Sensitivity of the Atlantic meridional overturning circulation to South Atlantic freshwater anomalies

The sensitivity of the Atlantic Meridional Overturning Circulation (AMOC) to changes in basin integrated net evaporation is highly dependent on the zonal salinity contrast at the southern border of the Atlantic. Biases in the freshwater budget strongly affect the stability of the AMOC in numerical models. The impact of these biases is investigated, by adding local anomaly patterns in the South Atlantic to the freshwater fluxes at the surface. These anomalies impact the freshwater and salt transport by the different components of the ocean circulation, in particular the basin-scale salt-advection feedback, completely changing the response of the AMOC to arbitrary perturbations. It is found that an appropriate dipole anomaly pattern at the southern border of the Atlantic Ocean can collapse the AMOC entirely even without a further hosing. The results suggest a new view on the stability of the AMOC, controlled by processes in the South Atlantic. <br/

The degradation of p53 and its major E3 ligase Mdm2 is differentially dependent on the proteasomal ubiquitin receptor S5a.

p53 and its major E3 ligase Mdm2 are both ubiquitinated and targeted to the proteasome for degradation. Despite the importance of this in regulating the p53 pathway, little is known about the mechanisms of proteasomal recognition of ubiquitinated p53 and Mdm2. In this study, we show that knockdown of the proteasomal ubiquitin receptor S5a/PSMD4/Rpn10 inhibits p53 protein degradation and results in the accumulation of ubiquitinated p53. Overexpression of a dominant-negative deletion of S5a lacking its ubiquitin-interacting motifs (UIM)s, but which can be incorporated into the proteasome, also causes the stabilization of p53. Furthermore, small-interferring RNA (siRNA) rescue experiments confirm that the UIMs of S5a are required for the maintenance of low p53 levels. These observations indicate that S5a participates in the recognition of ubiquitinated p53 by the proteasome. In contrast, targeting S5a has no effect on the rate of degradation of Mdm2, indicating that proteasomal recognition of Mdm2 can be mediated by an S5a-independent pathway. S5a knockdown results in an increase in the transcriptional activity of p53. The selective stabilization of p53 and not Mdm2 provides a mechanism for p53 activation. Depletion of S5a causes a p53-dependent decrease in cell proliferation, demonstrating that p53 can have a dominant role in the response to targeting S5a. This study provides evidence for alternative pathways of proteasomal recognition of p53 and Mdm2. Differences in recognition by the proteasome could provide a means to modulate the relative stability of p53 and Mdm2 in response to cellular signals. In addition, they could be exploited for p53-activating therapies. This work shows that the degradation of proteins by the proteasome can be selectively dependent on S5a in human cells, and that this selectivity can extend to an E3 ubiquitin ligase and its substrate

Genotype x environment interactions in eggplant for fruit phenolic acid content

Eggplant fruit are a rich source of phenolic acids that influence fruit culinary quality and antioxidant content. We evaluated the influence of production environments and stability of diverse genotypes across environments for eggplant fruit phenolic acid content. Ten Solanum melongena accessions consisting of five F-1 hybrid cultivars, three open-pollinated cultivars and two land race accessions, plus one S. macrocarpon and one S. aethiopicum accession, were grown at two locations under greenhouse and open field environments. Twenty phenolic acid conjugates were identified in fruit flesh and assigned to six classes that included hydroxycinnamic acid amides, caffeoylquinic acid esters, hydroxycinnamoylquinic acid esters, malonylcaffeoylquinic acid esters, di-hydroxycinnamoylquinic acid esters, and other hydroxycinnamic acid conjugates. There were significant differences among accessions for total phenolic acid conjugate content and for all six classes. There were no significant differences detected among the environments for any of the variables. However, the environment x accession interaction was highly significant for all phenolic acid classes. Broad-sense heritability estimates for all six phenolic acid classes were high, ranging from 0.64 to 0.96. Stability analysis demonstrated widespread instability for phenolic acid content across environments. Stability of the predominant caffeoylquinic acid esters class positively influenced stability of total phenolic acid content for some but not all genotypes. High heritability, coupled with highly significant genotype x environment interactions suggests that stability estimates may improve the efficiency of breeding new genotypes with predictable performance across environments.Stommel, JR.; Whitaker, B.; Haynes, K.; Prohens Tomás, J. (2015). Genotype x environment interactions in eggplant for fruit phenolic acid content. Euphytica. 205(3):823-836. doi:10.1007/s10681-015-1415-2S8238362053Allard RW, Bradshaw AD (1964) Implications of genotype–environment interactions in applied plant breeding. Crop Sci 4:503–507Baixauli C (2001) Berenjena. In: Nuez F, Liacer G (eds) La horticultura española. Ediciones de Horticultura, Reus, pp 104–108Bravo L (1998) Polyphenols: chemistry, dietary sources, metabolism, and nutritional significance. Nutr Rev 56:317–333Dixon RA, Pavia NL (1995) Stress-induced phenylpropanoid metabolism. Plant Cell 7:1085–1097Dogan M, Arslan O, Dogan S (2002) Substrate specificity, heat inactivation and inhibition of polyphenol oxidase from different aubergine cultivars. Int J Food Sci Technol 37:415–423Dos Santos MD, Almeida MC, Lopes NP, de Souza GE (2006) Evaluation of the anti-inflammatory, analgesic and anti-pyretic activities of the natural polyphenol chlorogenic acid. Biol Pharm Bull 29:2236–2240Fernandez GCJ (1991) Analysis of genotype × environment interaction by stability estimates. HortScience 26:947–950García-Salas P, Gómez-Caravaca AM, Morales-Soto A, Segura-Carretero A, Fernández-Gutiérrez A (2014) Identification and quantification of phenolic compounds in diverse cultivars of eggplant grown in different seasons by high-performance liquid chromatography coupled to diode array detector and electrospray-quadrupole-time of flight-mass spectrometry. Food Res Int 57:114–122Hanson PM, Yang RY, Tsou SCS, Ledesma K, Engle L, Lee TC (2006) Diversity in eggplant (Solanum melongena) for superoxide scavenging activity, total phenolics, and ascorbic acid. J Food Compos Anal 19:594–600Kang MS (1989) A new SAS program for calculating stability variance parameters. J Hered 80:415Klein RM (1990) Failure of supplementary ultraviolet radiation to enhance flower color under greenhouse conditions. HortScience 25:307–308Knapp SJ, Stroup WW, Ross WM (1985) Exact confidence intervals for heritability on a progeny mean basis. Crop Sci 25:192–194Luthria D, Singh AP, Wilson T, Vorsa N, Banuelos GS, Vinyard BT (2010) Influence of conventional and organic agricultural practices on the phenolic content in eggplant pulp: plant to plant variation. Food Chem 121:406–411Ma C, Whitaker BD, Kennelly EJ (2010) New 5-O-caffeoylquinic acid derivatives in fruit of wild eggplant relative S. viarum. J Agric Food Chem 58:9645–9651Manach C, Scalbert A, Morand C, Remesy C, Jimenez L (2004) Polyphenols: food sources and bioavailability. Am J Clin Nutr 79:727–747Mennella G, Scalzo R, Fibiani M, D’Alessandro A, Francese G, Toppino L, Acciarri N, Almeida AE, Rotino GL (2012) Chemical and bioactive quality traits during fruit ripening in eggplant (S. melongena L.) and allied species. J Agric Food Chem 60:11821–11831Meyer RS, Karol KG, Little DP, Nee MH, Litt A (2012) Phylogeographic relationships among Asian eggplants and new perspectives on eggplant domestication. Mol Phylogenet Evol 63:685–701Ong KW, Hsu A, Tan BK (2012) Chlorogenic acid stimulates glucose transport in skeletal muscle via AMPK activation: a contributor to the beneficial effects of coffee on diabetes. PLoS One 7:e32718Payyavula RS, Duroy AN, Kuhl JC, Pantoha A, Pillai SS (2012) Differential effects of environment on potato phenylpropanoid and carotenoid expression. BMC Plant Biol 12:39Plazas M, Prohens J, Cuñat AN, Vilanova S, Gramazio P, Herraiz FJ, Andújar I (2014) Reducing capacity, chlorogenic acid content and biological activity in a collection of scarlet (Solanum aethiopicum) and gboma (S. macrocarpon) eggplants. Int J Mol Sci 15:17221–17241Prior RL (2003) Fruits and vegetables in the prevention of cellular oxidative damage. Am J Clin Nutr 78:570S–578SPritts M, Luby J (1990) Stability indices for horticultural crops. HortScience 25:740–745Prohens J, Rodriguez-Burruezo A, Raigon MD, Nuez F (2007) Total phenolic acid concentration and browning susceptibility in a collection of different varietal types and hybrids of eggplant: implications for breeding for higher nutritional quality and reduced browning. J Am Soc Hortic Sci 132:638–646Prohens J, Whitaker BD, Plazas M, Vilanova S, Hurtado M, Blasco M, Gramazio P, Stommel JR (2013) Genetic diversity in morphological characters and phenolic acids content resulting from an interspecific cross between eggplant, Solanum melongena, and its wild ancestor (S. incancum). Ann Appl Biol 162:242–257Raigon MD, Prohens J, Munoz-Falcon JE, Nuez F (2008) Comparison of eggplant landraces and commercial varieties for fruit content of phenolics, minerals, dry matter and protein. J Food Compos Anal 21:370–376Raigon MD, Rodriguez-Burruezo A, Prohens J (2010) Effects of organic and conventional cultivation methods on composition of eggplant fruits. Agric Food Chem 58:6833–6840San Jose R, Sanchez-Mata MC, Camara M, Prohens J (2014) Eggplant fruit composition as affected by the cultivation environment and genetic constitution. J Sci Food Agric 94:2774–2784Sato Y, Itagaki S, Kurokawa T, Ogur J, Kobayashi M, Hirano T, Sugawara M, Iseki K (2011) In vitro and in vivo antioxidant properties of chlorogenic acid and caffeic acid. Int J Pharm 403:136–138Setimela PS, Vivek B, Banziger M, Crossa J, Maideni F (2007) Evaluation of early to medium maturing open pollinated maize varieties in SADC region using GGE biplot based on the SREG model. Field Crop Res 103:161–169Shukla GK (1972) Some statistical aspects of partitioning genotype environment components of variability. Heredity 29:237–245Stommel JR, Whitaker BD (2003) Phenolic acid content and composition of eggplant fruit in a germplasm core subset. J Am Soc Hortic Sci 128:704–710Suzuki A, Yamamoto N, Jokura H, Yamamoto M, Fujii A, Tokimitsu I, Saito I (2006) Chlorogenic acid attenuates hypertension and improves endothelial function in spontaneously hypertensive rats. J Hypertens 24:1065–1073University of Maryland (2007) Commercial vegetable production recommendations, University of Maryland Cooperative Extension Service Bulletin 236. College Park, MDWhitaker BD, Stommel JR (2003) Distribution of hydroxycinnamic acid conjugates in fruit of commercial eggplant (Solanum melongena L.) cultivars. J Agric Food Chem 51:3448–3454Winter M, Herrmann K (1986) Esters and glucosides of hydroxycinnamic acids in vegetables. J Agric Food Chem 34:616–620Wu S, Meyer RS, Whitaker BD, Litt A, Kennelly EJ (2013) A New liquid chromatography-mass spectrometry-based strategy to integrate chemistry, morphology, and evolution of eggplant (Solanum) species. J Chromatogr A 1314:154–172Yang JS, Liu CW, Ma YS, Weng SW, Tang NY, Wu SH, Ji BC, Ma CY, Ko YC, Funayama S, Kuo CL (2012) Chlorogenic acid induces apoptotic cell death in U937 leukemia cells through caspase- and mitochondria-dependent pathways. In Vivo 26:971–97

RNAseq Analyses Identify Tumor Necrosis Factor-Mediated Inflammation as a Major Abnormality in ALS Spinal Cord

ALS is a rapidly progressive, devastating neurodegenerative illness of adults that produces disabling weakness and spasticity arising from death of lower and upper motor neurons. No meaningful therapies exist to slow ALS progression, and molecular insights into pathogenesis and progression are sorely needed. In that context, we used high-depth, next generation RNA sequencing (RNAseq, Illumina) to define gene network abnormalities in RNA samples depleted of rRNA and isolated from cervical spinal cord sections of 7 ALS and 8 CTL samples. We aligned \u3e50 million 2X150 bp paired-end sequences/sample to the hg19 human genome and applied three different algorithms (Cuffdiff2, DEseq2, EdgeR) for identification of differentially expressed genes (DEG’s). Ingenuity Pathways Analysis (IPA) and Weighted Gene Co-expression Network Analysis (WGCNA) identified inflammatory processes as significantly elevated in our ALS samples, with tumor necrosis factor (TNF) found to be a major pathway regulator (IPA) and TNFα-induced protein 2 (TNFAIP2) as a major network “hub” gene (WGCNA). Using the oPOSSUM algorithm, we analyzed transcription factors (TF) controlling expression of the nine DEG/hub genes in the ALS samples and identified TF’s involved in inflammation (NFkB, REL, NFkB1) and macrophage function (NR1H2::RXRA heterodimer). Transient expression in human iPSC-derived motor neurons of TNFAIP2 (also a DEG identified by all three algorithms) reduced cell viability and induced caspase 3/7 activation. Using high-density RNAseq, multiple algorithms for DEG identification, and an unsupervised gene co-expression network approach, we identified significant elevation of inflammatory processes in ALS spinal cord with TNF as a major regulatory molecule. Overexpression of the DEG TNFAIP2 in human motor neurons, the population most vulnerable to die in ALS, increased cell death and caspase 3/7 activation. We propose that therapies targeted to reduce inflammatory TNFα signaling may be helpful in ALS patients

Inhibition of N-linked glycosylation impairs ALK phosphorylation and disrupts pro-survival signaling in neuroblastoma cell lines

<p>Abstract</p> <p>Background</p> <p>The Anaplastic Lymphoma Kinase (ALK) is an orphan receptor tyrosine kinase, which undergoes post-translational N-linked glycosylation. The catalytic domain of ALK was originally identified in the t(2;5) translocation that produces the unglycosylated oncogenic protein NPM-ALK, which occurs in Anaplastic Large Cell Lymphoma (ALCL). Recently, both germline and somatic activating missense mutations of ALK have been identified in neuroblastoma (NB), a pediatric cancer arising from neural crest cells. Moreover, we previously reported that ALK expression is significantly upregulated in advanced/metastatic NB. We hypothesized that ALK function may depend on N-linked glycosylation and that disruption of this post-translational modification would impair ALK activation, regardless the presence of either gene mutations or overexpression.</p> <p>Methods</p> <p>We employed tunicamycin to inhibit N-linked glycosylation. The following ALK-positive NB cell lines were used: SH-SY5Y and KELLY (ALK mutation F1174L), UKF-NB3 (ALK mutation R1275Q) and NB1 (ALK amplification). As a control, we used the NB cell lines LA1-5S and NB5 (no ALK expression), and the ALCL cell line SU-DHL1 (NPM-ALK).</p> <p>Results</p> <p>Tunicamycin treatment of ALK-positive NB cells resulted in a hypoglycosylated ALK band and in decreased amounts of mature full size receptor. Concomitantly, we observed a marked reduction of mature ALK phosphorylation. On the contrary, tunicamycin had no effects on NPM-ALK phosphorylation in SU-DHL1 cells. Moreover, phosphorylation levels of ALK downstream effectors (AKT, ERK1/2, STAT3) were clearly impaired only in ALK mutated/amplified NB cell lines, whereas no significant reduction was observed in both ALK-negative and NPM-ALK-positive cell lines. Furthermore, inhibition of N-linked glycosylation considerably impaired cell viability only of ALK mutated/amplified NB cells. Finally, the cleavage of the Poly-ADP-ribose-polymerase (PARP) suggested that apoptotic pathways may be involved in cell death.</p> <p>Conclusions</p> <p>In this study we showed that inhibition of N-linked glycosylation affects ALK phosphorylation and disrupts downstream pro-survival signaling, indicating that inhibition of this post-translational modification may be a promising therapeutic approach. However, as tunicamycin is not a likely candidate for clinical use other approaches to alter N-linked glycosylation need to be explored. Future studies will assess whether the efficacy in inhibiting ALK activity might be enhanced by the combination of ALK specific small molecule and N-linked glycosylation inhibitors.</p

Location of chlorogenic acid biosynthesis pathway and polyphenol oxidase genes in a new interspecific anchored linkage map of eggplant

© Gramazio et al.; licensee BioMed Central. 2014. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated

Erratum: Production and validation of scintillating structural components from low-background Poly(ethylene naphthalate)

[no abstract available

A mathematical framework for critical transitions: normal forms, variance and applications

Critical transitions occur in a wide variety of applications including mathematical biology, climate change, human physiology and economics. Therefore it is highly desirable to find early-warning signs. We show that it is possible to classify critical transitions by using bifurcation theory and normal forms in the singular limit. Based on this elementary classification, we analyze stochastic fluctuations and calculate scaling laws of the variance of stochastic sample paths near critical transitions for fast subsystem bifurcations up to codimension two. The theory is applied to several models: the Stommel-Cessi box model for the thermohaline circulation from geoscience, an epidemic-spreading model on an adaptive network, an activator-inhibitor switch from systems biology, a predator-prey system from ecology and to the Euler buckling problem from classical mechanics. For the Stommel-Cessi model we compare different detrending techniques to calculate early-warning signs. In the epidemics model we show that link densities could be better variables for prediction than population densities. The activator-inhibitor switch demonstrates effects in three time-scale systems and points out that excitable cells and molecular units have information for subthreshold prediction. In the predator-prey model explosive population growth near a codimension two bifurcation is investigated and we show that early-warnings from normal forms can be misleading in this context. In the biomechanical model we demonstrate that early-warning signs for buckling depend crucially on the control strategy near the instability which illustrates the effect of multiplicative noise.Comment: minor corrections to previous versio

Diversity and relationships in key traits for functional and apparent quality in a collection of eggplant: fruit phenolics content, antioxidant activity, polyphenol oxidase activity, and browning

This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Agricultural and Food Chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work seehttp://dx.doi.org/10.1021/jf402429kEggplant (Solanum melongena) varieties with increased levels of phenolics in the fruit present enhanced functional quality, but may display greater fruit flesh browning. We evaluated 18 eggplant accessions for fruit total phenolics content, chlorogenic acid content, DPPH scavenging activity, polyphenol oxidase (PPO) activity, liquid extract browning, and fruit flesh browning. For all the traits we found a high diversity, with differences among accessions of up to 3.36-fold for fruit flesh browning. Variation in total content in phenolics and in chlorogenic acid content accounted only for 18.9% and 6.0% in the variation in fruit flesh browning, and PPO activity was not significantly correlated with fruit flesh browning. Liquid extract browning was highly correlated with chlorogenic acid content (r = 0.852). Principal components analysis (PCA) identified four groups of accessions with different profiles for the traits studied. Results suggest that it is possible to develop new eggplant varieties with improved functional and apparent quality.This project has been funded by Universitat Politecnica de Valencia through the grants SP20120681 and PAID-06-11 Nr. 2082, and by Ministerio de Economia y Competitividad Grant AGL2012-34213 (jointly funded by FEDER).Plazas Ávila, MDLO.; López Gresa, MP.; Vilanova Navarro, S.; Torres Vidal, C.; Hurtado Ricart, M.; Gramazio, P.; Andújar Pérez, I.... (2013). Diversity and relationships in key traits for functional and apparent quality in a collection of eggplant: fruit phenolics content, antioxidant activity, polyphenol oxidase activity, and browning. Journal of Agricultural and Food Chemistry. 61(37):8871-8879. https://doi.org/10.1021/jf402429kS88718879613

Modeling the Basal Dynamics of P53 System

The tumor suppressor p53 has become one of most investigated genes. Once activated by stress, p53 leads to cellular responses such as cell cycle arrest and apoptosis.Most previous models have ignored the basal dynamics of p53 under nonstressed conditions. To explore the basal dynamics of p53, we constructed a stochastic delay model by incorporating two negative feedback loops. We found that protein distribution of p53 under nonstressed condition is highly skewed with a fraction of cells showing high p53 levels comparable to those observed under stressed conditions. Under nonstressed conditions, asynchronous and spontaneous p53 pulses are triggered by basal DNA double strand breaks produced during normal cell cycle progression. The first peaking times show a predominant G1 distribution while the second ones are more widely distributed. The spontaneous pulses are triggered by an excitable mechanism. Once initiated, the amplitude and duration of pulses remain unchanged. Furthermore, the spontaneous pulses are filtered by ataxia telangiectasia mutated protein mediated posttranslational modifications and do not result in substantial p21 transcription. If challenged by externally severe DNA damage, cells generate synchronous p53 pulses and induce significantly high levels of p21. The high expression of p21 can also be partially induced by lowering the deacetylation rate.Our results demonstrated that the dynamics of p53 under nonstressed conditions is initiated by an excitable mechanism and cells become fully responsive only when cells are confronted with severe damage. These findings advance our understanding of the mechanism of p53 pulses and unlock many opportunities to p53-based therapy