Succinate-producing microbiota drives tuft cell hyperplasia to protect against Clostridioides difficile.

The role of microbes and their metabolites in modulating tuft cell (TC) dynamics in the large intestine and the relevance of this pathway to infections is unknown. Here, we uncover that microbiome-driven colonic TC hyperplasia protects against Clostridioides difficile infection. Using selective antibiotics, we demonstrate increased type 2 cytokines and TC hyperplasia in the colon but not in the ileum.

Anatomical-guided third-generation laser balloon ablation for the treatment of paroxysmal atrial fibrillation assessed by continuous rhythm monitoring: results from a multicentre prospective study.

Aims: The third-generation laser balloon (LB3) is an established ablation device for pulmonary vein isolation (PVI) that allows direct visualization of the anatomical target. Equipped with an automatic circumferential laser delivery modality, it aims at continuous circumferential PVI, improving both acute and clinical outcomes. We sought to evaluate the clinical efficacy of LB3 ablation using an anatomical-based approach without verifying electrical isolation.

Distinct components of nucleoside-modified messenger RNA vaccines cooperate to instruct efficient germinal center responses.

Nucleoside-modified mRNA vaccines elicit protective antibodies through their ability to promote T follicular helper (Tfh) cells. The lipid nanoparticle (LNP) component of mRNA vaccines possesses inherent adjuvant activity. However, to what extent the nucleoside-modified mRNA can be sensed and contribute to Tfh cell responses remains largely undefined.

Microbiota encoded fatty-acid metabolism expands tuft cells to protect tissues homeostasis during infection in the large intestine.

Metabolic byproducts of the intestinal microbiota are crucial in maintaining host immune tone and shaping inter-species ecological dynamics. Among these metabolites, succinate is a driver of tuft cell (TC) differentiation and consequent type 2 immunity-dependent protection against invading parasites in the small intestine. Succinate is also a growth enhancer of the nosocomial pathogen in the large intestine.

Embryonic type 3 innate lymphoid cells sense maternal dietary cholesterol to control local Peyer's patch development.

Lymphoid tissue inducer (LTi) cells develop during intrauterine life and rely on developmental programs to initiate the organogenesis of secondary lymphoid organs (SLOs). This evolutionary conserved process endows the fetus with the ability to orchestrate the immune response after birth and to react to the triggers present in the environment. While it is established that LTi function can be shaped by maternal-derived cues and is critical to prepare the neonate with a functional scaffold to mount immune response, the cellular mechanisms that control anatomically distinct SLO organogenesis remain unclear.

An epithelial cell-derived metabolite tunes immunoglobulin A secretion by gut-resident plasma cells.

Immunoglobulin A (IgA) secretion by plasma cells, terminally differentiated B cells residing in the intestinal lamina propria, assures microbiome homeostasis and protects the host against enteric infections. Exposure to diet-derived and commensal-derived signals provides immune cells with organizing cues that instruct their effector function and dynamically shape intestinal immune responses at the mucosal barrier. Recent data have described metabolic and microbial inputs controlling T cell and innate lymphoid cell activation in the gut; however, whether IgA-secreting lamina propria plasma cells are tuned by local stimuli is completely unknown.

Long-term comparisons of atrial fibrillation ablation outcomes with a cryoballoon or laser-balloon: A propensity-matched analysis based on continuous rhythm monitoring.

Objective: Cryoballoon (CB) and laser-balloon (LB) catheter ablation (CA) has been demonstrated to achieve durable and effective pulmonary vein isolation (PVI). Only one head-to-head comparison with an intermittent rhythm monitor strategy is currently available. The aim of this study was to compare acute and long-term outcomes of CB and LB atrial fibrillation ablation procedures, by using a continuous rhythm monitoring strategy.

The cholesterol metabolite 25-hydroxycholesterol restrains the transcriptional regulator SREBP2 and limits intestinal IgA plasma cell differentiation.

Diets high in cholesterol alter intestinal immunity. Here, we examined how the cholesterol metabolite 25-hydroxycholesterol (25-HC) impacts the intestinal B cell response. Mice lacking cholesterol 25-hydroxylase (CH25H), the enzyme generating 25-HC, had higher frequencies of immunoglobulin A (IgA)-secreting antigen-specific B cells upon immunization or infection.

Dysbiosis exacerbates colitis by promoting ubiquitination and accumulation of the innate immune adaptor STING in myeloid cells.

Alterations in the cGAS-STING DNA-sensing pathway affect intestinal homeostasis. We sought to delineate the functional role of STING in intestinal inflammation. Increased STING expression was a feature of intestinal inflammation in mice with colitis and in humans afflicted with inflammatory bowel disease.

Second-generation laser balloon ablation for the treatment of atrial fibrillation assessed by continuous rhythm monitoring: the LIGHT-AF study.

Aims: Balloon-based technologies have been developed to simplify catheter ablation of atrial fibrillation (AF), to improve the clinical outcome of the procedure and to achieve durable pulmonary vein isolation (PVI). The objective of this study is to evaluate the safety and efficacy of second-generation laser balloon (LB2) ablation in the treatment of AF using a continuous cardiac rhythm monitoring strategy. Atrial tachyarrhythmias (ATas) recurrences were assessed with implantable cardiac monitors (ICMs) or devices.

Cryoballoon ablation for paroxysmal atrial fibrillation: mid-term outcome evaluated by ECG monitoring with an implantable loop recorder.

Background: The success rate after cryoballoon ablation (CB-A) performed for paroxysmal atrial fibrillation (PAF) might be overestimated by traditional noninvasive monitoring techniques. The purpose of this study was to evaluate the mid-term outcome of CB-A in patients with PAF implanted with an implantable loop recorder (ILR) after the procedure.

Methods: Between January 2017 and March 2019, all patients who underwent CB-A for PAF and who were subsequently implanted with an ILR were retrospectively included.

Synthesis of a CGRP Receptor Antagonist via an Asymmetric Synthesis of 3-Fluoro-4-aminopiperidine.

A practical and efficient enantioselective synthesis of the calcitonin gene-related peptide receptor antagonist 1 has been developed. The key structural component of the active pharmaceutical ingredient is a syn-1,2-amino-fluoropiperidine 4. Two approaches were developed to synthesize this important pharmacophore.

IBTK contributes to B-cell lymphomagenesis in Eμ-myc transgenic mice conferring resistance to apoptosis.

Increasing evidence supports the involvement of IBTK in cell survival and tumor growth. Previously, we have shown that IBTK RNA interference affects the wide genome expression and RNA splicing in cell-type specific manner. Further, the expression of IBTK gene progressively increases from indolent to aggressive stage of chronic lymphocytic leukemia and decreases in disease remission after therapy.

Monitoring multiple myeloma by idiotype-specific peptide binders of tumor-derived exosomes.

Tumor-derived exosomes (TDEs) play a pivotal role in tumor establishment and progression, and are emerging biomarkers for tumor diagnosis in personalized medicine. To date, there is a lack of efficient technology platforms for exosome isolation and characterization. Multiple myeloma (MM) is an incurable B-cell malignancy due to the rapid development of drug-resistance.

IBTK Differently Modulates Gene Expression and RNA Splicing in HeLa and K562 Cells.

The gene encodes the major protein isoform IBTKα that was recently characterized as substrate receptor of Cul3-dependent E3 ligase, regulating ubiquitination coupled to proteasomal degradation of Pdcd4, an inhibitor of translation. Due to the presence of Ankyrin-BTB-RCC1 domains that mediate several protein-protein interactions, IBTKα could exert expanded regulatory roles, including interaction with transcription regulators. To verify the effects of IBTKα on gene expression, we analyzed HeLa and K562 cell transcriptomes by RNA-Sequencing before and after knock-down by shRNA transduction.

A novel compact mass detection platform for the open access (OA) environment in drug discovery and early development.

A new 'compact mass detector' co-developed with an instrument manufacturer (Waters Corporation) as an interface for liquid chromatography (LC), specifically Ultra-high performance LC(®) (UPLC(®) or UHPLC) analysis was evaluated as a potential new Open Access (OA) LC-MS platform in the Drug Discovery and Early Development space. This new compact mass detector based platform was envisioned to provide increased reliability and speed while exhibiting significant cost, noise, and footprint reductions. The new detector was evaluated in batch mode (typically 1-3 samples per run) to monitor reactions and check purity, as well as in High Throughput Screening (HTS) mode to run 24, 48, and 96 well plates.

Impairment of T cell development and acute inflammatory response in HIV-1 Tat transgenic mice.

Immune activation and chronic inflammation are hallmark features of HIV infection causing T-cell depletion and cellular immune dysfunction in AIDS. Here, we addressed the issue whether HIV-1 Tat could affect T cell development and acute inflammatory response by generating a transgenic mouse expressing Tat in lymphoid tissue. Tat-Tg mice showed thymus atrophy and the maturation block from DN4 to DP thymic subpopulations, resulting in CD4(+) and CD8(+) T cells depletion in peripheral blood.

CRL3IBTK Regulates the Tumor Suppressor Pdcd4 through Ubiquitylation Coupled to Proteasomal Degradation.

The human inhibitor of Bruton's tyrosine kinase isoform α (IBtkα) is a BTB protein encoded by the IBTK gene, which maps to chromosomal locus 6q14.1, a mutational hot spot in lymphoproliferative disorders. Here, we demonstrate that IBtkα forms a CRL3(IBTK) complex promoting its self-ubiquitylation.

Discovery of MK-8970: an acetal carbonate prodrug of raltegravir with enhanced colonic absorption.

Developing new antiretroviral therapies for HIV-1 infection with potential for less frequent dosing represents an important goal within drug discovery. Herein, we present the discovery of ethyl (1-((4-((4-fluorobenzyl)carbamoyl)-1-methyl-2-(2-(5-methyl- 1,3,4-oxadiazole-2-carboxamido)propan-2-yl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)ethyl) carbonate (MK-8970), a highly optimized prodrug of raltegravir (Isentress). Raltegravir is a small molecule HIV integrase strand-transfer inhibitor approved for the treatment of HIV infection with twice-daily administration.

Effect of chromogranin A-derived vasostatin-1 on laser-induced choroidal neovascularization in the mouse.

Purpose: To verify the effect of vasostatin-1 (VS-1), an anti-angiogenic fragment of chromogranin A, in the prevention of choroidal neovascularization (CNV) in an established mouse model of laser-induced ocular neovascularization.

Methods: Bruch's membrane, the innermost layer of the choroid, was broken by laser photocoagulation in C57/Bl6 mice, to induce CNV. Mice were then treated daily for 14 days by intraperitoneal injection of VS-1 or vehicle (6 mice/group).

The effects of sulodexide on both clinical and molecular parameters in patients with mixed arterial and venous ulcers of lower limbs.

Background: Mixed venous and arterial ulcers account for approximately 15%-30% of all venous leg ulcerations. Several studies have shown that matrix metalloproteinases (MMPs) and neutrophil gelatinase-associated lipocalin (NGAL) play a central role in the pathophysiology of venous and arterial diseases. Some studies have shown the efficacy of glycosaminoglycans, such as sulodexide (SDX), in treating patients with leg ulcers.

A noninvasive index of atrial remodeling in patients with paroxysmal and persistent atrial fibrillation: a pilot study.

Purpose: This study aims to develop a noninvasive atrial remodeling index (RI) to separate patients presenting paroxysmal atrial fibrillation (ParAF) from those with sustained persistent atrial fibrillation (PerAF), that is, AF episodes interrupted 7 days or more after the onset.

Methods: Signal-averaged P-wave duration (SAPWd) and left atrial anteroposterior diameter (LADd) were measured in 33 ParAF patients, in 26 sustained PerAF patients, and in 18 control subjects. By using SAPWd and LADd, a dichotomous (0/1) RI was created.