Cell surface engineering of renal cell carcinoma with glycosylphosphatidylinositol-anchored TIMP-1 blocks TGF-beta 1 activation and reduces regulatory ID gene expression

Tissue inhibitor of metalloproteinase 1 (TIMP-1) controls matrix metalloproteinase activity through 1:1 stoichiometric binding. Human TIMP-1 fused to a glycosylphosphatidylinositol (GPI) anchor (TIMP-1-GPI) shifts the activity of TIMP-1 from the extracellular matrix to the cell surface. TIMP-1-GPI treated renal cell carcinoma cells show increased apoptosis and reduced proliferation. Transcriptomic profiling and regulatory pathway mapping were used to identify the potential mechanisms driving these effects. Significant changes in the DNA binding inhibitors, TGF-beta 1/SMAD and BMP pathways resulted from TIMP-1-GPI treatment. These events were linked to reduced TGF-beta 1 signaling mediated by inhibition of proteolytic processing of latent TGF-beta 1 by TIMP-1-GPI

Peritumoral administration of GPI-anchored TIMP-1 inhibits colon carcinoma growth in Rag-2 gamma chain-deficient mice

Exogenous application of recombinant TIMP-1 protein modified by addition of a glycosylphosphatidylinositol (GPI) anchor allows efficient insertion of the fusion protein into cell membranes. This `cell surface engineering' leads to changes in the proteolytic environment. TIMP-1-GPI shows enhanced as well as novel in vitro biological activities including suppression of proliferation, reduced migration, and inhibition of invasion of the colon carcinoma cell line SW480. Treatment of SW480 tumors implanted in Rag (-/-) common gamma chain (-/-) C57BL/6 mice with peritumorally applied TIMP-1-GPI, control rhTIMP-1 protein, or vehicle shows that TIMP-1-GPI leads to a significant reduction in tumor growth

Floquet topological phase transitions induced by uncorrelated or correlated disorder

The impact of weak disorder and its spatial correlation on the topology of a Floquet system is not well understood so far. In this study, we investigate a model closely related to a two-dimensional Floquet system that has been realized in experiments. In the absence of disorder, we determine the phase diagram and identify a new phase characterized by edge states with alternating chirality in adjacent gaps. When weak disorder is introduced, we examine the disorder-averaged Bott index and analyze why the anomalous Floquet topological insulator is favored by both uncorrelated and correlated disorder, with the latter having a stronger effect. For a system with a ring-shaped gap, the Born approximation fails to explain the topological phase transition, unlike for a system with a point-like gap.Comment: 6+3 pages, 3 + 2 figure

A non-coding regulatory variant in the 5'-region of the MITF gene is associated with white-spotted coat in Brown Swiss cattle.

Recently, the Swiss breeding association reported an increasing number of white-spotted cattle in the Brown Swiss breed, which is normally solid brown coloured. A total of 60 Brown Swiss cattle with variably sized white abdominal spots, facial markings and depigmented claws were collected for this study. A genome-wide association study using 40k SNP genotypes of 20 cases and 1619 controls enabled us to identify an associated genome region on chromosome 22 containing the MITF gene, encoding the melanogenesis associated transcription factor. Variants at the MITF locus have been reported before to be associated with white or white-spotted phenotypes in other species such as horses, dogs and mice. Whole-genome sequencing of a single white-spotted cow and subsequent genotyping of 172 Brown Swiss cattle revealed two significantly associated completely linked single nucleotide variants (rs722765315 and rs719139527). Both variants are located in the 5'-regulatory region of the bovine MITF gene, and comparative sequence analysis showed that the variant rs722765315, located 139 kb upstream of the transcription start site of the bovine melanocyte-specific MITF transcript, is situated in a multi-species conserved sequence element which is supposed to be regulatory important. Therefore, we hypothesize that rs722765315 represents the most likely causative variant for the white-spotting phenotype observed in Brown Swiss cattle. Presence of the mutant allele in a heterozygous or homozygous state supports a dominant mode of inheritance with incomplete penetrance and results in a variable extent of coat colour depigmentation

Biolabile ferrous iron bearing nanoparticles in glacial sediments

Glaciers and ice sheets are a significant source of nanoparticulate Fe, which is potentially important in sustaining the high productivity observed in the near-coastal regions proximal to terrestrial ice cover. However, the bioavailability of particulate iron is poorly understood, despite its importance in the ocean Fe inventory. We combined high-resolution imaging and spectroscopy to investigate the abundance, morphology and valence state of particulate iron in glacial sediments. Our results document the widespread occurrence of amorphous and Fe(II)-rich and Fe(II)-bearing nanoparticles in Arctic glacial meltwaters and iceberg debris, compared to Fe(III)-rich dominated particulates in an aeolian dust sample. Fe(II) is thought to be highly biolabile in marine environments. Our work shows that glacially derived Fe is more labile than previously assumed, and consequently that glaciers and ice sheets are therefore able to export potentially bioavailable Fe(II)-containing nanoparticulate material to downstream ecosystems, including those in a marine setting. Our findings provide further evidence that Greenland Ice Sheet meltwaters may provide biolabile particulate Fe that may fuel the large summer phytoplankton bloom in the Labrador Sea, and that Fe(II)-rich particulates from a region of very high productivity downstream of a polar ice sheet may be glacial in origin

A de novo germline mutation of DLX3 in a Brown Swiss calf with tricho-dento-osseus-like syndrome.

OBJECTIVE A novel congenital disorder affecting a calf was observed, and its phenotype and genetic mutation identified. ANIMAL A six-month-old female Brown Swiss calf. METHODS Diagnostic investigation and whole genome sequencing of a case parent trio was performed. RESULTS The calf had a dull kinky coat with mild hypotrichosis, and teeth with brown staining and enamel defects. Histological examination of skin biopsies was compatible with a follicular dysplasia. Radiography and computed tomography revealed thickening of the skull bones and large pulp cavities with a marked thinning of enamel affecting all teeth. A de novo germline mutation affecting the distal-less homeobox gene (DLX3) was identified. The 10 bp frameshift mutation in exon 3 of the bovine DLX3 gene is predicted to replace the second C-terminal transactivation domain of the wild-type protein by a recoded peptide of 99 amino acids without any sequence similarity. CONCLUSION AND CLINICAL IMPORTANCE A causative mutation for a sporadic phenotype resembling human tricho-dento-osseous syndrome was identified after detection of a de novo germline mutation in the DLX3 gene

APOB-associated cholesterol deficiency in Holstein cattle is not a simple recessive disease.

In 2015, cholesterol deficiency (CD) was reported for the first time as a new recessive defect in Holstein cattle. After GWAS mapping and identification of a disease-associated haplotype, a causative loss-of-function variant in APOB was identified. CD-clinically affected APOB homozygotes showed poor development, intermittent diarrhea and hypocholesterolemia and, consequently, a limited life expectation. Herein, we present a collection of 18 cases clinically diagnosed as CD-affected APOB heterozygotes. CD-clinically affected heterozygotes show reduced cholesterol and triglyceride blood concentrations. The differences in total blood cholesterol and triglycerides between nine CD-clinically affected and 36 non-affected heterozygotes were significant. As only some APOB heterozygotes show the clinical CD phenotype, we assume that the penetrance is reduced in heterozygotes compared to the fully penetrant effect observed in homozygotes. We conclude that APOB-associated CD represents most likely an incomplete dominant inherited metabolic disease with incomplete penetrance in heterozygotes

Investigation of potential causes for the development of porcine ear necrosis: different study designs--comparable results?

During the last years two studies for the investigation of the etiology of porcine ear necrosis were carried out at the Clinic for Swine of the University of Veterinary Medicine Vienna. In study 1, parameters, which are discussed in this context, were collected by veterinary practitioners by completing specially designed questionnaires in farms with symptoms of the porcine ear necrosis syndrome. In study 2, samples of piglets and feed were collected for laboratory analysis of the most important infectious agents as well as mycotoxins. In the present manuscript, the results of both projects were compared. Even if the selection criteria of both studies differed, the affected age class was comparable (5.5 to ten weeks of life in study 1 and six to ten weeks of life in study 2). The herd-specific prevalence of the porcine ear necrosis syndrome varied considerably with percentages between 2 and 10, respectively, to 100%. The evaluation of questionnaires in study 1 showed that 51% of the farms had problems with cannibalism. Particles of plant material, which were frequently seen on the histologic slides of study 2, could have got into the tissue by chewing the ears of the pen mates or cannibalism. Whereas in study 1 the negative effect of parameters as high pig density, suboptimal climate, missing enrichment material and bad quality of feed and water were considered, in study 2 all these factors were checked at sample collection and ruled out as precursor for cannibalism. In both studies bacterial agents proved to be a crucial co-factor for the expansion of the necroses to deeper tissue layers, whereas viral pathogens were classified less important. In both projects it was not possible to estimate the direct impact of infectious agents and mycotoxins as direct trigger of the necroses as well as their participation as co-factors or precursor in the sense of an immunosuppression or previous damage of blood vessels or tissue

PASSAge - Personalized Mobility, Assistance and Service Systems in an Ageing Society : PASSAge - Personalisierte Mobilität, Assistenz und Service Systeme in einer alternden Gesellschaft

The demographic change in modern societies has a significant impact on the future planning of self-determined mobility and mobility means. An optimized accessibility of the means of transportation is required, as well as their connection towards buildings and residences. These connections have to be modular and compatible to the mobility means of the users. Barrier-free accessibility according to the existing norms can address these problems only partially. Broader and holistic concepts are needed here. The project PASSAge aims at the implementation of seamless mobility chains that smoothly connect private, semi-public and public space. Mobility shall be ensured by the extension of existing mobility means with user-oriented components. The project follows the approach to complement the barrier-free access and usage of public transportation with mostly electrically powered compact vehicles and micro vehicles. These have to be adopted by physical means and information technology means to residences and building structures. The goal is to develop a flexible socio-technical infrastructure with a multitude of mobility means and modular building, thus creating synergy effects. Core to this approach is the development of business models, which allow for and ensure the allocation and co-ordination of mobility services. Interfaces will be created for all compact vehicles and micro vehicles that extend their functionality both digitally and physically and thereby enable their ubiquitous connection to the envisioned services.Godkänd; 2013; 20121026 (matkra