The lymphoid tyrosine phosphatase LYP, encoded by the PTPN22 gene, is a critical regulator of signaling in T cells and recently emerged as a candidate target for therapy of autoimmune diseases. Here, by library screening, we identified a series of noncompetitive inhibitors of LYP that showed activity in primary T cells. Kinetic analysis confirmed that binding of the compounds to the phosphatase is nonmutually exclusive with respect to a known bidentate competitive inhibitor. The mechanism of action of the lead inhibitor compound 4e was studied by a combination of hydrogen/deuterium-exchange mass spectrometry and molecular modeling. The results suggest that the inhibitor interacts critically with a hydrophobic patch located outside the active site of the phosphatase. Targeting of secondary allosteric sites is viewed as a promising yet unexplored approach to develop pharmacological inhibitors of protein tyrosine phosphatases. Our novel scaffold could be a starting point to attempt development of “nonactive site” anti-LYP pharmacological agents.

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Background: In August 2020, Sputnik V was registered as Gam-COVID-Vac by the Russian Ministry of Health, and since December 2020 it has been distributed in 61 countries worldwide. On 25 February 2021, the Republic of San Marino started its vaccination campaign, which includes Sputnik V. Our aim was to describe the adverse events following immunization (AEFIs) with this vaccine through participant-based active surveillance in the country. Methods: Beginning from 4 March to 8 April 2021, a nationwide study was conducted on San Marino's population aged 18À89 years who received one or two doses of Sputnik V. E-questionnaire dissemination occurred through e-mails, QR-codes or live/phone interviews~7 days after the first and second vaccine dose. A descriptive analysis was conducted to quantify AEFI incidence on both occasions, stratifying results by type and severity of symptoms. Findings: Mean age of the 2558 vaccine recipients was 66 §14 years. First-dose AEFI incidence was 53.3% (systemic reactions at 42.2%), while second-dose AEFI incidence was 66.8% (systemic reactions at 50.4%) (n = 1288). In general, 76.0% of two-dose recipients reported some AEFIs after either vaccine dose, and 2.1% suffered severe reactions; in 60-to 89-year-olds (n = 1021), AEFI incidence was 70.0%, with 53.0% of subjects describing systemic reactions and 0.8% reporting severe symptoms. The most frequent symptoms were local pain, asthenia, headache and joint pain. Interpretation: Our results, albeit preliminary, suggest that Sputnik V has a high tolerability profile in the population aged 60 years in terms of short-term AEFIs.

BackgroundBeing highly self-efficacious is a key factor in successful chronic disease self-management. In the context of measuring self-efficacy in type 2 diabetes management, the Diabetes Management Self-Efficacy Scale (DMSES) is the most widely used scale. The aim of this study was to adapt the English version of the scale to Italian and to evaluate the psychometric properties of the Italian version of DMSES in type 2 diabetes (IT-DMSES).MethodsWe conducted a cross-sectional study of people with type 2 diabetes attending the Endocrine-Metabolic Disease Care Unit of the Internal Medicine Department of San Marino State Hospital between October 2016 and February 2017.Patients completed a socio-demographic and clinical data form, the IT-DMSES and 3 self-report questionnaires measuring diabetes distress (PAID-5), psychological well-being (WHO-5) and depression (PHQ-9).Psychometric testing included construct validity (principal component analysis), internal consistency (Cronbach’s α coefficient) and convergent/discriminant validity (Spearman’s correlation coefficient).Decision tree analysis was performed to classify patients into homogeneous subgroups of self-efficacy based on their demographic and clinical characteristics.ResultsParticipants were 110 males and 55 females, mean age of 65.2 years (SD ± 9), 56.9% had been diagnosed for 1–15 years, 63% had HbA1c level > 53 mmol/mol. Two main factors underlain the construct of self-efficacy in diabetes management: ‘Disease Management’ and “Lifestyles Management”. Disease Management had a good reliability (α = .849) and Lifestyle Management had an excellent reliability (α = .902) indicating that the instrument is internally consistent. A negative and weak correlation was found between Lifestyle management, PAID-5 (r = − 0.258, p = < 0.01) and PHQ-9 (r = − 0.274, p = < 0.01) and a positive one with WHO-5 (r = 0.325, p < 0.01) supporting convergent validity. Disease management was uncorrelated with PAID-5 (r = − 0.142, p = 0.083), PHQ-9 (r = − 0.145, p = 0.076) and weekly correlated with WHO-5 (r = 0.170, p = 0.037) confirming discriminant validity. Higher levels of self-efficacy in lifestyle management were found in patients diagnosed for at least 1 year up to 15 years and aged > 65 years and the poorest self-efficacy was found in males < 65 years.ConclusionsResults support the validity and reliability of IT-DMSES. The scale can be used in research and clinical practice to monitor type 2 diabetes self-management over time.Electronic supplementary materialThe online version of this article (10.1186/s12955-018-0901-3) contains supplementary material, which is available to authorized users.

Endothelin-1 (ET-1) is an endothelial-derived 21-amino-acid peptide with potent vasoconstrictor and mitogenic properties implicated in several cardiovascular disorders. To evaluate the plasma ET-1 response to mental stress in patients with intermittent claudication, plasma endothelin concentrations were measured by radioimmunoassay in 15 claudicant outpatients (13 men and 2 women; mean age 62 +/- 4 years) and in 15 sex- and age-matched healthy control subjects (12 men and 3 women; mean age 60 +/- 8 years) before and after mental arithmetic performed for 10 minutes. Venous blood samples were drawn from an antecubital vein at baseline, at the end of the mental arithmetic, and at 10 minutes of recovery. Baseline ET-1 values were higher in patients with intermittent claudication as compared with control subjects (4.5 +/- 0.5 pmol/L and 2.2 +/- 0.3 pmol/L, respectively, p < 0.0001). At the end of mental stress, ET-1 levels rose significantly in both groups from baseline (p < 0.001) reaching a higher value in patients with intermittent claudication than in control subjects (5.6 +/- 0.7 pmol/L and 2.4 +/- 0.4 pmol/L, respectively, p < 0.0001). The percent increases (delta%) in ET-1 plasma concentrations from baseline in response to mental stress were significantly greater in claudicant patients than in control subjects (+23 +/- 9% and +9 +/- 7%, respectively, p < 0.0001). ET-1 plasma concentrations returned to baseline values similarly in both groups at minute 10 of the recovery period. These findings show that acute mental stress causes an exaggerated release of ET-1 in patients with intermittent claudication and suggest that this could be a potential pathophysiological mechanism through which mental stress may trigger adverse acute cardiac events and accelerate progression of atherosclerosis in these patients.