Talin1 dysfunction is genetically linked to systemic capillary leak syndrome.

Systemic capillary leak syndrome (SCLS) is a rare life-threatening disorder due to profound vascular leak. The trigger and the cause of the disease are currently unknown and there is no specific treatment. Here, we identified a rare heterozygous splice-site variant in the TLN1 gene in a familial SCLS case, suggestive of autosomal dominant inheritance with incomplete penetrance.

Mitochondrial mechanotransduction through MIEF1 coordinates the nuclear response to forces.

Tissue-scale architecture and mechanical properties instruct cell behaviour under physiological and diseased conditions, but our understanding of the underlying mechanisms remains fragmentary. Here we show that extracellular matrix stiffness, spatial confinements and applied forces, including stretching of mouse skin, regulate mitochondrial dynamics. Actomyosin tension promotes the phosphorylation of mitochondrial elongation factor 1 (MIEF1), limiting the recruitment of dynamin-related protein 1 (DRP1) at mitochondria, as well as peri-mitochondrial F-actin formation and mitochondrial fission.

drive synovial hyperplasia and arthritis by targeting cell cycle inhibitors and chromatin remodeling components.

miRNAs constitute fine-tuners of gene expression and are implicated in a variety of diseases spanning from inflammation to cancer. miRNA expression is deregulated in rheumatoid arthritis (RA); however, their specific role in key arthritogenic cells such as the synovial fibroblast (SF) remains elusive. Previous studies have shown that expression is upregulated in RA SFs.

ProteoCure: A European network to fine-tune the proteome.

Proteins are essential molecular actors in every cellular process. From their synthesis to their degradation, they are subject to continuous quality control mechanisms to ensure that they fulfil cellular needs in proper and timely fashion. Proteostasis is a key process allowing cells or organisms to maintain an appropriate but dynamic equilibrium of their proteome (the ensemble of all their proteins).

Immunological synapse formation between T regulatory cells and cancer-associated fibroblasts promotes tumour development.

Cancer-associated fibroblasts (CAFs) have emerged as a dominant non-hematopoietic cell population in the tumour microenvironment, serving diverse functions in tumour progression. However, the mechanisms via which CAFs influence the anti-tumour immunity remain poorly understood. Here, using multiple tumour models and biopsies from cancer patients, we report that α-SMA CAFs can form immunological synapses with Foxp3 regulatory T cells (Tregs) in tumours.

Protein aggregation and therapeutic strategies in SOD1- and TDP-43- linked ALS.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with severe socio-economic impact. A hallmark of ALS pathology is the presence of aberrant cytoplasmic inclusions composed of misfolded and aggregated proteins, including both wild-type and mutant forms. This review highlights the critical role of misfolded protein species in ALS pathogenesis, particularly focusing on Cu/Zn superoxide dismutase (SOD1) and TAR DNA-binding protein 43 (TDP-43), and emphasizes the urgent need for innovative therapeutic strategies targeting these misfolded proteins directly.

Biomimetic Approach of Brain Vasculature Rapidly Characterizes Inter- and Intra-Patient Migratory Diversity of Glioblastoma.

Glioblastomas exhibit remarkable heterogeneity at various levels, including motility modes and mechanoproperties that contribute to tumor resistance and recurrence. In a recent study using gridded micropatterns mimicking the brain vasculature, glioblastoma cell motility modes, mechanical properties, formin content, and substrate chemistry are linked. Now is presented, SP2G (SPheroid SPreading on Grids), an analytic platform designed to identify the migratory modes of patient-derived glioblastoma cells and rapidly pinpoint the most invasive sub-populations.

Choline Metabolites Reverse Differentially the Habituation Deficit and Elevated Memory of Tau Null Drosophila.

Impaired neuronal plasticity and cognitive decline are cardinal features of Alzheimer's disease and related Tauopathies. Aberrantly modified Tau protein and neurotransmitter imbalance, predominantly involving acetylcholine, have been linked to these symptoms. In Drosophila, we have shown that dTau loss specifically enhances associative long-term olfactory memory, impairs foot shock habituation, and deregulates proteins involved in the regulation of neurotransmitter levels, particularly acetylcholine.

Activation and Functions of Col6a1+ Fibroblasts in Colitis-Associated Cancer.

Cancer-associated fibroblasts (CAFs) comprise a group of heterogeneous subpopulations with distinct identities indicative of their diverse origins, activation patterns, and pro-tumorigenic functions. CAFs originate mainly from resident fibroblasts, which are activated upon different stimuli, including growth factors and inflammatory mediators, but the extent to which they also maintain some of their homeostatic properties, at least at the earlier stages of carcinogenesis, is not clear. In response to cytokines, such as interleukin 1 (IL-1) and tumor necrosis factor (TNF), as well as microbial products, CAFs acquire an immunoregulatory phenotype, but its specificity and pathophysiological significance in individual CAF subsets is yet to be determined.

Infection and inflammation stimulate expansion of a CD74 Paneth cell subset to regulate disease progression.

Paneth cells (PCs), a specialized secretory cell type in the small intestine, are increasingly recognized as having an essential role in host responses to microbiome and environmental stresses. Whether and how commensal and pathogenic microbes modify PC composition to modulate inflammation remain unclear. Using newly developed PC-reporter mice under conventional and gnotobiotic conditions, we determined PC transcriptomic heterogeneity in response to commensal and invasive microbes at single cell level.

Harmonisation of education, training and continuing professional development for laboratory animal caretakers, technicians and technologists: Report of the FELASA-EFAT Working Group.

Competent, confident and caring laboratory animal caretakers, technicians and technologists (LAS staff) are vital for good animal welfare, high-quality science and a secure Culture of Care. This requires high-quality education, training, supervision and continuing professional development (CPD) of LAS staff. However, there is a lack of harmonisation regarding how this education and training is conducted among European countries, and nor are there recommendations adapted to Directive 2010/63/EU.

Repurposing the antipsychotic drug amisulpride for targeting synovial fibroblast activation in arthritis.

Synovial fibroblasts (SFs) are key pathogenic drivers in rheumatoid arthritis (RA). Their in vivo activation by TNF is sufficient to orchestrate full arthritic pathogenesis in animal models, and TNF blockade proved efficacious for a high percentage of patients with RA albeit coinducing rare but serious side effects. Aiming to find new potent therapeutics, we applied the L1000CDS2 search engine, to repurpose drugs that could reverse the pathogenic expression signature of arthritogenic human TNF-transgenic (hTNFtg) SFs.

Cortical interneuron specification and diversification in the era of big data.

Inhibition in the mammalian cerebral cortex is mediated by a small population of highly diverse GABAergic interneurons. These largely local neurons are interspersed among excitatory projection neurons and exert pivotal regulation on the formation and function of cortical circuits. We are beginning to understand the extent of GABAergic neuron diversity and how this is generated and shaped during brain development in mice and humans.

HuR modulation counteracts lipopolysaccharide response in murine macrophages.

Lipopolysaccharide (LPS) exposure to macrophages induces an inflammatory response, which is regulated at the transcriptional and post-transcriptional levels. HuR (ELAVL1) is an RNA-binding protein that regulates cytokines and chemokines transcripts containing AU/U-rich elements (AREs) and mediates the LPS-induced response. Here, we show that small-molecule tanshinone mimics (TMs) inhibiting HuR-RNA interaction counteract LPS stimulus in macrophages.

Human Tau Aggregates Are Permissive to Protein Synthesis-Dependent Memory in Tauopathy Models.

Tauopathies including Alzheimer's disease, are characterized by progressive cognitive decline, neurodegeneration, and intraneuronal aggregates comprised largely of the axonal protein Tau. It has been unclear whether cognitive deficits are a consequence of aggregate accumulation thought to compromise neuronal health and eventually lead to neurodegeneration. We use the tauopathy model and mixed-sex populations to reveal an adult onset pan-neuronal Tau accumulation-dependent decline in learning efficacy and a specific defect in protein synthesis-dependent memory (PSD-M), but not in its protein synthesis-independent variant.

SEGCOND predicts putative transcriptional condensate-associated genomic regions by integrating multi-omics data.

Motivation: The compartmentalization of biochemical reactions, involved in the activation of gene expression in the eukaryotic nucleus, leads to the formation of membraneless bodies through liquid-liquid phase separation. These formations, called transcriptional condensates, appear to play important roles in gene regulation as they are assembled through the association of multiple enhancer regions in 3D genomic space. To date, we are still lacking efficient computational methodologies to identify the regions responsible for the formation of such condensates, based on genomic and conformational data.

The 3D enhancer network of the developing T cell genome is shaped by SATB1.

Mechanisms of tissue-specific gene expression regulation via 3D genome organization are poorly understood. Here we uncover the regulatory chromatin network of developing T cells and identify SATB1, a tissue-specific genome organizer, enriched at the anchors of promoter-enhancer loops. We have generated a T-cell specific Satb1 conditional knockout mouse which allows us to infer the molecular mechanisms responsible for the deregulation of its immune system.

Differential Effects of Human Tau Isoforms to Neuronal Dysfunction and Toxicity in the Drosophila CNS.

Accumulation of highly post-translationally modified tau proteins is a hallmark of neurodegenerative disorders known as tauopathies, the most common of which is Alzheimer's disease. Although six tau isoforms are found in the human brain, the majority of animal and cellular tauopathy models utilize a representative single isoform. However, the six human tau isoforms present overlapping but distinct distributions in the brain and are differentially involved in particular tauopathies.

Mical modulates Tau toxicity via cysteine oxidation in vivo.

Tau accumulation is clearly linked to pathogenesis in Alzheimer's disease and other Tauopathies. However, processes leading to Tau fibrillization and reasons for its pathogenicity remain largely elusive. Mical emerged as a novel interacting protein of human Tau expressed in Drosophila brains.

Inactivation of AUF1 in Myeloid Cells Protects From Allergic Airway and Tumor Infiltration and Impairs the Adenosine-Induced Polarization of Pro-Angiogenic Macrophages.

The four isoforms of the RNA-binding protein hnRNPD/AUF1 have been proposed to limit the use of inflammatory mRNAs in innate immune cells. Mice engineered to lack AUF1s in all tissues are sensitive to acute inflammatory assaults; however, they also manifest complex degenerations obscuring assessment of AUF1s' roles in innate immune cells. Here, we restricted a debilitating AUF1 mutation to the mouse myeloid lineage and performed disease-oriented phenotypic analyses to assess the requirement of AUF1s in variable contexts of innate immune reactivity.

Vascular cell-matrix adhesion in development and cancer.

The development and homeostasis of vertebrate organisms depend on the "tree of life", in other words, the intricate network of vascular tubes composed of endothelial cells attached to the basement membrane and surrounded by perivascular cells. Although many studies have revealed the fundamental role of cytokines, growth factors and Notch signalling in vascular morphogenesis, we still lack sufficient understanding of the molecular mechanisms controlling the various steps of the angiogenic processes. Emerging data highlight that cell adhesions are key players in vascular morphogenesis.

Collagen 1a1 Expression by Airway Macrophages Increases In Fibrotic ILDs and Is Associated With FVC Decline and Increased Mortality.

Within the Interstitial Lung Diseases (ILD), patients with idiopathic pulmonary fibrosis (IPF) and a subset of those with non-IPF fibrotic ILD have a distinct clinical phenotype of progression despite management. This group of patients has been collectively termed the progressive fibrotic phenotype (PFP). Their early recognition may facilitate access to antifibrotic therapies to prevent or slow progression.

Fundamentally different roles of neuronal TNF receptors in CNS pathology: TNFR1 and IKKβ promote microglial responses and tissue injury in demyelination while TNFR2 protects against excitotoxicity in mice.

Background: During inflammatory demyelination, TNF receptor 1 (TNFR1) mediates detrimental proinflammatory effects of soluble TNF (solTNF), whereas TNFR2 mediates beneficial effects of transmembrane TNF (tmTNF) through oligodendroglia, microglia, and possibly other cell types. This model supports the use of selective inhibitors of solTNF/TNFR1 as anti-inflammatory drugs for central nervous system (CNS) diseases. A potential obstacle is the neuroprotective effect of solTNF pretreatment described in cultured neurons, but the relevance in vivo is unknown.