bluuebunny/crossref_metadata_2025 huggingface dataset:
A study of the Repeated Actions Diary in patients suffering from obsessive compulsive disorder
Authors: Bouvard Martine , Fournet Nathalie , Denis Anne , Achachi Ouafae , Purdon Christine
Published: December 2019

The structured Repeated Action Diary (RAD) collects in vivo data on compulsions and their various characteristics. Certain compulsions (i.e., those ending because the patient feels certain that it is safe to stop) are then compared with uncertain compulsions. The compulsion profile in patients with obsessive compulsive disorder (OCD) was assessed by using the RAD. Thirty‐two patients from two sources participated in the study. Before pooling the two subgroups, we checked that they did not differ significantly with regard to demographic and clinical variables. Patients reported several categories of compulsion. The most frequently reported compulsions were washing and checking. In a given person, checking compulsions (in contrast to washing compulsions) were often produced by several different obsessions. Almost all the patients reported repeating the compulsions because of a need to feel sure. There were far more “certain” compulsions than “uncertain” compulsions. The number of repetitions was significantly lower for certain compulsions than for uncertain compulsions. The person felt greater relief from guilt and responsibility and a greater decrease in discomfort at the end of a compulsive episode for certain compulsions than for uncertain compulsions. In conclusion, the need to ritualize (prompted by uncertainty, i.e., potential danger) might explain the maintenance (or posttreatment recurrence) of OCD in many patients. The need for certainty in the completion of a compulsion may be worth considering as a therapeutic tool. The development of an approach based on the need for certainty might help to improve treatment outcomes.
A pharmacokinetics study of orally administered higenamine in rats using LC–MS/MS for doping control analysis
Authors: Wang Rui , Xiong Xiaoping , Yang Ming , He Sirui , Xu Xiaoping
Published: December 2019

According to WADA guidelines, the presence of Higenamine (HG) in urine should not be ≥10 ng/mL. HG is widely found in materials used in Chinese herbal medicines as well as food and additives. This paper is the first method wherein a rat model has been used to evaluate the pharmacokinetics of orally administered HG by LC–MS/MS and would be helpful in doping control analysis. The method was found to be linear over a concentration range of 0.5(lower limit of quantification, LLOQ)–500 ng/mL for plasma and 0.5(LLOQ)–1000 ng/mL for urine. The values for intra‐ and inter‐day accuracy and precision did not deviate by >12.25% for HG in plasma and 5.87% in urine. Extraction recoveries of HG were 70.30–86.71% from plasma and 74.93%–79.29% from urine. HG was stable in plasma and urine after the extraction process and when exposed to different storage conditions. The findings of this study could provide some reference value for the assessment of HG misuse and for the control of intake and external application of HG‐related materials (foods and medicinal herbs). Our key findings are that high levels of external application or oral administration of HG‐rich materials may lead to a positive urine test for HG in athletes.
Food availability modulates temperature‐dependent effects on growth, reproduction, and survival in Daphnia magna
Authors: Betini Gustavo S. , Wang Xueqi , Avgar Tal , Guzzo Matthew M. , Fryxell John M.
Published: December 2019

Reduced body size and accelerated life cycle due to warming are considered major ecological responses to climate change with fitness costs at the individual level. Surprisingly, we know little about how relevant ecological factors can alter these life history trade‐offs and their consequences for individual fitness. Here, we show that food modulates temperature‐dependent effects on body size in the water flea Daphnia magna and interacts with temperature to affect life history parameters. We exposed 412 individuals to a factorial manipulation of food abundance and temperature, tracked each reproductive event, and took daily measurements of body size from each individual. High temperature caused a reduction in maximum body size in both food treatments, but this effect was mediated by food abundance, such that low food conditions resulted in a reduction of 20% in maximum body size, compared with a reduction of 4% under high food conditions. High temperature resulted in an accelerated life cycle, with pronounced fitness cost at low levels of food where only a few individuals produced a clutch. These results suggest that the mechanisms affecting the trade‐off between fast growth and final body size are food‐dependent, and that the combination of low levels of food and high temperature could potentially threaten viability of ectotherms.
Ecosystem scale evapotranspiration and CO2 exchange in burned and unburned peatlands: Implications for the ecohydrological resilience of carbon stocks to wildfire
Authors: Morison M. Q. , Petrone R. M. , Wilkinson S. L. , Green A. , Waddington J. M.
Published: December 2019

Boreal peatlands represent a significant global store of soil carbon, which are subject to increasing natural and anthropogenic disturbance. Wildfire is the single largest disturbance to boreal forest and wetlands annually. Critical to the long‐term carbon storage function in peatlands is the (re‐)establishment of a near‐surface water table following wildfire. This has been recently shown to in part be facilitated by post‐fire reductions in water losses via evapotranspiration (ET). However, reduced ET may also have cascade impacts on other ecohydrological processes in recovering peatlands, such as a reduction in carbon sequestration. To investigate the linked cycles of evaporative loss and carbon exchange in burned peatlands, the burned and unburned peatlands in Alberta, Canada, were instrumented with eddy covariance systems to monitor continuous fluxes of energy, carbon dioxide, and water vapour, over two summer seasons (2013 and 2014; 2–3 years post‐burn). The burned site showed significant changes to respiration and productivity and a shift in the partitioning of available energy (significantly larger Bowen ratio; mean values of 1.19 and 1.10 at the burned and unburned sites, respectively), as well as a significant reduction in ET rates. Decreases in respiration did not offset the decrease in primary productivity, and the burned site was significantly less productive than the reference site on a net production basis for the available data period. This provides direct observations of ET and CO2 fluxes at a novel ecosystem scale to show the impacts of fire on short‐term (2–3 years) post‐burn ecosystem ecohydrological function.
Design and testing of highly transparent concentrator photovoltaic modules for efficient dual‐land‐use applications
Authors: Sato Daisuke , Yamada Noboru
Published: December 2019

Two types of highly transparent concentrator photovoltaic (CPV) modules that separately utilize direct sunlight and diffuse sunlight for efficient dual‐land‐use applications were designed and tested. The type A module, comprising a typical‐scale CPV lens and solar cells, has a completely direct‐diffuse‐separated design for power generation and other solar applications. On the other hand, the type B module, consisting of a microscale CPV lens and solar cells, was designed to increase the amount of direct sunlight transmitted based on an intentional reduction in the ratio of the lens aperture area to the module aperture area. In experiments, both modules exhibit higher electricity yields and module‐transmitted irradiances (MTIs) than those of a conventional partially transparent flat photovoltaic module with 17% efficiency Si solar cells. Furthermore, the modules show direct normal irradiance‐based efficiencies of 26.7% (type A) and 18.5% (type B) while simultaneously showing MTI‐to‐global normal irradiance ratios of 15.3%‐63.7% (type A) and 38.0%‐63.8% (type B) under various irradiance conditions. Thus, an irradiance of at least 160 W/m2 under the modules can be achieved even when they are arrayed without gaps (at a ground coverage ratio = 1).
Bioavailability Assessment of Metals in Freshwater Environments: A Historical Review
Authors: Adams William , Blust Ronny , Dwyer Robert , Mount David , Nordheim Eirik , Rodriguez Patricio H. , Spry Doug
Published: December 2019

Many metals (aluminum, cadmium, cobalt, copper, nickel, lead, zinc) are widely studied environmental contaminants because of their ubiquity, potential toxicity to aquatic life, and tendency for toxicity to vary widely as a function of water chemistry. The interactions between metal and water chemistry influence metal “bioavailability,” an index of the rate and extent to which the metal reaches the site of toxic action. The implications of metal bioavailability for ecological risk assessment are large, with as much as a 100-fold variability across a range of water chemistries in surface waters. Beginning as early as the 1930s, considerable research effort was expended toward documenting and understanding metal bioavailability as a function of total and dissolved metal, water hardness, natural organic matter, pH, and other water characteristics. The understanding of these factors and improvements in both analytical and computational chemistry led to the development of modeling approaches intended to describe and predict the relationship between water chemistry and metal toxicity, including the free ion activity model, the gill surface interaction model, the biotic ligand model, and additional derivatives and regression models that arose from similar knowledge. The arc of these scientific advances can also be traced through the evolution of the US Environmental Protection Agency's ambient water quality criteria over the last 50 yr, from guidance in the “Green Book” (1968) to metal-specific criteria produced in the last decade. Through time, water quality criteria in many jurisdictions have incorporated increasingly sophisticated means of addressing metal bioavailability. The present review discusses the history of scientific understanding of metal bioavailability and the development and application of models to incorporate this knowledge into regulatory practice. Environ Toxicol Chem 2019;39:48–59. © 2019 SETAC
Best Practices for Derivation and Application of Thresholds for Metals Using Bioavailability-Based Approaches
Authors: Van Genderen Eric , Stauber Jenny L. , Delos Charles , Eignor Diana , Gensemer Robert W. , McGeer James , Merrington Graham , Whitehouse Paul
Published: December 2019

The primary goal of the present study is to provide a broad view of best practices for evaluating bioavailability models for metals for use in the protection of aquatic life. We describe the state of the science regarding 1) the evaluation and selection of ecotoxicity data, 2) the selection of bioavailability models for use in normalization, and 3) subsequent application of bioavailability models. Although many examples of normalization steps exist worldwide, a scheme is proposed to evaluate and select a model that takes account of its representativeness (water chemistry and taxonomic coverage of the ecotoxicity data set) and validation performance. Important considerations for a suitable model are the quantity of inputs needed, accuracy, and ease of use, all of which are needed to set protective values for aquatic life and to use these values to evaluate potential risks to organisms in receiving waters. Although the end results of different model application approaches may be broadly similar, the differences in these application frameworks ultimately come down to a series of trade-offs between who needs to collect the data and use the bioavailability model, the different requirements of spatial scales involved (e.g., regional vs site-specific values), and model predictiveness and protectiveness. Ultimately, understanding the limits and consequences of these trade-offs allows for selection of the most appropriate model and application framework to best provide the intended levels of aquatic life protection. Environ Toxicol Chem 2019;39:118–130. © 2019 SETAC
Validation of Bioavailability-Based Toxicity Models for Metals
Authors: Garman Emily R. , Meyer Joseph S. , Bergeron Christine M. , Blewett Tamzin A. , Clements William H. , Elias Michael C. , Farley Kevin J. , Gissi Francesca , Ryan Adam C.
Published: December 2019

Regulatory jurisdictions worldwide are increasingly incorporating bioavailability-based toxicity models into development of protective values (PVALs) for freshwater and saltwater aquatic life (e.g., water quality criteria, standards, and/or guidelines) for metals. Use of such models for regulatory purposes should be contingent on their ability to meet performance criteria as specified through a model-validation process. Model validation generally involves an assessment of a model's appropriateness, relevance, and accuracy. We review existing guidance for validation of bioavailability-based toxicity models, recommend questions that should be addressed in model-validation studies, discuss model study type and design considerations, present several new ways to evaluate model performance in validation studies, and suggest a framework for use of model validation in PVAL development. We conclude that model validation should be rigorous but flexible enough to fit the user's purpose. Although a model can never be fully validated to a level of zero uncertainty, it can be sufficiently validated to fit a specific purpose. Therefore, support (or lack of support) for a model should be presented in such a way that users can choose their own level of acceptability. We recommend that models be validated using experimental designs and endpoints consistent with the data sets that were used to parameterize and calibrate the model and validated across a broad range of geographically and ecologically relevant water types. Environ Toxicol Chem 2019;39:101–117. © 2019 SETAC
Development of Empirical Bioavailability Models for Metals
Authors: Brix Kevin V. , DeForest David K. , Tear Lucinda , Peijnenburg Willie , Peters Adam , Middleton Ellie T. , Erickson Russ
Published: December 2019

Recently, there has been renewed interest in the development and use of empirical models to predict metal bioavailability and derive protective values for aquatic life. However, there is considerable variability in the conceptual and statistical approaches with which these models have been developed. In the present study, we review case studies of empirical bioavailability model development, evaluating and making recommendations on key issues, including species selection, identifying toxicity-modifying factors (TMFs) and the appropriate environmental range of these factors, use of existing toxicity data sets and experimental design for developing new data sets, statistical considerations in deriving species-specific and pooled bioavailability models, and normalization of species sensitivity distributions using these models. We recommend that TMFs be identified from a combination of available chemical speciation and toxicity data and statistical evaluations of their relationships to toxicity. Experimental designs for new toxicity data must be sufficiently robust to detect nonlinear responses to TMFs and should encompass a large fraction (e.g., 90%) of the TMF range. Model development should involve a rigorous use of both visual plotting and statistical techniques to evaluate data fit. When data allow, we recommend using a simple linear model structure and developing pooled models rather than retaining multiple taxa-specific models. We conclude that empirical bioavailability models often have similar predictive capabilities compared to mechanistic models and can provide a relatively simple, transparent tool for predicting the effects of TMFs on metal bioavailability to achieve desired environmental management goals. Environ Toxicol Chem 2019;39:85–100. © 2019 SETAC
An adaptive resource placement policy by optimizing live VM migration for ITS applications in vehicular cloud network
Authors: Midya Sadip , Roy Asmita , Majumder Koushik , Phadikar Santanu
Published: December 2019

Vehicular cloud computing (VCC) is a promising approach that uses cloud computing techniques in vehicular environment to execute smart applications. Vehicular environment is characterized by high mobility. This requires the services executed by a vehicular resource in a vehicular cloud to be migrated before it leaves a network. Migration is also required when a service‐requesting vehicle has to leave a network before its request is executed. Moreover, to balance the network load, virtual machine (VM) migration is desired as, at times, a single physical host may become overloaded. In this work, we propose an adaptive resource placement policy by optimizing live VM migration process in vehicular cloud network. The Pareto optimal mapping of migrating VMs to a physical host is carried out using a hybrid optimized algorithm, which is the combination of particle swarm optimization and genetic algorithm. The optimization is done by maximizing a fitness function that is developed by considering significant quality‐of‐service (QoS) parameters, such as network latency, migration delay, power consumption, and vehicular mobility. These QoS parameters are mathematically formulated in view of a vehicular network. The proposed algorithm reduces migration latency, transmission latency, and service delay. It also distributes the load among the available physical hosts within a cloud system, thus reducing the average wait time for each cloud user. Simulation results exhibit significant decrease in waiting time, service delay, and migration delay. It is also shown that the proposed algorithm reduces total power consumption of the system.
Optimal energy beamforming under per‐antenna power constraint
Authors: Rezaei Zahra , Yazdian Ehsan , Tabataba Foroogh S. , Gazor Saeed
Published: December 2019

Energy beamforming (EB) is a key technique to enhance the efficiency of wireless power transfer. In this paper, we study the optimal EB under per‐antenna power constraint (PAC), which is more practical than the conventional sum‐power constraint. We consider a multiantenna energy transmitter with PAC that broadcasts wireless energy to multiple energy receivers (ER)s. We consider sum‐energy maximization problem with PAC and provide the optimal solution structure for the general case. This optimal structure implies that sending one energy beam is optimal under PAC, which means that the rank of transmit covariance matrix is one similar to sum‐power constraint. We also derive closed‐form solutions for two special cases and propose two suboptimal solutions for general case, which performs very close to optimal beamforming.
Does the facilitator of a scenario development activity need substantive knowledge of the focal topic?
Authors: Wright George , Cairns George
Published: December 2019

This short paper focuses on the facilitation of scenario development activity using the intuitive logics method. Counter‐intuitively, substantive knowledge of the focal scenario topic is not crucial. More important is the facilitator's active, intelligent involvement with participants over the whole of the scenario development process. In scenario development within a single organization, it is useful to have an assistant from the host organization who has both substantive knowledge of the focal topic and an interest in learning about scenario thinking. Within multi‐agency interventions, important issues for the facilitator to resolve are the potentially conflicted goals of participants and the extent of the involvement of senior‐level decision makers.
Ordered multinomial regression for genetic association analysis of ordinal phenotypes at Biobank scale
Authors: German Christopher A. , Sinsheimer Janet S. , Klimentidis Yann C. , Zhou Hua , Zhou Jin J.
Published: December 2019

Logistic regression is the primary analysis tool for binary traits in genome‐wide association studies (GWAS). Multinomial regression extends logistic regression to multiple categories. However, many phenotypes more naturally take ordered, discrete values. Examples include (a) subtypes defined from multiple sources of clinical information and (b) derived phenotypes generated by specific phenotyping algorithms for electronic health records (EHR). GWAS of ordinal traits have been problematic. Dichotomizing can lead to a range of arbitrary cutoff values, generating inconsistent, hard to interpret results. Using multinomial regression ignores trait value hierarchy and potentially loses power. Treating ordinal data as quantitative can lead to misleading inference. To address these issues, we analyze ordinal traits with an ordered, multinomial model. This approach increases power and leads to more interpretable results. We derive efficient algorithms for computing test statistics, making ordinal trait GWAS computationally practical for Biobank scale data. Our method is available as a Julia package OrdinalGWAS.jl. Application to a COPDGene study confirms previously found signals based on binary case–control status, but with more significance. Additionally, we demonstrate the capability of our package to run on UK Biobank data by analyzing hypertension as an ordinal trait.
CCS takes centre stage
Authors: Cozier Muriel
Published: December 2019

The words ‘high level’ and ‘carbon capture and storage’ (CCS) are beginning to crop up in the same sentence more frequently. CCS has indeed made its way into the high‐level discussions on which tools need to be deployed to mitigate climate change. In this article GHGS&T's Muriel Cozier reviews the European High Level Conference on Carbon Capture and Storage and looks to see if CCS has, at last, come of age. © 2019 Society of Chemical Industry and John Wiley & Sons, Ltd.
Regulation of food intake by astrocytes in the brainstem dorsal vagal complex
Authors: MacDonald Alastair J. , Holmes Fiona E. , Beall Craig , Pickering Anthony E. , Ellacott Kate L. J.
Published: December 2019

A role for glial cells in brain circuits controlling feeding has begun to be identified with hypothalamic astrocyte signaling implicated in regulating energy homeostasis. The nucleus of the solitary tract (NTS), within the brainstem dorsal vagal complex (DVC), integrates vagal afferent information from the viscera and plays a role in regulating food intake. We hypothesized that astrocytes in this nucleus respond to, and influence, food intake. Mice fed high‐fat chow for 12 hr during the dark phase showed NTS astrocyte activation, reflected in an increase in the number (65%) and morphological complexity of glial‐fibrillary acidic protein (GFAP)‐immunoreactive cells adjacent to the area postrema (AP), compared to control chow fed mice. To measure the impact of astrocyte activation on food intake, we delivered designer receptors exclusively activated by designer drugs (DREADDs) to DVC astrocytes (encompassing NTS, AP, and dorsal motor nucleus of the vagus) using an adeno‐associated viral (AAV) vector (AAV‐GFAP‐hM3Dq_mCherry). Chemogenetic activation with clozapine‐N‐oxide (0.3 mg/kg) produced in greater morphological complexity in astrocytes and reduced dark‐phase feeding by 84% at 4 hr postinjection compared with vehicle treatment. hM3Dq‐activation of DVC astrocytes also reduced refeeding after an overnight fast (71% lower, 4 hr postinjection) when compared to AAV‐GFAP‐mCherry expressing control mice. DREADD‐mediated astrocyte activation did not impact locomotion. hM3Dq activation of DVC astrocytes induced c‐FOS in neighboring neuronal feeding circuits (including in the parabrachial nucleus). This indicates that NTS astrocytes respond to acute nutritional excess, are involved in the integration of peripheral satiety signals, and can reduce food intake when activated.
Modulation of Biliary Cancer Chemo‐Resistance Through MicroRNA‐Mediated Rewiring of the Expansion of CD133+ Cells
Authors: Carotenuto Pietro , Hedayat Somaieh , Fassan Matteo , Cardinale Vincenzo , Lampis Andrea , Guzzardo Vincenza , Vicentini Caterina , Scarpa Aldo , Cascione Luciano , Costantini Daniele , Carpino Guido , Alvaro Domenico , Ghidini Michele , Trevisani Francesco , Te Poele Robert , Salati Massimiliano , Ventura Sofia , Vlachogiannis Georgios , Hahne Jens C. , Boulter Luke , Forbes Stuart J. , Guest Rachel V. , Cillo Umberto , Said‐Huntingford Ian , Begum Ruwaida , Smyth Elizabeth , Michalarea Vasiliki , Cunningham David , Rimassa Lorenza , Santoro Armando , Roncalli Massimo , Kirkin Vladimir , Clarke Paul , Workman Paul , Valeri Nicola , Braconi Chiara
Published: December 2019

Background and Aims

Changes in single microRNA (miRNA) expression have been associated with chemo‐resistance in biliary tract cancers (BTCs). However, a global assessment of the dynamic role of the microRNome has never been performed to identify potential therapeutic targets that are functionally relevant in the BTC cell response to chemotherapy.

Approach and Results

High‐throughput screening (HTS) of 997 locked nucleic acid miRNA inhibitors was performed in six cholangiocarcinoma cell lines treated with cisplatin and gemcitabine (CG) seeking changes in cell viability. Validation experiments were performed with mirVana probes. MicroRNA and gene expression was assessed by TaqMan assay, RNA‐sequencing, and in situ hybridization in four independent cohorts of human BTCs. Knockout of microRNA was achieved by CRISPR‐CAS9 in CCLP cells (MIR1249KO) and tested for effects on chemotherapy sensitivity in vitro and in vivo. HTS revealed that MIR1249 inhibition enhanced chemotherapy sensitivity across all cell lines. MIR1249 expression was increased in 41% of cases in human BTCs. In validation experiments, MIR1249 inhibition did not alter cell viability in untreated or dimethyl sulfoxide–treated cells; however, it did increase the CG effect. MIR1249 expression was increased in CD133+ biliary cancer cells freshly isolated from the stem cell niche of human BTCs as well as in CD133+ chemo‐resistant CCLP cells. MIR1249 modulated the chemotherapy‐induced enrichment of CD133+ cells by controlling their clonal expansion through the Wnt‐regulator FZD8. MIR1249KO cells had impaired expansion of the CD133+ subclone and its enrichment after chemotherapy, reduced expression of cancer stem cell markers, and increased chemosensitivity. MIR1249KO xenograft BTC models showed tumor shrinkage after exposure to weekly CG, whereas wild‐type models showed only stable disease over treatment.

Conclusions

MIR1249 mediates resistance to CG in BTCs and may be tested as a target for therapeutics.
Investigation of multiphasic 3D‐bioplotted scaffolds for site‐specific chondrogenic and osteogenic differentiation of human adipose‐derived stem cells for osteochondral tissue engineering applications
Authors: Mellor Liliana F. , Nordberg Rachel C. , Huebner Pedro , Mohiti‐Asli Mahsa , Taylor Michael A. , Efird William , Oxford Julia T. , Spang Jeffrey T. , Shirwaiker Rohan A. , Loboa Elizabeth G.
Published: December 2019

Osteoarthritis is a degenerative joint disease that limits mobility of the affected joint due to the degradation of articular cartilage and subchondral bone. The limited regenerative capacity of cartilage presents significant challenges when attempting to repair or reverse the effects of cartilage degradation. Tissue engineered medical products are a promising alternative to treat osteochondral degeneration due to their potential to integrate into the patient's existing tissue. The goal of this study was to create a scaffold that would induce site‐specific osteogenic and chondrogenic differentiation of human adipose‐derived stem cells (hASC) to generate a full osteochondral implant. Scaffolds were fabricated using 3D‐bioplotting of biodegradable polycraprolactone (PCL) with either β‐tricalcium phosphate (TCP) or decellularized bovine cartilage extracellular matrix (dECM) to drive site‐specific hASC osteogenesis and chondrogenesis, respectively. PCL‐dECM scaffolds demonstrated elevated matrix deposition and organization in scaffolds seeded with hASC as well as a reduction in collagen I gene expression. 3D‐bioplotted PCL scaffolds with 20% TCP demonstrated elevated calcium deposition, endogenous alkaline phosphatase activity, and osteopontin gene expression. Osteochondral scaffolds comprised of hASC‐seeded 3D‐bioplotted PCL‐TCP, electrospun PCL, and 3D‐bioplotted PCL‐dECM phases were evaluated and demonstrated site‐specific osteochondral tissue characteristics. This technique holds great promise as cartilage morbidity is minimized since autologous cartilage harvest is not required, tissue rejection is minimized via use of an abundant and accessible source of autologous stem cells, and biofabrication techniques allow for a precise, customizable methodology to rapidly produce the scaffold.
Rac1 Inhibition Via Srgap2 Restrains Inflammatory Osteoclastogenesis and Limits the Clastokine, SLIT3
Authors: Shin Bongjin , Kupferman Justine , Schmidt Ewoud , Polleux Franck , Delany Anne M , Lee Sun-Kyeong
Published: December 2019

The Rac1-specific guanosine triphosphatase (GTPase)-activating protein Slit-Robo GAP2 (Srgap2) is dramatically upregulated during RANKL-induced osteoclastogenesis. Srgap2 interacts with the cell membrane to locally inhibit activity of Rac1. In this study, we determined the role of Srgap2 in the myeloid lineage on bone homeostasis and the osteoclastic response to TNFα treatment. The bone phenotype of mice specifically lacking Srgap2 in the myeloid lineage (Srgap2 f/f:LysM-Cre; Srgap2 conditional knockout [cKO]) was investigated using histomorphometric analysis, in vitro cultures and Western blot analysis. Similar methods were used to determine the impact of TNFα challenge on osteoclast formation in Srgap2 cKO mice. Bone parameters in male Srgap2 cKO mice were unaffected. However, female cKO mice displayed higher trabecular bone volume due to increased osteoblast surface and bone formation rate, whereas osteoclastic parameters were unaltered. In vitro, cells from Srgap2 cKO had strongly enhanced Rac1 activation, but RANKL-induced osteoclast formation was unaffected. In contrast, conditioned medium from Srgap2 cKO osteoclasts promoted osteoblast differentiation and had increased levels of the bone anabolic clastokine SLIT3, providing a possible mechanism for increased bone formation in vivo. Rac1 is rapidly activated by the inflammatory cytokine TNFα. Supracalvarial injection of TNFα caused an augmented osteoclastic response in Srgap2 cKO mice. In vitro, cells from Srgap2 cKO mice displayed increased osteoclast formation in response to TNFα. We conclude that Srgap2 plays a prominent role in limiting osteoclastogenesis during inflammation through Rac1, and restricts expression of the paracrine clastokine SLIT3, a positive regulator of bone formation. © 2019 American Society for Bone and Mineral Research.
Dimerization energetics of the G‐protein coupled bile acid receptor TGR5 from all‐atom simulations
Authors: Wäschenbach Lucas , Gertzen Christoph G. W. , Keitel Verena , Gohlke Holger
Published: December 2019

We describe the first extensive energetic evaluation of GPCR dimerization on the atomistic level by means of potential of mean force (PMF) computations and implicit solvent/implicit membrane end‐point free energy calculations (MM‐PBSA approach). Free energies of association computed from the PMFs show that the formation of both the 1/8 and 4/5 interface is energetically favorable for TGR5, the first GPCR known to be activated by hydrophobic bile acids and neurosteroids. Furthermore, formation of the 1/8 interface is favored over that of the 4/5 interface. Both results are in line with our previous FRET experiments in live cells. Differences in lipid‐protein interactions are identified to contribute to the observed differences in free energies of association. A per‐residue decomposition of the MM‐PBSA effective binding energy reveals hot spot residues specific for both interfaces that form clusters. This knowledge may be used to guide the design of dimerization inhibitors or perform mutational studies to explore physiological consequences of distorted TGR5 association. Finally, we characterized the role of Y111, located in the conserved (D/E)RY motif, as a facilitator of TGR5 interactions. The types of computations performed here should be transferable to other transmembrane proteins that form dimers or higher oligomers as long as good structural models of the dimeric or oligomeric states are available. Such computations may help to overcome current restrictions due to an imperfect energetic representation of protein association at the coarse‐grained level. © 2019 The Authors. Journal of Computational Chemistry published by Wiley Periodicals LLC.
Association of polymorphisms in MALAT1 with the risk of endometrial cancer in Southern Chinese women
Authors: Chen Guange , Zhang Mingyao , Liang Zongwen , Chen Sailing , Chen Feng , Zhu Jiawei , Zhao Manman , He Jing , Hua Wenfeng , Duan Ping
Published: December 2019

Background

Endometrial cancer is the most common gynecologic malignancy worldwide. Polymorphisms in MALAT1 have been demonstrated to play critical roles in cancer. However, the roles of MALAT1 polymorphisms in the etiology of endometrial cancer have not been well documented.

Methods

We genotyped three MALAT1 polymorphisms in 249 endometrial cancer cases and 446 cancer‐free female controls using quantitative polymerase chain reaction with TaqMan probes. To estimate the association between MALAT1 polymorphisms (rs591291 C>T, rs664589 C>G, and rs4102217 G>C) and the risk of endometrial cancer, an unconditional logistic regression model was conducted to calculate the odds ratio (OR) and the 95% confidence interval (CI), adjusting for surgery history, menopause, number of deliveries, BMI, and FIGO stage.

Results

We found that the MALAT1 rs664589 C>G polymorphism was significantly associated with endometrial cancer risk (heterogeneous: adjusted OR = 0.57, 95% CI = 0.34‐0.93, P = .026; homogenous: adjusted OR = 3.74, 95% CI = 1.12‐12.45, P = .032; and recessive: adjusted OR = 4.06, 95% CI = 1.22‐13.48, P = .022). Stratified analysis further demonstrated that the MALAT1 rs664589 C>G polymorphism significantly increased the risk of endometrial cancer susceptibility in patients with no history of surgery, more deliveries, BMI between 25 and 29.9, and FIGO stages II‐III. Compared with the wild‐type GCG haplotype carriers, individuals with CGG haplotypes had a higher risk of developing endometrial cancer.

Conclusion

The MALAT1 rs664589 C>G polymorphism was associated with a significant increase in endometrial cancer risk.
Predictive value of long non‐coding RNA intersectin 1‐2 for occurrence and in‐hospital mortality of severe acute pancreatitis
Authors: Li Jun , Bu Xiaofen , Chen Xuanlan , Xiong Peng , Chen Zhen , Yu Li
Published: December 2019

Background

This study aimed to investigate the predictive value of long non‐coding RNA intersectin 1‐2 (lnc‐ITSN1‐2) for severe acute pancreatitis (SAP) risk, and its correlation with disease severity and in‐hospital mortality in SAP patients.

Methods

Plasma samples from 60 SAP, 60 moderate‐severe acute pancreatitis (MSAP) and 60 mild acute pancreatitis (MAP) patients were collected within 24 hours, and plasma samples from 60 age and gender‐matched healthy controls (HCs) were collected when enrollment. Lnc‐ITSN1‐2 was detected by reverse transcription‐quantitative polymerase chain reaction. In AP patients, disease severity was evaluated and in‐hospital deaths were recorded.

Results

Lnc‐ITSN1‐2 was increased in SAP patients compared with MSAP, MAP patients, and HCs, and it is well‐discriminated SAP patients from MSAP patients (area under curve (AUC): 0.699, 95% confidence interval (CI): 0.605‐0.792), MAP patients (AUC: 0.862, 95% CI: 0.798‐0.926), and HCs (AUC: 0.958, 95% CI: 0.925‐0.990). For disease severity, lnc‐ITSN1‐2 was positively correlated with Ranson's score, acute pathologic and chronic health evaluation (APACHE) II score, sequential organ failure assessment (SOFA) score, and C‐reactive protein (CRP) in SAP patients, MSAP patients, and MAP patients; meanwhile, the correlation coefficients were highest in SAP patients. Furthermore, lnc‐ITSN1‐2 displayed a good predictive value for increased in‐hospital mortality in SAP (AUC: 0.803, 95% CI: 0.673‐0.933) and MSAP (AUC: 0.854, 95% CI: 0.752‐0.956) patients, which was similar with several common prognostic factors (including Ranson's score, APACHE II score, SOFA score, and CRP).

Conclusion

Lnc‐ITSN1‐2 might be a potential biomarker for discrimination of SAP to improve the prognosis of SAP patients.
miR‐647 inhibits glioma cell proliferation, colony formation and invasion by regulating HOXA9
Authors: Qin Kun , Tian Ge , Chen Guangzhong , Zhou Dong , Tang Kai
Published: December 2019

Background

MicroRNA‐647 (miR‐647) has been reported to regulate tumor development, although its role in glioma remains unclear.

Methods

miR‐647 expression in glioma cells and normal cells was measured using a quantitative real‐time polymerase chain reaction. The effects of miR‐647 expression on glioma cell proliferation, cell apoptosis, colony formation and cell invasion were measured using a cell counting kit‐8 assay, flow cytometry, a colony formation assay and a transwell invasion assay. Luciferase activity reporter and western blot assays were conducted to explore whether homeobox A9 (HOXA9) was a direct target of miR‐647.

Results

We found that miR‐647 expression was downregulated in glioma cell lines compared to the normal cell line. Overexpression of miR‐647 inhibits glioma cell proliferation, colony formation and cell invasion, although it promotes apoptosis in vitro. HOXA9 was validated a direct target of miR‐647 and the overexpression of HOXA9 reversed the effects of miR‐647 on glioma cell behavior.

Conclusions

The identification of the miR‐647/HOXA9 axis will advance our understanding underlying glioma progression and provide novel therapeutic targets for glioma treatment.
Formal [3 + 2] cycloaddition of azomethine ylides generated in situ with unactivated cyclic imines: A facile approach to tricyclic imidazolines derivatives
Authors: Wang Kai‐Kai , Li Yan‐Li , Wang Zhan‐Yong , Ma Xueji , Mei Ya‐Lei , Zhang Shan‐Shan , Chen Rongxiang
Published: December 2019

A simple and efficient method for the synthesis of tricyclic imidazolines derivatives via [3 + 2] 1,3‐dipolar cycloaddition between nonstabilized azomethine ylide generated in situ with unactivated cyclic imines is reported here. The method provided easy and mild access to various fused tricyclic hexahydroimidazo[5,1‐a]isoquinolines in excellent yields (up to 96%). This protocol is simple and easy to handle.
Comparison of the pH‐dependent formation of His and Cys heptapeptide complexes of nickel(II), copper(II), and zinc(II) as determined by ion mobility‐mass spectrometry
Authors: Yousef Enas N. , Angel Laurence A.
Published: December 2019

The analog methanobactin (amb) peptide with the sequence ac‐His1‐Cys2‐Gly3‐Pro4‐Tyr5‐His6‐Cys7 (amb5A) will bind the metal ions of zinc, nickel, and copper. To further understand how amb5A binds these metals, we have undertaken a series of studies of structurally related heptapeptides where one or two of the potential His or Cys binding sites have been replaced by Gly, or the C‐terminus has been blocked by amidation. The studies were designed to compare how these metals bind to these sequences in different pH solutions of pH 4.2 to 10 and utilized native electrospray ionization (ESI) with ion mobility‐mass spectrometry (IM‐MS) which allows for the quantitative analysis of the charged species produced during the reactions. The native ESI conditions were chosen to conserve as much of the solution‐phase behavior of the amb peptides as possible and an analysis of how the IM‐MS results compare with the expected solution‐phase behavior is discussed. The oligopeptides studied here have applications for tag‐based protein purification methods, as therapeutics for diseases caused by elevated metal ion levels or as inhibitors for metal‐protein enzymes such as matrix metalloproteinases.
Wide QRS complex and the risk of major arrhythmic events in Brugada syndrome patients: A systematic review and meta‐analysis
Authors: Rattanawong Pattara , Kewcharoen Jakrin , Techorueangwiwat Chol , Kanitsoraphan Chanavuth , Mekritthikrai Raktham , Prasitlumkum Narut , Puttapiban Prapaipan , Mekraksakit Poemlarp , Vutthikraivit Wasawat , Sorajja Dan
Published: December 2019

Background

Brugada syndrome (BrS) is an inherited arrhythmic disease associated with an increased risk of major arrhythmic events (MAE). Previous studies reported that a wide QRS complex may be useful as a predictor of MAE in BrS patients. We aimed to assess the correlation of wide QRS complex with MAE by a systematic review and meta‐analysis.

Methods

We comprehensively searched the databases of MEDLINE and EMBASE from inception to June 2019. Included studies were cohort and case control studies that reported QRS duration and the relationship between wide QRS complex (>120 milliseconds) and MAE (sudden cardiac death, sudden cardiac arrest, ventricular fibrillation, sustained ventricular tachycardia, or appropriate shock). Data from each study were combined using the random‐effects model.

Results

Twenty‐two studies from 2007 to 2018 were included in this meta‐analysis involving 4,814 BrS patients. The mean age was 46.1 ± 12.8 years. The patients were predominately men (77.6%). Wide QRS duration was an independent predictor of MAE (pooled risk ratio 1.55, 95% confidence interval: 1.04‐2.30, P = .30, I2 = 38.4%). QRS duration was wider in BrS who had history of MAE (weight mean difference = 8.12 milliseconds, 95% confidence interval: 5.75‐10.51 milliseconds).

Conclusions

Our study demonstrated that QRS duration is wider in BrS who had history of MAE, and a wide QRS complex is associated with 1.55 times higher risk of MAE in BrS populations. Wide QRS complex can be considered for risk stratification in prediction of MAE in patients with BrS, especially when considering implantable cardioverter‐defibrillator placement in asymptomatic patients.
Audience perceptions of high‐status ties and network advantage: The market for coaching jobs in the National Collegiate Athletic Association (2000–2011)
Authors: Halgin Daniel S. , Borgatti Stephen P. , Mehra Ajay , Soltis Scott
Published: December 2019

Social ties with high‐status others can be a potent signal of an individual's underlying quality and future promise. Individuals in competitive markets, therefore, have an incentive to publicly claim connections to high‐status others. However, cognitive limitations and biases can make social network connections difficult for observers to reliably discern, and claims to high‐status ties can go unrecognized by the audience. Our core contention is that claims to high‐status affiliation are advantageous only when the audience recognizes the claim—unrecognized claims, like unreliable signals, do not deliver advantage and can backfire. Further, we draw on the literature on imprinting and develop arguments for why some people are more likely to make claims to high‐status ties and why some claims to high‐status ties are more likely than others to be recognized by the audience. We test our arguments with data from the market for head coaching jobs in NCAA basketball (2000–2011). Our study contributes to the sparse literature on how social network ties that exist in the minds of third‐party observers influence individual attainment in market settings; and it offers new insights into how imprinting processes shape the perception and use of high‐status network ties.
Development and validation of a nomogram for predicting overall survival of node‐negative ampullary carcinoma
Authors: Huang Xi‐Tai , Huang Chen‐Song , Chen Wei , Cai Jian‐Peng , Gan Tian‐Tian , Zhao Ying , Liu Qi , Liang Li‐Jian , Yin Xiao‐Yu
Published: December 2019

Background

The accuracy of the current staging system for predicting the overall survival (OS) of patients with ampullary carcinoma (AC) is still unsatisfactory, especially in node‐negative (N0) patients. We aimed at establishing a nomogram to accurately predict OS in N0 AC.

MethodS

This study enrolled 697 N0 AC patients from the Surveillance, Epidemiology, and End Results database (design cohort [DC], n = 697) and the First Affiliated Hospital of Sun Yat‐sen University (validation cohort [VC], n = 112), who underwent surgical resection. The nomogram was established by using prognostic factors determined by univariate and multivariate regression analyses.

Results

The nomogram for OS was developed by using four independent prognostic factors, including age, grade, T stage, and a number of examined lymph nodes. The C‐index of a nomogram for OS in DC and VC was 0.665 and 0.731, respectively. Calibration curves showed good consistency of the nomogram. The nomogram had a better accuracy in predicting OS compared with conventional staging system (P < .05). On the basis of nomogram‐predicted scores, the patients were stratified into groups with different risk. The OS of low‐risk patients was significantly longer than high‐risk ones (P ≤ .010).

Conclusions

The nomogram could be used to predict the OS of N0 AC. It could help guide further treatment in clinical practice.
miR‐574‐3p inhibits proliferation and invasion in esophageal cancer by targeting FAM3C and MAPK1
Authors: Jin Ling‐Li , Zhang Shao‐Jun , Lu Guang‐Xin , Lv Fei , Shang Rui , Yang Jie
Published: December 2019

Esophageal cancer is considered as one of the leading malignancies. MicroRNA‐574‐3p (miR‐574‐3p) was used as a postoperative prognostic indicator in patients with esophageal squamous cell carcinoma. However, the underlying mechanism miR‐574‐3p involvement in esophageal cancer remains unclear. In this study, the expression of miR‐574‐3p was reduced in esophageal cancer tissues and cells. In vitro, miR‐574‐3p mimics and inhibitor were transfected into esophageal cancer cells (TE‐1 and TE‐8 cells) to up‐ or downregulating of miR‐574‐3p. miR‐574‐3p inhibited proliferation, migration and invasion, and promoted apoptosis in esophageal cancer cells. In addition, miR‐574‐3p was confirmed to target family with sequence similarity 3 member C (FAM3C) and mitogen‐activated protein kinase 1 (MAPK1). miR‐574‐3p suppressed phosphoinositide 3‐kinase (PI3K)/protein kinase B (AKT) and rapidly accelerated fibrosarcoma (Raf)/mitogen‐activated protein kinase (MEK)/extracellular signal‐regulated kinase (ERK) signaling via regulating FAM3C and MAPK1. In vivo, overexpression of miR‐574‐3p suppressed tumor growth in mice. Our findings indicated that miR‐574‐3p repressed proliferation and invasion of esophageal cancer via regulation of FAM3C and MAPK1, which provides a new biomarker for esophageal cancer treatment.