Quantifying the Energetics and Length Scales of Carbon Segregation to Fe Symmetric Tilt Grain Boundaries Using Atomistic Simulations

Segregation of impurities to grain boundaries plays an important role in both the stability and macroscopic behavior of polycrystalline materials. The research objective in this work is to better characterize the energetics and length scales involved with the process of solute and impurity segregation to grain boundaries. Molecular dynamics simulations are used to calculate the segregation energies for carbon within multiple grain boundary sites over a database of 125 symmetric tilt grain boundaries in Fe. The simulation results show that the majority of atomic sites near the grain boundary have segregation energies lower than in the bulk. Moreover, depending on the boundary, the segregation energies approach the bulk value approximately 5-12 \AA\ away from the center of the grain boundary, providing an energetic length scale for carbon segregation. A subsequent data reduction and statistical representation of this dataset provides critical information such as about the mean segregation energy and the associated energy distributions for carbon atoms as a function of distance from the grain boundary, which quantitatively informs higher scale models with energetics and length scales necessary for capturing the segregation behavior of impurities in Fe. The significance of this research is the development of a methodology capable of ascertaining segregation energies over a wide range of grain boundary character (typical of that observed in polycrystalline materials), which herein has been applied to carbon segregation in a specific class of grain boundaries in iron

Activity of a Novel bcl-2/bcl-xL-Bispecific Antisense Oligonucleotide Against Tumors of Diverse Histologic Origins

Background: Increased expression of the anti-apoptotic proteins Bcl-2 and Bcl-xL is involved in the development and progression of many tumors. We recently reported that the bcl-2/bcl-xL-bispecific antisense oligonucleotide 4625 induces apoptosis in lung carcinoma cells. To further assess the therapeutic potential of oligonucleotide 4625, we investigated its effect on a series of human tumor cell lines of diverse histologic origins in vitro and in vivo. Methods: Oligonucleotide 4625-mediated inhibition of bcl-2 and bcl-xL expression in vitro was measured in breast carcinoma cells with the use of reverse transcription-polymerase chain reaction (PCR), real-time PCR, and western blotting. Cytotoxicity was assessed in several different cell lines by measurement of tumor cell growth, propidium iodide uptake, and nuclear apoptosis. The in vivo activity of oligonucleotide 4625 was determined by the inhibition of growth of established tumor xenografts in nude mice, immunohistochemical staining of Bcl-2 and Bcl-x proteins in the tumors, and western blotting of tumor lysates. Apoptosis in tumor xenografts was detected with the use of in situ TUNEL (i.e., terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-digoxigenin nick end labeling) staining. All statistical tests are two-sided. Results: In breast carcinoma cells, oligonucleotide 4625 treatment reduced bcl-2 and bcl-xL messenger RNA levels in a dose-dependent manner. At 600 nM, oligonucleotide 4625 reduced Bcl-2 and Bcl-xL protein levels to 25% (95% confidence interval [CI] = 16% to 34%) and 20% (95% CI = 14% to 26%), respectively, of the levels in untreated cells and it decreased viability in all cell lines mainly by inducing apoptosis. In vivo, oligonucleotide 4625 statistically significantly inhibited the growth of breast and colorectal carcinoma xenografts by 51% (95% CI = 28% to 74%) and 59% (95% CI = 44% to 74%), respectively, relative to those treated with control oligonucleotide 4626; it also reduced Bcl-2 and Bcl-xL protein levels and induced tumor cell apoptosis. Conclusion: The bcl-2/bcl-xL-bispecific antisense oligonucleotide 4625 merits further study as a novel compound for cancer therap

Identification of a new murine tumor necrosis factor receptor locus that contains two novel murine receptors for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL).

Tumor necrosis factor (TNF) ligand and receptor superfamily members play critical roles in diverse developmental and pathological settings. In search for novel TNF superfamily members, we identified a murine chromosomal locus that contains three new TNF receptor-related genes. Sequence alignments suggest that the ligand binding regions of these murine TNF receptor homologues, mTNFRH1, -2 and -3, are most homologous to those of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors. By using a number of in vitro ligand-receptor binding assays, we demonstrate that mTNFRH1 and -2, but not mTNFRH3, bind murine TRAIL, suggesting that they are indeed TRAIL receptors. This notion is further supported by our demonstration that both mTNFRH1:Fc and mTNFRH2:Fc fusion proteins inhibited mTRAIL-induced apoptosis of Jurkat cells. Unlike the only other known murine TRAIL receptor mTRAILR2, however, neither mTNFRH2 nor mTNFRH3 has a cytoplasmic region containing the well characterized death domain motif. Coupled with our observation that overexpression of mTNFRH1 and -2 in 293T cells neither induces apoptosis nor triggers NFkappaB activation, we propose that the mTnfrh1 and mTnfrh2 genes encode the first described murine decoy receptors for TRAIL, and we renamed them mDcTrailr1 and -r2, respectively. Interestingly, the overall sequence structures of mDcTRAILR1 and -R2 are quite distinct from those of the known human decoy TRAIL receptors, suggesting that the presence of TRAIL decoy receptors represents a more recent evolutionary event

Convergent origination of a Drosophila-like dosage compensation mechanism in a reptile lineage

Sex chromosomes differentiated from different ancestral autosomes in various vertebrate lineages. Here, we trace the functional evolution of the XY Chromosomes of the green anole lizard (Anolis carolinensis), on the basis of extensive high-throughput genome, transcriptome and histone modification sequencing data and revisit dosage compensation evolution in representative mammals and birds with substantial new expression data. Our analyses show that Anolis sex chromosomes represent an ancient XY system that originated at least ≈160 million years ago in the ancestor of Iguania lizards, shortly after the separation from the snake lineage. The age of this system approximately coincides with the ages of the avian and two mammalian sex chromosomes systems. To compensate for the almost complete Y Chromosome degeneration, X-linked genes have become twofold up-regulated, restoring ancestral expression levels. The highly efficient dosage compensation mechanism of Anolis represents the only vertebrate case identified so far to fully support Ohno’s original dosage compensation hypothesis. Further analyses reveal that X up-regulation occurs only in males and is mediated by a male-specific chromatin machinery that leads to global hyperacetylation of histone H4 at lysine 16 specifically on the X Chromosome. The green anole dosage compensation mechanism is highly reminiscent of that of the fruit fly, Drosophila melanogaster. Altogether, our work unveils the convergent emergence of a Drosophila-like dosage compensation mechanism in an ancient reptilian sex chromosome system and highlights that the evolutionary pressures imposed by sex chromosome dosage reductions in different amniotes were resolved in fundamentally different ways

Prevalence of renal impairment and its association with cardiovascular risk factors in a general population: results of the Swiss SAPALDIA study

Background. Impaired renal function is evolving as an independent marker of the risk of cardiovascular morbidity and mortality. Little is known about the prevalence of impaired renal function and its relationship to cardiovascular risk factors in the Swiss general population. Methods. SAPALDIA comprises a random sample of the Swiss population established in 1991, originally to investigate the health effects of long-term exposure to air pollution. Participants were reassessed in 2002/3 and blood measurements were obtained (n = 6317). Renal function was estimated using the Cockcroft-Gault equation and the modified MDRD (four-component) equation incorporating age, race, gender and serum creatinine level. Results. The estimated prevalence of impaired renal function [estimated glomerular filtration rate <60 ml/min/1.73 m2] differed substantially between men and women, particularly at higher ages, and amounted to 13% [95% confidence interval (CI) 10-16%] and 36% (95% CI 32-40%) in men and women, respectively, of 65 years or older. Smoking, obesity, blood lipid levels, high systolic blood pressure and hyperuricaemia were all more common in men when compared with women. These cardiovascular risk factors were also associated independently with creatinine in both women and men. Women were less likely to receive cardiovascular drugs, in particular angiotensin-converting enzyme inhibitors and β-blockers, when compared with men of the same age. Conclusion. Moderate renal impairment seems to be prevalent in the general population, with an apparent excess in females which is not explained by conventional cardiovascular risk factors. The unexpected finding questions the validity of the prediction equations, in particular in female

Use it or lose it! Cognitive activity as a protec-tive factor for cognitive decline associated with Alzheimer's disease.

Because of the worldwide aging of populations, Alzheimer's disease and other dementias constitute a devastating experience for patients and families as well as a major social and economic burden for both healthcare systems and society. Multiple potentially modifiable cardiovascular and lifestyle risk factors have been associated with this disease. Thus, modifying these risk factors and identifying protective factors represent important strategies to prevent and delay disease onset and to decrease the social burden. Based on the cognitive reserve hypothesis, evidence from epidemiological studies shows that low education and cognitive inactivity constitute major risk factors for dementia. This indicates that a cognitively active lifestyle may protect against cognitive decline or delay the onset of dementia. We describe a newly developed preventive programme, based on this evidence, to stimulate and increase cognitive activity in older adults at risk for cognitive decline. This programme, called "BrainCoach", includes the technique of "motivational interviewing" to foster behaviour change. If the planned feasibility study is successful, we propose to add BrainCoach as a module to the already existing "Health Coaching" programme, a Swiss preventive programme to address multiple risk factors in primary care

EMI Security Architecture

This document describes the various architectures of the three middlewares that comprise the EMI software stack. It also outlines the common efforts in the security area that allow interoperability between these middlewares. The assessment of the EMI Security presented in this document was performed internally by members of the Security Area of the EMI project

The CPLEAR Electromagnetic Calorimeter

A large-acceptance lead/gas sampling electromagnetic calorimeter (ECAL) was constructed for the CPLEAR experiment to detect photons from decays of $\pi^0$s with momentum $p_{\pi^0} \le 800$ MeV$/c$. The main purpose of the ECAL is to determine the decay vertex of neutral-kaon decays \ko \rightarrow \pi^0\pi^0 \rightarrow 4 \gamma and \ko \rightarrow \pi^0\pi^0\pi^0 \rightarrow 6 \gamma. This requires a position-sensitive photon detector with high spatial granularity in $r$-, $\varphi$-, and $z$-coordinates. The ECAL --- a barrel without end-caps located inside a magnetic field of 0.44 T --- consists of 18 identical concentric layers. Each layer of $1/3$ radiation length (X${_0}$) contains a converter plate followed by small cross-section high-gain tubes of 2640 mm active length which are sandwiched by passive pick-up strip plates. The ECAL, with a total of $6$ X${_0}$, has an energy resolution of $\sigma (E)/E \approx 13\% / \sqrt{E(\mathrm{GeV})}$ and a position resolution of 4.5 mm for the shower foot. The shower topology allows separation of electrons from pions. The design, construction, read-out electronics, and performance of the detector are described

What is Intellectual Freedom Today? An Invitation to Think the Event

The pubmed search term “pastoris[Title] AND (express[Title] OR produced[Title] OR expression[Title] OR production[Title])” yielded 877 hits in December 2008, dated from 1987 to 2009. At the same time, the search term “pastoris[Title] AND (bioreactor[Title] OR fed-batch[Title] OR continuous[Title] OR fermentations[Title] OR large-scale[Title] OR fermentation[Title] OR pilot[Title])” returned 92 hits –published between 1990 and 2009. This analysis is somewhat superficial and ostentatious, but it suggests that the majority of researchers publishing on Pichia use it as a tool for rather than an object of their work. This is not to say that the majority should change their focus, but in fact researchers sometimes face difficulties when the need to obtain useful amounts of a target protein produced in Pichia calls for scale-up from the benchtop protocols to a bioreactor-based process. This chapter attempts to provide a reliable protocol for AOX1-driven bioreactor production of secreted scFvs or other proteins

Combining integral equation closures with force density functional theory for the study of inhomogeneous fluids

Classical density functional theory (DFT) is a powerful framework to study inhomogeneous fluids. Its standard form is based on the knowledge of a generating free energy functional. If this is known exactly, then the results obtained by using standard DFT or its alternative, recently developed version, force–DFT, are the same. If the free energy functional is known only approximately then these two routes produce different outcomes. However, as we show in this work, force–DFT has the advantage that it is also implementable without knowledge of the free energy functional, by using instead liquid-state integral equation closures. This broadens the range of systems that can be explored, since free energy functionals are generally difficult to approximate. In this paper we investigate the utility of using inhomogeneous integral equation closures within force–DFT thus demonstrating the versatility and accuracy of this approach