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- The Major Facilitator Superfamily Transporter ZIFL2 Modulates Cesium and Potassium Homeostasis in ArabidopsisPublication . Remy, E.; Cabrito, T. R.; Batista, R. A.; Teixeira, M. C.; Sa-Correia, I.; Duque, P.Potassium (K(+)) is an essential mineral nutrient for plant growth and development, with numerous membrane transporters and channels having been implicated in the maintenance and regulation of its homeostasis. The cation cesium (Cs(+)) is toxic for plants but shares similar chemical properties to the K(+) ion and hence competes with its transport. Here, we report that K(+) and Cs(+) homeostasis in Arabidopsis thaliana also requires the action of ZIFL2 (Zinc-Induced Facilitator-Like 2), a member of the Major Facilitator Superfamily (MFS) of membrane transporters. We show that the Arabidopsis ZIFL2 is a functional transporter able to mediate K(+) and Cs(+) influx when heterologously expressed in yeast. Promoter-reporter, reverse transcription-PCR and fluorescent protein fusion experiments indicate that the predominant ZIFL2.1 isoform is targeted to the plasma membrane of endodermal and pericyle root cells. ZIFL2 loss of function and overexpression exacerbate and alleviate plant sensitivity, respectively, upon Cs(+) and excess K(+) supply, also influencing Cs(+) whole-plant partitioning. We propose that the activity of this Arabidopsis MFS carrier promotes cellular K(+) efflux in the root, thereby restricting Cs(+)/K(+) xylem loading and subsequent root to shoot translocation under conditions of Cs(+) or high K(+) external supply.
- Association of TCR/CD3, PTPN22, CD28 and ZAP70 gene polymorphisms with type 1 diabetes risk in Tunisian population: Family based association studyPublication . Ferjeni, Zouidi; Bouzid, D.; Fourati, H.; Stayoussef, M.; Abida, O.; Kammoun, T.; Hachicha, M.; Penha-Gonçalves, C.; Masmoudi, H.Type 1 diabetes (T1D) is caused by an immune-mediated destruction of the insulin-producing β-cells. Several studies support the involvement of T cell activation molecules in the pathogenesis of T1D. In order to underline the role of the genes involved in this activation pathway, we investigated, using the Sequenom MassARRAY platform, 45 single-nucleotide polymorphisms (SNPs) belonging to TCR/CD3, CD28, ZAP70, and PTPN22 genes in 59 T1D Tunisian families. In the current study, we identified an association with rs706 (Z score=2.782; p=0.005) of TCRβ gene. We also demonstrated that rs10918706 in the intron of the CD3z gene was associated with increased risk of T1D (Z score 2.137; p=0.032). In the same region, rs2949655 (Z score=2.101; p=0.035) and rs1214611 (Z score=4.036; p=0.00005) showed a genotype association with the risk of T1D. When haplotypes were constructed, GAA haplotype displayed significant association with T1D (Z score=2.135; p=0.032), while GGA haplotype (Z score=-1.988; p=0.046) was negatively associated with the disease. We also identified an association with rs3181096 (Z score=2.177; p=0.029), rs17695937 (Z score =2.111; p=0.034) and rs2488457 (Z score=2.219; p=0.026), respectively of CD28, ZAP70 and PTPN22 genes. In addition, our results suggest a significant effect on T1D susceptibility for AC (Z score=2.30; p=0.02) and CTGGC (Z score=2.309, p=0.02) haplotypes of ZAP70 and PTPN22 genes, respectively. While, the GTCT (Z score=-2.114, p=0.034) and CTAGG (Z score=-2.121, p=0.033) haplotypes of CD28 and PTPN22 genes, may confer protection against T1D. These findings confirm the role of PTPN22 and CD28 involved in the T cell activation pathway in the development of T1D in Tunisian families. Interestingly, ZAP70 and TCRβ/CD3z seem to contribute to the susceptibility to the disease in our population. However, this finding has to be confirmed in further studies.
- Characterization of the neural stem cell gene regulatory network identifies OLIG2 as a multifunctional regulator of self-renewalPublication . Mateo, Juan L; van den Berg, Debbie L C; Haeussler, Maximilian; Drechsel, Daniela; Gaber, Zachary B; Castro, Diogo S; Robson, Paul; Crawford, Gregory E; Flicek, Paul; Ettwiller, Laurence; Wittbrodt, Joachim; Guillemot, François; Martynoga, BenThe gene regulatory network (GRN) that supports neural stem cell (NS cell) self-renewal has so far been poorly characterized. Knowledge of the central transcription factors (TFs), the noncoding gene regulatory regions that they bind to, and the genes whose expression they modulate will be crucial in unlocking the full therapeutic potential of these cells. Here, we use DNase-seq in combination with analysis of histone modifications to identify multiple classes of epigenetically and functionally distinct cis-regulatory elements (CREs). Through motif analysis and ChIP-seq, we identify several of the crucial TF regulators of NS cells. At the core of the network are TFs of the basic helix-loop-helix (bHLH), nuclear factor I (NFI), SOX, and FOX families, with CREs often densely bound by several of these different TFs. We use machine learning to highlight several crucial regulatory features of the network that underpin NS cell self-renewal and multipotency. We validate our predictions by functional analysis of the bHLH TF OLIG2. This TF makes an important contribution to NS cell self-renewal by concurrently activating pro-proliferation genes and preventing the untimely activation of genes promoting neuronal differentiation and stem cell quiescence.
- Neurogenomic mechanisms of social plasticityPublication . Cardoso, S. D.; Teles, M. C.; Oliveira, R. F.Group-living animals must adjust the expression of their social behaviour to changes in their social environment and to transitions between life-history stages, and this social plasticity can be seen as an adaptive trait that can be under positive selection when changes in the environment outpace the rate of genetic evolutionary change. Here, we propose a conceptual framework for understanding the neuromolecular mechanisms of social plasticity. According to this framework, social plasticity is achieved by rewiring or by biochemically switching nodes of a neural network underlying social behaviour in response to perceived social information. Therefore, at the molecular level, it depends on the social regulation of gene expression, so that different genomic and epigenetic states of this brain network correspond to different behavioural states, and the switches between states are orchestrated by signalling pathways that interface the social environment and the genotype. Different types of social plasticity can be recognized based on the observed patterns of inter- versus intra-individual occurrence, time scale and reversibility. It is proposed that these different types of social plasticity rely on different proximate mechanisms at the physiological, neural and genomic level.
- Curcumin Inhibits Gastric Inflammation Induced by Helicobacter Pylori Infection in a Mouse ModelPublication . Santos, António; Lopes, Teresa; Oleastro, Mónica; Gato, Inês; Floch, Pauline; Benejat, Lucie; Chaves, Paula; Pereira, Teresa; Seixas, Elsa; Machado, Jorge; Guerreiro, AntónioHelicobacter pylori (H. pylori) infection triggers a sequence of gastric alterations starting with an inflammation of the gastric mucosa that, in some cases, evolves to gastric cancer. Efficient vaccination has not been achieved, thus it is essential to find alternative therapies, particularly in the nutritional field. The current study evaluated whether curcumin could attenuate inflammation of the gastric mucosa due to H. pylori infection. Twenty-eight C57BL/6 mice, were inoculated with the H. pylori SS1 strain; ten non-infected mice were used as controls. H. pylori infection in live mice was followed-up using a modified 13C-Urea Breath Test (13C-UBT) and quantitative real-time polymerase chain reaction (PCR). Histologically confirmed, gastritis was observed in 42% of infected non-treated mice at both 6 and 18 weeks post-infection. These mice showed an up-regulation of the expression of inflammatory cytokines and chemokines, as well as of toll-like receptors (TLRs) and MyD88, at both time points. Treatment with curcumin decreased the expression of all these mediators. No inflammation was observed by histology in this group. Curcumin treatment exerted a significant anti-inflammatory effect in H. pylori-infected mucosa, pointing to the promising role of a nutritional approach in the prevention of H. pylori induced deleterious inflammation while the eradication or prevention of colonization by effective vaccine is not available.
- Evolutionary Patterns in Coiled-CoilsPublication . Surkont, J.; Pereira-Leal, J. B.Models of protein evolution are used to describe evolutionary processes, for phylogenetic analyses and homology detection. Widely used general models of protein evolution are biased toward globular domains and lack resolution to describe evolutionary processes for other protein types. As three-dimensional structure is a major constraint to protein evolution, specific models have been proposed for other types of proteins. Here, we consider evolutionary patterns in coiled-coil forming proteins. Coiled-coils are widespread structural domains, formed by a repeated motif of seven amino acids (heptad repeat). Coiled-coil forming proteins are frequently rods and spacers, structuring both the intracellular and the extracellular spaces that often form protein interaction interfaces. We tested the hypothesis that due to their specific structure the associated evolutionary constraints differ from those of globular proteins. We showed that substitution patterns in coiled-coil regions are different than those observed in globular regions, beyond the simple heptad repeat. Based on these substitution patterns we developed a coiled-coil specific (CC) model that in the context of phylogenetic reconstruction outperforms general models in tree likelihood, often leading to different topologies. For multidomain proteins containing both a coiled-coil region and a globular domain, we showed that a combination of the CC model and a general one gives higher likelihoods than a single model. Finally, we showed that the model can be used for homology detection to increase search sensitivity for coiled-coil proteins. The CC model, software, and other supplementary materials are available at http://www.evocell.org/cgl/resources (last accessed January 29, 2015).
- Upscale and downscale energy transfer over the tropical Pacific revealed by scatterometer windsPublication . King, Gregory P.; Vogelzang, Jur; Stoffelen, AdThe direction of the energy cascade in the mesoscales of atmospheric turbulence is investigated using near-surface winds over the tropical Pacific measured by satellite scatterometers SeaWinds (QuikSCAT) and ASCAT (MetOp-A). The tropical Pacific was subdivided into nine regions, classified as rainy or dry. Longitudinal third-order along-track structure functions inline image and skewness inline image were calculated as a function of separation inline image for each region and month during the period November 2008 to October 2009. We find that the results support both downscale and upscale interpretations, depending on region and month. The results indicate that normally energy cascades downscale, but cascades upscale over the cold tongue in the cold season and over the west Pacific in summer months. An explanation is offered based on the heating or cooling of the air by the underlying sea surface temperature. It is also found that the signature of intermittent small-scale (<100 km) events could be identified in graphs of inline image, implying that this diagnostic may be useful in the studies of tropical disturbances.
- Model Checking to Assess T-Helper Cell PlasticityPublication . Abou-Jaoudé, Wassim; Monteiro, Pedro T.; Naldi, Aurélien; Grandclaudon, Maximilien; Soumelis, Vassili; Chaouiya, Claudine; Thieffry, DenisComputational modeling constitutes a crucial step toward the functional understanding of complex cellular networks. In particular, logical modeling has proven suitable for the dynamical analysis of large signaling and transcriptional regulatory networks. In this context, signaling input components are generally meant to convey external stimuli, or environmental cues. In response to such external signals, cells acquire specific gene expression patterns modeled in terms of attractors (e.g., stable states). The capacity for cells to alter or reprogram their differentiated states upon changes in environmental conditions is referred to as cell plasticity. In this article, we present a multivalued logical framework along with computational methods recently developed to efficiently analyze large models. We mainly focus on a symbolic model checking approach to investigate switches between attractors subsequent to changes of input conditions. As a case study, we consider the cellular network regulating the differentiation of T-helper (Th) cells, which orchestrate many physiological and pathological immune responses. To account for novel cellular subtypes, we present an extended version of a published model of Th cell differentiation. We then use symbolic model checking to analyze reachability properties between Th subtypes upon changes of environmental cues. This allows for the construction of a synthetic view of Th cell plasticity in terms of a graph connecting subtypes with arcs labeled by input conditions. Finally, we explore novel strategies enabling specific Th cell polarizing or reprograming events.
- Second-order structure function analysis of scatterometer winds over the Tropical PacificPublication . King, Gregory P.; Vogelzang, Jur; Stoffelen, AdKolmogorov second-order structure functions are used to quantify and compare the small-scale information contained in near-surface ocean wind products derived from measurements by ASCAT on MetOp-A and SeaWinds on QuikSCAT. Two ASCAT and three SeaWinds products are compared in nine regions (classified as rainy or dry) in the tropical Pacific between 10°S and 10°N and 140° and 260°E for the period November 2008 to October 2009. Monthly and regionally averaged longitudinal and transverse structure functions are calculated using along-track samples. To ease the analysis, the following quantities were estimated for the scale range 50 to 300 km and used to intercompare the wind products: (i) structure function slopes, (ii) turbulent kinetic energies ( inline image), and (iii) vorticity-to-divergence ratios. All wind products are in good qualitative agreement, but also have important differences. Structure function slopes and inline image differ per wind product, but also show a common variation over time and space. Independent of wind product, longitudinal slopes decrease when sea surface temperature exceeds the threshold for onset of deep convection (about 28°C). In rainy areas and in dry regions during rainy periods, ASCAT has larger divergent inline image than SeaWinds, while SeaWinds has larger vortical inline image than ASCAT. Differences between SeaWinds and ASCAT vortical inline image and vorticity-to-divergence ratios for the convectively active months of each region are large.