On the relativistic iron line and soft excess in the Seyfert 1 galaxy Markarian 335

We report on a 133 ks XMM-Newton observation of the Seyfert 1 galaxy Markarian 335. The 0.4-12 keV spectrum contains an underlying power law continuum, a soft excess below 2 keV, and a double-peaked iron emission feature in the 6-7 keV range. We investigate the possibility that the double-peaked emission might represent the characteristic signature of the accretion disc. Detailed investigations show that a moderately broad, accretion disc line is most likely present, but that the peaks may be owing to narrower components from more distant material. The peaks at 6.4 and 7 keV can be identified, respectively, with the molecular torus in active galactic nucleus unification schemes, and very highly ionized, optically thin gas filling the torus. The X-ray variability spectra on both long (~100 ks) and short (~1 ks) timescales disfavour the recent suggestion that the soft excess is an artifact of variable, moderately ionized absorption.Comment: 6 pages, 2 figures, accepted for publication in MNRA

Recurrent ~24 h Periods in RXTE ASM Data

Analysis of data from the Rossi X-ray Timing Explorer satellite's All Sky Monitor instrument for several X-ray binary sources has identified a recurrent \~24 h period. This period is sometimes highly significant, giving rise to the possibility of it being identified as an orbital or super-orbital period. Further analysis has revealed the same period in a number of other X-ray sources. As a result this period has been discounted as spurious, described variously as arising from daily variations in background levels and beating between the sampling period and long-term secular trends in the light curves. We present here an analysis of the spurious periods and show that the dominant mechanism is in fact spectral leakage of low-frequency power present in the light curves.Comment: 9 Pages, 10 figures, 1 table, submitted to PASA 20th December 2004. Added 1 page of text and 3 figures to clarify results and discussion. Resubmitted 16th May 2005. Accepted 25th June 200

A tetraoxane-based antimalarial drug candidate that overcomes PfK13-C580Y dependent artemisinin resistance

Documento escrito por un elevado número de autores/as, solo se referencia el/la que aparece en primer lugar y los/as autores/as pertenecientes a la UC3M.K13 gene mutations are a primary marker of artemisinin resistance in Plasmodium falciparum malaria that threatens the long-term clinical utility of artemisinin-based combination therapies, the cornerstone of modern day malaria treatment. Here we describe a multinational drug discovery programme that has delivered a synthetic tetraoxane-based molecule, E209, which meets key requirements of the Medicines for Malaria Venture drug candidate profiles. E209 has potent nanomolar inhibitory activity against multiple strains of P. falciparum and P. vivax in vitro, is efficacious against P. falciparum in in vivo rodent models, produces parasite reduction ratios equivalent to dihydroartemisinin and has pharmacokinetic and pharmacodynamic characteristics compatible with a single-dose cure. In vitro studies with transgenic parasites expressing variant forms of K13 show no cross-resistance with the C580Y mutation, the primary variant observed in Southeast Asia. E209 is a superior next generation endoperoxide with combined pharmacokinetic and pharmacodynamic features that overcome the liabilities of artemisinin derivatives.This work was supported by grants from the European Union (Antimal, FP6, S.A.W., P.M.O’N.), the Medicines for Malaria Venture (S.A.W., P.M.O’N., G.A.B., G.L.N., R.K.A.), the NIH (R01 AI109023 to D.A.F.), the Global Health and Innovative Technology (GHIT) Fund (G2015-120, S.A.W., P.M.O’N., G.A.B, G.L.N.) and Medical Research Council, United Kingdom (G0700654, M.H.-L.W., A.E.M., I.M.C.)

Incidence of surgical site infection following caesarean section: a systematic review and meta-analysis protocol

Introduction: Caesarean section (CS) rates have increased globally during the past three decades. Surgical site infection (SSI) following CS is a common cause of morbidity with reported rates of 3 -15%. SSI represents a substantial burden to the health system including increased length of hospitalisation and costs of postdischarge care. The definition of SSI varies with the postoperative follow-up period among different health systems, resulting in differences in the reporting of SSI incidence. We propose to conduct the first systematic review and meta-analysis to determine the pooled estimate for the overall incidence of SSI following CS. Methods and analysis: We will perform a comprehensive search to identify all potentially relevant published studies on the incidence of SSI following CS reported from 1992 in the English language. Electronic databases including PubMed, CINAHL, EMBASE and Scopus will be searched using a detailed search strategy. Following study selection, full-text paper retrieval, data extraction and synthesis, we will appraise study quality and risk of bias and assess heterogeneity. Incidence data will be combined where feasible in a meta-analysis using Stata software and fixed-effects or random-effects models as appropriate. This systematic review will be reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Ethics and dissemination: Ethical approval is not required as this review will use published data. The review will evaluate the overall incidence of SSI following CS and will provide the first quantitative estimate of the magnitude of SSI. It will serve as a benchmark for future studies, identify research gaps and remaining challenges, and emphasise the need for appropriate prevention and control measures for SSI post-CS. A manuscript reporting the results of the systematic review and meta-analysis will be submitted to a peer-reviewed journal and presented at scientific conferences. Trial registration number CRD42015024426

Mesenchymal Migration as a Therapeutic Target in Glioblastoma

Extensive infiltration of the surrounding healthy brain tissue is a cardinal feature of glioblastomas, highly lethal brain tumors. Deep infiltration by the glioblastoma cells renders complete surgical excision difficult and contemporary adjuvant therapies have had little impact on long-term survival. Thus, deep infiltration and resistance to irradiation and chemotherapy remain a major cause of patient mortality. Modern therapies specifically targeted to this unique aspect of glioblastoma cell biology hold significant promise to substantially improve survival rates for glioblastoma patients. In the present paper, we focus on the role of adhesion signaling molecules and the actin cytoskeleton in the mesenchymal mode of motility that characterizes invading glioblastoma cells. We then review current approaches to targeting these elements of the glioblastoma cell migration machinery and discuss other aspects of cell migration that may improve the treatment of infiltrating glioblastoma

Near-Earth Space Radiation Models

Review of models of the near-Earth space radiation environment is presented, including recent developments in trapped proton and electron, galactic cosmic ray and solar particle event models geared toward spacecraft electronics applications

On the ordeal of quinolone preparation via cyclisation of aryl-enamines; synthesis and structure of ethyl 6-methyl-7-iodo-4-(3-iodo-4-methylphenoxy)-quinoline-3-carboxylate

Recent studies directed to the design of compounds targeting the bc(1) protein complex of Plasmodium falciparum, the parasite responsible for most lethal cases of malaria, identified quinolones (4-oxo-quinolines) with low nanomolar inhibitory activity against both the enzyme and infected erythrocytes. The 4-oxo-quinoline 3-ester chemotype emerged as a possible source of potent bc(1) inhibitors, prompting us to expand the library of available analogs for SAR studies and subsequent lead optimization. We now report the synthesis and structural characterization of unexpected ethyl 6-methyl-7-iodo-4-(3-iodo-4-methylphenoxy)quinoline-3-carboxylate, a 4-aryloxy-quinoline 3-ester formed during attempted preparation of 6-methyl-7-iodo-4-oxo-quinoline-3-carboxylate (4-oxo-quinoline 3-ester). We propose that the 4-aryloxy-quinoline 3-ester derives from 6-methyl-7-iodo-4-hydroxy-quinoline-3-carboxylate (4-hydroxy-quinoline 3-ester), the enol form of 6-methyl-7-iodo-4-oxo-quinoline-3-carboxylate. Formation of the 4-aryloxy-quinoline 3-ester confirms the impact of quinolone/hydroxyquinoline tautomerism, both on the efficiency of synthetic routes to quinolones and on pharmacologic profiles. Tautomers exhibit different cLogP values and interact differently with the enzyme active site. A structural investigation of 6-methyl-7-iodo-4-oxo-quinoline-3-carboxylate and 6-methyl-7-iodo-4-hydroxy-quinoline-3-carboxylate, using matrix isolation coupled to FTIR spectroscopy and theoretical calculations, revealed that the lowest energy conformers of 6-methyl-7-iodo-4-hydroxy-quinoline-3-carboxylate, lower in energy than their most stable 4-oxo-quinoline tautomer by about 27 kJ mol(-1), are solely present in the matrix, while the most stable 4-oxo-quinoline tautomer is solely present in the crystalline phase.Fundacao para a Ciencia e Tecnologia (FCT - Portugal) [UID/Multi/04326/2013]; QREN-COMPETE-UE; CCMAR; FCT [SFRH/BD/81821/2011, RECI/BBB-BQB/0230/2012, UI0313/QUI/2013, UID/FIS/04564/2016]; FEDER/COMPETE-UE; [PTDC/QEQ-QFI/3284/2014 - POCI-01-0145-FEDER-016617]info:eu-repo/semantics/publishedVersio

Antimalarial agents as therapeutic tools against toxoplasmosis: a short bridge between two distant illnesses

Toxoplasmosis is an infectious disease with paramount impact worldwide, affecting many vulnerable populations and representing a significant matter of concern. Current therapies used against toxoplasmosis are based essentially on old chemotypes, which fail in providing a definitive cure for the disease, placing the most sensitive populations at risk for irreversible damage in vital organs, culminating in death in the most serious cases. Antimalarial drugs have been shown to possess key features for drug repurposing, finding application in the treatment of other parasite-borne illnesses, including toxoplasmosis. Antimalarials provide the most effective therapeutic solutions against toxoplasmosis and make up for the majority of currently available antitoxoplasmic drugs. Additionally, other antiplasmodial drugs have been scrutinized and many promising candidates have emanated in recent developments. Available data demonstrate that it is worthwhile to explore the activity of classical and most recent antimalarial chemotypes, such as quinolines, endoperoxides, pyrazolo[1,5-a]pyrimidines, and nature-derived peptide-based parasiticidal agents, in the context of toxoplasmosis chemotherapy, in the quest for encountering more effective and safer tools for toxoplasmosis control or eradication.Fundação para a Ciência e Tecnologia (FCT): UID/MULTI/04326/2019 (CCMAR), UID/QUI/00313/2019 (CQC), PTDC/MAR-BIO/4132/2014, SFRH/BD/140249/2018 (AS).info:eu-repo/semantics/publishedVersio