bluuebunny/crossref_metadata_2025_split huggingface dataset:
Detection of Clonally Expanded Hepatocytes in Chimpanzees with Chronic Hepatitis B Virus Infection
Authors: Mason William S. , Low Huey-Chi , Xu Chunxiao , Aldrich Carol E. , Scougall Catherine A. , Grosse Arend , Clouston Andrew , Chavez Deborah , Litwin Samuel , Peri Suraj , Jilbert Allison R. , Lanford Robert E. 
Published: June 2009

ABSTRACTDuring a hepadnavirus infection, viral DNA integrates at a low rate into random sites in the host DNA, producing unique virus-cell junctions detectable by inverse nested PCR (invPCR). These junctions serve as genetic markers of individual hepatocytes, providing a means to detect their subsequent proliferation into clones of two or more hepatocytes. A previous study suggested that the livers of 2.4-year-old woodchucks (Marmota monax) chronically infected with woodchuck hepatitis virus contained at least 100,000 clones of >1,000 hepatocytes (W. S. Mason, A. R. Jilbert, and J. Summers, Proc. Natl. Acad. Sci. USA102:1139-1144, 2005). However, possible correlations between sites of viral-DNA integration and clonal expansion could not be explored because the woodchuck genome has not yet been sequenced. In order to further investigate this issue, we looked for similar clonal expansion of hepatocytes in the livers of chimpanzees chronically infected with hepatitis B virus (HBV). Liver samples for invPCR were collected from eight chimpanzees chronically infected with HBV for at least 20 years. Fifty clones ranging in size from ∼35 to 10,000 hepatocytes were detected using invPCR in 32 liver biopsy fragments (∼1 mg) containing, in total, ∼3 × 107liver cells. Based on searching the analogous human genome, integration sites were found on all chromosomes except Y, ∼30% in known or predicted genes. However, no obvious association between the extent of clonal expansion and the integration site was apparent. This suggests that the integration site per se is not responsible for the outgrowth of large clones of hepatocytes.
The Adenovirus E4orf4 Protein Induces G
2
/M Arrest and Cell Death by Blocking Protein Phosphatase 2A Activity Regulated by the B55 Subunit
Authors: Li Suiyang , Brignole Claudine , Marcellus Richard , Thirlwell Sara , Binda Olivier , McQuoid Monica J. , Ashby Danita , Chan Helen , Zhang Zhiying , Miron Marie-Joëlle , Pallas David C. , Branton Philip E. 
Published: June 2009

ABSTRACT

Human adenovirus E4orf4 protein is toxic in human tumor cells. Its interaction with the Bα subunit of protein phosphatase 2A (PP2A) is critical for cell killing; however, the effect of E4orf4 binding is not known. Bα is one of several mammalian B-type regulatory subunits that form PP2A holoenzymes with A and C subunits. Here we show that E4orf4 protein interacts uniquely with B55 family subunits and that cell killing increases with the level of E4orf4 expression. Evidence suggesting that Bα-specific PP2A activity, measured in vitro against phosphoprotein substrates, is reduced by E4orf4 binding was obtained, and two potential B55-specific PP2A substrates, 4E-BP1 and p70
S6K
, were seen to be hypophosphorylated in vivo following expression of E4orf4. Furthermore, treatment of cells with low levels of the phosphatase inhibitor okadaic acid or coexpression of the PP2A inhibitor I
1
PP2A
enhanced E4orf4-induced cell killing and G
2
/M arrest significantly. These results suggested that E4orf4 toxicity results from the inhibition of B55-specific PP2A holoenzymes, an idea that was strengthened by an observed growth arrest resulting from treatment of H1299 cells with Bα-specific RNA interference. We believe that E4orf4 induces growth arrest resulting in cell death by reducing the global level of B55-specific PP2A activity, thus preventing the dephosphorylation of B55-specific PP2A substrates, including those involved in cell cycle progression.
Epigenetic Modulation of Gene Expression from Quiescent Herpes Simplex Virus Genomes
Authors: Ferenczy Michael W. , DeLuca Neal A. 
Published: June 2009

ABSTRACT

The ability of herpes simplex virus to persist in cells depends on the extent of viral-gene expression, which may be controlled by epigenetic mechanisms. We used quiescent infection with the viral mutants d109 and d106 to explore the effects of cell type and the presence of the viral protein ICP0 on the expression and chromatin structure of the human cytomegalovirus (HCMV) tk and gC promoters on the viral genome. Expression from the HCMV promoter on the d109 genome decreased with time and was considerably less in HEL cells than in Vero cells. Expression from the HCMV promoter in d106 was considerably more abundant than in d109, and this increased with time in both cell types. The same pattern of expression was seen on the tk and gC genes on the viral genomes, although the levels of tk and gC RNA were approximately 10
2
- and 10
5
-fold lower than those of wild-type virus in d106 and d109, respectively. In micrococcal-nuclease digestion experiments, nucleosomes were evident on the d109 genome, and the amount of total H3 as determined by chromatin immunoprecipitation was considerably greater on d109 than d106 genomes. The acetylation of histone H3 on the d106 genomes was evident at early and late times postinfection in Vero cells, but only at late times in HEL cells. The same pattern was observed for H3 acetylated on lysine 9. Trimethylation of H3K9 on d109 genomes was evident only at late times postinfection in Vero cells, while it was observed both early and late in HEL cells. Heterochromatin protein 1γ (HP1γ) was generally present only on d109 genomes at late times postinfection of HEL cells. The observations of chromatin structure correlate with the expression patterns of the three analyzed genes on the quiescent genomes. Therefore, several mechanisms generally affect the expression and contribute to the silencing of persisting genomes. These are the abundance of nucleosomes, the acetylation state of the histones, and heterochromatin. The extents to which these different mechanisms contribute to repression vary in different cell types and are counteracted by the presence of ICP0.
Transient Expression of Herpes Simplex Virus Type 1 ICP22 Represses Viral Promoter Activity and Complements the Replication of an ICP22 Null Virus
Authors: Bowman J. Jason , Orlando Joseph S. , Davido David J. , Kushnir Anna S. , Schaffer Priscilla A. 
Published: June 2009

ABSTRACTOf the five herpes simplex virus type 1 immediate early (IE) proteins, the least is known about the function of ICP22 during productive infection and latency. Research characterizing the physical and functional properties of the protein has been limited because ICP22 has proven to be difficult to express in transient assays. In addition, genetic analysis of ICP22 has been complicated by the fact that the C terminus of ICP22 is expressed as a discrete protein product. In order to characterize properties of mutant and wild-type ICP22, we developed a transient expression system. We found that ICP22 can be expressed at detectable levels when placed under the control of the cytomegalovirus IE promoter, confirming recent observations by K. A. Fraser and S. A. Rice (J. Virol. 81:5091-5101, 2007). We extended this analysis to show that ICP22 can also be expressed from its own promoter in the presence of other viral factors, either by coexpression with ICP0 or by infection with an ICP22 null virus. Notably, infection of cells transfected with an ICP22 expression vector yielded ICP22 protein that was modified in a manner similar to that of ICP22 protein detected in wild-type-infected cells. We go on to demonstrate that the failure of ICP22 protein to be expressed in transiently transfected cells was not due to inactivity of the ICP22 promoter, but rather to the ability of ICP22 to inhibit expression of reporter gene activity, including its own, in transient assays. Of special note was the observation that expression of ICP22 was sufficient to prevent transactivation of reporter genes by ICP0. Finally, transient expression of ICP22 was sufficient to complement replication of an ICP22 null virus, demonstrating that this system can be used to study functional properties of ICP22. Collectively, this transient expression system facilitates tests of the physical and functional properties of ICP22 and ICP22 mutants prior to introduction of mutant genes into the viral genome.
Protective Anti-Hepatitis B Virus Responses in Rhesus Monkeys Primed with a Vectored Measles Virus and Boosted with a Single Dose of Hepatitis B Surface Antigen
Authors: Reyes-del Valle Jorge , Hodge Gregory , McChesney Michael B. , Cattaneo Roberto 
Published: June 2009

ABSTRACT
The widely used hepatitis B virus (HBV) vaccine is based on three doses of hepatitis B surface antigen (HBsAg) protein. We previously showed that vectored measles viruses (MV) expressing HBsAg retain measles vaccine function in monkeys but do not induce a protective anti-HBs response in all animals. We show here that a single dose of HBsAg protein following a three-dose vaccination regimen with an optimized HBsAg-expressing MV elicits protective anti-HBs responses in all four vaccinated Rhesus monkeys. Vaccination strategies coupling the effective, long-term immunity elicited by the high-coverage MV vaccine to prophylactic HBV immunity are discussed.
Analysis of Human Immunodeficiency Virus Type 1 Viremia and Provirus in Resting CD4+T Cells Reveals a Novel Source of Residual Viremia in Patients on Antiretroviral Therapy
Authors: Brennan Timothy P. , Woods John O. , Sedaghat Ahmad R. , Siliciano Janet D. , Siliciano Robert F. , Wilke Claus O. 
Published: June 2009

ABSTRACTHighly active antiretroviral therapy (HAART) can reduce human immunodeficiency virus type 1 (HIV-1) viremia to clinically undetectable levels. Despite this dramatic reduction, some virus is present in the blood. In addition, a long-lived latent reservoir for HIV-1 exists in resting memory CD4+T cells. This reservoir is believed to be a source of the residual viremia and is the focus of eradication efforts. Here, we use two measures of population structure—analysis of molecular variance and the Slatkin-Maddison test—to demonstrate that the residual viremia is genetically distinct from proviruses in resting CD4+T cells but that proviruses in resting and activated CD4+T cells belong to a single population. Residual viremia is genetically distinct from proviruses in activated CD4+T cells, monocytes, and unfractionated peripheral blood mononuclear cells. The finding that some of the residual viremia in patients on HAART stems from an unidentified cellular source other than CD4+T cells has implications for eradication efforts.
Suicide among male regular UK Armed Forces personnel, 1984–2007
Authors: Fear N T , Ward V R , Harrison K , Davison L , Williamson S , Blatchley N F 
Published: June 2009

Objective:To examine the number of suicide and open verdict deaths in the regular UK Armed Forces and to make comparisons with the UK general population.Methods:Age and calendar year-adjusted standardised mortality ratios (SMRs) and 95% CI were calculated to compare the number of suicides among the UK Armed Forces with the general population of the UK.Results:Between 1984 and 2007, there were 694 suicide and open verdict deaths among male UK Armed Forces personnel. The UK Armed Forces had statistically significantly fewer suicides than expected compared with the UK general population (SMR = 58, 95% CI 54 to 63, based on 694 deaths). This was evident for each of the three Services (Naval Service, Army and Royal Air Force). For each age group, the number of suicides in each Service was lower than the number expected based on UK general population rates, except for Army males under 20 years of age, where there were 1.5 times more deaths than expected (SMR = 150, 95% CI 118 to 190, based on 68 deaths).Conclusion:The UK Armed Forces are subject to a number of unique occupational stressors, so it is reassuring that they experience lower than expected numbers of suicides in comparison with the UK general population. This is true for each Service and all age groups except young Army males.
The Solvability of a New System of Nonlinear Variational-Like Inclusions
Authors: Liu Zeqing , Liu Min , Ume Jeong Sheok , Kang Shin Min 
Published: June 2009

AbstractWe introduce and study a new system of nonlinear variational-like inclusions involving "Equation missing"-"Equation missing"-maximal monotone operators, strongly monotone operators, "Equation missing"-strongly monotone operators, relaxed monotone operators, cocoercive operators, "Equation missing"-relaxed cocoercive operators, "Equation missing"-"Equation missing"-relaxed cocoercive operators and relaxed Lipschitz operators in Hilbert spaces. By using the resolvent operator technique associated with "Equation missing"-"Equation missing"-maximal monotone operators and Banach contraction principle, we demonstrate the existence and uniqueness of solution for the system of nonlinear variational-like inclusions. The results presented in the paper improve and extend some known results in the literature.
Thiopurine methyltransferase genetics is not a major risk factor for secondary malignant neoplasms after treatment of childhood acute lymphoblastic leukemia on Berlin-Frankfurt-Münster protocols
Authors: Stanulla Martin , Schaeffeler Elke , Möricke Anja , Coulthard Sally A. , Cario Gunnar , Schrauder André , Kaatsch Peter , Dördelmann Michael , Welte Karl , Zimmermann Martin , Reiter Alfred , Eichelbaum Michel , Riehm Hansjörg , Schrappe Martin , Schwab Matthias 
Published: June 2009

AbstractThiopurine methyltransferase (TPMT)is involved in the metabolism of thiopurines such as 6-mercaptopurine and 6-thioguanine. TPMT activity is significantly altered by genetics, and heterozygous and even more homozygous variant people reveal substiantially decreased TPMT activity. Treatment for childhood acute lymphoblastic leukemia (ALL) regularly includes the use of thiopurine drugs. Importantly, childhood ALL patients with low TPMT activity have been considered to be at increased risk of developing therapy-associated acute myeloid leukemia and brain tumors. In the present study, we genotyped 105 of 129 patients who developed a secondary malignant neoplasm after ALL treatment on 7 consecutive German Berlin-Frankfurt-Münster trials for all functionally relevant TPMT variants. Frequencies of TPMT variants were similarly distributed in secondary malignant neoplasm patients and the overall ALL patient population of 814 patients. Thus, TPMT does not play a major role in the etiology of secondary malignant neoplasm after treatment for childhood ALL, according to Berlin-Frankfurt-Münster strategies.
Impact of HLA disparity in the graft-versus-host direction on engraftment in adult patients receiving reduced-intensity cord blood transplantation
Authors: Matsuno Naofumi , Wake Atsushi , Uchida Naoyuki , Ishiwata Kazuya , Araoka Hideki , Takagi Shinsuke , Tsuji Masanori , Yamamoto Hisashi , Kato Daisuke , Matsuhashi Yoshiko , Seo Sachiko , Masuoka Kazuhiro , Miyakoshi Shigesaburo , Makino Shigeyoshi , Yoneyama Akiko , Kanda Yoshinobu , Taniguchi Shuichi 
Published: June 2009

Abstract
Delayed engraftment or graft failure is one of the major complications after cord blood transplantation (CBT). To investigate factors impacting engraftment, we conducted a retrospective analysis of adult patients who underwent reduced-intensity CBT at our institute, in which preparative regimens mainly consisted of fludarabine, melphalan, and total body irradiation with graft-versus-host (GVH) disease prophylaxis using single calcineurin inhibitors. Among 152 evaluable patients, the cumulative incidence of neutrophil engraftment was 89%. High total nucleated cell and CD34+ cell dose were associated with the faster speed and higher probability of engraftment. In addition, the degree of human leukocyte antigen (HLA) mismatch in the GVH direction was inversely associated with engraftment kinetics, whereas no statistically significant association was observed with the degree of HLA mismatch in the host-versus-graft direction. Similarly, the number of HLA class I antigens mismatched in the GVH direction, but not in the host-versus-graft direction, showed a negative correlation with engraftment kinetics. HLA disparity did not have significant impact on the development of GVH disease or survival. This result indicates the significant role of HLA disparity in the GVH direction in the successful engraftment, raising the novel mechanism responsible for graft failure in CBT.
Role of tissue factor in a mouse model of thrombotic microangiopathy induced by antiphospholipid antibodies
Authors: Seshan Surya V. , Franzke Claus-Werner , Redecha Patricia , Monestier Marc , Mackman Nigel , Girardi Guillermina 
Published: June 2009

AbstractUsing different mouse monoclonal and human antiphospholipid (aPL) antibodies, we developed a new animal model of renal injury that shares many features with thrombotic microangiopathy (TMA). We found that more than 1 mechanism/signaling pathway is involved in glomerular injury induced by aPL antibodies in this model. Both complement-dependent and complement-independent pathways were identified that lead to glomerular endothelial cell damage and renal function impairment. We also found that C5a-C5aR interaction is a crucial step for the activation of the coagulation cascade and glomerular injury induced by complement-activating antibodies. In addition, our studies demonstrated complement-independent mechanisms in which reactivity with β2 glycoprotein I (β2GPI) plays an important role in aPL-induced glomerular damage and renal failure. Independently of the mechanism responsible for aPL-induced TMA, mice that express low levels of tissue factor (TF) were protected from glomerular injury. That genetic reduction of TF prevents renal injury induced by different aPL antibodies indicates that TF is a common mediator of glomerular damage and a possible target for selective pharmacologic intervention. Treatment with pravastatin, which down-regulates glomerular TF synthesis, prevents aPL-induced TMA in this mouse model, thus emphasizing that targeting TF might be a good therapeutic intervention in patients with TMA.
KW-2449, a novel multikinase inhibitor, suppresses the growth of leukemia cells with FLT3 mutations or T315I-mutated BCR/ABL translocation
Authors: Shiotsu Yukimasa , Kiyoi Hitoshi , Ishikawa Yuichi , Tanizaki Ryohei , Shimizu Makiko , Umehara Hiroshi , Ishii Kenichi , Mori Yumiko , Ozeki Kazutaka , Minami Yosuke , Abe Akihiro , Maeda Hiroshi , Akiyama Tadakazu , Kanda Yutaka , Sato Yuko , Akinaga Shiro , Naoe Tomoki 
Published: June 2009

Abstract
KW-2449, a multikinase inhibitor of FLT3, ABL, ABL-T315I, and Aurora kinase, is under investigation to treat leukemia patients. In this study, we examined its possible modes of action for antileukemic effects on FLT3-activated, FLT3 wild-type, or imatinib-resistant leukemia cells. KW-2449 showed the potent growth inhibitory effects on leukemia cells with FLT3 mutations by inhibition of the FLT3 kinase, resulting in the down-regulation of phosphorylated-FLT3/STAT5, G1 arrest, and apoptosis. Oral administration of KW-2449 showed dose-dependent and significant tumor growth inhibition in FLT3-mutated xenograft model with minimum bone marrow suppression. In FLT3 wild-type human leukemia, it induced the reduction of phosphorylated histone H3, G2/M arrest, and apoptosis. In imatinib-resistant leukemia, KW-2449 contributed to release of the resistance by the simultaneous down-regulation of BCR/ABL and Aurora kinases. Furthermore, the antiproliferative activity of KW-2449 was confirmed in primary samples from AML and imatinib-resistant patients. The inhibitory activity of KW-2449 is not affected by the presence of human plasma protein, such as α1-acid glycoprotein. These results indicate KW-2449 has potent growth inhibitory activity against various types of leukemia by several mechanisms of action. Our studies indicate KW-2449 has significant activity and warrants clinical study in leukemia patients with FLT3 mutations as well as imatinib-resistant mutations.
MicroRNA: mIR-ly regulators of DNMT?
Authors: Griffiths Elizabeth A. , Gore Steven D. 
Published: June 2009

Abstract
In this issue of Blood, Garzon and colleagues present evidence for a functional role of miR 29b in controlling DNMT levels in leukemia. Their work may provide insight into the mechanism of action of the azanucleotides and could potentially offer the first pharmacologically active miRNA.
Escaping the niche
Authors: Handin Robert 
Published: June 2009

Abstract
In this issue of Blood, Zou and colleagues unravel a long-standing mystery—how megakaryocyte precursors make the transition from the collagen-rich osteoblastic bone marrow niche to the collagen-poor vascular niche while expressing 2 receptors that interact with collagen—GpVI and the α2β1 integrin.
Dissecting VHL-associated pathologies
Authors: Metzen Eric , Brockmeier Ulf 
Published: June 2009

Abstract
In this issue of Blood, van Rooijen and colleagues demonstrate that zebrafish carrying a mutation in the von Hippel Lindau gene (VHL) develop Chuvash polycythemia, a hereditary human disease characterized by the dysregulation of hypoxia-inducible proteins including erythropoietin.
The evolution of YidC/Oxa/Alb3 family in the three domains of life: a phylogenomic analysis
Authors: Zhang Yu-Juan , Tian Hai-Feng , Wen Jian-Fan 
Published: June 2009

Abstract

Background
YidC/Oxa/Alb3 family includes a group of conserved translocases that are essential for protein insertion into inner membranes of bacteria and mitochondria, and thylakoid membranes of chloroplasts. Because mitochondria and chloroplasts are of bacterial origin, Oxa and Alb3, like many other mitochondrial/chloroplastic proteins, are hypothetically derived from the pre-existing protein (YidC) of bacterial endosymbionts. Here, we test this hypothesis and investigate the evolutionary history of the whole YidC/Oxa/Alb3 family in the three domains of life.

Results
Our comprehensive analyses of the phylogenetic distribution and phylogeny of the YidC/Oxa/Alb3 family lead to the following findings: 1) In archaea, YidC homologs are only sporadically distributed in Euryarchaeota; 2) Most bacteria contain only one YidC gene copy; some species in a few taxa (Bacillus, Lactobacillales, Actinobacteria and Clostridia) have two gene copies; 3) Eukaryotic Oxa and Alb3 have two separate prokaryotic origins, but they might not arise directly from the YidC of proteobacteria and cyanobacteria through the endosymbiosis origins of mitochondrium and chloroplast, respectively; 4) An ancient duplication occurred on both Oxa and Alb3 immediately after their origins, and thus most eukaryotes generally bear two Oxa and two Alb3. However, secondary loss, duplication or acquisition of new domain also occurred on the two genes in some lineages, especially in protists, resulting in a rich diversity or adaptive differentiation of the two translocases in these lineages.

Conclusion
YidC is distributed in bacteria and some Euryarchaeota. Although mitochondrial Oxa and chloroplastic Alb3 are derived from the prokaryotic YidC, their origin might be not related to the endosymbiosis events of the two organelles. In some eukaryotic lineages, especially in protists, Oxa and Alb3 have diverse evolutionary histories. Finally, a model for the evolutionary history of the entire YidC/Oxa/Alb3 family in the three domains of life is proposed.