bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differential Adeno-Associated Virus Serotype-Specific Interaction Patterns with Synthetic Heparins and Other Glycans
Authors: Mietzsch Mario , Broecker Felix , Reinhardt Anika , Seeberger Peter H. , Heilbronn Regine 
Published: December 2013

ABSTRACT
All currently identified primary receptors of adeno-associated virus (AAV) are glycans. Depending on the AAV serotype, these carbohydrates range from heparan sulfate proteoglycans (HSPG), through glycans with terminal α2-3 or α2-6 sialic acids, to terminal galactose moieties. Receptor identification has largely relied on binding to natural compounds, defined glycan-presenting cell lines, or enzyme-mediated glycan modifications. Here, we describe a comparative binding analysis of highly purified, fluorescent-dye-labeled AAV vectors of various serotypes on arrays displaying over 600 different glycans and on a specialized array with natural and synthetic heparins. Few glycans bind AAV specifically in a serotype-dependent manner. Differential glycan binding was detected for the described sialic acid-binding AAV serotypes 1, 6, 5, and 4. The natural heparin binding serotypes AAV2, -3, -6, and -13 displayed differential binding to selected synthetic heparins. AAV7, -8, -rh.10, and -12 did not bind to any of the glycans present on the arrays. For discrimination of AAV serotypes 1 to 6 and 13, minimal binding moieties are identified. This is the first study to differentiate the natural mixed heparin binding AAV serotypes 2, 3, 6, and 13 by differential binding to specific synthetic heparins. Also, sialic acid binding AAVs display differential glycan binding specificities. The findings are relevant for further dissection of AAV host cell interaction. Moreover, the definition of single AAV-discriminating glycan binders opens the possibility for glycan microarray-based discrimination of AAV serotypes in gene therapy.
Enhanced Central Nervous System Transduction with Lentiviral Vectors Pseudotyped with RVG/HIV-1gp41 Chimeric Envelope Glycoproteins
Authors: Trabalza Antonio , Eleftheriadou Ioanna , Sgourou Argyro , Liao Ting-Yi , Patsali Petros , Lee Heyne , Mazarakis Nicholas D. 
Published: December 2013

ABSTRACT

To investigate the potential benefits which may arise from pseudotyping the HIV-1 lentiviral vector with its homologous gp41 envelope glycoprotein (GP) cytoplasmic tail (CT), we created chimeric RVG/HIV-1gp41 GPs composed of the extracellular and transmembrane sequences of RVG and either the full-length gp41 CT or C terminus gp41 truncations sequentially removing existing conserved motifs. Lentiviruses (LVs) pseudotyped with the chimeric GPs were evaluated in terms of particle release (physical titer), biological titers, infectivity, and
in vivo
central nervous system (CNS) transduction. We report here that LVs carrying shorter CTs expressed higher levels of envelope GP and showed a higher average infectivity than those bearing full-length GPs. Interestingly, complete removal of GP CT led to vectors with the highest transduction efficiency. Removal of all C-terminal gp41 CT conserved motifs, leaving just 17 amino acids (aa), appeared to preserve infectivity and resulted in a significantly increased physical titer. Furthermore, incorporation of these 17 aa in the RVG CT notably enhanced the physical titer.
In vivo
stereotaxic delivery of LV vectors exhibiting the best
in vitro
titers into rodent striatum facilitated efficient transduction of the CNS at the site of injection. A particular observation was the improved retrograde transduction of neurons in connected distal sites that resulted from the chimeric envelope R5 which included the “Kennedy” sequence (Ken) and lentivirus lytic peptide 2 (LLP2) conserved motifs in the CT, and although it did not exhibit a comparable high titer upon pseudotyping, it led to a significant increase in distal retrograde transduction of neurons.

IMPORTANCE
In this study, we have produced novel chimeric envelopes bearing the extracellular domain of rabies fused to the cytoplasmic tail (CT) of gp41 and pseudotyped lentiviral vectors with them. Here we report novel effects on the transduction efficiency and physical titer of these vectors, depending on CT length and context. We also managed to achieve increased neuronal transduction
in vivo
in the rodent CNS, thus demonstrating that the efficiency of these vectors can be enhanced following merely CT manipulation. We believe that this paper is a novel contribution to the field and opens the way for further attempts to surface engineer lentiviral vectors and make them more amenable for applications in human disease.
Histone Deacetylase Inhibitors Potentiate Vesicular Stomatitis Virus Oncolysis in Prostate Cancer Cells by Modulating NF-κB-Dependent Autophagy
Authors: Shulak Laura , Beljanski Vladimir , Chiang Cindy , Dutta Sucharita M. , Van Grevenynghe Julien , Belgnaoui S. Mehdi , Nguyên Thi Lien-Anh , Di Lenardo Thomas , Semmes O. John , Lin Rongtuan , Hiscott John 
Published: December 2013

ABSTRACT
Vesicular stomatitis virus (VSV) is an oncolytic virus that induces cancer cell death through activation of the apoptotic pathway. Intrinsic resistance to oncolysis is found in some cell lines and many primary tumors as a consequence of residual innate immunity to VSV. In resistant-tumor models, VSV oncolytic potential can be reversibly stimulated by combination with epigenetic modulators, such as the histone deacetylase inhibitor vorinostat. Based on this reversible effect of vorinostat, we reasoned that critical host genes involved in oncolysis may likewise be reversibly regulated by vorinostat. A transcriptome analysis in prostate cancer PC3 cells identified a subset of NF-κB target genes reversibly regulated by vorinostat, as well as a group of interferon (IFN)-stimulated genes (ISGs). Consistent with the induction of NF-κB target genes, vorinostat-mediated enhancement of VSV oncolysis increased hyperacetylation of NF-κB RELA/p65. Additional bioinformatics analysis revealed that NF-κB signaling also increased the expression of several autophagy-related genes. Kinetically, autophagy preceded apoptosis, and apoptosis was observed only when cells were treated with both VSV and vorinostat. VSV replication and cell killing were suppressed when NF-κB signaling was inhibited using pharmacological or genetic approaches. Inhibition of autophagy by 3-methyladenine (3-MA) enhanced expression of ISGs, and either 3-MA treatment or genetic ablation of the autophagic marker Atg5 decreased VSV replication and oncolysis. Together, these data demonstrate that vorinostat stimulates NF-κB activity in a reversible manner via modulation of RELA/p65 signaling, leading to induction of autophagy, suppression of the IFN-mediated response, and subsequent enhancement of VSV replication and apoptosis.
Novel Attenuated Chikungunya Vaccine Candidates Elicit Protective Immunity in C57BL/6 mice
Authors: Hallengärd David , Kakoulidou Maria , Lulla Aleksei , Kümmerer Beate M. , Johansson Daniel X. , Mutso Margit , Lulla Valeria , Fazakerley John K. , Roques Pierre , Le Grand Roger , Merits Andres , Liljeström Peter 
Published: December 2013

ABSTRACTChikungunya virus (CHIKV) is a reemerging mosquito-borne alphavirus that has caused severe epidemics in Africa and Asia and occasionally in Europe. As of today, there is no licensed vaccine available to prevent CHIKV infection. Here we describe the development and evaluation of novel CHIKV vaccine candidates that were attenuated by deleting a large part of the gene encoding nsP3 or the entire gene encoding 6K and were administered as viral particles or infectious genomes launched by DNA. The resulting attenuated mutants were genetically stable and elicited high magnitudes of binding and neutralizing antibodies as well as strong T cell responses after a single immunization in C57BL/6 mice. Subsequent challenge with a high dose of CHIKV demonstrated that the induced antibody responses protected the animals from viremia and joint swelling. The protective antibody response was long-lived, and a second homologous immunization further enhanced immune responses. In summary, this report demonstrates a straightforward means of constructing stable and efficient attenuated CHIKV vaccine candidates that can be administered either as viral particles or as infectious genomes launched by DNA.IMPORTANCESimilar to other infectious diseases, the best means of preventing CHIKV infection would be by vaccination using an attenuated vaccine platform which preferably raises protective immunity after a single immunization. However, the attenuated CHIKV vaccine candidates developed to date rely on a small number of attenuating point mutations and are at risk of being unstable or even sensitive to reversion. We report here the construction and preclinical evaluation of novel CHIKV vaccine candidates that have been attenuated by introducing large deletions. The resulting mutants proved to be genetically stable, attenuated, highly immunogenic, and able to confer durable immunity after a single immunization. Moreover, these mutants can be administered either as viral particles or as DNA-launched infectious genomes, enabling evaluation of the most feasible vaccine modality for a certain setting. These CHIKV mutants could represent stable and efficient vaccine candidates against CHIKV.
The Tobacco mosaic virus Movement Protein Associates with but Does Not Integrate into Biological Membranes
Authors: Peiró Ana , Martínez-Gil Luis , Tamborero Silvia , Pallás Vicente , Sánchez-Navarro Jesús A. , Mingarro Ismael 
Published: December 2013

ABSTRACT

Plant positive-strand RNA viruses require association with plant cell endomembranes for viral translation and replication, as well as for intra- and intercellular movement of the viral progeny. The membrane association and RNA binding of the
Tobacco mosaic virus
(TMV) movement protein (MP) are vital for orchestrating the macromolecular network required for virus movement. A previously proposed topological model suggests that TMV MP is an integral membrane protein with two putative α-helical transmembrane (TM) segments. Here we tested this model using an experimental system that measured the efficiency with which natural polypeptide segments were inserted into the ER membrane under conditions approximating the
in vivo
situation, as well as
in planta
. Our results demonstrated that the two hydrophobic regions (HRs) of TMV MP do not span biological membranes. We further found that mutations to alter the hydrophobicity of the first HR modified membrane association and precluded virus movement. We propose a topological model in which the TMV MP HRs intimately associate with the cellular membranes, allowing maximum exposure of the hydrophilic domains of the MP to the cytoplasmic cellular components.

IMPORTANCE
To facilitate plant viral infection and spread, viruses encode one or more movement proteins (MPs) that interact with ER membranes. The present work investigated the membrane association of the 30K MP of
Tobacco mosaic virus
(TMV), and the results challenge the previous topological model, which predicted that the TMV MP behaves as an integral membrane protein. The current data provide greatly needed clarification of the topological model and provide substantial evidence that TMV MP is membrane associated only at the cytoplasmic face of the membrane and that neither of its domains is integrated into the membrane or translocated into the lumen. Understanding the topology of MPs in the ER is vital for understanding the role of the ER in plant virus transport and for predicting interactions with host factors that mediate resistance to plant viruses.
Which factors influence decisions to transfer and treat patients with acute intracerebral haemorrhage and which are associated with prognosis? A retrospective cohort study
Authors: Abid Kamran A , Vail Andy , Patel Hiren C , King Andrew T , Tyrrell Pippa J , Parry-Jones Adrian R 
Published: December 2013

ObjectivesTo identify factors associated with the decision to transfer and/or operate on patients with intracerebral haemorrhage (ICH) at a UK regional neurosurgical centre and test whether these decisions were associated with patient survival.DesignRetrospective cohort study.Setting14 acute and specialist hospitals served by the neurosurgical unit at Salford Royal NHS Foundation Trust, Salford, UK.ParticipantsAll patients referred acutely to neurosurgery from January 2008 to October 2010.Outcome measuresPrimary outcome was survival and secondary outcomes were transfer to the neurosurgical centre and acute neurosurgery.ResultsWe obtained clinical data from 1364 consecutive spontaneous patients with ICH and 1175 cases were included in the final analysis. 140 (12%) patients were transferred and 75 (6%) had surgery. In a multifactorial analysis, the decision to transfer was more likely with younger age, women, brainstem and cerebellar location and larger haematomas. Risk of death in the following year was higher with advancing age, lower Glasgow Coma Scale, larger haematomas, brainstem ICH and intraventricular haemorrhage. The transferred patients had a lower risk of death relative to those remaining at the referring centre whether they had surgery (HR 0.46, 95% CI 0.32 to 0.67) or not (HR 0.41, 95% CI 0.22 to 0.73). Acute management decisions were included in the regression model for the 227 patients under either stroke medicine or neurosurgery at the neurosurgical centre and early do-not-resuscitate orders accounted for much of the observed difference, independently associated with an increased risk of death (HR 4.8, 95% CI 2.7 to 8.6).ConclusionsThe clear association between transfer to a specialist centre and survival, independent of established prognostic factors, suggests aggressive supportive care at a specialist centre may improve survival in ICH and warrants further investigation in prospective studies.
Investigating the cost-effectiveness of health information technologies: a systematic review protocol
Authors: Sheikh Aziz , Nurmatov Ulugbek B , Cresswell Kathrin , Bates David 
Published: December 2013

IntroductionThere is a need to develop new, more cost-effective models of healthcare and in this vein there is a considerable international interest in exploiting the potential offered by major developments in health information technologies (HITs). Very substantial investments are, as a result, now being made globally, but these still probably only represent a fraction of the investments needed if healthcare is to make the transition from the paper to the digital era. Investing greater resources is, however, inherently challenging and unpopular at a time of financial austerity and this is furthermore complicated by the thus far variable evidence of health benefits and demonstrable short-term to medium-term returns associated with investments in HITs.ObjectivesBuilding on our related systematic overviews investigating the impact of HITs, we now seek to estimate the cost-effectiveness of HITs and as a secondary aim to identify potentially transferable lessons in relation to how to realise returns on investments in these technologies.MethodsWe will conduct a systematic review to identify the empirical evidence base surrounding the return on investments from implementing HITs. Two reviewers will independently search major international databases for published, unpublished and on-going experimental and quasi-experimental studies of interest published during the period 1990–2013. These searches of bibliographic databases will be supplemented by contacting an international panel of experts. There will be no restriction on the language of publication of studies. Studies will be critically appraised using the Critical Appraisal Skills Programme (CASP) Economic Evaluations checklist. In view of the anticipated heterogeneity in intervention investigated, study design and health system contexts, we will undertake a descriptive, narrative and interpretative synthesis of data.Ethics and disseminationEthical approval is not required.ResultsThese will be presented in one manuscript. The protocol is registered with the International Prospective Register for Systematic Reviews (PROSPERO) CRD42013005294.
Association between reduced stillbirth rates in England and regional uptake of accreditation training in customised fetal growth assessment
Authors: Gardosi Jason , Giddings Sally , Clifford Sally , Wood Lynne , Francis André 
Published: December 2013

ObjectiveTo assess the effect that accreditation training in fetal growth surveillance and evidence-based protocols had on stillbirth rates in England and Wales.DesignAnalysis of mortality data from Office of National Statistics.SettingEngland and Wales, including three National Health Service (NHS) regions (West Midlands, North East and Yorkshire and the Humber) which between 2008 and 2011 implemented training programmes in customised fetal growth assessment.PopulationLive births and stillbirths in England and Wales between 2007 and 2012.Main outcome measureStillbirth.ResultsThere was a significant downward trend (p=0.03) in stillbirth rates between 2007 and 2012 in England to 4.81/1000, the lowest rate recorded since adoption of the current stillbirth definition in 1992. This drop was due to downward trends in each of the three English regions with high uptake of accreditation training, and led in turn to the lowest stillbirth rates on record in each of these regions. In contrast, there was no significant change in stillbirth rates in the remaining English regions and Wales, where uptake of training had been low. The three regions responsible for the record drop in national stillbirth rates made up less than a quarter (24.7%) of all births in England. The fall in stillbirth rate was most pronounced in the West Midlands, which had the most intensive training programme, from the preceding average baseline of 5.73/1000 in 2000–2007 to 4.47/1000 in 2012, a 22% drop which is equivalent to 92 fewer deaths a year. Extrapolated to the whole of the UK, this would amount to over 1000 fewer stillbirths each year.ConclusionsA training and accreditation programme in customised fetal growth assessment with evidence-based protocols was associated with a reduction in stillbirths in high-uptake areas and resulted in a national drop in stillbirth rates to their lowest level in 20 years.
Mobile phone text messages for improving adherence to antiretroviral therapy (ART): an individual patient data meta-analysis of randomised trials
Authors: Mbuagbaw Lawrence , van der Kop Mia L , Lester Richard T , Thirumurthy Harsha , Pop-Eleches Cristian , Ye Chenglin , Smieja Marek , Dolovich Lisa , Mills Edward J , Thabane Lehana 
Published: December 2013

ObjectivesOur objectives were to analyse the effects of text messaging versus usual care in improving adherence to antiretroviral therapy (ART) in people living with HIV using individual patient data meta-analysis. Adjusted, sensitivity and subgroup analyses were conducted.Setting3 randomised controlled trials conducted between 2010 and 2012 in rural and urban centres in Cameroon and Kenya (two studies) were used.ParticipantsA total of 1166 participants were included in this analysis (Cameroon=200; Kenya=428 and 538).Primary and secondary outcomesThe primary outcome was adherence to ART >95%. The secondary outcomes were mortality, losses to follow-up, transfers and withdrawals.ResultsText messaging improved adherence to ART (OR 1.38; 95% CIs 1.08 to 1.78; p=0.012), even after adjustment for baseline covariates (OR 1.46; 95% CI 1.13 to 1.88; p=0.004). Primary education (compared with no formal education) was associated with a greater intervention effect on adherence (OR 1.65; 95% CI 1.10 to 2.48; p=0.016) and also showed a significant subgroup effect (p=0.039). In sensitivity analysis, our findings were robust to a modified threshold of adherence, multiple imputation for missing data and aggregate level data pooling, but not to fixed-effects meta-analyses using generalised estimation equations. There was a significant subgroup effect for long weekly (p=0.037), short weekly text messages (p=0.014) and interactive messaging (p=0.010). Text messaging did not significantly affect any of the secondary outcomes.ConclusionsText messaging has a significant effect on adherence to ART, and this effect is influenced by level of education, gender, timing (weekly vs daily) and interactivity. We recommend the use of interactive weekly text messaging to improve adherence to ART, which is most effective in those with at least a primary level of education.
The Oxford Renal (OxRen) cross-sectional study of chronic kidney disease in the UK
Authors: Hill Nathan R , Lasserson Daniel , Fatoba Samuel , O'Callaghan Chris A , Pugh Chris , Perera-Salazar Rafael , Shine Brian , Thompson Ben , Wolstenholme Jane , McManus Richard , Hobbs F D Richard 
Published: December 2013

IntroductionChronic kidney disease (CKD) diagnosed with objective measures of kidney damage and function has been recognised as a major public health burden. Independent of age, sex, ethnicity and comorbidity, strong associations exist between cardiovascular disease, mortality, morbidity and CKD, defined by reduced glomerular filtration rate and increased urinary albumin excretion. Detection of CKD within the population is therefore a priority for health systems.Methods and analysis15 000 patients aged 60 years or over meeting the inclusion criteria will be invited to the study. Recruitment will be stratified to represent the distribution of socioeconomic position in the UK general population. Patients will be excluded if terminally ill (expected survival <1 year), or if they have received a solid organ transplant. Patients will attend up to two screening visits, to determine if they have CKD, followed by an assessment visit where demographic and physiological parameters will be recorded alongside questionnaires on exercise, diet, cognitive assessment and quality of life. Blood and urine specimens will be taken for immediate routine assays as well as for freezing pending peptide and genetic studies. Patients will have office and home blood pressure measurements as well as pulse wave velocity assessment. Healthcare costs of screening and subsequent monitoring will be calculated.Ethics and disseminationThe protocol and related documents have been approved by NRES Committee South Central—Oxford B—Reference 13/SC/0020.
NUP98 Fusion Oncoproteins Promote Aneuploidy by Attenuating the Mitotic Spindle Checkpoint
Authors: Salsi Valentina , Ferrari Silvia , Gorello Paolo , Fantini Sebastian , Chiavolelli Francesca , Mecucci Cristina , Zappavigna Vincenzo 
Published: December 2013

Abstract
NUP98 is a recurrent fusion partner in chromosome translocations that cause acute myelogenous leukemia. NUP98, a nucleoporin, and its interaction partner Rae1, have been implicated in the control of chromosome segregation, but their mechanistic contributions to tumorigenesis have been unclear. Here, we show that expression of NUP98 fusion oncoproteins causes mitotic spindle defects and chromosome missegregation, correlating with the capability of NUP98 fusions to cause premature securin degradation and slippage from an unsatisfied spindle assembly checkpoint (SAC). NUP98 fusions, unlike wild-type NUP98, were found to physically interact with the anaphase promoting complex/cyclosome (APC/C)Cdc20 and to displace the BubR1 SAC component, suggesting a possible mechanistic basis for their interference with SAC function. In addition, NUP98 oncoproteins displayed a prolonged half-life in cells. We found that NUP98 stability is controlled by a PEST sequence, absent in NUP98 oncoproteins, whose deletion reproduced the aberrant SAC-interfering activity of NUP98 oncoproteins. Together, our findings suggest that NUP98 oncoproteins predispose myeloid cells to oncogenic transformation or malignant progression by promoting whole chromosome instability. Cancer Res; 74(4); 1079–90. ©2013 AACR.