bluuebunny/crossref_metadata_2025 huggingface dataset:
Anxiety and distress following receipt of results from routine HPV primary testing in cervical screening: The psychological impact of primary screening (PIPS) study
Authors: McBride Emily , Marlow Laura A.V. , Forster Alice S. , Ridout Deborah , Kitchener Henry , Patnick Julietta , Waller Jo
Published: June 2019

We used a cross‐sectional survey to examine short‐term anxiety and distress in women receiving different results following routine human papillomavirus (HPV) primary testing at cervical screening. Participants were women aged 24–65 (n = 1,127) who had attended screening at one of five sites piloting HPV primary screening in England, including a control group with normal cytology who were not tested for HPV. Women completed a postal questionnaire ~2 weeks after receiving their screening result. Unadjusted mean anxiety scores ranged from 32.9 (standard deviation [SD] = 12.2) in HPV‐negative women to 42.1 (SD = 14.9) in women who were HPV‐positive with abnormal cytology. In adjusted analyses, anxiety was significantly higher in women testing HPV‐positive with either normal cytology (mean difference [MD] = 3.5, CI: 0.6–6.4) or abnormal cytology (MD = 7.2, CI: 3.7–10.6), than the control group. Distress was slightly higher in women who tested HPV‐positive with abnormal cytology (MD = 0.9, CI: 0.02–1.8), than the control group. We also found increased odds of very high anxiety in women who tested HPV‐positive with normal or abnormal cytology compared to the control group. This pattern of results was only observed among women receiving their first HPV‐positive result, not among women found to have persistent HPV at 12‐month follow‐up. Testing HPV‐positive with normal cytology for the first time, is associated with elevated anxiety despite carrying very low immediate cervical cancer risk. However, receiving the same test result at 12‐month early recall does not appear to be associated with higher anxiety, suggesting anxiety may normalise with repeated exposure and/or over time.
Detection of mitochondrial dysfunction in vitro by laser‐induced autofluorescence
Authors: Raghushaker Chandavalli R. , Chandra Subhash , Chakrabarty Sanjiban , Kabekkodu Shama P. , Satyamoorthy Kapaettu , Mahato Krishna K.
Published: June 2019

Mitochondrion plays a significant role in a variety of biological functions. Because of their diverse character and location in the cellular systems, mitochondria commonly get exposed to various extrinsic and intrinsic cellular stresses. The present study reports a novel approach to detection of mitochondrial dysfunction based on tryptophan autofluorescence of its proteins in mouse liver, using laser‐induced fluorescence (LIF) as a tool. Mitochondria, isolated from the mouse liver, were initially tested for purity and integrity using lactate dehydrogenase and succinate dehydrogenase (SDH) assays. Mitochondrial stress was induced by treating the isolated mitochondria with heavy metals at 10 and 0.01 mM for sodium arsenite and mercuric chloride, respectively. Upon treatment with the heavy metal, tryptophan autofluorescence quenching was recorded at 281 nm excitation. The functional integrity of the mitochondria treated with heavy metals was evaluated by measuring SDH and cytochrome c oxidase activities at various concentrations of mitochondria, which showed impaired activity as compared to control upto a concentration of 6.25 μg. A significant shift was also observed in the autofluorescence of proteins upto the level below 1 μg, suggesting their conformational change and hence altered structural integrity of mitochondria. Circular dichroism spectroscopy data of the mitochondrial proteins treated with heavy metals further validates their conformational change as compared to untreated control. The present study clearly shows that the LIF can be a novel detection tool to detect altered structural integrity of cellular mitochondria upon stress, and it also possesses the potentiality to combine with other interdisciplinary modalities.
MembrFactory: A Force Field and composition Double Independent Universal Tool for Constructing Polyamide Reverse Osmosis Membranes
Authors: Li Ke , Li Shanlong , Huang Wei , Yu Chunyang , Zhou Yongfeng
Published: June 2019

The topmost polyamide (PA) layer of the thin‐film‐composite reverse osmosis (RO) membrane is the most important part in the membrane‐based RO technology. With the aid of molecular dynamics simulations, many PA layer‐related features in the RO process can be revealed. With many novel types of PA RO membranes out of trimesoyl chloride/m‐phenylenediamine monomers developed in the laboratory, a convenient model building tool for these PA layer systems is urgently needed to conduct the theoretical analysis. Here, we develop a new universal toolkit for constructing PA RO membranes, named as MembrFactory, which combines flexibility of force fields and membrane compositions. A key characteristic of our approach is the use of monomers as the starting state, and the final membrane model was obtained automatically by stepwise reaction between the functional groups on the monomers. The reliability of MembrFactory has been validated by constructing several common PA RO membranes. © 2019 Wiley Periodicals, Inc.
Trend analysis and change point detection of seasonal and annual precipitation in Iran
Authors: Salehi Somayeh , Dehghani Majid , Mortazavi Sayed M. , Singh Vijay P.
Published: June 2019

The aim of this study was to analyse spatial and temporal homogeneity and trends in seasonal and annual precipitation and their fluctuations during 1957–2016 in Iran. For testing homogeneity, the Pettitt‐Whitney–Mann, the Standard Normal Homogeneity or Alexandersson's SNHT, Buishand's and the Von Neumann tests were used and for trend analysis, Mann‐Kendall and Sequential Mann‐Kendall tests were used. Homogeneity tests showed that most of the seasonal and annual precipitation time series were homogeneous and the change point was detected only at a few stations. Results indicated that in general, there was an upward trend during 1957–1986, followed by a significant downward trend during 1987–2016. The sequential Mann‐Kendall test detected several possible change points over time, although most of them were found statistically non‐significant at 95% confidence level. Upward and downward trends started in annual and seasonal precipitation after 1960 and 1990, respectively, at most stations, except in spring. In spring, an upward trend started after 1990 at some stations which showed a shift in precipitation from winter to spring. Also, the Sen's slope estimator indicated a higher downward trend in the northern parts of Iran. Two findings are worthy of note based on the results of this study. First, in general, a significant downward trend occurred in the whole country after1990. Second, a shift in precipitation from winter to spring was detected at some stations in different homogeneous regions.
Rice protein reduces DNA damage by activating the p53 pathway and stimulating endogenous antioxidant response in growing and adult rats
Authors: Liang Mingcai , Li Hui , Wang Zhengxuan , Cai Liang , Yang Lin
Published: June 2019

BACKGROUND

Reactive oxygen species (ROS) can cause DNA damage. Rice protein (RP) inhibits ROS accumulation. However, a link between the reduction of ROS‐derived DNA damage and the intake of RP is far from clear. The main objective of this study is to elucidate the effects of RPs on the reduction of DNA damage in growing and adult rats.

RESULTS

An intake of RP for 2 weeks significantly reduced the hepatic accumulation of ROS and 8‐hydroxydeoxyguanosine (8‐OHdG) in growing and adult rats, whereas the hepatic p53 content was markedly increased by RPs. After 2 weeks' feeding, the mRNA levels and protein expressions of p53, ataxia‐telangiectasia mutated (ATM), and Checkpoint kinase 2 (Chk2) were up‐regulated by RPs, whereas Murine Double Minute 2 (MDM2) expressions were markedly inhibited by RPs, resulting in more p53 being translocated into the nucleus. Nuclear factor erythroid 2 (NF‐E2)‐related factor 2 (Nrf2) was activated by RP by reducing Kelch‐like ECH‐associated protein 1 (Keap1), resulting in the up‐regulation of antioxidant expressions of catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) in RP groups.

CONCLUSION

Rice protein can exert an endogenous antioxidant activity to reduce ROS‐derived DNA damage by activating the Nrf2‐Keap1 pathway. This study suggests that the activation of the ATM‐Chk2‐p53 pathway might be one of the mechanisms exerted by RP for reducing DNA damage in growing and adult rats. © 2019 Society of Chemical Industry
A novel identification method for CPPU‐treated kiwifruits based on images
Authors: Yan Bin , Guo Wenchuan
Published: June 2019

BACKGROUND

The application of exogenous plant growth regulator, for example forchlorfenuron (CPPU), on kiwifruits has become an important factor that influences kiwifruit economic efficiency and the health development of the kiwifruit industry. Owing to the slight difference in calyx shape between the kiwifruits treated with CPPU (CPPU‐treated kiwifruits) and the kiwifruits without CPPU treatment (CPPU‐untreated kiwifruits), this study aims to provide a cheap, quick, convenient, and non‐destructive method for identifying CPPU‐treated kiwifruits based on the images of kiwifruits captured at visible lights.

RESULTS

The identification method includes three steps. Firstly, the kiwifruit was extracted from the background by using Otsu algorithm, hole filling operation and ‘bwareaopen’ function. Secondly, the calyx was extracted by using corrosion, image enhancement, hole filling and closing operations. Finally, the length/width ratio of the minimum enclosing rectangle of calyx region was calculated. The kiwifruit was regarded as a CPPU‐treated kiwifruit if the length/width ratio of the rectangle was higher than 1.6. Otherwise, the kiwifruit was regarded as a CPPU‐untreated one. The method had the total identification accuracy rate of 90.0% when the kiwifruit images were captured either by utilizing a smartphone at normal lighting condition or by using an image acquisition system.

CONCLUSION

The programs run on computer and smartphone were developed, and they could realize kiwifruit identification in 0.6 s and 2 s, respectively. The study makes identifying CPPU‐treated kiwifruits in online processing be realizable, and offers a convenient method for kiwifruit consumers. © 2019 Society of Chemical Industry
Online preconcentration and determination of chondroitin sulfate, dermatan sulfate and hyaluronic acid in biological and cosmetic samples using capillary electrophoresis
Authors: Chindaphan Kanokporn , Wongravee Kanet , Nhujak Thumnoon , Dissayabutra Thasinas , Srisa‐Art Monpichar
Published: June 2019

Capillary electrophoresis with large‐volume sample stacking using an electroosmotic flow pump was developed for the determination of chondroitin sulfate, dermatan sulfate, and hyaluronic acid. Central composite design was used to simultaneously optimize the parameters for capillary electrophoresis separation. The optimized capillary electrophoresis conditions were 200 mM sodium dihydrogen phosphate, 200 mM butylamine, and 0.5% w/v polyethylene glycol as a background electrolyte, pH 4 and ‐16 kV. Exploiting large‐volume sample stacking using an electroosmotic flow pump, the sensitivity of the proposed capillary electrophoresis system coupled with UV detection was significantly improved with limits of detection of 3, 5, 1 mg/L for chondroitin sulfate, dermatan sulfate, and hyaluronic acid, respectively. The developed method was applied to the determination of chondroitin sulfate and hyaluronic acid in cell culture media, cerebrospinal fluid, cosmetic products, and supplementary samples with highly acceptable accuracy and precision. Therefore, the proposed capillary electrophoresis approach was found to be simple, rapid, and reliable for the determination of chondroitin sulfate, dermatan sulfate, and hyaluronic acid in cell culture media, cerebrospinal fluid, cosmetic, and supplementary samples without sample pretreatment.
Two‐dimensional liquid chromatography with active solvent modulation for studying monomer incorporation in copolymer dispersants
Authors: Yang Peilin , Gao Wei , Zhang Tianlan , Pursch Matthias , Luong Jim , Sattler Wesley , Singh Anurima , Backer Scott
Published: June 2019

A pseudo‐comprehensive two‐dimensional liquid chromatography approach with size exclusion chromatography in the first dimension and gradient reversed‐phase liquid chromatography in the second dimension was successfully developed for the characterization of vinyl acetate/acrylic acid copolymers and vinyl acetate/itaconic acid/acrylic acid terpolymers. Active solvent modulation was exploited to prevent the polymer breakthrough in the second dimension separation caused by the strong solvent used in the first dimension. The conditions of the active solvent modulation valve were optimized to achieve sufficient on‐line dilution and to completely prevent polymer breakthrough without adding excessive time to the modulation cycle. Using this approach, copolymers made with different monomer ratios and processes were studied. Heterogeneous composition distribution due to insufficient monomer incorporation was detected in some of the copolymer samples. We demonstrated that with active solvent modulation, the two‐dimensional liquid chromatography approach is no longer limited to water‐soluble polymers and can be used for a broader range of polymers and copolymers.
Asymmetric risk impacts of Chinese tourists to Taiwan
Authors: Chang Chia‐Lin , Hsu Shu‐Han , McAleer Michael
Published: June 2019

Since 2008, when Taiwan's President Ma Ying‐Jeou relaxed the Cross‐Strait policy, China has become Taiwan's largest source of international tourism. In order to understand the risk persistence of Chinese tourists, the paper investigates the short‐run and long‐run persistence of shocks to the change rate of Chinese tourists to Taiwan, which is a novel empirical analysis. The daily data used for the empirical analysis are from January 1, 2013, to February 28, 2018. McAleer's fundamental equation in tourism finance is used to link the change rate of tourist arrivals and the change in tourist revenues. Three widely used univariate conditional volatility models, namely, GARCH(1,1), GJR(1,1), and EGARCH(1,1), are used to measure the short‐run and long‐run persistence of shocks, as well as symmetric, asymmetric, and leverage effects. Three different heterogeneous autoregressive (HAR) models, HAR(1), HAR(1,7) and HAR(1,7,28), are considered as alternative mean equations for capturing a variety of long memory effects. The mean equations associated with GARCH(1,1), GJR(1,1), and EGARCH(1,1) are used to analyze the risk persistence of the change in Chinese tourists. The exponential smoothing process is used to adjust the seasonality around the trend in Chinese tourists. The empirical results show asymmetric impacts of positive and negative shocks on the volatility of the change in the number of group‐type and medical‐type tourists, whereas individual‐type tourists display a symmetric volatility pattern. Somewhat unusually, leverage effects are observed in EGARCH for medical‐type tourists, which shows a negative correlation between shocks in tourist numbers and the subsequent shocks to volatility. For both group‐type and medical‐type tourists, the asymmetric impacts on volatility show that negative shocks have larger effects than do positive shocks. The leverage effect in EGARCH for medical‐type tourists implies that larger shocks would decrease volatility in the change in the numbers of medical‐type tourists. These novel empirical results suggest that Taiwan's tourism authorities should act to prevent the negative shocks for the group‐type and medical‐type Chinese tourists to dampen the shocks that arise from having fewer Chinese tourists to Taiwan.
Festivalscapes and the visitor experience: An application of the Stimulus Organism Response approach
Authors: Chen Zhaoyu , King Brian , Suntikul Wantanee
Published: June 2019

This paper presents a framework that articulates the complete tourist experience with reference to a traditional local event in Macau—A‐Ma Festival. The Stimulus Organism Response (S‐O‐R) framework is deployed to depict the festival experience as a continuous and multistage process. The festivalscape concept provides an elaboration of the festival construct by considering how attendees form enduring attitudes. The authors use the concept as a medium for conveying key festival messages and values from the attendee perspective. They identified a high incidence of spontaneous involvement in the festival. Festival attendance provided respondents with a considerable enhancement of the destination experience.
Prevalence and proliferation of antibiotic resistance genes in the subtropical mangrove wetland ecosystem of South China Sea
Authors: Zhao Huaxian , Yan Bing , Mo Xueyan , Li Pu , Li Baoqin , Li Quanwen , Li Nan , Mo Shuming , Ou Qian , Shen Peihong , Wu Bo , Jiang Chengjian
Published: June 2019

The emerging pollutants antibiotic resistance genes (ARGs) are prevalent in aquatic environments such as estuary. Coastal mangrove ecosystems always serve as natural wetlands for receiving sewage which always carry ARGs. Currently, the research considering ARG distribution in mangrove ecosystems gains more interest. In this work, we investigated the diversity of ARGs in an urban estuary containing mangrove and nonmangrove areas of the South China Sea. A total of 163 ARGs that classified into 22 resistance types and six resistance mechanisms were found. ARG abundance of the samples in the estuary is between 0.144 and 0.203. This is within the general range of Chinese estuaries. The difference analysis showed that abundances of total ARGs, six most abundant ARGs (mtrA, rpoB, rpoC, rpsL, ef‐Tu, and parY), the most abundant resistance types (elfamycin, multidrug, and peptide), and the most abundant resistance mechanism (target alteration) were significantly lower in mangrove sediment than that in nonmangrove sediment (p < 0.05). Network and partial redundancy analysis showed that sediment properties and mobile genetic elements were the most influential factors impacting ARG distribution rather than microbial community. The two factors collectively explain 51.22% of the differences of ARG distribution. Our study indicated that mangrove sediments have the capacity to remove ARGs. This work provides a research paradigm for analysis of ARG prevalence and proliferation in the subtropical marine coastal mangrove ecosystem.
Association of genetic polymorphism of PC‐1 gene (rs1044498 Lys121Gln) with insulin‐resistant type 2 diabetes mellitus in Punjabi Population of Pakistan
Authors: Albegali Abdullah Abdo , Shahzad Muhammad , Ullah Muhammad Ikram , Mahmood Saqib , Rashid Maryam
Published: June 2019

Background

Insulin resistance (IR), known to reduce the response to insulin action, develops with obesity leading to type 2 diabetes mellitus (T2DM). The PC‐1 gene has been associated with dyslipidemia, polycystic ovarian disease and T2DM in different regions of the world. The objective of the present study was to investigate the genetic association of PC‐1 rs1044498 polymorphism with insulin resistance in type 2 diabetes in the Punjabi population of Pakistan.

Methods

This study was carried out on 161 healthy controls and 161 patients of T2DM with insulin resistance. Whole blood was collected for DNA extraction and molecular studies. PCR‐RFLP with AvaII was performed to determine the genotype in cases and controls. Chi‐square and Hardy Weinberg analyses were carried out. Statistical analysis was performed by SPSS software.

Results

The demographic data of cases and controls showed significant differences for different parameters like glucose, insulin, Homeostatic model assessment‐insulin resistance (HOMA‐IR) and lipid profiles (p < 0.000). Different statistical models revealed that all the dominant models were found associated in between alleles for disease risk (p < 0.001) while no association of PC‐1 rs1044498 (K121Q) polymorphism was found with insulin‐resistant parameters in T2DM cases.

Conclusion

Overall, the results indicate that the K121Q polymorphism was not found associated with insulin resistance in type 2 diabetes in a Pakistani Punjabi population. This is the first‐ever report about the genotype of PC‐1 gene in this population.
miR‐33a inhibits cell growth in renal cancer by downregulation of MDM4 expression
Authors: Jiang Kehua , Sun Fa , Zhu Jianguo , Luo Guangheng , Ban Yong , Zhang Peng
Published: June 2019

Background

MicroRNA‐33a (miR‐33a) plays the role of the tumor suppressor gene by regulating the expression level of downstream genes. However, the effects of miR‐33a in renal cell cancer (RCC) remain unknown. Our study was designed to investigate the expression level and potential function of miR‐33a in RCC.

Methods

RT‐qPCR was applied to measure the levels of miR‐33a in RCC tissues and cell lines. Western blotting and luciferase reporter assay were used to detect the relationship between miR‐33a and Mouse double minute 4 (MDM4) in RCC cells. CCK‐8 and flow cytometry were applied to detected cell viability and cell cycle. Animal models and TUNEL assay were applied to detect the effect of miR‐33a on the growth of RCC and cell apoptosis.

Results

We found that the levels of miR‐33a were significantly decreased in RCC tissues and cell lines. Moreover, the low expression of miR‐33a in RCC patients indicated a shorter overall survival (OS). Notably, MDM4 as a direct target of miR‐33a in RCC, the expression level of MDM4 was significantly increased in RCC cells group than the control group. Furthermore, miR‐33a overexpression significantly inhibited RCC cells growth than the control group, while the inhibitory effects of miR‐33a were reversed upon the overexpression of MDM4. Luciferase reporter assays showed that there was a direct interaction between miR‐33a and 3′ UTR of MDM4 mRNA. In vivo, tumor volumes and weight were significantly decreased in the transfected miR‐33a mimics group than the control group.

Conclusion

Taken together, our study indicates that miR‐33a inhibits RCC cell growth by targeting MDM4.
Design and implementation of a passive edge filter with high bandwidth and slope
Authors: Yucel Murat , Koyuncu Onur
Published: June 2019

In this study, passive edge filter design was implemented by using I‐6, I‐25, M‐5, M‐12 erbium‐doped fibers. For this purpose, first the highest bandwidth and the steepest slope regions of the erbium‐doped fibers were determined in the simulation environment. The experimental setup was realized by using the most appropriate lengths of erbium‐doped fibers found in the simulation study. For I‐25 erbium‐doped fiber, an edge filter with a bandwidth of 32.8 nm and a slope angle of 50.77° was obtained.
Evaluation of a Portable Electrosedation System for Anesthetizing Mature Channel Catfish
Authors: Chatakondi Nagaraj G , Kelly Anita M
Published: June 2019

Hybrid catfish (female Channel Catfish Ictalurus punctatus × male Blue Catfish I. furcatus) fry are produced by hormone-induced spawning of Channel Catfish in hatcheries. Anesthetics are used routinely to reduce handling stress by limiting the activation of the hypothalamic–pituitary–interrenal axis hormones. As a comparison, the present study determined the efficacy of electrosedation using a portable electrosedation system (PES) and its feasibility for possible application in hybrid catfish hatcheries. The PES was evaluated at 100 V and a 25% duty cycle at 30, 60, 90, or 100 Hz to anesthetize mature Channel Catfish to stage IV of sedation. The PES was compared to the chemical sedatives tricaine methanesulfonate (MS-222; 200 mg/L) and metomidate hydrochloride (Aquacalm; 6 mg/L). The PES at 30 Hz anesthetized Channel Catfish in 4 s, significantly faster than the 120 s needed for MS-222. However, the mean (±SE) time to recover from anesthesia and mean plasma cortisol response were similar (P > 0.05) with MS-222 (104 ± 9 s; 35 ng/mL) and the PES (119 ± 15 s; 32 ng/mL). Relative fecundity of fish sedated by the PES and MS-222 averaged 5,222 and 5,593 eggs/kg of body weight (BW), respectively; percent hatch averaged 46.9% and 50.4%, respectively; and hybrid catfish fry production averaged 1,644 and 1,711 fry/kg BW, respectively. Relative fecundity, percent hatch, and hybrid fry production were not significantly different between the PES and MS-222 groups (P > 0.05). No internal injuries were noted in any of the fish subjected to electrosedation. The PES at 30 Hz effectively anesthetized female Channel Catfish with a quicker induction time, provided moderate time to recover from anesthesia, and elicited a cortisol response, with no known internal injuries. The results suggest that the PES has the potential to replace MS-222 usage in hybrid catfish hatcheries. The PES is environmentally safe, does not expire or degrade, and requires no disposal or withdrawal period.
Effects of Cecropin Transgenesis and Interspecific Hybridization on the Resistance to Ichthyophthirius multifiliis in Channel Catfish and Female Channel Catfish × Male Blue Catfish Hybrids
Authors: Elaswad Ahmed , Khalil Karim , Ye Zhi , Alsaqufi Ahmed , Abdelrahman Hisham , Su Baofeng , Perera Dayan A , Dong Sheng , Abass Nermeen , Dunham Rex
Published: June 2019

The resistance of Channel Catfish Ictalurus punctatus, hybrid catfish (female Channel Catfish × male Blue Catfish I. furcatus [CB hybrids]), and Channel Catfish and hybrid catfish expressing the introduced cecropin B gene to Ichthyophthirius multifiliis infestation was investigated in two experiments. In experiment I, four fingerling groups were challenged, including cecropin-transgenic Channel Catfish, cecropin-transgenic CB hybrids, non-transgenic Channel Catfish, and non-transgenic CB hybrids. Non-transgenic Channel Catfish survived for a shorter time than the other three groups. Survival rate was significantly different between non-transgenic Channel Catfish and the other groups, which had similar survival rates. In experiment II, non-transgenic CB hybrids had a less severe infestation than non-transgenic Channel Catfish. Mortality rates were 62.4% and 40.2% for non-transgenic Channel Catfish and CB hybrids, respectively. The mean survival time for non-transgenic hybrids was significantly longer (>5 d) than that of non-transgenic Channel Catfish. The results suggest that genetic enhancement of Ichthyophthirius resistance can be accomplished in Channel Catfish by either cecropin transgenesis or interspecific hybridization. In addition to survival rate, improving survival time is important because the extension of survival time provides greater opportunity to apply treatments to stop the protozoan infestation.
Coupled and decoupled stabilized mixed finite element methods for nonstationary dual‐porosity‐Stokes fluid flow model
Authors: Al Mahbub Md. Abdullah , He Xiaoming , Nasu Nasrin Jahan , Qiu Changxin , Zheng Haibiao
Published: June 2019

In this paper, we propose and analyze two stabilized mixed finite element methods for the dual‐porosity‐Stokes model, which couples the free flow region and microfracture‐matrix system through four interface conditions on an interface. The first stabilized mixed finite element method is a coupled method in the traditional format. Based on the idea of partitioned time stepping, the four interface conditions, and the mass exchange terms in the dual‐porosity model, the second stabilized mixed finite element method is decoupled in two levels and allows a noniterative splitting of the coupled problem into three subproblems. Due to their superior conservation properties and convenience of the computation of flux, mixed finite element methods have been widely developed for different types of subsurface flow problems in porous media. For the mixed finite element methods developed in this article, no Lagrange multiplier is used, but an interface stabilization term with a penalty parameter is added in the temporal discretization. This stabilization term ensures the numerical stability of both the coupled and decoupled schemes. The stability and the convergence analysis are carried out for both the coupled and decoupled schemes. Three numerical experiments are provided to demonstrate the accuracy, efficiency, and applicability of the proposed methods.
Sustained remission with azacitidine monotherapy and an aberrant precursor B‐lymphoblast population in juvenile myelomonocytic leukemia
Authors: Hashmi Saman K. , Punia Jyotinder N. , Marcogliese Andrea N. , Gaikwad Amos S. , Fisher Kevin E. , Roy Angshumoy , Rao Pulivarthi , Lopez‐Terrada Dolores H. , Ringrose Jo , Loh Mignon L. , Niemeyer Charlotte M. , Rau Rachel E.
Published: June 2019

Juvenile myelomonocytic leukemia (JMML) has a poor prognosis in general, with hematopoietic stem cell transplant (HSCT) remaining the standard of care for cure. The hypomethylating agent, azacitidine, has been used as a bridging therapy to transplant. However, no patients have been treated with azacitidine without an HSCT post azacitidine. We report on an infant with JMML with somatic KRAS G12A mutation and monosomy 7 who achieved sustained remission following azacitidine monotherapy. He also developed an aberrant B‐lymphoblast population which declined with similar kinetics as his JMML‐associated abnormalities, suggesting that a B‐lymphoblast population in JMML does not always progress to acute leukemia.
Intraoperative Unfractionated Heparin Unresponsiveness during Endovascular Repair of a Ruptured Abdominal Aortic Aneurysm following Administration of Andexanet Alfa for the Reversal of Rivaroxaban
Authors: Eche Ifeoma Mary , Elsamadisi Pansy , Wex Nicole , Wyers Mark C. , Brat Gabriel A. , Cunningham Katherine , Bauer Kenneth A.
Published: June 2019

The authors describe a case of unfractionated heparin (UFH) unresponsiveness in the operating room secondary to reversal of rivaroxaban with coagulation factor Xa (recombinant) inactivated‐zhzo (andexanet alfa). A 70‐year‐old man with a known 4.5‐ to 5.0‐cm abdominal aortic aneurysm and atrial fibrillation managed with rivaroxaban presented with severe right‐sided flank pain radiating to the left side of his abdomen. Computed tomography‐angiography on arrival demonstrated a left retroperitoneal hematoma and a suspected ruptured abdominal aortic aneurysm. He received andexanet alfa to reverse rivaroxaban prior to an emergent endovascular aneurysm repair. During surgery, he received a total of 14,000 units (167 units/kg) of UFH with minimal changes in activated clotting time (132–144 sec; baseline 135 sec [reference range 74–137 sec]). This case highlights the potential complications of using UFH anticoagulation following reversal of factor Xa inhibitors with andexanet alfa and underscores the importance of peri‐procedural anticoagulation planning. For patients who require intra‐operative anticoagulation, providers should consider anticoagulation reversal with prothrombin complex concentrate instead of andexanet alfa or administration of a parenteral direct thrombin inhibitor, such as argatroban or bivalirudin during the surgical procedure.
PVDF/PMMA dielectric films with notably decreased dielectric loss and enhanced high‐temperature tolerance
Authors: Nie Run‐Pan , Li Yue , Jia Li‐Chuan , Lei Jun , Huang Hua‐Dong , Li Zhong‐Ming
Published: June 2019

Polymer dielectrics generally have comparatively low dielectric constant, operating temperatures, and/or high dielectric loss, which limits their uses especially in harsh environment. In this article, a novel trilayered nanocomposite film (TNF) was constructed via solution‐casting and, subsequently, hot‐pressing process, which was composed of two outer layers of polyvinylidene fluoride (PVDF, high dielectric constant) and a middle layer of polymethyl methacrylate (PMMA, high glass transition temperature, Tg). The two outer layers of TNF were filled with barium strontium titanate nanoparticles to further increase the dielectric constant of PVDF. The PMMA in the middle layer was used to largely suppress the dielectric loss and simultaneously improve the temperature tolerance of TNF. Results show that the introduction of PMMA induced oriented crystal formation in the interface regions between PVDF and PMMA components. Moreover, most of the impurity ions were dramatically immobilized by partly oriented α crystals and high Tg PMMA layer until the temperature exceeded 120 °C. Therefore, the TNFs showed a high‐temperature tolerance and notably decreased loss, which are promising for widespread energy storage applications where harsh working conditions are present. © 2019 Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2019, 57, 1043–1052
Losing a parent to cancer as a teenager: Family cohesion in childhood, teenage, and young adulthood as perceived by bereaved and non‐bereaved youths
Authors: Birgisdóttir Dröfn , Bylund Grenklo Tove , Nyberg Tommy , Kreicbergs Ulrika , Steineck Gunnar , Fürst Carl J.
Published: June 2019

Objective

The aim of this study was to investigate levels of perceived family cohesion during childhood, teenage years, and young adulthood in cancer‐bereaved youths compared with non‐bereaved peers.

Methods

In this nationwide, population‐based study, 622 (73%) young adults (aged 18‐26) who had lost a parent to cancer 6 to 9 years previously, when they were teenagers (aged 13–16), and 330 (78%) non‐bereaved peers from a matched random sample answered a study‐specific questionnaire. Associations were assessed using multivariable logistic regression.

Results

Compared with non‐bereaved youths, the cancer‐bereaved participants were more likely to report poor family cohesion during teenage years (odds ratio [OR] 1.6, 95% CI, 1.0‐2.4, and 2.3, 95% CI, 1.5‐3.5, for paternally and maternally bereaved youths, respectively). This was also seen in young adulthood among maternally bereaved participants (OR 2.5; 95% CI, 1.6‐4.1), while there was no difference between paternally bereaved and non‐bereaved youths. After controlling for a number of covariates (eg, year of birth, number of siblings, and depression), the adjusted ORs for poor family cohesion remained statistically significant. In a further analysis stratified for gender, this difference in perceived poor family cohesion was only noted in females.

Conclusion

Teenage loss of a parent to cancer was associated with perceived poor family cohesion during teenage years. This was also noted in young adulthood among the maternally bereaved. Females were more likely to report poor family cohesion. Our results indicate a need for increased awareness of family cohesion in bereaved‐to‐be families with teenage offspring, with special attention to gender roles.
Testosterone levels and androgen receptor copy number variations in castration‐resistant prostate cancer treated with abiraterone or enzalutamide
Authors: Lolli Cristian , De Lisi Delia , Conteduca Vincenza , Gurioli Giorgia , Scarpi Emanuela , Schepisi Giuseppe , Ravaglia Giorgia , Menna Cecilia , Farolfi Alberto , Altavilla Amelia , Burgio Salvatore Luca , Tonini Giuseppe , Santini Daniele , De Giorgi Ugo
Published: June 2019

Purpose

Our study aims to investigate the association between copy number of the androgen receptor (AR) and testosterone levels in metastatic castration‐resistant prostate cancer (mCRPC) treated with second‐generation antiandrogen therapies.

Materials and Methods

We retrospectively collected data from mCRPC treated with abiraterone acetate and enzalutamide. Serum testosterone levels were collected at baseline, at 3 months since the start of therapy and at disease progression. A cohort of cases treated with docetaxel was also used to evaluate the impact of testosterone levels.

Results

Patients treated with abiraterone with AR copy number aberrations and basal testosterone levels below 0.09 nmol/L had worse progression‐free survival (PFS) compared to patients with no
AR copy number abnormalities (8.5 vs 2.9 months,
P = 0.005). No relevant differences were observed in the enzalutamide group with a PFS of 3.9 months (no
AR gain) vs 2.7 months (
AR gain,
P = 0.004) for patients with below 0.09 nmol/L testosterone levels. Similar results are obtained for univariate analysis for overall survival (OS). The negative prognostic role of
AR copy number gain in OS for both treatment groups (25.5 vs 10.6 months,
P = 0.0002 for abiraterone and 14.1 vs 8.3 months,
P = 0.031 for enzalutamide) was confirmed, and it was recognized the negative prognostic impact of testosteronemia below 0.09 only for patients treated with enzalutamide (8.8 vs 42.8 months,
P = 0.016). On multivariate analysis for patients treated with abiraterone, low testosterone levels below 0.09 and plasma
AR gain were significantly associated with worse PFS and OS. These data are confirmed in the enzalutamide group for PFS.

Conclusions

Testosterone levels and the AR copy number alterations were considered as independent prognostic factors. The results of this study show that serum testosteronemia associated with changes in copy number of AR gene could represent a noninvasive biomarker useful to identify a subgroup of patients with worse prognosis that can benefit less from second‐generation antiandrogen therapies in the mCRPC setting.
Physiologically‐Based Pharmacokinetic Modeling of Atorvastatin Incorporating Delayed Gastric Emptying and Acid‐to‐Lactone Conversion
Authors: Morse Bridget L. , Alberts Jeffrey J. , Posada Maria M. , Rehmel Jessica , Kolur Anil , Tham Lai San , Loghin Corina , Hillgren Kathleen M. , Hall Stephen D. , Dickinson Gemma L.
Published: June 2019

The drug–drug interaction profile of atorvastatin confirms that disposition is determined by cytochrome P450 (CYP) 3A4 and organic anion transporting polypeptides (OATPs). Drugs that affect gastric emptying, including dulaglutide, also affect atorvastatin pharmacokinetics (PK). Atorvastatin is a carboxylic acid that exists in equilibrium with a lactone form in vivo. The purpose of this work was to assess gastric acid–mediated lactone equilibration of atorvastatin and incorporate this into a physiologically‐based PK (PBPK) model to describe atorvastatin acid, lactone, and their major metabolites. In vitro acid‐to‐lactone conversion was assessed in simulated gastric fluid and included in the model. The PBPK model was verified with in vivo data including CYP3A4 and OATP inhibition studies. Altering the gastric acid–lactone equilibrium reproduced the change in atorvastatin PK observed with dulaglutide. The model emphasizes the need to include gastric acid–lactone conversion and all major atorvastatin‐related species for the prediction of atorvastatin PK.
Quantitative Systems Pharmacology Model of a Masked, Tumor‐Activated Antibody
Authors: Stroh Mark , Sagert Jason , Burke John M. , Apgar Joshua F. , Lin Lin , Millard Bjorn L. , Kavanaugh W. Michael
Published: June 2019

PROBODY therapeutics (Pb‐Tx) are protease‐activatable prodrugs of monoclonal antibodies (mAbs) designed to target tumors where protease activity is elevated while avoiding normal tissue. They are composed of a parentalmAb, a mask that inhibits antibody binding to target, and a protease‐cleavable substrate between the mask and themAb. We report a quantitative systems pharmacology model for the rational design and clinical translation of Pb‐Tx. The model adequately described monkey pharmacokinetic data following the administration of six anti‐CD166 Pb‐Tx of varying mask strength and substrate cleavability and captured the trend of decreasing Pb‐Tx systemic clearance with increasing mask strength. Projections to humans suggested both higher levels of Pb‐Tx in tumor relative to parentalmAb and an optimal mask strength for maximizing tumor receptor–mediated uptake. Simulations further suggested the majority of circulating species in humans would be intact/masked Pb‐Tx, with no significant flux of cleaved/activated species from tumor to the systemic compartment.
Cannabis sativa L. extract and cannabidiol inhibit in vitro mediators of skin inflammation and wound injury
Authors: Sangiovanni Enrico , Fumagalli Marco , Pacchetti Barbara , Piazza Stefano , Magnavacca Andrea , Khalilpour Saba , Melzi Gloria , Martinelli Giulia , Dell'Agli Mario
Published: June 2019

Skin inflammatory diseases result from complex events that include dysregulation and abnormal expression of inflammatory mediators or their receptors in skin cells. The present study investigates the potential effect of a Cannabis sativa L. ethanolic extract standardized in cannabidiol as antiinflammatory agent in the skin, unraveling the molecular mechanisms in human keratinocytes and fibroblasts. The extract inhibited the release of mediators of inflammation involved in wound healing and inflammatory processes occurring in the skin. The mode of action involved the impairment of the nuclear factor‐kappa B (NF‐κB) pathway since the extract counteracted the tumor necrosis factor‐alpha‐induced NF‐κB‐driven transcription in both skin cell lines. Cannabis extract and cannabidiol showed different effects on the release of interleukin‐8 and vascular endothelial growth factor, which are both mediators whose genes are dependent on NF‐κB. The effect of cannabidiol on the NF‐κB pathway and metalloproteinase‐9 (MMP‐9) release paralleled the effect of the extract thus making cannabidiol the major contributor to the effect observed. Down‐regulation of genes involved in wound healing and skin inflammation was at least in part due to the presence of cannabidiol. Our findings provide new insights into the potential effect of Cannabis extracts against inflammation‐based skin diseases.
Sample acidification has a predictable effect on isotopic ratios of particulate organic matter along the Chilean coast
Authors: Barrios‐Guzmán Carmen , Sepúlveda Maritza , Docmac Felipe , Zarate Patricia , Reyes Hernán , Harrod Chris
Published: June 2019

Rationale

Stable isotopes of carbon and nitrogen have proved to be valuable tools for researchers working across the different subfields of ecology. However, the chemical pretreatment of samples prior to analytical determination of stable isotope ratios can influence the results, and therefore conclusions regarding the ecology of the taxon or system under study. Here, we determined the effect of vapor acidification with concentrated HCl on the δ13C and δ15N values of particulate organic matter (POM), which are commonly used as baselines for studies of trophic ecology, or to understand oceanographic patterns.

Methods

Samples of marine POM were obtained along a large‐scale latitudinal gradient (ca 3000 km) along the Chilean coast, along with a range of oceanographic variables thought to potentially influence inorganic carbon at each sampling location. A random subset of 50 samples was divided into two parts: one acidified by HCl fumigation treatment, and the other acting as a control. We compared paired differences in δ13C and δ15N values measured by continuous flow isotope ratio mass spectrometry and used a model selection approach to examine which oceanographic factor best explained shifts in values following acid treatment.

Results

Acidification resulted in statistically significant reductions in both δ13C and δ15N values, but the effect was relatively small. The model that best explained the differences between acidified and non‐acidified δ13C values included depth, salinity and sea‐surface temperature at the sampling point. A regression of acidified on non‐acidified δ13C values shows that the treatment effect was strongest on samples more depleted in 13C.

Conclusions

The differences between δ13C and δ15N values in acidified and non‐acidified samples are linear and predictable. This implies that the nature of the POM and its possible alteration during the acid treatment are important factors that support the reliable determination of the values of δ13C and δ15N of POM.
Biohybrid Nanoparticles to Negotiate with Biological Barriers
Authors: Mohammadi M. Rezaa , Corbo Claudia , Molinaro Roberto , Lakey Jonathan R. T.
Published: June 2019

Incapability of effective cross‐talk with biological environments has partly impaired the in vivo functionality of nanoparticles (NPs). Homing, biodistribution, and function of NPs could be engineered through regulating their interactions with in vivo niches. Inspired by communications in biological systems, endowing a “biological identity” to synthetic NPs is one approach to control their biodistribution, and immunonegotiation profiles. This synthetic‐biological combination is referred to as biohybrid NPs, which comprise both i) engineerable, readily producible, and trackable synthetic NPs as well as ii) biological moieties with the capability to cross‐talk with immunological barriers. Here, the latest understanding on the in vivo interactions of NPs, biological barriers they face, and emerging methods for quantitative measurements of NPs' biodistribution are reviewed. Some key biomolecules that have emerged as negotiators with the immune system in the context of cancer and autoimmunity, and their inspirations on biohybrid NPs are introduced. Critical design considerations for efficient cross‐talk between NPs and innate and adaptive immunity followed by hybridization methods are also discussed. Finally, clinical translation challenges and future perspectives regarding biohybrid NPs are discussed.
An adaptive plan‐oriented and continuous software migration to cloud in dynamic enterprises
Authors: Nabavi Seyyed Yahya , Bushehrian Omid
Published: June 2019

Replacing existing software/hardware components with their equivalent cloud services is an important decision faced by IT managers in today's enterprises. A variety of possible migration targets and cloud services with too many configurations and cost models, disparate and changing strategic objectives of the enterprise management that triggers the migration process, and the complex structure of the legacy applications make software migration to the cloud a challenging issue. In contrast to the existing approaches that model the migration process as an optimization problem to find the optimal deployment of software components on cloud services without presenting a practical migration plan, in this paper, a plan‐oriented migration approach is proposed by which the enterprise management is able to follow migration steps of a valid plan. All valid plans are modeled using a labeled transition system, and a recommender engine directs the management through the possible migration paths using predefined fitness functions. It was observed that, particularly in dynamic and changing conditions that a flexible migration plan is essential, the proposed plan‐oriented method is very much effective in satisfying the enterprise strategic objectives. Evaluations have been performed using two quality indicators: total cost of ownership and scalability index.
Stereocontrolled Synthesis of Functionalized Azaheterocycles from Carbocycles through Oxidative Ring Opening/Reductive Ring Closing Protocols
Authors: Kiss Loránd , Ouchakour Lamiaa , Ábrahámi Renáta A. , Nonn Melinda
Published: June 2019

Fluorine‐containing organic scaffolds are of significant interest in medicinal chemistry. The incorporation of fluorine into biomolecules can lead to remarkable changes in their physical, chemical, and biological properties. There are already many drugs on the market, which contain at least one fluorine atom. Saturated functionalized azaheterocycles as bioactive substances have gained increasing attention in pharmaceutical chemistry. Due to the high biorelevance of organofluorine molecules and the importance of N‐heterocyclic compounds, selective stereocontrolled procedures to the access of new fluorine‐containing saturated N‐heterocycles are considered to be a hot research topic. This account summarizes the synthesis of functionalized and fluorine‐containing saturated azaheterocycles starting from functionalized cycloalkenes and based on oxidative ring cleavage of diol intermediates followed by ring expansion with reductive amination.