A fragment merging approach towards the development of small molecule inhibitors of Mycobacterium tuberculosis EthR for use as ethionamide boosters.

With the ever-increasing instances of resistance to frontline TB drugs there is the need to develop novel strategies to fight the worldwide TB epidemic. Boosting the effect of the existing second-line antibiotic ethionamide by inhibiting the mycobacterial transcriptional repressor protein EthR is an attractive therapeutic strategy. Herein we report the use of a fragment based drug discovery approach for the structure-guided systematic merging of two fragment molecules, each binding twice to the hydrophobic cavity of EthR from M. tuberculosis. These together fill the entire binding pocket of EthR. We elaborated these fragment hits and developed small molecule inhibitors which have a 100-fold improvement of potency in vitro over the initial fragments.We also thank the Bill and Melinda Gates Foundation and the EU FP7 MM4TB Grant n°260872, the ERC-STG INTRACELLTB Grant n°260901, the Agence Nationale de la Recherche (ANR-10-EQPX-04-01), the Feder (12001407 (D-AL) Equipex Imaginex BioMed) and the Région Nord Pas de Calais, France, for providing funding to support this work.This is the final version of the article. It first appeared from the Royal Society of Chemistry via http://dx.doi.org/10.1039/C5OB02630

Xylem water transport is influenced by age and winter pruning characteristics in grapevine (<i>Vitis vinifera</i>)

In order to investigate the effect of age and pruning characteristics on grapevine hydraulic conduction, a study was carried out between 2017 and 2020. Two pruning regimes (respecting or not sap flow pathways) and two vine age levels (older and younger vine plants) were considered and compared on two different vineyard plots located in French north-east Jura region and in south-west Bordeaux one. The assessment of pruning characteristics in relation to sap flow pathway was based on a visual characterization of the external wood aspect of the trunk and arms and consisted of a set of criteria involving the number, size and position of pruning wounds. Sap flow measurements of entire vine plants were carried out using the Xyl’em® tool, as well as an assessment of the necrotized, living and conductive xylem area in the trunks and arms after Phloxine staining. The biomass of the vegetation was also assessed. Results showed that vines pruned without considering the sap flow pathways had a 40-to-50% less conductive sap flow than vines pruned taking into account the sap pathway. No difference was observed with vine age within each pruning regime. However, for the vineyard plot where the amount of conductive xylem area was assessed, older vines that were not pruned to respect the sap pathways showed a smaller area of living wood as well as conductive wood than the older ones pruned to respect the sap flows. The amount of living and conductive areas of these vines was equivalent to that of younger vines pruned to respect sap pathways. These older vines also showed less vegetative biomass. These results show that pruning without taking into account the sap pathways has a negative impact on the conduction of xylem sap pathways in grapevines, both in terms of hydraulic efficiency and quantity of living and conducting tissues. However, the possible consequences of these reductions on grapevine physiological functions still need to be further investigated

Finite Element Prediction of Elastic Recoil after Stent Implantation

Peer reviewed: YesNRC publication: Ye

Adaptive optics with an infrared pyramid wavefront sensor at Keck

The study of cold or obscured, red astrophysical sources can significantly benefit from adaptive optics (AO) systems employing infrared (IR) wavefront sensors. One particular area is the study of exoplanets around M-dwarf stars and planet formation within protoplanetary disks in star-forming regions. Such objects are faint at visible wavelengths but bright enough in the IR to be used as a natural guide star for the AO system. Doing the wavefront sensing at IR wavelengths enables high-resolution AO correction for such science cases, with the potential to reach the contrasts required for direct imaging of exoplanets. To this end, a new near-infrared pyramid wavefront sensor (PyWFS) has been added to the Keck II AO system, extending the performance of the facility AO system for the study of faint red objects. We present the Keck II PyWFS, which represents a number of firsts, including the first PyWFS installed on a segmented telescope and the first use of an IR PyWFS on a 10-m class telescope. We discuss the scientific and technological advantages offered by IR wavefront sensing and present the design and commissioning of the Keck PyWFS. In particular, we report on the performance of the Selex Avalanche Photodiode for HgCdTe InfraRed Array detector used for the PyWFS and highlight the novelty of this wavefront sensor in terms of the performance for faint red objects and the improvement in contrast. The system has been commissioned for science with the vortex coronagraph in the NIRC2 IR science instrument and is being commissioned alongside a new fiber injection unit for NIRSPEC. We present the first science verification of the system—to facilitate the study of exoplanets around M-type stars

Adaptive optics with an infrared pyramid wavefront sensor at Keck

The study of cold or obscured, red astrophysical sources can significantly benefit from adaptive optics (AO) systems employing infrared (IR) wavefront sensors. One particular area is the study of exoplanets around M-dwarf stars and planet formation within protoplanetary disks in star-forming regions. Such objects are faint at visible wavelengths but bright enough in the IR to be used as a natural guide star for the AO system. Doing the wavefront sensing at IR wavelengths enables high-resolution AO correction for such science cases, with the potential to reach the contrasts required for direct imaging of exoplanets. To this end, a new near-infrared pyramid wavefront sensor (PyWFS) has been added to the Keck II AO system, extending the performance of the facility AO system for the study of faint red objects. We present the Keck II PyWFS, which represents a number of firsts, including the first PyWFS installed on a segmented telescope and the first use of an IR PyWFS on a 10-m class telescope. We discuss the scientific and technological advantages offered by IR wavefront sensing and present the design and commissioning of the Keck PyWFS. In particular, we report on the performance of the Selex Avalanche Photodiode for HgCdTe InfraRed Array detector used for the PyWFS and highlight the novelty of this wavefront sensor in terms of the performance for faint red objects and the improvement in contrast. The system has been commissioned for science with the vortex coronagraph in the NIRC2 IR science instrument and is being commissioned alongside a new fiber injection unit for NIRSPEC. We present the first science verification of the system—to facilitate the study of exoplanets around M-type stars

Clinical and molecular characterization of 17q21.31 microdeletion syndrome in 14 French patients with mental retardation.

International audienceChromosome 17q21.31 microdeletion was one of the first genomic disorders identified by chromosome microarrays. We report here the clinical and molecular characterization of a new series of 14 French patients with this microdeletion syndrome. The most frequent clinical features were hypotonia, developmental delay and facial dysmorphism, but scaphocephaly, prenatal ischemic infarction and perception deafness were also described. Genotyping of the parents showed that the parent from which the abnormality was inherited carried the H2 inversion polymorphism, confirming that the H2 allele is necessary, but not sufficient to generate the 17q21.31 microdeletion. Previously reported molecular analyses of patients with 17q21.31 microdeletion syndrome defined a 493 kb genomic fragment that was deleted in most patients after taking into account frequent copy number variations in normal controls, but the deleted interval was significantly smaller (205 kb) in one of our patients, encompassing only the MAPT, STH and KIAA1267 genes. As this patient presents the classical phenotype of 17q21.31 syndrome, these data make it possible to define a new minimal critical region of 160.8 kb, strengthening the evidence for involvement of the MAPT gene in this syndrome

Loss-of-function variants in CUL3 cause a syndromic neurodevelopmental disorder

Purpose De novovariants inCUL3(Cullin-3 ubiquitin ligase) have been strongly associated with neurodevelopmental disorders (NDDs), but no large case series have been reported so far. Here we aimed to collect sporadic cases carrying rare variants inCUL3,describe the genotype-phenotype correlation, and investigate the underlying pathogenic mechanism.MethodsGenetic data and detailed clinical records were collected via multi-center collaboration. Dysmorphic facial features were analyzed using GestaltMatcher. Variant effects on CUL3 protein stability were assessed using patient-derived T-cells.ResultsWe assembled a cohort of 35 individuals with heterozygousCUL3variants presenting a syndromic NDD characterized by intellectual disability with or without autistic features. Of these, 33 have loss-of-function (LoF) and two have missense variants.CUL3LoF variants in patients may affect protein stability leading to perturbations in protein homeostasis, as evidenced by decreased ubiquitin-protein conjugatesin vitro. Specifically, we show that cyclin E1 (CCNE1) and 4E-BP1 (EIF4EBP1), two prominent substrates of CUL3, fail to be targeted for proteasomal degradation in patient-derived cells.ConclusionOur study further refines the clinical and mutational spectrum ofCUL3-associated NDDs, expands the spectrum of cullin RING E3 ligase-associated neuropsychiatric disorders, and suggests haploinsufficiency via LoF variants is the predominant pathogenic mechanism

Recommendations for acquisition, interpretation and reporting of whole body low dose CT in patients with multiple myeloma and other plasma cell disorders: a report of the IMWG Bone Working Group

Whole Body Low Dose CT (WBLDCT) has important advantages as a first-line imaging modality for bone disease assessment in patients with plasma cell disorders and has been included in the 2014 International Myeloma Working Group (IMWG) criteria for multiple myeloma (MM) definition. Nevertheless, standardization guidelines for the optimal use of WBLDCT in MM patients are still lacking, preventing its more widespread use, both in daily practice and clinical trials. The aim of this report by the Bone Group of the IMWG is to provide practical recommendations for the acquisition, interpretation and reporting of WBLDCT in patients with multiple myeloma and other plasma cell disorders