Low frequency dynamics of the nitrogenase MoFe protein via femtosecond pump probe spectroscopy - Observation of a candidate promoting vibration

We have used femtosecond pump-probe spectroscopy (FPPS) to study the FeMo-cofactor within the nitrogenase (N2ase) MoFe protein from Azotobacter vinelandii. A sub-20-fs visible laser pulse was used to pump the sample to an excited electronic state, and a second sub-10-fs pulse was used to probe changes in transmission as a function of probe wavelength and delay time. The excited protein relaxes to the ground state with a ~1.2ps time constant. With the short laser pulse we coherently excited the vibrational modes associated with the FeMo-cofactor active site, which are then observed in the time domain. Superimposed on the relaxation dynamics, we distinguished a variety of oscillation frequencies with the strongest band peaks at ~84, 116, 189, and 226cm(-1). Comparison with data from nuclear resonance vibrational spectroscopy (NRVS) shows that the latter pair of signals comes predominantly from the FeMo-cofactor. The frequencies obtained from the FPPS experiment were interpreted with normal mode calculations using both an empirical force field (EFF) and density functional theory (DFT). The FPPS data were also compared with the first reported resonance Raman (RR) spectrum of the N2ase MoFe protein. This approach allows us to outline and assign vibrational modes having relevance to the catalytic activity of N2ase. In particular, the 226cm(-1) band is assigned as a potential 'promoting vibration' in the H-atom transfer (or proton-coupled electron transfer) processes that are an essential feature of N2ase catalysis. The results demonstrate that high-quality room-temperature solution data can be obtained on the MoFe protein by the FPPS technique and that these data provide added insight to the motions and possible operation of this protein and its catalytic prosthetic group

Rural Malta : first results of the joint Belgo-Maltese survey project

The paper presents the first interdisciplinary results of a joint survey project in the north-west of Malta, with finds ranging from the Prehistoric till the Early Modern period. Three permanently inhabited sites were encountered dating to at least the late 6th or early 5th century BCE, with a clearer attestation in the Hellenistic/Roman and Late Antique periods. The resulting reconstructed settlement pattern of the Phoenician/Punic period suggests a managed landscape that seems to be a good reflexion of what is happening in North Africa and elsewhere in the central and western Mediterranean. At least from the Roman period on, these sites seem to have specialised on the production of olive oil.peer-reviewe

Is prolonged infusion of piperacillin/tazobactam and meropenem in critically ill patients associated with improved pharmacokinetic/pharmacodynamic and patient outcomes? An observation from the Defining Antibiotic Levels in Intensive care unit patients (DALI) cohort

Objectives:We utilized the database of the Defining Antibiotic Levels in Intensive care unit patients (DALI) study to statistically compare the pharmacokinetic/pharmacodynamic and clinical outcomes between prolonged-infusion and intermittent-bolus dosing of piperacillin/tazobactam and meropenem in critically ill patients using inclusion criteria similar to those used in previous prospective studies.Methods: This was a post hoc analysis of a prospective, multicentre pharmacokinetic point-prevalence study (DALI), which recruited a large cohort of critically ill patients from 68 ICUs across 10 countries.Results: Of the 211 patients receiving piperacillin/tazobactam and meropenem in the DALI study, 182 met inclusion criteria. Overall, 89.0% (162/182) of patients achieved the most conservative target of 50% fT(> MIC) (time over which unbound or free drug concentration remains above the MIC). Decreasing creatinine clearance and the use of prolonged infusion significantly increased the PTA for most pharmacokinetic/pharmacodynamic targets. In the subgroup of patients who had respiratory infection, patients receiving beta-lactams via prolonged infusion demonstrated significantly better 30 day survival when compared with intermittent-bolus patients [86.2% (25/29) versus 56.7% (17/30); P=0.012]. Additionally, in patients with a SOFA score of >= 9, administration by prolonged infusion compared with intermittent-bolus dosing demonstrated significantly better clinical cure [73.3% (11/15) versus 35.0% (7/20); P=0.035] and survival rates [73.3% (11/15) versus 25.0% (5/20); P=0.025].Conclusions: Analysis of this large dataset has provided additional data on the niche benefits of administration of piperacillin/tazobactam and meropenem by prolonged infusion in critically ill patients, particularly for patients with respiratory infections

Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with longacting bronchodilators: two randomised clinical trials

Background Patients with chronic obstructive pulmonary disease (COPD) have few options for treatment. The efficacy and safety of the phosphodiesterase-4 inhibitor roflumilast have been investigated in studies of patients with moderate-to-severe COPD, but not in those concomitantly treated with longacting inhaled bronchodilators. The effect of roflumilast on lung function in patients with COPD that is moderate to severe who are already being treated with salmeterol or tiotropium was investigated. Methods In two double-blind, multicentre studies done in an outpatient setting, after a 4-week run-in, patients older than 40 years with moderate-to-severe COPD were randomly assigned to oral roflumilast 500 mu g or placebo once a day for 24 weeks, in addition to salmeterol (M2-127 study) or tiotropium (M2-128 study). The primary endpoint was change in prebronchodilator forced expiratory volume in 1s (FEV(1)). Analysis was by intention to treat. The studies are registered with ClinicalTrials.gov, number NCT00313209 for M2-127, and NCT00424268 for M2-128. Findings In the salmeterol plus roflumilast trial, 466 patients were assigned to and treated with roflumilast and 467 with placebo; in the tiotropium plus roflumilast trial, 371 patients were assigned to and treated with roflumilast and 372 with placebo. Compared with placebo, roflumilast consistently improved mean prebronchodilator FEV(1) by 49 mL (p<0.0001) in patients treated with salmeterol, and 80 mL (p<0.0001) in those treated with tiotropium. Similar improvement in postbronchodilator FEV(1) was noted in both groups. Furthermore, roflumilast had beneficial effects on other lung function measurements and on selected patient-reported outcomes in both groups. Nausea, diarrhoea, weight loss, and, to a lesser extent, headache were more frequent in patients in the roflumilast groups. These adverse events were associated with increased patient withdrawal. Interpretation Roflumilast improves lung function in patients with COPD treated with salmeterol or tiotropium, and could become an important treatment for these patients

Scaling the state: Egypt in the third millennium BC

Discussions of the early Egyptian state suffer from a weak consideration of scale. Egyptian archaeologists derive their arguments primarily from evidence of court cemeteries, elite tombs, and monuments of royal display. The material informs the analysis of kingship, early writing, and administration but it remains obscure how the core of the early Pharaonic state was embedded in the territory it claimed to administer. This paper suggests that the relationship between centre and hinterland is key for scaling the Egyptian state of the Old Kingdom (ca. 2,700-2,200 BC). Initially, central administration imagines Egypt using models at variance with provincial practice. The end of the Old Kingdom demarcates not the collapse, but the beginning of a large-scale state characterized by the coalescence of central and local models

Population genetics of sexual conflict in the genomic era

Sexual conflict occurs when selection acts in opposing directions on males and females. Case studies in both vertebrates and invertebrates indicate that sexual conflict maintains genetic diversity through balancing selection, which might explain why many populations show more genetic variation than expected. Recent population genomic approaches based on different measures of balancing selection have suggested that sexual conflict can arise over survival, not just reproductive fitness as previously thought. A fuller understanding of sexual conflict will provide insight into its contribution to adaptive evolution and will reveal the constraints it might impose on populations

Impact of VMAT-IMRT compared to 3D conformal radiotherapy on anal sphincter dose distribution in neoadjuvant chemoradiation of rectal cancer.

BackgroundNeoadjuvant radio- or chemoradiation (nIRT) therapy is the standard treatment for loco-regional advanced rectal cancer patients of the lower or middle third. Currently, intensity modulated radiation therapy (IMRT) is not the recommended radiation technique even though IMRT has advantages compared to 3D-radiation regarding dose sparing to organs at risk like small bowel and urinary bladder. So far, the benefit of IMRT concerning the anal sphincter complex is not examined. With this study we intended to evaluate the dose distribution on the anal sphincters of rectal cancer patients treated with IMRT in comparison with 3D-techniques.MethodsWe selected 16 patients for the IMRT-group and 16 patients for the 3D-group with rectal cancer of the middle third who were treated in our institute. All patients received 45Gy in a chemoradiation protocol. Patients in both groups were matched regarding stage, primary tumor distance to the anal verge and size of the tumor. We delineated the internal and external anal sphincters, the addition of both sphincters and the levator ani muscle in all patients. Subsequently, we evaluated and compared dose parameters of the different sphincters in both groups and analysed the configuration of the isodoses in the area of the caudal radiation field, respectively.ResultsMost of the relevant dose parameters of the caudal sphincters (Dmean, Dmedian, V10-V40) were significantly reduced in the IMRT-group compared to the 3D-group. Accordingly, the isodoses at the caudal edge of the target volume in the IMRT group demonstrated a steep dose fall. The levator ani muscle always was included into the planned target volumes and received the full dose in both groups.ConclusionsThe modern VMAT-IMRT can significantly reduce the dose to the anal sphincters for rectal cancer patients of the middle third who were treated with conventional chemoradiation therapy

Quelle est aujourd'hui en France la formation à la recherche des thésards en médecine générale?

POITIERS-BU Médecine pharmacie (861942103) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF