A theoretical link between gradient and nonlocal elasticity models, including higher order boundary conditions

The paper presents a recently developed rational derivation of the strain gradient elasticity model from the nonlocal (or integral) model. This kind of derivations are generally recovered just by an expansion into a Taylor series of the nonlocal strain field up to a certain order, and then operating the integration (or averaging) over the spatial interaction domain. The latter procedure is fully consistent when the analysis is performed over an unbounded domain, but when a classical bounded domain is analyzed it lacks in reproducing the so-called higher-order boundary conditions. In the present contributions the complete derivation is achieved employing an extended version of the Principle of Virtual Power (PVP), written in a special form in order to comply with the nonsimple nature of the nonlocal material. Namely, extra terms are invoked in both internal and external virtual power

Symmetric Galerkin boundary element method.

This review concerns a methodology for solving numerically, to engineering purposes, boundary and initial-boundary value roblems by a peculiar approach characterized by the following features: the continuous formulation is centered on integral equations based on the combined use of single-layer and double-layer sources, so that the integral operator turns out to be symmetric with respect to a suitable bilinear form; the discretization is performed either on a variational basis or by a Galerkin weighted residual procedure, the interpolation and weight functions being chosen so that the variables in the approximate formulation are generalized variables in Prager's sense. As main consequences of the above provisions, symmetry is exhibited by matrices with a key role in the algebraized versions, some quadratic forms have a clear energy meaning, variational properties characterize the solutions and other results, invalid in traditional boundary element methods, enrich the theory underlying the computational applications. The present survey outlines recent theoretical and computational developments of the title methodology with particular reference to linear elasticity, elastoplasticity, fracture mechanics, time-dependent problems, variational approaches, singular integrals, approximation issues, sensitivity analysis, coupling of boundary and finite elements, computer implementations. Areas and aspects which at present require further research are dentified and comparative assessments are attempted with respect to traditional boundary integral-element methods

Strain gradient elasticity within the symmetric BEM formulation

The symmetric Galerkin Boundary Element Method is used to address a class of strain gradient elastic materials featured by a free energy function of the (classical) strain and of its (first) gradient. With respect to the classical elasticity, additional response variables intervene, such as the normal derivative of the displacements on the boundary, and the work-coniugate double tractions. The fundamental solutions - featuring a fourth order partial differential equations (PDEs) system - exhibit singularities which in 2D may be of the order 1/ r 4 . New techniques are developed, which allow the elimination of most of the latter singularities. The present paper has to be intended as a research communication wherein some results, being elaborated within a more general paper [1], are reported

Dislocations and cracks in generalized continua

Dislocations play a key role in the understanding of many phenomena in solid state physics, materials science, crystallography and engineering. Dislocations are line defects producing distortions and self-stresses in an otherwise perfect crystal lattice. In particular, dislocations are the primary carrier of crystal plasticity and in dislocation based fracture mechanics.Comment: arXiv admin note: text overlap with arXiv:1708.0529

miR-34a Promotes Vascular Smooth Muscle Cell Calcification by Downregulating SIRT1 (Sirtuin 1) and Axl (AXL Receptor Tyrosine Kinase).

Objective- Vascular calcification (VC) is age dependent and a risk factor for cardiovascular and all-cause mortality. VC involves the senescence-induced transdifferentiation of vascular smooth muscle cells (SMCs) toward an osteochondrogenic lineage resulting in arterial wall mineralization. miR-34a increases with age in aortas and induces vascular SMC senescence through the modulation of its target SIRT1 (sirtuin 1). In this study, we aimed to investigate whether miR-34a regulates VC. Approach and Results- We found that miR-34a and Runx2 (Runt-related transcription factor 2) expression correlates in young and old mice. Mir34a <sup>+/+</sup> and Mir34a <sup>-/-</sup> mice were treated with vitamin D, and calcium quantification revealed that Mir34a deficiency reduces soft tissue and aorta medial calcification and the upregulation of the VC Sox9 (SRY [sex-determining region Y]-box 9) and Runx2 and the senescence p16 and p21 markers. In this model, miR-34a upregulation was transient and preceded aorta mineralization. Mir34a <sup>-/-</sup> SMCs were less prone to undergo senescence and under osteogenic conditions deposited less calcium compared with Mir34a <sup>+/+</sup> cells. Furthermore, unlike in Mir34a <sup>+/+</sup> SMC, the known VC inhibitors SIRT1 and Axl (AXL receptor tyrosine kinase) were only partially downregulated in calcifying Mir34a <sup>-/-</sup> SMC. Strikingly, constitutive miR-34a overexpression to senescence-like levels in human aortic SMCs increased calcium deposition and enhanced Axl and SIRT1 decrease during calcification. Notably, we also showed that miR-34a directly decreased Axl expression in human aortic SMC, and restoration of its levels partially rescued miR-34a-dependent growth arrest. Conclusions- miR-34a promotes VC via vascular SMC mineralization by inhibiting cell proliferation and inducing senescence through direct Axl and SIRT1 downregulation, respectively. This miRNA could be a good therapeutic target for the treatment of VC

Determinants of passive antibody efficacy in SARS-CoV-2 infection: a systematic review and meta-analysis

Background: Randomised controlled trials of passive antibodies as treatment and prophylaxis for COVID-19 have reported variable efficacy. However, the determinants of efficacy have not been identified. We aimed to assess how the dose and timing of administration affect treatment outcome. Methods: In this systematic review and meta-analysis, we extracted data from published studies of passive antibody treatment from Jan 1, 2019, to Jan 31, 2023, that were identified by searching multiple databases, including MEDLINE, PubMed, and ClinicalTrials.gov. We included only randomised controlled trials of passive antibody administration for the prevention or treatment of COVID-19. To compare administered antibody dose between different treatments, we used data on in-vitro neutralisation titres to normalise dose by antibody potency. We used mixed-effects regression and model fitting to analyse the relationship between timing, dose and efficacy. Findings: We found 58 randomised controlled trials that investigated passive antibody therapies for the treatment or prevention of COVID-19. Earlier clinical stage at treatment initiation was highly predictive of the efficacy of both monoclonal antibodies (p<0·0001) and convalescent plasma therapy (p=0·030) in preventing progression to subsequent stages, with either prophylaxis or treatment in outpatients showing the greatest effects. For the treatment of outpatients with COVID-19, we found a significant association between the dose administered and efficacy in preventing hospitalisation (relative risk 0·77; p<0·0001). Using this relationship, we predicted that no approved monoclonal antibody was expected to provide more than 30% efficacy against some omicron (B.1.1.529) subvariants, such as BQ.1.1. Interpretation: Early administration before hospitalisation and sufficient doses of passive antibody therapy are crucial to achieving high efficacy in preventing clinical progression. The relationship between dose and efficacy provides a framework for the rational assessment of future passive antibody prophylaxis and treatment strategies for COVID-19. Funding: The Australian Government Department of Health, Medical Research Future Fund, National Health and Medical Research Council, the University of New South Wales, Monash University, Haematology Society of Australia and New Zealand, Leukaemia Foundation, and the Victorian Government

Human immunotypes impose selection on viral genotypes through viral epitope specificity

BACKGROUND: Understanding the genetic interplay between human hosts and infectious pathogens is crucial for how we interpret virulence factors. Here, we tested for associations between HIV and host genetics, and interactive genetic effects on viral load (VL) in HIV+ ART-naive clinical trial participants. METHODS: HIV genomes were sequenced and the encoded amino acid (AA) variants were associated with VL, human single nucleotide polymorphisms (SNPs) and imputed HLA alleles, using generalized linear models with Bonferroni correction. RESULTS: Human (388,501 SNPs) and HIV (3,010 variants) genetic data was available for 2,122 persons. Four HIV variants were associated with VL (p-values<1.66×10 -5). Twelve HIV variants were associated with a range of 1-512 human SNPs (p-value<4.28×10 -11). We found 46 associations between HLA alleles and HIV variants (p-values<1.29×10 -7). We found HIV variants and immunotypes when analyzed separately, were associated with lower VL, whereas the opposite was true when analyzed in concert. Epitope binding prediction showed HLA alleles to be weaker binders of associated HIV AA variants relative to alternative variants on the same position. CONCLUSIONS: Our results show the importance of immunotype specificity on viral antigenic determinants, and the identified genetic interplay puts emphasis that viral and human genetics should be studied in the context of each other

Design and implementation of an international, multi-arm, multi-stage platform master protocol for trials of novel SARS-CoV-2 antiviral agents: Therapeutics for Inpatients with COVID-19 (TICO/ACTIV-3)

BACKGROUND/AIMS: Safe and effective therapies for COVID-19 are urgently needed. In order to meet this need, the Accelerating COVID-19 Therapeutic Interventions and Vaccines public-private partnership initiated the Therapeutics for Inpatients with COVID-19. Therapeutics for Inpatients with COVID-19 is a multi-arm, multi-stage platform master protocol, which facilitates the rapid evaluation of the safety and efficacy of novel candidate antiviral therapeutic agents for adults hospitalized with COVID-19. Five agents have so far entered the protocol, with rapid answers already provided for three of these. Other agents are expected to enter the protocol throughout 2021. This protocol contains a number of key design and implementation features that, along with challenges faced by the protocol team, are presented and discussed. METHODS: Three clinical trial networks, encompassing a global network of clinical sites, participated in the protocol development and implementation. Therapeutics for Inpatients with COVID-19 utilizes a multi-arm, multi-stage design with an agile and robust approach to futility and safety evaluation at 300 patients enrolled, with subsequent expansion to full sample size and an expanded target population if the agent shows an acceptable safety profile and evidence of efficacy. Rapid recruitment to multiple agents is enabled through the sharing of placebo, the confining of agent-specific information to protocol appendices, and modular consent forms. In collaboration with the Food and Drug Administration, a thorough safety data collection and Data and Safety Monitoring Board schedule was developed for the study of potential therapeutic agents with limited in-human data in hospitalized patients with COVID-19. RESULTS: As of 8 August 2021, five agents have entered the Therapeutics for Inpatients with COVID-19 master protocol and a total of 1909 participants have been randomized to one of these agents or matching placebo. There were a number of challenges faced by the study team that needed to be overcome in order to successfully implement Therapeutics for Inpatients with COVID-19 across a global network of sites. These included ensuring drug supply and reliable recruitment allowing for changing infection rates across the global network of sites, the need to balance the collection of data and samples without overburdening clinical staff and obtaining regulatory approvals across a global network of sites. CONCLUSION: Through a robust multi-network partnership, the Therapeutics for Inpatients with COVID-19 protocol has been successfully used across a global network of sites for rapid generation of efficacy data on multiple novel antiviral agents. The protocol design and implementation features used in this protocol, and the approaches to address challenges, will have broader applicability. Mechanisms to facilitate improved communication and harmonization among country-specific regulatory bodies are required to achieve the full potential of this approach in dealing with a global outbreak

Biomarker-indicated extent of oxidation of plant-derived organic carbon (OC) in relation to geomorphology in an arsenic contaminated Holocene aquifer, Cambodia

The poisoning of rural populations in South and Southeast Asia due to high groundwater arsenic concentrations is one of the world’s largest ongoing natural disasters. It is important to consider environmental processes related to the release of geogenic arsenic, including geomorphological and organic geochemical processes. Arsenic is released from sediments when iron-oxide minerals, onto which arsenic is adsorbed or incorporated, react with organic carbon (OC) and the OC is oxidised. In this study we build a new geomorphological framework for Kandal Province, a highly studied arsenic affected region of Cambodia, and tie this into wider regional environmental change throughout the Holocene. Analyses shows that the concentration of OC in the sediments is strongly inversely correlated to grainsize. Furthermore, the type of OC is also related to grain size with the clay containing mostly (immature) plant derived OC and sand containing mostly thermally mature derived OC. Finally, analyses indicate that within the plant derived OC relative oxidation is strongly grouped by stratigraphy with the older bound OC more oxidised than younger OC

Field, Experimental, and Modeling Study of Arsenic Partitioning across a Redox Transition in a Bangladesh Aquifer

To understand redox-dependent arsenic partitioning, we performed batch sorption and desorption experiments using aquifer sands subjected to chemical and mineralogical characterization. Sands collected from the redox transition zone between reducing groundwater and oxic river water at the Meghna riverbank with HCl extractable Fe(III)/Fe ratio ranging from 0.32 to 0.74 are representative of the redox conditions of aquifers common in nature. One brown suboxic sediment displayed a partitioning coefficient (K_d) of 7-8 L kg^-1 at equilibrium with 100 μg L^-1 As(III), while two gray reducing sediments showed K_d of 1-2 L kg^-1. Lactate amendment to aquifer sands containing 91 mg kg^-1 P-extractable As resulted in the reduction of As and Fe with sediment Fe(III)/Fe decreasing from 0.54 to 0.44, and mobilized an equivalent of 64 mg kg^-1 As over a month. Desorption of As from nonlactate-amended sediment was negligible with little change in sediment Fe(III)/Fe. This release of As is consistent with microbial reduction of Fe(III) oxyhydroxides and the resulting decrease in the number of surface sites on Fe(III) oxyhydroxides. Arsenic partitioning (K_d) in iron-rich, sulfur-poor aquifers with circumneutral pH is redox-dependent and can be estimated by HCl leachable sediment Fe(III)/Fe ratio with typical Fe concentrations