bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evidence of Pervasive Biologically Functional Secondary Structures within the Genomes of Eukaryotic Single-Stranded DNA Viruses
Authors: Muhire Brejnev Muhizi , Golden Michael , Murrell Ben , Lefeuvre Pierre , Lett Jean-Michel , Gray Alistair , Poon Art Y. F. , Ngandu Nobubelo Kwanele , Semegni Yves , Tanov Emil Pavlov , Monjane Adérito Luis , Harkins Gordon William , Varsani Arvind , Shepherd Dionne Natalie , Martin Darren Patrick 
Published: November 2013

ABSTRACT

Single-stranded DNA (ssDNA) viruses have genomes that are potentially capable of forming complex secondary structures through Watson-Crick base pairing between their constituent nucleotides. A few of the structural elements formed by such base pairings are, in fact, known to have important functions during the replication of many ssDNA viruses. Unknown, however, are (i) whether numerous additional ssDNA virus genomic structural elements predicted to exist by computational DNA folding methods actually exist and (ii) whether those structures that do exist have any biological relevance. We therefore computationally inferred lists of the most evolutionarily conserved structures within a diverse selection of animal- and plant-infecting ssDNA viruses drawn from the families
Circoviridae
,
Anelloviridae
,
Parvoviridae
,
Nanoviridae
, and
Geminiviridae
and analyzed these for evidence of natural selection favoring the maintenance of these structures. While we find evidence that is consistent with purifying selection being stronger at nucleotide sites that are predicted to be base paired than at sites predicted to be unpaired, we also find strong associations between sites that are predicted to pair with one another and site pairs that are apparently coevolving in a complementary fashion. Collectively, these results indicate that natural selection actively preserves much of the pervasive secondary structure that is evident within eukaryote-infecting ssDNA virus genomes and, therefore, that much of this structure is biologically functional. Lastly, we provide examples of various highly conserved but completely uncharacterized structural elements that likely have important functions within some of the ssDNA virus genomes analyzed here.
Antigenic Properties of the HIV Envelope on Virions in Solution
Authors: Ray Krishanu , Mengistu Meron , Lewis George K. , Lakowicz Joseph R. , DeVico Anthony L. 
Published: November 2013

ABSTRACT

The structural flexibility found in human immunodeficiency virus (HIV) envelope glycoproteins creates a complex relationship between antigenicity and sensitivity to antiviral antibodies. The study of this issue in the context of viral particles is particularly problematic as conventional virus capture approaches can perturb antigenicity profiles. Here, we employed a unique analytical system based on fluorescence correlation spectroscopy (FCS), which measures antibody-virion binding with all reactants continuously in solution. Panels of nine anti-envelope monoclonal antibodies (MAbs) and five virus types were used to connect antibody binding profiles with neutralizing activities. Anti-gp120 MAbs against the 2G12 or b12 epitope, which marks functional envelope structures, neutralized viruses expressing CCR5-tropic envelopes and exhibited efficient virion binding in solution. MAbs against CD4-induced (CD4i) epitopes considered hidden on functional envelope structures poorly bound these viruses and were not neutralizing. Anti-gp41 MAb 2F5 was neutralizing despite limited virion binding. Similar antigenicity patterns occurred on CXCR4-tropic viruses, except that anti-CD4i MAbs 17b and 19e were neutralizing despite little or no virion binding. Notably, anti-gp120 MAb PG9 and anti-gp41 MAb F240 bound to both CCR5-tropic and CXCR4-tropic viruses without exerting neutralizing activity. Differences in the virus production system altered the binding efficiencies of some antibodies but did not enhance antigenicity of aberrant gp120 structures. Of all viruses tested, only JRFL pseudoviruses showed a direct relationship between MAb binding efficiency and neutralizing potency. Collectively, these data indicate that the antigenic profiles of free HIV particles generally favor the exposure of functional over aberrant gp120 structures. However, the efficiency of virion-antibody interactions in solution inconsistently predicts neutralizing activity
in vitro
.
Mutations in the N Terminus of the øX174 DNA Pilot Protein H Confer Defects in both Assembly and Host Cell Attachment
Authors: Young Lindsey N. , Hockenberry Alyson M. , Fane Bentley A. 
Published: November 2013

ABSTRACT

The øX174 DNA pilot protein H forms an oligomeric DNA-translocating tube during penetration. However, monomers are incorporated into 12 pentameric assembly intermediates, which become the capsid's icosahedral vertices. The protein's N terminus, a predicted transmembrane helix, is not represented in the crystal structure. To investigate its functions, a series of absolute and conditional lethal mutations were generated. The absolute lethal proteins, a deletion and a triple substitution, were efficiently incorporated into virus-like particles lacking infectivity. The conditional lethal mutants, bearing cold-sensitive (
cs
) and temperature-sensitive (
ts
) point mutations, were more amenable to further analyses. Viable particles containing the mutant protein can be generated at the permissive temperature and subsequently analyzed at the restrictive temperature. The characterized
cs
defect directly affected host cell attachment. In contrast,
ts
defects were manifested during morphogenesis. Particles synthesized at permissive temperature were indistinguishable from wild-type particles in their ability to recognize host cells and deliver DNA. One mutation conferred an atypical
ts
synthesis phenotype. Although the mutant protein was efficiently incorporated into virus-like particles at elevated temperature, the progeny appeared to be kinetically trapped in a temperature-independent, uninfectious state. Thus, substitutions in the N terminus can lead to H protein misincorporation, albeit at wild-type levels, and subsequently affect particle function. All mutants exhibited recessive phenotypes, i.e., rescued by the presence of the wild-type H protein. Thus, mixed H protein oligomers are functional during DNA delivery. Recessive and dominant phenotypes may temporally approximate H protein functions, occurring before or after oligomerization has gone to completion.
Patellofemoral osteoarthritis is prevalent and associated with worse symptoms and function after hamstring tendon autograft ACL reconstruction
Authors: Culvenor Adam G , Lai Courtney C H , Gabbe Belinda J , Makdissi Michael , Collins Natalie J , Vicenzino Bill , Morris Hayden G , Crossley Kay M 
Published: November 2013

ObjectivesTo evaluate the compartmental distribution of knee osteoarthritis (OA) after anterior cruciate ligament reconstruction (ACLR), to determine if patellofemoral or tibiofemoral OA is more strongly associated with knee symptoms and function, and to evaluate the contribution of associated injuries and surgical delay to the development of OA.MethodsThis cross-sectional study recruited 70 participants who underwent hamstring tendon (HT) ACLR 5–10 years previously. Radiographic OA was assessed according to the Osteoarthritis Research Society International (OARSI) criteria. Knee symptoms were assessed with the Knee Injury and Osteoarthritis Outcome Score (KOOS) and Anterior Knee Pain Scale (AKPS), while function was assessed with three lower limb tasks (hop-for-distance, one-leg rise and side-hop). Multivariate and binary logistic regression analyses were performed to assess the relationship between OA and symptomatic/functional outcomes and associated injuries/surgical delay, respectively.ResultsRadiographic OA was observed in the patellofemoral (47%) and tibiofemoral joints (31%). Pain, symptoms and quality of life on the KOOS and the AKPS were associated with severity of patellofemoral OA (standardised regression coefficient (β)=−0.3 to −0.5, p=0.001–0.042), whereas only the KOOS-pain subscale was associated with tibiofemoral OA (β=−0.3, p=0.037). For each functional task, greater patellofemoral OA severity was associated with worse performance, independent of tibiofemoral OA severity (β=−0.3 to −0.4, p=0.001–0.026). Medial meniscal and patellofemoral chondral lesions at surgery were associated with tibiofemoral and patellofemoral OA development at follow-up, respectively, while a longer surgery delay was associated with patellofemoral OA.ConclusionsPatellofemoral OA is common following HT ACLR and is associated with worse knee-related symptoms, including anterior knee pain, and decreased functional performance.
The UK Freedom of Information Act (2000) in healthcare research: a systematic review
Authors: Fowler Alexander J , Agha Riaz A , Camm Christian F , Littlejohns Peter 
Published: November 2013

ObjectivesTo assess the use and utility of the Freedom of Information Act (2000) in healthcare research since 2005 and to determine if any particular feature of studies found led to greater data acquisition.DesignPRISMA compliant systematic review.ParticipantsAn extensive literature search was performed of EMBASE, MEDLINE, CINAHL, psychINFO, BNI, AMED, HMIC and Health business elite databases from January 2005 to January 2013 using terms ‘Freedom of information’, ‘Freedom of information act’ and ‘Freedom of information act 2000’. Papers were considered for publication if they described utilising the UK Freedom of information act to gather data for healthcare research. 16 articles met these criteria.Primary and Secondary outcome measuresPrimary outcome was the number and characteristics of studies utilising the Freedom of Information Act to collect the data for healthcare research. Secondary outcome measures were any features that improved data acquisition rates (including to whom the request was made, the number of questions asked per request, etc.)Results16 articles described utilising the Freedom of Information Act for healthcare research, and these investigated a broad range of topics. The median number of requests made was 86 (range 1–172), the total number of requests was 1732. A total of 15 817 pieces of data were retrieved by all studies. The amount of data collected was defined as the number of questions asked multiplied by the number of full responses. A median of five questions were asked per study (range 5–6.5) and the overall response rate was 86%. The National Health Service litigation authority responded to 100% of requests, while Primary Care Trusts had the lowest response rate of 81% for healthcare bodies. A positive correlation between number of requests made and data obtained (0.508, p<0.05) and number of requests made and increased response rate (0.737, p<0.01), both reached the statistical significance.ConclusionsResearchers should make greater use of the Act to access the information they need that is not otherwise disclosed. We discuss the issues with the research utilising the Act and how future research of this type could be optimised.
Understanding the investigators: a qualitative study investigating the barriers and enablers to the implementation of local investigator-initiated clinical trials in Ethiopia
Authors: Franzen Samuel R P , Chandler Clare , Enquselassie Fikre , Siribaddana Sisira , Atashili Julius , Angus Brian , Lang Trudie 
Published: November 2013

ObjectivesClinical trials provide ‘gold standard’ evidence for policy, but insufficient locally relevant trials are conducted in low-income and middle-income countries. Local investigator-initiated trials could generate highly relevant data for national governments, but information is lacking on how to facilitate them. We aimed to identify barriers and enablers to investigator-initiated trials in Ethiopia to inform and direct capacity strengthening initiatives.DesignExploratory, qualitative study comprising of in-depth interviews (n=7) and focus group discussions (n=3).SettingFieldwork took place in Ethiopia during March 2011.ParticipantsLocal health researchers with previous experiences of clinical trials or stakeholders with an interest in trials were recruited through snowball sampling (n=20).Outcome measuresDetailed discussion notes were analysed using thematic coding analysis and key themes were identified.ResultsAll participants perceived investigator-initiated trials as important for generating local evidence. System and organisational barriers included: limited funding allocation, weak regulatory and administrative systems, few learning opportunities, limited human and material capacity and poor incentives for conducting research. Operational hurdles were symptomatic of these barriers. Lack of awareness, confidence and motivation to undertake trials were important individual barriers. Training, knowledge sharing and experience exchange were key enablers to trial conduct and collaboration was unanimously regarded as important for improving capacity.ConclusionsBarriers to trial conduct were found at individual, operational, organisational and system levels. These findings indicate that to increase locally led trial conduct in Ethiopia, system wide changes are needed to create a more receptive and enabling research environment. Crucially, the creation of research networks between potential trial groups could provide much needed practical collaborative support through sharing of financial and project management burdens, knowledge and resources. These findings could have important implications for capacity-strengthening initiatives but further research is needed before the results can be generalised more widely.
The Hudson Bay Lithospheric Experiment (HuBLE): insights into Precambrian plate tectonics and the development of mantle keels
Authors: Bastow I. D. , Eaton D. W. , Kendall J.-M. , Helffrich G. , Snyder D. B. , Thompson D. A. , Wookey J. , Darbyshire F. A. , Pawlak A. E. 
Published: November 2013

Abstract
Hudson Bay Lithospheric Experiment (HuBLE) was designed to understand the processes that formed Laurentia and the Hudson Bay basin within it. Receiver function analysis shows that Archaean terranes display structurally simple, uniform thickness, felsic crust. Beneath the Palaeoproterozoic Trans-Hudson Orogen (THO), thicker, more complex crust is interpreted as evidence for a secular evolution in crustal formation from non-plate-tectonic in the Palaeoarchaean to fully developed plate tectonics by the Palaeoproterozoic. Corroborating this hypothesis, anisotropy studies reveal 1.8 Ga plate-scale THO-age fabrics. Seismic tomography shows that the Proterozoic mantle has lower wavespeeds than surrounding Archaean blocks; the Laurentian keel thus formed partly in post-Archaean times. A mantle transition zone study indicates ‘normal’ temperatures beneath the Laurentian keel, so any cold mantle down-welling associated with the regional free-air gravity anomaly is probably confined to the upper mantle. Focal mechanisms from earthquakes indicate that present-day crustal stresses are influenced by glacial rebound and pre-existing faults. Ambient-noise tomography reveals a low-velocity anomaly, coincident with a previously inferred zone of crustal stretching, eliminating eclogitization of lower crustal rocks as a basin formation mechanism. Hudson Bay is an ephemeral feature, caused principally by incomplete glacial rebound. Plate stretching is the primary mechanism responsible for the formation of the basin itself.
IRP2 Regulates Breast Tumor Growth
Authors: Wang Wei , Deng Zhiyong , Hatcher Heather , Miller Lance D. , Di Xiumin , Tesfay Lia , Sui Guangchao , D'Agostino Ralph B. , Torti Frank M. , Torti Suzy V. 
Published: November 2013

Abstract
Experimental and epidemiologic evidence suggests that dysregulation of proteins involved in iron metabolism plays a critical role in cancer. The mechanisms by which cancer cells alter homeostatic iron regulation are just beginning to be understood. Here, we demonstrate that iron regulatory protein 2 (IRP2) plays a key role in iron accumulation in breast cancer. Although both IRP1 and IRP2 are overexpressed in breast cancer, the overexpression of IRP2, but not IRP1, is associated with decreased ferritin H and increased transferrin receptor 1 (TfR1). Knockdown of IRP2 in triple-negative MDA-MB-231 human breast cancer cells increases ferritin H expression and decreases TfR1 expression, resulting in a decrease in the labile iron pool. Further, IRP2 knockdown reduces growth of MDA-MB-231 cells in the mouse mammary fat pad. Gene expression microarray profiles of patients with breast cancer demonstrate that increased IRP2 expression is associated with high-grade cancer. Increased IRP2 expression is observed in luminal A, luminal B, and basal breast cancer subtypes, but not in breast tumors of the ERBB2 molecular subtype. These results suggest that dysregulation of IRP2 is an early nodal point underlying altered iron metabolism in breast cancer and may contribute to poor outcome of some patients with breast cancer. Cancer Res; 74(2); 497–507. ©2013 AACR.
Prognostic and Therapeutic Impact of Argininosuccinate Synthetase 1 Control in Bladder Cancer as Monitored Longitudinally by PET Imaging
Authors: Allen Michael D. , Luong Phuong , Hudson Chantelle , Leyton Julius , Delage Barbara , Ghazaly Essam , Cutts Rosalind , Yuan Ming , Syed Nelofer , Lo Nigro Cristiana , Lattanzio Laura , Chmielewska-Kassassir Malgorzata , Tomlinson Ian , Roylance Rebecca , Whitaker Hayley C. , Warren Anne Y. , Neal David , Frezza Christian , Beltran Luis , Jones Louise J. , Chelala Claude , Wu Bor-Wen , Bomalaski John S. , Jackson Robert C. , Lu Yong-Jie , Crook Tim , Lemoine Nicholas R. , Mather Stephen , Foster Julie , Sosabowski Jane , Avril Norbert , Li Chien-Feng , Szlosarek Peter W. 
Published: November 2013

AbstractTargeted therapies have yet to have significant impact on the survival of patients with bladder cancer. In this study, we focused on the urea cycle enzyme argininosuccinate synthetase 1 (ASS1) as a therapeutic target in bladder cancer, based on our discovery of the prognostic and functional import of ASS1 in this setting. ASS1 expression status in bladder tumors from 183 Caucasian and 295 Asian patients was analyzed, along with its hypothesized prognostic impact and association with clinicopathologic features, including tumor size and invasion. Furthermore, the genetics, biology, and therapeutic implications of ASS1 loss were investigated in urothelial cancer cells. We detected ASS1 negativity in 40% of bladder cancers, in which multivariate analysis indicated worse disease-specific and metastasis-free survival. ASS1 loss secondary to epigenetic silencing was accompanied by increased tumor cell proliferation and invasion, consistent with a tumor-suppressor role for ASS1. In developing a treatment approach, we identified a novel targeted antimetabolite strategy to exploit arginine deprivation with pegylated arginine deiminase (ADI-PEG20) as a therapeutic. ADI-PEG20 was synthetically lethal in ASS1-methylated bladder cells and its exposure was associated with a marked reduction in intracellular levels of thymidine, due to suppression of both uptake and de novo synthesis. We found that thymidine uptake correlated with thymidine kinase-1 protein levels and that thymidine levels were imageable with [18F]-fluoro-L-thymidine (FLT)–positron emission tomography (PET). In contrast, inhibition of de novo synthesis was linked to decreased expression of thymidylate synthase and dihydrofolate reductase. Notably, inhibition of de novo synthesis was associated with potentiation of ADI-PEG20 activity by the antifolate drug pemetrexed. Taken together, our findings argue that arginine deprivation combined with antifolates warrants clinical investigation in ASS1-negative urothelial and related cancers, using FLT-PET as an early surrogate marker of response. Cancer Res; 74(3); 896–907. ©2013 AACR.
Monitoring Chemotherapeutic Response by Hyperpolarized 13C-Fumarate MRS and Diffusion MRI
Authors: Mignion Lionel , Dutta Prasanta , Martinez Gary V. , Foroutan Parastou , Gillies Robert J. , Jordan Bénédicte F. 
Published: November 2013

Abstract
Targeted chemotherapeutic agents often do not result in tumor shrinkage, so new biomarkers that correlate with clinical efficacy are needed. In this study, we investigated noninvasive imaging protocols to monitor responses to sorafenib, a multikinase inhibitor approved for treatment of renal cell and hepatocellular carcinoma. Healthy cells are impermeable to fumarate, so conversion of this metabolite to malate as detected by 13C-magnetic resonance spectroscopy (MRS) has been suggested as one marker for cell death and treatment response in tumors. Diffusion MRI also has been suggested as a measure of therapy-induced cytotoxic edema because viable cells act as a diffusion barrier in tissue. For these reasons, we assessed sorafenib responses using hyperpolarized 13C-fumarate, diffusion-weighted MRI (DW-MRI) in a xenograft model of human breast cancer in which daily administration of sorafenib was sufficient to stabilize tumor growth. We detected signals from fumarate and malate following intravenous administration of hyperpolarized fumarate with a progressive increase in the malate-to-fumarate (MA/FA) ratio at days 2 to 5 after sorafenib infusion. The apparent diffusion coefficient (ADC) measured by DW-MRI increased in the treated group consistent with cytotoxic edema. However, the MA/FA ratio was a more sensitive marker of therapeutic response than ADC, with 2.8-fold versus 1.3-fold changes, respectively, by day 5 of drug treatment. Histologic analyses confirmed cell death in the sorafenib-treated cohort. Notably, 13C-pyruvate-to-lactate conversion was not affected by sorafenib in the breast cancer model examined. Our results illustrate how combining hyperpolarized substrates with DW-MRI can allow noninvasive monitoring of targeted therapeutic responses at relatively early times after drug administration. Cancer Res; 74(3); 686–94. ©2013 AACR.