Parkinsonism-associated Protein DJ-1/Park7 Is a Major Protein Deglycase That Repairs Methylglyoxal- and Glyoxal-glycated Cysteine,Arginine, and Lysine Residues

Glycation is an inevitable nonenzymatic covalent reaction between proteins and endogenous reducing sugars or dicarbonyls (methylglyoxal, glyoxal) that results in protein inactivation. DJ-1 was reported to be a multifunctional oxidative stress response protein with poorly defined function. Here, we show that human DJ-1 is a protein deglycase that repairs methylglyoxal- and glyoxal-glycated amino acids and proteins by acting on early glycation intermediates and releases repaired proteins and lactate or glycolate, respectively. DJ-1 deglycates cysteines, arginines, and lysines (the three major glycated amino acids) of serum albumin, glyceraldehyde-3-phosphate dehydrogenase, aldolase, and aspartate aminotransferase and thus reactivates these proteins. DJ-1 prevented protein glycation in an Escherichia coli mutant deficient in the DJ-1 homolog YajL and restored cell viability in glucose-containing media. These results suggest that DJ-1-associated Parkinsonism results from excessive protein glycation and establishes DJ-1 as a major anti-glycation and anti-aging protein.     

Bicyclic heteroaryl inhibitors of stearoyl-CoA desaturase: from systemic to liver-targeting inhibitors

Optimization of a lead thiazole amide MF-152 led to the identification of potent bicyclic heteroaryl SCD1 inhibitors with good mouse pharmacokinetic profiles. In a view to target the liver for efficacy and to avoid SCD1 inhibition in the skin and eyes where adverse effects were previously observed in rodents, representative systemically-distributed SCD1 inhibitors were converted into liver-targeting SCD1 inhibitors.     

Contextual Information and Differential Responses to Alarm Whistles in California Ground Squirrels

In the field, we videotaped the reactions of squirrels to playbacks of 1, 3 and 5 whistle vocalizations at two sound intensities differing by 10 dB. The squirrels reacted by running to boulders or burrows and freezing. As time progressed following playbacks, freezing declined and squirrels resumed feeding, locomotion and grooming. With increasing numbers of whistles, squirrels were more likely to run and less likely to mount a boulder. With more high intensity whistles, squirrels froze quadrupedally more and bipedally less. Freezing postures did not vary as a function of the number of low-intensity whistles. Walking was suppressed least by 1 and 3 whistles at low intensity, and inhibited most by all high-intensity whistles as well as by the low-intensity 5-whistle playback. When the squirrel was on a boulder, quadrupedal freezing was more common than bipedal freezing. Off the boulder, the two freezing postures were equally likely. We propose that squirrels assessed risk from information encoded in the whistle(s) and contextual to it, and varied their reactions as a function of apparent risk.     

Reversing systemic inflammatory response syndrome with chemokine receptor pepducins

We describe a new therapeutic approach for the treatment of lethal sepsis using cell-penetrating lipopeptides-termed pepducins-that target either individual or multiple chemokine receptors. Interleukin-8 (IL-8), a ligand for the CXCR1 and CXCR2 receptors, is the most potent endogenous proinflammatory chemokine in sepsis. IL-8 levels rise in blood and lung fluids to activate neutrophils and other cells, and correlate with shock, lung injury and high mortality. We show that pepducins derived from either the i1 or i3 intracellular loops of CXCR1 and CXCR2 prevent the IL-8 response of both receptors and reverse the lethal sequelae of sepsis, including disseminated intravascular coagulation and multi-organ failure in mice. Conversely, pepducins selective for CXCR4 cause a massive leukocytosis that does not affect survival. CXCR1 and CXCR2 pepducins conferred nearly 100% survival even when treatment was postponed, suggesting that our approach might be beneficial in the setting of advanced disease.     

Enantioselective synthesis of 2- and 3-substituted 2,3-dihydro[1,4]dioxino[2,3-b]pyridine derivatives and enantiomeric purity control by capillary electrophoresis

A rapid and simple procedure for enantioselective preparation of 2- and 3-substituted 2,3-dihydro[1,4]dioxino[2,3-b]pyridine derivatives (A and B, respectively) is described. The enantiomeric purity of each isomer was determined by capillary electrophoresis using a dual-cyclodextrin system (S-beta-CD/beta-CD) dissolved in formic acid-ammonia buffer (pH 4, ionic strength 50 mM).     

Brainstem structures responsible for paradoxical sleep onset and maintenance

This paper is dedicated to our mentor, Michel Jouvet who inspired our career and transmitted to us his passion for the study of the mechanisms responsible for paradoxical sleep genesis and also that of its still mysterious functions. We expose in the following the progresses in the knowledge in this field brought during 40 years by Michel Jouvet and his team and more recently by the members of a new CNRS laboratory in which we aim to pursue in the path opened by Michel Jouvet.     

Strain improvement of fungal insecticides for controlling insect pests and vector-borne diseases

Insect pathogenic fungi play an important natural role in controlling insect pests. However, few have been successfully commercialized due to low virulence and sensitivity to abiotic stresses that produce inconsistent results in field applications. These limitations are inherent in most naturally occurring biological control agents but development of recombinant DNA techniques has made it possible to significantly improve the insecticidal efficacy of fungi and their tolerance to adverse conditions, including UV. These advances have been achieved by combining new knowledge derived from basic studies of the molecular biology of these pathogens, technical developments that enable very precise regulation of gene expression, and genes encoding insecticidal proteins from other organisms, particularly spiders and scorpions. Recent coverage of genomes is helping determine the identity, origin, and evolution of traits needed for diverse lifestyles and host switching. In future, such knowledge combined with the precision and malleability of molecular techniques will allow design of multiple pathogens with different strategies and host ranges to be used for different ecosystems, and that will avoid the possibility of the host developing resistance. With increasing public concern over the continued use of synthetic chemical insecticides, these new types of biological insecticides offer a range of environmental-friendly options for cost-effective control of insect pests.     

Identification of a novel coronavirus from a beluga whale by using a panviral microarray

The emergence of viruses such as severe acute respiratory syndrome coronavirus and Nipah virus has underscored the role of animal reservoirs in human disease and the need for reservoir surveillance. Here, we used a panviral DNA microarray to investigate the death of a captive beluga whale in an aquatic park. A highly divergent coronavirus, tentatively named coronavirus SW1, was identified in liver tissue from the deceased whale. Subsequently, the entire genome of SW1 was sequenced, yielding a genome of 31,686 nucleotides. Phylogenetic analysis revealed SW1 to be a novel virus distantly related to but most similar to group III coronaviruses.     

Increased resistance to generalist herbivores in invasive populations of the California poppy (Eschscholzia californica)

Escape from enemies in the native range is often assumed to contribute to the successful invasion of exotic species. Following optimal defence theory, which assumes a trade‐off between herbivore resistance and plant growth, some have predicted that the success of invasive species could be the result of the evolution of lower resistance to herbivores and increased allocation of resources to growth and reproduction. Lack of evidence for ubiquitous costs of producing plant toxins, and the recognition that invasive species may escape specialist, but not generalist enemies, has led to a new prediction: invasive species may escape ecological trade‐offs associated with specialist herbivores, and evolve increased, rather than decreased, production of defensive compounds that are effective at deterring generalist herbivores in the introduced range. We tested the performance of two generalist lepidopteran herbivores, Trichoplusia ni and Orgyia vetusta, when raised on diets of native and invasive populations of the California poppy, Eschscholzia californica. Pupae of T. ni were significantly larger when reared on native populations. Similarly, caterpillars of O. vetusta performed significantly better when raised on native populations, indicating that invasive populations of the California poppy are more resistant to herbivores than native populations. The chance of successful establishment of some non‐indigenous plant species may be increased by retaining resistance to generalist herbivores, and in some cases, invasive species may be able to escape ecological trade‐offs in their new range and evolve, as we observed, even greater resistance to generalist herbivores than native plants.