A theoretical model for determining thermal conductivity of porous solid materials

Paper presented at the 9th International Conference on Heat Transfer, Fluid Mechanics and Thermodynamics, Malta, 16-18 July, 2012.In present study a new-developed simple algebraic equation is used to find out the effective thermal conductivity of new–produced composite materials that have nonhomogenous microscopic porosity. Thermal power plant ashes, tragacanth and portland cement are used as binding components of these porous composite materials. By varying the mixing ratio of three components, 24 samples have been produced. Effective thermal conductivity coefficients obtained by the algebraic method is then compared to the ones obtained by experimental measurement techniques. The theoretical results are found to be agreeable with the experimental results.dc201

Resource dedication problem in a multi-project environment

There can be different approaches to the management of resources within the context of multi-project scheduling problems. In general, approaches to multiproject scheduling problems consider the resources as a pool shared by all projects. On the other hand, when projects are distributed geographically or sharing resources between projects is not preferred, then this resource sharing policy may not be feasible. In such cases, the resources must be dedicated to individual projects throughout the project durations. This multi-project problem environment is defined here as the resource dedication problem (RDP). RDP is defined as the optimal dedication of resource capacities to different projects within the overall limits of the resources and with the objective of minimizing a predetermined objective function. The projects involved are multi-mode resource constrained project scheduling problems with finish to start zero time lag and non-preemptive activities and limited renewable and nonrenewable resources. Here, the characterization of RDP, its mathematical formulation and two different solution methodologies are presented. The first solution approach is a genetic algorithm employing a new improvement move called combinatorial auction for RDP, which is based on preferences of projects for resources. Two different methods for calculating the projects’ preferences based on linear and Lagrangian relaxation are proposed. The second solution approach is a Lagrangian relaxation based heuristic employing subgradient optimization. Numerical studies demonstrate that the proposed approaches are powerful methods for solving this problem

Heschl's gyrus is more sensitive to tone level than non-primary auditory cortex

Previous neuroimaging studies generally demonstrate a growth in the cortical response with an increase in sound level. However, the details of the shape and topographic location of such growth remain largely unknown. One limiting methodological factor has been the relatively sparse sampling of sound intensities. Additionally, most studies have either analysed the entire auditory cortex without differentiating primary and non-primary regions or have limited their analyses to Heschl's gyrus (HG). Here, we characterise the pattern of responses to a 300-Hz tone presented in 6-dB steps from 42 to 96 dB sound pressure level as a function of its sound level, within three anatomically defined auditory areas; the primary area, on HG, and two non-primary areas, consisting of a small area lateral to the axis of HG (the anterior lateral area, ALA) and the posterior part of auditory cortex (the planum temporale, PT). Extent and magnitude of auditory activation increased non-linearly with sound level. In HG, the extent and magnitude were more sensitive to increasing level than in ALA and PT. Thus, HG appears to have a larger involvement in sound-level processing than does ALA or PT

P.025 Efficacy and safety results of the avalglucosidase alfa phase 3 COMET trial in participants with late-onset Pompe disease (LOPD)

Background: Phase 3 COMET trial (NCT02782741) compares avalglucosidase alfa (n=51) with alglucosidase alfa (n=49) in treatment-naïve LOPD. Methods: Primary objective: determine avalglucosidase alfa effect on respiratory muscle function. Secondary/other objectives include: avalglucosidase alfa effect on functional endurance, inspiratory/expiratory muscle strength, lower/upper extremity muscle strength, motor function, health-related quality of life, safety. Results: At Week 49, change (LSmean±SE) from baseline in upright forced vital capacity %predicted was greater with avalglucosidase alfa (2.89%±0.88%) versus alglucosidase alfa (0.46%±0.93%)(absolute difference+2.43%). The primary objective, achieving statistical non-inferiority (p=0.0074), was met. Superiority testing was borderline significant (p=0.0626). Week 49 change from baseline in 6-minute walk test was 30.01-meters greater for avalglucosidase alfa (32.21±9.93m) versus alglucosidase alfa (2.19±10.40m). Positive results for avalglucosidase alfa were seen for all secondary/other efficacy endpoints. Treatment-emergent adverse events (AEs) occurred in 86.3% of avalglucosidase alfa-treated and 91.8% of alglucosidase alfa-treated participants. Five participants withdrew, 4 for AEs, all on alglucosidase alfa. Serious AEs occurred in 8 avalglucosidase alfa-treated and 12 alglucosidase alfa-treated participants. IgG antidrug antibody responses were similar in both. High titers and neutralizing antibodies were more common for alglucosidase alfa. Conclusions: Results demonstrate improvements in clinically meaningful outcome measures and a more favorable safety profile with avalglucosidase alfa versus alglucosidase alfa. Funding: Sanofi Genzym

Intrauterine growth restriction and placental angiogenesis

Background: Vascular endothelial growth factor (VEGF), basic-fibroblast growth factor (b-FGF), and endothelial nitric oxide synthase (eNOS) are factors that take part in placental angiogenesis. They are highly expressed during embryonic and fetal development, especially in the first trimester. In this study, we aimed to investigate the role of placental angiogenesis in the development of intrauterine growth restriction (IUGR) by comparing the levels of expression of VEGF-A, b-FGF, and eNOS in normal-term pregnancy and IUGR placentas.Methods: The expression of VEGF-A, b-FGF, and eNOS was studied using the avidin-biotin-peroxidase method in placental tissues diagnosed as normal (n = 55) and IUGR (n = 55). Results were evaluated in a semi-quantitative manner.Results: The expression of all the markers was significantly higher (p < 0.001) in cytotrophoblasts, syncytiotrophoblasts, extravillous trophoblasts, vascular smooth muscle cells, chorionic villous stromal cells, and villous vascular endothelial cells of the IUGR placentas when compared with those collected from normal-term pregnancies.Conclusion: Increased expression of VEGF-A, b-FGF, and eNOS may be the result of inadequate uteroplacental perfusion, supporting the proposal that abnormal angiogenesis plays a role in the pathophysiology of IUGR. © 2010 Barut et al; licensee BioMed Central Ltd

SMURF1 Amplification Promotes Invasiveness in Pancreatic Cancer

Pancreatic cancer is a deadly disease, and new therapeutic targets are urgently needed. We previously identified DNA amplification at 7q21-q22 in pancreatic cancer cell lines. Now, by high-resolution genomic profiling of human pancreatic cancer cell lines and human tumors (engrafted in immunodeficient mice to enrich the cancer epithelial fraction), we define a 325 Kb minimal amplicon spanning SMURF1, an E3 ubiquitin ligase and known negative regulator of transforming growth factor β (TGFβ) growth inhibitory signaling. SMURF1 amplification was confirmed in primary human pancreatic cancers by fluorescence in situ hybridization (FISH), where 4 of 95 cases (4.2%) exhibited amplification. By RNA interference (RNAi), knockdown of SMURF1 in a human pancreatic cancer line with focal amplification (AsPC-1) did not alter cell growth, but led to reduced cell invasion and anchorage-independent growth. Interestingly, this effect was not mediated through altered TGFβ signaling, assayed by transcriptional reporter. Finally, overexpression of SMURF1 (but not a catalytic mutant) led to loss of contact inhibition in NIH-3T3 mouse embryo fibroblast cells. Together, these findings identify SMURF1 as an amplified oncogene driving multiple tumorigenic phenotypes in pancreatic cancer, and provide a new druggable target for molecularly directed therapy

Integrin α3β1–dependent β-catenin phosphorylation links epithelial Smad signaling to cell contacts

Injury-initiated epithelial to mesenchymal transition (EMT) depends on contextual signals from the extracellular matrix, suggesting a role for integrin signaling. Primary epithelial cells deficient in their prominent laminin receptor, α3β1, were found to have a markedly blunted EMT response to TGF-β1. A mechanism for this defect was explored in α3-null cells reconstituted with wild-type (wt) α3 or point mutants unable to engage laminin 5 (G163A) or epithelial cadherin (E-cadherin; H245A). After TGF-β1 stimulation, wt epithelial cells but not cells expressing the H245A mutant internalize complexes of E-cadherin and TGF-β1 receptors, generate phospho-Smad2 (p-Smad2)–pY654–β-catenin complexes, and up-regulate mesenchymal target genes. Although Smad2 phosphorylation is normal, p-Smad2–pY654–β-catenin complexes do not form in the absence of α3 or when α3β1 is mainly engaged on laminin 5 or E-cadherin in adherens junctions, leading to attenuated EMT. These findings demonstrate that α3β1 coordinates cross talk between β-catenin and Smad signaling pathways as a function of extracellular contact cues and thereby regulates responses to TGF-β1 activation

Targeted Inactivation of p12Cdk2ap1, CDK2 Associating Protein 1, Leads to Early Embryonic Lethality

Targeted disruption of murine Cdk2ap1, an inhibitor of CDK2 function and hence G1/S transition, results in the embryonic lethality with a high penetration rate. Detailed timed pregnancy analysis of embryos showed that the lethality occurred between embryonic day 3.5 pc and 5.5 pc, a period of implantation and early development of implanted embryos. Two homozygous knockout mice that survived to term showed identical craniofacial defect, including a short snout and a round forehead. Examination of craniofacial morphology by measuring Snout Length (SL) vs. Face Width (FW) showed that the Cdk2ap1+/− mice were born with a reduced SL/FW ratio compared to the Cdk2ap1+/+ and the reduction was more pronounced in Cdk2ap1−/− mice. A transgenic rescue of the lethality was attempted by crossing Cdk2ap1+/− animals with K14-Cdk2ap1 transgenic mice. Resulting Cdk2ap1+/−:K14-Cdk2ap1 transgenic mice showed an improved incidence of full term animals (16.7% from 0.5%) on a Cdk2ap1−/− background. Transgenic expression of Cdk2ap1 in Cdk2ap1−/−:K14-Cdk2ap1 animals restored SL/FW ratio to the level of Cdk2ap1+/−:K14-Cdk2ap1 mice, but not to that of the Cdk2ap1+/+:K14-Cdk2ap1 mice. Teratoma formation analysis using mESCs showed an abrogated in vivo pluripotency of Cdk2ap1−/− mESCs towards a restricted mesoderm lineage specification. This study demonstrates that Cdk2ap1 plays an essential role in the early stage of embryogenesis and has a potential role during craniofacial morphogenesis

Prostate cancer in male BRCA1 and BRCA2 mutation carriers has a more aggressive phenotype

There is a high and rising prevalence of prostate cancer (PRCA) within the male population of the United Kingdom. Although the relative risk of PRCA is higher in male BRCA2 and BRCA1 mutation carriers, the histological characteristics of this malignancy in these groups have not been clearly defined. We present the histopathological findings in the first UK series of BRCA1 and BRCA2 mutation carriers with PRCA. The archived histopathological tissue sections of 20 BRCA1/2 mutation carriers with PRCA were collected from histopathology laboratories in England, Ireland and Scotland. The cases were matched to a control group by age, stage and serum PSA level of PRCA cases diagnosed in the general population. Following histopathological evaluation and re-grading according to current conventional criteria, Gleason scores of PRCA developed by BRCA1/2 mutation carriers were identified to be significantly higher (Gleason scores 8, 9 or 10, P=0.012) than those in the control group. Since BRCA1/2 mutation carrier status is associated with more aggressive disease, it is a prognostic factor for PRCA outcome. Targeting screening to this population may detect disease at an earlier clinical stage which may therefore be beneficial