Evolution of vertebrate steroid receptors from an ancestral estrogen receptor by ligand exploitation and serial genome expansions

The evolution of novelty in tightly integrated biological systems, such as hormones and their receptors, seems to challenge the theory of natural selection: it has not been clear how a new function for any one part (such as a ligand) can be selected for unless the other members of the system (e.g., a receptor) are already present. Here I show—based on identification and phylogenetic analysis of steroid receptors in basal vertebrates and reconstruction of the sequences and functional attributes of ancestral proteins—that the first steroid receptor was an estrogen receptor, followed by a progesterone receptor. Genome mapping and phylogenetic analyses indicate that the full complement of mammalian steroid receptors evolved from these ancient receptors by two large-scale genome expansions, one before the advent of jawed vertebrates and one after. Specific regulation of physiological processes by androgens and corticoids are relatively recent innovations that emerged after these duplications. These findings support a model of ligand exploitation in which the terminal ligand in a biosynthetic pathway is the first for which a receptor evolves; selection for this hormone also selects for the synthesis of intermediates despite the absence of receptors, and duplicated receptors then evolve affinity for these substances. In this way, novel hormone-receptor pairs are created, and an integrated system of increasing complexity elaborated. This model suggests that ligands for some “orphan” receptors may be found among intermediates in the synthesis of ligands for phylogenetically related receptors.

Irreversibility of cellular aging and neoplastic transformation: a clonal analysis.

Prolonged incubation of NIH 3T3 cells under the growth constraint of confluence results in a persistent impairment of proliferation when the cells are subcultured at low density and a greatly increased probability of neoplastic transformation in assays for transformation. These properties, along with the large accumulation of age pigment bodies in the confluent cells, are cardinal cellular characteristics of aging in organisms and validate the system as a model of cellular aging. Two cultures labeled alpha and beta were obtained after prolonged confluence; both were dominated by cells that were both slowed in growth at low population density and enhanced in growth capacity at high density, a marker of neoplastic transformation. An experiment was designed to study the reversibility of these age-related properties by serial subculture at low density of the two uncloned cultures and their progeny clones derived from assuredly single cells. Both uncloned cultures had many transformed cells and a reduced growth rate on subculture. Serial subculture resulted in a gradual increase in growth rates of both populations, but a reversal of transformation only in the alpha population. The clones originating from both populations varied in the degree of growth impairment and neoplastic transformation. None of the alpha clones increased in growth rate on low density passage nor did the transformed clones among them revert to normal growth behavior. The fastest growing beta clone was originally slower than the control clone, but caught up to it after four weekly subcultures. The other beta clones retained their reduced growth rates. Four of the five beta clones, including the fastest grower, were transformed, and none reverted on subculture. We conclude that the apparent reversal of impaired growth and transformation in the uncloned parental alpha population resulted from the selective growth at low density of fast growing nontransformed clones. The reversal of impaired growth in the uncloned parental beta population was also the result of selective growth of fast growing clones, but in this case they were highly transformed so no apparent reversal of transformation occurred. The clonal results indicate that neither the impaired growth nor the neoplastic transformation found in aging cells is reversible. We discuss the possible contribution of epigenetic and genetic processes to these irreversible changes.

Analysis of analogue models by helical X-ray computed tomography

The aim of analogue model experiments in geology is to simulate structures in nature under specific imposed boundary conditions using materials whose rheological properties are similar to those of rocks in nature. In the late 1980s, X-ray computed tomography (CT) was first applied to the analysis of such models. In early studies only a limited number of cross-sectional slices could be recorded because of the time involved in CT data acquisition, the long cooling periods for the X-ray source and computational capacity. Technological improvements presently allow an almost unlimited number of closely spaced serial cross-sections to be acquired and calculated. Computer visualization software allows a full 3D analysis of every recorded stage. Such analyses are especially valuable when trying to understand complex geological structures, commonly with lateral changes in 3D geometry. Periodic acquisition of volumetric data sets in the course of the experiment makes it possible to carry out a 4D analysis of the model, i.e. 3D analysis through time. Examples are shown of 4D analysis of analogue models that tested the influence of lateral rheological changes on the structures obtained in contractional and extensional settings.

United States historical climatology network (HCN) serial temperature and precipitation data /

Twenty-eight microfiches (11 x 15 cm.) in pocket mounted on cover p. [3]. Header title: Historical climate network--temperature and precipitation data plots.

Three-dimensional analysis of eutectic grains in hypoeutectic Al-Si alloys

An approach to the qualitative analysis of quenched microstructures in three dimensions is presented and demonstrated on unmodified and Sr-modified Al-10% Si samples. The samples were repeatedly polished to obtain a series of digital images through the depth of the microstructure. A three-dimensional reconstruction of the microstructure was obtained by assembling the images of the serial sections. Reconstructions were made of unmodified and Sr-modified Al-Si eutectic grains that were quenched during eutectic solidification. The three-dimensional reconstructions show that strontium modification changes the size and morphology of the Al-Si eutectic grains. Sr-modified eutectic grains are large approximately spherical grains and grow with a high interface velocity. In the unmodified alloy, many small eutectic grains grow from the dendrite arm tips. The unmodified eutectic grains appear to grow from the dendrite tips into the undercooled liquid, rather than back-filling the dendrite envelope, possibly continuing to grow in the same manner as the equiaxed dendrites. (C) 2004 Elsevier B.V. All rights reserved.

The imaging of Samoa in illustrated magazines and serial encyclopedias in the early 20th-century

Drawing on English language sources and material relating to the colonial administrations of Western Samoa (now Samoa) and American Samoa, this examination of photographically illustrated serial encyclopaedias and magazines proposes an alternative historical analysis of the colonial imaging of Samoa, the most extensively covered field in Oceanic photographic studies. Though photographs published between 1890s and World War II were often 'recycled', without acknowledging the fact that they were taken much earlier, and despite claims in the text of illustrated publications of an unchanged, enduring, archaic tradition in Samoa, the amazing variety of photographic content often offered contradictory evidence, depicting a modern, adaptive and progressive Samoa. Contrary to orthodox historical analysis, the images of Samoa in illustrated magazines and encyclopaedias were not limited to a small repetitive gallery of partially clothed women and costumed chiefs; and the ways in which readers understood Samoa from photographs and text raises questions still to be explored.

To link or not to link: a test of the case linkage principles using serial car theft data

The purpose of the present study is to test the case linkage principles of behavioural consistency and behavioural distinctiveness using serial vehicle theft data. Data from 386 solved vehicle thefts committed by 193 offenders were analysed using Jaccard's, regression and Receiver Operating Characteristic analyses to determine whether objectively observable aspects of crime scene behaviour could be used to distinguish crimes committed by the same offender from those committed by different offenders. The findings indicate that spatial behaviour, specifically the distance between theft locations and between dump locations, is a highly consistent and distinctive aspect of vehicle theft behaviour; thus, intercrime and interdump distance represent the most useful aspects of vehicle theft for the purpose of case linkage analysis. The findings have theoretical and practical implications for understanding of criminal behaviour and for the development of decision-support tools to assist police investigation and apprehension of serial vehicle theft offenders.

Conditional volatility and firm size:an empirical analysis of UK equity portfolios

The techniques and insights from two distinct areas of financial economic modelling are combined to provide evidence of the influence of firm size on the volatility of stock portfolio returns. Portfolio returns are characterized by positive serial correlation induced by the varying levels of non-synchronous trading among the component stocks. This serial correlation is greatest for portfolios of small firms. The conditional volatility of stock returns has been shown to be well represented by the GARCH family of statistical processes. Using a GARCH model of the variance of capitalization-based portfolio returns, conditioned on the autocorrelation structure in the conditional mean, striking differences related to firm size are uncovered.

Three essays on entrepreneurial entry, serial entrepreneurship, and labor turnover

This study explores two important aspects of entrepreneurship — liquidity constraints and serial entrepreneurs, with an additional analysis of occupational choice among wage workers. In the first essay, I revisit the question of whether entrepreneurs face liquidity constraints in business formation. The principle challenge is that wealth is correlated with unobserved ability, and adequate instruments are often difficult to identify. This paper uses the son's birth order as an instrument for household wealth. I exploit the data available in the Korean Labor and Income Panel Study, and find evidence of liquidity constraints associated with self-employment in South Korea. The second essay develops and tests a model that explains entry into serial entrepreneurship and the performance of serial entrepreneurs as the result of selection on innate ability. The model supposes that agents establish businesses with imperfect information about their entrepreneurial ability and the profitability of business ideas. Agents continually observe signals with which they update their beliefs, and this process eventually determines their next business choice. Selection on ability induces a positive correlation between entrepreneurial experience (measured by previous business earnings and founding experience) and serial business formation, as well as its subsequent performance. The predictions in the model are tested using panel data from the NLSY79. The analysis permits a distinction to be made between selection on innate ability and learning by doing. Motivated by previous empirical findings that white-collar workers had higher turnover rates than blue-collar workers during firm expansion, the third essay further examines job turnover among workers with or without specific skills. I present a search-matching model, which predicts that when firm growth is driven by technological advance, workers whose skills are specific to the obsolete technology show a higher tendency to separate from their jobs. This hypothesis is tested with data from the PSID. I find supportive evidence that in the context of technological change, having an occupation requiring specific skills, such as computer specialists or engineers, increases the odds of job separation by nearly eight percent. ^

Serial evolutionary networks of within-patient HIV-1 sequences reveal patterns of evolution of X4 strains

Background The HIV virus is known for its ability to exploit numerous genetic and evolutionary mechanisms to ensure its proliferation, among them, high replication, mutation and recombination rates. Sliding MinPD, a recently introduced computational method [1], was used to investigate the patterns of evolution of serially-sampled HIV-1 sequence data from eight patients with a special focus on the emergence of X4 strains. Unlike other phylogenetic methods, Sliding MinPD combines distance-based inference with a nonparametric bootstrap procedure and automated recombination detection to reconstruct the evolutionary history of longitudinal sequence data. We present serial evolutionary networks as a longitudinal representation of the mutational pathways of a viral population in a within-host environment. The longitudinal representation of the evolutionary networks was complemented with charts of clinical markers to facilitate correlation analysis between pertinent clinical information and the evolutionary relationships. Results Analysis based on the predicted networks suggests the following:: significantly stronger recombination signals (p = 0.003) for the inferred ancestors of the X4 strains, recombination events between different lineages and recombination events between putative reservoir virus and those from a later population, an early star-like topology observed for four of the patients who died of AIDS. A significantly higher number of recombinants were predicted at sampling points that corresponded to peaks in the viral load levels (p = 0.0042). Conclusion Our results indicate that serial evolutionary networks of HIV sequences enable systematic statistical analysis of the implicit relations embedded in the topology of the structure and can greatly facilitate identification of patterns of evolution that can lead to specific hypotheses and new insights. The conclusions of applying our method to empirical HIV data support the conventional wisdom of the new generation HIV treatments, that in order to keep the virus in check, viral loads need to be suppressed to almost undetectable levels.

Transcriptomic Analysis of the Host Response and Innate Resilience to Enterotoxigenic Escherichia coli Infection in Humans.

BACKGROUND: Enterotoxigenic Escherichia coli (ETEC) is a globally prevalent cause of diarrhea. Though usually self-limited, it can be severe and debilitating. Little is known about the host transcriptional response to infection. We report the first gene expression analysis of the human host response to experimental challenge with ETEC. METHODS: We challenged 30 healthy adults with an unattenuated ETEC strain, and collected serial blood samples shortly after inoculation and daily for 8 days. We performed gene expression analysis on whole peripheral blood RNA samples from subjects in whom severe symptoms developed (n = 6) and a subset of those who remained asymptomatic (n = 6) despite shedding. RESULTS: Compared with baseline, symptomatic subjects demonstrated significantly different expression of 406 genes highlighting increased immune response and decreased protein synthesis. Compared with asymptomatic subjects, symptomatic subjects differentially expressed 254 genes primarily associated with immune response. This comparison also revealed 29 genes differentially expressed between groups at baseline, suggesting innate resilience to infection. Drug repositioning analysis identified several drug classes with potential utility in augmenting immune response or mitigating symptoms. CONCLUSIONS: There are statistically significant and biologically plausible differences in host gene expression induced by ETEC infection. Differential baseline expression of some genes may indicate resilience to infection.

Non-conventional advertising formats in television versus spots: An analysis based on the generated recall

Advertising investment and audience figures indicate that television continues to lead as a mass advertising medium. However, its effectiveness is questioned due to problems such as zapping, saturation and audience fragmentation. This has favoured the development of non-conventional advertising formats. This study provides empirical evidence for the theoretical development. This investigation analyzes the recall generated by four non-conventional advertising formats in a real environment: short programme (branded content), television sponsorship, internal and external telepromotion versus the more conventional spot. The methodology employed has integrated secondary data with primary data from computer assisted telephone interviewing (CATI) were performed ad-hoc on a sample of 2000 individuals, aged 16 to 65, representative of the total television audience. Our findings show that non-conventional advertising formats are more effective at a cognitive level, as they generate higher levels of both unaided and aided recall, in all analyzed formats when compared to the spot.

Development of Imaging Mass Spectrometry Analysis of Lipids in Biological and Clinically Relevant Applications

La spectrométrie de masse mesure la masse des ions selon leur rapport masse sur charge. Cette technique est employée dans plusieurs domaines et peut analyser des mélanges complexes. L’imagerie par spectrométrie de masse (Imaging Mass Spectrometry en anglais, IMS), une branche de la spectrométrie de masse, permet l’analyse des ions sur une surface, tout en conservant l’organisation spatiale des ions détectés. Jusqu’à présent, les échantillons les plus étudiés en IMS sont des sections tissulaires végétales ou animales. Parmi les molécules couramment analysées par l’IMS, les lipides ont suscité beaucoup d'intérêt. Les lipides sont impliqués dans les maladies et le fonctionnement normal des cellules; ils forment la membrane cellulaire et ont plusieurs rôles, comme celui de réguler des événements cellulaires. Considérant l’implication des lipides dans la biologie et la capacité du MALDI IMS à les analyser, nous avons développé des stratégies analytiques pour la manipulation des échantillons et l’analyse de larges ensembles de données lipidiques. La dégradation des lipides est très importante dans l’industrie alimentaire. De la même façon, les lipides des sections tissulaires risquent de se dégrader. Leurs produits de dégradation peuvent donc introduire des artefacts dans l’analyse IMS ainsi que la perte d’espèces lipidiques pouvant nuire à la précision des mesures d’abondance. Puisque les lipides oxydés sont aussi des médiateurs importants dans le développement de plusieurs maladies, leur réelle préservation devient donc critique. Dans les études multi-institutionnelles où les échantillons sont souvent transportés d’un emplacement à l’autre, des protocoles adaptés et validés, et des mesures de dégradation sont nécessaires. Nos principaux résultats sont les suivants : un accroissement en fonction du temps des phospholipides oxydés et des lysophospholipides dans des conditions ambiantes, une diminution de la présence des lipides ayant des acides gras insaturés et un effet inhibitoire sur ses phénomènes de la conservation des sections au froid sous N2. A température et atmosphère ambiantes, les phospholipides sont oxydés sur une échelle de temps typique d’une préparation IMS normale (~30 minutes). Les phospholipides sont aussi décomposés en lysophospholipides sur une échelle de temps de plusieurs jours. La validation d’une méthode de manipulation d’échantillon est d’autant plus importante lorsqu’il s’agit d’analyser un plus grand nombre d’échantillons. L’athérosclérose est une maladie cardiovasculaire induite par l’accumulation de matériel cellulaire sur la paroi artérielle. Puisque l’athérosclérose est un phénomène en trois dimension (3D), l'IMS 3D en série devient donc utile, d'une part, car elle a la capacité à localiser les molécules sur la longueur totale d’une plaque athéromateuse et, d'autre part, car elle peut identifier des mécanismes moléculaires du développement ou de la rupture des plaques. l'IMS 3D en série fait face à certains défis spécifiques, dont beaucoup se rapportent simplement à la reconstruction en 3D et à l’interprétation de la reconstruction moléculaire en temps réel. En tenant compte de ces objectifs et en utilisant l’IMS des lipides pour l’étude des plaques d’athérosclérose d’une carotide humaine et d’un modèle murin d’athérosclérose, nous avons élaboré des méthodes «open-source» pour la reconstruction des données de l’IMS en 3D. Notre méthodologie fournit un moyen d’obtenir des visualisations de haute qualité et démontre une stratégie pour l’interprétation rapide des données de l’IMS 3D par la segmentation multivariée. L’analyse d’aortes d’un modèle murin a été le point de départ pour le développement des méthodes car ce sont des échantillons mieux contrôlés. En corrélant les données acquises en mode d’ionisation positive et négative, l’IMS en 3D a permis de démontrer une accumulation des phospholipides dans les sinus aortiques. De plus, l’IMS par AgLDI a mis en évidence une localisation différentielle des acides gras libres, du cholestérol, des esters du cholestérol et des triglycérides. La segmentation multivariée des signaux lipidiques suite à l’analyse par IMS d’une carotide humaine démontre une histologie moléculaire corrélée avec le degré de sténose de l’artère. Ces recherches aident à mieux comprendre la complexité biologique de l’athérosclérose et peuvent possiblement prédire le développement de certains cas cliniques. La métastase au foie du cancer colorectal (Colorectal cancer liver metastasis en anglais, CRCLM) est la maladie métastatique du cancer colorectal primaire, un des cancers le plus fréquent au monde. L’évaluation et le pronostic des tumeurs CRCLM sont effectués avec l’histopathologie avec une marge d’erreur. Nous avons utilisé l’IMS des lipides pour identifier les compartiments histologiques du CRCLM et extraire leurs signatures lipidiques. En exploitant ces signatures moléculaires, nous avons pu déterminer un score histopathologique quantitatif et objectif et qui corrèle avec le pronostic. De plus, par la dissection des signatures lipidiques, nous avons identifié des espèces lipidiques individuelles qui sont discriminants des différentes histologies du CRCLM et qui peuvent potentiellement être utilisées comme des biomarqueurs pour la détermination de la réponse à la thérapie. Plus spécifiquement, nous avons trouvé une série de plasmalogènes et sphingolipides qui permettent de distinguer deux différents types de nécrose (infarct-like necrosis et usual necrosis en anglais, ILN et UN, respectivement). L’ILN est associé avec la réponse aux traitements chimiothérapiques, alors que l’UN est associé au fonctionnement normal de la tumeur.

A social and gender analysis of Northern Province, Zambia: Qualitative evidence that supports the use of a gender transformative approach

A qualitative social and gender analysis was carried out in June 2015 in Luwingu and Mbala Districts in Northern Province, Zambia. The research explored the norms and power relations at various institutional levels that constrain certain social groups from benefiting from programmatic investments aimed at improving livelihoods, health status, and food and nutrition security within the Irish Aid Local Development Programme (IALDP). This technical paper provides a summary of the research findings, lessons learned and suggests options for action the IALDP could consider to help bring about gender transformative change in the lives and livelihoods of poor and vulnerable people.

Petr Eben's oratorio Apologia Sokratus (1967) and ballet Curses and Blessings (1983): An interpretative analysis of the symbolism behind the text settings and musical style

The Czech composer Petr Eben (1927-2007) has written music in all genres except symphony, but he is highly recognized for his organ and choral compositions, which are his preferred genres. His vocal works include choral songs and vocal-instrumental works at a wide range of difficulty levels, from simple pedagogical songs to very advanced and technically challenging compositions. This study examines two of Eben‘s vocal-instrumental compositions. The oratorio Apologia Sokratus (1967) is a three-movement work; its libretto is based on Plato‘s Apology of Socrates. The ballet Curses and Blessings (1983) has a libretto compiled from numerous texts from the thirteenth to the twentieth centuries. The formal design of the ballet is unusual—a three-movement composition where the first is choral, the second is orchestral, and the third combines the previous two played simultaneously. Eben assembled the libretti for both compositions and they both address the contrasting sides of the human soul, evil and good, and the everlasting fight between them. This unity and contrast is the philosophical foundation for both compositions. The dissertation discusses the multileveled meanings behind the text settings and musical style of the oratorio and ballet in analyses focusing on the text, melodic and harmonic construction, and symbolism. Additional brief analyses of other vocal and vocal-instrumental compositions by Eben establish the ground for the examination of the oratorio and ballet and for understanding features of the composer‘s musical style. While the oratorio Apologia Sokratus was discussed in short articles in the 1970s, the ballet Curses and Blessings has never previously been addressed within Eben scholarship. The dissertation examines the significant features of Eben‘s music. His melodic style incorporates influences as diverse as Gregorian chant and folk tunes on the one hand, and modern vocal techniques such as Sprechgesang and vocal aleatoricism on the other. His harmonic language includes bitonality and polytonality, used to augment the tonal legacy of earlier times, together with elements of pitch collections and limited serial procedures as well as various secundal and quartal harmonic sonorities derived from them. His music features the vibrant rhythms of folk music, and incorporates other folk devices like ostinato, repetitive patterns, and improvisation.