bluuebunny/crossref_metadata_2025_split huggingface dataset:
Preventing Cleavage of the Respiratory Syncytial Virus Attachment Protein in Vero Cells Rescues the Infectivity of Progeny Virus for Primary Human Airway Cultures
Authors: Corry Jacqueline , Johnson Sara M. , Cornwell Jessica , Peeples Mark E. 
Published: November 2015

ABSTRACT
All live attenuated respiratory syncytial virus (RSV) vaccines that have advanced to clinical trials have been produced in Vero cells. The attachment (G) glycoprotein in virions produced in these cells is smaller than that produced in other immortalized cells due to cleavage. These virions are 5-fold less infectious for primary well-differentiated human airway epithelial (HAE) cell cultures. Because HAE cells are isolated directly from human airways, Vero cell-grown vaccine virus would very likely be similarly inefficient at initiating infection of the nasal epithelium following vaccination, and therefore, a larger inoculum would be required for effective vaccination. We hypothesized that Vero cell-derived virus containing an intact G protein would be more infectious for HAE cell cultures. Using protease inhibitors with increasing specificity, we identified cathepsin L to be the protease responsible for cleavage. Our evidence suggests that cleavage occurs in the late endosome or lysosome during endocytic recycling. Cathepsin L activity was 100-fold greater in Vero cells than in HeLa cells. In addition, cathepsin L was able to cleave the G protein in Vero cell-grown virions but not in HeLa cell-grown virions, suggesting a difference in G-protein posttranslational modification in the two cell lines. We identified by mutagenesis amino acids important for cleavage, and these amino acids included a likely cathepsin L cleavage site. Virus containing a modified, noncleavable G protein produced in Vero cells was 5-fold more infectious for HAE cells in culture, confirming our hypothesis and indicating the value of including such a mutation in future live attenuated RSV vaccines.

IMPORTANCE
Worldwide, RSV is the second leading infectious cause of infant death, but no vaccine is available. Experimental live attenuated RSV vaccines are grown in Vero cells, but during production the virion attachment (G) glycoprotein is cleaved. Virions containing a cleaved G protein are less infectious for primary airway epithelial cells, the natural RSV target. In the study described here we identified the protease responsible, located the cleavage site, and demonstrated that cleavage likely occurs during endocytic recycling. Moreover, we showed that the infectivity of Vero cell-derived virus for primary airway epithelial cells is increased 5-fold if the virus contains a mutation in the G protein that prevents cleavage. The blocking of cleavage should improve RSV vaccine yield, consequently reducing production costs. Posttranslational cleavage of the fusion glycoprotein of many viruses plays an essential role in activation; however, cleavage of the RSV G protein is a novel example of a detrimental effect of cleavage on virus infectivity.
Knockdown of Autophagy Inhibits Infectious Hepatitis C Virus Release by the Exosomal Pathway
Authors: Shrivastava Shubham , Devhare Pradip , Sujijantarat Nanthiya , Steele Robert , Kwon Young-Chan , Ray Ranjit , Ray Ratna B. 
Published: November 2015

ABSTRACT
Hepatitis C virus (HCV) is a major cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma in humans. We showed previously that HCV induces autophagy for viral persistence by preventing the innate immune response. Knockdown of autophagy reduces extracellular HCV release, although the precise mechanism remains unknown. In this study, we observed that knockdown of autophagy genes enhances intracellular HCV RNA and accumulates infectious virus particles in cells. Since HCV release is linked with the exosomal pathway, we examined whether autophagy proteins associate with exosomes in HCV-infected cells. We observed an association between HCV and the exosomal marker CD63 in autophagy knockdown cells. Subsequently, we observed that levels of extracellular infectious HCV were significantly lower in exosomes released from autophagy knockdown cells. To understand the mechanism for reduced extracellular infectious HCV in the exosome, we observed that an interferon (IFN)-stimulated BST-2 gene is upregulated in autophagy knockdown cells and associated with the exosome marker CD63, which may inhibit HCV assembly or release. Taken together, our results suggest a novel mechanism involving autophagy and exosome-mediated HCV release from infected hepatocytes.

IMPORTANCE
Autophagy plays an important role in HCV pathogenesis. Autophagy suppresses the innate immune response and promotes survival of virus-infected hepatocytes. The present study examined the role of autophagy in secretion of infectious HCV from hepatocytes. Autophagy promoted HCV trafficking from late endosomes to lysosomes, thus providing a link with the exosome. Inhibition of HCV-induced autophagy could be used as a strategy to block exosome-mediated virus transmission.
Human Immunodeficiency Virus Type 1 Monoclonal Antibodies Suppress Acute Simian-Human Immunodeficiency Virus Viremia and Limit Seeding of Cell-Associated Viral Reservoirs
Authors: Bolton Diane L. , Pegu Amarendra , Wang Keyun , McGinnis Kathleen , Nason Martha , Foulds Kathryn , Letukas Valerie , Schmidt Stephen D. , Chen Xuejun , Todd John Paul , Lifson Jeffrey D. , Rao Srinivas , Michael Nelson L. , Robb Merlin L. , Mascola John R. , Koup Richard A. 
Published: November 2015

ABSTRACT
Combination antiretroviral therapy (cART) administered shortly after human immunodeficiency virus type 1 (HIV-1) infection can suppress viremia and limit seeding of the viral reservoir, but lifelong treatment is required for the majority of patients. Highly potent broadly neutralizing HIV-1 monoclonal antibodies (MAbs) can reduce plasma viremia when administered during chronic HIV-1 infection, but the therapeutic potential of these antibodies during acute infection is unknown. We tested the ability of HIV-1 envelope glycoprotein-specific broadly neutralizing MAbs to suppress acute simian-human immunodeficiency virus (SHIV) replication in rhesus macaques. Four groups of macaques were infected with SHIV-SF162P3 and received (i) the CD4-binding-site MAb VRC01; (ii) a combination of a more potent clonal relative of VRC01 (VRC07-523) and a V3 glycan-dependent MAb (PGT121); (iii) daily cART, all on day 10, just prior to expected peak plasma viremia; or (iv) no treatment. Daily cART was initiated 11 days after MAb administration and was continued for 13 weeks in all treated animals. Over a period of 11 days after a single administration, MAb treatment significantly reduced peak viremia, accelerated the decay slope, and reduced total viral replication compared to untreated controls. Proviral DNA in lymph node CD4 T cells was also diminished after treatment with the dual MAb. These data demonstrate the virological effect of potent MAbs and support future clinical trials that investigate HIV-1-neutralizing MAbs as adjunctive therapy with cART during acute HIV-1 infection.

IMPORTANCE
Treatment of chronic HIV-1 infection with potent broadly neutralizing HIV-1 MAbs has been shown to significantly reduce plasma viremia. However, the antiviral effect of MAb treatment during acute HIV-1 infection is unknown. Here, we demonstrate that MAbs targeting the HIV-1 envelope glycoprotein both suppress acute SHIV plasma viremia and limit CD4 T cell-associated viral DNA. These findings provide support for clinical trials of MAbs as adjunctive therapy with antiretroviral therapy during acute HIV-1 infection.
Genetics, Receptor Binding, Replication, and Mammalian Transmission of H4 Avian Influenza Viruses Isolated from Live Poultry Markets in China
Authors: Liang Libin , Deng Guohua , Shi Jianzhong , Wang Shuai , Zhang Qianyi , Kong Huihui , Gu Chunyang , Guan Yuntao , Suzuki Yasuo , Li Yanbing , Jiang Yongping , Tian Guobin , Liu Liling , Li Chengjun , Chen Hualan 
Published: November 2015

ABSTRACT
H4 avian influenza virus (AIV) is one of the most prevalent influenza virus subtypes in the world. However, whether H4 AIVs pose a threat to public health remains largely unclear. Here, we analyzed the phylogenetic relationships, receptor binding properties, replication, and transmissibility in mammals of H4 AIVs isolated from live poultry markets in China between 2009 and 2012. Genomic sequence analysis of 36 representative H4 viruses revealed 32 different genotypes, indicating that these viruses are undergoing complex and frequent reassortment events. All 32 viruses tested could replicate in the respiratory organs of infected mice without prior adaptation. Receptor binding analysis demonstrated that the H4 AIVs bound to α-2,6-linked glycans, although they retained the binding preference for α-2,3-linked glycans. When we tested the direct-contact transmission of 10 H4 viruses in guinea pigs, we found that three viruses did not transmit to any of the contact animals, one virus transmitted to one of three contact animals, and six viruses transmitted to all three contact animals. When we further tested the respiratory droplet transmissibility of four of the viruses that transmitted efficiently via direct contact, we found that three of them could transmit to one or two of the five exposed animals. Our study demonstrates that the current circulating H4 AIVs can infect, replicate in, and transmit to mammalian hosts, thereby posing a potential threat to human health. These findings emphasize the continual need for enhanced surveillance of H4 AIVs.

IMPORTANCE
Numerous surveillance studies have documented the wide distribution of H4 AIVs throughout the world, yet the biological properties of H4 viruses have not been well studied. In this study, we found that multiple genotypes of H4 viruses are cocirculating in the live poultry markets of China and that H4 viruses can replicate in mice, possess human-type receptor binding specificity, and transmit between guinea pigs via direct contact. Strikingly, some H4 strains also can transmit via respiratory droplet, albeit with limited efficiency. These results clearly show the potential threat posed by H4 viruses to public health.
Enhanced Immune Responses to HIV-1 Envelope Elicited by a Vaccine Regimen Consisting of Priming with Newcastle Disease Virus Expressing HIV gp160 and Boosting with gp120 and SOSIP gp140 Proteins
Authors: Khattar Sunil K. , DeVico Anthony L. , LaBranche Celia C. , Panda Aruna , Montefiori David C. , Samal Siba K. 
Published: November 2015

ABSTRACT
Newcastle disease virus (NDV) expressing HIV-1 BaL gp160 was evaluated either alone or with monomeric BaL gp120 and BaL SOSIP gp140 protein in a prime-boost combination in guinea pigs to enhance envelope (Env)-specific humoral and mucosal immune responses. We showed that a regimen consisting of an NDV prime followed by a protein boost elicited stronger serum and mucosal Th-1-biased IgG responses and neutralizing antibody responses than NDV-only immunizations. Additionally, these responses were higher after the gp120 than after the SOSIP gp140 protein boost.
Improving fluid balance monitoring on the wards
Authors: Jeyapala Sobanakumari , Gerth Alice , Patel Aarti , Syed Nazia 
Published: November 2015

AbstractClinical experience and nursing metrics have consistently identified poor documentation of fluid balance monitoring at Milton Keynes University Hospital, compromising patient safety and quality of care. This project aimed to increase the percentage of fluid balance charts correctly completed on the wards.Three areas for improvement were identified: understanding the importance of good fluid balance monitoring, correct identification of patients requiring monitoring, and ease of completion of fluid balance charts. Three interventions were deployed on two acute medical awards in consecutive cycles; 1) small group education for staff, 2) creation of board magnets to aid the multidisciplinary team to identify patients requiring monitoring, 3) modification of the current fluid balance chart. Questionnaires were utilised to highlight improvements with current charts and measured staff awareness pre and post education. Each intervention was implemented for one week followed by daily surveys for four days to monitor compliance.Initial results showed a range of 6-12 charts used daily per ward. Of these 0-45% of them were correctly filled. Post education there was a reduced number of inappropriate charts. Introduction of board magnets improved correlation between doctors and nurses in identification of patients (52% before, 77% after magnets). Following modification there was a subjective improvement in the quality of chart completion.This study highlighted that understanding and use of fluid balance monitoring can be improved for nurses, health care assistants (HCAs), and doctors. These improvements allow better documentation and safer patient care. As a result, Milton Keynes University Hospital is investing in magnets and modified charts for a Trust-wide pilot.
Exploring the transition from curative care to palliative care: a systematic review of the literature
Authors: Gardiner Clare , Ingleton Christine , Gott Merryn , Ryan Tony 
Published: November 2015

BackgroundUK policy guidance on treatment and care towards the end of life identifies a need to better recognise patients who are likely to be in the last 12 months of life. Health and social care professionals have a key role in initiating and managing a patient's transition from ‘curative care’ to palliative care. The aim of this paper is to provide a systematic review of evidence relating to the transition from curative care to palliative care within UK settings.MethodFour electronic databases were searched for studies published between 1975 and March 2010. Inclusion criteria were all UK studies relating to the transition from curative care to palliative care in adults over the age of 18. Selected studies were independently reviewed, data were extracted, quality was assessed and data were synthesised using a descriptive thematic approach.ResultsOf the 1464 articles initially identified, 12 papers met the criteria for inclusion. Four themes emerged from the literature: (1) patient and carer experiences of transitions; (2) recognition and identification of the transition phase; (3) optimising and improving transitions; and (4) defining and conceptualising transitions.ConclusionsThe literature suggests that little is known about the potentially complex transition to palliative care. Evidence suggests that continuity of care and multidisciplinary collaboration are crucial in order to improve the experience of patients making the transition. An important role is outlined for generalist providers of palliative care. Incorporating palliative care earlier in the disease trajectory and implementing a phased transition appear key components of optimum care.
Improving care and support for people with progressive illness in primary care
Authors: Harrison N , Cavers D , Campbell C , Murray S A 
Published: November 2015

AbstractIntroduction and aimsThe Palliative Care Directed Enhanced Service (DES) was introduced in Scotland in 2008/2009 to stimulate anticipatory care by GP practice teams. We aimed to evaluate how practices were implementing this by assessing how they wereidentifying patients for their palliative care register (PCR),assessing/reviewing needs,sharing information with out of hours (OOH) providers,using the Liverpool Care Pathway (LCP).MethodsSix practices were recruited from three Scottish Health Boards. Data were collected on current palliative care patients and on patients dying in the previous 6 months; semi-structured interviews were conducted with GPs, district nurses (DN) and administrative staff (total 20) and with patients and bereaved relatives (total 11); the researcher observed multidisciplinary practice meetings.ResultsOnly 29% of patients were on the PCR prior to death (range 10–38% between practices). Of these, 69% had cancer, 17% organ failure and 14% dementia or physical frailty and 25% died in hospital (cf. 44% of all deaths). 52% on the current PCR had a record of preferred place of care and 35% of resuscitation status. Practices valued better focused and structured palliative care, improved communication with OOH providers and introduction of the LCP but raised some difficulties in including non-cancer patients on the PCR. Patients and relatives appreciated pro-active care.ConclusionDespite this initiative few patients were identified for palliative care. However when identified, their multidisciplinary and OOH care improved and hospital admissions to die decreased. Practices must identify more patients earlier for palliative care.
How many people need expert symptom assessment but are not in the last year of life?
Authors: Maher J. , McConnel H. 
Published: November 2015

IntroductionEarlier palliative assessment and support for symptom self management may reduce distress and health resource use in incurable illness. The end of life tariff includes assessment of unstable symptoms, even if not in the last year of life. Current hospital recording systems do not allow timely identification of these individuals. Understanding how many people have palliative needs but are not in the last year of life will be increasingly important.Aims and MethodsTo identify people living with cancer at different phases across the care pathway including those at risk of developing complex symptoms, with progressive illness or at end of life. Using available data and clinically led assumptions we make indicative estimates of the number of people in different health states – particularly those with palliative care needs and not in the last year of life.ResultsWe estimate pathway phases for breast, prostate, colorectal and lung cancers. For example, we estimate that in one year 48,000 women develop breast cancer in the UK and 12,000 are in the last year of life 24,000 have progressive illness and are not in the last year of life.ConclusionWe provide ‘good enough’ estimates of the number of patients with different health needs and transition points in the cancer care pathway to stimulate debate and inform commissioners about areas of need. While cancer is seen to have the most predictable pattern of deterioration, as more incurable cancers become treatable, illness trajectories will become more comparable to other chronic illness. A similar approach might be taken with other illnesses.
Lymphocyte subsets contribute to the degree of lobulitis and ductitis in sclerosing lymphocytic lobulitis of the breast
Authors: Chen Lin-Ying , Tsang Julia Y S , Ni Yun-Bi , Chan Siu-Ki , Chan Kui-Fat , Zhang Sheng , Tse Gary M 
Published: November 2015

AimsSclerosing lymphocytic lobulitis (SLL) of the breast is characterised by lymphocytic lobulitis, ductitis, vasculitis and dense keloidal fibrosis with epithelioid fibroblasts. However, the subsets of the infiltrating lymphocytes and their contribution to disease progression have not been fully explored.MethodsCD20, CD3, CD4, CD8 and regulatory T (Treg) lymphocytes were evaluated in the epithelial and vascular areas in SLL. The relationship between the lymphocyte subset in different regions and the degree of inflammation was analysed.ResultsLymphocytic infiltration was mainly located in peri-lobular, peri-ductal and peri-vascular areas. No significant differences between CD20 and CD3 lymphocytes were found in peri-epithelial areas. However, there were more intra-ductal/lobular epithelial CD3 than CD20 lymphocytes (p<0.001). For T lymphocyte subsets, more CD4 than CD8 lymphocytes were found in the peri-lobular/vascular regions (p≤0.026); but an opposite trend was seen in the intra-ductal/lobular regions (p<0.001). In the peri-lobular/vascular regions, generally, different lymphocyte subsets correlated with each other. Interestingly, in the peri-ductal region, only CD4 lymphocytes showed significant correlations with all other subsets (p≤0.020). Regarding their relationship with the degree of inflammation, significant positive correlations were observed for all subsets in peri-vascular/lobular regions (p≤0.045). Only regulatory T cells, but not the others, at the peri-ductal region showed significant correlation with the degree of inflammation at all three regions (p≤0.014).ConclusionsIn addition to B lymphocyte subsets, T lymphocyte subsets could be involved differently in SLL. CD4 lymphocytes may have a pivotal role in recruiting other subsets to the inflamed site, and triggered the cascade of inflammatory changes resulting in fibrosis.
Evolution of small-scale flow barriers in German Rotliegend siliciclastics
Authors: Busch Benjamin , Winkler Rebecca , Osivandi Keyvan , Nover Georg , Amann-Hildenbrand Alexandra , Hilgers Christoph 
Published: November 2015

Abstract
Many siliciclastic reservoirs contain millimetre-scale diagenetic and structural phenomena affecting fluid flow. We identified three major types of small-scale flow barriers in a clastic Rotliegend hydrocarbon reservoir: cataclastic deformation bands; dissolution seams; and bedding-parallel cementation. Deformation bands of various orientations were analysed on resistivity image logs and in core material. They are mainly conjugates, and can be used to validate seismically observable faults and infer subseismic faults. Bedding-parallel dissolution seams are related to compaction and post-date at least one set of deformation bands. Bedding-parallel cementation is accumulated in coarser-grained layers and depends on the amount of clay coatings.
Apparent permeability data related to petrographical image interpretation visualizes the impact of flow barriers on reservoir heterogeneity. Transmissibility multiplier calculations indicate the small efficiency of the studied deformation bands on flow properties in the reservoir. Deformation bands reduce the host-rock permeability by a maximum of two orders of magnitude. However, host-rock anisotropies are inferred to reduce the permeability by a maximum of four orders of magnitude. The relative timing of these flow barriers, as well as the assessment of reservoir heterogeneities, are the basis for state-of-the-art reservoir prediction modelling.
Burial estimates constrained by clumped isotope thermometry: example of the Lower Cretaceous Qishn Formation (Haushi-Huqf High, Oman)
Authors: John Cédric M. 
Published: November 2015

Abstract

Accurate determination of the thermal history of sedimentary basins is critical to constrain the timing of diagenetic processes. Here, clumped isotope palaeothermometry is used to estimate minimum burial depth of the Lower Cretaceous Qishn Formation in east central Oman. Fossil oysters were collected in a soft argillaceous unit, thin-sectioned, and studied under petrographical and cathodoluminescence microscopy, revealing a variable state of shell preservations with early silica replacement of carbonate and late-stage calcite cementation. Clumped isotopes values varied from 0.602 to 0.666‰, with the best-preserved oyster shell yielding a temperature of 37 ± 4°C and a calculated oxygen isotope ratio in seawater (δ
18
O
seawater
) compatible with Cretaceous seawater having experienced moderate evaporation (1.0–1.5‰ VSMOW). The new minimum estimates for the burial depth of the Qishn Formation is 1.0–1.2 km, based on the temperature difference between the well-preserved oyster and the partially neomorphosed oyster recording the highest burial temperature (63 ± 4°C). This is in excess of what was predicted by previous studies (<400 m), but compatible with conodonts alteration index temperatures (<80°C). This study highlights the potential of clumped isotopes as a quantitative tool to estimate temperature and burial depth in fine-grained carbonate succession where fluid inclusions are absent, and offers a new tool to constrain the thermal histories of sedimentary basins.