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| 1 | Characterization of hepatitis B virus X gene quasispecies complexity in mono-infection and hepatitis delta virus superinfection显示文摘Hepatitis delta virus(HDV) seems to strongly suppress hepatitis B virus(HBV)replication, although little is known about the mechanism of this interaction. Both these viruses show a dynamic distribution of mutants, resulting in viral quasispecies. Next-generation sequencing is a viable approach for analyzing the composition of these mutant spectra. As the regulatory hepatitis B X protein(HBx) is essential for HBV replication, determination of HBV X gene(HBX)quasispecies complexity in HBV/HDV infection compared to HBV monoinfection may provide information on the interactions between these two viruses.AIM To compare HBV quasispecies complexity in the HBX 5' region between chronic hepatitis delta(CHD) and chronic HBV mono-infected patients.METHODS Twenty-four untreated patients were included: 7/24(29.2%) with HBeAgnegative chronic HBV infection(CI, previously termed inactive carriers), 8/24(33.3%) with HBeAg-negative chronic hepatitis B(CHB) and 9/24(37.5%) with CHD. A serum sample from each patient was first tested for HBV DNA levels.The HBX 5' region [nucleotides(nt) 1255-1611] was then PCR-amplified for subsequent next-generation sequencing(MiSeq, Illumina, United States). HBV quasispecies complexity in the region analyzed was evaluated using incidencebased indices(number of haplotypes and number of mutations), abundancebased indices(Hill numbers of order 1 and 2), and functional indices(mutation frequency and nucleotide diversity). We also evaluated the pattern of nucleotide changes to investigate which of them could be the cause of the quasispecies complexity.RESULTS CHB patients showed higher median HBV-DNA levels [5.4 logIU/mL,interquartile range(IQR) 3.5-7.9] than CHD(3.4 logIU/mL, IQR 3-7.6)(P = n.s.)or CI(3.2 logIU/mL, IQR 2.3-3.5)(P < 0.01) patients. The incidence and abundance indices indicated that HBV quasispecies complexity was significantly greater in CI than CHB. A similar trend was observed in CHD patients, although only Hill numbers of order 2 showed statistically significant differences(CHB2.81, IQR 1.11-4.57 vs CHD 8.87, 6.56-11.18, P = 0.038). There were no significant differences in the functional indices, but CI and CHD patients also showed a trend towards greater complexity than CHB. No differences were found for any HBV quasispecies complexity indices between CHD and CI patients. G-to-A and C-to-T nucleotide changes, characteristic of APOBEC3 G, were higher in CHD and CI than in CHB in genotype A haplotypes, but not in genotype D. The proportion of nt G-to-A vs A-to-G changes and C-to-T vs T-to-C changes in genotype A and D haplotypes in CHD patients showed no significant differences. In CHB and CI the results of these comparisons were dependent on HBV genotype.CONCLUSION The lower-replication CHD and CI groups show a trend to higher quasispecies complexity than the higher-replication CHB group. The mechanisms associated with this greater complexity require elucidation. | Cristina Godoy David Tabernero Sara Sopena Josep Gregori Maria Francesca Cortese Carolina González Rosario Casillas Mar?al Yll Ariadna Rando Rosa López-Martínez Josep Quer Gloria González-Aseguinolaza Rafael Esteban Mar Riveiro-Barciela Maria Buti Francisco Rodríguez-Frías | 2019 | World Journal of Gastroenterology2019，25，13： | 6 |
| 2 | Detection of hyper-conserved regions in hepatitis B virus X gene potentially useful for gene therapy显示文摘AIM To detect hyper-conserved regions in the hepatitis B virus(HBV) X gene(HBX) 5' region that could be candidates for gene therapy.METHODS The study included 27 chronic hepatitis B treatmentnaive patients in various clinical stages(from chronic infection to cirrhosis and hepatocellular carcinoma, both HBeA g-negative and HBeA g-positive), and infected with HBV genotypes A-F and H. In a serum sample from each patient with viremia > 3.5 log IU/m L, the HBX 5' end region [nucleotide(nt) 1255-1611] was PCRamplified and submitted to next-generation sequencing(NGS). We assessed genotype variants by phylogenetic analysis, and evaluated conservation of this region by calculating the information content of each nucleotide position in a multiple alignment of all unique sequences(haplotypes) obtained by NGS. Conservation at the HBx protein amino acid(aa) level was also analyzed.RESULTS NGS yielded 1333069 sequences from the 27 samples, with a median of 4578 sequences/sample(2487-9279, IQR 2817). In 14/27 patients(51.8%), phylogenetic analysis of viral nucleotide haplotypes showed a complex mixture of genotypic variants. Analysis of the information content in the haplotype multiple alignments detected 2 hyper-conserved nucleotide regions, one in the HBX upstream non-coding region(nt 1255-1286) and the other in the 5' end coding region(nt 1519-1603). This last region coded for a conserved amino acid region(aa 63-76) that partially overlaps a Kunitz-like domain.CONCLUSION Two hyper-conserved regions detected in the HBX 5' end may be of value for targeted gene therapy, regardless of the patients' clinical stage or HBV genotype. | Carolina González David Tabernero Maria Francesca Cortese Josep Gregori Rosario Casillas Mar Riveiro-Barciela Cristina Godoy Sara Sopena Ariadna Rando Marcal Yll Rosa Lopez-Martinez Josep Quer Rafael Esteban Maria Buti Francisco Rodríguez-Frías | 2018 | World Journal of Gastroenterology2018，24，19： | 6 |
| 3 | Analysis of hepatitis B virus preS1 variability and prevalence of the rs2296651 polymorphism in a Spanish population显示文摘AIM To determine the variability/conservation of the domain of hepatitis B virus(HBV) pre S1 region that interacts with sodium-taurocholate cotransporting polypeptide(hereafter, NTCP-interacting domain) and the prevalence of the rs2296651 polymorphism(S267 F, NTCP variant) in a Spanish population. METHODS Serum samples from 246 individuals were included and divided into 3 groups: patients with chronic HBV infection(CHB)(n = 41, 73% Caucasians), patients with resolved HBV infection(n = 100, 100% Caucasians) and an HBV-uninfected control group(n = 105, 100% Caucasians). Variability/conservation of the amino acid(aa) sequences of the NTCPinteracting domain,(aa 2-48 in viral genotype D) and a highly conserved pre S1 domain associated with virion morphogenesis(aa 92-103 in viral genotype D) were analyzed by next-generation sequencing and compared in 18 CHB patients with viremia > 4 log IU/mL. The rs2296651 polymorphism was determined in all individuals in all 3 groups using an in-house real-time PCR melting curve analysis.RESULTS The HBV pre S1 NTCP-interacting domain showed a high degree of conservation among the examined viral genomes especially between aa 9 and 21(in the genotype D consensus sequence). As compared with the virion morphogenesis domain, the NTCPinteracting domain had a smaller proportion of HBV genotype-unrelated changes comprising > 1% of the quasispecies(25.5% vs 31.8%), but a larger proportion of genotype-associated viral polymorphisms(34% vs 27.3%), according to consensus sequences from Gen Bank patterns of HBV genotypes A to H. Variation/conservation in both domains depended on viral genotype, with genotype C being the most highly conserved and genotype E the most variable(limited finding, only 2 genotype E included). Of note, proline residues were highly conserved in both domains, and serine residues showed changes only to threonine or tyrosine in the virion morphogenesis domain. The rs2296651 polymorphism was not detected in any participant.CONCLUSION In our CHB population, the NTCP-interacting domain was highly conserved, particularly the proline residues and essential amino acids related with the NTCP interaction, and the prevalence of rs2296651 was low/null. | Rosario Casillas David Tabernero Josep Gregori Irene Belmonte Maria Francesca Cortese Carolina González Mar Riveiro-Barciela Rosa Maria López Josep Quer Rafael Esteban Maria Buti Francisco Rodríguez-Frías | 2018 | World Journal of Gastroenterology2018，24，6： | 5 |
| 4 | Interleukin-9 enhances in?terleukin-5 receptor expression, differentiation , and survival of hu?man eosinophils 显示文摘 | Gounni AS Gregory B Nutku E | 2000 | Blood2000，96，6： | 1 |
| 5 | Fluid Therapy in Resuscitated Sepsis Less Is More显示文摘 | Lakshmi D Gregory AS | 2008 | chest2008，133，： | 1 |
| 6 | A comparative study of ultra-deep pyrosequencing and cloning to quantitatively analyze the viral quasispecies using hepatitis B virus infection as a model显示文摘 | Clara Ramírez Josep Gregori Maria Buti David Tabernero Sílvia Camós Rosario Casillas Josep Quer Rafael Esteban Maria Homs Francisco Rodriguez-Frías | 2013 | Antiviral Research2013，，2： | 1 |
| 7 | Interleukin-9 enhances interleukin-5 receptor expression,differentiation,and survival of human eosinophils显示文摘 | Gounni AS Gregory B Nutku E | 2000 | Blood2000，96，6： | 1 |
| 8 | The effect of long-term soil management on the physical and biological resilience of a range of arable and grassland soils in England显示文摘 | Gregory AS Watts CW Griffiths BS | | 0，，： | 1 |
| 9 | Interleukin-9 enhancesinterleukin-5 receptor expression differentiation and survival of human eosinophils 显示文摘 | Gounni AS Gregory B Nutku E | 2000 | Blood2000，96，6： | 1 |
| 10 | Impairments in microvascular reactivity are related to organ failure in human sepsis显示文摘 | Kevin CD Angela SD Gregory AS | 2007 | Am J Physiol Heart Circ Physiol2007，293，2： | 1 |
| 11 | The Wnt signaling inhibitor dickkopf-1 is required for reentry into the cell cycle of human adult stem cells from bone marrow显示文摘 | Gregory CA Singh H Perry AS | 2003 | J Biol Chem2003，278，28： | 1 |
| 12 | Robot Hand-Eye Coordination Based on Stereo Vision 显示文摘 | Gregory D Hager Wen-Chung Chang AS Morse | 1995 | IEEE Control Systems Magazine1995，15，1： | 1 |
| 13 | Fluid therapy in resuscitated sepsis,less is more显示文摘 | Lakshmi D Gregory AS | 2008 | Chest2008，133，： | 1 |
| 14 | Interleukin-9 enhances interleukin-5 receptor expression,differentiation,and survival of human eosinophils显示文摘 | Gounni AS Gregory B Nutku E | 1996 | Blood1996，，6： | 1 |
| 15 | Interleukin-9 enhances interleukin-5 receptor expression, differentiation and survival of human eosinophils 显示文摘 | Gounni AS Gregory B Nutku E | 2000 | Blood2000，96，6： | 1 |
| 16 | Dkk-l-derived synthetic peptides and lithium chloride for the control and recovery of adult stem cells from bone marrow 显示文摘 | Gregory CA Perry AS Reyes E | 2005 | J Biol Chem2005，280，3： | 1 |
| 17 | Lentiviral-mediated RNAi inhibition of Sbds in murine hematopoietic progenitors impairs their hematopoietic potential显示文摘 | Rawls AS Gregory AD Woloszynek JR | 2007 | Blood2007，110，7： | 1 |
| 18 | Molecular epidemiology and putative origin of hepatitis C virus in random volunteers from Argentina显示文摘AIM:To study the subtype prevalence and the phylogenetic relatedness of hepatitis C virus(HCV)sequences obtained from the Argentine general population,a large cohort of individuals was analyzed.METHODS:Healthy Argentinian volunteers(n=6251)from 12 provinces representing all geographical regions of the country were studied.All parents or legal guardians of individuals younger than 18 years provided informed written consent for participation.The corresponding written permission from all municipal authorities was obtained from each city or town where subjects were to be included.HCV RNA reverse transcription-polymerase chain reaction products were sequenced and phylogenetically analyzed.The 5’untranslated region(5’UTR)was used for RNA detection and initial genotype classification.The NS5B polymerase region,encompassing nt 8262-8610,was used for subtyping.RESULTS:An unexpectedly low prevalence of HCV infection in the general population(0.32%)was observed.Our data contrasted with previous studies that reported rates ranging from 1.5%to 2.5%,mainly performed in selected populations of blood donors or vulnerable groups.The latter values are in keeping with the prevalence reported by the 2007 Argentinian HCV Consensus(approximately 2%).HCV subtypes weredistributed as follows:1a(25%),1b(25%),2c(25%),3a(5%),and 2j(5%).Two isolates ascribed either to genotype 1(5%)or to genotype 3(5%)by 5’UTR phylogenetic analysis could not be subtyped.Subtype 1a sequences comprised a highly homogeneous population and clustered with United States sequences.Genotype1b sequences represented a heterogeneous population,suggesting that this genotype might have been introduced from different sources.Most subtype 2c sequences clustered close to the 2c reported from Italy and Southern France.CONCLUSION:HCV has a low prevalence of 0.32%in the studied general population of Argentina.The pattern of HCV introduction and transmission in Argentina appears to be a consequence of multiple events and different for each subtype. | Noemí del Pino José Raúl Oubia Francisco Rodríguez-Frías Juan Ignacio Esteban María Buti Teresa Otero Josep Gregori Damir García-Cehic Silvia Camos María Cubero Rosario Casillas Jaume Guàrdia Rafael Esteban Josep Quer | 2013 | World Journal of Gastroenterology2013，19，35： | 1 |
| 19 | Intedeukin-9 enhancesinter- leukin-5 receptor expression differentiation and survival of human eo- sinophils显示文摘 | Gounni AS Gregory B Nutku E | 2000 | Blood2000，96，6： | 1 |
| 20 | The Wnt signaling inhibitor Dickkopf-1 is required for reentry into the cell cycle of human adult stem cells from bone marrow显示文摘 | Gregory CA Slngh H Perry AS | 2003 | J Biol Chem2003，278，28： | 1 |
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