Structure-function relationships of the alpha1b-adrenergic receptor.

The alpha1b-adrenergic receptor (AR) is a member of the large superfamily of seven transmembrane domain (TMD) G protein-coupled receptors (GPCR). Combining site-directed mutagenesis of the alpha1b-AR with computational simulations of receptor dynamics, we have explored the conformational changes underlying the process of receptor activation, i.e. the transition between the inactive and active states. Our findings suggest that the structural constraint stabilizing the alpha1b-AR in the inactive form is a network of H-bonding interactions amongst conserved residues forming a polar pocket and R143 of the DRY sequence at the end of TMDIII. We have recently reported that point mutations of D142, of the DRY sequence and of A293 in the distal portion of the third intracellular loop resulted in ligand-independent (constitutive) activation of the alpha1b-AR. These constitutively activating mutations could induce perturbations resulting in the shift of R143 out of the polar pocket. The main role of R143 may be to mediate receptor activation by triggering the exposure of several basic amino acids of the intracellular loops towards the G protein. Our investigation has been extended also to the biochemical events involved in the desensitization process of alpha1b-AR. Our results indicate that immediately following agonist-induced activation, the alpha1b-AR can undergo rapid agonist-induced phosphorylation and desensitization. Different members of the G protein coupled receptor kinase family can play a role in agonist-induced regulation of the alpha1b-AR. In addition, constitutively active alpha1b-AR mutants display different phosphorylation and internalization features. The future goal is to further elucidate the molecular mechanism underlying the complex equilibrium between activation and inactivation of the alpha1b-AR and its regulation by pharmacological substances. These findings can help to elucidate the mechanism of action of various agents displaying properties of agonists or inverse agonists at the adrenergic system.

CUBN is a gene locus for albuminuria.

Identification of genetic risk factors for albuminuria may alter strategies for early prevention of CKD progression, particularly among patients with diabetes. Little is known about the influence of common genetic variants on albuminuria in both general and diabetic populations. We performed a meta-analysis of data from 63,153 individuals of European ancestry with genotype information from genome-wide association studies (CKDGen Consortium) and from a large candidate gene study (CARe Consortium) to identify susceptibility loci for the quantitative trait urinary albumin-to-creatinine ratio (UACR) and the clinical diagnosis microalbuminuria. We identified an association between a missense variant (I2984V) in the CUBN gene, which encodes cubilin, and both UACR (P = 1.1 × 10(-11)) and microalbuminuria (P = 0.001). We observed similar associations among 6981 African Americans in the CARe Consortium. The associations between this variant and both UACR and microalbuminuria were significant in individuals of European ancestry regardless of diabetes status. Finally, this variant associated with a 41% increased risk for the development of persistent microalbuminuria during 20 years of follow-up among 1304 participants with type 1 diabetes in the prospective DCCT/EDIC Study. In summary, we identified a missense CUBN variant that associates with levels of albuminuria in both the general population and in individuals with diabetes.

Vetus Testamentum cum glossa ordinaria, pars.

Avec arguments. Cant. canticorum V,11-VIII,14 (1) ; Osee I,3-XIV,10 (9) ; Joel I,6-III,21 (38) ; Amos I,1-IX,15 (48) ; Abdias I,7-21 (68) ; Jonas I,1-IV,11 (70v) ; Mich. I,6-VII,20 (77) ; Nahum I,1-III,19 (89v) ; Habacuc I,2-III,19 (95) ; Sophonias I,1-III,20 (102v) ; Agg. I,2-II,24 (110) ; Zachar. I,3-XIV,21 (115) ; Malach. I,4-IV,6 (139).

Biblia Sancti Martialis Lemovicensis, pars. I

Deuteron. (2) ; Josue (14) ; Judices (22v) ; Ruth, I,1-22 (31v) ; Isaias (32) ; Jeremias (48v) ; Jeremiae Lament. et Oratio jusqu'au v. 3 (66v, 67v) ; Ezechiel, III, 17, etc. (68) ; Daniel, I, 1-XIV, 19 (84) ; XII Proph. min. depuis Os., IV, 9, etc. (90) ; Job (104) ; Psalmi, I,1-LXXXVII,11 (112). En marge des ff. 109v-110 et 118v, prières (XIIIe-XIVe s.) : « Domine Deus omnipotens, qui es trinus... », « Mane intende ad me... »

[Lettre autographe signée d'Henri Montan Berton, Villers-en-Braye, par Neufchâtel, 25 juillet 1841] (copie manuscrite)

Critique du métier de compositeur. - Comprend aussi une copie

Copies et extraits de divers documents.

Contient : Chartes de Beaulieu ; Accord entre Guillaume, comte de Toulouse, et Raimond, comte de Barcelone ; Lettre de Besly à Oihénart ; Mandement d'Alfonse de Poitiers au sénéchal d'Agen ; Coutumes de Bayonne ; Pièces diverses de la Chambre des comptes ; Registre de Jean, duc de Bourbon ; Accord entre Jean, duc de Guyenne et de Lancastre, et Raimond de Montaut ; Accord entre Charles VII, et le comte de Comminges ; Capitulation de Fronsac ; Accord entre [Roger], seigneur de Camoys, et la cité de Bordeaux (1453 ; cf. D. de Beaucourt, Hist. de Charles VII, t. V, p. 279) ; Enquête faite par Guillaume Jouvenel des Ursins et Jean d'Estouteville, au sujet de la prise de Castillon ; Absolution accordée par Charles VII aux habitants de Bordeaux ; Règlement sur le fait de la justice de Bordeaux ; Mémoire sur l'état et le gouvernement de la cité de Bordeaux ; Mémoire (en espagnol) sur la conservation de la Guyenne et de la cité de Bayonne ; Serments prêtés au roi de France par le duc de Nemours, le comte d'Armagnac et le seigneur d'Albret ; Serment prêté au roi par le duc de Guyenne, son frère ; Instructions données à Me Pierre Noir, envoyé auprès du pape par le roi ; Rapport sur diverses dépositions faites au procès du duc de Nemours ; Extrait du procès-verbal de Me Cousinot touchant le cardinal Balue ; Instructions données par le roi à Olivier le Roux et à Louis Nyvart ; Instructions données au comte de Comminges, gouverneur de Guyenne ; Traité entre les rois de France et de Castille ; Traité entre Charles VIII et Ludovic-Maria Sforza, duc de Milan ; Pièces relatives à la concession à Gaston, comte de Foix, d'une rente de 1500 livres tournois ; Pariage entre Roger, comte de Foix, et l'abbé de Boulbonne ; Concession à Roger-Bernard, comte de Foix, par Philippe IV des droits de celui-ci sur Pamiers ; Prise de possession de ladite ville au nom de Gaston, comte de Foix ; Accord entre Charles VI et Archembaut de Grailly, comte de Foix ; Mandement de Charles VIII pour la restitution des fiefs du seigneur d'Albret ; Extraits de registres de la Chambre des comptes touchant le pays de Gaure ; Pièces concernant la cession du comté de Gaure au seigneur d'Albret ; Dénombrement des fiefs appartenant à Françoise de Lomagne ; Accord entre le duc d'Albret et Gilles de Lomagne, seigneur de Montagnac

Livre des Morts de Nésyménou. Egyptien 127

Fragment 4 :Col. 1 : scène du champ des souchets.Col. 2 + vignette : chapitre 111 (formule pour connaître les bas des Occidentaux). La vignette montre le défunt en adoration devant Horus.Col. 3 + vignette : chapitre 113 (formule pour connaître les bas de Nekhen). Le défunt est en adoration devant une divinité à tête de chacal.Col. 4 + vignette : chapitre 115 (?) (formule pour connaître les bas d'Hermopolis). La vignette montre le défunt debout devant une divinité.Fragment 2 :Col. 1 + vignette (fragmentaires) : chapitre 116 avec titre "formule pour connaître les bas d'Héliopolis". La vignette montre le défunt devant deux divinités.Col. 2 + vignette : chapitre 117 (formule pour prendre les chemins de Rosetjaou). La vignette montre une divinité à tête de chacal devant une tombe.Col. 3 (très fragmentaire) : chapitre 124 (?) (formule pour faire une transformation en phénix). Fragment 3 : Col. 1 + vignette : ? La vignette montre le défunt incliné.Col. 2 : chapitre 125.Fragment 1 :Col. 1 (fragmentaire).Col. 2 (fragmentaire) : la vignette correspond au chapitre 126 et montre quatre babouins au bord d'un lac.

Livre des Morts de Djéhoutyirydès. Egyptien 130

Col. 1, x+ 1-10 et vignette : chapitre 25, titre en lacune ("Formule pour faire que le défunt se souvienne de son nom dans la nécropole"). La vignette montre le défunt officiant devant un double de lui-même.Col. 1, x+11-22 et vignette : chapitre 26 avec titre rubriqué : "Formule pour lui donner son coeur dans la nécropole". La vignette montre le défunt accroupi devant l'oiseau-ba.Col. 2, x+1-13 et vignette : chapitre 27 avec titre en lacune (Formule pour empêcher que l'on retire le coeur d'un homme de son contrôle dans la nécropole). La vignette montre le défunt accroupi devant quatre divinités assises.Col. 2, x+14-22 et vignette : chapitre 30 avec titre rubriqué : "Formule pour empêcher que le coeur du défunt ne s'oppose à lui dans la nécropole". La vignette montre le défunt en adoration devant un scarabée (de coeur).Col. 3 et vignette : chapitre 42 avec titre en lacune ("Formule pour éviter le massacre qui se déroule dans Néninésou). La vignette montre le défunt transperçant un serpent.Col. 4, x+1-10 et vignette : chapitre 43 avec titre en lacune ("Formule pour empêcher qu'on ne tranche la tête d'un homme dans la nécropole"). La vignette montre le défunt debout devant trois têtes.Col. 4, x+11-22 et vignette : chapitre 44 avec titre rubriqué : "Formule pour ne pas mourir de nouveau dans la nécropole". On voit le défunt entrer dans une chapelle.

An exploratory study for the discovery of non-invasive hepatocellular carcinoma biomarkers among high-risk hepatitis C virus infected patients

Hepatocellular Carcinoma (HCC) is a major healthcare problem, representing the third most common cause of cancer-related mortality worldwide. Chronic infections with Hepatitis B virus (HBV) and/or Hepatitis C virus (HCV) are the major risk factors for the development of HCC. The incidence of HBV -associated HCC is in decline as a result of an effective HBV vaccine; however, since an equally effective HCV vaccine has not yet been developed, there are 130 million HCV infected patients worldwide who are at a high-risk for developing HCC. Because reliable parameters and/or tools for the early detection of HCC among high-risk individuals are severely lacking, HCC patients are always diagnosed at a late stage where surgical solutions or effective treatment are not possible. Using urine as a non-invasive sample source, two different approaches (proteomic-based and genomic-based approaches) were pursued with the common goal of discovering potential biomarker candidates for the early detection of HCC among high-risk chronic HCV infected patients. Urine was collected from 106 HCV infected Egyptian patients, 32 of whom had already developed HCC and 74 patients who were diagnosed as HCC-free at the time of initial sample collection. In addition to these patients, urine samples were also collected from 12 healthy control individuals. Total urinary proteins, Trans-renal nucleic acid (Tr-NA) and microRNA (miRNA) were isolated from urine using novel methodologies and silicon carbide-loaded spin columns. In the first, "proteomic-based", approach, liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) was used to identify potential candidates from pooled urine samples. This was followed by validating relative expression levels of proteins present in urine among all the patients using quantitative real time-PCR (qRT-PCR). This approach revealed that significant over-expression of three proteins: DJ-1, Chromatin Assembly Factor-1 (CAF-1) and 11 Moemen Abdalla HCC Biomarkers Heat Shock Protein 60 (HSP60), were characteristic events among HCC-post HCV infected patients. As a single-based HCC biomarker, CAF-1 over-expression identified HCC among HCV infected patients with a specificity of 90%, sensitivity of 66% and with an overall diagnostic accuracy of 78%. Moreover, the CAF-lIHSP60 tandem identified HCC among HCV infected patients with a specificity of 92%, sensitivity of 61 % and with an overall diagnostic accuracy of 77%. In the second genomic-based approach, two different approaches were processed. The first approach was the miRNA-based approach. The expression levels of miRNAs isolated from urine were studied using the Illumina MicroRNA Expression Profiling Assay. This was followed by qRT-PCR-based validation of deregulated expression of identified miRNA candidates among all the patients. This approach shed the light on the deregulated expression of a number of miRNAs, which may have a role in either the development of HCC among HCV infected patients (i.e. miR-640, miR-765, miR-200a, miR-521 and miR-520) or may allow for a better understanding of the viral-host interaction (miR-152, miR-486, miR-219, miR452, miR-425, miR-154 and miR-31). Moreover, the deregulated expression of both miR-618 and miR-650 appeared to be a common event among HCC-post HCV infected patients. The results of the search for putative targets of these two miRNA suggested that miR-618 may be a potent oncogene, as it targets the tumor-suppressor gene Low density lipoprotein-related protein 12 (LPR12), while miR-650 may be a potent tumor-suppressor gene, as it is supposed to downregulate the TNF receptor-associated factor-4 (TRAF4) oncogene. The specificity of miR-618 and miR-650 deregulated expression patterns for the early detection of HCC among HCV infected patients was 68% and 58%, respectively, whereas the sensitivity was 64% and 72%, respectively. When the deregulated expression of both miRNAs was combined as a tandem biomarker, the specificity and the sensitivity were 75% and 58% respectively. 111 Moemen Abdalla HCC Biomarkers In the second, "Trans-renal nucleic acid-based", approach, the urinary apoptotic nucleic acid (uaNA) levels of 70ng/mL or more were found to be a good predictor of HCC among chronic HCV infected patients. The specificity and the sensitivity of this diagnostic approach were 76% and 86%, respectively, with an overall diagnostic value of 81 %. The uaNA levels positively correlated to HCC disease progression as monitored by epigenetic changes of a panel of eight tumor-suppressor genes (TSGs) using methylation-sensitive PCR. Moreover, the pairing of high uaNA levels (:::: 70 ng/mL) and CAF-1 over-expreSSIOn produced a highly specific (l 00%) multiple-based HCC biomarker with an acceptable sensitivity of 64%, and with a diagnostic accuracy of 82%. In comparison to the previous pairing, the uaNA levels (:::: 70 ng/mL) in tandem with HSP60 over-expression was less specific (89%) but highly sensitive (72%), resulting in a diagnostic accuracy of 64%. The specificities of miR-650 deregulated expression in combination with either high uaNA content or HSP 60 over-expression were 82% and 79%, respectively, whereas, the sensitivities of these combinations were 64% and 58%, respectively. The potential biomarkers identified in this study compare favorably with the diagnostic accuracy of the a-fetoprotein levels test, which has a specificity of 75%, sensitivity of 68% and an overall diagnostic accuracy of 70%. Here we present an intriguing study which shows the significance of using urine as a noninvasive sample source for the identification of promising HCC biomarkers. We have also introduced new techniques for the isolation of different urinary macromolecules, especially miRNA, from urine. Furthermore, we strongly recommend the potential biomarkers indentified in this study as focal points of any future research on HCC diagnosis. A larger testing pool will determine if their use is practical for mass population screening. This explorative study identified potential targets that merit further investigation for the development of diagnostically accurate biomarkers isolated from 1-2 mL urine samples that were acquired in a non-invasive manner.