Formation and structure of the ferryl [Fe=O] in-termediate in the non-haem iron halogenase SyrB2: classical and QM/MM modelling agree

To rationalise mechanistically the intriguing regio- and chemoselectivity patterns for different substrates of the non-haem iron/2-oxoglutarate dependent halogenase SyrB2, it is crucial to elucidate the structure of the pivotal [FeIV[double bond, length as m-dash]O] intermediate. We have approached the problem by a combination of classical and QM/MM modelling. We present complete atomistic models of SyrB2 in complex with its native substrate L-threonine as well as L-α-amino butyric acid and L-norvaline (all conjugated to the pantetheine tether), constructed by molecular docking and extensive MD simulations. We evaluate five isomers of the [Fe[double bond, length as m-dash]O] intermediate in these simulations, with a view to identifying likely structures based on a simple “reaction distance” measure. Starting from models of the resting state, we then use QM/MM calculations to investigate the formation of the [Fe[double bond, length as m-dash]O] species for all three substrates, identifying the intermediates along the O2 activation/decarboxylation pathway on the S = 1, 2, and 3 potential-energy surfaces. We find that, despite differences in the detailed course of the reaction, essentially all pathways produce the same [Fe[double bond, length as m-dash]O] structure, in which the oxido is directed away from the substrate

A hypothalamic channel-system in the inferior lobes of a trigger-fish (Rhinecanthus aculeatus, Balistidae)

In the course of a general investigation of the optic system in some trigger-fishes, a hypothalamic, ventricular channel-system with pores, leading to the outside of the brain, has been discovered in the inferior lobes ofRhinecanthus aculeatus (Balistidae). A description of the morphological relations of the channel-system to the blood-vessel-supply and the cranium suggests that the organ-systems involved form a functional unit. The possibility of a hormone-producing system is discussed in the light of physiological and ecological aspects

The fluorine-NHC gauche effect: a structural and computational study

Herein, we report the synthesis and X-ray structural analysis of a collection of fluorinated metal N-heterocyclic carbenes (Ag, Au, Pd, Rh, Ir) and their precursor salts. The common structural feature of these species is a flanking fluoroethyl group which is either freely rotating or embedded within a bicyclic framework. Solid state analysis confirmed a gauche conformational preference in all cases with the fluorine adopting a syn clinal arrangement (ϕ[NCCF] ~ 60°) with respect to the triazolium nitrogen at the vicinal position of the NHC. A density functional theory analysis was employed to quantify these effects and evaluate the influence of electronic modulation of the carbenic carbon [(C=N+); neutral carbene (C:); metal-bound carbene (C=M)], on the relative gauche / anti preference, thus highlighting the potential of this conformational phenomenon as a useful molecular design strategy for controlling the topology of organometallic complexes

Overstating the evidence - double counting in meta-analysis and related problems

Background: The problem of missing studies in meta-analysis has received much attention. Less attention has been paid to the more serious problem of double counting of evidence. Methods: Various problems in overstating the precision of results from meta-analyses are described and illustrated with examples, including papers from leading medical journals. These problems include, but are not limited to, simple double-counting of the same studies, double counting of some aspects of the studies, inappropriate imputation of results, and assigning spurious precision to individual studies. Results: Some suggestions are made as to how the quality and reliability of meta-analysis can be improved. It is proposed that the key to quality in meta-analysis lies in the results being transparent and checkable. Conclusions: Existing quality check lists for meta-analysis do little to encourage an appropriate attitude to combining evidence and to statistical analysis. Journals and other relevant organisations should encourage authors to make data available and make methods explicit. They should also act promptly to withdraw meta-analyses when mistakes are found

Adult native septic arthritis: a review of 10 years of experience and lessons for empirical antibiotic therapy.

Objectives To review the epidemiology of native septic arthritis to establish local guidelines for empirical antibiotic therapy as part of an antibiotic stewardship programme. Methods We conducted a 10 year retrospective study based on positive synovial fluid cultures and discharge diagnosis of septic arthritis in adult patients. Microbiology results and medical records were reviewed. Results Between 1999 and 2008, we identified 233 episodes of septic arthritis. The predominant causative pathogens were methicillin-susceptible Staphylococcus aureus (MSSA) and streptococci (respectively, 44.6% and 14.2% of cases). Only 11 cases (4.7%) of methicillin-resistant S. aureus (MRSA) arthritis were diagnosed, among which 5 (45.5%) occurred in known carriers. For large-joint infections, amoxicillin/clavulanate or cefuroxime would have been appropriate in 84.5% of cases. MRSA and Mycobacterium tuberculosis would have been the most frequent pathogens that would not have been covered. In contrast, amoxicillin/clavulanate would have been appropriate for only 75.3% of small-joint infections (82.6% if diabetics are excluded). MRSA and Pseudomonas aeruginosa would have been the main pathogens not covered. Piperacillin/tazobactam would have been appropriate in 93.8% of cases (P < 0.01 versus amoxicillin/clavulanate). This statistically significant advantage is lost after exclusion of diabetics (P = 0.19). Conclusions Amoxicillin/clavulanate or cefuroxime would be adequate for empirical coverage of large-joint septic arthritis in our area. A broad-spectrum antibiotic would be significantly superior for small-joint infections in diabetics. Systematic coverage of MRSA is not justified, but should be considered for known carriers. These recommendations are applicable to our local setting. They might also apply to hospitals sharing the same epidemiology

Understanding Variation in Sets of N-of-1 Trials.

A recent paper in this journal by Chen and Chen has used computer simulations to examine a number of approaches to analysing sets of n-of-1 trials. We have examined such designs using a more theoretical approach based on considering the purpose of analysis and the structure as regards randomisation that the design uses. We show that different purposes require different analyses and that these in turn may produce quite different results. Our approach to incorporating the randomisation employed when the purpose is to test a null hypothesis of strict equality of the treatment makes use of Nelder's theory of general balance. However, where the purpose is to make inferences about the effects for individual patients, we show that a mixed model is needed. There are strong parallels to the difference between fixed and random effects meta-analyses and these are discussed

Unterschiede im Leistungsverhalten von Gesunden zwischen Fahrrad- und Laufbandergometrie

Problemstellung: Zur Überprüfung des Ausdauertrainingseffektes während einer Terrainkur ist die Laufbandergometrie der Belastung auf dem Fahrrad vorzuziehen, da hierbei dieselben Muskeln beansprucht werden wie während des Trainings. Allerdings gelingt es wegen der frühzeitigen subjektiven Erschöpfung der Kurpatienten nur selten, Milchsäurewerte oberhalb der aeroben/anaeroben Schwelle zu erzielen. Gegenstand: Die vorliegende Studie mit Gesunden befaßt sich mit den Fragen, warum sich Kurpatienten auf dem Laufband metabolisch betrachtet nicht genügend ausbelasten lassen, und welches die entscheidenden Unterschiede in der Art der Belastung zwischen Laufband- und Fahrradergometer sind. Versuchsplan: 27 gesunde Testpersonen wurden auf dem Fahrrad- und Laufbandergometer submaximal belastet. Die Belastung wurde nach einem standardisierten Verfahren in 0,33 W/kg-Schritten gesteigert. Wichtigste Meßparameter waren Herzfrequenz und Milchsäurespiegel. Ergebnisse: Während der Laufbandergometrie lagen Herzfrequenz und Sauerstoffbedarf des Myokards zum Erreichen der gleichen Wattstufe signifikant höher (1,0 W/kg:p≤0,001; 1,33 W/kg: p≤0,01; 2,0 W/kg: n.s.; Erholung: p≤0,001) als auf dem Fahrrad. Dagegen zeigte sich bei gegebener Herzfrequenz von 130/min und bei derselben höchsten erreichten Wattstufe auf dem Laufband ein um 0,7 mmol/1 bzw. l,0mmol/l signifikant (p≤0,01) niedrigerer Laktatanstieg als auf dem Fahrradergometer. Schlußfolgerung: Die Ergebnisse zeigten somit eine stärkere kardiale Ausschöpfung auf dem Laufbandergometer. Die aeroben/anaerobe Schwelle wird dagegen auf dem Laufband später als auf dem Fahrrad erreicht

Draft Genome Sequences of Two Carbapenemase-Producing Acinetobacter baumannii Clinical Strains Isolated from Albanian and Togolese Patients.

We report here the draft genome sequences of two multidrug-resistant Acinetobacter baumannii clinical strains, H31499 and H31506, which were isolated at the Lausanne University Hospital in 2015 from an Albanian and a Togolese patient, respectively

Does respiratory infection due to Chlamydia pneumoniae still exist?

Does respiratory infection due to Chlamydia pneumoniae still exist