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.

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.

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.

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.

Measurement properties of disease activity instruments in peripheral spondyloarthritis: a post-hoc analysis of the CRESPA trial.

Background: Unravelling the performance of disease activity measures in peripheral spondyloarthritis (pSpA) is crucial for the development of clinical studies. We aimed to evaluate the construct validity and discriminatory capacity of various instruments assessing disease activity and response criteria in patients with pSpA.

Methods: Post-hoc analysis of the CRESPA randomised controlled trial including patients with early active pSpA.

A 96-Well Ultrafiltration Approach for the High-Throughput Proteome Analysis of Extracellular Vesicles Isolated From Conditioned Medium.

Extracellular vesicles (EVs), nanoscale vesicles that are secreted by cells, are critical mediators of intercellular communication and play a crucial role in diverse pathologies such as cancer development. Therefore, EVs are regarded as having high potential in the clinic, both for diagnostic and therapeutic applications. Unfortunately, EVs reside in complex biofluids and their consistent preparation at sufficient purity for mass spectrometry-based proteomics has proven to be challenging, especially when increased high-throughput is required.

Continuous FACS Sorting of Double Emulsion Picoreactors with a 3D-Printed Vertical Mixer.

High-throughput screening and directed evolution using microfluidic picoreactors have produced high-activity enzymes. In this approach, a substrate is coencapsulated with a candidate enzyme, and individual picoreactors are sorted based on an activity reporter. While many approaches use water-in-oil droplets (single emulsions) for fluorescence-activated droplet sorting (FADS) on custom-fabricated microfluidic devices that require integrated optics and electronics, recent approaches have lowered the engineering barriers to adoption by using simple microfluidic droplet generators to produce water-in-oil-in-water droplets (double emulsion picoreactors, DEs) that can be sorted with commercial FACS (fluorescence-activated cell sorting).

KIL transcription factors facilitate embryo growth in maize by promoting endosperm elimination via lytic cell death.

The endosperm is a transient nutritive tissue in plant seeds. During maize (Zea mays) grain development, 2 distinct endosperm cell death processes occur: in 1 process, the endosperm adjacent to the embryo scutellum (EAS) is completely dismantled; in the other, the starchy endosperm (SE) retains nutrient-packed cell corpses after grain filling. Here, we show that SE cell death degrades some organelles including the mitochondria and the endoplasmic reticulum, while preserving protein bodies, starch granules, and chromatin.

A Minimally Invasive Transthoracic Injection Technique for Reproducible Intrapleural Delivery in Mice.

The development of standardised, reproducible preclinical models is essential for advancing pleural mesothelioma (PM) research. Here, we present a simple and reliable minimally invasive transthoracic intrapleural injection technique that could improve the efficiency of orthotopic PM model generation. By incorporating a simple needle sleeve to control the injection depth, this method eliminates the need for surgery or general anaesthesia, reducing technical complexity and animal stress while ensuring precise delivery into the pleural cavity.

Detection of antibodies against the African parasite Trypanosoma brucei using synthetic glycosylphosphatidylinositol oligosaccharide fragments.

Unlabelled: () parasites cause two major infectious diseases in Africa: African trypanosomiasis in humans (HAT) and Nagana in animals. Despite the enormous economic and social impact, vaccines and reliable diagnostic measures are still lacking for these diseases. The main obstacle to developing accurate diagnostic methods and an active vaccine is the parasite’s ability for antigenic variation, impairment of B cell maturation, and loss of B cell memory which collectively prevent the development of a long-lasting, effective immune response.

Cytotoxic NK Cells Impede Response to Checkpoint Immunotherapy in Melanoma with an Immune-Excluded Phenotype.

Unlabelled: Immune checkpoint blockade (ICB) has revolutionized cancer treatment. Unfortunately, the inability of lymphocytes to infiltrate the tumor nest, a phenomenon known as immune exclusion, drastically limits ICB responsiveness. Analyzing the immune landscape of matched pre- and early on-treatment biopsies of patients with melanoma undergoing ICB therapy, we observed a significant increase in cytotoxic NK cells in early on-treatment biopsies from nonresponders.

Morphological Profiling of Imaging Flow Cytometry Data Uncovers Heterogeneity in Infected Gephyrocapsa huxleyi Cultures.

Phytoplankton, such as the coccolitophore Gephyrocapsa huxleyi (G. huxleyi), has a major ecological impact through photosynthesis-the production of oxygen and organic material. A significant threat to G.

Primidone: a clinically promising candidate for the treatment of psoriasis.

Using clinically relevant animal models, we have recently demonstrated that the anticonvulsant primidone (Liskantin), approved by the FDA for the treatment of various forms of epilepsy, can effectively block RIPK1 enzymatic activity, which mediates cell death, and consequently prevent RIPK1 cytotoxicity and associated inflammatory responses. Based on these findings, we now reveal both a preventive and, more importantly, a therapeutic effect of primidone in the imiquimod (IMQ)-induced psoriasis-like inflammation model. Notably, the protective effect of IMQ in this necroinflammatory disease is directly correlated with inhibition of the activated state of RIPK1 (as monitored by auto-phosphorylation on Ser166/T169), a critical marker that had been missing in the highly contradictory studies that have previously been published.

Ultrapotent SARS coronavirus-neutralizing single-domain antibodies that clamp the spike at its base.

Therapeutic monoclonal antibodies can prevent severe disease in SARS-CoV-2 exposed individuals. However, currently circulating virus variants have evolved to gain significant resistance to nearly all neutralizing human immune system-derived therapeutic monoclonal antibodies that had previously been emergency-authorized for use in the clinic. Here, we describe the discovery of a panel of single-domain antibodies (VHHs) directed against the spike protein S2 subunit that broadly neutralize SARS-CoV-1 and -2 with unusually high potency.

Evaluation of out-of-distribution detection methods for data shifts in single-cell transcriptomics.

Automatic cell-type annotation methods assign cell-type labels to new, unlabeled datasets by leveraging relationships from a reference RNA-seq atlas. However, new datasets may include labels absent from the reference dataset or exhibit feature distributions that diverge from it. These scenarios can significantly affect the reliability of cell type predictions, a factor often overlooked in current automatic annotation methods.

Co-targeting of VEGFR2 and PD-L1 promotes survival and vasculature normalization in pleural mesothelioma.

Pleural mesothelioma (PM) is an aggressive cancer caused by asbestos exposure, with limited treatment options and poor prognosis, highlighting the need for more effective therapies. Combining immune checkpoint blockade with anti-angiogenic therapy has shown potential in other cancers. Our study investigated the combined inhibition of PD-L1 and VEGFR2 in a mouse model of PM.

Ocular Graft-Versus-Host Disease in Allogeneic Stem Cell Transplant Recipients: A Longitudinal Cohort Study Evaluating Ocular Surface Parameters Before and After Transplantation.

Purpose: The objective of this longitudinal cohort study was to identify predictors of progression to ocular graft-versus-host disease in allogeneic hematopoietic stem cell transplant recipients.

Methods: Patients (n = 49) were examined before hematopoietic stem cell transplantation (HSCT) and 3, 6, 12, 24, and 36 months after HSCT. Outcome measures included ocular surface disease index questionnaire, Schirmer I test, corneal fluorescein staining, tear break-up time, and tear cytokine concentration.

The gut-brain axis in Alzheimer's disease is shaped by commensal gut microbiota derived extracellular vesicles.

Emerging clinical and experimental evidence highlight the involvement of gut microbiota in the onset and progression of neurodegenerative diseases such as Alzheimer's disease (AD) via neuroinflammatory processes along the gut-brain axis. Despite this, the precise mechanisms governing gut microbial involvement in AD remain elusive. In this study, we observed that AD mice raised under germ-free (GF) conditions, display a reduced amyloid-β (Aβ) pathology, accompanied by a shift in microglial cells toward a less inflammatory state and increased phagocytotic efficiency.