Selective Carbon-Carbon Bond Cleavage of Cyclopropylamine Derivatives.

This review summarizes synthetic developments reported from 1987 to 2019 that exploit C-C single bond cleavage of cyclopropylamine-based systems. The synthetic and mechanistic aspects of key methodologies are highlighted, and examples where aminocyclopropanes are exploited as key intermediates in multistep synthesis are also discussed. The review encompasses cases where aminocyclopropanes participate in polar reactions, pericyclic processes, radical-based reactions, and C-C bond activations

GMF Severs Actin-Arp2/3 Complex Branch Junctions by a Cofilin-like Mechanism

SummaryBackgroundBranched actin filament networks driving cell motility, endocytosis, and intracellular transport are assembled in seconds by the Arp2/3 complex and must be equally rapidly debranched and turned over. One of the only factors known to promote debranching of actin networks is the yeast homolog of glia maturation factor (GMF), which is structurally related to the actin filament-severing protein cofilin. However, the identity of the molecular mechanism underlying debranching and whether this activity extends to mammalian GMF have remained open questions.ResultsUsing scanning mutagenesis and total internal reflection fluorescence microscopy, we show that GMF depends on two separate surfaces for debranching. One is analogous to the G-actin and F-actin binding site on cofilin, but we show using fluorescence anisotropy and chemical crosslinking that it instead interacts with actin-related proteins in the Arp2/3 complex. The other is analogous to a second F-actin binding site on cofilin, which in GMF appears to contact the first actin subunit in the daughter filament. We further show that GMF binds to the Arp2/3 complex with low nanomolar affinity and promotes the open conformation. Finally, we show that this debranching activity and mechanism are conserved for mammalian GMF.ConclusionsGMF debranches filaments by a mechanism related to cofilin-mediated severing, but in which GMF has evolved to target molecular junctions between actin-related proteins in the Arp2/3 complex and actin subunits in the daughter filament of the branch. This activity and mechanism are conserved in GMF homologs from evolutionarily distant species

A Comparison of the Dynamics of S100B, S100A1, and S100A6 mRNA Expression in Hippocampal CA1 Area of Rats during Long-Term Potentiation and after Low-Frequency Stimulation

The interest in tissue- and cell-specific S100 proteins physiological roles in the brain remains high. However, necessary experimental data for the assessment of their dynamics in one of the most important brain activities, its plasticity, is not sufficient. We studied the expression of S100B, S100A1, and S100A6 mRNA in the subfield CA1 of rat hippocampal slices after tetanic and low-frequency stimulation by real-time PCR. Within 30 min after tetanization, a 2–4 fold increase of the S100B mRNA level was observed as compared to the control (intact slices) or to low-frequency stimulation. Subsequently, the S100B mRNA content gradually returned to baseline. The amount of S100A1 mRNA gradually increased during first hour and maintained at the achieved level in the course of second hour after tetanization. The level of S100A6 mRNA did not change following tetanization or low-frequency stimulation

The fluorescence analysis of laser photolysis of phenols in water

Оцифровано в НБ ТГ

Impact of hypoglycemia on daily life of type 2 diabetes patients in Ukraine

This study evaluates the impact of hypoglycemia on the lives of Ukrainian patients with type 2 diabetes mellitus. The secondary objective was to explore patient-physician relationships and the attitudes of patients towards various informational resources on diabetes management. Three focus groups with 26 patients were conducted. Qualitative information was evaluated using content analysis. The results show that patients with type 2 diabetes mellitus in Ukraine are adapting to potential attacks of hypoglycemia; however, they still experience periodic manifestations of hypoglycemia that significantly affect their psychological well-being. This result is similar to observations made in other countries. Ukrainian patients >40 years old mainly receive information on disease management from endocrinologists, and rarely use internet resources on diabetes management. Information provision was especially important at the early stage of the disease, when patients lack information on hypoglycemia manifestations and could therefore fail to identify and manage it properly

Efficacy and Safety of PEGylated Interferons for Relapsing-Remitting Multiple Sclerosis in Adult Patients: Results of Matching-Adjusted Indirect Comparison

Introduction. Beta interferons are effective and safe agents for the treatment of relapsing-remitting multiple sclerosis (RRMS). PEGylated interferons have been developed in order to increase patient adherence. Direct comparisons of the efficacy and safety of PEGylated interferons have not yet been conducted. Our objective was to evaluate the efficacy and safety of SamPEG-IFN-β1a versus PEG-IFN-β1a in adult patients with RRMS. Materials and methods. We conducted a systematic search of randomized clinical trials (RCTs) using the PubMed, Embase and eLIBRARY.RU databases. Efficacy was assessed based on the proportion of patients with disease relapses and the annualized relapse rate (ARR) during the 1st and the 2nd years of treatment. Safety was assessed by the number of patients with adverse events (AEs), serious AEs (SAEs), and any AEs that led to the treatment discontinuation. We conducted pairwise matching-adjusted indirect comparison (MAIC) to assess comparative efficacy of PEGylated IFNs. To evaluate the efficacy, hypotheses of non-inferiority of SamPEG-IFN-β1a to PEG-IFN-β1a and superiority of SamPEG-IFN-β1a over PEG-IFN-β1a were tested. Results. Based on results of the systematic review, four articles were selected wherein the results of phase 3 clinical trial of PEG-IFN-β1a and phase 2–3 clinical trial of SamPEG-IFN-β1a were described. In PEG-IFN-β1a group (n = 512) the agent was administered once every 2 weeks, in SamPEGIFN-β1a group (n = 114) the agent was administered at a dose of 240 μg. The analysis results confirmed the hypothesis of SamPEG-IFN-β1a non-inferiority to PEG-IFN-β1a in efficacy, while SamPEG-IFN-β1a superiority over PEG-IFN-β1a in efficacy was not confirmed. The hypothesis of SamPEG-IFN-β1a superiority over PEG-IFN-β1a in safety was also confirmed based on a significantly lower incidence of SAEs and any AEs that led to treatment discontinuation. Conclusions. The proportion of patients with relapses and the ARR in 1 year and in 2 years of therapy indicates that SamPEG-IFN-β1a is non-inferior to PEG-IFN-β1a in efficacy. SamPEG-IFN-B1a demonstrated a more favourable safety profile than PEG-IFN-B1a as showing less odds of SAEs and AEs leading to treatment discontinuation

Genome-wide significant association with seven novel multiple sclerosis risk loci

Objective: A recent large-scale study in multiple sclerosis (MS) using the ImmunoChip platform reported on 11 loci that showed suggestive genetic association with MS. Additional data in sufficiently sized and independent data sets are needed to assess whether these loci represent genuine MS risk factors. Methods: The lead SNPs of all 11 loci were genotyped in 10 796 MS cases and 10 793 controls from Germany, Spain, France, the Netherlands, Austria and Russia, that were independent from the previously reported cohorts. Association analyses were performed using logistic regression based on an additive model. Summary effect size estimates were calculated using fixed-effect meta-analysis. Results: Seven of the 11 tested SNPs showed significant association with MS susceptibility in the 21 589 individuals analysed here. Meta-analysis across our and previously published MS case-control data (total sample size n=101 683) revealed novel genome-wide significant association with MS susceptibility (p<5×10−8) for all seven variants. This included SNPs in or near LOC100506457 (rs1534422, p=4.03×10−12), CD28 (rs6435203, p=1.35×10−9), LPP (rs4686953, p=3.35×10−8), ETS1 (rs3809006, p=7.74×10−9), DLEU1 (rs806349, p=8.14×10−12), LPIN3 (rs6072343, p=7.16×10−12) and IFNGR2 (rs9808753, p=4.40×10−10). Cis expression quantitative locus effects were observed in silico for rs6435203 on CD28 and for rs9808753 on several immunologically relevant genes in the IFNGR2 locus. Conclusions: This study adds seven loci to the list of genuine MS genetic risk factors and further extends the list of established loci shared across autoimmune diseases