Susceptibility genes in the pathogenesis of murine lupus

Systemic lupus erythematosus (SLE) is the paradigm of a multisystem autoimmune disease in which genetic factors strongly influence susceptibility. Through genome scans and congenic dissection, numerous loci associated with lupus susceptibility have been defined and the complexity of the inheritance of this disease has been revealed. In this review, we provide a brief description of animal models of SLE, both spontaneous models and synthetic models, with an emphasis on the B6 congenic model derived from analyses of the NZM2410 strain. A hypothetical model of disease progression that organizes many of the identified SLE susceptibility loci in three distinct biological pathways that interact to mediate disease pathogenesis is also described. We finally discuss our recent fine mapping analysis, which revealed a cluster of loci that actually comprise the Sle1 locus

Churn Prediction using MapReduce and HBase.

The mobile telecommunication market is rapidly increasing with numerous service providers stepping in the market. This makes the customer think to leave the service provided by one service provider and move to another service provider for some better offers. This project is an attempt to design and implement an application that can take Customer Records as input and give Customer churn prediction details as output. It will enable service provider to know in advance about the valuable customer who are about to churn. By merely giving customer data records as input, user can get the desired customer behaviour pattern, which is the churn output. The output obtained will basically distinguish the churners and the non-churners. The system is built using Apache Hadoop, Apache HBase and a Data Mining Algorithm under MapReduce code. The use of Hadoop framework makes it easy to process the large datasets containing the information of customers. DOI: 10.17762/ijritcc2321-8169.150317

Expression of hepatocytic- and biliary-specific transcription factors in regenerating bile ducts during hepatocyte-to-biliary epithelial cell transdifferentiation

Background\ud Under compromised biliary regeneration, transdifferentiation of hepatocytes into biliary epithelial cells (BEC) has been previously observed in rats, upon exposure to BEC-specific toxicant methylene dianiline (DAPM) followed by bile duct ligation (BDL), and in patients with chronic biliary liver disease. However, mechanisms promoting such transdifferentiation are not fully understood. In the present study, acquisition of biliary specific transcription factors by hepatocytes leading to reprogramming of BEC-specific cellular profile was investigated as a potential mechanism of transdifferentiation in two different models of compromised biliary regeneration in rats.\ud \ud Results\ud In addition to previously examined DAPM + BDL model, an experimental model resembling chronic biliary damage was established by repeated administration of DAPM. Hepatocyte to BEC transdifferentiation was tracked using dipetidyl dipeptidase IV (DDPIV) chimeric rats that normally carry DPPIV only in hepatocytes. Following DAPM treatment, ~20% BEC population turned DPPIV-positive, indicating that they are derived from DPPIV-positive hepatocytes. New ductules emerging after DAPM + BDL and repeated DAPM exposure expressed hepatocyte-associated transcription factor hepatocyte nuclear factor (HNF) 4α and biliary specific transcription factor HNF1β. In addition, periportal hepatocytes expressed biliary marker CK19 suggesting periportal hepatocytes as a potential source of transdifferentiating cells. Although TGFβ1 was induced, there was no considerable reduction in periportal HNF6 expression, as observed during embryonic biliary development.\ud \ud Conclusions\ud Taken together, these findings indicate that gradual loss of HNF4α and acquisition of HNF1β by hepatocytes, as well as increase in TGFβ1 expression in periportal region, appear to be the underlying mechanisms of hepatocyte-to-BEC transdifferentiation

Exploring Venus with Balloons - Science Objectives and Mission Architectures for Small and Medium-Class Missions

This presentation was part of the session : Current Planetary Probe Science and TechnologySixth International Planetary Probe WorkshopFollowing the trailblazing flights of the 1985 twin Soviet VEGA balloons, missions to fly in the skies of Venus have been proposed to both NASA's Discovery Program and ESA's Cosmic Visions amd are currently being planned for NASA's next Frontiers Mission opportunity. Such missions will answer fundamental science issues highlighted in a variety of high-level NASA-authorized science documents in recent years, including the Decadal Study, various NASA roadmaps, and recommendations coming out of the Venus Exploration Analysis Group (VEXAG). Such missions would in particular address key questions of Venus's origin, evolution, and current state, including detailed measurements of (1) trace gases associated with Venus's active photo- and thermo-chemistry and (2) measurements of vertical motions and local temperature which characterize convective and wave processes. As an example of what can be done with small and medium class missions (less than $900M and$500M, respectively), the Venus Aerostatic-Lift Observatories for in-situ Research (VALOR) Discovery and New Frontiers mission concepts will be discussed. Floating in Venus's rapid windstream near an altitude of 55 km, VALOR's twin balloon-borne aerostats will sample rare gases and trace chemicals and measure vertical and horizontal motions and cloud aerosols within Venus's dynamic middle cloud layer. Each balloon will explore a distinctive dynamical/meteorological region within Venus's energetic atmosphere as each circles the globe for over a week, with one drifting in the cloudy north polar region and the other flying in the less-cloudy but more convective temperate region. The New Frontiers concept would carry several drop sondes that would provide vertical profiles from 55 km down to the surface of temperature, pressure, winds, and the abundances of key reactive gases including SO2, CO, and H2O. In addition, each drop sonde would obtain stereoscopic images and spectra of the surface. Each of these VALOR missions would test a variety of scenarios for the origin, formation, and evolution of Venus by sampling all the noble gases and their isotopes, especially the heaviest elements never reliably measured previously, xenon and krypton. Riding the gravity and planetary waves of Venus a la the VEGA balloons in 1985, the VALOR balloons would sample in particular the chemistry and dynamics of Venus's sulfur-cloud meteorology. Tracked by an array of Earth-based telescopes, zonal, meridional, and vertical winds would be measured with unprecedented precision. Such measurements will help in developing our fundamental understanding of (1) the circulation of Venus, including the role of waves in powering the planet's poorly-understood super-rotation, (2) the nature of Venus's sulfur cycle, key to Venus's current climate, and (3) how Earth's neighbor formed and evolved over the aeons.NAS

MAPIR: An Airborne Polarmetric Imaging Radiometer in Support of Hydrologic Satellite Observations

In this age of dwindling water resources and increasing demands, accurate estimation of water balance components at every scale is more critical to end users than ever before. Several near-term Earth science satellite missions are aimed at global hydrologic observations. The Marshall Airborne Polarimetric Imaging Radiometer (MAPIR) is a dual beam, dual angle polarimetric, scanning L band passive microwave radiometer system developed by the Observing Microwave Emissions for Geophysical Applications (OMEGA) team at MSFC to support algorithm development and validation efforts in support of these missions. MAPIR observes naturally-emitted radiation from the ground primarily for remote sensing of land surface brightness temperature from which we can retrieve soil moisture and possibly surface or water temperature and ocean salinity. MAPIR has achieved Technical Readiness Level 6 with flight heritage on two very different aircraft, the NASA P-3B, and a Piper Navajo

Microglial signalling pathway deficits associated with the patient derived R47H TREM2 variants linked to AD indicate inability to activate inflammasome

The R47H variant of the microglial membrane receptor TREM2 is linked to increased risk of late onset Alzheimer's disease. Human induced pluripotent stem cell derived microglia (iPS-Mg) from patient iPSC lines expressing the AD-linked R47Hhet TREM2 variant, common variant (Cv) or an R47Hhom CRISPR edited line and its isogeneic control, demonstrated that R47H-expressing iPS-Mg expressed a deficit in signal transduction in response to the TREM2 endogenous ligand phosphatidylserine with reduced pSYK-pERK1/2 signalling and a reduced NLRP3 inflammasome response, (including ASC speck formation, Caspase-1 activation and IL-1beta secretion). Apoptotic cell phagocytosis and soluble TREM2 shedding were unaltered, suggesting a disjoint between these pathways and the signalling cascades downstream of TREM2 in R47H-expressing iPS-Mg, whilst metabolic deficits in glycolytic capacity and maximum respiration were reversed when R47H expressing iPS-Mg were exposed to PS+ expressing cells. These findings suggest that R47H-expressing microglia are unable to respond fully to cell damage signals such as phosphatidylserine, which may contribute to the progression of neurodegeneration in late-onset AD

Prediction of clinical outcomes using the pyrolysis, gas chromatography, and differential mobility spectrometry (Py-GC-DMS) system

AbstractBiological and molecular heterogeneity of human diseases especially cancers contributes to variations in treatment response, clinical outcome, and survival. The addition of new disease- and condition-specific biomarkers to existing clinical markers to track cancer heterogeneity provides possibilities for further assisting clinicians in predicting clinical outcomes and making choices of treatment options. Ionization patterns derived from biological specimens can be adapted for use with existing clinical markers for early detection, patient risk stratification, treatment decision making, and monitoring disease progression. In order to demonstrate the application of pyrolysis, gas chromatography, and differential mobility spectrometry (Py-GC-DMS) for human diseases to predict the outcome of diseases, we analyzed the ionized spectral signals generated by instrument ACB2000 (ACBirox universal detector 2000, ACBirox LLC, NJ, USA) from the serum samples of Mantle Cell Lymphoma (MCL) patients. Here, we have used mantle cell lymphoma as a disease model for a conceptual study only and based on the ionization patterns of the analyzed serum samples, we developed a multivariate algorithm comprised of variable selection and reduction steps followed by receiver operating characteristic curve (ROC) analysis to predict the probability of a good or poor clinical outcome as a means of estimating the likely success of a particular treatment option. Our preliminary study performed with small cohort provides a proof of concept demonstrating the ability of this system to predict the clinical outcome for human diseases with high accuracy suggesting the promising application of pyrolysis, gas chromatography, and differential mobility spectrometry (Py-GC-DMS) in the field of medicine

Dense genotyping of immune-related loci in idiopathic inflammatory myopathies confirms HLA alleles as the strongest genetic risk factor and suggests different genetic background for major clinical subgroups

OBJECTIVES: The idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of rare autoimmune diseases characterised by muscle weakness and extramuscular manifestations such as skin rashes and interstitial lung disease. We genotyped 2566 IIM cases of Caucasian descent using the Immunochip; a custom array covering 186 established autoimmune susceptibility loci. The cohort was predominantly comprised of patients with dermatomyositis (DM, n=879), juvenile DM (JDM, n=481), polymyositis (PM, n=931) and inclusion body myositis (n=252) collected from 14 countries through the Myositis Genetics Consortium. RESULTS: The human leucocyte antigen (HLA) and PTPN22 regions reached genome-wide significance (