We have identified a small interfering RNA (siRNA) motif, consisting entirely of 2'-O-methyl and 2'-fluoro nucleotides, that displays enhanced plasma stability and increased in vitro potency. At one site, this motif showed remarkable >500-fold improvement in potency over the unmodified siRNA. This marks the first report of such a potent fully modified motif, which may represent a useful design for therapeutic oligonucleotides.

Background: It is well-established that the etiology of type 2 diabetes differs between individuals. Insulin resistance (IR) may develop in different tissues, but the severity of IR may differ in key metabolic organs such as the liver and skeletal muscle. Recent evidence suggests that these distinct tissue-specific IR phenotypes may also respond differentially to dietary macronutrient composition with respect to improvements in glucose metabolism.Objective: The main objective of the PERSON study is to investigate the effects of an optimal vs. suboptimal dietary macronutrient intervention according to tissue-specific IR phenotype on glucose metabolism and other health outcomes.Methods: In total, 240 overweight/obese (BMI 25 – 40 kg/m2) men and women (age 40 – 75 years) with either skeletal muscle insulin resistance (MIR) or liver insulin resistance (LIR) will participate in a two-center, randomized, double-blind, parallel, 12-week dietary intervention study. At screening, participants undergo a 7-point oral glucose tolerance test (OGTT) to determine the hepatic insulin resistance index (HIRI) and muscle insulin sensitivity index (MISI), classifying each participant as either “No MIR/LIR,” “MIR,” “LIR,” or “combined MIR/LIR.” Individuals with MIR or LIR are randomized to follow one of two isocaloric diets varying in macronutrient content and quality, that is hypothesized to be either an optimal or suboptimal diet, depending on their tissue-specific IR phenotype (MIR/LIR). Extensive measurements in a controlled laboratory setting as well as phenotyping in daily life are performed before and after the intervention. The primary study outcome is the difference in change in disposition index, which is the product of insulin sensitivity and first-phase insulin secretion, between participants who received their hypothesized optimal or suboptimal diet.Discussion: The PERSON study is one of the first randomized clinical trials in the field of precision nutrition to test effects of a more personalized dietary intervention based on IR phenotype. The results of the PERSON study will contribute knowledge on the effectiveness of targeted nutritional strategies to the emerging field of precision nutrition, and improve our understanding of the complex pathophysiology of whole body and tissue-specific IR.Clinical Trial Registration:https://clinicaltrials.gov/ct2/show/NCT03708419, clinicaltrials.gov as NCT03708419.

Background & aims: Physical activity (PA) breaks may effectively attenuate the detrimental impact of prolonged sitting on acute cognitive performance, perceivable benefits (e.g. mood), vascular function, and metabolic health. To date, the impact of meal composition on the effects of sedentary behavior and/ or PA breaks on health has been scarcely studied. Therefore, our aim was to investigate whether meal composition alters how sedentary behavior and PA breaks affect these acute health outcomes. Methods: A total of 24 overweight and obese, sedentary adults completed four conditions in randomized order in a cross-over design: [a] high-protein, low-fat breakfast (HPLF) þ 4hrs uninterrupted sitting (SIT), [b] HPLF þ 4hrs interrupted sitting (ACT; 5-min cycling every 30 min), [c] Western breakfast (WEST; higher in fats/simple sugars, lower in protein/fiber) þ SIT, [d] WEST þ ACT. WEST and HPLF were isocaloric. Linear mixed models were used to examine changes in cognitive performance (Test of Attentional Performance), perceivable benefits (Likert-scales, Profile of Mood States questionnaire), vascular health (carotid artery reactivity, blood pressure), and metabolic health (post-breakfast glucose, insulin, lipids). Results: Independent of meal composition, we did not observe any effect of PA breaks on cognitive performance, vascular health and post-breakfast lipid responses. PA breaks delayed post-breakfast mood and vigor decrements, as well as increases in fatigue and sleepiness (all p < 0.05), but effects were independent of meal composition (p > 0.05). WEST resulted in higher post-breakfast glucose levels compared to HPLF (p < 0.05), while PA breaks did not impact this response (p > 0.05). PA breaks reduced post-breakfast insulin (p < 0.05), which did not differ between meals (p > 0.05). Conclusions: The acute impact of PA breaks and/or prolonged sitting on cognitive performance, perceivable benefits, and vascular and metabolic health was not altered by the composition of a single meal in overweight/obese, sedentary adults. Possibly, breaking up prolonged sitting, rather than meal composition, is a more potent strategy to impact acute health outcomes, such as perceivable benefits and insulin levels.