bluuebunny/crossref_metadata_2025_split huggingface dataset:
Residues of the Rotavirus RNA-Dependent RNA Polymerase Template Entry Tunnel That Mediate RNA Recognition and Genome Replication
Authors: Ogden Kristen M. , Ramanathan Harish N. , Patton John T. 
Published: December 2010

ABSTRACT

To replicate its segmented, double-stranded RNA (dsRNA) genome, the rotavirus RNA-dependent RNA polymerase, VP1, must recognize viral plus-strand RNAs (+RNAs) and guide them into the catalytic center. VP1 binds to the conserved 3′ end of rotavirus +RNAs via both sequence-dependent and sequence-independent contacts. Sequence-dependent contacts permit recognition of viral +RNAs and specify an autoinhibited positioning of the template within the catalytic site. However, the contributions to dsRNA synthesis of sequence-dependent and sequence-independent VP1-RNA interactions remain unclear. To analyze the importance of VP1 residues that interact with +RNA on genome replication, we engineered mutant VP1 proteins and assayed their capacity to synthesize dsRNA
in vitro
. Our results showed that, individually, mutation of residues that interact specifically with RNA bases did not diminish replication levels. However, simultaneous mutations led to significantly lower levels of dsRNA product, presumably due to impaired recruitment of +RNA templates. In contrast, point mutations of sequence-independent RNA contact residues led to severely diminished replication, likely as a result of improper positioning of templates at the catalytic site. A noteworthy exception was a K419A mutation that enhanced the initiation capacity and product elongation rate of VP1. The specific chemistry of Lys419 and its position at a narrow region of the template entry tunnel appear to contribute to its capacity to moderate replication. Together, our findings suggest that distinct classes of VP1 residues interact with +RNA to mediate template recognition and dsRNA synthesis yet function in concert to promote viral RNA replication at appropriate times and rates.
Human Cytomegalovirus Activates Glucose Transporter 4 Expression To Increase Glucose Uptake during Infection
Authors: Yu Yongjun , Maguire Tobi G. , Alwine James C. 
Published: December 2010

ABSTRACT
Glucose transport into mammalian cells is mediated by a group of glucose transporters (GLUTs) on the plasma membrane. Human cytomegalovirus (HCMV)-infected human fibroblasts (HFs) demonstrate significantly increased glucose consumption compared to mock-infected cells, suggesting a possible alteration in glucose transport during infection. Inhibition of GLUTs by using cytochalasin B indicated that infected cells utilize GLUT4, whereas normal HFs use GLUT1. Quantitative reverse transcription-PCR and Western analysis confirmed that GLUT4 levels are greatly increased in infected cells. In contrast, GLUT1 was eliminated by a mechanism involving the HCMV major immediate-early protein IE72. The HCMV-mediated induction of GLUT4 circumvents characterized controls of GLUT4 expression that involve serum stimulation, glucose concentration, and nuclear functions of ATP-citrate lyase (ACL). In infected cells the well-characterized Akt-mediated translocation of GLUT4 to the cell surface is also circumvented; GLUT4 localized on the surface of infected cells that were serum starved and had Akt activity inhibited. The significance of GLUT4 induction for the success of HCMV infection was indicated using indinavir, a drug that specifically inhibits glucose uptake by GLUT4. The addition of the drug inhibited glucose uptake in infected cells as well as viral production. Our data show that HCMV-specific mechanisms are used to replace GLUT1, the normal HF GLUT, with GLUT4, the major glucose transporter in adipose tissue, which has a 3-fold-higher glucose transport capacity.
Identification of New Functional Regions in Hepatitis C Virus Envelope Glycoprotein E2
Authors: Albecka Anna , Montserret Roland , Krey Thomas , Tarr Alexander W. , Diesis Eric , Ball Jonathan K. , Descamps Véronique , Duverlie Gilles , Rey Felix , Penin François , Dubuisson Jean 
Published: December 2010

ABSTRACT
Little is known about the structure of the envelope glycoproteins of hepatitis C virus (HCV). To identify new regions essential for the function of these glycoproteins, we generated HCV pseudoparticles (HCVpp) containing HCV envelope glycoproteins, E1 and E2, from different genotypes in order to detect intergenotypic incompatibilities between these two proteins. Several genotype combinations were nonfunctional for HCV entry. Of interest, a combination of E1 from genotype 2a and E2 from genotype 1a was nonfunctional in the HCVpp system. We therefore used this nonfunctional complex and the recently described structural model of E2 to identify new functional regions in E2 by exchanging protein regions between these two genotypes. The functionality of these chimeric envelope proteins in the HCVpp system and/or the cell-cultured infectious virus (HCVcc) was analyzed. We showed that the intergenotypic variable region (IgVR), hypervariable region 2 (HVR2), and another segment in domain II play a role in E1E2 assembly. We also demonstrated intradomain interactions within domain I. Importantly, we also identified a segment (amino acids [aa] 705 to 715 [segment 705-715]) in the stem region of E2, which is essential for HCVcc entry. Circular dichroism and nuclear magnetic resonance structural analyses of the synthetic peptide E2-SC containing this segment revealed the presence of a central amphipathic helix, which likely folds upon membrane binding. Due to its location in the stem region, segment 705-715 is likely involved in the reorganization of the glycoprotein complexes taking place during the fusion process. In conclusion, our study highlights new functional and structural regions in HCV envelope glycoprotein E2.
MDC1 Cleavage by Caspase-3: A Novel Mechanism for Inactivating the DNA Damage Response during Apoptosis
Authors: Solier Stéphanie , Pommier Yves 
Published: December 2010

Abstract
Recently, we identified the “apoptotic ring,” containing phosphorylated histone H2AX (γ-H2AX), as an early chromatin modification during apoptosis. Because γ-H2AX initiates the DNA damage response (DDR), we tested whether the apoptotic H2AX response leads to the full recruitment of the DDR factors that normally coordinate DNA repair and cell-cycle checkpoints. We show that the apoptotic H2AX response does not recruit the DDR factors because MDC1 (mediator of DNA damage checkpoint protein 1), which normally binds to γ-H2AX in response to DNA damage and amplifies the DDR, is cleaved by caspase-3. This cleavage separates the BRCT and FHA domains of MDC1 and constitutes a novel mechanism for the inactivation of DNA repair in apoptotic cells. Also, we show that downregulation of MDC1 increases the apoptotic response to TRAIL. Together, these results implicate MDC1 in the cellular apoptotic response. Cancer Res; 71(3); 906–13. ©2010 AACR.
Angiocrine Factors Modulate Tumor Proliferation and Motility through EphA2 Repression of Slit2 Tumor Suppressor Function in Endothelium
Authors: Brantley-Sieders Dana M. , Dunaway Charlene M. , Rao Meghana , Short Sarah , Hwang Yoonha , Gao Yandong , Li Deyu , Jiang Aixiang , Shyr Yu , Wu Jane Y. , Chen Jin 
Published: December 2010

Abstract
It is well known that tumor-derived proangiogenic factors induce neovascularization to facilitate tumor growth and malignant progression. However, the concept of “angiocrine” signaling, in which signals produced by endothelial cells elicit tumor cell responses distinct from vessel function, has been proposed, yet remains underinvestigated. Here, we report that angiocrine factors secreted from endothelium regulate tumor growth and motility. We found that Slit2, which is negatively regulated by endothelial EphA2 receptor, is one such tumor suppressive angiocrine factor. Slit2 activity is elevated in EphA2-deficient endothelium. Blocking Slit activity restored angiocrine-induced tumor growth/motility, whereas elevated Slit2 impaired growth/motility. To translate our findings to human cancer, we analyzed EphA2 and Slit2 expression in human cancer. EphA2 expression inversely correlated with Slit2 in the vasculature of invasive human ductal carcinoma samples. Moreover, analysis of large breast tumor data sets revealed that Slit2 correlated positively with overall and recurrence-free survival, providing clinical validation for the tumor suppressor function for Slit2 in human breast cancer. Together, these data support a novel, clinically relevant mechanism through which EphA2 represses Slit2 expression in endothelium to facilitate angiocrine-mediated tumor growth and motility by blocking a tumor suppressive signal. Cancer Res; 71(3); 976–87. ©2010 AACR.
Role of Ribosomal Protein RPS2 in Controlling let-7a Expression in Human Prostate Cancer
Authors: Wang Min , Hu Youji , Amatangelo Michael D. , Stearns Mark E. 
Published: December 2010

Abstract
We discovered that an inverse relationship exists in the expression of ras/c-myc and ribosomal protein RPS2 with pre-let-7a-1/let-7a/let-7f miRNA and prostate tumor cell malignancy. Nonmalignant IBC-10a cells expressed low levels of ras/RPS2 and elevated pre-let-7a-1/let-7a/let-7f miRNA, whereas the reverse occurred in malignant PCa-20a and PC-3ML cells. Stable transfection of IBC-10a cells with pBABE.ras and pBABE.RPS2 induced ras, c-myc, and RPS2 expression, whereas the levels of let-7a/let-7f miRNA dropped to near zero. Conversely, in pBABE.pre-let-7a-1 transfected PCa-20a and PC-3ML clones, let-7a/let-7f increased whereas ras, RPS2, and c-myc dropped greater than 5-fold. Electrophoretic mobility shift assays, antibody “supershift” assays and immunoprecipitation assays revealed that RPS2 specifically binds pre-let-7a-1 to block RNA processing. Immunoflourescent studies and Northern blots confirmed that RPS2 complexes with pre-let-7a-1 (i.e., in episomal structures) to block processing to let-7a/let-7f, indicating RPS2 may prevent let-7a miRNA expression to indirectly promote oncogene expression. Functional studies further showed that the colony-forming ability (CFA) and invasive activities of IBC-10a cells were significantly enhanced in pBABE-ras.IBC-10a and pBABE-RPS2-IBC-10a clones. Conversely, with the “knockdown” of ras and RPS2 in malignant PC-3ML cells (i.e., in pLKO.TRC.shRNA.ras.PC3-ML, pLKO.TRC.shRNA.RPS2.PC-3ML transfected cells), there was both a loss of these functions and a loss of tumorigenesis in SCID mice. Likewise, with the overexpression of let-7a/let-7f in pBABE.pre-let-7a-1.PC-3ML clones (and PCa-20a clones), CFAs, invasive activities in vitro, and tumorigenesis in vivo were significantly reduced. These results show for the first time that RPS2 blocks pre-let-7a-1 processing to enable ras and c-myc expression and the transformation of primary tumor cells. Mol Cancer Res; 9(1); 36–50 ©2011 AACR.
Evaluation of the South Pacific Convergence Zone in IPCC AR4 Climate Model Simulations of the Twentieth Century
Authors: Brown Josephine R. , Power Scott B. , Delage Francois P. , Colman Robert A. , Moise Aurel F. , Murphy Bradley F. 
Published: December 2010

Abstract
Understanding how the South Pacific convergence zone (SPCZ) may change in the future requires the use of global coupled atmosphere–ocean models. It is therefore important to evaluate the ability of such models to realistically simulate the SPCZ. The simulation of the SPCZ in 24 coupled model simulations of the twentieth century is examined. The models and simulations are those used for the Fourth Assessment Report (AR4) of the Intergovernmental Panel on Climate Change (IPCC). The seasonal climatology and interannual variability of the SPCZ is evaluated using observed and model precipitation. Twenty models simulate a distinct SPCZ, while four models merge intertropical convergence zone and SPCZ precipitation. The majority of models simulate an SPCZ with an overly zonal orientation, rather than extending in a diagonal band into the southeast Pacific as observed. Two-thirds of models capture the observed meridional displacement of the SPCZ during El Niño and La Niña events. The four models that use ocean heat flux adjustments simulate a better tropical SPCZ pattern because of a better representation of the Pacific sea surface temperature pattern and absence of cold sea surface temperature biases on the equator. However, the flux-adjusted models do not show greater skill in simulating the interannual variability of the SPCZ. While a small subset of models does not adequately reproduce the climatology or variability of the SPCZ, the majority of models are able to capture the main features of SPCZ climatology and variability, and they can therefore be used with some confidence for future climate projections.
Revealing the molecular relationship between type 2 diabetes and the metabolic changes induced by a very-low-carbohydrate low-fat ketogenic diet
Authors: Farrés Judith , Pujol Albert , Coma Mireia , Ruiz Jose Luis , Naval Jordi , Mas José Manuel , Molins Agustí , Fondevila Joan , Aloy Patrick 
Published: December 2010

AbstractBackgroundThe prevalence of type 2 diabetes is increasing worldwide, accounting for 85-95% of all diagnosed cases of diabetes. Clinical trials provide evidence of benefits of low-carbohydrate ketogenic diets in terms of clinical outcomes on type 2 diabetes patients. However, the molecular events responsible for these improvements still remain unclear in spite of the high amount of knowledge on the primary mechanisms of both the diabetes and the metabolic state of ketosis. Molecular network analysis of conditions, diseases and treatments might provide new insights and help build a better understanding of clinical, metabolic and molecular relationships among physiological conditions. Accordingly, our aim is to reveal such a relationship between a ketogenic diet and type 2 diabetes through systems biology approaches.MethodsOur systemic approach is based on the creation and analyses of the cell networks representing the metabolic state in a very-low-carbohydrate low-fat ketogenic diet. This global view might help identify unnoticed relationships often overlooked in molecule or process-centered studies.ResultsA strong relationship between the insulin resistance pathway and the ketosis main pathway was identified, providing a possible explanation for the improvement observed in clinical trials. Moreover, the map analyses permit the formulation of some hypothesis on functional relationships between the molecules involved in type 2 diabetes and induced ketosis, suggesting, for instance, a direct implication of glucose transporters or inflammatory processes. The molecular network analysis performed in the ketogenic-diet map, from the diabetes perspective, has provided insights on the potential mechanism of action, but also has opened new possibilities to study the applications of the ketogenic diet in other situations such as CNS or other metabolic dysfunctions.
Antimicrobial resistance patterns and prevalence of class 1 and 2 integrons in Shigella flexneri and Shigella sonnei isolated in Uzbekistan
Authors: Madiyarov Ruslan S , Bektemirov Amir M , Ibadova Gulnara A , Abdukhalilova Gulnara K , Khodiev Aybek V , Bodhidatta Ladaporn , Sethabutr Orntipa , Mason Carl J 
Published: December 2010

Abstract

Background
Shigella is a frequent cause of bacterial dysentery in the developing world. Treatment with effective antibiotics is recommended for shigellosis, but options become limited due to globally emerging resistance. One of the mechanisms for the development of resistance utilizes integrons. This study described the antibiotic susceptibility and the presence of class 1 and 2 integrons in S. flexneri and S. sonnei isolated in Uzbekistan.

Results
We studied 31 isolates of S. flexneri and 21 isolates of S. sonnei isolated in Uzbekistan between 1992 and 2007 for the susceptibility or resistance to ampicillin (Am), chloramphenicol (Cl), tetracycline (Te), co-trimoxazole (Sxt), kanamycin (Km), streptomycin (Str), gentamicin (Gm), cefazolin (Czn), cefoperazone (Cpr), cefuroxime (Cur), ceftazidime (Ctz), nalidixic acid (NA) and ciprofloxacin (Cip). Am/Str/Cl/Te and Am/Str/Cl/Te/Sxt resistance patterns were found most frequently in S. flexneri. Single isolates were resistant to aminoglycoside, quinolones and cephalosporins. The resistance patterns were different in the two species. Integrons were detected in 93.5% of S. flexneri (29/31) and 81.0% of S. sonnei (17/21) isolates. In addition, 61.3% of S. flexneri (19/31) isolates and 19.0% of S. sonnei (4/21) isolates carried both classes of integrons. In 29.0% of S. flexneri (9/31) isolates, only class 1 integrons were identified. In S. flexneri isolates, the presence of class 1 integrons was associated with resistance to ampicillin and chloramphenicol. Only Class 2 integrons were present in 61.9% of S. sonnei (13/21) isolates.

Conclusions
Our study documents antibiotic resistance among Shigella spp. in Uzbekistan. Ninety percent of Shigella strains were resistant to previously used antibiotics. Differences among S. flexneri and S. sonnei isolates in patterns of antimicrobial resistance to routinely used shigellosis antibiotics were observed. The majority of S. flexneri were resistant to ampicillin, chloramphenicol, tetracycline and streptomycin. Class 1 and 2 integrons were widely present in these Shigella strains. Resistance to ampicillin/chloramphenicol was associated with the presence of class 1 integrons. Though several mechanisms are possible, the resistance of Shigella isolates to ampicillin/chloramphenicol may be associated with the expression of genes within class 1 integrons.
Estimating permeability of sandstone samples by nuclear magnetic resonance and spectral-induced polarization
Authors: Weller Andreas , Nordsiek Sven , Debschütz Wolfgang 
Published: December 2010

Two techniques to estimate permeability are compared in this paper: nuclear magnetic resonance (NMR) and spectral-induced polarization (SIP). Both methods are based on relaxation processes. NMR records the relaxation of hydrogen nuclei after excitation in an external magnetic field. The phenomenon of induced polarization can be characterized by a relaxation of ions after excitation by an electric field. Hydrogen nuclei are concentrated in the pore water, the current flow is restricted to the pore space for most reservoir rocks, and permeability is related to the pore space geometry. Based on the similarity between fluid movement and current flow in the pore space, different relations have been published linking parameters derived from NMRand SIP data to predict permeability. NMR, SIP and permeability data have been acquired on 53 sandstone samples of the cretaceous Bahariya Formation (Western Desert, Egypt) including 27 samples showing a lamination that causes anisotropy. We compare the applicability of known and generalized relations for permeability prediction including isotropic and anisotropic samples. Because NMR relaxation ignores directionality of pore space geometry, the known relations provide only a weak accuracy in permeability estimation. The integrating parameters derived from a Debye decomposition of SIP data are partly sensitive to anisotropy. A generalized power-law relation using resistivity, chargeability, and mean relaxation time provide a reliable permeability prediction for isotropic and anisotropic samples.
The Cyclic Pentapeptide d-Arg3FC131, a CXCR4 Antagonist, Induces Apoptosis of Somatotrope Tumor and Inhibits Tumor Growth in Nude Mice
Authors: Kim Jeong Mo , Lee Yong-ho , Ku Cheol Ryong , Lee Eun Jig 
Published: December 2010

AbstractThe interaction between the chemokine stromal cell-derived factor 1 and its receptor CXCR4 plays an important role in GH production and cell proliferation in normal and tumorous pituitary somatotrope cells. Therefore, the chemokine receptor CXCR4 could be an attractive target for antitumor drugs in patients with acromegaly. A synthetic antagonist of CXCR4, cyclic pentapeptide d-Arg3FC131 (c[Gly1-d-Tyr2-d-Arg3-Arg4-Nal5]) significantly inhibited GH production and proliferation of GH3 somatotrope tumor cells in vitro. It also induced apoptosis of GH3 cells through activation of the caspase-3 pathway. Systemic administration of d-Arg3FC131 inhibited the growth of GH3 cell xenografts in immunodeficient nude mice by inducing apoptosis and suppressing the proliferation of tumor cells. These results indicate that d-Arg3FC131 might have potential for the treatment of pituitary tumors producing excess GH in patients with acromegaly.
Intramolecular Condensation of 1,2-C6H4(CH2RH)2 (R = O, S, and NH) to Yield Heterocyclic Compounds over Halide-cluster Catalysts
Authors: Nagashima Sayoko , Kamiguchi Satoshi , Kudo Kentaro , Sasaki Tomoaki , Chihara Teiji 
Published: December 2010

Abstract
1,2-Benzenedimethanol was reacted under a helium stream in the presence of [(Nb6Cl12)Cl2(H2O)4]·4H2O supported on silica gel. When the temperature was raised above 200 °C, catalytic activity of the cluster for cyclization appeared, yielding 1,3-dihydroisobenzofuran in 91% selectivity at 350 °C. The corresponding halide clusters of tantalum and tungsten also catalyzed the reaction. cis-1,2-Cyclohexanedimethanol and 1,4-butanediol exclusively produced the corresponding furans. 1,2-Benzenedimethanamine and 1,2-benzenedimethanethiol selectively afforded isoindoline and 1,3-dihydrobenzo[c]thiophene, respectively.
Cancer protection of soy resembles cancer protection during pregnancy
Authors: Rohr Uwe D. , Gocan Anca G. , Bachg Doris , Schindler Adolf E. 
Published: December 2010

Abstract
It has been established that carrying a pregnancy to full-term at an early age can protect against contracting cancer by up to 50% in later life. The trophoblast theory of cancer states that trophoblast and cancer tissue are very similar. New findings suggest that the loss of fetal cells during pregnancy resemble those cells responsible for causing metastasis in cancer. Fetal cells and spreading cancer cells are highly proliferative. They are similar to stem cells, exhibiting no or low hormone receptor expression, and require a hormone receptor independent mechanism for control. Control of membrane stability during pregnancy is of vital importance for a successful pregnancy and is mediated by androstenediol and 2-methoxyestradiol. 2-Methoxyestradiol has no hormone receptor affinity and elicits strong anticancer effects particularly against cancer stem cells and fetal cells, for which currently no treatment has yet been established. There is a discussion whether pregnancy reduces cancer stem cells in the breast. Soy isoflavones are structurally similar to both hormones, and elicit strong anticancer effects and antiangiogenesis via inhibition of NF-κB, even in hormone receptor independent breast cancers seen in epidemiologic studies. The trophoblast theory of cancer could help to explain why soy baby nutrition formulas have no effect on baby physiology, other than the nutritional aspect, although soy elicits many effects on the adult immune system. To survive the immune system of the mother, the immune system of the fetus has to be separated; otherwise, the reduction of the immune system in the mother, a necessary feature for the blastocyst to grow, would immediately reduce the immunity for the fetus and endanger its survival. Similar to a fetus, newly born babies show immune insensitive to Th1 and Th2 cytokines, which are necessary and crucial for regulating the immune system of the mother, thus raising the risk of the baby of developing allergies and neurodermatitis. Gene expression studies in vitro as well as in circulating tumor cells from patients consuming a fermented soy product support the antiangiogenic as well as antiproliferative effects of soy.