Observation of tW production in the single-lepton channel in pp collisions at root s=13 TeV

A measurement of the cross section of the associated production of a single top quark and a W boson in final states with a muon or electron and jets in proton-proton collisions at root s = 13 TeV is presented. The data correspond to an integrated luminosity of 36 fb(-1) collected with the CMS detector at the CERN LHC in 2016. A boosted decision tree is used to separate the tW signal from the dominant t (t) over bar background, whilst the subleading W+jets and multijet backgrounds are constrained using data-based estimates. This result is the first observation of the tW process in final states containing a muon or electron and jets, with a significance exceeding 5 standard deviations. The cross section is determined to be 89 +/- 4 (stat) +/- 12 (syst) pb, consistent with the standard model.Peer reviewe

Development of a FACS-based assay for evaluating antiviral potency of compound in dengue infected peripheral blood mononuclear cells

Dengue fever is the most important arthropod-transmitted viral disease affecting humans. It is a blood-borne disease characterized by persistent fever and joint pain. In the blood, primary peripheral blood mononuclear cells (PBMCs), in particular monocytes, are the main target of the dengue virus (DENV). These cells are poorly permissive for in vitro dengue virus infection and their infectivity varies from donor to donor. To overcome this barrier, an anti-dengue antibody was used to improve the infectivity of DENV-2 clinical isolates to PBMCs, the monocytic leukemia cell line, THP-1 and the granulocyte cell line, KU812. A higher throughput 96-well-format assay based on a fluorescent-activated cell sorter could potentially be developed to evaluate the antiviral potency of compounds in DENV-infected PBMCs in vitro. The results correlate well with data obtained by a standard plaque assay. Altogether, an assay has been developed that enables evaluation of the antiviral activity of test compounds in a physiologically-relevant cell system (PBMCs). These screening processes are urgently needed for dengue drug discovery. © 2013 Elsevier B.V

4D semantic cardiac magnetic resonance image synthesis on XCAT anatomical model

We propose a hybrid controllable image generation method to synthesize anatomically meaningful 3D+t labeled Cardiac Magnetic Resonance (CMR) images. Our hybrid method takes the mechanistic 4D eXtended CArdiac Torso (XCAT) heart model as the anatomical ground truth and synthesizes CMR images via a data-driven Generative Adversarial Network (GAN). We employ the state-of-the-art SPatially Adaptive De-normalization (SPADE) technique for conditional image synthesis to preserve the semantic spatial information of ground truth anatomy. Using the parameterized motion model of the XCAT heart, we generate labels for 25 time frames of the heart for one cardiac cycle at 18 locations for the short axis view. Subsequently, realistic images are generated from these labels, with modality-specific features that are learned from real CMR image data. We demonstrate that style transfer from another cardiac image can be accomplished by using a style encoder network. Due to the flexibility of XCAT in creating new heart models, this approach can result in a realistic virtual population to address different challenges the medical image analysis research community is facing such as expensive data collection. Our proposed method has a great potential to synthesize 4D controllable CMR images with annotations and adaptable styles to be used in various supervised multi-site, multi-vendor applications in medical image analysis

Structure activity relationships of 4-hydroxy-2-pyridones: A novel class of antituberculosis agents

Pyridone 1 was identified from a high-throughput cell-based phenotypic screen against Mycobacterium tuberculosis (Mtb) including multi-drug resistant tuberculosis (MDR-TB) as a novel anti-TB agent and subsequently optimized series using cell-based Mtb assay. Preliminary structure activity relationship on the isobutyl group with higher cycloalkyl groups at 6-position of pyridone ring has enabled us to significant improvement of potency against Mtb. The lead compound 30j, a dimethylcyclohexyl group on the 6-position of the pyridone, displayed desirable in vitro potency against both drug sensitive and multi-drug resistant TB clinical isolates. In addition, 30j displayed favorable oral pharmacokinetic properties and demonstrated in vivo efficacy in mouse model. These results emphasize the importance of 4-hydroxy-2-pyridones as a new chemotype and further optimization of properties to treat MDR-TB

Design, synthesis and biological evaluation of indole-2-carboxamides, a promising class of anti-tuberculosis agents

Indole-2-carboxamides have been identified as a promising class of anti-tuberculosis agents from phenotypic whole cell high-throughput screening against mycobacteria. One of the hits KCD644, an N-cyclohexyl-4,6-dimethyl-1H-indole-2-carboxamide had low µM potency, high in vitro mouse liver microsomal clearance and low aqueous solubility. Structure activity relationship studies revealed that attaching further small alkyl groups to the cyclohexyl ring significantly improved activity against Mycobacterium tuberculosis (Mtb) but reduced aq solubility. Further, chloro, fluoro or cyano substitutions on the 4- and 6-positions of the indole ring and mono or dimethyl substitution on the 4-position of the cyclohexyl ring significantly improved both in vitro and in vivo metabolic stability. KDZ304 and KDZ349, the lead candidates from this study displayed improved in vitro activity compared to the current standard TB drugs. The low aq solubility of compounds in the series could not be mitigated due to the correlation of lipophilicity with potency against Mtb. However, both compounds displayed favorable in vivo pharmacokinetic properties in rodents when dosed in a microemulsion preconcentrate formulation (MEPC). Both KDZ304 and KDZ349 delivered good oral exposure and also demonstrated in vivo efficacy in a mouse model. Thus, indole-2-carboxamides represent a promising new class of anti-TB agents

Where Brain, Body and World Collide

The production cross section of electrons from semileptonic decays of beauty hadrons was measured at mid-rapidity (|y| < 0.8) in the transverse momentum range 1 < pt < 8 Gev/c with the ALICE experiment at the CERN LHC in pp collisions at a center of mass energy sqrt{s} = 7 TeV using an integrated luminosity of 2.2 nb^{-1}. Electrons from beauty hadron decays were selected based on the displacement of the decay vertex from the collision vertex. A perturbative QCD calculation agrees with the measurement within uncertainties. The data were extrapolated to the full phase space to determine the total cross section for the production of beauty quark-antiquark pairs

Discovery of Tetrahydropyrazolopyrimidine Carboxamide De-rivatives as Potent and Orally Active Novel Anti-Tubercular Agents

ABSTRACT: Tetrahydropyrazolopyrimidine scaffold was identified as a hit series from a Mycobacterium tuberculosis (Mtb) whole cell high through-put screening (HTS) campaign. A series of derivatives of this class were synthesized to evaluate their structure-activity relationship (SAR) and structure-property relationship (SPR). Compound 9 showed potent bactericidal effect and activity against multi-drug resistant tuberculosis (MDR TB) strains. Furthermore compound 9 had a promising in vivo DMPK profile in mouse and exhibited potent in vivo activity in a mouse efficacy model, achieving a reduction of 3.5 log CFU of Mtb after oral administration to infected mice once a day at 100 mg/kg for 28 days. Thus the compound 9 is a potential candidate for inclusion in combination therapies for both drug-sensitive and drug-resistant TB

Indolcarboxamide, a promising pre-clinical candidate for the treatment of multi drug resistant tuberculosis

To combat the drug resistance in tuberculosis, new chemotherapeutics active against multi-drug resistant Mycobacterium tuberculosis are urgently needed. We have identified and characterized the indolcarboxamides as a new class of anti-tubercular bactericidal agents. Genetics and lipid profiling studies identified the molecular target of indolcarboxamides as mmpL3, a transporter of TMM, a promiscuous target essential for mycobacterial cell wall biosynthesis. Two lead candidates NITD-304 and NITD-349 showed a significantly potent anti-TB activity against both drug sensitive and multi-drug resistant clinical Mtb isolates. Both compounds displayed favorable pharmacokinetic properties after oral administration in pre-clinical species. NITD-304 and NITD-349 showed no apparent inhibition of major CYP enzymes and are highly efficacious in both acute and chronic TB mouse efficacy models. Furthermore, we have assessed in vitro and in vivo safety profile of both candidates including two weeks exploratory rat toxicology studies. NITD-304 and NITD-349 show the adequate therapeutic index to justify further development for inclusion in the combination therapies for drug sensitive as well as drug resistant TB