Structurally diverse mitochondrial branched chain aminotransferase (BCATm) leads with varying binding modes identified by fragment screening

Inhibitors of mitochondrial branched chain aminotransferase (BCATm), identified using fragment screening, are described. This was carried out using a combination of STD-NMR, thermal melt (Tm), and biochemical assays to identify compounds that bound to BCATm, which were subsequently progressed to X-ray crystallography, where a number of exemplars showed significant diversity in their binding modes. The hits identified were supplemented by searching and screening of additional analogues, which enabled the gathering of further X-ray data where the original hits had not produced liganded structures. The fragment hits were optimized using structure-based design, with some transfer of information between series, which enabled the identification of ligand efficient lead molecules with micromolar levels of inhibition, cellular activity, and good solubility

A united statement of the global chiropractic research community against the pseudoscientific claim that chiropractic care boosts immunity.

BACKGROUND: In the midst of the coronavirus pandemic, the International Chiropractors Association (ICA) posted reports claiming that chiropractic care can impact the immune system. These claims clash with recommendations from the World Health Organization and World Federation of Chiropractic. We discuss the scientific validity of the claims made in these ICA reports. MAIN BODY: We reviewed the two reports posted by the ICA on their website on March 20 and March 28, 2020. We explored the method used to develop the claim that chiropractic adjustments impact the immune system and discuss the scientific merit of that claim. We provide a response to the ICA reports and explain why this claim lacks scientific credibility and is dangerous to the public. More than 150 researchers from 11 countries reviewed and endorsed our response. CONCLUSION: In their reports, the ICA provided no valid clinical scientific evidence that chiropractic care can impact the immune system. We call on regulatory authorities and professional leaders to take robust political and regulatory action against those claiming that chiropractic adjustments have a clinical impact on the immune system

Le rôle de l'estime de soi implicite dans la modulation des préférences olfactives

L'interprétation de l'effet classique de propagation des alternatives mis en avant par Brehm en 1956 en termes de réduction de la dissonance cognitive est, aujourd'hui, contestée. La théorie de l'auto-ancrage propose une explication alternative à cet effet. L'étude présente à donc pour but de tester si la manipulation de l'estime de soi implicite permet une modulation de l'effet « free-choice » comme le propose cette théorie. Nous avons donc manipulé de manière implicite l'estime de soi des participants afin de voir si celle-ci influence l'effet de la propagation des alternatives. Les résultats montrent que ce dernier a bien été répliqué. Cependant, la manipulation de l'estime de soi par conditionnement évaluatif subliminal semble ne pas avoir été efficace. Nous ne pouvons donc pas conclure que l'effet de propagation des alternatives est modulé par l'estime de soi des individus

Fucoidan-functionalized polysaccharide submicroparticles loaded with alteplase for efficient targeted thrombolytic therapy

International audienceIntravenous administration of fibrinolytic drugs is the standard treatment of acute thrombotic diseases. However, current fibrinolytics exhibit limited clinical efficacy because of their short plasma half-lives and might trigger hemorrhagic transformations. Therefore, it is mandatory to develop innovative nanomedicine-based solutions for more efficient and safer thrombolysis with biocompatible and biodegradable thrombustargeted nanocarrier. Herein, fucoidan-functionalized hydrogel polysaccharide submicroparticles with high biocompatibility are elaborated by the inverse miniemulsion / crosslinking method. They are loaded with the gold standard fibrinolytic-alteplaseto direct site-specific fibrinolysis due to nanomolar interactions between fucoidan and P-selectin overexpressed on activated platelets and endothelial cells in the thrombus area. The thrombus targeting properties of these particles are validated in a microfluidic assay containing recombinant P-selectin and activated platelets under arterial and venous blood shear rates as well as in vivo. The experiments on the murine model of acute thromboembolic ischemic stroke support this product's therapeutic efficacy, revealing a faster recanalization rate in the middle cerebral artery than with free alteplase, which reduces post-ischemic cerebral infarct lesions and blood-brain barrier permeability. Altogether, this proof-of-concept study demonstrates the potential of a biomaterial-based targeted nanomedicine for the precise treatment of acute thrombotic events, such as ischemic stroke

Deciphering the influence of physicochemical and microbial parameters of the human digestive tract on orally-ingested microplastics using in vitro gut models

International audienc

Deciphering the influence of physicochemical and microbial parameters of the human digestive tract on orally-ingested microplastics using in vitro gut models

International audienc

In vitro models of gut digestion across childhood: current developments, challenges and future trends

International audienceThe human digestion is a multi-step and multi-compartment process essential for human health, at the heart of many issues raised by academics, the medical world and industrials from the food, nutrition and pharma fields. In the first years of life, major dietary changes occur and are concomitant with an evolution of the whole child digestive tract anatomy and physiology, including colonization of gut microbiota. All these phenomena are influenced by child exposure to environmental compounds, such as drugs (especially antibiotics) and food pollutants, but also childhood infections. Due to obvious ethical, regulatory and technical limitations, in vivo approaches in animal and human are more and more restricted to favor complementary in vitro approaches. This review summarizes current knowledge on the evolution of child gut physiology from birth to 3 years old regarding physicochemical, mechanical and microbial parameters. Then, all the available in vitro models of the child digestive tract are described, ranging from the simplest static mono-compartmental systems to the most sophisticated dynamic and multi-compartmental models, and mimicking from the oral phase to the colon compartment. Lastly, we detail the main applications of child gut models in nutritional, pharmaceutical and microbiological studies and discuss the limitations and challenges facing this field of research

Le marché des marges sociales

Dans leurs modes de production, de gestion et de légitimation, les nombreuses catégorisations des acteurs qui peuplent les « marges sociales » interpellent les anthropologues. Comment appréhender ces marges dans les sociétés actuelles où la précarisation et la stigmatisation fabriquent, en leur cœur même, en nombre croissant, des « marginaux » économiques et sociaux ? Quelles sont, malgré l’imposition des dispositifs de gestion, les stratégies des acteurs, leurs capacités de négociation et leurs logiques de subjectivation ? Dans une perspective comparative, ce dossier donne à voir des figures diverses des marges sociales et permet de comprendre le poids des dispositifs managériaux et sécuritaires qui les encadrent. Salariés, bénévoles ainsi que tous ceux qui bénéficient des services ou en sont exclus mettent en lumière, malgré tout, des lignes d’émancipation sociale. The numerous categorizations of the actors who populate the “social margins” question anthropologists in their modes of production, management and legitimization. How can we grasp these margins in today’s societies, where precariousness and stigmatization produce and are producing, at their very heart, in increasing numbers, economic and social “marginalized” people / “outsiders”? Despite the imposition of management systems, what are the actors’ strategies, their negotiation skills and their logic of subjectivation? From a comparative perspective, this dossier shows various figures of social margins and allows us to understand the weight of the managerial and security systems that frame them. Employees, volunteers and all those who benefit from or are excluded from services highlight, despite everything, lines of social emancipation

The discovery of in vivo active mitochondrial branched-chain aminotransferase (BCATm) inhibitors by hybridizing fragment and HTS hits

The hybridization of hits, identified by complementary fragment and high throughput screens, enabled the discovery of the first series of potent inhibitors of mitochondrial branched-chain aminotransferase (BCATm) based on a 2-benzylamino-pyrazolo[1,5-a]pyrimidinone-3-carbonitrile template. Structure-guided growth enabled rapid optimization of potency with maintenance of ligand efficiency, while the focus on physicochemical properties delivered compounds with excellent pharmacokinetic exposure that enabled a proof of concept experiment in mice. Oral administration of 2-((4-chloro-2,6-difluorobenzyl)amino)-7-oxo-5-propyl-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carbonitrile 61 significantly raised the circulating levels of the branched-chain amino acids leucine, isoleucine, and valine in this acute study