bluuebunny/crossref_metadata_2025_split huggingface dataset:
Establishment and Characterization of a Lethal Mouse Model for the Angola Strain of Marburg Virus
Authors: Qiu Xiangguo , Wong Gary , Audet Jonathan , Cutts Todd , Niu Yulian , Booth Stephanie , Kobinger Gary P. 
Published: August 2014

ABSTRACT

Infections with Marburg virus (MARV) and Ebola virus (EBOV) cause severe hemorrhagic fever in humans and nonhuman primates (NHPs) with fatality rates up to 90%. A number of experimental vaccine and treatment platforms have previously been shown to be protective against EBOV infection. However, the rate of development for prophylactics and therapeutics against MARV has been lower in comparison, possibly because a small-animal model is not widely available. Here we report the development of a mouse model for studying the pathogenesis of MARV Angola (MARV/Ang), the most virulent strain of MARV. Infection with the wild-type virus does not cause disease in mice, but the adapted virus (MARV/Ang-MA) recovered from liver homogenates after 24 serial passages in severe combined immunodeficient (SCID) mice caused severe disease when administered intranasally (i.n.) or intraperitoneally (i.p.). The median lethal dose (LD
50
) was determined to be 0.015 50% TCID
50
(tissue culture infective dose) of MARV/Ang-MA in SCID mice, and i.p. infection at a dose of 1,000× LD
50
resulted in death between 6 and 8 days postinfection in SCID mice. Similar results were obtained with immunocompetent BALB/c and C57BL/6 mice challenged i.p. with 2,000× LD
50
of MARV/Ang-MA. Virological and pathological analyses of MARV/Ang-MA-infected BALB/c mice revealed that the associated pathology was reminiscent of observations made in NHPs with MARV/Ang. MARV/Ang-MA-infected mice showed most of the clinical hallmarks observed with Marburg hemorrhagic fever, including lymphopenia, thrombocytopenia, marked liver damage, and uncontrolled viremia. Virus titers reached 10
8
TCID
50
/ml in the blood and between 10
6
and 10
10
TCID
50
/g tissue in the intestines, kidney, lungs, brain, spleen, and liver. This model provides an important tool to screen candidate vaccines and therapeutics against MARV infections.

IMPORTANCE
The Angola strain of Marburg virus (MARV/Ang) was responsible for the largest outbreak ever documented for Marburg viruses. With a 90% fatality rate, it is similar to Ebola virus, which makes it one of the most lethal viruses known to humans. There are currently no approved interventions for Marburg virus, in part because a small-animal model that is vulnerable to MARV/Ang infection is not available to screen and test potential vaccines and therapeutics in a quick and economical manner. To address this need, we have adapted MARV/Ang so that it causes illness in mice resulting in death. The signs of disease in these mice are reminiscent of wild-type MARV/Ang infections in humans and nonhuman primates. We believe that this will be of help in accelerating the development of life-saving measures against Marburg virus infections.
Novel Denisovan and Neanderthal Retroviruses
Authors: Lee Adam , Huntley Derek , Aiewsakun Pakorn , Kanda Ravinder K. , Lynn Claire , Tristem Michael 
Published: August 2014

ABSTRACT
Following the recent availability of high-coverage genomes for Denisovan and Neanderthal hominids, we conducted a screen for endogenized retroviruses, identifying six novel, previously unreported HERV-K(HML2) elements (HERV-K is human endogenous retrovirus K). These elements are absent from the human genome (hg38) and appear to be unique to archaic hominids. These findings provide further evidence supporting the recent activity of the HERV-K(HML2) group, which has been implicated in human disease. They will also provide insights into the evolution of archaic hominids.
Dissection of the Antibody Response against Herpes Simplex Virus Glycoproteins in Naturally Infected Humans
Authors: Cairns Tina M. , Huang Zhen-Yu , Whitbeck J. Charles , Ponce de Leon Manuel , Lou Huan , Wald Anna , Krummenacher Claude , Eisenberg Roselyn J. , Cohen Gary H. 
Published: August 2014

ABSTRACTRelatively little is known about the extent of the polyclonal antibody (PAb) repertoire elicited by herpes simplex virus (HSV) glycoproteins during natural infection and how these antibodies affect virus neutralization. Here, we examined IgGs from 10 HSV-seropositive individuals originally classified as high or low virus shedders. All PAbs neutralized virus to various extents. We determined which HSV entry glycoproteins these PAbs were directed against: glycoproteins gB, gD, and gC were recognized by all sera, but fewer sera reacted against gH/gL. We previously characterized multiple mouse monoclonal antibodies (MAbs) and mapped those with high neutralizing activity to the crystal structures of gD, gB, and gH/gL. We used a biosensor competition assay to determine whether there were corresponding human antibodies to those epitopes. All 10 samples had neutralizing IgGs to gD epitopes, but there were variations in which epitopes were seen in individual samples. Surprisingly, only three samples contained neutralizing IgGs to gB epitopes. To further dissect the nature of these IgGs, we developed a method to select out gD- and gB-specific IgGs from four representative sera via affinity chromatography, allowing us to determine the contribution of antibodies against each glycoprotein to the overall neutralization capacity of the serum. In two cases, gD and gB accounted for all of the neutralizing activity against HSV-2, with a modest amount of HSV-1 neutralization directed against gC. In the other two samples, the dominant response was to gD.IMPORTANCEAntibodies targeting functional epitopes on HSV entry glycoproteins mediate HSV neutralization. Virus-neutralizing epitopes have been defined and characterized using murine monoclonal antibodies. However, it is largely unknown whether these same epitopes are targeted by the humoral response to HSV infection in humans. We have shown that during natural infection, virus-neutralizing antibodies are principally directed against gD, gB, and, to a lesser extent, gC. While several key HSV-neutralizing epitopes within gD and gB are commonly targeted by human serum IgG, others fail to induce consistent responses. These data are particularly relevant to the design of future HSV vaccines.
Naturally Arising Strains of Polyomaviruses with Severely Attenuated MicroRNA Expression
Authors: Chen Chun Jung , Burke James M. , Kincaid Rodney P. , Azarm Kristopher D. , Mireles Noel , Butel Janet S. , Sullivan Christopher S. 
Published: August 2014

ABSTRACT

Several different polyomaviruses (PyVs) encode microRNAs (miRNAs) that regulate viral as well as host gene expression. However, the functions of polyomaviral miRNAs, particularly during
in vivo
infection, remain poorly understood. Here we identify rare naturally arising PyVs that are severely attenuated or null for miRNA expression. We identify hypomorphic or null strains for miRNA expression from rhesus macaque simian virus 40 (SV40) and human JC virus. These strains were isolated from immunocompromised hosts and derive from insertions or deletions in the viral DNA that preserve the amino acid reading frame of opposing-strand large T antigen gene. Characterization of the SV40 miRNA hypomorph, K661, shows that it is inhibited at the early miRNA biogenesis step of Drosha-mediated processing. Despite having a nonrearranged enhancer, which a previous study has shown renders some PyVs more susceptible to the autoregulatory activities of the miRNA, restoring miRNA expression to K661 has little effect on virus growth in either immortalized or primary monkey kidney cells. Thus, in addition to any effect of accompanying genomic elements, these results suggest that the cellular context also determines susceptibility to PyV miRNA-mediated effects. Combined, these results demonstrate that polyomaviruses lacking miRNAs can arise infrequently and that the functional importance of polyomaviral miRNAs is context dependent, consistent with an activity connected to the immune status of the host.

IMPORTANCE
Diverse virus families encode miRNAs, yet much remains unknown about viral miRNA function and contribution to the infectious cycle. Polyomaviruses (PyVs) are small DNA viruses, long known to be important as etiological agents of rare diseases and valuable models of DNA virus infection. Here, in immunosuppressed hosts, we uncover rare naturally arising variants of different PyVs that have lost the ability to express miRNAs. This represents some of the only known natural viruses to have lost miRNA expression. By probing the biogenesis pathways of these variants, we uncover that miRNA expression is lost via small insertions or deletions that render the transcripts resistant to early steps of miRNA biogenesis while preserving the reading frame of the opposing T antigen transcripts. Overall, our study informs how miRNA genes evolve/devolve in viruses and suggests that miRNA function is exquisitely dependent not only on viral genomic context but also on the cellular and host environment.
Gammaherpesvirus Latency Differentially Impacts the Generation of Primary versus Secondary Memory CD8+T Cells during Subsequent Infection
Authors: Barton Erik S. , Rajkarnikar Sujana , Langston P. Kent , Price Madeline J. , Grayson Jason M. 
Published: August 2014

ABSTRACTUnlike laboratory animals, humans are infected with multiple pathogens, including the highly prevalent herpesviruses. The purpose of these studies was to determine the effect of gammaherpesvirus latency on T cell number and differentiation during subsequent heterologous viral infections. Mice were first infected with murine gammaherpesvirus 68 (MHV68), a model of Epstein-Barr virus (EBV) infection, and then after latency was established, they were challenged with the Armstrong strain of lymphocytic choriomeningitis virus (LCMV). The initial replication of LCMV was lower in latently infected mice, and the maturation of dendritic cells was abated. Although the number of LCMV-specific effector CD8+T cells was not altered, they were skewed to a memory phenotype. In contrast, LCMV-specific effector CD4+T cells were increased in latently infected mice compared to those in mice infected solely with LCMV. When the memory phase was reached, latently infected mice had an LCMV-specific memory T cell pool that was increased relative to that found in singly infected mice. Importantly, LCMV-specific memory CD8+T cells had decreased CD27 and increased killer cell lectin-like receptor G1 (KLRG1) expression. Upon secondary challenge, LCMV-specific secondary effector CD8+T cells expanded and cleared the infection. However, the LCMV-specific secondary memory CD8+T cell pool was decreased in latently infected animals, abrogating the boosting effect normally observed following rechallenge. Taken together, these results demonstrate that ongoing gammaherpesvirus latency affects the number and phenotype of primary versus secondary memory CD8+T cells during acute infection.IMPORTANCECD8+T cells are critical for the clearance of intracellular pathogens, including viruses, certain bacteria, and tumors. However, current models for memory CD8+T cell differentiation are derived from pathogen-free laboratory mice challenged with a single pathogen or vaccine vector. Unlike laboratory animals, all humans are infected with multiple acute and chronic pathogens, including the highly prevalent herpesviruses Epstein-Barr virus (EBV), cytomegalovirus (CMV), herpes simplex viruses (HSV), and varicella-zoster virus (VZV). The purpose of these studies was to determine the effect of gammaherpesvirus latency on T cell number and differentiation during subsequent heterologous viral infections. We observed that ongoing gammaherpesvirus latency affects the number and phenotype of primary versus secondary memory CD8+T cells during acute infection. These results suggest that unlike pathogen-free laboratory mice, infection or immunization of latently infected humans may result in the generation of T cells with limited potential for long-term protection.
Epstein-Barr Virus Blocks the Autophagic Flux and Appropriates the Autophagic Machinery To Enhance Viral Replication
Authors: Granato Marisa , Santarelli Roberta , Farina Antonella , Gonnella Roberta , Lotti Lavinia Vittoria , Faggioni Alberto , Cirone Mara 
Published: August 2014

ABSTRACT
Autophagy is a catabolic pathway that helps cells to survive under stressful conditions. Cells also use autophagy to clear microbiological infections, but microbes have learned how to manipulate the autophagic pathway for their own benefit. The experimental evidence obtained in this study suggests that the autophagic flux is blocked at the final steps during the reactivation of Epstein-Barr virus (EBV) from latency. This is indicated by the level of the lipidated form of LC3 that does not increase in the presence of bafilomycin and by the lack of colocalization of autophagosomes with lysosomes, which correlates with reduced Rab7 expression. Since the inhibition of the early phases of autophagy impaired EBV replication and viral particles were observed in autophagic vesicles in the cytoplasm of producing cells, we suggest that EBV exploits the autophagic machinery for its transportation in order to enhance viral production. The autophagic block was not mediated by ZEBRA, an immediate-early EBV lytic gene, whose transfection in Ramos, Akata, and 293 cells promoted a complete autophagic flux. The block occurred only when the complete set of EBV lytic genes was expressed. We suggest that the inhibition of the early autophagic steps or finding strategies to overcome the autophagic block, allowing viral degradation into the lysosomes, can be exploited to manipulate EBV replication.

IMPORTANCE
This study shows, for the first time, that autophagy is blocked at the final degradative steps during EBV replication in several cell types. Through this block, EBV hijacks the autophagic vesicles for its intracellular transportation and enhances viral production. A better understanding of virus-host interactions could help in the design of new therapeutic approaches against EBV-associated malignancies.
Peripheral labour market position and risk of disability pension: a prospective population-based study
Authors: Gustafsson Klas , Aronsson Gunnar , Marklund Staffan , Wikman Anders , Floderus Birgitta 
Published: August 2014

ObjectiveTo investigate what impact individuals’ position in a labour market core–periphery structure may have on their risk of disability pension (DP) in general and specifically on their risk of DP based on mental or musculoskeletal diagnoses.MethodsThe study comprised 45 567 individuals who had been interviewed for the annual Swedish Surveys of Living Conditions (1992–2007). The medical DP diagnoses were obtained from the Swedish Social Insurance Agency (1993–2011). The assumed predictors were studied in relation to DP by Cox's proportional hazards regression. The analyses were stratified on sex and age, controlling for social background and self-reported long-standing illness at baseline.ResultsAll three indicators underlying the categorisation of the core–periphery structure: employment income, work hours and unemployment, increased the risk of DP in all strata. The risk of DP tended to increase gradually the more peripheral the labour market position was. The risk estimates for DP in general and for DP based on mental diagnoses were particularly high among men aged 20–39 years.ConclusionsThe core–periphery position of individuals, representing their labour market attachment, was found to be a predictor of future DP. The association was most evident among individuals below 40 years of age with regard to DP based on mental diagnoses. This highlights the need for preventative measures that increase the participation of young people in working life.
Risk factors for suicidal thoughts in adolescence-a prospective cohort study: the Young-HUNT study
Authors: Strandheim Arve , Bjerkeset Ottar , Gunnell David , Bjørnelv Sigrid , Holmen Turid Lingaas , Bentzen Niels 
Published: August 2014

ObjectivesExamining the associations between health and lifestyle factors recorded in the participants’ early teens and development of suicidal thoughts recorded 4 years later.DesignPopulation-based prospective cohort study.SettingsAll students in the two relevant year classes in Nord-Trøndelag County were invited, 80% attended both waves of data collection.Participants2399 secondary school students who participated in the Young-HUNT1 study in 1995–1997 (13–15 years old) were included in a follow-up study 4 years later (17–19 years old).Primary outcome measureSuicidal thoughts reported at age 17–19 years.Results408 (17%, 95% CI 15.5% to 18.5%) of the adolescents reported suicidal thoughts at follow-up, 158 (14.2%, CI 13.6% to 16.4%) boys and 250 (19.5%, CI 18.8% to 22.0%) girls. Baseline anxiety and depressive symptoms (adjusted OR (aOR) 1.9, CI 1.4 to 2.6), conduct problems (aOR 1.8, CI 1.3 to 2.6), overweight (aOR 1.9 CI 1.4 to 2.4), and muscular pain and tension (aOR 1.8, CI 1.4 to 2.4), were all associated with reporting suicidal thoughts at follow-up.ConclusionsOne in six young adults experienced suicidal thoughts, girls predominating. Suicidal thoughts were most strongly associated with symptoms of anxiety/depression, conduct problems, pain/tension and overweight reported when participants were 13–15 years old. Specific preventive efforts in these groups might be indicated. Future research should investigate whether similar associations are seen with suicide/suicidal attempts as endpoints.
Age at obesity and association with subsequent dementia: record linkage study
Authors: Wotton Clare J , Goldacre Michael J 
Published: August 2014

Abstract

Objective
Obesity in mid-life may increase the risk of subsequent dementia. Our objective was to study this risk, focusing on differences by age at the time of recording of obesity, in a large defined population.

Methods
A record linkage cohort study was undertaken using national administrative statistical data on hospital care and mortality in England, 1999–2011. A cohort of 451 232 people with obesity and a control cohort was constructed. Results were expressed as age-specific risk ratios comparing the two cohorts.

Results
The risk ratio for dementia in people admitted to hospital with obesity aged 30–39 years was significantly increased at 3.5 (95% CI 2.1 to 5.6). Risk ratios for dementia then gradually reduced with increasing age at obesity from 1.7 (95% CI 1.3 to 2.2) in people aged 40–49 years when obesity was first recorded to 1.4 (95% CI 1.3 to 1.5) in those aged 60–69 years. People in their 70s when obesity was recorded had neither an increased nor a reduced risk of subsequent dementia at 0.97 (95% CI 0.93 to 1.01), and those aged ≥80 years had a reduced risk of subsequent dementia at 0.78 (95% CI 0.74 to 0.82).

Conclusions
Obesity is associated with a risk of dementia in a way that appears to vary with age. Investigation of the mechanisms mediating this association might give insights into the biology of both conditions.
Endowing the Standard Model with a new r-symmetry
Authors: Chang Ngee-Pong 
Published: August 2014

In the Standard Model, there is the single Higgs field, ϕ, which gives rise to constituent quark and lepton masses. The Yukawa coupling is a highly complex set of 3 × 3 matrices, resulting in many textures of quark and lepton masses. In this talk, we propose to transfer the complexity of the Yukawa coupling matrices to a family of Higgs fields, so that the Yukawa coupling itself becomes a simple interaction. In the context of an Enriched Standard Model, we introduce a new r-symmetry in the extended SU(2)L × U(1)Y × U(1)R model and show how a particularly simple scenario results in a near degeneracy of masses in the 126 GeV region, with a hierarchy of heavier masses suggested by the quark and lepton texture mass matrices.
The complexity of the comparator circuit value problem
Authors: Cook Stephen A. , Filmus Yuval , Lê Dai Tri Man 
Published: August 2014

In 1990, Subramanian [1990] defined the complexity class CC as the set of problems log-space reducible to the comparator circuit value problem (CCV). He and Mayr showed that NL ⊆ CC ⊆ P, and proved that in addition to CCV several other problems are complete for CC, including the stable marriage problem, and finding the lexicographically first maximal matching in a bipartite graph. Although the class has not received much attention since then, we are interested in CC because we conjecture that it is incomparable with the parallel class NC which also satisfies NL ⊆ NC ⊆ P, and note that this conjecture implies that none of the CC-complete problems has an efficient polylog time parallel algorithm. We provide evidence for our conjecture by giving oracle settings in which relativized CC and relativized NC are incomparable.
We give several alternative definitions of CC, including (among others) the class of problems computed by uniform polynomial-size families of comparator circuits supplied with copies of the input and its negation, the class of problems AC0-reducible to Ccv, and the class of problems computed by uniform AC0 circuits with AXccv gates. We also give a machine model for CC, which corresponds to its characterization as log-space uniform polynomial-size families of comparator circuits. These various characterizations show that CC is a robust class. Our techniques also show that the corresponding function class FCC is closed under composition. The main technical tool we employ is universal comparator circuits.
Other results include a simpler proof of NL ⊆ CC, a more careful analysis showing the lexicographically first maximal matching problem and its variants are CC-complete under AC0 many-one reductions, and an explanation of the relation between the Gale--Shapley algorithm and Subramanian’s algorithm for stable marriage.
This article continues the previous work of Cook et al. [2011], which focused on Cook-Nguyen style uniform proof complexity, answering several open questions raised in that article.
SIX1 Promotes Tumor Lymphangiogenesis by Coordinating TGFβ Signals That Increase Expression of VEGF-C
Authors: Liu Dan , Li Li , Zhang Xiao-Xue , Wan Dong-Yi , Xi Bi-Xin , Hu Zheng , Ding Wen-Cheng , Zhu Da , Wang Xiao-Li , Wang Wei , Feng Zuo-Hua , Wang Hui , Ma Ding , Gao Qing-Lei 
Published: August 2014

Abstract
Lymphatic vessels are one of the major routes for the dissemination of cancer cells. Malignant tumors release growth factors such as VEGF-C to induce lymphangiogenesis, thereby promoting lymph node metastasis. Here, we report that sine oculis homeobox homolog 1 (SIX1), expressed in tumor cells, can promote tumor lymphangiogenesis and lymph node metastasis by coordinating with TGFβ to increase the expression of VEGF-C. Lymphangiogenesis and lymph node metastasis in cervical cancer were closely correlated with higher expression of SIX1 in tumor cells. By enhancing VEGF-C expression in tumor cells, SIX1 could augment the promoting effect of tumor cells on the migration and tube formation of lymphatic endothelial cells (LEC) in vitro and lymphangiogenesis in vivo. SIX1 enhanced TGFβ-induced activation of SMAD2/3 and coordinated with the SMAD pathway to modulate VEGF-C expression. Together, SIX1 and TGFβ induced much higher expression of VEGF-C in tumor cells than each of them alone. Despite its effect in promoting VEGF-C expression, TGFβ could inhibit lymphangiogenesis by directly inhibiting tube formation by LECs. However, the increased production of VEGF-C not only directly promoted migration and tube formation of LECs but also thwarted the inhibitory effect of TGFβ on LECs. That is, tumor cells that expressed high levels of SIX1 could promote lymphangiogenesis and counteract the negative effects of TGFβ on lymphangiogenesis by increasing the expression of VEGF-C. These findings provide new insights into tumor lymphangiogenesis and the various roles of TGFβ signaling in tumor regulation. Our results also suggest that SIX1/TGFβ might be a potential therapeutic target for preventing lymph node metastasis of tumor. Cancer Res; 74(19); 5597–607. ©2014 AACR.