Loss of TDP-43 oligomerization or RNA binding elicits distinct aggregation patterns.

Aggregation of the RNA-binding protein TAR DNA-binding protein 43 (TDP-43) is the key neuropathological feature of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). In physiological conditions, TDP-43 is predominantly nuclear, forms oligomers, and is contained in biomolecular condensates assembled by liquid-liquid phase separation (LLPS). In disease, TDP-43 forms cytoplasmic or intranuclear inclusions.

Left ventricular assist devices promote changes in the expression levels of platelet microRNAs.

Introduction: MicroRNAs (miRs) emerged as promising diagnostic and therapeutic biomarkers in cardiovascular diseases. The potential clinical utility of platelet miRs in the setting of left ventricular assist device (LVAD) support is unexplored.

Methods: We prospectively measured he expression levels of 12 platelet miRs involved in platelet activation, coagulation, and cardiovascular diseases in LVAD patients by quantitative real-time polymerase chain reaction.

Human seminal plasma stimulates the migration of CD11c+ mononuclear phagocytes to the apical side of the colonic epithelium without altering the junctional complexes in an human intestinal model.

Introduction: Human immunodeficiency virus type 1 (HIV) transmission mostly occurs through the genital and intestinal mucosae. Although HIV-1 transmission has been extensively investigated, gaps remain in understanding the initial steps of HIV entry through the colonic mucosa. We previously showed that HIV can selectively trigger mononuclear phagocytes (MNP) to migrate within colonic epithelial cells to sample virions.

RNA-seq profiling reveals different pathways between remodeled vessels and myocardium in hypertrophic cardiomyopathy.

Objective: Coronary microvascular dysfunction (CMD) is a key pathophysiological feature of hypertrophic cardiomyopathy (HCM), contributing to myocardial ischemia and representing a critical determinant of patients' adverse outcome. The molecular mechanisms underlying the morphological and functional changes of CMD are still unknown. Aim of this study was to obtain insights on the molecular pathways associated with microvessel remodeling in HCM.

Myosins and MyomiR Network in Patients with Obstructive Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiomyopathy. The molecular mechanisms determining HCM phenotypes are incompletely understood. Myocardial biopsies were obtained from a group of patients with obstructive HCM (n = 23) selected for surgical myectomy and from 9 unused donor hearts (controls).

Identification of CX3CR1 mononuclear phagocyte subsets involved in HIV-1 and SIV colorectal transmission.

The difficulty to unambiguously identify the various subsets of mononuclear phagocytes (MNPs) of the intestinal has hindered our understanding of the initial events occurring after mucosal exposure to HIV-1. Here, we compared the composition and function of MNP subsets at steady-state and following and viral exposure in human and macaque colorectal tissues. Combined evaluation of CD11c, CD64, CD103, and CX3CR1 expression allowed to differentiate MNPs subsets common to both species.

Confocal Blood Flow Videomicroscopy of Thrombus Formation over Human Arteries and Local Targeting of P2X7.

Atherothrombosis exposes vascular components to blood. Currently, new antithrombotic therapies are emerging. Herein we investigated thrombogenesis of human arteries with/without atherosclerosis, and the interaction of coagulation and vascular components, we and explored the anti-thrombogenic efficacy of blockade of the P2X purinoceptor 7 (P2X7).

Myocardial blood flow in patients with hypertrophic cardiomyopathy receiving perindopril (CARAPaCE): a pilot study.

Aims: Coronary microvascular dysfunction (CMD) represents a powerful independent predictor of adverse outcome in hypertrophic cardiomyopathy (HCM). No treatment for CMD exists. The angiotensin-converting enzyme (ACE)-inhibitor perindopril improves myocardial blood flow (MBF) in animal models of cardiac hypertrophy and in hypertensive patients.

Mitochondrial Energetics and Ca2-Activated ATPase in Obstructive Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is the most common genetic disease of the myocardium associated to mutations in sarcomeric genes, but the link between genotype and phenotype remains poorly understood. Magnetic resonance spectroscopy studies have demonstrated impaired cardiac energetics in patients with HCM, and altered mitochondria were described in biopsies, but little is known about possible perturbations of mitochondrial function and adenosine triphosphate (ATP) production/consumption. The aim of this study was to investigate possible abnormalities in mitochondrial enzymes generating/scavenging reactive oxygen species, and changes in the Ca-activated ATPases in myocardial tissue from patients with obstructive HCM undergoing surgical myectomy compared to unused donor hearts (CTRL).

Trehalose administration in C57BL/6N old mice affects healthspan improving motor learning and brain anti-oxidant defences in a sex-dependent fashion: a pilot study.

Aim of this study was to characterize the effects of oral trehalose administration (2%w/v) on healthspan in old mice. Trehalose was administered in drinking water for 1 month to male and female C57BL/6N mice aged 25-months. After behavioral phenotyping (grip strength, beam walking and rotarod tests), autophagy (LC3-II/actin) and oxidative stress were tested in the cerebral cortex and gastrocnemius muscle.

IL-1β/MMP9 activation in primary human vascular smooth muscle-like cells: Exploring the role of TNFα and P2X7.

Background: Vascular smooth muscle cells exhibit phenotypic plasticity in response to microenvironmental stimuli and contribute to vascular remodelling through mechanisms only partially understood. In atherosclerosis, P2X-purinoceptor7 (P2X7) has been related to interleukin-1β (IL-1β) and metalloproteinase 9 (MMP9). The hypoxia-inducible factor-1alpha (HIF1α) was associated to remodelling.

Phosphorylation of nuclear Tau is modulated by distinct cellular pathways.

Post-translational protein modification controls the function of Tau as a scaffold protein linking a variety of molecular partners. This is most studied in the context of microtubules, where Tau regulates their stability as well as the distribution of cellular components to defined compartments. However, Tau is also located in the cell nucleus; and is found to protect DNA.

The calcium-binding type III repeats domain of thrombospondin-2 binds to fibroblast growth factor 2 (FGF2).

Thrombospondin (TSP)-1 and TSP-2 share similar structures and functions, including a remarkable antiangiogenic activity. We have previously demonstrated that a mechanism of the antiangiogenic activity of TSP-1 is the interaction of its type III repeats domain with fibroblast growth factor-2 (FGF2), affecting the growth factor bioavailability and angiogenic activity. Since the type III repeats domain is conserved in TSP-2, this study aimed at investigating whether also TSP-2 retained the ability to interact with FGF2.

Split GFP technologies to structurally characterize and quantify functional biomolecular interactions of FTD-related proteins.

Protein multimerization in physiological and pathological conditions constitutes an intrinsic trait of proteins related to neurodegeneration. Recent evidence shows that TDP-43, a RNA-binding protein associated with frontotemporal dementia and amyotrophic lateral sclerosis, exists in a physiological and functional nuclear oligomeric form, whose destabilization may represent a prerequisite for misfolding, toxicity and subsequent pathological deposition. Here we show the parallel implementation of two split GFP technologies, the GFP bimolecular and trimolecular fluorescence complementation (biFC and triFC) in the context of TDP-43 self-assembly.

P2X7 receptor antagonism modulates IL-1β and MMP9 in human atherosclerotic vessels.

In atherosclerosis, matrix metallopeptidases (MMPs) contribute to plaque rupture through weakening of the fibrous cap. Pleiotropic P2X purinoceptor 7 (P2X7), expressed in the carotid plaque (PL), is involved in interleukin 1 beta (IL-1β) release that may influence MMP9 generation, thus their possible modulation through acting on P2X7 was investigated. P2X7-related machinery was characterized and the effects of P2X7 antagonists (A740003, KN62) and MMPs inhibitors (Batimastat, Ro28-2653) were studied in ex-vivo tissue cultures of human PL's vs.

Functional and dynamic polymerization of the ALS-linked protein TDP-43 antagonizes its pathologic aggregation.

TDP-43 is a primarily nuclear RNA-binding protein, whose abnormal phosphorylation and cytoplasmic aggregation characterizes affected neurons in patients with amyotrophic lateral sclerosis and frontotemporal dementia. Here, we report that physiological nuclear TDP-43 in mouse and human brain forms homo-oligomers that are resistant to cellular stress. Physiological TDP-43 oligomerization is mediated by its N-terminal domain, which can adopt dynamic, solenoid-like structures, as revealed by a 2.

Adaptive immunity against gut microbiota enhances apoE-mediated immune regulation and reduces atherosclerosis and western-diet-related inflammation.

Common features of immune-metabolic and inflammatory diseases such as metabolic syndrome, diabetes, obesity and cardiovascular diseases are an altered gut microbiota composition and a systemic pro-inflammatory state. We demonstrate that active immunization against the outer membrane protein of bacteria present in the gut enhances local and systemic immune control via apoE-mediated immune-modulation. Reduction of western-diet-associated inflammation was obtained for more than eighteen weeks after immunization.

Early left atrial tissue features in patients with chronic mitral regurgitation and sinus rhythm: Alterations of not remodeled left atria.

Objective: Left atrial (LA) enlargement, a compensatory mechanism in chronic mitral regurgitation (MR) increasing the risk of atrial fibrillation (AF) and predictive of cardiac events, involves structural alterations. We characterized LA features in patients in sinus rhythm with severe degree of MR, similar degrees of left ventricular remodeling but divergent LA size.

Methods: Among a consecutive series of 163 patients in stable sinus rhythm undergoing isolated mitral valve surgery for severe non-rheumatic MR, two groups were arbitrarily selected according to their LA size (antero-posterior): NRLA group (non-remodeled LA) included 8 patients with LA≤40mm, RLA group (remodeled LA) included 8 patients with LA>55mm.

Integrating computational and chemical biology tools in the discovery of antiangiogenic small molecule ligands of FGF2 derived from endogenous inhibitors.

The FGFs/FGFRs system is a recognized actionable target for therapeutic approaches aimed at inhibiting tumor growth, angiogenesis, metastasis, and resistance to therapy. We previously identified a non-peptidic compound (SM27) that retains the structural and functional properties of the FGF2-binding sequence of thrombospondin-1 (TSP-1), a major endogenous inhibitor of angiogenesis. Here we identified new small molecule inhibitors of FGF2 based on the initial lead.

Thrombospondin-1 is part of a Slug-independent motility and metastatic program in cutaneous melanoma, in association with VEGFR-1 and FGF-2.

Differently from most transformed cells, cutaneous melanoma expresses the pleiotropic factor thrombospondin-1 (TSP-1). Herein, we show that TSP-1 (RNA and protein), undetectable in four cultures of melanocytes and a RGP melanoma, was variously present in 13 cell lines from advanced melanomas or metastases. Moreover, microarray analysis of 55 human lesions showed higher TSP-1 expression in primary melanomas and metastases than in common and dysplastic nevi.

R5 HIV-1 envelope attracts dendritic cells to cross the human intestinal epithelium and sample luminal virions via engagement of the CCR5.

The gastrointestinal tract is a principal route of entry and site of persistence of human immunodeficiency virus type 1 (HIV-1). The intestinal mucosa, being rich of cells that are the main target of the virus, represents a primary site of viral replication and CD4(+) T-cell depletion. Here, we show both in vitro and ex vivo that HIV-1 of R5 but not X4 phenotype is capable of selectively triggering dendritic cells (DCs) to migrate within 30 min between intestinal epithelial cells to sample virions and transfer infection to target cells.