bluuebunny/crossref_metadata_2025 huggingface dataset:
Modular Covalent Graphene Functionalization with C60 and the Endohedral Fullerene Sc3N@C80: A Facile Entry to Synthetic‐Carbon‐Allotrope Hybrids
Authors: Wei Tao , Martin Oliver , Yang Shangfeng , Hauke Frank , Hirsch Andreas
Published: November 2018

Two novel graphene‐fullerene hybrid structures, containing C60 and endohedral Sc3N@C80 bound to graphene, instead of the formerly used graphene oxide, were efficiently synthesized via a reductive activation/exfoliation approach starting from pristine graphite. The structures of these multifunctional hybrid systems were unambiguously characterized by statistical Raman spectroscopy, TG‐MS, TG‐GC‐MS, and LD‐TOF mass spectroscopy, confirming the covalent bonding of the respective C60/Sc3N@C80 moieties to the pristine graphene. Furthermore, assisted by temperature‐dependent Raman spectroscopy studies the corresponding defunctionalization processes were also investigated. Finally, the formation of a carbon allotrope hybrid material on the basis of C60/Sc3N@C80 moieties coupled to graphene could be visualized by HRTEM.
Prediction on the Origin of Selectivities in Base‐controlled Switchable NHC‐catalyzed Transformations
Authors: Wang Yang , Qu Ling‐Bo , Wei Donghui
Published: November 2018

The base‐controlled mechanisms for N‐heterocyclic carbene (NHC)‐catalyzed divergent [3+3] and [3+2] annulation reactions were examined by using the DFT method. The reaction initiates with the complexation of NHC and enal to give the Breslow intermediate, which diverges afterward. Then, the azomethine imine can either react with the Breslow intermediate to give the six‐membered ring product or the β‐carbon protonation occurs for forming the enolate intermediate controlled by different bases. The formed enolate intermediate reacts with azomethine imine to afford the five‐membered ring product. The calculated results show that only the base K2CO3 can facilitate the structural transformation between homoenolate and enolate to switch the chemoselectivity; therefore, the [3+3] annulation happens preferentially in the presence of base DBU while the other situation occurs with K2CO3 as base. The NCI analysis results reveal that the stereoselectivity is predominately determined by the π⋅⋅⋅π, C−H⋅⋅⋅O, and C−H⋅⋅⋅N interactions. The obtained mechanistic insights should provide valuable clues for the rational design of these kinds of divergent reactions.
EMF exposure variation among MRI sequences from pediatric examination protocols
Authors: Frankel Jennifer , Hansson Mild Kjell , Olsrud Johan , Wilén Jonna
Published: November 2018

The magnetic resonance imaging (MRI) exposure environment is unique due to the mixture and intensity of magnetic fields involved. Current safety regulations are based on well‐known acute effects of heating and neuroexcitation while the scientific grounds for possible long‐term effects from MRI exposure are lacking. Epidemiological research requires careful exposure characterization, and as a first step toward improved exposure assessment we set out to characterize the MRI‐patient exposure environment. Seven MRI sequences were run on a 3‐Tesla scanner while the radiofrequency and gradient magnetic fields were measured inside the scanner bore. The sequences were compared in terms of 14 different exposure parameters. To study within–sequence variability, we varied sequence settings such as flip angle and slice thickness one at a time, to determine if they had any impact on exposure endpoints. There were significant differences between two or more sequences for all fourteen exposure parameters. Within–sequence differences were up to 60% of the corresponding between‐sequence differences, and a 5–8 fold exposure increase was caused by variations in flip angle, slice spacing, and field of view. MRI exposure is therefore not only sequence‐specific but also patient‐ and examination occurrence‐specific, a complexity that requires careful consideration for an MRI exposure assessment in epidemiological studies to be meaningful. Bioelectromagnetics. 40:3–15, 2019. © 2018 The Authors. Bioelectromagnetics Published by Wiley Periodicals, Inc.
Gelatin‐polysaccharide composite scaffolds for 3D cell culture and tissue engineering: Towards natural therapeutics
Authors: Afewerki Samson , Sheikhi Amir , Kannan Soundarapandian , Ahadian Samad , Khademhosseini Ali
Published: November 2018

Gelatin is a promising material as scaffold with therapeutic and regenerative characteristics due to its chemical similarities to the extracellular matrix (ECM) in the native tissues, biocompatibility, biodegradability, low antigenicity, cost‐effectiveness, abundance, and accessible functional groups that allow facile chemical modifications with other biomaterials or biomolecules. Despite the advantages of gelatin, poor mechanical properties, sensitivity to enzymatic degradation, high viscosity, and reduced solubility in concentrated aqueous media have limited its applications and encouraged the development of gelatin‐based composite hydrogels. The drawbacks of gelatin may be surmounted by synergistically combining it with a wide range of polysaccharides. The addition of polysaccharides to gelatin is advantageous in mimicking the ECM, which largely contains proteoglycans or glycoproteins. Moreover, gelatin–polysaccharide biomaterials benefit from mechanical resilience, high stability, low thermal expansion, improved hydrophilicity, biocompatibility, antimicrobial and anti‐inflammatory properties, and wound healing potential. Here, we discuss how combining gelatin and polysaccharides provides a promising approach for developing superior therapeutic biomaterials. We review gelatin–polysaccharides scaffolds and their applications in cell culture and tissue engineering, providing an outlook for the future of this family of biomaterials as advanced natural therapeutics.
Helpful aspects of bereavement counselling: An interpretative phenomenological analysis
Authors: Simonsen Gurid , Cooper Mick
Published: November 2018

Aim

The purpose of this study was to deepen an understanding of the practices that bereaved clients find helpful in counselling.

Method

Semi‐structured qualitative interviews were conducted with seven clients who had participated in counselling for bereavement within a voluntary organisation in Scotland. Data were thematically analysed within an overall framework of interpretative phenomenological analysis.

Findings

Respondents identified five helpful aspects of counselling. First, the independence of the counsellor: That they were outside the family and social network. Second, the counsellor's skilled listening: Being attentive, welcoming, demonstrating competence and being ‘to the point’. Third, the non‐directivity of the counselling work: Being allowed to take the lead and to talk on a range of issues, both bereavement and non‐bereavement related. Fourth, having their unhelpful thinking challenged, being encouraged to see things from a broader perspective and through addressing their feelings of guilt and anger. Fifth, by having their responses to bereavement normalised through psycho‐education and therapist self‐disclosure.

Conclusion

The findings support previous research which suggests that both more, and less, directive interventions can be helpful for clients who experience bereavement. This is consistent with a pluralistic perspective, which holds that no one therapeutic orientation has a monopoly on helpful therapeutic practices. The findings suggest that helpful practice with bereaved clients may involve a client‐led approach in which there is the establishment of a strong, supportive and attentive therapeutic relationship, but in which the therapist also brings in more directive interventions to help the client normalise and address their feelings.
Synthesis and Biochemical Evaluation of Nicotinamide Derivatives as NADH Analogue Coenzymes in Ene Reductase
Authors: Falcone Natashya , She Zhe , Syed Jebreil , Lough Alan , Kraatz Heinz‐Bernhard
Published: November 2018

Nicotinamide and pyridine‐containing conjugates have attracted a lot of attention in research as they have found use in a wide range of applications including as redox flow batteries and calcium channel blockers, in biocatalysis, and in metabolism. The interesting redox character of the compounds’ pyridine/dihydropyridine system allows them to possess very similar characteristics to the natural chiral redox agents NAD+/NADH, even mimicking their functions. There has been considerable interest in designing and synthesizing NAD+/NADH mimetics with similar redox properties. In this research, three nicotinamide conjugates were designed, synthesized, and characterized. Molecular structures obtained through X‐ray crystallography were obtained for two of the conjugates, thereby providing more detail on the bonding and structure of the compounds. The compounds were then further evaluated for biochemical properties, and it was found that one of the conjugates possessed similar functions and characteristics to the natural NADH. This compound was evaluated in the active enzyme, enoate reductase; like NADH, it was shown to help reduce the C=C double bond of three substrates and even outperformed the natural coenzyme. Kinetic data are reported.
Percutaneous management of periprocedural coronary sinus Reducer migration
Authors: Tzanis Georgios , Durante Alessandro , Mitomo Satoru , Giannini Francesco
Published: November 2018

Coronary sinus Reducer represents a novel therapeutic option for refractory angina. As emerging evidence of both reduction in angina symptoms and reduction of myocardial ischemia burden might lead to increased Reducer implantations, knowledge on how to manage potential complications is of clinical importance. We report a successful management of scaffold migration in right atrium.
One‐Step Synthesis of Vacancy‐Rich MnO2−x/Reduced Graphene Oxide Composite Film for High Electrochemical Performance
Authors: Peng Ruichao , Wang Haonan , Wei Xinya , Wu Zaikun , Yu Ping , Luo Yunbai
Published: November 2018

High electrochemical performance is important to achieve practical application of energy storage devices. It has been found recently that it is hard to achieve high capacity and high stability simultaneously using a single electrode material. Thus, constructing composite electrode materials which can combine the advantages of different materials together is an efficient approach to improve the electrochemical properties. In this work, we have built a vacancy‐rich MnO2−x/reduced graphene oxide (rGO) composite film through a facile one‐step route. In the synthesis process, GO nanosheets were reduced into rGO to improve the electronic conductivity, while Mn2+ was oxidized to MnO2 with vacancies. The obtained vacancy‐rich MnO2−x/rGO composite showed a superior electrochemical performance: The specific capacitance reached 675.5 F/g at a current density of 0.5 A/g and the material demonstrated high capacitance retention (96.1 % after 10000 cycles). Besides, the symmetric electrochemical capacitor based on the vacancy‐rich MnO2−x/rGO composite electrode can achieve a high energy density (8.42 mWh/cm3) and power density (3.78 W/cm3) as well as excellent stability.
Baby steps: Pregnancy outcomes after human epidermal growth factor receptor 2–targeted therapy
Authors: Bines Jose , Tevaarwerk Amye J.
Published: November 2018

The article by Lambertini et al in this issue of Cancer presents novel data regarding pregnancy and cancer outcomes after human epidermal growth factor receptor 2 (HER2)–targeted therapy for patients with early‐stage breast cancer. However, much more remains to be learned regarding these outcomes.
Effects of Rifamycin Coadministration on Bedaquiline Desmethylation in Healthy Adult Volunteers
Authors: Healan Amanda M. , Salata Robert A. , Griffiss J. McLeod , Proskin Howard M. , O'Riordan Mary Ann , Gray Wesley A. , Blumer Jeffrey L.
Published: November 2018

There is an urgent need to identify safe and effective combination treatments for multidrug‐resistant (MDR) Mycobacterium tuberculosis infection (TB). Bedaquiline, a new diarylquinoline, is approved for the treatment of MDR pulmonary TB in combination with other drugs, which could include rifabutin, which is also used to treat drug‐resistant TB. Both rifabutin and bedaquiline are metabolized via cytochrome P450 3A4, and rifabutin is an inducer of this enzyme. Bedaquiline is metabolized into its primary N‐monodesmethyl metabolite, M2, and further desmethylated into an N‐didesmethyl metabolite, M3. Both metabolites are cytotoxic and induce phospholipidosis. The effect of rifabutin on the generation and disposition of the 2 metabolites was investigated in healthy adult volunteers coadministered bedaquiline and either rifabutin or rifampin. Subjects received single oral doses (400 mg) of bedaquiline on days 1 and 29. Oral rifabutin (300 mg) or rifampin (600 mg) were given daily on days 20–41. In the rifabutin group maximum M2 concentrations (Cmax) increased significantly (P < .001) from 47.59 to 79.53 ng/mL, and clearance slowed slightly (P = .01). This resulted in significantly (P < .001) increased overall exposure (area under the concentration‐time curve [AUC0‐τ]). Peak concentrations of M3 increased approximately 3‐fold with little decline thereafter. In rifampin recipients M2 Cmax doubled (48.44 to 101.52 ng/mL), but M2 clearance and time to Cmax significantly (P < .001) increased, and AUC0‐∞ and mean residence time significantly decreased (P < .001). Peak M3 concentrations increased 4‐fold and rapidly declined. Although both rifamycins accelerate desmethylation of bedaquiline and M2, differences in clearance resulted in sustained elevations of both metabolites during rifabutin, but not rifampin, treatment.
An area‐efficient FFT processor for the OFDMA transceiver communication system
Authors: Nirmala N. , Sumathi S.
Published: November 2018

Orthogonal frequency division multiplexing (OFDM) is a well‐organized multiplexing scheme, which is long‐established in recent wireless and communication standards. OFDM resembles a system of exchanging information done with a nonflat channel called Discrete Multi‐Tone modulation (DMT) and Coded OFDM (COFDM). The data stream in this frequency modulation is divided across narrowband channels to limit interference and crosstalk. One of the extreme needs of OFDM is reasonable to be straight mean while sending and receiving systems. OFDM is extremely preferred for rapid data transmission and radio access method. In this paper, OFDM transceiver is carried out and implemented on FPGA. In addition, 128‐point IFFT/FFT pipelined architecture is proposed with the aim of optimizing area, frequency, and circuit complexity.
Exciton‐Coupled Circular Dichroism Characterization of Monotopically Binding Guests in Host−Guest Complexes with a Bis(zinc porphyrin) Tweezer
Authors: Olsson Sandra , Schäfer Clara , Blom Magnus , Gogoll Adolf
Published: November 2018

A stiff‐stilbene‐linked bisporphyrin tweezer with inherent helicity was used for exciton‐coupled circular dichroism (ECCD) characterization of a series of monotopically binding amine guest molecules. CD signals were observed for a variety of monoamines at relatively low tweezer/amine (host/guest) ratios between 1 : 10 to 1 : 70. For the amines producing the most intense CD signals, a binding stoichiometry of 1 : 2 was found. A likely explanation is the presence of guest‐guest interactions in the complexes. This is supported by the correlation observed between CD signal intensity and magnitude of possible noncovalent binding between the guests, which can be divided into three groups showing no, moderate and strong response, respectively. Further support for this rationalization comes from molecular modelling.
Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for the Use of Potent Volatile Anesthetic Agents and Succinylcholine in the Context of RYR1 or CACNA1S Genotypes
Authors: Gonsalves Stephen G. , Dirksen Robert T. , Sangkuhl Katrin , Pulk Rebecca , Alvarellos Maria , Vo Teresa , Hikino Keiko , Roden Dan , Klein Teri E. , Poler S. Mark , Patel Sephalie , Caudle Kelly E. , Gordon Ronald , Brandom Barbara , Biesecker Leslie G.
Published: November 2018

The identification in a patient of 1 of the 50 variants in the RYR1 or CACNA1S genes reviewed here should lead to a presumption of malignant hyperthermia susceptibility (MHS). MHS can lead to life‐threatening reactions to potent volatile anesthetic agents or succinylcholine. We summarize evidence from the literature supporting this association and provide therapeutic recommendations for the use of these agents in patients with these RYR1 or CACNA1S variants (updates at https://cpicpgx.org/guidelines and www.pharmgkb.org).
Phenylbutazone blood and urine concentrations, pharmacokinetics, and effects on biomarkers of inflammation in horses following intravenous and oral administration of clinical doses
Authors: Knych Heather K. , Arthur Rick M. , McKemie Dan S. , Seminoff Kelsey , Hamamoto‐Hardman Briana , Kass Philip H.
Published: November 2018

Phenylbutazone (PBZ) is a potent mon‐steroidal anti‐inflammatory drug used commonly in performance horses. The objectives of the current study were to describe blood and urine concentrations and the pharmacokinetics of PBZ and its metabolites following intravenous (IV) and oral administration and to describe the duration of pharmacodynamic effect. To that end, 17 horses received an IV administration and 18 horses an oral administration of 2 g of PBZ. Blood and urine samples were collected prior to and for up to 96 hours post drug administration. Whole blood samples were collected at various time points and challenged with lipopolysaccharide or calcium ionophore to induce ex vivo synthesis of eicosanoids. Concentrations of PBZ and eicosanoids were measured using liquid chromatography–tandem mass spectrometry (LC–MS/MS) and non‐compartmental pharmacokinetic analysis performed on concentration data from IV and oral administration. Serum concentrations of PBZ and its metabolites were below the limit of quantitation at 96 hours post administration. The volume of distribution at steady state, systemic clearance, and terminal half‐life was 0.194 ± 0.019 L/kg, 23.9 ± 4.48 mL/h/kg, and 10.9 ± 5.32 hours, respectively. The terminal half‐life following oral administration was 13.4 ± 3.01 (paste) and 15.1 ± 3.96 hours (tablets). Stimulation of PBZ treated whole blood with lipopolysaccharide and calcium ionophore resulted in an inhibition of TXB2, PGE2, LTB4 and 15‐HETE production for a prolonged period of time post drug administration. The results of this study suggest that PBZ has a prolonged anti‐inflammatory following IV or oral administration of 2 g to horses.
An ecohydraulics virtual watershed: Integrating physical and biological variables to quantify aquatic habitat quality
Authors: Benjankar Rohan , Tonina Daniele , McKean James A. , Sohrabi Mohammad M. , Chen Qiuwen , Vidergar Dmitri
Published: November 2018

Advances in remote sensing coupled with numerical modelling allow us to build a “virtual ecohydraulics watershed” at the micro‐habitat scale. This approach is an integrated modelling framework with a cascade of models including physical (hydrologic, hydraulic, and stream water temperature) and biological (fish habitat) modelling at a resolution and extent important for aquatic and terrestrial organisms. We applied this approach to quantify the impacts of discharges and water temperature on habitat quality and spatial/temporal habitat use patterns of bull trout, a federally listed species along the South Fork Boise River.

We coupled process‐based snow melt and hydrologic models to predict water availability within the watershed. The model fed one‐ and two‐dimensional hydrodynamic models to predict stream hydraulics and water temperature using high‐resolution (meter scale) river bathymetric data. This information was then used in an aquatic habitat modelling to characterize habitat quality distribution as a function of discharges. Our results showed that the summer thermal regime of river system would alter available habitat. The high spatial resolution analysis allows modelling to predict the importance of lateral habitats, which serve as vital refugia during high‐flow events for many fish species. The advances in remote sensing, numerical modelling, and understanding of physical‐biological processes provide us an opportunity to conceptualize new process‐based integrated modelling tools to analyse human impacts at a catchment scale, for example, dam operation and climatic variability on aquatic habitat and status, and further to develop restoration protocols in a virtual domain before field studies are developed and/or structures built.
Phase Control of Ferromagnetic Copper(II) Carbonate Coordination Polymers through Reagent Concentration
Authors: Mulrooney David Z. T. , Clements John E. , Ericsson Daniel J. , Price Jason R. , Kühne Irina A. , Coles Simon J. , Kepert Cameron J. , Keene Tony D.
Published: November 2018

A significant degree of control over the dimensionality and magnetic connectivity of CuII carbonate coordination polymers is achieved through varying the concentration of ammonia in the reactant solution. Higher concentration leads to a two‐dimensional ferromagnetic [Cu3(2,4′‐bipy)6(CO3)2]n2n+ kagome structure while lower concentration develops a ferromagnetic [Cu(2,4′‐bipy)2(H2O)2][Cu(2,4′‐bipy)2(CO3)2] chain (where 2,4′‐bipy = 2,4′‐bipyridine). The carbonate anion in the structures arises from the fixation of atmospheric CO2 by the basic ammonia solution. Modelling the magnetic susceptibility of 1 and 2 reveals ferromagnetic interactions with J/kB = +28.1 K for 1 and +13.99 K for 2. (H = –J). The use of a monodentate polypyridine ligand results in the suppression of the superexchange pathway between layers in 1, removing the metamagnetic behaviour seen in related compounds where a ditopic ligand presents the ability for the layer to couple antiferromagnetically. Attempts to substitute 2,4′‐bipy for 4‐(N,N‐dimethylamino)pyridine (4‐dmap) result in a discrete species [Cu(4‐ampy)4](ClO4)2 (3).
Direct Electrolysis and Detection of Single Nanosized Water Emulsion Droplets in Organic Solvent Using Stochastic Collisions
Authors: Lee Jungeun , Ho Thy L. T. , Kim Hae‐Young , Park Jun Hui , Kim Byung‐Kwon
Published: November 2018

We studied the electrochemical detection of single nanosized water emulsion droplets in organic solution using the electrochemical collision technique on an ultramicroelectrode (UME). In this experiment, the detection system for water droplets does not require any kind of redox species in organic solvent. Only water molecules in the water droplets were considered. When water droplets collided with the UME surface, anodic current spikes were observed in the chronoamperometry, resulting from the electrolysis of water molecules in the water droplets. From the collision frequency and integrated current spike, concentrations and size distributions of water droplets in organic solvent can be determined.
Preventive effects of combinative natural foods produced by elite crop varieties rich in anticancer effects on N‐nitrosodiethylamine‐induced hepatocellular carcinoma in rats
Authors: Zheng Jingui , He Jun , Liao Sufeng , Cheng Zuxin , Lin Jinke , Huang Ke , Li Xiaocen , Zheng Kaibin , Chen Xuanyang , Lin Lihui , Xia Fagang , Liu Jianghong , Xu Ming , Chen Tuansheng , Huang Xinying , Cao Xiaohua , Yang Zhijian
Published: November 2018

The World Cancer Research Fund International has released 32 anticancer effects (ACEs) that targeted every stage of cancer processes. Thus, we designed two formulas of natural food combination Diet I and Diet II, mainly produced by elite crop varieties rich in ACEs with different mixture ratios, and evaluated their cancer preventive effects on N‐nitrosodiethylamine (NDEA)‐induced hepatocarcinogenesis. After 20 weeks of dietary intervention, Diet I and Diet II reduced incidence, size, and number of hepatic nodules (p < 0.01) and prevented hepatic tumor formation in NDEA‐induced hepatocarcinogenesis rats. Low‐grade hepatic dysplasia incidence was 20% for Diet II and 40% for Diet I, and apparent hepatocellular carcinomas (HCC) rates were both 0, while 90% HCC in control diet treatment group (p < 0.01). Diet I and Diet II ameliorated abnormal liver function enzymes, reduced serum alpha fetal protein, tumor‐specific growth factor, dickkopf‐related protein 1, tumor necrosis factor‐alpha and interleukin‐6 levels, regulated hepatic phase I and II xenobiotic‐metabolizing enzymes, enhanced antioxidant capacity, suppressed NDEA‐initiated oxidative DNA damage, and induced apoptosis coupled to down‐regulation of proinflammatory, invasion, and angiogenesis markers. Daily intake of combination diet produced from ACEs‐rich elite crop varieties can effectively prevent or delay occurrence and development of NDEA‐induced hepatocarcinogenesis in rats.
Effect of Increasing Age on Brain Dysfunction in Cirrhosis
Authors: Liu Runping , Ahluwalia Vishwadeep , Kang Jason D. , Ghosh Siddhartha S. , Zhou Huiping , Li Yunzhou , Zhao Derrick , Gurley Emily , Li Xiaojiaoyang , White Melanie B. , Fagan Andrew , Lippman H. Robert , Wade James B. , Hylemon Phillip B. , Bajaj Jasmohan S.
Published: November 2018

Patients with cirrhosis are growing older, which could have an impact on brain dysfunction beyond hepatic encephalopathy. Our aim was to study the effect of concomitant aging and cirrhosis on brain inflammation and degeneration using human and animal experiments. For the human study, age‐matched patients with cirrhosis and controls between 65 and 85 years underwent cognitive testing, quality of life (QOL) assessment, and brain magnetic resonance (MR) spectroscopy and resting state functional MR imaging (rs‐fMRI) analysis. Data were compared between groups. For the animal study, young (10‐12 weeks) and old (1.5 years) C57BL/6 mice were given either CCl4 gavage to develop cirrhosis or a vehicle control and were followed for 12 weeks. Cortical messenger RNA (mRNA) expression of inflammatory mediators (interleukin [IL]‐6, IL‐1β, transforming growth factor β [TGF‐β], and monocyte chemoattractant protein 1), sirtuin‐1, and gamma‐aminobutyric acid (GABA)‐ergic synaptic plasticity (neuroligin‐2 [NLG2], discs large homolog 4 [DLG4], GABA receptor, subunit gamma 1/subunit B1 [GABRG1/B1]) were analyzed and compared between younger/older control and cirrhotic mice. The human study included 46 subjects (23/group). Patients with cirrhosis had worse QOL and cognition. On MR spectroscopy, patients with cirrhosis had worse changes related to ammonia and lower N‐acetyl aspartate, whereas rs‐fMRI analysis revealed that these patients demonstrated functional connectivity changes in the frontoparietal cortical region compared to controls. Results of the animal study showed that older mice required lower CCl4 to reach cirrhosis. Older mice, especially with cirrhosis, demonstrated higher cortical inflammatory mRNA expression of IL‐6, IL‐1β, and TGF‐β; higher glial and microglial activation; and lower sirtuin‐1 expression compared to younger mice. Older mice also had lower expression of DLG4, an excitatory synaptic organizer, and higher NLG2 and GABRG1/B1 receptor expression, indicating a predominantly inhibitory synaptic organization. Conclusion: Aging modulates brain changes in cirrhosis; this can affect QOL, cognition, and brain connectivity. Cortical inflammation, microglial activation, and altered GABA‐ergic synaptic plasticity could be contributory.
A comprehensive gene–environment interaction analysis in Ovarian Cancer using genome‐wide significant common variants
Authors: Kim Sehee , Wang Miao , Tyrer Jonathan P. , Jensen Allan , Wiensch Ashley , Liu Gang , Lee Alice W. , Ness Roberta B. , Salvatore Maxwell , Tworoger Shelley S. , Whittemore Alice S. , Anton‐Culver Hoda , Sieh Weiva , Olson Sara H. , Berchuck Andrew , Goode Ellen L. , Goodman Marc T. , Doherty Jennifer Anne , Chenevix‐Trench Georgia , Rossing Mary Anne , Webb Penelope M. , Giles Graham G. , Terry Kathryn L. , Ziogas Argyrios , Fortner Renée T. , Menon Usha , Gayther Simon A. , Wu Anna H. , Song Honglin , Brooks‐Wilson Angela , Bandera Elisa V. , Cook Linda S. , Cramer Daniel W. , Milne Roger L. , Winham Stacey J. , Kjaer Susanne K. , Modugno Francesmary , Thompson Pamela J. , Chang‐Claude Jenny , Harris Holly R. , Schildkraut Joellen M. , Le Nhu D. , Wentzensen Nico , Trabert Britton , Høgdall Estrid , Huntsman David , Pike Malcolm C. , Pharoah Paul D.P. , Pearce Celeste Leigh , Mukherjee Bhramar
Published: November 2018

As a follow‐up to genome‐wide association analysis of common variants associated with ovarian carcinoma (cancer), our study considers seven well‐known ovarian cancer risk factors and their interactions with 28 genome‐wide significant common genetic variants. The interaction analyses were based on data from 9971 ovarian cancer cases and 15,566 controls from 17 case–control studies. Likelihood ratio and Wald tests for multiplicative interaction and for relative excess risk due to additive interaction were used. The top multiplicative interaction was noted between oral contraceptive pill (OCP) use (ever vs. never) and rs13255292 (p value = 3.48 × 10−4). Among women with the TT genotype for this variant, the odds ratio for OCP use was 0.53 (95% CI = 0.46–0.60) compared to 0.71 (95%CI = 0.66–0.77) for women with the CC genotype. When stratified by duration of OCP use, women with 1–5 years of OCP use exhibited differential protective benefit across genotypes. However, no interaction on either the multiplicative or additive scale was found to be statistically significant after multiple testing correction. The results suggest that OCP use may offer increased benefit for women who are carriers of the T allele in rs13255292. On the other hand, for women carrying the C allele in this variant, longer (5+ years) use of OCP may reduce the impact of carrying the risk allele of this SNP. Replication of this finding is needed. The study presents a comprehensive analytic framework for conducting gene–environment analysis in ovarian cancer.
Prognostic significance of microsatellite‐instability in gastric and gastroesophageal junction cancer patients undergoing neoadjuvant chemotherapy
Authors: Haag Georg Martin , Czink Elena , Ahadova Aysel , Schmidt Thomas , Sisic Leila , Blank Susanne , Heger Ulrike , Apostolidis Leonidas , Berger Anne Katrin , Springfeld Christoph , Lasitschka Felix , Jäger Dirk , von Knebel Doeberitz Magnus , Kloor Matthias
Published: November 2018

Perioperative systemic treatment is standard of care for Caucasian patients with locally advanced, resectable gastric adenocarcinoma. The prognostic relevance of the microsatellite instability (MSI) status in patients undergoing neoadjuvant chemotherapy followed by resection is unclear. We analyzed the association of the MSI status with histological regression and clinical outcome in patients undergoing neoadjuvant systemic treatment. Tumor tissue from patients undergoing neoadjuvant chemotherapy followed by resection for gastric or gastroesophageal‐junction adenocarcinoma was analyzed for MSI status using a mononucleotide marker panel encompassing the markers BAT25, BAT26, and CAT25. Histological regression, relapse‐free survival and overall survival were calculated and correlated with MSI status. We identified the MSI‐H phenotype in 9 (8.9%) out of 101 analyzed tumors. Though a poor histological response was observed in eight out of nine MSI‐H patients, overall survival was significantly better for patients with MSI‐H compared to MSS tumors (median overall survival not reached vs. 38.6 months, log‐rank test p = 0.014). Among MSI‐H patients, an unexpected long‐term survival after relapse was observed. Our data indicate that the MSI‐H phenotype is a favorable prognostic marker in gastric cancer patients undergoing neoadjuvant treatment. The benefit of perioperative cytotoxic treatment in patients with MSI‐H gastric cancer, however, remains questionable. Future trials should stratify patients according to their MSI status, and novel treatment modalities focusing on MSI‐H tumors should be considered.
A method for the gross analysis of global protein acylation by gas–liquid chromatography
Authors: Mohammadzadeh Fatemeh , Hosseini Vahid , Mehdizadeh Amir , Dani Christian , Darabi Masoud
Published: November 2018

Protein acylation is a posttranslational modification in which an amino acid residue of a protein is acylated by a fatty acid. This process plays a key role in regulating proteomic function. Studies of protein acylation have relied on the development and application of extremely complicated molecular methods. However, global protein acylation can be profiled following hydrolysis of fatty acyl groups from cellular proteins. The present study aimed to develop a method for analysis of global protein acylation using gas–liquid chromatography (GLC). The total protein was extracted from the human hepatocellular carcinoma (HepG2) cell line. Protein sedimentation and extensive wash were combined with differential O‐, S‐, or N‐acyl hydrolysis using sodium hydroxide (NaOH), hydroxylamine (NH2OH), or hydrochloric acid (HCl), respectively. GLC with a flame ionization detector system was used to analyze changes in the fatty acid composition of the released lipids. The effect of selective inhibition of monounsaturated fatty acid (MUFA) synthesis on global protein acylation and the expression of reprogramming markers were determined to further validate the proposed profiling approach. In all hydrolysis conditions, the amount of myristate released was significantly higher than of other fatty acids. Notable differences were observed in the release of individual fatty acids among the hydrolyzing agents. Only NH2OH could release significant amounts of palmitoleate (>2.5‐fold vs. NaOH and HCl). The acylation assay indicates that treatment with a chemical inhibitor of monounsaturated fatty acid synthesis led to an overall increase in saturated fatty acid O‐ and N‐acylation, and a decrease in palmitoleate O‐ and S‐acylation of cellular proteins (<−15%). This was accompanied by significant reductions in the gene expression of the reprogramming markers Oct4 (−26%, P < 0.01) and Sox2 (−40%, P < 0.01). GLC‐based analysis of global protein acylation affords a semi‐quantitative method that can be used to assess the gross changes in the protein acylation profile during cell differentiation and reprogramming. © 2018 IUBMB Life, 71(3):340–346, 2019
The JAK1 Inhibitor Upadacitinib Has No Effect on the Pharmacokinetics of Levonorgestrel and Ethinylestradiol: A Study in Healthy Female Subjects
Authors: Mohamed Mohamed‐Eslam F. , Trueman Sheryl , Feng Tian , Friedman Alan , Othman Ahmed A.
Published: November 2018

Upadacitinib is a novel selective oral Janus kinase 1 (JAK) inhibitor being developed for treatment of several inflammatory diseases. Oral contraceptives are anticipated to be a common concomitant medication in the target patient populations. This study was designed to evaluate the effect of multiple doses of upadacitinib on the pharmacokinetics of ethinylestradiol and levonorgestrel in healthy female subjects. This phase I, single‐center, open‐label, 2‐period crossover study evaluated the effect of multiple doses of 30 mg once daily extended‐release upadacitinib on the pharmacokinetics of a single oral dose of ethinylestradiol/levonorgestrel (0.03/0.15 mg; administered alone in period 1 and on day 12 of a 14‐day regimen of upadacitinib in period 2) in 22 healthy female subjects. The ratios (90% confidence intervals) for maximum plasma concentration and area under the plasma drug concentration–time curve from time zero to infinity following administration of ethinylestradiol/levonorgestrel with upadacitinib compared with administration of ethinylestradiol/ levonorgestrel alone were 0.96 (0.89–1.02) and 1.1 (1.04–1.19), respectively, for ethinylestradiol, and 0.96 (0.87–1.06) and 0.96 (0.85–1.07), respectively, for levonorgestrel. The harmonic mean terminal half‐life for ethinylestradiol (7.7 vs 7.0 hours) and levonorgestrel (37.1 vs 33.1 hours) was similar in the presence and absence of upadacitinib. Ethinylestradiol and levonorgestrel were bioequivalent in the presence and absence of upadacitinib. Therefore, upadacitinib can be administered concomitantly with oral contraceptives containing ethinylestradiol or levonorgestrel.
An endogenous aryl hydrocarbon receptor ligand enhances de novo generation of regulatory T cells in humans
Authors: Zamali Imen , Rekik Raja , Belhadj Hmida Nadia , Ben Hmid Ahlem , Kammoun Ons , Barbouche Mohamed-Ridha , Ben Ahmed Mélika
Published: November 2018

The aromatic hydrocarbons receptor (AhR) is a ligand-dependent transcription factor that plays a role in mediating toxicity to xenobiotics. Its key role in immune regulation has been recently demonstrated. Recent data pointed to the efficacy of ITE (2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester), a nontoxic ligand of AhR, in experimental models of inflammatory diseases. Such effect was mainly through the expansion of regulatory T cells (Tregs). Similarly, TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin), a toxic ligand of AhR, has been shown to exert comparable effects on Tregs in mice. Herein, we showed that ITE has no effects on natural Tregs. However, it supports the de novo generation of Tregs in humans while promoting their suppressive functions. Our data bring new elements supporting the use of ITE in human therapy of inflammatory diseases.

ITE, a non-toxic endogenous aryl hydrocarbon receptor ligand, enhances de novo generation of regulatory T cells in humans and promotes their suppressive functions.
Non‐stationary intensity‐duration‐frequency curves integrating information concerning teleconnections and climate change
Authors: Ouarda Taha B. M. J. , Yousef Latifa A. , Charron Christian
Published: November 2018

Rainfall intensity‐duration‐frequency (IDF) curves are commonly used for the design of water resources infrastructure. Numerous studies reported non‐stationarity in meteorological time series. Neglecting to incorporate non‐stationarities in hydrological models may lead to inaccurate results. The present work focuses on the development of a general methodology that copes with non‐stationarities that may exist in rainfall, by making the parameters of the IDF relationship dependent on the covariates of time and climate oscillations. In the recent literature, non‐stationary models are generally fit on data series of specific durations. In the approach proposed here, a single model with a separate functional relation with the return period and the rainfall duration is instead defined. This model has the advantage of being simpler and extending the effective sample size. Its parameters are estimated with the maximum composite likelihood method. Two sites in Ontario, Canada and one site in California, USA, exhibiting non‐stationary behaviours are used as case studies to illustrate the proposed method. For these case studies, the time and the climate indices Atlantic Multi‐decadal Oscillation (AMO) and Western Hemisphere Warm Pool (WHWP) for the stations in Canada, and the time and the climate indices Southern Oscillation Index (SOI) and Pacific Decadal Oscillation (PDO) for the stations in United States are used as covariates. The Gumbel and the generalized extreme value distributions are used as the time‐dependent functions in the numerator of the general IDF relationship. Results show that the non‐stationary framework for IDF modelling provides a better fit to the data than its stationary counterpart according to the Akaike information criterion. Results indicate also that the proposed generalized approach is more robust than the common approach especially for stations with short rainfall records (e.g., R2 of 0.98 compared to 0.69 for duration of 30 min and a sample size of 27 years).
A 1200+ year reconstruction of temperature extremes for the northeastern Mediterranean region
Authors: Klippel Lara , Krusic Paul J. , Konter Oliver , St. George Scott , Trouet Valerie , Esper Jan
Published: November 2018

Proxy evidence is necessary to place current temperature and hydroclimatic changes in a long‐term context and to assess the full range of natural and anthropogenic climate forcings. Here, we present the first millennium‐length reconstruction of late summer (August–September) temperature variability for the Mediterranean region. We compiled 132 maximum latewood density (MXD) tree‐ring series of living and relict Pinus heldreichii trees from a network of four high‐elevation sites in the Pindus Mountains of Greece. Forty series reach back into the first millennium and the oldest sample dates to 575 CE. At annual to decadal scales, the record correlates significantly with August–September temperatures over the Balkan Peninsula and northeastern Mediterranean (r1950–2014 = 0.71, p < 0.001). We produce two reconstructions emphasizing interannual and decadal scale variance over the past millennium. Analysis of temperature extremes reveals the coldest summers occurred in 1035, 1117, 1217, 1884 and 1959 and the coldest decades were 1061–1070 and 1811–1820. The warmest summers occurred in 1240 and 1474, and the warmest decades were 1141–1150 and 1481–1490. Comparison of this new reconstruction with MXD‐based summer temperature reconstructions across Europe reveals synchronized occurrences of extreme cool summers in the northeastern Mediterranean, and an antiphase‐relationship with warm summer temperatures over the British Isles and Scandinavia. This temperature dipole is related to anomalies in the latitudinal position of the North Atlantic Jet. Despite the representation of common atmospheric forcing patterns, the occurrence of warm extremes is limited to few events, suggesting potential weaknesses of MXD to record warm temperature anomalies. In addition, we acknowledge problems in the observational data to capture local temperature variability due to small scale topographic differences in this high‐elevation landscape. At a broader geographical scale, the occurrence of common cold summer extremes is restricted to years with volcanically induced changes in radiative forcing.
Bacteria‐Targeted Supramolecular Photosensitizer Delivery Vehicles for Photodynamic Ablation Against Biofilms
Authors: Gao Yifan , Wang Jing , Hu Dengfeng , Deng Yongyan , Chen Tingting , Jin Qiao , Ji Jian
Published: November 2018

Photodynamic therapy (PDT) is believed to be a potent method for biofilm treatments. However, undesired damage to normal cells may be caused due to the nonselective nature of PDT. Therefore, targeted PDT is preferred on one hand to enhance antimicrobial effects and on the other hand to reduce cytotoxicity to normal cells. For this purpose, novel bacteria‐targeted photosensitizer delivery micelles are fabricated, taking advantage of α‐cyclodextrin (α‐CD)/polyethylene glycol (PEG) supramolecular assembly. Hydrophilic antimicrobial peptide (AMP) Magainin I is covalently bound with PEG, working as a bacterial targeting group as well as the stabilizing shell of the supramolecular micelles. Photosensitizer Chlorin e6 (Ce6) is grafted onto α‐CD. The micelles exhibit excellent bacterial targeting effects. Compared to α‐CD‐Ce6, the supramolecular micelles possess enhanced biofilm killing ability against Gram (−) Pseudomonas aeruginosa biofilms and Gram (+) methicillin‐resistant Staphylococcus aureus (MRSA) biofilms while reducing cytotoxicity to NIH/3T3 model cells.
Effects of vitamin D and calcium on expression of MSH2 and transforming growth factors in normal‐appearing colorectal mucosa of sporadic colorectal adenoma patients: A randomized clinical trial
Authors: Kwan Albert K. , Um Caroline Y. , Rutherford Robin E. , Seabrook March E. , Barry Elizabeth L. , Fedirko Veronika , Baron John A. , Bostick Roberd M.
Published: November 2018

Abnormal expression of the DNA mismatch repair protein MSH2 and autocrine/paracrine transforming growth factors TGFα (growth promoter) and TGFβ1 (growth inhibitor) is common during colorectal carcinogenesis. To estimate vitamin D and calcium effects on these biomarkers in the normal‐appearing colorectal mucosa of sporadic colorectal adenoma patients, we conducted a pilot, randomized, double‐blinded, placebo‐controlled, modified 2 × 2 factorial chemoprevention clinical trial (N = 104) of supplemental vitamin D3 (1000 IU daily) and calcium (1200 mg daily), alone and in combination, versus placebo over 1 year. The expression of the three biomarkers and Ki‐67/mib‐1 in colorectal crypts in biopsies of normal‐appearing rectal mucosa were detected using automated immunohistochemistry and quantified using image analysis. In the vitamin D3 and vitamin D3 plus calcium groups, relative to their reference groups, in the upper 40% (differentiation zone) of crypts, it was estimated that, respectively, the MSH2/mib‐1 ratio increased by 47% (P = 0.14) and 62% (P = 0.08), TGFβ1 expression increased by 41% (P = 0.25) and 78% (P = 0.14), and the TGFα/TGFβ1 ratio decreased by 25% (P = 0.31) and 44% (P = 0.13). Although not statistically significant, these results support further research into (i) whether supplemental vitamin D3, alone or in combination with calcium, may increase DNA mismatch repair relative to proliferation, increase TGFβ1 expression, and decrease autocrine/paracrine growth promotion relative to growth inhibition in the colorectal epithelium, all hypothesized to reduce risk for colorectal carcinogenesis; and (ii) the expression of MSH2 relative to mib‐1, TGFβ1 alone, and TGFα relative to TGFβ1 in the normal‐appearing rectal mucosa as potential modifiable, pre‐neoplastic markers of risk for colorectal neoplasms.
High Molecular Weight Polystyrene Obtained by Cationic Emulsion Polymerization Catalyzed by Imidazolium‐Based Ionic Liquid
Authors: Patrocinio Vinicius M. B. , Agner Tamara , Dutra Gabriel V. S. , Machado Fabricio , Neto Brenno A. D. , Araújo Pedro H. H. , Sayer Claudia
Published: November 2018

The ionic liquid 1‐n‐butyl‐3‐methylimidazolium heptachlorodiferrate (BMI.Fe2Cl7) is efficiently used as catalyst in the cationic emulsion polymerization of styrene. The effect of different reaction temperatures, surfactant, and ionic liquid concentrations on polymer properties as molecular weight distribution and particle size is evaluated. High weight average molecular weights, above 1000 kDa, are achieved at 70% of conversion in 100 nm polystyrene particles formed mainly by micellar nucleation. Particle sizes and molecular weights increase with the decrease of the amount of surfactant. Even at low concentrations, BMI.Fe2Cl7/styrene molar ratio equal to 1/1000, the ionic liquid proves to be efficient for the emulsion polymerization of styrene, and lower ionic liquid concentrations lead to the formation of longer polymer chains.
Homophtalonitrile for Multicomponent Reactions: Syntheses and Optical Properties of o‐Cyanophenyl‐ or Indol‐3‐yl‐Substituted Chromeno[2,3‐c]isoquinolin‐5‐Amines
Authors: Festa Alexey A. , Storozhenko Olga A. , Golantsov Nikita E. , Subramani Karthikeyan , Novikov Roman A. , Zaitseva Snezhana O. , Baranov Mikhail S. , Varlamov Alexey V. , Voskressensky Leonid G.
Published: November 2018

Malononitrile is a useful reagent for multicomponent reactions with hundreds of methods developed. In this paper, we suggest α‐(cyano)‐o‐tolunitrile (homophtalonitrile) to work as a vinylogous malononitrile. Thus, a organocatalytic pseudo‐three‐component reaction of homopthalonitrile (2 equiv) and o‐hydroxybenzaldehyde, leading to the diastereoselective formation of 5‐amino‐12H‐chromeno[2,3‐c]isoquinolin‐12‐yl)(cyano)methyl)benzonitriles, was discovered. The possibility to employ other nucleophiles was demonstrated for indoles, and a sequential three‐component reaction of homophtalonitrile, o‐hydroxybenzaldehyde, and (aza)indole, giving 12‐(1H‐Indol‐3‐yl)‐12H‐chromeno[2,3‐c]isoquinolin‐5‐amines, was developed. The photophysical properties of the synthesized compounds have been studied, revealing high fluorescence quantum yields (42–70 %) for indol‐3‐yl substituted 12H‐chromeno[2,3‐c]isoquinolin‐5‐amines and reversible fluorescence quenching under acidic conditions.