Identification of a biomarker panel for colorectal cancer diagnosis

Background: Malignancies arising in the large bowel cause the second largest number of deaths from cancer in the Western World. Despite progresses made during the last decades, colorectal cancer remains one of the most frequent and deadly neoplasias in the western countries. Methods: A genomic study of human colorectal cancer has been carried out on a total of 31 tumoral samples, corresponding to different stages of the disease, and 33 non-tumoral samples. The study was carried out by hybridisation of the tumour samples against a reference pool of non-tumoral samples using Agilent Human 1A 60- mer oligo microarrays. The results obtained were validated by qRT-PCR. In the subsequent bioinformatics analysis, gene networks by means of Bayesian classifiers, variable selection and bootstrap resampling were built. The consensus among all the induced models produced a hierarchy of dependences and, thus, of variables. Results: After an exhaustive process of pre-processing to ensure data quality–lost values imputation, probes quality, data smoothing and intraclass variability filtering–the final dataset comprised a total of 8, 104 probes. Next, a supervised classification approach and data analysis was carried out to obtain the most relevant genes. Two of them are directly involved in cancer progression and in particular in colorectal cancer. Finally, a supervised classifier was induced to classify new unseen samples. Conclusions: We have developed a tentative model for the diagnosis of colorectal cancer based on a biomarker panel. Our results indicate that the gene profile described herein can discriminate between non-cancerous and cancerous samples with 94.45% accuracy using different supervised classifiers (AUC values in the range of 0.997 and 0.955).

[G_Oñati_Arantzazu] Documentación fotográfica del Apostolado y la Piedad del exterior del Monasterio de Arantzazu (Oñati, Gipuzkoa)

[ES] Conjunto de figuras en piedra de gran porte (unos 4 metros de altura cada una), lo componen 14 figuras en la zona baja del apostolado y un conjunto de 2 personajes más formando la Piedad en la parte superior. Se trata de formas esquemáticas de perfil redondeado que corresponden artísticamente a una de las corrientes más destacadas del siglo XX.

Numerical Analyses of Transonic Fluid/Structure interaction in Aircraft Engineering

Through the coupling between aerodynamic and structural governing equations, a fully implicit multiblock aeroelastic solver was developed for transonic fluid/stricture interaction. The Navier-Stokes fluid equations are solved based on LU-SGS (lower-upper symmetric Gauss-Seidel) Time-marching subiteration scheme and HLLEW (Harten-Lax-van Leer-Einfeldt-Wada) spacing discretization scheme and the same subiteration formulation is applied directly to the structural equations of motion in generalized coordinates. Transfinite interpolation (TFI) is used for the grid deformation of blocks neighboring the flexible surfaces. The infinite plate spline (IPS) and the principal of virtual work are utilized for the data transformation between fluid and structure. The developed code was fort validated through the comparison of experimental and computational results for the AGARD 445.6 standard aeroelastic wing. In the subsonic and transonic range, the calculated flutter speeds and frequencies agree well with experimental data, however, in the supersonic range, the present calculation overpredicts the experimental flutter points similar to other computations. Then the flutter character of a complete aircraft configuration is analyzed through the calculation of the change of structural stiffness. Finally, the phenomenon of aileron buzz is simulated for the weakened model of a supersonic transport wing/body model at Mach numbers of 0.98 and l.05. The calculated unsteady flow shows, on the upper surface, the shock wave becomes stronger as the aileron deflects downward, and the flow behaves just contrary on the lower surface of the wing. Corresponding to general theoretical analysis, the flow instability referred to as aileron buzz is induced by a stronger shock alternately moving on the upper and lower surfaces of wing. For the rigid structural model, the flow is stable at all calculated Mach numbers as observed in experiment

Submarine landslides : selected studies in the U.S. Exclusive Economic Zone

Submarine Landslides: An Introduction 1 By RIo Lee, W.C. Schwab, and J.S. Booth U.S. Atlantic Continental Slope Landslides: Their Distribution, General Anributes, and Implications 14 By J.S. Booth, D.W. O'Leary, Peter Popenoe, and W.W. Danforth Submarine Mass Movement, a Formative Process of Passive Continental Margins: The Munson-Nygren Landslide Complex and the Southeast New England Landslide Complex 23 By D.W. O'Leary The Cape Fear Landslide: Slope Failure Associated with Salt Diapirism and Gas Hydrate Decomposition 40 By Peter Popenoe, E.A. Schmuck, and W.P. Dillon Ancient Crustal Fractures Control the Location and Size of Collapsed Blocks at the Blake Escarpment, East of Florida 54 By W.P. Dillon, J.S. Risch, K.M. Scanlon, P.C. Valentine, and Q.J. Huggett Tectonic and Stratigraphic Control on a Giant Submarine Slope Failure: Puerto Rico Insular Slope 60 By W.C. Schwab, W.W. Danforth, and K.M. Scanlon Slope Failure of Carbonate Sediment on the West Florida Slope 69 By D.C. Twichell, P.C. Valentine, and L.M. Parson Slope Failures in an Area of High Sedimentation Rate: Offshore Mississippi River Delta 79 By J.M. Coleman, D.B. Prior, L.E. Garrison, and H.J. Lee Salt Tectonics and Slope Failure in an Area of Salt Domes in the Northwestern Gulf of Mexico 92 By B.A. McGregor, R.G. Rothwell, N.H. Kenyon, and D.C. Twichell Slope Stability in Regions 01 Sea-Floor Gas Hydrate: Beaufort Sea Continental Slope 97 By R.E. Kayen and H.J. Lee Mass Movement Related to Large Submarine Canyons Along the Beringian Margin, Alaska 104 By P.R. Carlson, H.A. Karl, B.D. Edwards, J.V. Gardner, and R. Hall Comparison of Tectonic and Stratigraphic Control of Submarine Landslides on the Kodiak Upper Continental Slope, Alaska 117 By M.A. Hampton Submarine Landslides That Had a Significant Impact on Man and His Activities: Seward and Valdez, Alaska 123 By M.A. Hampton, R.W. Lemke, and H.W. Coulter Processes Controlling the Style of Mass Movement in Glaciomarine Sediment: Northeastern Gulf of Alaska 135 By W.C. Schwab and H.J. Lee Contents V VI Contents Liquefaction of Continental Shelf Sediment: The Northern California Earthquake of 1980 143 By M.E. Field A Submarine Landslide Associated with Shallow Sea-Floor Gas and Gas Hydrates off Northern California 151 By M.E. Field and J.H. Barber, Jr. Sur Submarine Landslide, a Deep-Water Sediment Slope Failure 158 By C.E. Gutmacher and W.R. Normark Seismically Induced Mudflow in Santa Barbara Basin, California 167 By B.D. Edwards, H.J. Lee, and M.E. Field Submarine Landslides in a Basin and Ridge Setting, Southern California 176 By M.E. Field and B.D. Edwards Giant Volcano-Related Landslides and the Development of the Hawaiian Islands 184 By W.R. Normark, J.G. Moore, and M.E. Torresan Submarine Slope Failures Initiated by Hurricane Iwa, Kahe Point, Oahu, Hawaii 197 By W.R. Normark, Pat Wilde, J.F. Campbell, T.E. Chase, and Bruce Tsutsui (PDF contains 210 pages)

三维离散元改进算法及其在三峡永久船闸高边坡工程中的应用

本文根据面－面接触模型，写出了三维离散元的物理方程及运动方程，对于接触刚度、阻尼系数、时步、计算控制及块体的滑动失稳判据等作了讨论。在NURBM－3D 长方体单元基础上改进了其划分单元的算法，依据岩体中三组真实的节理面划分平行六面体单元，实现了网格的自动剖分，从而可以将单元视为真实的岩块，更客观地体现了节理面对岩体稳定性的影响。运用改进后的三维离散元方法，编制了计算程序，对三峡工程永久船闸高连坡开挖进行了模拟。计算过程包括初始地应力场模拟、岩体开挖过程两个阶段。模拟计算首先给出了为水平、垂直节理面所切割的长方体单元情况下的应力场分析，考证了程序的可行性。将已有的三峡永久船闸实测节理简化为三组节理，完成了初始地应力场的模拟，给出了分四步开挖后的岩体位移场和应力场，计算出岩体开挖过程中产生滑动块体的位置，其结果可以定性地表明：沿节理面的块体滑动是边坡失稳的主要模式。编制的后处理程序提供了计算数据库与绘图软件Origin的接口，可以画出任意剖面或节理面上的应力等值线、位移矢量图及滑动块体分布图，由此可以直观判断岩体不稳定区域和高应力区范围。编制的计算程序在PC机上计算了10万块体单元，用于模拟大型工程，其计算结果与有限元及类似的连续介质模型相比更为合理，为用离散元法进一步研究可变形块体及岩体的蠕变提供了一种切实可行的工具。将离散元法应用于大型工程三维计算是可行的，但在本构模型建立、岩体破坏参数选择等方面均有等于更深入的研究，其结果也有待于更多工程的验证。

Hydrazides and hydrazones as versatile Michael-Donors for iminium-catalyzed conjugate addition reactions

396 : il., graf.

1-42 beta-Amyloid peptide requires PDK1/nPKC/Rac 1 pathway to induce neuronal death

1-42 beta-Amyloid (A beta(1-42)) peptide is a key molecule involved in the development of Alzheimer's disease. Some of its effects are manifested at the neuronal morphological level. These morphological changes involve loss of neurites due to cytoskeleton alterations. However, the mechanism of A beta(1-42) peptide activation of the neurodegenerative program is still poorly understood. Here, A beta(1-42) peptide-induced transduction of cellular death signals through the phosphatidylinositol 3-kinase (PI3K)/phosphoinositol- dependent kinase (PDK)/novel protein kinase C (nPKC)/Rac 1 axis is described. Furthermore, pharmacological inhibition of PDK1 and nPKC activities blocks Rac 1 activation and neuronal cell death. Our results provide insights into an unsuspected connection between PDK1, nPKCs and Rac 1 in the same signal-transduction pathway and points out nPKCs and Rac 1 as potential therapeutic targets to block the toxic effects of A beta(1-42) peptide in neurons.

Role of G protein coupled inwardly rectifier K+ channels (GIRK) on the neurobiology depression

353 págs.

Asymmetric organocatalytic cascade reactions

302 p. : gráf.

Qualitätsvergleich zwischen panierten Filetportionen aus einfach- und doppelgefrorenen TK-Blöcken

Single and double frozen fillet blocks of Alaska pollack and cod both commercially processed of unknown shelf life were further processed to breaded battered portions. The quality of these fillet portions were compared using sensory (QDA), physical and chemical methods. It was difficult to differentiate between SF and DF fillets by sensory method because of the absence of differences in flavour attributes. While no differences could to be found in the texture of cod fillets, in Alaska pollack fillets some texture attributes were significantly different. These differences could not be verified by instrumental texture measurement. In all cases the lightness was different between SF and DF fillets. Probably, after having fixed L* values for SF fillets of commercially important fish species as limit this could be employed in the future to differentiate between single and double frozen products. Due to the unknown shelf life it is difficult to evaluate the results. Therefore, the investigation of the influence of double freezing on the quality needs a special sample preparation. The use of randomly taken commercially processed samples seems not to be useful.

High-Strength Composite Fibers: Realizing True Potential of Carbon Nanotubes in Polymer Matrix through Continuous Reticulate Architecture and Molecular Level Couplings

Carbon nanotubes have unprecedented mechanical properties as defect-free nanoscale building blocks, but their potential has not been fully realized in composite materials due to weakness at the interfaces. Here we demonstrate that through load-transfer-favored three-dimensional architecture and molecular level couplings with polymer chains, true potential of CNTs can be realized in composites as Initially envisioned. Composite fibers with reticulate nanotube architectures show order of magnitude improvement in strength compared to randomly dispersed short CNT reinforced composites reported before. The molecular level couplings between nanotubes and polymer chains results in drastic differences in the properties of thermoset and thermoplastic composite fibers, which indicate that conventional macroscopic composite theory falls to explain the overall hybrid behavior at nanoscale.

Discrepancias en el seno de la burguesía guipuzcoana en torno a la libertad de comercio y el traslado de aduanas durante los siglos XVIII y XIX

[ES] El objetivo del presente artículo es demostrar y analizar las discrepancias que hubo en el seno de la burguesía guipuzcoana durante los siglos XVIII y XIX en torno a la habilitación de los puertos guipuzcoanos para el comercio directo con América y el traslado de aduanas desde el interior a la costa. Para ello, se acude a la extensa historiografía que se ha ocupado del tema y se hace un análisis crítico de cierto número de representaciones enviadas por el grupo de comerciantes disidentes, con el fin de llevar a cabo un reco- rrido por el debate en torno a ambas cuestiones, que se prolongó desde el advenimiento de la dinastía borbónica hasta los decretos de 1841. A pesar de la visión unívoca que se ha dado del mencionado debate, según la cual parti- ciparon dos bloques perfectamente diferenciados, la documentación muestra una mayor heterogeneidad en las posturas, de manera que en el seno de la burguesía comercial se perciben ciertas divisiones y discrepancias. Si bien es cierto que en un principio los bloques parecen tener un discurso claramente beligerante, aunque también existen todavía puntos de coincidencia, a medi- da que transcurre el tiempo, las posturas se van radicalizando y diversifi- cando, creando una mayor heterogeneidad.

Einfluß von Eis- und Tiefgefrierlagerung/Auftauen auf die Länge von Seefischfilets

The objective was to study the influence of biological and processing conditions on the evaluation of a conversion factor between fillet length and fish size. This paper presents changes of the length and weight of skinless fillets from various marine fish species in relation to the ice storage time and to the deep freezing / thawing process. The biochemical changes during rigor mortis lead to considerable reduction in length of skinless fillets during ice storage and deep freezing / thawing of fillet blocks. The investigations were undertaken during various cruises of the FFS „Walther Herwig III“.

Non-contiguous protein recombination

Swapping sequence elements among related proteins can produce chimeric proteins with novel behaviors and improved properties such as enhanced stability. Although homologous mutations are much more conservative than random mutations, chimeras of distantly-related proteins have a low probability of retaining fold and function. Here, I introduce a new tool for protein recombination that identifies structural blocks that can be swapped among homologous proteins with minimal disruption. This non-contiguous recombination approach enables design of chimeras and libraries of chimeras with less disruption than can be achieved by swapping blocks of sequence. Less disruption means that one can generate libraries with higher fractions of functional enzymes and enables recombination of more distant homologs.

Using this new tool I design and construct many functional chimeric cellulases. I illustrate the structurally conservative nature of this recombination by creating a functional prokaryotic-eukaryotic chimera and solving its structure. I also show how non-contiguous recombination can be used to efficiently identify stabilizing mutations that have been incorporated into homologs in nature.

Pharmacology and pore-forming domains of the cystic fibrosis transmembrane conductance regulator

The cystic fibrosis transmembrane conductance regulator (CFTR) is a chloride channel member of the ATP-binding cassette (ABC) superfamily of membrane proteins. CFTR has two homologous halves, each consisting of six transmembrane spanning domains (TM) followed by a nucleotide binding fold, connected by a regulatory (R) domain. This thesis addresses the question of which domains are responsible for Cl^- selectivity, i.e., which domains line the channel pore.

To address this question, novel blockers of CFTR were characterized. CFTR was heterologously expressed in Xenopus oocytes to study the mechanism of block by two closely related arylaminobenzoates, diphenylamine-2-carboxylic acid (DPC) and flufenamic acid (FFA). Block by both is voltage-dependent, with a binding site ≈ 40% through the electric field of the membrane. DPC and FFA can both reach their binding site from either side of the membrane to produce a flickering block of CFTR single channels. In addition, DPC block is influenced by Cl^- concentration, and DPC blocks with a bimolecular forward binding rate and a unimolecular dissociation rate. Therefore, DPC and FFA are open-channel blockers of CFTR, and a residue of CFTR whose mutation affects their binding must line the pore.

Screening of site-directed mutants for altered DPC binding affinity reveals that TM-6 and TM-12 line the pore. Mutation of residue 5341 in TM-6 abolishes most DPC block, greatly reduces single-channel conductance, and alters the direction of current rectification. Additional residues are found in TM-6 (K335) and TM-12 (T1134) whose mutations weaken or strengthen DPC block; other mutations move the DPC binding site from TM-6 to TM-12. The strengthened block and lower conductance due to mutation T1134F is quantitated at the single-channel level. The geometry of DPC and of the residues mutated suggest α-helical structures for TM-6 and TM-12. Evidence is presented that the effects of the mutations are due to direct side-chain interaction, and not to allosteric effects propagated through the protein. Mutations are also made in TM-11, including mutation S1118F, which gives voltage-dependent current relaxations. The results may guide future studies on permeation through ABC transporters and through other Cl^- channels.