bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hepatitis C Virus Stimulates Low-Density Lipoprotein Receptor Expression To Facilitate Viral Propagation
Authors: Syed Gulam Hussain , Tang Huihui , Khan Mohsin , Hassanein Tarek , Liu Jingwen , Siddiqui Aleem 
Published: December 2013

ABSTRACT

Lipids play a crucial role in multiple aspects of hepatitis C virus (HCV) life cycle. HCV modulates host lipid metabolism to enrich the intracellular milieu with lipids to facilitate its proliferation. However, very little is known about the influence of HCV on lipid uptake from bloodstream. Low-density lipoprotein receptor (LDLR) is involved in uptake of cholesterol rich low-density lipoprotein (LDL) particles from the bloodstream. The association of HCV particles with lipoproteins implicates their role in HCV entry; however, the precise role of LDLR in HCV entry still remains controversial. Here, we investigate the effect of HCV infection on LDLR expression and the underlying mechanism(s) involved. We demonstrate that HCV stimulates LDLR expression in both HCV-infected Huh7 cells and in liver tissue from chronic hepatitis C patients. Fluorescence activated cell sorting and immunofluorescence analysis revealed enhanced cell surface and total expression of LDLR in HCV-infected cells. Increased LDLR expression resulted in the enhanced uptake of lipoprotein particles by HCV-infected cells. Analysis of
LDLR
gene promoter identified a pivotal role of sterol-regulatory element binding proteins (SREBPs), in the HCV-mediated stimulation of LDLR transcription. In addition, HCV negatively modulated the expression of proprotein convertase subtilisin/kexin type 9 (PCSK9), a protein that facilitates LDLR degradation. Ectopic expression of wild-type PCSK9 or gain-of-function PCSK9 mutant negatively affected HCV replication. Overall, our results demonstrate that HCV regulates LDLR expression at transcriptional and posttranslational level via SREBPs and PCSK9 to promote lipid uptake and facilitate viral proliferation.

IMPORTANCE
HCV modulates host lipid metabolism to promote enrichment of lipids in intracellular environment, which are essential in multiple aspects of HCV life cycle. However, very little is known about the influence of HCV on lipid uptake from the bloodstream. LDLR is involved in uptake of cholesterol rich lipid particles from bloodstream. In this study, we investigated the effect of HCV on LDLR expression and the underlying mechanism triggered by the virus to modulate LDLR expression. Our observations suggest that HCV upregulates LDLR expression at both the protein and the transcript levels and that this upregulation likely contributes toward the uptake of serum lipids by infected hepatocytes. Abrogation of HCV-mediated upregulation of LDLR inhibits serum lipid uptake and thereby perturbs HCV replication. Overall, our findings highlight the importance of serum lipid uptake by infected hepatocytes in HCV life cycle.
Hepatitis C Virus Impairs Natural Killer Cell-Mediated Augmentation of Complement Synthesis
Authors: Kim Hangeun , Bose Sandip K. , Meyer Keith , Ray Ranjit 
Published: December 2013

ABSTRACTNatural killer (NK) cells and the complement system play critical roles in the first line of defense against pathogens. The synthesis of complement components C4 and C3 is transcriptionally downregulated by hepatitis C virus (HCV) core and NS5A proteins, and this negative regulation is apparent in chronically HCV-infected patients. In this study, we have examined the potential contribution of an NK cell line as a model in regulating complement synthesis. Coculture of NK cells (NK3.3) with human hepatoma cells (Huh7.5) expressing HCV core or NS5A protein led to a significant increase in C4 and C3 complement synthesis via enhanced specific transcription factors. Reestablishment of complement protein expression was found to be mediated by direct interaction between NKG2D on NK cells and the hepatocyte protein major histocompatibility complex class I-related chains A and B (MICA/B) and not to be associated with specific cytokine signaling events. On the other hand, C4 and C3 synthesis remained impaired in a coculture of NK cells and Huh7.5 cells infected with cell culture-grown HCV. The association between these two cell types through NKG2D and MICA/B was examined further, with MICA/B expression in HCV-infected hepatocytes found to remain inhibited during coculture. Further experiments revealed that the HCV NS2 and NS5B proteins are responsible for the HCV-associated decrease in MICA/B. These results suggest that HCV disables a key receptor ligand in infected hepatoma cells, thereby inhibiting the ability of infected cells to respond to stimuli from NK cells to positively regulate complement synthesis.IMPORTANCEThe complement system contributes to the protection of the host from virus infection. However, the involvement of complement in viral hepatitis has not been well documented. Whether NK cells affect complement component expression in HCV-infected hepatocytes remains unknown. Here, we have shown how HCV subverts the ability of NK cells to positively mediate complement protein expression.
Recruitment of PI4KIIIβ to Coxsackievirus B3 Replication Organelles Is Independent of ACBD3, GBF1, and Arf1
Authors: Dorobantu Cristina M. , van der Schaar Hilde M. , Ford Lauren A. , Strating Jeroen R. P. M. , Ulferts Rachel , Fang Ying , Belov George , van Kuppeveld Frank J. M. 
Published: December 2013

ABSTRACT

Members of the
Enterovirus
(poliovirus [PV], coxsackieviruses, and human rhinoviruses) and
Kobuvirus
(Aichi virus) genera in the
Picornaviridae
family rely on PI4KIIIβ (phosphatidylinositol-4-kinase IIIβ) for efficient replication. The small membrane-anchored enteroviral protein 3A recruits PI4KIIIβ to replication organelles, yet the underlying mechanism has remained elusive. Recently, it was shown that kobuviruses recruit PI4KIIIβ through interaction with ACBD3 (acyl coenzyme A [acyl-CoA]-binding protein domain 3), a novel interaction partner of PI4KIIIβ. Therefore, we investigated a possible role for ACBD3 in recruiting PI4KIIIβ to enterovirus replication organelles. Although ACBD3 interacted directly with coxsackievirus B3 (CVB3) 3A, its depletion from cells by RNA interference did not affect PI4KIIIβ recruitment to replication organelles and did not impair CVB3 RNA replication. Enterovirus 3A was previously also proposed to recruit PI4KIIIβ via GBF1/Arf1, based on the known interaction of 3A with GBF1, an important regulator of secretory pathway transport and a guanine nucleotide exchange factor (GEF) of Arf1. However, our results demonstrate that inhibition of GBF1 or Arf1 either by pharmacological inhibition or depletion with small interfering RNA (siRNA) treatment did not affect the ability of 3A to recruit PI4KIIIβ. Furthermore, we show that a 3A mutant that no longer binds GBF1 was capable of recruiting PI4KIIIβ, even in ACBD3-depleted cells. Together, our findings indicate that unlike originally envisaged, coxsackievirus recruits PI4KIIIβ to replication organelles independently of ACBD3 and GBF1/Arf1.

IMPORTANCE
A hallmark of enteroviral infection is the generation of new membranous structures to support viral RNA replication. The functionality of these “replication organelles” depends on the concerted actions of both viral nonstructural proteins and co-opted host factors. It is thus essential to understand how these structures are formed and which cellular components are key players in this process. GBF1/Arf1 and ACBD3 have been proposed to contribute to the recruitment of the essential lipid-modifying enzyme PI4KIIIβ to enterovirus replication organelles. Here we show that the enterovirus CVB3 recruits PI4KIIIβ by a mechanism independent of both GBF1/Arf1 and ACBD3. This study shows that the strategy employed by coxsackievirus to recruit PI4KIIIβ to replication organelles is far more complex than initially anticipated.
Can we reduce costs and prevent more unintended pregnancies? A cost of illness and cost-effectiveness study comparing two methods of EHC
Authors: Thomas Christine M , Cameron Sharon 
Published: December 2013

ObjectivesTo calculate the cost of an unintended pregnancy in 2011 and use this cost in a cost-effectiveness model comparing ulipristal acetate (UPA) with levonorgestrel (LNG) for emergency hormonal contraception (EHC).DesignRetrospective analysis of published data sources and published cost-effectiveness model.SettingWomen presenting in primary care in England for EHC within 24 or 72 h of unprotected sexual intercourse (UPSI).InterventionsEHC of either LNG (1.5 mg) or UPA (30 mg).Primary and secondary outcome measuresThe primary outcome measure is the number and direct and indirect costs of an unintended pregnancy. The secondary outcome measure is the consequence of unintended pregnancy: miscarriage, abortion, ectopic pregnancy, stillbirth or live birth.ResultsFrom the comparative clinical studies of EHC we observe that if 125 women receive either LNG or UPA within 72 h of UPSI, there will be one less pregnancy due to method failure in the UPA group than in the LNG group. We calculate the cost of an unintended pregnancy to be £1663 in direct healthcare costs rising to £2922 with the inclusion of social costs. Using these costs in the comparative cost-effectiveness model shows that it costs £194 less in direct health costs alone to prevent one more pregnancy with UPA than with LNG. The inclusion of social costs of pregnancy increases this cost-saving potential to £1453 for each extra pregnancy avoided with UPA compared with LNG.ConclusionsClinical trials have demonstrated the superior efficacy of UPA compared with LNG as a method of EHC. Given that it costs less overall in health and social costs of pregnancy while preventing more pregnancies, UPA is said to be the dominant treatment, and primary care services should shift to offering UPA as the preferred oral option to women presenting within 24 and 72 h of UPSI.
Variability in initial response to standard clopidogrel therapy, delayed conversion to clopidogrel hyper-response, and associated thromboembolic and hemorrhagic complications in patients undergoing endovascular treatment of unruptured cerebral aneurysms
Authors: Delgado Almandoz Josser E , Kadkhodayan Yasha , Crandall Benjamin M , Scholz Jill M , Fease Jennifer L , Tubman David E 
Published: December 2013

Background and purposeVariability in response to clopidogrel therapy is increasingly being recognized as an important factor in thromboembolic and hemorrhagic complications encountered after neurointerventional procedures. This study aims to determine the variability in response to clopidogrel therapy and associated complications in patients undergoing endovascular treatment of unruptured cerebral aneurysms.MethodsWe recorded baseline patient characteristics, co-administered medications, P2Y12 reaction units (PRU) values with VerifyNow, clopidogrel dosing, and thromboembolic and hemorrhagic complications in patients undergoing endovascular treatment of unruptured cerebral aneurysms at our institution during a 19 month period.Results100 patients were included in the study, 76 women and 24 men, mean age 57.3 years. 15 patients exhibited an initial clopidogrel hypo-response (PRU >240) and 21 patients an initial clopidogrel hyper-response (PRU <60). 36 patients had a follow-up VerifyNow test performed without changes to the standard 75 mg daily clopidogrel dose, which demonstrated that 59% of patients who had initially been within the target 60–240 PRU range exhibited a delayed conversion to clopidogrel hyper-response. In our cohort, a clopidogrel hypo-response was associated with a significantly increased risk of thromboembolic complications in patients undergoing cerebral aneurysm treatment with stent assistance or the pipeline embolization device (60%, p=0.003), while a clopidogrel hyper-response was associated with a significantly increased risk of major hemorrhagic complications in all patients undergoing endovascular treatment of cerebral aneurysms (11%, p=0.016).ConclusionsWe found wide and dynamic variability in response to clopidogrel therapy in patients undergoing endovascular treatment of unruptured cerebral aneurysms, which was significantly associated with thromboembolic and major hemorrhagic complications in our cohort.
A CONFIGURABLE BOSE–CHAUDHURI–HOCQUENGHEM CODEC ARCHITECTURE FOR FLASH CONTROLLER APPLICATIONS
Authors: FREUDENBERGER JÜRGEN , SPINNER JENS 
Published: December 2013

Error correction coding (ECC) has become one of the most important tasks of flash memory controllers. The gate count of the ECC unit is taking up a significant share of the overall logic. Scaling the ECC strength to the growing error correction requirements has become increasingly difficult when considering cost and area limitations. This work presents a configurable encoding and decoding architecture for binary Bose–Chaudhuri–Hocquenghem (BCH) codes. The proposed concept supports a wide range of code rates and facilitates a trade-off between throughput and space complexity. Commonly, hardware implementations for BCH decoding perform many Galois field multiplications in parallel. We propose a new decoding technique that uses different parallelization degrees depending on the actual number of errors. This approach significantly reduces the number of required multipliers, where the average number of decoding cycles is even smaller than with a fully parallel implementation.
INVESTIGATION OF UNCERTAINTY FROM CREEP AND CREEP RECOVERY OF FORCE CALIBRATION RESULT IN ACCORDANCE WITH ISO 376:2011
Authors: CHAEMTHET KITTIPONG , AMORNSAKUN CHANCHAI , SUMYONG NOPPADON , CHANGPAN TAWAT , HEAMAWATANACHAI SUMET 
Published: December 2013

This paper presents an investigation of the uncertainties from creep and creep recovery of force proving instruments calibrated at NIMT in year 2012 and 2013. In this study, the NIMT's 100kN deadweight force standard machine was used as a standard to calibrate force proving instruments (from various manufacturers and models) in accordance with ISO 376:2011. The comparison of creep uncertainties calculated from creep measured at maximum load (Cmax), creep recovery measured at zero load (Czero) and reversibility errors were also investigated. The results of this study show that, for most of the calibration results (>60%), the maximum value between WCmax/WCzero and WCzero/WCmax were larger than 2. Indicating that, WCmax and WCzero could not assume to be equal. For the comparison between creep uncertainties calculated from creep error and reversibility error, more than 80% of the calibration results, the creep uncertainties calculated from reversibility were larger than 3 time of the calculated values form creep measurement. These gave conclusion that, for the unknown history of creep and reversibility characteristic of instruments, it is more appropriate to estimate the uncertainty of creep from reversibility error.
DEVELOPMENT OF A MACHINE-VISION-BASED SYSTEM FOR RECORDING OF FORCE CALIBRATION DATA
Authors: HEAMAWATANACHAI SUMET , CHAEMTHET KITTIPONG , CHANGPAN TAWAT 
Published: December 2013

This paper presents the development of a new system for recording of force calibration data using machine vision technology. Real time camera and computer system were used to capture images of the reading from the instruments during calibration. Then, the measurement images were transformed and translated to numerical data using optical character recognition (OCR) technique. These numerical data along with raw images were automatically saved to memories as the calibration database files. With this new system, the human error of recording would be eliminated. The verification experiments were done by using this system for recording the measurement results from an amplifier (DMP 40) with load cell (HBM-Z30-10kN). The NIMT's 100-kN deadweight force standard machine (DWM-100kN) was used to generate test forces. The experiments setup were done in 3 categories; 1) dynamics condition (record during load changing), 2) statics condition (record during fix load), and 3) full calibration experiments in accordance with ISO 376:2011. The captured images from dynamics condition experiment gave >94% without overlapping of number. The results from statics condition experiment were >98% images without overlapping. All measurement images without overlapping were translated to number by the developed program with 100% accuracy. The full calibration experiments also gave 100% accurate results. Moreover, in case of incorrect translation of any result, it is also possible to trace back to the raw calibration image to check and correct it. Therefore, this machine-vision-based system and program should be appropriate for recording of force calibration data.
Activation of the NOTCH Pathway in Head and Neck Cancer
Authors: Sun Wenyue , Gaykalova Daria A. , Ochs Michael F. , Mambo Elizabeth , Arnaoutakis Demetri , Liu Yan , Loyo Myriam , Agrawal Nishant , Howard Jason , Li Ryan , Ahn Sun , Fertig Elana , Sidransky David , Houghton Jeffery , Buddavarapu Kalyan , Sanford Tiffany , Choudhary Ashish , Darden Will , Adai Alex , Latham Gary , Bishop Justin , Sharma Rajni , Westra William H. , Hennessey Patrick , Chung Christine H. , Califano Joseph A. 
Published: December 2013

Abstract
NOTCH1 mutations have been reported to occur in 10% to 15% of head and neck squamous cell carcinomas (HNSCC). To determine the significance of these mutations, we embarked upon a comprehensive study of NOTCH signaling in a cohort of 44 HNSCC tumors and 25 normal mucosal samples through a set of expression, copy number, methylation, and mutation analyses. Copy number increases were identified in NOTCH pathway genes, including the NOTCH ligand JAG1. Gene set analysis defined a differential expression of the NOTCH signaling pathway in HNSCC relative to normal tissues. Analysis of individual pathway-related genes revealed overexpression of ligands JAG1 and JAG2 and receptor NOTCH3. In 32% of the HNSCC examined, activation of the downstream NOTCH effectors HES1/HEY1 was documented. Notably, exomic sequencing identified 5 novel inactivating NOTCH1 mutations in 4 of the 37 tumors analyzed, with none of these tumors exhibiting HES1/HEY1 overexpression. Our results revealed a bimodal pattern of NOTCH pathway alterations in HNSCC, with a smaller subset exhibiting inactivating NOTCH1 receptor mutations but a larger subset exhibiting other NOTCH1 pathway alterations, including increases in expression or gene copy number of the receptor or ligands as well as downstream pathway activation. Our results imply that therapies that target the NOTCH pathway may be more widely suitable for HNSCC treatment than appreciated currently. Cancer Res; 74(4); 1091–104. ©2013 AACR.
Molecular Pathways: Response and Resistance to BRAF and MEK Inhibitors in BRAFV600E Tumors
Authors: Thakur Meghna Das , Stuart Darrin D. 
Published: December 2013

Abstract
The RAS–RAF–MEK (MAP–ERK kinase)–ERK (extracellular signal–regulated kinase) pathway plays a central role in driving proliferation, survival, and metastasis signals in tumor cells, and the prevalence of oncogenic mutations in RAS and BRAF and upstream nodes makes this pathway the focus of significant oncology drug development efforts. This focus has been justified by the recent success of BRAF and MEK inhibitors in prolonging the lives of patients with BRAFV600E/K-mutant melanoma. Although it is disappointing that cures are relatively rare, this should not detract from the value of these agents to patients with cancer and the opportunity they provide in allowing us to gain a deeper understanding of drug response and resistance. These insights have already provided the basis for the evaluation of alternative dosing regimens and combination therapies in patients with melanoma. Clin Cancer Res; 20(5); 1074–80. ©2013 AACR.
Thrombin generation using the calibrated automated thrombinoscope to assess reversibility of dabigatran and rivaroxaban
Authors: Thom James , Wood Alicia , Phillips Michael , Muhammad Shoaib , Baker Ross , Herrmann Richard 
Published: December 2013

SummaryThe new direct-acting anticoagulants such as dabigatran and rivaroxaban are usually not monitored but may be associated with haemorrhage, particularly where renal impairment occurs. They have no effective “antidotes”. We studied 17 patients receiving dabigatran 150 mg twice daily for non-valvular atrial fibrillation and 15 patients receiving rivaroxaban 10 mg daily for the prevention of deep venous thrombosis after hip or knee replacement surgery. We assessed the effect of these drugs on commonly used laboratory tests and Calibrated Automated Thrombogram (CAT) using plasma samples. We also assessed effects in fresh whole blood citrated patient samples using thromboelastography on the TEG and the ROTEM. The efficacy of nonspecific haemostatic agents prothrombin complex concentrate (PCC), Factor VIII Inhibitor By-passing Activity (FEIBA) and recombinant activated factor VII (rVIIa) were tested by reversal of abnormal thrombin generation using the CAT. Concentrations added ex vivo were chosen to reflect doses normally given in vivo. Dabigatran significantly increased the dynamic parameters of the TEG and ROTEM and the lag time of the CAT. It significantly reduced the endogenous thrombin potential (ETP) and reduced the peak height of the CAT. Rivaroxaban did not affect the TEG and ROTEM parameters but did increase the lag time and reduce ETP and peak height of the CAT. For both drugs, these parameters were significantly and meaningfully corrected by PCC and FEIBA and to a lesser but still significant extent by rFVIIa. These results may be useful in devising a reversal strategy in patients but clinical experience will be needed to verify them.
Cardiovascular Disease and Cognitive Decline in Postmenopausal Women: Results From the Women's Health Initiative Memory Study
Authors: Haring Bernhard , Leng Xiaoyan , Robinson Jennifer , Johnson Karen C. , Jackson Rebecca D. , Beyth Rebecca , Wactawski‐Wende Jean , von Ballmoos Moritz Wyler , Goveas Joseph S. , Kuller Lewis H. , Wassertheil‐Smoller Sylvia 
Published: December 2013

Background

Data on cardiovascular diseases (
CVD
) and cognitive decline are conflicting. Our objective was to investigate if
CVD
is associated with an increased risk for cognitive decline and to examine whether hypertension, diabetes, or adiposity modify the effect of
CVD
on cognitive functioning.

Methods and Results

Prospective follow‐up of 6455 cognitively intact, postmenopausal women aged 65 to 79 years old enrolled in the
W
omen's
H
ealth
I
nitiative
M
emory
S
tudy (
WHIMS
).
CVD
was determined by self‐report. For cognitive decline, we assessed the incidence of mild cognitive impairment (
MCI
) or probable dementia (
PD
) via modified mini‐mental state examination (3 MS) score, neurocognitive, and neuropsychiatric examinations. The median follow‐up was 8.4 years. Women with
CVD
tended to be at increased risk for cognitive decline compared with those free of
CVD
(hazard ratio [
HR
], 1.29; 95%
CI
: 1.00, 1.67). Women with myocardial infarction or other vascular disease were at highest risk (
HR
, 2.10; 95%
CI
: 1.40, 3.15 or
HR
, 1.97; 95%
CI
: 1.34, 2.87). Angina pectoris was moderately associated with cognitive decline (
HR
1.45; 95%
CI
: 1.05, 2.01) whereas no significant relationships were found for atrial fibrillation or heart failure. Hypertension and diabetes increased the risk for cognitive decline in women without
CVD
. Diabetes tended to elevate the risk for
MCI
/
PD
in women with
CVD
. No significant trend was seen for adiposity.

Conclusions

CVD
is associated with cognitive decline in elderly postmenopausal women. Hypertension and diabetes, but not adiposity, are associated with a higher risk for cognitive decline. More research is warranted on the potential of
CVD
prevention for preserving cognitive functioning.