A blue light receptor that mediates RNA binding and translational regulation

Sensory photoreceptor proteins underpin light-dependent adaptations in nature and enable the optogenetic control of organismal behavior and physiology. We identified the bacterial light-oxygen-voltage (LOV) photoreceptor PAL that sequence-specifically binds short RNA stem loops with around 20 nM affinity in blue light and weaker than 1 µM in darkness. A crystal structure rationalizes the unusual receptor architecture of PAL with C-terminal LOV photosensor and N-terminal effector units. The light-activated PAL–RNA interaction can be harnessed to regulate gene expression at the RNA level as a function of light in both bacteria and mammalian cells. The present results elucidate a new signal-transduction paradigm in LOV receptors and conjoin RNA biology with optogenetic regulation, thereby paving the way toward hitherto inaccessible optoribogenetic modalities

Molecular architecture of the human protein deacetylase Sirt1 and its regulation by AROS and resveratrol

Sirtuins are NAD+-dependent protein deacetylases regulating metabolism, stress responses and ageing processes. Among the seven mammalian Sirtuins, Sirt1 is the physiologically best-studied isoform. It regulates nuclear functions such as chromatin remodelling and gene transcription, and it appears to mediate beneficial effects of a low calorie diet which can partly be mimicked by the Sirt1 activating polyphenol resveratrol. The molecular details of Sirt1 domain architecture and regulation, however, are little understood. It has a unique N-terminal domain and CTD (C-terminal domain) flanking a conserved Sirtuin catalytic core and these extensions are assumed to mediate Sirt1-specific features such as homo-oligomerization and activation by resveratrol. To analyse the architecture of human Sirt1 and functions of its N- and C-terminal extensions, we recombinantly produced Sirt1 and Sirt1 deletion constructs as well as the AROS (active regulator of Sirt1) protein. We then studied Sirt1 features such as molecular size, secondary structure and stimulation by small molecules and AROS. We find that Sirt1 is monomeric and has extended conformations in its flanking domains, likely disordered especially in the N-terminus, resulting in an increased hydrodynamic radius. Nevertheless, both termini increase Sirt1 deacetylase activity, indicating a regulatory function. We also find an unusual but defined conformation for AROS protein, which fails, however, to stimulate Sirt1. Resveratrol, in contrast, activates the Sirt1 catalytic core independent of the terminal domains, indicating a binding site within the catalytic core and suggesting that small molecule activators for other isoforms might also exist

The 10Be contents of SNC meteorites

Several authors have explored the possibility that the Shergottites, Nakhlites, and Chassigny (SNC) came from Mars. The spallogenic gas contents of the SNC meteorites have been used to: constrain the sizes of the SNC's during the last few million years; to establish groupings independent of the geochemical ones; and to estimate the likelihood of certain entries in the catalog of all conceivable passages from Mars to Earth. The particular shielding dependence of Be-10 makes the isotope a good probe of the irradiation conditions experienced by the SNC meteorites. The Be-10 contents of nine members of the group were measured using the technique of accelerator mass spectrometry. The Be-10 contents of Nakhla, Governador Valadares, Chassigny, and probably Lafayette, about 20 dpm/kg, exceed the values expected from irradiation of the surface of a large body. The Be-10 data therfore do not support scenario III of Bogard et al., one in which most of the Be-10 in the SNC meteorites would have formed on the Martian surface; they resemble rather the Be-10 contents found in many ordinary chondrites subjected to 4 Pi exposures. The uncertainties of the Be-10 contents lead to appreciable errors in the Be-10 ages, t(1) = -1/lambda ln(1 Be-10/Be-10). Nonetheless, the Be-10 ages are consistent with the Ne-21 ages calculated assuming conventional, small-body production rates and short terrestrial ages for the finds. It is believed that this concordance strengthens the case for at least 3 different irradiation ages for the SNC meteorites. Given the similar half-thicknesses of the Be-10 and Ne-21 production rates, the ratios of the Be-10 and Ne-21 contents do not appear consistent with common ages for any of the groups. In view of the general agreement between the Be-10 and Ne-21 ages it does not seem useful at this time to construct multiple-stage irradiation histories for the SNC meteorites

Comparison of voluntary food intake and palatability of commercial weight loss diets in healthy dogs and cats

Background Obesity in dogs and cats is usually managed by dietary energy restriction using a purpose-formulated weight loss diet, but signs of hunger and begging commonly occur causing poor owner compliance. Altering diet characteristics so as to reduce voluntary food intake (VFI) can improve the likelihood of success, although this should not be at the expense of palatability. The aim of the current study was to compare the VFI and palatibility of novel commercially available canine and feline weight loss diets. Methods The relative performance of two canine (C1 and C2) and two feline (F1 and F2) diets was assessed in groups of healthy adult dogs and cats, respectively. Diets varied in energy, protein, fibre, and fat content. To assess canine VFI, 12 (study 1) and 10 (study 2) dogs were offered food in 4 meals, for 15 min on each occasion, with hourly intervals between the meals. For feline VFI, 12 cats were offered food ad libitum for a period of 18 h per day over 5 consecutive days. The palatability studies used separate panels of 37 dogs and 30 cats, with the two diets being served, side-by-side, in identical bowls. Results In dogs, VFI was significantly less for diet C1 than diet C2 when assessed on energy intake (study 1, 42% less, P = 0.032; study 2, 28% less, P = 0.019), but there was no difference in gram weight intake (study 1: P = 0.964; study 2: P = 0.255). In cats, VFI was 17% less for diet F1 than diet F2 when assessed by energy intake (P < 0.001), but there was again no difference in gram weight (P = 0.207). There was no difference in palatability between the two canine diets (P = 0.490), whilst the panel of cats diet preferred F1 to F2 (P < 0.001). Conclusion Foods with different characteristics can decrease VFI without affecting palatability in both dogs and cats. The effects seen could be due to decreased energy content, decreased fat content, increased fibre content, different fibre source, and increased protein content. Further studies are now needed to determine whether similar findings occur in obese dogs and cats on controlled weight loss programmes

SYNTHESIS OF GRAPHITIC CARBON NANOSTRUCTURES AND USE AS ELECTROCATALYST FOR OXYGEN REDUCTION REACTION

Graphitic carbon nanostructure (GCN) was synthesized by a simple procedure using cobalt(II) gluconate as a precursor and used as a catalyst support for polymer electrolyte membrane (PEM) fuel cell cathode. A novel stabilization procedure was developed to enhance the thermal stability of the GCN support. Support stabilization resulted in well-defined crystalline graphitic hollow structures as confirmed by highresolution transmission electron microscope (HRTEM). The prepared GCNs are used as support for depositing platinum nanoparticles (size) by modified polyol process. Rotating ring disk electrode (RRDE) and fuel cell studies were carried out to evaluate the catalyst performance. Cycling studies (0.6-1.0 V vs. RHE) performed on RRDE indicated better catalyst stability when compared to commercial Pt/C catalyst

Concert Des Anges

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The difficulty of beating the Taxman

The Taxman game has proven to be hard to solve optimally, so efforts have been made to find heuristic strategies that do well in practice. We present results on the NP-hardness of a variant of the game via an equivalence to a particular kind of graph matching problem. Furthermore this equivalence is used to derive a winning strategy for all $n$ along with efficiently computable lower and upper bounds on the optimal achievable score

Structures, Substrates, and Regulators of Mammalian Sirtuins – Opportunities and Challenges for Drug Development

Sirtuins are NAD+-dependent protein deacetylases regulating metabolism, stress responses, and aging processes. Mammalia have seven Sirtuin isoforms, Sirt1–7, which differ in their substrate specificities and subcellular localizations. The physiological functions of Sirtuins make them interesting therapeutic targets, which has stimulated extensive efforts on development of small molecule Sirtuin modulators. Yet, most Sirtuin inhibitors show limited potency and/or isoform specificity, and the mechanism of Sirtuin activation by small molecules remains obscure. Accumulating information on Sirtuin substrates, structures, and regulation mechanisms offer new opportunities for the challenging task to develop potent and specific small molecule modulators for mammalian Sirtuins for in vivo studies and therapeutic applications. We therefore recapitulate advances in structural and mechanistic studies on substrate recognition and deacetylation by Sirtuins, and in the characterization of compounds and molecular mechanisms regulating their activity. We then discuss challenges and opportunities from these findings for Sirtuin-targeted drug development efforts