bluuebunny/crossref_metadata_2025 huggingface dataset:
Acadesine Circumvents Azacitidine Resistance in Myelodysplastic Syndrome and Acute Myeloid Leukemia
Authors: Cluzeau Thomas , Furstoss Nathan , Savy Coline , El Manaa Wejdane , Zerhouni Marwa , Blot Lauriane , Calleja Anne , Dufies Maeva , Dubois Alix , Ginet Clemence , Mounier Nicolas , Garnier Georges , Raynaud Sophie , Rohrlich Pierre Simon , Peterlin Pierre , Stamatoullas Aspasia , Chermat Fatiha , Fenaux Pierre , Jacquel Arnaud , Robert Guillaume , Auberger Patrick
Published: December 2019

Myelodysplastic syndrome (MDS) defines a group of heterogeneous hematologic malignancies that often progresses to acute myeloid leukemia (AML). The leading treatment for high-risk MDS patients is azacitidine (Aza, Vidaza®), but a significant proportion of patients are refractory and all patients eventually relapse after an undefined time period. Therefore, new therapies for MDS are urgently needed. We present here evidence that acadesine (Aca, Acadra®), a nucleoside analog exerts potent anti-leukemic effects in both Aza-sensitive (OCI-M2S) and resistant (OCI-M2R) MDS/AML cell lines in vitro. Aca also exerts potent anti-leukemic effect on bone marrow cells from MDS/AML patients ex-vivo. The effect of Aca on MDS/AML cell line proliferation does not rely on apoptosis induction. It is also noteworthy that Aca is efficient to kill MDS cells in a co-culture model with human medullary stromal cell lines, that mimics better the interaction occurring in the bone marrow. These initial findings led us to initiate a phase I/II clinical trial using Acadra® in 12 Aza refractory MDS/AML patients. Despite a very good response in one out 4 patients, we stopped this trial because the highest Aca dose (210 mg/kg) caused serious renal side effects in several patients. In conclusion, the side effects of high Aca doses preclude its use in patients with strong comorbidities.
Genomic Prediction and Indirect Selection for Grain Yield in US Pacific Northwest Winter Wheat Using Spectral Reflectance Indices from High-Throughput Phenotyping
Authors: Lozada Dennis N. , Godoy Jayfred V. , Ward Brian P. , Carter Arron H.
Published: December 2019

Secondary traits from high-throughput phenotyping could be used to select for complex target traits to accelerate plant breeding and increase genetic gains. This study aimed to evaluate the potential of using spectral reflectance indices (SRI) for indirect selection of winter-wheat lines with high yield potential and to assess the effects of including secondary traits on the prediction accuracy for yield. A total of five SRIs were measured in a diversity panel, and F5 and doubled haploid wheat breeding populations planted between 2015 and 2018 in Lind and Pullman, WA. The winter-wheat panels were genotyped with 11,089 genotyping-by-sequencing derived markers. Spectral traits showed moderate to high phenotypic and genetic correlations, indicating their potential for indirect selection of lines with high yield potential. Inclusion of correlated spectral traits in genomic prediction models resulted in significant (p < 0.001) improvement in prediction accuracy for yield. Relatedness between training and test populations and heritability were among the principal factors affecting accuracy. Our results demonstrate the potential of using spectral indices as proxy measurements for selecting lines with increased yield potential and for improving prediction accuracy to increase genetic gains for complex traits in US Pacific Northwest winter wheat.
Interference with the Cannabinoid Receptor CB1R Results in Miswiring of GnRH3 and AgRP1 Axons in Zebrafish Embryos
Authors: Zuccarini Giulia , D’Atri Ilaria , Cottone Erika , Mackie Ken , Shainer Inbal , Gothilf Yoav , Provero Paolo , Bovolin Patrizia , Merlo Giorgio Roberto
Published: December 2019

The G protein-coupled cannabinoid receptors type 1 (CB1R) and type 2 (CB2R), and their endocannabinoid (eCBs) ligands, have been implicated in several aspects of brain wiring during development. Here we aim to assess whether interfering with CB1R affects development, neuritogenesis and pathfinding of GnRH and AgRP neurons, forebrain neurons that control respectively reproduction and appetite. We pharmacologically and genetically interfered with CB1R in zebrafish strains with fluorescently labeled GnRH3 and the AgRP1 neurons. By applying CB1R antagonists we observed a reduced number of GnRH3 neurons, fiber misrouting and altered fasciculation. Similar phenotypes were observed by CB1R knockdown. Interfering with CB1R also resulted in a reduced number, misrouting and poor fasciculation of the AgRP1 neuron’s axonal projections. Using a bioinformatic approach followed by qPCR validation, we have attempted to link CB1R functions with known guidance and fasciculation proteins. The search identified stathmin-2, a protein controlling microtubule dynamics, previously demonstrated to be coexpressed with CB1R and now shown to be downregulated upon interference with CB1R in zebrafish. Together, these results raise the likely possibility that embryonic exposure to low doses of CB1R-interfering compounds could impact on the development of the neuroendocrine systems controlling sexual maturation, reproduction and food intake.
Endoplasmic Reticulum Stress Pathway, the Unfolded Protein Response, Modulates Immune Function in the Tumor Microenvironment to Impact Tumor Progression and Therapeutic Response
Authors: Ramirez Manuel U. , Hernandez Salvador R. , Soto-Pantoja David R. , Cook Katherine L.
Published: December 2019

Despite advances in cancer therapy, several persistent issues remain. These include cancer recurrence, effective targeting of aggressive or therapy-resistant cancers, and selective treatments for transformed cells. This review evaluates the current findings and highlights the potential of targeting the unfolded protein response to treat cancer. The unfolded protein response, an evolutionarily conserved pathway in all eukaryotes, is initiated in response to misfolded proteins accumulating within the lumen of the endoplasmic reticulum. This pathway is initially cytoprotective, allowing cells to survive stressful events; however, prolonged activation of the unfolded protein response also activates apoptotic responses. This balance is key in successful mammalian immune response and inducing cell death in malignant cells. We discuss how the unfolded protein response affects cancer progression, survival, and immune response to cancer cells. The literature shows that targeting the unfolded protein response as a monotherapy or in combination with chemotherapy or immunotherapies increases the efficacy of these drugs; however, systemic unfolded protein response targeting may yield deleterious effects on immune cell function and should be taken into consideration. The material in this review shows the promise of both approaches, each of which merits further research.
Radar Emitter Identification under Transfer Learning and Online Learning
Authors: Feng Yuntian , Cheng Yanjie , Wang Guoliang , Xu Xiong , Han Hui , Wu Ruowu
Published: December 2019

At present, there are two main problems in the commonly used radar emitter identification methods. First, when the distribution of training data and testing data is quite different, the identification accuracy is low. Second, the traditional identification methods usually include an offline training stage and online identifying stage, which cannot achieve the real-time identification of the radar emitter. Aimed at the above problems, this paper proposes a radar emitter identification method based on transfer learning and online learning. First, for the case where the target domain contains only a small number of labeled samples, the TrAdaBoost method is used as the basic learning framework to train a support vector machine, which can obtain useful knowledge from the source domain to aid in the identification of the target domain. Then, for the case where the target domain does not contain labeled samples, the Expectation-Maximization algorithm is used to filter the unlabeled samples in the target domain to generate the available training data. Finally, to make the identification quickly and accurately, we propose a radar emitter identification method, based on online learning to ensure real-time updating of the model. Simulation experiments show that the proposed method, based on transfer learning and online learning, has higher identification accuracy and good timeliness.
Warming Increases Pollen Lipid Concentration in an Invasive Thistle, with Minor Effects on the Associated Floral-Visitor Community
Authors: Russo Laura , Keller Joseph , Vaudo Anthony D. , Grozinger Christina M. , Shea Katriona
Published: December 2019

Climate warming is likely to change the ways in which plants interact with their insect mutualists, for example through changes in phytochemistry. In particular, this may have implications for the ways in which we manage noxious weeds, which may spread more quickly if they experience stronger mutualistic interactions. We grew the invasive nodding thistle, Carduus nutans, in two experimental treatments in the field: either passively warmed with open top chambers or at ambient temperatures. We collected pollen from thistles in each treatment and analysed the total protein, lipid, and carbohydrate content. We observed no difference in the pollen protein or carbohydrate content, but the total lipid content of the pollen was significantly higher in warmed plants. We conducted a total of 12.75 h of observations of putatively mutualistic, flower-visiting insects. In addition, we spent 4.17 h collecting bees that visited thistle inflorescences in the treatments, allowing us to identify them to species. We found a significant increase in the abundance of flower-visiting insects in the observations, but not bee abundance in collections. In addition, there was no treatment effect on the number of flower-visiting morphotypes in the observations, or bee species richness in the collections. However, a nonparametric test did identify a significant effect of warming on the composition of flower-visiting morphotypes in observations and bee species in collections. Overall, the warming treatment significantly increased lipid content of the pollen, but had relatively weak effects on insect visitation patterns. However, these effects may be amplified at larger spatial and temporal scales or higher temperatures.
Deubiquitinase USP29 Governs MYBBP1A in the Brains of Parkinson’s Disease Patients
Authors: Jo Areum , Lee Yunjong , Park Chi-Hu , Shin Joo-Ho
Published: December 2019

The inactivation of parkin by mutation or post-translational modification contributes to dopaminergic neuronal death in Parkinson’s disease (PD). The substrates of parkin, FBP1 and AIMP2, are accumulated in the postmortem brains of PD patients, and it was recently suggested that these parkin substrates transcriptionally activate deubiquitinase USP29. Herein, we newly identified 160 kDa myb-binding protein (MYBBP1A) as a novel substrate of USP29. Knockdown of parkin increased the level of AIMP2, leading to ultimately USP29 and MYBBP1A accumulation in SH-SY5Y cells. Notably, MYBBP1A was downregulated in the ventral midbrain (VM) of Aimp2 knockdown mice, whereas the upregulation of MYBBP1A was observed in the VM of inducible AIMP2 transgenic mice, as well as in the substantia nigra of sporadic PD patients. These results suggest that AIMP2 upregulates USP29 and MYBBP1A in the absence of parkin activity, contributing to PD pathogenesis.
Correction: Impact of Pregnancy on Intra-Host Genetic Diversity of Influenza A Viruses in Hospitalised Women: A Retrospective Cohort Study. J. Clin. Med. 2020, 9, 1974
Authors: Destras Gregory , Pichon Maxime , Simon Bruno , Valette Martine , Escuret Vanessa , Bolze Pierre-Adrien , Dubernard Gil , Gaucherand Pascal , Lina Bruno , Josset Laurence
Published: December 2019

The authors wish to make the following corrections to this paper [...]
Exterior and Internal Uniform Loading of Pt Nanoparticles on Yolk-Shell La2O3 by Acoustic Levitation Synthesis with Enhanced Photocatalytic Performance
Authors: Qin Ming , Chang Qing , Yu Yinkai , Wu Hongjing
Published: December 2019

By the deposition of noble metal nanoparticles on a metal oxide substrate with a specific micro-/nanostructure, namely, yolk-shell structure, a remarkable improvement in photocatalytic performance can be achieved by the composites. Nevertheless, noble metal nanoparticles only distribute on the surface shell of metal oxide substrates when the conventional wet-chemistry reduction approach is employed. Herein, we proposed a novel acoustic levitation synthesis of Pt nanoparticles deposited on yolk-shell La2O3. The composites not only displayed well-defined, homogeneous distribution of Pt NPs on the exterior shell of La2O3 and the interior La2O3 core, but an enhanced chemical interaction between Pt and La2O3. The unique structure not only can display improved photocatalytic degradation rate toward methyl orange, but also may show great potential in fields of hydrogen generation, environmental protection, etc. The novel acoustic levitation synthesis can supplement the methodology of synthesizing well dispersed noble metal oxides over the whole yolk-shell structure through noble metal NPs deposition method.
Filling Capacity Evaluation of Self-Compacting Concrete in Rock-Filled Concrete
Authors: Liu Wenju , Pan Jianwen
Published: December 2019

The good filling performance of self-compacting concrete (SCC) to pre-placed assembly of rocks is essential for quality of rock-filled concrete (RFC). In this study, a theoretical model is proposed to evaluate the filling capacity of SCC in porous media that is simplified to approximate the assembly of rocks. Numerical simulation of SCC flow in the porous media is carried out based on the computational fluid dynamics. The effects of yield stress of SCC and size and shape of grains in the porous media on the filling capacity of SCC are considered. The inclination of the free surface of the distribution of SCC at flow stoppage is defined to evaluate the filling capacity of SCC in the porous media. According to the theoretical model, the inclination is directly proportional to the yield stress of the SCC and the blocking effect of grains, while inversely proportional to the grain size. The numerical simulation provides consistent results with the theoretical model. The results suggest the use of rounded large rocks and SCC with low yield stress to ensure good quality of RFC.
Phase and Orientation Control of NiTiO3 Thin Films
Authors: Bratvold Jon Einar , Fjellvåg Helmer , Nilsen Ola
Published: December 2019

Subtle changes in the atomic arrangement of NiTiO3 in the ilmenite structure affects its symmetry and properties. At high temperatures, the cations are randomly distributed throughout the structure, resulting in the corundum structure with R−3c symmetry. Upon cooling, the cations order in alternating layers along the crystallographic c axis, resulting in the ilmenite structure with R−3 symmetry. Related to this is the R3c symmetry, where the cations alternate both perpendicularly and along the c axis. NiTiO3 with the latter structure is highly interesting as it exhibits ferroelectric properties. The close relationship between structure and properties for ilmenite-related structures emphasizes the importance of being able to control the symmetry during synthesis. We show that the orientation and symmetry of thin films of NiTiO3 formed by atomic layer deposition (ALD) can be controlled by choice of substrate. The disordered phase (R−3c), previously only observed at elevated temperatures, have been deposited at 250 °C on α-Al2O3 substrates, while post-deposition annealing at moderate temperatures (650 °C) induces ordering (R−3). We have in addition explored the symmetry and epitaxial orientation obtained when deposited on substrates of LaAlO3(100), SrTiO3(100) and MgO(100). The presented work demonstrates the possibilities of ALD to form metastable phases through choice of substrates.
Influence Mechanism of Cu Layer Thickness on Photoelectric Properties of IWO/Cu/IWO Films
Authors: Han Fengbo , Zhao Wenyuan , Bi Ran , Tian Feng , Li Yadan , Zheng Chuantao , Wang Yiding
Published: December 2019

Transparent conductive IWO/Cu/IWO (W-doped In2O3) films were deposited on quartz substrates by magnetron sputtering of IWO and Cu in the Ar atmosphere. The X-ray diffraction (XRD) patterns identified the cubic iron–manganese ore crystal structure of the IWO layers. The influence of the thickness of the intermediate ultra-thin Cu layers on the optical and electrical properties of the multilayer films was analyzed. As the Cu layer thickness increases from 4 to 10 nm, the multilayer resistivity gradually decreases to 4.5 × 10−4 Ω·cm, and the optical transmittance in the mid-infrared range increases first and then decreases with a maximum of 72%, which serves as an excellent candidate for the mid-infrared transparent electrode.
Comparison of the Abdominal Wall Muscle Thickness in Female Rugby Players Versus Non-Athletic Women: A Cross-Sectional Study
Authors: Abuín-Porras Vanesa , de la Cueva-Reguera Mónica , Benavides-Morales Pedro , Ávila-Pérez Rocío , de la Cruz-Torres Blanca , Pareja-Galeano Helios , Blanco-Morales María , Romero-Morales Carlos
Published: December 2019

Background and Objectives: Rugby players engage in demanding, high loading muscular activity in the spine. Study of the abdominal wall architecture in female rugby athletes is relevant to the possible muscular asymmetry secondary to sport practice and the relationship between the abdominal wall and the pelvic floor muscles. Activation of the transversus abdominis (TrAb) generates an increase in the bladder neck muscle. Moreover, an increased interrecti distance (IRD) is related to urinary incontinence and has a higher prevalence in athletic women. The aim of the present study was to compare and quantify, with ultrasound imaging (USI), the thickness of the transversus abdominis (TrAb), external oblique (EO), internal oblique (IO), rectus abdominis (RA), and interrecti distance (IRD) in female rugby players versus non-athletic women in order to improve upon existing knowledge about abdominal wall configuration in female athletes. Materials and Methods: A sample of 32 women was recruited at the Universidad Europea Research Lab and divided in two groups: a rugby group (n = 16) and a non-athletic women group (n = 16). The thickness of the TrAb, EO, IO, RA, and IRD were assessed by USI in both groups. Results: There were statistically significant differences for the ultrasound evaluation thickness of the right TrAb (p = 0.011; d = 0.10), EO (p = 0.045; d = 0.74), IO (p = 0.003; d = 1.32), and RA (p = 0.001; d = 1.38) showing a thickness increase for the rugby group with respect to the control group. For the IRD thickness, there were no significant differences (p > 0.05) between groups. Conclusions: An increased TrAb, IO, EO, and RA thickness may be shown in female rugby players versus non-athletic women. Nevertheless, statistically relevant differences were not found for the IRD between both groups.
Study on Dynamic Mechanical Properties and Constitutive Model Construction of TC18 Titanium Alloy
Authors: Zhang Changming , Mu Anle , Wang Yun , Zhang Hui
Published: December 2019

In order to investigate the static and dynamic mechanical properties of TC18 titanium alloy, the quasi-static stress–strain curve of TC18 titanium alloy under room temperature was obtained by DNS 100 electronic universal testing machine (Changchun Institute of Mechanical Science Co., Ltd., Changchun, China). Meanwhile, the flow stress–strain curves under different temperatures and strain rates are analyzed by split Hopkinson pressure bar (SHPB) device with synchronous assembly system. On the basis of the two experimental data, the JC constitutive model under the combined action of high temperature and impact load is established using the linear least squares method. The results show the following: the yield strength and flow stress of TC18 titanium alloy increase slowly with the increase of the strain rate, and the strain value corresponding to the yield strength is reduced. With the increase of strain, the flow stress increases at first and then decreases at different temperatures. The strain value corresponding to the transition point rises with the temperature increase, and the corresponding stress value remains basically unchanged. With the increase of experimental temperature, the flow stress shows a downward trend, and the JC constitutive model can predict the plastic flow stress well.
A 3D FEM-Based Numerical Analysis of the Sheet Metal Strip Flowing Through Drawbead Simulator
Authors: Trzepiecinski Tomasz , Fejkiel Romuald
Published: December 2019

Drawbeads are elements of the stamping die and they are used to compensate material flow resistance around the perimeter of the drawpiece or to change the stress state in specific regions of the drawpiece. This paper presents the results of experimental and numerical analyses of tests of sheet metal flowing through a drawbead. The tests have been carried out using a special tribological simulator of the drawbead. Experimental tests to determine the coefficient of friction (COF) have been carried out for three widths of sheet metal strip and two drawbead heights. The three-dimensional (3D) elastic-plastic numerical computations were performed using the MSC. Marc program. Special attention was given to the effect of material flow through the drawbead on the distribution of the normal stress on the tool-sheet interface. The mesh sensitivity analysis based on the value of the drawing force of the specimen being pulled through the drawbead allowed an optimal mesh size to be determined. The errors between the numerically predicted values of the COF and the values experimentally determined ranged from about 0.95% to 7.1% in the cases analysed. In the case of a drawbead height of 12 mm, the numerical model overestimated the value of the COF for all specimen widths analysed. By contrast, in the case of a drawbead height of 18 mm, all experimentally determined friction coefficients are underestimated by Finite Element Method (FEM). This was explained by the different character of sheet deformation under friction and frictionless conditions. An increase in the drawbead height, with the same sheet width, increases the value of the COF.
Flow Characteristics of the Entrance Region with Roughness Effect within Rectangular Microchannels
Authors: Li Haiwang , Li Yujia , Huang Binghuan , Xu Tiantong
Published: December 2019

We conducted systematic numerical investigations of the flow characteristics within the entrance region of rectangular microchannels. The effects of the geometrical aspect ratio and roughness on entrance lengths were analyzed. The incompressible laminar Navier–Stokes equations were solved using finite volume method (FVM). In the simulation, hydraulic diameters ( D h ) ranging from 50 to 200 µm were studied, and aspect ratios of 1, 1.25, 1.5, 1.75, and 2 were considered as well. The working fluid was set as water, and the Reynolds number ranged from 0.5 to 100. The results showed a good agreement with the conducted experiment. Correlations are proposed to predict the entrance lengths of microchannels with respect to different aspect ratios. Compared with other correlations, these new correlations are more reliable because a more practical inlet condition was considered in our investigations. Instead of considering the influence of the width and height of the microchannels, in our investigation we proved that the critical role is played by the aspect ratio, representing the combination of the aforementioned parameters. Furthermore, the existence of rough elements obviously shortens the entrance region, and this effect became more pronounced with increasing relative roughness and Reynolds number. A similar effect could be seen by shortening the roughness spacing. An asymmetric distribution of rough elements decreased the entrance length compared with a symmetric distribution, which can be extrapolated to other irregularly distributed forms.
3D Printed Wavy Scaffolds Enhance Mesenchymal Stem Cell Osteogenesis
Authors: Ji Shen , Guvendiren Murat
Published: December 2019

There is a growing interest in developing 3D porous scaffolds with tunable architectures for bone tissue engineering. Surface topography has been shown to control stem cell behavior including differentiation. In this study, we printed 3D porous scaffolds with wavy or linear patterns to investigate the effect of wavy scaffold architecture on human mesenchymal stem cell (hMSC) osteogenesis. Five distinct wavy scaffolds were designed using sinusoidal waveforms with varying wavelengths and amplitudes, and orthogonal scaffolds were designed using linear patterns. We found that hMSCs attached to wavy patterns, spread by taking the shape of the curvatures presented by the wavy patterns, exhibited an elongated shape and mature focal adhesion points, and differentiated into the osteogenic lineage. When compared to orthogonal scaffolds, hMSCs on wavy scaffolds showed significantly enhanced osteogenesis, indicated by higher calcium deposition, alkaline phosphatase activity, and osteocalcin staining. This study aids in the development of 3D scaffolds with novel architectures to direct stem osteogenesis for bone tissue engineering.
Cupriavidus sp. HN-2, a Novel Quorum Quenching Bacterial Isolate, is a Potent Biocontrol Agent Against Xanthomonas campestris pv. campestris
Authors: Ye Tian , Zhou Tian , Li Qiting , Xu Xudan , Fan Xinghui , Zhang Lianhui , Chen Shaohua
Published: December 2019

Diffusible signal factor (DSF) represents a family of widely conserved quorum sensing (QS) signals involved in the regulation of virulence factor production in many Gram-negative bacterial pathogens. Quorum quenching, which disrupts QS either by degradation of QS signals or interference of signal generation or perception, is a promising strategy for prevention and control of QS-mediated bacterial infections. In this study, a novel DSF-degrading strain, HN-2, was isolated from contaminated soil and identified as Cupriavidus sp. The isolate exhibited superior DSF degradation activity and completely degraded 2 mmol·L–1 of DSF within 24 h. Analysis of the degradation products of DSF by gas chromatography–mass spectrometry led to the identification of trans-2-decenoic acid methyl ester as the main intermediate product, suggesting that DSF could be degraded by oxidation and hydroxylation. Moreover, this study presents for the first time, evidence that Cupriavidus sp. can reduce the black rot disease caused by Xanthomonas campestris pv. campestris (Xcc). Application of the HN-2 strain as a biocontrol agent could substantially reduce the disease severity. These findings reveal the biochemical basis of a highly efficient DSF-degrading bacterial isolate and present a useful agent for controlling infectious diseases caused by DSF-dependent bacterial pathogens.
Trends in Modeling, Design, and Optimization of Multiphase Systems in Minerals Processing
Authors: Cisternas Luis , Lucay Freddy , Botero Yesica
Published: December 2019

Multiphase systems are important in minerals processing, and usually include solid–solid and solid–fluid systems, such as in wet grinding, flotation, dewatering, and magnetic separation, among several other unit operations. In this paper, the current trends in the process system engineering tasks of modeling, design, and optimization in multiphase systems, are analyzed. Different scales of size and time are included, and therefore, the analysis includes modeling at the molecular level (molecular dynamic modeling) and unit operation level (e.g., computational fluid dynamic, CFD), and the application of optimization for the design of a plant. New strategies for the modeling, design, and optimization of multiphase systems are also included, with a strong focus on the application of artificial intelligence (AI) and the combination of experimentation and modeling with response surface methodology (RSM). The integration of different modeling techniques such as CFD with discrete element simulation (DEM) and response surface methodology (RSM) with artificial neural networks (ANN) is included. The paper finishes with tools to study the uncertainty, both epistemic and stochastic, based on uncertainty and global sensitivity analyses, which is present in all mineral processing operations. It is shown that all of these areas are very active and can help in the understanding, operation, design, and optimization of mineral processing that involves multiphase systems. Future needs, such as meso-scale modeling, are highlighted.
Application of Switchable Hydrophobicity Solvents for Extraction of Emerging Contaminants in Wastewater Samples
Authors: Lasarte-Aragonés Guillermo , Álvarez-Lueje Alejandro , Salazar Ricardo , Toledo-Neira Carla
Published: December 2019

In the present work, the effectiveness of switchable hydrophobicity solvents (SHSs) as extraction solvent (N,N-Dimethylcyclohexylamine (DMCA), N,N-Diethylethanamine (TEA), and N,N-Benzyldimethylamine (DMBA)) for a variety of emerging pollutants was evaluated. Different pharmaceutical products (nonsteroidal anti-inflammatory drugs (NSAIDs), hormones, and triclosan) were selected as target analytes, covering a range of hydrophobicity (LogP) of 3.1 to 5.2. The optimized procedure was used for the determination of the target pharmaceutical analytes in wastewater samples as model analytical problem. Absolute extraction recoveries were in the range of 51% to 103%. The presented method permits the determination of the target analytes at the low ng mL−1 level, ranging from 0.8 to 5.9 (except for Triclosan, 106 ng mL−1) with good precision (relative standard deviation lower than 6%) using high-pressure liquid chromatography (HPLC) combined with ultraviolet (DAD) and fluorescence (FLR) detection. The microextraction alternative resulted in a fast, simple, and green method for a wide variety of analytes in environmental water sample. The results suggest that this type of solvent turns out to be a great alternative for the determination of different analytes in relatively complex water samples.
(Q)SAR Models of HIV-1 Protein Inhibition by Drug-Like Compounds
Authors: Stolbov Leonid A. , Druzhilovskiy Dmitry S. , Filimonov Dmitry A. , Nicklaus Marc C. , Poroikov Vladimir V.
Published: December 2019

Despite the achievements of antiretroviral therapy, discovery of new anti-HIV medicines remains an essential task because the existing drugs do not provide a complete cure for the infected patients, exhibit severe adverse effects, and lead to the appearance of resistant strains. To predict the interaction of drug-like compounds with multiple targets for HIV treatment, ligand-based drug design approach is widely applied. In this study, we evaluated the possibilities and limitations of (Q)SAR analysis aimed at the discovery of novel antiretroviral agents inhibiting the vital HIV enzymes. Local (Q)SAR models are based on the analysis of structure–activity relationships for molecules from the same chemical class, which significantly restrict their applicability domain. In contrast, global (Q)SAR models exploit data from heterogeneous sets of drug-like compounds, which allows their application to databases containing diverse structures. We compared the information for HIV-1 integrase, protease and reverse transcriptase inhibitors available in the EBI ChEMBL, NIAID HIV/OI/TB Therapeutics, and Clarivate Analytics Integrity databases as the sources for (Q)SAR training sets. Using the PASS and GUSAR software, we developed and validated a variety of (Q)SAR models, which can be further used for virtual screening of new antiretrovirals in the SAVI library. The developed models are implemented in the freely available web resource AntiHIV-Pred.
The N’-Substituted Derivatives of 5-Chloro-3-Methylisothiazole-4-Carboxylic Acid Hydrazide with Antiproliferative Activity
Authors: Jęśkowiak Izabela , Ryng Stanisław , Świtalska Marta , Wietrzyk Joanna , Bryndal Iwona , Lis Tadeusz , Mączyński Marcin
Published: December 2019

Thanks to the progress in oncology, pharmacological treatment of cancer is gaining in importance and in the near future anti-cancer chemotherapeutics are expected to be the main method of treatment for cancer diseases. What is more, the search for new anti-cancer compounds with the desired application properties is constantly underway. As a result of designed syntheses, we obtained some new N’-substituted 5-chloro-3-methylisothiazole-4-carboxylic acid hydrazide derivatives with anticancer activity. The structure of new compounds was determined by mass spectrometry (MS), elemental analysis, proton nuclear magnetic resonance spectroscopy (1H-NMR), carbon nuclear magnetic resonance spectroscopy (13C-NMR), 1H-13C NMR correlations and infrared spectroscopy (IR). Moreover, the structures of the compounds were confirmed by crystallographic examination. The antiproliferative MTT tests for 11 prepared compounds was conducted towards human biphenotypic B cell myelomonocytic leukemia MV4-11. SRB test was used to examine their potential anticancer activity towards human colon adenocarcinoma cell lines sensitive LoVo, resistant to doxorubicin LoVo/DX, breast adenocarcinoma MCF-7 and normal non-tumorigenic epithelial cell line derived from mammary gland MCF-10A. The most active compound was 5-chloro-3-methyl-N′-[(1E,2E)-(3-phenyloprop-2-en-1-ylidene]isothiazole-4-carbohydrazide, which showed the highest antiproliferative activity against all tested cell lines.
A Combined Mechanochemical and Calcination Route to Mixed Cobalt Oxides for the Selective Catalytic Reduction of Nitrophenols
Authors: Shultz Lorianne R. , McCullough Bryan , Newsome Wesley J. , Ali Haider , Shaw Thomas E. , Davis Kristopher O. , Uribe-Romo Fernando J. , Baudelet Matthieu , Jurca Titel
Published: December 2019

Para-, or 4-nitrophenol, and related nitroaromatics are broadly used compounds in industrial processes and as a result are among the most common anthropogenic pollutants in aqueous industrial effluent; this requires development of practical remediation strategies. Their catalytic reduction to the less toxic and synthetically desirable aminophenols is one strategy. However, to date, the majority of work focuses on catalysts based on precisely tailored, and often noble metal-based nanoparticles. The cost of such systems hampers practical, larger scale application. We report a facile route to bulk cobalt oxide-based materials, via a combined mechanochemical and calcination approach. Vibratory ball milling of CoCl2(H2O)6 with KOH, and subsequent calcination afforded three cobalt oxide-based materials with different combinations of CoO(OH), Co(OH)2, and Co3O4 with different crystallite domains/sizes and surface areas; Co@100, Co@350 and Co@600 (Co@###; # = calcination temp). All three prove active for the catalytic reduction of 4-nitrophenol and related aminonitrophenols. In the case of 4-nitrophenol, Co@350 proved to be the most active catalyst, therein its retention of activity over prolonged exposure to air, moisture, and reducing environments, and applicability in flow processes is demonstrated.
Comparative Study on Pharmacokinetics of Four Active Compounds in Rat Plasma after Oral Administration of Raw and Wine Processed Chuanxiong Rhizoma
Authors: Ning Yan , Pei Ke , Cao Gang , Cai Hao , Liu Xiao , Cao Lilong , Zhang Shuosheng , Cai Baochang
Published: December 2019

In Chinese medicine, the effect of promoting blood circulation and removing stasis could be enhanced after Chuanxiong Rhizoma is processed by wine. However, the relevant mechanism remains unclear. In this manuscript, a rapid and sensitive quantification method employing ultrahigh performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) was established and validated to simultaneously determine butylidenephthalide, ligustilide, senkyunolide A and ferulic acid in rat plasma after oral administration of raw Chuanxiong Rhizoma (RCR) and wine-processed Chuanxiong Rhizoma (WCR) respectively. All analytes were extracted from plasma by proteins precipitation with methanol. Chromatographic separation was carried out on a Hypersil GOLD C18 column by using a gradient mobile phase system of acetonitrile and water with 0.01% formic acid, the flow rate was 0.3 mL/min. For exact mass detecting, quick switching mode was used, positive and negative ions could be detected in one injection. The pharmacokinetic profiles of four components in the two groups were evaluated and compared. The results showed that, compared to the RCR group, the Vd and AUC0→t values of four active compounds were increased and decreased respectively in WCR group, which revealed the effect of wine processing to Chuanxiong Rhizoma: the stronger the effect, the wider the distribution.
A Novel Method for Notable Reducing Phase Transition Temperature of VO2 Films for Smart Energy Efficient Windows
Authors: Guan Huan , Zhang Dongping , Yang Yu , Liu Yi , Zhong Aihua , He Qicong , Qi Jiahua , Fan Ping
Published: December 2019

Although Vanadium dioxide (VO2) has a potential application value for smart energy efficient windows because of its unique phase transition characteristic, there are still many obstacles that need to be overcome. One challenge is to reduce its high transition temperature (ζc = 68 °C) to near room temperature without causing its phase transition performance degradation. In this paper, a novel method was employed that covered a 3 nm ultra-thin heavy Cr-doped VO2 layer on the pure VO2 films. Compared with the as-grown pure VO2, obviously, phase transition temperature decreasing from 59.5 °C to 48.0 °C was observed. Different from previous doping techniques, almost no phase transition performance weakening occurred. Based on the microstructure and electrical parameters measurement results, the mechanism of ζc reducing was discussed. The upper ultra-thin heavy Cr-doped layer may act as the induced role of phase transition. With temperature increasing, carrier concentration increased from the upper heavy Cr-doped layer to the bottom pure VO2 layer by diffusion, and induced the carrier concentration reach to phase transition critical value from top to bottom gradually. The present method is not only a simpler technique, but also avoids expensive alloy targets.
Antidiabetic Properties of Curcumin II: Evidence from In Vivo Studies
Authors: Den Hartogh Danja J. , Gabriel Alessandra , Tsiani Evangelia
Published: December 2019

Type 2 diabetes mellitus (T2DM) is a growing metabolic disease characterized by insulin resistance and hyperglycemia. Current preventative and treatment approaches to insulin resistance and T2DM lack in efficacy, resulting in the need for new approaches to prevent and treat the disease. In recent years, epidemiological studies have suggested that diets rich in fruits and vegetables have beneficial health effects, including protection against insulin resistance and T2DM. Curcumin, a polyphenol found in turmeric, and curcuminoids have been reported to have antioxidant, anti-inflammatory, hepatoprotective, nephroprotective, neuroprotective, immunomodulatory and antidiabetic properties. The current review (II of II) summarizes the existing in vivo studies examining the antidiabetic effects of curcumin.
A Pilot Randomized Crossover Trial Assessing the Safety and Short-Term Effects of Walnut Consumption by Patients with Chronic Kidney Disease
Authors: Sanchis Pilar , Molina Marilisa , Berga Francisco , Muñoz Elena , Fortuny Regina , Costa-Bauzá Antonia , Grases Felix , Buades Juan Manuel
Published: December 2019

The aim of this study of patients with chronic kidney disease (CKD) is to assess the safety of daily consumption of walnuts on the physiological levels of phosphorous, potassium, parathyroid hormone (PTH), and fibroblast growth factor 23 (FGF23), and to assess the short-term benefits of this intervention on risk factors associated with cardiovascular events. This led us to perform a prospective, randomized, crossover, pilot clinical trial examined 13 patients with CKD. Subjects were randomly assigned to a diet of 30 g of walnuts per day or the control diet. After 30 days, each group was given a 30-day washout period, and then switched to the alternate diet for 30 days. Urinary and serum levels of phosphorous and potassium, multiple vascular risk factors, and urinary inositol phosphates (InsPs) were measured at baseline and at the end of the intervention period. Our results showed that the walnut dietary supplement led to reduced blood pressure, LDL cholesterol, and albumin excretion, but had no effect on the physiological levels of phosphorous, potassium, PTH, and FGF23. This is the first report to show that daily consumption of walnuts by patients with CKD does not alter their physiological levels of phosphorous, potassium, PTH, and FGF23 when included in a sodium-, protein-, phosphate-, and potassium-controlled diet, and it could be an effective strategy for reducing cardiovascular risk in patients with CKD.
Dextran-Curcumin Nanoparticles as a Methotrexate Delivery Vehicle: A Step Forward in Breast Cancer Combination Therapy
Authors: Curcio Manuela , Cirillo Giuseppe , Tucci Paola , Farfalla Annafranca , Bevacqua Emilia , Vittorio Orazio , Iemma Francesca , Nicoletta Fiore Pasquale
Published: December 2019

With the aim to effectively deliver methotrexate (MTX) to breast cancer cells, we designed a nanocarrier system (DC) derived from the self-assembly of a dextran-curcumin conjugate prepared via enzyme chemistry with immobilized laccase acting as a solid biocatalyst. Nanoparticles consisted of homogeneously dispersed nanospheres with a mean diameter of 290 nm, as characterized by combined transmission electron microscopy and dynamic light scattering investigations. DC was able to control the MTX release overtime (t1/2 value of 310 min), with cell internalization studies proving its presence inside MCF-7 cytoplasm. Finally, improved MTX efficacy was obtained in viability assays, and attributed to the synergy of curcumin moieties and loaded MTX as underlined by a combination index (CI) < 1.
Bio- Fortification of Angelica gigas Nakai Nano-Powder Using Bio-Polymer by Hot Melt Extrusion to Enhance the Bioaccessibility and Functionality of Nutraceutical Compounds
Authors: Azad Md Obyedul Kalam , Kang Wie Soo , Lim Jung Dae , Park Cheol Ho
Published: December 2019

Angelica gigas Nakai (AGN) is a popular traditional herbal medicine which has been used to alleviate various human diseases in Korea since ancient times. However, the low bioaccessibility of the nutraceutical compounds of AGN results in a poor water solubility, thereby limiting bioavailability. In this regard, a ternary AGN–biopolymer–plasticizer composite (AGNC) was developed to enhance the bioaccessibility of nutraceutical compounds from extrudate AGN formulations manufactured by hot melt extrusion (HME). The AGNC was prepared with extrudate AGN (EAGN) using different hydroxypropyl methylcellulose (HPMC) biopolymers (5% w/w) viz.: hypromellose phthalate (HP), hypromellose (AN), and hypromellose (CN) along with acetic acid (AA) (0.1 M, 20% w/v) as a plasticizer. The non-extrudate fresh AGN (FAGN) powder was used as a control. The physicochemical properties of the extrudate formulations and control were characterized by differential scanning calorimetry (DSC) and Fourier-transform infrared spectroscopy (FTIR). DSC analysis showed a lower enthalpy (ΔH) (12.22 J/g) and lower glass transition temperature (Tg) (41 °C) in HP-AA-EAGN compared to the control. FTIR confirmed the physical crosslinking between AGN and biopolymer in the extrudate composite and demonstrated that some functional groups formed viz., -OH and -CH2. The obtained result also shows that the particle size was reduced by 341 nm, and solubility was increased by 65.5% in HP-AA-EAGN compared to the control (1499 nm, 29.4%, respectively). The bioaccessibility of the total phenolic content and the total flavonoids—including decursin (D) and decursinol angelate (DA)—were significantly higher in HP-AA-EAGN compared to the control. The 2,2-diphenyl-1 picryl hydrazyl (DPPH) free radical scavenging capacity and ferric reducing antioxidant power assay (FRAP) indicated that the HP-AA-EAGN formulation preserves a greater antioxidant profile than the other formulations. Finally, it is summarized that the addition of acidified HP biopolymer increased the bioaccessibility, functionality, and improved the physicochemical properties of nutraceutical compounds in the extrudate AGN formulation.
Dispersibility and Storage Stability Optimization of High Dose Isoniazid Dry Powder Inhalation Formulations with L-Leucine or Trileucine
Authors: Sibum Imco , Hagedoorn Paul , Kluitman Markus P. G. , Kloezen Martijn , Frijlink Henderik W. , Grasmeijer Floris
Published: December 2019

Tuberculosis is the leading cause of death from a single infectious pathogen worldwide. Lately, the targeted delivery of antibiotics to the lungs via inhalation has received increasing interest. In a previous article, we reported on the development of a spray-dried dry powder isoniazid formulation containing an L-leucine coating. It dispersed well but had poor physical stability. In this study, we aimed to improve the stability by improving the leucine coating. To this end, we optimized the spray-drying conditions, the excipient content, and the excipient itself. Using L-leucine, the tested excipient contents (up to 5%) did not result in a stable powder. Contrary to L-leucine, the stability attained with trileucine was satisfactory. Even when exposed to 75% relative humidity, the formulation was stable for at least three months. The optimal formulation contained 3% trileucine w/w. This formulation resulted in a maximum fine particle dose of 58.00 ± 2.56 mg when a nominal dose of 80 mg was dispersed from the Cyclops® dry powder inhaler. The improved moisture protection and dispersibility obtained with trileucine are explained by its amorphous nature and a higher surface enrichment during drying. Dispersion efficiency of the device decreases at higher nominal doses.
Spironolactone-Loaded LeciPlexes as Potential Topical Delivery Systems for Female Acne: In Vitro Appraisal and Ex Vivo Skin Permeability Studies
Authors: Salama Ayman , Badran Mohamed , Elmowafy Mohammed , Soliman Ghareb M.
Published: December 2019

Spironolactone (SP), an aldosterone antagonist with anti-androgen properties, has shown promising results in the treatment of female acne. However, its systemic side effects limit its clinical benefits. This study aimed to prepare and evaluate LeciPlexes for SP topical delivery. LeciPlexes were prepared by a one-step procedure and characterized using various techniques. Optimum LeciPlex preparation was incorporated into 1% methylcellulose gel and SP permeability was tested ex vivo in Sprague-Dawley rat skin. The maximum drug encapsulation efficiency obtained was 93.6 ± 6.9% and was dependent on the drug/phospholipid and surfactant/phospholipid ratios. A zeta potential of +49.3 ± 3.5 to +57.7 ± 3.3 mV and a size of 108 ± 25.3 to 668.5 ± 120.3 nm were observed for the LeciPlexes. FT-IR and DSC studies confirmed the incorporation of SP into the LeciPlexes through hydrophobic and hydrogen bonding interactions. SP release from the LeciPlex formulations was significantly slower than from the drug suspension. Cumulative SP permeated through rat skin from LeciPlex gel was about 2-fold higher than SP control gel. Cumulative SP deposited in the stratum corneum and other skin layers from the LeciPlex gel was about 1.8- and 2.6-fold higher than SP control gel, respectively. This new SP LeciPlex formulation is a promising carrier for the treatment of female acne.