Sharp comparison and maximum principles via horizontal normal mapping in the Heisenberg group

In this paper we solve a problem raised by Gutiérrez and Montanari about comparison principles for H−convex functions on subdomains of Heisenberg groups. Our approach is based on the notion of the sub-Riemannian horizontal normal mapping and uses degree theory for set-valued maps. The statement of the comparison principle combined with a Harnack inequality is applied to prove the Aleksandrov-type maximum principle, describing the correct boundary behavior of continuous H−convex functions vanishing at the boundary of horizontally bounded subdomains of Heisenberg groups. This result answers a question by Garofalo and Tournier. The sharpness of our results are illustrated by examples.

Molecular epidemiological studies on genetic predispositions to squamous cell carcinoma of the head and neck

Two molecular epidemiological studies were conducted to examine associations between genetic variation and risk of squamous cell carcinoma of the head and neck (SCCHN). In the first study, we hypothesized that genetic variation in p53 response elements (REs) may play roles in the etiology of SCCHN. We selected and genotyped five polymorphic p53 REs as well as a most frequently studied p53 codon 72 (Arg72Pro, rs1042522) polymorphism in 1,100 non-Hispanic White SCCHN patients and 1,122 age-and sex-matched cancer-free controls recruited at The University of Texas M. D. Anderson Cancer Center. In multivariate logistic regression analysis with adjustment for age, sex, smoking and drinking status, marital status and education level, we observed that the EOMES rs3806624 CC genotype had a significant effect of protection against SCCHN risk (adjusted odds ratio= 0.79, 95% confidence interval =0.64–0.98), compared with the -838TT+CT genotypes. Moreover, a significantly increased risk associated with the combined genotypes of p53 codon 72CC and EOMES -838TT+CT was observed, especially in the subgroup of non-oropharyneal cancer patients. The values of false-positive report probability were also calculated for significant findings. In the second study, we assessed the association between SCCHN risk and four potential regulatory single nucleotide polymorphisms (SNPs) of DEC1 (deleted in esophageal cancer 1) gene, a candidate tumor suppressor gene for esophageal cancer. After adjustment for age, sex, and smoking and drinking status, the variant -606CC (i.e., -249CC) homozygotes had a significantly reduced SCCHN risk (adjusted odds ratio = 0.71, 95% confidence interval = 0.52–0.99), compared with the -606TT homozygotes. Stratification analyses showed that a reduced risk associated with the -606CC genotype was more pronounced in subgroups of non-smokers, non-drinkers, younger subjects (defined as ≤ 57 years), carriers of TP53 Arg/Arg (rs1042522) genotype, patients with oropharyngeal cancer or late-stage SCCHN. Further in silico analysis revealed that the -249 T-to-C change led to a gain of a transcription factor binding site. Additional functional analysis showed that the -249T-to-C change significantly enhanced transcriptional activity of the DEC1 promoter and the DNA-protein binding activity. We conclude that the DEC1 promoter -249 T>C (rs2012775) polymorphism is functional, modulating susceptibility to SCCHN among non-Hispanic Whites. Additional large-scale, preferably population-based studies are needed to validate our findings.^

IDENTIFYING GENETIC VARIANTS AND CHARACTERIZING THEIR ROLE IN CLUBFOOT

Clubfoot is a common, complex birth defect affecting 4,000 newborns in the United States and 135,000 world-wide each year. The clubfoot deformity is characterized by inward and rigid downward displacement of one or both feet, along with persistent calf muscle hypoplasia. Despite strong evidence for a genetic liability, there is a limited understanding of the genetic and environmental factors contributing to the etiology of clubfoot. The studies described in this dissertation were performed to identify variants and/or genes associated with clubfoot. Genome-wide linkage scan performed on ten multiplex clubfoot families identified seven new chromosomal regions that provide new areas to search for clubfoot genes. Troponin C (TNNC2) the strongest candidate gene, located in 20q12-q13.11, is involved in muscle contraction. Exon sequencing of TNNC2 did not identify any novel coding variants. Interrogation of fifteen muscle contraction genes found strong associations with SNPs located in potential regulatory regions of TPM1 (rs4075583 and rs3805965), TPM2 (rs2025126 and rs2145925) and TNNC2 (rs383112 and rs437122). In previous studies, a strong association was found with rs3801776 located in the basal promoter of HOXA9, a gene also involved in muscle development and patterning. Altogether, this data suggests that SNPs located in potential regulatory regions of genes involved in muscle development and function could alter transcription factor binding leading to changes in gene expression. Functional analysis of 3801776/HOXA9, rs2025126/TPM2 and rs2145925/TPM2 showed altered protein binding, which significantly influenced promoter activity. Although the ancestral allele (G) of rs4075583/TPM1 creates a DNA-protein complex, it did not affect TPM1 promoter activity. However and importantly, in the context of a haplotype, rs4075583/G significantly decreased TPM1 promoter activity. These results suggest dysregulation of multiple skeletal muscle genes, TPM1, TPM2, TNNC2 and HOXA9, working in concert may contribute to clubfoot. However, specific allelic combinations involving these four regulatory SNPs did not confer a significantly higher risk for clubfoot. Other combinations of these variants are being evaluated. Moreover, these variants may interact with yet to be discovered variants in other genes to confer a higher clubfoot risk. Collectively, we show novel evidence for the role of skeletal muscle genes in clubfoot indicating that there are multiple genetic factors contributing to this complex birth defect.

{\it cis\/} -acting elements and {\it trans\/} -acting factors that control serum amyloid A gene expression during inflammation

To understand how the serum amyloid A (SAA) genes are regulated, the cis-acting elements and trans-acting factors involved in the regulation of mouse SAA3 and rat SAA1 genes expression during inflammation were analyzed.^ To identify DNA sequences involved in the liver-specific expression of the mouse SAA3 gene, the 5$\sp\prime$ flanking region of this gene was analyzed by transient transfection studies. Results suggest that C/EBP, a liver-enriched transcription factor, plays an important role for the enhanced expression of the mouse SAA3 gene in hepatocytes.^ Transfection studies of the regulation of the expression of rat SAA1 gene indicated that a 322 bp fragment ($-$304 to +18) of the gene contains sufficient information for cytokine-induced expression of the reporter gene in a liver cell-specific manner. Further functional analysis of the 5$\sp\prime$ flanking region of the rat SAA1 gene demonstrated that a 65 bp DNA fragment ($-$138/$-$73) can confer cytokine-inducibility onto a heterologous promoter both in liver and nonliver cells. DNase I footprint and gel retardation assays identified five putative cis-regulatory elements within the 5$\sp\prime$ flanking region of the gene: one inducible element, a NF$\kappa$B binding site and four constitutive elements. Two constitutive elements, footprint regions I and III, were identified as C/EBP binding sites with region III having over a 10-fold higher affinity for C/EBP binding than region I. Functional analysis of the cis-elements indicated that C/EBP(I) and C/EBP(III) confer liver cell-specific activation onto a heterologous promoter, while sequences corresponding to the NF$\kappa$B element and C/EBP(I) impart cytokine responsiveness onto the heterologous promoter. These results suggest that C/EBP(I) possesses two functions: liver-specific activation and cytokine responsiveness. The identification of two cytokine responsive elements (NF$\kappa$B and C/EBP(I)), and two liver-specific elements (C/EBP(I) and C/EBP(III)) implies that multiple cis-acting elements are involved in the regulation of the expression of the rat SAA1 gene. The tissue-specific and cytokine-induced expression of rat SAA1 gene is likely the result of the interactions of these cis-acting elements with their cognate trans-acting factors as well as the interplay between the different cis-acting elements and their binding factors. (Abstract shortened with permission of author.) ^

A novel DNA damage inducible inhibitor of p53

p53 is required for the maintenance of the genomic stability of cells. Mutations in the p53 tumor-suppressor gene occur in more than 50% of human cancers of diverse types. In addition, 70% of families with Li-Fraumeni syndrome have a germline mutation in p53, predisposing these individuals to multiple forms of cancer. In response to DNA damage, p53 becomes stabilized and activated. However the exact mechanism by which DNA damage signals the stabilization and activation of p53 still remains elusive. The biochemical activity of p53 that is required for tumor suppression, and presumably the cellular response to DNA damage, involves the ability of the protein to bind to specific DNA sequences and to function as a transcription factor. For the downstream targets, p53 transactivates many genes involved in growth arrest, apoptosis and DNA repair such as p21, Bax and GADD45, respectively. An open question in the field is how cells can determine the downstream effects of p53. ^ We hypothesize that, through its associated proteins, p53 can differentially transactivate its target genes, which determine its downstream effect. Additionally, p53 interacting proteins may be involved in signaling for the stabilization and activation of p53. Therefore, a key aspect to understanding p53 function is the identification and analysis of proteins that interact with it. We have employed the Sos recruitment system (SRS), a cytoplasmic yeast two-hybrid screen to identify p53 interacting proteins. The SRS is based on the ability of Sos to activate Ras when it becomes localized to the plasma membrane. The system takes advantage of an S. cerevisiae strain, cdc25-2 temperature sensitive mutant, harboring a mutation in Sos. In this strain, fusion proteins containing a truncated Sos will only localize to the membrane by protein-protein interaction, which allows growth at non-permissive temperature. This system allows the use of intact transcriptional activators such as p53. ^ To date, using a modified SRS library screen to identify p53 interacting proteins, I have identified p53 (known to interact with itself) and a novel p53-interacting protein (PIP). PIP is a specific p53 interacting protein in the SRS. The interaction of p53 and PIP was further confirmed by performing in vitro and in vivo binding assays. In the in vivo binding study, the interaction can only be detected in the presence of ionizing radiation suggesting that this interaction might be involved in DNA-damage induced p53-signalling pathway. After screening cDNA and genomic libraries, a full-length PIP-cDNA clone ( ∼ 3kb) was obtained which encodes a protein of 429 amino acids with calculated molecular weight of 46 kDa. The results of genebank search indicated that the PIP is an unidentified gene and contains a conserved ring-finger domain, which is present in a diverse family of regulatory proteins involved in different aspects of cellular function. Northern blot analysis revealed that the size of its messenge is approximately 3 kb preferentially expressed in brain, heart, liver and kidney. The PIP protein is mainly located in the cytoplasm as determined by the cellular localization of a green fluorescence fusion protein. Preliminary functional analysis revealed that PIP downregulated the transactivation activity of p53 on both p21 and mdm2 promoters. Thus, PIP may be a novel negative regulator of p53 subsequent to DNA damage. ^

Micro- and picoplankton in waters of the Saint Paul Island, Pribilof Islands, Bering Sea

On the basis of materials collected in June-August 1994 characteristic data on microplankton were gathered in three biotopes of the eastern shelf of the Bering Sea: open shelf (coastal zone), the harbor, and the salt lagoon of Saint Paul Island (Pribiof Islands). The following parameters of microplanktonic communities were analyzed: abundance, biomass, and production of autotrophic picoplankton (picoalgae and cyanobacteria); abundance, biomass, growth rate constant, and production of bacterioplankton; role of filiform bacteria in bacterioplankton; species composition of heterotrophic flagellates and ciliates, their abundance, and biomass. Growth rates and consumption rates of picoplankton and bacterioplankton by heterotrophic nano- and microplankton were estimated in the experiments using the dilution method. Temporal dynamics of all structural and functional parameters of microplankton were analyzed. The minor role of autotrophic picoplankton and significant role of bacterioplankton as well as heterotrophic nano- and microplankton in planktonic communities of studied biotopes during summer months was shown. During certain periods, bacterial biomass was as high as 50-65% of phytoplankton biomass, and production of bacteria was as high as 20-40% of primary production. In the middle of the season biomass of nano- and microheterotrophic organisms in different biotopes exceeded biomass of mesozooplankton 2-10 times. Average consumption of bacterial production by nano- and microplankton during the period of observations was 85-94%.

Mesozooplankton of the northern Barents Sea in October 1998

Qualitative and quantitative mesozooplankton composition was examined on materials collected during an expedition carried out in October 1998 onboard the research icebreaker Akademik Fedorov. At different stations number of species varied from 25 to 33; wet biomass - from 20 to 109 g/m**2. Flux of autochthonous organic matter through plankton communities calculated from data on structural and functional analysis was from 2 to 40 mg C/m**2/day.

The Zero-Removing Property and Lagrange-Type Interpolation Series

The classical Kramer sampling theorem, which provides a method for obtaining orthogonal sampling formulas, can be formulated in a more general nonorthogonal setting. In this setting, a challenging problem is to characterize the situations when the obtained nonorthogonal sampling formulas can be expressed as Lagrange-type interpolation series. In this article a necessary and sufficient condition is given in terms of the zero removing property. Roughly speaking, this property concerns the stability of the sampled functions on removing a finite number of their zeros.

Characterization of four bifunctional plant IAM/PAM-amidohydrolases capable of contributing to auxin biosynthesis.

Amidases [EC 3.5.1.4] capable of converting indole-3-acetamide (IAM) into the major plant growth hormone indole-3-acetic acid (IAA) are assumed to be involved in auxin de novo biosynthesis. With the emerging amount of genomics data, it was possible to identify over forty proteins with substantial homology to the already characterized amidases from Arabidopsis and tobacco. The observed high conservation of amidase-like proteins throughout the plant kingdom may suggest an important role of theses enzymes in plant development. Here, we report cloning and functional analysis of four, thus far, uncharacterized plant amidases from Oryza sativa, Sorghum bicolor, Medicago truncatula, and Populus trichocarpa. Intriguingly, we were able to demonstrate that the examined amidases are also capable of converting phenyl-2-acetamide (PAM) into phenyl-2-acetic acid (PAA), an auxin endogenous to several plant species including Arabidopsis. Furthermore, we compared the subcellular localization of the enzymes to that of Arabidopsis AMI1, providing further evidence for similar enzymatic functions. Our results point to the presence of a presumably conserved pathway of auxin biosynthesis via IAM, as amidases, both of monocot, and dicot origins, were analyzed.

La transformación de las grandes estaciones europeas con la llegada de la Alta Velocidad. El caso de Atocha

La aparición del tren de alta velocidad en Europa en las últimas décadas del siglo XX supuso el resurgir de un medio de transporte en progresivo declive desde la popularización del automóvil y del avión. La decadencia del ferrocarril había supuesto en muchos casos el abandono, o incluso la demolición, de estaciones históricas y el deterioro de su entorno urbano. Como reacción a esa desatención surgió, también en el último cuarto de siglo, una mayor conciencia social preocupada por la conservación del patrimonio construido del ferrocarril. La necesidad de adaptación de las grandes estaciones de ferrocarril para dar servicio al nuevo sistema de transporte, junto con el interés por poner en valor sus construcciones históricas y su céntrico entorno, ha dado como resultado la realización de importantes transformaciones. El objeto de la presente investigación es el estudio de las transformaciones que han sufrido las grandes estaciones europeas del siglo XIX con la llegada del tren de alta velocidad, profundizando de manera especial en el caso más significativo que tenemos en nuestro país: la estación de Atocha. En el ámbito europeo es donde se localizan los ejemplos más relevantes de estaciones que tuvieron gran trascendencia en el siglo XIX y que ahora, con la llegada de la Alta Velocidad, vuelven a recuperar su grandeza. En España, el crecimiento de la Alta Velocidad en los últimos años ha sido extraordinario, hasta situarse como el segundo país del mundo con más kilómetros de líneas de alta velocidad en operación y, en consecuencia, se ha construido un gran número de estaciones adaptadas a este servicio. El caso más notable es el de la estación de Atocha, que desde la llegada del AVE en 1992 hasta el día de hoy, se ha convertido en uno de los complejos ferroviarios más importantes del mundo. El trabajo parte del estudio de otros referentes europeos, como las Gares de París, la estación de St Pancras en Londres y de otras cinco estaciones del centro de Europa –Amsterdam Centraal, Antwerpen Centraal, Köln Hauptbahnhof, Frankfurt (Main) Hauptbahnhof y la Gare de Strasbourg–, para establecer el marco analítico sobre el que se profundiza con la estación de Atocha. El proceso de transformación de la estación de Atocha se ha gestado a través de una serie de proyectos que han ido configurando la estación hasta el momento actual y planteando la previsión de futuro: el proyecto del Plan General de Madrid, el concurso de ideas para el diseño de la estación, la estación de Cercanías, la estación de Alta Velocidad y Largo Recorrido, la ampliación de esta para separar los flujos por niveles, los Estudios Informativos del Nuevo Complejo Ferroviario de la Estación de Atocha y su primera fase de construcción. Estos siete proyectos son objeto de un análisis en tres niveles: análisis cronológico, análisis funcional y análisis formal. La estación de Atocha fue la primera estación histórica europea en sufrir una gran transformación vinculada a la llegada de la Alta Velocidad. Aporta el entendimiento de la estación como un todo y la intermodalidad como sus principales valores, además de la gran mejora urbana que supuso la «operación Atocha», y adolece de ciertas carencias en su desarrollo comercial, vinculadas en parte a la presencia del jardín tropical, y de un pobre espacio en las salas de embarque para los pasajeros de salidas. La estación de Atocha completa su transformación a partir de su renovación funcional, manteniendo la carga simbólica de su historia. De la confrontación del caso de Atocha con otras importantes estaciones europeas resulta la definición de las principales consecuencias de la llegada de la Alta Velocidad a las grandes terminales europeas y la identificación de los elementos clave en su transformación. Las consecuencias principales son: la potenciación de la intermodalidad con otros medios de transporte, el desarrollo comercial no necesariamente destinado a los usuarios de los servicios ferroviarios, y la puesta en valor de la antigua estación y de su entorno urbano. Por su parte, los elementos clave en la transformación de las grandes estaciones tienen que ver directamente con la separación de flujos, el entendimiento de la estación por niveles, la dotación de nuevos accesos laterales y la construcción de una nueva gran cubierta para los nuevos andenes. La preeminencia de unos elementos sobre otros depende del carácter propio de cada estación y de cada país, de la magnitud de la intervención y, también, de la estructura y composición de los equipos encargados del diseño de la nueva estación. En la actualidad, nos encontramos en un momento interesante respecto a las estaciones de Alta Velocidad. Tras el reciente atentado frustrado en el Thalys que viajaba de Ámsterdam a París, se ha acordado establecer controles de identidad y equipajes en todas las estaciones de la red europea de alta velocidad, lo que implicará modificaciones importantes en las grandes estaciones que, probablemente, tomarán el modelo de la estación de Atocha como referencia. ABSTRACT The emergence of the high speed train in Europe in the last few decades of the 20th century represented the resurgence of a means of transport in progressive decline since the popularization of the car and the airplane. The railway decay brought in many cases the abandonment, or even the demolition, of historical stations and the deterioration of its urban environment. In response to that neglect, a greater social awareness towards the preservation of the railway built heritage raised up, also in the last quarter-century. The need for adaptation of the great railway stations to serve the new transport system, along with the interest in enhancing the historical buildings and its central locations, had resulted in important transformations. The subject of current investigation is the study of the transformations that the great 19th century European stations have experienced with the arrival of the high speed rail, deepening in particular in the most significant case we have in Spain: Atocha railway station. At European level is where the most relevant examples of stations which have had a great significance in the 19th century and now, with the arrival of the high speed train, have regain their greatness, are located. In Spain, the growth of the high speed rail over the past few years has been outstanding. Today is the second country in the world with the longest high speed rail network in operation and, therefore, with a great number of new stations adapted to this service. The most remarkable case is Atocha station. Since the arrival of the AVE in 1992, the station has become one of the world's most important railway hub. The research starts with the study of other European reference points, as the Gares of Paris, St Pancras station in London and five other stations of Central Europe –Amsterdam Centraal, Antwerpen Centraal, Köln Hauptbahnhof, Frankfurt (Main) Hauptbahnhof y la Gare de Strasbourg–, to establish the analytical framework that will be deepen with Atocha station. The transformation process of Atocha station has been created through a number of projects that have forged the station to date and have raised the sights in the future: the project of the General Urban Development Plan, the ideas competition for the station design, the Suburban train station, the High Speed and Long Distance station, its enlargement in order to separate passenger flows in different levels, the 'Masterplans' for the new Atocha transport hub and its first phase of construction. These seven projects are under scrutiny at three levels: chronological analysis, functional analysis and formal analysis. Atocha station was the first European historical station to undergo a great transformation tied to the arrival of the high speed rail. It brings the understanding of the station as a whole and the intermodality as its greatest values, besides the great urban improvement of the 'Atocha operation', and suffers from certain shortcomings in its commercial development, partly linked to the presence of the tropical garden, and from a poor space in the departure lounges. Atocha station completes its transformation on the basis of its functional renewal, keeping the symbolic charge of its history. The confrontation of Atocha case with the great European stations results in the definition of the principal consequences of the high speed rail arrival to the great European terminals and the identification of the key elements in its transformation. The principal consequences are: the empowering of the intermodality with other means of transport, of the commercial development, not necessarily intended for railway services users, and the enhancement of the old station and its urban environment. On the other hand, the key elements in the transformation of the great stations are directly related with the separation of passenger flows, the understanding of the station in different levels, the placement of new lateral accesses and the construction of a new deck over the new platforms. The pre-eminence of some elements over the others depends on the particular nature of each station and each country, on the scale of the intervention and also in the structure and composition of the teams in charge of the new station design. Nowadays, this is an interesting time concerning the high speed rail stations. After the recent foiled terrorist attempt in the Thalys train travelling from Amsterdam to Paris, it was agreed to establish passenger and luggage controls in every European high speed rail station. This will mean important changes in these great stations, which probably will take Atocha station's model as a reference.