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Dengue disease is caused by four different flavivirus (1) serotypes, which infect 390 million people yearly with 25% symptomatic cases (2) and for which no licensed vaccine is available. Recent phase III vaccine trials showed partial protection, and in particular no protection for dengue virus serotype 2 (refs 3,4). Structural studies so far have characterized only epitopes recognized by serotype-specific human antibodies (5,6). We recently isolated human antibodies potently neutralizing all four dengue virus serotypes (7). Here we describe the X-ray structures of four of these broadly neutralizing antibodies in complex with the envelope glycoprotein E from dengue virus serotype 2, revealing that the recognition determinants are at a serotype-invariant site at the E-dimer interface, including the exposed main chain of the E fusion loop (8) and the two conserved glycan chains. This 'E-dimer-dependent epitope' is also the binding site for the viral glycoprotein prM during virus maturation in the secretory pathway of the infected cell (9), explaining its conservation across serotypes and highlighting an Achilles' heel of the virus with respect to antibody neutralization. These findings will be instrumental for devising novel immunogens to protect simultaneously against all four serotypes of dengue virus., Exposed at the surface of infectious mature dengue virus (DENV) particles, protein E is the sole target of neutralizing antibodies. It displays an icosahedral arrangement in which 90 E dimers [...]

Materials produced by additive manufacturing (AM) often have different microstructures from those obtained using conventional metallurgy (CM), which can have significant impacts on the materials' durability, and in particular, resistance to corrosion. In this study, we were concerned with the susceptibility to pitting and environmentally assisted cracking (EAC) of 17-4PH martensitic stainless steel (MSS). We focused on the evolution from pitting to EAC, and the behaviour of MSS produced by AM was compared with that of its CM counterpart. Potentiodynamic polarisation tests were combined with chronoamperometry measurements performed without and with mechanical loading to study both stable and metastable pitting and the influence of stress on these processes. EAC tests were carried out and combined with observations of fracture surfaces. MSS produced by AM was more resistant to pit initiation due to fewer and finer NbC particles. However, the propagation kinetics of stable pits were higher for this MSS due to a higher amount of reversed austenite. The stress was found to stabilise the metastable pits and to accelerate the propagation of stable pits, which resulted in an increased susceptibility to EAC of the MSS produced by AM. These results clearly highlighted the fact that the reversed austenite amount has to be perfectly controlled in AM processes. [ABSTRACT FROM AUTHOR]

Chikungunya virus (CHIKV) is an emerging mosquito-borne alphavirus that has caused widespread outbreaks of debilitating human disease in the past five years (1). CHIKV invasion of susceptible cells is mediated by two viral glycoproteins, E1 and E2, which carry the main antigenic determinants and form an icosahedral shell at the virion surface. Glycoprotein E2, derived from furin cleavage of the p62 precursor into E3 and E2, is responsible for receptor binding, and E1 for membrane fusion. In the context of a concerted multidisciplinary effort to understand the biology of CHIKV (2), here we report the crystal structures of the precursor p62-E1 heterodimer and of the mature E3-E2-E1 glycoprotein complexes. The resulting atomic models allow the synthesis of a wealth of genetic, biochemical, immunological and electron microscopy data accumulated over the years on alphaviruses in general. This combination yields a detailed picture of the functional architecture of the 25 MDa alphavirus surface glycoprotein shell. Together with the accompanying report on the structure of the Sindbis virus E2-E1 heterodimer at acidic pH (ref. 3), this work also provides new insight into the acid-triggered conformational change on the virus particle and its inbuilt inhibition mechanism in the immature complex., Although the symptoms of the disease were first described in the eighteenth century (4), CHIKV was first isolated only in 1952 during a dengue outbreak in Tanzania (5). The name [...]

Protein PknH possesses an autokinase activity and belongs to large STPK family found in macobacterium tuberculosis. EmbR possesses an FHA domain, a newly described phosphoprotein recognition domain, which plays an essential role in PknH-EmbR interaction and phosphorylation of EmbR by PknH.

The porosity of the anodic films grown on aluminium substrates depends on various operating conditions related to the anodization electrolyte and to the applied electrical parameters, as well as to the substrate itself. In the present study, three different aluminium substrates were studied and anodized: AA 1050 (rolled; thickness = 1 mm), AA 2024 T3 (rolled; 1 mm), and AA 2024 T3 (machined; 3 mm). For each type of anodic film, the porosity, as well as its changes during anodization, was accurately characterized using both field‐emission gun scanning electron microscopy (FEG‐SEM) and a reanodization technique. Moreover, for the first time, the corresponding tortuosity was quantified for all studied substrates. Results for rolled AA 2024 T3 and for machined AA 2024 T3 especially showed significant differences in tortuosity values, contributing towards clarifying, in part, their different wettability characteristics or anticorrosion behaviour, so far not clearly explained. [ABSTRACT FROM AUTHOR]

Background: Several studies have shown that NNRTI/PI-based triple therapy could be safely administered as a 4 days (4D) or 5 days (5D) a week maintenance strategy. We report here our experience of using an integrase inhibitor (INSTI)-based 4D/5D regimen in virologically suppressed HIV patients.Methods: This cohort study enrolled adult patients on ART with viral load (VL) <50 copies/mL for >1 year, who switched to an INSTI-based triple regimen given 4D/5D a week. The primary endpoint was the virological efficacy rate at Week (W) 48, with virological failure defined as confirmed VL ≥50 copies/mL.Results: A total of 73 patients were included (n = 28 for 4D, n = 45 for 5D): 54 men (74%), median (IQR) age 51 (45-57) years, ART duration 10 (6-18) years and duration of viral suppression 5 (2-9) years at baseline. As of 25 March 2019, the median follow-up was 21 (14-35) months, with a total of 161 patient-years of follow-up; all patients had reached the W24 visit, 66 (90%) W48 and 34 (47%) W96. Four patients discontinued the strategy: virological failure (n = 2) at W60 and W67, respectively, switch for renal toxicity (n = 1) at W28 and switch to rilpivirine/dolutegravir (n = 1) at W65. Overall the rate of virological success (95% CI) was 100% (94%-100%) at W24 and W48 and 93.7% (79.8%-98.2%) at W96.Conclusions: While waiting for the final results of the large randomized QUATUOR ANRS-170 study, our real-life results suggest that the use of an intermittent maintenance triple-drug regimen given as a weekend (2 or 3 days) off is as effective with an INSTI-based regimen as with a PI or an NNRTI. [ABSTRACT FROM AUTHOR]

Background: Enadenotucirev (formerly ColoAd1) is a tumor-selective chimeric adenovirus with demonstrated preclinical activity. This phase 1 Mechanism of Action study assessed intravenous (IV) delivery of enadenotucirev in patients with resectable colorectal cancer (CRC), non-small-cell lung cancer (NSCLC), urothelial cell cancer (UCC), and renal cell cancer (RCC) with a comparator intratumoral (IT) dosed CRC patient cohort. Methods: Seventeen patients scheduled for primary tumor resection were enrolled. IT injection of enadenotucirev (CRC only) was administered as a single dose (≤ 3 × 1011 viral particles [vp]) on day 1, followed by resection during days 8-15. IV infusion of enadenotucirev was administered by three separate doses (1 × 1012 vp) on days 1, 3, and 5, followed by resection during days 8-15 (CRC) or days 10-25 (NSCLC, UCC, and RCC). Enadenotucirev activity was measured using immunohistochemical staining of nuclear viral hexon and quantitative polymerase chain reaction for viral genomic DNA. Results: Delivery of enadenotucirev was observed in most tumor samples following IV infusion, with little or no demonstrable activity in normal tissue. This virus delivery (by both IV and IT dosing) was accompanied by high local CD8+ cell infiltration in 80% of tested tumor samples, suggesting a potential enadenotucirev-driven immune response. Both methods of enadenotucirev delivery were well tolerated, with no treatment-associated serious adverse events. Conclusions: This study provides key delivery and feasibility data to support the use of IV infusion of enadenotucirev, or therapeutic transgene-bearing derivatives of it, in clinical trials across a range of epithelial tumors, including the ongoing combination study of enadenotucirev with the checkpoint inhibitor nivolumab. It also provides insights into the potential immune-stimulating properties of enadenotucirev. [ABSTRACT FROM AUTHOR]

Understanding the structural basis of actin cytoskeleton remodeling requires stabilization of actin monomers, oligomers, and filaments in complex with partner proteins, using various biochemical strategies. Here, we report a dramatic destabilization of the dynamic interaction with a model β-thymosin/WH2 domain induced by mutations in actin. This result underlines that mutant actins should be used with prudence to characterize interactions with intrinsically disordered partners as destabilization of dynamic interactions, although identifiable by NMR, may be invisible to other structural techniques. It also highlights how both β-thymosin/WH2 domains and actin tune local structure and dynamics in regulatory processes involving intrinsically disordered domains. [ABSTRACT FROM AUTHOR]

This study deals with propagation kinetics of intergranular corrosion defects. It complements previous works focused on the development of a procedure called "T2C (Tensile Test for Corrosion)." This procedure was previously applied on samples of 2024 alloy submitted to a continuous immersion test in 1MNaCl solution. The aim of the present study was to determine if a modification in the way in which the samples are corroded impacts the ability to use this procedure. Therefore, the applicability of the T2C procedure to cyclic corrosion tests was evaluated. Intergranular corrosion defects developed during cyclic corrosion tests were characterized by using a statistical approach. The geometry of the tensile specimens was optimized to allow the T2C procedure to be applied in conditions expected as adequate. Results showed that, for cyclic corrosion tests, due to the branched morphology of the intergranular corrosion defects and the effects of hydrogen embrittlement, the T2C procedure cannot provide an estimation of the mean depth of the intergranular corrosion defects. However, depending on the cyclic corrosion tests, it allowed the maximal depth of the intergranular corrosion defects or the thickness of the corrosion-induced damage zone (defects + hydrogen affected zone) to be determined. [ABSTRACT FROM AUTHOR]

Microstructural states produced by each step of the manufacturing process leading to the production of automotive strand arms in 6101 aluminum alloy (AA6101) for wiring harnesses were investigated in relation to their corrosion behavior in NaCl solution. The observed corrosion morphology, i.e., pitting corrosion or intergranular corrosion, was strongly dependent on the precipitation state, i.e., mainly the presence of intergranular Mg2Si precipitates. A 'grain size - corrosion resistance' relationship was also evidenced with an ennoblement of the corrosion potential for wires heavily cold drawn, which were characterized by a nanometric grain size. Dislocation density as well as the homogeneity of alloying element distribution were also found to be relevant parameters for explaining the electrochemical behavior of each microstructural state. Plastic deformation and recrystallization phenomena occurring during the manufacturing process were found to be associated with redistribution of alloying elements, which impeded the formation of intergranular Mg2Si precipitates. Therefore, in the present study, the cold drawing process was found to increase the intergranular corrosion resistance of AA6101. [ABSTRACT FROM AUTHOR]

The corrosion behavior of a Friction Stir Welding joint in 2050-T3 Al-Cu-Li alloy was studied in 1 M NaCl solution and the influence of T8 post-welding heat treatment on its corrosion susceptibility was analyzed. After exposure to 1 M NaCl solution, the heat affected zone (HAZ) of the weld without post-welding heat treatment was found to be the most extensively corroded zone with extended intergranular corrosion damage while, following T8 post-welding heat treatment, no intergranular corrosion was observed in the HAZ and the global corrosion behavior of the weld was significantly improved. The corrosion damage observed on the welded joints after immersion in 1 M NaCl solution was compared to that obtained after 750 h Mastmaasis Wet Bottom tests. The same corrosion damage was observed. Various stationary electrochemical tests were carried out on the global welded joint and/or each of the metallurgical zones of the welded joint to understand the corrosion damage observed. TEM observations helped in bringing meaningful elements to analyze the intrinsic electrochemical behavior of the different zones of the weld related to their microstructure. However, galvanic coupling tests showed that galvanic coupling effects between the different zones of the weld were at least partially responsible for its corrosion behavior. [ABSTRACT FROM AUTHOR]

In the present work, a first attempt was made to determine propagation laws of intergranular corrosion defects for Al 2024 T351 in various NaCl solutions as a first step for future predictive modeling of 2024 alloy. In a first step, the effect of chloride concentration on the susceptibility to intergranular corrosion of 2024 alloy was studied using current-potential curves. In a second step, conventional immersion tests were performed in chloride-containing solutions and statistical analysis was carried out to determine the depth of the intergranular corrosion defects, depending on the chloride concentration and on the immersion time. The results were compared to those obtained by measuring the load to failure of precorroded tensile specimens versus preimmersion time in a chloride solution. The latter method was selected to measure the depth of the intergranular defects even though results showed that it was not possible to use it for chloride concentrations higher than 3 M and immersion times longer than 1200 h, considering the chloride concentrations and the durations of immersion studied in this work. Thus, empirical propagation laws are proposed for chloride contents as high as 3 M and immersion times as long as 1200 h. [ABSTRACT FROM AUTHOR]

The dissolution mechanism of S-phase particles in 2024-T35t aluminum alloy at open-circuit potential in chloride-containing sulfate solutions was investigated using atomic force microscopy (AFM), scanning Kelvin probe force microscopy (SKPFM), and secondary ion mass spectroscopy (SIMS). The combination of the three techniques allowed the correlation between SKPFM measurements and the corrosion behavior of AA2024 to be confirmed, leading to a better understanding of the electrochemical behavior of S-phase particles. A three-step mechanism for the dissolution and accompanying processes occurring near S particles was proposed: (i) preferential aluminum and magnesium dissolution, (ii) galvanic coupling between the copper-enriched particles and the surrounding matrix, leading to an increased passivity of the matrix around the particles, and (iii) copper deposition around the corroded particles. [ABSTRACT FROM AUTHOR]

The corrosion behavior of a pure aluminum/pure copper couple in a weakly conductive sulfate solution was investigated. Potential and current distributions on the surface of the model couple at the beginning of immersion were obtained by solving the Laplace equation using a finite element method (FEM) algorithm. The potential distribution predicted by the calculations was checked using a Ag/AgCl microreference electrode. A good agreement was found between experimental and theoretical results. It was shown that the reaction occurring at the copper electrode was oxygen reduction, while aluminum remote from the Al/Cu interface remained in the passive state. Moreover, calculations predicted a large cathodic current, related to an increase in oxygen reduction, restricted to copper at the Al/Cu interface. This led to a local pH increase reaching values higher than 9, allowing the dissolution of aluminum to occur close to the interface. Combining these data with optical and scanning electron microscope observations after 24 h of immersion in the sodium sulfate solution allowed a three-step mechanism to be proposed to explain the corrosion damage, and particularly the presence of a copper deposit on the aluminum surface, some distance from the Al/Cu interface, a phenomenon currently observed in commercial copper-rich aluminum alloys. [ABSTRACT FROM AUTHOR]