bluuebunny/crossref_metadata_2025_split huggingface dataset:
Vaccination with a Fusion Protein That Introduces HIV-1 Gag Antigen into a Multitrimer CD40L Construct Results in Enhanced CD8
+
T Cell Responses and Protection from Viral Challenge by Vaccinia-Gag
Authors: Gupta Sachin , Termini James M. , Raffa Francesca N. , Williams Cindi-Ann , Kornbluth Richard S. , Stone Geoffrey W. 
Published: November 2013

ABSTRACT

CD40 ligand (CD40L, CD154) is a membrane protein that is important for the activation of dendritic cells (DCs) and DC-induced CD8
+
T cell responses. To be active, CD40L must cluster CD40 receptors on responding cells. To produce a soluble form of CD40L that clusters CD40 receptors necessitates the use of a multitrimer construct. With this in mind, a tripartite fusion protein was made from surfactant protein D (SPD), HIV-1 Gag as a test antigen, and CD40L, where SPD serves as a scaffold for the multitrimer protein complex. This SPD-Gag-CD40L protein activated CD40-bearing cells and bone marrow-derived DCs
in vitro
. Compared to a plasmid for Gag antigen alone (pGag), DNA vaccination of mice with pSPD-Gag-CD40L induced an increased number of Gag-specific CD8
+
T cells with increased avidity for major histocompatibility complex class I-restricted Gag peptide and improved vaccine-induced protection from challenge by vaccinia-Gag virus. The importance of the multitrimeric nature of the complex was shown using a plasmid lacking the N terminus of SPD that produced a single trimer fusion protein. This plasmid, pTrimer-Gag-CD40L, was only weakly active on CD40-bearing cells and did not elicit strong CD8
+
T cell responses or improve protection from vaccinia-Gag challenge. An adenovirus 5 (Ad5) vaccine incorporating SPD-Gag-CD40L was much stronger than Ad5 expressing Gag alone (Ad5-Gag) and induced complete protection (i.e., sterilizing immunity) from vaccinia-Gag challenge. Overall, these results show the potential of a new vaccine design in which antigen is introduced into a construct that expresses a multitrimer soluble form of CD40L, leading to strongly protective CD8
+
T cell responses.
Increased Sequence Coverage through Combined Targeting of Variant and Conserved Epitopes Correlates with Control of HIV Replication
Authors: Sunshine Justine , Kim Moon , Carlson Jonathan M. , Heckerman David , Czartoski Julie , Migueles Stephen A. , Maenza Janine , McElrath M. Juliana , Mullins James I. , Frahm Nicole 
Published: November 2013

ABSTRACT

A major challenge in the development of an HIV vaccine is that of contending with the extensive sequence variability found in circulating viruses. Induction of HIV-specific T-cell responses targeting conserved regions and induction of HIV-specific T-cell responses recognizing a high number of epitope variants have both been proposed as strategies to overcome this challenge. We addressed the ability of cytotoxic T lymphocytes from 30 untreated HIV-infected subjects with and without control of virus replication to recognize all clade B Gag sequence variants encoded by at least 5% of the sequences in the Los Alamos National Laboratory HIV database (1,300 peptides) using gamma interferon and interleukin-2 (IFN-γ/IL-2) FluoroSpot analysis. While targeting of conserved regions was similar in the two groups (
P
= 0.47), we found that subjects with control of virus replication demonstrated marginally lower recognition of Gag epitope variants than subjects with normal progression (
P
= 0.05). In viremic controllers and progressors, we found variant recognition to be associated with viral load (
r
= 0.62,
P
= 0.001). Interestingly, we show that increased overall sequence coverage, defined as the overall proportion of HIV database sequences targeted through the Gag-specific repertoire, is inversely associated with viral load (
r
= −0.38,
P
= 0.03). Furthermore, we found that sequence coverage, but not variant recognition, correlated with increased recognition of a panel of clade B HIV founder viruses (
r
= 0.50,
P
= 0.004). We propose sequence coverage by HIV Gag-specific immune responses as a possible correlate of protection that may contribute to control of virus replication. Additionally, sequence coverage serves as a valuable measure by which to evaluate the protective potential of future vaccination strategies.
Evolution of Bovine Ephemeral Fever Virus in the Australian Episystem
Authors: Trinidad Lee , Blasdell Kim R. , Joubert D. Albert , Davis Steven S. , Melville Lorna , Kirkland Peter D. , Coulibaly Fasséli , Holmes Edward C. , Walker Peter J. 
Published: November 2013

ABSTRACT

Bovine ephemeral fever virus (BEFV) is an arthropod-borne rhabdovirus that causes a debilitating disease of cattle in Africa, Asia, and Australia; however, its global geodynamics are poorly understood. An evolutionary analysis of G gene (envelope glycoprotein) ectodomain sequences of 97 BEFV isolates collected from Australia during 1956 to 2012 revealed that all have a single common ancestor and are phylogenetically distinct from BEFV sampled in other geographical regions. The age of the Australian clade is estimated to be between 56 and 65 years, suggesting that BEFV has entered the continent on few occasions since it was first reported in 1936 and that the 1955-1956 epizootic was the source of all currently circulating viruses. Notably, the Australian clade has evolved as a single genetic lineage across the continent and at a high evolutionary rate of ∼10
−3
nucleotide substitutions/site/year. Screening of 66 isolates using monoclonal antibodies indicated that neutralizing antigenic sites G1, G2, and G4 have been relatively stable, although variations in site G3a/b defined four antigenic subtypes. A shift in an epitope at site G3a, which occurred in the mid-1970s, was strongly associated with a K218R substitution. Similarly, a shift at site G3b was associated primarily with substitutions at residues 215, 220, and 223, which map to the tip of the spike on the prefusion form of the G protein. Finally, we propose that positive selection on residue 215 was due to cross-reacting neutralizing antibody to Kimberley virus (KIMV).

IMPORTANCE
This is the first study of the evolution of BEFV in Australia, showing that the virus has entered the continent only once during the past 50 to 60 years, it is evolving at a relatively constant rate as a single genetic lineage, and although the virus is relatively stable antigenically, mutations have resulted in four antigenic subtypes. Furthermore, the study shows that the evolution of BEFV in Australia appears to be driven, at least in part, by cross-reactive antibodies to KIMV which has a similar distribution and ecology but has not been associated with disease. As BEFV and KIMV are each known to be present in Africa and Asia, this interaction may occur on a broader geographic scale.
The Connection Domain Mutation N348I in HIV-1 Reverse Transcriptase Enhances Resistance to Etravirine and Rilpivirine but Restricts the Emergence of the E138K Resistance Mutation by Diminishing Viral Replication Capacity
Authors: Xu Hong-Tao , Colby-Germinario Susan P. , Oliveira Maureen , Han Yingshan , Quan Yudong , Zanichelli Veronica , Wainberg Mark A. 
Published: November 2013

ABSTRACTClinical resistance to rilpivirine (RPV), a novel nonnucleoside reverse transcriptase (RT) inhibitor (NNRTI), is associated an E-to-K mutation at position 138 (E138K) in RT together with an M184I/V mutation that confers resistance against emtricitabine (FTC), a nucleoside RT inhibitor (NRTI) that is given together with RPV in therapy. These two mutations can compensate for each other in regard to fitness deficits conferred by each mutation alone, raising the question of why E138K did not arise spontaneously in the clinic following lamivudine (3TC) use, which also selects for the M184I/V mutations. In this context, we have investigated the role of a N348I connection domain mutation that is prevalent in treatment-experienced patients. N348I confers resistance to both the NRTI zidovudine (ZDV) and the NNRTI nevirapine (NVP) and was also found to be associated with M184V and to compensate for deficits associated with the latter mutation. Now, we show that both N348I alone and N348I/M184V can prevent or delay the emergence of E138K under pressure with RPV or a related NNRTI, termed etravirine (ETR). N348I also enhanced levels of resistance conferred by E138K against RPV and ETR by 2.2- and 2.3-fold, respectively. The presence of the N348I or M184V/N348I mutation decreased the replication capacity of E138K virus, and biochemical assays confirmed that N348I, in a background of E138K, impaired RT catalytic efficiency and RNase H activity. These findings help to explain the low viral replication capacity of viruses containing the E138K/N348I mutations and how N348I delayed or prevented the emergence of E138K in patients with M184V-containing viruses.
A Cell-Biased Effect of Estrogen in Prion Infection
Authors: Molloy Brendan , McMahon Hilary E. M. 
Published: November 2013

ABSTRACT

Prion disorders are associated with the accumulation of a misfolded form (PrP
Sc
) of the normal prion protein, PrP
C
. Here, we show that estrogen acts as a regulator of the processes of both prion infection and prion maintenance. Estrogen was found to be cell biased in its effect; it protected cells against prion infection in a prevention mode and enabled prion maintenance in a treatment mode. These processes were regulated by the estrogen receptor subtypes Erα and Erβ. By using specific receptor agonists, Erα was found to be the main receptor active in slowing prion infection, whereas in chronically infected cells, although Erα allowed partial maintenance of PrP
Sc
levels, Erβ was the main receptor involved in maintaining PrP
Sc
in a treatment paradigm. A cell-biased effect of estrogen has been reported for other neurodegenerative disorders, including Alzheimer's disease. Estrogen's effect is dependent on the cell's health status, which impacts the use of estrogen. This work also identified that by targeting the estrogen receptors with the selective estrogen receptor modulators tamoxifen (Tam) and 4-hydroxy-tamoxifen (OHT), PrP
Sc
could be cleared from prion-infected cell culture. Tam and OHT had half-maximal inhibitory concentrations for clearance of PrP
Sc
of 0.47 μM and 0.14 nM, respectively. This work identifies further factors involved in the prion disease process, and through antagonism of the estrogen system, we demonstrate that the estrogen system is a target for controlling PrP
Sc
levels.
APOBEC3 Deaminases Induce Hypermutation in Human Papillomavirus 16 DNA upon Beta Interferon Stimulation
Authors: Wang Zhe , Wakae Kousho , Kitamura Kouichi , Aoyama Satoru , Liu Guangyan , Koura Miki , Monjurul Ahasan M. , Kukimoto Iwao , Muramatsu Masamichi 
Published: November 2013

ABSTRACT
Apolipoprotein B mRNA-editing catalytic polypeptide 3 (APOBEC3) proteins are interferon (IFN)-inducible antiviral factors that counteract various viruses such as hepatitis B virus (HBV) and human immunodeficiency virus type 1 (HIV-1) by inducing cytidine (C)-to-uracil (U) mutations in viral DNA and inhibiting reverse transcription. However, whether APOBEC3 proteins (A3s) can hypermutate human papillomavirus (HPV) viral DNA and exhibit antiviral activity in human keratinocyte remains unknown. Here we examined the involvement of A3s in the HPV life cycle using cervical keratinocyte W12 cells, which are derived from low-grade lesions and retain episomal HPV16 genomes in their nuclei. We focused on the viral E2 gene as a potential target for A3-mediated hypermutation because this gene is frequently found as a boundary sequence in integrated viral DNA. Treatment of W12 cells with beta interferon (IFN-β) increased expression levels of A3s such as A3A, A3F, and A3G and induced C-to-U conversions in the E2 gene in a manner depending on inhibition of uracil DNA glycosylase. Exogenous expression of A3A and A3G also induced E2 hypermutation in W12 cells. IFN-β-induced hypermutation was blocked by transfection of small interfering RNAs against A3G (and modestly by those against A3A). However, the HPV16 episome level was not affected by overexpression of A3A and A3G in W12 cells. This study demonstrates that endogenous A3s upregulated by IFN-β induce E2 hypermutation of HPV16 in cervical keratinocytes, and a pathogenic consequence of E2 hypermutation is discussed.
Headache after lumbar puncture: randomised crossover trial of 22-gauge versus 25-gauge needles
Authors: Crock Catherine , Orsini Francesca , Lee Katherine J , Phillips Roderic J 
Published: November 2013

ObjectivesTo compare the frequency of headache and the procedure time following lumbar puncture (LP) using a 25-gauge needle compared to a 22-gauge needle.Design4-period crossover blinded randomised controlled trial.SettingOncology unit, Royal Children's Hospital, Melbourne.PatientsChildren aged 4–15 years at enrolment having LPs as part of their treatment for leukaemia.InterventionsEach child was allocated a random sequence of four LPs, two with a 22-gauge and two with a 25-gauge needle.Outcome measuresThe presence of post-LP headache. Secondary outcomes included the presence of any headache, procedure time and impact of headache on the family.ResultsData on 341 procedures in 93 randomised children were analysed. There was little difference in the incidence of post-LP headache between the two needle sizes (22-gauge 7.2%, 95% CI 3.8 to 12.2; 25-gauge 4.6%, 95% CI 2.0 to 8.9, p=0.3) or in the incidence of any headache (22-gauge 18% 95% CI 12.5 to 24.6; 25-gauge 15%, 95% CI 10.0 to 21.1, p=0.4). Use of the 25-gauge needle was associated with longer procedure times. The incidence of post-LP headache showed little evidence of an age effect (OR =1.1, 95% CI 0.98 to 1.3) and was higher in girls than in boys (11% vs 3%, respectively, OR=3.3, 95% CI 1.3 to 8.4, p=0.014). Fifty-five per cent of families with a child with a post-LP headache assessed the overall functional impact as moderate or severe.ConclusionsThere was little difference in the occurrence of post-LP headache or any headache between procedures carried out using the 22-gauge or 25-gauge needles. Depending on the circumstances of the procedure and the experience of the operator, either gauge may be appropriate for an LP in a child.
Predictive role of C reactive protein in stroke recurrence after cardioembolic stroke: the Fukuoka Stroke Registry
Authors: Kuwashiro Takahiro , Sugimori Hiroshi , Ago Tetsuro , Kuroda Junya , Kamouchi Masahiro , Kitazono Takanari ,   for the FSR Investigators (see appendix)
Published: November 2013

ObjectivesWe investigated the clinical characteristics of patients with stroke recurrence in the first year after cardioembolic stroke, and determined the predictors associated with recurrence.DesignA prospective cohort study.SettingMulticentre study at the Fukuoka prefecture in Japan.ParticipantsWe enroled 2084 consecutive patients who were hospitalised in stroke centres within 7 days of onset from June 2007 to October 2009. The clinical characteristics of patients were assessed on admission, and the clinical course of all patients was followed for 1 year.ResultsOf all patients, 425 (234 men, 76±11 years of age) had cardioembolic stroke and were included in this study. Fifty-one patients (12%) suffered a recurrence during the follow-up period. Age (HR 1.04, 95% CI 1.01 to 1.06, p=0.014), and level of C reactive protein (HR 1.01, 95% CI 1.00 to 1.02, p=0.018) on admission were significantly associated with recurrence in the univariate analyses. Male gender (HR 0.61, 95% CI 0.35 to 1.05, p=0.076), body mass index (HR 0.94, 95% CI 0.87 to 1.01, p=0.093), hypertension (HR 0.59, 95% CI 0.33 to 1.06, p=0.079), diastolic blood pressure (HR 0.99, 95% CI 0.97 to 1.00, p=0.087) and haematocrit (HR 0.95, 95% CI 0.91 to 1.00, p=0.052) were marginally significant in the univariate Cox analyses. Multivariate Cox proportional hazards analysis showed that age (HR 1.03, 95% CI 1.00 to 1.06, p=0.031, per 1-year increase), and C reactive protein (HR 1.01, 95% CI 1.00 to 1.02, p=0.022, per 1 mg/L increase) were independent predictors of a recurrence in the first year after cardioembolic stroke.ConclusionsIn patients with cardioembolic ischaemic stroke, age and C reactive protein are independent risk factors for recurrence in the first year after onset.
Type 1 plasminogen activator inhibitor as a common risk factor for cancer and ischaemic vascular disease: the EPICOR study
Authors: Iacoviello Licia , Agnoli Claudia , De Curtis Amalia , di Castelnuovo Augusto , Giurdanella Maria Concetta , Krogh Vittorio , Mattiello Amalia , Matullo Giuseppe , Sacerdote Carlotta , Tumino Rosario , Vineis Paolo , de Gaetano Giovanni , Panico Salvatore , Donati Maria Benedetta 
Published: November 2013

ObjectivesWe examined the association of plasminogen activator inhibitor-1 (PAI-1) levels with colorectal cancer, breast cancer, acute coronary syndrome (ACS) and ischaemic stroke.DesignNested case-cohort study.SettingThe European Prospective Investigation into Cancer and Nutrition-Italy cohort.ParticipantsA centre-stratified random sample of 850 participants (286 men, 564 women) was selected as subcohort and compared with 303 colorectal cancers, 617 breast cancers, 688 ACS and 158 ischaemic strokes, in a mean follow-up of 9.11 years.Main outcomes and measuresPrimary incident cases of colon cancer, breast cancer, ACS and ischaemic stroke. PAI-1 levels were measured in citrated plasma by ELISA. HR and 95% CI, adjusted by relevant confounders and stratified by centre, were estimated by a Cox regression model using Prentice method.ResultsIndividuals in the highest compared with the lowest quartile of PAI-1 had significantly increased risk of colorectal cancer (RR=2.28; 95% CI 1.46 to 3.55; P for trend<0.0012), breast cancer (HR=1.70; 95% CI 1.21 to 2.39; p<0.0055), ACS (HR=2.57; 95% CI 1.75 to 3.77; p<0.001) and ischaemic stroke (HR=2.27; 95% CI 1.28 to 4.03; p<0.0017), after adjustment for sex and age. Additional adjustment for disease-specific confounders, insulin or other metabolic variables did not modify the associations. Risk of colon cancer was stronger for men and for whole and distal colon localisation. Risk for breast cancer was stronger in postmenopausal women.ConclusionsOur data provide the first evidence that elevated levels of PAI-1 are potential risk factors for colorectal and breast cancer and a common pathway for cancer and cardiovascular disease.
Socioeconomic and disability consequences of injuries in the Sudan: a community-based survey in Khartoum State
Authors: El Tayeb Sally , Abdalla Safa , Heuch Ivar , Van den Bergh Graziella 
Published: November 2013

BackgroundFatal and non-fatal injuries are of increasing public health concern globally, particularly in low and middle-income countries. Injuries sustained by individuals also impact society, creating a loss of productivity with serious economic consequences. In Sudan, there is no documentation of the burden of injuries on individuals and society.MethodsA community-based survey was performed in Khartoum State, using a stratified two-stage cluster sampling technique. Households were selected in each cluster by systematic random sampling. Face-to-face interviews during October and November 2010 were conducted. Fatal injuries occurring during 5 years preceding the survey and non-fatal injuries occurring during 12 months preceding interviews were included.ResultsThe total number of individuals included was 5661, residing in 973 households. There were 28 deaths due to injuries out of a total of 129 reported deaths over 5 years. A total of 441 cases of non-fatal injuries occurred during the 12 months preceding the survey. The number of disability days differed significantly between mechanisms of injury. Road traffic crashes and falls caused the longest duration of disability. Men had a higher probability than women of losing a job due to an injury.ConclusionsThis study demonstrates the importance of prioritising prevention of road traffic crashes and falls. The loss of productivity in lower socioeconomic strata highlights the need for social security policies. Further research is needed for estimating the economic cost of injuries in Sudan.
Location-based HIV behavioural surveillance among MSM in Auckland, New Zealand 2002–2011: condom use stable and more HIV testing
Authors: Saxton Peter J W , Dickson Nigel P , Hughes Anthony J 
Published: November 2013

ObjectivesOver the last decade, annual HIV diagnoses among men who have sex with men (MSM) in New Zealand increased, then stabilised in 2006 and have not increased further. The aim was to examine trends in behaviours in order to better understand this pattern and inform community-based prevention.MethodsFrom 2002 to 2011, we conducted five repeat cross-sectional behavioural surveillance surveys among MSM at community locations in Auckland (fair day, gay bars, sex-on-site venues; n=6091). Participation was anonymous and self-completed. Recruitment methods were consistent at each round.ResultsOverall, the samples became more ethnically diverse and less gay community attached over time. Condom use during anal intercourse was stable across three partnering contexts (casual, current regular fuckbuddy, current regular boyfriend), with a drop among casual contacts in 2011 only. In the 6 months prior to surveys, there was a gradual decline over time in the proportion reporting >20 male partners, an increase in acquiring partners from the internet and increases in engagement in anal intercourse in some partnering contexts. HIV testing in the 12 months prior to surveys rose from 35.1% in 2002 to 50.4% in 2011, mostly from 2008.ConclusionsThis first indepth examination of trends in HIV-related behaviours among five consecutive large and diverse samples of MSM in New Zealand does not suggest condom use is declining. However, subtle changes in sexual networks and partnering may be altering the epidemic determinants in this population and increasing exposure.
Randomized, Controlled Trial of Ultrasound-Assisted Catheter-Directed Thrombolysis for Acute Intermediate-Risk Pulmonary Embolism
Authors: Kucher Nils , Boekstegers Peter , Müller Oliver J. , Kupatt Christian , Beyer-Westendorf Jan , Heitzer Thomas , Tebbe Ulrich , Horstkotte Jan , Müller Ralf , Blessing Erwin , Greif Martin , Lange Philipp , Hoffmann Ralf-Thorsten , Werth Sebastian , Barmeyer Achim , Härtel Dirk , Grünwald Henriette , Empen Klaus , Baumgartner Iris 
Published: November 2013

Background—
In patients with acute pulmonary embolism, systemic thrombolysis improves right ventricular (RV) dilatation, is associated with major bleeding, and is withheld in many patients at risk. This multicenter randomized, controlled trial investigated whether ultrasound-assisted catheter-directed thrombolysis (USAT) is superior to anticoagulation alone in the reversal of RV dilatation in intermediate-risk patients.

Methods and Results—

Fifty-nine patients (63±14 years) with acute main or lower lobe pulmonary embolism and echocardiographic RV to left ventricular dimension (RV/LV) ratio ≥1.0 were randomized to receive unfractionated heparin and an USAT regimen of 10 to 20 mg recombinant tissue plasminogen activator over 15 hours (n=30; USAT group) or unfractionated heparin alone (n=29; heparin group). Primary outcome was the difference in the RV/LV ratio from baseline to 24 hours. Safety outcomes included death, major and minor bleeding, and recurrent venous thromboembolism at 90 days. In the USAT group, the mean RV/LV ratio was reduced from 1.28±0.19 at baseline to 0.99±0.17 at 24 hours (
P
<0.001); in the heparin group, mean RV/LV ratios were 1.20±0.14 and 1.17±0.20, respectively (
P
=0.31). The mean decrease in RV/LV ratio from baseline to 24 hours was 0.30±0.20 versus 0.03±0.16 (
P
<0.001), respectively. At 90 days, there was 1 death (in the heparin group), no major bleeding, 4 minor bleeding episodes (3 in the USAT group and 1 in the heparin group;
P
=0.61), and no recurrent venous thromboembolism.

Conclusions—
In patients with pulmonary embolism at intermediate risk, a standardized USAT regimen was superior to anticoagulation with heparin alone in reversing RV dilatation at 24 hours, without an increase in bleeding complications.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01166997.