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Background Photoperiod signals provide important cues by which plants regulate their growth and development in response to predictable seasonal changes. Phytochromes, a family of red and far-red light receptors, play critical roles in regulating flowering time in response to changing photoperiods. A previous study showed that loss-of-function mutations in either PHYB or PHYC result in large delays in heading time and in the differential regulation of a large number of genes in wheat plants grown in an inductive long day (LD) photoperiod. Results We found that under non-inductive short-day (SD) photoperiods, phyB-null and phyC-null mutants were taller, had a reduced number of tillers, longer and wider leaves, and headed later than wild-type (WT) plants. The delay in heading between WT and phy mutants was greater in LD than in SD, confirming the importance of PHYB and PHYC in accelerating heading date in LDs. Both mutants flowered earlier in SD than LD, the inverse response to that of WT plants. In both SD and LD photoperiods, PHYB regulated more genes than PHYC. We identified subsets of differentially expressed and alternatively spliced genes that were specifically regulated by PHYB and PHYC in either SD or LD photoperiods, and a smaller set of genes that were regulated in both photoperiods. We found that photoperiod had a contrasting effect on transcript levels of the flowering promoting genes VRN-A1 and PPD-B1 in phyB and phyC mutants compared to the WT. Conclusions Our study confirms the major role of both PHYB and PHYC in flowering promotion in LD conditions. Transcriptome characterization revealed an unexpected reversion of the wheat LD plants into SD plants in the phyB-null and phyC-null mutants and identified flowering genes showing significant interactions between phytochromes and photoperiod that may be involved in this phenomenon. Our RNA-seq data provides insight into light signaling pathways in inductive and non-inductive photoperiods and a set of candidate genes to dissect the underlying developmental regulatory networks in wheat.
Nestor Kippes; Carl Vangessel; James Hamilton; Ani Akpinar; Hikmet Budak; Jorge Dubcovsky; Stephen Pearce. Effect of phyB and phyC loss-of-function mutations on the wheat transcriptome under short and long day photoperiods. BMC Plant Biology 2020, 20, 1 -17.
AMA StyleNestor Kippes, Carl Vangessel, James Hamilton, Ani Akpinar, Hikmet Budak, Jorge Dubcovsky, Stephen Pearce. Effect of phyB and phyC loss-of-function mutations on the wheat transcriptome under short and long day photoperiods. BMC Plant Biology. 2020; 20 (1):1-17.
Chicago/Turabian StyleNestor Kippes; Carl Vangessel; James Hamilton; Ani Akpinar; Hikmet Budak; Jorge Dubcovsky; Stephen Pearce. 2020. "Effect of phyB and phyC loss-of-function mutations on the wheat transcriptome under short and long day photoperiods." BMC Plant Biology 20, no. 1: 1-17.
BackgroundPhotoperiod signals provide important cues by which plants regulate their growth and development in response to predictable seasonal changes. Phytochromes, a family of red and far-red light receptors, play critical roles in regulating flowering time in response to changing photoperiods. A previous study showed that loss-of-function mutations in either PHYB or PHYC result in large delays in heading time and in the differential regulation of a large number of genes in wheat plants grown in an inductive long day (LD) photoperiod.ResultsWe found that under non-inductive short-day (SD) photoperiods, phyB-null and phyC-null mutants were taller, had a reduced number of tillers, longer and wider leaves, and headed later than wild-type plants. Unexpectedly, both mutants flowered earlier in SD than LD, the inverse response to that of wild-type plants. We observed a larger number of differentially expressed genes between mutants and wild-type under SD than under LD, and in both cases, the number was larger for phyB than for phyC. We identified subsets of differentially expressed and alternatively spliced genes that were specifically regulated by PHYB and PHYC in either SD or LD photoperiods, and a smaller set of genes that were regulated in both photoperiods. We observed significantly higher transcript levels of the flowering promoting genes VRN-A1, PPD-B1 and GIGANTEA in the phy-null mutants in SD than in LD, which suggests that they could contribute to the earlier flowering of the phy-null mutants in SD than in LD.ConclusionsOur study revealed an unexpected reversion of the wheat LD plants into SD plants in the phyB-null and phyC-null mutants and identified candidate genes potentially involved in this phenomenon. Our RNA-seq data provides insight into light signaling pathways in inductive and non-inductive photoperiods and a set of candidate genes to dissect the underlying developmental regulatory networks in wheat.
Nestor Kippes; Carl Vangessel; James Hamilton; Ani Akpinar; Hikmet Budak; Jorge Dubcovsky; Stephen Pearce. Effect of phyB and phyC loss-of-function mutations on the wheat transcriptome under short and long day photoperiods. 2020, 1 .
AMA StyleNestor Kippes, Carl Vangessel, James Hamilton, Ani Akpinar, Hikmet Budak, Jorge Dubcovsky, Stephen Pearce. Effect of phyB and phyC loss-of-function mutations on the wheat transcriptome under short and long day photoperiods. . 2020; ():1.
Chicago/Turabian StyleNestor Kippes; Carl Vangessel; James Hamilton; Ani Akpinar; Hikmet Budak; Jorge Dubcovsky; Stephen Pearce. 2020. "Effect of phyB and phyC loss-of-function mutations on the wheat transcriptome under short and long day photoperiods." , no. : 1.
In the original version of this article, PCR fragments and digestion product sizes for the VRN-B2 and VRN-D2 markers were not accurate. The corrected sizes are detailed below.
Nestor Kippes; Andrew Chen; Xiaoqin Zhang; Adam J. Lukaszewski; Jorge Dubcovsky. Correction to: Development and characterization of a spring hexaploid wheat line with no functional VRN2 genes. Theoretical and Applied Genetics 2018, 131, 2269 -2269.
AMA StyleNestor Kippes, Andrew Chen, Xiaoqin Zhang, Adam J. Lukaszewski, Jorge Dubcovsky. Correction to: Development and characterization of a spring hexaploid wheat line with no functional VRN2 genes. Theoretical and Applied Genetics. 2018; 131 (10):2269-2269.
Chicago/Turabian StyleNestor Kippes; Andrew Chen; Xiaoqin Zhang; Adam J. Lukaszewski; Jorge Dubcovsky. 2018. "Correction to: Development and characterization of a spring hexaploid wheat line with no functional VRN2 genes." Theoretical and Applied Genetics 131, no. 10: 2269-2269.
Winter wheats require a long exposure to cold temperatures (vernalization) to accelerate flowering. However, varieties differ in the length of the period of cold required to saturate the vernalization response. Here we show that single nucleotide polymorphisms (SNP) at the binding site of the GRP2 protein in the VRN-A1 first intron (henceforth, RIP3) are associated with significant differences in heading time after a partial vernalization treatment. The ancestral winter VRN-A1 allele in 'Triple Dirk C' has one SNP in the RIP3 region (1_SNP) relative to the canonical RIP3 sequence, whereas the derived 'Jagger' allele has three SNPs (3_SNPs). Both varieties have a single VRN-A1 copy encoding identical proteins. In an F2 population generated from a cross between these two varieties, plants with the 3_SNPs haplotype headed significantly earlier (P < 0.001) than those with the 1_SNP haplotype, both in the absence of vernalization (17 days difference) and after 3-weeks of vernalization (11 days difference). Plants with the 3_SNPs haplotype showed higher VRN-A1 transcript levels than those with the 1_SNP haplotype. The 3_SNPs haplotype was also associated with early heading in a panel of 127 winter wheat varieties grown in three separate controlled-environment experiments under partial vernalization (36 to 54 days, P < 0.001) and one experiment under field conditions (21 d, P < 0.0001). The RIP3 polymorphisms can be used by wheat breeders to develop winter wheat varieties adapted to regions with different duration or intensity of the cold season.
Néstor Kippes; Mohammed Guedira; Lijuan Lin; María A. Alvarez; Gina L. Brown-Guedira; Jorge Dubcovsky. Single nucleotide polymorphisms in a regulatory site of VRN-A1 first intron are associated with differences in vernalization requirement in winter wheat. Molecular Genetics and Genomics 2018, 293, 1231 -1243.
AMA StyleNéstor Kippes, Mohammed Guedira, Lijuan Lin, María A. Alvarez, Gina L. Brown-Guedira, Jorge Dubcovsky. Single nucleotide polymorphisms in a regulatory site of VRN-A1 first intron are associated with differences in vernalization requirement in winter wheat. Molecular Genetics and Genomics. 2018; 293 (5):1231-1243.
Chicago/Turabian StyleNéstor Kippes; Mohammed Guedira; Lijuan Lin; María A. Alvarez; Gina L. Brown-Guedira; Jorge Dubcovsky. 2018. "Single nucleotide polymorphisms in a regulatory site of VRN-A1 first intron are associated with differences in vernalization requirement in winter wheat." Molecular Genetics and Genomics 293, no. 5: 1231-1243.
In cereal crops such as wheat, an optimal timing of developmental transitions is required to maximize grain yield. Many of these developmental changes are precisely regulated by changes in the duration, intensity or quality of light. Phytochromes are dimeric photoreceptors that absorb light maximally in the red and far-red wavelengths and induce large-scale transcriptional changes in response to variation in light quality. In wheat, PHYC is required for early flowering under long days. However, it is currently unknown whether this function requires the presence of PHYB. In this study, we characterized the role of PHYB in wheat development and used RNA-seq to analyze and compare the transcriptomes of phyB-null and phyC-null TILLING mutants. Under long-day photoperiods, phyB-null plants exhibit a severe delay in flowering comparable to the delay observed in phyC-null plants. These results demonstrate that both genes are required for the induction of wheat flowering under long days. Using replicated RNA-seq studies we identified 82 genes that are significantly up or down regulated in both the phyB-null and phyC-null mutant relative to their respective wild-type controls. Among these genes are several well-characterized positive regulators of flowering, including PPD1, FT1 and VRN1. Eight-fold more genes were differentially regulated only in the phyB-null mutant (2202) than only in the phyC-null mutant (261). The PHYB-regulated genes were enriched in components of the auxin, gibberellin and brassinosteroid biosynthesis and signaling pathways, and in transcription factors with putative roles in regulating vegetative development and shade-avoidance responses. Several genes involved in abiotic stress tolerance pathways were also found to be regulated by PHYB. PHYB and PHYC are both required for the photoperiodic induction of wheat flowering, whereas PHYB alone regulates a large number of genes involved in hormone biosynthesis and signaling, shade-avoidance response, and abiotic stress tolerance. Our analysis provides a comprehensive overview of the PHYB- and PHYC-mediated transcriptional changes during light signaling, and an initial step towards the dissection of this regulatory gene network in wheat. This further dissection will be required to explore the individual phytochrome-mediated developmental responses and to evaluate their potential to improve wheat adaptation to changing environments. The online version of this article (doi:10.1186/s12870-016-0831-3) contains supplementary material, which is available to authorized users.
Stephen Pearce; Nestor Kippes; Andrew Chen; Juan Manuel Debernardi; Jorge Dubcovsky. RNA-seq studies using wheat PHYTOCHROME B and PHYTOCHROME C mutants reveal shared and specific functions in the regulation of flowering and shade-avoidance pathways. BMC Plant Biology 2016, 16, 141 .
AMA StyleStephen Pearce, Nestor Kippes, Andrew Chen, Juan Manuel Debernardi, Jorge Dubcovsky. RNA-seq studies using wheat PHYTOCHROME B and PHYTOCHROME C mutants reveal shared and specific functions in the regulation of flowering and shade-avoidance pathways. BMC Plant Biology. 2016; 16 (1):141.
Chicago/Turabian StyleStephen Pearce; Nestor Kippes; Andrew Chen; Juan Manuel Debernardi; Jorge Dubcovsky. 2016. "RNA-seq studies using wheat PHYTOCHROME B and PHYTOCHROME C mutants reveal shared and specific functions in the regulation of flowering and shade-avoidance pathways." BMC Plant Biology 16, no. 1: 141.
The combination of three non-functional alleles of the flowering repressor VRN2 results in a spring growth habit in wheat. In temperate cereals with a winter growth habit, a prolonged exposure to low temperatures (vernalization) accelerates flowering. Before vernalization, the VRN2 locus plays a central role in maintaining flowering repression. Non-functional VRN2 alleles result in spring growth habit and are frequent in diploid wheat and barley. However, in hexaploid wheat, the effect of these non-functional VRN2 alleles is masked by gene redundancy. In this study, we developed a triple VRN2 mutant (synthetic vrn2-null) in hexaploid wheat by combining the non-functional VRN-A2 allele present in most polyploid wheats with a VRN-B2 deletion from tetraploid wheat, and a non-functional VRN-D2 allele from Aegilops tauschii (Ae. tauschii) (the donor of hexaploid wheat D genome). Non-vernalized vrn2-null plants flowered 118 days (P < 2.8E-07) earlier than the winter control, and showed a limited vernalization response. The functional VRN-B2 allele is expressed at higher levels than the functional VRN-D2 allele and showed a stronger repressive effect under partial vernalization (4 °C for 4 weeks), and also in non-vernalized plants carrying only a functional VRN-B2 or VRN-D2 in heterozygous state. These results suggest that different combinations of VRN-B2 and VRN-D2 alleles can be a used to modulate the vernalization response in regions with mild winters. Spring vrn2-null mutants have been selected repeatedly in diploid wheat and barley, suggesting that they may have an adaptative value and that may be useful in hexaploid wheat. Spring wheat breeders can use these new alleles to improve wheat adaptation to different or changing environments.
Nestor Kippes; Andrew Chen; Xiaoqin Zhang; Adam J. Lukaszewski; Jorge Dubcovsky. Development and characterization of a spring hexaploid wheat line with no functional VRN2 genes. Theoretical and Applied Genetics 2016, 129, 1417 -1428.
AMA StyleNestor Kippes, Andrew Chen, Xiaoqin Zhang, Adam J. Lukaszewski, Jorge Dubcovsky. Development and characterization of a spring hexaploid wheat line with no functional VRN2 genes. Theoretical and Applied Genetics. 2016; 129 (7):1417-1428.
Chicago/Turabian StyleNestor Kippes; Andrew Chen; Xiaoqin Zhang; Adam J. Lukaszewski; Jorge Dubcovsky. 2016. "Development and characterization of a spring hexaploid wheat line with no functional VRN2 genes." Theoretical and Applied Genetics 129, no. 7: 1417-1428.
Wheat varieties with a winter growth habit require long exposures to low temperatures (vernalization) to accelerate flowering. Natural variation in four vernalization genes regulating this requirement has favored wheat adaptation to different environments. The first three genes (VRN1–VRN3) have been cloned and characterized before. Here we show that the fourth gene,VRN-D4, originated by the insertion of a ∼290-kb region from chromosome arm 5AL into the proximal region of chromosome arm 5DS. The inserted 5AL region includes a copy ofVRN-A1that carries distinctive mutations in its coding and regulatory regions. Three lines of evidence confirmed that this gene isVRN-D4: it cosegregated withVRN-D4in a high-density mapping population; it was expressed earlier than otherVRN1genes in the absence of vernalization; and induced mutations in this gene resulted in delayed flowering.VRN-D4was found in most accessions of the ancient subspeciesTriticum aestivumssp.sphaerococcumfrom South Asia. This subspecies showed a significant reduction of genetic diversity and increased genetic differentiation in the centromeric region of chromosome 5D, suggesting thatVRN-D4likely contributed to local adaptation and was favored by positive selection. Three adjacent SNPs in a regulatory region of theVRN-D4first intron disrupt the binding ofGLYCINE-RICH RNA-BINDING PROTEIN 2(TaGRP2), a known repressor ofVRN1expression. The same SNPs were identified inVRN-A1alleles previously associated with reduced vernalization requirement. These alleles can be used to modulate vernalization requirements and to develop wheat varieties better adapted to different or changing environments.
Nestor Kippes; Juan Debernardi; Hans A. Vasquez-Gross; Bala Ani Akpinar; Hikmet Budak; Kenji Kato; Shiaoman Chao; Eduard Akhunov; Jorge Dubcovsky. Identification of theVERNALIZATION 4gene reveals the origin of spring growth habit in ancient wheats from South Asia. Proceedings of the National Academy of Sciences 2015, 112, E5401 -E5410.
AMA StyleNestor Kippes, Juan Debernardi, Hans A. Vasquez-Gross, Bala Ani Akpinar, Hikmet Budak, Kenji Kato, Shiaoman Chao, Eduard Akhunov, Jorge Dubcovsky. Identification of theVERNALIZATION 4gene reveals the origin of spring growth habit in ancient wheats from South Asia. Proceedings of the National Academy of Sciences. 2015; 112 (39):E5401-E5410.
Chicago/Turabian StyleNestor Kippes; Juan Debernardi; Hans A. Vasquez-Gross; Bala Ani Akpinar; Hikmet Budak; Kenji Kato; Shiaoman Chao; Eduard Akhunov; Jorge Dubcovsky. 2015. "Identification of theVERNALIZATION 4gene reveals the origin of spring growth habit in ancient wheats from South Asia." Proceedings of the National Academy of Sciences 112, no. 39: E5401-E5410.
Wheat vernalization requirement is mainly controlled by the VRN1, VRN2, VRN3, and VRN4 genes. The first three have been cloned and have homoeologs in all three genomes. VRN4 has been found only in the D genome (VRN-D4) and has not been cloned. We constructed a high-density genetic map of the VRN-D4 region and mapped VRN-D4 within a 0.09 cM interval in the centromeric region of chromosome 5D. Using telocentric 5D chromosomes generated from the VRN-D4 donor Triple Dirk F, we determined that VRN-D4 is located on the short arm. The VRN-D4 candidate region is colinear with a 2.24 Mb region on Brachypodium distachyon chromosome 4, which includes 127 predicted genes. Ten of these genes have predicted roles in development but we detected no functional polymorphisms associated to VRN-D4. Two recombination events separated VRN-D4 from TaVIL-D1, the wheat homolog of Arabidopsis vernalization gene VIL1, confirming that this gene is not a candidate for VRN-D4. We detected significant interactions between VRN-D4 and other four genes controlling vernalization requirement (Vrn-A1, Vrn-B1, Vrn-D1, and Vrn-B3), which confirmed that VRN-D4 is part of the vernalization pathway and that it is either upstream or is part of the regulatory feedback loop involving VRN1, VRN2 and VRN3 genes. The precise mapping of VRN-D4 and the characterization of its interactions with other vernalization genes provide valuable information for the utilization of VRN-D4 in wheat improvement and for our current efforts to clone this vernalization gene.
Néstor Kippes; Jie Zhu; Andrew Chen; Leonardo Vanzetti; Adam Lukaszewski; Hidetaka Nishida; Kenji Kato; Jan Dvorak; Jorge Dubcovsky. Fine mapping and epistatic interactions of the vernalization gene VRN-D4 in hexaploid wheat. Molecular Genetics and Genomics 2013, 289, 47 -62.
AMA StyleNéstor Kippes, Jie Zhu, Andrew Chen, Leonardo Vanzetti, Adam Lukaszewski, Hidetaka Nishida, Kenji Kato, Jan Dvorak, Jorge Dubcovsky. Fine mapping and epistatic interactions of the vernalization gene VRN-D4 in hexaploid wheat. Molecular Genetics and Genomics. 2013; 289 (1):47-62.
Chicago/Turabian StyleNéstor Kippes; Jie Zhu; Andrew Chen; Leonardo Vanzetti; Adam Lukaszewski; Hidetaka Nishida; Kenji Kato; Jan Dvorak; Jorge Dubcovsky. 2013. "Fine mapping and epistatic interactions of the vernalization gene VRN-D4 in hexaploid wheat." Molecular Genetics and Genomics 289, no. 1: 47-62.
Secreted Protein, Acidic and Rich in Cysteine (SPARC) is a matricellular protein involved in many biological processes and found over-expressed in cirrhotic livers. By mean of a genetic approach we herein provide evidence from different in vivo liver disease models suggesting a profibrogenic role for SPARC. Two in vivo models of liver fibrosis, based on TAA administration and bile duct ligation, were developed on SPARC wild-type (SPARC+/+) and knock-out (SPARC−/−) mice. Hepatic SPARC expression was analyzed by qPCR. Fibrosis was assessed by Sirius Red staining, and the maturation state of collagen fibers was analyzed using polarized light. Necroinflammatory activity was evaluated by applying the Knodell score and liver inflammatory infiltration was characterized by immunohistochemistry. Hepatic stellate cell activation was assessed by α-SMA immunohistochemistry. In addition, pro-fibrogenic genes and inflammatory cytokines were measured by qPCR and/or ELISA. Liver gene expression profile was analyzed in SPARC−/− and SPARC+/+ mice using Affymetrix Mouse Gene ST 1.0 array. SPARC expression was found induced in fibrotic livers of mouse and human. SPARC−/− mice showed a reduction in the degree of inflammation, mainly CD4+ cells, and fibrosis. Consistently, collagen deposits and mRNA expression levels were decreased in SPARC−/− mice when compared to SPARC+/+ mice; in addition, MMP-2 expression was increased in SPARC−/− mice. A reduction in the number of activated myofibroblasts was observed. Moreover, TGF-β1 expression levels were down-regulated in the liver as well as in the serum of TAA-treated knock-out animals. Ingenuity Pathway Analysis (IPA) analysis suggested several gene networks which might involve protective mechanisms of SPARC deficiency against liver fibrogenesis and a better established machinery to repair DNA and detoxify from external chemical stimuli. Overall our data suggest that SPARC plays a significant role in liver fibrogenesis. Interventions to inhibit SPARC expression are suggested as promising approaches for liver fibrosis treatment.
Catalina Atorrasagasti; Estanislao Peixoto; Jorge B. Aquino; Néstor Kippes; Mariana Malvicini; Laura Alaniz; Mariana García; Flavia Piccioni; Esteban J. Fiore; Juan Bayo; Ramon Bataller; Elizabeth Guruceaga; Fernando Corrales; Osvaldo Podhajcer; Guillermo Mazzolini. Lack of the Matricellular Protein SPARC (Secreted Protein, Acidic and Rich in Cysteine) Attenuates Liver Fibrogenesis in Mice. PLOS ONE 2013, 8, e54962 .
AMA StyleCatalina Atorrasagasti, Estanislao Peixoto, Jorge B. Aquino, Néstor Kippes, Mariana Malvicini, Laura Alaniz, Mariana García, Flavia Piccioni, Esteban J. Fiore, Juan Bayo, Ramon Bataller, Elizabeth Guruceaga, Fernando Corrales, Osvaldo Podhajcer, Guillermo Mazzolini. Lack of the Matricellular Protein SPARC (Secreted Protein, Acidic and Rich in Cysteine) Attenuates Liver Fibrogenesis in Mice. PLOS ONE. 2013; 8 (2):e54962.
Chicago/Turabian StyleCatalina Atorrasagasti; Estanislao Peixoto; Jorge B. Aquino; Néstor Kippes; Mariana Malvicini; Laura Alaniz; Mariana García; Flavia Piccioni; Esteban J. Fiore; Juan Bayo; Ramon Bataller; Elizabeth Guruceaga; Fernando Corrales; Osvaldo Podhajcer; Guillermo Mazzolini. 2013. "Lack of the Matricellular Protein SPARC (Secreted Protein, Acidic and Rich in Cysteine) Attenuates Liver Fibrogenesis in Mice." PLOS ONE 8, no. 2: e54962.
Liver cirrhosis is characterized by an excessive accumulation of extracellular matrix components, including hyaluronan (HA). In addition, cirrhosis is considered a pre-neoplastic disease for hepatocellular carcinoma (HCC). Altered HA biosynthesis is associated with cancer progression but its role in HCC is unknown. 4-Methylumbelliferone (4-MU), an orally available agent, is an HA synthesis inhibitor with anticancer properties. In this work, we used an orthotopic Hepa129 HCC model established in fibrotic livers induced by thioacetamide. We evaluated 4-MU effects on HCC cells and hepatic stellate cells (HSCs) in vitro by proliferation, apoptosis and cytotoxicity assays; tumor growth and fibrogenesis were also analyzed in vivo. Our results showed that treatment of HCC cells with 4-MU significantly reduced tumor cell proliferation and induced apoptosis, while primary cultured hepatocytes remained unaffected. 4-MU therapy reduced hepatic and systemic levels of HA. Tumors systemically treated with 4-MU showed the extensive areas of necrosis, inflammatory infiltrate and 2–3-fold reduced number of tumor satellites. No signs of toxicity were observed after 4-MU therapy. Animals treated with 4-MU developed a reduced fibrosis degree compared with controls (F1-2 vs F2-3, respectively). Importantly, 4-MU induced the apoptosis of HSCs in vitro and decreased the amount of activated HSCs in vivo. In conclusion, our results suggest a role for 4-MU as an anticancer agent for HCC associated with advanced fibrosis.
Flavia Piccioni; Mariana Malvicini; Mariana G Garcia; Andrés Rodriguez; Catalina Atorrasagasti; Nestor Kippes; Ignacio T Piedra Buena; Manglio M Rizzo; Juan Bayo; Jorge B Aquino; Manuela Viola; Alberto Passi; Laura Alaniz; Guillermo Mazzolini. Antitumor effects of hyaluronic acid inhibitor 4-methylumbelliferone in an orthotopic hepatocellular carcinoma model in mice. Glycobiology 2011, 22, 400 -410.
AMA StyleFlavia Piccioni, Mariana Malvicini, Mariana G Garcia, Andrés Rodriguez, Catalina Atorrasagasti, Nestor Kippes, Ignacio T Piedra Buena, Manglio M Rizzo, Juan Bayo, Jorge B Aquino, Manuela Viola, Alberto Passi, Laura Alaniz, Guillermo Mazzolini. Antitumor effects of hyaluronic acid inhibitor 4-methylumbelliferone in an orthotopic hepatocellular carcinoma model in mice. Glycobiology. 2011; 22 (3):400-410.
Chicago/Turabian StyleFlavia Piccioni; Mariana Malvicini; Mariana G Garcia; Andrés Rodriguez; Catalina Atorrasagasti; Nestor Kippes; Ignacio T Piedra Buena; Manglio M Rizzo; Juan Bayo; Jorge B Aquino; Manuela Viola; Alberto Passi; Laura Alaniz; Guillermo Mazzolini. 2011. "Antitumor effects of hyaluronic acid inhibitor 4-methylumbelliferone in an orthotopic hepatocellular carcinoma model in mice." Glycobiology 22, no. 3: 400-410.