β-Carboline-3-carboxamide Antimalarials: Structure-Activity Relationship, ADME-Tox Studies, and Resistance Profiling.

The development of parasite resistance to both artemisinin derivatives and their partner drugs jeopardizes the effectiveness of the artemisinin combination therapy. Thus, the discovery of new antimalarial drugs, with new mechanisms of action, is urgently needed. We recently disclosed that β-carboline was orally efficacious in -infected mice and that it showed low cross-resistance between susceptible and four different drug-resistant strains.

Anti-Malarial Activity of Amentoflavone Isolated from Leaf of Calophyllum Tomentosum Wight.

Calophyllum tomentosum belonging to Clusiaceae family is an Indian medicinal plant used as folklore medicine to cure various kinds of diseases reported in Ayurveda, and the leaves of the plant are also used as an active ingredient for the preparation of a botanical medicine known as 'Punnaga', 'Surapunnaga' and 'Tamoil' among other common names. Chemical profiling of the methanol extract of the defatted leaf revealed the presence of amentoflavone (1) as one of the constituents along with coumarins, terpenoids, steroids, and apetalic acids. Structural determination of amentoflavone (1) has been conducted by chemical, spectral, and spectrometric methods in comparison with spectral values available in the literature and confirmed by a single crystal X-ray diffraction study.

Aptamer-Based Imaging of Polyisoprenoids in the Malaria Parasite.

Dolichols are isoprenoid end-products of the mevalonate and 2-methyl-D-erythritol-4-phosphate pathways. The synthesis of dolichols is initiated with the addition of several molecules of isopentenyl diphosphate to farnesyl diphosphate. This reaction is catalyzed by a -prenyltransferase and leads to the formation of polyprenyl diphosphate.

Cripowellins Pause Intraerythrocytic Development at the Ring Stage.

Cripowellins from are known pesticidal and have potent antiplasmodial activity. To gain mechanistic insights to this class of natural products, studies to determine the timing of action of cripowellins within the asexual intraerythrocytic cycle of were performed and led to the observation that this class of natural products induced reversible cytostasis in the ring stage within the first 24 h of treatment. The transcriptional program necessary for to progress through the asexual intraerythrocytic life cycle is well characterized.

Malaria Box-Inspired Discovery of -Aminoalkyl-β-carboline-3-carboxamides, a Novel Orally Active Class of Antimalarials.

Virtual ligand screening of a publicly available database of antimalarial hits using a pharmacophore derived from antimalarial MMV008138 identified TCMDC-140230, a tetrahydro-β-carboline amide, as worthy of exploration. All four stereoisomers of this structure were synthesized, but none potently inhibited growth of the malaria parasite . Interestingly, , a minor byproduct of these syntheses, proved to be potent against and was orally efficacious (40 mg/kg) in an mouse model of malaria.

Enantiopure Benzofuran-2-carboxamides of 1-Aryltetrahydro-β-carbolines Are Potent Antimalarials .

The tetrahydro-β-carboline scaffold has proven fertile ground for the discovery of antimalarial agents (e.g., MMV008138 () and cipargamin ()).

Promoting health equity for deaf patients through the electronic health record.

Language status can be conceptualized as an equity-relevant variable, particularly for non-English-speaking populations. Deaf and hard-of-hearing (DHH) individuals who use American Sign Language (ASL) to communicate comprise one such group and are understudied in health services research. DHH individuals are at high-risk of receiving lower-quality care due to ineffective patient-provider communication.

Resistance to Some But Not Other Dimeric Lindenane Sesquiterpenoid Esters Is Mediated by Mutations in a Esterase.

Unique lindenane sesquiterpenoid dimers from spp. were recently identified with promising antiplasmodial activity and potentially novel mechanisms of action. To gain mechanistic insights to this new class of natural products, selection of resistance to the most active antiplasmodial compound, chlorajaponilide C, was explored.

Probing the B- & C-rings of the antimalarial tetrahydro-β-carboline MMV008138 for steric and conformational constraints.

The antimalarial candidate MMV008138 (1a) is of particular interest because its target enzyme (IspD) is absent in human. To achieve higher potency, and to probe for steric demand, a series of analogs of 1a were prepared that featured methyl-substitution of the B- and C-rings, as well as ring-chain transformations. X-ray crystallography, NMR spectroscopy and calculation were used to study the effects of these modifications on the conformation of the C-ring and orientation of the D-ring.

An International Perspective on the Tools and Concepts for Effluent Toxicity Assessments in the Context of Animal Alternatives: Reduction in Vertebrate Use.

Since the 1940s, effluent toxicity testing has been used to assess potential ecological impacts of effluents and help determine necessary treatment options for environmental protection prior to release. Strategic combinations of toxicity tests, analytical tools, and biological monitoring have been developed. Because the number of vertebrates utilized in effluent testing is thought to be much greater than that used for individual chemical testing, there is a new need to develop strategies to reduce the numbers of vertebrates (i.

The sensitivity of a deep-sea fish species (Anoplopoma fimbria) to oil-associated aromatic compounds, dispersant, and Alaskan North Slope crude oil.

A predominant concern following oil spills is toxicity to aquatic organisms. However, few data are available on effects in deep-sea cold water fishes. The present study had 3 major objectives.

Biological Studies and Target Engagement of the 2- C-Methyl-d-Erythritol 4-Phosphate Cytidylyltransferase (IspD)-Targeting Antimalarial Agent (1 R,3 S)-MMV008138 and Analogs.

Malaria continues to be one of the deadliest diseases worldwide, and the emergence of drug resistance parasites is a constant threat. Plasmodium parasites utilize the methylerythritol phosphate (MEP) pathway to synthesize isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP), which are essential for parasite growth. Previously, we and others identified that the Malaria Box compound MMV008138 targets the apicoplast and that parasite growth inhibition by this compound can be reversed by supplementation of IPP.

Isolation, structure elucidation, and synthesis of antiplasmodial quinolones from Crinum firmifolium.

Antiplasmodial bioassay guided fractionation of a Madagascar collection of Crinum firmifolium led to the isolation of seven compounds. Five of the seven compounds were determined to be 2-alkylquinolin-4(1H)-ones with varying side chains. Compounds 1 and 4 were determined to be known compounds with reported antiplasmodial activities, while 5 was believed to be a new branched 2-alkylquinolin-4(1H)-one, however, it was isolated in limited quantities and in admixture and therefore was synthesized to confirm its structure as a new antiplasmodial compound.

Measurement of outcomes for patients with centralising versus non-centralising neck pain.

Objective: The purpose of this study is to determine whether individuals with neck pain who demonstrate centralisation of symptoms have more favourable outcome than individuals who do not demonstrate centralisation.

Methods: Eleven subjects with neck pain were evaluated and treated by two physical therapists certified in Mechanical Diagnosis and Therapy (MDT). Eleven physical therapy patients underwent a routine initial evaluation and were treated 2-3 times per week using MDT principles and other physical therapy interventions.

Use of carbonated water in reduction of adjacent gastric activity in 456 consecutive technetium-99m myocardial perfusion imaging studies.

Background: Small, observational trials have suggested a reduction in adjacent gastric activity with ingestion of soda water in myocardial perfusion imaging (MPI). We report our findings prior to and after implementation of soda water in 467 consecutive MPI studies.

Methods: Consecutive MPI studies performed at a high-volume facility referred for vasodilator (VD) or exercise treadmill testing (ETT) were retrospectively reviewed before and after implementation of the soda water protocol.

Quantitative Trait Loci Associated with the Tocochromanol (Vitamin E) Pathway in Barley.

The Genome-Wide Association Studies approach was used to detect Quantitative Trait Loci associated with tocochromanol concentrations using a panel of 1,466 barley accessions. All major tocochromanol types- α-, β-, δ-, γ-tocopherol and tocotrienol- were assayed. We found 13 single nucleotide polymorphisms associated with the concentration of one or more of these tocochromanol forms in barley, seven of which were within 2 cM of sequences homologous to cloned genes associated with tocochromanol production in barley and/or other plants.

Improved quantification of CSF bilirubin in the presence of hemoglobin using least squares curve-fitting.

Subarachnoid hemorrhage (SAH) is a dangerous neurological event with a very short time window for early diagnosis. Clinical diagnoses performed in a lab seek to quantify bilirubin in cerebrospinal fluid (CSF) as a biomarker for SAHs; however laboratory assays suffer from lengthy protocols, interference from hemoglobin, and the availability of expertise. Substantial improvements in the determination of bilirubin concentration in the presence of hemoglobin in CSF are demonstrated in this work.

Point-of-care device for quantification of bilirubin in skin tissue.

Steady state diffuse reflectance spectroscopy is a nondestructive method for obtaining biochemical and physiological information from skin tissue. In medical conditions such as neonatal jaundice excess bilirubin in the blood stream diffuses into the surrounding tissue leading to a yellowing of the skin. Diffuse reflectance measurement of the skin tissue can provide real time assessment of the progression of a disease or a medical condition.