bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Hepatitis B Virus (HBV) HBx Protein Activates AKT To Simultaneously Regulate HBV Replication and Hepatocyte Survival
Authors: Rawat Siddhartha , Bouchard Michael J. 
Published: October 2014

ABSTRACT

Chronic infection with hepatitis B virus (HBV) is a risk factor for developing liver diseases such as hepatocellular carcinoma (HCC). HBx is a multifunctional protein encoded by the HBV genome; HBx stimulates HBV replication and is thought to play an important role in the development of HBV-associated HCC. HBx can activate the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway in some cell lines; however, whether HBx regulates PI3K/AKT signaling in normal hepatocytes has not been evaluated. In studies described here, we assessed HBx activation of PI3K/AKT signaling in an
ex vivo
model of cultured primary hepatocytes and determined how this HBx activity affects HBV replication. We report that HBx activates AKT in primary hepatocytes and that the activation of AKT decreases HBV replication and HBV mRNA and core protein levels. We show that the transcription factor hepatocyte nuclear factor 4α (HNF4α) is a target of HBx-regulated AKT, and we link HNF4α to HBx-regulated AKT modulation of HBV transcription and replication. Although we and others have shown that HBx stimulates and is likely required for HBV replication, we now report that HBx also activates signals that can diminish the overall level of HBV replication. While this may seem counterintuitive, we show that an important effect of HBx activation of AKT is inhibition of apoptosis. Consequently, our studies suggest that HBx balances HBV replication and cell survival by stimulating signaling pathways that enhance hepatocyte survival at the expense of higher levels of HBV replication.

IMPORTANCE
Chronic hepatitis B virus (HBV) infection is a common cause of the development of liver cancer. Regulation of cell signaling pathways by the HBV HBx protein is thought to influence the development of HBV-associated liver cancer. HBx stimulates, and may be essential for, HBV replication. We show that HBx activates AKT in hepatocytes to reduce HBV replication. While this seems contradictory to an essential role of HBx during HBV replication, HBx activation of AKT inhibits hepatocyte apoptosis, and this may facilitate persistent, noncytopathic HBV replication. AKT regulates HBV replication by reducing the activity of the transcription factor hepatocyte nuclear factor 4α (HNF4α). HBx activation of AKT may contribute to the development of liver cancer by facilitating persistent HBV replication, augmenting the dedifferentiation of hepatocytes by inhibiting HNF4α functions, and activating AKT-regulated oncogenic pathways. AKT-regulated factors may provide therapeutic targets for inhibiting HBV replication and the development of HBV-associated liver cancer.
Enhanced Transgene Expression from Recombinant Single-Stranded D-Sequence-Substituted Adeno-Associated Virus Vectors in Human Cell Lines
In Vitro
and in Murine Hepatocytes
In Vivo
Authors: Ling Chen , Wang Yuan , Lu Yuan , Wang Lina , Jayandharan Giridhara R. , Aslanidi George V. , Li Baozheng , Cheng Binbin , Ma Wenqin , Lentz Thomas , Ling Changquan , Xiao Xiao , Samulski R. Jude , Muzyczka Nicholas , Srivastava Arun 
Published: October 2014

ABSTRACT

We have previously reported that the removal of a 20-nucleotide sequence, termed the D sequence, from both ends of the inverted terminal repeats (ITRs) in the adeno-associated virus serotype 2 (AAV2) genome significantly impairs rescue, replication, and encapsidation of the viral genomes (X. S. Wang, S. Ponnazhagan, and A. Srivastava, J Mol Biol 250:573–580, 1995; X. S. Wang, S. Ponnazhagan, and A. Srivastava, J Virol 70:1668–1677, 1996). Here we describe that replacement of only one D sequence in either ITR restores each of these functions, but DNA strands of only single polarity are encapsidated in mature progeny virions. Since most commonly used recombinant AAV vectors contain a single-stranded DNA (ssDNA), which is transcriptionally inactive, efficient transgene expression from AAV vectors is dependent upon viral second-strand DNA synthesis. We have also identified a transcription suppressor sequence in one of the D sequences, which shares homology with the binding site for the cellular NF-κB-repressing factor (NRF). The removal of this D sequence from, and replacement with a sequence containing putative binding sites for transcription factors in, single-stranded AAV (ssAAV) vectors significantly augments transgene expression both in human cell lines
in vitro
and in murine hepatocytes
in vivo
. The development of these genome-modified ssAAV vectors has implications not only for the basic biology of AAV but also for the optimal use of these vectors in human gene therapy.

IMPORTANCE
The results of the studies described here not only have provided novel insights into some of the critical steps in the life cycle of a human virus, the adeno-associated virus (AAV), that causes no known disease but have also led to the development of novel recombinant AAV vectors which are more efficient in allowing increased levels of gene expression. Thus, these studies have significant implications for the potential use of these novel AAV vectors in human gene therapy.
Impact and Regulation of Lambda Interferon Response in Human Metapneumovirus Infection
Authors: Baños-Lara Ma. Del Rocío , Harvey Lindsey , Mendoza Alexander , Simms Dawn , Chouljenko Vladimir N. , Wakamatsu Nobuko , Kousoulas K. Gus , Guerrero-Plata Antonieta 
Published: October 2014

ABSTRACTHuman metapneumovirus (hMPV) is a respiratory paramyxovirus that is distributed worldwide and induces significant airway morbidity. Despite the relevance of hMPV as a pathogen, many aspects of the immune response to this virus are still largely unknown. In this report, we focus on the antiviral immune response, which is critical for viral clearance and disease resolution. Usingin vitroandin vivosystems, we show that hMPV is able to induce expression of lambda interferon 1 (IFN-λ1), IFN-λ2, IFN-λ3, and IFN-λ4. The induction of IFN-λ expression by hMPV was dependent on interferon regulatory factor 7 (IRF-7) expression but not on IRF-3 expression. Treatment of hMPV-infected mice with IFN-λ reduced the disease severity, lung viral titer, and inflammatory response in the lung. Moreover, the IFN-λ response induced by the virus was regulated by the expression of the hMPV G protein. These results show that type III interferons (IFN-λs) play a critical protective role in hMPV infection.IMPORTANCEHuman metapneumovirus (hMPV) is a pathogen of worldwide importance. Despite the relevance of hMPV as a pathogen, critical aspects of the immune response induced by this virus remain unidentified. Interferons (IFNs), including IFN-λ, the newest addition to the interferon family, constitute an indispensable part of the innate immune response. Here, we demonstrated that IFN-λ exhibited a protective role in hMPV infectionin vitroand in an experimental mouse model of infection.
Determining universal processes related to best outcome in emergency abdominal surgery: a multicentre, international, prospective cohort study
Authors: Bhangu Aneel , Fitzgerald J Edward , Fergusson Stuart , Khatri Chetan , Holmer Hampus , Søreide Kjetil , Harrison Ewen M 
Published: October 2014

IntroductionEmergency abdominal surgery outcomes represent an internationally important marker of healthcare quality and capacity. In this study, a novel approach to investigating global surgical outcomes is proposed, involving collaborative methodology using ‘snapshot’ clinical data collection over a 2-week period. The primary aim is to identify internationally relevant, modifiable surgical practices (in terms of modifiable process, equipment and clinical management) associated with best care for emergency abdominal surgery.Methods and analysisThis is a multicentre, international, prospective cohort study. Any hospital in the world performing acute surgery can participate, and any patient undergoing emergency intraperitoneal surgery is eligible to enter the study. Centres will collect observational data on patients for a 14-day period during a 5-month window and required data points will be limited to ensure practicality for collaborators collecting data. The primary outcome measure is the 24 h perioperative mortality, with 30-day perioperative mortality as a secondary outcome measure. During registration, participants will undertake a survey of available resources and capacity based on the WHO Tool for Situational Analysis.Ethics and disseminationThe study will not affect clinical care and has therefore been classified as an audit by the South East Scotland Research Ethics Service in Edinburgh, Scotland. Baseline outcome measurement in relation to emergency abdominal surgery has not yet been undertaken at an international level and will provide a useful indicator of surgical capacity and the modifiable factors that influence this. This novel methodological approach will facilitate delivery of a multicentre study at a global level, in addition to building international audit and research capacity.Trial registration numberThe study has been registered with ClinicalTrials.gov (Identifier:NCT02179112).
Pancreatic Cancer–Derived Exosomes Cause Paraneoplastic β-cell Dysfunction
Authors: Javeed Naureen , Sagar Gunisha , Dutta Shamit K. , Smyrk Thomas C. , Lau Julie S. , Bhattacharya Santanu , Truty Mark , Petersen Gloria M. , Kaufman Randal J. , Chari Suresh T. , Mukhopadhyay Debabrata 
Published: October 2014

Abstract
Purpose: Pancreatic cancer frequently causes diabetes. We recently proposed adrenomedullin as a candidate mediator of pancreatic β-cell dysfunction in pancreatic cancer. How pancreatic cancer–derived adrenomedullin reaches β cells remote from the cancer to induce β-cell dysfunction is unknown. We tested a novel hypothesis that pancreatic cancer sheds adrenomedullin-containing exosomes into circulation, which are transported to β cells and impair insulin secretion.
Experimental Methods: We characterized exosomes from conditioned media of pancreatic cancer cell lines (n = 5) and portal/peripheral venous blood of patients with pancreatic cancer (n = 20). Western blot analysis showed the presence of adrenomedullin in pancreatic cancer-exosomes. We determined the effect of adrenomedullin-containing pancreatic cancer exosomes on insulin secretion from INS-1 β cells and human islets, and demonstrated the mechanism of exosome internalization into β cells. We studied the interaction between β-cell adrenomedullin receptors and adrenomedullin present in pancreatic cancer-exosomes. In addition, the effect of adrenomedullin on endoplasmic reticulum (ER) stress response genes and reactive oxygen/nitrogen species generation in β cells was shown.
Results: Exosomes were found to be the predominant extracellular vesicles secreted by pancreatic cancer into culture media and patient plasma. Pancreatic cancer-exosomes contained adrenomedullin and CA19-9, readily entered β cells through caveolin-mediated endocytosis or macropinocytosis, and inhibited insulin secretion. Adrenomedullin in pancreatic cancer exosomes interacted with its receptor on β cells. Adrenomedullin receptor blockade abrogated the inhibitory effect of exosomes on insulin secretion. β cells exposed to adrenomedullin or pancreatic cancer exosomes showed upregulation of ER stress genes and increased reactive oxygen/nitrogen species.
Conclusions: Pancreatic cancer causes paraneoplastic β-cell dysfunction by shedding adrenomedullin+/CA19-9+ exosomes into circulation that inhibit insulin secretion, likely through adrenomedullin-induced ER stress and failure of the unfolded protein response. Clin Cancer Res; 21(7); 1722–33. ©2014 AACR.
See related commentary by Korc, p. 1508
Molecular simulation studies of human coagulation factor VIII C domain-mediated membrane binding
Authors: Du Jiangfeng , Wichapong Kanin , Hackeng Tilman M. , Nicolaes Gerry A. F 
Published: October 2014

SummaryThe C-terminal C domains of activated coagulation factor VIII (FVIIIa) are essential to membrane binding of this crucial coagulation cofactor protein. To provide an overall membrane binding mechanism for FVIII, we performed simulations of membrane binding through coarsegrained molecular dynamics simulations of the C1 and C2 domain, and the combined C-domains (C1+C2). We found that the C1 and C2 domain have different membrane binding properties. The C1 domain uses hydrophobic spikes 3 and 4, of its total of four spikes, as major loops to bind the membrane, whereas all four of its hydrophobic loops of the C2 domain appear essential for membrane binding. Interestingly, in the C1+C2 system, we observed cooperative binding of the C1 and C2 domains such that all four C2 domain spikes bound first, after which all four loops of the C1 domain inserted into the membrane, while the net binding energy was higher than that of the sum of the isolated C domains. Several residues, mutations of which are known to cause haemophilia A, were identified as key residues for membrane binding. In addition to these known residues, we identified residues from the C1 and C2 domains, which are involved in the membrane binding process, that have not been reported before as a cause for haemophilia A, but which contribute to overall membrane binding and which are likely candidates for novel causative missense mutations in haemophilia A.
Observation of Moisture Tendencies Related to Shallow Convection
Authors: Bellenger H. , Yoneyama K. , Katsumata M. , Nishizawa T. , Yasunaga K. , Shirooka R. 
Published: October 2014

Abstract
Tropospheric moisture is a key factor controlling the global climate and its variability. For instance, moistening of the lower troposphere is necessary to trigger the convective phase of a Madden–Julian oscillation (MJO). However, the relative importance of the processes controlling this moistening has yet to be quantified. Among these processes, the importance of the moistening by shallow convection is still debated. The authors use high-frequency observations of humidity and convection from the Research Vessel (R/V) Mirai that was located in the Indian Ocean ITCZ during the Cooperative Indian Ocean Experiment on Intraseasonal Variability/Dynamics of the MJO (CINDY/DYNAMO) campaign. This study is an initial attempt to directly link shallow convection to moisture variations within the lowest 4 km of the atmosphere from the convective scale to the mesoscale. Within a few tens of minutes and near shallow convection occurrences, moisture anomalies of 0.25–0.5 g kg−1 that correspond to tendencies on the order of 10–20 g kg−1 day−1 between 1 and 4 km are observed and are attributed to shallow convective clouds. On the scale of a few hours, shallow convection is associated with anomalies of 0.5–1 g kg−1 that correspond to tendencies on the order of 1–4 g kg−1 day−1 according to two independent datasets: lidar and soundings. This can be interpreted as the resultant mesoscale effect of the population of shallow convective clouds. Large-scale advective tendencies can be stronger than the moistening by shallow convection; however, the latter is a steady moisture supply whose importance can increase with the time scale. This evaluation of the moistening tendency related to shallow convection is ultimately important to develop and constrain numerical models.
Bias Adjustment of AVHRR SST and Its Impacts on Two SST Analyses
Authors: Huang Boyin , Wang Wanqiu , Liu Chunying , Banzon Viva , Zhang Huai-Min , Lawrimore Jay 
Published: October 2014

AbstractSea surface temperature (SST) observations from satellite-based Advanced Very High Resolution Radiometer (AVHRR) instrument exhibit biases. Adjustments necessary for removing the AVHRR biases have been studied by progressive experiments. These experiments show that the biases are sensitive to various parameters, including the length of the input data window, the base-function empirical orthogonal teleconnections (EOTs), the ship–buoy SST adjustment, and a shift in grid system. The difference in bias adjustments due to these parameters can be as large as 0.3°–0.5°C in the tropical Pacific at the monthly time scale.The AVHRR bias adjustments were designed differently in the daily optimum interpolation SST (DOISST) and the Extended Reconstructed SST datasets that ingest AVHRR SSTs (ERSSTsat). The different AVHRR bias adjustments result in the differences in SST datasets in DOISST and ERSSTsat. Comparisons show that the SST difference between these two datasets results largely from the difference in the AVHRR bias adjustments and little from SST analysis methods in the Niño-3.4 region, as well as in the global oceans. For example, the average difference of the Niño-3.4 SSTs between DOISST and ERSSTsat is approximately 0.12°C due to the bias adjustments and is about 0.01°C due to the analysis methods.This study finds that the DOISST datasets can be improved by using the revised AVHRR bias adjustment of a wider input data window, updated EOTs, and a shifted grid system in DOISST. Improvements can also be made by including a ship–buoy SST adjustment, a zonal SST adjustment, or revised EOTs without damping in the high latitudes in ERSSTsat.
Production, Procurement and Inflation: A Market Model for Foodgrains
Authors: K.U. Gopakumar , Pandit V. 
Published: October 2014

Rapid rise in the prices of foodgrains and their continued upsurge is a matter of concern not only for the government and policy makers but also for anyone concerned with social welfare. This is particularly so because the increased prices of basic food items cause great distress to the poor sections of society who spend a large part of their income on food. Thus, a clear understanding of the causes of inflation is necessary for framing the right policy to tackle the problem. The current study tries to examine how prices are determined in the Indian foodgrain market. This requires a slightly different approach from the conventional demand and supply framework as government intervenes in the market through open-market operations. To this end, we propose a structural model, explaining the behaviour of foodgrain prices for the period 1980–81 through 2011–12 incorporating the role of government interventions. Our results confirm that there is a strong impact of demand- as well as supply-side factors. However, when it comes to controlling inflation, demand-side management turns out to be highly significant. Under supply-side management, increased capital stock is found to be important, in so far as it significantly boosts production. Government intervention through procurement and off-take plays a stabilising role. JELClassification: E31, Q11, Q18
Modelling India’s External Sector: Review and Some Empirics
Authors: Bhanumurthy N.R. , Bose Sukanya , Panda Swayamsiddha 
Published: October 2014

In the aftermath of the global food and fuel price spikes, and the recent global financial crisis, understanding of external sector behaviour has become crucial. The transmission mechanism of external sector shocks to domestic macroeconomic variables is essential for undertaking relevant policies to mitigate the adverse impact of such shocks. Here an attempt has been made to review the theoretical and empirical issues relating to India’s external sector behaviour and to present a suitable analytical framework for macro modelling. JEL Classification: F4, C3
Comparison of digital nerve sensory recovery after repair using loupe or operating microscope magnification
Authors: Thomas P. R. , Saunders R. J. , Means K. R. 
Published: October 2014

Our purpose was to determine whether there was a significant difference in sensory recovery after digital nerve repair using loupe magnification or an operating microscope. We identified patients aged 21–75 who had primary proper digital nerve repairs at least 24 months before our study. A total of 12 patients with 13 digital nerve injuries repaired with loupe magnification and nine patients with 12 digital nerve injuries repaired using the operating microscope, agreed to return for assessment by a therapist blinded to treatment. We found no significant difference in sensory recovery between the two groups as measured by static two-point discrimination, moving two-point discrimination, and Semmes–Weinstein monofilament. There were also no significant differences in average Disabilities of the Arm Shoulder and Hand or visual analogue pain scores. Level of evidence: IV
A phase 1/1b study of rituximab, bendamustine, and ibrutinib in patients with untreated and relapsed/refractory non-Hodgkin lymphoma
Authors: Maddocks Kami , Christian Beth , Jaglowski Samantha , Flynn Joseph , Jones Jeffery A. , Porcu Pierluigi , Wei Lai , Jenkins Cynthia , Lozanski Gerard , Byrd John C. , Blum Kristie A. 
Published: October 2014

Key Points
Combined R-bendamustine and ibrutinib is well tolerated in patients with relapsed/refractory NHL, with promising efficacy in MCL and FL.
A comprehensive resource of genomic, epigenomic and transcriptomic sequencing data for the black truffle Tuber melanosporum
Authors: Chen Pao-Yang , Montanini Barbara , Liao Wen-Wei , Morselli Marco , Jaroszewicz Artur , Lopez David , Ottonello Simone , Pellegrini Matteo 
Published: October 2014

Abstract

Background
Tuber melanosporum, also known in the gastronomic community as “truffle”, features one of the largest fungal genomes (125 Mb) with an exceptionally high transposable element (TE) and repetitive DNA content (&gt;58%). The main purpose of DNA methylation in fungi is TE silencing. As obligate outcrossing organisms, truffles are bound to a sexual mode of propagation, which together with TEs is thought to represent a major force driving the evolution of DNA methylation. Thus, it was of interest to examine if and how T. melanosporum exploits DNA methylation to maintain genome integrity.

Findings
We performed whole-genome DNA bisulfite sequencing and mRNA sequencing on different developmental stages of T. melanosporum; namely, fruitbody (“truffle”), free-living mycelium and ectomycorrhiza. The data revealed a high rate of cytosine methylation (&gt;44%), selectively targeting TEs rather than genes with a strong preference for CpG sites. Whole genome DNA sequencing uncovered multiple TE-enriched, copy number variant regions bearing a significant fraction of hypomethylated and expressed TEs, almost exclusively in free-living mycelium propagated in vitro. Treatment of mycelia with 5-azacytidine partially reduced DNA methylation and increased TE transcription. Our transcriptome assembly also resulted in the identification of a set of novel transcripts from 614 genes.

Conclusions
The datasets presented here provide valuable and comprehensive (epi)genomic information that can be of interest for evolutionary genomics studies of multicellular (filamentous) fungi, in particular Ascomycetes belonging to the subphylum, Pezizomycotina. Evidence derived from comparative methylome and transcriptome analyses indicates that a non-exhaustive and partly reversible methylation process operates in truffles.