S1P/S1PR4 Promotes the Differentiation of CD8 tissue-resident memory T Cells Aggravating Bile Duct Injury in Biliary Atresia.

Background And Aims: Biliary atresia (BA) is a severe neonatal cholangiopathy characterized by progressive inflammation and fibrosis. We aimed to systematically investigate BA pathology using integrated multi-omics.

Methods: Multi-omics integration of BA and control livers revealed sphingolipid dysregulation.

Ferroptosis and iron-based therapies in infections: From pathogenesis to treatment.

is a globally prevalent multidrug-resistant pathogen that causes severe infections, particularly in immunocompromised individuals. This review focuses on the dual role of iron in infections: as a critical nutrient for bacterial growth and as a mediator of host cell ferroptosis, a form of iron-dependent cell death. We summarize how manipulates iron metabolism to induce ferroptosis in host cells, thereby promoting its own survival and pathogenicity.

A Conserved FABP5 Macrophage Subset Promotes Fibrosis and Carcinogenesis in Advanced Liver Disease.

Background And Aims: The relationship between chronic liver disease and liver cancer remains poorly understood, and treatment options for advanced liver disease remain limited. This study aims to elucidate the dynamic evolution of cellular and molecular alterations from normal liver to diseased liver.

Methods: Single-cell RNA sequencing was performed to profile the dynamic cellular variations from normal liver to diseased liver.

Septal LYVE1 macrophages control adipocyte stem cell adipogenic potential.

Tissue macrophages reside in anatomically distinct subtissular niches that shape their identity and function. In white adipose tissue (WAT), we identified three macrophage populations with distinct localization, turnover, and phenotypes. Septal adipose tissue macrophages (sATMs), marked by CD209b and lymphatic vessel endothelial hyaluronan receptor 1, were long-lived and positioned in close proximity to adipocyte stem cells (ASCs) within the WAT septum.

Enhanced Transdermal Delivery of Lidocaine Hydrochloride via Dissolvable Microneedles (LH-DMNs) for Rapid Local Anesthesia.

Microneedles represent an emerging transdermal drug delivery platform offering painless, minimally invasive penetration of the stratum corneum. This study addresses limitations of conventional lidocaine hydrochloride formulations, such as slow onset and poor patient compliance, by developing lidocaine hydrochloride-loaded dissolvable microneedles (LH-DMNs) for rapid local anesthesia. LH-DMNs were fabricated via centrifugal casting using polyvinyl alcohol (PVA) as the matrix material in polydimethylsiloxane (PDMS) negative molds, which imparts high mechanical strength to the microneedles.

The STUB1-TPIT axis regulates the secretion of adrenocorticotrophic hormone in cushing disease.

Background: Cushing's disease (CD) is a clinical syndrome caused by excessive secretion of adrenocorticotropic hormone (ACTH) from a pituitary corticotroph adenoma, resulting in adrenal cortical hyperplasia and overproduction of cortisol. The T-box transcription factor (TPIT) is crucial for regulating ACTH secretion in pituitary corticotroph adenomas. This study aims to explore the ubiquitin-mediated degradation of TPIT and identify potential pharmaceutical agents for treating CD.

Human brain cell types shape host-rabies virus transcriptional interactions revealing a preexisting pro-viral astrocyte subpopulation.

How virus-host cell interactions and innate immune antagonism shape neurotropic infection dynamics across diverse brain cell types is largely unknown. To "unmask" and study how innate immune inhibition affects cell-type-specific transcriptional regulation of the human and viral genome, we perform single-cell RNA sequencing of human brain cell co-cultures, comparing an isolate of rabies virus (RABV) to its mutant incapable of antagonizing interferon- and nuclear factor (NF)-κB-dependent responses. RABV gene expression is shaped by host cell type.

Jawbone mesenchymal stromal cells attenuate acute inflammation via hematopoietic niche reinforcement.

Background: The bone marrow microenvironment, comprising various cell types and molecular signals, finely orchestrates the self-renewal and lineage commitment of hematopoietic stem cells (HSCs). Although most investigations have centered on mesenchymal stem cells (MSCs) from long bones, the distinct properties and immunoregulatory functions of craniofacial bone marrow derived MSCs remain largely unexplored. Notably, jawbone MSCs not only exhibit a robust capacity for promoting hematopoietic regeneration but also offer therapeutic potential in infectious diseases.

An age-related decrease in leptin contributes to CD8 T cell aging in the tumor microenvironment.

T cell dysfunction with age underlies an increased incidence of cancer in elderly individuals; however, how T cell aging is triggered in the tumor microenvironment is unclear. Here, we show that an age-associated reduction in adipocyte-derived leptin contributes to the accumulation of tumor-infiltrating senescent CD8 T cells. Single-cell profiling of human and mouse cancer tissues reveals that the frequency of intratumoral senescent CD8 T cells increases with age, leading to a weak antitumor effect.

High fructose consumption aggravates inflammation by promoting effector T cell generation via inducing metabolic reprogramming.

The intake of sugars, especially glucose and fructose, has significantly increased with the change of lifestyle. Excessive intake of sugar has been proven to be associated with tumors and inflammatory diseases. Fructose directly mediates innate immune responses; however, whether it can directly regulate T-cell immunity remains unknown.

ST6GAL1-Mediated Sialylation Stabilizes PD-L1 and Drives Immunosuppressive Tumor Microenvironment in Colorectal Cancer.

Abnormal glycogene expression is a recognized cancer hallmark, but its impact on the colorectal cancer (CRC) tumor microenvironment (TME) remains unclear. Utilizing bioinformatics analysis on TCGA and GEO datasets, a seven-glycogene signature is identified for precise glycogene-based classification in CRC. ST6GAL1, a key focus, emerges as a significant predictor of poor prognosis, with its upregulation linked to unfavorable outcomes in CRC.

SATB1 is a key regulator of quiescence in stem-like CD8 T cells.

Stem-like progenitor CD8 T (T) cells sustain cytotoxic immunity during chronic infection and cancer through quiescence, multipotency and self-renewal, hallmarks shared with memory T cells. However, how these properties are maintained under persistent antigen stimulation remains unclear. Here we identify the genomic organizer SATB1 as selectively enriched in both T and memory CD8 T cells.

Targeting MondoA-TXNIP restores antitumour immunity in lactic-acid-induced immunosuppressive microenvironment.

In the tumour microenvironment, accumulated lactic acid (LA) promotes tumour immune evasion by facilitating regulatory T cell (T) immunosuppressive function and restraining CD8 T cell cytotoxicity, but the underlying mechanism remains elusive. Here we report that transcriptional factor MondoA-induced thioredoxin interacting protein (TXNIP) transcription is a common feature of both T and CD8 T cells in response to lactic acid. In contrast to reduction in immunosuppressive capacity in MondoA-deficient T cells, loss of MondoA enhanced CD8 T cell cytotoxic function in the lactic-acid-induced immunosuppressive microenvironment, by restoring glucose uptake and glycolysis.

Integrative proteogenomic characterization of Wilms tumor.

Wilms tumor (WT), the most common pediatric renal malignancy, exhibits a relatively low mutational burden compared to adult cancers, which hinders the development of targeted therapies. To elucidate the molecular landscape of WT, we perform integrative proteomic, phosphoproteomic, transcriptomic, and whole-exome sequencing analyses of WT and normal kidney tissue adjacent to tumor. Our multi-omics approach uncovers prognostic genetic alterations, distinct molecular subgroups, immune microenvironment features, and potential biomarkers and therapeutic targets.

CCR7 dendritic cells expressing both IL-23A and IL-12B potentially contribute to psoriasis relapse.

Interleukin (IL)-23 is the master pathogenic cytokine in psoriasis and neutralization of IL-23 alleviates psoriasis. Psoriasis relapses after the withdrawal of anti-IL-23 antibodies, and the persistence of IL-23-producing cells potentially contributes to such recurrence, but the cellular source of IL-23 is unclear. Here we show that IL4I1CD200CCR7 dendritic cells (CCR7 DC) are the main producer of IL-23 by concomitantly expressing the IL-23A and IL-12B subunits in human psoriatic skin.

The Nα-acetyl-L-lysine/Loxl2/HO promotes intestinal tumor growth in Drosophila and cell proliferation in human colorectal cancer.

A cancer-associated microbiome is considered a carcinogen capable of affecting tumor initiation and/or progression. However, little is known about the molecular mechanisms of tumor-microbiome interactions. Here, we show that Staphylococcus sciuri promotes Drosophila intestinal tumor growth by inducing intestinal stem cell (ISC) division.

Use of the PaO/FiO ratio in acute pulmonary embolism: a simple and reliable parameter to predict the risk stratification.

Background: Acute pulmonary embolism (APE) is a common pulmonary vascular disease with its incidence rising year by year. Accurate diagnosis and early risk stratification of patients with APE are crucial for treatment follow-up, especially for patients with intermediate-to-high and high-risk. The aim of this study is to explore the value of blood gas parameters, especially arterial partial pressure of oxygen/fraction of inspired oxygen (PaO/FiO) ratio (P/F ratio), in evaluating the risk stratification of APE.

Diet-derived galactose reprograms hepatocytes to prevent T cell exhaustion and elicit antitumour immunity.

Dietary nutrients are inextricably linked to antitumour immune responses. However, the effect of diet-derived galactose on antitumour immunity remains unclear. Here we show that dietary galactose augments CD8 T cell immunity to suppress tumour progression.

A pan-KRAS inhibitor and its derived degrader elicit multifaceted anti-tumor efficacy in KRAS-driven cancers.

KRAS remains a challenging therapeutic target with limited effective inhibitors currently available. Here, we report the discovery of MCB-294, a potent dual-state pan-KRAS inhibitor capable of binding both the active (GTP-bound) and inactive (GDP-bound) forms of KRAS. MCB-294 engages the switch-II pocket through a water-mediated hydrogen-bond network and selectively inhibits KRAS over NRAS and HRAS.

Immune system influence on physiology.

The immune system's central function is to maintain homeostasis by guarding the organism against dangerous external and internal stressors. Immunity's operational toolbox contains diverse processes, such as phagocytosis, antigen recognition, cell killing, and secretion of cytokines and antibodies. Although immune cells interact with each other, they also communicate with cells typically associated with other organ systems, including the nervous, circulatory, metabolic, musculoskeletal, endocrine, and hematopoietic.

Dose-escalation studies of mesenchymal stromal cell therapy for decompensated liver cirrhosis: phase Ia/Ib results and immune modulation insights.

Decompensated liver cirrhosis (DLC) is characterized by severe liver dysfunction and immune dysregulation, posing significant treatment challenges. Mesenchymal stromal cell (MSC) therapy has shown promise in DLC treatment, but the optimal dosing strategies and dose-dependent therapeutic mechanisms in humans remain unclear, limiting its clinical application. We conducted sequential Phase Ia/Ib trials using a single-arm, dose-escalation design to evaluate the safety and tolerability of MSC therapy in DLC patients while also exploring its immunomodulatory effects and gathering preliminary therapeutic signals.

Inhibition of the Caveolin-1 pathway promotes apoptosis and overcomes pan-tyrosine kinase inhibitor resistance in hepatocellular carcinoma.

Resistance to multi-tyrosine kinase inhibitors (TKI) is a major clinical concern in advanced hepatocellular carcinoma (HCC). Herein, we aimed to uncover the mechanisms underlying pan-TKI resistance and to identify potential therapeutic targets. We used multiple TKI-resistant HCC cell lines to identify caveolin-1 (CAV1) as a key driver of therapeutic resistance.

Transcription factors TCF4 and KLF4 respectively control the development of the DC2A and DC2B lineages.

Conventional dendritic cells (cDCs) are a heterogeneous population of professional antigen-presenting cells that bridge innate and adaptive immunity. Many studies in mice have identified various populations of cDCs whose inter-relationships and discrete identities, as well as their link to plasmacytoid DCs (pDCs), have not been cohesively addressed. Here, by combining single-cell sequencing, transcription factor fate-mapping models, conditional knockout models and adoptive transfer, we show that Klf4 expression clearly separates cDC lineage from the pDC lineage, and defined two pre-DC2 subsets: Siglec-HCD115 pre-DC2s and Siglec-HCD115 pre-DC2s.

OGG1 augments the transcriptional activation of to promote iTreg differentiation for IBD alleviation.

8-oxo-7,8-dihydroguanine (8-oxoG), the most frequent form of oxidative-DNA-base lesion caused by ROS, is recognized and repaired by 8-oxoguanine DNA glycosylase 1 (OGG1) through base excision repair (BER) pathway. Beyond its role in DNA repair, OGG1 has been shown to promote transcriptional activation of proinflammatory mediators and contribute to both acute and chronic lung inflammation. However, pioneering studies have shown an anti-inflammation role for OGG1 in inflammatory bowel disease (IBD), but its underlying molecular mechanism remains unclear.