Proteomic analysis of the cerebrospinal fluid of patients with Creutzfeldt-Jakob disease

So far, only the detection of 14-3-3 proteins in cerebrospinal fluid (CSF) has been accepted as diagnostic criterion for Creutzfeldt-Jakob disease (CJD). However, this assay cannot be used for screening because of the high rate of false-positive results, whereas patients with variant CJD are often negative for 14-3-3 proteins. The aim of this study was to compare the spot patterns of CSF by 2-dimensional polyacrylamide gel electrophoresis (2D-PAGE) to search for a CJD-specific spot pattern. We analyzed the CSF of 28 patients {[}11 CJD, 9 Alzheimer's disease ( AD), 8 nondemented controls (NDC)] employing 2D-PAGE which was optimized for minimal volumes of CSF (0.1 ml; 7-cm strips). All samples were run at least three times, gels were silver stained and analyzed by an analysis software and manually revised. We could consistently match 268 spots which were then compared between all groups. By the use of 5 spots, we were able to differentiate CJD from AD or NDC with a sensitivity of 100%. CJD could also be distinguished from both groups by using a heuristic clustering algorithm of 2 spots. We conclude that this proteomic approach can differentiate CJD from other diseases and may serve as a model for other neurodegenerative diseases. Copyright (C) 2007 S. Karger AG, Basel

GPR43 deficiency protects against podocyte insulin resistance in diabetic nephropathy through the restoration of AMPKα activity

RATIONALE: Albuminuria is an early clinical feature in the progression of diabetic nephropathy (DN). Podocyte insulin resistance is a main cause of podocyte injury, playing crucial roles by contributing to albuminuria in early DN. G protein-coupled receptor 43 (GPR43) is a metabolite sensor modulating the cell signalling pathways to maintain metabolic homeostasis. However, the roles of GPR43 in podocyte insulin resistance and its potential mechanisms in the development of DN are unclear. METHODS: The experiments were conducted by using kidney tissues from biopsied DN patients, streptozotocin (STZ) induced diabetic mice with or without global GPR43 gene knockout, diabetic rats treated with broad-spectrum oral antibiotics or fecal microbiota transplantation, and cell culture model of podocytes. Renal pathological injuries were evaluated by periodic acid-schiff staining and transmission electron microscopy. The expression of GPR43 with other podocyte insulin resistance related molecules was checked by immunofluorescent staining, real-time PCR, and Western blotting. Serum acetate level was examined by gas chromatographic analysis. The distribution of gut microbiota was measured by 16S ribosomal DNA sequencing with faeces. RESULTS: Our results demonstrated that GPR43 expression was increased in kidney samples of DN patients, diabetic animal models, and high glucose-stimulated podocytes. Interestingly, deletion of GPR43 alleviated albuminuria and renal injury in diabetic mice. Pharmacological inhibition and knockdown of GPR43 expression in podocytes increased insulin-induced Akt phosphorylation through the restoration of adenosine 5'-monophosphate-activated protein kinase α (AMPKα) activity. This effect was associated with the suppression of AMPKα activity through post-transcriptional phosphorylation via the protein kinase C-phospholipase C (PKC-PLC) pathway. Antibiotic treatment-mediated gut microbiota depletion, and faecal microbiota transplantation from the healthy donor controls substantially improved podocyte insulin sensitivity and attenuated glomerular injury in diabetic rats accompanied by the downregulation of the GPR43 expression and a decrease in the level of serum acetate. CONCLUSION: These findings suggested that dysbiosis of gut microbiota-modulated GPR43 activation contributed to albuminuria in DN, which could be mediated by podocyte insulin resistance through the inhibition of AMPKα activity

High-density information storage in an absolutely defined aperiodic sequence of monodisperse copolyester

Synthesis of a polymer composed of a large discrete number of chemically distinct monomers in an absolutely defined aperiodic sequence remains a challenge in polymer chemistry. The synthesis has largely been limited to oligomers having a limited number of repeating units due to the difficulties associated with the step-by-step addition of individual monomers to achieve high molecular weights. Here we report the copolymers of ??-hydroxy acids, poly(phenyllactic-co-lactic acid) (PcL) built via the cross-convergent method from four dyads of monomers as constituent units. Our proposed method allows scalable synthesis of sequence-defined PcL in a minimal number of coupling steps from reagents in stoichiometric amounts. Digital information can be stored in an aperiodic sequence of PcL, which can be fully retrieved as binary code by mass spectrometry sequencing. The information storage density (bit/Da) of PcL is 50% higher than DNA, and the storage capacity of PcL can also be increased by adjusting the molecular weight (~38???kDa)

Geospatial information infrastructures

Manual of Digital Earth / Editors: Huadong Guo, Michael F. Goodchild, Alessandro Annoni .- Springer, 2020 .- ISBN: 978-981-32-9915-3Geospatial information infrastructures (GIIs) provide the technological, semantic,organizationalandlegalstructurethatallowforthediscovery,sharing,and use of geospatial information (GI). In this chapter, we introduce the overall concept and surrounding notions such as geographic information systems (GIS) and spatial datainfrastructures(SDI).WeoutlinethehistoryofGIIsintermsoftheorganizational andtechnologicaldevelopmentsaswellasthecurrentstate-of-art,andreflectonsome of the central challenges and possible future trajectories. We focus on the tension betweenincreasedneedsforstandardizationandtheever-acceleratingtechnological changes. We conclude that GIIs evolved as a strong underpinning contribution to implementation of the Digital Earth vision. In the future, these infrastructures are challengedtobecomeflexibleandrobustenoughtoabsorbandembracetechnological transformationsandtheaccompanyingsocietalandorganizationalimplications.With this contribution, we present the reader a comprehensive overview of the field and a solid basis for reflections about future developments

miRMaid: a unified programming interface for microRNA data resources

<p>Abstract</p> <p>Background</p> <p>MicroRNAs (miRNAs) are endogenous small RNAs that play a key role in post-transcriptional regulation of gene expression in animals and plants. The number of known miRNAs has increased rapidly over the years. The current release (version 14.0) of miRBase, the central online repository for miRNA annotation, comprises over 10.000 miRNA precursors from 115 different species. Furthermore, a large number of decentralized online resources are now available, each contributing with important miRNA annotation and information.</p> <p>Results</p> <p>We have developed a software framework, designated here as miRMaid, with the goal of integrating miRNA data resources in a uniform web service interface that can be accessed and queried by researchers and, most importantly, by computers. miRMaid is built around data from miRBase and is designed to follow the official miRBase data releases. It exposes miRBase data as inter-connected web services. Third-party miRNA data resources can be modularly integrated as miRMaid plugins or they can loosely couple with miRMaid as individual entities in the World Wide Web. miRMaid is available as a public web service but is also easily installed as a local application. The software framework is freely available under the LGPL open source license for academic and commercial use.</p> <p>Conclusion</p> <p>miRMaid is an intuitive and modular software platform designed to unify miRBase and independent miRNA data resources. It enables miRNA researchers to computationally address complex questions involving the multitude of miRNA data resources. Furthermore, miRMaid constitutes a basic framework for further programming in which microRNA-interested bioinformaticians can readily develop their own tools and data sources.</p

Bright X-ray radiation from plasma bubbles in an evolving laser wakefield accelerator

We show that the properties of the electron beam and bright X-rays produced by a laser wakefield accelerator can be predicted if the distance over which the laser self-focuses and compresses prior to self-injection is taken into account. A model based on oscillations of the beam inside a plasma bubble shows that performance is optimised when the plasma length is matched to the laser depletion length. With a 200~TW laser pulse this results in an X-ray beam with median photon energy of 20 keV, $> 10^{9}$ photons per shot and a peak brightness of $4 \times 10^{23}$ photons s$^{-1}$ mrad$^{-2}$ mm$^{-2}$ (0.1 % BW)$^{-1}$

A review of physical supply and EROI of fossil fuels in China

This paper reviews China’s future fossil fuel supply from the perspectives of physical output and net energy output. Comprehensive analyses of physical output of fossil fuels suggest that China’s total oil production will likely reach its peak, at about 230 Mt/year (or 9.6 EJ/year), in 2018; its total gas production will peak at around 350 Bcm/year (or 13.6 EJ/year) in 2040, while coal production will peak at about 4400 Mt/year (or 91.9 EJ/year) around 2020 or so. In terms of the forecast production of these fuels, there are significant differences among current studies. These differences can be mainly explained by different ultimately recoverable resources assumptions, the nature of the models used, and differences in the historical production data. Due to the future constraints on fossil fuels production, a large gap is projected to grow between domestic supply and demand, which will need to be met by increasing imports. Net energy analyses show that both coal and oil and gas production show a steady declining trend of EROI (energy return on investment) due to the depletion of shallow-buried coal resources and conventional oil and gas resources, which is generally consistent with the approaching peaks of physical production of fossil fuels. The peaks of fossil fuels production, coupled with the decline in EROI ratios, are likely to challenge the sustainable development of Chinese society unless new abundant energy resources with high EROI values can be found

Polymorphisms of toll-like receptors 2 and 9 and severity and prognosis of bacterial meningitis in Chinese children

Toll-like receptors (TLRs) play a crucial role in innate immunity, protecting the host from bacterial pathogens. We investigated whether bacterial meningitis (BM) in children was associated with gene polymorphisms in TLR2 (rs3804099), TLR3 (rs3775291 and rs3775290) and TLR9 (rs352139 and rs352140). Blood samples were taken from 218 child patients with confirmed BM and 330 healthy adult controls (HC) and polymorphisms of these genes were analyzed by PCR-based sequencing. For TLR2 rs3804099, frequencies of the minor allele C were markedly higher in patients with severe BM (defined as CSF glucose concentration <= 1.5 mmol/L and seizures) than those without (43.5% and 40.1% vs. 30.1% and 29.1%, p = 0.008 and p = 0.016, respectively). For TLR9 rs352139, patients who carried genotype AA and minor allele A developed seizures less often than those without (OR = 0.289, p = 0.003 and OR = 0.568, p = 0.004, respectively). However, for TLR9 rs352140, patients who carried genotype TT and minor allele T developed seizures more often than those without (OR = 3.385, p = 0.004 and OR = 1.767, p = 0.004, respectively). Our finding suggested that genetic variations in TLR2 and TLR9 are associated with severity and prognosis of bacterial meningitis in Chinese children. However, the results should be interpreted with caution since the number of subjects included was limited

Cost-Effectiveness of Genotypic Antiretroviral Resistance Testing in HIV-Infected Patients with Treatment Failure

BACKGROUND: Genotypic antiretroviral resistance testing (GRT) in HIV infection with drug resistant virus is recommended to optimize antiretroviral therapy, in particular in patients with virological failure. We estimated the clinical effect, cost and cost-effectiveness of using GRT as compared to expert opinion in patients with antiretroviral treatment failure. METHODS: We developed a mathematical model of HIV disease to describe disease progression in HIV-infected patients with treatment failure and compared the incremental impact of GRT versus expert opinion to guide antiretroviral therapy. The analysis was conducted from the health care (discount rate 4%) and societal (discount rate 2%) perspective. Outcome measures included life-expectancy, quality-adjusted life-expectancy, health care costs, productivity costs and cost-effectiveness in US Dollars per quality-adjusted life-year (QALY) gained. Clinical and economic data were extracted from the large Swiss HIV Cohort Study and clinical trials. RESULTS: Patients whose treatment was optimized with GRT versus expert opinion had an increase in discounted life-expectancy and quality-adjusted life-expectancy of three and two weeks, respectively. Health care costs with and without GRT were $US 421,000 and$US 419,000, leading to an incremental cost-effectiveness ratio of $US 35,000 per QALY gained. In the analysis from the societal perspective, GRT versus expert opinion led to an increase in discounted life-expectancy and quality-adjusted life-expectancy of three and four weeks, respectively. Health care costs with and without GRT were$US 551,000 and $US 549,000, respectively. When productivity changes were included in the analysis, GRT was cost-saving. CONCLUSIONS: GRT for treatment optimization in HIV-infected patients with treatment failure is a cost-effective use of scarce health care resources and beneficial to the society at large

Clinical Implication of Targeting of Cancer Stem Cells

The existence of cancer stem cells (CSCs) is receiving increasing interest particularly due to its potential ability to enter clinical routine. Rapid advances in the CSC field have provided evidence for the development of more reliable anticancer therapies in the future. CSCs typically only constitute a small fraction of the total tumor burden; however, they harbor self-renewal capacity and appear to be relatively resistant to conventional therapies. Recent therapeutic approaches aim to eliminate or differentiate CSCs or to disrupt the niches in which they reside. Better understanding of the biological characteristics of CSCs as well as improved preclinical and clinical trials targeting CSCs may revolutionize the treatment of many cancers. Copyright (c) 2012 S. Karger AG, Base