Massive damage generation accompanying pyramidal slip in hexagonal-close packed magnesium: an origin for its high hardening and brittleness

Mg represents a group of technically important hexagonal-close packed (hcp) metals whose mechanical behaviors are very different from body-centered cubic (bcc) and face-centered cubic (fcc) metals and the underlying mechanisms remain poorly-understood. It has been long known that Mg has high hardening and low ductility, and this was conventionally attributed to the scarce of active pyramidal slip. Recently immobilization of pyramidal dislocations was proposed to be the origins. Here we present a different scenario that has hitherto never been reported for Mg: mobile screw pyramidal dislocations double cross-slip and continue to double cross-slip as they glide, generating abundant vacancy clusters on the slipped planes. These vacancy clusters hinder subsequent dislocation motion and thus directly result in hardening; their accumulation as plastic deformation proceeds eventually causes premature fracture, i.e. brittleness. The massive damage accompanying pyramidal slip discovered here provides a different explanation for the long known hardening and brittleness of Mg, and suggests that sufficient amount of pyramidal dislocations could still be insufficient to effectively accommodate plasticity. Stabilizing pyramidal dislocation motion to avoid cross-slip and subsequent damage generation is also essential for property-improvement. The instability of pyramidal slip, manifested as continuous cross-slip here (could be different elsewhere), originates from its huge Burgers vector and could be a common feature of its kind. The detailed cross-slip mechanism also provides insights into the poorly known instabilities and complicated behavior of dislocations in a broader range of crystals with low symmetry and/or large Burgers vectors, including other hcp metals and ceramics.Comment: 32 pages, 6 figure

Genetic incorporation of the protein transduction domain of Tat into Ad5 fiber enhances gene transfer efficacy

<p>Abstract</p> <p>Background</p> <p>Human adenovirus serotype 5 (Ad5) has been widely explored as a gene delivery vector for a variety of diseases. Many target cells, however, express low levels of Ad5 native receptor, the Coxsackie-Adenovirus Receptor (CAR), and thus are resistant to Ad5 infection. The Protein Transduction Domain of the HIV Tat protein, namely PTD_tat, has been shown to mediate protein transduction in a wide range of cells. We hypothesize that re-targeting Ad5 vector via the PTD_tatmotif would improve the efficacy of Ad5-mediated gene delivery.</p> <p>Results</p> <p>In this study, we genetically incorporated the PTD_tatmotif into the knob domain of Ad5 fiber, and rescued the resultant viral vector, Ad5.PTD_tat. Our data showed the modification did not interfere with Ad5 binding to its native receptor CAR, suggesting Ad5 infection via the CAR pathway is retained. In addition, we found that Ad5.PTD_tatexhibited enhanced gene transfer efficacy in all of the cell lines that we have tested, which included both low-CAR and high-CAR decorated cells. Competitive inhibition assays suggested the enhanced infectivity of Ad5.PTD_tatwas mediated by binding of the positively charged PTD_tatpeptide to the negatively charged epitopes on the cells' surface. Furthermore, we investigated <it>in vivo </it>gene delivery efficacy of Ad5.PTD_tatusing subcutaneous tumor models established with U118MG glioma cells, and found that Ad5.PTD_tatexhibited enhanced gene transfer efficacy compared to unmodified Ad5 vector as analyzed by a non-invasive fluorescence imaging technique.</p> <p>Conclusion</p> <p>Genetic incorporation of the PTD_tatmotif into Ad5 fiber allowed Ad5 vectors to infect cells via an alternative PTD_tattargeting motif while retaining the native CAR-mediated infection pathway. The enhanced infectivity was demonstrated in both cultured cells and in <it>in vivo </it>tumor models. Taken together, our study identifies a novel tropism expanded Ad5 vector that may be useful for clinical gene therapy applications.</p

The instantly blocking-based fluorescent immunochromatographic assay for the detection of SARS-CoV-2 neutralizing antibody

IntroductionAt present, there is an urgent need for the rapid and accurate detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neutralizing antibodies (NAbs) to evaluate the ability of the human body to resist coronavirus disease 2019 (COVID-19) after infection or vaccination. The current gold standard for neutralizing antibody detection is the conventional virus neutralization test (cVNT), which requires live pathogens and biosafety level-3 (BSL-3) laboratories, making it difficult for this method to meet the requirements of large-scale routine detection. Therefore, this study established a time-resolved fluorescence-blocking lateral flow immunochromatographic assay (TRF-BLFIA) that enables accurate, rapid quantification of NAbs in subjects.MethodsThis assay utilizes the characteristic that SARS-CoV-2 neutralizing antibody can specifically block the binding of the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein and angiotensin-converting enzyme 2 (ACE2) to rapidly detect the content of neutralizing antibody in COVID-19-infected patients and vaccine recipients.ResultsWhen 356 samples of vaccine recipients were measured, the coincidence rate between this method and cVNT was 88.76%, which was higher than the coincidence rate of 76.97% between cVNT and a conventional chemiluminescence immunoassay detecting overall binding anti-Spike-IgG. More importantly, this assay does not need to be carried out in BSL-2 or 3 laboratories.DiscussionTherefore, this product can detect NAbs in COVID-19 patients and provide a reference for the prognosis and outcome of patients. Simultaneously, it can also be applied to large-scale detection to better meet the needs of neutralizing antibody detection after vaccination, making it an effective tool to evaluate the immunoprotective effect of COVID-19 vaccines

Derivation of a Triple Mosaic Adenovirus for Cancer Gene Therapy

A safe and efficacious cancer medicine is necessary due to the increasing population of cancer patients whose particular diseases cannot be cured by the currently available treatment. Adenoviral (Ad) vectors represent a promising therapeutic medicine for human cancer therapy. However, several improvements are needed in order for Ad vectors to be effective cancer therapeutics, which include, but are not limited to, improvement of cellular uptake, enhanced cancer cell killing activity, and the capability of vector visualization and tracking once injected into the patients. To this end, we attempted to develop an Ad as a multifunctional platform incorporating targeting, imaging, and therapeutic motifs. In this study, we explored the utility of this proposed platform by generating an Ad vector containing the poly-lysine (pK), the herpes simplex virus type 1 (HSV-1) thymidine kinase (TK), and the monomeric red fluorescent protein (mRFP1) as targeting, tumor cell killing, and imaging motifs, respectively. Our study herein demonstrates the generation of the triple mosaic Ad vector with pK, HSV-1 TK, and mRFP1 at the carboxyl termini of Ad minor capsid protein IX (pIX). In addition, the functionalities of pK, HSV-1 TK, and mRFP1 proteins on the Ad vector were retained as confirmed by corresponding functional assays, indicating the potential multifunctional application of this new Ad vector for cancer gene therapy. The validation of the triple mosaic Ad vectors also argues for the ability of pIX modification as a base for the development of multifunctional Ad vectors

HIV Antigen Incorporation within Adenovirus Hexon Hypervariable 2 for a Novel HIV Vaccine Approach

Adenoviral (Ad) vectors have been used for a variety of vaccine applications including cancer and infectious diseases. Traditionally, Ad-based vaccines are designed to express antigens through transgene expression of a given antigen. However, in some cases these conventional Ad-based vaccines have had sub-optimal clinical results. These sub-optimal results are attributed in part to pre-existing Ad serotype 5 (Ad5) immunity. In order to circumvent the need for antigen expression via transgene incorporation, the “antigen capsid-incorporation” strategy has been developed and used for Ad-based vaccine development in the context of a few diseases. This strategy embodies the incorporation of antigenic peptides within the capsid structure of viral vectors. The major capsid protein hexon has been utilized for these capsid incorporation strategies due to hexon's natural role in the generation of anti-Ad immune response and its numerical representation within the Ad virion. Using this strategy, we have developed the means to incorporate heterologous peptide epitopes specifically within the major surface-exposed domains of the Ad capsid protein hexon. Our study herein focuses on generation of multivalent vaccine vectors presenting HIV antigens within the Ad capsid protein hexon, as well as expressing an HIV antigen as a transgene. These novel vectors utilize HVR2 as an incorporation site for a twenty-four amino acid region of the HIV membrane proximal ectodomain region (MPER), derived from HIV glycoprotein gp41 (gp41). Our study herein illustrates that our multivalent anti-HIV vectors elicit a cellular anti-HIV response. Furthermore, vaccinations with these vectors, which present HIV antigens at HVR2, elicit a HIV epitope-specific humoral immune response

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Inverse hall-petch relationship in nanocrystalline tantalum

Tantalum polycrystals (grain sizes varying from 2.5 to 30 nm) generated by Voronoi tessellation were subjected to tension and compression under uniaxial strain loading at strain rates on the order of 108–109 s−1 using molecular dynamics (MD) simulations. In contrast with MD simulations of FCC metals, the response in tension is significantly different from that in compression. In tension, fracture is initiated at grain boundaries perpendicular to the loading direction. It propagates along grain boundaries with limited plastic deformation, at a stress in the range 10–14 GPa. This brittle intergranular failure is a consequence of the high strain rate imposed by MD, leading to a stress that exceeds the grain-boundary cohesive strength. Thus, grain-boundary separation is the principal failure mechanism. In compression, on the other hand, there is considerable plastic deformation within the grains. This occurs at stresses higher than failure in tension. The difference between tensile and compressive response for tantalum is attributed to the difficulty in generating dislocations, in contrast with FCC metals, where tensile failure occurs by void nucleation at grain boundaries associated with partial and perfect dislocation emission. In BCC tantalum, both grain-boundary sliding and dislocation emission are much more difficult. The compressive yield stress is found to increase with grain size in the 2.5 nmThe compressive yield stress is found to increase with grain size in the 2.5 nm<d <30 nm region. This inverse Hall?Petch relationship is analyzed in terms of the contributions of dislocation motion and grain-boundary shear to plastic deformation. As the grain size is increased the contribution of grain-boundary sliding is decreased and plastic strain is accommodated by dislocation and motion. In tensile deformation, on the other hand, this behavior is not observed.Fil: Tang, Yizhe. University Of California At San Diego; Estados Unidos;Fil: Bringa, Eduardo Marcial. Universidad Nacional de Cuyo. Facultad de Ciencias Exactas y Naturales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Mendoza; ArgentinaFil: Meyers, Marc A.. University Of California At San Diego; Estados Unidos