Central nervous system distributional kinetics of selected histone deacetylase inhibitors.

Histone deacetylase expression and activity are often dysregulated in central nervous system (CNS) tumors, providing a rationale for investigating histone deacetylase inhibitors (HDACIs) in selected brain tumor patients. Although many HDACIs have shown potential in in vitro studies, they have had modest efficacy in vivo. This lack of activity could be due to insufficient CNS exposure to the unbound drug.

Metabolically Stable Adenylation Inhibitors of Biotin Protein Ligase as Antibacterial Agents.

The antibacterial agent Bio-AMS is metabolized in vivo through hydrolysis of the central acyl-sulfamide linker leading to high clearance and release of a moderately cytotoxic metabolite . Herein, we disclose analogues designed to prevent the metabolism of the central acyl-sulfamide moiety through steric hindrance or attenuation of the acyl-sulfamide electrophilicity. was identified as a metabolically stable analogue with a single-digit nanomolar dissociation constant for biotin protein ligase (BPL) and minimum inhibitory concentrations (MICs) against and ranging from 0.

Protecting Group Control of Hydroxyketone-Hemiketal Tautomeric Equilibrium Enables the Stereoselective Synthesis of a 1-Azido -Nucleoside.

The synthesis of 1-azido -nucleosides is described to expand the set of azide-functionalized nucleosides for bioorthogonal applications and as potential antiviral drugs. Lewis acid-promoted azidation of a nucleoside hemiketal resulted in the formation of a tetrazole through a Schmidt reaction manifold. Conformational control to prevent ring-chain tautomerism enabled efficient 1-azidation with complete β-diastereoselectivity.

Evaluation of corn fermented protein on the fecal microbiome of cats.

Co-products from the ethanol industry, such as distillers dried grains with solubles (DDGS), can provide alternative protein sources for pet food. Corn fermented protein (CFP) is produced using postfermentation technology to split the protein and yeast from fiber prior to drying. This results in a higher protein ingredient compared to DDGS, increasing its appeal for pet food.

Mycobacterial biotin synthases require an auxiliary protein to convert dethiobiotin into biotin.

Lipid biosynthesis in the pathogen Mycobacterium tuberculosis depends on biotin for posttranslational modification of key enzymes. However, the mycobacterial biotin synthetic pathway is not fully understood. Here, we show that rv1590, a gene of previously unknown function, is required by M.

Processing of corn-based dog foods through pelleting, baking and extrusion and their effect on apparent total tract digestibility and colonic health of adult dogs.

Different food processing parameters may alter starch granule structure and its cooking degree. With lower thermomechanical energy, more resistant starch (RS) is retained in the food, which may benefit gastrointestinal (GI) health. The objective of this study was to determine the effect of food processing on dietary utilization and dog gut health.

Evaluation of Soybean Ingredients in Pet Foods Applications: Systematic Review.

Soybean use has been low in pet foods, even though they are an excellent source of protein, polyunsaturated fatty acids, and gut fermentable fibers. The purpose of this evaluation was to conduct a systematic review of the public literature to explore how soybeans have been researched for pet food applications since 2000 and to provide strengths, weaknesses, opportunities, and threats for soybeans in the pet food industry. The review covered a total of 44 articles related to soybean ingredients and their potential value in the pet food arena.

Efficacy of Liquid Smoke to Mitigate Infestations of the Storage Mite, , in a Model Semi-Moist Pet Food.

The storage mite infests a wide range of food products including pet food. Control of this mite depends on chemical methods such as fumigation and spraying with insecticides. Methyl bromide was used as a fumigant for high-value stored products, especially to control mite infestation in dry-cured hams and cheeses, but it is now banned for most uses in many countries because of its atmospheric ozone-depleting effects.

Comparison of the Effect of Corn-fermented Protein and Traditional Ingredients on the Fecal Microbiota of Dogs.

Corn-fermented protein (CFP), a co-product from the ethanol industry, is produced using post-fermentation technology to split the protein and yeast from fiber prior to drying. The objective of this study was to determine the effect of CFP compared to traditional ingredients on the fecal microbiota of dogs. The four experimental diets included a control with no yeast and diets containing either 3.

Blocking ADP-ribosylation expands the anti-mycobacterial spectrum of rifamycins.

The clinical utility of rifamycins against non-tuberculous mycobacterial (NTM) disease is limited by intrinsic drug resistance achieved by ADP-ribosyltransferase Arr. By blocking the site of ribosylation, we recently optimized a series of analogs with substantially improved potency against . Here, we show that a representative member of this series is significantly more potent than rifabutin against major NTM pathogens expressing Arr, providing a powerful medicinal chemistry approach to expand the antimycobacterial spectrum of rifamycins.

Diet production and utilization of corn fermented protein compared to traditional yeast in healthy adult cats.

The inclusion of yeast in pet food can provide health benefits and increase palatability. Corn fermented protein is a co-product from ethanol production which contains approximately 20% to 25% yeast. The objective of this study was to determine the effects of the yeast in CFP on diet production and utilization when fed to healthy adult cats.

ADP-ribosylation-resistant rifabutin analogs show improved bactericidal activity against drug-tolerant in caseum surrogate.

Necrotic lesions and cavities filled with caseum are a hallmark of mycobacterial pulmonary disease. Bronchocavitary disease is associated with poor treatment outcomes. In caseum surrogate, entered an extended stationary phase showing tolerance to killing by most current antibiotics, suggesting that caseum persisters contribute to the poor performance of available treatments.

Fluorescence lifetime FRET assay for live-cell high-throughput screening of the cardiac SERCA pump yields multiple classes of small-molecule allosteric modulators.

We have used FRET-based biosensors in live cells, in a robust high-throughput screening (HTS) platform, to identify small-molecules that alter the structure and activity of the cardiac sarco/endoplasmic reticulum calcium ATPase (SERCA2a). Our primary aim is to discover drug-like small-molecule activators that improve SERCA's function for the treatment of heart failure. We have previously demonstrated the use of an intramolecular FRET biosensor, based on human SERCA2a, by screening two different small validation libraries using novel microplate readers that detect the fluorescence lifetime or emission spectrum with high speed, precision, and resolution.

Metabolically distinct roles of NAD synthetase and NAD kinase define the essentiality of NAD and NADP in .

Nicotinamide adenine dinucleotide (NAD) and its phosphorylated derivative (NADP) are essential cofactors that participate in hundreds of biochemical reactions and have emerged as therapeutic targets in cancer, metabolic disorders, neurodegenerative diseases, and infections, including tuberculosis. The biological basis for the essentiality of NAD(P) in most settings, however, remains experimentally unexplained. Here, we report that inactivation of the terminal enzyme of NAD synthesis, NAD synthetase (NadE), elicits markedly different metabolic and microbiologic effects than those of the terminal enzyme of NADP biosynthesis, NAD kinase (PpnK), in ().

Fault Detection and Identification in an Acid Gas Removal Unit Using Deep Autoencoders.

An acid gas removal unit (AGRU) in a natural gas processing plant is designed specifically to remove acidic components, such as carbon dioxide (CO) and hydrogen sulfide (HS), from the natural gas. The occurrence of faults, such as foaming, and to a lesser extent, damaged trays and fouling, in AGRUs is a commonly encountered problem; however, they are the least studied in the open literature. Hence, in this paper, shallow and deep sparse autoencoders with SoftMax layers are investigated to facilitate early detection of these three faults before any significant financial loss.

Apparent total tract digestibility and palatability of extruded diets with graded levels of whole soybeans by dogs.

Fat has high energy density and is considered one of the primary energy sources for dogs, however, increasing fat level in dry dog food has been challenging due to the lubrication and limitation of the coating system. The objective was to determine the effect of whole soybeans (WSB) on nutrient digestibility, stool quality, and palatability by dogs. The corn gluten meal, chicken fat, and brewers rice were replaced by WSB at 10, 20, and 30% (WSB10, WSB20, and WSB30, respectively) in the base diet (WSB0).

Effects of container type and size on thermal processing characteristics and B-vitamin retention of canned cat food.

Introduction: Rigid cans were the traditional container for canned cat foods, but semi-rigid trays/tubs and flexible pouches are popular options as well. Despite this, little is published on the effects of canned cat food container characteristics on thermal processing and retention of B-vitamins. Therefore, the objective was to evaluate the effects of container size and type on thermal processing and B-vitamin retention.

Effects of liquid smoke preparations on shelf life and growth of wild type mold and in a model semi moist pet food.

Liquid smoke is a naturally derived flavor component and preservative with known antimicrobial properties. To our knowledge, there is a paucity of information on antifungal potential of liquid smoke against toxigenic fungi like that produce mycotoxins in human and pet foods. Semi-moist pet food with high moisture content (20-30%) is susceptible to mold contamination and requires intervention.

Polyfluorinated salicylic acid analogs do not interfere with siderophore biosynthesis.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb) is a leading cause of infectious disease mortality. The salicylic acid derived small molecule siderophores known as mycobactins are essential in vivo for iron acquisition of Mtb where iron is restricted in the host. Herein, we synthesize and explore the mechanism of action of polyfluorinated salicylic acid derivates, which were previously reported to possess potent antimycobacterial activity.

Application of Acidulants to Control spp. in Rendered Animal Fats and Oils with Different Levels of Unsaturation.

-contaminated pet foods could potentially become a source of human salmonellosis. This study evaluated the survival of without and with the addition of acidulants in different fat types (chicken fat (CF), canola oil (CO), Menhaden fish oil (FO), lard (La), and tallow (Ta)) commonly used to coat dry pet food kibbles. The minimum inhibitory concentration (MIC) of individual acidulants and the combination were determined using the broth microdilution method.

Gram Scale Synthesis of Membrane-Active Antibacterial 4-Quinolone Lead Compound.

An improved method for the synthesis of a new quinolone class of antibiotics, which are exceptionally potent against gram-positive bacteria, has been developed and the structure confirmed by single-crystal X-ray analysis. In the course of synthesis, using either Chan-Lam coupling or Buchwald-Hartwig amination, we have shown that the careful choice of protecting group at the C4 position of the quinoline is required for selective amination at the C5 position and subsequent deprotection to avoid the formation of a novel pyrido[4,3,2-]quinazoline tetracycle.

PROTAC antibiotics: the time is now.

Introduction: Novel antibiotics are needed to keep antibiotic resistance at bay and to improve treatment of the many drug-susceptible infections for which current therapies achieve poor cure rates. While revolutionizing human therapeutics, the concept of targeted protein degradation (TPD) by bifunctional proteolysis targeting chimeras (PROTACs) has not yet been applied to the discovery of antibiotics. A major obstacle precluding successful translation of this strategy to antibiotic development is that bacteria lack the E3 ligase-proteasome system exploited by human PROTACs to facilitate target degradation.