bluuebunny/crossref_metadata_2025_split huggingface dataset:
Negative Autoregulation of Epstein-Barr Virus (EBV) Replicative Gene Expression by EBV SM Protein
Authors: Verma Dinesh , Ling Chen , Johannsen Eric , Nagaraja Tirumuru , Swaminathan Sankar 
Published: June 2009

ABSTRACT
The Epstein-Barr virus (EBV) SM protein is essential for lytic EBV DNA replication and virion production. When EBV replication is induced in cells infected with an SM-deleted recombinant EBV, approximately 50% of EBV genes are expressed inefficiently. When EBV replication is rescued by transfection of SM, SM enhances expression of these genes by direct and indirect mechanisms. While expression of most EBV genes is either unaffected or enhanced by SM, expression of several genes is decreased in the presence of SM. Expression of BHRF1, a homolog of cellular bcl-2, is particularly decreased in the presence of SM. Investigation of the mechanism of BHRF1 downregulation revealed that SM downregulates expression of the immediate-early EBV transactivator R. In EBV-infected cells, R-responsive promoters, including the BHRF1 and SM promoters, were less active in the presence of SM, consistent with SM inhibition of R expression. SM decreased spliced R mRNA levels, supporting a posttranscriptional mechanism of R inhibition. R and BHRF1 expression were also found to decrease during later stages of EBV lytic replication in EBV-infected lymphoma cells. These data indicate that feedback regulation of immediate-early and early genes occurs during the lytic cycle of EBV regulation.
Ebola Virus VP35 Antagonizes PKR Activity through Its C-Terminal Interferon Inhibitory Domain
Authors: Schümann Michael , Gantke Thorsten , Mühlberger Elke 
Published: June 2009

ABSTRACT
Ebola virus VP35 contains a C-terminal cluster of basic amino acids required for double-stranded RNA (dsRNA) binding and inhibition of interferon regulatory factor 3 (IRF3). VP35 also blocks protein kinase R (PKR) activation; however, the responsible domain has remained undefined. Here we show that the IRF inhibitory domain of VP35 mediates the inhibition of PKR and enhances the synthesis of coexpressed proteins. In contrast to dsRNA binding and IRF inhibition, alanine substitutions of at least two basic amino acids are required to abrogate PKR inhibition and enhanced protein expression. Moreover, we show that PKR activation is not only blocked but reversed by Ebola virus infection.
Simian Virus 40 Small T Antigen Activates AMPK and Triggers Autophagy To Protect Cancer Cells from Nutrient Deprivation
Authors: Kumar Sravanth Hindupur , Rangarajan Annapoorni 
Published: June 2009

ABSTRACT
As tumors grow larger, they often experience an insufficient supply of oxygen and nutrients. Hence, cancer cells must develop mechanisms to overcome these stresses. Using an in vitro transformation model where the presence of the simian virus 40 (SV40) small T (ST) antigen has been shown to be critical for tumorigenic transformation, we investigated whether the ST antigen has a role to play in regulating the energy homeostasis of cancer cells. We find that cells expressing the SV40 ST antigen (+ST cells) are more resistant to glucose deprivation-induced cell death than cells lacking the SV40 ST antigen (−ST cells). Mechanistically, we find that the ST antigen mediates this effect by activating a nutrient-sensing kinase, AMP-activated protein kinase (AMPK). The basal level of active, phosphorylated AMPK was higher in +ST cells than in −ST cells, and these levels increased further in response to glucose deprivation. Additionally, inhibition of AMPK in +ST cells increased the rate of cell death, while activation of AMPK in −ST cells decreased the rate of cell death, under conditions of glucose deprivation. We further show that AMPK mediates its effects, at least in part, by inhibiting mTOR (mammalian target of rapamycin), thereby shutting down protein translation. Finally, we show that +ST cells exhibit a higher percentage of autophagy than −ST cells upon glucose deprivation. Thus, we demonstrate a novel role for the SV40 ST antigen in cancers, where it functions to maintain energy homeostasis during glucose deprivation by activating AMPK, inhibiting mTOR, and inducing autophagy as an alternate energy source.
A Conformational Switch in Human Immunodeficiency Virus gp41 Revealed by the Structures of Overlapping Epitopes Recognized by Neutralizing Antibodies
Authors: Pejchal Robert , Gach Johannes S. , Brunel Florence M. , Cardoso Rosa M. , Stanfield Robyn L. , Dawson Philip E. , Burton Dennis R. , Zwick Michael B. , Wilson Ian A. 
Published: June 2009

ABSTRACTThe membrane-proximal external region (MPER) of the human immunodeficiency virus (HIV) envelope glycoprotein (gp41) is critical for viral fusion and infectivity and is the target of three of the five known broadly neutralizing HIV type 1 (HIV-1) antibodies, 2F5, Z13, and 4E10. Here, we report the crystal structure of the Fab fragment of Z13e1, an affinity-enhanced variant of monoclonal antibody Z13, in complex with a 12-residue peptide corresponding to the core epitope (W670NWFDITN677) at 1.8-Å resolution. The bound peptide adopts an S-shaped conformation composed of two tandem, perpendicular helical turns. This conformation differs strikingly from the α-helical structure adopted by an overlapping MPER peptide bound to 4E10. Z13e1 binds to an elbow in the MPER at the membrane interface, making relatively few interactions with conserved aromatics (Trp672 and Phe673) that are critical for 4E10 recognition. The comparison of the Z13e1 and 4E10 epitope structures reveals a conformational switch such that neutralization can occur by the recognition of the different conformations and faces of the largely amphipathic MPER. The Z13e1 structure provides significant new insights into the dynamic nature of the MPER, which likely is critical for membrane fusion, and it has significant implications for mechanisms of HIV-1 neutralization by MPER antibodies and for the design of HIV-1 immunogens.
Transcription of the Herpes Simplex Virus Latency-Associated Transcript Promotes the Formation of Facultative Heterochromatin on Lytic Promoters
Authors: Cliffe Anna R. , Garber David A. , Knipe David M. 
Published: June 2009

ABSTRACT
An important question in virology is the mechanism(s) by which persistent viruses such as the herpesviruses and human immunodeficiency virus (HIV) establish a latent infection in specific types of cells. In the case of herpesviruses, herpes simplex virus (HSV) infection of epithelial cells results in a lytic infection, whereas latent infection is established in sensory neurons. Recent studies have shown the importance of chromatin structure in the regulation of latent infection for both HSV and HIV. For HSV, we have shown previously that the viral latency-associated transcript (LAT) promotes lytic gene silencing and the association of one heterochromatin marker, dimethylation of lysine 9 on histone H3 (H3K9me2), with viral lytic genes. In this study, we further defined the structure of latent viral chromatin by examining the heterochromatin markers on histones associated with the HSV latent genome. We detected the H3K9me2, H3K9me3, and H3K27me3 modifications, with H3K27me3, which is indicative of facultative heterochromatin, exhibiting the highest enrichment on all viral promoters tested. A modification associated with cellular centromeric heterochromatin, H4K20me3, was not detected. A mutant virus containing a 1.8-kbp deletion within the LAT region showed reduced levels of the facultative heterochromatin marker (H3K27me3) along with H3K9me3 during latency, whereas a viral mutant defective for the LAT promoter showed a specific reduction in H3K27me3. Cellular long, noncoding RNAs induce facultative heterochromatin, and this study shows that transcription of a viral noncoding RNA can also induce facultative heterochromatin to promote lytic gene silencing during latency.
Host Cell Detection of Noncoding Stuffer DNA Contained in Helper-Dependent Adenovirus Vectors Leads to Epigenetic Repression of Transgene Expression
Authors: Ross P. Joel , Kennedy Michael A. , Parks Robin J. 
Published: June 2009

ABSTRACT
Helper-dependent adenovirus (hdAd) vectors have shown great promise as therapeutic gene delivery vehicles in gene therapy applications. However, the level and duration of gene expression from hdAd can differ considerably depending on the nature of the noncoding stuffer DNA contained within the vector. For example, an hdAd containing 22 kb of prokaryotic DNA (hdAd-prok) expresses its transgene 60-fold less efficiently than a similar vector containing eukaryotic DNA (hdAd-euk). Here we have determined the mechanistic basis of this phenomenon. Although neither vector was subjected to CpG methylation and both genomes associated with cellular histones to similar degrees, hdAd-prok chromatin was actively deacetylated. Insertion of an insulator element between the transgene and the bacterial DNA derepressed hdAd-prok, suggesting that foreign DNA nucleates repressive chromatin structures that spread to the transgene. We found that Sp100B/Sp100HMG and Daxx play a role in repressing transgene expression from hdAd and act independently of PML bodies. Thus, we have identified nuclear factors involved in recognizing foreign DNA and have determined the mechanism by which associated genes are repressed.
Human VAP-C Negatively Regulates Hepatitis C Virus Propagation
Authors: Kukihara Hiroshi , Moriishi Kohji , Taguwa Shuhei , Tani Hideki , Abe Takayuki , Mori Yoshio , Suzuki Tetsuro , Fukuhara Takasuke , Taketomi Akinobu , Maehara Yoshihiko , Matsuura Yoshiharu 
Published: June 2009

ABSTRACTHuman vesicle-associated membrane protein-associated protein (VAP) subtype A (VAP-A) and subtype B (VAP-B) are involved in the regulation of membrane trafficking, lipid transport and metabolism, and the unfolded protein response. VAP-A and VAP-B consist of the major sperm protein (MSP) domain, the coiled-coil motif, and the C-terminal transmembrane anchor and form homo- and heterodimers through the transmembrane domain. VAP-A and VAP-B interact with NS5B and NS5A of hepatitis C virus (HCV) through the MSP domain and the coiled-coil motif, respectively, and participate in the replication of HCV. VAP-C is a splicing variant of VAP-B consisting of the N-terminal half of the MSP domain of VAP-B followed by the subtype-specific frameshift sequences, and its biological function has not been well characterized. In this study, we have examined the biological functions of VAP-C in the propagation of HCV. VAP-C interacted with NS5B but not with VAP-A, VAP-B, or NS5A in immunoprecipitation analyses, and the expression of VAP-C inhibited the interaction of NS5B with VAP-A or VAP-B. Overexpression of VAP-C impaired the RNA replication of the HCV replicon and the propagation of the HCV JFH1 strain, whereas overexpression of VAP-A and VAP-B enhanced the replication. Furthermore, the expression of VAP-C was observed in various tissues, whereas it was barely detected in the liver. These results suggest that VAP-C acts as a negative regulator of HCV propagation and that the expression of VAP-C may participate in the determination of tissue tropism of HCV propagation.
Hepatitis C Virus NS2 Protein Contributes to Virus Particle Assembly via Opposing Epistatic Interactions with the E1-E2 Glycoprotein and NS3-NS4A Enzyme Complexes
Authors: Phan Tung , Beran Rudolf K. F. , Peters Christopher , Lorenz Ivo C. , Lindenbach Brett D. 
Published: June 2009

ABSTRACTThe hepatitis C virus NS2 protein has been recently implicated in virus particle assembly. To further understand the role of NS2 in this process, we conducted a reverse genetic analysis of NS2 in the context of a chimeric genotype 2a infectious cell culture system. Of 32 mutants tested, all were capable of RNA replication and 25 had moderate-to-severe defects in virus assembly. Through forward genetic selection for variants capable of virus spread, we identified second-site mutations in E1, E2, NS2, NS3, and NS4A that suppressed NS2 defects in assembly. Two suppressor mutations, E1 A78T and NS3 Q221L, were further characterized by additional genetic and biochemical experiments. Both mutations were shown to suppress other NS2 defects, often with mutual exclusivity. Thus, several NS2 mutants were enhanced by NS3 Q221L and inhibited by E1 A78T, while others were enhanced by E1 A78T and inhibited by NS3 Q221L. Furthermore, we show that the NS3 Q221L mutation lowers the affinity of native, full-length NS3-NS4A for functional RNA binding. These data reveal a complex network of interactions involving NS2 and other viral structural and nonstructural proteins during virus assembly.
Ultradeep Pyrosequencing Detects Complex Patterns of CD8
+
T-Lymphocyte Escape in Simian Immunodeficiency Virus-Infected Macaques
Authors: Bimber Benjamin N. , Burwitz Benjamin J. , O'Connor Shelby , Detmer Ann , Gostick Emma , Lank Simon M. , Price David A. , Hughes Austin , O'Connor David 
Published: June 2009

ABSTRACT

Human and simian immunodeficiency viruses (HIV/SIV) exhibit enormous sequence heterogeneity within each infected host. Here, we use ultradeep pyrosequencing to create a comprehensive picture of CD8
+
T-lymphocyte (CD8-TL) escape in SIV-infected macaques, revealing a previously undetected complex pattern of viral variants. This increased sensitivity enabled the detection of acute CD8-TL escape as early as 17 days postinfection, representing the earliest published example of CD8-TL escape in intrarectally infected macaques. These data demonstrate that pyrosequencing can be used to study the evolution of CD8-TL escape during immunodeficiency virus infection with an unprecedented degree of sensitivity.
Immune-mediated and chronic inflammatory disease in people with sarcoidosis: disease associations in a large UK database
Authors: Rajoriya N , Wotton C J , Yeates D G R , Travis S P L , Goldacre M J 
Published: June 2009

AbstractBackgroundSarcoidosis is a multi-system disorder characterised by non-caseating granulomas. Coexistence of sarcoidosis with immune-mediated and chronic inflammatory diseases has been described in case series. However, the coexistence of two different diseases in individuals can occur by chance, even if each of the diseases is rare.AimTo determine whether sarcoidosis necessitating hospital admission or day-case care coexists with a range of immune-mediated and chronic inflammatory diseases more commonly than expected by chance.DesignAnalysis of an epidemiological database of hospital admission and day-case statistics, spanning 30 years.Results1510 patients with sarcoidosis were identified (mean age 44 years, median follow-up 19 years) who had been admitted to hospital or day-case care. Significant associations in the sarcoidosis cohort were identified with systemic lupus erythematosus (odds ratio (OR) 8.3; 95% CI 2.7 to 19.4), autoimmune chronic hepatitis (OR 6.7; 95% CI 1.8 to 17.1), multiple sclerosis (OR 3.3; 95% CI 1.7 to 5.6), coeliac disease (OR 3.1; 95% CI 1.01 to 7.3), thyrotoxicosis (OR 2.5; 95% CI 1.4 to 4.0), myxoedema (OR 2.2; 95% CI 1.2 to 3.7) and ulcerative colitis (OR 2.1; 95% CI 1.1 to 3.7). Weaker associations were found for diabetes mellitus with a first admission aged 30–49 years (OR 2.9; 95% CI 2.1 to 4.0) or age &gt;50 (OR 1.7; 95% CI 1.2 to 2.3), but not for people age &lt;30. No significant association with Crohn’s disease (OR 1.52; 95% CI 0.61 to 3.14) or primary biliary cirrhosis (OR 3.75; 95% CI 0.77 to 11.0),was found. When all immune-mediated and chronic inflammatory diseases for which associations were sought were combined, the overall rate ratio associated with sarcoidosis was 2.2 (95% CI 1.9 to 2.6).ConclusionThis study adds epidemiological evidence to information from clinical reports that there is a connection between sarcoidosis and other immune-mediated and chronic inflammatory diseases.
New insulins and new insulin regimens: a review of their role in improving glycaemic control in patients with diabetes
Authors: Crasto W , Jarvis J , Khunti K , Davies M J 
Published: June 2009

Abstract
Effective glycaemic control can reduce and potentially prevent the microvascular and macrovascular complications of diabetes. Insulin is the mainstay of treatment for type 1 diabetes and is indicated in patients with type 2 diabetes who do no achieve optimal glycaemic control despite the use of oral hypoglycaemic agents. The advent of the so-called “designer” insulins, the insulin analogues, has offered new opportunities in the clinical management of diabetes. This review examines the efficacy of the different analogue insulins introduced thus far and goes on to explain their pharmacodynamics and pharmacokinetics. The review also examines the different types of insulin regimen currently used in clinical practice and discusses some of the factors that influence the choice of a particular insulin regimen. Further, irrespective of the insulin regimen used, the importance of prompt initiation and ongoing titration of insulin treatment to achieve optimal glycaemic targets is emphasised.
Causes of mortality in diabetes mellitus: data from a tertiary teaching hospital in India
Authors: Zargar A H , Wani A I , Masoodi S R , Bashir M I , Laway B A , Gupta V K , Wani F A 
Published: June 2009

Abstract

Background
Mortality studies can show the relative contribution of diabetes to mortality in the total population, and they can provide important descriptions of the changes in causes and frequency of diabetes mortality over time.

Objective
To find the mortality pattern in people with diabetes admitted to a tertiary care hospital in a developing country, using underlying/contributory causes of death.

Methods
In this retrospective study, mortality trends among people with diabetes admitted to Sher-i-Kashmir Institute of Medical Sciences, Srinagar, Kashmir, India were reviewed by screening the hospital records of all people with diabetes who died over the last 9 years, carrying forward earlier observations from the same centre.

Results
Of 234 776 people admitted to the centre during the review period, 16 690 (7.11%) died; 741 (383 men) of these had diabetes mellitus mentioned on the death certificate. The mean (SD) age at death for people with diabetes was 60.07 (13.62) years in men and 57.36 (13.40) years in women. The leading contributory causes of death were infections (40.9%), chronic renal failure (33.6%), coronary artery disease (16.9%), cerebrovascular disease (13.2%), chronic obstructive pulmonary disease (6.9%), acute renal failure (6.2%), malignancy (4.2%), hypoglycaemia (3.5%) and diabetic ketoacidosis (3.4%). The cause of death could not be ascertained in 2.8% of cases; in 52.9%, 36.3% and 8.0% cases one, two and three or more causes, respectively, were recorded as the cause of death.

Conclusions
The aetiological spectrum of mortality in people with diabetes at this Indian centre continues to be dominated by infections and renal failure, which is different from that in the developed world, where coronary artery disease and cerebrovascular disease are the principal causes of death in people with diabetes.
TIME DELAY FOR DISPERSIVE SYSTEMS IN QUANTUM SCATTERING THEORY
Authors: TIEDRA DE ALDECOA RAFAEL 
Published: June 2009

We consider time delay and symmetrized time delay (defined in terms of sojourn times) for quantum scattering pairs {H0 = h(P), H}, where h(P) is a dispersive operator of hypoelliptic-type. For instance, h(P) can be one of the usual elliptic operators such as the Schrödinger operator h(P) = P2 or the square-root Klein–Gordon operator [Formula: see text]. We show under general conditions that the symmetrized time delay exists for all smooth even localization functions. It is equal to the Eisenbud–Wigner time delay plus a contribution due to the non-radial component of the localization function. If the scattering operator S commutes with some function of the velocity operator ∇h(P), then the time delay also exists and is equal to the symmetrized time delay. As an illustration of our results, we consider the case of a one-dimensional Friedrichs Hamiltonian perturbed by a finite rank potential. Our study puts into evidence an integral formula relating the operator of differentiation with respect to the kinetic energy h(P) to the time evolution of localization operators.
Strong Convergence of an Iterative Method for Equilibrium Problems and Variational Inequality Problems
Authors: Li Hong Yu , Li Hong Zhi 
Published: June 2009

AbstractWe introduce an iterative method for finding a common element of the set of solutions of equilibrium problems, the set of solutions of variational inequality problems, and the set of fixed points of finite many nonexpansive mappings. We prove strong convergence of the iterative sequence generated by the proposed iterative algorithm to the unique solution of a variational inequality, which is the optimality condition for the minimization problem.
A Hybrid Iterative Scheme for Equilibrium Problems, Variational Inequality Problems, and Fixed Point Problems in Banach Spaces
Authors: Cholamjiak Prasit 
Published: June 2009

AbstractThe purpose of this paper is to introduce a new hybrid projection algorithm for finding a common element of the set of solutions of the equilibrium problem and the set of the variational inequality for an inverse-strongly monotone operator and the set of fixed points of relatively quasi-nonexpansive mappings in a Banach space. Then we show a strong convergence theorem. Using this result, we obtain some applications in a Banach space.
Fixed Points of Multivalued Maps in Modular Function Spaces
Authors: Kutbi Marwan A. , Latif Abdul 
Published: June 2009

AbstractThe purpose of this paper is to study the existence of fixed points for contractive-type and nonexpansive-type multivalued maps in the setting of modular function spaces. We also discuss the concept of "Equation missing"-modular function and prove fixed point results for weakly-modular contractive maps in modular function spaces. These results extend several similar results proved in metric and Banach spaces settings.
The Ottoman Monetary Crisis of 1585 Revisited
Authors: Tezcan Baki 
Published: June 2009

AbstractIn 1585-8, the Ottoman silver currency, the akçe, was officially devalued by 100% against the Venetian gold ducat and foreign silver currencies, and its silver content was reduced by 44%. Some scholars have interpreted this devaluation and debasement as a consequence of the silver influx from the Americas, whereas others have referred to the difficulties that the Ottoman state had to face in financing its war effort against the Safavids in Persia. This study suggests that the unification of a number of distinct regional monetary zones in an interregional imperial economy by the second half of the sixteenth century must be regarded as an important factor that contributed to the monetary crisis of 1585. En 1585-88, l'akçe, la monnaie d'argent ottomane, fut dévaluée officiellement de 100% par rapport au ducat d'or vénitien et les monnaies d'argent étrangères, et le pourcentage d'argent en fut réduit de 44%. Certains chercheurs interprètent cette dévaluation et cette dépréciation comme étant la conséquence de l'influx d'argent venant des Amériques, tandisque d'autres attribuent les problèmes de l'état ottoman au financement des guerres contre les Safavides d'Iran. Cette contribution suggère que l'unification d'un bon nombre de zones monétaires régionales qui différaient entre elles en une seule économie impériale interrégionale dans la seconde moitié du XVIe siècle doit être regardée comme un facteur important ayant contribué à la crise monétaire de 1585.