Assessement of tensile strength of graphites by the iosipescu coupon test

Polycrystalline graphites are widely used in the metallurgical, nuclear and aerospace industries. Graphites are particulated composites manufactured with a mixture of coke with pitch, and changes in relative proportions of these materials cause modifications in their mechanical properties. Uniaxial tension tests must be avoided for mechanical characterization in this kind of brittle material, due to difficulties in making the relatively long specimens and premature damages caused during testing set-up. On other types of tests, e.g. bending tests, the specimens are submitted to combined stress states (normal and transverse shear stresses). The Iosipescu shear test, is performed in a beam with two 90° opposite notches machined at the mid-length of the specimens, by applying two forces couples, so that a pure and uniform shear stress state is generated at the cross section between the two notches. When a material is isotropic and brittle, a failure at 45° in relation to the beam long axis can take place, i.e., the tensile normal stress acts parallel to the lateral surface of the notches, controls the failure and the result of the shear test is numerically equivalent to the tensile strength. This work has evaluated a graphite of the type used in rocket nozzles by the Iosipescu test and the resulted stress, ~11 MPa, was found to be equal to the tensile strength. Thus, the tensile strength can be evaluated just by a single and simple experiment, thus avoiding complicated machining of specimen and testing set-up

Systems-pharmacology dissection of a drug synergy in imatinib-resistant CML

Occurrence of the BCR-ABL[superscript T315I] gatekeeper mutation is among the most pressing challenges in the therapy of chronic myeloid leukemia (CML). Several BCR-ABL inhibitors have multiple targets and pleiotropic effects that could be exploited for their synergistic potential. Testing combinations of such kinase inhibitors identified a strong synergy between danusertib and bosutinib that exclusively affected CML cells harboring BCR-ABL[superscript T315I]. To elucidate the underlying mechanisms, we applied a systems-level approach comprising phosphoproteomics, transcriptomics and chemical proteomics. Data integration revealed that both compounds targeted Mapk pathways downstream of BCR-ABL, resulting in impaired activity of c-Myc. Using pharmacological validation, we assessed that the relative contributions of danusertib and bosutinib could be mimicked individually by Mapk inhibitors and collectively by downregulation of c-Myc through Brd4 inhibition. Thus, integration of genome- and proteome-wide technologies enabled the elucidation of the mechanism by which a new drug synergy targets the dependency of BCR-ABL[superscript T315I] CML cells on c-Myc through nonobvious off targets

School Effects on the Wellbeing of Children and Adolescents

Well-being is a multidimensional construct, with psychological, physical and social components. As theoretical basis to help understand this concept and how it relates to school, we propose the Self-Determination Theory, which contends that self-determined motivation and personality integration, growth and well-being are dependent on a healthy balance of three innate psychological needs of autonomy, relatedness and competence. Thus, current indicators involve school effects on children’s well-being, in many diverse modalities which have been explored. Some are described in this chapter, mainly: the importance of peer relationships; the benefits of friendship; the effects of schools in conjunction with some forms of family influence; the school climate in terms of safety and physical ecology; the relevance of the teacher input; the school goal structure and the implementation of cooperative learning. All these parameters have an influence in promoting optimal functioning among children and increasing their well-being by meeting the above mentioned needs. The empirical support for the importance of schools indicates significant small effects, which often translate into important real-life effects as it is admitted at present. The conclusion is that schools do make a difference in children’s peer relationships and well-being

Contrasting Biogeographic and Diversification Patterns in Two Mediterranean-Type Ecosystems

The five Mediterranean regions of the world comprise almost 50,000 plant species (ca 20% of the known vascular plants) despite accounting for less than 5% of the world’s land surface. The ecology and evolutionary history of two of these regions, the Cape Floristic Region and the Mediterranean Basin, have been extensively investigated, but there have been few studies aimed at understanding the historical relationships between them. Here, we examine the biogeographic and diversification processes that shaped the evolution of plant diversity in the Cape and the Mediterranean Basin using a large plastid data set for the geophyte family Hyacinthaceae (comprising ca. 25% of the total diversity of the group), a group found mainly throughout Africa and Eurasia. Hyacinthaceae is a predominant group in the Cape and the Mediterranean Basin both in terms of number of species and their morphological and ecological variability. Using state-of-the-art methods in biogeography and diversification, we found that the Old World members of the family originated in sub-Saharan Africa at the Paleocene–Eocene boundary and that the two Mediterranean regions both have high diversification rates, but contrasting biogeographic histories. While the Cape diversity has been greatly influenced by its relationship with sub-Saharan Africa throughout the history of the family, the Mediterranean Basin had no connection with the latter after the onset of the Mediterranean climate in the region and the aridification of the Sahara. The Mediterranean Basin subsequently contributed significantly to the diversity of neighbouring areas, especially Northern Europe and the Middle East, whereas the Cape can be seen as a biogeographical cul-de-sac, with only a few dispersals toward sub-Saharan Africa. The understanding of the evolutionary history of these two important repositories of biodiversity would benefit from the application of the framework developed here to other groups of plants present in the two regions

Identification and genomic location of a reniform nematode (Rotylenchulus reniformis) resistance locus (Renari) introgressed from Gossypium aridum into upland cotton (G. hirsutum)

In this association mapping study, a tri-species hybrid, [Gossypium arboreum × (G. hirsutum × G. aridum)2], was crossed with MD51ne (G. hirsutum) and progeny from the cross were used to identify and map SSR markers associated with reniform nematode (Rotylenchulus reniformis) resistance. Seventy-six progeny (the 50 most resistant and 26 most susceptible) plants were genotyped with 104 markers. Twenty-five markers were associated with a resistance locus that we designated Renari and two markers, BNL3279_132 and BNL2662_090, mapped within 1 cM of Renari. Because the SSR fragments associated with resistance were found in G. aridum and the bridging line G 371, G. aridum is the likely source of this resistance. The resistance is simply inherited, possibly controlled by a single dominant gene. The markers identified in this project are a valuable resource to breeders and geneticists in the quest to produce cotton cultivars with a high level of resistance to reniform nematode

Inhibition of MLC Phosphorylation Restricts Replication of Influenza Virus—A Mechanism of Action for Anti-Influenza Agents

Influenza A viruses are a severe threat worldwide, causing large epidemics that kill thousands every year. Prevention of influenza infection is complicated by continuous viral antigenic changes. Newer anti-influenza agents include MEK/ERK and protein kinase C inhibitors; however, the downstream effectors of these pathways have not been determined. In this study, we identified a common mechanism for the inhibitory effects of a significant group of anti-influenza agents. Our studies showed that influenza infection activates a series of signaling pathways that converge to induce myosin light chain (MLC) phosphorylation and remodeling of the actin cytoskeleton. Inhibiting MLC phosphorylation by blocking RhoA/Rho kinase, phospholipase C/protein kinase C, and HRas/Raf/MEK/ERK pathways with the use of genetic or chemical manipulation leads to the inhibition of influenza proliferation. In contrast, the induction of MLC phosphorylation enhances influenza proliferation, as does activation of the HRas/Raf/MEK/ERK signaling pathway. This effect is attenuated by inhibiting MLC phosphorylation. Additionally, in intracellular trafficking studies, we found that the nuclear export of influenza ribonucleoprotein depends on MLC phosphorylation. Our studies provide evidence that modulation of MLC phosphorylation is an underlying mechanism for the inhibitory effects of many anti-influenza compounds

Lost in translation: Returning germline genetic results in genome-scale cancer research

Background: The return of research results (RoR) remains a complex and well-debated issue. Despite the debate, actual data related to the experience of giving individual results back, and the impact these results may have on clinical care and health outcomes, is sorely lacking. Through the work of the Australian Pancreatic Cancer Genome Initiative (APGI) we: (1) delineate the pathway back to the patient where actionable research data were identified; and (2) report the clinical utilisation of individual results returned. Using this experience, we discuss barriers and opportunities associated with a comprehensive process of RoR in large-scale genomic research that may be useful for others developing their own policies. Methods: We performed whole-genome (n = 184) and exome (n = 208) sequencing of matched tumour-normal DNA pairs from 392 patients with sporadic pancreatic cancer (PC) as part of the APGI. We identified pathogenic germline mutations in candidate genes (n = 130) with established predisposition to PC or medium-high penetrance genes with well-defined cancer associated syndromes or phenotypes. Variants from candidate genes were annotated and classified according to international guidelines. Variants were considered actionable if clinical utility was established, with regard to prevention, diagnosis, prognostication and/or therapy. Results: A total of 48,904 germline variants were identified, with 2356 unique variants undergoing annotation and in silico classification. Twenty cases were deemed actionable and were returned via previously described RoR framework, representing an actionable finding rate of 5.1%. Overall, 1.78% of our cohort experienced clinical benefit from RoR. Conclusion: Returning research results within the context of large-scale genomics research is a labour-intensive, highly variable, complex operation. Results that warrant action are not infrequent, but the prevalence of those who experience a clinical difference as a result of returning individual results is currently low