An Emerging Role for Ticks as Vectors of Tularaemia in Sweden.

Background: The zoonotic bacterium Francisella tularensis, the causative agent of tularaemia, can be transmitted to humans via multiple routes, including through contact with infected animals, contaminated water or arthropod vectors. Ticks have not previously been described as transmitting the disease in Sweden. Recently, Ixodid tick species have expanded their latitudinal and altitudinal range in Sweden to areas where the disease is endemic.

Targeting Tularemia: Clinical, Laboratory, and Treatment Outcomes From an 11-year Retrospective Observational Cohort in Northern Sweden.

Background: Tularemia is an important reemerging disease with a multimodal transmission pattern. Treatment outcomes of current recommended antibiotic regimens (including ciprofloxacin and doxycycline) remain unclear. In this retrospective cohort study, we report clinical, laboratory, geographical, and treatment outcomes of laboratory-confirmed tularemia cases over an 11-year period in Northern Sweden.

Pharmacodynamic Evaluation of Dosing, Bacterial Kill, and Resistance Suppression for Zoliflodacin Against in a Dynamic Hollow Fiber Infection Model.

Antimicrobial resistance in is threatening the treatment and control of gonorrhea globally, and new treatment options are imperative. Utilizing our dynamic hollow fiber infection model (HFIM), we examined the pharmacodynamics of the first-in-class spiropyrimidinetrione (DNA gyrase B inhibitors), zoliflodacin, against the reference strains World Health Organization F (susceptible to all relevant antimicrobials) and WHO X (extensively drug resistant, including resistance to ceftriaxone) over 7 days. Dose-range experiments with both strains, simulating zoliflodacin single oral dose regimens of 0.

The first wide-scale drug repurposing screen using the Prestwick Chemical Library (1200 bioactive molecules) against Neisseria gonorrhoeae identifies high in vitro activity of auranofin and many additional drugs.

Treatment options for gonorrhoea are scarce. Drug repurposing of bioactive molecules approved for other conditions might therefore be of value. We developed a method for wide-scale, systematic drug repurposing screen to identify molecules with activity against Neisseria gonorrhoeae and screened the Prestwick Chemical Library (1200 FDA-approved drugs).

Hepatocyte Hyperproliferation upon Liver-Specific Co-disruption of Thioredoxin-1, Thioredoxin Reductase-1, and Glutathione Reductase.

Energetic nutrients are oxidized to sustain high intracellular NADPH/NADP ratios. NADPH-dependent reduction of thioredoxin-1 (Trx1) disulfide and glutathione disulfide by thioredoxin reductase-1 (TrxR1) and glutathione reductase (Gsr), respectively, fuels antioxidant systems and deoxyribonucleotide synthesis. Mouse livers lacking both TrxR1 and Gsr sustain these essential activities using an NADPH-independent methionine-consuming pathway; however, it remains unclear how this reducing power is distributed.

Screening of nerve agent markers with hollow fiber-chemosorption of phosphonic acids.

This report describes a method developed for extracting nerve gas markers such as phosphonic acids from urine and other aqueous samples. It involves single-step microextraction with chemosorption to hollow fibers that have been pre-soaked in a solution containing a derivatization reagent (3,5 triflouro methyl benzene diazomethane). The derivatives it forms with phosphonic acids can be sensitively detected by mass spectrometric detectors operating in negative chemical ionization (NCI) mode.

Auranofin and N-heterocyclic carbene gold-analogs are potent inhibitors of the bacteria Helicobacter pylori.

Auranofin is an FDA-approved gold-containing compound used for the treatment of rheumatoid arthritis. Recent reports of antimicrobial activity against protozoa and bacteria indicate that auranofin targets the reductive enzyme thioredoxin reductase (TrxR). We evaluated auranofin as well as five auranofin analogs containing N-heterocyclic carbenes (instead of the triethylphosphane present in auranofin) and five gold-carbene controls for their ability to inhibit or kill Helicobacter pylori in vitro Auranofin completely inhibited bacterial growth at 1.

Ebselen and analogs as inhibitors of Bacillus anthracis thioredoxin reductase and bactericidal antibacterials targeting Bacillus species, Staphylococcus aureus and Mycobacterium tuberculosis.

Background: Bacillus anthracis is the causative agent of anthrax, a disease associated with a very high mortality rate in its invasive forms.

Methods: We studied a number of ebselen analogs as inhibitors of B. anthracis thioredoxin reductase and their antibacterial activity on Bacillus subtilis, Staphylococcus aureus, Bacillus cereus and Mycobacterium tuberculosis.

Activity assays of mammalian thioredoxin and thioredoxin reductase: fluorescent disulfide substrates, mechanisms, and use with tissue samples.

Thioredoxin (Trx) is a protein disulfide reductase that, together with nicotinamide adenine dinucleotide phosphate (NADPH) and thioredoxin reductase (TrxR), controls oxidative stress or redox signaling via thiol redox control. Human cytosolic Trx1 has Cys32 and Cys35 as the active site and three additional cysteine residues (Cys62, Cys69, and Cys73), which by oxidation generates inactive Cys62 to Cys69 two-disulfide Trx. This, combined with TrxR with a broad substrate specificity, complicates assays of mammalian Trx and TrxR.

Ebsulfur is a benzisothiazolone cytocidal inhibitor targeting the trypanothione reductase of Trypanosoma brucei.

Trypanosoma brucei is the causing agent of African trypanosomiasis. These parasites possess a unique thiol redox system required for DNA synthesis and defense against oxidative stress. It includes trypanothione and trypanothione reductase (TryR) instead of the thioredoxin and glutaredoxin systems of mammalian hosts.

Structural determination of nerve agent markers using gas chromatography mass spectrometry after derivatization with 3-pyridyldiazomethane.

Nerve agents are a class of organophosphorous chemicals that are prohibited under the Chemical Weapons Convention. Their degradation products, phosphonic acids, are analyzed as markers of nerve agent contamination and use. Because the phosphonic acids are non-volatile and very polar, their identification by GC-MS requires a derivatization step prior to analysis.

Inhibition of bacterial thioredoxin reductase: an antibiotic mechanism targeting bacteria lacking glutathione.

Increasing antibiotic resistance makes the identification of new antibacterial principles an urgent task. The thioredoxin system including thioredoxin reductase (TrxR), thioredoxin (Trx), and NADPH plays critical roles in cellular DNA synthesis and defense against oxidative stress. Notably, TrxR is very different in structure and mechanism in mammals and bacteria.

Bacillus anthracis thioredoxin systems, characterization and role as electron donors for ribonucleotide reductase.

Bacillus anthracis is the causative agent of anthrax, which is associated with a high mortality rate. Like several medically important bacteria, B. anthracis lacks glutathione but encodes many genes annotated as thioredoxins, thioredoxin reductases, and glutaredoxin-like proteins.

Investigating biodiversity trajectories using scenarios--lessons from two contrasting agricultural landscapes.

Agriculture is the major land use at a global scale. In addition to food production, multifunctionality of landscapes, including values and ecosystem services like biodiversity, recreation and culture, is now focus for management. This study explores how a scenario approach, involving different stakeholders, may help to improve landscape management for biodiversity conservation.

Safe, facile radical-based reduction and hydrosilylation reactions in a microreactor using tris(trimethylsilyl)silane.

A highly efficient system for tris(trimethylsilyl)silane (TTMSS) mediated deoxygenation, dehalogenation and hydrosilylation reactions is described in a microstructured device; this convenient platform enables the scale up of radical-based processes.

Fluorination reactions in microreactors.

The DAST-mediated conversion of a range of alcohols to the corresponding fluorides in a microstructured device is described. This safe, practical fluorination method will facilitate reactions currently challenging on large scale.

Trimethylaluminium mediated amide bond formation in a continuous flow microreactor as key to the synthesis of rimonabant and efaproxiral.

A safe, functional-group-tolerant and high-throughput version of the trimethylaluminium mediated amide bond formation reaction has been developed in a microreactor system; rimonabant and efaproxiral were prepared to illustrate the utility of the method.

High-resolution structures of oxidized and reduced thioredoxin reductase from Helicobacter pylori.

The crystal structures of homodimeric thioredoxin reductase (TrxR) from the gastric pathogen Helicobacter pylori in complex with NADP(+) have been determined for the oxidized and reduced form of the enzyme at 1.7 and 1.45 A resolution, respectively.

Enecarbamates as imine surrogates: nucleophilic addition of 1,3-dicarbonyl compounds to enecarbamates.

[reaction: see text] Novel Mannich-type reactions of 1,3-dicarbonyl compounds with enecarbamates have been developed. Stable and storable enecarbamates work as surrogates of aliphatic aldehyde-derived imines, which are known to be difficult to isolate and store.

Synthesis of a C-glycoside analogue of beta-D-galactosyl hydroxylysine and incorporation in a glycopeptide from type II collagen.

A stereoselective synthesis of the C-glycoside analogue of beta-D-galactosyl-(5R,2S)-hydroxylysine (1) has been achieved starting from tetra-O-benzyl-D-galactopyranosyl lactone. The synthesis involved establishment of three stereogenic centers in an unambiguous manner. A facially selective Grignard reaction followed by a silane reduction was used for the anomeric position of the C-galactose residue.

A total synthesis of hydroxylysine in protected form and investigations of the reductive opening of p-methoxybenzylidene acetals.

A synthesis of (2S,5R)-5-hydoxylysine, based on (R)-malic acid and Williams glycine template as chiral precursors, has been developed. This afforded hydroxylysine, suitably protected for direct use in peptide synthesis, in 32% yield over the 13-step sequence. Regioselective reductive opening of a p-methoxybenzylidene acetal and alkylation of the Williams glycine template were key steps in the synthetic sequence.

Synthesis of a C-glycoside analogue of beta-D-galactosylthreonine.

A C-linked analogue of beta-D-galactosylthreonine has been prepared from 2,3,4,6-tetra-O-benzyl-D-galactopyranolactone (1) in 14 steps. Three stereogenic centers were created during the synthesis, with the anomeric center of the C-glycoside being generated first by addition of a Grignard reagent to 1 and subsequent reduction of the intermediate hemiacetal with triethylsilane. The two stereogenic centers in the threonine moiety were both established by alkylation of Evans' chiral N-acyloxazolidinone enolates.