The geometry and topology of the Universe

Basierend auf der allgemeinen Relativitätstheorie, wird argumentiert, dass die räumliche Komponente der Raumzeit mit einer dreidimensionalen, orientierbaren, lokal homogenen, zusammenhängenden, glatten und vollständigen Riemann'schen Mannigfaltigkeit M ohne Rand beschrieben werden kann. Das Hauptbestreben der vorliegenden Arbeit ist die Klassifikation der möglichen M nach ihrer Geometrie und Topologie. Vollständige und lokal homogene Mannigfaltigkeiten M können als Quotienten einer einfach zusammenhängenden und homogenen Mannigfaltigkeit N nach einer Untergruppe G der Isometriegruppe von N dargestellt werden. G operiert frei und eigentlich diskontinuierlich of der universellen Überlagerung N. Die geometrische Struktur auf M wird von N induziert und somit ist eine Klassifikation der Geometrien auf einfach zusammenhängenden Mannigfaltigkeiten ausreichend. Vervollständigt wird die Klassifikation durch Thurstons Geometrisierungstheorem, welches besagt, dass M mit einer geometrischen Struktur versehen werden kann, welche auf einer der acht Modellgeoemtrien modelliert wurde. Die von Beobachtungsdaten gestützte Einschränkung auf lokal isotrope Mannigfaltigkeiten reduziert das Problem der Klassifikation der möglichen Topologien von M auf das dreidimensionale Clifford-Klein'sche Raumproblem. Dieses ist äquivalent mit der Klassifikation diskreter Untergruppen von Isometriegruppem einfach zusammenhängender Mannigfaltigkeiten konstanter Krümmung, welche frei auf eben diesen operieren. Diese Klassifikation erlaubt es uns, eine Liste möglicher Kanditaten für die räumliche Komponente des Universums mit flacher oder sphärischer Geometrie anzugeben. Für hyperbolische Raumformen ist bis jetzt keine strukturelle Klassifikation bekannt. Jede kompakte Raumform kann als Fundamentalpolyeder mit paarweise identifizierten Seiten dargestellt werden. Mit Hilfe dieser Darstellung wird abschließend auf die Methoden der Kosmischen Topologie eingegangen. Im Gegensatz zu den Methoden der Standardkosmologie versuchen diese nicht nur die Geometrie, sondern auch die Topologie des uns umgebenden Raums zu bestimmen.Based on the General Theory of Relativity, I argue that the spatial part of space-time can be described by a three-dimensional, orientable, locally homogeneous, connected, smooth and complete Riemannian manifold M without boundary. The main topic of this work is to classify all the possible M by their topology and geometry. Complete and locally homogeneous manifolds M can be represented as the quotient of a simply-connected and homogeneous manifold N by a subgroup G of the isometry group of N which is acting freely and properly discontinuous on the universal covering space N. The geometric structure on M is induced by N, hence, the classification of all geometric structures on M can be done by classifying all simply-connected three-dimensional geometries. Finally, Thurston's Geometrization Theorem states that M has a geometry, modelled on one of the eight three-dimesional model geometries. Supported by observational data, we restrict ourselves to locally isotropic manifolds, reducing the classification of the possible topologies of M to the three-dimensional Clifford-Klein space form problem. It can be solved by classifying all discrete subgroups of the isometry groups of the simply-connected manifolds of constant curvature which act freely on them. For the spherical and flat case this classification enables us to list all canditates for the spatial part of the universe with a flat respectively spherical geometry. So far, there is no known structural classification of the hyperbolic space forms. Every compact space form can be described as a gluing manifold, which is a fundamental polyhedron with identified sides as pairs. In closing, the methods used by Cosmic Topology with the help of this "inner view" are presented. These, as opposed to the methods used by Standard Cosmology, try to determine not only the geometry, but also the topology of the space surrounding us

Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead.

Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology

Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead

Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety ‘Mode of Action’ framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology

Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead

Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/ mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety ‘Mode of Action’ framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology

Competing sorting signals guide endolyn along a novel route to lysosomes in MDCK cells

We have examined the trafficking of the mucin-like protein endolyn in transfected, polarized MDCK cells using biochemical approaches and immunofluorescence microscopy. Although endolyn contains a lysosomal targeting motif of the type YXXΦ and was localized primarily to lysosomes at steady state, significant amounts of newly synthesized endolyn were delivered to the apical cell surface. Antibodies to endolyn, but not lamp-2, were preferentially internalized from the apical plasma membrane and efficiently transported to lysosomes. Analysis of endolyn–CD8 chimeras showed that the lumenal domain of endolyn contains apical targeting information that predominates over basolateral information in its cytoplasmic tail. Interestingly, surface polarity of endolyn was independent of O-glycosylation processing, but was reversed by disruption of N-glycosylation using tunicamycin. At all times, endolyn was soluble in cold Triton X-100, suggesting that apical sorting was independent of sphingolipid rafts. Our data indicate that a strong, N-glycan-dependent apical targeting signal in the lumenal domain directs endolyn into a novel biosynthetic pathway to lysosomes, which occurs via the apical surface of polarized epithelial cells

Specific N-Glycans Direct Apical Delivery of Transmembrane, but Not Soluble or Glycosylphosphatidylinositol-anchored Forms of Endolyn in Madin-Darby Canine Kidney Cells

The sialomucin endolyn is a transmembrane protein with a unique trafficking pattern in polarized Madin-Darby canine kidney cells. Despite the presence of a cytoplasmic tyrosine motif that, in isolation, is sufficient to mediate basolateral sorting of a reporter protein, endolyn predominantly traverses the apical surface en route to lysosomes. Apical delivery of endolyn is disrupted in tunicamycin-treated cells, implicating a role for N-glycosylation in apical sorting. Site-directed mutagenesis of endolyn's eight N-glycosylation sites was used to identify two N-glycans that seem to be the major determinants for efficient apical sorting of the protein. In addition, apical delivery of endolyn was disrupted when terminal processing of N-glycans was blocked using glycosidase inhibitors. Missorting of endolyn occurred independently of the presence or absence of the basolateral sorting signal, because apical delivery was also inhibited by tunicamycin when the cytoplasmic tyrosine motif was mutated. However, we found that apical secretion of a soluble mutant of endolyn was N-glycan independent, as was delivery of glycosylphosphatidylinositol-anchored endolyn. Thus, specific N-glycans are only essential for the apical sorting of transmembrane endolyn, suggesting fundamental differences in the mechanisms by which soluble, glycosylphosphatidylinositol-anchored, and transmembrane proteins are sorted

Relationship between age (= duration of hearing loss) and total test score for prelingually deaf individuals.

Age and test score are not significantly correlated. (DOCX)</p

Fixed effects table with recognition score as dependent variable.

Signif. codes: 0 ’***’ 0.001 ’**’ 0.01 ’*’ 0.05 ’.’ 0.1 ’ ’ 1. Note: Reference category for calculation was “Category: Numbers”. (DOCX)</p

List of long sentences presented to the participants.

(DOCX)</p

List of medium long sentences presented to the participants.

(DOCX)</p