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Two studies were conducted to determine the effects of diet and feed additive on growth and carcass characteristics of lambs and cattle destined for all natural markets. In Exp. 1, 48 Dorset × Hampshire lambs (initial BW 29.4 ± 0.1 kg) were used in a randomized complete block experiment to determine the effects of Aspergillus oryzae extract, Amaferm (AMF) supplementation (1 g/d) in an 85% concentrate diet on growth and carcass characteristics. Lambs were allotted to 12 pens (4 lambs per pen), and blocked by sex and BW. Lambs were fed until the average BW of each pen reached a target BW (55.4 kg for wethers and 50.0 kg for ewes), at which time the entire pen of lambs was slaughtered. Amaferm resulted in a greater (P = 0.07) G:F. In Exp. 2, 168 crossbred steers (initial BW 300 ± 0.7 kg) were used in a trial with a 3 × 2 factorial arrangement of treatments to examine the effects of 0.5 g/d of Saccaromyces cervisiae boulardii CNCM 1079-Levucell SB (LEV), or 3 g/d of AMF with 2 corn sources, dry whole-shelled corn or high moisture corn, on growth and carcass characteristics. Neither LEV nor AMF improved (P > 0.10) carcass characteristics compared with control or non-feed-supplemented steers. Addition of LEV to high-concentrate, corn-based diets did not improve (P > 0.10) growth performance of feedlot steers. However, addition of AMF to a diet composed of dry whole-shelled corn resulted in an improvement (P < 0.05) in G:F (0.208 vs. 0.194). Results indicate that at the amounts fed, AMF may improve G:F for lambs and steers fed dry corn-based finishing diets. [ABSTRACT FROM AUTHOR]

Both signal transducer and activator of transcription 3 (STAT3) and SALL4 are important in maintaining the pluripotent and self-renewal state of embryonic stem cells. We hypothesized that STAT3, a latent transcriptional factor, may regulate the gene expression of SALL4. In support of this hypothesis, DNA sequence analysis of the SALL4 gene promoter revealed four putative STAT3-binding sites. Using a SALL4-luciferase reporter gene assay, we found that modulation of the STAT3 activity significantly up-regulated the luciferase activity. By chromatin immunoprecipitation, the segment of the SALL4 promoter showing the highest affinity to STAT3 was localized to -366 to -163, in which there was only one putative STAT3 binding site starting at -199. Site-directed mutagenesis of all four putative STAT3-binding sites in the SALL4 promoter significantly reduced its responsiveness to STAT3, although the most dramatic effect was seen at the binding site starting at -199. We further tested the functional relationship between STAT3 and SALL4 using MDA-MB-231, a breast cell line carrying constitutive SALIA expression and STAT3 activity. Down-regulation of the STAT3 activity using a dominant-negative construct resulted in a significant decrease in the expression of SALL4. To conclude, our data suggest that STAT3 and SALL4 probably cooperate in both physiological and pathological states. [ABSTRACT FROM AUTHOR]

One of the characteristic features of anaplastic lymphoma kinase (ALK)(+), anaplastic large cell lymphoma (ALK(+)ALCL) is the constitutive activation of signal transducers and activators of transcription-3 (STAT3), a defect believed to be important for the pathogenesis of these tumors. In this report, we describe the existence of an autocrine stimulatory loop involving interleukin-22 (IL-22) that contributes to STAT3 activation and tumorigenicity of ALK(+)ALCL. The IL-22 receptor, a heterodimer composed of IL-22R1 and IL-10R2, was expressed in all ALK(+)ALCL cell lines and tumors examined. The expression of IL-22R1 in ALK(+)ALCL is aberrant, as this protein is absent in benign lymphocytes. Although ALK(+)ALCL cells produce endogenous IL-22, addition of recombinant IL-22 to ALK(+)ALCL cell lines significantly increased STAT3 activation, cell proliferation and colony formation in soft agar. Opposite biological effects were observed in cells treated with recombinant IL-22 binding protein (a naturally occurring IL-22 decoy) or IL-22-neutralizing antibody. Nucleophosmin (NPM)-ALK, the characteristic fusion gene oncoprotein expressed in ALK(+)ALCL, directly contributes to the aberrant expression of IL-22R1, as transfection of NPM-ALK in Jurkat cells-induced IL-22R1 expression and IL-22-mediated STAT3 activation. To conclude, for the first time, we demonstrate the importance of the IL-22 autocrine pathway in a lymphoid malignancy, and reveal yet another novel function of NPM-ALK. [ABSTRACT FROM AUTHOR]

There has recently been significant progress in our understanding of the mechanisms that regulate ageing, and it has been shown that changes in single genes can dramatically extend lifespan and increase resistance to many diseases. Furthermore, many of these genes belong to evolutionarily conserved pathways that also control energy metabolism. In this review, we describe the shared molecular machinery that regulates ageing and energy metabolism. Although drugs to slow ageing face severe regulatory hurdles, it is likely that an understanding of ageing pathways will help to identify novel drug targets to treat metabolic disorders and other age-related diseases. [ABSTRACT FROM AUTHOR]

We previously reported a genomewide linkage study for human longevity using 308 long-lived individuals (LLI) (centenarians or near-centenarians) in 137 sibships anal identified statistically significant linkage within chromosome 4 near microsatellite D4S1564. This interval spans 12 million bp and contains &Sime;50 putative genes. To identify the specific gene and gene variants impacting lifespan, we performed a haplotype-based fine-mapping study of the interval. The resulting genetic association study identified a haplotype marker within microsomal transfer protein as a modifier of human lifespan. This same variant was tested in a second cohort of LLI from France, and although the association was not replicated, there was evidence for statistical distortion in the form of Hardy Weinberg disequilibrium. Microsomal transfer protein has been identified as the rate-limiting step in lipoprotein synthesis and may affect longevity by subtly modulating this pathway. This study provides proof of concept for the feasibility of using the genomes of LLI to identify genes impacting longevity. [ABSTRACT FROM AUTHOR]

The rise time of an auditory prepulse was varied to determine whether the onset transient of the prepulse is of primary importance in the modification of the acoustic startle reflex. In Experiment 1, 20-ms long discrete prepulses were presented at a lead time of 150 ms, and prepulse rise time was varied from 0.1 to 20 ms. Although all prepulses resulted in decreased response amplitude (inhibition of startle), varying rise time from 0.1 to 20 ms had no effect on reflex modification. These results suggest that the startle response is not sensitive to prepulse rise time changes in the range used here. In Experiment 2, continuous prepulses (in which lead time equals duration) were presented. Several of these prepulses had a lead time of 150 ms and rise times ranging from 0.1 to 150 ms, whereas others had a rise time of 0.1 ms and lead times of 50 to 150 ms. The results showed that only the fast-rising, 50-ms lead time prepulse decreased response amplitude, with the other prepulses having no effect on amplitude, relative to control responding. Rise time changes generally had no effect on responding, but responses were larger at longer lead times than at shorter lead times. Response probability was inhibited by fast-rising prepulses at lead times of 50 to 130 ms. Together with the results of Experiment 1, these findings suggest that startle reflex inhibition is determined by the onset of a prepulse, and that this inhibition is not sensitive to small changes in prepulse rise time. Also, startle reflex facilitation is determined by the steady-state portion of the prepulse, and this effect is sensitive to prepulse duration. The inhibitory and facilitatory effects combine to determine the amount and direction of reflex modification, and these effects have different time courses, suggesting different mechanisms. It is suggested that reflex modification is due to the activation of a transient system for startle inhibition and a sustained system for startle facilitation. [ABSTRACT FROM AUTHOR]

Introduction et but de l’étude Il est reconnu que chez les femmes ménopausées, le microbiote intestinal pourrait influencer le risque de cancer du sein. Aussi, le microbiote peut agir à plusieurs niveaux dont la modulation du métabolisme. Parmi les fonctions métaboliques régulées, le métabolisme intestinal, lipidique et lipoprotéique, apparaît une cible de choix des bactéries. Celles-ci pourront réguler, par exemple le facteur de transcription liver X receptor (LXR), régulateur de gènes du métabolisme lipidique et glucidique et reconnu comme cible potentielle d’une prévention nutritionnelle ou pharmacologique des cancers. Notre hypothèse est donc que les eaux fécales, contenant des métabolites d’origine bactérienne de patientes atteintes de cancer du sein, pourraient moduler l’expression de gènes impliqués dans le métabolisme intestinal, lipidique et lipoprotéique. Pour explorer cette hypothèse, nous avons comparé l’effet d’eaux fécales de patientes atteintes de cancer du sein sur l’expression de gènes du modèle cellulaire intestinal Caco-2 : LXR, ABCG5 (gène régulé par LXR), microsomal triglycerides transfer protein (MTP) et l’ApoA-IV (protéine exclusivement intestinale). L’expression de ces gènes a été analysée en lien avec le microbiote fécal et les données cliniques des patientes. Matériel et méthodes Les données cliniques et les échantillons fécaux de 28 patientes atteintes de cancer du sein ont été collectés. L’ADN bactérien extrait à partir des échantillons fécaux a été amplifié par qPCR en utilisant les séquences spécifiques pour les groupes bactériens différents. Les eaux fécales (EF) des patientes ont été recueillies par centrifugation et filtrées sur filtres 0,2 μm puis diluées (1 :10) dans du milieu de culture cellulaire. Les cellules Caco-2 cultivées sur supports semi-perméables ont été incubées avec les EF des patientes. Après 24 h d’incubation, les ARNm des cellules ont été extraits pour analyser l’expression des gènes par qPCR. Résultats et analyse statistique Parmi les échantillons EF, 64,3 % ont induit l’expression d’ ApoA-IV , entre 2 et 5 fois, par rapport aux cellules non traitées et aucun échantillon n’a réduit cette expression. Parmi les échantillons EF, 21,4 % ont induit l’expression de LXR , entre 2 et 4,3 fois, par rapport aux cellules non traitées et seulement deux ont réduit cette expression. Parmi les échantillons EF, 21,4 % ont induit l’expression relative d’ ABCG5 de 2 à 3 fois et seulement trois ont réduit cette expression. Cinq échantillons EF ont augmenté l’expression de MTP et aucune diminution de la MTP n’a été constatée. L’analyse de l’expression des gènes des cellules Caco-2 et les données cliniques des patientes montre des relations positives entre l’ ApoA-IV et le stade clinique ( p = 0,02) et la taille de la tumeur ( p = 0,03). Nous avons également trouvé que l’expression de l’ ApoA-IV est corrélée aux pourcentages de F.prausnitzii et R.intestinalis des patientes ( p = 0,03 et 0,04). Conclusion L’eau fécale des patientes atteintes de cancer du sein est capable de modifier l’expression de certains gènes impliqués dans le métabolisme intestinal des lipides et des lipoprotéines. Les modifications de l’expression de l’ ApoA-IV sont liées aux données cliniques et au microbiote intestinal de patientes. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the effectiveness of a black light lens as visual aid in composite restoration removal. Lost tooth structure, residual composite, and removal time were compared for operators with different levels of experience. Methods: Occlusal preparations in 24 matched‐pair extracted molars were etched, bonded, restored with composite, and thermocycled. The restored teeth were radiographed and two faculty and two student doctors removed the restorations with or without a black light lens while time was recorded. Digital scans of the cavity before and after restoration removal were used to calculate lost tooth structure and residual composite. Results: Removal of restorations resulted in tooth structure loss and left residual composite. The use of the black light lens had no significant effect (two‐way ANOVA; p value >0.05). However, operator experience significantly affected operating times and average depth of tooth structure loss (two‐way ANOVA; p value <0.05). Student doctors assisted by the black light lost less tooth structure than experienced operators and improved their operating times (multiple comparisons; p value <0.05). Conclusions: The black light lens did not conserve tooth structure or avoid composite remnants compared to routine operation, nor affected the operating time. However, less‐experienced operators did benefit from the black light in conserving tooth structure and time. Clinical Significance: Replacement of defective composite restorations is a regular practice in restorative dentistry. When existing composite restorations are removed, loss of tooth structure is unavoidable. A black light lens might improve the ability of operators with less experience to conserve tooth structure even though it did not provide benefits for the experienced operators. [ABSTRACT FROM AUTHOR]

Introduction et but de l’étude Le cancer du sein est le cancer le plus fréquent chez la femme et le surpoids est un facteur de risque reconnu. Par ailleurs, de très nombreuses études suggèrent que le microbiote intestinal joue un rôle important dans diverses situations physiopathologiques, notamment le cancer et l’obésité. Notre objectif est d’évaluer la relation entre la composition du microbiote et les caractéristiques clinico-biologiques de patientes atteintes de cancer du sein précoce. Matériel et méthodes Les données clinicobiologiques et les fèces de 32 patientes atteintes de cancer du sein précoce (moyenne d’âge 61,8 ans, 80 % ménopausées) ont été collectées. L’ADN bactérien fécal a été amplifié par PCR, en ciblant les gènes spécifiques 16S des ARNm de: Bacteroidetes, Firmicutes, Lactobacillales, Coriobacteriaceae, Bifidobacterium sp., Escherichia/Shigella sp., Blautia sp., Clostridum coccoides cluster, Clostridium leptum clus ter , Roseburia intestinalis cluster, Eggerthella lenta cluster et Fae-calibacterium prausnitzii. Les expressions des gènes sont comparées, en fonction du stade clinique des patientes mais également de leur Indice de Masse Corporel (IMC). Résultats et Analyse statistique Les patientes souffrent de carcinome canalaire infiltrant (81 %) et lobulaire infiltrant (19 %), avec un grade histopronostique majoritairement II (62,5 % grade II vs 15,6 % grade I et 21,9 % grade III, respectivement). Les patientes présentent des stades TNM 0 (n =15), I (n =7), II (n =8) et III (n =2). La surexpression tumorale des récepteurs hormonaux est confirmée pour plus de 80 % des sujets ; 15 % surexpriment HER2. L’IMC moyen est de 24,4 kg/m 2 [min-max: 18,5–36,5 kg/m 2 ], avec 28,1 % et 12,5 % des patientes en surpoids et/ou obèses, respectivement. Aucune différence du nombre de bactéries totales et de la plupart des groupes bactériens étudiés est observée, quelles que soient les caractéristiques clinico-biologiques considérées. Seul le nombre de Blautia sp. est augmenté de façon significative chez les patientes de grade III (10,6 ± 0,2 log copies. g -1 , n =7) comparativement au grade I (10,2 ± 0,2, n =5, p =0,029). Par ailleurs, des proportions significativement augmentées de F prausnitzii, Blautia sp et E lenta cluster sont mises en évidence entre ces 2 groupes de patientes, ainsi qu’avec les patientes présentant un stade clinique II et III (n =10) comparativement au stade clinique 0 (n =15). De plus, des augmentations significatives des proportions de Bifidobacterium sp et des bactéries C coccoides cluster sont observées (p < 0,05) chez les patientes présentant un carcinome lobulaire infiltrant (n =26), comparativement au carcinome canalaire infiltrant (n =6) (2,5 ± 5,7 vs 0,2 ± 0,3% et 32,9 ± 23,5 vs 21,4 ± 8,6%, respectivement). Conclusion Notre étude met en évidence une différence de composition du microbiote intestinal selon les caractéristiques cliniques des patientes atteintes de cancer du sein précoce. Ces résultats préliminaires nécessitent d’être confirmés, et ouvrent un champ d’exploration vers de nouvelles études visant à clarifier le lien entre le cancer du sein et microbiote intestinal. [ABSTRACT FROM AUTHOR]

New Experiments With Spheres-Gas (NEWS-G) is a direct dark matter detection experiment using Spherical Proportional Counters (SPCs) with light noble gases to search for low-mass Weakly Interacting Massive Particles (WIMPs). We report the results from the first physics run taken at the Laboratoire Souterrain de Modane (LSM) with SEDINE, a 60 cm diameter prototype SPC operated with a mixture of Ne + CH 4 (0.7%) at 3.1 bars for a total exposure of 9.6 kg · days. New constraints are set on the spin-independent WIMP-nucleon scattering cross-section in the sub-GeV/c 2 mass region. We exclude cross-sections above 4.4 × 10 − 37 cm 2 at 90% confidence level (C.L.) for a 0.5 GeV/c 2 WIMP. The competitive results obtained with SEDINE are promising for the next phase of the NEWS-G experiment: a 140 cm diameter SPC to be installed at SNOLAB by summer 2018. [ABSTRACT FROM AUTHOR]

Highlights: [•] RNA-Seq reveals global expression profile of genes in cochlear sensory epithelium. [•] RNA-Seq data are consistent with qRT-PCR data. [•] Acoustic trauma induces a widespread change in gene expression. [•] Complement pathway is implicated in cochlear responses to acoustic trauma. [ABSTRACT FROM AUTHOR]

Background: Left ventricular assist devices (LVADs) implanted in patients with severe congestive heart failure (CHF) as a bridge to transplantation have been shown to reverse chamber enlargement, regress cellular hypertrophy, and increase contractility. The purpose of this study was to gain a better understanding of the molecular changes associated with increased contractility after LVAD support.Methods: We took tissue sections from the left ventricular apex of 12 patients with CHF who were undergoing LVAD insertion (pre-LVAD) and from the LV free wall of those same patients before transplantation (post-LVAD). To control for sample-site differences, we obtained samples from the same regions in 7 patients with CHF who were undergoing transplantation without LVAD support and in 4 non- failing donor hearts. Gene expression was then probed on a custom DNA array containing 2,700 cardiac-enriched cDNA clones.Results: Calcium-handling genes were up-regulated by LVAD support, as previously reported. Sarcomeric genes were the other principle class of genes up-regulated by LVAD support, consistent with a possible restoration of sarcomere structure in reverse ventricular remodeling. However, a decrease in the fibrous component of the myocardium, also potentially involved in reverse remodeling, was not evident at the level of gene transcription because fibroblast markers were either unchanged or up-regulated. The remaining regulated genes did not fall into any defined functional class.Conclusions: Changes in the regulation of sarcomeric, calcium-handling, and fibroblast genes during LVAD support indicate a cardiac molecular adaptation to mechanical unloading. These molecular changes may play a role in the observed increase in contractile function during reverse remodeling. [Copyright &y& Elsevier]

Background: Metagenomic next-generation sequencing (NGS) of cerebrospinal fluid (CSF) has the potential to identify a broad range of pathogens in a single test.Methods: In a 1-year, multicenter, prospective study, we investigated the usefulness of metagenomic NGS of CSF for the diagnosis of infectious meningitis and encephalitis in hospitalized patients. All positive tests for pathogens on metagenomic NGS were confirmed by orthogonal laboratory testing. Physician feedback was elicited by teleconferences with a clinical microbial sequencing board and by surveys. Clinical effect was evaluated by retrospective chart review.Results: We enrolled 204 pediatric and adult patients at eight hospitals. Patients were severely ill: 48.5% had been admitted to the intensive care unit, and the 30-day mortality among all study patients was 11.3%. A total of 58 infections of the nervous system were diagnosed in 57 patients (27.9%). Among these 58 infections, metagenomic NGS identified 13 (22%) that were not identified by clinical testing at the source hospital. Among the remaining 45 infections (78%), metagenomic NGS made concurrent diagnoses in 19. Of the 26 infections not identified by metagenomic NGS, 11 were diagnosed by serologic testing only, 7 were diagnosed from tissue samples other than CSF, and 8 were negative on metagenomic NGS owing to low titers of pathogens in CSF. A total of 8 of 13 diagnoses made solely by metagenomic NGS had a likely clinical effect, with 7 of 13 guiding treatment.Conclusions: Routine microbiologic testing is often insufficient to detect all neuroinvasive pathogens. In this study, metagenomic NGS of CSF obtained from patients with meningitis or encephalitis improved diagnosis of neurologic infections and provided actionable information in some cases. (Funded by the National Institutes of Health and others; PDAID ClinicalTrials.gov number, NCT02910037.). [ABSTRACT FROM AUTHOR]

Trimethyl bismuth (TMBi) is a “heavy” transparent and dielectric organometallic liquid. This paper focuses on the measurement of TMBi’s optical properties relevant for particle detection. We measured the TMBi transmission curve and refraction index versus wavelength, as well as the light production yield and the timing performance on a small size cell. [ABSTRACT FROM PUBLISHER]

The CaLIPSO project focuses on the development of an innovative energetic-photon detector. The detector uses a “heavy” organometallic liquid: the TriMethyl Bismuth (TMBi), 82% by weight of Bismuth. TMBi efficiently converts through the photo-electric effect photons of energies below 1 MeV. The ionisation signal and light produced in the liquid are both detected. Beyond the measurement of gamma photon energies, this detector will allow locating photon interactions in the detector in three dimensions down to 1~\mm^3 and a sub nanosecond timing accuracy. All these desirable properties can be obtained simultaneously with liquid TMBi detector. [ABSTRACT FROM PUBLISHER]

Background: To assess consumers' acceptance of a new fibre, it is essential to evaluate its digestive tolerance after ingestion. We aimed to determine the tolerance of increasing dosages of Promitor™ Soluble Gluco Fibre (SGF; Tate&Lyle, Hoffman Estates, IL, USA) up to 70 g fibre per day using a validated gastrointestinal composite score. Methods: A composite score of gastrointestinal tolerance integrating gastrointestinal symptoms, stool frequency and consistency was applied. To statistically validate this composite score, the gastrointestinal tolerance of inulin (10 g versus 20 g containing, respectively, 9 g versus 18 g of fibre) was assessed in 18 healthy volunteers in a randomised double-blind placebo-controlled cross-over study. Second, in a double-blind placebo-controlled cross-over study with 20 healthy volunteers, the gastrointestinal tolerance of SGF in both acute and 'spread over the day' conditions of consumption was assessed. Results: By contrast to 10 g, 20 g of inulin demonstrated a significant difference in composite score compared to placebo [ P < 0.001, difference = 7.6; 95% confidence interval (CI) = 3.8-11.3]. These values were considered as reference during the second study. In acute conditions, 40 g of SGF fibre was the highest (threshold) dose tested that indicates the digestive tolerance criteria (difference from placebo on the composite score <7.6 and upper limit of the 95% CI <11.3); this is twice the amount tolerated for inulin. In 'spread over the day' conditions, 65 g of SGF fibre was the threshold dose ( P < 0.001, difference = 6.5; 95% CI = 3.4-9.5). Conclusions: The results of the present study demonstrate that 40 g of SGF fibre, when consumed as a single dose, and 65 g of SGF fibre, when consumed in multiple-doses, across the day are well-tolerated by healthy volunteers. [ABSTRACT FROM AUTHOR]

A mutation in the LMNA gene is responsible for the most dramatic form of premature aging, Hutchinson-Gilford progeria syndrome (HGPS). Several recent studies have suggested that protein products of this gene might have a role in normal physiological cellular senescence. To explore further LMNA's possible role in normal aging, we genotyped 16 SNPs over a span of 75.4 kb of the LMNA gene on a sample of long-lived individuals (LLI) (US Caucasians with age ≥ 95 years, N = 873) and genetically matched younger controls ( N = 443). We tested all common nonredundant haplotypes (frequency ≥ 0.05) based on subgroups of these 16 SNPs for association with longevity. The most significant haplotype, based on four SNPs, remained significant after adjustment for multiple testing (OR = 1.56, P = 2.5 × 10−5, multiple-testing-adjusted P = 0.0045). To attempt to replicate these results, we genotyped 3619 subjects from four independent samples of LLI and control subjects from (i) the New England Centenarian Study (NECS) ( N = 738), (ii) the Southern Italian Centenarian Study (SICS) ( N = 905), (iii) France ( N = 1103), and (iv) the Einstein Ashkenazi Longevity Study ( N = 702). We replicated the association with the most significant haplotype from our initial analysis in the NECS sample (OR = 1.60, P = 0.0023), but not in the other three samples ( P > 0.15). In a meta-analysis combining all five samples, the best haplotype remained significantly associated with longevity after adjustment for multiple testing in the initial and follow-up samples (OR = 1.18, P = 7.5 × 10−4, multiple-testing-adjusted P = 0.037). These results suggest that LMNA variants may play a role in human lifespan. [ABSTRACT FROM AUTHOR]

Interleukin-21 (IL-21) has been recently shown to modulate the growth of specific types of B-cell neoplasm. Here, we studied the biological effects of IL-21 in mantle cell lymphoma (MCL). All MCL cell lines and tumors examined expressed the IL-21 receptor. Addition of recombinant IL-21 (rIL-21) in vitro effectively induced STAT1 activation and apoptosis in MCL cells. As STAT1 is known to have tumor-suppressor functions, we hypothesized that STAT1 is important in mediating IL-21-induced apoptosis in MCL cells. In support of this hypothesis, inhibition of STAT1 expression using siRNA significantly decreased the apoptotic responses induced by IL-21. To further investigate the mechanism of IL-21-mediated apoptosis, we employed oligonucleotide arrays to evaluate changes in the expression of apoptosis-related genes induced by rIL-21; rIL-21 significantly upregulated three proapoptotic proteins (BIK, NIP3 and HARAKIRI) and downregulated two antiapoptotic proteins (BCL-2 and BCL-XL/S) as well as tumor necrosis factor-α. Using an ELISA-based assay, we demonstrated that rIL-21 significantly decreased the DNA binding of nuclear factor-κB, a transcriptional factor known to be a survival signal for MCL cells. To conclude, IL-21 can effectively induce apoptosis in MCL via a STAT1-dependent pathway. Further understanding of IL-21-mediated apoptosis in MCL may be useful in designing novel therapeutic approaches for this disease. [ABSTRACT FROM AUTHOR]

Purpose: The European Radiobiology Archives (ERA), together with corresponding Japanese and American databases, hold data from nearly all experimental animal radiation biology studies carried out between 1960 and 1998, involving more than 300,000 animals. The Federal Office for Radiation Protection, together with the University of Cambridge have undertaken to transfer the existing ERA archive to a web-based database to maximize its usefulness to the scientific community and bring data coding and structure of this legacy database into congruence with currently accepted semantic standards for anatomy and pathology. Methods: The accuracy of the primary data input was assessed and improved. The original rodent pathology nomenclature was recoded to replace the local 'DIS-ROD' (Disease Rodent) formalism with Mouse Pathology (MPATH) and Mouse Anatomy (MA) ontology terms. A pathology panel sampled histopathological slide material and compared the original diagnoses with currently accepted diagnostic criteria. Results: The overall non-systematic error rate varied among the studies between 0.26% and 4.41%, the mean error being 1.71%. The errors found have been corrected and the studies thus controlled have been annotated. The majority of the original pathology terms have been successfully translated into a combination of MPATH and MA ontology terms. Conclusions: ERA has the potential of becoming a world-wide radiobiological research tool for numerous applications, such as the re-analysis of existing data with new approaches in the light of new hypotheses and techniques, and using the database as an information resource for planning future animal studies. When the database is opened for new data it may be possible to offer long-term storage of data from recent and future animal studies. [ABSTRACT FROM AUTHOR]

Selon le CIRC, plus de 10 % des cancers seraient liés à une alimentation déséquilibrée et un surpoids. La localisation mammaire est la plus fréquente chez la femme et concerne chaque année, en France, près de 50 000 patientes. Notre étude a pour objectif de clarifier le rôle des acides gras oméga 3 sur la sévérité de la pathologie mammaire, selon la nature des lipoprotéines qui les transportent. L'étude a été réalisée chez des patientes atteintes de pathologie mammaire cancéreuse (n = 100, CRB-Tumorothèque -ICO) se différenciant par leur index de prolifération (KI67 < 20 % ou Prolif- et KI67 > 30 % ou Prolif +). Les caractéristiques clinicobiologiques des patientes ont été collectées. Apolipoprotéines et acides gras oméga3 sériques ont été quantifiés par LC-MS/MS après séparation des lipoprotéines contenant l'apo B (LpB) ou ne la contenant pas (LpA). Les critères principaux de l'étude ont fait l'objet d'une analyse univariée par régression logistique sur les 2 groupes de patientes, exprimés en mediane [25è–75è, OR [5è–95è. Les patientes sont majoritairement atteintes de Carcinome Infiltrant de Type Non Spécifique ou CITNS (98 %), le groupe Prolif- étant significativement plus âgé (63,8 ans [43–79] vs 55,4 ans [27–82]; p < 0.001, T student, moyenne [min–max]), sans différence d'IMC. Les caractéristiques carcinologiques des 2 groupes diffèrent avec 100 % de tumeurs Recepteurs Hormonaux+ (RH +) pour Prolif−, et plus de 30 % de tumeurs triple négatives (RH− et HER2−) pour Prolif+. Les concentrations sériques d'EPA sont identiques dans les 2 cohortes Prolif− vs + (1,07 [0,84–1,41] vs 1,02 [0,77–1,40], OR 1,2 [0,71–2,02], mais différent selon les lipoparticules qui les transportent. Ainsi, le ratio entre l'EPA contenu dans les lipoparticules LpB et les lipoparticules LpA (EPA LpB/EPA LpA) est significativement plus élevé dans le groupe Prolif− vs + (0,1[0,05–0,2] vs 0,05[0,02–0,008], OR < 0,001[<0,001–0,005], p < 0,001). Ceci s'explique principalement par un « enrichissement » en EPA dans les LpB de la cohorte Prolif−, avec une augmentation significative du ratio molaire EPA/apoB dans les LpB: 0,05[0,02–0,09] vs 0,03[0,01–0,05], OR < 0,001 [<0,001–0,02], p < 0,01), respectivement pour Prolif− et Prolif+, sans modification du ratio molaire EPA/apoAI dans les LpA. Aucune différence significative entre les 2 cohortes concernant les concentrations de DHA n'est observée. Les taux sériques d'EPA des lipoparticules contenant l'apolipoprotéine B (VLDL et LDL) varient selon la sévérité de la pathologie cancéreuse mammaire avec des taux plus élevés dans les situations les moins péjoratives. Cette étude préliminaire suggère donc un effet protecteur spécifique de certains AG oméga3 transportés par des lipoparticules spécifiques. Une confirmation de ces observations cliniques est envisagée à travers une approche mécanistique in vitro. [ABSTRACT FROM AUTHOR]

OBJECTIVE:: To explore metabolic and cellular modifications induced during childhood obesity, in a novel animal model of obese mini-piglets. DESIGN:: A total of 10 four-month old Yucatan mini-pigs were followed from prepuberty to adulthood. Animals were divided into two groups. The first one had been overfed (OF) a western-type diet and the second one had been normally fed a control recommended human-type diet (NF). MEASUREMENTS:: Plasma insulin-like growth factor 1 (IGF-1), insulin, leptin, nonesterified fatty acids, triglycerides (TGs) and glucose were determined at sexual maturity and at young adulthood. Quantitative gene expressions of peroxysome-proliferator-activated receptors (PPARs), glucose transporter 4, insulin receptor, IGF-1, leptin and interleukin-6 (IL-6) in skeletal muscle, adipose tissue and liver were also measured at both stages. Adult insulin sensitivity was measured via euglycaemic-hyperinsulinaemic clamps. RESULTS:: Increased body weight in adult OF pigs was associated with increased body size and low insulin sensitivity. Sexually mature OF pigs had higher IGF-1 plasma concentrations than their lean littermates (P<0.05). In the OF group, TGs and glucose were both decreased (P<0.05). Muscle PPAR?andain OF pubescent pigs as compared to NF pigs were 11 times higher and 20 times lower, respectively (P<0.01). CONCLUSION:: Obesity and insulin resistance induced by overfeeding mini-pigs during development and puberty were not associated with the cluster of metabolic modifications frequently observed in their adult littermates. Increased IGF-1 concentrations and modifications of skeletal muscle PPAR (aand?) expressions may help the young obese pig to partially regulate its glycaemia and triglyceridaemia through an increase of fat mass, which maintains its high insulin sensitivity.International Journal of Obesity (2005) 29, 324-333. doi:10.1038/sj.ijo.0802823 Published online 11 January 2005 [ABSTRACT FROM AUTHOR]

BACKGROUNDS AND AIMS:: Insulin resistance related to obesity and diabetes is characterized by an increase in plasma TG-rich lipoprotein concentrations. Apolipoprotein (apo) E plays a crucial role in the metabolism of these lipoproteins and particularly in the hepatic clearance of their remnants. The aim of this study was to explore apoE kinetics of obese subjects and to determine what parameters could influence its metabolism. METHODS:: Using stable-isotope labelling technique ([2H3]-leucine-primed constant infusion) and monocompartmental model (SAAM II computer software), we have studied the plasma kinetics of very-low-density lipoprotein (VLDL) and high-density lipoprotein (HDL) apoE in 12 obese subjects (body mass index (BMI) 27.4–36.6 kg/m2): Seven were type 2 diabetics (age 47–65 y; HbA1c 7.1–10.2%) and five were non-diabetics (age 40–51 y, HbA1c: 4.9–5.3%). Six of the diabetic subjects were insulin resistant as assessed by insulin sensitivity index (HOMA 2.6–10.0), while non-diabetic subjects were all insulin sensitive (HOMA 1.2–2.1). RESULTS:: Plasma VLDL and HDL apoE concentrations were significantly higher in diabetic than in non-diabetic subjects (5.74±1.60 vs 1.46±1.74 mg/l, P<0.01 and 17.81±6.67 vs 9.97±3.32 mg/l, P<0.05). These increased levels were associated with significantly higher absolute production rate (APR) of VLDL and HDL apoE (0.714±0.343 vs 0.130±0.200 mg/kg/day, P<0.01, and 0.197±0.087 vs 0.080±0.060 mg/kg/day, P<0.05, respectively) while no significant difference was found for fractional catabolic rate (FCR) of VLDL and HDL apoE (3.44±1.64 vs 1.97±0.84/day and 0.30±0.12 vs 0.19±0.09/day, respectively). In the whole population, BMI was not correlated with any of apoE kinetic data. HOMA was positively correlated with FCR of VLDL apoE (r=0.64, P<0.05) and tended to be correlated with APR of VLDL... [ABSTRACT FROM AUTHOR]

BACKGROUND: Obesity is frequently associated with an increase in the early inflammation marker C-reactive protein (CRP), insulin resistance and changes in lipoprotein metabolism. Increased CRP is known as an independent cardiovascular risk factor. Since the apolipoproteins (apo) E and CIII components of HDL are associated with reduced cardiovascular risk and since apoE has in vitro anti-inflammatory effect, we have investigated the relationships between apoE, apoCIII (in apoB and non apoB containing lipoproteins) and CRP in obese adults. METHODS: The following parameters from 34 healthy obese fasting women (age 22-64y, body mass index (BMI) 2868kg/m²) were measured: (1) ApoE and apoCIII, in total plasma, in apoB-(E LpB, CIII LpB) and non-apoB-containing lipoproteins (E LpnonB, CIII LpnonB); (2) CRP and cytokine secreted by adipose tissue (TNF-α and its soluble receptor TNFR2); (3) triglyceride, HDL-cholesterol, systolic blood pressure, diastolic blood pressure, waist and hip circumferences, insulin, glucose. HOMA, a marker of insulin sensitivity, and the ratio E/CIII in LpB and LpnonB were calculated. RESULTS: CRP was positively correlated with BMI (P < 0.05), waist circumference (WC, P < 0.05), triglyceride (P< 0.05) and negatively correlated with apoE (P< 0.01) and E LpnonB (P < 0.05). Two multiple regression models including parameters related to CRP with a P < 0.25 were run stepwise to assess their independent contribution to CRP concentration. In the first model (including BMI, WC, HOMA, insulin, triglyceride, apoE, E LpnonB), apoE was the best predictor of CRP (P=0.01) together with triglyceride (P= 0.02) and BMI (P= 0.08). The second model took into account E/CIII LpnonB ratio with the parameters included in the first model. In this second model, E/CIII LpnonB was the best predictor of CRP (P=0.007), explaining 39% of CRP variance. CONCLUSION: ApoE is strongly correlated with CRP and could have an anti-inflammatory effect in vivo in obese... [ABSTRACT FROM AUTHOR]

Aims: To assess the association of hypertensive status and antihypertensive drug treatment with lipid and haemostatic levels in middle-aged men. Methods and results: Hypertensive status, antihypertensive drug treatment, total and high-density lipoprotein (HDL) cholesterol, triglyceride, apoproteins A-I and B, lipoparticles LpA-I, LpE:B and Lp(a), fibrinogen, plasminogen activator inhibitor-1 (PAI-1) activity and factor VII were assessed in a sample of men 50-59 years living in France (n = 7050) and Northern Ireland (n = 2374). After adjustment for age, body mass index, smoking status, educational level, country, alcohol drinking and hypolipidaemic drug treatment, untreated hypertensive subjects had higher levels of total cholesterol, triglyceride, apoproteins A-I and B and PAI-I activity than normotensive subjects. On univariate analysis, diuretics decreased total and HDL-cholesterol and apoproteins AI and B; those differences remained after multivariate adjustment. Treatment with beta-blockers decreased total and HDL-cholesterol, apoprotein A-I and LpA-I, and this effect remained after multivariate adjustment. Calcium channel blockers decreased total cholesterol and apoproteins A-I and B; those differences remained significant after multivariate adjustment. ACE inhibitors decreased total cholesterol, triglycerides, apoprotein B and LpE:B; and this effect remained after multivariate adjustment. Analysis of the subjects on monotherapy showed beta-blockers to decrease total cholesterol and HDL parameters and angiotersin-converting enzyme (ACE) inhibitors to decrease low-density lipoprotein (LDL)-related parameters, while no effect was found for the other antihypertensive drugs. Conclusions: Hypertensive status is associated with an unfavourable lipid and haemostatic profile in middle-aged men. Antihypertensive treatment with beta-blockers decreases HDL parameters, whereas treatment with ACE inhibitors appears to decrease total cholesterol and LDL-related parameters. [ABSTRACT FROM AUTHOR]

CaLIPSO is an innovative photon detector concept designed for high precision brain PET imaging. For the first time, liquid trimethylbismuth is used as sensitive medium. The detector operates as a time-projection chamber and detects both Cherenkov light and charge signal. Indeed, each 511-keV photon releases a single primary electron that triggers a Cherenkov radiation and ionizes the medium. As trimethylbismuth has never been studied before, we measured its free ion yield defined as the number of electron–ion pairs released by the primary electron. To this end, we developed a low-noise measuring system to determine the weak current induced by a 60Co source in the liquid with an accuracy better than 5 fA for an electric field up to 7 kV/cm. We used tetramethylsilane as benchmark liquid to validate the apparatus and we measured a zero-field free ion yield of 0.53 ＋/−0.03 in agreement with literature. However, we found a zero-field free ion yield of 0.083 ＋/−0.003 for trimethylbismuth, which is a factor 7 lower than the typical values for similar dielectric liquids. Quantum chemistry computations on heavy atoms tend to demonstrate the high ability of trimethylbismuth to capture electrons, which could explain this weak value. This recombination mechanism marks a new step in understanding charge transport in liquid detectors. Finally, to verify the detectability of individual charge pulses, we developed a charge pulse measurement system which has been successfully validated with TMSi. Measurements with TMBi are ongoing. [ABSTRACT FROM AUTHOR]

FcRn mediates recycling and transcytosis of IgG and albumin in various cell types. The MHC-class-I-like protein of the FcRn heterodimer is encoded by FCGRT. Few determinants of variable FCGRT expression in humans have been identified so far. In this study, we investigated the presence of DNA methylation in regulatory regions of FCGRT in samples of human liver and myocardium tissue, and we examined the impact of FCGRT methylation on FcRn expression in model cell lines. Quantitative DNA methylation analysis of the FCGRT locus revealed differentially methylated regions in DNA from liver and myocardium. Methylation status in individual CpG sites correlated with FCGRT mRNA expression. Data from model cell lines suggest that differential methylation in the −1058 to −587 bp regulatory region of FCGRT contributes to FcRn expression. Chromatin immunoprecipitation assays indicate that CpG site methylation impacts the binding of the methylation sensitive transcription factors Zbtb7a and Sp1. This study provides a foundation to further define the contribution of epigenetic factors during the control of FcRn expression and IgG traffic in human tissues. [ABSTRACT FROM AUTHOR]

Introduction et but de l’étude Le syndrome métabolique est associé chez les femmes ménopausées à une augmentation du risque de cancer du sein. Les habitudes alimentaires peuvent être la cause de la survenue de ce syndrome. Notre objectif est d’analyser les habitudes alimentaires de patientes nouvellement diagnostiquées pour leur cancer du sein en lien avec la présence d’un syndrome métabolique (NCEP-ATPIII) et leur statut ménopausique. Matériel et méthodes Les habitudes alimentaires sur 3 jours de patientes (n = 98), récemment diagnostiquées pour leur cancer du sein non métastatique hormonodépendant, ont été analysées (logiciel Nutrilog©) avant leur chirurgie. Les apports nutritionnels de base (énergétique, protidique, lipidique, glucidique) ainsi que de différents nutriments ont été analysés en lien avec la présence du syndrome métabolique (SM + /SM-) et le statut ménopausique des patientes (M + /M − ). Résultats et Analyse statistique La population étudiée (moyenne d’âge de 59,2 ± 12,6 ans) est majoritairement ménopau-sée (66 %). Les patientes ont un bon état général (PS = 0 > 90%). La prévalence du syndrome métabolique (SM + ) est de l’ordre de 30 % . La quasi-totalité des sujets SM + est ménopausée (90 %). Le taux de réponse aux questionnaires alimentaires est de 94 % . Cependant, seuls 56 questionnaires répondent aux critères de validité des enquêtes alimentaires (apport énergétique/métabolisme basal > 1,35). Le statut SM semble interagir avec la réponse aux questionnaires alimentaires : 44 % des questionnaires non validés ont été renseignés par des patientes SM + . L’apport énergétique total moyen de la population étudiée est de 2113,4 ± 331 kcal/j (n =56 questionnaires). Les glucides représentent 44,8 % de l’apport énergétique total (AET) ; les protides 17,4 % de l’AET et les lipides 37,9 % de l’AET. Ces paramètres ne diffèrent pas entre les sous populations SM + /SM-et M + /M-. L’apport moyen en acides gras saturés de 31,7 ± 11,1 g/j (soit 44,7 % des AGT et 13,9 % de l’AET), en acides gras mono insaturés de 27,3 ± 9,7 g/j (soit 37,7 % des AGT et 12 % de l’AET) et en acides gras polyinsaturés de 12,3 ± 5,8 g/j (soit 17,2 % des AGT et 5,4 % de l’AET). L’apport en acides gras monoinsaturés des patientes SM + est significativement plus élevé que celui des patientes SM - (33,4 ± 12,2 g/j vs 24,6 ± 7,1g/j, respectivement). Conclusion Les habitudes alimentaires de la population étudiée mettent en évidence une alimentation hypoglucidique, hyperprotidique et légèrement hyperlipidique, par rapport aux apports nutritionnels conseillés. Ces apports nutritionnels ne diffèrent pas selon le statut SM et M, à l’exception d’un apport accru en acides gras monoinsaturés chez les patientes SM + . Il semble que la présence d’un syndrome métabolique impacte sur la qualité des enquêtes alimentaires. Concernant les minéraux, outre un apport excessif en sodium, les apports sont en adéquation avec les recommandations nutritionnelles, notamment avec un apport de calcium accru chez les patientes M + [ABSTRACT FROM AUTHOR]

Inbred male mice typically prefer to mate with females of a different, non-self H-2 haplotype. To determine whether this natural preference is irrevocable or results from familial imprinting, a test system was used which relied on previous observations that B6 males (H-2b) mate preferentially with congenic B6-H-2k rather than B6 females, and B6-H-22k males with B6 females. Ihis preference was reversed in B6 males fostered by B6-H-2k parents and in B6-H-2k males fostered by B6 parents, preference in these cases favoring the same H-2 type. IThus, H-2 selective mating preference is acquired by imprinting on familial H-2 types. [ABSTRACT FROM AUTHOR]