Identification of GSK3186899/DDD853651 as a Preclinical Development Candidate for the Treatment of Visceral Leishmaniasis

The leishmaniases are diseases that affect millions of people across the world, in particular visceral leishmaniasis (VL) which is fatal unless treated. Current standard of care for VL suffers from multiple issues and there is a limited pipeline of new candidate drugs. As such, there is a clear unmet medical need to identify new treatments. This paper describes the optimization of a phenotypic hit against Leishmania donovani, the major causative organism of VL. The key challenges were to balance solubility and metabolic stability while maintaining potency. Herein, strategies to address these shortcomings and enhance efficacy are discussed, culminating in the discovery of preclinical development candidate GSK3186899/DDD853651 (<b>1</b>) for VL

Genetic integrity of European wildcats: Variation across biomes mandates geographically tailored conservation strategies

Hybridisation between domestic and wild taxa can pose severe threats to wildlife conservation, and human-induced hybridisation, often linked to species' introductions and habitat degradation, may promote reproductive opportunities between species for which natural interbreeding would be highly unlikely. Using a biome-specific approach, we examine the effects of a suite of ecological drivers on the European wildcat's genetic integrity, while assessing the role played by protected areas in this process. We used genotype data from 1217 putative European wildcat samples from 13 European countries to assess the effects of landcover, disturbance and legal landscape protection on the European wildcat's genetic integrity across European biomes, through generalised linear models within a Bayesian framework. Overall, we found European wildcats to have genetic integrity levels above the wildcat-hybrid threshold (ca. 83%; threshold = 80%). However, Mediterranean and Temperate Insular biomes (i.e., Scotland) revealed lower levels, with 74% and 46% expected genetic integrity, respectively. We found that different drivers shape the level of genetic introgression across biomes, although forest integrity seems to be a common factor promoting European wildcat genetic integrity. Wildcat genetic integrity remains high, regardless of landscape legal protection, in biomes where populations appear to be healthy and show recent local range expansions. However, in biomes more susceptible to hybridisation, even protected areas show limited effectiveness in mitigating this threat. In the face of the detected patterns, we recommend that species conservation and management plans should be biome- and landscape-context-specific to ensure effective wildcat conservation, especially in the Mediterranean and Temperate Insular biomes.Thanks are due to FCT/MCTES for the financial support to cE3c (UIDB/00329/2020), through national funds, and the co-funding by the FEDER, within the PT2020 Partnership Agreement and Compete 2020. PM was supported by UID/BIA/50027/2021 with funding from FCT/MCTES through national funds. FDR was supported by a postdoctoral contract from the University of Málaga (I Plan Propio de Investigación y Transferencia, call 2020). This study was partly funded by research projects CGL2009-10741, funded by the Spanish Ministry of Science and Innovation and EU-FEDER, and OAPN 352/2011, funded by the Organismo Autónomo Parques Nacionales (Spain). Luxembourg sample collection has been co-funded by the Ministry of Environment, Climate and Sustainable Development of Luxembourg. We would like to thank the Bavarian Forest National Park Administration for the approval and support in collecting samples.Peer reviewe

TOI-836 : a super-Earth and mini-Neptune transiting a nearby K-dwarf

Funding: TGW, ACC, and KH acknowledge support from STFC consolidated grant numbers ST/R000824/1 and ST/V000861/1, and UKSA grant ST/R003203/1.We present the discovery of two exoplanets transiting TOI-836 (TIC 440887364) using data from TESS Sector 11 and Sector 38. TOI-836 is a bright (T = 8.5 mag), high proper motion (∼200 mas yr−1), low metallicity ([Fe/H]≈−0.28) K-dwarf with a mass of 0.68 ± 0.05 M⊙ and a radius of 0.67 ± 0.01 R⊙. We obtain photometric follow-up observations with a variety of facilities, and we use these data-sets to determine that the inner planet, TOI-836 b, is a 1.70 ± 0.07 R⊕ super-Earth in a 3.82 day orbit, placing it directly within the so-called ‘radius valley’. The outer planet, TOI-836 c, is a 2.59 ± 0.09 R⊕ mini-Neptune in an 8.60 day orbit. Radial velocity measurements reveal that TOI-836 b has a mass of 4.5 ± 0.9 M⊕, while TOI-836 c has a mass of 9.6 ± 2.6 M⊕. Photometric observations show Transit Timing Variations (TTVs) on the order of 20 minutes for TOI-836 c, although there are no detectable TTVs for TOI-836 b. The TTVs of planet TOI-836 c may be caused by an undetected exterior planet.Publisher PDFPeer reviewe

TOI-836: A super-Earth and mini-Neptune transiting a nearby K-dwarf

We present the discovery of two exoplanets transiting TOI-836 (TIC 440887364) using data from TESS Sector 11 and Sector 38. TOI-836 is a bright ($T = 8.5$ mag), high proper motion ($\sim\,200$ mas yr$^{-1}$), low metallicity ([Fe/H]$\approx\,-0.28$) K-dwarf with a mass of $0.68\pm0.05$ M$_{\odot}$ and a radius of $0.67\pm0.01$ R$_{\odot}$. We obtain photometric follow-up observations with a variety of facilities, and we use these data-sets to determine that the inner planet, TOI-836 b, is a $1.70\pm0.07$ R$_{\oplus}$ super-Earth in a 3.82 day orbit, placing it directly within the so-called 'radius valley'. The outer planet, TOI-836 c, is a $2.59\pm0.09$ R$_{\oplus}$ mini-Neptune in an 8.60 day orbit. Radial velocity measurements reveal that TOI-836 b has a mass of $4.5\pm0.9$ M$_{\oplus}$ , while TOI-836 c has a mass of $9.6\pm2.6$ M$_{\oplus}$. Photometric observations show Transit Timing Variations (TTVs) on the order of 20 minutes for TOI-836 c, although there are no detectable TTVs for TOI-836 b. The TTVs of planet TOI-836 c may be caused by an undetected exterior planet

Évolution des caractéristiques physico-chimiques et écotoxicologiques des sédiments accumulés dans un bassin de retenue-décantation : premiers résultats du projet ANR CABRRES.

National audienceDetention basins are valuable facilities for urban stormwater management from the standpoint of both flood control and mitigating particulate pollutants by means of settling processes. Trapped sediments represent specific waste. The amount and the characterization of these accumulated sediments are also a very important issue for practitioners because these solids have to be frequently removed and managed as waste. A physical and chemical characteristics (metals, PAHs, pesticides) and ecotoxicological evaluation of these contaminated sediments have been carried out in the framework of CABRRES French programme. Sediments accumulated over about 6 months and 6 years in retention/detention basin located in the east of Lyon, France, were sampled at five different points. These preliminary results show: spatial variability for Cd, Pb, Zn and Σ16 PAHs, with the higher contamination at one point; and an ecotoxicological risk for accumulated sediments over about 6 years. These preliminary results may contribute to improve the management of detention basins in term of maintenance frequency and appropriate ways to recycle sediments.Les bassins de retenue-décantation sont très souvent utilisés pour la gestion des eaux pluviales dans les villes. Ils permettent de diminuer les risques d’inondations et de réduire les rejets de polluants parti culaires dans les milieux récepteurs (sol/nappe). Leur fonctionnement sur le long terme pose cependant le problème de la gestion des sédiments accumulés en leur sein. Afin de suivre leurs transformations (physique, chimique, écotoxicologique), une caractérisation physicochimique – éléments traces métalliques, hydrocarbures aromatiques polycycliques (HAP), pesticides – ainsi qu’une évaluation écotoxicologique ont été réalisées sur les sédiments accumulés dans un bassin de rétention de grande taille localisé dans l’est lyonnais (France). Cinq points ont été échantillonnés sur deux périodes d’accumulation des sédiments à la suite du curage du bassin (6 mois et 6 ans). Les résultats de cette étude préliminaire ont mis en évidence : une hétérogénéité spatiale en matière de contamination pour Cd, Pb, Zn et Σ16HAPs, avec des teneurs en polluants élevées en un point particulier; et un risque écotoxique pour les sédiments accumulés depuis 6 ans. Ces résultats préliminaires donnent des orientations en matière de fréquence de curage de ces bassins et de choix de filières de traitement et de valorisation des sédiments

Role-playing games in cybercartography: Multiple perspectives and critical thinking

This article discusses the use of computer games in cybercartography and how computer game characteristics can enhance the design of cybercartographic products. We focus on investigating multiple perspectives through role play in a geospatial virtual environment. The ways in which literature and film support multiple perspectives can guide us in our design efforts for developing cybercatographic atlases. We explore the potential of games for presenting multiple points of view in an environmental context through the modification of an existing computer game that includes quest narratives and character interaction as well as role play. Active engagement with different characters and the environment in role-playing games encourages exploration and learning, and these interactions give a player the opportunity to discover diverse points of view and develop different ways of solving problems. Multiple points of view in cybercartography can offer a plurality of voices on critical issues. In particular, information presented in maps can stimulate ideas and encourage critical thinking. This leads us to conclude that the engaging and emotional dimensions of computer games can be combined with the multiple perspectives they offer to attract new atlas users and to provide them with a more critical perspective on geographic and environmental information

A Deep Learning Method for Quantification of Femoral Head Necrosis Based on Routine Hip MRI for Improved Surgical Decision Making

(1) Background: To evaluate the performance of a deep learning model to automatically segment femoral head necrosis (FHN) based on a standard 2D MRI sequence compared to manual segmentations for 3D quantification of FHN. (2) Methods: Twenty-six patients (thirty hips) with avascular necrosis underwent preoperative MR arthrography including a coronal 2D PD-w sequence and a 3D T1 VIBE sequence. Manual ground truth segmentations of the necrotic and unaffected bone were then performed by an expert reader to train a self-configuring nnU-Net model. Testing of the network performance was performed using a 5-fold cross-validation and Dice coefficients were calculated. In addition, performance across the three segmentations were compared using six parameters: volume of necrosis, volume of unaffected bone, percent of necrotic bone volume, surface of necrotic bone, unaffected femoral head surface, and percent of necrotic femoral head surface area. (3) Results: Comparison between the manual 3D and manual 2D segmentations as well as 2D with the automatic model yielded significant, strong correlations (Rp > 0.9) across all six parameters of necrosis. Dice coefficients between manual- and automated 2D segmentations of necrotic- and unaffected bone were 75 ± 15% and 91 ± 5%, respectively. None of the six parameters of FHN differed between the manual and automated 2D segmentations and showed strong correlations (Rp > 0.9). Necrotic volume and surface area showed significant differences (all p p > 0.05). (4) Conclusions: Our deep learning model to automatically segment femoral necrosis based on a routine hip MRI was highly accurate. Coupled with improved quantification for volume and surface area, as opposed to 2D angles, staging and course of treatment can become better tailored to patients with varying degrees of AVN

SOLIS IV. Hydrocarbons in the OMC-2 FIR4 Region, a Probe of Energetic Particle Irradiation of the Region

We report new interferometric images of cyclopropenylidene, c-C$_3$H$_2$, towards the young protocluster OMC-2 FIR\,4. The observations were performed at 82 and 85 GHz with the NOrthern Extended Millimeter Array (NOEMA) as part of the project Seeds Of Life In Space (SOLIS). In addition, IRAM-30m data observations were used to investigate the physical structure of OMC-2 FIR\,4. We find that the c-C$_3$H$_2$ gas emits from the same region where previous SOLIS observations showed bright HC$_5$N emission. From a non-LTE analysis of the IRAM-30m data, the c-C$_3$H$_2$ gas has an average temperature of $\sim$40K, a H$_2$ density of $\sim$3$\times$10$^{5}$~cm$^{-3}$, and a c-C$_3$H$_2$ abundance relative to H$_2$ of ($7\pm1$)$\times$10$^{-12}$. In addition, the NOEMA observations provide no sign of significant c-C$_3$H$_2$ excitation temperature gradients across the region (about 3-4 beams), with T$_{ex}$ in the range 8$\pm$3 up to 16$\pm$7K. We thus infer that our observations are inconsistent with a physical interaction of the OMC-2 FIR\,4 envelope with the outflow arising from OMC-2 FIR\,3, as claimed by previous studies. The comparison of the measured c-C$_3$H$_2$ abundance with the predictions from an astrochemical PDR model indicates that OMC-2 FIR\,4 is irradiated by a FUV field $\sim$1000 times larger than the interstellar one, and by a flux of ionising particles $\sim$4000 times larger than the canonical value of $1\times10^{-17}$~s$^{-1}$ from the Galaxy cosmic rays, which is consistent with our previous HC$_5$N observations. This provides an important and independent confirmation of other studies that one or more sources inside the OMC-2 FIR\,4 region emit energetic ($\geq10$~MeV) particles.Comment: Accepted for publication in ApJ - 14 pages, 10 figures, 4 table