La programmmation foetale de la dysfonction vasculaire pulmonaire chez la souris : rôle des mécanismes épigénétiques = Fetal programming of pulmonary vascular dysfunction in mice : role of epigenetic mechanisms

Rapport de synthèseDes événements pathologiques survenant pendant la période foetale prédisposent la descendance aux maladies cardiovasculaires systémiques. Il existe peu de connaissances au sujet de la circulation pulmonaire et encore moins quant aux mécanismes sous-jacents. La sous-alimentation maternelle pendant la grossesse peut représenter un modèle d'investigation de ces mécanismes, parce que chez l'animal et l'homme elle est associée à une dysfonction vasculaire systémique chez la progéniture. Chez le rat, la diète restrictive pendant la grossesse induit une augmentation du stress oxydatif dans le placenta. Les dérivés de l'oxygène sont connus pour induire des altérations épigénétiques et peuvent traverser la barrière placentaire. Nous avons dès lors spéculé que chez la souris la diète restrictive pendant la grossesse induit une dysfonction vasculaire pulmonaire chez sa progéniture qui serait liée à un mécanisme épigénétique.Pour tester cette hypothèse, nous avons examiné la fonction vasculaire pulmonaire et la méthylation de l'ADN pulmonaire à la fin de 2 semaines d'exposition à l'hypoxie chez la progéniture de souris soumises à une diète restrictive pendant la grossesse et des souris contrôles. Nous avons trouvé que la vasodilatation endothélium-dépendante de l'artère pulmonaire in vitro était défectueuse, et que l'hypertension pulmonaire et l'hypertrophie ventriculaire droite induites par l'hypoxie in vivo étaient exagérées chez la progéniture de souris soumises à une diète restrictive pendant la grossesse. Cette dysfonction vasculaire pulmonaire était associée avec une altération de la méthylation de l'ADN pulmonaire. L'administration d'inhibiteurs de la déacétylase des histones, le Butyrate et la Trichostatine-A à la progéniture de souris soumises à une diète restrictive pendant la grossesse a normalisé la méthylation de l'ADN et la fonction vasculaire pulmonaire. Finalement, l'administration du nitroxyde Tempol aux mères durant la diète restrictive pendant la grossesse a prévenu la dysfonction vasculaire et la dysméthylation chez la progéniture.Ces découvertes démontrent que chez la souris la sous-alimentation pendant la gestation induit une dysfonction vasculaire chez la progéniture qui est causée par un mécanisme épigénétique. Il est possible qu'un mécanisme similaire soit impliqué dans la programmation foetale de la dysfonction vasculaire chez les humains.

Experimental analysis and computer prediction of CTF/NFI transcription factor DNA binding sites.

Accurate prediction of transcription factor binding sites is needed to unravel the function and regulation of genes discovered in genome sequencing projects. To evaluate current computer prediction tools, we have begun a systematic study of the sequence-specific DNA-binding of a transcription factor belonging to the CTF/NFI family. Using a systematic collection of rationally designed oligonucleotides combined with an in vitro DNA binding assay, we found that the sequence specificity of this protein cannot be represented by a simple consensus sequence or weight matrix. For instance, CTF/NFI uses a flexible DNA binding mode that allows for variations of the binding site length. From the experimental data, we derived a novel prediction method using a generalised profile as a binding site predictor. Experimental evaluation of the generalised profile indicated that it accurately predicts the binding affinity of the transcription factor to natural or synthetic DNA sequences. Furthermore, the in vitro measured binding affinities of a subset of oligonucleotides were found to correlate with their transcriptional activities in transfected cells. The combined computational-experimental approach exemplified in this work thus resulted in an accurate prediction method for CTF/NFI binding sites potentially functioning as regulatory regions in vivo.

Data Acquisition and Computer Plotting of Delamtect Data, HR-269, 1985

The overall system is designed to permit automatic collection of delamination field data for bridge decks. In addition to measuring and recording the data in the field, the system provides for transferring the recorded data to a personal computer for processing and plotting. This permits rapid turnaround from data collection to a finished plot of the results in a fraction of the time previously required for manual analysis of the analog data captured on a strip chart recorder. In normal operation the Delamtect provides an analog voltage for each of two channels which is proportional to the extent of any delamination. These voltages are recorded on a strip chart for later visual analysis. An event marker voltage, produced by a momentary push button on the handle, is also provided by the Delamtect and recorded on a third channel of the analog recorder.

Programming of marginal zone B-cell fate by basic Kruppel-like factor (BKLF/KLF3).

Splenic marginal zone (MZ) B cells are a lineage distinct from follicular and peritoneal B1 B cells. They are located next to the marginal sinus where blood is released. Here they pick up antigens and shuttle the load onto follicular dendritic cells inside the follicle. On activation, MZ B cells rapidly differentiate into plasmablasts secreting antibodies, thereby mediating humoral immune responses against blood-borne type 2 T-independent antigens. As Krüppel-like factors are implicated in cell differentiation/function in various tissues, we studied the function of basic Krüppel-like factor (BKLF/KLF3) in B cells. Whereas B-cell development in the bone marrow of KLF3-transgenic mice was unaffected, MZ B-cell numbers in spleen were increased considerably. As revealed in chimeric mice, this occurred cell autonomously, increasing both MZ and peritoneal B1 B-cell subsets. Comparing KLF3-transgenic and nontransgenic follicular B cells by RNA-microarray revealed that KLF3 regulates a subset of genes that was similarly up-regulated/down-regulated on normal MZ B-cell differentiation. Indeed, KLF3 expression overcame the lack of MZ B cells caused by different genetic alterations, such as CD19-deficiency or blockade of B-cell activating factor-receptor signaling, indicating that KLF3 may complement alternative nuclear factor-κB signaling. Thus, KLF3 is a driving force toward MZ B-cell maturation.

Consumer Advisory: The Drive to Destroy: Removing data from computer hard drives, storage devices & wireless phones, June 2014

The Attorney General’s Consumer Protection Division receives hundreds of calls and consumer complaints every year. Follow these tips to avoid unexpected expense and disappointments. This record is about: The Drive to Destroy: Removing data from computer hard drives, storage devices & wireless phones

Micro-Computer Based Linear Scheduling Application for Highway Construction Project Control, HR-339A, 1995

This report describes a new approach to the problem of scheduling highway construction type projects. The technique can accurately model linear activities and identify the controlling activity path on a linear schedule. Current scheduling practices are unable to accomplish these two tasks with any accuracy for linear activities, leaving planners and manager suspicious of the information they provide. Basic linear scheduling is not a new technique, and many attempts have been made to apply it to various types of work in the past. However, the technique has never been widely used because of the lack of an analytical approach to activity relationships and development of an analytical approach to determining controlling activities. The Linear Scheduling Model (LSM) developed in this report, completes the linear scheduling technique by adding to linear scheduling all of the analytical capabilities, including computer applications, present in CPM scheduling today. The LSM has tremendous potential, and will likely have a significant impact on the way linear construction is scheduled in the future.

A Computer Based Information System for County Equipment Cost Records, Interim Report, HR-173, 1975

This report describes the work accomplished to date on research project HR-173, A Computer Based Information System for County Equipment Cost Records, and presents the initial design for this system. The specific topics discussed here are findings from the analysis of information needs, the system specifications developed from these findings, and the proposed system design based upon the system specifications. The initial system design will include tentative input designs for capturing input data, output designs to show the output formats and the items to be output for use in decision making, file design showing the organization of information to be kept on each piece of equipment in the computer data file, and general system design explaining how the entire system will operate. The Steering Committee appointed by Iowa Highway Research Board is asked to study this report, make appropriate suggestions, and give approval to the proposed design subject to any suggestions made. This approval will permit the designer to proceed promptly with the development of the computer program implementation phase of the design.

A Computer Based Information System for County Equipment Cost Records, Final Report, HR-173, 1975

This appendix is divided into three sections. The first section contains abstracts of each of the eight computer programs in the system, instructions for keypunching the three input documents, and computer operating instructions pertaining to each program. The second section contains system flowcharts for the entire system as well as program flowcharts for each program. The last section contains PL/l program listings of each program.

How important are interview methods and questionnaire designs in research on self-reported juvenile delinquency? An experimental comparison of internet vs. paper-and-pencil questionnaires and different definitions of the reference period

There has been relatively little change over recent decades in the methods used in research on self-reported delinquency. Face-to-face interviews and selfadministered interviews in the classroom are still the predominant alternatives envisaged. New methods have been brought into the picture by recent computer technology, the Internet, and an increasing availability of computer equipment and Internet access in schools. In the autumn of 2004, a controlled experiment was conducted with 1,203 students in Lausanne (Switzerland), where "paper-and-pencil" questionnaires were compared with computer-assisted interviews through the Internet. The experiment included a test of two different definitions of the (same) reference period. After the introductory question ("Did you ever..."), students were asked how many times they had done it (or experienced it), if ever, "over the last 12 months" or "since the October 2003 vacation". Few significant differences were found between the results obtained by the two methods and for the two definitions of the reference period, in the answers concerning victimisation, self-reported delinquency, drug use, failure to respond (missing data). Students were found to be more motivated to respond through the Internet, take less time for filling out the questionnaire, and were apparently more confident of privacy, while the school principals were less reluctant to allow classes to be interviewed through the Internet. The Internet method also involves considerable cost reductions, which is a critical advantage if self-reported delinquency surveys are to become a routinely applied method of evaluation, particularly so in countries with limited resources. On balance, the Internet may be instrumental in making research on self-reported delinquency far more feasible in situations where limited resources so far have prevented its implementation.