Ambient temperature fracture strength of pure alumina

The fracture of alumina copper-vapor laser tubes has led to great interest in the mechanical properties of pure alumina ({alpha}-Al{sub 2}O{sub 3}) in the Copper Laser Program. In particular, knowledge of the fracture strength of the alumina used to make these tubes is required at temperatures ranging from ambient to 1500{degree}C. The purpose of the work reported here was to confirm that the fracture strength data reasonably well describe the behavior of the alumina used in the Copper Laser Program. The goal was to make this investigation with the minimum of effort and cost. To this end, only ambient temperature tests were planned

The elevated temperature tensile properties of S-200E commercially pure beryllium

Experiments were performed at 300-100 C in longitudinal and transverse orientations at quasi-static strain rate 5.5 {times} 10{sup {minus}4}s{sup {minus}1}. Results show that the stress-strain curve is smooth, without yield points or serrations. Yield stress and ultimate tensile stress decrease monotonically with temperature. Similar strengths were measured for both orientations. Failure elongation vs temperature is complex

Investigation of MicroRNA-134 as a Target against Seizures and SUDEP in a Mouse Model of Dravet Syndrome

Dravet syndrome (DS) is a catastrophic form of pediatric epilepsy mainly caused by noninherited mutations in the SCN1A gene. DS patients suffer severe and life-threatening focal and generalized seizures which are often refractory to available anti-seizure medication. Antisense oligonucleotides (ASOs) based approaches may offer treatment opportunities in DS. MicroRNAs are short noncoding RNAs that play a key role in brain structure and function by post-transcriptionally regulating gene expression, including ion channels. Inhibiting miRNA-134 (miR-134) using an antimiR ASO (Ant-134) has been shown to reduce evoked seizures in juvenile and adult mice and reduce epilepsy development in models of focal epilepsy. The present study investigated the levels of miR-134 and whether Ant-134 could protect against hyperthermia-induced seizures, spontaneous seizures and mortality (SUDEP) in F1.Scn1a(1/)tm1kea mice. At P17, animals were intracerebroventricular in-jected with 0.1–1 nmol of Ant-134 and subject to a hyperthermia challenge at postnatal day (P)18. A second cohort of P21 F1.Scn1a(1/)tm1kea mice received Ant-134 and were followed by video and EEG monitoring until P28 to track the incidence of spontaneous seizures and SUDEP. Hippocampal and cortical levels of miR-134 were similar between wild-type (WT) and F1.Scn1a(1/)tm1kea mice. Moreover, Ant-134 had no effect on hyperthermia-induced seizures, spontaneous seizures and SUDEP incidence were unchanged in Ant-134-treated DS mice. These findings suggest that targeting miR-134 does not have therapeutic applications in DS

The P2X7 receptor contributes to seizures and inflammation-driven long-lasting brain hyperexcitability following hypoxia in neonatal mice.

Neonatal seizures represent a clinical emergency. However, current anti-seizure medications fail to resolve seizures in ~50% of infants. The P2X7 receptor (P2X7R) is an important driver of inflammation, and evidence suggests that P2X7R contributes to seizures and epilepsy in adults. However, no genetic proof has yet been provided to determine what contribution P2X7R makes to neonatal seizures, its effects on inflammatory signalling during neonatal seizures, and the therapeutic potential of P2X7R-based treatments on long-lasting brain excitability. Neonatal seizures were induced by global hypoxia in 7-day-old mouse pups (P7). The role of P2X7Rs during seizures was analysed in P2X7R-overexpressing and knockout mice. Treatment of wild-type mice after hypoxia with the P2X7R antagonist JNJ-47965567 was used to determine the effects of the P2X7R on long-lasting brain hyperexcitability. Cell type-specific P2X7R expression was analysed in P2X7R-EGFP reporter mice. RNA sequencing was used to monitor P2X7R-dependent hippocampal downstream signalling. P2X7R deletion reduced seizure severity, whereas P2X7R overexpression exacerbated seizure severity and reduced responsiveness to anti-seizure medication. P2X7R deficiency led to an anti-inflammatory phenotype in microglia, and treatment of mice with a P2X7R antagonist reduced long-lasting brain hyperexcitability. RNA sequencing identified several pathways altered in P2X7R knockout mice after neonatal hypoxia, including a down-regulation of genes implicated in inflammation and glutamatergic signalling. Treatments based on targeting the P2X7R may represent a novel therapeutic strategy for neonatal seizures with P2X7Rs contributing to the generation of neonatal seizures, driving inflammatory processes and long-term hyperexcitability states

Common activation of canonical Wnt signaling in pancreatic adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDA) is an extremely aggressive malignancy, which carries a dismal prognosis. Activating mutations of the Kras gene are common to the vast majority of human PDA. In addition, recent studies have demonstrated that embryonic signaling pathway such as Hedgehog and Notch are inappropriately upregulated in this disease. The role of another embryonic signaling pathway, namely the canonical Wnt cascade, is still controversial. Here, we use gene array analysis as a platform to demonstrate general activation of the canonical arm of the Wnt pathway in human PDA. Furthermore, we provide evidence for Wnt activation in mouse models of pancreatic cancer. Our results also indicate that Wnt signaling might be activated downstream of Hedgehog signaling, which is an early event in PDA evolution. Wnt inhibition blocked proliferation and induced apoptosis of cultured adenocarcinoma cells, thereby providing evidence to support the development of novel therapeutical strategies for Wnt inhibition in pancreatic adenocarcinoma

Antagomir-mediated suppression of microRNA-134 reduces kainic acid-induced seizures in immature mice

MicroRNAs are short non-coding RNAs that negatively regulate protein levels and perform important roles in establishing and maintaining neuronal network function. Previous studies in adult rodents have detected upregulation of microRNA-134 after prolonged seizures (status epilepticus) and demonstrated that silencing microRNA-134 using antisense oligonucleotides, termed antagomirs, has potent and long-lasting seizure-suppressive effects. Here we investigated whether targeting microRNA-134 can reduce or delay acute seizures in the immature brain. Status epilepticus was induced in 21 day-old (P21) male mice by systemic injection of 5 mg/kg kainic acid. This triggered prolonged electrographic seizures and select bilateral neuronal death within the CA3 subfield of the hippocampus. Expression of microRNA-134 and functional loading to Argonaute-2 was not significantly changed in the hippocampus after seizures in the model. Nevertheless, when levels of microRNA-134 were reduced by prior intracerebroventricular injection of an antagomir, kainic acid-induced seizures were delayed and less severe and mice displayed reduced neuronal death in the hippocampus. These studies demonstrate targeting microRNA-134 may have therapeutic applications for the treatment of seizures in children

Enhanced tensile ductility in Al-Mg alloys by solid-solution interactions

The development of methods for obtaining high tensile elongation in aluminum alloys is of great importance for the practical forming of near-net-shape parts. Current superplastic alloys are limited in use by high material costs. The utilization of solute-drag creep processes, the approach used in this study, to obtain enhanced tensile ductility in aluminum alloys has lead to tensile elongations of up to 325% in simple, binary Al-Mg alloys with coarse grain sizes. This method has the advantage of lowering processing costs in comparison with superplastic alloys because a fine grain size is not necessary. Whereas superplastic alloys typically have a strain-rate sensitivity of m = 0.5, the enhanced ductility Al-Mg alloys typically exhibit m = 0.3 where maximum ductility is observed. Although a strain-rate sensitivity of rn = 0.5 can lead to elongations of over 1000% (superplastic materials) a value of m = 0.3 is shown experimentally to be sufficient for obtaining elongations of 150% to a maximum observed of 325%. Enhanced ductility is also affected strongly by ternary alloying additions, such as Mn, for which a preliminary understanding is pursued

Creep fracture during solute-drag creep and superplastic deformation

Creep fracture behavior has been studied in Al-Mg and Al-Mg-Mn alloys undergoing solute-drag creep and in microduplex stainless steel undergoing both solute-drag creep and superplastic deformation. Failure in these materials is found to be controlled by two mechanisms, neck formation and cavitation. The mechanism of creep fracture during solute-drag creep in Al-Mg is found to change from necking-controlled fracture to cavitation-controlled fracture as Mn content is increased. Binary Al-Mg material fails by neck formation during solute-drag creep, and cavities are formed primarily in the neck region due to high hydrostatic stresses. Ternary alloys of Al-Mg- Mn containing 0.25 and 0.50 wt % Mn exhibit more uniform cavitation, with the 0.50 Mn alloy clearly failing by cavity interlinkage. Failure in the microduplex stainless steel is dominated by neck formation during solute-drag creep deformation but is controlled by cavity growth and interlinkage during superplastic deformation. Cavitation was measured at several strains, and found to increase as an exponential function of strain. An important aspect of cavity growth in the stainless steel is the long latency time before significant cavitation occurs. For a short latency period, cavitation acts to significantly reduce ductility below that allowed by neck growth alone. This effect is most pronounced in materials with a high strain-rate sensitivity, for which neck growth occurs very slowly

Cellular dissection of malaria parasite invasion of human erythrocytes using viable Plasmodium knowlesi merozoites

Plasmodium knowlesi, a zoonotic parasite causing severe-to-lethal malaria disease in humans, has only recently been adapted to continuous culture with human red blood cells (RBCs). In comparison with the most virulent human malaria, Plasmodium falciparum, there are, however, few cellular tools available to study its biology, in particular direct investigation of RBC invasion by blood-stage P. knowlesi merozoites. This leaves our current understanding of biological differences across pathogenic Plasmodium spp. incomplete. Here, we report a robust method for isolating viable and invasive P. knowlesi merozoites to high purity and yield. Using this approach, we present detailed comparative dissection of merozoite invasion (using a variety of microscopy platforms) and direct assessment of kinetic differences between knowlesi and falciparum merozoites. We go on to assess the inhibitory potential of molecules targeting discrete steps of invasion in either species via a quantitative invasion inhibition assay, identifying a class of polysulfonate polymer able to efficiently inhibit invasion in both, providing a foundation for pan-Plasmodium merozoite inhibitor development. Given the close evolutionary relationship between P. knowlesi and P. vivax, the second leading cause of malaria-related morbidity, this study paves the way for inter-specific dissection of invasion by all three major pathogenic malaria species

Functional modelling of complex multi‑disciplinary systems using the enhanced sequence diagram

YesThis paper introduces an Enhanced Sequence Diagram (ESD) as the basis for a structured framework for the functional analysis of complex multidisciplinary systems. The ESD extends the conventional sequence diagrams (SD) by introducing a rigorous functional flow-based modelling schemata to provide an enhanced basis for model-based functional requirements and architecture analysis in the early systems design stages. The proposed ESD heuristics include the representation of transactional and transformative functions required to deliver the use case sequence, and fork and join nodes to facilitate analysis of combining and bifurcating operations on flows. A case study of a personal mobility device is used to illustrate the deployment of the ESD methodology in relation to three common product development scenarios: (i) reverse engineering, (ii) the introduction of a specific technology to an existent system; and (iii) the introduction of a new feature as user-centric innovation for an existing system, at a logical design level, without reference to any solution. The case study analysis provides further insights into the effectiveness of the ESD to support function modelling and functional requirements capture, and architecture development. The significance of this paper is that it establishes a rigorous ESD-based functional analysis methodology to guide the practitioner with its deployment, facilitating its impact to both the engineering design and systems engineering communities, as well as the design practice in the industry