Copper-Catalyzed C-C Cross-Couplings of Tertiary Alkyl Halides with Anilines Enabled by Cyclopropenimine-Based Ligands.

Catalytic cross-couplings of tertiary alkyl electrophiles with carbon nucleophiles offer a powerful platform for constructing quaternary carbon centers, which are prevalent in bioactive molecules. However, these reactions remain underdeveloped primarily because of steric challenges that impede efficient bond formation. Herein, we describe the copper-catalyzed synthesis of such centers through the C(sp3)-C(sp2) bond-forming reaction between tertiary alkyl halides and arene rings of aniline derivatives, enabled by the strategic implementation of bidentate bis(cyclopropenimine) ligands. The copper catalyst bound by two imino-nitrogen atoms of these ligands, which have never been employed in metal catalysis previously, is highly effective in rapidly activating tertiary halides to generate alkyl radicals, allowing them to react with aryl nucleophiles under mild conditions with remarkably short reaction times (1-2 h). Various tertiary halides bearing carbonyl functional groups can be coupled with secondary or primary anilines, furnishing a range of quaternary carbon centers in good yields. Several mechanistic observations support the generation of copper(II) species and alkyl radicals which as a result elucidate the steps in the proposed catalytic cycle.

Physicians' Agreement on and Implementation of the 2019 European Alliance of Associations for Rheumatology Vaccination Guideline: An International Survey.

Objective: To evaluate the perspective of healthcare professionals towards the 2019 European Alliance of Associations for Rheumatology (EULAR) vaccination guideline in patients with autoimmune inflammatory rheumatic diseases (AIIRD). Methods: Healthcare professionals who care for patients with AIIRD were invited to participate in an online survey regarding their perspective on the 2019 update of the EULAR recommendations for vaccination in adult patients with AIIRD. Level of agreement and implementation of the 6 overarching principles and 9 recommendations were rated on a 5-point Likert scale (1~5). Results: Survey responses of 371 healthcare professionals from Asia (42.2%) and North America (41.6%), Europe (13.8%), and other countries were analyzed. Only 16.3% of participants rated their familiarity with the 2019 EULAR guideline as 5/5 ("very well"). There was a high agreement (≥4/5 rating) with the overarching principles, except for the principles applying to live-attenuated vaccines. There was a high level of agreement with the recommendations regarding influenza and pneumococcal vaccinations; implementation of these recommendations was also high. Participants also reported a high level of agreement with the remaining recommendations but did not routinely implement these recommendations. Conclusion: The 2019 update of EULAR recommendations for the vaccination of adult patients with AIIRD is generally thought to be important by healthcare professionals, although implementation of adequate vaccination is often lacking. Better education of healthcare providers may be important to optimize the vaccination coverage for patients with AIIRD.

Physician Perspectives on Vaccination in Patients With Autoimmune Inflammatory Rheumatic Diseases: An International Survey.

OBJECTIVE: To evaluate the perspective of physicians who care for patients with autoimmune inflammatory rheumatic disease (AIIRD) toward vaccination. METHODS: Physicians who care for patients with AIIRD were invited to participate in an online survey regarding their vaccination perspectives in adult patients with AIIRD. RESULTS: Survey responses of 370 physicians from Asia (41.1%), North America (41.6%), Europe (13.8%), and other countries (3.5%) were analyzed. Participants stated that rheumatologists (58.2%) should be primarily responsible for vaccination coverage, followed by general internists (19.3%) and family medicine practitioners (12.8%). Additionally, 96.7% of participants considered vaccination very important (≥ 4/5 rating) for patients with AIIRD. Despite these sentiments, only one-third (37%) reported vaccinating the majority (≥ 60%) of their patients. CONCLUSION: Physicians who care for patients with AIIRD agree that vaccines are effective and safe in patients with AIIRD. Unfortunately, they often do not ensure that their patients are adequately vaccinated. Further studies are needed to investigate how to improve vaccination coverage for this high-risk patient population.

The Gender Association of the SIRT1 rs7895833 Polymorphism with Pediatric Obesity: A 3-Year Panel Study.

OBJECTIVES: Sirtuin 1 (SIRT1), a longevity-associated gene, has pleiotropic functions. We investigated whether SIRT1 variation is associated with pediatric obesity. METHODS: During 3 years of follow-up of 219 children (101 boys, 118 girls) aged 8 or 9 years at baseline, obesity parameters such as anthropometrics, plasma lipid and insulin resistance profiles, and nutrient intakes were analyzed with regard to 3 genotypes of SIRT1 rs7895833 (GG, GA, and AA). RESULTS: The prevalence of obesity including overweight had increased from 18.3% (in 2007) to 25.1% (in 2010), and the incidence of obesity over 3 years from nonobesity at the baseline was 11.7%. In the obesity group (BMI >85th percentile) that had been nonobese 3 years before, the frequency of the GA+AA genotypes was higher than that of the GG genotype. Among the total number of subjects, the values for criteria for obesity such as BMI and waist circumference were higher in the GA+AA group than in the GG group. In boys, the reductions in total cholesterol and low-density lipoprotein cholesterol levels in the GG group were considerably greater than those in the GA+AA group, even though the changes in carbohydrate, fat, and protein intake in the GG group were higher than in the GA+AA group. In girls, the reductions in fasting blood sugar and homeostatic model assessment insulin resistance (HOMA-IR) levels were greater in the GA+AA group than in the GG group, despite unchanged energy intakes over 3 years. CONCLUSIONS: We identified an association between SIRT1 variation and pediatric obesity in Korean children with a gender difference.

Epigallocatechin-3-gallate suppresses galactose-alpha1,4-galactose-1beta,4-glucose ceramide expression in TNF-alpha stimulated human intestinal epithelial cells through inhibition of MAPKs and NF-kappaB.

Intestinal epithelial cells (IECs) have been known to produce galactose-alpha1,4-galactose-beta1,4-glucose ceramide (Gb3) that play an important role in the mucosal immune response. The regulation of Gb3 is important to prevent tissue damage causing shiga like toxin. Epigallocatechin-3-gallate (EGCG) has been studied as anti-carcinogenic, anti-oxidant, anti-angiogenic, and anti-viral activities, and anti-diabetic. However, little is known between the expressions of Gb3 on IECs. The aim of this study was to examine the inhibitory effect of EGCG, a major ingredient of green tea, on Gb3 production via mitogen-activated protein kinases (MAPKs) and nuclear factor-kappaB (NF-kappaB) in the TNF-alpha stimulated human colon epithelial cells, HT29. To investigate how Gb3 is regulated, ceramide glucosyltransferase (CGT), lactosylceramide synthase (GalT2), and Gb3 synthase (GalT6) were analyzed by RT-PCR in HT 29 cells exposed to TNF-alpha in the presence or absence of EGCG. EGCG dose-dependently manner, inhibits TNF-alpha induced Gb3 expression by blocking in both the MAPKs and NF-kappaB pathways in HT29 cells. TNF-alpha enhanced CGT, GalT2 and GalT6 mRNA levels and EGCG suppressed the level of these enzymes enhanced by TNF-alpha treatment.