Pathogenic, Total Loss-of-Function DYRK1B Variants Cause Monogenic Obesity Associated With Type 2 Diabetes.

OBJECTIVE: Rare variants in DYRK1B have been described in some patients with central obesity, type 2 diabetes, and early-onset coronary disease. Owing to the limited number of conducted studies, the broader impact of DYRK1B variants on a larger scale has yet to be investigated. RESEARCH DESIGN AND METHODS: DYRK1B was sequenced in 9,353 participants from a case-control study for obesity and type 2 diabetes. Each DYRK1B variant was functionally assessed in vitro. Variant pathogenicity was determined using criteria from the American College of Medical Genetics and Genomics (ACMG). The effect of pathogenic or likely pathogenic (P/LP) variants on metabolic traits was assessed using adjusted mixed-effects score tests. RESULTS: Sixty-five rare, heterozygous DYRK1B variants were identified and were not associated with obesity or type 2 diabetes. Following functional analyses, 20 P/LP variants were pinpointed, including 6 variants that exhibited a fully inhibitory effect (P/LP-null) on DYRK1B activity. P/LP and P/LP-null DYRK1B variants were associated with increased BMI and obesity risk; however, the impact was notably more pronounced for the P/LP-null variants (effect of 8.0 ± 3.2 and odds ratio of 7.9 [95% CI 1.2-155]). Furthermore, P/LP-null variants were associated with higher fasting glucose and type 2 diabetes risk (effect of 2.9 ± 1.0 and odds ratio of 4.8 [95% CI 0.85-37]), while P/LP variants had no effect on glucose homeostasis. CONCLUSIONS: P/LP, total loss-of-function DYRK1B variants cause monogenic obesity associated with type 2 diabetes. This study underscores the significance of conducting functional assessments in order to accurately ascertain the tangible effects of P/LP DYRK1B variants.

Introduction of Mobile Health Tools to Support Ebola Surveillance and Contact Tracing in Guinea.

Challenges in data availability and quality have contributed to the longest and deadliest Ebola epidemic in history that began in December 2013. Accurate surveillance data, in particular, has been difficult to access, as it is often collected in remote communities. We describe the design, implementation, and challenges of implementing a smartphone-based contact tracing system that is linked to analytics and data visualization software as part of the Ebola response in Guinea. The system, built on the mobile application CommCare and business intelligence software Tableau, allows for real-time identification of contacts who have not been visited and strong accountability of contact tracers through timestamps and collection of GPS points with their surveillance data. Deployment of this system began in November 2014 in Conakry, Guinea, and was expanded to a total of 5 prefectures by April 2015. To date, the mobile system has not replaced the paper-based system in the 5 prefectures where the program is active. However, as of April 30, 2015, 210 contact tracers in the 5 prefectures were actively using the mobile system to collectively monitor 9,162 contacts. With proper training, some investment in technical hardware, and adequate managerial oversight, there is opportunity to improve access to surveillance data from difficult-to-reach communities in order to inform epidemic control strategies while strengthening health systems to reduce risk of future disease outbreaks.

Base-catalyzed efficient tandem [3 + 3] and [3 + 2 + 1] annulation-aerobic oxidative benzannulations.

An efficient synthesis of substituted benzenes via a base-catalyzed [3 + 3] aerobic oxidative aromatization of α,ß-unsaturated carbonyl compounds with dimethyl glutaconate was reported. All the reactions were carried out under mild, metal-free conditions to afford the products in high to excellent yields with molecular oxygen as the sole oxidant and water as the sole byproduct. Furthermore, a more convenient tandem [3 + 2 + 1] aerobic oxidative aromatization reaction was developed through the in situ generation of the α,ß-unsaturated carbonyl compounds from aldehydes and ketones.

Tandem [5+1] annulation-isocyanide cyclization: efficient synthesis of hydroindolones.

A new strategy for the rapid construction of functionalized reduced indoles starting from activated methylene isocyanides and 1,5-dielectrophilic 5-oxohepta-2,6-dienoates (and their equivalents) through a [5+1] annulation-isocyanide cyclization cascade under basic conditions has been developed. This strategy allows the synthesis of polysubstituted dihydroindolones and tetrahydroindolones in high to excellent yields under extremely mild conditions in a single step.