244 research outputs found
Identification of the Photoreceptor Transcriptional Co-Repressor SAMD11 as Novel Cause of Autosomal Recessive Retinitis Pigmentosa
Retinitis pigmentosa (RP), the most frequent form of inherited retinal dystrophy is characterized by progressive photoreceptor degeneration. Many genes have been implicated in RP development, but several others remain to be identified. Using a combination of homozygosity mapping, whole-exome and targeted next-generation sequencing, we found a novel homozygous nonsense mutation in SAMD11 in five individuals diagnosed with adult-onset RP from two unrelated consanguineous Spanish families. SAMD11 is ortholog to the mouse major retinal SAM domain (mr-s) protein that is implicated in CRX-mediated transcriptional regulation in the retina. Accordingly, protein-protein network analysis revealed a significant interaction of SAMD11 with CRX. Immunoblotting analysis confirmed strong expression of SAMD11 in human retina. Immunolocalization studies revealed SAMD11 was detected in the three nuclear layers of the human retina and interestingly differential expression between cone and rod photoreceptors was observed. Our study strongly implicates SAMD11 as novel cause of RP playing an important role in the pathogenesis of human degeneration of photoreceptors.This work was supported by several grants from the Spanish Centre for Biomedical Network Research on Rare Diseases (CIBERER)(06/07/0036), Instituto de Salud Carlos III (ISCIII, Spanish Ministry of Health)/FEDER, including FIS (PI013/00226) and RETICS (RD09/0076/00101 and RD12/0034/0010), Ministry of Economy and Competitiveness (MINECO), including FEDER (BFU2012-36845), and BIO2011-27069, Conselleria de EducaciĂł of the Valencia Community (PROMETEOII/2014/025), Spanish National Organization of the Blind (ONCE) and the Spanish Fighting Blindness Foundation (FUNDALUCE). M.C. was sponsored by the Miguel Servet Program for Researchers in the Spanish National Health Service (CP12/03256) and RSA by Sara Borrel Postdoctoral Program (CD12/00676), both from the ISCIII/FEDER. A.A-F. was sponsored by CIBERER, RPC is supported by FundaciĂłn Conchita RĂĄbago (FCR), L.C is sponsored by RETICS (RD12/0034/0010) from ISCIII and L.d.S. was supported by CAPES Foundation, Ministry of Education of Brazil
Sodium signaling and astrocyte energy metabolism.
The Na(+) gradient across the plasma membrane is constantly exploited by astrocytes as a secondary energy source to regulate the intracellular and extracellular milieu, and discard waste products. One of the most prominent roles of astrocytes in the brain is the Na(+) -dependent clearance of glutamate released by neurons during synaptic transmission. The intracellular Na(+) load collectively generated by these processes converges at the Na,K-ATPase pump, responsible for Na(+) extrusion from the cell, which is achieved at the expense of cellular ATP. These processes represent pivotal mechanisms enabling astrocytes to increase the local availability of metabolic substrates in response to neuronal activity. This review presents basic principles linking the intracellular handling of Na(+) following activity-related transmembrane fluxes in astrocytes and the energy metabolic pathways involved. We propose a role of Na(+) as an energy currency and as a mediator of metabolic signals in the context of neuron-glia interactions. We further discuss the possible impact of the astrocytic syncytium for the distribution and coordination of the metabolic response, and the compartmentation of these processes in cellular microdomains and subcellular organelles. Finally, we illustrate future avenues of investigation into signaling mechanisms aimed at bridging the gap between Na(+) and the metabolic machinery. GLIA 2016;64:1667-1676
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 TomĂĄs, J. (2015). Genotype x environment interactions in eggplant for fruit phenolic acid content. 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HortScience 25:307â308Knapp SJ, Stroup WW, Ross WM (1985) Exact confidence intervals for heritability on a progeny mean basis. Crop Sci 25:192â194Luthria 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 121:406â411Ma C, Whitaker BD, Kennelly EJ (2010) New 5-O-caffeoylquinic acid derivatives in fruit of wild eggplant relative S. viarum. J Agric Food Chem 58:9645â9651Manach C, Scalbert A, Morand C, Remesy C, Jimenez L (2004) Polyphenols: food sources and bioavailability. Am J Clin Nutr 79:727â747Mennella G, Scalzo R, Fibiani M, DâAlessandro 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 60:11821â11831Meyer RS, Karol KG, Little DP, Nee MH, Litt A (2012) Phylogeographic relationships among Asian eggplants and new perspectives on eggplant domestication. Mol Phylogenet Evol 63:685â701Ong 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, AndĂșjar 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 15:17221â17241Prior RL (2003) Fruits and vegetables in the prevention of cellular oxidative damage. Am J Clin Nutr 78:570Sâ578SPritts M, Luby J (1990) Stability indices for horticultural crops. HortScience 25:740â745Prohens 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 132:638â646Prohens 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 162:242â257Raigon 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. 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Genomic Instability, Defective Spermatogenesis, Immunodeficiency, and Cancer in a Mouse Model of the RIDDLE Syndrome
Eukaryotic cells have evolved to use complex pathways for DNA damage signaling and repair to maintain genomic integrity. RNF168 is a novel E3 ligase that functions downstream of ATM,Îł-H2A.X, MDC1, and RNF8. It has been shown to ubiquitylate histone H2A and to facilitate the recruitment of other DNA damage response proteins, including 53BP1, to sites of DNA break. In addition, RNF168 mutations have been causally linked to the human RIDDLE syndrome. In this study, we report that Rnf168â/â mice are immunodeficient and exhibit increased radiosensitivity. Rnf168â/â males suffer from impaired spermatogenesis in an age-dependent manner. Interestingly, in contrast to H2a.xâ/â, Mdc1â/â, and Rnf8â/â cells, transient recruitment of 53bp1 to DNA double-strand breaks was abolished in Rnf168â/â cells. Remarkably, similar to 53bp1 inactivation, but different from H2a.x deficiency, inactivation of Rnf168 impairs long-range V(D)J recombination in thymocytes and results in long insertions at the class-switch junctions of B-cells. Loss of Rnf168 increases genomic instability and synergizes with p53 inactivation in promoting tumorigenesis. Our data reveal the important physiological functions of Rnf168 and support its role in both Îł-H2a.x-Mdc1-Rnf8-dependent and -independent signaling pathways of DNA double-strand breaks. These results highlight a central role for RNF168 in the hierarchical network of DNA break signaling that maintains genomic integrity and suppresses cancer development in mammals
Role of Haptoglobin in Polycystic Ovary Syndrome (PCOS), Obesity and Disorders of Glucose Tolerance in Premenopausal Women
alleles of the haptoglobin 뱉chain polymorphism reduce the anti-oxidant properties and increase the pro-inflammatory actions of this acute-phase protein in a gene-dosage fashion. We hypothesized that the haptoglobin polymorphism might contribute to the increased oxidative stress and low-grade chronic inflammation frequently associated with polycystic ovary syndrome, obesity, and abnormalities of glucose tolerance.<0.001), yet no association was found between obesity and haptoglobin genotypes. No differences were observed in haptoglobin levels or genotype frequencies depending on glucose tolerance. Fifty percent of the variation in serum haptoglobin concentrations was explained by the variability in serum C-reactive protein concentrations, BMI, insulin sensitivity and haptoglobin genotypes. alleles suggests that the anti-oxidant and anti-inflammatory properties of haptoglobin may be reduced in these patients
Histone H2AX stabilizes broken DNA strands to suppress chromosome breaks and translocations during V(D)J recombination
The H2AX core histone variant is phosphorylated in chromatin around DNA double strand breaks (DSBs) and functions through unknown mechanisms to suppress antigen receptor locus translocations during V(D)J recombination. Formation of chromosomal coding joins and suppression of translocations involves the ataxia telangiectasia mutated and DNA-dependent protein kinase catalytic subunit serine/threonine kinases, each of which phosphorylates H2AX along cleaved antigen receptor loci. Using Abelson transformed preâB cell lines, we find that H2AX is not required for coding join formation within chromosomal V(D)J recombination substrates. Yet we show that H2AX is phosphorylated along cleaved IgÎș DNA strands and prevents their separation in G1 phase cells and their progression into chromosome breaks and translocations after cellular proliferation. We also show that H2AX prevents chromosome breaks emanating from unrepaired RAG endonuclease-generated TCR-α/ÎŽ locus coding ends in primary thymocytes. Our data indicate that histone H2AX suppresses translocations during V(D)J recombination by creating chromatin modifications that stabilize disrupted antigen receptor locus DNA strands to prevent their irreversible dissociation. We propose that such H2AX-dependent mechanisms could function at additional chromosomal locations to facilitate the joining of DNA ends generated by other types of DSBs
Genome-wide inference of regulatory networks in Streptomyces coelicolor
Background: The onset of antibiotics production in Streptomyces species is co-ordinated with differentiation events. An understanding of the genetic circuits that regulate these coupled biological phenomena is essential to discover and engineer the pharmacologically important natural products made by these species. The availability of genomic tools and access to a large warehouse of transcriptome data for the model organism, Streptomyces coelicolor, provides incentive to decipher the intricacies of the regulatory cascades and develop biologically meaningful hypotheses.
Results: In this study, more than 500 samples of genome-wide temporal transcriptome data, comprising wild-type and more than 25 regulatory gene mutants of Streptomyces coelicolor probed across multiple stress and medium conditions, were investigated. Information based on transcript and functional similarity was used to update a previously-predicted whole-genome operon map and further applied to predict transcriptional networks constituting modules enriched in diverse functions such as secondary metabolism, and sigma factor. The predicted network displays a scale-free architecture with a small-world property observed in many biological networks. The networks were further investigated to identify functionally-relevant modules that exhibit functional coherence and a consensus motif in the promoter elements indicative of DNA-binding elements.
Conclusions: Despite the enormous experimental as well as computational challenges, a systems approach for integrating diverse genome-scale datasets to elucidate complex regulatory networks is beginning to emerge. We present an integrated analysis of transcriptome data and genomic features to refine a whole-genome operon map and to construct regulatory networks at the cistron level in Streptomyces coelicolor. The functionally-relevant modules identified in this study pose as potential targets for further studies and verification.
Unfolded protein response in cancer: the Physician's perspective
The unfolded protein response (UPR) is a cascade of intracellular stress signaling events in response to an accumulation of unfolded or misfolded proteins in the lumen of the endoplasmic reticulum (ER). Cancer cells are often exposed to hypoxia, nutrient starvation, oxidative stress and other metabolic dysregulation that cause ER stress and activation of the UPR. Depending on the duration and degree of ER stress, the UPR can provide either survival signals by activating adaptive and antiapoptotic pathways, or death signals by inducing cell death programs. Sustained induction or repression of UPR pharmacologically may thus have beneficial and therapeutic effects against cancer. In this review, we discuss the basic mechanisms of UPR and highlight the importance of UPR in cancer biology. We also update the UPR-targeted cancer therapeutics currently in clinical trials
Characterization of supplementary cementitious materials by thermal analysis
Working Group 1 of RILEM TC 238-SCM âHydration and microstructure of concrete with supplementary cementitious materials (SCMs)â is defining best practices for the physical and chemical characterization of SCMs, and this paper focusses on their thermal analysis. Thermogravimetric analysis (TGA) can provide valuable data on the chemical and mineralogical composition of SCMs. Loss-on-ignition (LOI) testing is a commonly used, standardized, but less sophisticated version of TGA that measures mass at endpoints only, with heating generally in air. In this paper we describe the use of TGA and LOI to characterize Portland cement with limestone additions, coal combustion fly ashes, ground-granulated blast furnace slag, calcined clays, and natural pozzolans. This paper outlines the value and limitations of TGA and LOI (in the formats defined in different standards regimes) for material characterization, and describes testing methods and analysis. TGA testing parameters affect the mass loss recorded at temperatures relevant for LOI measurements (700â1000 °C) of slags and fly ashes, mainly associated with oxidation reactions taking place upon heating. TGA of clays and natural pozzolans is utilized to identify optimal calcination conditions leading to dehydroxylation and consequent structural amorphization, particularly for kaolinite. However, dehydroxylation and amorphization do not occur at similar temperatures for all clays, limiting the applicability of TGA for this purpose. Although TGA is widely utilized for characterization of SCMs, the testing parameters significantly affect the results obtained, and TGA results require careful interpretation. Therefore, standardization of TGA testing conditions, particularly for LOI determination of slags and fly ashes, is required
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