bluuebunny/crossref_metadata_2025 huggingface dataset:
Controlling an SN2 Reaction by Electronic and Vibrational Excitation: Tip‐Induced Ether Cleavage on Si(001)
Authors: Mette Gerson , Adamkiewicz Alexa , Reutzel Marcel , Koert Ulrich , Dürr Michael , Höfer Ulrich
Published: January 2019

Controlling chemical reactions beyond thermally activated reaction schemes can open alternative reaction channels, and thus lead to new final products. Herein, we show for tetrahydrofuran (THF) cleavage on Si(001), the surface analogue of an SN2 reaction, that excitation by electrons from the tip of a scanning tunneling microscope (STM) not only opens new reaction channels, but that different final products can be selectively addressed by the type of excitation: Above a threshold voltage of 2.5 V, direct excitation by electron transfer into the antibonding C−O orbital of the THF molecules induces ether cleavage of the datively bonded intermediate of THF on Si(001). Below the threshold, ether cleavage is induced by multiple excitation of vibrational modes. In both modes of excitation, additional final configurations were observed when compared to the thermally activated reaction. The branching ratios of the final configurations are different for the two different excitation mechanisms, which in turn can be controlled by the applied sample bias.
Rotational Signatures of Dispersive Stacking in the Formation of Aromatic Dimers
Authors: Fatima Mariyam , Steber Amanda L. , Poblotzki Anja , Pérez Cristóbal , Zinn Sabrina , Schnell Melanie
Published: January 2019

The aggregation of aromatic species is dictated by inter‐ and intramolecular forces. Not only is characterizing these forces in aromatic growth important for understanding grain formation in the interstellar medium, but it is also imperative to comprehend biological functions. We report a combined rotational spectroscopic and quantum‐chemical study on three homo‐dimers, comprising of diphenyl ether, dibenzofuran, and fluorene, to analyze the influence of structural flexibility and the presence of heteroatoms on dimer formation. The structural information obtained shows clear similarities between the dimers, despite their qualitatively different molecular interactions. All dimers are dominated by dispersion interactions, but the dibenzofuran dimer is also influenced by repulsion between the free electron pairs of the oxygen atoms and the π‐clouds. This study lays the groundwork for understanding the first steps of molecular aggregation in systems with aromatic residues.
Reverse Arene Sandwich Structures Based upon π‐Hole⋅⋅⋅[MII] (d8 M=Pt, Pd) Interactions, where Positively Charged Metal Centers Play the Role of a Nucleophile
Authors: Rozhkov Anton V. , Krykova Mariya A. , Ivanov Daniil M. , Novikov Alexander S. , Sinelshchikova Anna A. , Volostnykh Marina V. , Konovalov Mikhail A. , Grigoriev Mikhail S. , Gorbunova Yulia G. , Kukushkin Vadim Yu.
Published: January 2019

The complexes [Pt(tpp)] (H2tpp=tetraphenylporphyrin), [M(acac)2] (M=Pd, Pt, Hacac=acetylacetone), and [Pd(ba)2] (Hba=benzoylacetone) were co‐crystallized with highly electron‐deficient arene systems to form reverse arene sandwich structures built by π‐hole⋅⋅⋅[MII] (d8M=Pt, Pd) interactions. The adduct [Pt(tpp)]⋅2 C6F6 is monomeric, whereas the diketonate 1:1 adducts form columnar infinity 1D‐stack assembled by simultaneous action of both π‐hole⋅⋅⋅[MII] and C⋅⋅⋅F interactions. The reverse sandwiches are based on noncovalent interactions and calculated ESP distributions indicate that in π‐hole⋅⋅⋅[MII] contacts, [MII] plays the role of a nucleophile.
General Cyclopropane Assembly by Enantioselective Transfer of a Redox‐Active Carbene to Aliphatic Olefins
Authors: Montesinos‐Magraner Marc , Costantini Matteo , Ramírez‐Contreras Rodrigo , Muratore Michael E. , Johansson Magnus J. , Mendoza Abraham
Published: January 2019

Asymmetric cyclopropane synthesis currently requires bespoke strategies, methods, substrates, and reagents, even when targeting similar compounds. This approach slows down discovery and limits available chemical space. Introduced herein is a practical and versatile diazocompound and its performance in the first unified asymmetric synthesis of functionalized cyclopropanes. The redox‐active leaving group in this reagent enhances the reactivity and selectivity of geminal carbene transfer. This effect allowed the asymmetric cyclopropanation of various olefins, including unfunctionalized aliphatic alkenes, that enables the three‐step total synthesis of (−)‐dictyopterene A. This unified synthetic approach delivers high enantioselectivities that are independent of the stereoelectronic properties of the functional groups transferred. Our results demonstrate that orthogonally differentiated diazocompounds are viable and advantageous equivalents of single‐carbon chirons.
Application of the thermal energy storage concept to novel epoxy–short carbon fiber composites
Authors: Dorigato A. , Fredi G. , Pegoretti A.
Published: January 2019

For the first time, multifunctional epoxy–short carbon fiber reinforced composites suitable for thermal energy storage technology were developed. Paraffin microcapsules (MC) and short carbon fibers (CFs) were added at different relative amounts to an epoxy matrix, and the microstructural and thermomechanical properties of the resulting materials were investigated. Scanning electron microscopy images of the composites showed a uniform distribution of the capsules within the matrix, with a rather good interfacial adhesion, while the increase in the polymer viscosity at elevated CF and MC amounts caused an increase in the void content. Differential scanning calorimetry tests revealed that melting enthalpy values (up to 60 J/g) can be obtained at high MC concentrations. The mixing and thermal curing of the composites did not lead to breakage of the capsules and to the consequent leakage of the paraffin out of the epoxy matrix. The thermal stability of the prepared composites is not negatively affected by the MC addition, and the temperatures at which the thermal degradation process begins were far above the curing or service temperature of the composites. Flexural and impact tests highlighted that the presence of MC reduces the mechanical properties of the samples, while CF positively contributes to retaining the original stiffness and mechanical resistance. © 2019 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2019, 136, 47434.
Property enhancement of poly(butylene succinate)/poly(ethyleneglycol‐co‐cyclohexane‐1,4‐dimethanolterephthalate) blends via high‐speed extrusion and in situ fibrillation
Authors: Fan Mao , Zhou Mi , Deng Sha , Chen Feng , Zhang Qin , Fu Qiang
Published: January 2019

In the current work, poly(butylene succinate)(PBS)/poly(ethylene glycol‐co‐cyclohexane‐1,4‐dimethanolterephthalate) (PETG) blends were first prepared by high‐speed extrusion melt processing, and the dependence of the dispersed morphology(phase size) was investigated as function of screw speed. Then, the prepared blends were subjected to a “melt extrusion‐uniaxial cold stretching” process to convert the dispersed phase into fibrillar structure, and the diameter change and property enhancement of PBS/PETG blends were further studied. It was found, at fixed ratio of PBS/PETG = 80/20 (wt/wt), the diameters of the PETG was changed from 2.25, 1.29, 1.11, 0.89 μm to 1.13, 0.64, 0.50, 0.38 μm, as increasing the screw speed from 150, 500, 700 rpm to 900 rpm, respectively. In addition, increasing the extrusion speed is favorable not only for smaller but more uniform dispersed phase particles, thus leading to finer microfibrils with narrower diameter distribution after cold stretching. As a result, the yield strength of PBS could be improved from 25.6 to 39.8 MPa for blend obtained via high‐speed extrusion and stretching. Our work is important for the preparation of polymer blends with improved property. © 2019 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2019, 136, 47549.
Cross‐layer security design for encrypted CPS based on modified security signalling game
Authors: Shen Jiajun , Feng Dongqin
Published: January 2019

Recent years have witnessed increasing cyber and physical attacks against encrypted cyber‐physical system (CPS) and the ensuing catastrophic consequences. A modified security signaling game (MSSG) model is proposed for capturing attack‐defense interactions and analyzing the cross‐layer security of encrypted CPS. Cyber real‐time performance and physical control performance are both considered in cross‐layer utility function. Theorems concerning the existence of pure‐strategy and mixed‐strategy perfect Bayesian Nash equilibrium (PBNE) are provided, based on which a cross‐layer security design algorithm is proposed for defender's optimal strategy against potential attacks. A numerical case is studied with the effectiveness of our method being proved.
Molecular dynamics insights into protein‐glycosaminoglycan systems from microsecond‐scale simulations
Authors: Bojarski Krzysztof K. , Sieradzan Adam K. , Samsonov Sergey A.
Published: January 2019

Heparin is a key player in cell signaling via its physical interactions with protein targets in the extracellular matrix. However, basic molecular level understanding of these highly biologically relevant intermolecular interactions is still incomplete. In this study, for the first time, microsecond‐scale MD simulations are reported for a complex between fibroblast growth factor 1 and heparin. We rigorously analyze this molecular system in terms of the conformational space, structural, energetic, and dynamic characteristics. We reveal that the conformational selection mechanism of binding denotes a recognition specificity determinant. We conclude that the length of the simulation could be crucial for evaluation of some of the analyzed parameters. Our data provide novel significant insights into the interactions in the fibroblast growth factor 1 complex with heparin, in particular, and into the physical‐chemical nature of protein‐glycosaminoglycan systems in general, which have potential applicability for biomaterials development in the area of regenerative medicine.
Proposal for a new classification for perihilar cholangiocarcinoma based on tumour depth
Authors: Shinohara K , Ebata T , Shimoyama Y , Nakaguro M , Mizuno T , Matsuo K , Nagino M
Published: January 2019

Background

The T system for distal cholangiocarcinoma has been revised from a layer-based to a depth-based approach in the current American Joint Committee on Cancer (AJCC) classification. In perihilar cholangiocarcinoma, tumour depth in the staging scheme has not yet been addressed. The aim of this study was to propose a new T system using measured tumour depth in perihilar cholangiocarcinoma.

Methods

Patients who underwent hepatectomy for perihilar cholangiocarcinoma between 2001 and 2014 were reviewed retrospectively. The vertical distance between the top of the tumour and deepest invasive cells was measured as invasive tumour thickness (ITT) by two independent pathologists. Log rank statistics were used to determine cut-off points, and the concordance (C) index was used to assess survival discrimination of each T system.

Results

ITT was measurable in all 440 patients, with a median value of 6·0 (range 0–45) mm. The median difference in ITT between observers was 0·6 (range 0–20) mm. Cut-off points for prognosis were 1, 5 and 8 mm. Five-year survival decreased with increasing ITT (P < 0·001): 67 per cent for ITT less than 1 mm (25 patients), 54·9 per cent for ITT 1 mm and over to less than 5 mm (138 patients), 43·4 per cent for ITT 5 mm and over to less than 8 mm (118 patients), and 32·2 per cent for ITT 8 mm and over (159 patients). The C-index of this classification was comparable to that of the current AJCC T classification (0·598 versus 0·589).

Conclusion

ITT is a reliable approach for making a depth assessment in perihilar cholangiocarcinoma. A four-tier ITT classification with cut-off points of 1, 5 and 8 mm is an adequate alternative to the current layer-based T classification.
Validation of an analytical method to quantify the permeation and penetration of flurbiprofen into human pharynx tissue
Authors: Turner Rob , Wevrett Sean Robert , Edmunds Suzanne , Brown Marc , Atkinson Robert , Shea Tim
Published: January 2019

The aim of this investigation was to develop receiver and extraction fluids, and subsequently validate an analytical method to quantify the permeation and penetration of flurbiprofen into human pharynx tissue using a Franz diffusion cell. The solubility and stability of flurbiprofen in a suitable receiver fluid, and a suitable extraction method and fluid to recover and quantitate flurbiprofen from human pharynx tissue, were investigated using high‐performance liquid chromatography (HPLC). The potential interference of human pharynx tissue in the receiver fluid was also investigated. The HPLC analytical method was successfully validated according to current guidelines. The final receiver fluid demonstrated sufficient solubility and stability, and the extraction method and fluid resulted in >95% recovery of flurbiprofen following exposure to human pharynx tissue. The lower limit of quantitation of flurbiprofen was 0.045 μg/mL in both the receiver and extraction fluids. There was no interference of the human pharynx tissue with the HPLC method. This investigation validated an analytical method for quantitating flurbiprofen, and determined a suitable receiver fluid and extraction method and fluid, which can be used to investigate the permeation and penetration of flurbiprofen through human pharynx tissue using the Franz diffusion cell method.
Coping with coopetition—Facing dilemmas in cooperation for sustainable development: The case of the Dutch smart grid industry
Authors: Planko Julia , Chappin Maryse M.H. , Cramer Jacqueline , Hekkert Marko P.
Published: January 2019

This paper is amongst the first to examine coopetition strategy for sustainable development at the network level. Companies who want to successfully implement complex innovative technologies that support sustainable development need to collaborate with other actors of the innovation ecosystem, including their competitors, so that they can develop standards, interoperable products, pool knowledge, and resources and bundle forces to compete against other technologies. Collaboration with competitors brings benefits, but also many risks. We investigated how firms cope with these risks when establishing an innovation ecosystem to implement a new technology in society. We conducted research in the Dutch smart grids sector and explored how these firms minimize inherent risks of coopetition. We found that system‐building actors in the Dutch smart grid field not only minimize inherent risks, but from the start of their collaboration they implement so‐called enablers to prevent these risks upfront.
The identity of Brexit: A cultural psychology analysis
Authors: Veltri Giuseppe A. , Redd Rozlyn , Mannarini Terri , Salvatore Sergio
Published: January 2019

In this paper, we propose a culturalist interpretation of the outcome of the Brexit referendum. This interpretation is grounded on the analysis of the U.K.'s cultural milieu, which is part of a more general study of the cultural milieus of several European countries. Specific to the United Kingdom, our analysis is based on a questionnaire carried out on a representative sample of U.K. respondents stratified by sociodemographic variables and geographic region (NUTS1). Responses to the questionnaire were subjected to multidimensional analysis—a combination of multiple correspondence analysis and cluster analysis.

Findings about the multicountry analysis show how cultural milieus are characterized by five basic, embodied, affect‐laden, generalized worldviews (defined as “Symbolic Universes”). Four out of five symbolic universes consist of a way of interpreting reality by a specific anchorage (i.e., the ethical norm, the institutional order, the emotional experience interpersonal bond, and the belongingness). One symbolic universe can be viewed as the anomic reaction to the failure of those anchorages. Focusing on Brexit, by means of a discriminant analysis, it is showed how the incidence of the symbolic universes (and of the underpinning basic dimensions of meaning within the 12 U.K. macroregions') enables to identify differentially the macroregions with high proportion of “leave” at the Brexit referendum against those with low proportion. More specifically, the high “leave” macroregion are characterized by higher relevance of cultural forms anchored on local identity/belongingness. Findings are discussed within the wider aims of the project and its implications for a cultural psychology informed policymaking.
Synthesis and Application of Methyl N,O‐Hydroxylamine Muramyl Peptides
Authors: Lazor Klare M. , Zhou Junhui , DeMeester Kristen E. , D'Ambrosio Elizabeth A. , Grimes Catherine L.
Published: January 2019

The innate immune system's interaction with bacterial cells plays a pivotal role in a variety of human diseases. Carbohydrate units derived from a component of bacterial cell wall, peptidoglycan (PG), are known to stimulate an immune response. Nonetheless, access to modified late‐stage peptidoglycan intermediates is limited due to their synthetic complexity. A method to rapidly functionalize PG fragments is needed to better understand the natural host–PG interactions. Here methyl N,O‐hydroxylamine linkers are incorporated onto a synthetic PG derivative, muramyl dipeptide (MDP). The modification of MDP maintained the ability to stimulate a nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐κB) immune response dependent on the expression of nucleotide‐binding oligomerization domain‐containing protein 2 (Nod2). Intrigued by this modification's maintenance of biological activity, several applications were explored. Methyl N,O‐hydroxylamine MDP was amendable to N‐hydroxylsuccinimide (NHS) chemistry for bioconjugation to fluorophores as well as a self‐assembled monolayer for Nod2 surface plasmon resonance analysis. Finally, linker incorporation was applicable to larger PG fragments, both enzymatically generated from Escherichia coli or chemically synthesized. This methodology provides rapid access to PG probes in one step and allows for the installation of a variety of chemical handles to advance the molecular understanding of PG and the innate immune system.
Silencing of MEG3 inhibited ox‐LDL‐induced inflammation and apoptosis in macrophages via modulation of the MEG3/miR‐204/CDKN2A regulatory axis
Authors: Yan Long , Liu Zhanchuan , Yin Haoyuan , Guo Zhenjie , Luo Qi
Published: January 2019

Atherosclerosis (AS) is one of the most common chronic inflammatory diseases and a major cause of morbidity and mortality. However, the underlying molecular mechanisms of the progression of AS are still largely unknown. Increasing evidence has demonstrated that long noncoding RNAs (lncRNAs) play important roles in a variety of biological processes and the physiological and pathological progression of human diseases. In this study, we aimed to explore the role and underlying molecular mechanism of lncRNA MEG3 in Raw264.7 cells treated with oxidized low‐density lipoprotein (ox‐LDL). First, we found that ox‐LDL inhibited the cell viability and proliferation, increased TNFα and IL1β secretion and induced the apoptosis of Raw264.7 cells. Second, we demonstrated that ox‐LDL upregulated MEG3 expression and that knockdown of MEG3 inhibited the action of ox‐LDL in Raw264.7 cells. Third, we showed that MEG3 sponged miR‐204 in Raw264.7 cells treated with ox‐LDL. Fourth, we demonstrated that miR‐204 regulated the expression of cyclin‐dependent kinase inhibitor 2A (CDKN2A) in Raw264.7 cells treated with ox‐LDL. Finally, we revealed that MEG3 exerted its function via the regulation of the MEG3/miR‐204/CDKN2A regulatory axis in Raw264.7 cells treated with ox‐LDL. In summary, our study identified the role of the MEG3/miR‐204/CDKN2A pathway in Raw264.7 cells treated with ox‐LDL, revealed a novel regulatory pathway in AS and indicated potential novel characteristic biomarkers and therapeutic targets for AS.
Functional prediction and characterization of Dip2 gene in mice
Authors: Ma Jun , Chen Li , He Xiao‐Xiao , Wang Ya‐Jun , Yu Hua‐Li , He Zi‐Xuan , Zhang Lu‐Qing , Zheng Yao‐Wu , Zhu Xiao‐Juan
Published: January 2019

Disconnected interacting protein 2 (DIP2) is a highly conserved protein family among invertebrates and vertebrates, but its function remains unclear. In this paper, we summarized the conservation of gene sequences and protein domains of DIP2 family members and predicted that they may have a similar functional role in acetyl‐coenzyme A (acetyl‐CoA) synthesis. We then used the most characterized member, disconnected interacting protein 2 homolog A (DIP2A), for further study. DIP2A is a cytoplasmic protein that is preferentially localized to mitochondria, and its acetyl‐CoA synthetase activity has been demonstrated in vitro. Furthermore, the level of acetyl‐CoA in HEK293 cells overexpressing DIP2A was increased, which is consistent with its metabolically related function. Together, these data enrich the evolutionary and functional characterization of dip2 genes and provide significant insights into the identification and application of other homologs of DIP2.
Simulation of Post‐Combustion CO2 Capture, a Comparison among Absorption, Adsorption and Membranes
Authors: Anselmi Hélène , Mirgaux Olivier , Bounaceur Roda , Patisson Fabrice
Published: January 2019

Post‐combustion CO2 capture was studied in the favorable context where the captured CO2 can be reused in a neighboring industrial process. Three technologies for CO2 capture, absorption by amines, adsorption on activated carbon, and separation using polymer membranes, were considered, modeled and compared. The three capture processes were designed for achieving the same performances. The models were integrated in a commercial flowsheeting software. The results show that, for a targeted CO2 purity of 95 %, the membrane process appears to be the least energy consuming. A next step will be to quantify the environmental benefits using life cycle assessment.
Double Cu‐Catalyzed Direct Csp3−H Azidation/CuAAC Reaction: A Direct Approach towards Demanding Triazole Conjugates
Authors: Brandhofer Tobias , Özdemir Aysegül , Gini Andrea , Mancheño Olga García
Published: January 2019

The first one‐pot procedure for the double copper(I)‐catalyzed oxidative Csp3−H azidation–CuAAC process, implying unstable azide intermediates and easy‐to‐remove reagents under water‐tolerant conditions, is presented. The combination of tert‐butyl hydroperoxide as oxidant and TMSN3 as azide source for the C−H bond azidation, which produces harmless side‐products such as tBuOH and H2O, probed to be perfectly compatible with the following cycloaddition step. Highly demanding 1,2,3‐triazoles could be then directly obtained in good overall yields by extraction or simple crystallization, thus avoiding chromatography purifications. The potential of this methodology, has also being highlighted by the successful reaction of alkynes presenting interesting complex biological moieties based for example on biotin, DNA base or cinchona alkaloid units.
Effective sapphire repellency treatment to reduce fouling of a focused beam reflectance measurement (FBRM) probe in bituminous systems
Authors: Saraka Colin , Machado Márcio B. , Webster Scott E. , Gomez Clara , Kresta Suzanne M.
Published: January 2019

The use of a focused beam reflectance measurement (FBRM) probe to track the chord length distribution dynamics in a bituminous system can be very challenging. Material coats the sapphire window of the probe and the quality of the data is compromised. The fouling index is a parameter used to assess the quality of the FBRM data. It is provided by the software and is the percentage similarity between two consecutive scans of the instrument, indicating how much of the reading has not changed due to material that is stuck to the optical window. When the FBRM was used in bitumen froth, the fouling index was higher than 90 %. In this work the significant reduction in fouling achieved with a sapphire repellency treatment is presented. The reduction in fouling was sufficient to detect broad trends in the FBRM data that will be used in future studies but was not sufficient to ensure quantitative measurement of the chord length distribution.
Energy Transfer of Peptide Ions Colliding with a Self‐Assembled Monolayer Surface. The Influence of Peptide Ion Size
Authors: Gu Meng , Yang Li , Hase William L , Sun Jianmin , Zhang Jiaxu
Published: January 2019

Summary of main observation and conclusion

Atomistic dynamics of protonated polyglycine, glyn‐H+ (n = 3, 5, and 7), colliding with a fluorinated octanethiol self‐assembled monolayer (F‐SAM) surface has been studied by trajectory calculations. The effects of peptide size on the collision processes and energy transfer efficiencies are emphasized and discussed in detail. The simulations show that the fraction of trapping, which is related to the soft‐landing process, dramatically drops with the increase in collision energy, but gently increases with the peptide size. The average energy transfer to the peptide ion's internal degrees of freedom, ΔEint, is compared with previous experiments. The limiting probability Po of energy transfer to the surface is given by fitting a function of Poexp(–b/Ei). Our results suggest that the efficiencies of energy transfer are less dependent on the masses, even the categories of the peptide ions, and are determined by the character of the surfaces.
Diamondoid Amino Acid‐Based Peptide Kinase A Inhibitor Analogues
Authors: Müller Janis , Kirschner Romina A. , Berndt Jan‐Philipp , Wulsdorf Tobias , Metz Alexander , Hrdina Radim , Schreiner Peter R. , Geyer Armin , Klebe Gerhard
Published: January 2019

The incorporation of diamondoid amino acids (DAAs) into peptide‐like drugs is a general strategy to improve lipophilicity, membrane permeability, and metabolic stability of peptidomimetic pharmaceuticals. We designed and synthesized five novel peptidic DAA‐containing kinase inhibitors of protein kinase A using a sophisticated molecular dynamics protocol and solid‐phase peptide synthesis. By means of a thermophoresis binding assay, NMR, and crystal structure analysis, we determined the influence of the DAAs on the secondary structure and binding affinity in comparison to the native protein kinase inhibitor, which is purely composed of proteinogenic amino acids. Affinity and binding pose are largely conserved. One variant showed 6.5‐fold potency improvement, most likely related to its increased side chain lipophilicity. A second variant exhibited slightly decreased affinity presumably due to loss of hydrogen‐bond contacts to surrounding water molecules of the first solvation shell.
Phase 1/2 study of DFP‐10917 administered by continuous intravenous infusion in patients with recurrent or refractory acute myeloid leukemia
Authors: Kantarjian Hagop M. , Jabbour Elias J. , Garcia‐Manero Guillermo , Kadia Tapan M. , DiNardo Courtney D. , Daver Naval G. , Borthakur Gautam , Jain Nitin , Waukau Jane B. , Kwari Monica I. , Ravandi Farhad , Anderson Barry D. , Iizuka Kenzo , Jin Cheng , Zhang Chun , Plunkett William K.
Published: January 2019

Background

DFP‐10917, a deoxycytidine nucleoside analogue, has a unique mechanism of action resulting in leukemic cell death when administered for prolonged periods at low doses. The current phase 1/2 study investigated the safety, maximum tolerated dose, and evidence of antileukemic activity for DFP‐10917 administered by 7‐day or 14‐day continuous intravenous infusion in patients with recurrent or refractory acute myeloid leukemia (AML).

Methods

In the phase 1 dose escalation portion of the study, patients were administered DFP‐10917 by 7‐day continuous intravenous infusion plus 21‐day rest (stage 1) or 14‐day continuous intravenous infusion plus 14‐day rest (stage 2). The primary objectives of phase 1 were to determine the maximum tolerated dose, the phase 2 dose, and the dose‐limiting toxicities (DLTs) of DFP‐10917. The primary objectives of phase 2 were to evaluate the overall response rate of DFP‐10917 using complete response (CR), CR without platelet recovery (CRp), CR with incomplete blood count recovery (CRi) or partial response.

Results

In stage 1 of phase 1 (4‐35 mg/m2/day as a 7‐day continuous intravenous infusion), a DLT of grade 3 diarrhea occurred at a dose of 35 mg/m2/day. In stage 2 of phase 1, a dose of 10 mg/m2/day as a 14‐day continuous intravenous infusion resulted in DLTs of prolonged hypocellularity, abdominal pain, diarrhea, and vomiting. The dose of 6 mg/m2/day as a 14‐day continuous intravenous infusion was found to be well tolerated and was selected for phase 2. Response rates in patients in phase 2 (N = 29) were 20.7% CR, 3.4% CRp, and 24.1% CRi. The overall response rate was 48.3% (95% confidence interval, 29.4%‐67.5%).

Conclusions

DFP‐10917 as a 14‐day continuous intravenous infusion at a dose of 6 mg/m2/day can be administered safely and appears to be effective in patients with recurrent or refractory AML. A phase 3 investigation comparing DFP‐10917 monotherapy versus standard of care in an early recurrent or refractory AML setting is warranted.
Borderline resectable pancreatic cancer—At the crossroads of precision medicine
Authors: Katz Matthew H. G. , Varadhachary Gauri R.
Published: January 2019

High‐level data have recently emerged that directly inform the care of patients with borderline resectable pancreatic cancer. Additional well‐conducted studies are necessary to increase the precision and efficacy of treatment.
Pharmacokinetics of Once‐Daily Extended‐Release Tacrolimus Tablets Versus Twice‐Daily Capsules in De Novo Liver Transplant
Authors: DuBay Derek A. , Teperman Lewis , Ueda Kimi , Silverman Andrew , Chapman William , Alsina Angel E. , Tyler Carmelina , Stevens Daniel R.
Published: January 2019

The pharmacokinetics of once‐daily extended‐release tacrolimus tablets (LCPT) in de novo liver transplantation have not been previously reported. In this phase II, randomized, open‐label study, de novo liver transplant recipients were randomized to LCPT 0.07–0.13 mg/kg/day (taken once daily; n = 29) or twice‐daily immediate‐release tacrolimus capsules (IR‐Tac) at 0.10–0.15 mg/kg/day (divided twice daily; n = 29). Subsequent doses of both drugs were adjusted to maintain tacrolimus trough concentrations of 5 to 20 ng/mL through day 90, and 5–15 ng/mL thereafter. Twenty‐four‐hour pharmacokinetic profiles were obtained on days 1, 7, and 14, with trough concentration and efficacy/safety monitoring through year 1. Similar proportions of patients in both groups achieved therapeutic trough concentrations on days 7 and 14 (day 7: LCPT = 78%, IR‐Tac = 75%; day 14: LCPT = 86%, IR‐Tac = 91%) as well as similar systemic and peak exposure. There was a robust correlation between drug concentration at time 0 and area under the concentration‐time curve for both LCPT and IR‐Tac (respectively, day 7: r = 0.86 and 0.79; day 14: r = 0.93 and 0.86; P < .0001 for all). Dose adjustments during days 1 to 14 were frequent. Thirty‐five patients completed the extended‐use period. No significant differences in adverse events were seen between groups. Incidence of biopsy‐proven acute rejection (LCPT = 6 and IR‐Tac = 4) was similar on day 360. Between formulations, overall exposure was similar at 1 week after transplant with the characteristic delayed‐release pharmacokinetic profile of LCPT demonstrated in this novel population. These data support further investigation of the safety and efficacy of LCPT in de novo liver transplantation.
Oral Antidiabetic Drugs: an Overview
Authors: Melander A.
Published: January 2019

Chronic hyperglycaemia, i.e. impaired glucose tolerance (IGT) and NIDDM, conveys a great risk of macrovascular disease. Both insulin resistance and impaired insulin secretion seem necessary to establish chronic hyperglycaemia, and untreated it appears to promote and worsen both insulin resistance and impaired insulin secretion. The prevention and treatment of chronic hyperglycaemia should include measures directed at both derangements, and the therapeutic goal should be normoglycaemia. As this is rarely achieved by non‐pharmacologic treatment alone, addition of oral antidiabetic drugs are often indicated. Their ability to attain euglycaemia is greater the earlier they are employed, but they should never be introduced until after optimization of non‐pharmacologic measures. Delayed early insulin response to glucose or a meal always accompanies chronic hyperglycaemia and is not normalized by non‐pharmacologic treatment. This justifies the use of insulin‐releasing drugs with a rapid onset of action, e.g. the sulphonylurea gliplzide. The non‐sulphonylureas, repaglinide and A‐4166, are even more rapid‐ and also short‐acting, representing a reduced risk of long‐lasting, and hence dangerous, hypoglycaemia. Continuous exposure to high concentrations of sulphonylureas may downregulate beta‐cell sensitivity. Maximum doses are much lower than previously assumed. The most effective improvers of insulin action seem to be the thiazolidinediones, but they are not yet marketed. Metformin is the only globally available drug for improving insulin action. It is as antihyperglycaemic as sulphonylureas but does not cause hyperinsulinaemia, weight increase or hypoglycaemia. The risk of lactic acidosis can be minimized by avoiding metformin in subjects with renal impairment. Combined treatment with sulphonylurea and metformin can be highly effective even in advanced NIDDM.
In Vivo Glucose Metabolism, Insulin Secretion and, Insulin Action in Europids with Non‐insulin‐dependent Diabetes Mellitus (NIDDM) and Their First‐degree Relatives
Authors: Beck-Nielsen H. , Henriksen J. Erik , Alford F. , Hother-Nielson O.
Published: January 2019

In this review we will mainly concentrate on the most common form of NIDDM in Europe, namely the form linked to overweight, arterial hypertension, dyslipoproteinaemia and coronary heart disease (CHD)—the Insulin Resistance Syndrome (IRS)1,2 This form of NIDDM seems to be growing epidemically world wide following the industrial growth or the 'cocacolanization', as it has been mentioned.3 Around 2–3% of the population in Europe suffers from this disease, but for subjects beyond 60 years of age the prevalence is 5–20 %.3 Thus, we face an enormous economical, social, and humanitarian challenge. Therefore it is important to continue the research on aetiology and pathophysiology of this syndrome. The results of treatment of NIDDM patients (often started at 60 years of age) have been rather disappointing; even properly treated NIDDM patients develop substantial complications, especially macroangiopathy/·3 Coronary heart disease is the main cause of death in these patients and the overall mortality rate in NIDDM patients is 3–4 times higher than in comparable non diabetic‐subjects.6 Furthermore, several complications may already be present at the diagnosis of the disease, which indicate that macroangiopathy may not be secondary to the diabetic state itself, but rather a part of the NIDDM phenotype.1 Based on these findings it seems obvious that the IRS must be diagnosed in the prediabetic states before macroangiopathy has started or reached a clinically manifest level. In this review, therefore, we will discuss the metabolic background of NIDDM and especially focus on the pathophysiological mechanisms leading to hyperglycaemia, i.e. alterations in glucose effectivenesss, insulin action and insulin secretion in prediabetic states.
Maturity Onset Diabetes of the Young (MODY)
Authors: Fajan S.S. , Bell G.I. , Bowden D.W. , Halter J.B. , Polonsky K.S.
Published: January 2019

MODY is a sub‐type of NIDDM. It is characterized by an early age of onset and autosomal dominant mode of inheritance. These features, and the availability of large multigenerational pedigrees, make MODY useful for genetic studies of diabetes. In the large 5‐generational RW pedigree, MODY is tightly linked to genetic markers on chromosome 20q. Affected subjects in this family show abnormalities of carbohydrate metabolism, varying from impaired glucose tolerance (IGT) to severe diabetes. Approximately 30 % of diabetic subjects become insulin‐requiring, and vascular complications occur. MODY is also linked to the glucokinase gene on chromosome 7p and many different mutations associated with MODY have been identified in this gene. MODY, due to mutations in the glucokinase gene, is a relatively mild form of diabetes with mild fasting hyperglycaemia and IGT in the majority. Clinical investigative studies indicate that the genetic or primary defect in MODY is characterized by deranged and deficient insulin secretion and not by insulin resistance. There are quantitative and qualitative differences in insulin secretory defects which differentiate subjects with MODY due to mutation in the gene on chromosome 20q from those with glucokinase mutations. These differences correlate with the severity of diabetes between these two genetic forms of MODY.
Retinoic acid signaling reduction recapitulates the effects of alcohol on embryo size
Authors: Shukrun Natalie , Shabtai Yehuda , Pillemer Graciela , Fainsod Abraham
Published: January 2019

Intrauterine growth restriction (IUGR) is commonly observed in human pregnancies and can result in severe clinical outcomes. IUGR is observed in Fetal Alcohol Syndrome (FAS) fetuses as a result of alcohol (ethanol) exposure during pregnancy. To further understand FAS, the severe form of Fetal Alcohol Spectrum Disorder, we performed an extensive quantitative analysis of the effects of ethanol on embryo size utilizing our Xenopus model. Ethanol‐treated embryos exhibited size reduction along the anterior–posterior axis. This effect was evident primarily from the hindbrain caudally, while rostral regions appeared refractive to ethanol‐induced size changes, also known as asymmetric IUGR. Interestingly, some embryo batches in addition to shortening from the hindbrain caudally also exhibited an alcohol‐dependent reduction of the anterior head domain, known as symmetric IUGR. To study the connection between ethanol exposure and reduced retinoic acid levels we treated embryos with the retinaldehyde dehydrogenase inhibitors, DEAB and citral. Inhibition of retinoic acid biosynthesis recapitulated the growth defects induced by ethanol affecting mainly axial elongation from the hindbrain caudally. To study the competition between ethanol clearance and retinoic acid biosynthesis we demonstrated that, co‐exposure to alcohol reduces the teratogenic effects of treatment with retinol (vitamin A), the retinoic acid precursor. These results further support the role of retinoic acid in the regulation of axial elongation.
Avoidant restrictive food intake disorder: First do no harm
Authors: Katzman Debra K. , Norris Mark L. , Zucker Nancy
Published: January 2019

Objective

This opinion piece offers some considerations, both medical and psychological, for the use of nasogastric tube (NGT) feedings in the treatment of avoidant restrictive food intake disorder (ARFID) in children and adolescents.

Method

Although there is empirical support for the use of NGT feedings in the treatment of anorexia nervosa, this evidence base does not exist for the treatment of ARFID. As such, there is need to delineate pragmatic considerations in the use of this procedure.

Results

Issues of medical necessity notwithstanding, we advise that the use of this procedure be considered more cautiously due to the oral sensitivities inherent in many individuals with ARFID and the potential psychological consequences. These sensitivities may make the experience of NGT feedings particularly aversive, with the potential of creating iatrogenic conditioned food aversions.

Discussion

This article encourages clinicians to give careful thought and attention when considering NGT feedings in children and adolescents with ARFID.
The independent and combined effects of floral traits distinguishing two pollination ecotypes of a moth‐pollinated orchid
Authors: Trunschke Judith , Sletvold Nina , Ågren Jon
Published: January 2019

Identifying traits and agents of selection involved in local adaptation is important for understanding population divergence. In southern Sweden, the moth‐pollinated orchid Platanthera bifolia occurs as a woodland and a grassland ecotype that differ in dominating pollinators. The woodland ecotype is taller (expected to influence pollinator attraction) and produces flowers with longer spurs (expected to influence efficiency of pollen transfer) compared to the grassland ecotype. We examined whether plant height and spur length affect pollination and reproductive success in a woodland population, and whether effects are non‐additive, as expected for traits influencing two multiplicative components of pollen transfer. We reduced plant height and spur length to match trait values observed in the grassland ecotype and determined the effects on pollen removal, pollen receipt, and fruit production. In addition, to examine the effects of naturally occurring variation, we quantified pollinator‐mediated selection through pollen removal and seed production in the same population. Reductions of plant height and spur length decreased pollen removal, number of flowers receiving pollen, mean pollen receipt per pollinated flower, and fruit production per plant, but no significant interaction effect was detected. The selection analysis demonstrated pollinator‐mediated selection for taller plants via female fitness. However, there was no current selection mediated by pollinators on spur length, and pollen removal was not related to plant height or spur length. The results show that, although both traits are important for pollination success and female fitness in the woodland habitat, only plant height was sufficiently variable in the study population for current pollinator‐mediated selection to be detected. More generally, the results illustrate how a combination of experimental approaches can be used to identify both traits and agents of selection.
The intrinsic predictability of ecological time series and its potential to guide forecasting
Authors: Pennekamp Frank , Iles Alison C. , Garland Joshua , Brennan Georgina , Brose Ulrich , Gaedke Ursula , Jacob Ute , Kratina Pavel , Matthews Blake , Munch Stephan , Novak Mark , Palamara Gian Marco , Rall Björn C. , Rosenbaum Benjamin , Tabi Andrea , Ward Colette , Williams Richard , Ye Hao , Petchey Owen L.
Published: January 2019

Successfully predicting the future states of systems that are complex, stochastic, and potentially chaotic is a major challenge. Model forecasting error (FE) is the usual measure of success; however model predictions provide no insights into the potential for improvement. In short, the realized predictability of a specific model is uninformative about whether the system is inherently predictable or whether the chosen model is a poor match for the system and our observations thereof. Ideally, model proficiency would be judged with respect to the systems’ intrinsic predictability, the highest achievable predictability given the degree to which system dynamics are the result of deterministic vs. stochastic processes. Intrinsic predictability may be quantified with permutation entropy (PE), a model‐free, information‐theoretic measure of the complexity of a time series. By means of simulations, we show that a correlation exists between estimated PE and FE and show how stochasticity, process error, and chaotic dynamics affect the relationship. This relationship is verified for a data set of 461 empirical ecological time series. We show how deviations from the expected PE–FE relationship are related to covariates of data quality and the nonlinearity of ecological dynamics. These results demonstrate a theoretically grounded basis for a model‐free evaluation of a system's intrinsic predictability. Identifying the gap between the intrinsic and realized predictability of time series will enable researchers to understand whether forecasting proficiency is limited by the quality and quantity of their data or the ability of the chosen forecasting model to explain the data. Intrinsic predictability also provides a model‐free baseline of forecasting proficiency against which modeling efforts can be evaluated.
Preparation of LaTiO2N Using Hydrothermally Synthesized La2Ti2O7 as a Precursor and Urea as a Nitriding Agent
Authors: Okada Ryoki , Katagiri Kiyofumi , Masubuchi Yuji , Inumaru Kei
Published: January 2019

A facile method was successfully developed to prepare perovskite‐type metal oxynitrides, LaTiO2N, from La2Ti2O7 as a precursor in an atmosphere of N2. Urea was employed as a solid‐state nitriding agent, instead of gaseous NH3, to increase the safety of the reaction. The hydrothermally prepared La2Ti2O7 precursor had a nanosheet morphology and contained La(OH)3 as a by‐product. Through the optimization of reaction conditions including heat‐treatment temperature and content of urea, single‐phase LaTiO2N could be obtained. In addition, we revealed that the La(OH)3 present in the La2Ti2O7 precursor played an important role in the nitriding process using urea. La2O2CN2 was generated by the reaction of La(OH)3 with the thermal decomposition products of urea at the medium temperature range. This indicated that the NH3 gas released from the thermal decomposition of urea did not directly cause nitridation of the La2Ti2O7 precursor.
Response to “The Seven‐Membered Ring in Bis‐Azuleno‐Naphthalene is Non‐Aromatic”
Authors: Uehara Keiji , Mei Peifeng , Murayama Tomohisa , Tani Fumito , Hayashi Hironobu , Suzuki Mitsuharu , Aratani Naoki , Yamada Hiroko
Published: January 2019

The magnetic properties of the compound (Az2) we have reported earlier were investigated by using NICSπ,zz and NICS‐XY scans by Stanger. His conclusions are that the seven‐membered ring in Az2 is not antiaromatic but non‐aromatic, thus the small paratropic values are the result of three diatropic moieties that surround this ring. Based on the same data, we discuss the ring current at the new seven‐membered ring carefully.
The nature and history of the South Qilian orogenic belt: Constraints from compositions of rivers' sediments and their detrital zircon U–Pb geochronology, Lu‐Hf isotopic compositions
Authors: Kang Huan , Chen Yuelong , Li Dapeng
Published: January 2019

Detrital zircon U–Pb dating, Hf isotopic data, and Nd isotopic compositions of river sediments are used to constrain crustal evolution processes of their provenance in the South Qilian orogenic belt. The detrital zircons from the Yuka, Tataleng, and Bayinguole rivers range in age from Neoarchean (2,772 Ma) to Permian (261 Ma), with age peaks at ca. 2.4 Ga, ca. 1.95 Ga, and ca. 0.45 Ga. Hf isotopic compositions of Paleoproterozoic, Pan‐African, and Caledonian zircon age groups display a wide range ofεHf(t) values, suggesting diverse sources of host magma of the zircon grains. The basement formation of the South Qilian orogenic belt from depleted mantle occurred at two stages; ca. 3.1–2.5 Ga and ca. 2.0–1.6 Ga. Meanwhile, the Nd model ages of silt‐mud from the region are between 1.98 Ga and 2.27 Ga with an average value of 2.12 Ga. Our study indicates that the Qilian oceanic plate formed between the Qaidam and Alxa blocks from late Neoproterozoic to Silurian. The South Qilian orogenic belt is a product of the Qilian Ocean closure and subsequent collision between the Qaidam Block and central Qilian belt during Ordovician–Silurian times. Combining regional tectonothermal events with new results of river sediments suggests that rifting from a continent and opening of the Qilian Ocean occurred at ca. 780–520 Ma, subduction of the oceanic crust at ca. 520–440 Ma, ocean closure and continental subduction at ca. 440–420 Ma, exhumation of subducted crust at ca. 420–400 Ma, and orogenic collapse and extension at ca. 400–360 Ma.