bluuebunny/crossref_metadata_2025 huggingface dataset:
Manipulation of Push–Pull System by Functionalization of Porphyrin at β‐Position for High‐Performance Solution‐Processable Ternary Resistive Memory Devices
Authors: Chan Hing , Lee Sai‐Ho , Poon Chun‐Ting , Ng Maggie , Yam Vivian Wing‐Wah
Published: December 2016

Through tailoring substituents at β‐positions of NiII porphyrin complexes in a push–pull system, multilevel resistive memory devices with high performance have been realized via solution‐processing fabrications. Promising ternary resistive memory behavior has been demonstrated by distinct “OFF”, “ON1” and “ON2” conductivity states with current ratios of 1:104:107, together with low first switching voltage (VTh1=2.1 V), well‐differentiable second threshold voltage (VTh2=3.1 V), low power consumption reading bias (1.0 V) as well as long retention time (>104 seconds), revealing their potential application in the field of ultra high‐density data storage. In contrast to the push–pull system, only a binary logic gate is found in push only or pull only complexes. The present study may provide a new design strategy and inspiration for the development of multistate memory devices through push–pull systems of this type.
Photoinduced Charge Separation Catalyzed by Manganese Oxides onto a Y‐Shaped Branching Acceptor Efficiently Preventing Charge Recombination
Authors: Yamamoto Kentaro , Takatsuka Kazuo
Published: December 2016

A full‐dimensional nonadiabatic electron wavepacket study is performed on Mn oxide catalytic charge separation to be created on an accepting molecular system, which is of Y‐shaped structure and has a track‐branching function for protons and electrons. This branching is necessary in cases in which the transferred electrons and protons are to be eventually carried to mutually different destinations without quick annihilation of the created pair (charge separation). However, as a result of the larger size of such a branched acceptor, the distance between the Mn oxide and the acceptor is so great that it is far from obvious whether an electron is successfully delivered through conical intersections. It is shown here that this can actually occur.
Contribution of Interpersonal Problems to Eating Disorder Psychopathology via Negative Affect in Treatment‐seeking Men and Women: Testing the Validity of the Interpersonal Model in an Understudied Population
Authors: Ivanova Iryna V. , Tasca Giorgio A. , Proulx Geneviève , Bissasda Hany
Published: December 2016

Research on the psychosocial correlates and theoretical frameworks of men presenting with eating disorders (ED) psychopathology is limited. This study compared treatment‐seeking men and women in terms of their levels of interpersonal functioning (affiliation and dominance), regulation of negative emotions (negative affect and instability) and ED psychopathology. The study also investigated the validity of the interpersonal model of ED in men. Results from the cross‐sectional data of 388 participants (137 men and 251 women) demonstrated that the structural models fit and that paths were invariant across men and women. There were significant indirect effects of interpersonal functioning on ED psychopathology, mediated through negative affect and instability, for both men and women. Negative affect and instability partially explain the relationship between interpersonal problems and ED psychopathology in treatment‐seeking men and women. Current findings highlight the need to evaluate the validity of the model using longitudinal designs to test whether men and women are likely to benefit equally from interpersonal therapies for ED. Copyright © 2016 John Wiley & Sons, Ltd.

Key Practitioner Message

Negative affect and instability mediated the relationship between interpersonal problems and eating disorder psychopathology for treatment‐seeking men and women.

There were no gender differences between levels of negative affect, emotional instability and interpersonal dysfunction, but women reported slightly higher eating concerns than men.

Interpersonal model is a framework that is applicable to understanding and potentially treating men with eating disorders.
Safety and efficacy of nonvitamin K antagonist oral anticoagulants versus warfarin in diabetic patients with atrial fibrillation: A study‐level meta‐analysis of phase III randomized trials
Authors: Patti Giuseppe , Di Gioia Giuseppe , Cavallari Ilaria , Nenna Antonio
Published: December 2016

In patients with atrial fibrillation (AF), the safety and efficacy of nonvitamin K antagonist oral anticoagulants (NOACs) vs warfarin according to diabetes mellitus (DM) status are not completely characterized. We performed a meta‐analysis to clarify whether in these patients the strategy of oral anticoagulation should be tailored to diabetes status. In this study‐level meta‐analysis, we included 4 randomized phase III trials comparing NOACs and warfarin in patients with nonvalvular AF; a total of 18 134 patients with DM and 40 454 without DM were overall considered. Incidence of the following outcome measures was evaluated during the follow‐up: stroke or systemic embolism, ischemic stroke, major bleeding, intracranial bleeding, and vascular death. Use of NOACs compared with warfarin reduced stroke/systemic embolism in diabetic (Risk Ratios [RR] 0.80, 95% CI 0.68‐0.93; P = .004) and nondiabetic patients (RR 0.83, 0.73‐0.93; P = .001) (P for interaction .72). No interaction between diabetes status and benefits of NOACs was found for the occurrence of ischemic stroke, major bleeding, or intracranial bleeding (P for interaction >.05 for each comparison). Reduction of vascular death rates with NOACs was significant in diabetic patients (4.97% vs 5.99% with warfarin; RR 0.83, 0.72‐0.96; P = .01), in whom absolute the reduction of this outcome measure was higher than in nondiabetics (1.02% vs 0.27%), although no interaction was present (P = .23). Results of this meta‐analysis support the safety and efficacy of NOACs compared with warfarin in diabetic patients with nonvalvular AF.
Cardiovascular risk factors and incident albuminuria in screen‐detected type 2 diabetes
Authors: Webb D.R. , Zaccardi F. , Davies M.J. , Griffin S.J. , Wareham N.J. , Simmons R.K. , Rutten G.E. , Sandbaek A. , Lauritzen T. , Borch‐Johnsen K. , Khunti K.
Published: December 2016

Background

It is unclear whether cardiovascular risk factor modification influences the development of renal disease in people with type 2 diabetes identified through screening. We determined predictors of albuminuria 5 years after a diagnosis of screen‐detected diabetes within the ADDITION‐Europe study, a pragmatic cardiovascular outcome trial of multifactorial cardiovascular risk management.

Methods

In 1826 participants with newly diagnosed, screen‐detected diabetes without albuminuria, we explored associations between risk of new albuminuria (≥2.5 mg mmol‐1 for males and ≥3.5 mg mmol‐1 for females) and (1) baseline cardio‐metabolic risk factors and (2) changes from baseline to 1 year in systolic blood pressure (ΔSBP) and glycated haemoglobin (ΔHbA1c) using logistic regression.

Results

Albuminuria developed in 268 (15%) participants; baseline body mass index and active smoking were independently associated with new onset albuminuria in 5 years after detection of diabetes. In a model adjusted for age, gender, baseline HbA1c and blood pressure, a 1% decrease in HbA1c and 5‐mm Hg decrease in SBP during the first year were independently associated with lower risks of albuminuria (odds ratio), 95% confidence interval: 0.76, 0.62 to 0.91 and 0.94, 0.88 to 1.01, respectively. Further adjustment did not materially change these estimates. There was no interaction between ΔSBP and ΔHbA1c in relation to albuminuria risk, suggesting likely additive effects on renal microvascular disease.

Conclusions

Baseline measurements and changes in HbA1c and SBP a year after diagnosis of diabetes through screening independently associate with new onset albuminuria 4 years later. Established multifactorial treatment for diabetes applies to cases identified through screening.
Genetic variation in resistance to leaf fungus indirectly affects spider density
Authors: Slinn Heather L. , Barbour Matthew A. , Crawford Kerri M. , Rodriguez‐Cabal Mariano A. , Crutsinger Gregory M.
Published: December 2016

Many host‐plants exhibit genetic variation in resistance to pathogens; however, little is known about the extent to which genetic variation in pathogen resistance influences other members of the host‐plant community, especially arthropods at higher trophic levels. We addressed this knowledge gap by using a common garden experiment to examine whether genotypes of Populus trichocarpa varied in resistance to a leaf‐blistering pathogen, Taphrina sp., and in the density of web‐building spiders, the dominant group of predatory arthropods. In addition, we examined whether variation in spider density was explained by variation in the density and size of leaf blisters caused by Taphrina. We found that P. trichocarpa genotypes exhibited strong differences in their resistance to Taphrina and that P. trichocarpa genotypes that were more susceptible to Taphrina supported more web‐building spiders, the dominant group of predatory arthropods. We suspect that this result is caused by blisters increasing the availability of suitable habitat for predators, and not due to variation in herbivores because including herbivore density as a covariate did not affect our models. Our study highlights a novel pathway by which genetic variation in pathogen resistance may affect higher trophic levels in arthropod communities.
Effects of predation and nutrient enrichment on the success and microbiome of a foundational coral
Authors: Shaver Elizabeth C. , Shantz Andrew A. , McMinds Ryan , Burkepile Deron E. , Vega Thurber Rebecca L. , Silliman Brian R.
Published: December 2016

By inflicting damage to prey tissues, consumer species may increase stress in prey hosts and reduce overall fitness (i.e., primary effects, such as growth or reproduction) or cause secondary effects by affecting prey interactions with other species such as microbes. However, little is known about how abiotic conditions affect the outcomes of these biotic interactions. In coral reef communities, both nutrient enrichment and predation have been linked to reduced fitness and disease facilitation in corals, yet no study to date has tested their combined effects on corals or their associated microbial communities (i.e., microbiomes). Here, we assess the effects of grazing by a prevalent coral predator (the short coral snail, Coralliophila abbreviata) and nutrient enrichment on staghorn coral, Acropora cervicornis, and its microbiomes using a factorial experiment and high‐throughput DNA sequencing. We found that predation, but not nutrients, significantly reduced coral growth and increased mortality, tissue loss, and turf algae colonization. Partial predation and nutrient enrichment both independently altered coral microbiomes such that one bacterial genus came to dominate the microbial community. Nutrient‐enriched corals were associated with significant increases in Rickettsia‐like organisms, which are currently one of several microbial groups being investigated as a disease agent in this coral species. However, we found no effects of nutrient enrichment on coral health, disease, or their predators. This research suggests that in the several months following coral transplantation (i.e., restoration) or disturbance (i.e., recovery), Caribbean acroporid corals appear to be highly susceptible to negative effects caused by predators, but not or not yet susceptible to nutrient enrichment despite changes to their microbial communities.
Ferrocene – 65 Years After
Authors: Okuda Jun
Published: December 2016

Abstract: A brief account of the discovery of ferrocene and a personal view of its significance are presented.
Synthesis and Characterization of a RuPt‐Based Photo‐Hydrogen‐Evolving Molecular Device Tethered to a Single Viologen Acceptor
Authors: Miyaji Masayuki , Kitamoto Kyoji , Ozawa Hironobu , Sakai Ken
Published: December 2016

A dinuclear RuIIPtII complex tethered to a methyl viologen (MV2+) unit {RuPt‐MV2+; [RuII(bpy)2{phen‐bpy(MV2+)}PtIICl2]4+, bpy = 2,2′‐bipyridine, phen = 5‐amino‐1,10‐phenanthroline} has been synthesized to investigate the effect of tethering a single pendant MV2+ acceptor on its photo‐hydrogen‐evolving (PHE) activity. Upon photoirradiation of RuPt‐MV2+ in the presence of EDTA as a sacrificial electron donor, the one‐electron‐reduced species of RuPt‐MV2+ {i.e., [RuII(bpy)2{phen‐bpy(MV+·)}PtIICl2]3+} is generated as a major photoproduct by intramolecular electron transfer (IET) from the 3MLCT excited state of the [RuII(bpy)2(phen)]2+ unit to the MV2+ unit, followed by subsequent reduction of the [RuIII(bpy)2(phen)]3+ unit by EDTA. Although RuPt‐MV2+ shows PHE activity in the presence of EDTA, the estimated turnover number (0.4) is smaller than that for the parent RuIIPtII system, which has no MV2+ tether. The relatively small driving force (0.08 eV) for the IET from the 3MLCT excited state of the [RuII(bpy)2(phen)]2+ unit to the PtIICl2(bpy) unit, which leads to the H2 formation, has been judged to be the major cause of the exceptionally low PHE activity observed for the present system.
Pd‐PEPPSI‐IPentCl‐Catalyzed Amination Using Aminotriphenylsilane as an Ammonia Surrogate
Authors: Lombardi Christopher , Mitchell David , Rodriguez Michael J. , Organ Michael G.
Published: December 2016

Coupling of Ph3SiNH2 with aryl halides by using Pd‐PEPPSI‐IPentCl {dichloro(3‐chloropyridyl)[4,5‐dichloro‐1,3‐bis(2,6‐dipent‐3‐ylphenyl)imidazol‐2‐ylidene]palladium(II)} yields triphenylsilyl‐protected anilines. These triphenylsilyl protected anilines can be isolated, alkylated without over‐alkylation, and the protecting group can be removed under mild acidic conditions or in the presence of fluoride to afford the secondary aniline product.
Benzoic Acid/TEMPO as a Highly Efficient Metal‐Free Catalyst System for Selective Oxidation of 5‐hydroxymethylfurfural into 2, 5‐diformylfuran
Authors: Li Jinlong , Lv Guangqiang , Lu Boqiong , Wang Yingxiong , Deng Tiansheng , Hou Xianglin , Yang Yongxing
Published: December 2016

The combination of benzoic acid and 2,2,6,6‐teramethylpiperidin‐1‐oxyl (TEMPO) afforded an efficient catalytic system for the aerobic oxidation of 5‐hydroxymethylfurfural (HMF) into 2,5‐diformylfuran (DFF) under certain conditions. The maximum conversion of 86.7 % for HMF was obtained with a nearly 77.8 % DFF yield at 1 mmol benzoic acid and 0.4 MPa oxygen pressure in acetonitrile. The aerobic oxidation ability of HMF into DFF depended on the electron density of the organic acid skeletal structure with the carboxyl group. Meanwhile, the catalyst system of benzoic acid/TEMPO also exhibited good performance for aerobic oxidation of other alcohols. Based on experimental results, we propose that the benzoic acid acted as the primary catalyst and TEMPO was the key co‐catalyst, oxidized into oxoammonium cation through electron transport and then regenerated by a superoxide radical during the reaction.
Positive Prognose
Authors: Manns Michael P.
Published: December 2016

Wenn Niere, Leber, Herz oder Lunge unheilbar erkrankt sind, ist eine Organtransplantation oft die letzte Hoffnung. Doch bei allen Fortschritten der modernen Medizin sind die Risiken weiterhin hoch — so bleibt das möglichst lange „Transplantatüberleben”︁ bei weitgehend uneingeschränkter Lebensqualität das oberste Ziel von Ärzten und Patienten.
Inkubator für neue Ideen
Authors: Winter Marten , Hahn Volker , Thier‐Lange Rebecca , Wirth Christian
Published: December 2016

Pfade durch den Komplexitäts‐Dschungel: Das Synthesezentrum des Deutschen Zentrums für integrative Biodiversitätsforschung setzt vorhandenes Wissen zu neuen Erkenntnissen zusammen
Karriere und Profilbildung
Authors: Heuermann Paul
Published: December 2016

40 Jahre Heisenberg‐Programm, zehn Jahre Heisenberg‐Professur: Wie die DFG auf den letzten Metern von Berufbarkeit zur Berufung Personen‐ und Strukturförderung verknüpft
Auf vielen Wegen für eine andere Welt
Authors: Deitelhoff Nicole , Daphi Priska , Anderl Felix
Published: December 2016

„Another World is Possible”︁: Unter diesem Motto kämpft eine transnationale Bewegung gegen die Globalisierung. Deren Wahrnehmung als ungerecht und zerstörerisch eint die Aktivistinnen und Aktivisten — doch die Formen ihres Protests sind ebenso verschieden wie ihre Nah‐ und Fernziele. Gerade in vergleichender Perspektive zeigt sich so das Repertoire sozialen Widerstands.
Richtig nützlich
Authors: Strohschneider Peter
Published: December 2016

Impact und kein Ende: Weltweit rührt das Effektivitäts‐Ideologem von Wissenschaftspolitik und Forschungsförderung in vergleichbarer Weise an den Grundfesten moderner Gesellschaften wie der Populismus. Richtig nützlich können Wissenschaft und Forschung aber nur dann sein, wenn nicht kurzfristige Nutzenerwartungen zum generellen Maßstab von Förderentscheidungen werden.
Es grünt so grün
Authors: Boy Jens , Mikutta Robert , Guggenberger Georg
Published: December 2016

In der Antarktis entsteht seit Jahrtausenden durch Erwärmung und Gletscherrückzug neues Land. Ein Netzwerk von Bodenwissenschaftlern, Algenforschern und Molekulargenetikern studiert den durch den Klimawandel noch forcierten Prozess. An ihm zeigt sich für das ganze Ökosystem Erde, wie durch die Koevolution von Pflanzen und Böden aus Geröll fruchtbare Natur wird.
Investor Sentiment and Credit Default Swap Spreads During the Global Financial Crisis
Authors: Lee Jeehye , Kim Sol , Park Yuen Jung
Published: December 2016

This paper examines whether investor sentiment can predict credit default swap (CDS) spread changes. Among several proxies for investor sentiment, change in equity put–call ratio performs best in predicting variation in CDS spread changes in both firm‐ and portfolio‐level regressions; in particular, the explanatory power of this proxy is greater for non‐investment‐grade firms than for investment‐grade firms. More importantly, sentiment may be a critical factor in determining CDS spread changes during the global financial crisis and may best explain the differences in CDS spread in the group of firms whose leverage ratio and stock volatility are highest. © 2016 Wiley Periodicals, Inc. Jrl Fut Mark 37:660–688, 2017
Effects of stressful life events on cerebral white matter hyperintensity progression
Authors: Johnson Anne D. , McQuoid Douglas R. , Steffens David C. , Payne Martha E. , Beyer John L. , Taylor Warren D.
Published: December 2016

Objective

Exposure to stressful events is associated with both occurrence of depression and also vascular disease. The objective of this study was to determine whether higher levels of stress exposure was related to measures of pathological brain aging, specifically white matter hyperintensity volumes, in older adults with and without depression.

Methods

The sample included 130 depressed and 110 never‐depressed older adults aged 60 years or older enrolled in a longitudinal study at an academic medical center. Participants completed clinical assessments, assessment of stressful event exposure and perceived stress, and magnetic resonance imaging at baseline and after 2 years. Analyses examined both cross‐sectional and longitudinal relationships between stress measures and white matter hyperintensity volumes.

Results

There were no statistically significant relationships observed between cross‐sectional baseline stress measures and either baseline hyperintensity volume or 2‐year change in hyperintensity volume. However, after controlling for demographic variables and baseline measures, change in stressor exposure was associated with change in hyperintensity volumes. In this analysis, increased stressor exposure was associated with greater increases in white matter hyperintensity volume, while reductions in stressor exposure were associated with less increase in hyperintensity volume. This relationship did not significantly differ based on the presence of either depression or medical comorbidities.

Conclusions

This work adds to a growing literature associating exposure to stressful events in later life with more rapid pathological brain aging. Work is needed to understand the physiological mechanisms by which stress exposure has this effect and examine whether stress reduction techniques may modify these observed outcomes. Copyright © 2016 John Wiley & Sons, Ltd.
Epicenters of dynamic connectivity in the adaptation of the ventral visual system
Authors: Prčkovska Vesna , Huijbers Willem , Schultz Aaron , Ortiz‐Teran Laura , Peña‐Gomez Cleofe , Villoslada Pablo , Johnson Keith , Sperling Reisa , Sepulcre Jorge
Published: December 2016

Objectives and design: Neuronal responses adapt to familiar and repeated sensory stimuli. Enhanced synchrony across wide brain systems has been postulated as a potential mechanism for this adaptation phenomenon. Here, we used recently developed graph theory methods to investigate hidden connectivity features of dynamic synchrony changes during a visual repetition paradigm. Particularly, we focused on strength connectivity changes occurring at local and distant brain neighborhoods.Principal observations: We found that connectivity reorganization in visual modal cortex—such as local suppressed connectivity in primary visual areas and distant suppressed connectivity in fusiform areas—is accompanied by enhanced local and distant connectivity in higher cognitive processing areas in multimodal and association cortex. Moreover, we found a shift of the dynamic functional connections from primary‐visual‐fusiform to primary‐multimodal/association cortex.Conclusions: These findings suggest that repetition‐suppression is made possible by reorganization of functional connectivity that enables communication between low‐ and high‐order areas.Hum Brain Mapp 38:1965–1976, 2017. ©2017 Wiley Periodicals, Inc.
Time course of gamma‐band oscillation associated with face processing in the inferior occipital gyrus and fusiform gyrus: A combined fMRI and MEG study
Authors: Uono Shota , Sato Wataru , Kochiyama Takanori , Kubota Yasutaka , Sawada Reiko , Yoshimura Sayaka , Toichi Motomi
Published: December 2016

Debate continues over whether the inferior occipital gyrus (IOG) or the fusiform gyrus (FG) represents the first stage of face processing and what role these brain regions play. We investigated this issue by combining functional magnetic resonance imaging (fMRI) and magnetoencephalography (MEG) in normal adults. Participants passively observed upright and inverted faces and houses. First, we identified the IOG and FG as face‐specific regions using fMRI. We applied beamforming source reconstruction and time–frequency analysis to MEG source signals to reveal the time course of gamma‐band activations in these regions. The results revealed that the right IOG showed higher gamma‐band activation in response to upright faces than to upright houses at 100 ms from the stimulus onset. Subsequently, the right FG showed greater gamma‐band response to upright faces versus upright houses at around 170 ms. The gamma‐band activation in the right IOG and right FG was larger in response to inverted faces than to upright faces at the later time window. These results suggest that (1) the gamma‐band activities occurs rapidly first in the IOG and next in the FG and (2) the gamma‐band activity in the right IOG at later time stages is involved in configuration processing for faces. Hum Brain Mapp 38:2067–2079, 2017. © 2017 Wiley Periodicals, Inc.
Interleukin 6–dependent genomic instability heralds accelerated carcinogenesis following liver regeneration on a background of chronic hepatitis
Authors: Lanton Tali , Shriki Anat , Nechemia‐Arbely Yael , Abramovitch Rinat , Levkovitch Orr , Adar Revital , Rosenberg Nofar , Paldor Mor , Goldenberg Daniel , Sonnenblick Amir , Peled Amnon , Rose‐John Stefan , Galun Eithan , Axelrod Jonathan H.
Published: December 2016

Liver cancer, which typically develops on a background of chronic liver inflammation, is now the second leading cause of cancer mortality worldwide. For patients with liver cancer, surgical resection is a principal treatment modality that offers a chance of prolonged survival. However, tumor recurrence after resection, the mechanisms of which remain obscure, markedly limits the long‐term survival of these patients. We have shown that partial hepatectomy in multidrug resistance 2 knockout (Mdr2–/–) mice, a model of chronic inflammation‐associated liver cancer, significantly accelerates hepatocarcinogenesis. Here, we explore the postsurgical mechanisms that drive accelerated hepatocarcinogenesis in Mdr2–/– mice by perioperative pharmacological inhibition of interleukin‐6 (IL6), which is a crucial liver regeneration priming cytokine. We demonstrate that inhibition of IL6 signaling dramatically impedes tumorigenesis following partial hepatectomy without compromising survival or liver mass recovery. IL6 blockade significantly inhibited hepatocyte cell cycle progression while promoting a hypertrophic regenerative response, without increasing apoptosis. Mdr2–/– mice contain hepatocytes with a notable persistent DNA damage response (γH2AX, 53BP1) due to chronic inflammation. We show that liver regeneration in this microenvironment leads to a striking increase in hepatocytes bearing micronuclei, a marker of genomic instability, which is suppressed by IL6 blockade. Conclusion: Our findings indicate that genomic instability derived during the IL6‐mediated liver regenerative response within a milieu of chronic inflammation links partial hepatectomy to accelerated hepatocarcinogenesis; this suggests a new therapeutic approach through the usage of an anti‐IL6 treatment to extend the tumor‐free survival of patients undergoing surgical resection. (Hepatology 2017;65:1600‐1611)
Eight weeks of ledipasvir/sofosbuvir is effective for selected patients with genotype 1 hepatitis C virus infection
Authors: Kowdley Kris V. , Sundaram Vinay , Jeon Christie Y. , Qureshi Kamran , Latt Nyan L. , Sahota Amandeep , Lott Stephen , Curry Michael P. , Tsai Naoky , Chaiyakunapruk Nathorn , Lee Yoori , Petersen Jorg , Buggisch Peter
Published: December 2016

Eight weeks duration of ledipasvir/sofosbuvir (LDV/SOF) can be considered in genotype 1 hepatitis C virus–infected patients who are treatment‐naive, do not have cirrhosis, and have a pretreatment viral load <6,000,000 IU/mL. The effectiveness of this regimen, however, has not been fully confirmed by real‐world experience. Using data from real‐world cohorts, we aimed to determine the effectiveness of 8 weeks of LDV/SOF treatment, examine variables associated with relapse after treatment with this regimen, and compare the effectiveness of 8 weeks and 12 weeks of LDV/SOF treatment. To evaluate the effectiveness of 8 weeks of therapy and characteristics associated with relapse, we used individual patient data from the IFI (Institut für Interdisziplinäre Medizin), Burman's Pharmacy, and Kaiser Permanente Southern California. All patients had fibrosis staging assessed with biopsy, transient elastography, or serum biomarkers. We also performed a systematic review and meta‐analysis of six additional real‐world cohorts, to compare effectiveness of 8 weeks to 12 weeks duration. In our pooled data analysis, 634 patients were treated for 8 weeks with LDV/SOF, of whom all had outcomes of cure or relapse without loss to follow‐up. Per protocol rates of sustained virologic response at 12 weeks were 98.1% (622/634) in the full cohort and 97.9% (571/583) among treatment‐eligible patients. Exact logistic regression revealed no specific patient characteristics associated with relapse. Our meta‐analysis of six additional real‐world cohorts, comprised of 5,637 patients, demonstrated similar risk for relapse between 8 weeks and 12 weeks of LDV/SOF (relative risk = 0.99, 95% confidence interval 0.98‐1.00). Conclusion: An 8‐week duration of treatment with LDV/SOF is highly effective in properly selected patients; greater use of this regimen is recommended. (Hepatology 2017;65:1094‐1103)
Aldehyde dehydrogenase‐2 (ALDH2) opposes hepatocellular carcinoma progression by regulating AMP‐activated protein kinase signaling in mice
Authors: Hou Guojun , Chen Lei , Liu Gang , Li Liang , Yang Yuan , Yan He‐Xin , Zhang Hui‐Lu , Tang Jing , Yang Ying Cheng , Lin Ximeng , Chen Xin , Luo Gui juan , Zhu Yanjing , Tang Shanhua , Zhang Jin , Liu Hui , Gu Qingyang , Zhao Ling‐Hao , Li Yixue , Liu Lei , Zhou Weiping , Wang Hongyang
Published: December 2016

Potential biomarkers that can be used to determine prognosis and perform targeted therapies are urgently needed to treat patients with hepatocellular carcinoma (HCC). To meet this need, we performed a screen to identify functional genes associated with hepatocellular carcinogenesis and its progression at the transcriptome and proteome levels. We identified aldehyde dedydrogenase‐2 (ALDH2) as a gene of interest for further study. ALDH2 levels were significantly lower at the mRNA and protein level in tumor tissues than in normal tissues, and they were even lower in tissues that exhibited increased migratory capacity. A study of clinical associations showed that ALDH2 is correlated with survival and multiple migration‐associated clinicopathological traits, including the presence of metastasis and portal vein tumor thrombus. The result of overexpressing or knocking down ALDH2 showed that this gene inhibited migration and invasion both in vivo and in vitro. We also found that ALDH2 altered the redox status of cells by regulating acetaldehyde levels and that it further activated the AMP‐activated protein kinase (AMPK) signaling pathway. Conclusion: Decreased levels of ALDH2 may indicate a poor prognosis in HCC patients, while forcing the expression of ALDH2 in HCC cells inhibited their aggressive behavior in vitro and in mice largely by modulating the activity of the ALDH2‐acetaldehyde‐redox‐AMPK axis. Therefore, identifying ALDH2 expression levels in HCC might be a useful strategy for classifying HCC patients and for developing potential therapeutic strategies that specifically target metastatic HCC. (Hepatology 2017;65:1628‐1644).
New classification of liver biopsy assessment for fibrosis in chronic hepatitis B patients before and after treatment
Authors: Sun Yameng , Zhou Jialing , Wang Lin , Wu Xiaoning , Chen Yongpeng , Piao Hongxin , Lu Lungen , Jiang Wei , Xu Youqing , Feng Bo , Nan Yuemin , Xie Wen , Chen Guofeng , Zheng Huanwei , Li Hai , Ding Huiguo , Liu Hui , Lv Fudong , Shao Chen , Wang Tailing , Ou Xiaojuan , Wang Bingqiong , Chen Shuyan , Wee Aileen , Theise Neil D. , You Hong , Jia Jidong
Published: December 2016

Liver fibrosis is the net result of dynamic changes between fibrogenesis and fibrolysis. Evidence has shown that antiviral therapy can reverse liver fibrosis or even early cirrhosis caused by hepatitis B virus. However, current evaluation systems mainly focus on the severity of, but not the dynamic changes in, fibrosis. Here, we propose a new classification to evaluate the dynamic changes in the quality of fibrosis, namely: predominantly progressive (thick/broad/loose/pale septa with inflammation); predominately regressive (delicate/thin/dense/splitting septa); and indeterminate, which displayed an overall balance between progressive and regressive scarring. Then, we used this classification to evaluate 71 paired liver biopsies of chronic hepatitis B patients before and after entecavir‐based therapy for 78 weeks. Progressive, indeterminate, and regressive were observed in 58%, 29%, and 13% of patients before treatment versus in 11%, 11%, and 78% after treatment. Of the 55 patients who showed predominantly regressive changes on posttreatment liver biopsy, 29 cases (53%) had fibrosis improvement of at least one Ishak stage, and, more interestingly, 25 cases (45%) had significant improvement in terms of Laennec substage, collagen percentage area, and liver stiffness despite remaining in the same Ishak stage. Conclusion: This new classification highlights the importance of assessing and identifying the dynamic changes in the quality of fibrosis, especially relevant in the era of antiviral therapy.(Hepatology 2017;65:1438‐1450)
Long noncoding RNA HULC modulates the phosphorylation of YB‐1 through serving as a scaffold of extracellular signal–regulated kinase and YB‐1 to enhance hepatocarcinogenesis
Authors: Li Dan , Liu Xuefeng , Zhou Jian , Hu Jie , Zhang Dongdong , Liu Jing , Qiao Yanyan , Zhan Qimin
Published: December 2016

Dysregulated expression of long noncoding RNAs has been reported in many types of cancers, indicating that it may play a critical role in tumorigenesis. The long noncoding RNA highly up‐regulated in liver cancer (HULC) was first characterized in hepatocellular carcinoma. However, the detailed mechanisms of HULC remain unclear. Here, we demonstrate a novel mechanism by which long noncoding RNA plays oncogenic roles through modulating the phosphorylation status of its interaction protein. First, we validated the markedly increased expression levels of HULC in hepatocellular carcinoma tissues compared to their adjacent noncancerous tissues. Furthermore, up‐regulation of HULC was correlated with grading and overall survival. Meanwhile, HULC could promote cell proliferation, migration, and invasion in vitro and inhibit cisplatin‐induced apoptosis. Moreover, we show that HULC specifically binds to Y‐box binding protein 1 (YB‐1) protein both in vitro and in vivo. YB‐1 is a major component of translationally inactive messenger ribonucleoprotein particles which keeps mRNA in a silent state. Our study further demonstrated that HULC could promote the phosphorylation of YB‐1 protein, which leads to the release of YB‐1 from its bound mRNA. As a consequence, translation of silenced oncogenic mRNAs would be activated, including cyclin D1, cyclin E1, and matrix metalloproteinase 3. In addition, we found that HULC promotes the phosphorylation of YB‐1 protein mainly through extracellular signal–regulated kinase. Conclusion: We demonstrate that HULC promotes the phosphorylation of YB‐1 through the extracellular signal–regulated kinase pathway, in turn regulates the interaction of YB‐1 with certain oncogenic mRNAs, and consequently accelerates the translation of these mRNAs in the process of tumorigenesis. (Hepatology 2017;65:1612‐1627)
Analysis of surgical interruption of the enterohepatic circulation as a treatment for pediatric cholestasis
Authors: Wang Kasper S. , Tiao Greg , Bass Lee M. , Hertel Paula M. , Mogul Douglas , Kerkar Nanda , Clifton Matthew , Azen Colleen , Bull Laura , Rosenthal Philip , Stewart Dylan , Superina Riccardo , Arnon Ronen , Bozic Molly , Brandt Mary L. , Dillon Patrick A. , Fecteau Annie , Iyer Kishore , Kamath Binita , Karpen Saul , Karrer Frederick , Loomes Kathleen M. , Mack Cara , Mattei Peter , Miethke Alexander , Soltys Kyle , Turmelle Yumirle P. , West Karen , Zagory Jessica , Goodhue Cat , Shneider Benjamin L. ,   on behalf of the Childhood Liver Disease Research Network (ChiLDReN)
Published: December 2016

To evaluate the efficacy of nontransplant surgery for pediatric cholestasis, 58 clinically diagnosed children, including 20 with Alagille syndrome (ALGS), 16 with familial intrahepatic cholestasis‐1 (FIC1), 18 with bile salt export pump (BSEP) disease, and 4 others with low γ‐glutamyl transpeptidase disease (levels <100 U/L), were identified across 14 Childhood Liver Disease Research Network (ChiLDReN) centers. Data were collected retrospectively from individuals who collectively had 39 partial external biliary diversions (PEBDs), 11 ileal exclusions (IEs), and seven gallbladder‐to‐colon (GBC) diversions. Serum total bilirubin decreased after PEBD in FIC1 (8.1 ± 4.0 vs. 2.9 ± 4.1 mg/dL, preoperatively vs. 12‐24 months postoperatively, respectively; P = 0.02), but not in ALGS or BSEP. Total serum cholesterol decreased after PEBD in ALGS patients (695 ± 465 vs. 457 ± 319 mg/dL, preoperatively vs. 12‐24 months postoperatively, respectively; P = 0.0001). Alanine aminotransferase levels increased in ALGS after PEBD (182 ± 70 vs. 260 ± 73 IU/L, preoperatively vs. 24 months; P = 0.03), but not in FIC1 or BSEP. ALGS, FIC1, and BSEP patients experienced less severely scored pruritus after PEBD (ALGS, 100% vs. 9% severe; FIC1, 64% vs. 10%; BSEP, 50% vs. 20%, preoperatively vs. >24 months postoperatively, respectively; P < 0.001). ALGS patients experienced a trend toward greater freedom from xanthomata after PEBD. There was a trend toward decreased pruritus in FIC1 after IE and GBC. Vitamin K supplementation increased in ALGS after PEBD (33% vs. 77%; P = 0.03). Overall, there were 15 major complications after surgery. Twelve patients (3 ALGS, 3 FIC1, and 6 BSEP) subsequently underwent liver transplantation. Conclusion: This was a multicenter analysis of nontransplant surgical approaches to intrahepatic cholestasis. Approaches vary, are well tolerated, and generally, although not uniformly, result in improvement of pruritus and cholestasis. (Hepatology 2017;65:1645‐1654).
Hepatitis B reactivation in occult viral carriers undergoing hematopoietic stem cell transplantation: A prospective study
Authors: Seto Wai‐Kay , Chan Thomas Sau‐Yan , Hwang Yu‐Yan , Wong Danny Ka‐Ho , Fung James , Liu Kevin Sze‐Hang , Gill Harinder , Lam Yuk‐Fai , Lau Eric H.Y. , Cheung Ka‐Shing , Lie Albert K.W. , Lai Ching‐Lung , Kwong Yok‐Lam , Yuen Man‐Fung
Published: December 2016

Hepatitis B virus (HBV) reactivation in hepatitis B surface antigen (HBsAg)–negative, antibody to hepatitis B core antigen (anti‐HBc)–positive patients after allogeneic hematopoietic stem cell transplantation (HSCT) has not been prospectively studied. HBsAg‐negative, anti‐HBc–positive patients with undetectable HBV DNA undergoing allogeneic HSCT were prospectively monitored every 4 weeks. The primary endpoint was HBV reactivation, defined as detectable HBV DNA (≥10 IU/mL). Secondary endpoints included overall survival, HBsAg positivity, and changes in liver biochemistry and antibody to HBsAg levels. Among 297 allogeneic HSCT recipients, 85 (28.7%) were HBsAg‐negative, anti‐HBc–positive, of whom 62 were recruited and monitored for a median of 48 (4‐104) weeks. The 2‐year cumulative HBV DNA detectability rate was 40.8%, occurring at a median of 44 (8‐100) weeks. Multivariate analysis showed that age ≥50 years (P = 0.004, hazard ratio = 8.2) and chronic graft‐versus‐host disease (P = 0.010, hazard ratio = 5.3) were significantly associated with HBV reactivation. Other clinical parameters, including baseline antibody to HBsAg status, serial changes in antibody to HBsAg levels, and donor serology, were not associated with HBV reactivation. Patients <50 years old and without chronic graft‐versus‐host disease, compared with the remaining patient cohort, had a significantly lower 2‐year cumulative HBV reactivation rate (5.6% versus 65.0%, P = 0.004). Entecavir successfully suppressed HBV DNA to undetectable levels, with no cases developing biochemical hepatitis. Conclusion: HBsAg‐negative, anti‐HBc–positive patients had a high rate of HBV reactivation after allogeneic HSCT, with determinants of HBV reactivation including age ≥50 years and chronic graft‐versus‐host disease; treatment strategies based on these parameters may prevent HBV reactivation and subsequent complications. (ClinicalTrials.gov identifier NCT01481649.) (Hepatology 2017;65:1451‐1461).
B‐cells with a FasL expressing regulatory phenotype are induced following successful anti‐tuberculosis treatment
Authors: van Rensburg Ilana C. , Kleynhans Léanie , Keyser Alana , Walzl Gerhard , Loxton Andre G.
Published: December 2016

Introduction

Studies show that B‐cells, in addition to producing antibodies and antigen‐presentation, are able to produce cytokines as well. These include regulatory cytokines such as IL‐10 by regulatory B‐cells. Furthermore, a rare regulatory subset of B‐cells have the potential to express FasL, which is a death‐inducing ligand. This subset of B‐cells have a positive role during autoimmune disease, but has not yet been studied during tuberculosis. These FasL‐expressing B‐cells are induced by bacterial LPS and CpG, thus we hypothesized that this phenotype might be induced during tuberculosis as well.

Methods

B‐cells from participants with TB (at diagnosis and during treatment) and controls were collected, and analyzed by means of real‐time PCR and flow cytometry. In addition to this, BAL was collected from TB participants as well and analyzed by means of MAGPix (multi‐cytokine) technology.

Results

Gene expression analysis show that FASL transcript levels increase by the end of treatment. Similarly, phenotypic analysis show that there is a higher frequency of FasL‐expressing B‐cells by the end of treatment.

Conclusion

Collectively, these results indicate that these FasL‐expressing B‐cells are being induced during anti‐TB treatment, and thus may play a positive role. Further studies are required to elucidate this.
N‐dihydrogalactochitosan as a potent immune activator for dendritic cells
Authors: El‐Hussein Ahmed , Lam Samuel S. K. , Raker Joseph , Chen Wei R. , Hamblin Michael R.
Published: December 2016

Immunotherapy has become one of the fastest growing areas of cancer research. A promising in situ autologous cancer vaccine (inCVAX) uses a novel immune activator, N‐dihydrogalactochitosan (GC), that possesses the ability to stimulate dendritic cells (DC). inCVAX is a combination treatment procedure involving treatment of the tumor with a thermal near‐infrared laser to liberate whole cell tumor antigens, followed by injection of GC (a glucosamine polymer with galactose attached to the amino groups) into the treated tumor thereby inducing a systemic antitumor immune response. Regression of both the treated tumor and distant untreated metastases has been observed in both nonclinical and clinical settings following inCVAX. We studied the stimulatory action of GC on relatively immature DCs (DC2.4 cell line) in vitro. GC at 1 mg/mL was a potent stimulator for DC with limited toxicity, giving increased expression of major histocompatibility complex class 2, CD80, and CD11c. Confocal imaging also revealed qualitatively increased uptake of antigen (Texas red‐labeled ovalbumin) by DCs after the introduction of GC. To visualize cellular uptake, GC was conjugated with FITC‐fluorophore revealing its cellular internalization after 8 hours. In some cases GC was more effective than the toxic TLR4 agonist, lipopolysaccharide. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 963–972, 2017.
The influence of substrate modulus on retinal pigment epithelial cells
Authors: White Corina , DiStefano Tyler , Olabisi Ronke
Published: December 2016

Although transplantation of retinal pigment epithelial (RPE) cells has shown promise for the treatment of retinal degenerative diseases, this therapeutic approach is not without challenges. Two major challenges are RPE cell dedifferentiation and inflammatory response following transplantation. The aim of this work is to understand how the rigidity of a scaffold, a relatively unexplored design aspect in retinal tissue engineering, affects RPE cells, particularly the pathways associated with the aforementioned challenges. Poly(ethylene glycol) diacrylate (PEGDA) of varying molecular weights from 3.4 to 20 kDa were photopolymerized to fabricate scaffolds. The Young's modulus of the scaffolds varied from 60 to 1200 kPa. A cell study was then conducted to test the effects of scaffold rigidity on RPE cells. A cell adhesion peptide motif of arginine‐glycine‐aspartic acid‐serine (RGDS) was conjugated to 60 and 1200 kPa scaffolds and ARPE‐19 cells, a human RPE cell line, were seeded onto these hydrogels. Cells grown on scaffolds demonstrated qualitatively different adhesion properties, metabolic activity, and gene expression at an mRNA level. IL‐6 and MCP‐1, two inflammation markers known to recruit microglial into the retina, had the same expression pattern with cells having the highest expression on the high modulus scaffold and lowest expression on the control substrate. This study demonstrates that scaffold rigidity, an important design parameter in other areas of tissue engineering, affects cell adhesion, activity, and expression of RPE cells. Though more exploration is needed, this begins to lay a foundation for optimizing scaffold rigidity to promote long‐term success of RPE scaffolds. © 2017 The Authors. Journal of Biomedical Materials Research Part A published by Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1260–1266, 2017.
Molecular genetic and biochemical responses in human airway epithelial cell cultures exposed to titanium nanoparticles in vitro
Authors: Aydın Elanur , Türkez Hasan , Hacımüftüoğlu Fazıl , Tatar Abdulgani , Geyikoğlu Fatime
Published: December 2016

Titanium nanoparticles (NPs) have very wide application areas such as paint, cosmetics, pharmaceuticals, and biomedical applications. And, to translate these nanomaterials to the clinic and industrial domains, their safety needs to be verified, particularly in terms of genotoxicity and cytotoxicity. Therefore, in this study, we aimed to investigate of cytotoxicity and changes in gene expression profiles influenced by commonly titanium (as titanium carbide, titanium carbo‐nitride, titanium (II) oxide, titanium (III) oxide, titanium (IV) oxide, titanium nitride, titanium silicon oxide) NPs in human alveolar epithelial (HPAEpiC) and pharynx (HPPC) cell lines in vitro since inhalation is an important pathway for exposure to these NPs. HPAEpiC and HPPC cells were treated with titanium (0–100 µg/mL), NPs for 24 and 48 h, and then cytotoxicity was detected by, [3‐(4,5‐dimethyl‐thiazol‐2‐yl) 2,5‐diphenyltetrazolium bromide] (MTT), uptake of neutral red (NR) and lactate dehydrogenase (LDH) release assays, while genotoxicity was also analyzed by cDNA array ‐ RT‐PCR assay. According to the results of MTT, NR and LDH assays, all tested NPs induced cytotoxicity on both HPAEpiC and HPPC cells in a time‐ and dose‐dependent manner. Determining and analyzing the gene expression profiles of HPAEpiC and HPPC cells, titanium NPs showed more changes in genes related to DNA damage or repair, oxidative stress, and apoptosis. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 2056–2064, 2017.
Nedd4 Deficiency in Vascular Smooth Muscle Promotes Vascular Calcification by Stabilizing pSmad1
Authors: Lee Ji-Hyun , Jeon Seon-Ae , Kim Byung-Gyu , Takeda Michiko , Cho Jae-Jin , Kim Dong-Ik , Kawabe Hiroshi , Cho Je-Yoel
Published: December 2016

The nonosseous calcification process such as atherosclerosis is one of the major complications in several types of metabolic diseases. In a previous study, we uncovered that aberrant activity of transforming growth factor β (TGF-β) signaling pathway could contribute to the vascular smooth muscle cells’ (VSMCs) calcification process. Also, we identified NEDD4 E3 ligase as a key suppressor of bone morphogenetic protein (BMP)/Smad pathway via a polyubiquitination-dependent selective degradation of C-terminal phosphorylated Smad1 (pSmad1) activated by TGF-β. Here, we further validated and confirmed the role of Nedd4 in in vivo vascular calcification progression. First, Nedd4 deletion in SM22α-positive mouse tissues (Nedd4fl/fl;SM22α-Cre) showed deformed aortic structures with disarranged elastin fibers at 24 weeks after birth. Second, vitamin D–induced aorta vascular calcification rate in Nedd4fl/fl;SM22α-Cre mice was significantly higher than their wild-type littermates. Nedd4fl/fl;SM22α-Cre mice showed a development of vascular calcification even at very low-level injection of vitamin D, but this was not exhibited in wild-type littermates. Third, we confirmed that TGF-β1–induced pSmad1 levels were elevated in Nedd4-deficient primary VSMCs isolated from Nedd4fl/fl;SM22α-Cre mice. Fourth, we further found that Nedd4fl/fl;SM22α-Cre mVSMCs gained mesenchymal cell properties toward osteoblast-like differentiation by a stable isotope labeling in cell culture (SILAC)-based proteomics analysis. Finally, epigenetic analysis revealed that methylation levels of human NEDD4 gene promoter were significantly increased in atherosclerosis patients. Collectively, abnormal expression or dysfunction of Nedd4 E3 ligase could be involved in vascular calcification of VSMCs by activating bone-forming signals during atherosclerosis progression. © 2016 American Society for Bone and Mineral Research.