bluuebunny/crossref_metadata_2025_split huggingface dataset:
The role of the hepatocyte cytokeratin network in bile formation and resistance to bile acid challenge and cholestasis in mice #
Authors: Fickert Peter , Fuchsbichler Andrea , Wagner Martin , Silbert Dagmar , Zatloukal Kurt , Denk Helmut , Trauner Michael 
Published: May 2009

Abstract
The intermediate filament cytoskeleton of hepatocytes is composed of keratin (K) 8 and K18 and has important mechanical and nonmechanical functions. However, the potential role of the K8/K18 network for proper membrane targeting of hepatocellular adenosine triphosphate–binding cassette transporters and bile formation is unknown. We therefore designed a comparative study in K8 and K18 knockout mice and respective wild-type controls to test the hypothesis that intermediate filaments of hepatocytes play a role in normal bile formation. In addition, we challenged mice either with a 1% cholic acid–supplemented diet or a diet containing the porphyrinogenic xenobiotic 3,5-diethoxycarbonyl-1,4-dihydrocollidine to determine the effect of K8/K18 loss on bile flow/composition and liver injury under different physiological and toxic stress stimuli. Protein expression levels and membrane localization of various transporters and anion exchangers were compared using western blotting and immunofluorescence microscopy, respectively, and bile flow and composition were determined under various experimental conditions. Our results demonstrate that loss of the intermediate filament network had no significant effect on bile formation and composition, as well as expression levels and membrane targeting of key hepatobiliary transporters under baseline and stress conditions. However, loss of K8 significantly increased liver injury in response to toxic stress. Conclusion: The intermediate filament network of hepatocytes is not specifically required for proper bile formation in mice. (Hepatology 2009.)
E2F4 and ribonucleotide reductase mediate S‐phase arrest in colon cancer cells treated with chlorophyllin
Authors: Chimploy Korakod , Díaz G. Dario , Li Qingjie , Carter Orianna , Dashwood Wan‐Mohaiza , Mathews Christopher K. , Williams David E. , Bailey George S. , Dashwood Roderick H. 
Published: May 2009

AbstractChlorophyllin (CHL) is a water‐soluble derivative of chlorophyll that exhibits cancer chemopreventive properties, but which also has been studied for its possible cancer therapeutic effects. We report here that human colon cancer cells treated with CHL accumulate in S‐phase of the cell cycle, and this is associated with reduced expression levels of p53, p21, and other G1/S checkpoint controls. At the same time, E2F1 and E2F4 transcription factors become elevated and exhibit increased DNA binding activity. In CHL‐treated colon cancer cells, bromodeoxyuridine pulse‐chase experiments provided evidence for the inhibition of DNA synthesis. Ribonucleotide reductase (RR), a pivotal enzyme for DNA synthesis and repair, was reduced at the mRNA and protein level after CHL treatment, and the enzymatic activity was inhibited in a concentration‐dependent manner both in vitro and in vivo. Immunoblotting revealed that expression levels of RR subunits R1, R2, and p53R2 were reduced by CHL treatment in HCT116 (p53+/+) and HCT116 (p53−/−) cells, supporting a p53‐independent mechanism. Prior studies have shown that reduced levels of RR small subunits can increase the sensitivity of colon cancer cells to clinically used DNA‐damaging agents and RR inhibitors. We conclude that by inhibiting R1, R2, and p53R2, CHL has the potential to be effective in the clinical setting, when used alone or in combination with currently available cancer therapeutic agents. © 2009 UICC
Characteristics of menstruation and pregnancy and the risk of lung cancer in women
Authors: Koushik Anita , Parent Marie‐Élise , Siemiatycki Jack 
Published: May 2009

AbstractLung tissue, both normal and cancerous, has been found to express estrogen receptors and patterns of expression have differed between men and women, suggesting a possible role for hormone‐related factors in lung carcinogenesis in women. Few epidemiological studies have examined hormone‐related variables and lung cancer risk and the findings have not been consistent. We investigated the association between characteristics of menstruation and pregnancy in relation to lung cancer risk in a population‐based case–control study carried out in Montreal, Canada, including 422 women with lung cancer and 577 controls. For each variable, odds ratios (OR) and 95% confidence intervals (CI) were estimated using unconditional logistic regression modeling. Associations were also examined according to level of smoking and by lung cancer histology. All statistical tests were two‐sided. Most characteristics of menstruation and pregnancy were not associated with lung cancer risk. However, an increased risk was observed for women who had had a non‐natural menopause, which predominantly included women who had had a bilateral oophorectomy, compared with women who had had a natural menopause (OR = 1.92, 95% CI: 1.22–3.01). An inverse association with age at menopause was suggested. These results did not vary by level of smoking and they were similar for adenocarcinomas compared with other histological types. Our results suggest that hormonal factors, related to early menopause and/or ovary removal, may play a role in the risk of lung cancer. Further studies are needed to confirm these findings, and to assess the possible contribution of hormone replacement therapy. © 2009 UICC
Modified heparins inhibit integrin αIIbβ3 mediated adhesion of melanoma cells to platelets in vitro and in vivo
Authors: Zhang ChunMei , Liu Yan , Gao YanGuang , Shen Jian , Zheng Sheng , Wei Min , Zeng XianLu 
Published: May 2009

AbstractThe adhesion of tumor cells with platelets is important in the process of tumor metastasis. A huge work has indicated that anti‐adhesion is an effective strategy for metastasis inhibition. In this article, we assess the role of platelet integrin αIIbβ3 in adhesion of melanoma cells to platelets and the effects of heparin and modified heparins on the adhesion in vitro and in vivo. We show that platelet integrin αIIbβ3 is involved in the interaction of human melanoma A375 cells with platelets, and the high affinity epitope resides on the αIIb subunit rather than β3 subunit. Heparin sulfate‐like proteoglycans on tumor cell surface are implicated in the adhesion of A375 cells to integrin αIIbβ3. We also show that RO‐heparin, CR‐heparin, N‐2,3‐DS‐heparin and 2,3‐O‐DS‐heparin can significantly inhibit A375 cells binding to the CHO cells expressing integrin αIIbβ3 under static and flow conditions, and remarkably inhibit the adhesion of A375 cells to the immobilized platelet layers under flow conditions. We find that A375 cells and B16F10 cells are arrested in the pulmonary vessels and adhered to platelets, and the initial interaction of tumor cells with platelets in lung vessel and long‐term establishment of metastatic foci can be inhibited by heparin as well as CR‐heparin and N‐2,3‐DS‐heparin. These data suggest that modified heparins can inhibit tumor cell‐platelet interaction mediated by platelet integrin αIIbβ3 and modified heparins may be a potential substitute for heparin in inhibiting tumor metastasis. © 2009 UICC
Overexpression of Sp1 leads to p53‐dependent apoptosis in cancer cells
Authors: Chuang Jian‐Ying , Wu Chien‐Hsing , Lai Ming‐Derg , Chang Wen‐Chang , Hung Jan‐Jong 
Published: May 2009

AbstractNumerous studies have documented that Sp1 expression level were elevated in various human cancers. However, the promoters of many pro‐apoptotic genes have been found to contain the Sp1 binding elements and are activated by Sp1 overexpression. To better understand the role and the mechanism of increased Sp1 levels on apoptosis, we used adenovirus to ectopically express GFP‐Sp1 protein in various cancer cell lines. First, in HeLa and A549 cells, we found that Sp1 overexpression suppressed the cell growth and increased the detection of sub‐G1 fraction, caspase‐3 cleavage, and annexin‐V signal revealed that apoptosis occurred. Furthermore, when cells entered the mitotic stage, the cell apoptosis was induced by Sp1 overexpression through affecting mitotic chromatin packaging. We also verified that p53 protein was accumulated and activated the p53‐dependent apoptotic pathways in the wild‐type p53 cells but not in the p53‐mutated or p53‐deleted cell lines when these cells were infected with adeno‐GFP‐Sp1 virus. In addition, A549 (p53+/+) cells could be protected from apoptosis under Sp1 overexpression when p53 was knockdown by p53 shRNA. Finally, H1299 (p53−/−) cell viability was significantly inhibited by adeno‐GFP‐Sp1 virus infection in the expression of p53. In conclusion, p53 was an essential factor for Sp1 overexpression‐induced apoptotic cell death in transforming cells. © 2009 UICC
Learning to sleep through the night: Solution or strain for mothers and young children?
Authors: Germo Gary R. , Goldberg Wendy A. , Keller Meret A. 
Published: May 2009

AbstractIs the process of helping infants and young children learn to sleep through the night a solution to family sleep problems or does it exacerbate matters for mother and child? Retrospective and current accounts from a nonclinical, convenience sample of 102 mothers of preschool‐aged children provided information on sleep issues from early infancy through preschool age. Child, mother, and parenting characteristics, along with family sleep arrangements, were differentially related to the age at which children learned to sleep through the night and to the extent of difficulty that characterized this experience. Mothers who indicated more difficulty as their children learned to sleep through the night also reported more depressive symptoms and more strain in the mother–child relationship. Later age at sleeping through the night was more common among early bedsharers, but timing of sleeping through the night was not associated with preschool children's reported independence in several nonsleep domains. Sleep arrangements and the importance placed on sleeping through the night were the strongest contributors to variance explained in whether children learned to sleep through the night during infancy or toddlerhood. When advising parents about sleep interventions, practitioners should seek to understand whether families' parenting values fit their nighttime sleep practices.
Video interaction guidance inviting transcendence of postpartum depressed mothers' self‐centered state and holding behavior
Authors: Vik Kari , Braten Stein 
Published: May 2009

AbstractBy sometimes evoking self‐absorbed and avoidance behaviors in new mothers, postnatal depression affects the quality of mother–infant interaction, which in turn may invoke distress and avoidance in the infant and cause even more lasting impairment in the child's development. Three depressed mothers, A, B, and C, are reported upon after having been offered counseling in accordance with the Marte Meo approach through jointly watching with the therapist video replays of themselves interacting with their newborns. Clinical vignettes are offered which indicate how empathic and positive support of a sensitive therapist can be helpful in inviting the mother's recognition of her importance to her infant and facilitating mutually gratifying interaction between mother and child. Protocol analyses of select sessions of video‐related therapy reveal that two of the mothers sometimes complete the therapist's unfinished statements in an other‐centered manner, thereby transcending their initial self‐centered state. This is most dramatic in the case of Mother A, who starts out in the first session almost incapable of speech, merely nodding or shaking her head. In addition to other indications of improved mother–infant interaction, comparison of pre‐ and postguidance windows regarding the three mothers' holding behaviors reveals a shift from an avoidance or anxious stance to closer and more secure holding.
Ab Initio quantum mechanical charge field study of hydrated bicarbonate ion: Structural and dynamical properties
Authors: Vchirawongkwin Viwat , Pribil Andreas B. , Rode Bernd M. 
Published: May 2009

AbstractThe ab initio quantum mechanical charge field molecular dynamics (QMCF MD) formalism was applied to simulate the bicarbonate ion, HCO3−, in aqueous solution. The difference in coordination numbers obtained by summation over atoms (6.6) and for the solvent‐accessible surface (5.4) indicates the sharing of some water molecules between the individual atomic hydration shells. It also proved the importance to consider the hydration of the chemically different atoms individually for the evaluation of structural and dynamical properties of the ion. The orientation of water molecules in the hydration shell was visualized by the θ–tilt surface plot. The mean residence time in the surroundings of the HCO3− ion classify it generally as a structure‐breaking ion, but the analysis of the individual ion‐water hydrogen bonds revealed a more complex behavior of the different coordination sites. © 2009 Wiley Periodicals, Inc. J Comput Chem, 2010
First‐principle calculations on CO oxidation catalyzed by a gold nanoparticle
Authors: Chen Hsin‐Tsung , Chang Jee‐Gong , Ju Shin‐Pon , Chen Hui‐Lung 
Published: May 2009

AbstractWe have elucidated the mechanism of CO oxidation catalyzed by gold nanoparticles through first‐principle density‐functional theory (DFT) calculations. Calculations on selected model show that the low‐coordinated Au atoms of the Au29 nanoparticle carry slightly negative charges, which enhance the O2 binding energy compared with the corresponding bulk surfaces. Two reaction pathways of the CO oxidation were considered: the Eley–Rideal (ER) and Langmuir–Hinshelwood (LH). The overall LH reaction O2(ads) + CO(gas) → O2(ads) + CO(ads) → OOCO(ads) → O(ads) + CO2(gas) is calculated to be exothermic by 3.72 eV; the potential energies of the two transition states (TSLH1 and TSLH2) are smaller than the reactants, indicating that no net activation energy is required for this process. The CO oxidation via ER reaction Au29 + O2(gas) + CO(gas) → Au29–O2(ads) + CO(gas) → Au29–CO3(ads) → Au29–O(ads) + CO2(gas) requires an overall activation barrier of 0.19 eV, and the formation of Au29–CO3(ads) intermediate possesses high exothermicity of 4.33 eV, indicating that this process may compete with the LH mechanism. Thereafter, a second CO molecule can react with the remaining O atom via the ER mechanism with a very small barrier (0.03 eV). Our calculations suggest that the CO oxidation catalyzed by the Au29 nanoparticle is likely to occur at or even below room temperature. To gain insights into high‐catalytic activity of the gold nanoparticles, the interaction nature between adsorbate and substrate is also analyzed by the detailed electronic analysis. © 2009 Wiley Periodicals, Inc. J Comput Chem, 2010
Neuron‐specific RNA interference using lentiviral vectors
Authors: Nielsen Troels Tolstrup , Marion Ingrid van , Hasholt Lis , Lundberg Cecilia 
Published: May 2009

AbstractBackgroundViral vectors have been used in several different settings for the delivery of small hairpin (sh) RNAs. However, most vectors have utilized ubiquitously‐expressing polymerase (pol) III promoters to drive expression of the hairpin as a result of the strict requirement for precise transcriptional initiation and termination. Recently, pol II promoters have been used to construct vectors for RNA interference (RNAi). By embedding the shRNA into a micro RNA‐context (miRNA) the endogenous miRNA processing machinery is exploited to achieve the mature synthetic miRNA (smiRNA), thereby expanding the possible promoter choices and eventually allowing cell type specific down‐regulation of target genes.MethodsIn the present study, we constructed lentiviral vectors expressing smiRNAs under the control of pol II promoters to knockdown gene expression in cell culture and in the brain.ResultsWe demonstrate robust knockdown of green fluorescent protein using lentiviral vectors driving RNAi from the ubiquitously‐expressing promoter of the cytomegalovirus (CMV) and, in addition, we show for the first time neuron‐specific knockdown in the brain using a neuron‐specific promoter. Furthermore, we show that the expression pattern of the presumed ubiquitously‐expressing CMV promoter changes over time from being expressed initially in neurons and glial cells to being expressed almost exclusively in neurons in later stages.ConclusionsIn the present study, we developed vectors for cell‐specific RNAi for use in the brain. This offers the possibility of specifically targeting RNAi to a subset of cells in a complex tissue and may prove to be of great importance in the design of future gene therapeutic paradigms. Copyright © 2009 John Wiley & Sons, Ltd.
Redirecting lentiviral vectors by insertion of integrin‐tageting peptides into envelope proteins
Authors: Morizono Kouki , Pariente Nonia , Xie Yiming , Chen Irvin S. Y. 
Published: May 2009

AbstractBackgroundTargeting gene therapy vectors that can home in on desired cell and tissue types in vivo comprise the ultimate gene delivery system. We have previously developed targeting lentiviral vectors by pseudotyping vectors with modified Sindbis virus envelope proteins. The envelope protein contains the Fc‐binding region of protein A (ZZ domain), so the virus can be conjugated with antibodies. The conjugated antibody mediates specific transduction of the cells and tissues expressing the target antigens, both in vitro and in vivo. However, more stable conjugation of targeting molecules would be optimal for use in immunocompetent animals, as well as in humans.MethodsWe inserted integrin‐targeting peptides into two sites of the targeting envelope proteins and determined whether the peptides serve as receptor‐binding regions of the envelope proteins and redirect the pseudotyped viruses.ResultsThe integrin‐targeting peptides can mediate binding to cells via the interaction with integrins on target cells and transduction. Peptides with a higher binding affinity increase titers of pseudotyped virus. We found two regions on the envelope protein that can accommodate insertion and serve as receptor‐binding regions. Combining the peptides in two distinct regions increased the titers of the virus.ConclusionsSuccessful incorporation of targeting molecules into the envelope protein will broaden the application of targeting vectors for a wide variety of experimental and clinical settings. Copyright © 2009 John Wiley & Sons, Ltd.
Hepatic insulin gene therapy diminishes liver glycogen despite insulin responsive transcriptional effects in diabetic CD‐1 mice
Authors: Zhang Jin‐an , Jia Dingwu , Olson Darin E. , Campbell Adam G. , Thulé Peter M. 
Published: May 2009

AbstractBackgroundHepatic insulin gene therapy (HIGT) produces near‐normal glycemia in diabetic rats. Hepatic insulin production is expected to stimulate glycogen storage. However, the effect of HIGT on hepatic glycogen metabolism in vivo is unknown.MethodsAfter administration of an adenoviral vector capable of inducing glucose responsive insulin production from hepatocytes, we evaluated circulating hormones, cytokines, hepatic gene expression and hepatic glycogen content in diabetic CD‐1 mice receiving intravenous streptozotocin. Nondiabetic mice and diabetic mice treated with empty adenovirus served as controls.ResultsPeripheral concentrations of human insulin in HIGT mice were less than concentrations of mouse insulin among controls. However, expression of insulin responsive genes in HIGT livers indicated a significant intra‐hepatic insulin effect, with expression changes reflecting appropriate responses to fed‐fasting transitions. Transcription factors (hepatocyte nuclear factor‐4α and peroxisome proliferator‐activated receptor γ co‐activator‐1α), as well as target genes (phospho‐enol‐pyruvate carboxykinase, glucose‐6‐phosphatase and glucokinase) exhibited insulin responsive expression. Despite producing near normal glycemia, HIGT diminished hepatic glycogen content in both fasted and fed mice. Serum cytokine responses revealed both vector‐related (monocyte chemoatractant protein‐1, interleukin‐6) and transgene specific (resistin, tumor necrosis factor α) effects.ConclusionsHIGT produces low circulating concentrations of insulin, but produces significant intra‐hepatic effects on gene expression. Despite controlling hyperglycemia, HIGT exerts unexpected insulin effects on hepatic carbohydrate metabolism. Although the precise mechanisms remain to be determined, they may relate to vector‐induced cytokine effects. Copyright © 2009 John Wiley & Sons, Ltd.
AAV gene therapy as a means to increase apolipoprotein (Apo) A‐I and high‐density lipoprotein‐cholesterol levels: correction of murine ApoA‐I deficiency
Authors: Vaessen Stefan F. C. , Veldman Robert Jan , Comijn Elisabeth M. , Snapper Jolanda , Sierts Jeroen A. , van den Oever Karin , Beattie Stuart G. , Twisk Jaap , Kuivenhoven Jan Albert 
Published: May 2009

AbstractBackgroundInherited apolipoprotein (Apo) A‐I deficiency is an orphan disorder characterized by high‐density lipoprotein (HDL)‐cholesterol deficiency and premature atherosclerosis. Constitutive over‐expression of ApoA‐I might provide a means to treat this disease. The present study provides a comprehensive evaluation of adeno‐associated virus (AAV)‐mediated ApoA‐I gene delivery to express human (h)ApoA‐I and correct the low HDL‐cholesterol phenotype associated with ApoA‐I deficiency.MethodsIn an effort to maximize AAV‐mediated gene expression, we performed head‐to‐head comparisons of recombinant AAVs with pseudotype capsids 1, 2, 6 and 8 administered by different routes with the use of five different liver‐specific promoters in addition to cytomegalovirus as single‐stranded or as self‐complementary (sc) AAV vectors.ResultsIntravenous administration of 1 × 1013 gc/kg scAAV8, in combination with the liver‐specific promoter LP1, in female ApoA‐I−/− mice resulted in hApoA‐I expression levels of 634 ± 69 mg/l, which persisted for the duration of the study (15 weeks). This treatment resulted in full recovery of HDL‐cholesterol levels with correction of HDL particle size and apolipoprotein composition. In addition, we observed increased adrenal cholesterol content and a significant increase in bodyweight in treated mice.ConclusionsThe present study demonstrates that systemic delivery of a scAAV8 vector provides a means for efficient liver expression of hApoA‐I, thereby correcting the lipid abnormalities associated with murine ApoA‐I deficiency. Importantly, the study demonstrates that AAV‐based gene therapy can be used to express therapeutic proteins at a high level for a prolonged period of time and, as such, provides a basis for further development of this strategy to treat hApoA‐I deficiency. Copyright © 2009 John Wiley & Sons, Ltd.
Reconstructing trees from two cards
Authors: Welhan Manuel 
Published: May 2009

AbstractLet 𝒯 be the class of unlabeled trees. An unlabeled vertex‐deleted subgraph of a tree T is called a card. A collection of cards is called a deck. We say that the tree T has a deck D if each card in D can be obtained by deleting distinct vertices of T. If T is the only unlabeled tree that has the deck D, we say that T is 𝒯‐reconstructible from D. We want to know how large of a deck D is necessary for T to be 𝒯‐reconstructible. We define 𝒯rn(T) as the minimum number of cards in a deck D such that T is 𝒯‐reconstructible from D. It is known that
𝒯rn(T)≤3, but it is conjectured that 𝒯rn(T)≤2 for all trees T. We prove that the conjecture holds for all homeomorphically irreducible trees. © 2009 Wiley Periodicals, Inc. J Graph Theory 63: 243–257, 2010
Kings in locally semicomplete digraphs
Authors: Wang Ruixia , Yang Aimin , Wang Shiying 
Published: May 2009

AbstractA k‐king in a digraph D is a vertex which can reach every other vertex by a directed path of length at most k. We consider k‐kings in locally semicomplete digraphs and mainly prove that all strong locally semicomplete digraphs which are not round decomposable contain a 2‐king. © 2009 Wiley Periodicals, Inc. J Graph Theory 63: 279–287, 2010