Thermal impact of underground car parks on urban groundwater.

Built-up areas are known to heavily impact the thermal regime of the shallow subsurface. In many cities, the answer to densification is to increase the height and depth of buildings, which leads to a steady growth in the number of underground car parks. These underground car parks are heated by waste heat from car engines and are typically several degrees warmer than the surrounding subsurface, which makes them a heat source for ambient subsurface and groundwater.

Gut-inhabiting Clostridia build human GPCR ligands by conjugating neurotransmitters with diet- and human-derived fatty acids.

Human physiology is regulated by endogenous signalling compounds, including fatty acid amides (FAAs), chemical mimics of which are made by bacteria. The molecules produced by human-associated microbes are difficult to identify because they may only be made in a local niche or they require a substrate sourced from the host, diet or other microbes. We identified a set of uncharacterized gene clusters in metagenomics data from the human gut microbiome.

Is thermal use of groundwater a pollution?

Thermal use of the shallow subsurface and its aquifers (< 400 m) is steadily increasing. Currently, more than 2800 aquifer thermal energy storage (ATES) systems are operating worldwide alongside more than 1.2 million ground source heat pump (GSHP) systems in Europe alone.

Systematic Chemogenetic Library Assembly.

Chemogenetic libraries, collections of well-defined chemical probes, provide tremendous value to biomedical research but require substantial effort to ensure diversity as well as quality of the contents. We have assembled a chemogenetic library by data mining and crowdsourcing institutional expertise. We are sharing our approach, lessons learned, and disclosing our current collection of 4,185 compounds with their primary annotated gene targets (https://github.

Riverine carbon dioxide evasion along a high-relief watercourse derived from seasonal dynamics of the water-atmosphere gas exchange.

The high-relief catchment of the Tavignanu River (Corsica Island, France) with an elevation range from sea level to 2622 m above sea level was investigated for its riverine carbon budget and stable carbon isotopes. Major riverine dissolved inorganic carbon (DIC or TCO) sources depended on seasons and sub-catchment lithology. In winter δC values of -2 to -7‰ (VPDB) indicated influences of atmospheric CO.

A remote-controlled adaptive medchem lab: an innovative approach to enable drug discovery in the 21st Century.

This article describes our experiences in creating a fully integrated, globally accessible, automated chemical synthesis laboratory. The goal of the project was to establish a fully integrated automated synthesis solution that was initially focused on minimizing the burden of repetitive, routine, rules-based operations that characterize more established chemistry workflows. The architecture was crafted to allow for the expansion of synthetic capabilities while also providing for a flexible interface that permits the synthesis objective to be introduced and manipulated as needed under the judicious direction of a remote user in real-time.

A panel of cytochrome P450 BM3 variants to produce drug metabolites and diversify lead compounds.

Herein we demonstrate that a small panel of variants of cytochrome P450 BM3 from Bacillus megaterium covers the breadth of reactivity of human P450s by producing 12 of 13 mammalian metabolites for two marketed drugs, verapamil and astemizole, and one research compound. The most active enzymes support preparation of individual metabolites for preclinical bioactivity and toxicology evaluations. Underscoring their potential utility in drug lead diversification, engineered P450 BM3 variants also produce novel metabolites by catalyzing reactions at carbon centers beyond those targeted by animal and human P450s.

Pharmacophore-based search, synthesis, and biological evaluation of anthranilic amides as novel blockers of the Kv1.5 channel.

The search for novel, potent Kv1.5 blockers based on an anthranilic amide scaffold employing a pharmacophore-based virtual screening approach is described. The synthesis and structure-activity relationships (SAR) with respect to inhibition of the Kv1.

Kinomics-structural biology and chemogenomics of kinase inhibitors and targets.

Classifying kinases based entirely on small molecule selectivity data is a new approach to drug discovery that allows scientists to understand relationships between targets. This approach combines the understanding of small molecules and targets, and thereby assists the researcher in finding new targets for existing molecules or understanding selectivity and polypharmacology of molecules in related targets. Currently, structural information is available for relatively few of the protein kinases encoded in the human genome (7% of the estimated 518); however, even the current knowledge base, when paired with structure-based design techniques, can assist in the identification and optimization of novel kinase inhibitors across the entire protein class.

Identification, synthesis, and activity of novel blockers of the voltage-gated potassium channel Kv1.5.

The voltage-gated potassium channel Kv1.5 is regarded as a promising target for the development of new atrial selective drugs with fewer side effects. In the present study the discovery of ortho,ortho-disubstituted bisaryl compounds as blockers of the Kv1.

Prolonged blood glucose reduction in mrp-2 deficient rats (GY/TR(-)) by the glucose-6-phosphate translocase inhibitor S 3025.

Chlorogenic acid derivatives are potent inhibitors of hepatic glucose production by inhibition of the glucose-6-phosphate translocase component of the hepatic glucose-6-phosphatase system. The pharmacological proof of concept was clearly demonstrated during i.v.

Hepatic uptake of synthetic chlorogenic acid derivatives by the organic anion transport proteins.

Chlorogenic acid derivatives were recently identified as novel, potent, and specific inhibitors of the hepatic glucose 6-phosphate translocase. Inhibition of the glucose 6-phosphate translocase leads to a decrease in hepatic glucose production, rendering chlorogenic acid derivatives as potential novel therapeutics in patients with type 2 diabetes. The present study examines the hepatic uptake mechanism of the radiolabeled chlorogenic acid derivative S 1743 into freshly isolated rat hepatocytes.

Alterations of carbohydrate and lipid intermediary metabolism during inhibition of glucose-6-phosphatase in rats.

S 4048 (1-[2-(4-Chloro-phenyl)-cyclopropylmethoxy]-3, 4-dihydroxy-5-(3-imidazo[4, 5-b]pyridin-1-yl-3-phenyl-acryloyloxy)-cyclohexanecarboxylic acid), a derivative of chlorogenic acid, specifically inhibits the glucose-6-phosphate translocating component T1 of the glucose-6-phosphatase system. Its pharmacological effect was studied on carbohydrate and lipid parameters in rats. In starved and fed rats, S 4048 caused a dose-dependent reduction of blood glucose levels with a corresponding increase in hepatic and renal glycogen and glucose-6-phosphate.

Identification of protein components of the microsomal glucose 6-phosphate transporter by photoaffinity labelling.

The glucose-6-phosphatase system catalyses the terminal step of hepatic glucose production from both gluconeogenesis and glycogenolysis and is thus a key regulatory factor of blood glucose homoeostasis. To identify the glucose 6-phosphate transporter T1, we have performed photoaffinity labelling of human and rat liver microsomes by using the specific photoreactive glucose-6-phosphate translocase inhibitors S 0957 and S 1743. Membrane proteins of molecular mass 70, 55, 33 and 31 kDa were labelled in human microsomes by [3H]S 0957, whereas in rat liver microsomes bands at 95, 70, 57, 54, 50, 41, 33 and 31 kDa were detectable.

Pharmacodynamic profile of a novel inhibitor of the hepatic glucose-6-phosphatase system.

The glucose-6-phosphatase (G-6-Pase) system catalyzes the terminal enzymatic step of gluconeogenesis and glycogenolysis. Inhibition of the G-6-Pase system in the liver is expected to result in a reduction of hepatic glucose production irrespective of the relative contribution of gluconeogenesis or glycogenolysis to hepatic glucose output. In isolated perfused rat liver, S-3483, a derivative of chlorogenic acid, produced concentration-dependent inhibition of gluconeogenesis and glycogenolysis in a similar concentration range.

Chlorogenic acid analogue S 3483: a potent competitive inhibitor of the hepatic and renal glucose-6-phosphatase systems.

S 3483, a synthetic derivative of chlorogenic acid (CHL), was found to be a reversible, linear competitive inhibitor of the glucose-6-phosphatase (Glc-6-Pase) system in rat renal microsomes and rat and human liver microsomes. The Ki for S 3483 in rat liver microsomes (129 nM) is three orders of magnitude smaller than the Ki for CHL. S 3483 up to 100 microM had no effect on the Glc-6-Pase enzyme activity or on the system inorganic pyrophosphatase activity (i.

Direct evidence for the involvement of two glucose 6-phosphate-binding sites in the glucose-6-phosphatase activity of intact liver microsomes. Characterization of T1, the microsomal glucose 6-phosphate transport protein by a direct binding assay.

S 5627 is a synthetic analogue of chlorogenic acid. S 5627 is a potent linear competitive inhibitor of glucose 6-phosphate (Glc-6-P) hydrolysis by intact microsomes (Ki = 41 nM) but is without effect on the enzyme in detergent- or NH4OH-disrupted microsomes. 3H-S 5627 was synthesized and used as a ligand in binding studies directed at characterizing T1, the Glc-6-P transporter.

Chlorogenic acid and hydroxynitrobenzaldehyde: new inhibitors of hepatic glucose 6-phosphatase.

We have studied the interactions of chlorogenic acid (CHL) and 2-hydroxy-5-nitrobenzaldehyde (HNB) with the components of the rat hepatic glucose 6-phosphatase (Glc-6-Pase) system. CHL and HNB are competitive inhibitors of glucose 6-phosphate (Glc-6-P) hydrolysis in intact microsomes with Ki values of 0.26 and 0.

Chlorogenic acid and synthetic chlorogenic acid derivatives: novel inhibitors of hepatic glucose-6-phosphate translocase.

The enzyme system glucose-6-phosphatase (EC 3.1.3.