ASAS recommendations on reporting axial spondyloarthritis clinical trials.

Objectives: This study aims to develop recommendations on reporting baseline features and outcomes from axial spondyloarthritis (axSpA) clinical trials based on the recently updated instrument set of the Assessment of SpondyloArthritis international Society (ASAS) core outcome set (COS).

Methods: A steering group (SG) convened a workgroup (WG), consisting of 13 ASAS members including rheumatologists, methodologists, epidemiologists, and 2 Young ASAS members. Recommendations on reporting axSpA trials baseline features and outcomes were developed in 3 steps: (1) the SG identified relevant baseline features from key axSpA clinical trials and formulated a proposal on how outcomes related to the instruments in the ASAS COS should be presented.

HNF4α contributes to hepatic CAR dysfunction in polymicrobial sepsis.

The constitutive androstane receptor (CAR), encoded by the gene, is a nuclear receptor mainly expressed in the liver, where it regulates (xenobiotic) drug and bile acid metabolism, bilirubin clearance and energy homeostasis. CAR has emerged as a promising therapeutic target for diabetes, fatty liver disease and alcoholic liver disease, but it has barely been investigated in the context of sepsis. Since alterations in drug metabolism have been observed in sepsis patients, who may also exhibit increased serum bilirubin and bile acid levels, we hypothesize that CAR function may be impaired during sepsis.

TAB2 controls a TAK1-independent cell death checkpoint at the level of TNFR1 complex II in the TNF pathway.

Tumor necrosis factor (TNF) signaling determines the cell's fate by promoting either survival or cell death via apoptosis, necroptosis or pyroptosis. Excessive or chronic cell death by TNF was shown to drive inflammatory pathologies, highlighting the importance of the mechanisms that normally block TNF cytotoxicity. This study investigates the role of TAB2, an adaptor protein traditionally linked to TAK1 activation in the TNF pathway.

Cytoskeletal control in adult microglia is essential to restore neurodevelopmental synaptic and cognitive deficits.

Synaptic dysfunction is a hallmark of neurodevelopmental disorders (NDDs), often linked to genes involved in cytoskeletal regulation. While the role of these genes has been extensively studied in neurons, microglial functions such as phagocytosis are also dependent on cytoskeletal dynamics. We demonstrate that disturbance of actin cytoskeletal regulation in microglia, modeled by genetically impairing the scaffold protein Disrupted-in-Schizophrenia 1 (DISC1), which integrates actin-binding proteins, causes a shift in actin regulatory balance favoring filopodial versus lamellipodial actin organization.

Pyrin inflammasome-driven erosive arthritis caused by unprenylated RHO GTPase signaling.

Geranylgeranyl pyrophosphate, a non-sterol intermediate of the mevalonate pathway, serves as the substrate for protein geranylgeranylation, a process catalyzed by geranylgeranyl transferase I (GGTase-I). Myeloid-specific deletion of Pggt1b, the gene coding for GGTase-I, leads to spontaneous and severe erosive arthritis in mice; however, the underlying mechanisms remained unclear. In this study, we demonstrate that arthritis in mice with myeloid-specific Pggt1b deficiency is driven by unprenylated GTP-bound small RHO family GTPases, which in turn trigger Pyrin (Mefv) inflammasome activation, GSDMD-dependent macrophage pyroptosis, and IL-1β secretion.

CytoNormPy Enables a Fast and Scalable Removal of Batch Effects in Cytometry Datasets.

Cytometry has evolved as a crucial technique in clinical diagnostics, clinical studies, and research. However, batch effects due to technical variation complicate the analysis of cytometry data in clinical and fundamental research settings and have to be accounted for. Here, we present a Python implementation of the widely used CytoNorm algorithm for the removal of batch effects, implementing the complete feature set of the recently published CytoNorm 2.

Teriflunomide Inhibits Human FOXP3 Regulatory T Cell Function by Interference With Mitochondrial Respiration.

Regulatory FOXP3 T cells (Tregs) have been characterized with unique metabolic demands, preferentially relying on fatty acid β-oxidation (FAO) and oxidative phosphorylation (OXPHOS). Several studies have indicated that Treg mitochondrial fitness is crucial for maintaining their stability and suppressive activity with an emphasis on complex-III of the electron transport chain (ETC). Dysfunctional Tregs isolated from patients with autoimmunity like multiple sclerosis (MS) show diminished mitochondrial respiration and the induction of a T helper (Th)1-like phenotype, characterized by increased production of interferon (IFN)-γ.

Lipid nanoparticles as a tool to dissect dendritic cell maturation pathways.

Depending on how antigens are being decoded by dendritic cells (DCs), their acquisition will induce a homeostatic or immunogenic maturation program. This determines how antigens are being presented and whether DCs instruct T cells to induce tolerance or immunity. So far, the field lacks proper tools to distinguish the two maturation states.

Fluorescence Characterization of Extracellular Vesicles Using Single-Molecule Confocal Microscopy.

Extracellular vesicles (EVs) are small, membrane-bound particles released by cells into the extracellular environment. They play a pivotal role in cell communication and have recently gained prominence as biomarkers. However, their low abundance and high heterogeneity challenge their accurate characterization using conventional approaches.

Sexual Dimorphism of Plasma and Tissue Proteomes in Human Calcific Aortic Valve Stenosis Pathogenesis.

Background: Calcific aortic valve stenosis is a global clinical burden, impacting around 2% of the population over 65 years of age. No pharmacotherapeutics exist, with surgical repair and transcatheter valve replacement being the only intervention. Females are underrepresented in studies of calcific aortic valve stenosis, leading to delay in timely intervention and increased mortality.

Advances in human myeloid-engrafting NSG-SGM3 and MISTRG mice.

Humanized mouse models with transgenic expression of human myelopoiesis-supporting growth factors have enhanced human myeloid cell engraftment and improved the study of human innate immune responses. Here, we discuss the remaining challenges associated with studying innate immunity in humanized NSG-SGM3 and MISTRG mice, as well as potential advances to overcome them.

CREB regulates Foxp3ST-2 T with enhanced IL-10 production.

Introduction: Regulatory T-cells (T) are characterized by the expression of Foxp3, a master regulator involved in the development and function of T. Foxp3 expression is dependent on activity of the Treg specific demethylated site (TSDR), which contains a CREB binding site. We aimed to find out how Foxp3 specific CREB deletion affects Treg expression and function.

Pre-formation loading of extracellular vesicles with exogenous molecules using photoporation.

Despite the natural capacity of extracellular vesicles (EVs) to encapsulate intracellular compounds and transfer these to nearby or distant recipient cells, the intentional loading of EVs with cargo molecules remains a challenging endeavor. Pre-formation EV loading (i.e.

Gradual DNA methylation changes reveal transcription factors implicated in metabolic dysfunction-associated steatotic liver disease progression and epigenetic age acceleration.

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease worldwide, but its pathophysiological mechanisms remain elusive. It is a progressive disease, encompassing hepatic steatosis, steatohepatitis with (out) fibrosis, and ultimately cirrhosis and hepatocellular carcinoma. DNA methylation (DNAm) is dysregulated in MASLD and may play a central role in its pathogenesis.

Antibody-mediated TGF-β1 activation for the treatment of diseases caused by deleterious T cell activity.

Transforming growth factor β1 (TGF-β1) is an immunosuppressive cytokine produced as a latent homodimer, in which mature TGF-β1 is encapsulated and kept inactive by the latency-associated peptide (LAP). The transmembrane protein GARP presents latent TGF-β1 on the surface of regulatory T cells (Tregs) to enable activation and release of mature TGF-β1 by integrins. Here, we derived monoclonal antibodies (mAbs) that activate latent TGF-β1 anchored on cells by a transmembrane protein.

ACLY inhibition promotes tumour immunity and suppresses liver cancer.

Immunosuppressive tumour microenvironments are common in cancers such as metabolic dysfunction-associated steatohepatitis (MASH)-driven hepatocellular carcinoma (HCC) (MASH-HCC). Although immune cell metabolism influences effector function, the effect of tumour metabolism on immunogenicity is less understood. ATP citrate lyase (ACLY) links substrate availability and mitochondrial metabolism with lipid biosynthesis and gene regulation.

VDAC2 brake release: unleashing inflammation via IFNγ.

Identification of therapeutic vulnerabilities in cancer remains a high priority for cancer research. A recent CRISPR/Cas9 screen identified that VDAC2 deletion in tumors enhanced their sensitivity to interferon-γ (IFNγ) through the release of mitochondrial DNA (mtDNA) and activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. These data suggest that VDAC2 inhibition could enhance antitumor therapies.

The immunology of asthma.

Asthma is a chronic inflammatory disease of the airways characterized by variable airway obstruction. In some patients with severe disease there are frequent disease flares, and some individuals develop irreversible airway obstruction. The immune system has a predominant effect on many aspects of the disease.

Epigenomic preconditioning of peripheral monocytes determines their transcriptional response to the tumor microenvironment.

Background: Monocytes are recruited to tumors and undergo transcriptional reprogramming resulting in tumor-promoting functions. Epigenomic features, such as post-translational modification of histones and chromatin accessibility, are key determinants of transcription factor binding and thereby play an important role in controlling transcriptional responses to the tissue environment. It remains unknown whether systemic tumor-associated signals could alter the epigenomic landscape of peripheral monocytes before they reach the tumor, thus shaping their subsequent response to the tumor microenvironment.

Nanobody-based Pannexin1 channel inhibitors increase survival after cardiac ischemia/reperfusion.

Reperfusion following myocardial infarction salvages the ischemic heart but paradoxically exacerbates injury. Yet, efficient treatment for cardiac ischemia/reperfusion injury is still missing in clinics. ATP release through Pannexin1 (PANX1) channels facilitates recruitment of leukocytes to the injured myocardium.

Unraveling mitochondrial pyruvate dysfunction to mitigate hyperlactatemia and lethality in sepsis.

Sepsis, killing 11 million people yearly, is associated with increased production of lactate-a metabolite mechanistically linked to mortality-complicating glucose administration in sepsis. To understand the mechanism behind hyperlactatemia, we applied the cecal ligation and puncture (CLP) model and studied all pyruvate processing routes in liver mitochondria during acute sepsis. Our data suggest that mitochondrial pyruvate-driven respiration is nearly nonexistent in sepsis, not due to insufficient pyruvate uptake or carboxylation, but due to a dysfunctional pyruvate dehydrogenase complex (PDC).

Ripk1 is critical for preserving effector regulatory T cells and the suppressive transcriptional program in regulatory T cells.

Ripk1 plays an important role as a regulator of programmed cell death processes such as apoptosis and necroptosis and is involved in initiating pro-inflammatory NF-κB signaling. Immune tolerance depends on the proper function and homeostasis of regulatory T (Treg) cells. Here, we show that specific ablation of Ripk1 in Treg cells leads to systemically reduced Treg cell numbers resulting in spontaneous whole-body pathology.

Combinatorial Synthesis and Evaluation of Trialkyl Galloyl Amidoamine Ionizable Lipids for mRNA Formulation.

Lipid nanoparticles (LNPs), containing ionizable cationic lipids, have attracted widespread interest in recent years, particularly following their use as mRNA delivery systems for COVID-19 vaccines. Here, we report on the combinatorial synthesis of galloyl amidoamine-based ionizable lipids. Starting from methyl gallate, three alkyl tails were substituted onto the aromatic ring, and the carboxylic acid was transformed into an ionizable tertiary amine headgroup.

Potential of biomarker-based enrichment strategies to identify critically ill patients for emerging cell death interventions.

Critically ill patients admitted to the intensive care unit (ICU) frequently suffer from sepsis and severe multiple organ dysfunction with underlying widespread cell death. Pyroptosis and ferroptosis are regulated cell death forms that may serve as potential therapeutic targets. Pyroptosis is a major detrimental factor driving sepsis, which typically results in excessive oxidative stress potentially inducing ferroptotic organ injury.