Critical determinants of estrogen receptor -mediated agonist activity

Exogenous ligands that bind to the estrogen receptor (ER) exhibit unique pharmacologies distinct from that observed with the endogenous hormone, 17β-estradiol (ED. Differential activity among ER ligands has been observed at the level of receptor binding, promoter interaction and transcriptional activation. Furthermore, xenoestrogens can display tissue-specific agonist activity on the cellular level, functioning as an agonist in one tissue and as an antagonist in another. That the same ligand, functioning through the same receptor, can produce differing agonist responses on the cellular level indicates that there are tissue-specific determinants of agonist activity. In these studies critical molecular determinants of agonist activity were characterized for several cell types. In the normal and neoplastic myometrium a proliferative response was dependent upon activation of AF2 of the ER, functioning as a determinant of agonism in this cell type. Progesterone receptor (PR) ligands transdominantly suppressed ER-mediated transcription and proliferation in uterine leiomyoma cells, indicating that ER/PR cross-talk can modulate agonist activity in a myometrial cell background. In the breast, the agonist response to ER ligands was investigated by employing a functional genomics approach to generate gene expression profiles. Treatment of breast cancer cells with the selective estrogen receptor modulator tamoxifen largely recapitulated the expression profile induced by treatment with the agonist E2, despite the well-characterized antiproliferative effects produced by tamoxifen in this cell type. While the expression of many genes involved in regulating cell cycle progression, including fos, myc, cdc25a, stk15 and cyclin A, were induced by both E2 and tamoxifen in breast cells, treatment with the agonist E2 specifically induced the expression of cyclin D1, fra-1 , and uracil DNA glycosylase. These results suggest that the inability of tamoxifen to transactivate expression of only a few key genes, functioning as cellular gatekeepers, prevent tamoxifen-treated breast cells from entering the cell cycle. Thus, the expression of these agonist-specific marker genes is a potential determinant of agonist activity at the cellular level in the breast. Collectively, studies in the breast and uterine myometrium have identified several mechanisms whereby ER ligands modulate ER-mediated signaling and provide insights into the biology of tissue-specific agonist activity in hormone-responsive tissues. ^

(Table 1) Results of measurements of production characteristics of phytoplankton and some physical parameters of the environment in the northeastern Norwegian Sea in July 1995

From July 4 to 18,1995 surface chlorophyll a concentrations (C_cs) and integral primary production (C_ps) were studied in the northeastern part of the Norwegian Sea (73°42'N; 13°16'E), over a test area where an accident of the nuclear submarine Komsomolets had taken place. It was found that during this interval C_cs decreased by factor of about 3.3 (from 0.78 to 0.24 mg/m**3); average chlorophyll concentration within the photo-synthetic layer (C_cl) decreased by factor of about 3.5 (from 0.97 to 0.28 mg/m**3). The value of C_ps in the water column varied slightly (from 445 to 539 mg C/m**2 per day), since decrease in C_cl was compensated both by 1.5-fold growth of the photosynthetic layer thickness (from 40 to 60 m) and by 2.1-fold increase in its average assimilation number (from 0.58 to 1.20 mg C/mg chl a per hour). Monthly averages of C_ps were obtained from published data on seasonal C_cs changes and on the level of incident solar irradiation. They were found to be less than 100 mg C/m**2 per day in March and October and 100-500 mg C/m**2 per day in April-June. Annual primary production calculated from above values was equal to 105 g C/m**2.

Diverging Development Paths of the Electronics Industry in Korea and Taiwan

This paper examines the process and mechanism of economic development in the Republic of Korea and Taiwan through a comparative analysis of the electronics industry in each country. The paper will show that in its initial stage of development, the electronics industry in both economies had the same type of dual structure: a domestic demand sector based on the protected domestic market, and an export sector intended to capitalize on low-wage labor for the international market. However, this dual structure in the two economies faded away after the mid-1970s as their respective indigenous export-oriented enterprises began to develop. But the primary industrial players in each economy were very different. In Korea they were comprehensive electronics manufacturers affiliated with chaebols, and in Taiwan they were small and medium-size enterprises. Differences in the two economies' development mechanisms have brought about this divergence in development paths. In Korea this mechanism has been characterized by the government's positive role and the chaebol's readiness to react to the government's leadership. In Taiwan the development mechanism has been based on the private sector independent from the government. As an extension of such diverged development paths, ICs and personal computers showed spectacular growth in Korea and Taiwan after the 1980s. The development of ICs in Korea was primarily the result of a decisive role played by the chaebol's sizable financial resources, while the competitiveness in personal computers largely reflected the agility and flexibility of Taiwanese small and medium-size enterprises.

A Critical Review of Opinion Polls relating to Iranian Voting Intentions: Problems of Research Methodology as applied to Complex Societies

After the 10th Iranian Presidential election on June 12, 2009, several public opinion polls taken in Iran attracted the attention of policy-makers and journalists around the world because of the political crisis that followed. In this paper I first review critically the polls conducted by the WPO (WorldPublicOpinion.org), PIPA (Program on International Policy Attitudes) at the University of Maryland. I also review an essay by Steven Kull, which is based on the aforementioned poll results and which in my opinion leads to false conclusions concerning Iran’s political prospects. I also discuss “An Analysis of Multiple Polls of the Iranian Public,” published by WPO-PIPA on February 3 2010. The present paper arrives at the overall conclusion that it is impossible to obtain an accurate image of political opinions in societies as complicated as that of Iran by concentrating on only one technique of research and analysis, especially when the political and social situation in the society concerned is in a state of constant flux.

Critical aspects of substrate nanopatterning for the ordered growth of GaN nanocolumns.

Precise and reproducible surface nanopatterning is the key for a successful ordered growth of GaN nanocolumns. In this work, we point out the main technological issues related to the patterning process, mainly surface roughness and cleaning, and mask adhesion to the substrate. We found that each of these factors, process-related, has a dramatic impact on the subsequent selective growth of the columns inside the patterned holes. We compare the performance of e-beam lithography, colloidal lithography, and focused ion beam in the fabrication of hole-patterned masks for ordered columnar growth. These results are applicable to the ordered growth of nanocolumns of different materials.

Critical Role of Two-Dimensional Island-Mediated Growth on the Formation of Semiconductor Heterointerfaces

We experimentally demonstrate a sigmoidal variation of the composition profile across semiconductor heterointerfaces. The wide range of material systems (III-arsenides, III-antimonides, III-V quaternary compounds, III-nitrides) exhibiting such a profile suggests a universal behavior. We show that sigmoidal profiles emerge from a simple model of cooperative growth mediated by twodimensional island formation, wherein cooperative effects are described by a specific functional dependence of the sticking coefficient on the surface coverage. Experimental results confirm that, except in the very early stages, island growth prevails over nucleation as the mechanism governing the interface development and ultimately determines the sigmoidal shape of the chemical profile in these two-dimensional grown layers. In agreement with our experimental findings, the model also predicts a minimum value of the interfacial width, with the minimum attainable value depending on the chemical identity of the species.

Integrated learning of production engineering software applications in a shipbuilding context

Acourse focused on the acquisition of integration competencies in ship production engineering, organized in collaboration with selected industry partners, is presented in this paper. The first part of the course is dedicated to Project Management: the students acquire skills in defining, using MS-PROJECT, the work breakdown structure (WBS), and the organization breakdown structure (OBS) in Engineering projects, through a series of examples of increasing complexity with the final one being the construction planning of a vessel. The second part of the course is dedicated to the use of a database manager, MS-ACCESS, in managing production related information.Aseries of increasing complexity examples is treated, the final one being the management of the piping database of a real vessel. This database consists of several thousand pipes, for which a production timing frame is defined connecting this part of the course with the first one. Finally, the third part of the course is devoted to working withFORAN,an Engineering Production application developed bySENERand widely used in the shipbuilding industry. With this application, the structural elements where all the outfittings will be located are defined through cooperative work by the students, working simultaneously in the same 3D model. In this paper, specific details about the learning process are given. Surveys have been posed to the students in order to get feedback from their experience as well as to assess their satisfaction with the learning process, compared to more traditional ones. Results from these surveys are discussed in the paper.

Descriptive study of production factors affecting performance traits in growing-finishing pgis in Spain.

The objective of this study was to build up a data set including productive performance and production factors data of growing-finishing (GF) pigs in Spain in order to perform a representative and reliable description of the traits of Spanish growing-finishing pig industry. Data from 764 batches from 452 farms belonging to nine companies (1,157,212 pigs) were collected between 2008 and 2010 through a survey including five parts: general, facilities, feeding, health status and performance. Most studied farms had only GF pigs on their facilities (94.7%), produced ‘industrial’ pigs (86.7%), had entire male and female (59.5%) and Pietrain-sired pigs (70.0%), housed between 13-20 pigs per pen (87.2%), had  50% of slatted floor (70%), single-space dry feeder (54.0%), nipple drinker (88.7%) and automatic ventilation systems (71.2%). A 75.0% of the farms used three feeding phases using mainly pelleted diets (91.0%), 61.3% performed three or more antibiotic treatments and 36.5% obtained water from the public supply. Continuous variables studied had the following average values: number of pigs placed per batch, 1,515 pigs; initial and final body weight, 19.0 and 108 kg; length of GF period, 136 days; culling rate, 1.4%; barn occupation, 99.7%; feed intake per pig and fattening cycle, 244 kg; daily gain, 0.657 kg; feed conversion ratio, 2.77 kg kg-1 and mortality rate, 4.3%. Data reflecting the practical situation of the Spanish growing and finishing pig production and it may contribute to develop new strategies in order to improve the productive and economic efficiency of GF pig units.

Cities Futures: A critical assessment of how future studies are applied to cities

Análisis critic de la aplicación de los estudios de future al campo de la planificación urbana

A short critical history of the application of genomics to animal breeding

Two scientific schools have been in coexistence from the beginning of genetics, one of them searching for factors of inheritance and the other one applying biometrical models to study the relationships between relatives. With the development of molecular genetics, the possibilities of detecting genes having a noticeable effect in traits augmented. Some genes with large or medium effects were localized in animals, although the most common result was to detect markers linked to these genes, allowing the possibility of assisting selection programs with markers. When a large amount of simple and inexpensive markers were available, the SNPs, new possibilities were opened since they did not need the presence of genes of large or medium effect controlling a trait, because the whole genome was scanned. Using a large amount of SNPs permits having a prediction of the breeding value at birth accurate enough to be used in some cases, like dairy cattle, to halve its generation interval. In other animal breeding programs, the implementation of genomic selection is less clear and the way in which it can be useful should be carefully studied. The need for large populations for associating phenotypic data and markers, plus the need for repeating the process continuously, complicates its application in some cases. The implementation of the information provided by the SNPs in current genetic programs has led to the development of complex statistical tools, joining the efforts of the two schools, factorial and biometrical, that nowadays work closely related.

A critical role of Lyn and Fyn for B cell responses to CD38 ligation and interleukin 5

CD38 ligation on mouse B cells by CS/2, an anti-mouse CD38 mAb, induced proliferation, interleukin 5 (IL-5) receptor α chain expression, and tyrosine phosphorylation of Bruton tyrosine kinase (Btk) from wild-type, but not from X chromosome-linked, immunodeficient mice. B cells from fyn-deficient (Fyn−/−) and lyn-deficient (Lyn−/−) mice showed an impaired response to mAb CS/2 for proliferation and IL-5 receptor α chain expression, and B cells from fyn/lyn double-deficient (Fyn/Lyn−/−) mice did not respond at all to mAb CS/2. The Btk activation by CD38 ligation was observed in B cells from Fyn−/− mice, and it was severely impaired in B cells from Lyn−/− and Fyn/Lyn−/− mice. CD38 expression on B cells from three mutant strains was comparable to that on control B cells. We infer from these results that both Fyn and Lyn are required and that their signals are synergistic for B cell triggering after CD38 ligation. Lyn is upstream of Btk activation in the CD38 signaling. Stimulation of B cells with IL-5 together with CD38 ligation induces not only IgM but also IgG1 secretion. Analysis of the synergistic effects of IL-5 and CD38 ligation on IgG1 secretion revealed the impaired IgG1 secretion of B cells from Lyn−/− and Fyn/Lyn−/− mice. These data imply that Lyn is involved in B cell triggering by CD38 ligation plus IL-5 for isotype switching.

Molecular switch in signal transduction: Reaction paths of the conformational changes in ras p21

Conformational changes in ras p21 triggered by the hydrolysis of GTP play an essential role in the signal transduction pathway. The path for the conformational change is determined by molecular dynamics simulation with a holonomic constraint directing the system from the known GTP-bound structure (with the γ-phosphate removed) to the GDP-bound structure. The simulation is done with a shell of water molecules surrounding the protein. In the switch I region, the side chain of Tyr-32, which undergoes a large displacement, moves through the space between loop 2 and the rest of the protein, rather than on the outside of the protein. As a result, the charged residues Glu-31 and Asp-33, which interact with Raf in the homologous RafRBD–Raps complex, remain exposed during the transition. In the switch II region, the conformational changes of α2 and loop 4 are strongly coupled. A transient hydrogen bonding complex between Arg-68 and Tyr-71 in the switch II region and Glu-37 in switch I region stabilizes the intermediate conformation of α2 and facilitates the unwinding of a helical turn of α2 (residues 66–69), which in turn permits the larger scale motion of loop 4. Hydrogen bond exchange between the protein and solvent molecules is found to be important in the transition. Possible functional implications of the results are discussed.

Domain-specific gene disruption reveals critical regulation of neuregulin signaling by its cytoplasmic tail

Neuregulins are a multi-isoform family of growth factors that activate members of the erbB family of receptor tyrosine kinases. The membrane-anchored isoforms contain the receptor-activating ligand in their extracellular domain, a single membrane-spanning region, and a long cytoplasmic tail. To evaluate the potential biological role of the intracellular domain of the membrane-anchored neuregulin isoforms, we used a domain-specific gene disruption approach to produce a mouse line in which only the region of the neuregulin gene encoding almost the entire intracellular domain was disrupted. Consistent with previous reports in which all neuregulin isoforms were disrupted, the resulting homozygous neuregulin mutants died at E10.5 of circulatory failure and displayed defects in neural and cardiac development. To further understand these in vivo observations, we evaluated a similarly truncated neuregulin construct after transient expression in COS-7 cells. This cytoplasmic tail-deleted mutant, unlike wild-type neuregulin isoforms, was resistant to proteolytic release of its extracellular-domain ligand, a process required for erbB receptor activation. Thus, proteolytic processing of the membrane-bound neuregulin isoforms involved in cranial ganglia and heart embryogenesis is likely developmentally regulated and is critically controlled by their intracellular domain. This observation indicates that erbB receptor activation by membrane-bound neuregulins most likely involves a unique temporally and spatially regulated “inside-out” signaling process that is critical for processing and release of the extracellular-domain ligand.

Ligation of intestinal epithelial CD1d induces bioactive IL-10: Critical role of the cytoplasmic tail in autocrine signaling

The intestinal epithelium is anatomically positioned to serve as the critical interface between the lumen and the mucosal immune system. In addition to MHC class I and II antigens, intestinal epithelia constitutively express the nonclassical MHC molecule CD1d, a transmembrane molecule with a short cytoplasmic tail expressed as a β2-microglobulin-associated 48-kDa glycoprotein and novel β2-microglobulin-independent 37-kDa nonglycosylated protein on intestinal epithelia. At present, it is not known whether extracellular ligands can signal intestinal epithelial CD1d. To define signaling of CD1d cytoplasmic tail, retrovirus-mediated gene transfer was used to generate stable cell lines expressing wild-type CD1d or a chimeric molecule (extracellular CD1d and cytoplasmic CD1a), and surface CD1d was triggered by antibody crosslinking. Although wild-type CD1d was readily activated (tyrosine phosphorylation), no demonstrable signal was evident in cell lines expressing the chimeric molecule. Subsequent studies revealed that anti-CD1d crosslinking specifically induces epithelial IL-10 mRNA and protein and is blocked by the tyrosine kinase inhibitor genistein. Further studies addressing epithelial-derived IL-10 revealed that anti-CD1d crosslinking attenuates IFN-γ signaling and that such attenuation is reversed by addition of functionally inhibitory IL-10 antibodies. These results define signaling through surface CD1d, and, importantly, they demonstrate that this pathway may serve to dampen epithelial proinflammatory signals.

Calcium electrogenesis in distal apical dendrites of layer 5 pyramidal cells at a critical frequency of back-propagating action potentials

Action potentials in juvenile and adult rat layer-5 neocortical pyramidal neurons can be initiated at both axonal and distal sites of the apical dendrite. However, little is known about the interaction between these two initiation sites. Here, we report that layer 5 pyramidal neurons are very sensitive to a critical frequency of back-propagating action potentials varying between 60 and 200 Hz in different neurons. Bursts of four to five back-propagating action potentials above the critical frequency elicited large regenerative potentials in the distal dendritic initiation zone. The critical frequency had a very narrow range (10–20 Hz), and the dendritic regenerative activity led to further depolarization at the soma. The dendritic frequency sensitivity was suppressed by blockers of voltage-gated calcium channels, and also by synaptically mediated inhibition. Calcium-fluorescence imaging revealed that the site of largest transient increase in intracellular calcium above the critical frequency was located 400–700 μm from the soma at the site for initiation of calcium action potentials. Thus, the distal dendritic initiation zone can interact with the axonal initiation zone, even when inputs to the neuron are restricted to regions close to the soma, if the output of the neuron exceeds a critical frequency.