Isochem (France)

Une cinquantaine d’articles relevant de la démographie au sens large ont été publiés dans la REMI depuis le tout premier numéro paru en 1985. Ils se caractérisent tous par leur interdisciplinarité qui les distingue des articles, centrés sur la mesure et la pure analyse des comportements démographiques, publiés au cours des décennies 1950, 1960 et 1980 dans des revues plus spécialisées. La REMI a donc joué un rôle précurseur. La migration internationale est par nature interdisciplinaire et les articles significatifs présentés ici sont représentatifs de la relation entre la démographie et l’économie, l’histoire, la sociologie et la science politique. Les articles publiés entre 1985 et 2020 sont listés dans les références bibliographiques finales.

Many chronic, age-related disorders could be mitigated by enhancing the activity of enzymes that regulate biochemical signaling pathways, but all known modes of enzyme activation rely on allosteric binding sites, which have only been identified in less than 10% of proteins. Sirtuins (SIRT1-7) are nicotinamide adenine dinucleotide (NAD+)-dependent deacylases playing critical roles in lifespan and age-related diseases. The physiological importance of sirtuins and the reduction in their catalytic activity with the age-related decline in NAD+ levels have stimulated intense interest in designing sirtuin-activating compounds; however, except for substrate-specific allosteric SIRT1 activators, methodologies for rational design of sirtuin-activating compounds are lacking. Here, we introduce methods for the activation of such enzymes that do not rely on allosteric binding sites, and we demonstrate their successful application to the discovery of first-in-class activators of sirtuin enzymes. We establish how all-atom simulations of an enzyme’s active site under the potential of a small molecule modulator can be used to identify molecular properties that achieve desired changes in local enzyme conformational degrees of freedom conducive to the enhancement of catalytic activity. We apply computational high-throughput screening based on this biophysical model for activation of sirtuin enzymes to the major mitochondrial sirtuin SIRT3, which plays a critical role in age-related disorders but does not have a known allosteric site; we thereby identify first-in-class, nonallosteric activators of this enzyme. These compounds are the first reported steady-state activators of the major mitochondrial sirtuin enzyme, and they operate according to a mode of action not shared by any existing drug. Two such compounds can almost double the catalytic efficiency of SIRT3 with respect to NAD+, thus compensating for the loss in SIRT3 activity that occurs due to the age-related decline in NAD+, and they may be developed for therapeutic applications to combat multiple types of age-related disorders. These discoveries establish a foundation for the development of a new class of drugs that function through the activation of enzymes by modulation of local conformational ensembles. Published by the American Physical Society 2024

1,2-Naphthoquinone-2-semicarbazone (i.e., naftazone) has been characterized by structural analysis (single-crystal X-ray diffraction, powder X-ray diffraction) and by thermal analysis (differential scanning calorimetry, DSC). Although this molecule has no chiral center, the two forms crystallize in chiral space groups: the stable form I (P212121, Z = 4, a = 5.1187(7) Å, b = 5.6092(7) Å, c = 34.847(5) Å; V = 1000.5(2) Å3) and the metastable form II (P21, Z = 2, a = 6.3349(1) Å, b = 3.9263(1) Å, c = 19.790(5) Å, β = 92.424(4)°; V = 491.8(2) Å3). At high concentration (c = 30 g·L−1), the pure stable form I crystallizes regardless of the antisolvent (water) addition rate. At low concentration (c = 15 g·L−1), the pure metastable form II crystallizes at low water addition rate (ψ = 100 mL·h−1); however, the structurally pure form I is also obtained with a high water addition rate (ψ = 72 × 103 mL·h−1). Concomitant polymorphs crystallize at intermediate antisolvent addition rate and concentration. Therefore in the majority of the operative conditions, these results appear to be in contradiction with Ostwald's rule of stages.

The solubility and diffusivity of water at 100° C, 95% relative humidity were studied for 14 stoichiometric epoxide-amine networks based on epoxide or amine mixtures. Neither the packing density nor the glass transition temperature nor the crosslink density seemed to play a significant role. The water absorption is essentially linked to the concentration of polar structures, but also decreases with the extent of intramolecular hydrogen bonding. This can be accurately predicted using a simple additive relationship. The diffusivity decreases with the hydrophilicity and packing density, but in a complex way probably involving the nature of hydrogen bonds between the water and the substrate.