Particle breakage criteria in discrete-element modelling

Previous work by the authors, using the discrete element method (DEM) has used the octahedral shear stress within a sphere together with a Weibull distribution of strengths and a size effect on average strength, to determine whether fracture occurs or not. This leads to fractal particle size distributions and a normal compression line which are consistent with experimental data. However there is no agreement in the literature as to what the fracture criterion should be and as yet it is not clear whether other criteria could lead to the correct evolution of voids ratio and particle size distribution under increasing stress. Various possibilities for the criterion have been studied in detail here to ascertain whether these other criteria may give the correct behaviour under normal compression. The use of the major principal stress within a particle, the mean stress, and the stress calculated from the maximum contact force on a particle are each investigated as alternatives to the octahedral shear stress. Only the criterion based on the maximum contact force is shown to give behaviour observed experimentally and the simulations shed further insight into the micro mechanics of normal compression

Force attractor in confined comminution of granular materials.

We reveal a novel attractor in the space of contact forces that bounds the behavior of granular materials during confined comminution. The attractor is reached asymptotically as the porosity reduces and the grain size distribution attains an ultimate power law scaling. The ultimate distribution of the contact forces follows a clear log-normal distribution, distinctively different from previous observations in uncrushable systems. Supporting evidence comes both from comprehensive discrete element simulations and a theoretical Apollonian model

SV40 Assembly In Vivo

The Simian virus 40 (SV40) capsid is a T = 7d icosahedral lattice ∼45 nm in diameter surrounding the ∼5 kb circular minichromosome. The outer shell is composed of 360 monomers of the major capsid protein VP1, tightly bound in 72 pentamers. VP1 is a jellyroll β-barrel, with extending N- and C-terminal arms. The N-terminal arms bind DNA and face the interior of the capsid. The flexible C-arms tie together the 72 pentamers in three distinct kinds of interactions, thus facilitating the formation of a T = 7 icosahedron from identical pentameric building blocks. Assembly in vivo was shown to occur by addition of capsomers around the DNA. We apply a combination of biochemical and genetic approaches to study SV40 assembly. Our in vivo and in vitro studies suggest the following model: one or two capsomers bind at a high affinity to ses, the viral DNA encapsidation signal, forming the nucleation centre for assembly. Next, multiple capsomers attach concomitantly, at lower affinity, around the minichromosome. This increases their local concentration facilitating rapid, cooperative assembly reaction. Formation of the icosahedron proceeds either by gradual addition of single pentamers to the growing shell or by concerted assembly of pentamer clusters

DEM of triaxial tests on crushable sand

This paper presents simulations of high-pressure triaxial shear tests on a crushable sand. The discrete element method is used, featuring a large number of particles and avoiding the use of agglomerates. The triaxial model features a flexible membrane, therefore allowing realistic deformation, and a simple breakage mechanism is implemented using the octahedral shear stress induced in the particles. The simulations show that particle crushing is essential to replicate the realistic behaviour of sand (in particular the volumetric contraction) in high-pressure shear tests. The general effects of crushing during shear are explored, including its effects on critical states, and the influence of particle strength and confining pressure on the degree of crushing are discussed

DEM of triaxial tests on crushable cemented sand

Using the discrete element method, triaxial simulations of cemented sand consisting of crushable particles are presented. The triaxial model used features a flexible membrane, allowing realistic deformation to occur, and cementation is modelled using inter-particle bonds. The effects of particle crushing are explored, as is the influence of cementation on the behaviour of the soil. An insight to the effects that cementation has on the degree of crushing is presented

‘Multi-Epitope-Targeted’ Immune-Specific Therapy for a Multiple Sclerosis-Like Disease via Engineered Multi-Epitope Protein Is Superior to Peptides

Antigen-induced peripheral tolerance is potentially one of the most efficient and specific therapeutic approaches for autoimmune diseases. Although highly effective in animal models, antigen-based strategies have not yet been translated into practicable human therapy, and several clinical trials using a single antigen or peptidic-epitope in multiple sclerosis (MS) yielded disappointing results. In these clinical trials, however, the apparent complexity and dynamics of the pathogenic autoimmunity associated with MS, which result from the multiplicity of potential target antigens and “epitope spread”, have not been sufficiently considered. Thus, targeting pathogenic T-cells reactive against a single antigen/epitope is unlikely to be sufficient; to be effective, immunospecific therapy to MS should logically neutralize concomitantly T-cells reactive against as many major target antigens/epitopes as possible. We investigated such “multi-epitope-targeting” approach in murine experimental autoimmune encephalomyelitis (EAE) associated with a single (“classical”) or multiple (“complex”) anti-myelin autoreactivities, using cocktail of different encephalitogenic peptides vis-a-vis artificial multi-epitope-protein (designated Y-MSPc) encompassing rationally selected MS-relevant epitopes of five major myelin antigens, as “multi-epitope-targeting” agents. Y-MSPc was superior to peptide(s) in concomitantly downregulating pathogenic T-cells reactive against multiple myelin antigens/epitopes, via inducing more effective, longer lasting peripheral regulatory mechanisms (cytokine shift, anergy, and Foxp3+ CTLA4+ regulatory T-cells). Y-MSPc was also consistently more effective than the disease-inducing single peptide or peptide cocktail, not only in suppressing the development of “classical” or “complex EAE” or ameliorating ongoing disease, but most importantly, in reversing chronic EAE. Overall, our data emphasize that a “multi-epitope-targeting” strategy is required for effective immune-specific therapy of organ-specific autoimmune diseases associated with complex and dynamic pathogenic autoimmunity, such as MS; our data further demonstrate that the “multi-epitope-targeting” approach to therapy is optimized through specifically designed multi-epitope-proteins, rather than myelin peptide cocktails, as “multi-epitope-targeting” agents. Such artificial multi-epitope proteins can be tailored to other organ-specific autoimmune diseases

Hexamethylcyclopentadiene: time-resolved photoelectron spectroscopy and ab initio multiple spawning simulations

Progress in our understanding of ultrafast light-induced processes in molecules is best achieved through a close combination of experimental and theoretical approaches. Direct comparison is obtained if theory is able to directly reproduce experimental observables. Here, we present a joint approach comparing time-resolved photoelectron spectroscopy (TRPES) with ab initio multiple spawning (AIMS) simulations on the MS-MR-CASPT2 level of theory. We disentangle the relationship between two phenomena that dominate the immediate molecular response upon light absorption: a spectrally dependent delay of the photoelectron signal and an induction time prior to excited state depopulation in dynamics simulations. As a benchmark molecule, we have chosen hexamethylcyclopentadiene, which shows an unprecedentedly large spectral delay of (310 \ub1 20) fs in TRPES experiments. For the dynamics simulations, methyl groups were replaced by "hydrogen atoms" having mass 15 and TRPES spectra were calculated. These showed an induction time of (108 \ub1 10) fs which could directly be assigned to progress along a torsional mode leading to the intersection seam with the molecular ground state. In a stepladder-type approach, the close connection between the two phenomena could be elucidated, allowing for a comparison with other polyenes and supporting the general validity of this finding for their excited state dynamics. Thus, the combination of TRPES and AIMS proves to be a powerful tool for a thorough understanding of ultrafast excited state dynamics in polyenes.Peer reviewed: YesNRC publication: Ye

Acute upper airway failure and mediastinal emphysema following a wire-guided percutaneous cricothyrotomy in a patient with severe maxillofacial trauma

Contains fulltext : 69538.pdf (publisher's version ) (Open Access)BACKGROUND: In the presence of severe maxillofacial trauma, management of the airway is important because this condition poses a significant threat to airway patency. That securing the airway is not always straightforward is described and illustrated in this paper. CASE: We present the case of a 23-year-old patient who sustained severe maxillofacial injury for which airway control was necessary. A wire-guided percutaneous dilation cricothyrotomy was performed, which was most probably the cause of an acute loss of airway patency. The literature regarding the role of percutaneous techniques in an elective and emergency setting is reviewed

Physiological Induction of Regulatory Qa-1-Restricted CD8+ T Cells Triggered by Endogenous CD4+ T Cell Responses

T cell-dependent autoimmune diseases are characterized by the expansion of T cell clones that recognize immunodominant epitopes on the target antigen. As a consequence, for a given autoimmune disorder, pathogenic T cell clones express T cell receptors with a limited number of variable regions that define antigenic specificity. Qa-1, a MHC class I-like molecule, presents peptides from the variable region of TCRs to Qa-1-restricted CD8+ T cells. The induction of Vß-specific CD8+ T cells has been harnessed in an immunotherapeutic strategy known as the “T cell vaccination” (TCV) that comprises the injection of activated and attenuated CD4+ T cell clones so as to induce protective CD8+ T cells. We hypothesized that Qa-1-restricted CD8+ regulatory T cells could also constitute a physiologic regulatory arm of lymphocyte responses upon expansion of endogenous CD4+ T cells, in the absence of deliberate exogenous T cell vaccination. We immunized mice with two types of antigenic challenges in order to sequentially expand antigen-specific endogenous CD4+ T cells with distinct antigenic specificities but characterized by a common Vß chain in their TCR. The first immunization was performed with a non-self antigen while the second challenge was performed with a myelin-derived peptide known to drive experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. We show that regulatory Vß-specific Qa-1-restricted CD8+ T cells induced during the first endogenous CD4+ T cell responses are able to control the expansion of subsequently mobilized pathogenic autoreactive CD4+ T cells. In conclusion, apart from the immunotherapeutic TCV, Qa-1-restricted specialized CD8+ regulatory T cells can also be induced during endogenous CD4+ T cell responses. At variance with other regulatory T cell subsets, the action of these Qa-1-restricted T cells seems to be restricted to the immediate re-activation of CD4+ T cells

Studying Early Lethality of 45,XO (Turner's Syndrome) Embryos Using Human Embryonic Stem Cells

Turner's syndrome (caused by monosomy of chromosome X) is one of the most common chromosomal abnormalities in females. Although 3% of all pregnancies start with XO embryos, 99% of these pregnancies terminate spontaneously during the first trimester. The common genetic explanation for the early lethality of monosomy X embryos, as well as the phenotype of surviving individuals is haploinsufficiency of pseudoautosomal genes on the X chromosome. Another possible mechanism is null expression of imprinted genes on the X chromosome due to the loss of the expressed allele. In contrast to humans, XO mice are viable, and fertile. Thus, neither cells from patients nor mouse models can be used in order to study the cause of early lethality in XO embryos. Human embryonic stem cells (HESCs) can differentiate in culture into cells from the three embryonic germ layers as well as into extraembryonic cells. These cells have been shown to have great value in modeling human developmental genetic disorders. In order to study the reasons for the early lethality of 45,XO embryos we have isolated HESCs that have spontaneously lost one of their sex chromosomes. To examine the possibility that imprinted genes on the X chromosome play a role in the phenotype of XO embryos, we have identified genes that were no longer expressed in the mutant cells. None of these genes showed a monoallelic expression in XX cells, implying that imprinting is not playing a major role in the phenotype of XO embryos. To suggest an explanation for the embryonic lethality caused by monosomy X, we have differentiated the XO HESCs in vitro an in vivo. DNA microarray analysis of the differentiated cells enabled us to compare the expression of tissue specific genes in XO and XX cells. The tissue that showed the most significant differences between the clones was the placenta. Many placental genes are expressed at much higher levels in XX cells in compare to XO cells. Thus, we suggest that abnormal placental differentiation as a result of haploinsufficiency of X-linked pseudoautosomal genes causes the early lethality in XO human embryos