Improving the prediction of the functional impact of cancer mutations by baseline tolerance transformation

High-throughput prioritization of cancer-causing mutations (drivers) is a key challenge of cancer genome projects, due to the number of somatic variants detected in tumors. One important step in this task is to assess the functional impact of tumor somatic mutations. A number of computational methods have been employed for that purpose, although most were originally developed to distinguish disease-related nonsynonymous single nucleotide variants (nsSNVs) from polymorphisms. Our new method, transformed Functional Impact score for Cancer (transFIC), improves the assessment of the functional impact of tumor nsSNVs by taking into account the baseline tolerance of genes to functional variants.

Role of structural saturation and geometry in the luminescence of silicon-based nanostructured materials

The structural saturation and stability, the energy gap, and the density of states of a series of small, silicon-based clusters have been studied by means of the PM3 and some ab initio (HF/6-31G* and 6-311++G**, CIS/6-31G* and MP2/6-31G*) calculations. It is shown that in order to maintain a stable nanometric and tetrahedral silicon crystallite and remove the gap states, the saturation atom or species such as H, F, Cl, OH, O, or N is necessary, and that both the cluster size and the surface species affect the energetic distribution of the density of states. This research suggests that the visible luminescence in the silicon-based nanostructured material essentially arises from the nanometric and crystalline silicon domains but is affected and protected by the surface species, and we have thus linked most of the proposed mechanisms of luminescence for the porous silicon, e.g., the quantum confinement effect due to the cluster size and the effect of Si-based surface complexes.

Gorilla genome structural variation reveals evolutionary parallelisms with chimpanzee

Structural variation has played an important role in the evolutionary restructuring of human and great ape genomes. Recent analyses have suggested that the genomes of chimpanzee and human have been particularly enriched for this form of genetic variation. Here, we set out to assess the extent of structural variation in the gorilla lineage by generating 10-fold genomic sequence coverage from a western lowland gorilla and integrating these data into a physical and cytogenetic framework of structural variation. We discovered and validated over 7665 structural changes within the gorilla lineage, including sequence resolution of inversions, deletions, duplications, and mobile element insertions. A comparison with human and other ape genomes shows that the gorilla genome has been subjected to the highest rate of segmental duplication. We show that both the gorilla and chimpanzee genomes have experienced independent yet convergent patterns of structural mutation that have not occurred in humans, including the formation of subtelomeric heterochromatic caps, the hyperexpansion of segmental duplications, and bursts of retroviral integrations. Our analysis suggests that the chimpanzee and gorilla genomes are structurally more derived than either orangutan or human genomes.

The effect of mutations in the DRY motif on the constitutive activity and structural instability of the histamine H(2) receptor.

In previous studies we showed that the wild-type histamine H(2) receptor stably expressed in Chinese hamster ovary cells is constitutively active. Because constitutive activity of the H(2) receptor is already found at low expression levels (300 fmol/mg protein) this receptor is a relatively unique member of the G-protein-coupled receptor (GPCR) family and a useful tool for studying GPCR activation. In this study the role of the highly conserved DRY motif in activation of the H(2) receptor was investigated. Mutation of the aspartate 115 residue in this motif resulted in H(2) receptors with high constitutive activity, increased agonist affinity, and increased signaling properties. In addition, the mutant receptors were shown to be highly structurally instable. Mutation of the arginine 116 residue in the DRY motif resulted also in a highly structurally instable receptor; expression of the receptor could only be detected after stabilization with either an agonist or inverse agonist. Moreover, the agonist affinity at the Arg-116 mutant receptors was increased, whereas the signal transduction properties of these receptors were decreased. We conclude that the Arg-116 mutant receptors can adopt an active conformation but have a decreased ability to couple to or activate the G(s)-protein. This study examines the pivotal role of the aspartate and arginine residues of the DRY motif in GPCR function. Disruption of receptor stabilizing constraints by mutation in the DRY motif leads to the formation of active GPCR conformations, but concomitantly to GPCR instability.

Silicon quantum dots embedded in a SiO2 matrix: From structural study to carrier transport properties

We study the details of electronic transport related to the atomistic structure of silicon quantum dots embedded in a silicon dioxide matrix using ab initio calculations of the density of states. Several structural and composition features of quantum dots (QDs), such as diameter and amorphization level, are studied and correlated with transport under transfer Hamiltonian formalism. The current is strongly dependent on the QD density of states and on the conduction gap, both dependent on the dot diameter. In particular, as size increases, the available states inside the QD increase, while the QD band gap decreases due to relaxation of quantum confinement. Both effects contribute to increasing the current with the dot size. Besides, valence band offset between the band edges of the QD and the silica, and conduction band offset in a minor grade, increases with the QD diameter up to the theoretical value corresponding to planar heterostructures, thus decreasing the tunneling transmission probability and hence the total current. We discuss the influence of these parameters on electron and hole transport, evidencing a correlation between the electron (hole) barrier value and the electron (hole) current, and obtaining a general enhancement of the electron (hole) transport for larger (smaller) QD. Finally, we show that crystalline and amorphous structures exhibit enhanced probability of hole and electron current, respectively.

Making a Modern Highway: Transformation of Iowa Roadways in the Mid-Twentieth Century, 2014

The booklet tells the history of the construction of the Iowa Highway 376 Bridge within the context of significant modernization and expansion of the highway system in Iowa in the 1950s. Curvy, narrow highways were widened and straightened and narrow iron truss bridges were replaced with more modern concrete and steel structures, changing the landscape of rural Iowa. Bridge engineer Herbert A Arthur, who designed the Iowa Highway 376 Bridge, was a prolific bridge engineer in the 1950s. This booklet serves to inform the public of this significant aspect of Iowa transportation history.

Structural variation and its effect on expression.

Structural variation, whether it is caused by copy number variants or present in a balanced form, such as reciprocal translocations and inversions, can have a profound and dramatic effect on the expression of genes mapping within and close to the rearrangement, as well as affecting others genome wide. These effects can be caused by altering the copy number of one or more genes or regulatory elements (dosage effect) or from physical disruption of links between regulatory elements and their associated gene or genes, resulting in perturbation of expression. Similarly, large-scale structural variants can result in genome-wide expression changes by altering the positions that chromosomes occupy within the nucleus, potentially disrupting not only local cis interactions, but also trans interactions that occur throughout the genome. Structural variation is, therefore, a significant factor in the study of gene expression and is discussed here in more detail.

High-Resolution Mass Spectrometry applied to the identification of new metabolites and transformation products of quinolones in chicken muscle tissues

The aim of this work was the identification of new metabolites and transformation products (TPs) in chicken muscle from Enrofloxacin (ENR), Ciprofloxacin (CIP), Difloxacin (DIF) and Sarafloxacin (SAR), which are antibiotics that belong to the fluoroquinolones family. The stability of ENR, CIP, DIF and SAR standard solutions versus pH degradation process (from pH 1.5 to 8.0, simulating the pH since the drug is administered until its excretion) and freeze-thawing (F/T) cycles was tested. In addition, chicken muscle samples from medicated animals with ENR were analyzed in order to identify new metabolites and TPs. The identification of the different metabolites and TPs was accomplished by comparison of mass spectral data from samples and blanks, using liquid chromatography coupled to quadrupole time-of-flight (LC-QqToF) and Multiple Mass Defect Filter (MMDF) technique as a pre-filter to remove most of the background noise and endogenous components. Confirmation and structure elucidation was performed by liquid chromatography coupled to linear ion trap quadrupole Orbitrap (LC-LTQ-Orbitrap), due to its mass accuracy and MS/MS capacity for elemental composition determination. As a result, 21 TPs from ENR, 6 TPs from CIP, 14 TPs from DIF and 12 TPs from SAR were identified due to the pH shock and F/T cycles. On the other hand, 14 metabolites were identified from the medicated chicken muscle samples. Formation of CIP and SAR, from ENR and DIF, respectively, and the formation of desethylene-quinolone were the most remarkable identified compounds.

Holism and structural realism

We first introduce structural realism as a position in the metaphysics of science, pointing out the way in which this position replaces intrinsic properties with relations so that it amounts to a holistic in contrast to an atomistic metaphysics. We argue in favour of a moderate version of structural realism that puts objects and relations on the same ontological footing and assess the general philosophical arguments for this position. The second section shows how structural realism gains support from quantum physics. The third section explains how structural realism can be applied to the metaphysics of space-time.

Synthetic Fabric to Improve Structural Capacity in Asphalt Overlays, HR-516, 1984

Iowa's first field application of synthetic engineering fabrics was on research project HR-158, "Prevention of Reflective Cracking in Asphalt Overlays". This research placed in September 1971 used three different engineering fabrics. A final report concluding generally favorable performance was distributed in May 1977. There have been a number of Iowa engineering fabric installations since that initial project.

Thermally-Induced Structural Transformations on Polymorphous Silicon

Polymorphous Si is a nanostructured form of hydrogenated amorphous Si that contains a small fraction of Si nanocrystals or clusters. Its thermally induced transformations such as relaxation, dehydrogenation, and crystallization have been studied by calorimetry and evolved gas analysis as a complementary technique. The observed behavior has been compared to that of conventional hydrogenated amorphous Si and amorphous Si nanoparticles. In the temperature range of our experiments (650700 C), crystallization takes place at almost the same temperature in polymorphous and in amorphous Si. In contrast, dehydrogenation processes reflect the presence of different hydrogen states. The calorimetry and evolved gas analysis thermograms clearly show that polymorphous Si shares hydrogen states of both amorphous Si and Si nanoparticles. Finally, the total energy of the main SiH group present in polymorphous Si has been quantified