Synthesis and evaluation of β-substituted fosmidomycin analogues as inhibitors of 1-deoxy-D-xylulose 5-phosphate reductoisomerase

Blocking the MEP pathway for isoprenoid biosynthesis offers interesting prospects for inhibiting Plasmodia growth. Fosmidomycin (1) and its homologue FR900098 (2) potently inhibit 1-deoxy-D-xylulose-5-phosphate reductoisomerase (Dxr), a key enzyme in this pathway. Although fosmidomycin is a remarkably safe antimalarial agent, low oral absorption, short serum half-life and malaria recrudescence preclude its use in monotherapy. The development of more lipophilic Dxr inhibitors able to passively permeate into cells with improved pharmacokinetic properties could lead to more efficacious agents. Previously, we discovered that analogue 4, featuring a 3,4-dichlorophenyl substituent in α-position of the phosphonate, surpasses fosmidomycin’s potency in inhibiting P. falciparum growth. Here we explored the introduction of aryl or aralkyl substituents at the β-position of the known hydroxamate analogue 3. We studied the effect of introducing substituents in β-position of the hydroxamate analogue 3. While direct addition of a β-aryl moiety resulted in poor P. falciparum Dxr inhibition, longer linkers between the carbon backbone and the phenyl ring were generally associated with better binding to the enzyme. X-ray structures of the parasite Dxr-inhibitor complexes show that the “longer” compounds generate a substantially different flap structure, in which a key tryptophan residue is displaced, and the aromatic group of the ligand lies between the tryptophan and the hydroxamate’s methyl group. Several analogues emerged as highly potent inhibitors of Plasmodium falciparum in vitro growth. In some cases (e.g. for compounds 7b and 7f) good Dxr inhibitory activity failed to translate in good in vitro activity against the parasite, which may be due to inefficient uptake. Compounds 5a-e likewise failed to inhibit EcDxr and MtbDxr while 6c was optimal for inhibition of these enzymes

Метод проектів у процесі музично-виконавської підготовки майбутнього вчителя музики

(uk) У статті визначається сутність інтегрованого методу художньо-творчих проектів, розкривається його специфіка у процесі музично-виконавської підготовки майбутніх учителів музики.(ru) В статье определяется сущность интегрированного метода художественно-творческих проэктов, раскрывается его специфика в процессе музыкально-исполнительской подготовки будущих учителей музыки

The Measurement of Territorial Differences in the Information Society

Glutamine synthetase (GS, EC 6.3.1.2; also known as γ-glutamyl:ammonia ligase) catalyzes the ATP-dependent condensation of glutamate and ammonia to form glutamine. The enzyme has essential roles in different tissues and species, which have led to its consideration as a drug or an herbicide target. In this article, we describe studies aimed at the discovery of new antimicrobial agents targeting Mycobacterium tuberculosis, the causative pathogen of tuberculosis. A number of distinct classes of GS inhibitors with an IC50 of micromolar value or better were identified via high-throughput screening. A commercially available purine analogue similar to one of the clusters identified (the diketopurines), 1-[(3,4-dichlorophenyl)methyl]-3,7-dimethyl-8-morpholin-4-yl-purine-2,6-dione, was also shown to inhibit the enzyme, with a measured IC50 of 2.5 ± 0.4 μM. Two X-ray structures are presented: one is a complex of the enzyme with the purine analogue alone (2.55-Å resolution), and the other includes the compound together with methionine sulfoximine phosphate, magnesium and phosphate (2.2-Å resolution). The former represents a relaxed, inactive conformation of the enzyme, while the latter is a taut, active one. These structures show that the compound binds at the same position in the nucleotide site, regardless of the conformational state. The ATP-binding site of the human enzyme differs substantially, explaining why it has an ∼ 60-fold lower affinity for this compound than the bacterial GS. As part of this work, we devised a new synthetic procedure for generating l-(SR)-methionine sulfoximine phosphate from l-(SR)-methionine sulfoximine, which will facilitate future investigations of novel GS inhibitors

What is the risk of acquiring SARS-CoV-2 from the use of public toilets?

Public toilets and bathrooms may act as a contact hub point where community transmission of SARS-CoV-2 occurs between users. The mechanism of spread would arise through three mechanisms: inhalation of faecal and/or urinary aerosol from an individual shedding SARS-CoV-2; airborne transmission of respiratory aerosols between users face-to-face or during short periods after use; or from fomite transmission via frequent touch sites such as door handles, sink taps, lota or toilet roll dispenser. In this respect toilets could present a risk comparable with other high throughput enclosed spaces such as public transport and food retail outlets. They are often compact, inadequately ventilated, heavily used and subject to maintenance and cleaning issues. Factors such as these would compound the risks generated by toilet users incubating or symptomatic with SARS-CoV-2. Furthermore, toilets are important public infrastructure since they are vital for the maintenance of accessible, sustainable and comfortable urban spaces. Given the lack of studies on transmission through use of public toilets, comprehensive risk assessment relies upon the compilation of evidence gathered from parallel studies, including work performed in hospitals and prior work on related viruses. This narrative review examines the evidence suggestive of transmission risk through use of public toilets and concludes that such a risk cannot be lightly disregarded. A range of mitigating actions are suggested for both users of public toilets and those that are responsible for their design, maintenance and management

Does the external remote controller’s reading correspond to the actual lengthening in magnetic-controlled growing rods?

Purpose Magnetic-controlled growing rods (MCGRs) are now routinely used in many centres to treat early-onset scoliosis (EOS). MCGR lengthening is done non-invasively by the external remote controller (ERC). Our experience suggests that there may be a discrepancy between the reported rod lengthening on the ERC and the actual rod lengthening. The aim of this study was to investigate this discrepancy. Methods This was a prospective series. Eleven patients who were already undergoing treatment for EOS using MCGRs were included in this study. Results One hundred and ninety-two sets of ultrasound readings were obtained (96 episodes of rod lengthening on dual-rod constructs) and compared to their ERC readings. Only 15/192 (7.8%) readings were accurate; 27 readings (14.9%) were false positive; and 8 readings (4.2%) were an underestimation while 142 readings (74.0%) were an overestimation by the ERC. Average over-reporting by the ERC was 5.31 times of the actual/ultrasound reading. When comparing interval radiographs with lengthening obtained on ultrasound, there was a discrepancy with an average overestimation of 1.35 times with ultrasound in our series. There was a significant difference between ERC and USS (p = 0.01) and ERC and XR (p = 0.001). However, there was no significant difference between USS and XR (p > 0.99). Conclusion The reading on the ERC does not equate to the actual rod lengthening. The authors would recommend that clinicians using the MCGR for the treatment of early-onset scoliosis include pre- and post-extension imaging (radiographs or ultrasound) to confirm extension lengths at each outpatient extension. In centres with ultrasound facilities, we would suggest that patients should have ultrasound to monitor each lengthening after distraction but also 6-month radiographs

Myocardial contrast echocardiography for the assessment of coronary blood flow reserve: Validation in humans

AbstractObjectives. The aim of this study was to validate the use of myocardial contrast echocardiography to determine coronary blood flow reserve in humans.Background. Although myocardial contrast echocardiogrephy has been used to accurately quantify coronary flow reserve in animals, validation for its use in humans to measure flow reserve is lacking.Methods. We analyzed the time-intensity curve from the anteroseptal region of the left ventricular short axis produced after a left main coronary artery injection of sonicated albumin before and after intracoronary administration of papaverine in 16 patients without angiographically significant coronary artery disease. The ratio of half-time of video intensity disappearance from peak intensity, variable of curve width, area under the timeintensity curve and corrected peak contrast intensity after papaverine compared with baseline were correlated with coronary flow reserve measured simultaneously with an intracoronary Doppler probe in the left anterior descending coronary artery.Results. There was a strong inverse correlation with half-time of contrast washout and coronary flow reserve (r = −0.76, p = 0.0007) and a strong positive correlation between the variable of curve width (which is inversely proportional to curve width) and coronary flow reserve (r = 0.71, p = O.002). There was a weak but significant inverse correlation between area under the timeintensity curve and coronary flow reserve (r = −0.54, p = 0.03) but no correlation between corrected peak contrast inteasity and coronary flow reserve (r = −036, p = NS), Despite the strong correlation for the ratios for half-time of contrast washout and variable of curve width and actual coronary flow reserve measured with intracoronary Doppler probe, the transit time ratios consistently underestimated coronary flow reserve.Conclusions. Myocardial contrast echocardiography performed with left main coronary artery injections of sonicated albumin can be utilized to measure coronary flow reserve in humans. Transit time variable ratios (half-time of contrast washout and variable of curve width) derived from the time-intensity curve correlate most strongly with coronary flow reserve