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.

The rise and fall of the medical mediated searcher

The relationship between the development of mediated online literature searching and the recruitment of medical librarians to fill positions as online searchers was investigated. The history of database searching by medical librarians was outlined and a content analysis of thirty-five years of job advertisements in MLA News from 1961 through 1996 was summarized. Advertisements for online searchers were examined to test the hypothesis that the growth of mediated online searching was reflected in the recruitment of librarians to fill positions as mediated online searchers in medical libraries. The advent of end-user searching was also traced to determine how this trend affected the demand for mediated online searching and job availability of online searchers. Job advertisements were analyzed to determine what skills were in demand as end-user searching replaced mediated online searching as the norm in medical libraries. Finally, the trend away from mediated online searching to support of other library services was placed in the context of new roles for medical librarians.

On the failure of de novo-designed peptides as biocatalysts.

While the elegance and efficiency of enzymatic catalysis have long tempted chemists and biochemists with reductionist leanings to try to mimic the functions of natural enzymes in much smaller peptides, such efforts have only rarely produced catalysts with biologically interesting properties. However, the advent of genetic engineering and hybridoma technology and the discovery of catalytic RNA have led to new and very promising alternative means of biocatalyst development. Synthetic chemists have also had some success in creating nonpeptide catalysts with certain enzyme-like characteristics, although their rates and specificities are generally much poorer than those exhibited by the best novel biocatalysts based on natural structures. A comparison of the various approaches from theoretical and practical viewpoints is presented. It is suggested that, given our current level of understanding, the most fruitful methods may incorporate both iterative selection strategies and rationally chosen small perturbations, superimposed on frameworks designed by nature.

Segregation of DNA polynucleotide strands into sister chromatids and the use of endoreduplicated cells to track sister chromatid exchanges induced by crosslinks, alkylations, or x-ray damage.

The method of Matsumoto and Ohta [Matsumoto, K. & Ohta, T. (1992) Chromosoma 102, 60-65; Matsumoto, K. & Ohta, T. (1995) Mutat. Res. 326, 93-98] to induce large numbers of endoreduplicated Chinese hamster ovary cells has now been coupled with the fluorescence-plus-Giemsa method of Perry and Wolff [Perry, P. & Wolff, S. (1974) Nature (London) 251, 156-158] to produce harlequin endoreduplicated chromosomes that after the third round of DNA replication are composed of a chromosome with a light chromatid and a dark chromatid in close apposition to its sister chromosome containing two light chromatids. Unless the pattern is disrupted by sister chromatid exchange (SCE), the dark chromatid is always in the center, so that the order of the chromatids is light-dark light-light. The advent of this method, which permits the observation of SCEs in endoreduplicated cells, makes it possible to determine with great ease in which cell cycle an SCE occurred. This now allows us to approach several vexing questions about the induction of SCEs (genetic damage and its repair) after exposure to various types of mutagenic carcinogens. The present experiments have allowed us to observe how many cell cycles various types of lesions that are induced in DNA by a crosslinking agent, an alkylating agent, or ionizing radiation, and that are responsible for the induction of SCEs, persist before being repaired and thus lose their ability to inflict genetic damage. Other experiments with various types of mutagenic carcinogens and various types of cell lines that have defects in different DNA repair processes, such as mismatch repair, excision repair, crosslink repair, and DNA-strand-break repair, can now be carried out to determine the role of these types of repair in removing specific types of lesions.

Hemodynamic effects of epidermal growth factor in conscious rats and monkeys.

The therapeutic application of growth factors to human disease has become closer to reality with the advent of faster means of synthesizing these molecules and novel drug delivery strategies. Epidermal growth factor (EGF) belongs to a large family of molecules with the ability to modulate growth. Purified extracts of EGF have been used clinically to modulate gastrointestinal secretion of hormones and accelerate healing. EGF is also reported to have both vascular smooth muscle contractile and relaxing activity Cardiovascular studies were performed with the bioactive 48-amino acid fragment of human EGF in rodents and primates to determine the effects of EGF on blood pressure and heart rate in conscious animals. Intravenous infusion of EGF induced an initial pressor response in rats followed by a prolonged decrease in blood pressure. In contrast, in monkeys, EGF had dose-related blood pressure-lowering effects only; significant hypotension was observed at doses ranging from 3 to 300 microg/kg i.v. Hypotension was associated with modest tachycardia in both species. To our knowledge, this is the first report of hemodynamic effects of EGF in primates, and it clearly documents that the mitogenic role of growth factors such as EGF is but one aspect of their physiology.

A prokaryotic origin for light-dependent chlorophyll biosynthesis of plants.

Flowering plants require light for chlorophyll synthesis. Early studies indicated that the dependence on light for greening stemmed in part from the light-dependent reduction of the chlorophyll intermediate protochlorophyllide to the product chlorophyllide. Light-dependent reduction of protochlorophyllide by flowering plants is contrasted by the ability of nonflowering plants, algae, and photosynthetic bacteria to reduce protochlorophyllide and, hence, synthesize (bacterio) chlorophyll in the dark. In this report, we functionally complemented a light-independent protochlorophyllide reductase mutant of the eubacterium Rhodobacter capsulatus with an expression library composed of genomic DNA from the cyanobacterium Synechocystis sp. PCC 6803. The complemented R. capsulatus strain is capable of synthesizing bacteriochlorophyll in the light, thereby indicating that a chlorophyll biosynthesis enzyme can function in the bacteriochlorophyll biosynthetic pathway. However, under dark growth conditions the complemented R. capsulatus strain fails to synthesize bacteriochlorophyll and instead accumulates protochlorophyllide. Sequence analysis demonstrates that the complementing Synechocystis genomic DNA fragment exhibits a high degree of sequence identity (53-56%) with light-dependent protochlorophyllide reductase enzymes found in plants. The observation that a plant-type, light-dependent protochlorophyllide reductase enzyme exists in a cyanobacterium indicates that light-dependent protochlorophyllide reductase evolved before the advent of eukaryotic photosynthesis. As such, this enzyme did not arise to fulfill a function necessitated either by the endosymbiotic evolution of the chloroplast or by multicellularity; rather, it evolved to fulfill a fundamentally cell-autonomous role.

The Sound of the Digital Global City

Madrid has been the center of Spanish musical scene and industry since the 80s, when “la movida” becomes the metaphor for the new colorful, young and cosmopolitan country established with the arrival of democracy. The city, in this way, is basically a place. But this sense of place started to crash with the arrival of digital music. In the new paradigm, intermediaries were supposed to disappear and music was something contained in networks and computers. The question now is how to integrate digital music, a nonphysical, individual experience, with the way in which the city of Madrid is lived through in musical terms. With the advent of digital music, concerts became the primary source of income for musicians. The centrality of the gig can be understood as the confirmation that we are living in an economy of experience. This centrality also reorganized the way in which music is produced and consumed: now, records are produced in order to create the opportunity of a musical event (band promote their tour as presentation of their latest recordings) that can be promoted in social networks and media; concerts are the places where musicians construct their fans’ communities and are the places were records are sold, not a way to know the band but to demonstrate both the support for the band and the status of the listeners. To study the place of music in the process of metropolization in Madrid we need to understand music as a field of tension

Distance Education and the Evolution of Online Learning in the United States

Online education is no longer a trend, rather it is mainstream. In the Fall of 2012, 69.1% of chief academic leaders indicated online learning was critical to their long-term strategy and of the 20.6 million students enrolled in higher education, 6.7 million were enrolled in an online course (Allen & Seaman, 2013; United States Department of Education, 2013). The advent of online education and its rapid growth has forced academic institutions and faculty to question the current styles and techniques for teaching and learning. As developments in educational technology continue to advance, the ways in which we deliver and receive knowledge in both the traditional and online classrooms will further evolve. It is necessary to investigate and understand the progression and advancements in educational technology and the variety of methods used to deliver knowledge to improve the quality of education we provide today and motivate, inspire, and educate the students of the 21st century. This paper explores the atioevolution of distance education beginning with correspondence and the use of parcel post, to radio, then to television, and finally to online education.

GATS and the Social Regulation of Services. IES WORKING PAPER 3/2010

Many service transactions are highly complex, and their quality is difficult to ascertain for consumers. In order to have properly functioning service markets, the services thus often require regulation. However, with the advent of the WTO, international trade in services has become increasingly rule-bound. GATS has considerable, intricate effects on social regulation due to the characteristics of services. The allocation of regulatory jurisdiction between home and host country, for example, is rendered difficult by the process-based nature of a lot of services. The WTO US – Gambling dispute settlement report is the first to address GATS disciplines on social regulation in a detailed manner. This working paper submits that the US - Gambling report has increased interference with domestic social regulation and created regulatory uncertainty for WTO members. However, it is also argued that the real impact of the GATS on social regulation can only be understood by looking beyond the text of the GATS. GATS disciplines may become amplified through their interaction with domestic and other international law. The GATS also contains some “political” counterbalancing mechanisms that allow members to renegotiate their commitments. It is argued that these political mechanisms strengthen subsidiarity in the GATS, and make WTO dispute settlement bodies accountable to WTO members.

Managerialism at the bottom of the pyramid: a case study in Brazil

Nas últimas décadas, a Base da Pirâmide tem sido cada vez mais debatida entre líderes ocidentais como a nova terra das oportunidades. Com o advento do neoliberalismo no campo do desenvolvimento na década de 1990, o papel da sociedade civil e, em particular, o de Organizações Não-Governamentais, passou a ser enfatizado como sendo central nas estratégias ocidentais no "Sul" do mundo. Os atores do desenvolvimento, no entanto, muitas vezes abordaram essas questões utilizando perspectivas tradicionais, que estavam geralmente fora de contexto. A tese foca na controvérsia em torno do uso de técnicas de gestão em cenários que diferem daqueles nos quais estas ferramentas têm sido desenvolvidas. Em particular, ela procura compreender em que medida o gerencialismo - a ideologia da gestão - está a influenciando as atividades de uma Organização Não-Governamental brasileira, a Galpão Aplauso. O estudo, usando uma estrutura teórica, analisa o relacionamento entre a ONG e seus parceiros, sublinhando os resultados de conflitos ideológicos. No geral, descobriu-se como o encontro das perspectivas do Norte e do Sul originou alguns debates que levaram, em parte, à aceitação de ideias gerencialistas, tais como a replicabilidade e sistematização de processos, enquanto que em alguns casos, eles intensificaram a resistência da ONG sobre conceitos como sustentabilidade financeira e transformação em um negócio social.

Morphometric measurements throughout ontogeny of selected planktic foraminiferal test species

Development plays an important part in shaping adult morphology and morphological disparity, yet its influence on evolutionary processes is seldom explored because of a lack of preservation of ontogenetic stages in the fossil record. By preserving their entire ontogenetic history within their test, and with the advent of high-resolution imaging techniques, planktic foraminifera allow us to investigate the influence of developmental constraints on disparity. Using Synchrotron radiation X-ray tomographic microscopy (SRXTM), we reconstruct the ontogenetic progression of seven species across several of the major morphotypic groups of planktic foraminifera, including morphotypes of a species exhibiting high phenotypic plasticity and closely related pseudo-cryptic sister-taxa. We show differences in growth patterns between the globigerinid species, which appear more tightly regulated within the framework of isometry from the neanic stage, and the globorotaliid species, whose adult stages present allometric trends. Morphological change through ontogeny results in a change in surface area to volume ratios. Different metabolic processes therefore dominate at different stages of ontogeny, changing the vulnerability of the organism to environmental influences over growth, from factors affecting diffusion rates in the juvenile to those affecting energy supply in the adult. These findings identify some of the parameters within which evolutionary mechanisms have to act.

Give back -- Saint Sophia : a report of the speeches delivered at the opening meeting of the crusade for the redemption of Saint Sophia, held at the Cannon Street Hotel, on Jan. 23rd, 1919 /

"Where the following resolution was moved from the chair and carried by acclamation: That this meeting urges the importance, on the grounds of justice to the long-suffering and oppressed Christians of the Turkish Empire, of the restauration of the great Christian Church of Saint Sophia to Christian worship.

Philosophy and development of religion /

"Translation of the Lectures from my German manuscript"--Pref.

The works of William Paley, D.D. : with additional sermons ... and a corrected account of the life and writings of the author /

Vols. 2-7 were also published separately.

Christianity and mankind : their beginnings and prospects /

v. 1-2. Hippolytus and his age; or, The beginnings and prospects of Christianity.--v. 3-4. Outlines of the philosophy of universal history, applied to language and religion.--v. 5-7. Analecta ante-nicaena.