Modeling of WEDM Parameters while Machining Mg-SiC Metal Matrix Composite

In this paper an attempt has been made to study the effects of the process parameters of wire cut electrical discharge machining (WEDM) on Magnesium-Silicon Carbide MMC with 5% SiC in particulate form. For the analysis, six factors, namely pulse on time, pulse off time, spark gap voltage, peak current, dielectric flushing pressure and servo feed have been taken and a Taguchi L16 orthogonal array for two levels was used. Response surface methodology was also used to develop second-order models for material removal rate (MRR) and surface roughness (SR). From the analysis of variances, it has been observed that pulse on time and pulse off time were the most significant parameters among all those observed in predicting the MRR and SR, respectively

TBK1 regulates regeneration of pancreatic β-cells

Small-molecule inhibitors of non-canonical IκB kinases TANK-binding kinase 1 (TBK1) and IκB kinase ε (IKKε) have shown to stimulate β-cell regeneration in multiple species. Here we demonstrate that TBK1 is predominantly expressed in β-cells in mammalian islets. Proteomic and transcriptome analyses revealed that genetic silencing of TBK1 increased expression of proteins and genes essential for cell proliferation in INS-1 832/13 rat β-cells. Conversely, TBK1 overexpression decreased sensitivity of β-cells to the elevation of cyclic AMP (cAMP) levels and reduced proliferation of β-cells in a manner dependent on the activity of cAMP-hydrolyzing phosphodiesterase 3 (PDE3). While the mitogenic effect of (E)3-(3-phenylbenzo[c]isoxazol-5-yl)acrylic acid (PIAA) is derived from inhibition of TBK1, PIAA augmented glucose-stimulated insulin secretion (GSIS) and expression of β-cell differentiation and proliferation markers in human embryonic stem cell (hESC)-derived β-cells and human islets. TBK1 expression was increased in β-cells upon diabetogenic insults, including in human type 2 diabetic islets. PIAA enhanced expression of cell cycle control molecules and β-cell differentiation markers upon diabetogenic challenges, and accelerated restoration of functional β-cells in streptozotocin (STZ)-induced diabetic mice. Altogether, these data suggest the critical function of TBK1 as a β-cell autonomous replication barrier and present PIAA as a valid therapeutic strategy augmenting functional β-cells

A genetic algorithm based method for stringent haplotyping of family data

<p>Abstract</p> <p>Background</p> <p>The linkage phase, or haplotype, is an extra level of information that in addition to genotype and pedigree can be useful for reconstructing the inheritance pattern of the alleles in a pedigree, and computing for example Identity By Descent probabilities. If a haplotype is provided, the precision of estimated IBD probabilities increases, as long as the haplotype is estimated without errors. It is therefore important to only use haplotypes that are strongly supported by the available data for IBD estimation, to avoid introducing new errors due to erroneous linkage phases.</p> <p>Results</p> <p>We propose a genetic algorithm based method for haplotype estimation in family data that includes a stringency parameter. This allows the user to decide the error tolerance level when inferring parental origin of the alleles. This is a novel feature compared to existing methods for haplotype estimation. We show that using a high stringency produces haplotype data with few errors, whereas a low stringency provides haplotype estimates in most situations, but with an increased number of errors.</p> <p>Conclusion</p> <p>By including a stringency criterion in our haplotyping method, the user is able to maintain the error rate at a suitable level for the particular study; one can select anything from haplotyped data with very small proportion of errors and a higher proportion of non-inferred haplotypes, to data with phase estimates for every marker, when haplotype errors are tolerable. Giving this choice makes the method more flexible and useful in a wide range of applications as it is able to fulfil different requirements regarding the tolerance for haplotype errors, or uncertain marker-phases.</p

Deferiprone: Pan-selective Histone Lysine Demethylase Inhibition Activity and Structure Activity Relationship Study

Deferiprone (DFP) is a hydroxypyridinone-derived iron chelator currently in clinical use for iron chelation therapy. DFP has also been known to elicit antiproliferative activities, yet the mechanism of this effect has remained elusive. We herein report that DFP chelates the Fe 2+ ion at the active sites of selected iron-dependent histone lysine demethylases (KDMs), resulting in pan inhibition of a subfamily of KDMs. Specifically, DFP inhibits the demethylase activities of six KDMs - 2A, 2B, 5C, 6A, 7A and 7B - with low micromolar IC 50 s while considerably less active or inactive against eleven KDMs - 1A, 3A, 3B, 4A-E, 5A, 5B and 6B. The KDM that is most sensitive to DFP, KDM6A, has an IC 50 that is between 7- and 70-fold lower than the iron binding equivalence concentrations at which DFP inhibits ribonucleotide reductase (RNR) activities and/or reduces the labile intracellular zinc ion pool. In breast cancer cell lines, DFP potently inhibits the demethylation of H3K4me3 and H3K27me3, two chromatin posttranslational marks that are subject to removal by several KDM subfamilies which are inhibited by DFP in cell-free assay. These data strongly suggest that DFP derives its anti-proliferative activity largely from the inhibition of a sub-set of KDMs. The docked poses adopted by DFP at the KDM active sites enabled identification of new DFP-based KDM inhibitors which are more cytotoxic to cancer cell lines. We also found that a cohort of these agents inhibited HP1-mediated gene silencing and one lead compound potently inhibited breast tumor growth in murine xenograft models. Overall, this study identified a new chemical scaffold capable of inhibiting KDM enzymes, globally changing histone modification profiles, and with specific anti-tumor activities

Comportamento à flexão de vigas eco-eficientes de ultra elevada durabilidade

Atualmente, o ecossistema mundial tem vindo a ser confrontado com problemas de grande importância, a elevada poluição do meio ambiente e a limitação dos recursos energéticos. Estes problemas têm contribuído para que a sustentabilidade da construção seja uma prioridade cada vez maior no presente e no futuro. A manutenção e a reabilitação do património construído surge como uma das medidas mais eficazes para prevenir ou reduzir o consumo de energia no setor da construção. No caso da construção nova, a tendência é para verificar-se um aumento da utilização de elementos estruturais pré-fabricados com partes betonadas em obra, obtendose uma maior rapidez de execução associada a um maior controlo de qualidade. O betão de ultra elevada durabilidade, reforçado com fibras metálicas, é considerado um material inovador desenvolvido nas últimas décadas, apresentando um conjunto de caraterísticas especiais, como a durabilidade, a facilidade de aplicação, as elevadas resistências mecânicas, tornando-o num produto particularmente atraente para a reabilitação e reforço de estruturas de betão. No entanto, este betão não deve ser produzido em grandes quantidades devido ao elevado consumo de cimento e adições, resultando em elevados custos económicos e ambientais. Considerando estas desvantagens é proposto que o betão de ultra elevada durabilidade seja usado apenas na camada de recobrimento, formando-se assim uma superskin que protege o elemento estrutural dos ambientes mais agressivos, isto é, aumenta a durabilidade das estruturas de betão sem que, no entanto, seja criado um impacte ambiental muito significativo (a quantidade de CO2 libertada para a atmosfera é menor devido ao menor consumo de cimento e adições). A presente dissertação pretende explorar o conceito de superskin do ponto de vista do comportamento estrutural, nomeadamente, estudar o comportamento de vigas sujeitas a esforços de flexão, compostas por uma camada exterior de betão de ultra elevada durabilidade, associado a um núcleo com betão eco-eficiente, com baixa dosagem de cimento, de modo a obter uma solução mais durável e ao mesmo tempo, ecologicamente mais eficiente. Foram realizadas oito vigas com diferentes taxas de armadura: quatro vigas produzidas apenas com betão com baixa dosagem de cimento (usadas como vigas de referência) e quatro vigas produzidas com um betão de ultra elevada durabilidade na camada de recobrimento e com um betão com baixa dosagem de cimento no núcleo. As diferentes taxas de armadura longitudinal permitem avaliar a influência da superskin em vigas com roturas dúcteis e frágeis. Com base nos dados recolhidos durante os ensaios experimentais estudou-se: (i) relação cargadeslocamento; (ii) os valores teóricos e experimentais do momento resistente; (iii) a evolução da curvatura nas secções críticas; (iv) a evolução da rigidez à flexão com a carga aplicada; (v) a ductilidade; e (vi) a fendilhação e o tipo de rotura. Da análise de resultados foi possível verificar que o recobrimento em betão de ultra elevada durabilidade é uma solução com aspetos muito positivos, nomeadamente, aumenta a resistência à flexão das vigas

Replication and Explorations of High-Order Epistasis Using a Large Advanced Intercross Line Pedigree

Dissection of the genetic architecture of complex traits persists as a major challenge in biology; despite considerable efforts, much remains unclear including the role and importance of genetic interactions. This study provides empirical evidence for a strong and persistent contribution of both second- and third-order epistatic interactions to long-term selection response for body weight in two divergently selected chicken lines. We earlier reported a network of interacting loci with large effects on body weight in an F2 intercross between these high– and low–body weight lines. Here, most pair-wise interactions in the network are replicated in an independent eight-generation advanced intercross line (AIL). The original report showed an important contribution of capacitating epistasis to growth, meaning that the genotype at a hub in the network releases the effects of one or several peripheral loci. After fine-mapping of the loci in the AIL, we show that these interactions were persistent over time. The replication of five of six originally reported epistatic loci, as well as the capacitating epistasis, provides strong empirical evidence that the originally observed epistasis is of biological importance and is a contributor in the genetic architecture of this population. The stability of genetic interaction mechanisms over time indicates a non-transient role of epistasis on phenotypic change. Third-order epistasis was for the first time examined in this study and was shown to make an important contribution to growth, which suggests that the genetic architecture of growth is more complex than can be explained by two-locus interactions only. Our results illustrate the importance of designing studies that facilitate exploration of epistasis in populations for obtaining a comprehensive understanding of the genetics underlying a complex trait

Haplotyping in Pedigrees via a Genetic Algorithm

Genome-wide screening for localization of disease genes necessitates the efficient reconstruction of haplotypes of members of a pedigree from genotype data at multiple loci. We propose a genetic algorithmic approach to haplotyping and show that it works fast, efficiently and reliably. This algorithm uses certain principles of biological evolution to find optimal solutions to complex problems. The optimality criterion used in the present problem is the minimum number of recombinations over possible haplotype configurations of members of a pedigree. The proposed algorithm is much less demanding in terms of data and assumption requirements compared to the currently used likelihood-based methods of haplotype reconstruction. It also provides multiple optimal haplotype configurations of a pedigree, if such multiple optima exist

TBK1 regulates regeneration of pancreatic β-cells

Small-molecule inhibitors of non-canonical IκB kinases TANK-binding kinase 1 (TBK1) and IκB kinase ε (IKKε) have shown to stimulate β-cell regeneration in multiple species. Here we demonstrate that TBK1 is predominantly expressed in β-cells in mammalian islets. Proteomic and transcriptome analyses revealed that genetic silencing of TBK1 increased expression of proteins and genes essential for cell proliferation in INS-1 832/13 rat β-cells. Conversely, TBK1 overexpression decreased sensitivity of β-cells to the elevation of cyclic AMP (cAMP) levels and reduced proliferation of β-cells in a manner dependent on the activity of cAMP-hydrolyzing phosphodiesterase 3 (PDE3). While the mitogenic effect of (E)3-(3-phenylbenzo[c]isoxazol-5-yl)acrylic acid (PIAA) is derived from inhibition of TBK1, PIAA augmented glucose-stimulated insulin secretion (GSIS) and expression of β-cell differentiation and proliferation markers in human embryonic stem cell (hESC)-derived β-cells and human islets. TBK1 expression was increased in β-cells upon diabetogenic insults, including in human type 2 diabetic islets. PIAA enhanced expression of cell cycle control molecules and β-cell differentiation markers upon diabetogenic challenges, and accelerated restoration of functional β-cells in streptozotocin (STZ)-induced diabetic mice. Altogether, these data suggest the critical function of TBK1 as a β-cell autonomous replication barrier and present PIAA as a valid therapeutic strategy augmenting functional β-cells