A structure-based proposal for the catalytic mechanism of the bacterial acid phosphatase AphA belonging to the DDDD superfamily of phosphohydrolases

The Escherichia coli gene aphA codes for a periplasmic acid phosphatase called AphA, belonging to class B bacterial phosphatases, which is part of the DDDD superfamily of phosphohydrolases. After our first report about its crystal structure, we have started a series of crystallographic studies aimed at understanding of the catalytic mechanism of the enzyme. Here, we report three crystal structures of the AphA enzyme in complex with the hydrolysis products of nucleoside monophosphate substrates and a fourth with a proposed intermediate analogue that appears to be covalently bound to the enzyme. Comparison with the native enzyme structure and with the available X-ray structures of different phosphatases provides clues about the enzyme chemistry and allows us to propose a catalytic mechanism for AphA, and to discuss it with respect to the mechanism of other bacterial and human phosphatases. (c) 2005 Elsevier Ltd. All rights reserved

Evidence of non-seed transmission of viruses in grapevine breeding material

The vertical transmission of viruses is an important phenomenon affecting a wide range of viruses and host plants. Nevertheless, the presence of virus in a seed does not always lead to seedling infection. In grapevine, seed transmission has been reported for many nepoviruses, but little is known about Leafroll, Rugose wood complex and Fleck diseases. Thus, the aim of this study is to monitor the virological condition of seedlings obtained by crosses between infected parents, analyzing the sanitary status of seedlings after the transfer in experimental fields. It was observed that, although the viral state of parents was quite compromised, viruses were not detected in any of the 150 progeny plants, demonstrating that the main grapevine viruses are at low risk for seed transmission

Altered two-dimensional strain measures of the right ventricle in patients with Brugada syndrome and arrhythmogenic right ventricular dysplasia/cardiomyopathy

Aims: Brugada syndrome (BrS) is an inherited channelopathy that can be characterized by mild right ventricular (RV) abnormalities that are not detectable with conventional echocardiography. The aim of this study was to evaluate the presence of RV abnormalities in BrS patients when compared with controls and a group of patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) using two-dimensional (2D) strain analysis. Methods and results: We enrolled 25 BrS, 15 ARVD/C patients, and 25 controls. Right and left ventricular dimension and systo-diastolic function were evaluated by conventional echocardiography. Longitudinal systolic strain (sS) peak, systolic and early diastolic strain rate of lateral RV segments were evaluated by 2D speckle tracking analysis. Left ventricle global and segmental strain measures were also evaluated. A reduced basal or mid-RV lateral sS were the parameters mostly associated with both BrS and ARVD/C. In BrS patients the minimum sS observed in these segments was significantly lower than that of controls (-28.9±3.2% vs. -32.3±3.2%, P: 0.002) but significantly greater than that evaluated in ARVD/C patients (-24.6 ±6.7%, P < 0.001 both vs. BrS and controls). No differences were found between the BrS and the control group when left ventricular strain measures were analysed. Conclusion: By 2D strain technique it is possible to observe mild abnormalities in RV systolic and diastolic function of BrS patients that are less pronounced than those observed in ARVD/C patients. These results help to better define the phenotypic characteristics of BrS patients and represent the basis for future studies aimed at testing their clinical usefulness in BrS patients

Electrocardiographic features, mapping and ablation of idiopathic outflow tract ventricular arrhythmias

Idiopathic outflow tract ventricular arrhythmias are ventricular tachycardias or premature ventricular contractions presumably not related to myocardial scar or disorders of ion channels. These arrhythmias have focal origin and display characteristic electrocardiographic features. The purpose of this article is to review the state of the art of diagnosis and treatment of idiopathic outflow tract ventricular arrhythmias

Direct oral anticoagulants versus vitamin K antagonists in patients with atrial fibrillation and cancer a meta-analysis

Background: Direct oral anticoagulants (DOACs) are recommended as first-line anticoagulants in patients with atrial fibrillation (AF). However, in patients with cancer and AF the efficacy and safety of DOACs are not well established. Objective: We performed a meta-analysis comparing available data regarding the efficacy and safety of DOACs vs vitamin K antagonists (VKAs) in cancer patients with non-valvular AF. Methods: An online search of Pubmed and EMBASE libraries (from inception to May, 1 2020) was performed, in addition to manual screening. Nine studies were considered eligible for the meta-analysis involving 46,424 DOACs users and 182,797 VKA users. Results: The use of DOACs was associated with reduced risks of systemic embolism or any stroke (RR 0.65; 95% CI 0.52–0.81; p 0.001), ischemic stroke (RR 0.84; 95% CI 0.74–0.95; p 0.007) and hemorrhagic stroke (RR 0.61; 95% CI 0.52–0.71; p 0.00001) as compared to VKA group. DOAC use was associated with significantly reduced risks of major bleeding (RR 0.68; 95% CI 0.50–0.92; p 0.01) and intracranial or gastrointestinal bleeding (RR 0.64; 95% CI 0.47–0.88; p 0.006). Compared to VKA, DOACs provided a non-statistically significant risk reduction of the outcomes major bleeding or non-major clinically relevant bleeding (RR 0.94; 95% CI 0.78–1.13; p 0.50) and any bleeding (RR 0.91; 95% CI 0.78–1.06; p 0.24). Conclusions: In comparison to VKA, DOACs were associated with a significant reduction of the rates of thromboembolic events and major bleeding complications in patients with AF and cancer. Further studies are needed to confirm our results

Does catheter ablation cure atrial fibrillation? Single-procedure outcome of drug-refractory atrial fibrillation ablation: A 6-year multicentre experience

Aims In the last decade, several approaches to ablating triggers and substrates of atrial fibrillation (AF) have been developed. However, most studies have reported data only on short- or medium-term follow-up. The aim of this study was to investigate whether the 1-year efficacy of catheter ablation for AF is predictive of long-term clinical success. Methods and results Between February 2001 and October 2003, 229 consecutive patients affected by drug-refractory paroxysmal or persistent AF underwent a single radiofrequency catheter ablation procedure (anatomical approach in 146 patients and electrophysiologically guided approach in 83 patients). Of these patients, 177 (mean age 59.1 \uc2\ub1 10.5 years, 57.6% with paroxysmal AF) were free from any atrial arrhythmia recurrence after 12 months. These 177 patients were subsequently followed up for at least another 24 months, by means of electrocardiogram and 24 h Holter monitoring. After a mean follow-up of 49.7 \uc2\ub1 13.3 months (range 36-83 months), 58.2% of the patients were free from any atrial arrhythmia recurrence (39.5% without antiarrhythmic drugs). The actuarial atrial arrhythmia recurrence rate was 13.0% at 2 years, 21.8% at 3 years, 35.0% at 4 years, 46.8% at 5 years, and 54.6% at 6 years. Atrial arrhythmia-free survival was similar in patients with paroxysmal or persistent AF, with and without antiarrhythmic drugs during the follow-up, who underwent electrophysiologically guided pulmonary vein (PV) isolation or anatomical PV ablation. Conclusion Even patients in whom catheter ablation prevents AF recurrence for 1 year should not be considered 'cured', since >40 of them will suffer AF recurrence over a long-term clinical follow-up

Targeting p53 and histone methyltransferases restores exhausted CD8+ T cells in HCV infection

Hepatitis C virus infection (HCV) represents a unique model to characterize, from early to late stages of infection, the T cell differentiation process leading to exhaustion of human CD8+ T cells. Here we show that in early HCV infection, exhaustion-committed virus-specific CD8+ T cells display a marked upregulation of transcription associated with impaired glycolytic and mitochondrial functions, that are linked to enhanced ataxia-telangiectasia mutated (ATM) and p53 signaling. After evolution to chronic infection, exhaustion of HCV-specific T cell responses is instead characterized by a broad gene downregulation associated with a wide metabolic and anti-viral function impairment, which can be rescued by histone methyltransferase inhibitors. These results have implications not only for treatment of HCV-positive patients not responding to last-generation antivirals, but also for other chronic pathologies associated with T cell dysfunction, including cancer

The tectonic puzzle of the Messina area (Southern Italy): Insights from new seismic reflection data

The Messina Strait, that separates peninsular Italy from Sicily, is one of the most seismically active areas of the Mediterranean. The structure and seismotectonic setting of the region are poorly understood, although the area is highly populated and important infrastructures are planned there. New seismic reflection data have identified a number of faults, as well as a crustal scale NE-trending anticline few km north of the strait. These features are interpreted as due to active right-lateral transpression along the north-eastern Sicilian offshore, coexisting with extensional and right-lateral transtensional tectonics in the southern Messina Strait. This complex tectonic network appears to be controlled by independent and overlapping tectonic settings, due to the presence of a diffuse transfer zone between the SE-ward retreating Calabria subduction zone relative to slab advance in the western Sicilian side