bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of a Neutralizing Epitope within Antigenic Domain 5 of Glycoprotein B of Human Cytomegalovirus
Authors: Wiegers Anna-Katharina , Sticht Heinrich , Winkler Thomas H. , Britt William J. , Mach Michael 
Published: October 2014

ABSTRACTHuman cytomegalovirus (HCMV) is an important, ubiquitous pathogen that causes severe clinical disease in immunocompromised individuals, such as organ transplant recipients and infants infectedin utero. The envelope glycoprotein B (gB) of HCMV is a major antigen for the induction of virus-neutralizing antibodies. We have begun to define target structures within gB that are recognized by virus-neutralizing antibodies. Antigenic domain 5 (AD-5) of gB has been identified as an important target for neutralizing antibodies in studies using human monoclonal antibodies (MAbs). Anti-AD-5 MAbs share a target site on gB, despite originating from different, healthy, HCMV-infected donors. Mutational analysis of AD-5 identified tyrosine 280 in combination with other surface-exposed residues (the YNND epitope) as critical for antibody binding. The YNND epitope is strictly conserved among different HCMV strains. Recombinant viruses carrying YNND mutations in AD-5 were resistant to virus-neutralizing MAbs. Competition enzyme-linked immunosorbent assays (ELISAs) with human HCMV-convalescent-phase sera from unselected donors confirmed the conserved antibody response for the YNND epitope in HCMV-infected individuals and, because a significant fraction of the gB AD-5 response was directed against the YNND epitope, further argued that this epitope is a major target of anti-AD-5 antibody responses. In addition, affinity-purified polyclonal anti-AD-5 antibodies prepared from individual sera showed reactivity to AD-5 and neutralization activity toward gB mutant viruses that were similar to those of AD-5-specific MAbs. Taken together, our data indicate that the YNND epitope represents an important target for anti-gB antibody responses as well as for anti-AD-5 virus-neutralizing antibodies.IMPORTANCEHCMV is a major global health concern, and a vaccine to prevent HCMV disease is a widely recognized medical need. Glycoprotein B of HCMV is an important target for neutralizing antibodies and hence an interesting molecule for intervention strategies, e.g., vaccination. Mapping the target structures of neutralizing antibodies induced by naturally occurring HCMV infection can aid in defining the properties required for a protective capacity of vaccine antigens. The data presented here extend our knowledge of neutralizing epitopes within gB to include AD-5. Collectively, our data will contribute to optimal vaccine design and development of antibody-based therapies.
Slaying the Trojan Horse: Natural Killer Cells Exhibit Robust Anti-HIV-1 Antibody-Dependent Activation and Cytolysis against Allogeneic T Cells
Authors: Gooneratne Shayarana L. , Richard Jonathan , Lee Wen Shi , Finzi Andrés , Kent Stephen J. , Parsons Matthew S. 
Published: October 2014

ABSTRACTMany attempts to design prophylactic human immunodeficiency virus type 1 (HIV-1) vaccines have focused on the induction of neutralizing antibodies (Abs) that block infection by free virions. Despite the focus on viral particles, virus-infected cells, which can be found within mucosal secretions, are more infectious than free virus bothin vitroandin vivo. Furthermore, assessment of human transmission couples suggests infected seminal lymphocytes might be responsible for a proportion of HIV-1 transmissions. Although vaccines that induce neutralizing Abs are sought, only some broadly neutralizing Abs efficiently block cell-to-cell transmission of HIV-1. As HIV-1 vaccines need to elicit immune responses capable of controlling both free and cell-associated virus, we evaluated the potential of natural killer (NK) cells to respond in an Ab-dependent manner to allogeneic T cells bearing HIV-1 antigens. This study presents data measuring Ab-dependent anti-HIV-1 NK cell responses to primary and transformed allogeneic T-cell targets. We found that NK cells are robustly activated in an anti-HIV-1 Ab-dependent manner against allogeneic targets and that tested target cells are subject to Ab-dependent cytolysis. Furthermore, the educated KIR3DL1+NK cell subset from HLA-Bw4+individuals exhibits an activation advantage over the KIR3DL1−subset that contains both NK cells educated through other receptor/ligand combinations and uneducated NK cells. These results are intriguing and important for understanding the regulation of Ab-dependent NK cell responses and are potentially valuable for designing Ab-dependent therapies and/or vaccines.IMPORTANCENK cell-mediated anti-HIV-1 antibody-dependent functions have been associated with protection from infection and disease progression; however, their role in protecting from infection with allogeneic cells infected with HIV-1 is unknown. We found that HIV-1-specific ADCC antibodies bound to allogeneic cells infected with HIV-1 or coated with HIV-1 gp120 were capable of activating NK cells and/or trigging cytolysis of the allogeneic target cells. This suggests ADCC may be able to assist in preventing infection with cell-associated HIV-1. In order to fully utilize NK cell-mediated Ab-dependent effector functions, it might also be important that educated NK cells, which hold the highest activation potential, can become activated against targets bearing HIV-1 antigens and expressing the ligands for self-inhibitory receptors. Here, we show that with Ab-dependent stimulation, NK cells expressing inhibitory receptors can mediate robust activation against targets expressing the ligands for those receptors.
Swine Interferon-Inducible Transmembrane Proteins Potently Inhibit Influenza A Virus Replication
Authors: Lanz Caroline , Yángüez Emilio , Andenmatten Dario , Stertz Silke 
Published: October 2014

ABSTRACT
Human interferon-inducible transmembrane proteins (IFITMs) were identified as restriction factors of influenza A virus (IAV). Given the important role of pigs in the zoonotic cycle of IAV, we cloned swine IFITMs (swIFITMs) and found two IFITM1-like proteins, one homologue of IFITM2, and a homologue of IFITM3. We show that swIFITM2 and swIFITM3 localize to endosomes and display potent antiviral activities. Knockdown of swIFITMs strongly reduced virus inhibition by interferon, establishing the swIFITMs as potent restriction factors in porcine cells.
Kaposi's Sarcoma-Associated Herpesvirus-Encoded Replication and Transcription Activator Impairs Innate Immunity via Ubiquitin-Mediated Degradation of Myeloid Differentiation Factor 88
Authors: Zhao Qinglan , Liang Deguang , Sun Rui , Jia Baosen , Xia Tian , Xiao Hui , Lan Ke 
Published: October 2014

ABSTRACT

Kaposi's sarcoma-associated herpesvirus (KSHV) is a human gammaherpesvirus with latent and lytic reactivation cycles. The mechanism by which KSHV evades the innate immune system to establish latency has not yet been precisely elucidated. Toll-like receptors (TLRs) are the first line of defense against viral infections. Myeloid differentiation factor 88 (MyD88) is a key adaptor that interacts with all TLRs except TLR3 to produce inflammatory factors and type I interferons (IFNs), which are central components of innate immunity against microbial infection. Here, we found that KSHV replication and transcription activator (RTA), which is an immediate-early master switch protein of viral cycles, downregulates MyD88 expression at the protein level by degrading MyD88 through the ubiquitin (Ub)-proteasome pathway. We identified the interaction between RTA and MyD88
in vitro
and
in vivo
and demonstrated that RTA functions as an E3 ligase to ubiquitinate MyD88. MyD88 also was repressed at the early stage of
de novo
infection as well as in lytic reactivation. We also found that RTA inhibited lipopolysaccharide (LPS)-triggered activation of the TLR4 pathway by reducing IFN production and NF-κB activity. Finally, we showed that MyD88 promoted the production of IFNs and inhibited KSHV LANA-1 gene transcription. Taken together, our results suggest that KSHV RTA facilitates the virus to evade innate immunity through the degradation of MyD88, which might be critical for viral latency control.

IMPORTANCE
MyD88 is an adaptor for all TLRs other than TLR3, and it mediates inflammatory factors and IFN production. Our study demonstrated that the KSHV RTA protein functions as an E3 ligase to degrade MyD88 through the ubiquitin-proteasome pathway and block the transmission of TLRs signals. Moreover, we found that KSHV inhibited MyD88 expression during the early stage of
de novo
infection as well as in lytic reactivation. These results provide a potential mechanism for the virus to evade innate immunity.
HIV virological failure and drug resistance among injecting drug users receiving first-line ART in China
Authors: Leng Xuebing , Liang Shujia , Ma Yanling , Dong Yonghui , Kan Wei , Goan Daniel , Hsi Jenny H , Liao Lingjie , Wang Jing , He Cui , Zhang Heng , Xing Hui , Ruan Yuhua , Shao Yiming 
Published: October 2014

ObjectiveTo explore HIV virological failure and drug resistance among injecting drug users (IDUs) receiving first-line antiretroviral treatment (ART) in China.DesignA series of cross-sectional surveys from 2003 to 2012 from the Chinese National HIV Drug Resistance (HIVDR) Surveillance and Monitoring Network.SettingChina.ParticipantsData were analysed by the Chinese National (HIVDR) Surveillance and Monitoring Network from 2003 to 2012. Demographic, ART and laboratory data (CD4+ cell count, viral load and drug resistance) were included. Factors associated with virological failure were identified by logistic regression analysis.Results929 of the 8556 individuals in the Chinese HIVDR database were IDUs receiving first-line ART. For these 929 IDUs, the median duration of treatment was 14 months (IQR 6.0–17.8). 193 of the 929 IDUs (20.8%) experienced virological failure (HIV viral load ≥1000 copies/mL). The prevalence of HIVDR among patients with virological failure was 38.9% (68/175). The proportion of patients with drug resistance to non-nucleoside reverse transcriptase inhibitor (NNRTIs), nucleoside reverse transcriptase inhibitor (NRTIs) and protease inhibitors (PIs) was 52.9%, 76.5% and 4.4%, respectively. Factors independently associated with virological failure include: ethnic minorities, junior high school education or less, farmers, self-reported missing doses in the past month, CD4 cell count at survey from 200 to 349 cells/mm3or from 0 to 199 cells/mm3, and residence of Guangxi and Yunnan provinces.ConclusionsThe proportion of virological failure was high among IDUs receiving first-line ART in China. However, better treatment outcomes were observed in Guangxi and Yunnan, which indicates the importance of ART education and adherence to intervention, especially for patients who are farmers, minorities or have a poor educational background.
Views of NHS commissioners on commissioning support provision. Evidence from a qualitative study examining the early development of clinical commissioning groups in England
Authors: Petsoulas Christina , Allen Pauline , Checkland Kath , Coleman Anna , Segar Julia , Peckham Stephen , Mcdermott Imelda 
Published: October 2014

ObjectiveThe 2010 healthcare reform in England introduced primary care-led commissioning in the National Health Service (NHS) by establishing clinical commissioning groups (CCGs). A key factor for the success of the reform is the provision of excellent commissioning support services to CCGs. The Government's aim is to create a vibrant market of competing providers of such services (from both for-profit and not-for-profit sectors). Until this market develops, however, commissioning support units (CSUs) have been created from which CCGs are buying commissioning support functions. This study explored the attitudes of CCGs towards outsourcing commissioning support functions during the initial stage of the reform.DesignThe research took place between September 2011 and June 2012. We used a case study research design in eight CCGs, conducting in-depth interviews, observation of meetings and analysis of policy documents.Setting/participantsWe conducted 96 interviews and observed 146 meetings (a total of approximately 439 h).ResultsMany CCGs were reluctant to outsource core commissioning support functions (such as contracting) for fear of losing local knowledge and trusted relationships. Others were disappointed by the absence of choice and saw CSUs as monopolies and a recreation of the abolished PCTs. Many expressed doubts about the expectation that outsourcing of commissioning support functions will result in lower administrative costs.ConclusionsGiven the nature of healthcare commissioning, outsourcing vital commissioning support functions may not be the preferred option of CCGs. Considerations of high transaction costs, and the risk of fragmentation of services and loss of trusted relationships involved in short-term contracting, may lead most CCGs to decide to form long-term partnerships with commissioning support suppliers in the future. This option, however, limits competition by creating ‘network closure’ and calls into question the Government's intention to create a vibrant market of commissioning support provision.
Designing quality improvement initiatives: the action effect method, a structured approach to identifying and articulating programme theory
Authors: Reed Julie E , McNicholas Christopher , Woodcock Thomas , Issen Laurel , Bell Derek 
Published: October 2014

BackgroundThe identification and articulation of programme theory can support effective design, execution and evaluation of quality improvement (QI) initiatives. Programme theory includes an agreed aim, potential interventions to achieve this aim, anticipated cause/effect relationships between the interventions and the aim and measures to monitor improvement. This paper outlines the approach used in a research and improvement programme to support QI initiatives in identifying and articulating programme theory: the action effect method.Background to method developmentBuilding on a previously used QI method, the driver diagram, the action effect method was developed using co-design and iteration over four annual rounds of improvement initiatives. This resulted in a specification of the elements required to fully articulate the programme theory of a QI initiative.The action effect methodThe action effect method is a systematic and structured process to identify and articulate a QI initiative's programme theory. The method connects potential interventions and implementation activities with an overall improvement aim through a diagrammatic representation of hypothesised and evidenced cause/effect relationships. Measure concepts, in terms of service delivery and patient and system outcomes, are identified to support evaluation.Discussion and conclusionsThe action effect method provides a framework to guide the execution and evaluation of a QI initiative, a focal point for other QI methods and a communication tool to engage stakeholders. A clear definition of what constitutes a well-articulated programme theory is provided to guide the use of the method and assessment of the fidelity of its application.
Characteristics of small areas with high rates of hospital-treated self-harm: deprived, fragmented and urban or just close to hospital? A national registry study
Authors: O'Farrell I B , Corcoran P , Perry I J 
Published: October 2014

BackgroundPrevious research has shown an inconsistent relationship between the spatial distribution of hospital treated self-harm and area-level factors such as deprivation and social fragmentation. However, many of these studies have been confined to urban centres, with few focusing on rural settings and even fewer studies carried out at a national level. Furthermore, no previous research has investigated if travel time to hospital services can explain the area-level variation in the incidence of hospital treated self-harm.MethodsFrom 2009 to 2011, the Irish National Registry of Deliberate Self Harm collected data on self-harm presentations to all hospital emergency departments in the country. The Registry uses standard methods of case ascertainment and also geocodes patient addresses to small area geographical level. Negative binomial regression was used to explore the ecological relationship between area-level self-harm rates and various area-level factors.ResultsDeprivation, social fragmentation and population density had a positive linear association with self-harm, with deprivation having the strongest independent effect. Furthermore, self-harm incidence was found to be elevated in areas that had shorter journey times to hospital. However, while this association became attenuated after controlling for other area-level factors it still remained statistically significant. A subgroup analysis examining the effect of travel time on specific methods of self-harm, found that this effect was most marked for self-harm acts involving minor self-cutting.ConclusionsSelf-harm incidence was influenced by proximity to hospital services, population density and social fragmentation; however, the strongest area-level predictor of self-harm was deprivation.
Elderly patients with intracranial aneurysms have higher quality of life after coil embolization: a decision analysis
Authors: Smith Michelle J , Sanborn Matthew R , Lewis Daniel J , Faught Ryan W F , Vakhshori Venus , Stein Sherman C 
Published: October 2014

ObjectiveTo develop a decision analytic model to calculate outcomes after treatment of cerebral aneurysms in elderly patients. Neurosurgical clipping and endovascular coiling for both ruptured and unruptured aneurysms were compared with predicted health-related quality of life (HRQoL) after treatment.MethodsA Medline search of articles published in English between 1995 and June 2012 was performed using key words: ‘intracranial aneurysms’, ‘treatment’, or various combinations of ‘elderly’, ‘older’, or ‘decade’. Reports that met inclusion criteria used either the Glasgow Outcome Score or the modified Rankin Scale for outcomes, age >69, and intracranial aneurysm that was treated by endovascular coiling or surgical clipping. Data were collected by performing a comprehensive review of published reports. Meta-analysis (inverse variance-weighted, random effects) was used to calculate pooled values for probabilities and HRQoL.ResultsHRQoL was significantly higher for patients with coiled rather than clipped aneurysms in both ruptured (p<0.01) and unruptured (p<0.01) aneurysm groups. Periprocedural mortality rates were significantly lower among patients with a coiled, unruptured aneurysm than among patients with a clipped, unruptured aneurysm (p=0.032). Sensitivity analysis and Monte Carlo simulation for both ruptured and unruptured aneurysms showed that overall HRQoL was significantly higher in coiled than in clipped patients.ConclusionsAs life expectancy increases, treatment of cerebral aneurysms in the elderly becomes more important. Given the results of this decision analysis and the continuous refinement in endovascular technology, embolization should strongly be considered as a first-line treatment for cerebral aneurysms in the elderly.
Cretaceous provenance change in the Hegang Basin and its connection with the Songliao Basin, NE China: evidence for lithospheric extension driven by palaeo-Pacific roll-back
Authors: Sun Mingdao , Chen Hanlin , Zhang Fengqi , Wilde Simon A. , Minna A. , Lin Xiubin , Yang Shufeng 
Published: October 2014

Abstract
The Cretaceous Hegang Basin is located on the Jiamusi Block, NE China, and separated from the Songliao Basin by the Lesser Xing'an Range (LXR). Seismic interpretation shows that the Chengzihe, Muling and Dongshan formations of the Hegang Basin thicken eastwards with westwards onlap, indicating that the LXR existed as a palaeo-uplift during that period, whereas the Houshigou Formation shows no thickness change, indicating that the LXR was possibly under water at this time. This is supported by results of detrital zircon analysis from the Hegang Basin in which the Chengzihe Formation is dominated by approximately 180 Ma zircons, which can only be provided by the LXR, whereas the Houshigou Formation records no Early Jurassic ages. This view is consistent with previous studies of the Songliao Basin for a provenance change between the Denglouku and Quantou formations. We conclude that the LXR was a highland during deposition of the Chengzihe, Muling and Dongshan formations but that it was under water when the Houshigou Formation was deposited. There was thus a connection between the Hegang and Songliao basins, which marks an eastwards migration of the depositional and extensional centre of the Songliao–Hegang basin system. This eastwards migration implies lithospheric extension driven by palaeo-Pacific roll-back.
EGFR Activation and Signaling in Cancer Cells Are Enhanced by the Membrane-Bound Metalloprotease MT4-MMP
Authors: Paye Alexandra , Truong Alice , Yip Cassandre , Cimino Jonathan , Blacher Silvia , Munaut Carine , Cataldo Didier , Foidart Jean Michel , Maquoi Erik , Collignon Joelle , Delvenne Philippe , Jerusalem Guy , Noel Agnès , Sounni Nor Eddine 
Published: October 2014

AbstractMT4-MMP (MMP-17) is a glycosylphosphatidyl inositol–anchored matrix metalloprotease expressed on the surface of cancer cells that promotes tumor growth and metastasis. In this report, we identify MT4-MMP as an important driver of cancer cell proliferation through CDK4 activation and retinoblastoma protein inactivation. We also determine a functional link between MT4-MMP and the growth factor receptor EGFR. Mechanistic experiments revealed direct association of MT4-MMP and its positive effects on EGFR phosphorylation in response to TGFα and EGF in cancer cells. Notably, the effects of MT4-MMP on proliferation and EGFR activation did not rely on metalloprotease activity. Clinically, MT4-MMP and EGFR expressions were correlated in human triple-negative breast cancer specimens. Altogether, our results identify MT4-MMP as a positive modifier of EGFR outside-in signaling that acts to cooperatively drive cancer cell proliferation. Cancer Res; 74(23); 6758–70. ©2014 AACR.
Molecular Characterization of Chronic-type Adult T-cell Leukemia/Lymphoma
Authors: Yoshida Noriaki , Karube Kennosuke , Utsunomiya Atae , Tsukasaki Kunihiro , Imaizumi Yoshitaka , Taira Naoya , Uike Naokuni , Umino Akira , Arita Kotaro , Suguro Miyuki , Tsuzuki Shinobu , Kinoshita Tomohiro , Ohshima Koichi , Seto Masao 
Published: October 2014

AbstractAdult T-cell leukemia/lymphoma (ATL) is a human T-cell leukemia virus type-1–induced neoplasm with four clinical subtypes: acute, lymphoma, chronic, and smoldering. Although the chronic type is regarded as indolent ATL, about half of the cases progress to acute-type ATL. The molecular pathogenesis of acute transformation in chronic-type ATL is only partially understood. In an effort to determine the molecular pathogeneses of ATL, and especially the molecular mechanism of acute transformation, oligo-array comparative genomic hybridization and comprehensive gene expression profiling were applied to 27 and 35 cases of chronic and acute type ATL, respectively. The genomic profile of the chronic type was nearly identical to that of acute-type ATL, although more genomic alterations characteristic of acute-type ATL were observed. Among the genomic alterations frequently observed in acute-type ATL, the loss of CDKN2A, which is involved in cell-cycle deregulation, was especially characteristic of acute-type ATL compared with chronic-type ATL. Furthermore, we found that genomic alteration of CD58, which is implicated in escape from the immunosurveillance mechanism, is more frequently observed in acute-type ATL than in the chronic-type. Interestingly, the chronic-type cases with cell-cycle deregulation and disruption of immunosurveillance mechanism were associated with earlier progression to acute-type ATL. These findings suggested that cell-cycle deregulation and the immune escape mechanism play important roles in acute transformation of the chronic type and indicated that these alterations are good predictive markers for chronic-type ATL. Cancer Res; 74(21); 6129–38. ©2014 AACR.