Activated Sludge Production Parameters and Nutrient Content of Organic Sludge Components.

An important part of biological treatment system design is quantifying the sludge production and the nutrient removal capacity. Influent wastewater COD fractionation, biomass growth and endogenous respiration directly impacts the composition of the mixed liquor solids in activated sludge systems. The objectives of this project were to determine the model kinetic and stoichiometric parameters associated with activated sludge production and the nutrient content (N and P) of unbiodegradable organic matter components. A complete sludge retention experiment was conducted over 70 days in a pilot-scale membrane bioreactor fed with a real municipal wastewater, and operated with alternating growth and famine periods. Experimental results were simulated and compared using the default values from two well-accepted model parameter sets. The General ASDM parameter set was found to better fit the experimental data than the Metcalf and Eddy parameter set, mainly to characterize endogenous respiration and the heterotrophic biomass concentration. An influent unbiodegradable organic particulate fraction (fXU,Inf) value of 0.16 g COD/g COD was determined by calibration of the accumulated sludge total COD, suspended solids and heterotrophic biomass concentrations. The nutrient content of the accumulated endogenous residue (XE) and influent unbiodegradable organic particulate (XU,Inf) components were calibrated to 0.030 and 0.100 g N/g COD and 0.035 and 0.008 g P/g COD, respectively. These values are in the range of those reported in the literature except for the high P content found in the endogenous residue, possibly due to the presence of coagulants added for P removal in the accumulated sludge. These results were consistent under the wide range of dynamic conditions tested and could improve model prediction of sludge production and composition.

Sleep deprivation impairs inhibitory control during wakefulness in adult sleepwalkers.

Sleepwalkers often complain of excessive daytime somnolence. Although excessive daytime somnolence has been associated with cognitive impairment in several sleep disorders, very few data exist concerning sleepwalking. This study aimed to investigate daytime cognitive functioning in adults diagnosed with idiopathic sleepwalking. Fifteen sleepwalkers and 15 matched controls were administered the Continuous Performance Test and Stroop Colour-Word Test in the morning after an overnight polysomnographic assessment. Participants were tested a week later on the same neuropsychological battery, but after 25 h of sleep deprivation, a procedure known to precipitate sleepwalking episodes during subsequent recovery sleep. There were no significant differences between sleepwalkers and controls on any of the cognitive tests administered under normal waking conditions. Testing following sleep deprivation revealed significant impairment in sleepwalkers' executive functions related to inhibitory control, as they made more errors than controls on the Stroop Colour-Word Test and more commission errors on the Continuous Performance Test. Sleepwalkers' scores on measures of executive functions were not associated with self-reported sleepiness or indices of sleep fragmentation from baseline polysomnographic recordings. The results support the idea that sleepwalking involves daytime consequences and suggest that these may also include cognitive impairments in the form of disrupted inhibitory control following sleep deprivation. These disruptions may represent a daytime expression of sleepwalking's pathophysiological mechanisms.

Mechanisms for Reduced Excess Sludge Production in the Cannibal Process.

Reducing excess sludge production is increasingly attractive as a result of rising costs and constraints with respect to sludge treatment and disposal. A technology in which the mechanisms remain not well understood is the Cannibal process, for which very low sludge yields have been reported. The objective of this work was to use modeling as a means to characterize excess sludge production at a full-scale Cannibal facility by providing a long sludge retention time and removing trash and grit by physical processes. The facility was characterized by using its historical data, from discussion with the staff and by conducting a sampling campaign to prepare a solids inventory and an overall mass balance. At the evaluated sludge retention time of 400 days, the sum of the daily loss of suspended solids to the effluent and of the waste activated sludge solids contributed approximately equally to the sum of solids that are wasted daily as trash and grit from the solids separation module. The overall sludge production was estimated to be 0.14 g total suspended solids produced/g chemical oxygen demand removed. The essential functions of the Cannibal process for the reduction of sludge production appear to be to remove trash and grit from the sludge by physical processes of microscreening and hydrocycloning, respectively, and to provide a long sludge retention time, which allows the slow degradation of the "unbiodegradable" influent particulate organics (XU,Inf) and the endogenous residue (XE). The high energy demand of 1.6 kWh/m³ of treated wastewater at the studied facility limits the niche of the Cannibal process to small- to medium-sized facilities in which sludge disposal costs are high but electricity costs are low.

Carboxymethyl Starch Films as Enteric Coatings: Processing and Mechanistic Insights.

This study proposes the application of carboxymethyl starch derivatives as tablet coatings affording gastro-protection. Carboxymethyl starch (CMS) films were obtained by casting of aqueous filmogenic starch solutions with or without plasticizers and their structural organization was followed using Fourier transform infrared (FTIR), Thermogravimetric analysis (TGA), X-ray diffraction (XRD). Together with data from mechanical tests (tensile strength, elongation, Young's modulus) the results were used to select filmogenic formulations adapted for coatings of tablets. The behaviour of these films was evaluated in simulated gastric and intestinal fluids. The effect of plasticizers (glycerol and sorbitol) on the starch organization, on the rate of drying of the films and on the water vapor absorption was also analyzed. Various types of starch have been compared and the best results were found with high amylose starch (HAS) that was carboxymethylated in an aqueous phase to obtain carboxymethyl high amylose starch (CMHAS). The CMHAS coating solutions containing sorbitol or glycerol as plasticizers have been applied with an industrial pan coater and the final tablets exhibited a good gastro-resistance (up to 2h) in simulated gastric fluid followed by disintegration in simulated intestinal fluid (SIF). The CMHAS derivatives present a high potential as coatings for nutraceutical and pharmaceutical solid dosage forms.

Modelling the degradation of endogenous residue and 'unbiodegradable' influent organic suspended solids to predict sludge production.

Activated sludge models have assumed that a portion of organic solids in municipal wastewater influent is unbiodegradable. Also, it is assumed that solids from biomass decay cannot be degraded further. The paper evaluates these assumptions based on data from systems operating at higher than typical sludge retention times (SRTs), including membrane bioreactor systems with total solids retention (no intentional sludge wastage). Data from over 30 references and with SRTs of up to 400 d were analysed. A modified model that considers the possible degradation of the two components is proposed. First order degradation rates of approximately 0.007 d(-1) for both components appear to improve sludge production estimates. Factors possibly influencing these degradation rates such as wastewater characteristics and bioavailability are discussed.

Anionic and Ampholytic High-Amylose Starch Derivatives as Excipients for Pharmaceutical and Biopharmaceutical Applications: Structure-Properties Correlations.

Many chemical modifications of starch are realized in organic (mostly methanol) phase, allowing high degrees of substitution (DS). Some of these materials are used as disintegrants. To expand the usage of starch derivative biopolymers as drug delivery system, various starch derivatives obtained in aqueous phase were evaluated with the aim to identify materials and procedures which would generate multifunctional excipients providing gastro-protection for controlled drug delivery. Chemical, structural and thermal characteristics of anionic and ampholytic High Amylose Starch (HAS) derivatives under powder (P), tablet (T) and film (F) forms were evaluated by X-ray Diffraction (XRD), Fourier Transformed Infrared (FTIR) and thermogravimetric analysis (TGA) methods and correlated with the behavior of tablets and films in simulated gastric and intestinal media. At low DS, the HAS carboxymethylation (CMHAS) in aqueous phase, generated tablets and films that were insoluble at ambient conditions. The CMHAS filmogenic solutions, with a lower viscosity, were easier to cast and gave smooth films without the use of plasticizer. Correlations were found between structural parameters and the properties of starch excipients. Compared to other starch modification procedures, the aqueous modification of HAS generated tunable multifunctional excipients that may be recommended for tablets and functional coatings for colon-targeted formulations.

Discovery of a new binding mode for a series of liver X receptor agonists.

Structural modification of a series of dual LXRα/ß agonists led to the identification of a new class of LXRß partial agonists. An X-ray co-crystal structure shows that a representative member of this series, pyrrole 5, binds to LXRß with a reversed orientation compared to 1.

Discovery and optimization of a series of liver X receptor antagonists.

The present report describes our efforts to convert an existing LXR agonist into an LXR antagonist using a structure-based approach. A series of benzenesulfonamides was synthesized based on structural modification of a known LXR agonist and was determined to be potent dual liver X receptor (LXR α/ß) ligands. Herein we report the identification of compound 54 as the first reported LXR antagonist that is suitable for pharmacological in vivo evaluation in rodents.

Synthesis of Metal-Loaded Carboxylated Biopolymers with Antibacterial Activity through Metal Subnanoparticle Incorporation.

Carboxymethyl starch (CMS) and carboxymethyl cellulose (CMC) loaded by highly dispersed metal subnanoparticles (MSNPs) showed antibacterial activity against E. coli and B. subtilis strains. Copper and silver were found to act in both cationic and zero-valence forms. The antibacterial activity depends on the metal species content but only up to a certain level. Silver cation (Ag+) showed higher antibacterial activity as compared to Ag0, which was, however, more effective than Cu0, due to weaker retention. The number of carboxyl groups of the biopolymers was found to govern the material dispersion in aqueous media, the metal retention strength and dispersion in the host-matrices. Cation and metal retention in both biopolymers was found to involve interactions with the oxygen atoms of both hydroxyl and carboxyl groups. There exists a ternary interdependence between the Zeta potential (ZP), pH induced by the biocidal agent and its particle size (PS). This interdependence is a key factor in the exchange processes with the surrounding species, including bacteria. Clay mineral incorporation was found to mitigate material dispersion, due to detrimental competitive clay:polymer interaction. This knowledge advancement opens promising prospects for manufacturing metal-loaded materials for biomedical applications.

Characterization of a KDM5 small molecule inhibitor with antiviral activity against hepatitis B virus.

Chronic hepatitis B (CHB) is a global health care challenge and a major cause of liver disease. To find new therapeutic avenues with a potential to functionally cure chronic Hepatitis B virus (HBV) infection, we performed a focused screen of epigenetic modifiers to identify potential inhibitors of replication or gene expression. From this work we identified isonicotinic acid inhibitors of the histone lysine demethylase 5 (KDM5) with potent anti-HBV activity. To enhance the cellular permeability and liver accumulation of the most potent KDM5 inhibitor identified (GS-080) an ester prodrug was developed (GS-5801) that resulted in improved bioavailability and liver exposure as well as an increased H3K4me3:H3 ratio on chromatin. GS-5801 treatment of HBV-infected primary human hepatocytes reduced the levels of HBV RNA, DNA and antigen. Evaluation of GS-5801 antiviral activity in a humanized mouse model of HBV infection, however, did not result in antiviral efficacy, despite achieving pharmacodynamic levels of H3K4me3:H3 predicted to be efficacious from the in vitro model. Here we discuss potential reasons for the disconnect between in vitro and in vivo efficacy, which highlight the translational difficulties of epigenetic targets for viral diseases.

A novel series of IKKß inhibitors part II: description of a potent and pharmacologically active series of analogs.

A novel series of (E)-1-((2-(1-methyl-1H-imidazol-5-yl) quinolin-4-yl) methylene) thiosemicarbazides was discovered as potent inhibitors of IKKß. In this Letter we document our efforts at further optimization of this series, culminating in 2 with submicromolar potency in a HWB assay and efficacy in a CIA mouse model.

A novel series of IKKß inhibitors part I: Initial SAR studies of a HTS hit.

A novel series of (E)-1-((2-(1-methyl-1H-imidazol-5-yl) quinolin-4-yl) methylene) thiosemicarbazides was discovered as potent inhibitors of IKKß. In this Letter we document our early efforts at optimization of the quinoline core, the imidazole and the semithiocarbazone moiety. Most potency gains came from substitution around the 6- and 7-positions of the quinoline ring. Replacement of the semithiocarbazone with a semicarbazone decreased potency but led to some measurable exposure.

The synthesis and SAR of novel diarylsulfone 11ß-HSD1 inhibitors.

In this communication, human 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) inhibitory activities of a novel series of diarylsulfones are described. Optimization of this series resulted in several highly potent 11ß-HSD1 inhibitors with excellent pharmacokinetic (PK) properties. Compound (S)-25 showed excellent efficacy in a non-human primate ex vivo pharmacodynamic model.

Identification of a PPARdelta agonist with partial agonistic activity on PPARgamma.

The discovery and optimization of a series of potent PPARdelta full agonists with partial agonistic activity against PPARgamma is described.

Synthesis and optimization of arylsulfonylpiperazines as a novel class of inhibitors of 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1).

The synthesis and SAR of a series of arylsulfonylpiperazine inhibitors of 11beta-HSD1 are described. Optimization rapidly led to potent, selective, and orally bioavailable inhibitors demonstrating efficacy in a cynomolgus monkey ex vivo enzyme inhibition model.

In vivo evaluation of targeted delivery of biological agents using barium sulfate.

This study was aimed to monitor the transit through the intestine by X-ray imaging using barium sulfate (BS) as tracer. The in vitro features of monolithic tablets were correlated with their in vivo behavior in order to provide a tool for the development of targeted formulations containing macromolecular bioactive agents. The impact of BS on various matrices (neutral, ionic) was studied in simulated fluids using the disintegration time (DT) as main parameter. Dry tablets were characterized by spectroscopic methods (X-ray diffraction and Infra-Red) and scanning electron microscopy (SEM). The selected formulations were followed in a beagle dog model. The in vivo and in vitro DT of tablets formulated with BS were compared. Results: anionic excipients carboxymethylcellulose (CMC) and carboxymethylstarch (CMS) protected the active ingredient from the gastric acidity, ensuring its targeted delivery in the intestine. The SEM analysis, before and after transit in simulated fluids, showed that BS remained in the tablets allowing their good follow-up in vivo. The incorporation of 30% protein in tablets with 40% BS had no impact on their behavior. In conclusion, BS and X-ray imagery could be a good alternative to scintigraphy for development of targeted formulations containing high molecular weight bioactive agents.

Discovery and initial SAR of arylsulfonylpiperazine inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1).

High-throughput screening of a small-molecule compound library resulted in the identification of a series of arylsulfonylpiperazines that are potent and selective inhibitors of human 11beta-Hydroxysteroid Dehydrogenase Type 1 (11beta-HSD1). Optimization of the initial lead resulted in the discovery of compound (R)-45 (11beta-HSD1 IC(50)=3nM).

Distinctive molecular inhibition mechanisms for selective inhibitors of human 11beta-hydroxysteroid dehydrogenase type 1.

11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) catalyzes the NADPH dependent interconversion of inactive cortisone to active cortisol. Excess 11beta-HSD1 or cortisol leads to insulin resistance and metabolic syndrome in animal models and in humans. Inhibiting 11beta-HSD1 activity signifies a promising therapeutic strategy in the treatment of Type 2 diabetes and related diseases. Herein, we report two highly potent and selective small molecule inhibitors of human 11beta-HSD1. While compound 1, a sulfonamide, functions as a simple substrate competitive inhibitor, compound 2, a triazole, shows the kinetic profile of a mixed inhibitor. Co-crystal structures reveal that both compounds occupy the 11beta-HSD1 catalytic site, but present distinct molecular interactions with the protein. Strikingly, compound 2 interacts much closer to the cofactor NADP+ and likely modifies its binding. Together, the structural and kinetic analyses demonstrate two distinctive molecular inhibition mechanisms, providing valuable information for future inhibitor design.

Discovery of a potent and selective prostaglandin D2 receptor antagonist, [(3R)-4-(4-chloro-benzyl)-7-fluoro-5-(methylsulfonyl)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl]-acetic acid (MK-0524).

The discovery of the potent and selective prostaglandin D2 (PGD2) receptor (DP) antagonist [(3R)-4-(4-chlorobenzyl)-7-fluoro-5-(methylsulfonyl)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl]-acetic acid (13) is presented. Initial lead antagonists 6 and 7 were found to be potent and selective DP antagonists (DP Ki = 2.0 nM for each); however, they both suffered from poor pharmacokinetic profiles, short half-lives and high clearance rates in rats. Rat bile duct cannulation studies revealed that high concentrations of parent drug were present in the biliary fluid (Cmax = 1100 microM for 6 and 3900 microM for 7). This pharmacokinetic liability was circumvented by replacing the 7-methylsulfone substituent present in 6 and 7 with a fluorine atom resulting in antagonists with diminished propensity for biliary excretion and with superior pharmacokinetic profiles. Further optimization led to the discovery of the potent and selective DP antagonist 13.