The Unique-5 and -6 Motifs of ZO-1 Regulate Tight Junction Strand Localization and Scaffolding Properties

The proper cellular location and sealing of tight junctions is assumed to depend on scaffolding properties of ZO-1, a member of the MAGUK protein family. ZO-1 contains a conserved SH3-GUK module that is separated by a variable region (unique-5), which in other MAGUKs has proven regulatory functions. To identify motifs in ZO-1 critical for its putative scaffolding functions, we focused on the SH3-GUK module including unique-5 (U5) and unique-6 (U6), a motif immediately C-terminal of the GUK domain. In vitro binding studies reveal U5 is sufficient for occludin binding; U6 reduces the affinity of this binding. In cultured cells, U5 is required for targeting ZO-1 to tight junctions and removal of U6 results in ectopically displaced junction strands containing the modified ZO-1, occludin, and claudin on the lateral cell membrane. These results provide evidence that ZO-1 can control the location of tight junction transmembrane proteins and reveals complex protein binding and targeting signals within its SH3-U5-GUK-U6 region. We review these findings in the context of regulated scaffolding functions of other MAGUK protein

A remembrance of things (best) forgotten: The 'allegorical past' and the feminist imagination

This is the author's PDF version of an article published in Feminist theology© 2012. The definitive version is available at http://fth.sagepub.com/This article discusses the US TV series Mad Men, which is set in an advertising agency in 1960s New York, in relation to two key elements which seem significant for a consideration of the current state of feminism in church and academy, both of which centre around what it means to remember or (not) to forget

Heidelberg-Studie 2000

Umfrage zum Leben und poltischen Problemen in Heidelberg. 1219 Telefoninterview

Laser-induced fluorescence of free diamondoid molecules

Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG geförderten) Allianz- bzw. Nationallizenz frei zugänglich.This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively.We observe the fluorescence of pristine diamondoids in the gas phase, excited using narrow band ultraviolet laser light. The emission spectra show well- defined features, which can be attributed to transitions from the excited electronic state into different vibrational modes of the electronic ground state. We assign the normal modes responsible for the vibrational bands, and determine the geometry of the excited states. Calculations indicate that for large diamondoids, the spectral bands do not result from progressions of single modes, but rather from combination bands composed of a large number of Delta v = 1 transitions. The vibrational modes determining the spectral envelope can mainly be assigned to wagging and twisting modes of the surface atoms. We conclude that our theoretical approach accurately describes the photophysics in diamondoids and possibly other hydrocarbons in general.DFG, FOR 1282, Controlling the electronic structure of semiconductor nanoparticles by doping and hybrid formatio

Self-assembly of pH-responsive fluorinated dendrimer-based particulates for drug delivery and noninvasive imaging

a b s t r a c t Dendrimers are nanoscale macromolecules with well-defined branching chemical structures. Control over the architecture and function of these structures has enabled many advances in materials science and biomedical applications. Though dendrimers are directly synthesized by iteration of simple repetitive steps, generation of the larger, more complex structures required for many biomedical applications by covalent synthetic methods has been challenging. Here we demonstrate a spontaneous self-assembly of poly(amidoamine) dendrimers into complex nanoscopic and microscopic particulates following partial fluorination of the constituent dendrimer subunits. These dense particulates exhibit a stimulus-induced response to low external pH that causes their disassembly over time, enabling controlled release of encapsulated agents. In addition, we show that these assemblies offer a sufficiently high density of fluorine spins to enable detection of their site-specific accumulation in vivo b

Bone morphogenetic protein modulator BMPER is highly expressed in malignant tumors and controls invasive cell behavior

Bone morphogenetic proteins (BMPs) are growth factors that exert important functions in cell proliferation, migration and differentiation. Till date, multiple human tumors have been reported to display a dysregulation of several members of the BMP pathway that is associated with enhanced malignant tumor growth and metastasis. BMPER (BMP endothelial cell precursor-derived regulator) is a direct BMP modulator that is necessary for BMPs to exert their full-range signaling activity. Moreover, BMPER is expressed by endothelial cells and their progenitors, and has pro-angiogenic features in these cells. Here, we describe the expression of BMPER in human specimens of lung, colon and cervix carcinomas and cell lines derived from such carcinomas. In contrast to healthy tissues, BMPER is highly expressed upon malignant deterioration. Functionally, loss of BMPER in the lung tumor cell line A549 impairs proliferation, migration, invasion as well as tumor cell-induced endothelial cell sprout formation. In contrast, stimulation of A549 cells with exogenous BMPER had no further effect. We found that the BMPER effect may be transduced by regulation of the BMP target transcription factor inhibitor of DNA binding 1 (Id1) and matrix metalloproteinases (MMPs) 9 and 2. These facilitators of cell migration are down-regulated when BMPER is absent. To prove the relevance of our in vitro results in vivo, we generated Lewis lung carcinoma cells with impaired BMPER expression and implanted them into the lungs of C57BL/6 mice. In this model, the absence of BMPER resulted in severely reduced tumor growth and tumor angiogenesis. Taken together, these data unequivocally demonstrate that the BMP modulator BMPER is highly expressed in malignant tumors and tumor growth is dependent on the presence of BMPER

Less than the sum of its parts : the dust-corrected Hα luminosity of star-forming galaxies explored at different spatial resolutions with MaNGA and MUSE

Funding: NVA would like to thank the University of St Andrews for providing support during her visit. NVA acknowledges support of the Royal Society and the Newton Fund via the award of a Royal Society–Newton Advanced Fellowship (grant NAF\R1\180403), and of Fundação de Amparo à Pesquisa e Inovação de Santa Catarina (FAPESC) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). AW acknowledges financial support from Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) process number 2019/01768-6. MG receives funding from the European Research Council (ERC) under the European Union Horizon 2020 research and innovative programme (MagneticYSOs programme, grant agreement Nber 679937). EWP, RSK, SR, SCOG and DR acknowledge funding from the Deutsche Forschungsgemeinschaft (DFG) via the Collaborative Research Center (SFB 881) ‘The Milky Way System (subprojects A1, B1, and B2) and from the Heidelberg Cluster of Excellence STRUCTURES in the framework of Germany’s Excellence Strategy (grant EXC-2181/1- 390900948).The Hα and Hβ emission line luminosities measured in a single integrated spectrum are affected in non-trivial ways by point-to-point variations in dust attenuation in a galaxy. This work investigates the impact of this variation when estimating global Hα luminosities corrected for the presence of dust by a global Balmer decrement. Analytical arguments show that the dust-corrected Hα luminosity is always underestimated when using the global Hα/Hβ flux ratio to correct for dust attenuation. We measure this effect on 156 face-on star-forming galaxies from the Mapping Nearby Galaxies at APO (MaNGA) survey. At 1–2 kpc spatial resolution, the effect is small but systematic, with the integrated dust-corrected Hα luminosity underestimated by 2–4 per cent (and typically not more than by 10 per cent), and depends on the specific star formation rate of the galaxy. Given the spatial resolution of MaNGA, these are lower limits for the effect. From Multi Unit Spectroscopic Explorer (MUSE) observations of NGC 628 with a resolution of 36 pc we find the discrepancy between the globally and the point-by-point dust-corrected Hα luminosity to be 14 ± 1 per cent, which may still underestimate the true effect. We use toy models and simulations to show that the true difference depends strongly on the spatial variance of the Hα/Hβ flux ratio, and on the slope of the relation between Hα luminosity and dust attenuation within a galaxy. Larger samples of higher spatial resolution observations are required to quantify the dependence of this effect as a function of galaxy properties.PostprintPeer reviewe

Claudin 7 expression and localization in the normal murine mammary gland and murine mammary tumors

INTRODUCTION: Claudins, membrane-associated tetraspanin proteins, are normally associated with the tight junctions of epithelial cells where they confer a variety of permeability properties to the transepithelial barrier. One member of this family, claudin 7, has been shown to be expressed in the human mammary epithelium and some breast tumors. To set the stage for functional experiments on this molecule, we examined the developmental expression and localization of claudin 7 in the murine mammary epithelium and in a selection of murine mammary tumors. METHOD: We used real-time polymerase chain reaction, in situ mRNA localization, and immunohistochemistry (IHC) to examine the expression and localization of claudin 7. Frozen sections were examined by digital confocal microscopy for colocalization with the tight-junction protein ZO1. RESULTS: Claudin 7 was expressed constitutively in the mammary epithelium at all developmental stages, and the ratio of its mRNA to that of keratin 19 was nearly constant through development. By IHC, claudin 7 was located in the basolateral part of the cell where it seemed to be localized to discrete vesicles. Scant colocalization with the tight-junction scaffolding protein ZO1 was observed. Similar results were obtained from IHC of the airway epithelium and some renal tubules; however, claudin 7 did partly colocalize with ZO1 in EPH4 cells, a normal murine mammary cell line, and in the epididymis. The molecule was localized in the cytoplasm of MMTV-neu and the transplantable murine tumor cell lines TM4, TM10, and TM40A, in which its ratio to cytokeratin was higher than in the normal mammary epithelium. CONCLUSION: Claudin 7 is expressed constitutively in the mammary epithelium at approximately equal levels throughout development as well as in the murine tumors examined. Although it is capable of localizing to tight junctions, in the epithelia of mammary gland, airway, and kidney it is mostly or entirely confined to punctate cytoplasmic structures, often near the basolateral surfaces of the cells and possibly associated with basolateral membranes. These observations suggest that claudin 7 might be involved in vesicle trafficking to the basolateral membrane, possibly stabilizing cytoplasmic vesicles or participating in cell–matrix interactions

First-line treatment and outcome of elderly patients with primary central nervous system lymphoma (PCNSL)—a systematic review and individual patient data meta-analysis

Evidence for prognosis and treatment of elderly patient with primary central nervous system is limited. High-dose methotrexate should be applied whenever possible, especially combination with oral alkylating agents is a promising approach. Further combinations with other intravenous drugs do not seem to improve outcome. More prospective trials designed for elderly PCNSL patients are warrante