ISG20L2: an RNA nuclease regulating T cell activation.

ISG20L2, a 3' to 5' exoribonuclease previously associated with ribosome biogenesis, is identified here in activated T cells as an enzyme with a preferential affinity for uridylated miRNA substrates. This enzyme is upregulated in T lymphocytes upon TCR and IFN type I stimulation and appears to be involved in regulating T cell function. ISG20L2 silencing leads to an increased basal expression of CD69 and induces greater IL2 secretion. However, ISG20L2 absence impairs CD25 upregulation, CD3 synaptic accumulation and MTOC translocation towards the antigen-presenting cell during immune synapsis. Remarkably, ISG20L2 controls the expression of immunoregulatory molecules, such as AHR, NKG2D, CTLA-4, CD137, TIM-3, PD-L1 or PD-1, which show increased levels in ISG20L2 knockout T cells. The dysregulation observed in these key molecules for T cell responses support a role for this exonuclease as a novel RNA-based regulator of T cell function.This study was supported by grant P2022/BMD7209- INTEGRAMUNE from the Comunidad de Madrid, a grant from “La Caixa” Banking Foundation (HR17-00016) to FS-M; the Spanish Ministerio de Ciencia e Innovación (PDC2021-121719-I00 and PID2020-120412RB-I00 to FS-M), grant from AECC, CIBER Cardiovascular (CB16/11/00272, Fondo de Investigación Sanitaria del Instituto de Salud Carlos III and co-funding by Fondo Europeo de Desarrollo Regional FEDER). The Centro Nacional de Investigaciones Cardiovasculares (CNIC) is supported by the Spanish Ministry of Economy and Competitiveness (MINECO) and the Pro-CNIC Foundation, and is a Severo Ochoa Center of Excellence (MINECO award SEV-2015- 0505). Vaňáčová’s laboratory is supported by the Czech Science Foundation (20-19617S and 23-07372S to S.V.) and the institutional support CEITEC 2020 (LQ1601). ARG and SGD are supported by a grant from the Spanish Ministry of Universities. Funding agencies do not have intervened in the design of the studies, with no copyright over the study.S

Beta-adrenergic drugs and risk of Parkinson\u27s disease: A systematic review and meta-analysis

BACKGROUND: Parkinson\u27s Disease (PD) is a neurodegenerative disorder manifested by rest tremor, rigidity, bradykinesia, and postural instability. Recent pharmaco-epidemiological studies evaluating beta-adrenergic drug use and risk of PD have reported conflicting findings. OBJECTIVES: This systematic review and meta-analyses evaluate the association between beta-adrenergic (agonists and antagonists) drugs\u27 use and PD. METHODS: An electronic literature search of eight databases was performed from inception to July 2021 to identify pharmaco-epidemiological studies (case-control and cohort) reporting the risk of PD in beta-adrenergic users compared to non-users. We used the generic inverse variance method and RevMan (5.3.5) to estimate pooled adjusted risk ratios (aRRs) of PD using a random-effects model. RESULTS: Of 3168 records, 15 studies (10 case-control; five cohort) with 6508,877 participants, including 87,011 PD cases, were included. In the pooled analysis (n = 10) including any beta-antagonist users, compared with non-users, the aRR for PD was 1.19 (CI: 1.05,1.35); for any beta-agonist users (n = 8) aRR for PD was 0.87 (CI: 0.78,0.97). Propranolol users had a significantly increased risk of PD (aRR:1.91; CI:1.20,3.06), whereas salbutamol use was associated with reduced risk of PD (aRR:0.95; CI:0.92,0.99). Significant heterogeneity (I CONCLUSIONS: Beta-antagonist use was associated with a modestly increased risk of PD, whereas beta-agonist use was associated with a modest decreased risk of PD. Future epidemiological studies should address the issues of protopathic bias and indirect association using appropriate epidemiological methods

Beta-Adrenergic Drugs and Risk of Parkinson\u27s Disease: a Systematic Review and Meta-Analysis

BACKGROUND: Parkinson\u27s Disease (PD) is a neurodegenerative disorder manifested by rest tremor, rigidity, bradykinesia, and postural instability. Recent pharmaco-epidemiological studies evaluating beta-adrenergic drug use and risk of PD have reported conflicting findings. OBJECTIVES: This systematic review and meta-analyses evaluate the association between beta-adrenergic (agonists and antagonists) drugs\u27 use and PD. METHODS: An electronic literature search of eight databases was performed from inception to July 2021 to identify pharmaco-epidemiological studies (case-control and cohort) reporting the risk of PD in beta-adrenergic users compared to non-users. We used the generic inverse variance method and RevMan (5.3.5) to estimate pooled adjusted risk ratios (aRRs) of PD using a random-effects model. RESULTS: Of 3168 records, 15 studies (10 case-control; five cohort) with 6508,877 participants, including 87,011 PD cases, were included. In the pooled analysis (n = 10) including any beta-antagonist users, compared with non-users, the aRR for PD was 1.19 (CI: 1.05,1.35); for any beta-agonist users (n = 8) aRR for PD was 0.87 (CI: 0.78,0.97). Propranolol users had a significantly increased risk of PD (aRR:1.91; CI:1.20,3.06), whereas salbutamol use was associated with reduced risk of PD (aRR:0.95; CI:0.92,0.99). Significant heterogeneity (I CONCLUSIONS: Beta-antagonist use was associated with a modestly increased risk of PD, whereas beta-agonist use was associated with a modest decreased risk of PD. Future epidemiological studies should address the issues of protopathic bias and indirect association using appropriate epidemiological methods