The Imipridone ONC213 Targets α-Ketoglutarate Dehydrogenase to Induce Mitochondrial Stress and Suppress Oxidative Phosphorylation in Acute Myeloid Leukemia.

Unlabelled: Eradication of acute myeloid leukemia (AML) is therapeutically challenging; many patients succumb to AML despite initially responding to conventional treatments. Here, we showed that the imipridone ONC213 elicits potent antileukemia activity in a subset of AML cell lines and primary patient samples, particularly in leukemia stem cells, while producing negligible toxicity in normal hematopoietic cells. ONC213 suppressed mitochondrial respiration and elevated α-ketoglutarate by suppressing α-ketoglutarate dehydrogenase (αKGDH) activity.

Facile Synthesis of Pure and Cr-Doped WO Thin Films for the Detection of Xylene at Room Temperature.

This paper focused on the preparation of pure and Cr-doped tungsten trioxide (WO) thin films using the spray pyrolysis method. Different techniques were adopted to analyze these films' structural and morphological properties. The X-ray detection analysis showed that the average crystallite size of the WO-nanostructured thin films increased as the Cr doping concentration increased.

A Curvilinear-Path Umbrella Sampling Approach to Characterizing the Interactions Between Rapamycin and Three FKBP12 Variants.

Rapamycin is an immunosuppressant macrolide that exhibits anti-proliferative properties through inhibiting the mTOR kinase. In fact, the drug first associates with the FKBP12 enzyme before interacting with the FRB domain of its target. Despite the availability of structural and thermodynamic information on the interaction of FKBP12 with rapamycin, the energetic and mechanistic understanding of this process is still incomplete.

Delineating Protein-Protein Curvilinear Dissociation Pathways and Energetics with Naïve Multiple-Walker Umbrella Sampling Simulations.

The protein-protein interaction energetics can be obtained by calculating the potential of mean force (PMF) from umbrella sampling (US) simulations, in which samplings are often enhanced along a predefined vector as the reaction coordinate. However, any slight change in the vector may significantly vary the calculated PMF, and therefore the energetics using a random choice of vector may mislead. A non-predefined curve path-based sampling enhancement approach is a natural alternative, but was relatively less explored for protein-protein systems.

Discovery and evaluation of novel FAAH inhibitors in neuropathic pain model.

Conceptual design and modification of urea moiety in chemotype PF-3845/04457845, the bench marking irreversible inhibitor of fatty acid amide hydrolase (FAAH), led to discovery of a novel nicotinamide-based lead 12a having reversible mechanism of action. Focused SAR around the pyridine heterocycle (Ar) in 12a (Tables 1 and 2) resulted into four shortlisted compounds, (-)-12a, (-)-12i, (-)-12l-m. The required (-)-enantiomers were obtained via diastereomeric resolution of a novel chiral dissymmetric intermediate 15.

Comparison of a high-throughput high-content intracellular Leishmania donovani assay with an axenic amastigote assay.

Visceral leishmaniasis is a neglected tropical disease with significant health impact. The current treatments are poor, and there is an urgent need to develop new drugs. Primary screening assays used for drug discovery campaigns have typically used free-living forms of the Leishmania parasite to allow for high-throughput screening.

A static-cidal assay for Trypanosoma brucei to aid hit prioritisation for progression into drug discovery programmes.

Human African Trypanosomiasis is a vector-borne disease of sub-Saharan Africa that causes significant morbidity and mortality. Current therapies have many drawbacks, and there is an urgent need for new, better medicines. Ideally such new treatments should be fast-acting cidal agents that cure the disease in as few doses as possible.

Mapping conformational transitions in cyclic AMP receptor protein: crystal structure and normal-mode analysis of Mycobacterium tuberculosis apo-cAMP receptor protein.

Cyclic AMP (cAMP) receptor protein, which acts as the sensor of cAMP levels in cells, is a well-studied transcription factor that is best known for allosteric changes effected by the binding of cAMP. Although genetic and biochemical data on the protein are available from several sources, structural information about the cAMP-free protein has been lacking. Therefore, the precise atomic events that take place upon binding of cAMP, leading to conformational changes in the protein and its activation to bind DNA, have been elusive.

The PPE18 of Mycobacterium tuberculosis interacts with TLR2 and activates IL-10 induction in macrophage.

The pathophysiological functions of proline-glutamic acid (PE)/proline-proline-glutamic acid (PPE) family of proteins of Mycobacterium tuberculosis are not well understood. In this study, we demonstrate that one of the PPE proteins, PPE18 can stimulate macrophages to secrete IL-10, known to favor a Th2 type response. The recombinant PPE18 was found to specifically interact with the TLR2 leading to an early and sustained activation of p38 MAPK, which is critical for IL-10 induction.

A virtual environment for esophageal intubation training.

Esophageal intubations are performed for urgent airway control in injured patients. Current methods of training include working on cadavers and mannequins, which lack the realism of a living human being. Work in this field has been limited due to the complex nature of simulating in real-time the interactive forces and deformations which occur during an actual patient intubation.

Utilization of virtual reality for endotracheal intubation training.

Tracheal intubation is performed for urgent airway control in injured patients. Current methods of training include working on cadavers and manikins, which lack the realism of a living human being. Work in this field has been limited due to the complex nature of simulating in real-time, the interactive forces and deformations which occur during an actual patient intubation.