bluuebunny/crossref_metadata_2025_split huggingface dataset:
De novo autoimmune hepatitis after liver transplantation
Authors: Lohse Ansgar W. , Weiler‐Norman Christina , Burdelski Martin 
Published: October 2007

The Kings College group was the first to describe a clinical syndrome similar to autoimmune hepatitis in children and young adults transplanted for non‐immune mediated liver diseases. They coined the term “de novo autoimmune hepatitis”. Several other liver transplant centres confirmed this observation. Even though the condition is uncommon, patients with de novo AIH are now seen in most of the major transplant centres.The disease is usually characterized by features of acute hepatitis in otherwise stable transplant recipients. The most characteristic laboratory hallmark is a marked hypergammaglobulinaemia. Autoantibodies are common, mostly ANA. We described also a case of LKM1‐positivity in a patients transplanted for Wilson's disease, however this patients did not develop clinical or histological features of AIH. Development of SLA/LP‐autoantibodies is also not described. Therefore, serologically de novo AIH appears to correspond to type 1 AIH. Like classical AIH patients respond promptly to treatment with increased doses of prednisolone and azathioprine, while the calcineurin inhibitors cyclosporine or tacrolimus areof very limited value – which is not surprising, as almost all patients develop de novo AIH while receiving these drugs. Despite the good response to treatment, most patients remain a clinical challenge as complete stable remissions are uncommon and flares, relapses and chronic disease activity can often occur.Pathogenetically this syndrome is intriguing. It is not clear, if the immune response is directed against allo‐antigens, neo‐antigens in the liver, or self‐antigens, possibly shared by donor and host cells. It is very likely that the inflammatory milieu due to alloreactive cells in the transplanted organ contribute to the disease process. Either leading to aberrant antigen presentation, or providing co‐stimulatory signals leading to the breaking of self‐tolerance. The development of this disease in the presence of treatment with calcineurin inhibitors supports the view held by most specialists in autoimmune hepatitis that these drugs, even though effective in acute disease, are not helpful in the long‐term management of autoimmune liver diseases.
Desires as Reasons1
Authors: SHEMMER YONATAN 
Published: October 2007

Humeans believe that at least some of our desires give us reasons for action. This view is widely accepted by social scientists and has some following among philosophers. In recent years important objections were raised against this position by Scanlon, Dancy, and others. The foundations of the Humean view have never been properly defended.In the first part of the paper I discuss some objections to the Humean position. In the second part I attempt to provide an argument for the claim that the Humean view gives us a plausible, even if not exclusive, understanding of our notion of reasons. The particular version of the Humean view I set out to defend is that only desires that the agent is not alienated from, and that are not impulses, are reason giving.
Knowing the Answer
Authors: SCHAFFER JONATHAN 
Published: October 2007

“ev’ry gambler knows that the secret to survivin’ is knowin’ what to throw away and knowing what to keep.” (Kenny Rogers)How should one understand knowledge‐whascriptions? That is, how should one understand claims such as “I know where the car is parked,” which feature an interrogative complement? The received view is that knowledge‐whreduces to knowledge thatp, wherephappens to be the answer to the questionQdenoted by thewh‐clause. I will argue that knowledge‐whincludes the question—to know‐whis to know thatp,as the answer to Q. I will then argue that knowledge‐thatincludes a contextually implicit question. I will conclude thatknowledge is a question‐relative state. Knowing is knowing the answer, and whether one knows the answer depends (in part) on the question.
Host‐parasitoid spatial dynamics in heterogeneous landscapes
Authors: H. Hirzel Alexandre , M. Nisbet Roger , W. Murdoch William 
Published: October 2007

This paper explores the effect of spatial processes in a heterogeneous environment on the dynamics of a host‐parasitoid interaction. The environment consists of a lattice of favourable (habitat) and hostile (matrix) hexagonal cells, whose spatial distribution is measured by habitat proportion and spatial autocorrelation (inverse of fragmentation). At each time step, a fixed fraction of both populations disperses to the adjacent cells where it reproduces following the Nicholson‐Bailey model. Aspects of the dynamics analysed include extinction, stability, cycle period and amplitude, and the spatial patterns emerging from the dynamics.We find that, depending primarily on the fraction of the host population that disperses in each generation and on the landscape geometry, five classes of spatio‐temporal dynamics can be objectively distinguished: spatial chaos, spirals, metapopulation, mainland‐island and spiral fragments. The first two are commonly found in theoretical studies of homogeneous landscapes. The other three are direct consequences of the heterogeneity and have strong similarities to dynamic patterns observed in real systems (e.g. extinction‐recolonisation, source‐sink, outbreaks, spreading waves).We discuss the processes that generate these patterns and allow the system to persist. The importance of these results is threefold: first, our model merges into a same theoretical framework dynamics commonly observed in the field that are usually modelled independently. Second, these dynamics and patterns are explained by dispersal rate and common landscape statistics, thus linking in a practical way population ecology to landscape ecology. Third, we show that the landscape geometry has a qualitative effect on the length of the cycles and, in particular, we demonstrate how very long periods can be produced by spatial processes.
DNA Fingerprinting Analysis of Breakthrough Outbreaks in Vaccine-Protected Poultry Stocks
Authors: Kardos G. , Turcsányi I. , Bistyák A. , Nagy J. , Kiss I. 
Published: October 2007

ABSTRACT

We report recurrent outbreaks of
Yersinia pseudotuberculosis
conjunctivitis in ducks and of fowl cholera in geese, occurring in stocks previously vaccinated with inactivated autogenous vaccines. Enterobacterial repetitive intergenic consensus sequence-based PCR and pulsed-field gel electrophoresis indicated reinfection with a new
Y. pseudotuberculosis
strain and vaccine evasion by the same
Pasteurella multocida
strain.
Molecular Epidemiology of TwoKlebsiella pneumoniaeMastitis Outbreaks on a Dairy Farm in New York State
Authors: Munoz Marcos A. , Welcome Francis L. , Schukken Ynte H. , Zadoks Ruth N. 
Published: October 2007

ABSTRACTKlebsiellaspp. have become an important cause of clinical mastitis in dairy cows in New York State. We describe the occurrence of twoKlebsiellamastitis outbreaks on a single dairy farm.Klebsiellaisolates from milk, feces, and environmental sources were compared using random amplified polymorphic DNA (RAPD)-PCR typing. The first mastitis outbreak was caused by a single strain ofKlebsiella pneumoniae, RAPD type A, which was detected in milk from eight cows. RAPD type A was also isolated from the rubber liners of milking machine units after milking of infected cows and from bedding in the outbreak pen. Predominance of a single strain could indicate contagious transmission of the organism or exposure of multiple cows to an environmental point source. No new cases with RAPD type A were observed after implementation of intervention measures that targeted the prevention of transmission via the milking machine as well as improvement of environmental hygiene. A second outbreak ofKlebsiellamastitis that occurred several weeks later was caused by multiple RAPD types, which rules out contagious transmission and indicates opportunistic infections originating from the environment. The diversity ofKlebsiellastrains as quantified with Simpson's index of discrimination was significantly higher for isolates from fecal, feed, and water samples than for isolates from milk samples. Several isolates from bedding material that had the phenotypic appearance ofKlebsiellaspp. were identified as beingRaoultella planticolaandRaoultella terrigenabased onrpoBsequencing.
Ebola Virus VP24 Proteins Inhibit the Interaction of NPI-1 Subfamily Karyopherin α Proteins with Activated STAT1
Authors: Reid St. Patrick , Valmas Charalampos , Martinez Osvaldo , Sanchez Freddy Mauricio , Basler Christopher F. 
Published: October 2007

ABSTRACT

The
Zaire ebolavirus
protein VP24 was previously demonstrated to inhibit alpha/beta interferon (IFN-α/β)- and IFN-γ-induced nuclear accumulation of tyrosine-phosphorylated STAT1 (PY-STAT1) and to inhibit IFN-α/β- and IFN-γ-induced gene expression. These properties correlated with the ability of VP24 to interact with the nuclear localization signal receptor for PY-STAT1, karyopherin α1. Here, VP24 is demonstrated to interact not only with overexpressed but also with endogenous karyopherin α1. Mutational analysis demonstrated that VP24 binds within the PY-STAT1 binding region located in the C terminus of karyopherin α1. In addition, VP24 was found to inhibit PY-STAT1 binding to both overexpressed and endogenous karyopherin α1. We assessed the binding of both PY-STAT1 and the VP24 proteins from Zaire, mouse-adapted Zaire, and Reston Ebola viruses for interaction with all six members of the human karyopherin α family. We found, in contrast to previous studies, that PY-STAT1 can interact not only with karyopherin α1 but also with karyopherins α5 and α6, which together comprise the NPI-1 subfamily of karyopherin αs. Similarly, all three VP24s bound and inhibited PY-STAT1 interaction with karyopherins α1, α5, and α6. Consistent with their ability to inhibit the karyopherin-PY-STAT1 interaction, Zaire, mouse-adapted Zaire, and Reston Ebola virus VP24s displayed similar capacities to inhibit IFN-β-induced gene expression in human and mouse cells. These findings suggest that VP24 inhibits interaction of PY-STAT1 with karyopherins α1, α5, or α6 by binding within the PY-STAT1 binding region of the karyopherins and that this function is conserved among the VP24 proteins of different Ebola virus species.
The U95 Protein of Human Herpesvirus 6B Interacts with Human GRIM-19: Silencing of U95 Expression Reduces Viral Load and Abrogates Loss of Mitochondrial Membrane Potential
Authors: Yeo W. M. , Isegawa Yuji , Chow Vincent T. K. 
Published: October 2007

ABSTRACT
To better understand the pathogenesis of human herpesvirus 6 (HHV-6), it is important to elucidate the functional aspects of immediate-early (IE) genes at the initial phase of the infection. To study the functional role of the HHV-6B IE gene encoding U95, we generated a U95-Myc fusion protein and screened a pretransformed bone marrow cDNA library for U95-interacting proteins, using yeast-two hybrid analysis. The most frequently appearing U95-interacting protein identified was GRIM-19, which belongs to the family of genes associated with retinoid-interferon mortality and serves as an essential component of the oxidative phosphorylation system. This interaction was verified by both coimmunoprecipitation and confocal microscopic coimmunolocalization. Short-term HHV-6B infection of MT-4 T-lymphocytic cells induced syncytial formation, resulted in decreased mitochondrial membrane potential, and led to progressively pronounced ultrastructural changes, such as mitochondrial swelling, myelin-like figures, and a loss of cristae. Compared to controls, RNA interference against U95 effectively reduced the U95 mRNA copy number and abrogated the loss of mitochondrial membrane potential. Our results indicate that the high affinity between U95 early viral protein and GRIM-19 may be closely linked to the detrimental effect of HHV-6B infection on mitochondria. These findings may explain the alternative cell death mechanism of expiration, as opposed to apoptosis, observed in certain productively HHV-6B-infected cells. The interaction between U95 and GRIM-19 is thus functionally and metabolically significant in HHV-6B-infected cells and may be a means through which HHV-6B modulates cell death signals by interferon and retinoic acid.
Binding Kinetics of Darunavir to Human Immunodeficiency Virus Type 1 Protease Explain the Potent Antiviral Activity and High Genetic Barrier
Authors: Dierynck Inge , De Wit Mieke , Gustin Emmanuel , Keuleers Inge , Vandersmissen Johan , Hallenberger Sabine , Hertogs Kurt 
Published: October 2007

ABSTRACT
The high incidence of cross-resistance between human immunodeficiency virus type 1 (HIV-1) protease inhibitors (PIs) limits their sequential use. This necessitates the development of PIs with a high genetic barrier and a broad spectrum of activity against PI-resistant HIV, such as tipranavir and darunavir (TMC114). We performed a surface plasmon resonance-based kinetic study to investigate the impact of PI resistance-associated mutations on the protease binding of five PIs used clinically: amprenavir, atazanavir, darunavir, lopinavir, and tipranavir. With wild-type protease, the binding affinity of darunavir was more than 100-fold higher than with the other PIs, due to a very slow dissociation rate. Consequently, the dissociative half-life of darunavir was much higher (>240 h) than that of the other PIs, including darunavir's structural analogue amprenavir. The influence of protease mutations on the binding kinetics was tested with five multidrug-resistant (MDR) proteases derived from clinical isolates harboring 10 to 14 PI resistance-associated mutations with a decreased susceptibility to various PIs. In general, all PIs bound to the MDR proteases with lower binding affinities, caused mainly by a faster dissociation rate. For amprenavir, atazanavir, lopinavir, and tipranavir, the decrease in affinity with MDR proteases resulted in reduced antiviral activity. For darunavir, however, a nearly 1,000-fold decrease in binding affinity did not translate into a weaker antiviral activity; a further decrease in affinity was required for the reduced antiviral effect. These observations provide a mechanistic explanation for darunavir's potent antiviral activity and high genetic barrier to the development of resistance.
Discrete Clusters of Virus-Encoded MicroRNAs Are Associated with Complementary Strands of the Genome and the 7.2-Kilobase Stable Intron in Murine Cytomegalovirus
Authors: Buck Amy H. , Santoyo-Lopez Javier , Robertson Kevin A. , Kumar Diwakar S. , Reczko Martin , Ghazal Peter 
Published: October 2007

ABSTRACT
The prevalence and importance of microRNAs (miRNAs) in viral infection are increasingly relevant. Eleven miRNAs were previously identified in human cytomegalovirus (HCMV); however, miRNA content in murine CMV (MCMV), which serves as an important in vivo model for CMV infection, has not previously been examined. We have cloned and characterized 17 novel miRNAs that originate from at least 12 precursor miRNAs in MCMV and are not homologous to HCMV miRNAs. In parallel, we applied a computational analysis, using a support vector machine approach, to identify potential precursor miRNAs in MCMV. Four of the top 10 predicted precursor sequences were cloned in this study, and the combination of computational and cloning analysis demonstrates that MCMV has the capacity to encode miRNAs clustered throughout the genome. On the basis of drug sensitivity experiments for resolving the kinetic class of expression, we show that the MCMV miRNAs are both early and late gene products. Notably, the MCMV miRNAs occur on complementary strands of the genome in specific regions, a feature which has not previously been observed for viral miRNAs. One cluster of miRNAs occurs in close proximity to the 5′ splice site of the previously identified 7.2-kb stable intron, implying a variety of potential regulatory mechanisms for MCMV miRNAs.
Venezuelan Equine Encephalitis Virus Replicon Particles Encoding Respiratory Syncytial Virus Surface Glycoproteins Induce Protective Mucosal Responses in Mice and Cotton Rats
Authors: Mok Hoyin , Lee Sujin , Utley Thomas J. , Shepherd Bryan E. , Polosukhin Vasiliy V. , Collier Martha L. , Davis Nancy L. , Johnston Robert E. , Crowe James E. 
Published: October 2007

ABSTRACT

Respiratory syncytial virus (RSV) is an important viral pathogen that causes severe lower respiratory tract infection in infants, the elderly, and immunocompromised individuals. There are no licensed RSV vaccines to date. To prevent RSV infection, immune responses in both the upper and lower respiratory tracts are required. Previously, immunization with Venezuelan equine encephalitis virus replicon particles (VRPs) demonstrated effectiveness in inducing mucosal protection against various pathogens. In this study, we developed VRPs encoding RSV fusion (F) or attachment (G) glycoproteins and evaluated the immunogenicity and efficacy of these vaccine candidates in mice and cotton rats. VRPs, when administered intranasally, induced surface glycoprotein-specific virus neutralizing antibodies in serum and immunoglobulin A (IgA) antibodies in secretions at the respiratory mucosa. In addition, fusion protein-encoding VRPs induced gamma interferon (IFN-γ)-secreting T cells in the lungs and spleen, as measured by reaction with an
H-2K

d

-restricted CD8
+
T-cell epitope. In animals vaccinated with F protein VRPs, challenge virus replication was reduced below the level of detection in both the upper and lower respiratory tracts following intranasal RSV challenge, while in those vaccinated with G protein VRPs, challenge virus was detected in the upper but not the lower respiratory tract. Close examination of histopathology of the lungs of vaccinated animals following RSV challenge revealed no enhanced inflammation. Immunization with VRPs induced balanced Th1/Th2 immune responses, as measured by the cytokine profile in the lungs and antibody isotype of the humoral immune response. These results represent an important first step toward the use of VRPs encoding RSV proteins as a prophylactic vaccine for RSV.
Enzymatically Active APOBEC3G Is Required for Efficient Inhibition of Human Immunodeficiency Virus Type 1
Authors: Miyagi Eri , Opi Sandrine , Takeuchi Hiroaki , Khan Mohammad , Goila-Gaur Ritu , Kao Sandra , Strebel Klaus 
Published: October 2007

ABSTRACT

APOBEC3G (APO3G) is a cellular cytidine deaminase with potent antiviral activity. Initial studies of the function of APO3G demonstrated extensive mutation of the viral genome, suggesting a model in which APO3G's antiviral activity is due to hypermutation of the viral genome. Recent studies, however, found that deaminase-defective APO3G mutants transiently expressed in virus-producing cells exhibited significant antiviral activity, suggesting that the antiviral activity of APO3G could be dissociated from its deaminase activity. To directly compare the antiviral activities of wild-type (wt) and deaminase-defective APO3G, we used two approaches: (i) we titrated wt and deaminase-defective APO3G in transient-transfection studies to achieve similar levels of virus-associated APO3G and (ii) we constructed stable cell lines and selected clones expressing comparable amounts of wt and deaminase-defective APO3G. Viruses produced under these conditions were tested for viral infectivity. The results from the two approaches were consistent and suggested that the antiviral activity of deaminase-defective APO3G was significantly lower than that of wt APO3G. We conclude that efficient inhibition of
vif
-defective human immunodeficiency virus type 1 requires catalytically active APO3G.
Primary Human Splenic Macrophages, but Not T or B Cells, Are the Principal Target Cells for Dengue Virus Infection In Vitro
Authors: Blackley Shanley , Kou Zhihua , Chen Huiyuan , Quinn Matthew , Rose Robert C. , Schlesinger Jacob J. , Coppage Myra , Jin Xia 
Published: October 2007

ABSTRACTUnderstanding the pathogenesis of dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) requires the precise identification of dengue virus (DV)-permissive target cells. In a previous study using unfractionated human peripheral blood mononuclear cells, we found that monocytes, but not B or T cells, were the principal DV-permissive cells in the absence of DV-immune pooled human sera (PHS) and the major mediators of antibody-dependent enhancement in the presence of PHS. To further identify DV-permissive target cells in other tissues and organs, we isolated human splenic mononuclear cells (MNCs), inoculated them with DV type 2 (strain 16681) in the presence or absence of PHS, and assessed their infection either directly using flow cytometry and reverse transcription-PCR (RT-PCR) assays or indirectly by plaque assay. We found that in the absence of PHS, a small proportion of splenic macrophages appeared to be positive for DV antigens in comparison to staining controls by the flow cytometric assay (0.77% ± 1.00% versus 0.18% ± 0.12%;P= 0.07) and that viral RNA was detectable by the RT-PCR assay in MNCs exposed to DV. Additionally, supernatants from cultures of DV-exposed MNCs contained infectious virions that were readily detectable by plaque assay. The magnitude of infection was significantly enhanced in splenic macrophages in the presence of highly diluted PHS (5.41% ± 3.53% versus 0.77% ± 1.00%;P= 0.001). In contrast, primary T and B cells were not infected in either the presence or absence of PHS. These results provide evidence, for the first time, that human primary splenic macrophages, rather than B or T cells, are the principal DV-permissive cells in the spleen and that they may be uniquely important in the initial steps of immune enhancement that leads to DHF/DSS in some DV-infected individuals.
The 29-Nucleotide Deletion Present in Human but Not in Animal Severe Acute Respiratory Syndrome Coronaviruses Disrupts the Functional Expression of Open Reading Frame 8
Authors: Oostra Monique , de Haan Cornelis A. M. , Rottier Peter J. M. 
Published: October 2007

ABSTRACT

One of the most striking and dramatic genomic changes observed in the severe acute respiratory syndrome coronavirus (SARS-CoV) isolated from humans soon after its zoonotic transmission from palm civets was the acquisition of a characteristic 29-nucleotide deletion. This occurred in open reading frame 8 (ORF8), one of the accessory genes unique to the SARS-CoV. The function of ORF8 and the significance of the deletion are unknown. The intact ORF8 present in animal and some early human isolates encodes a 122-amino-acid polypeptide (8ab
+
), which we expressed in cells using the vaccinia virus T7 expression system. It was found to contain a cleavable signal sequence, which directs the precursor to the endoplasmic reticulum (ER) and mediates its translocation into the lumen. The cleaved protein became N-glycosylated, assembled into disulfide-linked homomultimeric complexes, and remained stably in the ER. The 29-nucleotide deletion splits ORF8 into two ORFs, 8a and 8b, encoding 39- and 84-residue polypeptides. The 8a polypeptide is likely to remain in the cytoplasm, as it is too small for its signal sequence to function and will therefore be directly released from the ribosome. However, we could not confirm this experimentally due to the lack of proper antibodies. ORF8b appeared not to be expressed in SARS-CoV-infected cells or when expressed from mRNA's mimicking mRNA8. This was due to the context of the internal AUG initiation codon, as we demonstrated after placing the ORF8b immediately behind the T7 promoter. A soluble, unmodified and monomeric 8b protein was now expressed in the cytoplasm, which was highly unstable and rapidly degraded. Clearly, the 29-nucleotide deletion disrupts the proper expression of the SARS-CoV ORF8, the implications of which are discussed.