The Role of MINK1 in Congenital Heart Disease: Regulation of Spemann Organizer Cell Fate and Multiciliated Cell Specification

Congenital Heart Disease (CHD) is the most common birth defect and leading cause of infant mortality, yet molecular mechanisms explaining CHD remain mostly unknown. Sequencing studies are identifying CHD candidate genes at a brisk rate including MINK1, a serine/threonine kinase. However, a plausible molecular mechanism connecting CHD and MINK1 is unknown. Here, we reveal that mink1 is required for proper heart development due to its role in left-right patterning. Mink1 regulates canonical Wnt signaling to define the cell fates of the Spemann organizer and the Left-Right Organizer, a ciliated structure that breaks bilateral symmetry in the vertebrate embryo. To identify Mink1 targets, we applied an unbiased proteomics approach and identified the high mobility group architectural transcription factor, Hmga2. We report that Hmga2 is necessary and sufficient for specifying Spemann’s Organizer. Indeed, we demonstrate that Hmga2 can induce Spemann Organizer cell fates even when Beta-catenin, a critical effector of the Wnt signaling pathway, is depleted. Finally, we describe a role for mink1 in specification of the Xenopus embryonic multiciliated epithelium, potentially indicating a risk for mucociliary clearance defects in CHD patients with MINK1 variants. In summary, we discover a transcription factor, Hmga2, downstream of Mink1 and Beta-catenin that is critical for the specification of Spemann’s Organizer, as well as the LRO defining a plausible mechanism for CHD. We also unearth an important potential avenue for postoperative treatment of CHD patients

Weight Strategy in Older Adults With Obesity: Calorie Restriction or Not?

PURPOSE OF REVIEW: Along with the marked increase in the population of older adults with obesity is the need for effective strategies to treat aging- and obesity-related complications. This review highlights recent progress in obesity management in older adults. RECENT FINDINGS: Although calorie restriction is needed to significantly reduce fat mass, an exercise protocol is crucial to ameliorate functional outcomes. The addition of a resistance exercise protocol improves the response of muscle protein synthesis to anabolic stimuli, preventing the calorie restriction-induced reduction in muscle and bone mass. The addition of an aerobic exercise protocol improves cardiorespiratory fitness and cognitive function. However, the addition of both aerobic and resistance exercise protocols to calorie restriction provides the greatest improvements in myocellular quality, frailty, and cardiometabolic and cognitive outcomes, translating into the greatest improvement in quality of life. Such comprehensive lifestyle intervention effectively improves glucometabolic control and age-relevant outcomes in older adults with diabetes. When combined with testosterone therapy, such lifestyle intervention also preserves muscle and bone mass in older, men with obesity and hypogonadism. SUMMARY: We conclude that calorie restriction among older adults with obesity should be prescribed in combination with both aerobic and resistance exercise to maximize benefits on overall health

Designed oligomers of cyanovirin-N show enhanced HIV neutralization

Cyanovirin-N (CV-N) is a small, cyanobacterial lectin that neutralizes many enveloped viruses, including human immunodeficiency virus type I (HIV-1). This antiviral activity is attributed to two homologous carbohydrate binding sites that specifically bind high mannose glycosylation present on envelope glycoproteins such as HIV-1 gp120. We created obligate CV-N oligomers to determine whether increasing the number of binding sites has an effect on viral neutralization. A tandem repeat of two CV-N molecules (CVN_2) increased HIV-1 neutralization activity by up to 18-fold compared to wild-type CV-N. In addition, the CVN_2 variants showed extensive cross-clade reactivity and were often more potent than broadly neutralizing anti-HIV antibodies. The improvement in activity and broad cross-strain HIV neutralization exhibited by these molecules holds promise for the future therapeutic utility of these and other engineered CV-N variants