bluuebunny/crossref_metadata_2025_split huggingface dataset:
Live Attenuated Tetravalent Dengue Virus Host Range Vaccine Is Immunogenic in African Green Monkeys following a Single Vaccination
Authors: Briggs Caitlin M. , Smith Katherine M. , Piper Amanda , Huitt Emerson , Spears Carla J. , Quiles Michelle , Ribeiro Mariana , Thomas Malcolm E. , Brown Dennis T. , Hernandez Raquel 
Published: April 2014

ABSTRACT

The causative agent of dengue fever, dengue virus (DENV), is transmitted by mosquitoes, and as distribution of these insects has expanded, so has dengue-related disease. DENV is a member of the
Flaviviridae
family and has 4 distinct serotypes (DENV-1, -2, -3, and -4). No lasting cross protection is afforded to heterologous serotypes following infection by any one of the individual serotypes. The presence of nonneutralizing antibodies to one serotype can facilitate the occurrence of more-severe dengue hemorrhagic fever through immune enhancement upon infection with a second serotype. For this reason, the development of a safe, tetravalent vaccine to produce a balanced immune response to all four serotypes is critical. We have developed a novel approach to produce safe and effective live-attenuated vaccines for DENV and other insect-borne viruses. Host range (HR) mutants of each DENV serotype were created by truncating transmembrane domain 1 of the E protein and selecting for strains of DENV that replicated well in insect cells but not mammalian cells. These vaccine strains were tested for immunogenicity in African green monkeys (AGMs). No vaccine-related adverse events occurred. The vaccine strains were confirmed to be attenuated
in vivo
by infectious center assay (ICA). Analysis by 50% plaque reduction neutralization test (PRNT
50
) established that by day 62 postvaccination, 100% of animals seroconverted to DENV-1, -2, -3, and -4. Additionally, the DENV HR tetravalent vaccine (HR-Tet) showed a tetravalent anamnestic immune response in 100% (16/16) of AGMs after challenge with wild-type (WT) DENV strains.

IMPORTANCE
We have generated a live attenuated viral (LAV) vaccine capable of eliciting a strong immune response in African green monkeys (AGMs) in a single dose. This vaccine is delivered by injecting one of four attenuated serotypes into each limb of the animal. 100% of animals given the vaccine generated antibodies against all 4 serotypes, and this response was found to be balanced in nature. This is also one of the first studies of dengue in AGMs, and our study suggests that viremia and antibody response in AGMs may be similar to those seen in DENV infection in humans.
A Broadly Neutralizing Human Monoclonal Antibody Directed against a Novel Conserved Epitope on the Influenza Virus H3 Hemagglutinin Globular Head
Authors: Benjamin Ebony , Wang Weijia , McAuliffe Josephine M. , Palmer-Hill Frances J. , Kallewaard Nicole L. , Chen Zhongying , Suzich JoAnn A. , Blair Wade S. , Jin Hong , Zhu Qing 
Published: April 2014

ABSTRACT

Most neutralizing antibodies elicited during influenza virus infection or vaccination target immunodominant, variable epitopes on the globular head region of hemagglutinin (HA), which leads to narrow strain protection. In this report, we describe the properties of a unique anti-HA monoclonal antibody (MAb), D1-8, that was derived from human B cells and exhibits potent, broad neutralizing activity across antigenically diverse influenza H3 subtype viruses. Based on selection of escape variants, we show that D1-8 targets a novel epitope on the globular head region of the influenza virus HA protein. The HA residues implicated in D1-8 binding are highly conserved among H3N2 viruses and are located proximal to antigenic site D. We demonstrate that the potent
in vitro
antiviral activity of D1-8 translates into protective activity in mouse models of influenza virus infection. Furthermore, D1-8 exhibits superior therapeutic survival benefit in influenza virus-infected mice compared to the neuraminidase inhibitor oseltamivir when treatment is started late in infection. The present study suggests the potential application of this monoclonal antibody for the therapeutic treatment of H3N2 influenza virus infection.

IMPORTANCE
Recently, a few globular head-targeting MAbs have been discovered that exhibit activity against different subtypes of influenza subtypes, such as H1; however, none of the previously described MAbs showed broadly neutralizing activity against diverse H3 viruses. In this report, we describe a human MAb, D1-8, that exhibits potent, broadly neutralizing activity against antigenically diverse H3 subtype viruses. The genotypic analysis of escape mutants revealed a unique putative epitope region in the globular head of H3 HA that is comprised of highly conserved residues and is distinct from the receptor binding site. Furthermore, we demonstrate that D1-8 exhibits superior therapeutic efficacy in influenza virus-infected mice compared to the neuraminidase inhibitor oseltamivir when treatment is started late in infection. In addition to describing a novel anti-globular head of H3 HA MAb with potent broadly neutralizing activity, our report suggests the potential of D1-8 for therapeutic treatment of seasonal influenza virus H3 infection.
Epstein-Barr Virus Infection Induces Indoleamine 2,3-Dioxygenase Expression in Human Monocyte-Derived Macrophages through p38/Mitogen-Activated Protein Kinase and NF-κB Pathways: Impairment in T Cell Functions
Authors: Liu Wan-li , Lin Yue-hao , Xiao Han , Xing Shan , Chen Hao , Chi Pei-dong , Zhang Ge 
Published: April 2014

ABSTRACT

Epstein-Barr virus (EBV) infection has been observed in tumor-infiltrated macrophages, but its infection effects on macrophage immune functions are poorly understood. Here, we showed that some macrophages in the tumor stroma of nasopharyngeal carcinoma (NPC) tissue expressed the immunosuppressive protein indoleamine 2,3-dioxygenase (IDO) more strongly than did tumor cells. EBV infection induced mRNA, protein, and enzymatic activity of IDO in human monocyte-derived macrophages (MDMs). Infection increased the production of tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6), whereas the neutralizing antibodies against TNF-α and IL-6 inhibited IDO induction. EBV infection also activated the mitogen-activated protein kinase (MAPK) p38 and NF-κB, and the inhibition of these two pathways with SB202190 and SN50 almost abrogated TNF-α and IL-6 production and inhibited IDO production. Moreover, the activation of IDO in response to EBV infection of MDMs suppressed the proliferation of T cells and impaired the cytotoxic activity of CD8
+
T cells, whereas the inhibition of IDO activity with 1-methyl-
l
-tryptophan (1-MT) did not affect T cell proliferation and function. These findings indicate that EBV-induced IDO expression in MDMs is substantially mediated by IL-6- and TNF-α-dependent mechanisms via the p38/MAPK and NF-κB pathways, suggesting that a possible role of EBV-mediated IDO expression in tumor stroma of NPC may be to create a microenvironment of suppressed T cell immune responses.

IMPORTANCE
CD8
+
cytotoxic T lymphocytes (CTLs) play an important role in the control of viral infections and destroy tumor cells. Activation of the tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase (IDO) in cancer tissues facilitates immune escape by the impairment of CTL functions. IDO expression was observed in some macrophages of the tumor stroma of nasopharyngeal carcinoma (NPC) tissue, and IDO could be induced in Epstein-Barr virus (EBV)-infected human monocyte-derived macrophages (MDMs). NPC cells and macrophages have been found to produce IDO in a gamma interferon (IFN-γ)-dependent manner. Instead, EBV-induced IDO expression in MDMs is substantially mediated by IL-6- and TNF-α-dependent mechanisms via the p38/MAPK and NF-κB pathways, which suppressed the proliferation of T cells and impaired the cytotoxic activity of CD8
+
T cells. This finding provides a new interpretation of the mechanism of immune escape of EBV and shows the immunosuppressive role of EBV-mediated IDO expression in tumor stroma of NPC.
The Stress Granule Component TIA-1 Binds Tick-Borne Encephalitis Virus RNA and Is Recruited to Perinuclear Sites of Viral Replication To Inhibit Viral Translation
Authors: Albornoz Amelina , Carletti Tea , Corazza Gianmarco , Marcello Alessandro 
Published: April 2014

ABSTRACT

Flaviviruses
are a major cause of disease in humans and animals worldwide. Tick-borne encephalitis virus (TBEV) is the most important arthropod-borne flavivirus endemic in Europe and is the etiological agent of tick-borne encephalitis, a potentially fatal infection of the central nervous system. However, the contributions of host proteins during TBEV infection are poorly understood. In this work, we investigate the cellular protein TIA-1 and its cognate factor TIAR, which are stress-induced RNA-binding proteins involved in the repression of initiation of translation of cellular mRNAs and in the formation of stress granules. We show that TIA-1 and TIAR interact with viral RNA in TBEV-infected cells. During TBEV infection, cytoplasmic TIA-1 and TIAR are recruited at sites of viral replication with concomitant depletion from stress granules. This effect is specific, since G3BP1, another component of these cytoplasmic structures, remains localized to stress granules. Moreover, heat shock induction of stress granules containing TIA-1, but not G3BP1, is inhibited in TBEV-infected cells. Infection of cells depleted of TIA-1 or TIAR by small interfering RNA (siRNA) or TIA-1
−/−
mouse fibroblasts, leads to a significant increase in TBEV extracellular infectivity. Interestingly, TIAR
−/−
fibroblasts show the opposite effect on TBEV infection, and this phenotype appears to be related to an excess of TIA-1 in these cells. Taking advantage of a TBE-luciferase replicon system, we also observed increased luciferase activity in TIA-1
−/−
mouse fibroblasts at early time points, consistent with TIA-1-mediated inhibition at the level of the first round of viral translation. These results indicate that, in response to TBEV infection, TIA-1 is recruited to sites of virus replication to bind TBEV RNA and modulate viral translation independently of stress granule (SG) formation.

IMPORTANCE
This study (i) extends previous work that showed TIA-1/TIAR recruitment at sites of flavivirus replication, (ii) demonstrates that TIAR behaves like TIA-1 as an inhibitor of viral replication using an RNA interference (RNAi) approach in human cells that contradicts the previous hypothesis based on mouse embryonic fibroblast (MEF) knockouts only, (iii) demonstrates that tick-borne encephalitis virus (TBEV) is capable of inducing bona fide G3BP1/eIF3/eIF4B-positive stress granules, (iv) demonstrates a differential phenotype of stress response proteins following viral infection, and (v) implicates TIA-1 in viral translation and as a modulator of TBEV replication.
Pathogenic Features Associated with Increased Virulence upon Simian Immunodeficiency Virus Cross-Species Transmission from Natural Hosts
Authors: Mandell Daniel T. , Kristoff Jan , Gaufin Thaidra , Gautam Rajeev , Ma Dongzhu , Sandler Netanya , Haret-Richter George , Xu Cuiling , Aamer Hadega , Dufour Jason , Trichel Anita , Douek Daniel C. , Keele Brandon F. , Apetrei Cristian , Pandrea Ivona 
Published: April 2014

ABSTRACT

While simian immunodeficiency viruses (SIVs) are generally nonpathogenic in their natural hosts, dramatic increases in pathogenicity may occur upon cross-species transmission to new hosts. Deciphering the drivers of these increases in virulence is of major interest for understanding the emergence of new human immunodeficiency viruses (HIVs). We transmitted SIVsab from the sabaeus species of African green monkeys (AGMs) to pigtailed macaques (PTMs). High acute viral replication occurred in all SIVsab-infected PTMs, yet the outcome of chronic infection was highly variable, ranging from rapid progression to controlled infection, which was independent of the dynamics of acute viral replication, CD4
+
T cell depletion, or preinfection levels of microbial translocation. Infection of seven PTMs with plasma collected at necropsy from a rapid-progressor PTM was consistently highly pathogenic, with high acute and chronic viral replication, massive depletion of memory CD4
+
T cells, and disease progression in all PTMs. The plasma inoculum used for the serial passage did not contain adventitious bacterial or viral contaminants. Single-genome amplification showed that this inoculum was significantly more homogenous than the inoculum directly derived from AGMs, pointing to a strain selection in PTMs. In spite of similar peak plasma viral loads between the monkeys in the two passages, immune activation/inflammation levels dramatically increased in PTMs infected with the passaged virus. These results suggest that strain selection and a massive cytokine storm are major factors behind increased pathogenicity of SIV upon serial passage and adaptation of SIVs to new hosts following cross-species transmission.

IMPORTANCE
We report here that upon cross-species transmission and serial passage of SIVsab from its natural host, the sabaeus African green monkey (AGM), to a new host, the pigtailed macaque (PTM), viral adaptation and increased pathogenicity involve strain selection and a massive cytokine storm. These results permit the design of strategies aimed at preventing cross-species transmission from natural hosts of SIVs to humans in areas of endemicity. Furthermore, our study describes a new animal model for SIV infection. As the outcomes of SIVsab infection in PTMs, African green monkeys, and rhesus macaques are different, the use of these systems enables comparative studies between pathogenic, nonpathogenic, and elite-controlled infections, to gain insight into the mechanisms of SIV immunodeficiency and comorbidities.
Deaths and major biographical events: a study of all cancer deaths in Germany from 1995 to 2009
Authors: Medenwald Daniel , Kuss Oliver 
Published: April 2014

ObjectiveTo determine if people dying from cancer are able to prolong their own life in order to experience a certain biographical event, or whether the appearance of such an occasion leads to increased deaths before the event.MethodsWe compared numbers of cancer deaths during a period of 1 week before and after biographically important occasions, which were birthday, Christmas and Easter. As a psychogenic postponement or hastening of death is most likely in chronic diseases (as opposed to accidents or cardiovascular events), we included cancer deaths only. We estimated relative risks (RRs) with their corresponding Bonferroni corrected CIs to assess effects of biographical events. All registered cancer deaths in Germany from 1995 to 2009 were included (3 257 520 individual deaths). Numbers of deaths were corrected for seasonality.ResultsConsidering all cases, there were noticeably more deaths than expected in the week preceding Christmas, leading to an RR of dying after the event of 0.987 (CI 0.978 to 0.997). Estimates indicating a hastening of death were consistent over several subgroups. Other occasions showed inconsistent results, especially there was no convincing postponement effect in our data.ConclusionsWhile there is no evidence of different death numbers before and after Easter and birthdays, the appearance of Christmas seems to increase deaths.
Association between hemodynamic conditions and occlusion times after flow diversion in cerebral aneurysms
Authors: Mut Fernando , Raschi Marcelo , Scrivano Esteban , Bleise Carlos , Chudyk Jorge , Ceratto Rosana , Lylyk Pedro , Cebral Juan R 
Published: April 2014

BackgroundEvaluation of flow diversion treatment of intracranial aneurysms is difficult owing to lack of knowledge of the target hemodynamic environment.ObjectiveTo identify hemodynamic conditions created after flow diversion that induce fast aneurysm occlusion.MethodsTwo groups of aneurysms treated with flow diverters alone were selected: (a) aneurysms completely occluded at 3 months (fast occlusion), and (b) aneurysms patent or incompletely occluded at 6 months (slow occlusion). A total of 23 aneurysms were included in the study. Patient-specific computational fluid dynamics models were constructed and used to characterize the hemodynamic environment immediately before and after treatment. Average post-treatment hemodynamic conditions between the fast and slow occlusion groups were statistically compared.ResultsAneurysms in the fast occlusion group had significantly lower post-treatment mean velocity (fast=1.13cm/s, slow=3.11cm/s, p=0.02), inflow rate (fast=0.47mL/s, slow=1.89mL/s, p=0.004) and shear rate (fast=20.52 1/s, slow=32.37 1/s, p=0.02) than aneurysms in the slow occlusion group. Receiver operating characteristics analysis showed that mean post-treatment velocity, inflow rate, and shear rate below a certain threshold could discriminate between aneurysms of the fast and slow occlusion groups with good accuracy (84%, 77%, and 76%, respectively).ConclusionsThe occlusion time of cerebral aneurysms treated with flow diverters can be predicted by the hemodynamic conditions created immediately after device implantation. Specifically, low post-implantation flow velocity, inflow rate, and shear rate are associated with fast occlusion times.
Banach algebras, Samelson products, and the Wang differential
Authors: Schochet Claude L. 
Published: April 2014

Assume that given a principal G bundle ζ : P → Sk (with k ≥ 2) and a Banach algebra B upon which G acts continuously. Let [Formula: see text] denote the associated bundle and let [Formula: see text] denote the associated Banach algebra of sections. Then π* GL Aζ⊗B is determined by a mostly degenerate spectral sequence and by a Wang differential [Formula: see text] We show that if B is a C*-algebra then the differential is given explicitly in terms of an enhanced Samelson product with the clutching map of the principal bundle. Analogous results hold after localization and in the setting of topological K-theory. We illustrate our technique with a close analysis of the invariants associated to the C*-algebra of sections of the bundle [Formula: see text] constructed from the Hopf bundle ζ : S7 → S4 and by the conjugation action of S3 on M2 = M2(ℂ). We compare and contrast the information obtained from the homotopy groups π*( U ◦Aζ⊗M2), the rational homotopy groups π*( U ◦Aζ⊗M2) ⊗ ℚ and the topological K-theory groups K*(Aζ⊗M2), where U ◦B is the connected component of the unitary group of the C*-algebra B.
Geomorphology of high-latitude coastal dunes: a review
Authors: Ruz M.-H. , Hesp P. A. 
Published: April 2014

Abstract
The purpose of this review is to assess if there are any specific processes and morphologies distinguishing coastal dunes developed in cold-climate conditions, in order to illustrate how climate can exert a control on coastal dune morphologies. In the Arctic, availability of sand supply and the duration of winter conditions are limiting factors for the development of large coastal dunes. They are small in size, and embryo dunes including nebkha are the dominant and often only coastal dune type. In milder subarctic settings, characterized by a longer surficial ice-free season, a greater variety of coastal dunes are found, mainly foredunes, blowouts and parabolic dunes. In subarctic areas, as along the SE coast of Hudson Bay, niveo-aeolian processes actively affect coastal dune development. These processes do not generally imprint permanent morphologies, although some distinctive sedimentary structures owing to the melting of snow are observed. The coastal dunes of the arctic regions differ from the dunes of subarctic and temperate regions mainly because of their limited spatial and morphological development. Extreme climatic conditions (low precipitation, extreme cold), and very limited vegetation growing season, combined with low sediment supply, explain the fact that only embryo dunes develop in arctic environments.
Selection of Personalized Patient Therapy through the Use of Knowledge-Based Computational Models That Identify Tumor-Driving Signal Transduction Pathways
Authors: Verhaegh Wim , van Ooijen Henk , Inda Márcia A. , Hatzis Pantelis , Versteeg Rogier , Smid Marcel , Martens John , Foekens John , van de Wiel Paul , Clevers Hans , van de Stolpe Anja 
Published: April 2014

Abstract
Increasing knowledge about signal transduction pathways as drivers of cancer growth has elicited the development of “targeted drugs,” which inhibit aberrant signaling pathways. They require a companion diagnostic test that identifies the tumor-driving pathway; however, currently available tests like estrogen receptor (ER) protein expression for hormonal treatment of breast cancer do not reliably predict therapy response, at least in part because they do not adequately assess functional pathway activity. We describe a novel approach to predict signaling pathway activity based on knowledge-based Bayesian computational models, which interpret quantitative transcriptome data as the functional output of an active signaling pathway, by using expression levels of transcriptional target genes. Following calibration on only a small number of cell lines or cohorts of patient data, they provide a reliable assessment of signaling pathway activity in tumors of different tissue origin. As proof of principle, models for the canonical Wnt and ER pathways are presented, including initial clinical validation on independent datasets from various cancer types. Cancer Res; 74(11); 2936–45. ©2014 AACR.
Nondisruptive p53 Mutations Are Associated with Shorter Survival in Patients with Advanced Non–Small Cell Lung Cancer
Authors: Molina-Vila Miguel A. , Bertran-Alamillo Jordi , Gascó Amaya , Mayo-de-las-Casas Clara , Sánchez-Ronco María , Pujantell-Pastor Laia , Bonanno Laura , Favaretto Adolfo G. , Cardona Andrés F. , Vergnenègre Alain , Majem Margarita , Massuti Bartomeu , Morán Teresa , Carcereny Enric , Viteri Santiago , Rosell Rafael 
Published: April 2014

AbstractPurpose: TP53 mutations in early-stage non–small cell lung cancer (NSCLC) may be associated with worse survival but their prognostic role in advanced NSCLC is controversial. In addition, it remains unclear whether mutated patients represent a clinically homogeneous group.Experimental Design: We retrospectively examined TP53 mutations and outcome in a training cohort of 318 patients with stage IIIB–IV NSCLC: 125 epidermal growth factor receptor (EGFR) wild-type (wt) and 193 EGFR mutated (mut). An independent validation cohort of 64 EGFR-mut patients was subsequently analyzed. Mutations were classified as “disruptive” and “nondisruptive” according to their predicted degree of disturbance of the p53 protein structure and function.Results: In the training cohort, TP53 mutations were found in 43 of the 125 EGFR-wt patients (34.4%). Of these, 28 had nondisruptive TP53 mutations and a median overall survival (OS) of 8.5 months, compared with 15.6 months for the remaining 97 patients (P = 0.003). In the EGFR-mut group, TP53 mutations were found in 50 of the 193 patients (25.9%). The OS for the 26 patients with TP53 nondisruptive mutations was 17.8 months versus 28.4 months for the remaining 167 patients (P = 0.04). In the validation cohort, the 11 patients with nondisruptive TP53 mutations had a median OS of 18.1 months compared with 37.8 months for the 53 remaining patients (P = 0.006). In multivariate analyses, nondisruptive TP53 mutations had an independent, significant association with a shorter OS.Conclusions: Nondisruptive mutations in the TP53 gene are an independent prognostic factor of shorter survival in advanced NSCLC. Clin Cancer Res; 20(17); 4647–59. ©2014 AACR.