Non-hierarchical logistic models and case-only designs for assessing susceptibility in population-based case-control studies

Mechanisms for the abnormal copper (Cu) accumulation in the liver of LEC rats were examined using primary cultured liver parenchymal cells prepared from mutant LEC rats and those from control LEA rats (original strain). The Cu and metallothionein (MT) mRNA levels in the liver of LEC rats were caused to decrease to the same levels as those of LEA rats by removing Cu in vivo selectively with tetrathiomolybdate. Cu was taken up by LEC rat cells to the same extent as LEA rat cells by exposure to low medium Cu and to a higher extent by exposure to high medium Cu, while the MT mRNA level in LEC rat cells increased dose-dependently at a much higher rate than that in LEA rats. MT mRNA levels in both cells were comparable by exposure to cadmium, zinc and dexamethasone. The results indicate that expression of MT mRNA is selectively enhanced by Cu in LEC cells despite the fact that uptake of Cu is comparable with normal cells.     

Producing content producers [computer animation]

Several off-the-shelf animation software packages provide extensive capabilities, obviating the need for studios to develop their own software, except for highly specialized effects and interfaces. These capabilities make it feasible for a university to educate students in animation production without years of software development. The author discusses The UTS School of Cinema-Television and The USC Computer Animation Laboratory in particular     

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Reduced skin tumor development in cyclin D1-deficient mice highlights the oncogenic ras pathway in vivo

Cyclin D1 is part of a cell cycle control node consistently deregulated in most human cancers. However, studies with cyclin D1-null mice indicate that it is dispensable for normal mouse development as well as cell growth in culture. Here, we provide evidence that ras-mediated tumorigenesis depends on signaling pathways that act preferentially through cyclin D1. Cyclin D1 expression and the activity of its associated kinase are up-regulated in keratinocytes in response to oncogenic ras. Furthermore, cyclin D1 deficiency results in up to an 80% decrease in the development of squamous tumors generated through either grafting of retroviral ras-transduced keratinocytes, phorbol ester treatment of ras transgenic mice, or two-stage carcinogenesis.     

Experiences from Exporting Major Proof Assistant Libraries

The interoperability of proof assistants and the integration of their libraries is a highly valued but elusive goal in the field of theorem proving. As a preparatory step, in previous work, we translated the libraries of multiple proof assistants, specifically the ones of Coq, HOL Light, IMPS, Isabelle, Mizar, and PVS into a universal format: OMDoc/MMT. Each translation presented great theoretical, technical, and social challenges, some universal and some system-specific, some solvable and some still open. In this paper, we survey these challenges and compare and evaluate the solutions we chose. We believe similar library translations will be an essential part of any future system interoperability solution, and our experiences will prove valuable to others undertaking such efforts.

     

Valuation of online social networks taking into account users’ interconnectedness

Online social networks have been gaining increasing economic importance in light of the rising number of their users. Numerous recent acquisitions priced at enormous amounts have illustrated this development and revealed the need for adequate business valuation models. The value of an online social network is largely determined by the value of its users, the relationships between these users, and the resulting network effects. Therefore, the interconnectedness of a user within the network has to be considered explicitly to get a reasonable estimate for its economic value. Established standard business valuation models, however, do not account for these aspects sufficiently. Thus, we propose an economic model for the valuation of online social networks, which takes into account the users’ interconnectedness within the network. Furthermore, we analyze different centrality measures, which can be used to quantify users’ interconnectedness in online social networks and propose a measure which is based on the PageRank-algorithm. Finally, the practical application of the model is illustrated by an example of the European online social network XING.com.     

X-ray Fluorescence Uptake Measurement of Functionalized Gold Nanoparticles in Tumor Cell Microsamples

Quantitative cellular in vitro nanoparticle uptake measurements are possible with a large number of different techniques, however, all have their respective restrictions. Here, we demonstrate the application of synchrotron-based X-ray fluorescence imaging (XFI) on prostate tumor cells, which have internalized differently functionalized gold nanoparticles. Total nanoparticle uptake on the order of a few hundred picograms could be conveniently observed with microsamples consisting of only a few hundreds of cells. A comparison with mass spectroscopy quantification is provided, experimental results are both supported and sensitivity limits of this XFI approach extrapolated by Monte-Carlo simulations, yielding a minimum detectable nanoparticle mass of just 5 pg. This study demonstrates the high sensitivity level of XFI, allowing non-destructive uptake measurements with very small microsamples within just seconds of irradiation time.     

Treatment of Stress Urinary Incontinence with Muscle Stem Cells and Stem Cell Components: Chances,Challenges and Future Prospects

Urinary incontinence (UI) is a major problem in health care and more than 400 million people worldwide suffer from involuntary loss of urine. With an increase in the aging population, UI is likely to become even more prominent over the next decades and the economic burden is substantial. Among the different subtypes of UI, stress urinary incontinence (SUI) is the most prevalent and focus of this review. The main underlying causes for SUI are pregnancy and childbirth, accidents with direct trauma to the pelvis or medical treatments that affect the pelvic floor, such as surgery or irradiation. Conservative approaches for the treatment of SUI are pelvic physiotherapy, behavioral and lifestyle changes, and the use of pessaries. Current surgical treatment options include slings, colposuspensions, bulking agents and artificial urinary sphincters. These treatments have limitations with effectiveness and bear the risk of long-term side effects. Furthermore, surgical options do not treat the underlying pathophysiological causes of SUI. Thus, there is an urgent need for alternative treatments, which are effective, minimally invasive and have only a limited risk for adverse effects. Regenerative medicine is an emerging field, focusing on the repair, replacement or regeneration of human tissues and organs using precursor cells and their components. This article critically reviews recent advances in the therapeutic strategies for the management of SUI and outlines future possibilities and challenges.     

An Engineered sgsh Mutant Zebrafish Recapitulates Molecular and Behavioural Pathobiology of Sanfilippo Syndrome A/MPS IIIA

Mucopolysaccharidosis IIIA (MPS IIIA, Sanfilippo syndrome type A), a paediatric neurological lysosomal storage disease, is caused by impaired function of the enzyme N-sulfoglucosamine sulfohydrolase (SGSH) resulting in impaired catabolism of heparan sulfate glycosaminoglycan (HS GAG) and its accumulation in tissues. MPS IIIA represents a significant proportion of childhood dementias. This condition generally leads to patient death in the teenage years, yet no effective therapy exists for MPS IIIA and a complete understanding of the mechanisms of MPS IIIA pathogenesis is lacking. Here, we employ targeted CRISPR/Cas9 mutagenesis to generate a model of MPS IIIA in the zebrafish, a model organism with strong genetic tractability and amenity for high-throughput screening. The sgsh^Δex5−6 zebrafish mutant exhibits a complete absence of Sgsh enzymatic activity, leading to progressive accumulation of HS degradation products with age. sgsh^Δex5−6 zebrafish faithfully recapitulate diverse CNS-specific features of MPS IIIA, including neuronal lysosomal overabundance, complex behavioural phenotypes, and profound, lifelong neuroinflammation. We further demonstrate that neuroinflammation in sgsh^Δex5−6 zebrafish is largely dependent on interleukin-1β and can be attenuated via the pharmacological inhibition of Caspase-1, which partially rescues behavioural abnormalities in sgsh^Δex5−6 mutant larvae in a context-dependent manner. We expect the sgsh^Δex5−6 zebrafish mutant to be a valuable resource in gaining a better understanding of MPS IIIA pathobiology towards the development of timely and effective therapeutic interventions.     

High Throughput Screening of Low Temperature SCR and SCD De-NOx Catalysts in Scanning Mass Spectrometer

High-throughput synthesis and screening methods have been developed for the discovery of highly active lead compounds for the selective catalytic reduction as well as direct decomposition of NO in the temperature range 200–300 °C. The discovery libraries for primary screening consisted of 16 × 16 catalyst arrays on 4in. square quartz wafers. Catalysts were prepared by robotic liquid dispensing techniques and screened for catalytic activity in Symyx' scanning mass spectrometer. The scanning mass spectrometer is a fast serial screening tool that uses flat wafer catalyst surfaces, local laser heating, a scanning/sniffing nozzle and a quadrupolar mass spectrometer to compare relative catalytic activities. The feed consisted of NO/NH₃ mixtures with optional O₂ cofeed and Kr as the internal standard in Ar carrier gas. QMS detection allowed for tracking of H₂O, N₂, NO, O₂, N₂O and Kr. Screening protocols for catalytic materials encompassed metal precursors and carriers for supported vanadia systems, extensive doping of V₂O₅/TiO₂, and broad screening of mixed redox metal oxides and supported base and noble metal systems. More than 500 samples could be screened in a single day. Active hits (high NO consumption accompanied by corresponding N₂ production) identified in discovery libraries were re-synthesized as focus libraries for lead confirmation and further optimization. These libraries used shallower compositional gradients, for example 56 points (compositions) per ternary, with four 56-point ternaries per 4in. wafer. Broad screening ternaries were generally 8 or 15 points. The focus libraries more clearly reveal the trends and provide guidelines for secondary screening and scale-up. High conversions were achieved in scanning mass spectrometer so the scalability risk is small for the short contact time reactions.