Synthesis and Biological Activity of Sugar-Fluorinated 2′,3′-dideoxy-4′-thioribofuranosyl Nucleosides

Abstract

The efficient DAST fluorination of deoxy-4′-thiopyrimidine nucleosides is reported. The cytidine analogue 3b was marginally effective against HIV.     

Unilateral Dampening of Bmp Activity by Nodal Generates Cardiac Left-Right Asymmetry

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Highlights? Cardiac laterality involves Nodal modulating an antimotogenic Bmp activity ? The Nodal target Hyaluronan synthase 2 unilaterally dampens Bmp signaling activity ? Nonmuscle myosin II is positively regulated by Bmp within cardiac tissue ? High levels of nonmuscle myosin II activity reduce cardiac cell motility     

Endurance training in mice increases the unfolded protein response induced by a high-fat diet

Certain conditions, such as several weeks of high-fat diet, disrupt endoplasmic reticulum (ER) homeostasis and activate an adaptive pathway referred as the unfolded protein response. When the unfolded protein response fails, the result is the development of inflammation and insulin resistance. These two pathological states are known to be improved by regular exercise training but the mechanisms remain largely undetermined. As it has recently been shown that the unfolded protein response is regulated by exercise, we hypothesised that concomitant treadmill exercise training (HFD+ex) prevents ER homeostasis disruption and its downstream consequences induced by a 6-week high-fat diet (HFD) in mice by activating the protective unfolded protein response. Several well-documented markers of the unfolded protein response were measured in the soleus and tibialis anterior muscles as well as in the liver and pancreas. In HFD mice, an increase in these markers was observed (from 2- to 15-fold, P?<?0.05) in all tissues studied. The combination of HFD+ex increased the expression of several markers further, up to 100 % compared to HFD alone (P?<?0.05). HFD increased inflammatory markers both in the plasma (IL-6 protein, 2.5?±?0.52-fold; MIP-1α protein, 1.3?±?0.13-fold; P?<?0.05) and in the tissues studied, and treadmill exercise attenuated the inflammatory state induced by HFD (P?<?0.05). However, treadmill exercise could not reverse HFD-induced whole body glucose intolerance, assessed by OGTT (AUC, 1.8?±?0.29-fold, P?<?0.05). In conclusion, our results show that a HFD activated the unfolded protein response in mouse tissues in vivo, and that endurance training promoted this response. We speculate that the potentiation of the unfolded protein response by endurance training may represent a positive adaptation protecting against further cellular stress.     

Evidence of current impact of climate change on life: a walk from genes to the biosphere

We review the evidence of how organisms and populations are currently responding to climate change through phenotypic plasticity, genotypic evolution, changes in distribution and, in some cases, local extinction. Organisms alter their gene expression and metabolism to increase the concentrations of several antistress compounds and to change their physiology, phenology, growth and reproduction in response to climate change. Rapid adaptation and microevolution occur at the population level. Together with these phenotypic and genotypic adaptations, the movement of organisms and the turnover of populations can lead to migration toward habitats with better conditions unless hindered by barriers. Both migration and local extinction of populations have occurred. However, many unknowns for all these processes remain. The roles of phenotypic plasticity and genotypic evolution and their possible trade‐offs and links with population structure warrant further research. The application of omic techniques to ecological studies will greatly favor this research. It remains poorly understood how climate change will result in asymmetrical responses of species and how it will interact with other increasing global impacts, such as N eutrophication, changes in environmental N : P ratios and species invasion, among many others. The biogeochemical and biophysical feedbacks on climate of all these changes in vegetation are also poorly understood. We here review the evidence of responses to climate change and discuss the perspectives for increasing our knowledge of the interactions between climate change and life.