Mammalian afferent nerve fibres

The original research work described in this thesis falls into three categories:- a) a study of mammalian myelinated and non-myelinated afferent nerve fibres and their endings, this forms the principal part, b) an examination of some properties of nerve-cells in the mammalian spinal cord and c) a minor section on the sympathetic nervous system.a) Afferent nerve fibres. The major advance described is the development of techniques which allow individual active afferent nerve fibres to be identified, and their conduction velocities to be measured, when they are in nerve strands containing many axons. By these means the diameters of the active fibres may be assessed. These techniques, combined with improved dissection methods, have made the non-myelinated axons in peripheral nerves accessible as functional single units. The results of applying the techniques first to visceral nerves, then to cutaneous nerves and finally to somatic muscle nerves, establish that the nerves to the abdominal viscera and to the skin contain an unexpected variety of non¬ myelinated afferent axons, as judged by the responses of the nerve-endings to quantitative mechanical, thermal and chemical stimuli. In the stomach there were both mechanically-sensitive and pH-sensitive units located in different layers of the stomach wall. In the skin there were mechanoreceptors and thermoreceptors of highly selective sensitivity. Some of these latter nerveendings and their afferent fibres could function as 'modality-specific' cutaneous transducers, with very considerable and unexplored implications in terms of central nervous function. The muscle afferent C fibres appear to be nociceptors. A detailed examination of single myelinated cutaneous afferent nerve-fibres also supports the thesis that the afferent fibres and their receptors have a selective sensitivity. A relation between the structure of afferent nerve-endings and the selective sensitivity of the afferent unit was clearly established for one particular nerve-ending - a 'cutaneous touch corpuscle' innervated by a thick myelinated axon. The dependence of the structure and sensitivity of the 'touch corpuscle' on its innervation was also established.b) Spinal cord neurones. The pattern of 'recurrent inhibitory' connections from motor axon collaterals to small interneurones (Renshaw cells) in the ventral horn of the lumbo-sacral spinal cord and from these interneurones to motorneurones displayed no reflex pattern. In general, there was feedback from motoraxons to adjacent Renshaw cells, which in turn fed back to the motoneuronal nucleus from which the motor-axons arose and also to other adjacent motor-neurones. There was a striking correlation between the intensity of recurrent inhibition and the function of the motor-neurone; those motor-neurones innervating slowly - contracting extensor muscles were most strongly inhibited.c) Sympathetic nervous system. Depletion of the stores of catecholamines and 5 -hydroxytryptamine in the brain of cats by reserpine treatment did not abolish sympathetic preganglionic efferent activity, so that the dramatic depressant action of reserpine on an animal is unlikely to be due to this depletion. The depressant effect of intravenously injected catecholamines on sympathetic preganglionic disch arge was shown to be exerted principally, if not entirely, by reflex mechanism not by a direct action on the central nervous system

p53 mutation in histologically normal mucosa of the aero-digestive tract is not a marker of increased risk for second primary carcinoma in head and neck cancer patients

Head and neck cancer patients are at high risk for developing second primary tumors. This is known as field cancerization of the aero-digestive tract. In a previous study, we showed that patients with multiple primary tumors were more likely to have p53 mutations in histologically normal mucosae than patients presenting with an isolated tumor. Based on this observation, we postulated that p53 mutations in normal tissue samples of patients bearing a single primary tumor could have a clinical value as a biomarker for the risk of developing second primary tumors. Thirty-five patients presenting with a single primary tumor were followed-up for a median of 51 months (range 1 month to 10.9 years) after biopsies of histologically normal squamous cell mucosa had been analyzed for p53 mutations with a yeast functional assay at the time of the primary tumor. During this follow-up, recurrences and non-sterilization of the primary tumor, occurrence of lymph node metastases, and of second primary tumors were evaluated. Sixteen (45.7%) patients were found to have p53 mutations in their normal squamous cell mucosa, and 19 (54.3%) patients showed no mutation. No relationship was found between p53 mutations and the occurrence of evaluated events during follow-up. Notably, the rate of second primary tumors was not associated with p53 mutations in the normal squamous mucosa. The correlation between p53 mutations in histologically normal mucosae and the incidence of second primary tumors is generally low. The benefit of analyzing p53 mutations in samples of normal squamous cell mucosa in every patient with a primary tumor of the head and neck is doubtfu

PENERAPAN MODEL PEMBELAJARAN KOOPERATIF TIPE MAKE A MATCH UNTUK MENINGKATKAN HASIL BELAJAR PKn SISWA KELAS III SD NEGERI 188 PEKANBARU

This research is in the background by the low learning outcomes of PKn-grade III students Negeri Elementary School 188 Pekanbaru, with an average class of 68.25. While the value of 40 students are only 17 students who achieve the minimum submission criteria. This research is a class action research  conducted aims to improve the learning outcomes of PKn-grade III students Negeri Elementary School 188 Pekanbaru by applying a cooperative model of make a match type. The subject of this study is a grade III student of State Elementary School 188 Pekanbaru year 2018/2019. The data collection instruments on this thesis are teacher activity sheets and student activities and learning outcomes. This thesis presents the data of the learning outcomes obtained from the average learning results before the 68.25 action increased by 12.63% on average to 76.87 on the I cycle. In the II cycle it increased to 19.41% with an average of 81.5. Teacher activity on first meeting cycle I gained a percentage of 62.5% of the category enough, at the second meeting experienced an increase by a percentage of 79.16% good category. Next cycle II first meeting of teacher activity also experienced an increase with a percentage of 83.33% good category, and the second meeting experienced another increase by the percentage of 95.83% very good category. In the results of the study, students began to understand the course of PKn lessons after they had the cooperative model of the Make a match type marked with increased teacher activity and student activities and the results of learning on each cycle. The results of the research in class III of State Elementary School 188 Pekanbaru proved that the implementation of model cooperative type make a match can be a result of learning the results of PKn-grade III students Negeri Elementary School 188 Pekanbar

Titrations without the Additions: The Efficient Determination of pKa Values Using NMR Imaging Techniques

It can be very informative to acquire NMR spectra of a sample as a function of the solution pH. Examples can be found in the design of host–guest complexes or in the determination of the pKa values of organic molecules. In the conventional procedure, a series of spectra must be recorded and the pH of the sample adjusted manually between successive NMR measurements. As an alternative to this laborious procedure, we demonstrate how controlled pH gradients may be established in 5 mm NMR tubes and analyzed using standard NMR equipment in a “single shot” experiment. Using 1H NMR imaging techniques and a set of NMR pH indicator compounds, we are able to measure the pH of a sample as a function of position along a pH gradient. We are thus able to obtain the necessary set of 1H NMR spectra as a function of pH from a single sample in a single NMR experiment. As proof of concept, we demonstrate how the technique may be employed for the determination of the pKa values of small organic molecules. We are able to measure pKa values from 1 to 11 to within 0.1 units of their literature values. The method is robust to variations in the setting of the pH gradients and can be readily implemented through an automated sample changer

Etude de FOXA1 dans les cellules épithéliales mammaires humaines

Les cancers du sein sont divisés en sous types définis par leur histologie, leur prolifération et l expression du récepteur aux œstrogènes ER. Notre étude porte sur le gène FOXA1 dans le sous-type luminal caractérisé par des cellules bien différenciées, peu prolifératives et exprimant fortement les protéines FOXA1 et ER. Des études suggèrent que FOXA1 est impliqué dans le développement de la glande mammaire, dans la différenciation et la prolifération des cellules mammaires. Dans ce cadre, mon projet de thèse s articulait autour de trois points ; développer un Knock-In au niveau du gène FOXA1, identifier le rôle de FOXA1 dans la différenciation mammaire et enfin rechercher le rôle des facteurs ER et FOXA1 dans la résistance à l hormonothérapie. De nombreux tests d intégration ciblée ont été réalisés à l aide de différentes matrices de recombinaison et de nucléases spécifiques, les ZFNs. Aucune intégration ciblée n a finalement été observée. Nous avons montré qu en fonction du contexte cellulaire, FOXA1 jouait différents rôles dans la différenciation cellulaire et l expression de la molécule d adhérence E-Cadhérine. Ces résultats suggèrent que FOXA1 influence l agressivité tumorale suivant le contexte cellulaire. Nous avons également identifié une amplification d ER et de FOXA1 dans les cellules tumorales résistantes à l hormonothérapie par une étude génomique. Les tests in vitro ont montré que la surexpression de FOXA1 augmenterait bien la résistance au fulvestrant mais la surexpression d ER aurait l effet inverse, suggérant l implication d autres facteurs. De futures recherches nous permettront d identifier ces facteurs et de préciser les rôles de FOXA1 et d ER dans la différenciation luminale, l agressivité tumorale et dans la réponse cellulaire à l hormonothérapieBreast cancers are divided into subtypes defined by their histology, proliferation and expression of estrogen receptor ER. Our study focuses on the FOXA1 gene in the luminal subtype characterized by well-differentiated cells, low proliferative and strongly expressing FOXA1 protein and ER. Studies suggest that FOXA1 is involved in the mammary gland development and in the differentiation and proliferation of mammary cells. In this context, my thesis project was structured around three points, develop a knock-in at the FOXA1 gene, identify the role of FOXA1 in mammary differentiation and finally explore the role of ER and FOXA1 in resistance to hormone therapy. Many targeted integration tests were performed using different matrix of recombination and specific nucleases, the ZFNs. No direct integration was finally observed. We showed that depending on the cell context, FOXA1 played different roles in cell differentiation and expression of E-cadherin, an adhesion molecule. These results suggest that FOXA1 influence tumor aggressiveness depending on the cell context. We also identified amplification of ER and FOXA1 in tumor cell resistant to hormone therapy by a genomic study. Surprisingly, in vitro tests showed that overexpression of FOXA1 increased resistance to fulvestrant whereas overexpression of ER would have the opposite effect, suggesting the involvement of other factors. Future research will allow us to identify these factors and to clarify the roles of ER and FOXA1 in luminal differentiation, tumor aggressiveness and response to hormone therapy.BORDEAUX1-Bib.electronique (335229901) / SudocSudocFranceF

Polyanionic Ligand Platforms for Methyl- and Dimethylaluminum Arrays

Trimethylaluminum finds widespread applications in chemical and materials synthesis, most prominently in its partially hydrolyzed form of methylalumoxane (MAO), which is used as a cocatalyst in the polymerization of olefins. This work investigates the sequential reactions of trimethylaluminum with hexaprotic phosphazenes (RNH)6P3N3 (=XH6) equipped with substituents R of varied steric bulk including tert-butyl (1H6), cyclohexyl (2H6), isopropyl (3H6), isobutyl (4H6), ethyl (5H6), propyl (6H6), methyl (7H6), and benzyl (8H6). Similar to MAO, the resulting complexes of polyanionic phosphazenates [XHn]n−6 accommodate multinuclear arrays of [AlMe2]+ and [AlMe]2+. Reactions were monitored by 31P NMR spectroscopy, and structures were determined by single-crystal X-ray diffraction. They included 1H4(AlMe2)2, 1H3(AlMe2)3, 2H3(AlMe2)3, 3(AlMe2)4AlMe, 4H­(AlMe2)5, 4(AlMe2)6, {5H­(AlMe2)4}2AlMe, 5(AlMe2)6, 6(AlMe2)6, {7(AlMe2)4AlMe}2, and 8(AlMe2)6. The study shows that subtle variations of the steric properties of the R groups influence the reaction pathways, levels of aggregation, and fluxional behavior. While [AlMe2]+ is the primary product of the metalation, [AlMe]2+ is utilized to alleviate overcrowding or to aid aggregation. At the later stages of metalation, [AlMe2]+ groups start to scramble around congested sites. The ligands proved to be very robust and extremely flexible, offering a unique platform to study complex multinuclear metal arrangements

Efficient pKa Determination in a Non-Aqueous Solvent using Chemical Shift Imaging

pKa is an important property of a molecule which impacts on many fields such as drug design, catalysis, reactivity and environmen-tal toxicity. It is often necessary to measure pKa in non-aqueous media due to the poor solubility of an analyte in water, for exam-ple many compounds of pharmaceutical interest. Although NMR methods to measure pKa in water are well established, determining pKa in organic solvents is laborious and problematic. We present an efficient one-shot method to determine the pKa of an analyte in organic solvent in a single measurement. Diffusion of an acid into a basic solution of the analyte and a set of pH indicators establishes a pH gradient in the NMR tube. The chemical shift of a pH sensitive resonance of the analyte and the pH of the solution are then determined simultaneously as a function of position along the pH gradient by recording a chemical shift image of the NMR tube. The pKa of the analyte is then determined using the Henderson-Hasselbalch equation. The method can be implemented in any laboratory with a gradient equipped NMR high-field spectrometer and is demonstrated for a range of pharmaceutical compounds and inorganic phosphazene bases