Intraclonal heterogeneity and distinct molecular mechanisms characterize the development of t(4;14) and t(11;14) myeloma.

We have used whole exome sequencing to compare a group of presentation t(4;14) with t(11;14) cases of myeloma to define the mutational landscape. Each case was characterized by a median of 24.5 exonic nonsynonymous single-nucleotide variations, and there was a consistently higher number of mutations in the t(4;14) group, but this number did not reach statistical significance. We show that the transition and transversion rates in the 2 subgroups are similar, suggesting that there was no specific mechanism leading to mutation differentiating the 2 groups. Only 3% of mutations were seen in both groups, and recurrently mutated genes include NRAS, KRAS, BRAF, and DIS3 as well as DNAH5, a member of the axonemal dynein family. The pattern of mutation in each group was distinct, with the t(4;14) group being characterized by deregulation of chromatin organization, actin filament, and microfilament movement. Recurrent RAS pathway mutations identified subclonal heterogeneity at a mutational level in both groups, with mutations being present as either dominant or minor subclones. The presence of subclonal diversity was confirmed at a single-cell level using other tumor-acquired mutations. These results are consistent with a distinct molecular pathogenesis underlying each subgroup and have important impacts on targeted treatment strategies. The Medical Research Council Myeloma IX trial is registered under ISRCTN68454111.

The Relationship between Materialistic Aspirations and Distinct Aspects of Psychological Well-being in a UK sample

The purpose of this research is to gain a deeper understanding of how materialistic aspirations are related to distinct aspects of psychological well-being. Research has consistently found a negative relationship between materialistic goals and well-being, but a review of the literature identified that the measures of well- being used in the majority of studies were measures of what Keyes (2002) describes as “subjective well-being” or “hedonic happiness”. Criticisms of these types of measures are that they fixate too much on the momentary experience of pleasure and don’t take into account what is meaningful and or what contributes to long lasting fulfilment. Very little research was found investigating the impact of materialism on “eudaimonic” well-being, which is found through doing what is worthwhile and realising ones potential and has been found to have a longer lasting impact on overall well-being (Huta & Ryan, 2010). To address this gap in the literature, a convenience sample of 113 adult subjects in the UK were recruited through Facebook and asked to respond to the Aspiration Index and the Psychological wellbeing scale. The relative importance placed on extrinsic (materialistic) and intrinsic aspirations was compared to the six dimensions of psychological well-being. In line with previous research, higher importance placed on materialistic aspirations for wealth, status and image were found to be negatively correlated with all aspects of psychological well-being. However, the strongest and only statistically significant negative correlation was between extrinsic aspirations and positive relations with others (r = -.256, p< 0.01). Positive relationships with other people form a central component of many theories of well- being and so this negative relationship may help to explain why materialistic aspirations are so consistently found to be negatively correlated to a variety of measures of well-being. Further research is needed to explore this relationship as no causation could be inferred.

Phocid seal leptin: tertiary structure and hydrophobic receptor binding site preservation during distinct leptin gene evolution

The cytokine hormone leptin is a key signalling molecule in many pathways that control physiological functions. Although leptin demonstrates structural conservation in mammals, there is evidence of positive selection in primates, lagomorphs and chiropterans. We previously reported that the leptin genes of the grey and harbour seals (phocids) have significantly diverged from other mammals. Therefore we further investigated the diversification of leptin in phocids, other marine mammals and terrestrial taxa by sequencing the leptin genes of representative species. Phylogenetic reconstruction revealed that leptin diversification was pronounced within the phocid seals with a high dN/dS ratio of 2.8, indicating positive selection. We found significant evidence of positive selection along the branch leading to the phocids, within the phocid clade, but not over the dataset as a whole. Structural predictions indicate that the individual residues under selection are away from the leptin receptor (LEPR) binding site. Predictions of the surface electrostatic potential indicate that phocid seal leptin is notably different to other mammalian leptins, including the otariids. Cloning the grey seal leptin binding domain of LEPR confirmed that this was structurally conserved. These data, viewed in toto, support a hypothesis that phocid leptin divergence is unlikely to have arisen by random mutation. Based upon these phylogenetic and structural assessments, and considering the comparative physiology and varying life histories among species, we postulate that the unique phocid diving behaviour has produced this selection pressure. The Phocidae includes some of the deepest diving species, yet have the least modified lung structure to cope with pressure and volume changes experienced at depth. Therefore, greater surfactant production is required to facilitate rapid lung re-inflation upon surfacing, while maintaining patent airways. We suggest that this additional surfactant requirement is met by the leptin pulmonary surfactant production pathway which normally appears only to function in the mammalian foetus.

Mafic and felsic plutonism in the Elvas region (SW Iberia, Portugal): two distinct Nd isotope sources and geodynamics

The occurrence of mafic (mainly gabbros and diorites) and felsic (syenites and granites) rocks, in close spatial association, in the Elvas region, at the northern part of the Ossa-Morena Zone, could be interpreted as a single bimodal (alkaline) plutonic complex. However, in spite of scarce isotopic (Sm-Nd) data, the co-magmatic origin of both rock groups (mafic and felsic) has already been questioned [1]. Based on the mineral chemistry of primary clinopyroxenes (Di–Hd, %En: 45.5 – 27.2) and representative whole-rock analyses, gabbros and diorites of the Elvas massif show a transitional character between alkaline and non-alkaline fields and wide compositions: SiO2 (42.47 – 58.00 wt%); TiO2 (0.24 – 1.68 wt%); Y/Nb (4.0 – 10.7); Th (0.1 – 6.8 ppm); Zr (18.6 – 576.9 ppm). The felsic group is composed by highly differentiated rocks which correspond to distinct levels of silica saturation and alkalinity. Peralkaline syenites usually present sodic (riebeckite) and sodic-calcic (aegirine-augite, ferrowinchite) inosilicates and reveal quite variable compositions: SiO2 (57.50 – 72.07 wt%); TiO2 (0.10 – 1.45 wt%); Th (1.7 – 67.0 ppm); Zr (133.0 – 4800.0 ppm). The alkaline granites show hedenbergite as the characteristic inosilicate, presenting relatively common compositions: SiO2 (61.85 – 78.06 wt%); TiO2 (0.21 – 0.58 wt%); Th (11.8 – 38.4 ppm); Zr (317.3 – 1234.6 ppm) [2]. Recent Sm-Nd isotopic results, on a total of 18 whole-rock samples (6 mafites and 12 felsites), allow new and more consistent interpretation concerning the petrogenesis of these plutonic rocks. Assuming an age of 490 Ma [3], the felsic rocks provide (0.6 < Nd490 < 4.3), similar to other contemporary (per)alkaline rocks of this region [4], reflecting magmatic extractions from time-integrated depleted mantle sources followed by variable and incomplete mixing (and/or AFC-type) processes with enriched, probably crustal sources. This alkaline/peralkaline magmatism is thought to represent the main regional record of the rifting event which presumably led to the opening of the Rheic Ocean. On the other hand, the mafic plutonic rocks of the Elvas massif cannot represent the magmatic precursors of these syenites and granites as they show completely distinct Nd isotopic ratios (3.7 < Nd490 < 1.2) indicating important contribution of long-term enriched (crustal) sources. Instead, considering the age and the Nd isotopic signature of other mafic plutonic unit emplaced nearby (the Campo Maior massif: ca. 370 Ma; 6.0 < Nd370 < 5.2) [5], and recalculating the isotopic ratios of the Elvas massif for the same age (4.3 < Nd370 < 1.6), it is plausible to consider that these plutons (Campo Maior and Elvas) can be coeval and representative of the Variscan magmatism in this region. In such hypothesis, the differences between these isotopic values could be explained, on a time-integrated basis, either by magmatic sources for the Elvas massif less enriched in LREE than the sources involved in the Campo Maior massif, or, if both plutonites share similar depleted mantle sources, by magmatic differentiation paths considerably affected by crustal contamination processes, which reached higher degrees in the Campo Maior massif.

GENETIC EVALUATION OF SEED TRAITS FROM INTRASPECIFIC CROSSING OF GENETICALLY DISTINCT WATERMELON VARIETIES

Citrullus lanatus (Thunb.) Matsumura and Nakai (Cucurbitaceae) is an important cucurbit crop worldwide. Global production of watermelon is about 90 million metric tonnes per annum, making it among the top five most consumed fresh fruits. The objective of this study was to evaluate seed variability in different segregating populations, and determine heritability of traits of watermelon. Interspecific crosses were made between two cultivars of C. lanatus (Bebu and Wlêwlê Small Seeds (WSS) were performed at Research Station of Nangui Abrogoua University in Abidjan, Côte d’Ivoire. There was wide variability between parental, F1, BC1 (first generation of back-crossing) and F2 seeds. Seeds of all hybrid populations were intermediate versus those of the parents. Also, crossing did not affect F1 and F2 seed characters, but affected those of BC1 because of maternal effects. Thus, back-crossing on Bebu cultivar produced seeds which looked like those of Bebu; while back-crossing on WSS cultivar produced seeds similar to those of WSS. Principal Component Analysis (PCA) and individuals repartitioning revealed that Bebu and WSS cultivars were genetically distinct and showed three main groups: two groups from each parental line and one from a recombinant line (hybrids). F2 population had a wide individual’s dispersion, and contained seeds of all other populations. High heritability was observed for all evaluated characters.

Cell surface Glut1 levels distinguish human CD4 and CD8 T lymphocyte subsets with distinct effector functions

International audience

Distinct immune responses of juvenile and adult oysters (Crassostrea gigas) to viral and bacterial infections

Since 2008, massive mortality events of Pacific oysters (Crassostrea gigas) have been reported worldwide and these disease events are often associated with Ostreid herpesvirus type 1 (OsHV-1). Epidemiological field studies have also reported oyster age and other pathogens of the Vibrio genus are contributing factors to this syndrome. We undertook a controlled laboratory experiment to simultaneously investigate survival and immunological response of juvenile and adult C. gigas at different time-points post-infection with OsHV-1, Vibrio tasmaniensis LGP32 and V. aestuarianus. Our data corroborates epidemiological studies that juveniles are more susceptible to OsHV-1, whereas adults are more susceptible to Vibrio. We measured the expression of 102 immune-genes by high-throughput RT-qPCR, which revealed oysters have different transcriptional responses to OsHV-1 and Vibrio. The transcriptional response in the early stages of OsHV-1 infection involved genes related to apoptosis and the interferon-pathway. Transcriptional response to Vibrio infection involved antimicrobial peptides, heat shock proteins and galectins. Interestingly, oysters in the later stages of OsHV-1 infection had a transcriptional response that resembled an antibacterial response, which is suggestive of the oyster's microbiome causing secondary infections (dysbiosis-driven pathology). This study provides molecular evidence that oysters can mount distinct immune response to viral and bacterial pathogens and these responses differ depending on the age of the host.

Structural Aspects of the Distinct Biochemical Properties of Glutaredoxin 1 and Glutaredoxin 2 from Saccharomyces cerevisiae

Glutaredoxins (Grxs) are small (9-12 kDa) heat-stable proteins that are ubiquitously distributed. In Saccharomyces cerevisiae, seven Grx enzymes have been identified. Two of them (yGrx1 and yGrx2) are dithiolic, possessing a conserved Cys-Pro-Tyr-Cys motif. Here, we show that yGrx2 has a specific activity 15 times higher than that of yGrx1, although these two oxidoreductases share 64% identity and 85% similarity with respect to their amino acid sequences. Further characterization of the enzymatic activities through two-substrate kinetics analysis revealed that yGrx2 possesses a lower Km for glutathione and a higher turnover than yGrx1. To better comprehend these biochemical differences, the pK(a) of the N-terminal active-site cysteines (Cys27) of these two proteins and of the yGrx2-C30S mutant were determined. Since the pK(a) values of the yGrx1 and yGix2 Cys27 residues are very similar, these parameters cannot account for the difference observed between their specific activities. Therefore, crystal structures of yGrx2 in the oxidized form and with a glutathionyl mixed disulfide were determined at resolutions of 2.05 and 1.91 angstrom, respectively. Comparisons of yGrx2 structures with the recently determined structures of yGrx1 provided insights into their remarkable functional divergence. We hypothesize that the substitutions of Ser23 and Gln52 in yGrx1 by Ala23 and Glu52 in yGrx2 modify the capability of the active-site C-terminal cysteine to attack the mixed disulfide between the N-terminal active-site cysteine and the glutathione molecule. Mutagenesis studies supported this hypothesis. The observed structural and functional differences between yGrx1 and yGrx2 may reflect variations in substrate specificity. (C) 2008 Elsevier Ltd. All rights reserved.

Abdominal hyperalgesia in secretory phospholipase A(2)-induced rat pancreatitis: Distinct roles of NK1 receptors

We investigated the potential of secretory phospholipase A(2) (sPLA(2))-induced pancreatitis to promote abdominal hyperalgesia, as well as to depolarize sensory fibres in vitro using a grease-gap technique. Pancreatitis was induced by the injection of sPLA(2) from Crotalus durissus terrificus (sPLA(2) Cdt, 300 mu g kg(-1)) venom into the common bile duct of rats. Pancreatic inflammatory signs, serum amylase levels and abdominal hyperalgesia were evaluated in rats treated or not with SR140333, a tachykinin NK1 receptor antagonist. Injection of sPLA(2) Cdt caused pancreatic oedema formation and increased pancreatic neutrophil infiltration and serum amylase at 4 h, which returned to normality by 24 h, except for the neutrophil infiltration, which was still increased at this time point. Animals injected with sPLA(2) exhibited a lower withdrawal threshold to electronic von Frey stimulation in the upper abdominal region at 4 h, but not 24 h, post-injection when compared with saline-injected rats. Pre-treatment of animals with SR140333 significantly reduced the sPLA(2) Cdt-induced abdominal hyperalgesia, without affecting the other parameters. Neither sPLA(2) Cdt nor sPLA(2) from Naja mocambique mocambique venom depolarized capsaicin-sensitive sensory fibres from rat vagus nerve, but they decreased the propagated compound action potentials in both A and C fibres. These data show for the first time that NK1 receptors play an important role in the early abdominal hyperalgesia in a rat model of sPLA(2)-induced pancreatitis, suggesting that these receptors are of importance in the development of pain in the pancreatitis condition. We also provide evidence that sPLA(2)s do not directly depolarize sensory fibres in vitro. (C) 2011 European Federation of International Association for the Study of Pain Chapters. Published by Elsevier Ltd. All rights reserved.

Environmental and genetic effects on production traits of ewes originally from distinct environments.

Wool production and reproductive performance components of similar genotypes, brought from distinct production areas, were evaluated during five years trial at similar environments, such as, joining season and stocking rate on winter improved pasture. The least squares means revealed that the origin (breed) effect concentrated upon the Corriedale ewes wool production, whereas in Romney females it affected the reproductive performance.

Microbial communities shifting in mangroves under distinct pollution state might name candidates for bioremediation programs.

2009

Bifidobacterium breve UCC2003 metabolises the human milk oligosaccharides lacto-N-tetraose and lacto-N-neo-tetraose through overlapping, yet distinct pathways

In this study, we demonstrate that the prototype B. breve strain UCC2003 possesses specific metabolic pathways for the utilisation of lacto-N-tetraose (LNT) and lacto-N-neotetraose (LNnT), which represent the central moieties of Type I and Type II human milk oligosaccharides (HMOs), respectively. Using a combination of experimental approaches, the enzymatic machinery involved in the metabolism of LNT and LNnT was identified and characterised. Homologs of the key genetic loci involved in the utilisation of these HMO substrates were identified in B. breve, B. bifidum, B. longum subsp. infantis and B. longum subsp. longum using bioinformatic analyses, and were shown to be variably present among other members of the Bifidobacterium genus, with a distinct pattern of conservation among human-associated bifidobacterial species.