Viral surface glycoproteins, gp120 and gp41, as potential drug targets against HIV-1: Brief overview one quarter of a century past the approval of zidovudine, the first anti-retroviral drug

The first anti-HIV drug, zidovudine (AZT), was approved by the FDA a quarter of a century ago, in 1985. Currently, anti-HIV drug-combination therapies only target HIV-1 protease and reverse transcriptase. Unfortunately, most of these molecules present numerous shortcoming; such as viral resistances and adverse effects. In addition, these drugs are involved in later stages of infection. Thus, it is necessary to develop new drugs that are able to block the first steps of viral life cycle. Entry of HIV-1 is mediated by its two envelope glycoproteins: gp120 and gp41. Upon gp120 binding to cellular receptors, gp41 undergoes a series of conformational changes from a non-fusogenic to a fusogenic conformation. The fusogenic core of gp41 is a trimer-of-hairpins structure in which three C-terminal helices pack against a central trimeric-coiled coil formed by three N-terminal helices. The formation of this fusogenic structure brings the viral and cellular membranes close together, a necessary condition for membrane fusion to occur. As gp120 and gp41 are attractive targets, the development of entry inhibitors represents an important avenue of anti-HIV drug therapy. The present review will focus on some general considerations about HIV, the main characteristics of gp120, gp41 and their inhibitors, with special emphasis on the advances of computational approaches employed in the development of bioactive compounds against HIV-1 entry process

Reading ecosystem services at the local scale through a territorial approach: The case of peri-urban agriculture in the thau Lagoon, Southern France

© 2015 by the author(s). In recent years, the ecosystem services (ES) concept has become a major paradigm for natural resource management. While policy-makers demand “hard” monetary evidence that nature conservation would be worth investing in, ongoing attempts are being made to formalize the concept as a scientifically robust “one size fits all” analytical framework. These attempts have highlighted several major limitations of the ES concept. First, to date, the concept has paid little attention to the role of humans in the production of ES. Second, the ongoing formalization of the ES concept is turning it into a “technology of globalization,” thereby increasingly ignoring the socio-cultural context and history within which ecosystems emerge. Third, economic valuation has been shown to limit local stakeholders in expressing their daily and immediate ways of interacting with their environment over and beyond extrinsic motivation provided by financial gains. We address these three limitations by analyzing a social evaluation of the roles of peri-urban farmland from a territorial perspective. Our case study is the Thau lagoon in southern France. We conducted in-depth interviews with a broad range of stakeholders and ran two participatory workshops. Using a territorial meta-model that distinguishes three levels— physical, logical, and existential—stakeholder data were analyzed to unravel the interplay of territorial elements at these three levels that gives rise to ES in two broad categories: food production and aesthetic landscape. The coupling of ES and territory concepts opens up several novel analytical perspectives. It allows partitioning of ES in a manner that “re-contextualizes” them and gives insight about both their physical constituents and their meaning at the territorial level. Additional research should incorporate the dynamics of service demand and supply, and further investigate options for implementation

Creep stability of the proposed AIDA mission target 65803 Didymos: I. Discrete cohesionless granular physics model

As the target of the proposed Asteroid Impact & Deflection Assessment (AIDA) mission, the near-Earth binary asteroid 65803 Didymos represents a special class of binary asteroids, those whose primaries are at risk of rotational disruption. To gain a better understanding of these binary systems and to support the AIDA mission, this paper investigates the creep stability of the Didymos primary by representing it as a cohesionless self-gravitating granular aggregate subject to rotational acceleration. To achieve this goal, a soft-sphere discrete element model (SSDEM) capable of simulating granular systems in quasi-static states is implemented and a quasi-static spin-up procedure is carried out. We devise three critical spin limits for the simulated aggregates to indicate their critical states triggered by reshaping and surface shedding, internal structural deformation, and shear failure, respectively. The failure condition and mode, and shear strength of an aggregate can all be inferred from the three critical spin limits. The effects of arrangement and size distribution of constituent particles, bulk density, spin-up path, and interparticle friction are numerically explored. The results show that the shear strength of a spinning self-gravitating aggregate depends strongly on both its internal configuration and material parameters, while its failure mode and mechanism are mainly affected by its internal configuration. Additionally, this study provides some constraints on the possible physical properties of the Didymos primary based on observational data and proposes a plausible formation mechanism for this binary system. With a bulk density consistent with observational uncertainty and close to the maximum density allowed for the asteroid, the Didymos primary in certain configurations can remain geo-statically stable without including cohesion.Comment: 66 pages, 24 figures, submitted to Icarus on 25/Aug/201

Cholera with severe renal failure in an Italian tourist returning from Cuba, July 2013

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Polar-Graded Multiferroic SrMnO3 Thin Films

Engineering defects and strains in oxides provides a promising route for the quest of thin film materials with coexisting ferroic orders, multiferroics, with efficient magnetoelectric coupling at room temperature. Precise control of the strain gradient would enable custom tailoring of the multiferroic properties but presently remains challenging. Here we explore the existence of a polar-graded state in epitaxially strained antiferromagnetic SrMnO3 thin films, whose polar nature was predicted theoretically and recently demonstrated experimentally. By means of aberration-corrected scanning transmission electron microscopy we map the polar rotation of the ferroelectric polarization with atomic resolution, both far from and near the domain walls, and find flexoelectricity resulting from vertical strain gradients. The origin of this particular strain state is a gradual distribution of oxygen vacancies across the film thickness, according to electron energy loss spectroscopy. Herein we present a chemistry-mediated route to induce polar rotations in oxygen-deficient multiferroic films, resulting in flexoelectric polar rotations and with potentially enhanced piezoelectricity

Study of the impact of tissue density heterogeneities on 3-dimensional abdominal dosimetry: comparison between dose kernel convolution and direct monte carlo methods.

Dose kernel convolution (DK) methods have been proposed to speed up absorbed dose calculations in molecular radionuclide therapy. Our aim was to evaluate the impact of tissue density heterogeneities (TDH) on dosimetry when using a DK method and to propose a simple density-correction method. METHODS: This study has been conducted on 3 clinical cases: case 1, non-Hodgkin lymphoma treated with (131)I-tositumomab; case 2, a neuroendocrine tumor treatment simulated with (177)Lu-peptides; and case 3, hepatocellular carcinoma treated with (90)Y-microspheres. Absorbed dose calculations were performed using a direct Monte Carlo approach accounting for TDH (3D-RD), and a DK approach (VoxelDose, or VD). For each individual voxel, the VD absorbed dose, D(VD), calculated assuming uniform density, was corrected for density, giving D(VDd). The average 3D-RD absorbed dose values, D(3DRD), were compared with D(VD) and D(VDd), using the relative difference Δ(VD/3DRD). At the voxel level, density-binned Δ(VD/3DRD) and Δ(VDd/3DRD) were plotted against ρ and fitted with a linear regression. RESULTS: The D(VD) calculations showed a good agreement with D(3DRD). Δ(VD/3DRD) was less than 3.5%, except for the tumor of case 1 (5.9%) and the renal cortex of case 2 (5.6%). At the voxel level, the Δ(VD/3DRD) range was 0%-14% for cases 1 and 2, and -3% to 7% for case 3. All 3 cases showed a linear relationship between voxel bin-averaged Δ(VD/3DRD) and density, ρ: case 1 (Δ = -0.56ρ + 0.62, R(2) = 0.93), case 2 (Δ = -0.91ρ + 0.96, R(2) = 0.99), and case 3 (Δ = -0.69ρ + 0.72, R(2) = 0.91). The density correction improved the agreement of the DK method with the Monte Carlo approach (Δ(VDd/3DRD) < 1.1%), but with a lesser extent for the tumor of case 1 (3.1%). At the voxel level, the Δ(VDd/3DRD) range decreased for the 3 clinical cases (case 1, -1% to 4%; case 2, -0.5% to 1.5%, and -1.5% to 2%). No more linear regression existed for cases 2 and 3, contrary to case 1 (Δ = 0.41ρ - 0.38, R(2) = 0.88) although the slope in case 1 was less pronounced. CONCLUSION: This study shows a small influence of TDH in the abdominal region for 3 representative clinical cases. A simple density-correction method was proposed and improved the comparison in the absorbed dose calculations when using our voxel S value implementation

SEOM clinical guidelines for pancreatic and biliary tract cancer (2020)

Pancreatic cancer (PC) and biliary tract cancer (BTC) are both aggressive and highly fatal malignancies. Nowadays we have a profound knowledge about the molecular landscape of these neoplasms and this has allowed new therapeutic options. Surgery is the only potentially curative therapy in both cancers, but disease recurrence is frequent. In PC, adjuvant treatment with mFOLFIRINOX has improved overall survival (OS) and in BTC adjuvant treatment with capecitabine seems to improve OS and relapse-free survival. Concomitant radio-chemotherapy could also be considered following R1 surgery in both neoplasms. Neoadjuvant treatment represents the best option for achieving an R0 resection in borderline PC. Upfront systemic chemotherapy is the treatment of choice in unresectable locally advanced PC and BTC; then locoregional therapy could be considered after an initial period of at least 3-4 months of systemic chemotherapy. In metastatic PC, FOLFIRINOX or Gemcitabine plus nab-paclitaxel have improved OS compared with gemcitabine alone. In metastatic BTC, cisplatin plus gemcitabine constitute the standard treatment. Progress in the knowledge of molecular biology has enabled the identification of new targets for therapy with encouraging results that could in the future improve the survival and quality of life of patients with PC and BTC

HARD PHOTON PRODUCTION IN NUCLEUS-NUCLEUS COLLISIONS AT 30 MeV/u AND 44 MeV/u

Doubly differential cross-sections for Bremsstrahlung production have been measured in the reactions 40Ar + 197Au at 30 MeV/u and 86Kr +12C, AgNat and 197Au at 44 MeV/u. A qualitative analysis of the characteristics of the γ-ray emission suggests strongly that the initial proton-neutron collisions are the main source of nuclear Bremsstrahlung

Nature of antiferromagnetic order in epitaxially strained multiferroic SrMnO3 thin films

Epitaxial films of SrMnO3 and bilayers of SrMnO3/La0.67Sr0.33MnO3 have been deposited by pulsed laser deposition on different substrates, namely, LaAlO3 (001), (LaAlO3)0.3(Sr2AlTaO6)0.7 (001), and SrTiO3 (001), allowing us to perform an exhaustive study of the dependence of antiferromagnetic order and exchange bias field on epitaxial strain. The Néel temperatures (TN) of the SrMnO3 films have been determined by low-energy muon spin spectroscopy. In agreement with theoretical predictions, TN is reduced as the epitaxial strain increases. From the comparison with first-principles calculations, a crossover from G-type to C-type antiferromagnetic orders is proposed at a critical tensile strain of around 1.6±0.1%. The exchange bias (coercive) field, obtained for the bilayers, increases (decreases) by increasing the epitaxial strain in the SrMnO3 layer, following an exponential dependence with temperature. Our experimental results can be explained by the existence of a spin-glass (SG) state at the interface between the SrMnO3 and La0.67Sr0.33MnO3 films. This SG state is due to the competition between the different exchange interactions present in the bilayer and favored by increasing the strain in the SrMnO3 layer