Overexpression of Na+/Mg2+ exchanger SLC41A1 attenuates pro-survival signaling

The Na+/Mg2+ exchanger SLC41A1 (A1), a key component of intracellular Mg homeostasis (IMH), is the major cellular Mg2+ efflux system, and its overexpression decreases [Mg2+]intracellular. IMH plays an important role in the regulation of many cellular processes, including cellular signaling. However, whether the overexpression of A1 and the consequent drop of [Mg2+]i impact on intracellular signaling is unknown. To examine the latter, we utilized dynamic mass redistribution (DMR) assay, PathScan® RTK signaling antibody (PRSA) array, confirmatory Western blot (WB) analyses of phosphorylation of kinases selected by PRSA, and mag-fura 2-assisted fast filter spectrometry (FFS). We demonstrate here that the overexpression of A1 quantitatively and qualitatively changes the DMR signal evoked by the application of PAR-1-selective activating peptide and/or by changing [Mg2+]extracellular in HEK293 cells. PRSA profiling of the phosphorylation of important signaling nodes followed by confirmatory WB has revealed that, in HEK293 cells, A1 overexpression significantly attenuates the phosphorylation of Akt/PKB on Thr308 and/or Ser473 and of Erk1/2 on Thr202/Tyr204 in the presence of 0 or 1 mM (physiological) Mg2+ in the bath solution. The latter is also true for SH-SY5Y and HeLa cells. Overexpression of A1 in HEK293 cells significantly lowers [Mg2+]i in the presence of [Mg2+]e = 0 or 1 mM. This correlates with the observed attenuation of prosurvival Akt/PKB – Erk1/2 signaling in these cells. Thus, A1 expression status and [Mg2+]e (and consequently also [Mg2+]i) modulate the complex physiological fingerprint of the cell and influence the activity of kinases involved in anti-apoptotic and, hence, pro-survival events in cells

Alzheimer’s Disease-Associated SNP rs708727 in SLC41A1 May Increase Risk for Parkinson’s Disease: Report from Enlarged Slovak Study

SLC41A1 (A1) SNPs rs11240569 and rs823156 are associated with altered risk for Parkinson’s disease (PD), predominantly in Asian populations, and rs708727 has been linked to Alzheimer’s disease (AD). In this study, we have examined a potential association of the three aforementioned SNPs and of rs9438393, rs56152218, and rs61822602 (all three lying in the A1 promoter region) with PD in the Slovak population. Out of the six tested SNPs, we have identified only rs708727 as being associated with an increased risk for PD onset in Slovaks. The minor allele (A) in rs708727 is associated with PD in dominant and completely over-dominant genetic models (ORD = 1.36 (1.05–1.77), p = 0.02, and ORCOD = 1.34 (1.04–1.72), p = 0.02). Furthermore, the genotypic triplet GG(rs708727) + AG(rs823156) + CC(rs61822602) might be clinically relevant despite showing a medium (h ≥ 0.5) size difference (h = 0.522) between the PD and the control populations. RandomForest modeling has identified the power of the tested SNPs for discriminating between PD-patients and the controls to be essentially zero. The identified association of rs708727 with PD in the Slovak population leads us to hypothesize that this A1 polymorphism, which is involved in the epigenetic regulation of the expression of the AD-linked gene PM20D1, is also involved in the pathoetiology of PD (or universally in neurodegeneration) through the same or similar mechanism as in AD

Nitrosobenzene: Reagent for the Mitsunobu Esterification Reaction

Nitrosobenzene has been demonstrated to participate in the Mitsunobu reaction in an analogous manner to dialkyl azodicarboxylates. The protocol using nitrosobenzene and triphenylphosphine (1:1) under mild conditions (0 °C) provides the ester derivatives of aliphatic and aromatic acids using various alcohols in moderate yield and with good enantioselectivity, giving the desired products predominantly with an inversion of configuration. The proposed mechanism, which is analogous to that observed using dialkyl azodicarboxylates, involves a nitrosobenzene–triphenylphosphine adduct and an alkoxytriphenylphosphonium ion and was supported by density functional theory calculations, 31P NMR spectroscopy, and experiments conducted with isotopically labeled substrates

SNPs rs11240569, rs708727, and rs823156 in SLC41A1 Do Not Discriminate Between Slovak Patients with Idiopathic Parkinson’s Disease and Healthy Controls: Statistics and Machine-Learning Evidence

Gene SLC41A1 (A1) is localized within Parkinson’s disease-(PD)-susceptibility locus PARK16 and encodes for the Na+/Mg2+-exchanger. The association of several A1 SNPs with PD has been studied. Two, rs11240569 and rs823156, have been associated with reduced PD-susceptibility primarily in Asian populations. Here, we examined the association of rs11240569, rs708727, and rs823156 with PD in the Slovak population and their power to discriminate between PD patients and healthy controls. The study included 150 PD patients and 120 controls. Genotyping was performed with the TaqMan® approach. Data were analyzed by conventional statistics and Random Forest machine-learning (ML) algorithm. Individually, none of the three SNPs is associated with an altered risk for PD-onset in Slovaks. However, a combination of genotypes of SNP-triplet GG(rs11240569)/AG(rs708727)/AA(rs823156) is significantly (p < 0.05) more frequent in the PD (13.3%) than in the control (5%) cohort. ML identified the power of the tested SNPs in isolation or of their singlets (joined), duplets and triplets to discriminate between PD-patients and healthy controls as zero. Our data further substantiate differences between diverse populations regarding the association of A1 polymorphisms with PD-susceptibility. Lack of power of the tested SNPs to discriminate between PD and healthy cases render their clinical/diagnostic relevance in the Slovak population negligible

Evaluation of lipoprotein(a) in the prevention and management of atherosclerotic cardiovascular disease: A survey among the Lipid Clinics Network

Background and aims: The European Atherosclerosis Society (EAS) Lipid Clinics Network promoted a survey in order to identify and understand how and when lipoprotein(a) [Lp(a)] is tested and clinically evaluated in lipid clinics throughout Europe, and the challenges that may prevent evaluation from being carried out. Methods: This survey was divided into three areas of inquiry: background and clinical setting information of clinicians, questions for doctors who claimed not to measure Lp(a), in order to understand what were the reasons for not ordering the test, and questions for doctors who measure Lp(a), to investigate the use of this value in the management of patients.Results: A total of 151 centres clinicians filled in the survey, out of 226 invited. The proportion of clinicians who declare to routinely measure Lp(a) in clinical practice was 75.5%. The most common reasons for not ordering the Lp(a) test were the lack of reimbursement or of treatment options, the non-availability of Lp(a) test, and the high cost of performing the laboratory test. The availability of therapies targeting this lipoprotein would result in a greater propensity of clinicians to start testing Lp(a). Among those who declared to routinely measure Lp(a), the Lp(a) measurement is mostly requested to further stratify patients' cardiovascular risk, and half of them recognized 50 mg/dL (approx. 110 nmol/L) as the threshold for increased cardiovascular risk due.Conclusions: These results warrant for a great deal of effort from scientific societies to address the barriers that limit the routine use of the measurement of Lp(a) concentration and to recognise the importance of Lp(a) as a risk factor

Global Impact of the COVID-19 Pandemic on Stroke Volumes and Cerebrovascular Events: One-Year Follow-up.

BACKGROUND AND OBJECTIVES Declines in stroke admission, intravenous thrombolysis, and mechanical thrombectomy volumes were reported during the first wave of the COVID-19 pandemic. There is a paucity of data on the longer-term effect of the pandemic on stroke volumes over the course of a year and through the second wave of the pandemic. We sought to measure the impact of the COVID-19 pandemic on the volumes of stroke admissions, intracranial hemorrhage (ICH), intravenous thrombolysis (IVT), and mechanical thrombectomy over a one-year period at the onset of the pandemic (March 1, 2020, to February 28, 2021) compared with the immediately preceding year (March 1, 2019, to February 29, 2020). METHODS We conducted a longitudinal retrospective study across 6 continents, 56 countries, and 275 stroke centers. We collected volume data for COVID-19 admissions and 4 stroke metrics: ischemic stroke admissions, ICH admissions, intravenous thrombolysis treatments, and mechanical thrombectomy procedures. Diagnoses were identified by their ICD-10 codes or classifications in stroke databases. RESULTS There were 148,895 stroke admissions in the one-year immediately before compared to 138,453 admissions during the one-year pandemic, representing a 7% decline (95% confidence interval [95% CI 7.1, 6.9]; p<0.0001). ICH volumes declined from 29,585 to 28,156 (4.8%, [5.1, 4.6]; p<0.0001) and IVT volume from 24,584 to 23,077 (6.1%, [6.4, 5.8]; p<0.0001). Larger declines were observed at high volume compared to low volume centers (all p<0.0001). There was no significant change in mechanical thrombectomy volumes (0.7%, [0.6,0.9]; p=0.49). Stroke was diagnosed in 1.3% [1.31,1.38] of 406,792 COVID-19 hospitalizations. SARS-CoV-2 infection was present in 2.9% ([2.82,2.97], 5,656/195,539) of all stroke hospitalizations. DISCUSSION There was a global decline and shift to lower volume centers of stroke admission volumes, ICH volumes, and IVT volumes during the 1st year of the COVID-19 pandemic compared to the prior year. Mechanical thrombectomy volumes were preserved. These results suggest preservation in the stroke care of higher severity of disease through the first pandemic year. TRIAL REGISTRATION INFORMATION This study is registered under NCT04934020