Beta cell mass and growth after syngeneic islet cell transplantation in normal and streptozocin diabetic C57BL/6 mice

In islet transplantation, nonimmunological factors such as limited growth capacity or increased death rate could reduce the beta cell mass in the graft and lead to failure of the transplant. We studied the evolution of beta cell replication and mass after transplantation of insufficient, minimally sufficient, or excessive islet tissue. Streptozocin diabetic C57BL/6 mice received 150 or 300 syngeneic islets under the kidney capsule and normal mice received 300 islets. In streptozocin diabetic mice 300 islets restored normoglycemia; beta cell replication in transplanted islets was similar to replication in normal pancreas and beta cell mass in the graft remained constant. In contrast, 150 islets were insufficient to achieve normoglycemia; beta cell replication was increased initially but not by 18 or 30 d despite persistent hyperglycemia, and beta cell mass fell progressively. When islets were transplanted into normal recipients, beta cell replication remained normal but beta cells underwent atrophy and mass in the graft was substantially reduced. Therefore, with a successful islet transplant, in diabetic mice beta cell replication and mass remain constant. In contrast, when insufficient islet tissue is transplanted an initial increase in beta cell replication can not compensate for a decline in beta cell mass. When excessive islet tissue is transplanted, beta cell mass is reduced despite normal beta cell replication.

Transplanted beta cell response to increased metabolic demand. Changes in beta cell replication and mass

We determined the capacity of transplanted beta cells to modify their replication and mass when stimulated by changes in metabolic demand. Five groups of Lewis rats were studied: group 1 (Tx-Px) had a 95% pancreatectomy 14 d after transplantation of 500 islets; group 2 (Px-Tx) had a 95% pancreatectomy 14 d before transplantation of 500 islets; group 3 (Tx) was transplanted with 500 islets; group 4 (Px) had a 95% pancreatectomy; and group 5 (normal) was neither transplanted nor pancreatectomized. Blood glucose was normal in Tx-Px and Tx groups at all times. Px-Tx and Px groups developed severe hyperglycemia after pancreatectomy that was corrected in Px-Tx group in 83% of rats 28 d after transplantation. Replication of transplanted beta cells increased in Tx-Px (1.15 +/- 0.12%) and Px-Tx (0.85 +/- 0.12%) groups, but not in Tx group (0.64 +/- 0.07%) compared with normal pancreatic beta cells (0.38 +/- 0.05%) (P < 0.001). Mean beta cell size increased in Tx-Px (311 +/- 14 microns2) and Px-Tx (328 +/- 13 microns2) groups compared with Tx (252 +/- 12 microns2) and normal (239 +/- 9 microns2) groups (P < 0.001). Transplanted beta cell mass increased in Tx-Px (1.87 +/- 0.51 mg) and Px-Tx (1.55 +/- 0.21 mg) groups compared with Tx group (0.78 +/- 0.17 mg) (P < 0.05). In summary, changes in transplanted beta cells prevented the development of hyperglycemia in Tx-Px rats. Transplanted beta cells responded to increased metabolic demand increasing their beta cell mass.

Identification of Novel Craniofacial Regulatory Domains Located far Upstream of SOX9 and Disrupted in Pierre Robin Sequence.

Mutations in the coding sequence of SOX9 cause campomelic dysplasia (CD), a disorder of skeletal development associated with 46,XY disorders of sex development (DSDs). Translocations, deletions, and duplications within a ∼2 Mb region upstream of SOX9 can recapitulate the CD-DSD phenotype fully or partially, suggesting the existence of an unusually large cis-regulatory control region. Pierre Robin sequence (PRS) is a craniofacial disorder that is frequently an endophenotype of CD and a locus for isolated PRS at ∼1.2-1.5 Mb upstream of SOX9 has been previously reported. The craniofacial regulatory potential within this locus, and within the greater genomic domain surrounding SOX9, remains poorly defined. We report two novel deletions upstream of SOX9 in families with PRS, allowing refinement of the regions harboring candidate craniofacial regulatory elements. In parallel, ChIP-Seq for p300 binding sites in mouse craniofacial tissue led to the identification of several novel craniofacial enhancers at the SOX9 locus, which were validated in transgenic reporter mice and zebrafish. Notably, some of the functionally validated elements fall within the PRS deletions. These studies suggest that multiple noncoding elements contribute to the craniofacial regulation of SOX9 expression, and that their disruption results in PRS.

Reheating in inflationary cosmologies: Geometric coupling of the "inflaton" to quantum fields

We propose a simple geometrical prescription for coupling a test quantum scalar field to an "inflaton" (classical scalar field) in the presence of gravity. When the inflaton stems from the compactification of a Kaluza-Klein theory, the prescription leaves no arbitrariness and amounts to a dimensional reduction of the Klein-Gordon equation. We discuss the possible relevance of this coupling to "reheating" in inflationary cosmologies.

Minimal analytical characterisation of engineered nanomaterials need for hazard assessment in biological matrices

The safe and responsible development of engineered nanomaterials (ENM), nanotechnology-based materials and products, together with the definition of regulatory measures and implementation of "nano"-legislation in Europe require a widely supported scientific basis and sufficient high quality data upon which to base decisions. At the very core of such a scientific basis is a general agreement on key issues related to risk assessment of ENMs which encompass the key parameters to characterise ENMs, appropriate methods of analysis and best approach to express the effect of ENMs in widely accepted dose response toxicity tests. The following major conclusions were drawn: Due to high batch variability of ENMs characteristics of commercially available and to a lesser degree laboratory made ENMs it is not possible to make general statements regarding the toxicity resulting from exposure to ENMs. 1) Concomitant with using the OECD priority list of ENMs, other criteria for selection of ENMs like relevance for mechanistic (scientific) studies or risk assessment-based studies, widespread availability (and thus high expected volumes of use) or consumer concern (route of consumer exposure depending on application) could be helpful. The OECD priority list is focussing on validity of OECD tests. Therefore source material will be first in scope for testing. However for risk assessment it is much more relevant to have toxicity data from material as present in products/matrices to which men and environment are be exposed. 2) For most, if not all characteristics of ENMs, standardized methods analytical methods, though not necessarily validated, are available. Generally these methods are only able to determine one single characteristic and some of them can be rather expensive. Practically, it is currently not feasible to fully characterise ENMs. Many techniques that are available to measure the same nanomaterial characteristic produce contrasting results (e.g. reported sizes of ENMs). It was recommended that at least two complementary techniques should be employed to determine a metric of ENMs. The first great challenge is to prioritise metrics which are relevant in the assessment of biological dose response relations and to develop analytical methods for characterising ENMs in biological matrices. It was generally agreed that one metric is not sufficient to describe fully ENMs. 3) Characterisation of ENMs in biological matrices starts with sample preparation. It was concluded that there currently is no standard approach/protocol for sample preparation to control agglomeration/aggregation and (re)dispersion. It was recommended harmonization should be initiated and that exchange of protocols should take place. The precise methods used to disperse ENMs should be specifically, yet succinctly described within the experimental section of a publication. 4) ENMs need to be characterised in the matrix as it is presented to the test system (in vitro/ in vivo). 5) Alternative approaches (e.g. biological or in silico systems) for the characterisation of ENMS are simply not possible with the current knowledge. Contributors: Iseult Lynch, Hans Marvin, Kenneth Dawson, Markus Berges, Diane Braguer, Hugh J. Byrne, Alan Casey, Gordon Chambers, Martin Clift, Giuliano Elia1, Teresa F. Fernandes, Lise Fjellsbø, Peter Hatto, Lucienne Juillerat, Christoph Klein, Wolfgang Kreyling, Carmen Nickel1, and Vicki Stone.

Performance Evaluation Of Iowa Bridge Decks Constructed With Epoxy-Coated Reinforcing Bars, RB06-011, 2011

Epoxy coatings have been used on the embedded reinforcing bars of bridge decks since the mid-1970s to mitigate deterioration caused by chloride-induced corrosion. The use of chloride-based deicers became common in the early 1960s and caused corrosion of conventional uncoated bars in bridge decks within 5 to 10 years of commencement of deicer applications. In response to this rapid deterioration, the National Bureau of Standards researched coatings to protect the reinforcement (National Bureau of Standards, 1975), resulting in the development of epoxy-coated reinforcing bars, which were used in bridge decks beginning in 1973. While corrosion-related deterioration has been prevalent on bridge decks with uncoated reinforcing bars in northern climates where the use of deicing salts is common, bridge decks constructed after 1973 with epoxy-coated reinforcing have shown good corrosion resistance with only limited exceptions. On the whole, previous laboratory and field studies regarding the performance of epoxy-coated reinforcing bars are very promising; however, some laboratory and field studies have yielded differing results. In recent years, maintenance personnel for the Iowa Department of Transportation (Iowa DOT) have reportedly performed patch repairs to some bridge decks reinforced with epoxy-coated bars. At one such bridge, the southbound US 65 bridge (Bridge No. 7788.5L065) over the Union Pacific Railroad near Bondurant in Polk County, Iowa, deck repairs were performed by Iowa DOT maintenance personnel in the Spring of 2010, based on our communications regarding this topic with Mr. Gordon Port of the Iowa DOT. These repairs were observed by engineers from the Iowa DOT Office of Bridges and Structures, who reported that significant corrosion was found at a number of epoxy-coated reinforcing bars uncovered during this patch work. These repairs were reportedly performed at spalls and delaminated areas corresponding to cracks over transverse reinforcing bars, and involved careful removal of the concrete from over the bars. Figures 1 through 4 contain photographs provided by Iowa DOT personnel showing the removal process (Figure 1), the conditions encountered (Figures 2 and 3), and close-up views of the corroded reinforcing (Figure 4). As a result of these observations, the Iowa Department of Transportation has requested this study to gain further understanding of the long-term performance of bridge decks reinforced with epoxy-coated bars. The two main objectives of this study are to determine the long-term effectiveness of the epoxy coatings and to determine the potential causes for the deterioration at locations where corrosion has occurred. Wiss, Janney, Elstner Associates, Inc. (WJE) and the Iowa DOT identified eight different bridge decks across Iowa for this study that were constructed using epoxy-coated reinforcing bars. A field investigation consisting of visual inspections, a delamination survey, a concrete cover survey, electrical testing for susceptibility to corrosion, and concrete sampling was conducted within a survey area deemed to be representative of the condition of each bridge deck. Laboratory testing, including chloride ion content testing, characterization of the extracted bars, petrographic examination of the concrete, and carbonation testing, was conducted on the core samples taken from each bridge deck.

An integrated encyclopedia of DNA elements in the human genome.

The human genome encodes the blueprint of life, but the function of the vast majority of its nearly three billion bases is unknown. The Encyclopedia of DNA Elements (ENCODE) project has systematically mapped regions of transcription, transcription factor association, chromatin structure and histone modification. These data enabled us to assign biochemical functions for 80% of the genome, in particular outside of the well-studied protein-coding regions. Many discovered candidate regulatory elements are physically associated with one another and with expressed genes, providing new insights into the mechanisms of gene regulation. The newly identified elements also show a statistical correspondence to sequence variants linked to human disease, and can thereby guide interpretation of this variation. Overall, the project provides new insights into the organization and regulation of our genes and genome, and is an expansive resource of functional annotations for biomedical research.

CDK9 regulates AR promoter selectivity and cell growth through serine 81 phosphorylation.

Previously we determined that S81 is the highest stoichiometric phosphorylation on the androgen receptor (AR) in response to hormone. To explore the role of this phosphorylation on growth, we stably expressed wild-type and S81A mutant AR in LHS and LAPC4 cells. The cells with increased wild-type AR expression grow faster compared with parental cells and S81A mutant-expressing cells, indicating that loss of S81 phosphorylation limits cell growth. To explore how S81 regulates cell growth, we tested whether S81 phosphorylation regulates AR transcriptional activity. LHS cells stably expressing wild-type and S81A mutant AR showed differences in the regulation of endogenous AR target genes, suggesting that S81 phosphorylation regulates promoter selectivity. We next sought to identify the S81 kinase using ion trap mass spectrometry to analyze AR-associated proteins in immunoprecipitates from cells. We observed cyclin-dependent kinase (CDK)9 association with the AR. CDK9 phosphorylates the AR on S81 in vitro. Phosphorylation is specific to S81 because CDK9 did not phosphorylate the AR on other serine phosphorylation sites. Overexpression of CDK9 with its cognate cyclin, Cyclin T, increased S81 phosphorylation levels in cells. Small interfering RNA knockdown of CDK9 protein levels decreased hormone-induced S81 phosphorylation. Additionally, treatment of LNCaP cells with the CDK9 inhibitors, 5,6-dichloro-1-β-D-ribofuranosylbenzimidazole and Flavopiridol, reduced S81 phosphorylation further, suggesting that CDK9 regulates S81 phosphorylation. Pharmacological inhibition of CDK9 also resulted in decreased AR transcription in LNCaP cells. Collectively these results suggest that CDK9 phosphorylation of AR S81 is an important step in regulating AR transcriptional activity and prostate cancer cell growth.

Recueil des poésies des troubadours, contenant leurs vies.

Contient : 1° Chansons ; « PEIRE D'ALVERNE » ; « PEIRE ROGIERS » ; « GUIRAUTZ DE BORNEILL » ; « BERNARTZ DE VENTEDORN » ; « GAUSELMS FAIDITZ » ; « PEIRE VIDALS » ; « ARNAUTZ DE MERUOILL » ; « PERDIGONS » ; « N'AIMERICS DE PIGUILLAN » ; « PEIROLS » ; « FOLQUET DE MARSEILLA » ; « ARNAUTZ DANIELS » ; « RAIMONS DE MIRAVAL » ; « PONZ DE CAPDUOILL » ; « RAEMBAUTZ DE VAQUEIRAS » ; « GUILLEMS DE SAINT LEIDIER » ; « GAUBERTZ DE POICIBOT » ; « LO VESCOMS DE SAINT ANTONI » ; « GUIRAUDOS LO ROS » ; « PEIRE RAIMONS DE TOLOSA » ; « RICHARTZ DE BERBESIEU » ; « GUI D'UISEL » ; « En LANFRANC CIGALLA » ; « BONIFACI CALBO » ; « En BERTHOLOME ÇORGI » ; « N'UCS BRUNECS » ; « GUILLEMS ADEMARS » ; « GUILLEMS DE CAPESTAING » ; « ELIAS CAIRELS » ; « PEIRE DE MAENSAC » ; « SAIL DE SCOLA » ; « PEIRE DEL PUOI » ; « LO REIS D'ARAGON » ; « RAIMONZ DE SALAS » ; « En BLANCATZ » ; « En BLANCASSETZ » ; « GUILLEMS FIGUERA » ; « PEIRE GUILLEMS » ; « RICAS NOVAS » ; « GUILLEM DE BALAUN » ; « DEUDE DE PRADAS » ; « CADENETZ » ; « MARCABRUS » ; « JORDANS BONELS » ; « JAUFRES RUDELS DE BLAIA » ; « PEIRE DE VALERIA » ; « RICHAUTZ DE TARASCON » ; « BERTRANS DEL POJET » ; « N'AIMERICS DE SARLAT » ; « SORDELS » ; « MONTAINGNACOT » ; « NA CASTELOZA » ; « N'AIMERICS DE BELENOI » ; « N'UCS DE SAINT CIRC » ; « N'ELIAS DE BARJOLS » ; « GUILLEMS DE LA TOR » ; « CERCAMONS » ; « ALBERTEZ DE GAPENSES » ; « LO MONGES DE MONTAUDON » ; « PISTOLETA » ; « N'AIMARS LO NEGRES » ; « GUILLEMS MAGRET » ; « N'ELIAS FONSALADA » ; « N'AZALAIS DE PORCARAGES » ; « BERRENGIERS DE PALAZOL » ; « UGO DE PENA » ; « LA COMTESSA DI DIA » ; « PEIRE BREMONZ LO TORZ » ; « GAUSERAN DE SAN LEIDIER » ; « GAUBERTZ AMIELS » ; « LO COMS DE PEITIEUS » ; « GUIRAUTZ DE CALANSON » ; « GUILLEMS RAINOLS D'AT » ; « RAEMBAUTZ D'AURENGA » ; « PEIRE MILON » ; « En RALMENZ BISTORTZ » ; « N'UC DE LA BACALARIA » ; « En RAMBAUTZ DE BEL JOC » ; « ARNAUT DE TINTIGNAC » ; « GUIRAUTZ DE SALAIGNAC » ; « PEIRE DE CORBIAC » ; « LO reis PEIRE D'ARAGON » ; « Responsa de PEIRE SALVAJE » ; « LO COMS DE FOIS » ; « LO reis PEIRE D'ARAGON » ; « LO COMS DE FOIS » ; 2° Tensons ; « En SAVARICS DE MAULLEON et En GAUSELLINS FAIDIT et En UGO DE LA BACALARIA » ; « N'AIMERICS DE PIGUILLAN ed En GUILLEM DE BERGUEDAN » ; « N'AIMERICS DE PIGUILLAN et En GAUSELMS FAIDITZ » ; « N'ALBERTETZ e N'AMERICS DE PIGUILLAN » ; « Em BLANCATZ et En RAMBAUTZ » ; « RAINAUTZ DE PON e seingner JAUFRE » ; « LO DAEFINS D'ALVERNE et En PERDIGONS » ; « GAUSELM FAIDITZ et En PERDIGONS » ; « N'UGO DE LA BACALARIA et En BELTRAM DE SAN FILITZ » ; « GUILLEMS RANOLS ed En MAGRET » ; « RICAUTZ DE TARASCON e N' GUIS DE CAVAILLON » ; « GUIRAUTZ DE BORNEILL el REIS D'ARRAGON » ; « PEIRE ROGIERS » ; « RAMBAUTZ ed En PEIRE ROGIERS » ; « PEIROLS et En BERNATZ DEL VENTEDORN » ; « ALBERTZ MARQUES » ; « BERNARTZ DE VENTADORN ed En PEIROLS » ; « GUILLEMS DE LA TOR e seigner N'IBERT » ; « RAMBAUTZ DE VAQUERAS e seingner COINE » ; « RAMBAUTZ DE VAQUERAS e de la domna » ; « ALBERTEZ et En GAUSELLMS FAIDITZ » ; « En BLANCATZ ed En PEIRE VIDALS » ; « BONAFE e seingn' En BLANCATZ » ; « GUILLEMS DE SAINT GREGORI et En BLANCATZ » ; « GUILLEMS DE LA TOR ed En SORDELS » ; « RAIMONS DE MIRAVAL ed En BELTRAN » ; « GUILLEMS GASMAR et En NEBLE » ; « PEIROLS et AMORS » ; « N'UC DE SAN CIRC e seingner COMS » ; « N'UC et En RECULAIRE » ; « GARINS LO BRUS e MESURA » ; « N'ELIAS e son cosin » ; « N'ARNAUTZ e seingner Em COMS » ; « D'En RAMBAUTZ e d'Enn AZEMARS » ; « LANFRANC CIGALA e Na GUILLELMA DE ROSERS » ; « D'En GIGO e d'En JORIS » ; « D'En SORDELS e d'En BERTRANS » ; « CADENET ed En GUIONET » ; « N'ELIAS e son cosin » ; « N'EGO DE LA BACALARIA ed En GAUSELIM FAIDITZ » ; « La tenzon de ROFIN e de domna H » ; « SAVARICS DE MALEON ed En PREBOST » ; « LO DALFIN ed En PEIROL » ; « ALBERTET et En GAUSSCELM FAIDITZ » ; « De N'EBLES e de son seingnor » ; « ALBERTETZ el monge » ; « BERTRAM DE GORDON et En PEIRE RAIMON » ; « La tenzon de l'oste e de GUILLEM » ; « La tenzon de seigner MONTAN e de la domna » ; 3° Sirventes ; « PEIRE CARDINAL » ; « BERTRANS DE BORN » ; « Sirventes del rei RICHART » ; « Sirventes del DALFIN D'ALVERNE » ; « LO DALFINS D'ALVERNE » ; « BERTRANS DEL POJET » ; « RAIMONS DE DURFORT » ; « TURCS MALECS » ; « ARNAUTZ DANIELS » ; « RAEMBAUTZ DE VAQUERAS » ; « GUILLEMS FIGUERA » ; « GUIRATZ DE BORNEILL » ; « LO MONGE DE POCIBOT » ; « En SORDEL » ; « BERTRANS DE LAMANON » ; « N'AIMERICS DE PIGUILLAN » ; « ALBERTETZ CAILLA » ; « FOLQUET DE ROMANS » ; « OGIERS » ; « PEIRE DE BARJAC » ; « PEIRE DE BOSIGNAC » ; « TOMIERS En PALAZIS » ; « RAIMONS D'AVIGNON » ; « GARINS D'APCHIER » ; « TORCAFOLS » ; « GARIS D'APCHIER » ; « TORCAFOLS » ; « GUILLEMS DE BERGUEDAN » ; « GUIRAUTZ DE LUC » ; « GAUSELM FAIDITZ » ; « GIRAUTZ DE SALAINGNAC » ; « LO MONGE DE MONTAUDON » ; « PEIRE DE LA CARAVANA » ; « PEIRE D'ALVERNE » ; « REFORSAT DE FOLCAQUIER » ; « PEIRE DE BRAGAIRAC » ; « BERNART DE LA BARDA » ; « AICARTZ DEL FOSSAT » ; « PEIRE DE BOSSIGNAC » ; « OGIERS » ; « MARCOAT » ; « PONS BARBA » ; « N'UC DE SAINT CIRC » ; « GAUSELM FAIDITZ » ; « PONZ DE CAPDUOILL » ; « N'AIMERICS DE PIGUILLAN »

Common variants near MC4R are associated with fat mass, weight and risk of obesity.

To identify common variants influencing body mass index (BMI), we analyzed genome-wide association data from 16,876 individuals of European descent. After previously reported variants in FTO, the strongest association signal (rs17782313, P = 2.9 x 10(-6)) mapped 188 kb downstream of MC4R (melanocortin-4 receptor), mutations of which are the leading cause of monogenic severe childhood-onset obesity. We confirmed the BMI association in 60,352 adults (per-allele effect = 0.05 Z-score units; P = 2.8 x 10(-15)) and 5,988 children aged 7-11 (0.13 Z-score units; P = 1.5 x 10(-8)). In case-control analyses (n = 10,583), the odds for severe childhood obesity reached 1.30 (P = 8.0 x 10(-11)). Furthermore, we observed overtransmission of the risk allele to obese offspring in 660 families (P (pedigree disequilibrium test average; PDT-avg) = 2.4 x 10(-4)). The SNP location and patterns of phenotypic associations are consistent with effects mediated through altered MC4R function. Our findings establish that common variants near MC4R influence fat mass, weight and obesity risk at the population level and reinforce the need for large-scale data integration to identify variants influencing continuous biomedical traits.

2013 Update in addiction medicine for the generalist.

Increasingly, patients with unhealthy alcohol and other drug use are being seen in primary care and other non-specialty addiction settings. Primary care providers are well positioned to screen, assess, and treat patients with alcohol and other drug use because this use, and substance use disorders, may contribute to a host of medical and mental health harms. We sought to identify and examine important recent advances in addiction medicine in the medical literature that have implications for the care of patients in primary care or other generalist settings. To accomplish this aim, we selected articles in the field of addiction medicine, critically appraised and summarized the manuscripts, and highlighted their implications for generalist practice. During an initial review, we identified articles through an electronic Medline search (limited to human studies and in English) using search terms for alcohol and other drugs of abuse published from January 2010 to January 2012. After this initial review, we searched for other literature in web-based or journal resources for potential articles of interest. From the list of articles identified in these initial reviews, each of the six authors independently selected articles for more intensive review and identified the ones they found to have a potential impact on generalist practice. The identified articles were then ranked by the number of authors who selected each article. Through a consensus process over 4 meetings, the authors reached agreement on the articles with implications for practice for generalist clinicians that warranted inclusion for discussion. The authors then grouped the articles into five categories: 1) screening and brief interventions in outpatient settings, 2) identification and management of substance use among inpatients, 3) medical complications of substance use, 4) use of pharmacotherapy for addiction treatment in primary care and its complications, and 5) integration of addiction treatment and medical care. The authors discuss each selected articles' merits, limitations, conclusions, and implication to advancing addiction screening, assessment, and treatment of addiction in generalist physician practice environments.