bluuebunny/crossref_metadata_2025 huggingface dataset:
Citation classics in central nervous system inflammatory demyelinating disease
Authors: Kim Jee‐Eun , Park Kang M. , Kim Yerim , Yoon Dae Y. , Bae Jong S.
Published: April 2017

Objectives

To identify and analyze the characteristics of the most influential articles about central nervous system (CNS) inflammatory demyelinating disease.

Materials and Methods

The Institute for Scientific Information (ISI) Web of Science database and the 2014 Journal Citation Reports Science Edition were used to retrieve the top 100 cited articles on CNS inflammatory demyelinating disease. The citation numbers, journals, years of publication, authorships, article types, subjects and main issues were analyzed. For neuromyelitis optica (NMO), articles that were cited more than 100 times were regarded as a citation classic and described separately.

Results

The top 100 cited articles were published between 1972 and 2011 in 13 journals. The highest number of articles (n = 24) was published in Brain, followed by The New England Journal of Medicine (n = 21). The average number of citations was 664 (range 330–3,897), and 64% of the articles were from the United States and the United Kingdom. The majority of the top 100 cited articles were related to multiple sclerosis (n = 87), and only a few articles reported on other topics such as NMO (n = 9), acute disseminated encephalomyelitis (n = 2) and optic neuritis (n = 2). Among the top 100 cited articles, 77% were original articles. Forty‐one citation classics were found for NMO.

Conclusions

Our study provides a historical perspective on the research progress on CNS inflammatory demyelinating disease and may serve as a guide for important advances and trends in the field for associated researchers.
Navigating the Rolling Hills of Justice: Mental Disabilities, Employment and the Evolving Jurisprudence of the Americans with Disabilities Act
Authors: Wylonis Lauren , Wylonis Nina T. , Sadoff Robert
Published: April 2017

Mental illness and disability affect millions of individuals yearly in the U.S. The most important legislation protecting the mentally disabled in the workplace in the U.S. over the last half century has been the Americans with Disabilities Act (ADA) and its associated legislation and guidance. Although the employee should first request reasonable accommodation with the employer, evaluation by a mental health professional is one of the initial steps for individuals who report significant psychiatric symptoms that are impairing their functioning at work in the U.S.. Important regulations and laws in the United States that are essential knowledge to performing thorough mental disability evaluations include the ADA and Americans with Disabilities Act Amendments Act of 2008 (ADAAA), Social Security Disability, Workers' Compensation, and private disability insurance. These laws differ in applicability and in their definitions of disability. Social Security Disability is applicable to workers who have long‐term impairments regardless of whether the disability arose on or off the job, while Worker's Compensation is specific to persons with work‐related illness and injuries that occur on the job (Reno, Williams, & Sengupta, ). The Social Security definition of a disabled person is a person who is not “able to engage in any substantial gainful activity because of a medically‐determinable physical or mental impairment(s): that is expected to result in death, or that has lasted or is expected to last for a continuous period of at least 12 months” (Social Security Red Book, ). However, the Workers' Compensation definition of what illnesses/injuries are compensated, the level of benefits and who provides the insurance are state‐specific. Due to these differences in definition of disability, it is essential for the mental health professional performing a mental disability evaluation to clarify with the referral source or referring agency which legislation and laws they feel are directly relevant to the specific situation before starting the evaluation. While the ADA and ADA Amendments Act of 2008 have had the greatest impact on the improvement of conditions for mentally disabled individuals in employment over the last 25 years, they have also been the most challenging by far for mental health experts to understand and apply (Cook, ). Interestingly, the ADA has had a much quicker effect on improving access to services for the medically disabled as compared with the mentally disabled in the U.S. (Ullman, Johnsen, Moss, & Burris, ). This article reviews the history and status of current ADA‐ and ADAAA‐related law and employment as well as Canadian disability law and global progress towards universal disability legislation as evidenced by the 2006 Convention on the Rights of Persons with Disabilities. Copyright © 2017 John Wiley & Sons, Ltd.
High‐fidelity iridal light transport simulations at interactive rates
Authors: Kravchenko Boris , Baranoski Gladimir V. G. , Chen Tenn Francis , Miranda Erik , Van Leeuwen Spencer R.
Published: April 2017

Predictive light transport models based on first‐principles simulation approaches have been proposed for complex organic materials. The driving force behind these efforts has been the high‐fidelity reproduction of material appearance attributes without one having to rely on the manipulation of ad hoc parameters. These models, however, are usually considered excessively time consuming for rendering and visualization applications requiring interactive rates. In this paper, we propose a strategy to address this open problem with respect to one of the most challenging of these organic materials, namely the human iris. More specifically, starting with the configuration of a predictive iridal light transport model on a parallel‐computing platform, we analyze the sensitivity of iridal appearance attributes to key model running parameters in order to achieve an optimal balance between fidelity and performance. We believe that the proposed strategy represents a step toward the real‐time and predictive synthesis of high‐fidelity iridal images for rendering and visualization applications, and it can be extended to other organic materials.
MAVE: Maze‐based immersive virtual environment for new presence and experience
Authors: Lee Jiwon , Jeong Kisung , Kim Jinmo
Published: April 2017

To provide users with a sense of presence and experience, this study presents a maze‐based immersive virtual environment (MAVE). MAVE consists of a new immersive virtual scene and immersive interaction optimized for such maze. The algorithm for calculating a finite maze is defined to automatically generate diverse maze patterns; an interactive editing function and sketch‐based maze retrieval make it easier to generate maze patterns intuitively. With the integration of these procedures, MAVE proposes a user‐oriented maze terrain authoring system that can reconstruct two‐dimensional maze patterns into three‐dimensional maze terrains. It also provides an interaction system that enables users to be immersed in a broad virtual maze environment within a limited space. As an Arduino‐based portable walking simulator, this system detects the user's steps as he or she walks in place and controls the user's motions in the virtual environment. This study confirms through various technical and statistical experiments that MAVE can lead to new research on immersion enhancement without virtual reality sickness via virtual reality content.
Carbohydrate Analogue Microarrays for Identification of Lectin‐Selective Ligands
Authors: Hyun Ji Young , Park Cheol Wan , Liu Yanna , Kwon Daeun , Park Seong‐Hyun , Park Sungjin , Pai Jaeyoung , Shin Injae
Published: April 2017

Fifty‐five mono‐ and disaccharide analogues were prepared and used for the construction of microarrays to uncover lectin‐selective ligands. The microarray study showed that two disaccharide analogues, 28′ and 44′, selectively bind to Solanum tuberosum lectin (STL) and wheat germ agglutinin (WGA), respectively. Cell studies indicated that 28′ and 44′ selectively block the binding of STL and WGA to mammalian cells, unlike the natural ligand LacNAc, which suppresses binding of both STL and WGA to cells.
Biocatalytic Asymmetric Phosphorylation Catalyzed by Recombinant Glycerate‐2‐Kinase
Authors: Hardt Norman , Kinfu Birhanu M. , Chow Jennifer , Schoenenberger Bernhard , Streit Wolfgang R. , Obkircher Markus , Wohlgemuth Roland
Published: April 2017

The efficient synthesis of pure d‐glycerate‐2‐phosphate is of great interest due to its importance as an enzyme substrate and metabolite. Therefore, we investigated a straightforward one‐step biocatalytic phosphorylation of glyceric acid. Glycerate‐2‐kinase from Thermotoga maritima was expressed in Escherichia coli, allowing easy purification. The selective glycerate‐2‐kinase‐catalyzed phosphorylation was followed by 31P NMR and showed excellent enantioselectivity towards phosphorylation of the d‐enantiomer of glyceric acid. This straightforward phosphorylation reaction and subsequent product isolation enabled the preparation of enantiomerically pure d‐glycerate 2‐phosphate. This phosphorylation reaction, using recombinant glycerate‐2‐kinase, yielded d‐glycerate 2‐phosphate in fewer reaction steps and with higher purity than chemical routes.
Rigidly Tethered Bis‐phosphoric Acids: Generation of Tunable Chiral Fluorescent Frameworks and Unexpected Selectivity for the Detection of Ferric Ions
Authors: Octa‐Smolin Frescilia , Mitra Raja , Thiele Maike , Daniliuc Constantin G. , Stegemann Linda , Strassert Cristian , Niemeyer Jochen
Published: April 2017

We describe the straightforward synthesis of a series of bis‐phosphoric acids (R,R)‐1 a–d, featuring two chiral 1,1′‐binaphthyl‐phosphoric acid units that are tethered by rigid, π‐conjugated linkers. The nature of the linker has a profound influence on the properties of the bis‐phosphoric acids, such as their self‐association behavior and their interaction with metal ions. This led to the identification of one preferred bis‐phosphoric acid (R,R)‐1 d, which shows selective fluorescence quenching in the presence of ferric ions (Fe3+). Thus, (R,R)‐1 d could be applied for the detection of Fe3+, even in the presence of a variety of other metal ions. The chiral nature of the bis‐phosphoric acid enables the interaction with Fe3+ to be followed by CD spectroscopy, providing a complementary detection mode with the same probe.
Chemical Synthesis of Modified Hyaluronic Acid Disaccharides
Authors: Mende Marco , Nieger Martin , Bräse Stefan
Published: April 2017

Herein we report a chemical synthesis towards new modified hyaluronic acid oligomers by using only commercially available d‐glucose and d‐glucosamine hydrochloride. The various protected hyaluronic acid disaccharides were synthesized bearing new functional groups at C‐6 of the β‐d‐glucuronic acid moiety with a view to structure‐related biological activity tests. The orthogonal protecting group pattern allows ready access to the corresponding higher oligomers. Also, 1H NMR studies of the new derivatives demonstrated the effect of the various functional groups on the intramolecular electronic environment.
A Metal‐Free Oxidative Dehydrogenative Diels–Alder Reaction for Selective Functionalization of Alkylbenzenes
Authors: Manna Srimanta , Antonchick Andrey P.
Published: April 2017

Functionalization of C(sp3)−H bonds under metal‐free reaction conditions is a great challenge due to poor bond reactivity. A novel metal‐free oxidative dehydrogenative Diels–Alder reaction of alkylbenzene derivatives with alkenes through C(sp3)−H bond functionalization is described. The developed oxidative method provides a straightforward approach to biologically relevant 1,4‐phenanthraquinone and isoindole derivatives from readily available starting materials. Furthermore, the synthesis of nitrostyrenes from enylbenzene derivatives by selective C(sp3)−H bond functionalization has been demonstrated.
Synthesis of Benzo[c]silole Derivatives Bearing a Tetrasubstituted Exocyclic C=C Double Bond by Palladium‐Catalyzed Domino Reactions
Authors: Wagner Patrick , Gulea Mihaela , Suffert Jean , Donnard Morgan
Published: April 2017

The synthesis of diversely substituted 2,3‐dihydro‐benzo[c]siloles through an unprecedented palladium‐catalyzed domino sequence is reported, involving a cyclocarbopalladation of an internal silylalkyne. This reaction proceeds with complete stereoselectivity to lead to a fully substituted exocyclic C=C double bond. Notably, the overall domino sequence appears to be crucial to obtain the desired cyclic vinylsilanes.
Engineered CaCO3 nanoparticles with targeting activity: A simple approach for a vascular intended drug delivery system
Authors: Ferrari Pier Francesco , Aliakbarian Bahar , Zattera Elena , Pastorino Laura , Palombo Domenico , Perego Patrizia
Published: April 2017

During the last decade, great attention has been paid to drug delivery systems that are able to induce a site‐specific and tunable release of biomolecules, attenuating the drawbacks of common therapy. The encapsulation of bioactive compounds, such as proteins and drugs, offers the advantage of enhancing the pharmacokinetics and bioavaliability of the entrapped molecules. The encapsulating technique and coating agents are chosen on the basis of the desired functionality of the final product, release kinetics, and fabrication costs. Calcium carbonate (CaCO3) is considered an ideal substrate to fabricate particles at the nanoscale level. In this work, CaCO3 nanoparticles were synthesized through a two‐step protocol which comprised complex coacervation and mineralization, and they were loaded with bovine serum albumin (BSA) as a model protein. The synthesized nanoparticles were then functionalized with the layer‐by‐layer (LbL) electrostatic self‐assembling technique using chitosan as a polycation and dextran sulphate as a polyanion. The multilayered architecture that covers CaCO3 nanoparticles prevented a burst release of BSA, resulting in 77.34 ± 1.22 % of the released protein, after 72 h of incubation. A horseradish peroxidase‐linked IgG was immobilized at the outer particle layer and its presence was detected via chemiluminescence. Multilayered and non‐multilayered nanoparticles were biocompatible until 7 days using EA. hy926 endothelial cells. Here, we report a cost‐effective protocol to obtain protein‐loaded CaCO3 nanoparticles (diameter < 155 nm) using a coacervate‐based synthesis system. Furthermore, with a very simple technique these nanoparticles were functionalized with antibodies, developing immuno‐nanoparticles to apply in the drug delivery field.
Therapeutic Effects of Selaginella tamariscina on the Model of Acute Gout with Hyperuricemia in Rats Based on Metabolomics Analysis
Authors: Chen Weijia , Wu Yi , Bi Rongbing , Liu Shu , Liu Zhongying , Liu Zhiqiang , Song Fengrui , Shi Yi
Published: April 2017

Gout is a disease of purine metabolic disorders which results from long‐term hyperuricemia and the sodium urate deposition in and around the joints. Selaginella tamariscina (ST) is an important traditional Chinese herbal medicine and is used for the treatment of gout and hyperuricemia. In this study, the rat model of acute gout with hyperuricemia was established by intraperitoneal injection of xanthine and oxonic acid potassium salt and articular injection monosodium urate (MSU). The effect of ST in the treatment of gout was investigated by measuring joint swelling, the expression of IL‐1β in serum and histological changes of joint by haematoxylin eosin (H&E) staining. Subsequently, urine metabolomics analysis for biomarkers discovery in acute gout with hyperuricemia rats was performed by the ultra‐performance liquid chromatography‐electrospray ionization quadruple time‐of‐flight mass spectrometry (UPLC‐ESI‐QTOF/MS) combined with chemometric approach. Principal component analysis (PCA) and orthogonal partial least squares‐discriminant analysis (OPLS‐DA) were used to detect potential biomarkers. A total of 18 potential biomarkers were identified mainly including tryptophan metabolism; tyrosine metabolism; lysine methylation; pyrimidine metabolism; purine metabolism; TCA cycle and fatty acid metabolisms. This study indicates that ST could efficiently ameliorate the disease of acute gout with hyperuricemia in rats. The related metabolic biomarkers could provide useful information and the metabolic mechanism could be used for further study about the model of acute gout with hyperuricemia in rats.
Solution‐Mediated Transformation of a 1D [Zn(Im)(HIm)2(OAc)] Precursor to Several Different 3D Zn(Im)2 Frameworks
Authors: Guan Youjun , Shi Qi , Dong Jinxiang
Published: April 2017

1D compound [Zn(Im)(HIm)2(OAc)] was used as a single precursor of metal and imidazole to prepare several 3‐dimensional (3D) Zn(Im)2 frameworks by solution‐mediated transformation. Specifically, three known topologies, zni, coi and crb (BCT) were obtained using a solution‐mediated transformation with CH3OH, DMF and DMA as solvent, respectively. Structural studies by 13C MAS NMR spectroscopy and TG imply that in the transformation process from 1D compound to coi‐[Zn(Im)2]•(DMF)x and crb‐[Zn(Im)2]•(DMA)x (ZIF‐1), DMF and DMA solvent molecules acted as structure‐directing agent and, therefore, were occluded inside the framework, respectively. In contrast, in the formation of zni‐[Zn(Im)2], no solvent molecules were present in the frameworks; therefore the transformation from 1D compound to zni was induced by temperature. Thus, solution‐mediated transformation of a single precursor (1D compound) approach was established for the synthesis of ZIFs.
Identification of Transthyretin Fibril Formation Inhibitors Using Structure‐Based Virtual Screening
Authors: Ortore Gabriella , Martinelli Adriano
Published: April 2017

Transthyretin (TTR) is the primary carrier for thyroxine (T4) in cerebrospinal fluid and a secondary carrier in blood. TTR is a stable homotetramer, but certain factors, genetic or environmental, could promote its degradation to form amyloid fibrils. A docking study using crystal structures of wild‐type TTR was planned; our aim was to design new ligands that are able to inhibit TTR fibril formation. The computational protocol was thought to overcome the multiple binding modes of the ligands induced by the peculiarity of the TTR binding site and by the pseudosymmetry of the site pockets, which generally weaken such structure‐based studies. Two docking steps, one that is very fast and a subsequent step that is more accurate, were used to screen the Aldrich Market Select database. Five compounds were selected, and their activity toward inhibiting TTR fibril formation was assessed. Three compounds were observed to be actives, two of which have the same potency as the positive control, and the other was found to be a promising lead compound. These results validate a computational protocol that is able to archive information on the key interactions between database compounds and TTR, which is valuable for supporting further studies.
In‐memory staging and data‐centric task placement for coupled scientific simulation workflows
Authors: Zhang Fan , Jin Tong , Sun Qian , Romanus Melissa , Bui Hoang , Klasky Scott , Parashar Manish
Published: April 2017

Coupled scientific simulation workflows are composed of heterogeneous component applications that simulate different aspects of the physical phenomena being modeled and that interact and exchange significant volumes of data at runtime. As the data volumes and generation rates keep growing, the traditional disk I/O–based data movement approach becomes cost prohibitive, and workflow requires more scalable and efficient approach to support the data movement. Moreover, the cost of moving large volume of data over system interconnection network becomes dominating and significantly impacts the workflow execution time. Minimize the amount of network data movement and localize data transfers are critical for reducing such cost. To achieve this, workflow task placement should exploit data locality to the extent possible and move computation closer to data. In this paper, we investigate applying in‐memory data staging and data‐centric task placement to reduce the data movement cost in large‐scale coupled simulation workflows. Specifically, we present a distributed data sharing and task execution framework that (1) co‐locates in‐memory data staging on application compute nodes to store data that needs to be shared or exchanged and (2) uses data‐centric task placement to map computations onto processor cores that a large portion of the data exchanges can be performed using the intra‐node shared memory. We also present the implementation of the framework and its experimental evaluation on Titan Cray XK7 petascale supercomputer.
Tandem Transformation of Nitro Compounds into N‐Methylated Amines: Greener Strategy for the Utilization of Methanol as a Methylating Agent
Authors: Paul Bhaskar , Shee Sujan , Chakrabarti Kaushik , Kundu Sabuj
Published: April 2017

A simple air‐ and moisture‐stable, highly efficient ruthenium NNN pincer complex is reported for the first time to catalyze the tandem transformation of various aromatic and aliphatic nitro compounds into the corresponding N‐methylated amines in up to 98 % yield by using methanol as a green methylating agent. Gram‐scale reactions of challenging nitro substrates demonstrated the practical application aspects of this catalytic system. Importantly, the N‐methylamine moiety could be smoothly introduced to various complex molecular structures without using any expensive palladium/phosphine/amine‐based cross‐coupling reactions.
FNAC aided diagnosis of clear cell sarcoma of kidney: Report of two cases in infants
Authors: Das Indranil , Das Ram Narayan , Dalal Bibhas Saha , Bisht Janki , Kanjilal Banhishikha , Chatterjee Uttara
Published: April 2017

Clear cell sarcoma of kidney (CCSK) is a rare aggressive malignant renal neoplasm with a high metastatic potential. Its outcome has however, improved with the advent of doxorubicin based neoadjuvant chemotherapy. Here, we present two cases of CCSK in infants diagnosed on cytology followed by nephrectomy. The first case presented in the neonatal period and had the unusual histological finding of islands of cartilage. The second case presented at the age of eight months. The possibility of CCSK should, therefore, be considered in the differential diagnoses of renal masses in infants as well as neonates. Diagn. Cytopathol. 2017;45:761–765. © 2017 Wiley Periodicals, Inc.
Prediction of harmful variants on mitochondrial genes: Test of habitat‐dependent and demographic effects in a euryhaline fish
Authors: Vasemägi Anti , Sulku Janne , Bruneaux Matthieu , Thalmann Olaf , Mäkinen Hannu , Ozerov Mikhail
Published: April 2017

Both effective population size and life history may influence the efficacy of purifying selection, but it remains unclear if the environment affects the accumulation of weakly deleterious nonsynonymous polymorphisms. We hypothesize that the reduced energetic cost of osmoregulation in brackish water habitat may cause relaxation of selective constraints at mitochondrial oxidative phosphorylation (OXPHOS) genes. To test this hypothesis, we analyzed 57 complete mitochondrial genomes of Pungitius pungitius collected from brackish and freshwater habitats. Based on inter‐ and intraspecific comparisons, we estimated that 84% and 68% of the nonsynonymous polymorphisms in the freshwater and brackish water populations, respectively, are weakly or moderately deleterious. Using in silico prediction tools (MutPred, SNAP2), we subsequently identified nonsynonymous polymorphisms with potentially harmful effect. Both prediction methods indicated that the functional effects of the fixed nonsynonymous substitutions between nine‐ and three‐spined stickleback were weaker than for polymorphisms within species, indicating that harmful nonsynonymous polymorphisms within populations rarely become fixed between species. No significant differences in mean estimated functional effects were identified between freshwater and brackish water nine‐spined stickleback to support the hypothesis that reduced osmoregulatory energy demand in the brackish water environment reduces the strength of purifying selection at OXPHOS genes. Instead, elevated frequency of nonsynonymous polymorphisms in the freshwater environment (Pn/Ps = 0.549 vs. 0.283; Fisher's exact test p = .032) suggested that purifying selection is less efficient in small freshwater populations. This study shows the utility of in silico functional prediction tools in population genetic and evolutionary research in a nonmammalian vertebrate and demonstrates that mitochondrial energy production genes represent a promising system to characterize the demographic, life history and potential habitat‐dependent effects of segregating amino acid variants.
Multi‐level Climate Governance in China
Authors: Schreurs Miranda
Published: April 2017

China is setting increasingly ambitious greenhouse gas targets and backing them up with a wide array of policies and programmes. How successful China will be in slowing and eventually reversing the growth in its greenhouse gas emissions will depend significantly on how well it does with policy implementation at the local and regional levels. This article examines how climate governance works in China's multi‐level governance structure. It explores why the Chinese leadership is taking climate change seriously, the nature of the policies and programmes being introduced, and the steps being taken to promote local environmental innovation and improve policy compliance. Copyright © 2017 John Wiley & Sons, Ltd and ERP Environment
Compression of 1,ω‐Diammonio‐oligo(ethylene glycol) Chains within the “Pyrene Box”
Authors: Dumitrescu Dan G. , Feng Wei‐Xu , Legrand Yves‐Marie , Petit Eddy , van der Lee Arie , Barboiu Mihail
Published: April 2017

The compressed conformations and degree of coiling of 1,ω‐diammonio‐oligo(ethylene glycol) (OEG) guests have been determined within the internal space of crystalline pyrene box host capsules. It was observed that the longest OEG chains have the tendency to fold in on themselves inside this confined medium. The phenomenon was observed in solution by NMR spectroscopy, and structural proof has been provided by single‐crystal X‐ray diffraction. The overall supramolecular spatial arrangement of the “pyrene box” system incorporating OEGs remains relatively unchanged compared with previously reported cages encapsulating alkane chains. However, some structural and dimensional variations/adaptations to accommodate coiled OEG guests of different sizes and shapes can be observed.
Simply Assembly of Acidic Nanospheres for Efficient Production of 5‐Ethoxymethylfurfural from 5‐Hydromethylfurfural and Fructose
Authors: Wang Zhongwei , Li Hu , Fang Chengjiang , Zhao Wenfeng , Yang Tingting , Yang Song
Published: April 2017

A series of organic–inorganic acidic hybrids in uniform nanospheres were prepared by self‐assembly of phosphotungstic acid (HPW) and pyridine (PY) or triethylamine (TEA) without using a template and surfactant. The prepared samples were characterized by XRD, TEM, FTIR, and N2 adsorption–desorption isotherms, and their surface acidity was determined by titration. Particularly, PY‐PW‐1 showed a predominant catalytic performance in the near complete etherification of 5‐hydromethylfurfural (HMF) to 5‐ethoxymethylfurfural (EMF) with a high yield of 90 % at 80 °C in 24 h, which might be ascribed to its relatively high acidity and smaller particle size. This kinetic study elucidated the superior activity of PY‐PW‐1 in the HMF‐to‐EMF conversion. Fructose could also be directly converted to EMF in a moderate yield of 55 % at an elevated temperature of 120 °C by a cascade reaction process. In addition, PY‐PW‐1 could be reused five times with no evident loss of its catalytic activity. Importantly, the downstream product of EMF (i.e., ethyl levulinate) in an excellent yield of 93 % could also be achieved from HMF by further increasing the reaction temperature to 140 °C.
Developing, choosing and using landscape evolution models to inform field‐based landscape reconstruction studies
Authors: Temme A.J.A.M. , Armitage J. , Attal M. , van Gorp Wouter , Coulthard T.J. , Schoorl J.M.
Published: April 2017

Landscape evolution models (LEMs) are an increasingly popular resource for geomorphologists as they can operate as virtual laboratories where the implications of hypotheses about processes over human to geological timescales can be visualized at spatial scales from catchments to mountain ranges. Hypothetical studies for idealized landscapes have dominated, although model testing in real landscapes has also been undertaken. So far however, numerical landscape evolution models have rarely been used to aid field‐based reconstructions of the geomorphic evolution of actual landscapes. To help make this use more common, we review numerical landscape evolution models from the point of view of model use in field reconstruction studies. We first give a broad overview of the main assumptions and choices made in many LEMs to help prospective users select models appropriate to their field situation. We then summarize for various timescales which data are typically available and which models are appropriate. Finally, we provide guidance on how to set up a model study as a function of available data and the type of research question. Copyright © 2017 John Wiley & Sons, Ltd.
Mortality effects of temperature changes in the United Kingdom
Authors: Seklecka Malgorzata , Pantelous Athanasios A. , O'Hare Colin
Published: April 2017

Temperature changes are known to affect the social and environmental determinants of health in various ways. Consequently, excess deaths as a result of extreme weather conditions may increase over the coming decades because of climate change. In this paper, the relationship between trends in mortality and trends in temperature change (as a proxy) is investigated using annual data and for specified (warm and cold) periods during the year in the UK. A thoughtful statistical analysis is implemented and a new stochastic, central mortality rate model is proposed. The new model encompasses the good features of the Lee and Carter (Journal of the American Statistical Association, 1992,87: 659–671) model and its recent extensions, and for the very first time includes an exogenous factor which is a temperature‐related factor. The new model is shown to provide a significantly better‐fitting performance and more interpretable forecasts. An illustrative example of pricing a life insurance product is provided and discussed.
Pentraxin‐3 modulates lipopolysaccharide‐induced inflammatory response and attenuates liver injury
Authors: Perea Luis , Coll Mar , Sanjurjo Lucia , Blaya Delia , Taghdouini Adil El , Rodrigo‐Torres Daniel , Altamirano José , Graupera Isabel , Aguilar‐Bravo Beatriz , Llopis Marta , Vallverdú Julia , Caballeria Joan , van Grunsven Leo A. , Sarrias Maria‐Rosa , Ginès Pere , Sancho‐Bru Pau
Published: April 2017

Acute‐on‐chronic liver injury is characterized by an important inflammatory response frequently associated with endotoxemia. In this context, acute‐phase proteins such as Pentraxin‐3 (PTX3) are released; however, little is known about their role in chronic liver disease. The aim of this study was to elucidate the role of PTX3 in liver injury. The role of PTX3 was evaluated in cultured human cells, liver tissue slices, and mice with acute‐on‐chronic liver injury. PTX3 expression was assessed in tissue and serum samples from 54 patients with alcoholic hepatitis. PTX3 expression was up‐regulated in animal models of liver injury and strongly induced by lipopolysaccharide (LPS). Liver cell fractionation showed that macrophages and activated hepatic stellate cells were the main cell types expressing PTX3 in liver injury. Ex vivo and in vivo studies showed that PTX3 treatment attenuated LPS‐induced liver injury, inflammation, and cell recruitment. Mechanistically, PTX3 mediated the hepatic stellate cell wound‐healing response. Moreover, PTX3 modulated LPS‐induced inflammation in human primary liver macrophages and peripheral monocytes by enhancing a TIR domain–containing adapter‐inducing interferon–dependent response and favoring a macrophage interleukin‐10‐like phenotype. Additionally, hepatic and plasma PTX3 levels were increased in patients with alcoholic hepatitis, a prototypic acute‐on‐chronic condition; and its expression correlated with disease severity scores, endotoxemia, infections, and short‐term mortality, thus suggesting that expression of PTX3 found in patients could be a counterregulatory response to injury. Conclusion: Experimental and human evidence suggests that, in addition to being a potential biomarker for alcoholic hepatitis, PTX3 participates in the wound‐healing response and attenuates LPS‐induced liver injury and inflammation; therefore, administration of PTX3 could be a promising therapeutic strategy in acute‐on‐chronic conditions, particularly those associated with endotoxemia. (Hepatology 2017;66:953–968).
Adult‐onset cystic fibrosis liver disease: Diagnosis and characterization of an underappreciated entity
Authors: Koh Christopher , Sakiani Sasan , Surana Pallavi , Zhao Xiongce , Eccleston Jason , Kleiner David E. , Herion David , Liang T. Jake , Hoofnagle Jay H. , Chernick Milica , Heller Theo
Published: April 2017

Cystic fibrosis (CF) liver disease (CFLD), a leading cause of death in CF, is mostly described in pediatric populations. Adult‐onset CFLD lacks sufficient characterization and diagnostic tools. A cohort of CF patients without CFLD during childhood were followed for up to 38 years with serologic testing, imaging, and noninvasive fibrosis markers. Historical CFLD diagnostic criteria were compared with newly proposed CFLD criteria. Thirty‐six CF patients were followed for a median of 24.5 years (interquartile range 15.6‐32.9). By the last follow‐up, 11 (31%) had died. With conventional criteria, 8 (22%) patients had CFLD; and by the new criteria, 17 (47%) had CFLD at a median age of 36.6 years (interquartile range 26.5‐43.2). By the new criteria, those with CFLD had higher median alanine aminotransferase (42 versus 27, P = 0.005), aspartate aminotransferase (AST; 26 versus 21, P = 0.01), direct bilirubin (0.13 versus 0.1, P = 0.01), prothrombin time (14.4 versus 12.4, P = 0.002), and AST‐to‐platelet ratio index (0.31 versus 0.23, P = 0.003) over the last 2 years of follow‐up. Subjects with a FibroScan >6.8 kPa had higher alanine aminotransferase (42 versus 28U/L, P = 0.02), AST (35 versus 25U/L, P = 0.02), AST‐to‐platelet ratio index (0.77 versus 0.25, P = 0.0004), and Fibrosis‐4 index (2.14 versus 0.74, P = 0.0003) and lower platelet counts (205 versus 293, P = 0.02). One CFLD patient had nodular regenerative hyperplasia. Longitudinally, mean platelet counts significantly declined in the CFLD group (from 310 to 230 U/L, P = 0.0005). Deceased CFLD patients had lower platelet counts than those alive with CFLD (143 versus 258 U/L, P = 0.004) or those deceased with no CFLD (143 versus 327U/L, P = 0.006). Conclusion: Adult‐onset CFLD may be more prevalent than previously described, which suggests a later wave of CFLD that impacts morbidity; routine liver tests, radiologic imaging, noninvasive fibrosis markers, and FibroScan can be used algorithmically to identify adult CFLD; and further evaluation in other CF cohorts should be performed for validation. (Hepatology 2017;66:591–601).
Development of a novel frailty index to predict mortality in patients with end‐stage liver disease
Authors: Lai Jennifer C. , Covinsky Kenneth E. , Dodge Jennifer L. , Boscardin W. John , Segev Dorry L. , Roberts John P. , Feng Sandy
Published: April 2017

Cirrhosis is characterized by muscle wasting, malnutrition, and functional decline that confer excess mortality not well quantified by the Model for End‐Stage Liver Disease (MELD) Sodium (MELDNa) score. We aimed to develop a frailty index to capture these extrahepatic complications of cirrhosis and enhance mortality prediction in patients with cirrhosis. Consecutive outpatients listed for liver transplantation at a single transplant center without MELD exceptions were assessed with candidate frailty measures. Best subset selection analyses with Cox regression identified subsets of frailty measures that predicted waitlist mortality (=death or delisting because of sickness). We selected the frailty index by balancing statistical accuracy with clinical utility. The net reclassification index (NRI) evaluated the %patients correctly reclassified by adding the frailty index to MELDNa. Included were 536 patients with cirrhosis with median MELDNa of 18. One hundred seven (20%) died/were delisted. The final frailty index consisted of: grip strength, chair stands, and balance. The ability of MELDNa and the frailty index to correctly rank patients according to their 3‐month waitlist mortality risk (i.e., concordance‐statistic) was 0.80 and 0.76, respectively, but 0.82 for MELDNa+frailty index together. Compared with MELDNa alone, MELDNa+frailty index correctly reclassified 16% of deaths/delistings (P = 0.005) and 3% of nondeaths/delistings (P = 0.17) with a total NRI of 19% (P < 0.001). Compared to those with robust frailty index scores (<20th percentile), cirrhotics with poor frailty index scores (>80th percentile) were more impaired by gait speed, difficulty with Instrumental Activities of Daily Living, exhaustion, and low physical activity (P < 0.001 for each). Conclusion: Our frailty index for patients with cirrhosis, comprised of three performance‐based metrics, has construct validity for the concept of frailty and improves risk prediction of waitlist mortality over MELDNa alone. (Hepatology 2017;66:564–574).
Up‐regulation of golgi α‐mannosidase IA and down‐regulation of golgi α‐mannosidase IC activates unfolded protein response during hepatocarcinogenesis
Authors: Tu Hsiao‐Chen , Hsiao Yung‐Chun , Yang Wan‐Yu , Tsai Shin‐Lin , Lin Hua‐Kuo , Liao Chong‐Yi , Lu Jeng‐Wei , Chou Yu‐Ting , Wang Horng‐Dar , Yuh Chiou‐Hwa
Published: April 2017

α‐1,2 mannosidases, key enzymes in N‐glycosylation, are required for the formation of mature glycoproteins in eukaryotes. Aberrant regulation of α‐1,2 mannosidases can result in cancer, although the underlying mechanisms are unclear. Here, we report the distinct roles of α‐1,2 mannosidase subtypes (MAN1A, MAN1B, ERMAN1, MAN1C) in the formation of hepatocellular carcinoma (HCC). Clinicopathological analyses revealed that the clinical stage, tumor size, α‐fetoprotein level, and invasion status were positively correlated with the expression levels of MAN1A1, MAN1B1, and MAN1A2. In contrast, the expression of MAN1C1 was decreased as early as stage I of HCC. Survival analyses showed that high MAN1A1, MAN1A2, and MAN1B1 expression levels combined with low MAN1C1 expression levels were significantly correlated with shorter overall survival rates. Functionally, the overexpression of MAN1A1 promoted proliferation, migration, and transformation as well as in vivo migration in zebrafish. Conversely, overexpression of MAN1C1 reduced the migration ability both in vitro and in vivo, decreased the colony formation ability, and shortened the S phase of the cell cycle. Furthermore, the expression of genes involved in cell cycle/proliferation and migration was increased in MAN1A1‐overexpressing cells but decreased in MAN1C1‐overexpressing cells. MAN1A1 activated the expression of key regulators of the unfolded protein response (UPR), while treatment with endoplasmic reticulum stress inhibitors blocked the expression of MAN1A1‐activated genes. Using the MAN1A1 liver‐specific overexpression zebrafish model, we observed steatosis and inflammation at earlier stages and HCC formation at a later stage accompanied by the increased expression of the UPR modulator binding immunoglobulin protein (BiP). These data suggest that the up‐regulation of MAN1A1 activates the UPR and might initiate metastasis. Conclusion: MAN1A1 represents a novel oncogene while MAN1C1 plays a role in tumor suppression in hepatocarcinogenesis. (Hepatology Communications 2017;1:230‐247)
Effects of M1 and M4 activation on excitatory synaptic transmission in CA1
Authors: Thorn Catherine A. , Popiolek Michael , Stark Eda , Edgerton Jeremy R.
Published: April 2017

Hippocampal networks are particularly susceptible to dysfunction in many neurodegenerative diseases and neuropsychiatric disorders including Alzheimer's disease, Lewy body dementia, and schizophrenia. CA1, a major output region of the hippocampus, receives glutamatergic input from both hippocampal CA3 and entorhinal cortex, via the Schaffer collateral (SC) and temporoammonic (TA) pathways, respectively. SC and TA inputs to CA1 are thought to be differentially involved in the retrieval of previously stored memories versus the encoding of novel information, and switching between these two crucial hippocampal functions is thought to critically depend on acetylcholine (ACh) acting at muscarinic receptors. In this study, we aimed to determine the roles of specific subtypes of muscarinic receptors in mediating the neuromodulatory effects of ACh on glutamatergic synaptic transmission in the SC and TA pathways of CA1. Using selective pharmacological activation of M1 or M4 receptors along with extracellular and intracellular electrophysiology recordings from adult rat hippocampal slices, we demonstrate that activation of M1 receptors increases spontaneous spike rates of neuronal ensembles in CA1 and increases the intrinsic excitability of pyramidal neurons and interneurons. Selective activation of M4 receptors inhibits glutamate release in the SC pathway, while leaving synaptic transmission in the TA pathway comparatively intact. These results suggest specific mechanisms by which M1 and M4 activation may normalize CA1 circuit activity following disruptions of signaling that accompany neurodegenerative dementias or neuropsychiatric disorders. These findings are of particular interest in light of clinical findings that xanomeline, an M1/M4 preferring agonist, was able to improve cognitive and behavioral symptoms in patients with Alzheimer's disease or schizophrenia.
Tracer‐based evidence of heterogeneity in subsurface flow and storage within a boreal hillslope
Authors: Koch Joshua C. , Toohey Ryan C. , Reeves Donald M.
Published: April 2017

Runoff from boreal hillslopes is often affected by distinct soil boundaries, including the frozen boundary and the organic‐mineral boundary (OMB), where highly porous and hydraulically conductive organic material overlies fine‐grained mineral soils. Viewed from the surface, ground cover appears as a patchwork on sub‐meter scales, with thick, moss mats interspersed with lichen‐covered, silty soils with gravel inclusions. We conducted a decameter‐scale subsurface tracer test on a boreal forest hillslope in interior Alaska to quantify locations and mechanisms of transport and storage in these soils, focusing on the OMB. A sodium bromide tracer was added as a slug addition to a pit and sampled at 40 down‐gradient wells, screened primarily at the OMB and within a 7 × 12 m well field. We maintained an elevated head in the injection pit for 8.5 hr to simulate a storm. Tracer breakthrough velocities ranged from <0.12 to 0.93 m hr−1, with the highest velocities in lichen‐covered soils. After 12 hr and cessation of the elevated head, the tracer coalesced and was only detected in thick mosses at a trough in the OMB. By 24 hr, approximately 17% of the tracer mass could be accounted for. The majority of the mass loss occurred between 4 and 12 hr, while the tracer was in contact with lichen‐covered soils, which is consistent with tracer transport into deeper flow paths via preferential flow through discrete gravelly areas. Slow breakthroughs suggest that storage and exchange also occurred in shallow soils, likely related to saturation and drainage in fine‐grained mineral soils caused by the elevated hydraulic head. These findings highlight the complex nature of storage and transmission of water and solutes from boreal hillslopes to streams and are particularly relevant given rapid changes to boreal environments related to climate change, thawing permafrost and increasing fire severity.
Interactions between groundwater and seasonally ice‐covered lakes: Using water stable isotopes and radon‐222 multilayer mass balance models
Authors: Arnoux Marie , Gibert‐Brunet Elisabeth , Barbecot Florent , Guillon Sophie , Gibson John , Noret Aurélie
Published: April 2017

Interactions between lakes and groundwater are of increasing concern for freshwater environmental management but are often poorly characterized. Groundwater inflow to lakes, even at low rates, has proven to be a key in both lake nutrient balances and in determining lake vulnerability to pollution. Although difficult to measure using standard hydrometric methods, significant insight into groundwater–lake interactions has been acquired by studies applying geochemical tracers. However, the use of simple steady‐state, well‐mixed models, and the lack of characterization of lake spatiotemporal variability remain important sources of uncertainty, preventing the characterization of the entire lake hydrological cycle, particularly during ice‐covered periods.

In this study, a small groundwater‐connected lake was monitored to determine the annual dynamics of the natural tracers, water stable isotopes and radon‐222, through the implementation of a comprehensive sampling strategy. A multilayer mass balance model was found outperform a well‐mixed, one‐layer model in terms of quantifying groundwater fluxes and their temporal evolution, as well as characterizing vertical differences.

Water stable isotopes and radon‐222 were found to provide complementary information on the lake water budget. Radon‐222 has a short response time, and highlights rapid and transient increases in groundwater inflow, but requires a thorough characterization of groundwater radon‐222 activity. Water stable isotopes follow the hydrological cycle of the lake closely and highlight periods when the lake budget is dominated by evaporation versus groundwater inflow, but continuous monitoring of local meteorological parameters is required. Careful compilation of tracer evolution throughout the water column and over the entire year is also very informative. The developed models, which are suitable for detailed, site‐specific studies, allow the quantification of groundwater inflow and internal dynamics during both ice‐free and ice‐covered periods, providing an improved tool for understanding the annual water cycle of lakes.
Natural antioxidant flavonoids in formalin‐induced mice paw inflammation; inhibition of mitochondrial sorbitol dehydrogenase activity
Authors: Mohammad F. Ebtehal , Hasan Wedad A. , Mohamed Eman G.
Published: April 2017

Flavonoids have reported to cover interesting multiple pharmacological properties. This study evaluated the effect of apigenin or silymarin in paw inflammation induced by formalin in mice. Mice were divided into four groups: I: positive control group; II: apigenin, 3 mg/kg (i.p.); III: silymarin 50 mg/kg (p.o.); IV: meloxicam 10 mg/kg (p.o.), the reference drug. Therapies were administered once a day for 7 days. The curative effects were assessed on inflammatory, oxidative stress and neurotransmitter biomarkers, and apoptosis. Both flavonoids induced marked improvement in paw licking time, paw edema %, malondialdehyde content, superoxide dismutase, and sorbitol dehydrogenase activities, with slight progress in paw interlukin‐1β. Additionally, silymarin augmented brain content of dopamine and norepinephrine. Furthermore, flavonoids induced marked decline in extent of apoptosis. So, the results spotlight on the good influence of apigenin or silymarin as anti‐inflammatory, antioxidant, and antiapoptotic agents in formalin‐induced mice paw inflammation to even a better extent than meloxicam.