Targeted disruption of gp130, a common signal transducer for the interleukin 6 family of cytokines, leads to myocardial and hematological disorders.

gp130 is a ubiquitously expressed signal-transducing receptor component shared by interleukin 6, interleukin 11, leukemia inhibitory factor, oncostatin M, ciliary neurotrophic factor, and cardiotrophin 1. To investigate physiological roles of gp130 and to examine pathological consequences of a lack of gp130, mice deficient for gp130 have been prepared. Embryos homozygous for the gp130 mutation progressively die between 12.5 days postcoitum and term. On 16.5 days postcoitum and later, they show hypoplastic ventricular myocardium without septal and trabecular defect. The subcellular ultrastructures in gp130-/- cardiomyocytes appear normal. The mutant embryos have greatly reduced numbers of pluripotential and committed hematopoietic progenitors in the liver and differentiated lineages such as T cells in the thymus. Some gp130-/- embryos show anemia due to impaired development of erythroid lineage cells. These results indicate that gp130 plays a crucial role in myocardial development and hematopoiesis during embryogenesis.

Contraction due to microtubule disruption is associated with increased phosphorylation of myosin regulatory light chain.

Microtubules have been proposed to function as rigid struts which oppose cellular contraction. Consistent with this hypothesis, microtubule disruption strengthens the contractile force exerted by many cell types. We have investigated alternative explanation for the mechanical effects of microtubule disruption: that microtubules modulate the mechanochemical activity of myosin by influencing phosphorylation of the myosin regulatory light chain (LC20). We measured the force produced by a population of fibroblasts within a collagen lattice attached to an isometric force transducer. Treatment of cells with nocodazole, an inhibitor of microtubule polymerization, stimulated an isometric contraction that reached its peak level within 30 min and was typically 30-45% of the force increase following maximal stimulation with 30% fetal bovine serum. The contraction following nocodazole treatment was associated with a 2- to 4-fold increase in LC20 phosphorylation. The increases in both force and LC20 phosphorylation, after addition of nocodazole, could be blocked or reversed by stabilizing the microtubules with paclitaxel (former generic name, taxol). Increasing force and LC20 phosphorylation by pretreatment with fetal bovine serum decreased the subsequent additional contraction upon microtubule disruption, a finding that appears inconsistent with a load-shifting mechanism. Our results suggest that phosphorylation of LC20 is a common mechanism for the contractions stimulated both by microtubule poisons and receptor-mediated agonists. The modulation of myosin activity by alterations in microtubule assembly may coordinate the physiological functions of these cytoskeletal components.

Mutações inativadoras no gene MKRN3 são causa de puberdade precoce central familial

A maioria dos casos de puberdade precoce central (PPC) em meninas permanece idiopática. A hipótese de uma causa genética vem se fortalecendo após a descoberta de alguns genes associados a este fenótipo, sobretudo aqueles implicados com o sistema kisspeptina (KISS1 e KISS1R). Entretanto, apenas casos isolados de PPC foram relacionados à mutação na kisspeptina ou em seu receptor. Até recentemente, a maioria dos estudos genéticos em PPC buscava genes candidatos selecionados com base em modelos animais, análise genética de pacientes com hipogonadismo hipogonadotrófico, ou ainda, nos estudos de associação ampla do genoma. Neste trabalho, foi utilizado o sequenciamento exômico global, uma metodologia mais moderna de sequenciamento, para identificar variantes associadas ao fenótipo de PPC. Trinta e seis indivíduos com a forma de PPC familial (19 famílias) e 213 casos aparentemente esporádicos foram inicialmente selecionados. A forma familial foi definida pela presença de mais de um membro afetado na família. DNA genômico foi extraído dos leucócitos do sangue periférico de todos os pacientes. O estudo de sequenciamento exômico global realizado pela técnica ILLUMINA, em 40 membros de 15 famílias com PPC, identificou mutações inativadoras em um único gene, MKRN3, em cinco dessas famílias. Pesquisa de mutação no MKRN3 realizada por sequenciamento direto em duas famílias adicionais (quatro pacientes) identificou duas novas variantes nesse gene. O MKRN3 é um gene de um único éxon, localizado no cromossomo 15 em uma região crítica para a síndrome de Prader Willi. O gene MKRN3 sofre imprinting materno, sendo expresso apenas pelo alelo paterno. A descoberta de mutações em pacientes com PPC familial despertou o interesse para a pesquisa de mutações nesse gene em 213 pacientes com PPC aparentemente esporádica por meio de reação em cadeia de polimerase seguida de purificação enzimática e sequenciamento automático direto (Sanger). Três novas mutações e duas já anteriormente identificadas, incluindo quatro frameshifts e uma variante missense, foram encontradas, em heterozigose, em seis meninas não relacionadas. Todas as novas variantes identificadas estavam ausentes nos bancos de dados (1000 Genomes e Exome Variant Server). O estudo de segregação familial em três dessas meninas com PPC aparentemente esporádica e mutação no MKRN3 confirmou o padrão de herança autossômica dominante com penetrância completa e transmissão exclusiva pelo alelo paterno, demonstrando que esses casos eram, na verdade, também familiares. A maioria das mutações encontradas no MKRN3 era do tipo frameshift ou nonsense, levando a stop códons prematuros e proteínas truncadas e, portanto, confirmando a associação com o fenótipo. As duas mutações missenses (p.Arg365Ser e p.Phe417Ile) identificadas estavam localizadas em regiões de dedo ou anel de zinco, importantes para a função da proteína. Além disso, os estudos in silico dessas duas variantes demonstraram patogenicidade. Todos os pacientes com mutação no MKRN3 apresentavam características clínicas e hormonais típicas de ativação prematura do eixo reprodutivo. A mediana de idade de início da puberdade foi de 6 anos nas meninas (variando de 3 a 6,5) e 8 anos nos meninos (variando de 5,9 a 8,5). Tendo em vista o fenômeno de imprinting, análise de metilação foi também realizada em um subgrupo de 52 pacientes com PPC pela técnica de MS-MLPA, mas não foram encontradas alterações no padrão de metilação. Em conclusão, este trabalho identificou um novo gene associado ao fenótipo de PPC. Atualmente, mutações inativadoras no MKRN3 representam a causa genética mais comum de PPC familial (33%). O MKRN3 é o primeiro gene imprintado associado a distúrbios puberais em humanos. O mecanismo preciso de ação desse gene na regulação da secreção de GnRH necessita de estudos adicionais

The Effects of Father Absence Due to Divorce: A Systems Interpretation.

In American society, the incidence of divorce continues to rise. In 1974, the estimate was that 40% of all new marriages would end in divorce. When children are involved, the mother usually regains custody. Although the number of children of divorce living with their fathers is increasing, it is still a small percent. In addition, the rate of remarriages is lower when children are involved (Hetherington.et al.,1977). Consequently, a large number of children are being raised in father-absent homes, and indications are that the numbers are increasing. A recent Denver Post article predicted that 50% of all children now being born will spend some of their childhood in a single-parent home. In terms of frequency, the father-absent family is becoming quite common, even "normal," yet it often continues to be considered a "broken" home and, when compared to the two-parent family, an inadequate structure in which to raise healthy children. Since father-absent families are so common these days, this opinion is in need of review.This paper will present a review of the father absence research in three areas: sex role development, cognitive development and personality development. The role of moderator variables will be discussed. And, finally,an open systems model will be proposed as a vehicle to better understand the effects of father absence and as a guide for future research.

Comparing Common Data Environment Platforms for Student Collaborative Working: A Case Study from Ulster University

PAS1192-2 (2013) outlines the “fundamental principles of Level 2 information modeling”, one of these principles is the use of what is commonly referred to as a Common Data Environment (CDE). A CDE could be described as an internet-enabled cloudhosting platform, accessible to all construction team members to access shared project information. For the construction sector to achieve increased productivity goals, the next generation of industry professionals will need to be educated in a way that provides them with an appreciation of Building Information Modelling (BIM) working methods, at all levels, including an understanding of how data in a CDE should be structured, managed, shared and published. This presents a challenge for educational institutions in terms of providing a CDE that addresses the requirements set out in PAS1192-2, and mirrors organisational and professional working practices without causing confusion due to over complexity. This paper presents the findings of a two-year study undertaken at Ulster University comparing the use of a leading industry CDE platform with one derived from the in-house Virtual Learning Environment (VLE), for the delivery of a student BIM project. The research methodology employed was a qualitative case study analysis, focusing on observations from the academics involved and feedback from students. The results of the study show advantages for both CDE platforms depending on the learning outcomes required.

Liverpool, England, 1836 (Image 1 of 3) (Raster Image)

This layer is a georeferenced raster image of the historic paper map entitled: This trigonometrical plan of the town and port of Liverpool : including the environs of Edge Hill & Toxteth Park, Kirkdale, Everton, Low Hill from actual survey, is by permission most respectfully dedicated to the worshipful the Mayor & Common Council by their most obedient and obliged very humble servant Michael Alexander Gage ; engraved by Thomas Starling, Wilmington Square, London. It was published as the Act directs ... by M.A. Gage in March 1st 1836. Scale [ca. 1:3,240]. This layer is image 1 of 3 total images of the three sheet source map, representing the southern portion of the map. The image inside the map neatline is georeferenced to the surface of the earth and fit to the 'British National Grid' coordinate system. All map collar and inset information is also available as part of the raster image, including any inset maps, profiles, statistical tables, directories, text, illustrations, index maps, legends, or other information associated with the principal map. This map shows features such as roads, drainage, built-up areas and selected buildings and industries, canals, docks, wharves, city districts, ground cover, parks and more. Includes text and tables. Includes text.This layer is part of a selection of digitally scanned and georeferenced historic maps from the Harvard Map Collection. These maps typically portray both natural and manmade features. The selection represents a range of originators, ground condition dates, scales, and map purposes.

Liverpool, England, 1836 (Image 2 of 3) (Raster Image)

This layer is a georeferenced raster image of the historic paper map entitled: This trigonometrical plan of the town and port of Liverpool : including the environs of Edge Hill & Toxteth Park, Kirkdale, Everton, Low Hill from actual survey, is by permission most respectfully dedicated to the worshipful the Mayor & Common Council by their most obedient and obliged very humble servant Michael Alexander Gage ; engraved by Thomas Starling, Wilmington Square, London. It was published as the Act directs ... by M.A. Gage in March 1st 1836. Scale [ca. 1:3,240]. This layer is image 2 of 3 total images of the three sheet source map, representing the central portion of the map. The image inside the map neatline is georeferenced to the surface of the earth and fit to the 'British National Grid' coordinate system. All map collar and inset information is also available as part of the raster image, including any inset maps, profiles, statistical tables, directories, text, illustrations, index maps, legends, or other information associated with the principal map. This map shows features such as roads, drainage, built-up areas and selected buildings and industries, canals, docks, wharves, city districts, ground cover, parks and more. Includes text and tables. Includes text.This layer is part of a selection of digitally scanned and georeferenced historic maps from the Harvard Map Collection. These maps typically portray both natural and manmade features. The selection represents a range of originators, ground condition dates, scales, and map purposes.

Liverpool, England, 1836 (Image 3 of 3) (Raster Image)

This layer is a georeferenced raster image of the historic paper map entitled: This trigonometrical plan of the town and port of Liverpool : including the environs of Edge Hill & Toxteth Park, Kirkdale, Everton, Low Hill from actual survey, is by permission most respectfully dedicated to the worshipful the Mayor & Common Council by their most obedient and obliged very humble servant Michael Alexander Gage ; engraved by Thomas Starling, Wilmington Square, London. It was published as the Act directs ... by M.A. Gage in March 1st 1836. Scale [ca. 1:3,240]. This layer is image 3 of 3 total images of the three sheet source map, representing the northern portion of the map. The image inside the map neatline is georeferenced to the surface of the earth and fit to the 'British National Grid' coordinate system. All map collar and inset information is also available as part of the raster image, including any inset maps, profiles, statistical tables, directories, text, illustrations, index maps, legends, or other information associated with the principal map. This map shows features such as roads, drainage, built-up areas and selected buildings and industries, canals, docks, wharves, city districts, ground cover, parks and more. Includes text and tables. Includes text.This layer is part of a selection of digitally scanned and georeferenced historic maps from the Harvard Map Collection. These maps typically portray both natural and manmade features. The selection represents a range of originators, ground condition dates, scales, and map purposes.

New York, 1808 (Raster Image)

This layer is a georeferenced raster image of the historic paper manuscript map entitled: A map of the state of New York : compiled from the latest authorities, including the turnpike roads now granted as also the principal common roads connected therewith, by Wm. McCalpin ; copied by C.D.E. [Christophe Daniel Ebeling] in 1814. Scale [ca. 1:1,350,000]. This is a manuscript copy of a map printed in 1808. Covers also adjacent portions of Vermont, New Hampshire, Massachusetts, Connecticut, New Jersey, and Ontario, Canada. The image inside the map neatline is georeferenced to the surface of the earth and fit to the Universal Transverse Mercator (UTM) Zone 18N NAD83 projection. All map collar and inset information is also available as part of the raster image, including any inset maps, profiles, statistical tables, directories, text, illustrations, index maps, legends, or other information associated with the principal map. This map shows features such as roads, villages, forts, drainage, counties, and more. This layer is part of a selection of digitally scanned and georeferenced historic maps from The Harvard Map Collection as part of the Imaging the Urban Environment project. Maps selected for this project represent major urban areas and cities of the world, at various time periods. These maps typically portray both natural and manmade features at a large scale. The selection represents a range of regions, originators, ground condition dates, scales, and purposes.

New York, N.Y. and vicinity, 1860 (Raster Image) (Image 2 of 2)

This layer is a georeferenced raster image of the historic paper map entitled: Map of the five cities of New York, Brooklyn, Jersey City, Hoboken & Hudson City : Plate no. 2, prepared by M. Dripps for Valentine's Manuel [sic] of the Corporation of the city of New York. It was published by Common Council in 1860. Scale not given. This layer is image 2 of 2 total images of the two sheet source map, representing the southern portion of the map. The image inside the map neatline is georeferenced to the surface of the earth and fit to the Universal Transverse Mercator (UTM) Zone 18N NAD83 projection. All map collar and inset information is also available as part of the raster image, including any inset maps, profiles, statistical tables, directories, text, illustrations, index maps, legends, or other information associated with the principal map. This map shows features such as roads, railroads, drainage, city wards, parks, cemeteries, pier and bulkhead lines, selected public buildings, and more. This layer is part of a selection of digitally scanned and georeferenced historic maps from The Harvard Map Collection as part of the Imaging the Urban Environment project. Maps selected for this project represent major urban areas and cities of the world, at various time periods. These maps typically portray both natural and manmade features at a large scale. The selection represents a range of regions, originators, ground condition dates, scales, and purposes.

New York, N.Y. and vicinity, 1860 (Raster Image) (Image 2 of 2)

This layer is a georeferenced raster image of the historic paper map entitled: Map of the five cities of New York, Brooklyn, Jersey City, Hoboken & Hudson City : Plate no. 1, prepared by M. Dripps for Valentine's Manuel [sic] of the Corporation of the city of New York. It was published by Common Council in 1860. Scale not given. This layer is image 1 of 2 total images of the two sheet source map, representing the northern portion of the map. The image inside the map neatline is georeferenced to the surface of the earth and fit to the Universal Transverse Mercator (UTM) Zone 18N NAD83 projection. All map collar and inset information is also available as part of the raster image, including any inset maps, profiles, statistical tables, directories, text, illustrations, index maps, legends, or other information associated with the principal map. This map shows features such as roads, railroads, drainage, city wards, parks, cemeteries, pier and bulkhead lines, selected public buildings, and more. This layer is part of a selection of digitally scanned and georeferenced historic maps from The Harvard Map Collection as part of the Imaging the Urban Environment project. Maps selected for this project represent major urban areas and cities of the world, at various time periods. These maps typically portray both natural and manmade features at a large scale. The selection represents a range of regions, originators, ground condition dates, scales, and purposes.

Lower Manhattan, New York, N.Y., 1778 (Raster Image)

This layer is a georeferenced raster image of the historic paper map entitled: This plan of the city of New York (within the palisades which were erected in the year 1745) was made for the purpose of shewing the progress and extent of the Great Fire which happened in the year 1776, the number of houses that was consumed, and also the Fire of 1778. It was published by Common Council for Valentine's Manual of the corporation of the city of New York, for the years ... 1866. Scale not given. Copy of a manuscript map. Covers Manhattan below Chambers St. The image inside the map neatline is georeferenced to the surface of the earth and fit to the Universal Transverse Mercator (UTM) Zone 18N NAD83 projection. All map collar and inset information is also available as part of the raster image, including any inset maps, profiles, statistical tables, directories, text, illustrations, index maps, legends, or other information associated with the principal map. This map shows features such as roads, fire areas (1776, 1778), drainage, selected public buildings (churches, markets, etc.) and more. Relief is shown by hachures. Includes ill. and index to points of interest. This layer is part of a selection of digitally scanned and georeferenced historic maps from The Harvard Map Collection as part of the Imaging the Urban Environment project. Maps selected for this project represent major urban areas and cities of the world, at various time periods. These maps typically portray both natural and manmade features at a large scale. The selection represents a range of regions, originators, ground condition dates, scales, and purposes.

Lower Manhattan, New York, N.Y., 1808 (Raster Image)

This layer is a georeferenced raster image of the historic paper map entitled: Plan of the city of New York, 1808. It was published by the New York Common Council in the Manual of the corporation of the city of New York, for the years ... 1852. Facsimile copied from D. Longworth's map of 1808. Scale [ca. 1:7,500]. Covers lower Manhattan and portion of Brooklyn. The image inside the map neatline is georeferenced to the surface of the earth and fit to the Universal Transverse Mercator (UTM) Zone 18N NAD83 projection. All map collar and inset information is also available as part of the raster image, including any inset maps, profiles, statistical tables, directories, text, illustrations, index maps, legends, or other information associated with the principal map. This map shows features such as roads, drainage, city wards, selected public buildings, ferry lines, wharves, and more. Relief is shown by hachures. Includes index to points of interest. This layer is part of a selection of digitally scanned and georeferenced historic maps from The Harvard Map Collection as part of the Imaging the Urban Environment project. Maps selected for this project represent major urban areas and cities of the world, at various time periods. These maps typically portray both natural and manmade features at a large scale. The selection represents a range of regions, originators, ground condition dates, scales, and purposes.

Manhattan, New York, N.Y., 1852 (Raster Image)

This layer is a georeferenced raster image of the historic paper map entitled: Map of the city of New York, shewing the original high water line and the location of the different farms and estates. It was published by Common Council in the Manual of the corporation of the city of New York, for the years ... 1852. Scale not given. Covers Manhattan below 51st St. The image inside the map neatline is georeferenced to the surface of the earth and fit to the Universal Transverse Mercator (UTM) Zone 18N NAD83 projection. All map collar and inset information is also available as part of the raster image, including any inset maps, profiles, statistical tables, directories, text, illustrations, index maps, legends, or other information associated with the principal map. This map shows features such as roads, drainage, original water lines, early farms and estate locations, and more. This layer is part of a selection of digitally scanned and georeferenced historic maps from The Harvard Map Collection as part of the Imaging the Urban Environment project. Maps selected for this project represent major urban areas and cities of the world, at various time periods. These maps typically portray both natural and manmade features at a large scale. The selection represents a range of regions, originators, ground condition dates, scales, and purposes.

Boston, Massachusetts -- Emerald Necklace parks, 1894 (Raster Image)

This layer is a georeferenced raster image of the historic paper map entitled: Plan of portion of park system from Common to Franklin Park : including Charles River Basin, Charlesbank, Commonwealth Avenue, Back Bay Fens, Muddy River Improvement, Leverett Park, Jamaica Park, Arborway and Arnold Arboretum, [by] William Jackson, city engineer ; Olmsted, Olmsted & Eliot, landscape architects. It was published in Jan. 1894. Scale [ca. 1:9,000]. Covers Boston parks collectively known as the "Emerald Necklace." The image inside the map neatline is georeferenced to the surface of the earth and fit to the Massachusetts State Plane Coordinate System, Mainland Zone (in Feet) (Fipszone 2001). All map collar and inset information is also available as part of the raster image, including any inset maps, profiles, statistical tables, directories, text, illustrations, or other information associated with the principal map. This map shows park features such as roads, paths, recreational buildings and facilities, ground cover, and drainage. Also includes features surrounding parks: city roads, railroads, drainage, some public buildings, and more. This layer is part of a selection of digitally scanned and georeferenced historic maps of Massachusetts from the Harvard Map Collection. These maps typically portray both natural and manmade features. The selection represents a range of regions, originators, ground condition dates (1755-1922), scales, and purposes. The digitized selection includes maps of: the state, Massachusetts counties, town surveys, coastal features, real property, parks, cemeteries, railroads, roads, public works projects, etc.