Identification and Characterization of Some Genes, Enzymes, and Metabolic Intermediates Belonging to the Bile Acid Aerobic Catabolic Pathway from Pseudomonas.

The study of the catabolic potential of microbial species isolated from different habitats has allowed the identification and characterization of bacteria able to assimilate bile acids and/or other steroids (e.g., testosterone and 4-androsten-3,17-dione) under aerobic conditions through the 9,10-seco pathway.

Isolation of Environmental Bacteria Able to Degrade Sterols and/or Bile Acids: Determination of Cholesterol Oxidase and Several Hydroxysteroid Dehydrogenase Activities in Rhodococcus, Gordonia, and Pseudomonas putida.

Interest about the isolation and characterization of steroid-catabolizing bacteria has increased over time due to the massive release of these recalcitrant compounds and their deleterious effects or their biotransformation derivatives as endocrine disruptors for wildlife, as well as their potential use in biotechnological approaches for the synthesis of pharmacological compounds. Thus, in this chapter, an isolation protocol to select environmental bacteria able to degrade sterols, bile acids, and androgens is shown. Moreover, procedures for the determination of cholesterol oxidase or different hydroxysteroid dehydrogenase activities in Pseudomonas putida DOC21, Rhodococcus sp.

Initial oral microbiota and the impact of delivery mode and feeding practices in 0 to 2 month-old infants.

The aim of this study was to describe the initial oral microbiota and how delivery mode and feeding practices impact its diversity in 0-2-month-old infants. This was a cross-sectional study that consisted of one collection of saliva samples from 0-2-month infants at baseline. Ten pairs of mothers and infants were selected.

Xerotolerance: A New Property in Genus.

The highly xerotolerant bacterium classified as sp. Helios isolated from a solar panel in Spain showed a close relationship to 255-15 isolated from Siberian permafrost. Xerotolerance has not been previously described as a characteristic of the extremely diverse genus, but both strains Helios and 255-15 showed higher xerotolerance than that described in the reference xerotolerant model strain  .

Discovery of a first-in-class reversible DNMT1-selective inhibitor with improved tolerability and efficacy in acute myeloid leukemia.

DNA methylation, a key epigenetic driver of transcriptional silencing, is universally dysregulated in cancer. Reversal of DNA methylation by hypomethylating agents, such as the cytidine analogs decitabine or azacytidine, has demonstrated clinical benefit in hematologic malignancies. These nucleoside analogs are incorporated into replicating DNA where they inhibit DNA cytosine methyltransferases DNMT1, DNMT3A and DNMT3B through irreversible covalent interactions.

Human Skin Permeation Enhancement Using PLGA Nanoparticles Is Mediated by Local pH Changes.

The steady improvement and optimization of transdermal permeation is a constant and challenging pharmaceutical task. In this study the influence of poly(lactide-co-glycolide) (PLGA) nanoparticles on the dermal permeation of the anti-inflammatory drug flufenamic acid (FFA) was investigated. For this aim, different vehicles under non-buffered and buffered conditions and different skin models (human heat separated epidermis and reconstructed human epidermis equivalents) were tested.

Encapsulation of Phenolic Compounds from a Grape Cane Pilot-Plant Extract in Hydroxypropyl Beta-Cyclodextrin and Maltodextrin by Spray Drying.

Grape canes, the main byproducts of the viticulture industry, contain high-value bioactive phenolic compounds, whose application is limited by their instability and poorly solubility in water. Encapsulation in cyclodextrins allows these drawbacks to be overcome. In this work, a grape cane pilot-plant extract (GC) was encapsulated in hydroxypropyl beta-cyclodextrin (HP--CD) by a spray-drying technique and the formation of an inclusion complex was confirmed by microscopy and infrared spectroscopy.

Hypoxia-induced depression of synaptic transmission becomes irreversible by intracellular accumulation of non-excitatory amino acids.

The intracellular accumulation of some amino acids (AAs), mainly glutamine, can contribute to brain edema observed during liver failure. We recently demonstrated that individual applications of high concentrations (10 mM) of some non-excitatory AAs increase the electrical resistance of hippocampal slices, indicating cell swelling. Therefore, we pondered whether an AA mixture's application might cause cell swelling at a physiological concentration range.

COVIDGR Dataset and COVID-SDNet Methodology for Predicting COVID-19 Based on Chest X-Ray Images.

Currently, Coronavirus disease (COVID-19), one of the most infectious diseases in the 21st century, is diagnosed using RT-PCR testing, CT scans and/or Chest X-Ray (CXR) images. CT (Computed Tomography) scanners and RT-PCR testing are not available in most medical centers and hence in many cases CXR images become the most time/cost effective tool for assisting clinicians in making decisions. Deep learning neural networks have a great potential for building COVID-19 triage systems and detecting COVID-19 patients, especially patients with low severity.

Exploiting binding-site arginines in drug design: Recent examples.

Active or allosteric site arginines can form diverse interactions with ligands including different types of cation-π interactions, H-bond interactions and non-bond, non-canonical interactions. This provides many opportunities for creative structure-based drug design to improve potency, introduce novelty, and modulate MoA (mode of action), and even to achieve selectivity. This digest will use some recent drug targets of interest as examples to illustrate different types of interactions and how these interactions impact on potency, MoA, and selectivity.

and induction of fetal hemoglobin with a reversible and selective DNMT1 inhibitor.

Pharmacological induction of fetal hemoglobin (HbF) expression is an effective therapeutic strategy for the management of beta-hemoglobinopathies such as sickle cell disease. DNA methyltransferase (DNMT) inhibitors 5-azacytidine (5-aza) and 5-aza-2'-deoxycytidine (decitabine) have been shown to induce fetal hemoglobin expression in both preclinical models and clinical studies, but are not currently approved for the management of hemoglobinopathies. We report here the discovery of a novel class of orally bioavailable DNMT1-selective inhibitors as exemplified by GSK3482364.

Discovery of Isoxazole Amides as Potent and Selective SMYD3 Inhibitors.

We report herein the discovery of isoxazole amides as potent and selective SET and MYND Domain-Containing Protein 3 (SMYD3) inhibitors. Elucidation of the structure-activity relationship of the high-throughput screening (HTS) lead compound provided potent and selective SMYD3 inhibitors. The SAR optimization, cocrystal structures of small molecules with SMYD3, and mode of inhibition (MOI) characterization of compounds are described.

Relation between muscle architecture and first metacarpal morphology, and its implications for human hand evolution.

Previous studies have proposed that our ability to produce and use stone tools was the primary selective pressure explaining the evolution of the human hand. Derived traits in humans include a robust first metacarpal and longer thumbs relative to the other fingers. Along with other anatomical peculiarities, humans can exert forceful precision and have powerful grips, and can resist loads during tool production and use.

Catabolism of biogenic amines in Pseudomonas species.

Biogenic amines (BAs; 2-phenylethylamine, tyramine, dopamine, epinephrine, norepinephrine, octopamine, histamine, tryptamine, serotonin, agmatine, cadaverine, putrescine, spermidine, spermine and certain aliphatic amines) are widely distributed organic molecules that play basic physiological functions in animals, plants and microorganisms. Pseudomonas species can grow in media containing different BAs as carbon and energy sources, a reason why these bacteria are excellent models for studying such catabolic pathways. In this review, we analyse most of the routes used by different species of Pseudomonas (P.

Intracellular accumulation of amino acids increases synaptic potentials in rat hippocampal slices.

The application of high concentrations of taurine induces long-lasting potentiation of synaptic responses and axon excitability. This phenomenon seems to require the contribution of a transport system with a low affinity for taurine. The prototypic taurine transporter TauT (SLC6A6) was discarded by experimental evidence obtained in TauT-KO mice.

Discovery of Potent and Selective Covalent Protein Arginine Methyltransferase 5 (PRMT5) Inhibitors.

Protein arginine methyltransferase 5 (PRMT5) is known to symmetrically dimethylate numerous cytosolic and nuclear proteins that are involved in a variety of cellular processes. Recent findings have revealed its potential as a cancer therapeutic target. PRMT5 possesses a cysteine (C449) in the active site, unique to PRMT5.

Steroids as Environmental Compounds Recalcitrant to Degradation: Genetic Mechanisms of Bacterial Biodegradation Pathways.

Steroids are perhydro-1,2-cyclopentanophenanthrene derivatives that are almost exclusively synthesised by eukaryotic organisms. Since the start of the Anthropocene, the presence of these molecules, as well as related synthetic compounds (ethinylestradiol, dexamethasone, and others), has increased in different habitats due to farm and municipal effluents and discharge from the pharmaceutical industry. In addition, the highly hydrophobic nature of these molecules, as well as the absence of functional groups, makes them highly resistant to biodegradation.

Identification and expression of the 11β-steroid hydroxylase from Cochliobolus lunatus in Corynebacterium glutamicum.

Hydroxylation of steroids has acquired special relevance for the pharmaceutical industries. Particularly, the 11β-hydroxylation of steroids is a reaction of biotechnological importance currently carried out at industrial scale by the fungus Cochliobolus lunatus. In this work, we have identified the genes encoding the cytochrome CYP103168 and the reductase CPR64795 of C.

Nucleoside protein arginine methyltransferase 5 (PRMT5) inhibitors.

Protein Arginine Methyltransferase 5 (PRMT5) is known to symmetrically dimethylate numerous cytosolic and nuclear proteins that are involved in a variety of cellular processes. Recent findings have revealed its potential as a cancer therapeutic target. PRMT5 selective inhibitors, GSK3326595, a substrate competitive inhibitor, and JNJ64619178, a SAM (S-adenosyl-l-methionine) mimetic/competitive inhibitor, have entered clinic trials for multiple cancer types.

Stress transfer and matrix-cohesive fracture mechanism in microfibrillated cellulose-gelatin nanocomposite films.

Microfibrillated cellulose (MFC) obtained from eucalyptus was embedded in gelatin from two sources; namely bovine and salmon gelatin. Raman spectroscopy revealed that stress is transferred more efficiently from bovine gelatin to the MFC when compared to salmon gelatin. Young's modulus, tensile strength, strain at failure and work of fracture of the nanocomposite films were improved by ∼67, 131, 43 y 243% respectively when using salmon gelatin as matrix material instead of bovine gelatin.

Nuisance Compounds, PAINS Filters, and Dark Chemical Matter in the GSK HTS Collection.

High-throughput screening (HTS) hits include compounds with undesirable properties. Many filters have been described to identify such hits. Notably, pan-assay interference compounds (PAINS) has been adopted by the community as the standard term to refer to such filters, and very useful guidelines have been adopted by the American Chemical Society (ACS) and subsequently triggered a healthy scientific debate about the pitfalls of draconian use of filters.

Histamine catabolism in Pseudomonas putida U: identification of the genes, catabolic enzymes and regulators.

In this study, the catabolic pathway required for the degradation of the biogenic amine histamine (Hin) was genetically and biochemically characterized in Pseudomonas putida U. The 11 proteins (HinABCDGHFLIJK) that participate in this pathway are encoded by genes belonging to three loci hin1, hin2 and hin3 and by the gene hinK. The enzymes HinABCD catalyze the transport and oxidative deamination of histamine to 4-imidazoleacetic acid (ImAA).

Steroid 11-Alpha-Hydroxylation by the Fungi Aspergillus nidulans and Aspergillus ochraceus.

Steroids are a group of natural compounds derived from the cyclopentane-perhydro-phenantrene nucleus that have a great interest for the pharmaceutical industries as a consequence of their physiological effects. Among their functions are anti-inflammatory, immunosuppressive, or contraceptive activities. Nowadays, microbial transformation of steroid precursors is winning relevance opposite to the chemical synthesis, since it allows for decreasing time, expenses, and environmental pollution.