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

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

Application de l'immunofluorescence a la detection de Phoma exigua var. foveata, agent de la gangrene de la pomme de terre

National audienceAn antiserum against Phoma exigua var. foveata was prepared using pycniospores of the fungus produced in pure culture. The indirect fluorescence antibody technique of NAIRN (1964) was used. The serum had an estimated titre of 1/4000, by immunofluorescence, and was specific for the spores of the variety foveata ; it could be used to differentiate between the varieties P. exigua var. exigua and P. exigua var. foveata, the latter variety being mainly responsible for potato gangrene. No immunofluorescence reaction was noted with other species of Phoma. A comparative study was carried out with the two varieties using immunofluorescence and the classical identification techniques of isolation on agar media after wound inoculation of tubers. A good correlation was obtained between the two identification techniques. Eight samples were positive in I.F. and seven with the isolation technique. Three to five spores were observed in each field of the microscope at magnification 500. Therefore the application of I.F. for the identification of this fungus appears to be useful and feasible.Un antisérum a été obtenu à partir des pycniospores de Phoma exigua var. foveata provenant d’une souche pure cultivée in vitro ; son titre, estimé en immunofluorescence, est de 1/4000e. La technique d’immunofluorescence (I.F.) indirecte de NAIRN (1964) a été utilisée. Le sérum réagit spécifiquement avec la variété foveata et seulement avec les spores de cette variété. Il ne révèle ni le mycélium de cette variété, ni la forme voisine, P. exigua var exigua; il permet donc de différencier les deux formes lorsqu’il s’agit de spores. De même, aucune réaction n’a été observée en I.F. avec d’autres espèces appartenant ou non au genre Phoma (tabl. 1). La recherche de la variété foveata, principal agent responsable de la gangrène de la pomme de terre a été réalisée sur tubercules de façon simultanée par I.F. et par la technique classique d’isolement sur milieu gélosé après blessure des tubercules ; les deux méthodes donnent des résultats très voisins puisque 8 lots sont positifs en I.F. contre 7 par la technique d’isolement. Chaque préparation provenant d’un lot infecté présentait en moyenne 3 à 5 spores par champ du microscope au grandissement 500. L’application de l’I.F à la détection de ce champignon sur pomme de terre paraît donc envisageable

Thermal modelling of a carbon/carbon composite material fabrication process

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Near-term nn to kk distillation protocols using graph codes

Noisy hardware forms one of the main hurdles to the realization of a near-term quantum internet. Distillation protocols allows one to overcome this noise at the cost of an increased overhead. We consider here an experimentally relevant class of distillation protocols, which distill $n$ to $k$ end-to-end entangled pairs using bilocal Clifford operations, a single round of communication and a possible final local operation depending on the observed measurement outcomes. In the case of permutationally invariant depolarizing noise on the input states, we find a correspondence between these distillation protocols and graph codes. We leverage this correspondence to find provably optimal distillation protocols in this class for several tasks important for the quantum internet. This correspondence allows us to investigate use cases for so-called non-trivial measurement syndromes. Furthermore, we detail a recipe to construct the circuit used for the distillation protocol given a graph code. We use this to find circuits of short depth and small number of two-qubit gates. Additionally, we develop a black-box circuit optimization algorithm, and find that both approaches yield comparable circuits. Finally, we investigate the teleportation of encoded states and find protocols which jointly improve the rate and fidelities with respect to prior art.Comment: 29 pages, 19 figure

The film-boiling densification process for C/C composite fabrication : from local scale to overall optimization

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