bluuebunny/crossref_metadata_2025_split huggingface dataset:
Airborne Transmission of Highly Pathogenic H7N1 Influenza Virus in Ferrets
Authors: Sutton Troy C. , Finch Courtney , Shao Hongxia , Angel Matthew , Chen Hongjun , Capua Ilaria , Cattoli Giovanni , Monne Isabella , Perez Daniel R. 
Published: April 2014

ABSTRACT
Avian H7 influenza viruses are recognized as potential pandemic viruses, as personnel often become infected during poultry outbreaks. H7 infections in humans typically cause mild conjunctivitis; however, the H7N9 outbreak in the spring of 2013 has resulted in severe respiratory disease. To date, no H7 viruses have acquired the ability for sustained transmission among humans. Airborne transmission is considered a requirement for the emergence of pandemic influenza, and advanced knowledge of the molecular changes or signature required for transmission would allow early identification of pandemic vaccine seed stocks, screening and stockpiling of antiviral compounds, and eradication efforts focused on flocks harboring threatening viruses. Thus, we sought to determine if a highly pathogenic influenza A H7N1 (A/H7N1) virus with no history of human infection could become capable of airborne transmission among ferrets. We show that after 10 serial passages, A/H7N1 developed the ability to be transmitted to cohoused and airborne contact ferrets. Four amino acid mutations (PB2 T81I, NP V284M, and M1 R95K and Q211K) in the internal genes and a minimal amino acid mutation (K/R313R) in the stalk region of the hemagglutinin protein were associated with airborne transmission. Furthermore, transmission was not associated with loss of virulence. These findings highlight the importance of the internal genes in host adaptation and suggest that natural isolates carrying these mutations be further evaluated. Our results demonstrate that a highly pathogenic avian H7 virus can become capable of airborne transmission in a mammalian host, and they support ongoing surveillance and pandemic H7 vaccine development.

IMPORTANCE
The major findings of this report are that a highly pathogenic strain of H7N1 avian influenza virus can be adapted to become capable of airborne transmission in mammals without mutations altering receptor specificity. Changes in receptor specificity have been shown to play a role in the ability of avian influenza viruses to cross the species barrier, and these changes are assumed to be essential. The work reported here challenges this paradigm, at least for the influenza viruses of the H7 subtype, which have recently become the focus of major attention, as they have crossed to humans.
Two Membrane-Associated Regions within the Nodamura Virus RNA-Dependent RNA Polymerase Are Critical for both Mitochondrial Localization and RNA Replication
Authors: Gant Vincent U. , Moreno Stephanie , Varela-Ramirez Armando , Johnson Kyle L. 
Published: April 2014

ABSTRACT

Viruses with positive-strand RNA genomes amplify their genomes in replication complexes associated with cellular membranes. Little is known about the mechanism of replication complex formation in cells infected with Nodamura virus. This virus is unique in its ability to lethally infect both mammals and insects. In mice and in larvae of the greater wax moth (
Galleria mellonella
), Nodamura virus-infected muscle cells exhibit mitochondrial aggregation and membrane rearrangement, leading to disorganization of the muscle fibrils on the tissue level and ultimately in hind limb/segment paralysis. However, the molecular basis for this pathogenesis and the role of mitochondria in Nodamura virus infection remains unclear. Here, we tested the hypothesis that Nodamura virus establishes RNA replication complexes that associate with mitochondria in mammalian cells. Our results showed that Nodamura virus replication complexes are targeted to mitochondria, as evidenced in biochemical, molecular, and confocal microscopy studies. More specifically, we show that the Nodamura virus RNA-dependent RNA polymerase interacts with the outer mitochondrial membranes as an integral membrane protein and ultimately becomes associated with functional replication complexes. These studies will help us to understand the mechanism of replication complex formation and the pathogenesis of Nodamura virus for mammals.

IMPORTANCE
This study will further our understanding of
Nodamura virus
(NoV) genome replication and its pathogenesis for mice. NoV is unique among the
Nodaviridae
in its ability to infect mammals. Here we show that NoV establishes RNA replication complexes (RCs) in association with mitochondria in mammalian cells. These RCs contain newly synthesized viral RNA and feature a physical interaction between mitochondrial membranes and the viral RNA-dependent RNA polymerase (RdRp), which is mediated by two membrane-associated regions. While the nature of the interaction needs to be explored further, it appears to occur by a mode distinct from that described for the insect nodavirus Flock House virus (FHV). The interaction of the NoV RdRp with mitochondrial membranes is essential for clustering of mitochondria into networks that resemble those described for infected mouse muscle and that are associated with fatal hind limb paralysis. This work therefore provides the first link between NoV RNA replication complex formation and the pathogenesis of this virus for mice.
Murine Gammaherpesvirus 68 Encoding Open Reading Frame 11 Targets TANK Binding Kinase 1 To Negatively Regulate the Host Type I Interferon Response
Authors: Kang Hye-Ri , Cheong Woo-Chang , Park Ji-Eun , Ryu Seungbo , Cho Hye-Jeong , Youn Hyunyee , Ahn Jin-Hyun , Song Moon Jung 
Published: April 2014

ABSTRACT
Upon viral infection, type I interferons, such as alpha and beta interferon (IFN-α and IFN-β, respectively), are rapidly induced and activate multiple antiviral genes, thereby serving as the first line of host defense. Many DNA and RNA viruses counteract the host interferon system by modulating the production of IFNs. In this study, we report that murine gammaherpesvirus 68 (MHV-68), a double-stranded DNA virus, encodes open reading frame 11 (ORF11), a novel immune modulator, to block IFN-β production. ORF11-deficient recombinant viruses induced more IFN-β production in fibroblast and macrophage cells than the MHV-68 wild type or a marker rescue virus. MHV-68 ORF11 decreased IFN-β promoter activation by various factors, the signaling of which converges on TBK1-IRF3 activation. MHV-68 ORF11 directly interacted with both overexpressed and endogenous TBK1 but not with IRF3. Physical interactions between ORF11 and endogenous TBK1 were further confirmed during virus replication in fibroblasts using a recombinant virus expressing FLAG-ORF11. ORF11 efficiently reduced interaction between TBK1 and IRF3 and subsequently inhibited activation of IRF3, thereby negatively regulating IFN-β production. Our domain-mapping study showed that the central domain of ORF11 was responsible for both TBK1 binding and inhibition of IFN-β induction, while the kinase domain of TBK1 was sufficient for ORF11 binding. Taken together, these results suggest a mechanism underlying inhibition of IFN-β production by a gammaherpesvirus and highlight the importance of TBK1 in DNA virus replication.

IMPORTANCE
Gammaherpesviruses are important human pathogens, as they are associated with various kinds of tumors. Upon virus infection, the type I interferon pathway is activated by a series of signaling molecules and stimulates antiviral gene expression. To subvert such interferon antiviral responses, viruses are equipped with multiple factors that can inhibit its critical steps. In this study, we took an unbiased genomic approach using a mutant library of murine gammaherpesvirus 68 to screen a novel viral immune modulator that negatively regulates the type I interferon pathway and identified ORF11 as a strong candidate. ORF11-deficient virus infection produced more interferon than the wild type in both fibroblasts and macrophages. During virus replication, ORF11 directly bound to TBK1, a key regulatory protein in the interferon pathway, and inhibited TBK1-mediated interferon production. Our results highlight a crucial role of TBK1 in controlling DNA virus infection and a viral strategy to curtail host surveillance.
Opioid substitution therapy as a strategy to reduce deaths in prison: retrospective cohort study
Authors: Larney Sarah , Gisev Natasa , Farrell Michael , Dobbins Timothy , Burns Lucinda , Gibson Amy , Kimber Jo , Degenhardt Louisa 
Published: April 2014

ObjectivesTo describe deaths in prison among opioid-dependent people, and examine associations between receipt of opioid substitution therapy (OST) and risk of death in prison.DesignRetrospective cohort study.SettingAdult prisons in New South Wales (NSW), Australia.Participants16 715 opioid-dependent people who were received to prison between 2000 and 2012.InterventionsOpioid substitution therapy.Primary outcome measuresNatural and unnatural (suicide, drug-induced, violent and other injury) deaths in prison.ResultsCohort members were in prison for 30 998 person-years (PY), during which time there were 51 deaths. The all-cause crude mortality rate (CMR) in prison was 1.6/1000 PY (95% CI 1.2 to 2.2/1000 PY), and the unnatural death CMR was 1.1/1000 PY (95% CI 0.8 to 1.6/1000 PY). Compared to time out of OST, the hazard of all-cause death was 74% lower while in OST (adjusted HR (AHR): 0.26; 95% CI 0.13 to 0.50), and the hazard of unnatural death was 87% lower while in OST (AHR: 0.13; 95% CI 0.05 to 0.35). The all-cause and unnatural death CMRs during the first 4 weeks of incarceration were 6.6/1000 PY (95% CI 3.8 to 10.6/1000 PY) and 5.5/1000 PY (95% CI 2.9 to 9.4/1000 PY), respectively. Compared to periods not in OST, the hazard of all-cause death during the first 4 weeks of incarceration was 94% lower while in OST (AHR: 0.06; 95% CI 0.01 to 0.48), and the hazard of unnatural death was 93% lower while in OST (AHR: 0.07; 95% CI 0.01 to 0.53).ConclusionsMortality of opioid-dependent prisoners was significantly lower while in receipt of OST.
Post-acute management of the acquired long QT syndrome
Authors: Barra Sérgio , Agarwal Sharad , Begley David , Providência Rui 
Published: April 2014

Abstract
The mechanisms underlying drug induced QT prolongation and the immediate treatment of torsade de pointes have been extensively studied but the post-acute management of the Acquired Long QT Syndrome (ALQTS) remains to be addressed. We aimed to review the state of the art data regarding risk stratification, arrhythmic prevention and treatment of patients with ALQTS. A comprehensive review of the scientific data collectable from MEDLINE, EMBASE and COCHRANE (from inception to April 2013) was performed, and descriptive and qualitative information was extracted from the most relevant manuscripts. QT prolonging drugs are widely used in hospital clinical practice, and several studies have shown a high prevalence of QT interval prolongation in patients admitted to hospital and a high rate of prescription of QT interval prolonging drugs to patients presenting with QT interval prolongation. Therefore, the acute and post-acute management of ALQTS is of the utmost importance. Avoidance of offending triggers, electrocardiographic screening, pacing at a relatively fast lower rate limit and using pause prevention programming (preferably with concomitant β blocker treatment), implantable defibrillators in the highest risk patients, genetic testing and counselling in selected cases, and family screening are among the potentially applicable strategies. The latter is justifiable by the fact that some studies unveiled a surprisingly similar positive mutation rate in drug induced LQTS compared with congenital LQTS, supporting the hypothesis that the former can be regarded as a latent form of the latter. Drug challenge with D,L-sotalol in suspected LQTS and treatment with a carvedilol analogue, verapamil or an Ikr activating drug are still in need of further investigation. The post-acute management of patients with ALQTS has received scarce attention in the past, probably due to the fact that it is considered a reversible phenomenon in most cases. Considering the relatively high risk of arrhythmic recurrence in the highest risk ALQTS patients, effective preventive and treatment strategies are warranted, and further research is needed.
Potential differences betweenLeptospiraserovars, host‐adapted (Bratislava) and incidental (Copenhageni), in determining reproductive disorders in embryo transfer recipient mares in Brazil
Authors: Pinna A. , Martins G. , Hamond C. , Medeiros M. A. , de Souza G. N. , Lilenbaum W. 
Published: April 2014

The objective was to investigate potential differences between twoLeptospiraserovars, host‐adapted (Bratislava) and incidental (Copenhageni), in causing reproductive disorders in mares. From August 2009 to March 2011, 608 adult recipient mares from eight studs located in the state of Rio de Janeiro, Brazil, were screened for leptospirosis. These mares were 3–8 years of age, of various breeds, and were managed in a semiextensive system (embryo transfer centres). According to the reproductive history of these mares, the studs were categorised as Group A (357 mares: high prevalence of reproductive problems), and Group B (251 mares: all pregnant). Of the 608 samples tested serologically, 273 (44.9 per cent) were reactive (titres ≥200), predominantly against Bratislava (62.3 per cent of reactive mares). In Group A, 247/357 sera (69.2 per cent) were reactive, with reactivity against Bratislava (64.8 per cent of reactive). By contrast, in Group B, only 26/251 sera (10.4 per cent) were reactive, the majority against Copenhageni (61.5 per cent of reactive). Seroreactivity against Bratislava was more likely to be associated (P<0.001) with reproductive problems than seroreactivity against Copenhageni; this association was true for early embryonic death (P<0.001), perinatal death (P<0.01), and abortion (P<0.001). Additionally, 29 urine samples were collected (from Group A mares) forLeptospiraspecies PCR, of which 16 were positive (55.2 per cent). We concluded that leptospirosis was associated with poor reproductive performance in embryo recipients, with the majority due to host‐adapted Bratislava.
Relationships between metabolite and IGF1 concentrations with fertility and production outcomes following left abomasal displacement
Authors: Lyons N. A. , Cooke J. S. , Wilson S. , van Winden S. C. , Gordon P. J. , Wathes D. C. 
Published: April 2014

Left displacement of the abomasum (LDA) is an important periparturient disorder of dairy cows. This study evaluated differences in metabolic parameters between case‐control pairs of cows (n=67) from 24 farms, and related these to outcomes in fertility and production. Cows with an assisted delivery were ×3 more likely to develop LDA, and affected cows tended to have had a longer dry period. At recruitment, cows with LDA tended to be in lower body condition accompanied by significantly higher circulating concentrations of β‐hydroxybutyrate (BHB), non‐esterified fatty acid (NEFA) and glucose and lower IGF1. Overall culling rate for all cows in the subsequent lactation was 22.5 per cent. Cows with LDA were not at increased odds of being culled but they produced, on average, 2272 l less milk and tended to have longer intervals to conception. Considering all cows irrespective of LDA status, the mean IGF1 level at recruitment was the only measured parameter associated with subsequent risk of culling (culled 11.7 ng/ml, not culled 23.5 ng/ml; P=0.005). Our findings support previous work indicating that poor insulin sensitivity through an uncoupling of the somatotrophic axis may be an important factor associated with LDA. Improved nutritional management of dry cows should reduce the incidence of both LDA and culling.
In situ
diffusion test of hydrogen gas in the Opalinus Clay
Authors: Vinsot A. , Appelo C. A. J. , Lundy M. , Wechner S. , Lettry Y. , Lerouge C. , Fernández A. M. , Labat M. , Tournassat C. , De Canniere P. , Schwyn B. , Mckelvie J. , Dewonck S. , Bossart P. , Delay J. 
Published: April 2014

Abstract

Hydrogen gas was injected, together with helium and neon, into a borehole in the low-diffusivity Opalinus Clay rock. The hydrogen partial pressure was at most 60 mbar. A water production flow rate from the surrounding rock of
c.
15 ml/day had been obtained previously, indicating that the test interval wall was presumably saturated with water. Helium and neon concentrations decreased as expected while taking into account dissolution and diffusion processes in the porewater. In contrast, the disappearance rate of hydrogen observed (2×10
−4
to 3×10
−4
mol/day/m
2
) was
c.
20 times larger than the calculated rate considering only dissolution and diffusion. The same rate was observed following a new hydrogen injection and over a six-month semi-continuous injection phase. Simultaneously, sulphate and iron concentrations decreased in the water, whereas sulphide became detectable. These evolutions may be due to biotic processes involving hydrogen oxidation, sulphate reduction and Fe(III) reduction.
Mechanical interpretations of the homogeneous nature of bentonite due to swelling
Authors: Kobayashi I. , Suzuki K. , Asano H. , Sellin P. , Svemar C. , Holmqvist M. 
Published: April 2014

Abstract
To achieve the high sealing capability required for the bentonite engineered barriers used in geological disposal facilities for radioactive waste, the bentonite should be highly compacted. Previous investigation of methods to enable such compaction has revealed that the construction methods used have an impact on the density distribution. However, these investigations focused on achieving the required average dry density in the bentonite barriers and little attention has been paid to the distribution of dry density. As a result, there has been a lack of understanding of how the construction method used affects this distribution, which is highly pertinent to the evaluation of the long-term performance of bentonite engineered barriers.
This paper first describes the residual density distribution after resaturation and then highlights how swelling behaviour can be studied and evaluated based on elasto-plastic theory. The conceptual understanding is that the buffer does not swell to achieve an entirely homogeneous density, but will reach an equilibrium state with a remaining gradient.
Indices of Paraoxonase and Oxidative Status Do Not Enhance the Prediction of Subclinical Cardiovascular Disease in Mixed-Ancestry South Africans
Authors: Macharia M. , Kengne A. P. , Blackhurst D. M. , Erasmus R. T. , Hoffmann M. , Matsha T. E. 
Published: March 2014

We evaluated the association of indices of paraoxonase (PON1) and oxidative status with subclinical cardiovascular disease (CVD) in mixed-ancestry South Africans. Participants were 491 adults (126 men) who were stratified by diabetes status and body mass index (BMI). Carotid intima-media thickness (CIMT) was used as a measure of subclinical CVD. Indices of PON1 and oxidative status were determined by measuring levels and activities (paraoxonase and arylesterase) of PON1, antioxidant activity (ferric reducing antioxidant power and trolox equivalent antioxidant capacity), and lipid peroxidation markers (malondialdehyde and oxidized LDL). Diabetic subjects (28.9%) displayed a significant decrease in PON1 status and antioxidant activity as well as increase in oxidized LDL and malondialdehyde. A similar profile was apparent across increasing BMI categories. CIMT was higher in diabetic than nondiabetic subjects(P<0.0001) but showed no variation across BMI categories. Overall, CIMT correlated negatively with indices of antioxidant activity and positively with measures of lipid oxidation. Sex, age, BMI, and diabetes altogether explained 29.2% of CIMT, with no further improvement from adding PON1 and/or antioxidant status indices. Though indices of PON1 and oxidative status correlate with CIMT, their measurements may not be useful for identifying subjects at high CVD risk in this population.
Multiple Periodic Solutions for Discrete Nicholson’s Blowflies Type System
Authors: Ding Hui-Sheng , Dix Julio G. 
Published: March 2014

This paper is concerned with the existence of multiple periodic solutions for discrete Nicholson’s blowflies type system. By using the Leggett-Williams fixed point theorem, we obtain the existence of three nonnegative periodic solutions for discrete Nicholson’s blowflies type system. In order to show that, we first establish the existence of three nonnegative periodic solutions for then-dimensional functional difference systemyk+1=Akyk+fk, yk-τ, k∈ℤ, whereAkis not assumed to be diagonal as in some earlier results. In addition, a concrete example is also given to illustrate our results.
Inflammation-Induced NFATc1–STAT3 Transcription Complex Promotes Pancreatic Cancer Initiation by KrasG12D
Authors: Baumgart Sandra , Chen Nai-Ming , Siveke Jens T. , König Alexander , Zhang Jin-San , Singh Shiv K. , Wolf Elmar , Bartkuhn Marek , Esposito Irene , Heßmann Elisabeth , Reinecke Johanna , Nikorowitsch Julius , Brunner Marius , Singh Garima , Fernandez-Zapico Martin E. , Smyrk Thomas , Bamlet William R. , Eilers Martin , Neesse Albrecht , Gress Thomas M. , Billadeau Daniel D. , Tuveson David , Urrutia Raul , Ellenrieder Volker 
Published: April 2014

Abstract
Cancer-associated inflammation is a molecular key feature in pancreatic ductal adenocarcinoma. Oncogenic KRAS in conjunction with persistent inflammation is known to accelerate carcinogenesis, although the underlying mechanisms remain poorly understood. Here, we outline a novel pathway whereby the transcription factors NFATc1 and STAT3 cooperate in pancreatic epithelial cells to promote KrasG12D-driven carcinogenesis. NFATc1 activation is induced by inflammation and itself accelerates inflammation-induced carcinogenesis in KrasG12D mice, whereas genetic or pharmacologic ablation of NFATc1 attenuates this effect. Mechanistically, NFATc1 complexes with STAT3 for enhancer–promoter communications at jointly regulated genes involved in oncogenesis, for example, Cyclin, EGFR and WNT family members. The NFATc1–STAT3 cooperativity is operative in pancreatitis-mediated carcinogenesis as well as in established human pancreatic cancer. Together, these studies unravel new mechanisms of inflammatory-driven pancreatic carcinogenesis and suggest beneficial effects of chemopreventive strategies using drugs that are currently available for targeting these factors in clinical trials.
Significance: Our study points to the existence of an oncogenic NFATc1–STAT3 cooperativity that mechanistically links inflammation with pancreatic cancer initiation and progression. Because NFATc1–STAT3 nucleoprotein complexes control the expression of gene networks at the intersection of inflammation and cancer, our study has significant relevance for potentially managing pancreatic cancer and other inflammatory-driven malignancies. Cancer Discov; 4(6); 688–701. ©2014 AACR.
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