bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hepatitis B Virus Polymerase Localizes to the Mitochondria, and Its Terminal Protein Domain Contains the Mitochondrial Targeting Signal
Authors: Unchwaniwala Nuruddin , Sherer Nathan M. , Loeb Daniel D. 
Published: July 2016

ABSTRACT
To understand subcellular sites of hepatitis B virus (HBV) replication, we visualized core (Cp), polymerase (Pol), and pregenomic RNA (pgRNA) in infected cells. Interestingly, we found that the majority of Pol localized to the mitochondria in cells undergoing viral replication. The mitochondrial localization of Pol was independent of both the cell type and other viral components, indicating that Pol contains an intrinsic mitochondrial targeting signal (MTS). Neither Cp nor pgRNA localized to the mitochondria during active replication, suggesting a role other than DNA synthesis for Pol at the mitochondria. The Pol of duck hepatitis B virus (DHBV) also localized to the mitochondria. This result indicates that localization of Pol to mitochondria is likely a feature of all hepadnaviruses. To map the MTS within HBV Pol, we generated a series of Pol-green fluorescent protein (Pol-GFP) fusions and found that a stretch spanning amino acids (aa) 141 to 160 of Pol was sufficient to target GFP to the mitochondria. Surprisingly, deleting aa 141 to 160 in full-length Pol did not fully ablate Pol's mitochondrial localization, suggesting that additional sequences are involved in mitochondrial targeting. Only by deleting the N-terminal 160 amino acids in full-length Pol was mitochondrial localization ablated. Crucial residues for pgRNA packaging are contained within aa 141 to 160, indicating a multifunctional role of this region of Pol in the viral life cycle. Our studies show an unexpected Pol trafficking behavior that is uncoupled from its role in viral DNA synthesis.

IMPORTANCE
Chronic infection by HBV is a serious health concern. Existing therapies for chronically infected individuals are not curative, underscoring the need for a better understanding of the viral life cycle to develop better antiviral therapies. To date, the most thoroughly studied function of Pol is to package the pgRNA and reverse transcribe it to double-stranded DNA within capsids. This study provides evidence for mitochondrial localization of Pol and defines the MTS. Recent findings have implicated a non-reverse transcription role for Pol in evading host innate immune responses. Mitochondria play an important role in controlling cellular metabolism, apoptosis, and innate immunity. Pol may alter one or more of these host mitochondrial functions to gain a replicative advantage and persist in chronically infected individuals.
An Ebola Virus-Like Particle-Based Reporter System Enables Evaluation of Antiviral Drugs
In Vivo
under Non-Biosafety Level 4 Conditions
Authors: Li Dapeng , Chen Tan , Hu Yang , Zhou Yu , Liu Qingwei , Zhou Dongming , Jin Xia , Huang Zhong 
Published: July 2016

ABSTRACT

Ebola virus (EBOV) is a highly contagious lethal pathogen. As a biosafety level 4 (BSL-4) agent, however, EBOV is restricted to costly BSL-4 laboratories for experimentation, thus significantly impeding the evaluation of EBOV vaccines and drugs. Here, we report an EBOV-like particle (EBOVLP)-based luciferase reporter system that enables the evaluation of anti-EBOV agents
in vitro
and
in vivo
outside BSL-4 facilities. Cotransfection of HEK293T cells with four plasmids encoding the proteins VP40, NP, and GP of EBOV and firefly luciferase (Fluc) resulted in the production of Fluc-containing filamentous particles that morphologically resemble authentic EBOV. The reporter EBOVLP was capable of delivering Fluc into various cultured cells in a GP-dependent manner and was recognized by a conformation-dependent anti-EBOV monoclonal antibody (MAb). Significantly, inoculation of mice with the reporter EBOVLP led to the delivery of Fluc protein into target cells and rapid generation of intense bioluminescence signals that could be blocked by the administration of EBOV neutralizing MAbs. This BSL-4-free reporter system should facilitate high-throughput screening for anti-EBOV drugs targeting viral entry and efficacy testing of candidate vaccines.

IMPORTANCE
Ebola virus (EBOV) researches have been limited to costly biosafety level 4 (BSL-4) facilities due to the lack of animal models independent of BSL-4 laboratories. In this study, we reveal that a firefly luciferase-bearing EBOV-like particle (EBOVLP) with typical filamentous EBOV morphology is capable of delivering the reporter protein into murine target cells both
in vitro
and
in vivo
. Moreover, we demonstrate that the reporter delivery can be inhibited both
in vitro
and
in vivo
by a known anti-EBOV protective monoclonal antibody, 13C6. Our work provides a BSL-4-free system that can facilitate the
in vivo
evaluation of anti-EBOV antibodies, drugs, and vaccines. The system may also be useful for mechanistic study of the viral entry process.
Investigating the association between prepregnancy body mass index and adverse pregnancy outcomes: a large cohort study of 536 098 Chinese pregnant women in rural China
Authors: Pan Yi , Zhang Shikun , Wang Qiaomei , Shen Haiping , Zhang Yiping , Li Yuanyuan , Yan Donghai , Sun Lizhou 
Published: July 2016

ObjectiveUnhealthy maternal weight before pregnancy increases the risk of various adverse pregnancy outcomes. We conducted a nutrition survey to provide baseline data on the prepregnant nutritional status of mothers in order to better understand the association between prepregnancy maternal body mass index (BMI) and adverse pregnancy outcomes.DesignA large, prospective, population-based cohort study.SettingData from the National Free Preconception Health Examination Project (NFPHEP) in China during 2010–2012.Participants536 098 pregnant women out of 2 120 131 were evaluated.Primary and secondary outcome measuresThe primary adverse pregnancy outcomes included preterm birth (PTB), low birth weight (LBW), spontaneous miscarriage (SM), ectopic pregnancy (EP) and stillbirth (SB). A χ2test was used to compare the prevalence of each BMI category during 2010–2012. Univariable and multiple logistic regression analyses were performed to assess the association between prepregnancy BMI and various adverse pregnancy outcomes.ResultsBetween 2010 and 2012, the average BMI decreased from 21.31 to 21.16, while underweight prevalence increased from 10.40% to 14.14%. An age-stratified subgroup analysis indicated that the underweight prevalence increased from 13.52% to 17.02% among women aged 21–24 and from 10.72% to 13.71% among women aged 25–34. Overweight prevalence increased from 9.84% to 10.75% (25–34 years) and from 17.10% to 19.20% (35–49 years). Obesity prevalence increased from 2.17% to 2.42% and from 4% to 4.2% among women aged 25–34 and 35–49 respectively. Prepregnancy underweight was associated with PTB, LBW and SM; overweight women had an increased risk of LBW; obese women had a higher risk of LBW, SM, EP and SB.ConclusionsWhile the average prepregnancy BMI decreased, the prevalence of underweight individuals in a very large population significantly increased. The abnormal prepregnancy BMIs were associated with increased risks of adverse pregnancy outcomes. Most notably, underweight prepregnant women appeared to be at a greater risk of developing adverse pregnancy outcomes in China's rural areas.
Glycated haemoglobin (HbA1c), diabetes and trajectories of change in episodic memory performance
Authors: Pappas Colleen , Andel Ross , Infurna Frank J , Seetharaman Shyam 
Published: July 2016

BackgroundAs the ageing population grows, it is important to identify strategies to moderate cognitive ageing.ObjectiveWe examined glycated haemoglobin (HbA1c) and diabetes in relation to level and change in episodic memory in older adults with and without diabetes.MethodsData from 4419 older adults with (n=950) and without (n=3469) diabetes participating in a nationally representative longitudinal panel study (the Health and Retirement Study) were examined. Average baseline age was 72.66 years and 58% were women. HbA1c was measured in 2006 and episodic memory was measured using immediate and delayed list recall over 4 biennial waves between 2006 and 2012. Growth curve models were used to assess trajectories of episodic memory change.ResultsIn growth curve models adjusted for age, sex, education, race, depressive symptoms and waist circumference, higher HbA1c levels and having diabetes were associated with poorer baseline episodic memory (p=0.036 and <0.001, respectively) and greater episodic memory decline (p=0.006 and 0.004, respectively). The effect of HbA1c on episodic memory decline was smaller than the effect of age. The results were stronger for women than men and were not modified by age or race. When the main analyses were estimated for those with and without diabetes separately, HbA1c was significantly linked to change in episodic memory only among those with diabetes.ConclusionsHigher HbA1c and diabetes were both associated with declines in episodic memory, with this relationship further exacerbated by having diabetes and elevated HbA1c. HbA1c appeared more important for episodic memory performance among women than men.
Mid-term and long-term follow-up of intracranial aneurysms treated by the p64 Flow Modulation Device: a multicenter experience
Authors: Briganti Francesco , Leone Giuseppe , Ugga Lorenzo , Marseglia Mariano , Macera Antonio , Manto Andrea , Delehaye Luigi , Resta Maurizio , Resta Mariachiara , Burdi Nicola , Nuzzi Nunzio Paolo , Divenuto Ignazio , Caranci Ferdinando , Muto Mario , Solari Domenico , Cappabianca Paolo , Maiuri Francesco 
Published: July 2016

BackgroundExperience with the endovascular treatment of cerebral aneurysms using the p64 Flow Modulation Device is still limited. This study discusses the results and complications of this new flow diverter device.Methods40 patients (30 women, 10 men) with 50 cerebral aneurysms treated in six Italian neurointerventional centers with the p64 Flow Modulation Device between April 2013 and September 2015 were retrospectively reviewed.ResultsComplete occlusion was obtained in 44/50 aneurysms (88%) and partial occlusion in 3 (6%). In the other three aneurysms (6%), two cases of asymptomatic in-stent thrombosis and one intraprocedural occlusion of the parent vessel occurred. Technical complications were observed in eight procedures (16%). Permanent morbidity due to acute in-stent thrombosis and consequent ischemic stroke occurred in one patient (2.5%). No delayed aneurysm rupture, subarachnoid or intraparenchymal hemorrhage, or ischemic complications occurred and there were no deaths.ConclusionsEndovascular treatment with the p64 Flow Modulation Device is a safe treatment for unruptured cerebral aneurysms, resulting in a high rate of occlusion. As with other flow diverter devices, we recommend this treatment mainly for large-necked aneurysms of the internal carotid artery siphon. However, endovascular treatment with the p64 device should also be encouraged in difficult cases such as aneurysms of the posterior circulation and beyond the circle of Willis.
A combined surface and groundwater storage project: the Elmadag dam (Turkey)
Authors: Apaydin Ahmet , Zengin Ercan 
Published: July 2016

Considering some of the problems of surface reservoirs, such as unsteady stream flow, high evaporation losses and loss of storage owing to sediment entrapment, subsurface dams may be an effective solution in arid–semiarid regions. Combined surface and groundwater dam projects can be developed to withdraw the additional water from the porous alluvial sediments beneath the surface reservoir. We describe the investigation, construction and operation of such a hydraulic structure: the Elmadag dam, near Ankara, Turkey, which stores both surface water and groundwater behind the dam. The height of the Elmadag dam is 26 m but most of the dam wall (15 m) is located beneath the surface, and is constructed in an alluvial sand–gravel aquifer. The surface and subsurface storage capacity of the dam is 3 × 10
6
m
3
and on average 80 l s
−1
was pumped between January 2014 and October 2015, which equates to a rate almost equal to the 2015 domestic water demand of Elmadag town. If the surface reservoir dries up temporarily, the dam will continue to provide a supply from groundwater. More importantly, even if the surface reservoir is filled with sediments, the dam will ensure its function by subsurface storage.
Deccan Plateau uplift: insights from parts of Western Uplands, Maharashtra, India
Authors: Kale Vivek S. , Dole Gauri , Upasani Devdutt , Pillai Shilpa Patil 
Published: July 2016

Abstract
The western edge of the Deccan Plateau (=Western Uplands) has been depicted in its evolutionary models to be a contiguous crustal block exposing structurally undisturbed subhorizontal stacks of Deccan Trap basalts.
The geomorphological and morphometric characteristics of this terrain, Quaternary fluvial sediments capping the Deccan Traps in some river basins, compounded with deformation features in the basalts, and in the overlying sediments, are compiled here. They demonstrate that the Western Upland region of the Deccan Plateau may be constituted of no less than three blocks with differential Quaternary uplift histories, rather than the entire region experiencing a unified uplift.
Bromodomain and Extraterminal Protein Inhibitor JQ1 Suppresses Thyroid Tumor Growth in a Mouse Model
Authors: Zhu Xuguang , Enomoto Keisuke , Zhao Li , Zhu Yuelin J. , Willingham Mark C. , Meltzer Paul , Qi Jun , Cheng Sheue-yann 
Published: July 2016

AbstractPurpose: New therapeutic approaches are needed for patients with thyroid cancer refractory to radioiodine treatment. An inhibitor of bromodomain and extraterminal domain (BET) proteins, JQ1, shows potent antitumor effects in hematological cancers and solid tumors. To evaluate whether JQ1 is effective against thyroid cancer, we examined antitumor efficacy of JQ1 using the ThrbPV/PVKrasG12D mouse, a model of anaplastic thyroid cancer.Experimental Design: We treated ThrbPV/PVKrasG12D mice with vehicle or JQ1 at a dose of 50 mg/kg body weight/day starting at the age of 8 weeks for a 10-week period and monitored thyroid tumor progression.Results: JQ1 markedly inhibited thyroid tumor growth and prolonged survival of these mice. Global differential gene expression analysis showed that JQ1 suppressed the cMyc (hereafter referred to as Myc) transcription program by inhibiting mRNA expression of Myc, ccnd1, and other related genes. JQ1-suppressed Myc expression was accompanied by chromatin remodeling as evidenced by increased expression of histones and hexamethylene bis-acetamide inducible 1, a suppressor of RNA polymerase II transcription elongation. Analyses showed that JQ1 decreased MYC abundance in thyroid tumors and attenuated the cyclin D1–CDK4–Rb–E2F3 signaling to decrease tumor growth. Further analysis indicated that JQ1 inhibited the recruitment of BDR4 to the promoter complex of the Myc and Ccnd1 genes in rat thyroid follicular PCCL3 cells, resulting in decreased MYC expression at the mRNA and protein levels to inhibit tumor cell proliferation.Conclusions: These preclinical findings suggest that BET inhibitors may be an effective agent to reduce thyroid tumor burden for the treatment of refractory thyroid cancer. Clin Cancer Res; 23(2); 430–40. ©2016 AACR.
Irreversible Inhibition of EGFR: Modeling the Combined Pharmacokinetic–Pharmacodynamic Relationship of Osimertinib and Its Active Metabolite AZ5104
Authors: Yates James W.T. , Ashton Susan , Cross Darren , Mellor Martine J. , Powell Steve J. , Ballard Peter 
Published: July 2016

Abstract
Osimertinib (AZD9291) is a potent, selective, irreversible inhibitor of EGFR-sensitizing (exon 19 and L858R) and T790M-resistant mutation. In vivo, in the mouse, it is metabolized to an active des-methyl metabolite, AZ5104. To understand the therapeutic potential in patients, this study aimed to assess the relationship between osimertinib pharmacokinetics, the pharmacokinetics of the active metabolite, the pharmacodynamics of phosphorylated EGFR reduction, and efficacy in mouse xenograft models of EGFR-driven cancers, including two NSCLC lines. Osimertinib was dosed in xenografted models of EGFR-driven cancers. In one set of experiments, changes in phosphorylated EGFR were measured to confirm target engagement. In a second set of efficacy studies, the resulting changes in tumor volume over time after repeat dosing of osimertinib were observed. To account for the contributions of both molecules, a mathematical modeling approach was taken to integrate the resulting datasets. The model was able to describe the pharmacokinetics, pharmacodynamics, and efficacy in A431, PC9, and NCI-H1975 xenografts, with the differences in sensitivity described by the varying potency against wild-type, sensitizing, and T790M-mutant EGFR and the phosphorylated EGFR reduction required to reduce tumor volume. It was inferred that recovery of pEGFR is slower after chronic dosing due to reduced resynthesis. It was predicted and further demonstrated that although inhibition is irreversible, the resynthesis of EGFR is such that infrequent intermittent dosing is not as efficacious as once daily dosing. Mol Cancer Ther; 15(10); 2378–87. ©2016 AACR.
Dose reduction of edoxaban preserves efficacy and safety for the treatment of venous thromboembolism
Authors: Wells Philip S. , Segers Annelise , Ageno Walter , Brekelmans Marjolein P. A. , Cohen Alexander T. , Meyer Guy , Grosso Michael A. , Raskob Gary , Weitz Jeffrey I. , Zhang George , Buller Harry , Verhamme Peter 
Published: July 2016

SummaryDirect oral anticoagulants simplify venous thromboembolism (VTE) treatment by obviating the need for coagulation monitoring. Nonetheless, renal function, body weight and P-glycoprotein inhibitors influence drug levels. The objective of this analysis was to determine whether reduction in edoxaban dose based on clinical criteria avoids excess drug exposure and preserves efficacy and safety in the Hokusai-VTE study. After initial heparin, patients received edoxaban or warfarin for 3-12 months. Edoxaban was given once daily at a dose of 60 mg, which was reduced to 30 mg in patients with a creatinine clearance of 30–50 ml/minute, body weight ≤60 kg or receiving certain P-glycoprotein inhibitors. The primary efficacy outcome was recurrent VTE and the principal safety outcome was major or clinically relevant non-major bleeding. A total of 8292 patients with acute VTE were randomised, 733 and 719 patients in the edoxaban and warfarin groups met the criteria for dose reduction. These patients were older, more often female or Asian and had more extensive VTE. Edoxaban levels were lower in the 30 mg edoxaban group. Rates of recurrent VTE and bleeding with the 30 mg and 60 mg edoxaban dose were comparable: VTE rates were 3.0 % and 3.2 % and clinically relevant bleeding rates were 7.9 % and 8.6 %, respectively. Rates of recurrent VTE and bleeding in the warfarin-treated patients meeting the criteria for dose reduction were 4.2 % and 12.8 %, respectively. The reduced dose edoxaban regimen maintained efficacy and safety compared with the 60 mg dose but was safer than warfarin in patients meeting the criteria for dose reduction.Supplementary Material to this article is available online at www.thrombosis-online.com.
Impacts of Local Soil Moisture Anomalies on the Atmospheric Circulation and on Remote Surface Meteorological Fields during Boreal Summer: A Comprehensive Analysis over North America
Authors: Koster Randal D. , Chang Yehui , Wang Hailan , Schubert Siegfried D. 
Published: July 2016

Abstract
A series of stationary wave model (SWM) experiments are performed in which the boreal summer atmosphere is forced, over a number of locations in the continental United States, with an idealized diabatic heating anomaly that mimics the atmospheric heating associated with a dry land surface. For localized heating within a large portion of the continental interior, regardless of the specific location of this heating, the spatial pattern of the forced atmospheric circulation anomaly (in terms of 250-hPa eddy streamfunction) is largely the same: a high anomaly forms over west-central North America and a low anomaly forms to the east. In supplemental atmospheric general circulation model (AGCM) experiments, similar results are found; imposing soil moisture dryness in the AGCM in different locations within the U.S. interior tends to produce the aforementioned pattern, along with an associated near-surface warming and precipitation deficit in the center of the continent. The SWM-based and AGCM-based patterns generally agree with composites generated using reanalysis and precipitation gauge data. The AGCM experiments also suggest that dry anomalies imposed in the lower Mississippi River valley have remote surface impacts of particularly large spatial extent, and a region along the eastern half of the U.S.–Canadian border is particularly sensitive to dry anomalies in a number of remote areas. Overall, the SWM and AGCM experiments support the idea of a positive feedback loop operating over the continent: dry surface conditions in many interior locations lead to changes in atmospheric circulation that act to enhance further the overall dryness of the continental interior.
Preoperative prediction of suboptimal resection in advanced ovarian cancer based on clinical and CT parameters
Authors: Son Hye Min , Kim See Hyung , Kwon Bo Ra , Kim Mi Jeong , Kim Chan Sun , Cho Seung Hyun 
Published: July 2016

Background Cytoreduction is important as a survival predictor in advanced ovarian cancer. Purpose To determine the prediction of suboptimal resection (SOR) in advanced ovarian cancer based on clinical and computed tomography (CT) parameters. Material and Methods Between 2007 and 2015, 327 consecutive patients with FIGO stage III–IV ovarian cancer and preoperative CT were included. During 2007–2012, patients were assigned to a derivation dataset ( n = 220) and the others were assigned to a validation dataset ( n = 107). Clinical parameters were reviewed and two radiologists assessed the presence or absence of tabulated parameters on CT images. Logistic regression analyses based on area under the receiver-operating characteristic curve (AUROC) were performed to identify variables predicting SOR, and generated simple score using Cox proportional hazards model. Results There was no statistical difference in patients’ characteristics in both datasets, except for residual disease ( P = 0.001). Optimal resection improved from 45.0% (99/220) in the derivation dataset to 64.4% (69/107) in the validation dataset. Logistic regression identified that Eastern Cooperative Oncology Group-performance status (ECOG-PS 2), involvements of peritoneum, diaphragm, bowel mesentery and suprarenal lymph nodes, and pleural effusion were independent variables of SOR. Overall AUROC for score predicting SOR was 0.761 with sensitivity, specificity, and positive and negative predictive values of 70.6%, 73.2%, 68.7%, and 91.9%, respectively. In the derivation dataset, AUROC was 0.792, with sensitivity of 71.4% and specificity of 74.3%, and AUROC of 0.758 with sensitivity of 69.2% and specificity of 72.8% in the validation dataset. Conclusion CT may be a useful preoperative predictor of SOR in advanced ovarian cancer.