Oxygen control of nif gene expression in Klebsiella pneumoniae depends on NifL reduction at the cytoplasmic membrane by electrons derived from the reduced quinone pool

In Klebsiella pneumoniae, the flavoprotein, NifL regulates NifA mediated transcriptional activation of the N 2 -fixation (nif) genes in response to molecular O 2 and ammonium. We investigated the influence of membrane-bound oxidoreductases on nif-regulation by biochemical analysis of purified NifL and by monitoring NifA-mediated expression of nifH¢-¢lacZ reporter fusions in different mutant backgrounds. NifL-bound FAD-cofactor was reduced by NADH only in the presence of a redox-mediator or inside-out vesicles derived from anaerobically grown K. pneumoniae cells, indicating that in vivo NifL is reduced by electrons derived from membrane-bound oxidoreductases of the anaerobic respiratory chain. This mechanism is further supported by three lines of evidence: First, K. pneumoniae strains carrying null mutations of fdnG or nuoCD showed significantly reduced nif-induction under derepressing conditions, indicating that NifL inhibition of NifA was not relieved in the absence of formate dehydrogenase-N or NADH:ubiquinone oxidoreductase. The same effect was observed in a heterologous Escherichia coli system carrying a ndh null allele (coding for NADH dehydrogenaseII). Second, studying nif-induction in K. pneumoniae revealed that during anaerobic growth in glycerol, under nitrogen-limitation, the presence of the terminal electron acceptor nitrate resulted in a significant decrease of nif-induction. The final line of evidence is that reduced quinone derivatives, dimethylnaphthoquinol and menadiol, are able to transfer electrons to the FAD-moiety of purified NifL. On the basis of these data, we postulate that under anaerobic and nitrogen-limited conditions, NifL inhibition of NifA activity is relieved by reduction of the FAD-cofactor by electrons derived from the reduced quinone pool, generated by anaerobic respiration, that favours membrane association of NifL. We further hypothesize that the quinol/quinone ratio is important for providing the signal to NifL

From caution to urgency: the evolution of HIV testing and counselling in Africa.

OBJECTIVE: To describe recent changes in policy on provider-initiated testing and counselling (PITC) for human immunodeficiency virus (HIV) infection in African countries and to investigate patients' experiences of and views about PITC. METHODS: A review of the published literature and of national HIV testing policies, strategic frameworks, plans and other relevant documents was carried out. FINDINGS: Of the African countries reviewed, 42 (79.2%) had adopted a PITC policy. Of the 42, all recommended PITC for the prevention of mother-to-child HIV transmission, 66.7% recommended it for tuberculosis clinics and patients, and 45.2% for sexually transmitted infection clinics. Moreover, 43.6% adopted PITC in 2005 or 2006. The literature search identified 11 studies on patients' experiences of and views about PITC in clinical settings in Africa. The clear majority regarded PITC as acceptable. However, women in antenatal clinics were not always aware that they had the right to decline an HIV test. CONCLUSION: Policy and practice on HIV testing and counselling in Africa has shifted from a cautious approach that emphasizes confidentiality to greater acceptance of the routine offer of HIV testing. The introduction of PITC in clinical settings has contributed to increased HIV testing in several of these settings. Most patients regard PITC as acceptable. However, other approaches are needed to reach people who do not consult health-care services

Benefits Analysis of Wind-Optimal Operations For Trans-Atlantic Flights

North Atlantic Tracks are trans-Atlantic routes across the busiest oceanic airspace in the world. This study analyzes and compares current flight-plan routes to wind-optimal routes for trans-Atlantic flights in terms of aircraft fuel burn, emissions and the associated climate impact. The historical flight track data recorded by EUROCONTROL's Central Flow Management Unit is merged with data from FAA's Enhanced Traffic Management System to provide an accurate flight movement database containing the highest available flight path resolution in both systems. The combined database is adopted for airspace simulation integrated with aircraft fuel burn and emissions models, contrail models, simplified climate response models, and a common climate metric to assess the climate impact of flight routes within the Organized Track System (OTS). The fuel burn and emissions for the tracks in the OTS are compared with the corresponding quantities for the wind-optimized routes to evaluate the potential environmental benefits of flying wind-optimal routes in North Atlantic Airspace. The potential fuel savings and reduction in emissions depend on existing inefficiencies in current flight plans, atmospheric conditions and location of the city-pairs. The potential benefits are scaled by comparing them with actual flight tests that have been conducted since 2010 between a few city-pairs in the transatlantic and trans-pacific region to improve fuel consumption and reduce the environmental impact of aviation

Emerging drugs for the treatment of vitiligo

Introduction: Vitiligo is a relatively common autoimmune depigmenting disorder of the skin. There has been a great advance in understanding the pathological basis, which has led to the development and utilization of various new molecules in treating vitiligo. This review aims at a comprehensively describing the treatments available and the emerging treatment aspects and the scope for future developments. Areas covered: This study comprehensively summarizes the current concepts in the pathogenesis of vitiligo with special focus on the cytokine and signaling pathways, which are the targets for newer drugs. JAK kinase signaling pathways and the cytokines involved are the focus of vitiligo treatment in current research, followed by antioxidant mechanisms and repigmenting mechanisms. Topical immunosuppressants may be an alternative to steroids in localized vitiligo. Newer repigmenting agents like basic fibroblast growth factors, afamelanotide have been included and a special emphasis is laid on the upcoming targeted immunotherapy. Expert opinion: The treatment of vitiligo needs to be multimodal with emphasis on targeting different limbs of the pathogenesis. Topical and oral JAK inhibitors are the most promising new class of drugs currently available for treating vitiligo and acts best in conjunction with NB-UVB

Laboratory Measurements of Fe XXIV Line Emission: 3→2 Transitions Near Excitation Threshold

Using the Electron Beam Ion Trap facility at Lawrence Livermore National Laboratory, we have measured relative cross sections for Fe XXIV line emission at electron energies between 0.7 and 3.0 keV. The measurements include line formation by direct electron impact excitation (DE), radiative cascades, resonant excitation (RE), and dielectronic recombination (DR) satellites with captured electrons in n≥5 levels. Good agreement with R-matrix and distorted wave calculations is found. In collisionally ionized plasmas, at temperatures near where the ion abundance peaks (kTe~1.7 keV), the RE contributions are found to be ≲5% of the line emission, while the DR satellites contribute ≲10%. While good agreement with state-of-the-art atomic physics calculations is found, there is less good agreement with existing spectral synthesis codes in common astrophysical use. For the Fe XXIV 3p3/2 → 2s1/2, 3p1/2 → 2s1/2, and 3d5/2 → 2p3/2 transitions, the synthesis code MEKAL underestimates the emissivity in coronal equilibrium by ~20% at temperatures near where the ion abundance peaks. In situations where the ionization balance is not solely determined by the electron temperature, RE and DR satellites may contribute a considerable fraction of the line emission

Light-based devices for the treatment of facial erythema and telangiectasia

Facial erythema is one of the most common outpatient complaints in dermatology. There are various causes of facial erythema and several devices are available for its treatment. Pulsed dye laser (PDL) and intense pulsed light (IPL) are the two common light devices used for these conditions. In this review, we evaluated the literature to assess efficacy of IPL versus PDL in facial erythema and telangiectasia. We searched published articles including clinical trials or reviews articles, case series, and case reports. Electronic databases (MEDLINE and PubMed) were searched to retrieve the articles. Reference lists of selected articles were also considered for the review. Articles published in English language until June 2021 were considered for this review

Challenges and new beginnings: Priorities for the EU’s new leadership. EPC Challenge Europe Issue 22, September 2014

Table of contents - State of the Union and key challenges for Europe's future, Janis A. Emmanouilidis and Paul Ivan; Europe’s economic challenges and the importance of ideas and innovation, Herman Van Rompuy; The growth challenge for Europe and the EMU, George Pagoulatos; Strengthening the euro area, Daniela Schwarzer; Social Europe. Can the EU again improve people's life prospects?, László Andor; Solidarity and cohesion, Pawel Swieboda; The single market and competitiveness – the challenges for the Juncker team, Malcolm Harbour; A European response to the resource and climate challenge, Jo Leinen; Renewal through international action? Options for EU foreign policy, Rosa Balfour; EU migration policy – new realities, new opportunities, Cecilia Malmström; Freedom of movement of persons – the building-block of European growth, Radoslaw Sikorski; Building up European leadership – an assessment of the recent process, Maria João Rodrigues; Populism in the EU: new threats to the open society?, Heather Grabbe; Differentiated Europe needs strong institutions, Alexander Stubb; Improving decision-making in the EU, Fabian Zuleeg; The need for a New Pact, Janis A. Emmanouilidis

Dacarbazine (DTIC) versus vaccination with autologous peptide-pulsed dendritic cells (DC) in first-line treatment of patients with metastatic melanoma: a randomized phase III trial of the DC study group of the DeCOG

Background: This randomized phase III trial was designed to demonstrate the superiority of autologous peptide-loaded dendritic cell (DC) vaccination over standard dacarbazine (DTIC) chemotherapy in stage IV melanoma patients. Patients and methods: DTIC 850 mg/m2 intravenously was applied in 4-week intervals. DC vaccines loaded with MHC class I and II-restricted peptides were applied subcutaneously at 2-week intervals for the first five vaccinations and every 4 weeks thereafter. The primary study end point was objective response (OR); secondary end points were toxicity, overall (OS) and progression-free survival (PFS). Results: At the time of the first interim analysis 55 patients had been enrolled into the DTIC and 53 into the DC-arm (ITT). OR was low (DTIC: 5.5%, DC: 3.8%), but not significantly different in the two arms. The Data Safety & Monitoring Board recommended closure of the study. Unscheduled subset analyses revealed that patients with normal serum LDH and/or stage M1a/b survived longer in both arms than those with elevated serum LDH and/or stage M1c. Only in the DC-arm did those patients with (i) an initial unimpaired general health status (Karnofsky = 100) or (ii) an HLA-A2+/HLA-B44− haplotype survive significantly longer than patients with a Karnofsky index <100 (P = 0.007 versus P = 0.057 in the DTIC-arm) or other HLA haplotypes (P = 0.04 versus P = 0.57 in DTIC-treated patients). Conclusions: DC vaccination could not be demonstrated to be more effective than DTIC chemotherapy in stage IV melanoma patients. The observed association of overall performance status and HLA haplotype with overall survival for patients treated by DC vaccination should be tested in future trials employing DC vaccine

Adhesive and conformational behaviour of mycolic acid monolayers

We have studied the pH-dependent interaction between mycolic acid (MA) monolayers and hydrophobic and hydrophilic surfaces using molecular (colloidal probe) force spectroscopy. In both cases, hydrophobic and hydrophilic monolayers (prepared by Langmuir-Blodgett and Langmuir-Schaefer deposition on silicon or hydrophobized silicon substrates, respectively) were studied. The force spectroscopy data, fitted with classical DLVO (Derjaguin, Landau, Verwey, and Overbeek) theory to examine the contribution of electrostatic and van der Waals forces, revealed that electrostatic forces are the dominant contribution to the repulsive force between the approaching colloidal probe and MA monolayers. The good agreement between data and the DLVO model suggest that beyond a few nm away from the surface, hydrophobic, hydration, and specific chemical bonding are unlikely to contribute to any significant extent to the interaction energy between the probe and the surface. The pH-dependent conformation of MA molecules in the monolayer at the solid-liquid interface was studied by ellipsometry, neutron reflectometry, and with a quartz crystal microbalance. Monolayers prepared by the Langmuir-Blodgett method demonstrated a distinct pH-responsive behaviour, while monolayers prepared by the Langmuir-Schaefer method were less sensitive to pH variation. It was found that the attachment of water molecules plays a vital role in determining the conformation of the MA monolayers. (C) 2010 Elsevier B.V. All rights reserved