bluuebunny/crossref_metadata_2025 huggingface dataset:
Preparation of Cuprous Oxide Nanoparticles Coated with Aminated Cellulose for the Photocatalytic Reduction of Carbon Dioxide to Methanol
Authors: Yisilamu Gunisakezi , Maimaiti Halidan , Awati Abuduheiremu , Zhang Dedong , Sun Fengchang , Xu Bo
Published: March 2018

The present study utilizes microcrystalline cellulose as the raw material to prepare nanoscale cellulose crystal (NCC) particles through a hybrid method incorporating mixed acid and ultrasonic treatment. Furthermore, the NCC undergoes a surface modification through SOCl2 chlorination and ethylenediamine (EDA) passivation, which generates graphitized aminated cellulose doped with nitrogen (NCC‐EDA). This product, due to the coordination and dispersion effects of the functional groups (e.g., amido group) on its surface, is in turn used to coat Cu2O nanoparticles derived from the in situ reduction of CuCl2⋅2 H2O, which leads to a composite photocatalyst Cu2O/NCC‐EDA with relatively high catalytic activity. Besides the structural characterization, the present study also examines the characteristics of CH3OH prepared by visible‐light‐based photocatalytic reduction of CO2/H2O. The results indicate that the prepared Cu2O/NCC‐EDA are spherical particles with a diameter of approximately 50 nm, which are in possession of a tree‐structured rough shell capable of absorbing an increased amount of CO2. Under the radiation of visible light, the Cu2O in the prepared product is activated, yielding photoelectron–hole pairs. Driven by the nitrogen in the carrier, the formed photoelectron–hole pairs are subject to an efficient separation, and are thereby consumed by the oxidation–reduction reaction. As a result, a high activity for the photocatalyzed reduction of CO2 is obtained.
A High Performance Air Cathode with the Hydrophobic Pores Distributed Continuously and in Gradient for Zinc‐Air Fuel Cells
Authors: Du Xianglong , Yan Zhao , Wang Erdong , Li Lifang
Published: March 2018

An efficient and durable air cathode is of great importance for the commercial application of zinc‐air fuel cell. In this work, a new air cathode with the hydrophobic pores distributed continuously and in gradient was prepared and characterized by the scanning electron microscope (SEM) combined with energy dispersive X‐ray spectroscopy (EDS). Compared with traditional air cathode, our new cathode exhibits attractive performance and lifetime, by which the maximum power density of 252 mW cm−2 and a stable discharge of 3600 h at 50 mA cm−2 are presented in zinc‐air fuel cells. Further investigation shows that the unique pores with the adequate size and hydrophobic property in current collector layer for the new cathode are helpful to prevent the water accumulation, and inhibit the formation of carbonate.
High resolution lake sediment record reveals self‐organized criticality in erosion processes regulated by internal feedbacks
Authors: Colombaroli D. , Gavin D.G. , Morey A.E. , Thorndycraft V.R.
Published: March 2018

Reconstruction of high‐frequency erosion variability beyond the instrumental record requires well‐dated, high‐resolution proxies from sediment archives. We used computed tomography (CT) scans of finely laminated silt layers from a lake‐sediment record in southwest Oregon to quantify the magnitude of natural landscape erosion events over the last 2000 years in order to compare with palaeorecords of climate, forest fire, and seismic triggers. Sedimentation rates were modeled from an age–depth relationship fit through five 14C dates and the 1964 AD 137Cs peak in which deposition time (yr mm‐1) varied inversely with the proportion of silt sediment measured by the CT profile. This model resulted in pseudo‐annual estimates of silt deposition for the last 2000 years. Silt accumulation during the past 80 years was strongly correlated with river‐discharge at annual and decadal scales, revealing that erosion was highly responsive to precipitation during the logging era (1930–present). Before logging the frequency–magnitude relationship displayed a power‐law distribution that is characteristic of complex feedbacks and self‐regulating mechanisms. The 100‐year and 10‐year erosion magnitude estimated in a 99‐year moving window varied by 1.7 and 1.0 orders of magnitude, respectively. Decadal erosion magnitude was only moderately positively correlated with a summer temperature reconstruction over the period 900–1900 AD. Magnitude of the seven largest events was similar to the cumulative silt accumulation anomaly, suggesting these events ‘returned the system’ to the long‐term mean rate. Instead, the occurrence of most erosion events was related to fire (silt layers preceded by high charcoal concentration) and earthquakes (the seven thickest layers often match paleo‐earthquake dates). Our data show how internal (i.e. sediment production) and external processes (natural fires or more stochastic events such as earthquakes) co‐determine erosion regimes at millennial time scales, and the extent to which such processes can be offset by recent large‐scale deforestation by logging. Copyright © 2018 John Wiley & Sons, Ltd.
Dynamic association and participant based adaptive streaming in small base station for live video conference on 5G networks
Authors: D Frederick Swartz Daniel , K.A Mohamed Junaid , B Jaison , J.T Anita Rose
Published: March 2018

Targeting to handle the explosive growth of mobile media streaming, the emerging fifth‐generation systems need to manage control plane and data plane appropriately. The control plane is used for node association in the heterogeneous cellular network and data plane for media streaming with heterogeneous user equipment. To satisfy the aforementioned requirements, we proposed a solution to alter the control plane and data plane by systematic usage of in‐network resource available in wireless edge (eg, macro, pico, and femto) small base stations (SBSs) for the deployment of smart association policies and media processing technique that improve the efficiency in fifth‐generation wireless networks. On the other hand, due to the broadcast nature of wireless medium, we introduce the media processing agent (MPA) that would reside in SBSs to process the media on the fly and then deliver streams adaptively to the participants. MPA can identify the presenter among the participant to create the server channel with media server and the observer can service from MPA itself. To better exploit the participant's node association with the nearby SBSs, association policies are enhanced with concerns on dynamic association with SBSs. In addition, we describe a heuristic algorithm that provides significant performance gains compared with the existing centralized processing schemes. Numerical results are presented with realistic parameters for the media processing speed, and the quality of delivery demonstrate up to 20% reduction in central processing unit usage over existing (centralized) media processing schemes.
Experimental comparisons in façade fire testing considering SP Fire 105 and the BS 8414‐1
Authors: Anderson J. , Boström L. , Jansson McNamee R. , Milovanović B.
Published: March 2018

A comparison between full‐scale façade fire tests where SP Fire 105 and BS 8414‐1 were used regarding repeatability and the use of modeling to discern changes in the setups is presented. Two test series according to BS 8414‐1 were repeated outside using the same façade systems on 2 different days, whereas for the SP Fire 105 a set of common façade systems in Sweden were tested indoors. In particular, the results show that the wind around the test setup may have a significant impact on the tests and that the heat exposure to the façade surface will depend on the thickness of the test specimen where an increased temperature in front of the façade, and a decreased temperature on the façade 2.1 m above the fire room, is observed experimentally. The heat exposure to the test specimen varies to a more limited extent when an uncontrollable free burning fire source is used (in this study heptane and wood, respectively) and that this variation increases when wind is present.
Foliar application of macro‐ and micronutrients for pest‐mites control in citrus crops
Authors: Chávez‐Dulanto Perla N. , Rey Benjamín , Ubillús Carlos , Rázuri Vicente , Bazán Rubén , Sarmiento Jorge
Published: March 2018

Panonychus citri McGregor (“Citrus red mite”) and Phyllocoptruta oleivora Ashmead (“Citrus rust mite”) are key pests of citrus crops in the Chancay valley, Peru, causing dramatical losses in yield and fruit quality. These pest‐mites affect food security in the area, where the small farming prevails, as the citrus crop is the main generating income source for most of households. Small farmers fight against these pest‐mites by spraying nutritional elements on leaves, as it is cheaper and less harmful than using a chemical miticide. Thus, the aim of this work was determining the influence of the foliar application of elements currently used by farmers (Calcium, Magnesium, Zinc, Copper, Iron, Manganese, and Boron) and a mix of all of them at two dosage levels on the population dynamic of these two key citrus pests on tangerine cv. Clemenules, along a whole crop season in the Chancay Valley. Panonychus citri was detected on leaves during the whole crop cycle, while Phyllocoptruta oleivora was visible during the third leaf and bloom shooting period. There were not statistical differences between dosages, but statistical differences were observed between treatments and the control, the latter registering the highest population level of both mites during the whole crop cycle. Application of Cu, Mn, Mg, and Zn did show the lowest P. citri population rates, while Fe, Mix, Cu, Mg, and Zn did show the lowest population levels of P. oleivora. The foliage analysis revealed that the nutritional content of leaves of tangerine trees under study during the crop cycle was mostly at optimal levels, according to the standards for the crop. These results support the current practice of farmers and confirm that the foliar application of microelements represents a potential pesticide alternative method for management/control of citrus mites, lowering production costs, avoiding excessive pesticide applications, and increasing yield and fruit quality.
On modeling of MPS‐based multiphase fluid flow with low density ratios
Authors: Pahar Gourabananda , Dhar Anirban
Published: March 2018

A divergence‐free moving particle semi‐implicit framework has been formulated for modeling of multiple miscible fluids having small density ratios (≤ 1.10) in the presence of free surface. A density‐weighted pressure gradient along with a hybrid free‐surface treatment is specifically adopted to incorporate the effect of marginal density difference through a higher‐order kernel. The hybrid free‐surface treatment reduces error in velocity divergence and resulting spurious velocity fluctuation in the vicinity of free surface for low‐velocity system. Scalar transport equation is resolved to update density associated with the particles at every time step. A total of 9 cases of lock‐exchange flow with different lock positions and density ratios have been utilized to validate the proposed framework. The model performs satisfactorily irrespective of lock positions and low density variations (3%‐9%).
The effect of settlement rules on the incentive to Bang the Close
Authors: Onur Esen , Reiffen David
Published: March 2018

Closing prices on financial exchanges are often used as reference prices in other contracts. As such, the robustness of the process determining closing prices is an important feature of exchanges. This paper examines whether the 2012 change in the Chicago Board of Trade's (CBT) closing price procedure made reference prices more robust, especially regarding potential manipulation. We propose a theoretical model exploring incentives to manipulate reference prices under two alternative closing price regimes. We test several predictions of the model using a proprietary data set comprised of individual transactions in CBT corn futures, and find empirical support for these predictions.
A Late Medieval motte‐and‐bailey settlement in a lowland river valley landscape of Central Poland
Authors: Kittel Piotr , Sikora Jerzy , Wroniecki Piotr
Published: March 2018

The Rozprza motte‐and‐bailey residence in Central Poland was inhabited from the third decade of the 14th century up to the 15th century A.D. and functioned as a seat of a noble family. It was situated in the place occupied previously by an Early Medieval open settlement and a later ring‐fort. The motte was constructed on the river terrace remnant adjoining a strongly expanding flood plain in the central part of the mid‐Luciąża River valley. The immediate surroundings of the stronghold were studied by means of archaeological excavations, detailed geological mapping (hand‐auger transects and trenching), and large‐scale aerial photography, as well as geochemical and geophysical (magnetic gradiometry and soil electrical resistance) prospection. All the results have been integrated within a GIS and supported by a set of 14C dates that allow for a detailed geomorphological reconstruction of the stronghold situation, including former river patterns, the local flood plain development, and the history of the Medieval fortress site with its moats. Our research provides insights into the late Holocene evolution of a small river valley and confirms the favorable conditions for the location of the motte on a terrace remnant protected by the system of moats and surrounding paleochannels and swampy areas within the valley floor.
APOE influences working memory in non‐demented elderly through an interaction with SPON1 rs2618516
Authors: Liu Zhen , Dai Xiangwei , Tao Wuhai , Liu Huilan , Li He , Yang Caishui , Zhang Junying , Li Xin , Chen Yaojing , Ma Chao , Pei Jing , Mao Haohao , Chen Kewei , Zhang Zhanjun
Published: March 2018

Exploring how risk genes cumulatively impair brain function in preclinical phase (i.e., in cognitively normal elderly) could provide critical insights into the pathophysiology of Alzheimer's disease (AD). Working memory impairment has always been a considerable cognitive deficit in AD, which is likely under complex genetic control. Though, the APOE ɛ4 allele could damage the working memory performance in normal elderly, dissociable results have been reported. This allele may exert specific effects in contexts with other genetic variants. The rs2618516 in the spondin 1 gene (SPON1) has been associated with AD risk and brain structure in the elderly. SPON1 may interact with APOE through processing the amyloid precursor protein and suppressing amyloid‐β levels. Using neuropsychological tasks from 710 individuals, we found significant SPON1 × APOE genotype interactions in working memory and executive function performances. Moreover, such interaction was also found in regional brain activations based on functional magnetic resonance imaging data with the n‐back working memory task performed in a sub‐cohort of 64 subjects. The effects of ɛ4 allele on activation of right inferior frontal gyrus, triangular part (IFGtriang.R) were modulated by rs2618516 in a working memory task. Furthermore, lower IFGtriang.R activation was associated with better cognitive functions. Moreover, the IFGtriang.R activation could mediate the impacts of SPON1 × APOE interactions on working memory performance. These findings suggested the importance of weighing APOE effects on brain activation under the working memory task within the context of the SPON1 genotype.
Physicians, sick leave certificates, and patients' subsequent employment outcomes
Authors: Ahammer Alexander
Published: March 2018

I analyze how general practitioners (GPs) indirectly affect their patients' employment outcomes by deciding the length of sick leaves. I use an instrumental variables framework where spell durations are identified through supply‐side certification measures. I find that a day of sick leave certified only because the worker's GP has a high propensity to certify sick leaves decreases the employment probability persistently by 0.45–0.69 percentage points, but increases the risk of becoming unemployed by 0.28–0.44 percentage points. These effects are mostly driven by workers with low job tenure. Several robustness checks show that endogenous matching between patients and GPs does not impair identification. My results bear important implications for doctors: Whenever medically justifiable, certifying shorter sick leaves to protect the employment status of the patient may be beneficial.
Bocca's hemipharyngo‐total laryngectomy for hypopharyngeal carcinoma to avoid reconstruction with a pedicled flap
Authors: Lucioni Marco , Lionello Marco , Salis Gianni , Bertolin Andy , Rizzotto Giuseppe
Published: March 2018

Background

Major pharyngeal defects after total pharyngolaryngectomy for hypopharyngeal squamous cell carcinoma (SCC) frequently demand reconstruction strategies that include myocutaneous pedicled flaps, such as the pectoralis major flap.

Methods

We retrospectively reviewed the clinical charts of 24 patients with hypopharyngeal SCC treated with Bocca's hemipharyngo‐total laryngectomy (HPTL) at our Institution.

Results

Eighteen patients (80%) experienced no disease recurrence after primary surgery and were alive with no evidence of disease after a mean follow‐up of 43 months. The 2‐year overall survival (OS) and disease‐specific survival (DSS) rates in our sample were 69% and 82%, respectively.

Conclusion

Bocca's HPTL enables an immediate neopharyngeal reconstruction, and is indicated in selected patients with intermediate to advanced hypopharyngeal tumors.
Poly ADP‐ribose polymerase‐1 as a potential therapeutic target in Merkel cell carcinoma
Authors: Ferrarotto Renata , Cardnell Robert , Su Shirley , Diao Lixia , Eterovic A. Karina , Prieto Victor , Morrisson William H. , Wang Jing , Kies Merrill S. , Glisson Bonnie S. , Byers Lauren Averett , Bell Diana
Published: March 2018

Background

Patients with metastatic Merkel cell carcinoma are treated similarly to small cell lung cancer (SCLC). Poly ADP‐ribose polymerase‐1 (PARP1) is overexpressed in SCLC and response to PARP inhibitors have been reported in patients with SCLC. Our study explores PARP as a therapeutic target in Merkel cell carcinoma.

Methods

We evaluated PARP1 expression and Merkel cell polyomavirus (MCPyV) in 19 patients with Merkel cell carcinoma. Target exome‐sequencing was performed in 14 samples. Sensitivity to olaparib was tested in 4 Merkel cell carcinoma cell lines.

Results

Most Merkel cell carcinomas (74%) express PARP1 at high levels. Mutations in DNA‐damage repair genes were identified in 9 samples (64%), occurred exclusively in head neck primaries, and correlated with TP53/RB1 mutations. The TP53/RB1 mutations were more frequent in MCPyV‐negative tumors. Sensitivity to olaparib was seen in the Merkel cell carcinoma line with highest PARP1 expression.

Conclusion

Based on PARP1 overexpression, DNA‐damage repair gene mutations, platinum sensitivity, and activity of olaparib in a Merkel cell carcinoma line, clinical trials with PARP inhibitors are warranted in Merkel cell carcinoma.
Myoepithelial carcinoma of the nasopharynx: Rare case report with clinicopathologic and immunohistochemical features review of literature
Authors: Chen Linyan , Fu Yiyun , Wang Haiyang , Yang Fuyao , Liu Jun , Xia Fan , Ma Xuelei
Published: March 2018

Background

Myoepithelial carcinoma is a rare salivary carcinoma, which most often arises from the major salivary glands. Only a few cases of myoepithelial carcinoma of the nasopharynx have been reported, thus, the treatment guideline and prognosis remain undefined.

Methods

We reported a case of nasopharyngeal myoepithelial carcinoma in a 31‐year‐old man. The tumor cells showed specific cell types and arrangements histologically, which were immunoreactive with myoepithelial markers. The patient received surgical excision with transpalatal approach. A literature review of previous cases was also presented.

Results

The patient reflected residual tumor 4 weeks later. After concurrent chemoradiotherapy (CRT), the tumor reduced and remained stable without signs of progression.

Conclusion

The nasopharyngeal mass with spindled, plasmacytoid, epithelioid, and clear cell types, was suggested to raise the suspicion of myoepithelial carcinoma in order to diagnose and treat early. The wide surgical excision followed by optimal adjuvant therapy might offer a mode of treatment with better survival results.
BRAFwild papillary thyroid carcinoma has two distinct mRNA expression patterns with different clinical behaviors
Authors: Kim Hyeung Kyoo , Lee Inhwa , Lee Jeonghun , Chang Hang‐Seok , Soh Euy Young , Park Il Seok , Kim Jin Hwan , Rho Young Soo , Lee Dong Jin
Published: March 2018

Background

Using a large set of genomic data from The Cancer Genome Atlas (TCGA), we classified BRAFwild papillary thyroid carcinomas (PTCs) into 2 subtypes with distinct molecular patterns and different clinical behaviors. We also suggested gene signatures (RAS‐score) to predict molecular subtypes and clinical behaviors of BRAFwild PTC.

Method

Integrated genomic analysis was done using all genomic data of PTC in TCGA data portal (https://tcga‐data.nci.nih.gov) and cancer browser (https://genome‐cancer.ucsc.edu). Using Gene Ontology and a logistic regression test, we selected gene signatures (RAS‐score) and applied this prediction model to the validation cohort (GSE60542).

Result

When we performed multiplatform genomic analysis, BRAFwild PTCs were divided into 2 molecular subtypes. Each subtype showed distinct molecular patterns and clinical behaviors. Gene signatures successfully predicted molecular subtype in another validation cohort.

Conclusion

We found that BRAFwild PTCs were divided into 2 molecular subtypes and each subtype showed distinct molecular patterns, different activated pathways, and different clinical behaviors.
Na+‐taurocholate cotransporting polypeptide inhibition has hepatoprotective effects in cholestasis in mice
Authors: Slijepcevic Davor , Roscam Abbing Reinout L.P. , Fuchs Claudia D. , Haazen Lizette C.M. , Beuers Ulrich , Trauner Michael , Oude Elferink Ronald P.J. , van de Graaf Stan F.J.
Published: March 2018

Accumulation of bile salts (BSs) during cholestasis leads to hepatic and biliary injury, driving inflammatory and fibrotic processes. The Na+‐Taurocholate Cotransporting Polypeptide (NTCP) is the major hepatic uptake transporter of BSs, and can be specifically inhibited by myrcludex B. We hypothesized that inhibition of NTCP dampens cholestatic liver injury. Acute cholestasis was induced in mice by a 3.5‐diethoxycarbonyl‐1.4‐dihydrocollidine (DDC) diet or by bile duct ligation (BDL). Chronic cholestasis was investigated in Atp8b1‐G308V and Abcb4/Mdr2 deficient mice. Mice were injected daily with myrcludex B or vehicle. Myrcludex B reduced plasma alkaline phosphatase (ALP) levels in DDC‐fed, Atp8b1‐G308V and BDL mice by 39%, 27% and 48% respectively. Expression of genes involved in fibrosis, proliferation and inflammation was reduced by myrcludex B treatment in DDC‐fed and Atp8b1‐G308V mice. NTCP‐inhibition increased plasma BS levels from 604±277 to 1746±719 μm in DDC‐fed mice, 432±280 to 762±288 μm in Atp8b1‐G308V mice and from 522±130 to 3625±378 μm in BDL mice. NTCP‐inhibition strongly aggravated weight loss in BDL mice, but not in other cholestatic models studied. NTCP‐inhibition reduced biliary BS output in DDC‐fed and Atp8b1‐G308V mice by ∼50% while phospholipid (PL) output was maintained, resulting in a higher PL/BS ratio. Conversely, liver injury in Abcb4 deficient mice, lacking biliary phospholipid output, was aggravated after myrcludex B treatment. Conclusion: NTCP‐inhibition by myrcludex B has hepatoprotective effects, by reducing BS load in hepatocytes and increasing the biliary PL/BS ratio. High micromolar plasma BS levels after NTCP‐inhibition were well tolerated. NTCP‐inhibition may be beneficial in selected forms of cholestasis. (Hepatology 2018).
Ubiquitin‐Specific Protease 4 Is an Endogenous Negative Regulator of Metabolic Dysfunctions in Nonalcoholic Fatty Liver Disease in Mice
Authors: Zhao Yichao , Wang Fang , Gao Lingchen , Xu Longwei , Tong Renyang , Lin Nan , Su Yuanyuan , Yan Yang , Gao Yu , He Jie , Kong Lingcong , Yuan Ancai , Zhuge Ying , Pu Jun
Published: March 2018

Nonalcoholic fatty liver disease (NAFLD), characterized by hepatic steatosis (HS), insulin resistance (IR), and inflammation, poses a high risk of cardiometabolic disorders. Ubiquitin specific protease 4 (USP4), a deubiquitinating enzyme, is pivotally involved in regulating multiple inflammatory pathways; however, the role of USP4 in NAFLD is unknown. Here, we report that USP4 expression was dramatically down‐regulated in livers from NAFLD patients and different NAFLD mouse models induced by high‐fat diet (HFD) or genetic deficiency (ob/ob) as well as in palmitate‐treated hepatocytes. Hepatocyte‐specific USP4 depletion exacerbated HS, IR, and inflammatory response in HFD‐induced NAFLD mice. Conversely, hepatic USP4 overexpression notably alleviated the pathological alterations in two different NAFLD models. Mechanistically, hepatocyte USP4 directly bound to and deubiquitinated transforming growth factor‐β activated kinase 1 (TAK1), leading to a suppression of the activation of downstream nuclear factor kappa B (NF‐κB) and c‐Jun N‐terminal kinase (JNK) cascades, which, in turn, reversed the disruption of insulin receptor substrate/protein kinase B/glycogen synthase kinase 3 beta (IRS‐AKT‐GSK3β) signaling. In addition, USP4‐TAK1 interaction and subsequent TAK1 deubiquitination were required for amelioration of metabolic dysfunctions. Conclusion: Collectively, the present study provides evidence that USP4 functions as a pivotal suppressor in NAFLD and related metabolic disorders. (Hepatology 2018; 00:000‐000).
PRDM8 exhibits antitumor activities toward hepatocellular carcinoma by targeting NAP1L1
Authors: Chen Zhiqiang , Gao Wen , Pu Liyong , Zhang Long , Han Guoyong , Zuo Xueliang , Zhang Yao , Li Xiangcheng , Shen Hongbing , Wu Jindao , Wang Xuehao
Published: March 2018

Hepatocellular carcinoma (HCC) is a major leading cause of cancer mortality worldwide. PRDI‐BF1 and RIZ homology domain containing 8 (PRDM8) is a key regulator in neural development and testis steroidogenesis; however, its role in liver carcinogenesis remains to be investigated. In this study, PRDM8 was found to be down‐regulated in HCC, which was linked with shorter recurrence‐free survival. Lentiviral‐based overexpression and knockdown approaches showed that PRDM8 inhibited HCC cell proliferation, migration, and invasion. PRDM8 caused G1/S cell cycle arrest and induced apoptosis. An in vivo tumor model confirmed the antitumor role of PRDM8 in HCC growth and metastasis. Mechanistic study showed that PRDM8 suppressed the PI3K/AKT/mTOR signaling cascade through the regulation of nucleosome assembly protein 1‐like 1 (NAP1L1). Conclusion: PRDM8 as a functional tumor suppressor is frequently down‐regulated in HCC. Through regulating NAP1L1, PRDM8 inhibits PI3K/AKT/mTOR signaling in HCC. PRDM8 is a potential target for therapies of HCC. (Hepatology 2018).
Acute hepatitis B virus infection in humanized chimeric mice has multiphasic viral kinetics
Authors: Ishida Yuji , Chung Tje Lin , Imamura Michio , Hiraga Nobuhiko , Sen Suranjana , Yokomichi Hiroshi , Tateno Chise , Canini Laetitia , Perelson Alan S. , Uprichard Susan L. , Dahari Harel , Chayama Kazuaki
Published: March 2018

Chimeric urokinase type plasminogen activator (uPA)/severely severe combined immunodeficiency (SCID) mice reconstituted with humanized livers are useful for studying hepatitis B virus (HBV) infection in the absence of an adaptive immune response. However, the detailed characterization of HBV infection kinetics necessary to enable in‐depth mechanistic studies in this in vivo HBV infection model is lacking. To characterize HBV kinetics post‐inoculation (p.i.) to steady state, 42 mice were inoculated with HBV. Serum HBV DNA was frequently measured from 1 minute to 63 days p.i. Total intrahepatic HBV DNA, HBV covalently closed circular DNA (cccDNA), and HBV RNA was measured in a subset of mice at 2, 4, 6, 10, and 13 weeks p.i. HBV half‐life (t1/2) was estimated using a linear mixed‐effects model. During the first 6 hours p.i., serum HBV declined in repopulated uPA/SCID mice with a t1/2 = 62 minutes (95% confidence interval [CI] = 59‐67). Thereafter, viral decline slowed followed by a 2‐day lower plateau. Subsequent viral amplification was multiphasic with an initial mean doubling time of t2 = 8 ± 3 hours followed by an interim plateau before prolonged amplification (t2 = 2 ± 0.5 days) to a final HBV steady state of 9.3 ± 0.3 log copies (cps)/mL. Serum HBV and intrahepatic HBV DNA were positively correlated (R2 = 0.98). Conclusion: HBV infection in uPA/SCID chimeric mice is highly dynamic despite the absence of an adaptive immune response. Serum HBV t1/2 in humanized uPA/SCID mice was estimated to be ∼1 hour regardless of inoculum size. The HBV acute infection kinetics presented here is an important step in characterizing this experimental model system so that it can be effectively used to elucidate the dynamics of the HBV life cycle and thus possibly reveal effective antiviral drug targets. (Hepatology 2018).
Link between gut‐microbiome derived metabolite and shared gene‐effects with hepatic steatosis and fibrosis in NAFLD
Authors: Caussy Cyrielle , Hsu Cynthia , Lo Min‐Tzu , Liu Amy , Bettencourt Ricki , Ajmera Veeral H. , Bassirian Shirin , Hooker Jonathan , Sy Ethan , Richards Lisa , Schork Nicholas , Schnabl Bernd , Brenner David A. , Sirlin Claude B. , Chen Chi‐Hua , Loomba Rohit ,   Genetics of NAFLD in Twins Consortium
Published: March 2018

Previous studies have shown that gut‐microbiome is associated with nonalcoholic fatty liver disease (NAFLD). We aimed to examine if serum metabolites, especially those derived from the gut‐microbiome, have a shared gene‐effect with hepatic steatosis and fibrosis. This is a cross‐sectional analysis of a prospective discovery cohort including 156 well‐characterized twins and families with untargeted metabolome profiling assessment. Hepatic steatosis was assessed using magnetic‐resonance‐imaging proton‐density‐fat‐fraction (MRI‐PDFF) and fibrosis using MR‐elastography (MRE). A twin additive genetics and unique environment effects (AE) model was used to estimate the shared gene‐effect between metabolites and hepatic steatosis and fibrosis. The findings were validated in an independent prospective validation cohort of 156 participants with biopsy‐proven NAFLD including shotgun metagenomics sequencing assessment in a subgroup of the cohort. In the discovery cohort, 56 metabolites including 6 microbial metabolites had a significant shared gene‐effect with both hepatic steatosis and fibrosis after adjustment for age, sex and ethnicity. In the validation cohort, 6 metabolites were associated with advanced fibrosis. Among them, only one microbial metabolite, 3‐(4‐hydroxyphenyl)lactate, remained consistent and statistically significantly associated with liver fibrosis in the discovery and validation cohort (fold‐change of higher‐MRE versus lower‐MRE: 1.78, P < 0.001 and of advanced versus no advanced fibrosis: 1.26, P = 0.037, respectively). The share genetic determination of 3‐(4‐hydroxyphenyl)lactate with hepatic steatosis was RG:0.57,95%CI:0.27‐0.80, P < 0.001 and with fibrosis was RG:0.54,95%CI:0.036‐1, P = 0.036. Pathway reconstruction linked 3‐(4‐hydroxyphenyl)lactate to several human gut‐microbiome species. In the validation cohort, 3‐(4‐hydroxyphenyl)lactate was significantly correlated with the abundance of several gut‐microbiome species, belonging only to Firmicutes, Bacteroidetes and Proteobacteria phyla, previously reported as associated with advanced fibrosis. Conclusion: This proof of concept study provides evidence of a link between the gut‐microbiome and 3‐(4‐hydroxyphenyl)lactate that shares gene‐effect with hepatic steatosis and fibrosis. (Hepatology 2018).
Nicotinamide adenine dinucleotide phosphate (reduced) oxidase 2 modulates inflammatory vigor during nonalcoholic fatty liver disease progression in mice
Authors: Mukherjee Rajib , Moreno‐Fernandez Maria E. , Giles Daniel A. , Cappelletti Monica , Stankiewicz Traci E. , Chan Calvin C. , Divanovic Senad
Published: March 2018

Nonalcoholic fatty liver disease (NAFLD) represents a disease spectrum ranging from benign steatosis to life‐threatening cirrhosis and hepatocellular carcinoma. Elevated levels of reactive oxygen species (ROS) and exacerbated inflammatory responses have been implicated in NAFLD progression. Nicotinamide adenine dinucleotide phosphate (reduced) oxidase 2 (NOX2; also known as gp91Phox), the main catalytic subunit of the nicotinamide adenine dinucleotide phosphate (reduced) oxidase complex, modulates ROS production, immune responsiveness, and pathogenesis of obesity‐associated metabolic derangements. However, the role of NOX2 in the regulation of immune cell function and inflammatory vigor in NAFLD remains underdefined. Here, we demonstrate that obesogenic diet feeding promoted ROS production by bone marrow, white adipose tissue, and liver immune cells. Genetic ablation of NOX2 impeded immune cell ROS synthesis and was sufficient to uncouple obesity from glucose dysmetabolism and NAFLD pathogenesis. Protection from hepatocellular damage in NOX2‐deficient mice correlated with reduced hepatic neutrophil, macrophage, and T‐cell infiltration, diminished production of key NAFLD‐driving proinflammatory cytokines, and an inherent reduction in T‐cell polarization toward Th17 phenotype. Conclusion: Current findings demonstrate a crucial role of the NOX2–ROS axis in immune cell effector function and polarization and consequent NAFLD progression in obesity. Pharmacologic targeting of NOX2 function in immune cells may represent a viable approach for reducing morbidity of obesity‐associated NAFLD pathogenesis. (Hepatology Communications 2018;2:546‐560)
NI‐0801, an anti‐chemokine (C‐X‐C motif) ligand 10 antibody, in patients with primary biliary cholangitis and an incomplete response to ursodeoxycholic acid
Authors: de Graaf Kathy L. , Lapeyre Geneviève , Guilhot Florence , Ferlin Walter , Curbishley Stuart M. , Carbone Marco , Richardson Paul , Moreea Sulleman , McCune C. Anne , Ryder Stephen D. , Chapman Roger W. , Floreani Annarosa , Jones David E. , de Min Cristina , Adams David H. , Invernizzi Pietro
Published: March 2018

NI‐0801 is a fully human monoclonal antibody against chemokine (C‐X‐C motif) ligand 10 (CXCL10), which is involved in the recruitment of inflammatory T cells into the liver. The safety and efficacy of NI‐0801 was assessed in patients with primary biliary cholangitis. In this open‐label phase 2a study, patients with primary biliary cholangitis with an inadequate response to ursodeoxycholic acid received six consecutive intravenous administrations of NI‐0801 (10 mg/kg) every 2 weeks. Patients were followed up for 3 months after the last infusion. Liver function tests, safety assessments, as well as pharmacokinetic and pharmacodynamic parameters were evaluated at different time points throughout the dosing period and the safety follow‐up period. Twenty‐nine patients were enrolled in the study and were treated with NI‐0801. The most frequently reported adverse events included headaches (52%), pruritus (34%), fatigue (24%), and diarrhea (21%). No study drug‐related serious adverse events were reported. NI‐0801 administration did not lead to a significant reduction in any of the liver function tests assessed at the end of the treatment period (i.e., 2 weeks after final NI‐0801 administration) compared to baseline. Conclusion: Despite clear pharmacologic responses in the blood, no therapeutic benefit of multiple administrations of NI‐0801 could be demonstrated. The high production rate of CXCL10 makes it difficult to achieve drug levels that lead to sustained neutralization of the chemokine, thus limiting its targetability. (Hepatology Communications 2018;2:492‐503)
Coding variants in PNPLA3 and TM6SF2 are risk factors for hepatic steatosis and elevated serum alanine aminotransferases caused by a glucagon receptor antagonist
Authors: Guzman Cristina B. , Duvvuru Suman , Akkari Anthony , Bhatnagar Pallav , Battioui Chakib , Foster Wendra , Zhang Xiaotian Michelle , Shankar Sudha S. , Deeg Mark A. , Chalasani Naga , Hardy Thomas A. , Kazda Christof M. , Pillai Sreekumar G.
Published: March 2018

LY2409021 is a glucagon receptor antagonist that was associated with hepatic steatosis and elevated aminotransferases in phase 2 diabetes studies. We investigated the relationship between selected genetic variants and hepatic steatosis and elevated alanine aminotransferases (ALTs) associated with LY2409021. Patients participated in a 6‐week placebo‐controlled trial (I1R‐MC‐GLDI [GLDI], n = 246) and a 52‐week placebo‐ and active comparator‐controlled trial (I1R‐MC‐GLDJ [GLDJ], n = 158). GLDJ had endpoints at 6 months, including measures of hepatic fat fraction (HFF) by magnetic resonance imaging. The five genes tested were patatin‐like phospholipase domain containing 3 (PNPLA3) (rs738409 and rs738491), transmembrane 6 superfamily member 2 (TM6SF2) (rs58542926), peroxisome proliferative activated receptor gamma coactivator 1 alpha (PPARGC1A) (rs4361373, rs3774921, rs2970849), adenylate cyclase 3 (ADCY3) (rs713586), and insulin‐like growth factor 1 (IGF‐1) (rs1520220). In GLDI, PNPLA3 I148M (P = 0.001) and TM6SF2 E167K (P = 0.001) were significantly associated with an increase in ALT at 6 weeks for LY2409021 but not for placebo. In GLDJ, PNPLA3 I148M showed the same effect (P = 0.007) on ALT at 6 months but the placebo or sitagliptin did not. In GLDJ, both PNPLA3 and TM6SF2 risk‐allele carriers showed increases in HFF that were numerically greater but not statistically significant. The carriers of PNPLA3 and/or TM6SF2 risk alleles showed significantly increased ALT (GLDI, +13.28 U/L in carriers versus +4.84 U/L in noncarriers, P = 4 × 10–5; GLDJ, +14.6 U/L in carriers versus +1.7 in noncarriers, P = 0.0018) and HFF (GLDJ, +5.35% in carriers versus 2.38% in noncarriers, P = 0.048). Elevation of transaminase and HFF were also noted in the noncarriers but at a significantly lower degree. Conclusion: The carriers of PNPLA3 and/or TM6SF2 variant alleles are at risk for hepatic steatosis and elevated ALT levels caused by LY2409021, a glucagon receptor antagonist. More studies are needed to investigate if our observations are generalizable to hepatic steatosis caused by other medications. (Hepatology Communications 2018;2:561‐570)
A real‐world observational cohort of patients with primary biliary cholangitis: TARGET‐primary biliary cholangitis study design and rationale
Authors: Levy Cynthia , Bowlus Christopher L. , Carey Elizabeth , Crawford Julie M. , Deane Karen , Mayo Marlyn J. , Kim W. Ray , Fried Michael W.
Published: March 2018

Primary biliary cholangitis (PBC) is a rare chronic cholestatic liver disease that may progress to biliary cirrhosis if left untreated. The first‐line therapy for PBC is ursodeoxycholic acid (UDCA). Unfortunately, 1 of 3 patients does not respond to UDCA. These patients are at risk for developing clinical events, including cirrhosis, complications of portal hypertension, hepatocellular carcinoma, liver transplant, or death. Recently, the U.S. Food and Drug Administration approved obeticholic acid to be used in certain patients with PBC. Off‐label therapies are also used, and several other therapies are currently under evaluation. Real‐world effectiveness of newly approved and off‐label therapies remains unknown. TARGET‐PBC is a 5‐year, longitudinal, observational study of patients with PBC that will evaluate the effectiveness of clinical practice interventions and provide practical information unobtainable in registration trials. Enrollment will take place at both academic and community sites. In addition to consenting to medical records review, participants will be asked to provide an annual blood sample and complete patient reported outcome surveys at predetermined intervals. Any available liver biopsies will be digitally preserved. Conclusion: Key study outcomes will be the evaluation of the safety and effectiveness of PBC interventions and the assessment of disease progression under real‐world conditions. (Hepatology Communications 2018;2:484‐491)
Translating the impact of knowledge management into knowledge‐based innovation: The neglected and mediating role of knowledge‐worker satisfaction
Authors: Shujahat Muhammad , Ali Bakhtiar , Nawaz Faisal , Durst Susanne , Kianto Aino
Published: March 2018

The purpose of knowledge management is innovation. However, this study proposes that the existence of knowledge management in the knowledge‐worker's work environment can nurture the overall satisfaction of knowledge worker. As the ultimate purpose of knowledge management is innovation performance, therefore, the satisfaction of knowledge worker as an outcome of knowledge management should be greater innovation performance. Consequently, the purpose of this study is to test the mediating role of satisfaction of knowledge worker between knowledge management and innovation. The study collected the data from 306 knowledge workers (engineers and managers) of software houses from Pakistan. The SmartPLS 3 Version 2.7 software that uses the PLS‐SEM (Partial Least Square‐Structural Equation Modelling) technique was used. The results indicate that satisfaction of knowledge worker mediates between two knowledge management processes (knowledge creation and knowledge sharing) and innovation significantly. However, it does not mediate between knowledge utilization and innovation significantly.
Development of novel monoclonal antibodies to dog leukocyte antigen DR displaying direct and immune‐mediated cytotoxicity toward canine lymphoma cell lines
Authors: Lisowska Marta , Pawlak Aleksandra , Kutkowska Justyna , Hildebrand Wojciech , Ugorski Maciej , Rapak Andrzej , Miazek Arkadiusz
Published: March 2018

Spontaneous canine lymphoma (CL) has become a promising, nonrodent model for advancing the therapeutic strategies of human hematological malignancies. As new resources for veterinary and comparative studies on CL‐associated antigens, we developed 2 novel mouse monoclonal antibodies, denoted B5 and E11, that recognized the canine major histocompatibility Class II DR antigens (dog leukocyte antigen DR). Using flow cytometry and solid phase immunoenzymatic assays, we showed that the antigens recognized by B5 and E11 were strongly expressed in several CL cell lines and the ex vivo canine neoplastic cells of B and mixed B/T immunophenotypes. Additionally, we evaluated a minimal cross‐reactivity of B5 and E11 with the human B‐cell line, Raji. By the ectopic expression of the hybrid murine/canine I‐E/DR dimers in the HEK293 cells, we demonstrated that the epitope of B5 was localized to the invariant DRα chain, whereas the epitope of E11 was collectively formed by the DRα and DRβ chains. Both epitopes were conformational and conserved in all the tested unrelated individuals of different dog breeds. In vitro treatment of 2 CL B‐cell lines (CLBL1 and CLB70) with B5 and E11 rapidly induced a direct apoptotic cell death. Similarily, both mouse monoclonal antibodies efficiently killed the above cell lines through the mechanisms of complement‐dependent and antibody‐mediated cellular phagocytosis. Collectively, our data support the further development of B5 and E11 as novel tools for dog leukocyte antigen DR‐targeted, preclinical trials involving CL.
Surviving neoliberalism, maintaining values: Community health mergers in Victoria, Australia
Authors: Roussy Véronique , Livingstone Charles
Published: March 2018

Purpose

Independent, not‐for‐profit community health services in the state of Victoria, Australia, provide one of that country's few models of comprehensive primary health care (PHC). Recent amalgamations among some such agencies created regional‐sized community health organisations, in a departure from this sector's traditionally small local structure. This study explored the motivations, desired outcomes, and decision‐making process behind these mergers.

Methodology

Qualitative exploratory study was based on 26 semistructured interviews with key informants associated with 2 community health mergers, which took place in 2014 in Victoria, Australia. Thematic data analysis was influenced by concepts derived from institutional theory.

Findings

Becoming bigger by merging was viewed as the best way to respond to mounting external pressures, such as increasingly neoliberal funding mechanisms, perceived as threatening survival. Desired outcomes were driven by comprehensive PHC values, and related to creating organisational capacity to continue providing quality services to disadvantaged communities.

Originality/value

This study offers insights into decision‐making processes geared towards protecting the comprehensiveness of PHC service delivery for disadvantaged communities, ensuring financial viability, and surviving neoliberal economic policy whilst preserving communitarian values. These are relevant to an international audience, within a global context of rising health inequities, increasingly tight fiscal environments, and growing neoliberal influences on health policymaking and funding.
Invisible cobwebs in teamwork—Impediments to the care of patients with heart failure: A qualitative study
Authors: Khoshab Hadi , Nouhi Esmat , Tirgari Batool , Ahmadi Fazlollah
Published: March 2018

Aim

This study was done to explore team member's perception regarding impediments to the care of patients with heart failure (HF).

Background

Complex, chronic HF patients require interprofessional teams to address their multiple health needs. Working in a team has some challenges in achieving goals. Sociocultural differences in Iranian therapeutic team members causes some impediments to provide effective care in the form of a team.

Methods

Data were collected through unstructured in‐depth interviews with 58 team members in caring for the patients with HF. The interviews were transcribed verbatim and analyzed using content analysis.

Results

Twelve subcategories and 5 categories were formed: inefficient supportive network, inadequacy of training and treatment, affectability and variability challenges for the team, arduous working conditions, and heavy physicians shadow on nursing. The final theme emerged as “Invisible cobwebs in teamwork.”

Conclusion

Despite teamwork being an efficient way of achieving goals, several impediments like a cobweb hinder it from becoming fully exploited. Teamwork has a desirable output when all the members feel the same sense of authority and see themselves in an integrated team and managers have a crucial role in removing these impediments.
An application of work engagement in the job demands–resources model to career development: Assessing gender differences
Authors: Lee Yunsoo , Eissenstat SunHee J.
Published: March 2018

The purpose of this study is to investigate the applicability of the job demands–resources (JD‐R) model to work engagement and career development based on the extended conceptual model proposed by Lee, Kwon, Kim, and Cho (2016). This study also aims to examine gender differences within this model. To achieve these goals, this study adopts a multigroup analysis using a sample from the Generations of Talent data set, which is composed of 1,997 employees in 11 countries. The results of the analysis show that career identity and perceived supervisor support are positively associated with work engagement, while work engagement is positively associated with career commitment and career satisfaction across the study's male and female groups. However, the effect of career development opportunities on work engagement is not significant, and there are no gender differences in the structural relationships among research variables. Given these results, this study suggests implications for both researchers and practitioners.