bluuebunny/crossref_metadata_2025 huggingface dataset:
Proposed Design Philosophy for Seismic-Resistant Buildings
Authors: Gunawan Nanang , Han Aylie , Gan Buntara Sthenly
Published: April 2019

Modern seismic design and technologies have undergone tremendous developments. In modern design codes, building structures subjected to high earthquake loads are allowed to experience plastic deformations without collapsing, and the design is permitted up to the ultimate strength. According to comparative results in Japan, the number of humans injured due to earthquakes is higher than the number of deaths/missing. Likewise, the number of residential buildings that collapsed are less than the partially damaged buildings. This outcome implies that residential buildings designed based on the revised seismic standards have good earthquake resistances. It also infers that the human deaths/injury casualties were not a result of the collapsed the structure, but due to the strong vibrations originated from the earthquake, yielding in the collapse of non-structural elements such as ceilings and bookshelves. This paper presents a proposed design philosophy that attempts to implement the effect of earthquakes to non-fatal human casualties
Monitoring the Shear Fatigue Response of Reinforced Concrete Beams Subjected to Moving Loads using Digital Image Correlation
Authors: Suryanto Benny , Staniforth George
Published: April 2019

A series of three reinforced concrete beams without shear reinforcement were tested to failure under a centre-span monotonic load, a centre-span pulsating load, and a stepwise-moving pulsating load. During each experiment, load-deflection response was continuously monitored and at several stages during the experiment, the load was briefly stopped for crack observations. In addition to this manual crack mapping, more detailed crack mappings were undertaken using the digital image correlation (DIC) technique, employing the open-source DIC software Ncorr. It was shown that while the three beams exhibited a similar mode of failure (i.e. shear), each beam displayed a rather distinctive overall behaviour, particularly with regard to the load-deflection response and the nature of crack initiation and propagation. Results from the DIC analysis are presented to provide direct evidence on the damage progression during the load cycles and discuss the reduced fatigue life exhibited by the beam subjected to stepwise-moving pulsating load
Flexible Breathable Nanomesh Electronic Devices for On‐Demand Therapy
Authors: Gong Min , Wan Pengbo , Ma Di , Zhong Mengjuan , Liao Meihong , Ye Jingjing , Shi Rui , Zhang Liqun
Published: April 2019

Flexible electronics are drawing tremendous interest for various applications in wearable healthcare biomonitoring, on‐demand therapy, and human–machine interactions. However, conventional plastic substrates with uncomfortableness, mechanical mismatches, and impermeability have limited the application of flexible on‐skin electronic devices for healthcare biomonitoring and on‐demand therapy. Herein, flexible breathable electronic devices with the capabilities of real‐time temperature sensing and timely on‐demand anti‐infection therapy at wound sites are presented. These devices are assembled from a crosslinked electrospun moxifloxacin hydrochloride (MOX)‐loaded thermoresponsive polymer nanomesh film with a conductive pattern. The conductive polymer nanomesh film demonstrates excellent flexibility, reliable breathability, and robust environmental stability. Furthermore, the assembled temperature sensor displays a linear relationship between the electrical resistance and temperature, potentially enabling real‐time biomonitoring of tissue temperature at the wound site. Smart artificial electronic skins (E‐skins) are assembled from the thermoresponsive polymer nanomesh film for spatial touching sensing mapping of temperature changes. Furthermore, the flexible temperature sensor is coupled with a wireless transmitter for real‐time wireless temperature monitoring. Notably, the thermoresponsive polymer nanomesh film can also be assembled as a highly efficient flexible heater to trigger the on‐demand release of antibiotics loaded in the fibers to eliminate bacterial colonization in the wound site once infection has occurred.
Miniaturized and Automated Synthesis of Biomolecules—Overview and Perspectives
Authors: Mattes Daniela S. , Jung Nicole , Weber Laura K. , Bräse Stefan , Breitling Frank
Published: April 2019

Chemical synthesis is performed by reacting different chemical building blocks with defined stoichiometry, while meeting additional conditions, such as temperature and reaction time. Such a procedure is especially suited for automation and miniaturization. Life sciences lead the way to synthesizing millions of different oligonucleotides in extremely miniaturized reaction sites, e.g., pinpointing active genes in whole genomes, while chemistry advances different types of automation. Recent progress in matrix‐assisted laser desorption/ionization mass spectrometry (MALDI‐MS) imaging could match miniaturized chemical synthesis with a powerful analytical tool to validate the outcome of many different synthesis pathways beyond applications in the life sciences. Thereby, due to the radical miniaturization of chemical synthesis, thousands of molecules can be synthesized. This in turn should allow ambitious research, e.g., finding novel synthesis routes or directly screening for photocatalysts. Herein, different technologies are discussed that might be involved in this endeavor. A special emphasis is given to the obstacles that need to be tackled when depositing tiny amounts of materials to many different extremely miniaturized reaction sites.
Fabrication of a Spherical Superstructure of Carbon Nanorods
Authors: Zou Lianli , Kitta Mitsunori , Hong Jinhua , Suenaga Kazutomo , Tsumori Nobuko , Liu Zheng , Xu Qiang
Published: April 2019

Hierarchical superstructures in nano/microsize have attracted great attention owing to their wide potential applications. Herein, a self‐templated strategy is presented for the synthesis of a spherical superstructure of carbon nanorods (SS‐CNR) in micrometers through the morphology‐preserved thermal transformation of a spherical superstructure of metal–organic framework nanorods (SS‐MOFNR). The self‐ordered SS‐MOFNR with a chestnut‐shell‐like superstructure composed of 1D MOF nanorods on the shell is synthesized by a hydrothermal transformation process from crystalline MOF nanoparticles. After carbonization in argon, the hierarchical SS‐MOFNR transforms into SS‐CNR, which preserves the original chestnut‐shell‐like superstructure with 1D porous carbon nanorods on the shell. Taking the advantage of this functional superstructure, SS‐CNR immobilized with ultrafine palladium (Pd) nanoparticles (Pd@SS‐CNR) exhibits excellent catalytic activity for formic acid dehydrogenation. This synthetic strategy provides a facile method to synthesize uniform spherical superstructures constructed from 1D MOF nanorods or carbon nanorods for applications in catalysis and energy storage.
Bioinspired High‐Adhesion Metallic Networks as Flexible Transparent Conductors
Authors: Dong Guanping , Liu Sai , Pan Minqiang , Zhou Guofu , Liu Jun‐Ming , Kempa Krzysztof , Gao Jinwei
Published: April 2019

While metallic networks, proposed recently as a replacement for transparent conducting oxides, show superior optoelectronic performance and mechanical flexibility, their adhesion to flexible substrates remains a problem. In this work, a high adhesion metallic network inspired by the ground‐gripping functionality of bamboo roots is developed. This network shows not only excellent optoelectronic performance but also superb adhesion to flexible substrates could be beneficial for flexible electronics.
3D Printing of Freestanding Overhanging Structures Utilizing an In Situ Light Guide
Authors: Lim Jongkyeong , Kim Young Kwon , Won Dong‐Joon , Choi In Ho , Lee Sangmin , Kim Joonwon
Published: April 2019

Conventional 3D printing methods require supporting material as a sacrificial layer to form a stable structure and to obtain the desired final product. The use of the supporting material causes several problems, such as damage to the surface of materials during the removal process. This results in considerable waste of materials, energy, and time. This paper proposes a new 3D printing method to create a freestanding overhanging structure that does not require supporting material. The printed hydrogel structure can guide and transmit light by utilizing an in situ light guide within the hydrogel, similar to an optical fiber. The results show that the curved angle at which the structure can grow at a constant rate can be controlled from 0° to ≈60°. In addition, hierarchical, branched, and helical structures can be easily created because the growth direction of the structure is freely adjustable. In future, by applying the proposed 3D printing method to a variety of functional material designs, the aim is to provide opportunities for various practical applications such as soft actuators, tissue engineering, and sensors.
Recent Progress in Active Optical Metasurfaces
Authors: Kang Lei , Jenkins Ronald P. , Werner Douglas H.
Published: April 2019

Evolving from metamaterials, optical metasurfaces not only inherit their unprecedented flexibility in tailoring light–matter interaction but also the generally fixed response determined by the metaatoms' geometries—an undesirable property that hinders the development of practical metadevices. Consequently, novel optical metasurfaces that can be tuned in an active manner are intensively studied in recent years. Due to their optically thin structures, optical metasurfaces present unique characteristics in the realization of dynamic tuning. In this review, a detailed summary of the recent advances in active optical metasurfaces is provided including discussions reviewing a variety of active materials and approaches that enable faster, stronger, and more accurate tuning. Beyond facilitating practical metadevices, studies of active metasurfaces have, and will continue to deepen the understandings of the interaction between light and nanostructured photonic architectures and to promote the development of nanofabrication techniques involving high‐complexity.
Kathodenmaterialien für wiederaufladbare Lithiumbatterien
Authors: Lee Wontae , Muhammad Shoaib , Sergey Chernov , Lee Hayeon , Yoon Jaesang , Kang Yong‐Mook , Yoon Won‐Sub
Published: April 2019

Die rasante Entwicklung vieler moderner Technologien erfordert einen erheblichen Energieverbrauch, infolgedessen steigt die Nachfrage nach fortschrittlichen Energiespeichern stark an. In den letzten zwei Jahrzehnten haben sich Lithiumionenbatterien, mit ihrer hohen Energie‐ und Leistungsdichte, als die robusteste Energiespeichertechnologie etabliert. Die Verbesserung der Kathodenmaterialien ist eine der Möglichkeiten, den Bedarf an noch besseren Batterien zu erfüllen. Die Entwicklung neuartiger Kathodenmaterialien durch Erhöhung der Zellspannung und ‐kapazität bei gleichzeitiger Stabilität ebnet daher den Weg zu den Li‐Akkus der nächsten Generation. Um dieses Ziel zu erreichen, sind das Verständnis der Materialprinzipien und das Erkennen der Probleme, mit denen moderne Kathodenmaterialien konfrontiert sind, wesentliche Voraussetzungen. Dieser Aufsatz stellt verschiedene Materialien für Hochenergiekathoden vor, die für die Konstruktion von Lithiumionenbatterien der nächsten Generation genutzt werden könnten. Hierzu gehören nickel‐ und lithiumreiche Schichtoxidmaterialien, Spinelloxide, Polyanionen, Steinsalzoxide mit Kationenfehlordnung und Konversionsmaterialien. Besonderes Augenmerk liegt auf den allgemeinen Reaktions‐ und Abbaumechanismen während des Betriebs sowie auf den wichtigsten Herausforderungen und Strategien zur Überwindung der Nachteile dieser Materialien.
Sub‐second variability in black‐hole X‐ray binary jets
Authors: Vincentelli F. M. , Casella P.
Published: April 2019

In the last 10 years, multiwavelength fast variability studies of low‐mass X‐ray binaries have shown a dramatic development. A key discovery was the detection of O‐IR sub‐second fluctuations in two black‐hole transients, lagging the X‐rays by ≈0.1 s. This demonstrated how the fluctuations observed in the inflow could be transferred to the jet, allowing, therefore, also to study in a completely new way the physical processes that take place at the base of the jet. In this article, we review the latest developments of the study of jets with this new approach, focusing on the results obtained with cross‐spectral analysis techniques.
Carbon quantum dots fluorescence quenching for potassium optode construction
Authors: Rahimi Mehdi , Mahani Mohamad , Hassani Zahra
Published: April 2019

Photophysical phenomena associated with carbon nanoparticles in combination with biocompatibility and readily functionalizable properties have attracted significant interest for sensing and imaging applications. A potassium ion optode based on the fluorescence quenching of carbon quantum dots (CQDs) was constructed. The CQDs were synthesized using a microwave method, citric acid and 2,2′‐(ethylene‐dioxy)bis(ethylamine). A quantum yield of 7.1% was calculated for the synthesized CQDs. A linear dynamic range of about one‐order of magnitude with a correlation coefficient of 0.99 was obtained. The optode was applied on real samples and a 0.60–1.60% error range was obtained relative to the ion‐selective electrode.
Restraint devices for repetitive transcranial magnetic stimulation in mice and rats
Authors: Zhang Chengliang , Lu Rulan , Wang Linxiao , Yun Wenwei , Zhou Xianju
Published: April 2019

Introduction

Repetitive transcranial magnetic stimulation has been widely used for the treatment of neurological and psychiatric diseases. Rodent animals including mice and rats are often used to investigate the potential cellular and molecular mechanisms for the therapeutic effects of repetitive transcranial magnetic stimulation. So far there is no report about an easy‐to‐use device to restrain rodent animals for repetitive transcranial magnetic stimulation.

Methods and Results

We introduced the design and use of the restraint device for mice or rats. In the mouse device, western blot and real‐time PCR analysis showed that，in stimulated mouse frontal cortex, 10 Hz high frequency stimulation for 10 sessions resulted in enhanced expression of NR2B‐containing N‐methyl‐D‐aspartic acid receptors and reduced α1 subunit of inhibitory GABAA receptors, whereas 0.5 Hz low frequency stimulation for 10 sessions caused decreased expression of NR2B subunit and increased α1 subunit of GABAA receptors. In the rat device, measures of motor evoke potentials indicated that 10 Hz stimulation for 10 sessions increased the excitability of stimulated cortex, whereas 0.5 Hz for 10 sessions reduced it.

Conclusions

These results suggested the effectiveness of the devices. Thus, the two devices are practical and easy‐to‐use to investigate the mechanisms of repetitive transcranial magnetic stimulation.
Association between frailty syndrome and survival in patients with pancreatic adenocarcinoma
Authors: Ngo‐Huang An , Holmes Holly M. , des Bordes Jude K. A. , Parker Nathan H. , Fogelman David , Petzel Maria Q. B. , Song Juhee , Bruera Eduardo , Katz Matthew H. G.
Published: April 2019

Background

Frailty is a syndrome characterized by weakness, slow gait, weight loss, exhaustion, and low activity. We sought to determine whether frailty was associated with age or stage in newly diagnosed patients with pancreatic ductal adenocarcinoma (PDAC), and determine its association with survival.

Methods

Consecutive patients with newly diagnosed PDAC of all stages underwent baseline assessment. Frailty (per Fried criteria) was defined as having three or more abnormalities in: grip strength, gait speed, weight loss, self‐reported exhaustion, or self‐reported physical activity. Baseline clinicodemographic characteristics, anatomic stage, performance status, and laboratory markers of prognosis were included. The association between baseline characteristics, frailty, and survival was determined. The associations of individual frailty measures with age, stage, comorbidities, and performance status were examined. Body composition was measured from computed tomographic images using SliceOMatic software.

Results

Of 150 patients enrolled, 8 were excluded because they did not have PDAC on final diagnosis. The median age was 65 years (range, 32‐89). Seventy‐nine patients (55.6%) were sarcopenic, and 36 (25.4%) were frail. Frailty was associated with increasing comorbidities (P = 0.03) and worse performance status (P < 0.01). During follow‐up, 79 patients (56%) died. Frailty was significantly associated with death during the follow‐up period (P < 0.001) for the entire cohort, including patients with curative (P = 0.038) and palliative (P = 0.003) treatment plans.

Conclusions

Frailty was seen frequently in patients with newly diagnosed PDAC and was not associated with increasing age or more advanced stage. Frailty was a predictor of survival, including patients treated with curative intent.
RAD18 may function as a predictor of response to preoperative concurrent chemoradiotherapy in patients with locally advanced rectal cancer through caspase‐9‐caspase‐3‐dependent apoptotic pathway
Authors: Yan Xueqi , Chen Jie , Meng You , He Chao , Zou Shitao , Li Peng , Chen Ming , Wu Jinchang , Ding Wei‐Qun , Zhou Jundong
Published: April 2019

Neoadjuvant chemoradiotherapy (nCRT) has been widely applied to improve the local control rate and survival rate in patients with locally advanced rectal cancer (LARC), yet only part of LARC patients would benefit from nCRT. Therefore, it is imperative to predict the therapeutic outcome of nCRT. Here, we showed that RAD18, an E3 ubiquitin‐linked enzyme, played a fundamental role in predicting the response of LARC patients to nCRT. According to clinical data, patients with low RAD18 expression level in their pre‐nCRT biopsies had a superior response to nCRT compared to those with high RAD18 expression. Inhibition of RAD18 expression in rectal cancer cells pronouncedly attenuated the proliferation and promoted apoptosis after exposing to irradiation or/and 5‐fluorouracil (5‐Fu). Downregulated RAD18 levels increased cell apoptosis by activating caspase‐9‐caspase‐3‐mediated apoptotic pathway, thus resulting in the enhancement of cell radiosensitivity and 5‐Fu susceptibility. Furthermore, a xenograft nude mouse model showed that silencing RAD18 significantly slowed tumor growth after irradiation or/and 5‐Fu in vivo. Collectively, these results implied that RAD18 could be a new biomarker to predict LARC patients who might benefit from nCRT and provide new strategies for clinical treatment of LARC.
Hyperthermic intraperitoneal chemotherapy (HIPEC) in combined treatment of locally advanced and intraperitonealy disseminated gastric cancer: A retrospective cooperative Central‐Eastern European study
Authors: Yarema Roman , Mielko Jerzy , Fetsych Taras , Ohorchak Myron , Skorzewska Magdalena , Rawicz‐Pruszyński Karol , Mashukov Artem , Maksimovsky Viatcheslav , Jastrzębski Tomasz , Polkowski Wojciech , Gyrya Petro , Kovalchuk Yuriy , Safiyan Victor , Karelin Ivan , Kopetskiy Viatcheslav , Kolesnik Olena , Kondratskiy Yuriy , Paskonis Marius
Published: April 2019

Background and Objectives

Clinical experience in Western Europe suggests that cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are promising methods in the management of gastric cancer (GC) with peritoneal metastases. However, there are almost no data on such treatment results in patient from Central‐Eastern European population.

Methods

A retrospective cooperative study was performed at 6 Central‐Eastern European HIPEC centers. HIPEC was used in 117 patients for the following indications: treatment of GC with limited overt peritoneal metastases (n = 70), adjuvant setting after radical gastrectomy (n = 37) and palliative approach for elimination of severe ascites without gastrectomy (n = 10).

Results

Postoperative morbidity and mortality rates were 29.1% and 5.1%, respectively. Median overall survival in the groups with therapeutic, adjuvant, and palliative indications was 12.6, 34, and 3.5 months. The only long‐term survivors occurred in the group with peritoneal cancer index (PCI) of 0‐6 points without survival difference in groups with PCI 7‐12 vs PCI 13 or more points.

Conclusions

GC patients with limited peritoneal metastases can benefit from CRS + HIPEC. Hyperthermic intraperitoneal chemotherapy could be an effective method of adjuvant treatment of GC with a high risk of intraperitoneal progression. No long‐term survival may be expected after palliative approach to HIPEC.
Design of and Stability Studies on Trefoil Knots Featuring RhCp* Building Blocks
Authors: Guo Bei‐Bei , Lin Yue‐Jian , Jin Guo‐Xin
Published: April 2019

Four flexible ligands with different lengths, degrees of flexibility, and steric bulk were synthesized and used to prepare metal‐directed assemblies. Interestingly, minor differences among the ligands led to products with dramatically different topologies: a binuclear D‐shaped macrocycle, tetranuclear rectangles, and hexanuclear trefoil knots. The interconversion of the trefoil‐shaped complexes was also investigated. This contribution introduces a rare ligand‐controlled trefoil–rectangle shape transformation in solution.
Peptide:MHCII Tetramer‐Based Cell Enrichment for the Study of Epitope‐Specific CD4+ T Cells
Authors: Kotov Dmitri I. , Jenkins Marc K.
Published: April 2019

Epitope‐specific CD4+ T cells can be labeled in complex cell mixtures from secondary lymphoid organs with fluorophore‐labeled peptide:major histocompatibility complex class II (p:MHCII) tetramers and then detected by flow cytometry. Magnetic enrichment of tetramer‐bound cells before flow cytometry increases the sensitivity of detection to the point where epitope‐specific cells can be studied even when very rare at early and late times after the host has been exposed to the epitope. This method is very useful for studying polyclonal epitope‐specific CD4+ T cells under physiological conditions. © 2019 by John Wiley & Sons, Inc.
Semi‐polar root exudates in natural grassland communities
Authors: Dietz Sophie , Herz Katharina , Döll Stefanie , Haider Sylvia , Jandt Ute , Bruelheide Helge , Scheel Dierk
Published: April 2019

In the rhizosphere, plants are exposed to a multitude of different biotic and abiotic factors, to which they respond by exuding a wide range of secondary root metabolites. So far, it has been unknown to which degree root exudate composition is species‐specific and is affected by land use, the local impact and local neighborhood under field conditions. In this study, root exudates of 10 common grassland species were analyzed, each five of forbs and grasses, in the German Biodiversity Exploratories using a combined phytometer and untargeted liquid chromatography‐mass spectrometry (LC‐MS) approach. Redundancy analysis and hierarchical clustering revealed a large set of semi‐polar metabolites common to all species in addition to species‐specific metabolites. Chemical richness and exudate composition revealed that forbs, such as Plantago lanceolata and Galium species, exuded more species‐specific metabolites than grasses. Grasses instead were primarily affected by environmental conditions. In both forbs and grasses, plant functional traits had only a minor impact on plant root exudation patterns. Overall, our results demonstrate the feasibility of obtaining and untargeted profiling of semi‐polar metabolites under field condition and allow a deeper view in the exudation of plants in a natural grassland community.
Translational repression of Ccl5 and Cxcl10 by 4E‐BP1 and 4E‐BP2 restrains the ability of mouse macrophages to induce migration of activated T cells
Authors: William Mirtha , Leroux Louis‐Philippe , Chaparro Visnu , Graber Tyson E. , Alain Tommy , Jaramillo Maritza
Published: April 2019

Signaling through the mechanistic target of rapamycin complex 1 (mTORC1) is a major regulatory node of pro‐inflammatory mediator production by macrophages (MΦs). However, it is still unclear whether such regulation relies on selective translational control by two of the main mTORC1 effectors, the eIF4E‐binding proteins 1 and 2 (4E‐BP1/2). By comparing translational efficiencies of immune‐related transcripts of MΦs from WT and 4E‐BP1/2 double‐KO (DKO) mice, we found that translation of mRNAs encoding the pro‐inflammatory chemokines CCL5 and CXCL10 is controlled by 4E‐BP1/2. Macrophages deficient in 4E‐BP1/2 produced higher levels of CCL5 and CXCL10 upon LPS stimulation, which enhanced chemoattraction of activated T cells. Consistent with this, treatment of WT cells with mTORC1 inhibitors promoted the activation of 4E‐BP1/2 and reduced CCL5 and CXCL10 secretion. In contrast, the phosphorylation status of eIF4E did not affect the synthesis of these chemokines since MΦs derived from mice harboring a non‐phosphorylatable form of the protein produced similar levels of CCL5 and CXCL10 to WT counterparts. These data provide evidence that the mTORC1‐4E‐BP1/2 axis contributes to regulate the production of chemoattractants by MΦs by limiting translation efficiency of Ccl5 and Cxcl10 mRNAs, and suggest that 4E‐BP1/2 act as immunological safeguards by fine‐tuning inflammatory responses in MΦs.
In Situ Decorating Coordinatively Unsaturated Fe Sites for Boosting Water Oxidation Performance of TiO2 Photoanode
Authors: Cui Weicheng , Bai Hongye , Qu Konggang , Wang Fagen , Guan Peng , Xu Dongbo , Fan Weiqiang , Shi Weidong
Published: April 2019

Kinetics play a critical role in the photoelectrochemical (PEC) system, whereas co‐catalysis is mainly responsible for reducing the reaction barrier and facilitates water splitting. Here, the unsaturated Fe sites through the metal‐organic framework (MOFs) structure promote the kinetics of water oxidation over TiO2 are successfully in situ decorated. This heterostructure further helps us to better understand the PEC behaviors of organic–inorganic hybrid systems. MIL‐100(Fe), as the typical MOFs model, is facilely achieved by an FeOOH sacrificial template method, a strategy which could anchor the compact and ultrathin MIL‐100(Fe) films on the surface of TiO2 to obtain abundant unsaturated Fe sites. The photocurrent density of MIL‐100(Fe)/TiO2 reaches about 2.4 times at 1.23 V vs reversible hydrogen electrode (RHE) compared with bare TiO2, and the incident photon to current conversion efficiency value increases up to 47% (at 390 nm). Furthermore, the photocurrent density of MIL‐100(Fe)/TiO2 is maintained at 84% after 3 h, showing that the organic component of MIL‐100(Fe) takes a nature of favorable stability. The configuration of MIL‐100(Fe)/TiO2 will bring a new insight for learning the basic function of unsaturated metal sites in the PEC system.
Defining Improvement in Nonalcoholic Steatohepatitis for Treatment Trial Endpoints: Recommendations From the Liver Forum
Authors: Cheung Amanda , Neuschwander‐Tetri Brent A. , Kleiner David E. , Schabel Elmer , Rinella Mary , Harrison Stephen , Ratziu Vlad , Sanyal Arun J. , Loomba Rohit , Jeannin Megnien Sophie , Torstenson Richard , Miller Veronica ,   on behalf of the Liver Forum Case Definitions Working Group
Published: April 2019

Identifying effective therapies for nonalcoholic steatohepatitis (NASH) with fibrosis is a pressing challenge, with 1%‐2% of the population in developed nations at risk of developing NASH cirrhosis and its complications. The design of NASH clinical therapeutic trials is hampered by the long period of minimally symptomatic disease that typically precedes the development of decompensated cirrhosis and the accompanying uncertainties regarding the best precirrhotic trial endpoints that reliably reflect a subsequent reduction in liver‐related morbidity and mortality. The Liver Forum is a multistakeholder organization comprised of academic, industry, and regulatory experts working from a regulatory science perspective to identify barriers, prioritize research, and identify solutions to accelerate therapeutic development for NASH. Past work of The Liver Forum has focused on recommendations for disease definitions and baseline parameters to be implemented in clinical trials that are designed to assess disease status and prevent progression to cirrhosis, liver transplantation, hepatocellular carcinoma, and death. The purpose of this summary is to review currently available clinical data to identify parameters that change in parallel with liver histology and are likely to reflect clinically meaningful reductions in the risk of developing cirrhosis and its complications. We review available data on exploratory histological, blood‐based, and imaging pharmacodynamic biomarkers that may reflect meaningful treatment responses and provide recommendations regarding measurements to be considered in phase 2 and 3 trials as well as during postmarketing monitoring trials.
Increasing participation in cervical screening by targeting long‐term nonattenders: Randomized health services study
Authors: Elfström Klara Miriam , Sundström Karin , Andersson Sonia , Bzhalava Zurab , Carlsten Thor Agneta , Gzoul Zohra , Öhman Daniel , Lamin Helena , Eklund Carina , Dillner Joakim , Törnberg Sven
Published: April 2019

High screening participation in the population is essential for optimal prevention of cervical cancer. Offering a high‐risk human papillomavirus (HPV) self‐test has previously been shown to increase participation. In this randomized health services study, we evaluated four strategies with regard to participation. Women who had not attended organized cervical screening in 10 years were eligible for inclusion. This group comprised 16,437 out of 413,487 resident women ages 33–60 (<4% of the screening target group). Among these 16,437 long‐term nonattenders, 8,000 women were randomized to either (i) a HPV self‐sampling kit sent directly; (ii) an invitation to order a HPV self‐sampling kit using a new open source eHealth web application; (iii) an invitation to call a coordinating midwife with questions and concerns; or (iv) the standard annual renewed invitation letter with prebooked appointment time (routine practice). Overall participation, by arm, was (i) 18.7%; (ii) 10.7%; (iii) 1.9%; and (iv) 1.7%. The relative risk of participation in Arm 1 was 11.0 (95% CI 7.8–15.5), 6.3 (95% CI 4.4–8.9) in Arm 2 and 1.1 (95% CI 0.7–1.7) in Arm 3, compared to Arm 4. High‐risk HPV prevalence among women who returned kits in study Arms 1 and 2 was 12.2%. In total, 63 women were directly referred to colposcopy from Arms 1 and 2; of which, 43 (68.3%) attended and 17 had a high‐grade cervical lesion (CIN2+) in histology (39.5%). Targeting long‐term nonattending women with sending or offering the opportunity to order self‐sampling kits further increased the participation in an organized screening program.
Abrogation of myofibroblast activities in metastasis and fibrosis by methyltransferase inhibition
Authors: Sala Laura , Franco‐Valls Héctor , Stanisavljevic Jelena , Curto Josue , Vergés Jordi , Peña Raúl , Duch Paula , Alcaraz Jordi , García de Herreros Antonio , Baulida Josep
Published: April 2019

Myofibroblasts are a population of highly contractile fibroblasts that express and require the activity of the transcription factor Snail1. Cancer‐associated fibroblasts (CAFs) correlate with low survival of cancer patients when present in the stroma of primary tumors. Remarkably, the presence of myofibroblastic CAFs (which express Snail1) creates mechanical properties in the tumor microenvironment that support metastasis. However, therapeutic blockage of fibroblast activity in patients with cancer is a double‐edged sword, as normal fibroblast activities often restrict tumor cell invasion. We used fibroblasts depleted of Snail1 or protein arginine methyltransferases 1 and 4 (PRMT1/‐4) to identify specific epigenetic modifications induced by TGFβ/Snail1. Furthermore, we analyzed the in vivo efficiency of methyltransferase inhibitors using mouse models of wound healing and metastasis, as well as fibroblasts isolated from patients with idiopathic pulmonary fibrosis (IPF). Mechanistically, TGFβ‐induced Snail1 promotes the epigenetic mark of asymmetrically dimethylated arginine. Critically, we found that inhibitors of methyltransferases prevent myofibroblast activity (but not regular fibroblast activity) in the extracellular matrix, both in cell culture and in vivo. In a mouse breast cancer model, the inhibitor sinefungin reduces both the myofibroblast activity in the tumor stroma and the metastatic burden in the lung. Two distinct inhibitors effectively blocked the exacerbated myofibroblast activity of patient‐derived IPF fibroblasts. Our data reveal epigenetic regulation of myofibroblast transdifferentiation in both wound healing and in disease (fibrosis and breast cancer). Thus, methyltransferase inhibitors are good candidates as therapeutic reagents for these diseases.
Capsule optoacoustic endoscopy for esophageal imaging
Authors: He Hailong , Stylogiannis Antonios , Afshari Parastoo , Wiedemann Tobias , Steiger Katja , Buehler Andreas , Zakian Christian , Ntziachristos Vasilis
Published: April 2019

Detection and monitoring of esophageal cancer severity require an imaging technique sensitive enough to detect early pathological changes in the esophagus and capable of analyzing the esophagus over 360 °in a non‐invasive manner. Optoacoustic endoscopy (COE) has been shown to resolve superficial vascular structure of the esophageal lumen in rats and rabbits using catheter‐type probes. Although these systems can work well in small animals, they are unsuitable for larger lumens with thicker walls as required for human esophageal screening, due to their lack of position stability along the full organ circumference, sub‐optimal acoustic coupling and limited signal‐to‐noise ratio (SNR). In this work, we introduce a novel capsule COE system that provides high‐quality 360° images of the entire lumen, specifically designed for typical dimensions of human esophagus. The pill‐shaped encapsulated probe consists of a novel and highly sensitive ultrasound transducer fitted with an integrated miniature pre‐amplifier, which increases SNR of 10 dB by minimizing artifacts during signal transmission compared to the configuration without the preamplifier. The scanner rotates helically around the central axis of the probe to capture three‐dimensional images with uniform quality. We demonstrate for the first time ex vivo volumetric vascular network images to a depth of 2 mm in swine esophageal lining using COE. Vascular information can be resolved within the mucosa and submucosa layers as confirmed by histology of samples stained with hematoxylin and eosin and with antibody against vascular marker CD31. COE creates new opportunities for optoacoustic screening of esophageal cancer in humans.
Lipofectamine 2000/siRNA complexes cause endoplasmic reticulum unfolded protein response in human endothelial cells
Authors: Li Zhengzheng , Zhang Chi , Wang Zhiting , Shen Jian , Xiang Pingping , Chen Xiao , Nan Jinliang , Lin Yinuo
Published: April 2019

Lipofectamine 2000 (Lipo2000) delivery system is commonly used for short interfering RNA (siRNA) transfection, whereas the cellular responses have attracted little attention. The purpose of this study is to evaluate the effect of siRNA transfection using Lipo2000 on cellular functions and the possible underlying mechanism. Primary human umbilical vein endothelial cells (HUVECs) and adult human coronary artery endothelial cell line (HCAECs) were treated with different concentrations of a Lipo2000/negative control siRNA (NC siRNA) complex or Lipo2000 for specific durations. The cell proliferation, apoptosis rate, and protein expression of claudin5 (CLDN5) and ETS‐related gene (ERG) were analyzed as indicators of cellular function. The effects of the Lipo2000/NC siRNA complex on cellular autophagy and endoplasmic reticulum (ER) unfolded protein response (UPR) were investigated by western blot and real‐time polymerase chain reaction analyses; autophagy was also evaluated by transmission electron microscopy. The Lipo2000/NC siRNA complex inhibited proliferation, downregulated various proteins, and increased the apoptosis in both HUVECs and HCAECs. Both autophagy and UPR were observed in HUVECs treated with the Lipo2000/NC siRNA complex, ER stress‐induced autophagy acted as a cellular protective factor against apoptosis, as inhibition of autophagy by chemical inhibitors increased the cell apoptosis rate. Chemical chaperones failed to prevent the Lipo2000/siRNA complex‐induced UPR. However, knockdown of protein kinase RNA‐like ER kinase and inositol‐requiring protein 1, instead of activating transcription factor‐6, partially ameliorated the UPR and reversed the protein level of CLDN5 and ERG downregulated by Lipo2000/NC siRNA complex. This study provides the first evidence that the Lipo2000‐mediated transport of siRNA leads to an increase in UPR and ER stress‐related apoptosis in endothelial cells.
Acute exposure to triphenyl phosphate inhibits the proliferation and cardiac differentiation of mouse embryonic stem cells and zebrafish embryos
Authors: Qi Zenghua , Chen Min , Song Yuanyuan , Wang Xiya , Li Bingkun , Chen Zhi‐Feng , Tsang Suk Ying , Cai Zongwei
Published: April 2019

Attention has recently paid to the interaction of triphenyl phosphate (TPHP) and body tissues, particularly within the reproductive and development systems, due to its endocrine‐disrupting properties. However, the acute effects of TPHP on early embryonic development remain unclear. Here, we used mouse embryonic stem cells (mESC) and zebrafish embryos to investigate whether TPHP is an embryo toxicant. First, we found that continuous exposure of TPHP decreased the proliferation and increased the apoptotic populations of mESCs in a concentration‐dependent manner. Results of mass spectrometry showed that the intracellular concentration of TPHP reached 39.45 ± 7.72 µg/g w/w after 3 hr of acute exposure with TPHP (38.35 μM) but gradually decreased from 3 hr to 48 hr. Additionally, DNA damage was detected in mESCs after a short‐term treatment with TPHP, which in turn, activated DNA damage responses, leading to cell cycle arrest by changing the expression levels of p53, proliferating cell nuclear antigen, and Y15‐phosphorylated Cdk I. Furthermore, our results revealed that short‐term treatment with TPHP disturbed cardiac differentiation by decreasing the expression levels of Oct4, Sox2, and Nanog and transiently reduced the glycolysis capacity in mESCs. In zebrafish embryos, exposure to TPHP resulted in broad, concentration‐dependent developmental defects and coupled with heart malformation and reduced heart rate. In conclusion, the two models demonstrate that acute exposure to TPHP affects early embryonic development and disturbs the cardiomyogenic differentiation.
Influence of temperature variation on incubation period, hatching success, sex ratio, and phenotypes in Caiman latirostris
Authors: Simoncini Melina S. , Leiva Pamela M.L. , Piña Carlos I. , Cruz Felix B.
Published: April 2019

Temperature is crucial for reptiles, also during embryonic development, particularly for species with temperature‐dependent sex determination. Under natural conditions, Broad‐snouted caiman (Caiman latirostris) eggs are influenced by thermal changes in the interior of the nest related to the external environmental temperature. As nests are subject to variations in temperature and most lab studies on crocodilian incubation have been carried out at constant temperatures, we were interested in determining how temperature fluctuations may affect the development of caiman embryos. We investigated the effects of incubation at constant temperatures (31°C, 32°C, and 33°C) and fluctuating temperatures (31 ± 2, 32 ± 1, and 32 ± 2°C) on the following aspects: incubation period duration, hatching success, sex ratio, total length, and body mass of C. latirostris hatchlings. Eggs incubated at 31°C produced 100% females, those at 32°C produced 71.6% females (however, the sex ratio was nest related), and at 33°C produced 100% males. We found a masculinizing effect when incubation was at 31 ± 2°C compared with a constant 31°C; and temperature fluctuations at 32°C (32 ± 1 and 32 ± 2°C) had a negative effect on hatchlings size and mass, and hatching success compared with constant incubation temperatures of 32°C and 33°C. Finally, the effect of temperature variation during the incubation period on sex ratio, hatching success, and phenotype depends on the mean temperature, as the fluctuation around 31°C affected the sex ratios and incubation period, and the fluctuation around 32°C affected hatchling success and size.
Review on the Versatility of Tungsten Oxide Coatings
Authors: Mardare Cezarina C. , Hassel Achim W.
Published: April 2019

Tungsten oxide is a versatile material with many advantages such as large availability and low fabrications costs. Additionally, it is suitable to be produced in the form of thin films or coatings, which makes it very attractive for many applications. In this Feature Article, the material properties such as crystallography, chemical stability, and semiconducting properties are presented, followed by examples of coating technologies. Furthermore, the relation between its structure and some of the very important applications fields such as electro‐ and photochromism, as well as pH sensing are analyzed in detail. Its auspicious semiconducting properties make it attractive to be used as photo(electro)catalyst, therefore applications of thin films based on WO3 are emphasized such as photoanodes for water splitting, in healthcare as antimicrobial material and for degradation of pollutants or for CO2 reduction. The article is concluded by a short overview of the current status of research employing tungsten oxide.
Vernonia amygdalina inhibited osteoarthritis development by anti‐inflammatory and anticollagenase pathways in cartilage explant and osteoarthritis‐induced rat model
Authors: Madzuki Iffah Nadhira , Lau Seng Fong , Abdullah Rasedee , Mohd Ishak Nur Iliyani , Mohamed Suhaila
Published: April 2019

Vernonia amygdalina (VA) is a medicinal tropical herb for diabetes and malaria and believed to be beneficial for joint pains. The antiosteorthritis effects of VA leaf in cartilage explant assays and on postmenopausal osteoarthritis (OA) rat model were investigated. The VA reduced the proteoglycan and nitric oxide release from the cartilage explants with interleukin 1β (IL‐1β) stimulation. For the preclinical investigation, ovariectomized (OVX) female rats were grouped (n = 8) into nontreated OA, OA + diclofenac (5 mg/kg), OA + VA extract (150 and 300 mg/kg), and healthy sham control. Monosodium iodoacetate was injected into the knee joints to accelerate OA development. After 8 weeks, the macroscopic, microscopic, and histological images showed that the OA rats treated with VA 300 mg/kg and diclofenac had significantly reduced cartilage erosions and osteophytes unlike the control OA rats. The extract significantly down‐regulated the inflammatory prostaglandin E2, nuclear factor κβ, IL‐1β, ADAMTS‐5, collagen type 10α1, and caspase3 in the OVX‐OA rats. It up‐regulated the anti‐inflammatory IL‐10 and collagen type 2α1 mRNA expressions, besides reducing serum collagenases (MMP‐3 and MMP‐13) and collagen type II degradation biomarker (CTX‐II) levels in these rats. The VA (containing various caffeoyl‐quinic acids, flavanone‐O‐rutinoside, luteolin, apigenin derivative and vernonioside D) suppressed inflammation, pain, collagenases as well as cartilage degradation, and improved cartilage matrix synthesis to prevent OA.
Thermal and Thermomechanical Responses Prediction of a Steel Ladle Using a Back‐Propagation Artificial Neural Network Combining Multiple Orthogonal Arrays
Authors: Hou Aidong , Jin Shengli , Harmuth Harald , Gruber Dietmar
Published: April 2019

To facilitate industrial vessel lining design for various material properties and lining configurations, a method, being composed of the back‐propagation artificial neural network (BP‐ANN) with multiple orthogonal arrays, is developed, and a steel ladle from secondary steel metallurgy is chosen for a case study. Ten geometrical and material property variations of this steel ladle lining are selected as inputs for the BP‐ANN model. A total of 160 lining configurations nearly evenly distributed within the ten variations space are designed for finite element (FE) simulations in terms of five orthogonal arrays. Leave‐One‐Out cross validation within various combinations of orthogonal arrays determines 7 nodes in the hidden layer, a minimum ratio of 16 between dataset size and number of input nodes, and a Bayesian regularization training algorithm as the optimal definitions for the BP‐ANN model. The thermal and thermomechanical responses of two optimal lining concepts from a previous study using the Taguchi method are predicted with acceptable accuracy.
What do implicit measures measure?
Authors: Brownstein Michael , Madva Alex , Gawronski Bertram
Published: April 2019

We identify several ongoing debates related to implicit measures, surveying prominent views and considerations in each. First, we summarize the debate regarding whether performance on implicit measures is explained by conscious or unconscious representations. Second, we discuss the cognitive structure of the operative constructs: are they associatively or propositionally structured? Third, we review debates about whether performance on implicit measures reflects traits or states. Fourth, we discuss the question of whether a person's performance on an implicit measure reflects characteristics of the person who is taking the test or characteristics of the situation in which the person is taking the test. Finally, we survey the debate about the relationship between implicit measures and (other kinds of) behavior.

This article is categorized under:

Philosophy > Representation

Psychology > Theory and Methods

Psychology > Prediction

Philosophy > Psychological Capacities
Enabling Emergent Workplace Design
Authors: Oppl Stefan , Stary Christian
Published: April 2019

This chapter offers a synthesis of the conceptual and methodological considerations of the previously presented frameworks and instruments. It adjusts the methodological concepts for eliciting, representing, and processing work knowledge for practical use. Based on elementary modeling constructs we provide a unifying framework that guides the design of organizational interventions when enabling the emergence of novel digital workplace designs and work practices. According to the architecture, support systems for organizational learning enable augmenting processes with work-relevant knowledge, including the execution of specified behavior representations. Overall goal is developing consensually shared workflow designs—developed for and by the actual set of people executing a workflow. The structured procedure allows a generalized architecture based on a common organizational memory and dedicated components for articulation, informed alignment through organizational learning support, and process prototyping.
Putting the Framework to Operation: Enabling Organizational Development Through Learning
Authors: Oppl Stefan , Stary Christian
Published: April 2019

This chapter instantiates the proposed framework for developing consensually shared workflow designs. It shows how the framework can be put to operation using instruments that have been successfully deployed in practice. These instruments enable articulation and alignment of work process knowledge, allow its representation and transfer within organizations, and facilitate acting on these representations for validation and implementation in diverse organizational settings. We here adopt an organizational learning perspective and situate the presented socio-technical instruments along a multi-perspective learning chain informed by the components of the framework. It thus offers instruments supporting the articulation and alignment of work process knowledge, its multi-faceted representation and flexible manipulation, as well as support for processing the resulting models for validation and refinement. Using the framework as a coherent lens on the requirements on support and the respective features of the instruments allows to offer an integrated view, which demonstrates digital work design support in organizational practice.