Mapping of DNA markers linked to the cystic fibrosis locus on the long arm of chromosome 7

We have used a panel of eight human/mouse somatic-cell hybrids, each containing various portions of human chromosome 7, and three patient cell lines with interstitial deletions on chromosome 7 for localization of six DNA markers linked to the cystic fibrosis locus. Our data suggest that D7S15 is located in the region 7cen→q22, that MET is located in 7q22→31, and that D7S8 and 7C22 are located in q22→q32. The hybridization results for COL1A2 and TCRB are consistent with their previous assignment to 7q21→q22 and 7q32, respectively. Given the location of these six markers and their linkage relationships, it is probable that the cystic fibrosis locus is in either the distal region of band q22 or the proximal region of q31. Using the same set of cell lines, we have also examined the location of another chromosome 7 marker PGY1. The data show that PGY1 is located in the region 7cen→q22, a position very different from its previous assignment.published_or_final_versio

The characterization, management, and future considerations for ErbB-family TKI-associated diarrhea.

PurposeDiarrhea is recognized as a common adverse event associated with tyrosine kinase inhibitors (TKIs), with those targeting the ErbB family of receptors being associated with the highest rate of diarrhea.MethodsThis paper reviews data on the incidence, timing, and duration of diarrhea associated with US Food and Drug Administration-approved ErbB family-targeted TKIs from the published literature, and sets forth recommendations for management.ResultsIn the absence of anti-diarrheal prophylaxis the incidence of any-grade diarrhea varies and typically occurs early during the course of treatment. Although it is difficult to determine if the incidence and severity of diarrhea is related to inhibition of a particular kinase target because of the multi-targeted and overlapping activity of many agents, evidence suggests that second-generation TKIs with broader target profiles (i.e., afatinib, lapatinib, neratinib) result in a higher incidence of diarrhea compared with highly specific first- (erlotinib, gefitinib) or third- (osimertinib) generation agents. The mechanisms responsible for TKI-associated diarrhea are not fully understood and are likely multi-factorial, involving dysregulated ion transport, inflammation, and mucosal injury. Management strategies have been developed-and continue to be refined-to prevent and reduce the severity and duration of TKI-associated diarrhea. For agents associated with more significant symptoms, anti-diarrheal prophylaxis reduces the incidence and severity of diarrhea, and ongoing studies are evaluating specific strategies to further reduce incidence and duration of TKI-associated diarrhea.ConclusionsContinued investigations into risk factors and pharmacogenomic markers for diarrhea may further improve management of this common toxicity

Analysis of the Multiple Stress Creep Recovery Asphalt Binder Test and Specifications for Use in Indiana

The Superpave specifications and equipment, introduced in 1993, represented a major advancement with respect to offering a better understanding of the behavior and characteristics of asphalt binders based on their rheological properties. However, the Superpave high-temperature test protocol has been shown to be inadequate for characterizing the high-temperature behavior (rutting resistance) of asphalt binders, particularly polymer modified ones. Recently, a specification based on the Multiple Stress Creep Recovery (MSCR) test has been proposed to address the shortcomings of the Superpave high-temperature binder specifications. This study aims to investigate the merits of implementing the MSCR test and specification as a replacement for the conventional high-temperature testing in the Performance Graded (PG) system. A statistical analysis was conducted on a dataset from Indiana Department of Transportation (INDOT) to see how MSCR and PG procedures differ in grading different binders used in the state. In addition, an experimental study was conducted using seventeen different modified and unmodified binders. In addition to binder tests, seven of the binders were selected to conduct asphalt mixture tests such as dynamic modulus and flow number. The results confirm that the MSCR test is a suitable replacement for the current PG high temperature test since it provides a better tool to rank modified asphalt binders as well as unmodified ones. That is, creep compliance from the MSCR test more fundamentally represents binder behavior at high temperatures compared to the PG rutting parameter. In addition, the very simplified approach, known as grade-bumping, used in the current PG system to account for high traffic levels and low speed limits can be eliminated when using the MSCR test. The MSCR test also provides a better coefficient of correlation (at both stress levels) with flow number test results than the PG rutting parameter, again indicating that it more accurately reflects binder performance at high temperatures

Determining of the Binder Content of Hot Mix Asphalt Containing Dolomitic Aggregates Using the Ignition Oven

The binder content of an HMA mix is one of the critical factors affecting the quality of the mix. The ignition oven is one widely used method for determining the binder content, however, its use is problematic with some types of aggregates, including dolomites. With these aggregates, the mass loss continues after the binder is burned off as the aggregates decompose and the test does not terminate at a stable mass. This study investigated the factors that affect this mass loss in problematic aggregates and developed a modified ignition oven procedure to limit this mass loss. The mass loss in the ignition oven was found to be both time and temperature dependent. The mass loss is also related to the binder content in the mixture. When the binder in the mixture ignites, the oven temperature increases and exceeds the pre-set test temperature. Temperature variations inside the ignition oven result in higher temperatures in the vicinity of the upper basket; these temperature differences are even more pronounced when the binder ignites. These higher temperatures can result in increased mass loss with problematic aggregates. A test temperature as low as 427°C was found to be effective for removing the binder from a mixture. Therefore a modified ignition oven procedure was developed to control the temperatures and limit the additional mass loss for problematic aggregates. The method involves placing half the total sample mass in the bottom basket only and running the ignition oven at a temperature of 427°C. This method was verified by testing six different plant produced mixes containing problematic aggregate and by comparing the results to results of the standard ignition oven method and to solvent extraction. The modified method is recommended for use with problematic aggregates or where the standard test method yields calibration factors greater than 1.0 or the test does not terminate automatically.

Cascading ecological effects from local extirpation of an ecosystem engineer in the Arava desert

The extinction of a single species from a local community may carry little cost in terms of species diversity, yet its loss eliminates its biotic and abiotic interactions. We describe such a scenario in the Arava desert, where different cultural and law enforcement practices exclude Dorcas gazelles (Gazella dorcas (Linnaeus, 1758)) from the Jordanian side of the border while protecting their populations on the Israeli side. We found that gazelles break the soil crust, formed in desert systems after annual flooding, thereby creating patches of loose and cooler sand that are used by pit-building antlions (Neuroptera: Myrmeleontidae). When we artificially broke the soil crust on both sides of the border, we found a significant increase in antlion density in these patches, but only on the Israeli side. On the Jordanian side, where no gazelles have been observed since the early 1980s, no antlions colonized either control or manipulated plots. Additional choice/no-choice feeding experiments, in which we offered antlions to lizards and birds, revealed that the effect of humans on gazelles cascades farther, as antlions serve as a palatable food source for both groups. Thus, the human-mediated loss of nontrophic interactions between gazelles and antlions cascades to the loss of trophic interactions between antlions and their predators

Experience with the Quality Assurance of the Superconducting Electrical Circuits of the LHC Machine

The coherence between the powering reference database for the LHC and the Electrical Quality Assurance (ELQA) is guaranteed on the procedural level. However, a challenge remains the coherence between the database, the magnet test and assembly procedures, and the connection of all superconducting circuits in the LHC machine. In this paper, the methods, tooling, and procedures for the ELQA during the assembly phase of the LHC will be presented in view of the practical experience gained in the LHC tunnel. Some examples of detected polarity errors and electrical non-conformities will be presented. The parameters measured at ambient temperature, such as the dielectric insulation of circuits, will be discussed

Concrete Patching Materials and Techniques and Guidelines for Hot Weather Concreting

High early strength (HES) concrete is becoming increasingly used to repair damaged concrete pavement sections. The use of HES concrete enables the repaired pavement to be opened to traffic within hours of placing the concrete. Rapid repair of concrete pavement is an attractive solution since the traveling public is not delayed by the repair of the pavement in addition to a decrease in the amount of exposure to traffic by construction personnel; however, there are challenges due to strict requirements for opening strength and severe penalties for not achieving the target strength. This project examined failure to obtain long term strength in the construction practices of long patches in concrete pavements. The work examined issues associated with temperature on sulfate balance, flexural strength prediction (maturity methods) considering the influence of moisture (effects of self-desiccation), shrinkage mitigation techniques (internal curing), and improving the overall durability of HES concrete patching materials

DNA methylation profiling of the human major histocompatibility complex: A pilot study for the Human Epigenome Project

The Human Epigenome Project aims to identify, catalogue, and interpret genome-wide DNA methylation phenomena. Occurring naturally on cytosine bases at cytosine-guanine dinucleotides, DNA methylation is intimately involved in diverse biological processes and the aetiology of many diseases. Differentially methylated cytosines give rise to distinct profiles, thought to be specific for gene activity, tissue type, and disease state. The identification of such methylation variable positions will significantly improve our understanding of genome biology and our ability to diagnose disease. Here, we report the results of the pilot study for the Human Epigenome Project entailing the methylation analysis of the human major histocompatibility complex. This study involved the development of an integrated pipeline for high-throughput methylation analysis using bisulphite DNA sequencing, discovery of methylation variable positions, epigenotyping by matrix-assisted laser desorption/ionisation mass spectrometry, and development of an integrated public database available at http://www.epigenome.org. Our analysis of DNA methylation levels within the major histocompatibility complex, including regulatory exonic and intronic regions associated with 90 genes in multiple tissues and individuals, reveals a bimodal distribution of methylation profiles (i.e., the vast majority of the analysed regions were either hypo- or hypermethylated), tissue specificity, inter-individual variation, and correlation with independent gene expression data

Methylation Markers for the Identification of Body Fluids and Tissues from Forensic Trace Evidence

The identification of body fluids is an essential tool for clarifying the course of events at a criminal site. The analytical problem is the fact that the biological material has been very often exposed to detrimental exogenous influences. Thereby, the molecular substrates used for the identification of the traces may become degraded. So far, most protocols utilize cell specific proteins or RNAs. Instead of measuring these more sensitive compounds this paper describes the application of the differential DNA-methylation. As a result of two genome wide screenings with the Illumina HumanMethylation BeadChips 27 and 450k we identified 150 candidate loci revealing differential methylation with regard to the body fluids venous blood, menstrual blood, vaginal fluid, saliva and sperm. Among them we selected 9 loci as the most promising markers. For the final determination of the methylation degree we applied the SNuPE-method. Because the degree of methylation might be modified by various endogenous and exogenous factors, we tested each marker with approximately 100 samples of each target fluid in a validation study. The stability of the detection procedure is proved in various simulated forensic surroundings according to standardized conditions. We studied the potential influence of 12 relatively common tumors on the methylation of the 9 markers. For this purpose the target fluids of 34 patients have been analysed. Only the cervix carcinoma might have an remarkable effect because impairing the signal of both vaginal markers. Using the Illumina MiSeq device we tested the potential influence of cis acting sequence variants on the methylation degree of the 9 markers in the specific body fluid DNA of 50 individuals. For 4 marker loci we observed such an influence either by sole SNPs or haplotypes. The identification of each target fluid is possible in arbitrary mixtures with the remaining four body fluids. The sensitivity of the individual body fluid tests is in the same range as for the forensic STR-analysis. It is the first forensic body fluid protocol which considers the exogenic and endogenic parameters potentially interfering with the true results

Automatic System for the D.C. High Voltage Qualification of the Superconducting Electrical Circuits of the LHC Machine

A d.c. high voltage test system has been developed to verify automatically the insulation resistance of the powering circuits of the LHC. In the most complex case, up to 72 circuits share the same volume inside cryogenic lines. Each circuit can have an insulation fault versus any other circuit or versus ground. The system is able to connect up to 80 circuits and apply a voltage up to 2 kV D.C. The leakage current flowing through each circuit is measured within a range of 1 nA to 1.6 mA. The matrix of measurements allows characterizing the paths taken by the currents and locating weak points of the insulation between circuits. The system is composed of a D.C. voltage source and a data acquisition card. The card is able to measure with precision currents and voltages and to drive up to 5 high voltage switching modules offering 16 channels each. A LabVIEW application controls the system for an automatic and safe operation. This paper describes the hardware and software design, the testing methodology and the results obtained during the qualification of the LHC superconducting circuits