Targeting Aquaporin Function:Potent Inhibition of Aquaglyceroporin-3 by a Gold-Based Compound

Aquaporins (AQPs) are membrane channels that conduct water and small solutes such as glycerol and are involved in many physiological functions. Aquaporin-based modulator drugs are predicted to be of broad potential utility in the treatment of several diseases. Until today few AQP inhibitors have been described as suitable candidates for clinical development. Here we report on the potent inhibition of AQP3 channels by gold(III) complexes screened on human red blood cells (hRBC) and AQP3-transfected PC12 cells by a stopped-flow method. Among the various metal compounds tested, Auphen is the most active on AQP3 (IC(50) = 0.8±0.08 µM in hRBC). Interestingly, the compound poorly affects the water permeability of AQP1. The mechanism of gold inhibition is related to the ability of Au(III) to interact with sulphydryls groups of proteins such as the thiolates of cysteine residues. Additional DFT and modeling studies on possible gold compound/AQP adducts provide a tentative description of the system at a molecular level. The mapping of the periplasmic surface of an homology model of human AQP3 evidenced the thiol group of Cys40 as a likely candidate for binding to gold(III) complexes. Moreover, the investigation of non-covalent binding of Au complexes by docking approaches revealed their preferential binding to AQP3 with respect to AQP1. The high selectivity and low concentration dependent inhibitory effect of Auphen (in the nanomolar range) together with its high water solubility makes the compound a suitable drug lead for future in vivo studies. These results may present novel metal-based scaffolds for AQP drug development

Solar Spectroscopy and (Pseudo-)Diagnostics of the Solar Chromosphere

I first review trends in current solar spectrometry and then concentrate on comparing various spectroscopic diagnostics of the solar chromosphere. Some are actually not at all chromospheric but just photospheric or clapotispheric and do not convey information on chromospheric heating, even though this is often assumed. Balmer Halpha is the principal displayer of the closed-field chromosphere, but it is unclear how chromospheric fibrils gain their large Halpha opacity. The open-field chromosphere seems to harbor most if not all coronal heating and solar wind driving, but is hardly seen in optical diagnostics.Comment: To appear in "Recent Advances in Spectroscopy: Astrophysical, Theoretical and Experimental Perspectives", eds. R.K. Chaudhuri, M.V. Mekkaden, A.V. Raveendran and A. Satya Narayanan, Astrophysics and Space Science Proceedings, Springer, Heidelberg, 2009. Revision: references corrected, new references added, minor text correction

Exploiting solar visible-range observations by inversion techniques: from flows in the solar subsurface to a flaring atmosphere

Observations of the Sun in the visible spectral range belong to standard measurements obtained by instruments both on the ground and in the space. Nowadays, both nearly continuous full-disc observations with medium resolution and dedicated campaigns of high spatial, spectral and/or temporal resolution constitute a holy grail for studies that can capture (both) the long- and short-term changes in the dynamics and energetics of the solar atmosphere. Observations of photospheric spectral lines allow us to estimate not only the intensity at small regions, but also various derived data products, such as the Doppler velocity and/or the components of the magnetic field vector. We show that these measurements contain not only direct information about the dynamics of solar plasmas at the surface of the Sun but also imprints of regions below and above it. Here, we discuss two examples: First, the local time-distance helioseismology as a tool for plasma dynamic diagnostics in the near subsurface and second, the determination of the solar atmosphere structure during flares. The methodology in both cases involves the technique of inverse modelling.Comment: 29 pages, 15 figures. Accepted for publication in the book "Reviews in Frontiers of Modern Astrophysics: From Space Debris to Cosmology" (eds Kabath, Jones and Skarka; publisher Springer Nature) funded by the European Union Erasmus+ Strategic Partnership grant "Per Aspera Ad Astra Simul" 2017-1-CZ01-KA203-03556

Current issues in medically assisted reproduction and genetics in Europe: research, clinical practice, ethics, legal issues and policy. European Society of Human Genetics and European Society of Human Reproduction and Embryology.

In March 2005, a group of experts from the European Society of Human Genetics and European Society of Human Reproduction and Embryology met to discuss the interface between genetics and assisted reproductive technology (ART), and published an extended background paper, recommendations and two Editorials. Seven years later, in March 2012, a follow-up interdisciplinary workshop was held, involving representatives of both professional societies, including experts from the European Union Eurogentest2 Coordination Action Project. The main goal of this meeting was to discuss developments at the interface between clinical genetics and ARTs. As more genetic causes of reproductive failure are now recognised and an increasing number of patients undergo testing of their genome before conception, either in regular health care or in the context of direct-to-consumer testing, the need for genetic counselling and preimplantation genetic diagnosis (PGD) may increase. Preimplantation genetic screening (PGS) thus far does not have evidence from randomised clinical trials to substantiate that the technique is both effective and efficient. Whole-genome sequencing may create greater challenges both in the technological and interpretational domains, and requires further reflection about the ethics of genetic testing in ART and PGD/PGS. Diagnostic laboratories should be reporting their results according to internationally accepted accreditation standards (International Standards Organisation - ISO 15189). Further studies are needed in order to address issues related to the impact of ART on epigenetic reprogramming of the early embryo. The legal landscape regarding assisted reproduction is evolving but still remains very heterogeneous and often contradictory. The lack of legal harmonisation and uneven access to infertility treatment and PGD/PGS fosters considerable cross-border reproductive care in Europe and beyond. The aim of this paper is to complement previous publications and provide an update of selected topics that have evolved since 2005

Manufacturing and Supply Chain Flexibility: Building an Integrative Conceptual Model Through Systematic Literature Review and Bibliometric Analysis

The purpose of this study is twofold: first, to establish the current themes on the topic of manufacturing and supply chain flexibility (MSCF), assess their level of maturity in relation to each other, identify the emerging ones and reflect on how they can inform each other, and second, to develop a conceptual model of MSCF that links different themes connect and highlight future research opportunities. The study builds on a sample of 222 articles published from 1996 to 2018 in international, peer-reviewed journals. The analysis of the sample involves two complementary approaches: the co-word technique to identify the thematic clusters as well as their relative standing and a critical reflection on the papers to explain the intellectual content of these thematic clusters. The results of the co-word analysis show that MSCF is a dynamic topic with a rich and complex structure that comprises five thematic clusters. The value chain, capability and volatility clusters showed research topics that were taking a central role in the discussion on MSCF but were not mature yet. The SC purchasing practices and SC planning clusters involved work that was more focused and could be considered more mature. These clusters were then integrated in a framework that built on the competence–capability perspective and identified the major structural and infrastructural elements of MSCF as well as its antecedents and consequences. This paper proposes an integrative framework helping managers keep track the various decisions they need to make to increase flexibility from the viewpoint of the entire value chain

Quality assessment of a new surgical simulator for neuroendoscopic training

Object. Ideal surgical training models should be entirely reliable, atoxic, easy to handle, and, if possible, low cost. All available models have their advantages and disadvantages. the choice of one or another will depend on the type of surgery to be performed. the authors created an anatomical model called the S.I.M.O.N.T. (Sinus Model Oto-Rhino Neuro Trainer) Neurosurgical Endotrainer, which can provide reliable neuroendoscopic training. the aim in the present study was to assess both the quality of the model and the development of surgical skills by trainees.Methods. the S.I.M.O.N.T. is built of a synthetic thermoretractable, thermosensible rubber called Neoderma, which, combined with different polymers, produces more than 30 different formulas. Quality assessment of the model was based on qualitative and quantitative data obtained from training sessions with 9 experienced and 13 inexperienced neurosurgeons. the techniques used for evaluation were face validation, retest and interrater reliability, and construct validation.Results. the experts considered the S.I.M.O.N.T. capable of reproducing surgical situations as if they were real and presenting great similarity with the human brain. Surgical results of serial training showed that the model could be considered precise. Finally, development and improvement in surgical skills by the trainees were observed and considered relevant to further training. It was also observed that the probability of any single error was dramatically decreased after each training session, with a mean reduction of 41.65% (range 38.7%-45.6%).Conclusions. Neuroendoscopic training has some specific requirements. A unique set of instruments is required, as is a model that can resemble real-life situations. the S.I.M.O.N.T. is a new alternative model specially designed for this purpose. Validation techniques followed by precision assessments attested to the model's feasibility. (DOI: 10.3171/2011.2.FOCUS10321)Universidade Federal de São Paulo, Discipline Neurosurg, Escola Paulista Med, São Paulo, BrazilCuritiba Neurol Inst, Curitiba, Parana, BrazilUniv Fed Pernambuco, Dept Gynecol, Recife, PE, BrazilUniversidade Federal de São Paulo, Discipline Neurosurg, Escola Paulista Med, São Paulo, BrazilWeb of Scienc

The liver receptor homolog-1 (LRH-1) is expressed in human islets and protects {beta}-cells against stress-induced apoptosis

Liver receptor homolog (LRH-1) is an orphan nuclear receptor (NR5A2) that regulates cholesterol homeostasis and cell plasticity in endodermal-derived tissues. Estrogen increases LRH-1 expression conveying cell protection and proliferation. Independently, estrogen also protects isolated human islets against cytokine-induced apoptosis. Herein, we demonstrate that LRH-1 is expressed in islets, including β-cells, and that transcript levels are modulated by 17β-estradiol through the estrogen receptor (ER)α but not ERβ signaling pathway. Repression of LRH-1 by siRNA abrogated the protective effect conveyed by estrogen on rat islets against cytokines. Adenoviral-mediated overexpression of LRH-1 in human islets did not alter proliferation but conferred protection against cytokines and streptozotocin-induced apoptosis. Expression levels of the cell cycle genes cyclin D1 and cyclin E1 as well as the antiapoptotic gene bcl-xl were unaltered in LRH-1 expressing islets. In contrast, the steroidogenic enzymes CYP11A1 and CYP11B1 involved in glucocorticoid biosynthesis were both stimulated in transduced islets. In parallel, graded overexpression of LRH-1 dose-dependently impaired glucose-induced insulin secretion. Our results demonstrate the crucial role of the estrogen target gene nr5a2 in protecting human islets against-stressed-induced apoptosis. We postulate that this effect is mediated through increased glucocorticoid production that blunts the pro-inflammatory response of islets