodes, and aqueous electrolytes restrict their rapid development. Herein, ethylene glycol-choline chloride (Eg-ChCl) based hydrated deep-eutectic electrolytes (HDEEs) are proposed for RZIBs. Also, a novel V10 O24 ·nH2 O@rGO composite is prepared and investigated in combination with HDEEs...

Dendritic cells (DCs) are major antigen-presenting cells that connect innate and adaptive immunity. Hepatic DCs are less activated and contribute to maintain the tolerogenic environment of the liver under steady state. Several studies indicated DCs in metabolic dysfunction-associated steatohepatitis (MASH), representing a substantial burden on healthcare systems due to its association with liver-related morbidity and mortality. Studies highlighted the potential disease-promoting role of liver DCs in the development of MASH while other experimental systems suggested their protective role...

INTRODUCTION: CARD11 is a lymphoid lineage-specific scaffold protein regulating the NF-κB activation downstream of the antigen receptor signal pathway. Defective CARD11 function results in abnormal development and differentiation of lymphocytes, especially thymic regulatory T cells (Treg). METHOD: In this study, we used patients' samples together with transgenic mouse models carrying pathogenic CARD11 mutations from patients to explore their effects on Treg development...

INTRODUCTION: The gut microbiota, T cell subsets, and cytokines participate in tuberculosis (TB) pathogenesis. To date, the mechanisms by which these factors interactively promote TB development at different time points remain largely unclear. In the context of this study, We looked into the microorganisms in the digestive tract, T cell types, and cytokines related to tuberculosis. METHODS: According to QIIME2, we analyzed 16SrDNA sequencing of the gut microbiome on the Illumina MiSeq...

BACKGROUND: Osteomyelitis is a severe bone marrow infection, whose pathogenesis is not yet fully understood. This study aims to explore the causal relationship between immune cell characteristics and osteomyelitis, hoping to provide new insights for the prevention and treatment of osteomyelitis. METHODS: Based on two independent samples, this study employed a two-sample Mendelian randomization (MR) analysis to assess the causal relationship between 731 immune cell characteristics (divided into seven groups) and osteomyelitis...

Kinetoplastid pathogens including Trypanosoma brucei , T. cruzi , and Leishmania species, are early diverged, eukaryotic, unicellular parasites. Functional understanding of many proteins from these pathogens has been hampered by limited sequence homology to proteins from other model organisms. Here we describe the development of a high-throughput deep mutational scanning approach in T. brucei that facilitates rapid and unbiased assessment of the impacts of many possible amino acid substitutions within a protein on cell fitness, as measured by relative cell growth...

BACKGROUND: Stroke is a disease with high morbidity, disability, and mortality. Immune factors play a crucial role in the occurrence of ischemic stroke (IS), but their exact mechanism is not clear. This study aims to identify possible immunological mechanisms by recognizing immune-related biomarkers and evaluating the infiltration pattern of immune cells. METHODS: We downloaded datasets of IS patients from GEO, applied R language to discover differentially expressed genes, and elucidated their biological functions using GO, KEGG analysis, and GSEA analysis...

Unraveling the complexities of T cell aging is essential for developing targeted interventions to enhance immune function in the elderly. This article for the Highlights of 2023 Series integrates recent findings published in 2023, offering a panoramic view of the current understanding of T cell aging and its implications.

INTRODUCTION: Hematopoietic progenitor kinase 1 (HPK1), a 97-kDa serine/threonine Ste20-related protein kinase, functions as an intracellular negative regulator, primarily in hematopoietic lineage cells, where it regulates T cells, B cells, dendritic cells and other immune cells. Loss of HPK1 kinase activity results in exacerbated cytokine secretion, enhanced T cell signaling, improved viral clearance, and thus increased restraint of tumor growth. These findings highlight HPK1 as a promising target for immuno-oncology treatments, culminating in the advancement of candidate compounds targeting HPK1 to clinical trials by several biotech enterprises...

T-bet, encoded by TBX21, is extensively expressed across various immune cell types, and orchestrates critical functions in their development, survival, and physiological activities. However, the role of T-bet in non-immune compartments, notably the epithelial cells, remains obscure. Herein, a Tet-O-T-bet transgenic mouse strain is generated for doxycycline-inducible T-bet expression in adult animals. Unexpectedly, ubiquitous T-bet overexpression causes acute diarrhea, intestinal damage, and rapid mortality...