bluuebunny/crossref_metadata_2025_split huggingface dataset:
Simultaneous Deletion of the
9GL
and
UK
Genes from the African Swine Fever Virus Georgia 2007 Isolate Offers Increased Safety and Protection against Homologous Challenge
Authors: O'Donnell Vivian , Risatti Guillermo R. , Holinka Lauren G. , Krug Peter W. , Carlson Jolene , Velazquez-Salinas Lauro , Azzinaro Paul A. , Gladue Douglas P. , Borca Manuel V. 
Published: October 2016

ABSTRACT

African swine fever virus (ASFV) is the etiological agent of a contagious and often lethal viral disease of domestic pigs that has significant economic consequences for the swine industry. The control of African swine fever (ASF) has been hampered by the unavailability of vaccines. Successful experimental vaccines have been derived from naturally occurring, cell culture-adapted, or genetically modified live attenuated ASFV. Recombinant viruses harboring engineered deletions of specific virulence-associated genes induce solid protection against challenge with parental viruses. Deletion of the
9GL
(
B119L
) gene in the highly virulent ASFV isolates Malawi Lil-20/1 (Mal) and Pretoriuskop/96/4 (Δ9GL viruses) resulted in complete protection when challenged with parental isolates. When similar deletions were created within the ASFV Georgia 2007 (ASFV-G) genome, attenuation was achieved but the protective and lethal doses were too similar. To enhance attenuation of ASFV-G, we deleted another gene,
UK
(
DP96R
), which was previously shown to be involved in attenuation of the ASFV E70 isolate. Here, we report the construction of a double-gene-deletion recombinant virus, ASFV-G-Δ9GL/ΔUK. When administered intramuscularly (i.m.) to swine, there was no induction of disease, even at high doses (10
6
HAD
50
). Importantly, animals infected with 10
4
50% hemadsorbing doses (HAD
50
) of ASFV-G-Δ9GL/ΔUK were protected as early as 14 days postinoculation when challenged with ASFV-G. The presence of protection correlates with the appearance of serum anti-ASFV antibodies, but not with virus-specific circulating ASFV-specific gamma interferon (IFN-γ)-producing cells. ASFV-G-Δ9GL/ΔUK is the first rationally designed experimental ASFV vaccine that protects against the highly virulent ASFV Georgia 2007 isolate as early as 2 weeks postvaccination.

IMPORTANCE
Currently, there is no commercially available vaccine against African swine fever. Outbreaks of the disease are devastating to the swine industry and are caused by circulating strains of African swine fever virus. Here, we report a putative vaccine derived from a currently circulating strain but containing two deletions in two separate areas of the virus, allowing increased safety. Using this genetically modified virus, we were able to vaccinate swine and protect them from developing ASF. We were able to achieve protection from disease as early as 2 weeks after vaccination, even when the pigs were exposed to a higher than normal concentration of ASFV.
CD8
+
T Cells and Macrophages Regulate Pathogenesis in a Mouse Model of Middle East Respiratory Syndrome
Authors: Coleman Christopher M. , Sisk Jeanne M. , Halasz Gabor , Zhong Jixin , Beck Sarah E. , Matthews Krystal L. , Venkataraman Thiagarajan , Rajagopalan Sanjay , Kyratsous Christos A. , Frieman Matthew B. 
Published: October 2016

ABSTRACT

Middle East respiratory syndrome coronavirus (MERS-CoV) is an important emerging pathogen that was first described in 2012. While the cell surface receptor for MERS-CoV has been identified as dipeptidyl peptidase 4 (DPP4), the mouse DPP4 homologue does not allow virus entry into cells. Therefore, development of mouse models of MERS-CoV has been hampered by the fact that MERS-CoV does not replicate in commonly available mouse strains. We have previously described a mouse model in which mDPP4 was replaced with hDPP4 such that hDPP4 is expressed under the endogenous mDPP4 promoter. In this study, we used this mouse model to analyze the host response to MERS-CoV infection using immunological assays and transcriptome analysis. Depletion of CD4
+
T cells, CD8
+
T cells, or macrophages has no effect on MERS-CoV replication in the lungs of infected mice. However, we found that depletion of CD8
+
T cells protects and depletion of macrophages exacerbates MERS-CoV-induced pathology and clinical symptoms of disease. Overall, we demonstrate an important role for the inflammatory response in regulating MERS-CoV pathogenesis
in vivo
.

IMPORTANCE
The Middle East respiratory syndrome coronavirus (MERS-CoV) is a highly pathogenic respiratory virus that emerged from zoonotic sources in 2012. Human infections are still occurring throughout Saudi Arabia at a 38% case fatality rate, with the potential for worldwide spread via air travel. In this work, we identify the host response to the virus and identify inflammatory pathways and cell populations that are critical for protection from severe lung disease. By understanding the immune response to MERS-CoV we can develop targeted therapies to inhibit pathogenesis in the future.
Remission of pre-diabetes to normal glucose tolerance in obese adults with high protein versus high carbohydrate diet: randomized control trial
Authors: Stentz Frankie B , Brewer Amy , Wan Jim , Garber Channing , Daniels Blake , Sands Chris , Kitabchi Abbas E 
Published: October 2016

ObjectiveRemission of pre-diabetes to normal is an important health concern which has had little success in the past. This study objective was to determine the effect on remission of pre-diabetes with a high protein (HP) versus high carbohydrate (HC) diet and effects on metabolic parameters, lean and fat body mass in prediabetic, obese subjects after 6 months of dietary intervention.Research design and methodsWe recruited and randomized 24 pre-diabetes women and men to either a HP (30% protein, 30% fat, 40% carbohydrate; n=12) or HC (15% protein, 30% fat, 55% carbohydrate; n=12) diet feeding study for 6 months in this randomized controlled trial. All meals were provided to subjects for 6 months with daily food menus for HP or HC compliance with weekly food pick-up and weight measurements. At baseline and after 6 months on the respective diets oral glucose tolerance and meal tolerance tests were performed with glucose and insulin measurements and dual energy X-ray absorptiometry scans.ResultsAfter 6 months on the HP diet, 100% of the subjects had remission of their pre-diabetes to normal glucose tolerance, whereas only 33.3% of subjects on the HC diet had remission of their pre-diabetes. The HP diet group exhibited significant improvement in (1) insulin sensitivity (p=0.001), (2) cardiovascular risk factors (p=0.04), (3) inflammatory cytokines (p=0.001), (4) oxidative stress (p=0.001), (5) increased percent lean body mass (p=0.001) compared with the HC diet at 6 months.ConclusionsThis is the first dietary intervention feeding study, to the best of our knowledge, to report 100% remission of pre-diabetes with a HP diet and significant improvement in metabolic parameters and anti-inflammatory effects compared with a HC diet at 6 months.Trial registration numberNCT0164284.
Injury incidence in a Premier League youth soccer academy using the consensus statement: a prospective cohort study
Authors: Renshaw Andrew , Goodwin Peter C 
Published: October 2016

BackgroundThere is an established risk of injury to young athletes exposed to high training loads. Identifying and monitoring injury risk is essential to aid prevention. The aim of this study was to use the consensus statement to determine the incidence and pattern of injury in 1 English Premier League soccer academy during 1 season.MethodsA prospective cohort study included 181 elite academy soccer players during the 2012–2013 season. Players were divided into 5 age groups between 9 and 18 years. The number, type and incidence of injuries were recorded during matches and training. Incidence was calculated per 1000 hours of exposure.Results127 injuries occurred during 29 346 hours of soccer exposure. 72% of injuries were non-contact related. Under (U)18 players sustained the highest number of match injuries. U12–14 players sustained the highest number of training injuries and injuries overall. U16 players sustained the highest number of severe injuries, and U18 players sustained the highest number of moderate injuries. U18 players sustained the highest number of injuries/1000 hours of training and overall. U15 players sustained the highest number of injuries/1000 hours of matches, the highest number of recurrent injuries and the highest incidence of recurrence. The most common injuries were muscle injuries in U15 and U18 players. The most common injury location was the anterior thigh, with the majority of these occurring in training.ConclusionsUsing the consensus statement, this study used a repeatable method to identify the injury profile of elite academy-level soccer players.
The Lancaster Field: progress in opening the UK's fractured basement play
Authors: Belaidi A. , Bonter D. A. , Slightam C. , Trice R. C. 
Published: October 2016

Abstract
To date, fractured crystalline basement reservoirs (basement) on the UK Continental Shelf (UKCS) have largely been underexplored, despite the fact that numerous indications of hydrocarbons have been reported from basement in wells dating back to the 1970s. As production from the UKCS continues to decline, and with the exploration potential of more traditional plays becoming increasingly mature, the potential of the overlooked and underrated basement play warrants further exploration. Over the last 10 years, Hurricane Energy (Hurricane) have deliberately set out to explore the potential of this untapped resource, focusing on the Rona Ridge trend, West of Shetland. The Lancaster Field has been penetrated by four wells and benefits from a full 3D seismic survey, and, as such, represents Hurricane's most de-risked basement asset. The level of understanding of the Lancaster reservoir is such that Hurricane is now working towards a phased field development. This paper provides a summary of the geology and reservoir characteristics of the Lancaster Discovery, and a description of the technical progress achieved, to date, in de-risking the Lancaster Field.
Exploration well failures from the UK North Sea
Authors: Mathieu Christian J. H. 
Published: October 2016

Abstract
The UK Oil & Gas Authority carried out post-well failure analyses of exploration and appraisal wells in the Moray Firth and the UK Central North Sea to fully understand the basis for drilling the prospects and the reasons why the prospects failed.
The data consisted of Tertiary, Mesozoic and Palaeozoic targets/segments associated with 97 wells drilled from 2003 to 2013. Seal was the primary reason for failure followed by trap, reservoir and charge. Root causes for failure were a lack of lateral seal, the absence of the target reservoir and the lack of a trap. The main pre-drill risk was not accurately predicted in over one-third of the cases and a third of the segments were targeted on the basis of perceived Direct Hydrocarbon Indicators.
This study identified a number of interpretation gaps and pitfalls that ultimately contributed to the well failures. These included poor integration, improper application of geophysics, lack of regional play context, and absent or ineffective peer review. Addressing these gaps in a comprehensive and systematic way is fundamental to improving exploration success rates.
The Bacchus development: dealing with geological uncertainty in a small high-pressure–high-temperature development
Authors: Rose Phil , Byerley Grant , Vaughan Owen 
Published: October 2016

Abstract
The Bacchus Field, discovered in 2004, is a small borderline high-pressure–high-temperature (HPHT) oil field 6.8 km east of the Forties Alpha Platform. The reservoir is Fulmar Sandstone with a rotated fault-block trap. The reservoir is typically thin (10–50 m) and difficult to image seismically. Compartmentalization was anticipated due to significant in-field faulting. The Bacchus development decision was made when considerable geological uncertainty remained.
The key risk-mitigation strategies employed during the development of Bacchus were to drill long horizontal wells, contacting multiple reservoir compartments, while maintaining a flexible development plan. The ability to react to unexpected results was facilitated by optimizing the development data-acquisition programme. Drilling risk and cost were minimized by exploiting existing well control for landing development wells, combined with pilot drilling in untested parts of the reservoir. Development wells were designed to be geometrically robust, minimizing the requirement for geo-steering. This ensured low wellbore tortuosity that did not compromise the completions. Bacchus was successfully developed despite the final distribution of reserves being radically different from the pre-development perception. It is argued that maintaining a flexible development plan was far more effective in maximizing the value of the Bacchus development than more extensive pre-development appraisal or modelling.
Flow velocity is relatively uniform in the coronary sinusal venous tree: structure-function relation
Authors: Wu Hao , Kassab Ghassan S. , Tan Wenchang , Huo Yunlong 
Published: October 2016

The structure and function of coronary venous vessels are different from those of coronary arteries and are much less understood despite the therapeutic significance of coronary sinus interventions. Here we aimed to perform a hemodynamic analysis in the entire coronary sinusal venous tree, which enhances the understanding of coronary venous circulation. A hemodynamic model was developed in the entire coronary sinusal venous tree reconstructed from casts and histological data of five swine hearts. Various morphometric and hemodynamic parameters were determined in each vessel and analyzed in the diameter-defined Strahler system. The findings demonstrate an area preservation between the branches of the coronary venous system that leads to relatively uniform flow velocity in different orders of the venous tree. Pressure and circumferential and wall shear stresses decreased abruptly from the smallest venules toward vessels of order −5 (80.4 ± 39.1 µm) but showed a more modest change toward the coronary sinus. The results suggest that vessels of order −5 denote a hemodynamic transition from the venular bed to the transmural subnetwork. In contrast with the coronary arterial tree, which obeys the minimum energy hypothesis, the coronary sinusal venous system complies with the area-preserving rule for efficient venous return, i.e., da Vinci’s rule. The morphometric and hemodynamic model serves as a physiological reference state to test various therapeutic rationales through the venous route. NEW & NOTEWORTHY A hemodynamic model is developed in the entire coronary sinusal venous tree of the swine heart. A key finding is that the coronary sinusal venous system complies with the area preservation rule for efficient venous return while the coronary arterial tree obeys the minimum energy hypothesis. This model can also serve as a physiological reference state to test various therapeutic rationales through the venous route.
Effect of hypohydration on thermoregulatory responses in men with low and high body fat exercising in the heat
Authors: Tucker Matthew A. , Caldwell Aaron R. , Butts Cory L. , Robinson Forrest B. , Reynebeau Haley C. , Kavouras Stavros A. , McDermott Brendon P. , Washington Tyrone A. , Turner Ronna C. , Ganio Matthew S. 
Published: October 2016

It is unclear whether men with low body fat (LO-BF) have impaired thermoregulation during exercise heat stress compared with those with high body fat (HI-BF) when euhydration (EU) is maintained. Furthermore, in LO-BF individuals, hypohydration (HY) impairs thermoregulatory responses during exercise heat stress, but it is unknown whether this occurs in HI-BF counterparts. The purpose of this study was to test the hypotheses that men with HI-BF have impaired thermoregulatory responses to exercise heat stress and that HY further exacerbates these impairments vs. LO-BF. Men with LO-BF [ n = 11, body mass (BM) 73.9 ± 8.5 kg, BF% 13.6 ± 3.8] and HI-BF ( n = 9, BM 89.6 ± 6.9 kg, BF% 30.2 ± 4.1), in a randomized crossover design, performed 60 min of upright cycling in a hot environment (40.3 ± 0.4°C, relative humidity 32.5 ± 1.9%) at a metabolic heat production rate of 6 W/kg BM and finished exercise either euhydrated (EU; 0.3 ± 1.2 vs. 0.3 ± 0.9% BM loss) or HY (−2.5 ± 1.1 vs. −1.7 ± 1.5% BM loss). Changes in rectal temperature (ΔTrec), local sweat rate (ΔLSR), and cutaneous vascular conductance (ΔCVC; %max) were measured throughout. When EU, LO-BF and HI-BF had similar CVC and LSR responses ( P > 0.05); however, LO-BF had a lower ΔTrec vs. HI-BF (0.92 ± 0.35 vs. 1.31 ± 0.32°C, P = 0.021). Compared with EU, HY increased end-exercise ΔTrec in LO-BF (0.47 ± 0.37°C, P < 0.01) but not in HI-BF (−0.06 ± 0.29°C, P > 0.05). HY, compared with EU, did not affect ΔLSR and ΔCVC in either group ( P > 0.05). We conclude that, when euhydrated, men with HI-BF have a greater increase in Trec vs. LO-BF but similar CVC and LSR. HY exacerbates increases in Trec in LO-BF but not HI-BF. NEW & NOTEWORTHY This is the first known investigation to compare thermoregulatory responses to exercise heat stress between men with high and low body fat (BF) in a physiologically uncompensable environment while simultaneously examining the confounding influence of hydration status. Both groups demonstrated similar sweating and cutaneous vasodilatory responses when euhydrated, despite vast differences in rectal temperature. Furthermore, in contrast to low BF, individuals with high BF demonstrated similar increases in core body temperature when either euhydrated or hypohydrated.
The acute inhibition of enteric glial metabolism with fluoroacetate alters calcium signaling, hemichannel function, and the expression of key proteins
Authors: McClain Jonathon L. , Gulbransen Brian D. 
Published: October 2016

Glia play key roles in the regulation of neurotransmission in the nervous system. Fluoroacetate (FA) is a metabolic poison widely used to study glial functions by disrupting the tricarboxylic acid cycle enzyme aconitase. Despite the widespread use of FA, the effects of FA on essential glial functions such as calcium (Ca2+) signaling and hemichannel function remain unknown. Therefore, our goal was to assess specifically the impact of FA on essential glial cell functions that are involved with neurotransmission in the enteric nervous system. To this end, we generated a new optogenetic mouse model to study specifically the effects of FA on enteric glial Ca2+signaling by crossing PC::G5-tdTomato mice with Sox10::creERT2mice. FA did not change the peak glial Ca2+response when averaged across all glia within a ganglion. However, FA decreased the percent of responding glia by 30% ( P < 0.05) and increased the peak Ca2+response of the glial cells that still exhibited a response by 26% ( P < 0.01). Disruption of Ca2+signaling with FA impaired the activity-dependent uptake of ethidium bromide through connexin-43 (Cx43) hemichannels ( P < 0.05) but did not affect baseline Cx43-dependent dye uptake. FA did not cause overt glial or neurodegeneration, but glial cells significantly increased glial fibrillary acid protein by 56% ( P < 0.05) following treatment with FA. Together, these data show that the acute impairment of glial metabolism with FA causes key changes in glial functions associated with their roles in neurotransmission and phenotypic changes indicative of reactive gliosis.NEW & NOTEWORTHY Our study shows that the acute impairment of enteric glial metabolism with fluoroacetate (FA) alters specific glial functions that are associated with the modification of neurotransmission in the gut. These include subtle changes to glial agonist-evoked calcium signaling, the subsequent disruption of connexin-43 hemichannels, and changes in protein expression that are consistent with a transition to reactive glia. These changes in glial function offer a mechanistic explanation for the effects of FA on peripheral neuronal networks.
CRLX101, a Nanoparticle–Drug Conjugate Containing Camptothecin, Improves Rectal Cancer Chemoradiotherapy by Inhibiting DNA Repair and HIF1α
Authors: Tian Xi , Nguyen Minh , Foote Henry P. , Caster Joseph M. , Roche Kyle C. , Peters Christian G. , Wu Pauline , Jayaraman Lata , Garmey Edward G. , Tepper Joel E. , Eliasof Scott , Wang Andrew Z. 
Published: October 2016

Abstract
Novel agents are needed to improve chemoradiotherapy for locally advanced rectal cancer. In this study, we assessed the ability of CRLX101, an investigational nanoparticle–drug conjugate containing the payload camptothecin (CPT), to improve therapeutic responses as compared with standard chemotherapy. CRLX101 was evaluated as a radiosensitizer in colorectal cancer cell lines and murine xenograft models. CRLX101 was as potent as CPT in vitro in its ability to radiosensitize cancer cells. Evaluations in vivo demonstrated that the addition of CRLX101 to standard chemoradiotherapy significantly increased therapeutic efficacy by inhibiting DNA repair and HIF1α pathway activation in tumor cells. Notably, CRLX101 was more effective than oxaliplatin at enhancing the efficacy of chemoradiotherapy, with CRLX101 and 5-fluorouracil producing the highest therapeutic efficacy. Gastrointestinal toxicity was also significantly lower for CRLX101 compared with CPT when combined with radiotherapy. Our results offer a preclinical proof of concept for CRLX101 as a modality to improve the outcome of neoadjuvant chemoradiotherapy for rectal cancer treatment, in support of ongoing clinical evaluation of this agent (LCC1315 NCT02010567). Cancer Res; 77(1); 112–22. ©2016 AACR.
Mechanisms through Which Hypoxia-Induced Caveolin-1 Drives Tumorigenesis and Metastasis in Hepatocellular Carcinoma
Authors: Mao Xiaowen , Wong Sivia Yuen Sze , Tse Edith Yuk Ting , Ko Frankie Chi Fat , Tey Sze Keong , Yeung Yin Shan , Man Kwan , Lo Regina Cheuk-Lam , Ng Irene Oi-Lin , Yam Judy Wai Ping 
Published: October 2016

Abstract
In solid tumors, hypoxia triggers an aberrant vasculogenesis, enhances malignant character, and elevates metastatic risk. The plasma membrane organizing protein caveolin-1 (Cav1) is increased in a variety of cancers, including hepatocellular carcinoma (HCC), where it contributes to metastatic capability. However, the reason for elevation of Cav1 in tumor cells and the mechanistic basis for its contributions to metastatic risk are not fully understood. Here, we show that in HCC cells, hypoxia elevates expression of Cav1, which then acts through the calcium-binding protein S100P to promote metastasis. Hypoxic regions of HCC xenografts displayed elevated expression of Cav1. Hypoxia promoted HCC cell migration and invasion and distant pulmonary metastases, whereas Cav1 silencing abolished these effects. Gene expression profiling revealed that hypoxia-induced Cav1 functioned as a positive regulator of S100P via activation of the NF-κB pathway. S100P elevation under hypoxic conditions was abrogated by silencing of Cav1 or NF-κB function. Conversely, restoring S100P in Cav1-silenced cells rescued the migratory potential of HCC cells along with tumor formation and lung metastasis. In clinical specimens of HCC, we observed S100P overexpression to correlate with venous invasion, microsatellites, direct liver invasion, and absence of tumor encapsulation. Collectively, our findings demonstrated how hypoxia-induced expression of Cav1 in HCC cells enhances their invasive and metastatic potential. Cancer Res; 76(24); 7242–53. ©2016 AACR.