bluuebunny/crossref_metadata_2025 huggingface dataset:
Ntrk1 Promotes Resistance to PD-1 Checkpoint Blockade in Mesenchymal Kras/p53 Mutant Lung Cancer
Authors: Konen Jessica M. , Rodriguez B. Leticia , Fradette Jared J. , Gibson Laura , Davis Denali , Minelli Rosalba , Peoples Michael D. , Kovacs Jeffrey , Carugo Alessandro , Bristow Christopher , Heffernan Timothy , Gibbons Don L.
Published: April 2019

The implementation of cancer immunotherapeutics for solid tumors including lung cancers has improved clinical outcomes in a small percentage of patients. However, the majority of patients show little to no response or acquire resistance during treatment with checkpoint inhibitors delivered as a monotherapy. Therefore, identifying resistance mechanisms and novel combination therapy approaches is imperative to improve responses to immune checkpoint inhibitors. To address this, we performed an in vivo shRNA dropout screen that focused on genes encoding for FDA-approved drug targets (FDAome). We implanted epithelial and mesenchymal Kras/p53 (KP) mutant murine lung cancer cells expressing the FDAome shRNA library into syngeneic mice treated with an anti-PD-1 antibody. Sequencing for the barcoded shRNAs revealed Ntrk1 was significantly depleted from mesenchymal tumors challenged with PD-1 blockade, suggesting it provides a survival advantage to tumor cells when under immune system pressure. Our data confirmed Ntrk1 transcript levels are upregulated in tumors treated with PD-1 inhibitors. Additionally, analysis of tumor-infiltrating T cell populations revealed that Ntrk1 can promote CD8+ T cell exhaustion. Lastly, we found that Ntrk1 regulates Jak/Stat signaling to promote expression of PD-L1 on tumor cells. Together, these data suggest that Ntrk1 activates Jak/Stat signaling to regulate expression of immunosuppressive molecules including PD-L1, promoting exhaustion within the tumor microenvironment.
Ion-Substituted Carbonated Hydroxyapatite Coatings for Model Stone Samples
Authors: Ion Rodica-Mariana , Iancu Lorena , Vasilievici Gabriel , Grigore Madalina Elena , Andrei Ramona Elena , Radu George-Ionut , Grigorescu Ramona Marina , Teodorescu Sofia , Bucurica Ioan Alin , Ion Mihaela-Lucia , Gheboianu Anca Irina , Radulescu Cristiana , Dulama Ioana Daniela
Published: April 2019

Carbonated hydroxyapatite derivatives (CHAp) and its metallic derivatives (Ag, Sr, Ba, K, Zn) have been prepared and characterized in this paper and their coating capacity on some model stone samples have been evaluated and discussed. These compounds were characterized by using several analytical tools, including X-ray diffraction analysis (XRD), thermogravimetric analysis (TGA), Fourier transform infrared spectroscopy (FTIR), to determine the purity of the CHAp sample. The XRD and FTIR results confirmed the presence of AB-carbonated type CHAp. The thermal analysis (TGA) established two stages of weight loss that occured during the heating process: The first weight loss between 30–225 °C corresponding to the partial carbonate release from OH-channel and the second one between 226–700 °C, corresponding to some thermal reactions, possibly to the generation of calcium phosphate. The efficiency and suitability of these products on model stone samples were evaluated by monitoring the resistance to artificial weather (freeze–thaw), and pore structure changes (surface area, pore volume, pore diameter). Meanwhile, optical microscopy (OM) and Scanning Electron Microscopy with Energy Dispersive Spectroscopy (SEM–EDS) techniques showed the particles size and surface morphology of the samples, as well as information on its chemical composition. Also, the compressive strength of these new compounds as coatings revealed a homogeneity and strengthen of these model stone samples.
Enhancement of Lysozyme Crystallization Using DNA as a Polymeric Additive
Authors: Zhang Bo , Wang Yao , Thi Shiki , Toong Vincent , Luo Ping , Fan Shilong , Xu Lijin , Yang Zhongqiang , Heng Jerry Y. Y.
Published: April 2019

This study reports the first experimental evidence of using DNA as a polymeric additive to enhance protein crystallization. Using three kinds of DNA with different molecular weights—calf DNA, salmon DNA, and herring DNA—this study showed an improvement in the success rate of lysozyme crystallization, as compared to control experiments, especially at low lysozyme concentration. The improvement of crystallization is particularly significant in the presence of calf DNA with the highest molecular weight. Calf DNA also speeds up the induction time of lysozyme crystallization and increases the number of crystals per drop. We hypothesized the effect of DNA on protein crystallization may be due to the combination of excluded volume effect, change of water’s surface tension, and the water competition effect. This work confirms predications of the potential use of DNA as a polymeric additive to enhance protein crystallization, potentially applied to systems with limited protein available or difficult to crystallize.
Design and Fabrication of the Reliable GaN Based Vertical-Cavity Surface-Emitting Laser via Tunnel Junction
Authors: Shen Chih-Chiang , Lu Yun-Ting , Yeh Yen-Wei , Chen Cheng-Yuan , Chen Yu-Tzu , Sher Chin-Wei , Lee Po-Tsung , Shih Ya-Hsuan , Lu Tien-Chang , Wu Tingzhu , Chiu Ching-Hsueh , Kuo Hao-Chung
Published: April 2019

In this study, we theoretically designed and experimentally fabricated an InGaN vertical-cavity surface-emitting laser (VCSEL) with a tunnel junction (TJ) structure. From numerical simulation results, the optical loss of the device can be reduced by a TJ structure. Additionally, the leakage current of the VCSEL with TJ structure was much smaller than that of the VCSEL with an Indium-Tin-Oxide (ITO) layer. We have been demonstrated that laser output performance is improved by using the TJ structure when compared to the typical VCSEL structure of the ITO layer. The output power obtained at 2.1 mW was enhanced by a factor of 3.5 by the successful reduction of threshold current density (Jth) from 12 to 8.5 kA/cm2, and the enlarged slope efficiency was due to less absorption in VCSEL with a TJ structure. Finally, the samples passed the high temperature (70 °C) and high operation current (1.5 × Jth) test for over 500 h.
Multistructure-Based Collaborative Online Distillation
Authors: Gao Liang , Lan Xu , Mi Haibo , Feng Dawei , Xu Kele , Peng Yuxing
Published: April 2019

Recently, deep learning has achieved state-of-the-art performance in more aspects than traditional shallow architecture-based machine-learning methods. However, in order to achieve higher accuracy, it is usually necessary to extend the network depth or ensemble the results of different neural networks. Increasing network depth or ensembling different networks increases the demand for memory resources and computing resources. This leads to difficulties in deploying depth-learning models in resource-constrained scenarios such as drones, mobile phones, and autonomous driving. Improving network performance without expanding the network scale has become a hot topic for research. In this paper, we propose a cross-architecture online-distillation approach to solve this problem by transmitting supplementary information on different networks. We use the ensemble method to aggregate networks of different structures, thus forming better teachers than traditional distillation methods. In addition, discontinuous distillation with progressively enhanced constraints is used to replace fixed distillation in order to reduce loss of information diversity in the distillation process. Our training method improves the distillation effect and achieves strong network-performance improvement. We used some popular models to validate the results. On the CIFAR100 dataset, AlexNet’s accuracy was improved by 5.94%, VGG by 2.88%, ResNet by 5.07%, and DenseNet by 1.28%. Extensive experiments were conducted to demonstrate the effectiveness of the proposed method. On the CIFAR10, CIFAR100, and ImageNet datasets, we observed significant improvements over traditional knowledge distillation.
Comparison of Different Hydraulic Fracturing Scenarios in Horizontal Wells Using XFEM Based on the Cohesive Zone Method
Authors: Li Jianxiong , Xiao Wen , Hao Guanzhong , Dong Shiming , Hua Wen , Li Xiaolong
Published: April 2019

Multistage hydraulic fracturing is a highly effective method for creating multiple transverse fractures to improve gas and oil reservoir production. It is critical to minimize the fracture spacing while also ensuring transverse propagation of fractures in multi-fractured horizontal wells. In this paper, a 3D fully coupled pore pressure-stress model based on the extended finite element method (XFEM) combined with the cohesive zone method is established to simulate five different fracturing scenarios in close spacing. The sensitivity of mesh size and the integration method are optimal, which are verified by the highly accurate traditional cohesive zone method. Then, the effect of five different fracturing scenarios on fracture geometries is compared. It is shown that spacing is a key parameter controlling fracture geometries in all fracturing scenarios. Alternative sequential and modified two-step fracturing can significantly reduce the influence of stress shadowing to generate more transverse fractures and form longer effective fractures. The sequential and two-step fracturing see an obvious improvement with increased fracture effective length when the spacing increases. The simultaneous fracturing technique can result in excessive closure of the middle fractures, which causes serious insertion of proppants. These results offer a new insight on optimization of hydraulic fracturing and can be a guidance for typical field cases.
Optimization of the Contracted Electric Power by Means of Genetic Algorithms
Authors: Alcayde Alfredo , Baños Raul , Arrabal-Campos Francisco M. , Montoya Francisco G.
Published: April 2019

An adequate selection of an energy provider and tariff requires us to analyze the different alternatives to choose one that satisfies your needs. In particular, choosing the right electricity tariff is essential for reducing company costs and improving competitiveness. This paper analyzes the energy consumption of large consumers that make intensive use of electricity and proposes the use of genetic algorithms for optimizing the tariff selection. The aim is to minimize electricity costs including two factors: the cost of power contracted and the heavy penalties for excess of power demand over the power contracted in certain time periods. In order to validate the proposed methodology, a case study based on the real data of energy consumption of a large Spanish university is presented. The results obtained show that the genetic algorithm and other bio-inspired approaches are able to reduce the costs associated to the electricity bill.
Towards an Automated, Fast and Interpretable Estimation Model of Heating Energy Demand: A Data-Driven Approach Exploiting Building Energy Certificates
Authors: Attanasio Antonio , Savino Piscitelli Marco , Chiusano Silvia , Capozzoli Alfonso , Cerquitelli Tania
Published: April 2019

Energy performance certification is an important tool for the assessment and improvement of energy efficiency in buildings. In this context, estimating building energy demand also in a quick and reliable way, for different combinations of building features, is a key issue for architects and engineers who wish, for example, to benchmark the performance of a stock of buildings or optimise a refurbishment strategy. This paper proposes a methodology for (i) the automatic estimation of the building Primary Energy Demand for space heating ( P E D h ) and (ii) the characterization of the relationship between the P E D h value and the main building features reported by Energy Performance Certificates (EPCs). The proposed methodology relies on a two-layer approach and was developed on a database of almost 90,000 EPCs of flats in the Piedmont region of Italy. First, the classification layer estimates the segment of energy demand for a flat. Then, the regression layer estimates the P E D h value for the same flat. A different regression model is built for each segment of energy demand. Four different machine learning algorithms (Decision Tree, Support Vector Machine, Random Forest, Artificial Neural Network) are used and compared in both layers. Compared to the current state-of-the-art, this paper brings a contribution in the use of data mining techniques for the asset rating of building performance, introducing a novel approach based on the use of independent data-driven models. Such configuration makes the methodology flexible and adaptable to different EPCs datasets. Experimental results demonstrate that the proposed methodology can estimate the energy demand with reasonable errors, using a small set of building features. Moreover, the use of Decision Tree algorithm enables a concise interpretation of the quantitative rules used for the estimation of the energy demand. The methodology can be useful during both designing and refurbishment of buildings, to quickly estimate the expected building energy demand and set credible targets for improving performance.
Social Engineering Attacks: A Survey
Authors: Salahdine Fatima , Kaabouch Naima
Published: April 2019

The advancements in digital communication technology have made communication between humans more accessible and instant. However, personal and sensitive information may be available online through social networks and online services that lack the security measures to protect this information. Communication systems are vulnerable and can easily be penetrated by malicious users through social engineering attacks. These attacks aim at tricking individuals or enterprises into accomplishing actions that benefit attackers or providing them with sensitive data such as social security number, health records, and passwords. Social engineering is one of the biggest challenges facing network security because it exploits the natural human tendency to trust. This paper provides an in-depth survey about the social engineering attacks, their classifications, detection strategies, and prevention procedures.
Model of Risk of Exposure to Lyme Borreliosis and Tick-Borne Encephalitis Virus-Infected Ticks in the Border Area of the Czech Republic (South Bohemia) and Germany (Lower Bavaria and Upper Palatinate)
Authors: Hönig Václav , Švec Pavel , Marek Lukáš , Mrkvička Tomáš , Dana Zubriková , Wittmann Maria (Vögerl) , Masař Ondřej , Szturcová Daniela , Růžek Daniel , Pfister Kurt , Grubhoffer Libor
Published: April 2019

In Europe, Lyme borreliosis (LB) and tick-borne encephalitis (TBE) are the two vector-borne diseases with the largest impact on human health. Based on data on the density of host-seeking Ixodes ricinus ticks and pathogen prevalence and using a variety of environmental data, we have created an acarological risk model for a region where both diseases are endemic (Czech Republic—South Bohemia and Germany—Lower Bavaria, Upper Palatinate). The data on tick density were acquired by flagging 50 sampling sites three times in a single season. Prevalence of the causative agents of LB and TBE was determined. Data on environmental variables (e.g., altitude, vegetation cover, NDVI, land surface temperature) were obtained from various sources and processed using geographical information systems. Generalized linear models were used to estimate tick density, probability of tick infection, and density of infected ticks for the whole area. A significantly higher incidence of human TBE cases was recorded in South Bohemia compared to Bavarian regions, which correlated with a lower tick density in Bavaria. However, the differences in pathogen prevalence rates were not significant. The model outputs were made available to the public in the form of risk maps, indicating the distribution of tick-borne disease risk in space.
A Time-Based Objective Measure of Exposure to the Food Environment
Authors: Scully Jason Y. , Moudon Anne Vernez , Hurvitz Philip M. , Aggarwal Anju , Drewnowski Adam
Published: April 2019

Exposure to food environments has mainly been limited to counting food outlets near participants’ homes. This study considers food environment exposures in time and space using global positioning systems (GPS) records and fast food restaurants (FFRs) as the environment of interest. Data came from 412 participants (median participant age of 45) in the Seattle Obesity Study II who completed a survey, wore GPS receivers, and filled out travel logs for seven days. FFR locations were obtained from Public Health Seattle King County and geocoded. Exposure was conceptualized as contact between stressors (FFRs) and receptors (participants’ mobility records from GPS data) using four proximities: 21 m, 100 m, 500 m, and ½ mile. Measures included count of proximal FFRs, time duration in proximity to ≥1 FFR, and time duration in proximity to FFRs weighted by FFR counts. Self-reported exposures (FFR visits) were excluded from these measures. Logistic regressions tested associations between one or more reported FFR visits and the three exposure measures at the four proximities. Time spent in proximity to an FFR was associated with significantly higher odds of FFR visits at all proximities. Weighted duration also showed positive associations with FFR visits at 21-m and 100-m proximities. FFR counts were not associated with FFR visits. Duration of exposure helps measure the relationship between the food environment, mobility patterns, and health behaviors. The stronger associations between exposure and outcome found at closer proximities (<100 m) need further research.
Global Brain Drain: How Can the Maslow Theory of Motivation Improve Our Understanding of Physician Migration?
Authors: Dohlman Lena , DiMeglio Matthew , Hajj Jihane , Laudanski Krzysztof
Published: April 2019

The migration of physicians from low-resource to high-resource settings is a prevalent global phenomenon that is insufficiently understood. Most low-income countries are severely understaffed with physicians, and the emigration of the already limited number of physicians to other countries can significantly reduce access to healthcare in the source country. Despite a growing interest in global capacity building in these countries by academic and non-governmental organizations in high-income countries, efforts to stem physician migration have been mostly unsuccessful. The authors reviewed the current literature for the motivational factors leading to physician migration in the context of Maslow’s hierarchy of human needs. Our study found that financial safety needs were major drivers of physician emigration. However, factors related to self-actualization such as the desire for professional development through training opportunities and research, were also major contributors. These findings highlight the multifactorial nature of physician motivations to emigrate from low-resource countries. Maslow’s Theory of Motivation may provide a useful framework for future studies evaluating the concerns of physicians in low-income countries and as a guide to incentivize retention.
LOXL2—A New Target in Antifibrogenic Therapy?
Authors: Puente Angela , Fortea Jose Ignacio , Cabezas Joaquin , Arias Loste Maria Teresa , Iruzubieta Paula , Llerena Susana , Huelin Patricia , Fábrega Emilio , Crespo Javier
Published: April 2019

The concept of liver fibrosis and cirrhosis being static and therefore irreversible is outdated. Indeed, both human and animal studies have shown that fibrogenesis is a dynamic and potentially reversible process that can be modulated either by stopping its progression and/or by promoting its resolution. Therefore, the study of the molecular mechanisms involved in the pathogenesis of liver fibrosis is critical for the development of future antifibrotic therapies. The fibrogenesis process, common to all forms of liver injury, is characterized by the increased deposition of extracellular matrix components (EMCs), including collagen, proteoglycans, and glycoproteins (laminin and fibronectin 2). These changes in the composition of the extracellular matrix components alter their interaction with cell adhesion molecules, influencing the modulation of cell functions (growth, migration, and gene expression). Hepatic stellate cells and Kupffer cells (liver macrophages) are the key fibrogenic effectors. The antifibrogenic mechanism starts with the activation of Ly6Chigh macrophages, which can differentiate into macrophages with antifibrogenic action. The research of biochemical changes affecting fibrosis irreversibility has identified lysyl oxidase-like 2 (LOXL2), an enzyme that promotes the network of collagen fibers of the extracellular matrix. LOXL2 inhibition can decrease cell numbers, proliferation, colony formations, and cell growth, and it can induce cell cycle arrest and increase apoptosis. The development of a new humanized IgG4 monoclonal antibody against LOXL2 could open the window of a new antifibrogenic treatment. The current therapeutic target in patients with liver cirrhosis should focus (after the eradication of the causal agent) on the development of new antifibrogenic drugs. The development of these drugs must meet three premises: Patient safety, in non-cirrhotic phases, down-staging or at least stabilization and slowing the progression to cirrhosis must be achieved; whereas in the cirrhotic stage, the objective should be to reduce fibrosis and portal pressure.
Cellular Cullin RING Ubiquitin Ligases: Druggable Host Dependency Factors of Cytomegaloviruses
Authors: Becker Tanja , Le-Trilling Vu Thuy Khanh , Trilling Mirko
Published: April 2019

Human cytomegalovirus (HCMV) is a ubiquitous betaherpesvirus that frequently causes morbidity and mortality in individuals with insufficient immunity, such as transplant recipients, AIDS patients, and congenitally infected newborns. Several antiviral drugs are approved to treat HCMV infections. However, resistant HCMV mutants can arise in patients receiving long-term therapy. Additionally, side effects and the risk to cause birth defects limit the use of currently approved antivirals against HCMV. Therefore, the identification of new drug targets is of clinical relevance. Recent work identified DNA-damage binding protein 1 (DDB1) and the family of the cellular cullin (Cul) RING ubiquitin (Ub) ligases (CRLs) as host-derived factors that are relevant for the replication of human and mouse cytomegaloviruses. The first-in-class CRL inhibitory compound Pevonedistat (also called MLN4924) is currently under investigation as an anti-tumor drug in several clinical trials. Cytomegaloviruses exploit CRLs to regulate the abundance of viral proteins, and to induce the proteasomal degradation of host restriction factors involved in innate and intrinsic immunity. Accordingly, pharmacological blockade of CRL activity diminishes viral replication in cell culture. In this review, we summarize the current knowledge concerning the relevance of DDB1 and CRLs during cytomegalovirus replication and discuss chances and drawbacks of CRL inhibitory drugs as potential antiviral treatment against HCMV.
Location Privacy Protection Systems in Presence of Service Quality and Energy Constraints
Authors: Tefera Mulugeta Kassaw , Yang Xiaolong
Published: April 2019

The wide-ranging application of location-based services (LBSs) through the use of mobile devices and wireless networks has brought about many critical privacy challenges. To preserve the location privacy of users, most existing location privacy-preserving mechanisms (LPPMs) modify their real locations associated with different pseudonyms, which come at a cost either in terms of resource consumption or quality of service, or both. However, we observed that the effect of resource consumption has not been discussed in existing studies. In this paper, we present the user-centric LPPMs against location inference attacks under the consideration of both service quality and energy constraints. Moreover, we modeled the precision-based and dummy-based mechanisms in the context of an existing LPPM framework, and also extended the linear program solutions applicable to them. This study allowed us to specify the LPPMs that decreased the precision of exposed locations or generated dummy locations of the users. Based on this, we evaluated the privacy protection effects of optimal location obfuscation function against an adversary’s inference attack function using real mobility datasets. The results indicate that dummy-based mechanisms provide better achievable location privacy under a given combination of service quality and energy constraints, and once a certain level of privacy is reached, both the precision-based and dummy-based mechanisms only perturb the exposed locations. The evaluation results also contribute to a better understanding for the LPPM design strategies and evaluation mechanism as far as the system resource utilization and service quality requirements are concerned.
Antimicrobial Effects of Chemically Functionalized and/or Photo-Heated Nanoparticles
Authors: Pezzi Luigia , Pane Alfredo , Annesi Ferdinanda , Losso Maria Adele , Guglielmelli Alexa , Umeton Cesare , De Sio Luciano
Published: April 2019

Antibiotic resistance refers to when microorganisms survive and grow in the presence of specific antibiotics, a phenomenon mainly related to the indiscriminate widespread use and abuse of antibiotics. In this framework, thanks to the design and fabrication of original functional nanomaterials, nanotechnology offers a powerful weapon against several diseases such as cancer and pathogenic illness. Smart nanomaterials, such as metallic nanoparticles and semiconductor nanocrystals, enable the realization of novel drug-free medical therapies for fighting against antibiotic-resistant bacteria. In the light of the latest developments, we highlight the outstanding capabilities of several nanotechnology-inspired approaches to kill antibiotic-resistant bacteria. Chemically functionalized silver and titanium dioxide nanoparticles have been employed for their intrinsic toxicity, which enables them to exhibit an antimicrobial activity while, in a different approach, photo-thermal properties of metallic nanoparticles have been theoretically studied and experimentally tested against several temperature sensitive (mesophilic) bacteria. We also show that it is possible to combine a highly localized targeting with a plasmonic-based heating therapy by properly functionalizing nanoparticle surfaces with covalently linked antibodies. As a perspective, the utilization of properly engineered and chemically functionalized nanomaterials opens a new roads for realizing antibiotic free treatments against pathogens and related diseases.
Characterization of Geometrical Changes of Spherical Advanced Pore Morphology (APM) Foam Elements during Compressive Deformation
Authors: Borovinšek Matej , Vesenjak Matej , Higa Yoshikazu , Shimojima Ken , Ren Zoran
Published: April 2019

The mechanical properties of Advanced Pore Morphology (APM) foam elements depend strongly upon their internal porous and external structural geometry. This paper reports on a detailed investigation of external (e.g. shape and size) and internal (e.g. distribution, size, number of pores) geometry and porosity changes of APM foam elements, during compressive loading by means of the ex-situ micro-Computed Tomography, and advanced digital image analysis and recognition. The results show that the porosity of APM foam elements decreases by only 25% at the engineering strain of 70% due to an increase of the number of pores at high stages of compressive deformation. The APM foam elements also exhibit a positive macroscopic Poisson’s ratio of υ = 0.2, which is uncharacteristic for cellular structures.
Effect of Cooling Methods on the Strength of Silico-ferrite of Calcium and Aluminum of Iron Ore Sinter during the Cooling Process
Authors: Zhang Xu , Bai Hao , Lu Xin , He Tian , Zhang Jian , Yuan Huanmei , Zhang Zefei
Published: April 2019

In the iron making process, a high mechanical strength is favorable for iron ore sinters in the blast furnace, and the bonding phase is regarded as one of the key components that determines the quality of the iron ore sinter, in which the silico-ferrite of calcium and aluminum (SFCA) is one of the typical phases. In this study, synthesized samples with different SFCA mass fractions were prepared to study the effect of different cooling methods on the strengths of the SFCA samples. The results showed that the strength of a sample could be improved by increasing the SFCA content during a temperature change. Further, the test results for the compressive strength suggested that the SFCA had a positive effect on the strength of the iron ore sinter during cooling, with slow cooling being significantly effective at preventing the generation of thermal stress. Moreover, the Biot number was introduced to normalize all of the cooling methods. The results showed that higher mechanical strengths for iron ore sinters will be obtained with higher SFCA content and lower Biot numbers, which will guide the evaluation of mechanical strength of iron ore sinter after the cooling process in industry.
A Mechanistic Model for the Extraction of Phenolics from Grapes During Red Wine Fermentation
Authors: Miller Konrad V. , Noguera Roberto , Beaver Jordan , Medina-Plaza Cristina , Oberholster Anita , Block David E.
Published: April 2019

Phenolic extraction is a critical part of red wine making. Though empirical models of phenolic extraction kinetics exist, the current level of mechanistic understanding does not allow for accurate predictions. In this work, we propose a mechanistic model for the extraction of phenolics from grape skins and seeds as a function of temperature and ethanol. This model examines the release of phenolics, the adsorption of phenolics onto grape material, and the disappearance of anthocyanins from solution. Additionally, we performed epifluorescence microscopy to explore our finding that seed tannins’ release rate appears independent of concentration, and found that the grape seed appears to ablate over fermentation. We also determined the activation energy of anthocyanin disappearance, in good agreement with similar systems. The proposed model results in an excellent fit, and increases the understanding of phenolic extraction and the ability to predict and optimize product outcome in red wine making.
Anti-Herpetic, Anti-Dengue and Antineoplastic Activities of Simple and Heterocycle-Fused Derivatives of Terpenyl-1,4-Naphthoquinone and 1,4-Anthraquinone
Authors: Roa-Linares Vicky C. , Miranda-Brand Yaneth , Tangarife-Castaño Verónica , Ochoa Rodrigo , García Pablo A. , Castro Mª Ángeles , Betancur-Galvis Liliana , San Feliciano Arturo
Published: April 2019

Quinones are secondary metabolites of higher plants associated with many biological activities, including antiviral effects and cytotoxicity. In this study, the anti-herpetic and anti-dengue evaluation of 27 terpenyl-1,4-naphthoquinone (NQ), 1,4-anthraquinone (AQ) and heterocycle-fused quinone (HetQ) derivatives was done in vitro against Human Herpesvirus (HHV) type 1 and 2, and Dengue virus serotype 2 (DENV-2). The cytotoxicity on HeLa and Jurkat tumor cell lines was also tested. Using plaque forming unit assays, cell viability assays and molecular docking, we found that NQ 4 was the best antiviral compound, while AQ 11 was the most active and selective molecule on the tested tumor cells. NQ 4 showed a fair antiviral activity against Herpesviruses (EC50: <0.4 µg/mL, <1.28 µM) and DENV-2 (1.6 µg/mL, 5.1 µM) on pre-infective stages. Additionally, NQ 4 disrupted the viral attachment of HHV-1 to Vero cells (EC50: 0.12 µg/mL, 0.38 µM) with a very high selectivity index (SI = 1728). The in silico analysis predicted that this quinone could bind to the prefusion form of the E glycoprotein of DENV-2. These findings demonstrate that NQ 4 is a potent and highly selective antiviral compound, while suggesting its ability to prevent Herpes and Dengue infections. Additionally, AQ 11 can be considered of interest as a leader for the design of new anticancer agents.
Investigating Stability and Tautomerization of Gossypol—A Spectroscopy Study
Authors: Wang Lulu , Liu Yanxia , Zhang Yagang , Yasin Akram , Zhang Letao
Published: April 2019

The stability of gossypol was investigated by the spectroscopic method. Gossypol was dissolved in three different solvents (CHCl3, DMSO, and CH3OH) under different storage conditions (dark and with nitrogen protection, natural light and with nitrogen protection, ambient air conditions) for different time intervals (0 days, 3 days, 5 days, 7 days, 15 days, 30 days, and 45 days) at room temperature. Then, the stability of gossypol was investigated by 1H NMR, UV-vis, and HPLC-QTOF-MS spectrometry. Results showed that gossypol existed in aldehyde–aldehyde form in chloroform within five days. Then, both aldehyde–aldehyde and lactol–lactol tautomeric forms existed and maintained a stable solution for 45 days. Gossypol dissolved in methanol mainly existed in aldehyde–aldehyde form. Only a tiny amount of lactol–lactol was found in freshly prepared methanol solution. Gossypol was found to only exist in lactol–lactol form between 30–45 days. Gossypol existed in aldehyde–aldehyde, lactol–lactol, and ketol–ketol forms in dimethyl sulfoxide, and there was a competitive relationship between aldehyde–aldehyde and lactol–lactol form during the 45 days. Among all the solvents and conditions studied, gossypol was found to be highly stable in chloroform. Under the tested conditions, the natural light and atmospheric oxygen had little effect on its stability. Although the spectroscopy data seemed to be changed over time in the three different solvents, it was actually due to the tautomeric transformation rather than molecular decomposition.
Alternate Ultrasound/Microwave Digestion for Deep Eutectic Hydro-distillation Extraction of Essential Oil and Polysaccharide from Schisandra chinensis (Turcz.) Baill
Authors: Li Jun-Han , Li Wei , Luo Sha , Ma Chun-Hui , Liu Shou-Xin
Published: April 2019

An alternating synergetic ultrasound/microwave method was applied to the simultaneous extraction of essential oils and polysaccharides with deep eutectic solvent (DES) from Schisandra chinensis. Under the optimal conditions, extract in the selected choline chloride-ethylene glycol 1:3 solvent yielded 12.2 mL/kg and 8.56 g/100g of essential oils and polysaccharides, respectively. The free radical scavenging and immunological activities of the polysaccharides and the antioxidant activity of the essential oils have also been investigated. The lymphocyte proliferation capacity was substantially improved by adding concanavalin A or lipopolysaccharides to polysaccharides (0.20 mg/mL). The IC50 values of the essential oils for scavenging DPPH obtained by hydro-distillation and DES ultrasound/microwave-assisted hydro-distillation (DES UMHD) were 52.34 µg/mL and 29.82 µg/mL, respectively. The essential oil obtained by DES UMHD had the highest reducing power (856.05 (TE)/g) at 150 g/mL and had the strongest inhibitory capacity (SC% = 18.12%). S. chinensis has the potential to be developed as a natural antioxidant.
Evaluation of Antibacterial Activity of Zinc-Doped Hydroxyapatite Colloids and Dispersion Stability Using Ultrasounds
Authors: Predoi Daniela , Iconaru Simona Liliana , Predoi Mihai Valentin , Motelica-Heino Mikael , Guegan Regis , Buton Nicolas
Published: April 2019

This study proves that the new developed zinc-doped hydroxyapatite (ZnHAp) colloids by an adapted sol-gel method can be widely used in the pharmaceutical, medical, and environmental industries. ZnHAp nanoparticles were stabilized in an aqueous solution, and their colloidal dispersions have been characterized by different techniques. Scanning Electron Microscopy (SEM) was used to get information on the morphology and composition of the investigated samples. Energy-dispersive X-ray spectroscopy (EDX) analysis confirmed the elemental compositions of ZnHAp colloidal dispersions. The homogeneous and uniform distribution of constituent elements (zinc, calcium, phosphorus, oxygen) was highlighted by the obtained elemental mapping results. The X-ray diffraction (XRD) results of the obtained samples showed a single phase corresponding to the hexagonal hydroxyapatite. The characteristic bands of the hydroxyapatite structure were also evidenced by Fourier-transform infrared spectroscopy (FTIR) analysis. For a stability assessment of the colloidal system, ζ-potential for the ZnHAp dispersions was estimated. Dynamic light scattering (DLS) was used to determine particles dispersion and hydrodynamic diameter (DHYD). The goal of this study was to provide for the first time information on the stability of ZnHAp particles in solutions evaluated by non–destructive ultrasound-based technique. In this work, the influence of the ZnHAp colloidal solutions stability on the development of bacteria, such as Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus), was also established for the first time. The antimicrobial activity of ZnHAp solutions was strongly influenced by both the stability of the solutions and the amount of Zn.
A Randomized Controlled Pilot Study to Assess Effects of a Daily Pistachio (Pistacia Vera) Afternoon Snack on Next-Meal Energy Intake, Satiety, and Anthropometry in French Women
Authors: Carughi Arianna , Bellisle France , Dougkas Anestis , Giboreau Agnès , Feeney Mary Jo , Higgs Jennette
Published: April 2019

Including nuts in the diet improves appetite control and does not lead to weight gain. However, for pistachios, evidence from randomized intervention studies is limited and there are no data on the effect of pistachios on satiety. The objective of this study was to assess the effect of daily consumption of pistachios as an afternoon snack on satiety, self-reported energy, self-reported nutrient intake, body weight, and body composition. This randomized controlled pilot study included two parallel groups of 30 healthy French women, in a free-living setting. For four weeks, groups were instructed to consume either 56 g (1318 kJ) of pistachios or 56 g of isoenergetic/equiprotein savory biscuits as an afternoon snack. Evening energy intake, changes in anthropometric measures, and daily intake of energy and selected nutrients were assessed. Visual analogue scales (VAS) were used to rate hunger, fullness, desire to eat, and prospective consumption. Satiety effects were not different between groups, as assessed by evening energy intake or VAS scores. Consuming pistachios or biscuits had no impact on body weight. Thiamin, vitamin B6, copper, and potassium intakes were significantly higher in the pistachio group. Consuming pistachios or biscuits as an afternoon snack resulted in similar post-snack food intake and subjective feelings of satiety. A daily pistachio snack for a month did not affect body weight or composition but it did improve micronutrient intake.
Nutraceuticals for the Treatment of Diabetic Retinopathy
Authors: Rossino Maria Grazia , Casini Giovanni
Published: April 2019

Diabetic retinopathy (DR) is one of the most common complications of diabetes mellitus and is characterized by degeneration of retinal neurons and neoangiogenesis, causing a severe threat to vision. Nowadays, the principal treatment options for DR are laser photocoagulation, vitreoretinal surgery, or intravitreal injection of drugs targeting vascular endothelial growth factor. However, these treatments only act at advanced stages of DR, have short term efficacy, and cause side effects. Treatment with nutraceuticals (foods providing medical or health benefits) at early stages of DR may represent a reasonable alternative to act upstream of the disease, preventing its progression. In particular, in vitro and in vivo studies have revealed that a variety of nutraceuticals have significant antioxidant and anti-inflammatory properties that may inhibit the early diabetes-driven molecular mechanisms that induce DR, reducing both the neural and vascular damage typical of DR. Although most studies are limited to animal models and there is the problem of low bioavailability for many nutraceuticals, the use of these compounds may represent a natural alternative method to standard DR treatments.
Investigating the Phospholipid Effect on the Bioaccessibility of Rosmarinic Acid-Phospholipid Complex through a Dynamic Gastrointestinal in Vitro Model
Authors: Huang Jiahao , Chen Peter X. , Rogers Michael A. , Wettig Shawn D.
Published: April 2019

Phyto-phospholipid complexes have been developed as a common way of improving the oral bioavailability of poorly absorbable phyto-pharmaceuticals; however, the complexation with phospholipids can induce positive or negative effects on the bioaccessibility of such plant-derived active ingredients in different parts of the gastrointestinal tract (GIT). The purpose of this study was to investigate the effects of phospholipid complexation on the bioaccessibility of a rosmarinic acid-phospholipid complex (RA-PLC) using the TNO dynamic intestinal model-1 (TIM-1). Preparation of RA-PLC was confirmed using X-ray diffraction, Fourier-transform infrared spectroscopy, partition coefficient measurement, and Caco-2 monolayer permeation test. Bioaccessibility parameters in different GIT compartments were investigated. Complexation by phospholipids reduced the bioaccessibility of RA in jejunum compartment, while maintaining the ileum bioaccessibility. The overall bioaccessibility of RA-PLC was lower than the unformulated drug, suggesting that the improved oral absorption from a previous animal study could be considered as a net result of decreased bioaccessibility overwhelmed by enhanced intestinal permeability. This study provides insights into the effects of phospholipid on the bioaccessibility of hydrophilic compounds, and analyzes them based on the relationship between bioaccessibility, membrane permeability, and bioavailability. Additionally, TIM-1 shows promise in the evaluation of dosage forms containing materials with complicated effects on bioaccessibility.
Achieving High Excipient Efficiency with Elastic Thermoplastic Polyurethane by Ultrasound Assisted Direct Compression
Authors: Galdón Eduardo , Casas Marta , Caraballo Isidoro
Published: April 2019

Ultrasound assisted compression (USAC) is a manufacturing technique which applies thermal and mechanical energy to the powder bed, producing tablets with improved characteristics compared to the direct compression process. This technology is ideal for thermoplastic materials, as polyurethanes, whose particles usually undergo a sintering process. Thermoplastic polyurethanes are widely used in sustained drug release systems but rarely seen in tablets due to their elastic properties. The aim of this work is to investigate the ability of USAC to manufacture sustained release matrix tablets based on elastic thermoplastic polyurethanes (TPU), overcoming the limitations of direct compression. The technological and biopharmaceutical characteristics of the TPU matrices have been evaluated, with special focus on the porous structure due to the implications on drug release. For the first time, USAC has been successfully employed for manufacturing elastic thermoplastic polyurethanes-based matrices. TPU tablets show an inert character with a sustained drug release governed by a diffusional mechanism. Initial porosity of matrices was similar in all batches studied, with no influence of drug particle size, and a fractal nature of the pore network has been observed. SEM microphotographs show the continuum medium created by the sintering of the polymer, responsible for the high excipient efficiency.
A New Strategy for the Synthesis of Hydroxyl Terminated Polystyrene-b-Polybutadiene-b-Polystyrene Triblock Copolymer with High Cis-1, 4 Content
Authors: Min Xin , Fan Xiaodong
Published: April 2019

This work reports the preparation of a hydroxyl terminated polystyrene-b-polybutadiene-b-polystyrene triblock copolymer (SBS) with high cis-1, 4 content via a novel nickel catalyst, [η3-Ni(CH2CHCHCH2OOCH3)][BPhF4]. FT-IR, 1H-NMR, and 13C NMR indicated that the polybutadiene segment of the copolymer contains greater than 90% cis-1, 4 structure, indicating achievement of the objective. Toward the functionalization goal, a hydroxyl group was successfully introduced at the end of the triblock copolymer (HO–SBS–OH). The results of gel permeation chromatography (GPC) revealed that the polymer is indeed a triblock copolymer, with no traces of homopolymer. Differential scanning calorimetry (DSC) showed that HO–SBS–OH synthesized using the novel catalyst had a lower glass transition temperature (Tg) than HO–SBS–OH synthesized with an alkyl lithium catalyst. Therefore, the polymer synthesized via the novel catalyst contains high cis-1,4 content and displays excellent low-temperature mechanical properties.
Synthesis and Photoinduced Anisotropy of Polymers Containing Nunchaku-Like Unit with an Azobenzene and a Mesogen
Authors: Wang Lingling , Zhang Yingchuan , Zhan Chenhao , You Yong , Zhang Hongxing , Ma Jinyi , Xiong Zhiyuan , Liu Xiaobo , Wei Renbo
Published: April 2019

A series of polymers containing nunchaku-like unit with an azo chromophore and a mesogen group was successfully prepared and photoinduced anisotropy of the obtained polymers was minutely investigated. Firstly, monomers containing nunchaku-like unit with an azo chromophore and a mesogen group linked by flexible group were synthesized. The structure of the monomers was confirmed via NMR COSY spectra. Subsequently, the obtained monomers were polymerized into corresponding polymers through RAFT polymerization. The prepared polymer samples were characterized through NMR, FTIR, gel permeation chromatography (GPC), and UV-vis testing while the thermal properties of the samples were investigated through differential scanning calorimeter (DSC) and thermogravimetric analysis (TGA) measurements. The photoinduced isomerization of the polymers, which was researched in situ via measuring UV-vis spectra of the polymer solutions and spin-coated films under irradiation with 450 nm light or putting in darkness, demonstrated the rapid trans-cis-trans isomerization of the polymers. When irradiated with a linearly polarized light, significant photoinduced birefringence and dichroism were observed, suggesting photoinduced isomerization of azobenzene can drive orientation of mesogen in the system. This study blazes a way to design the optical materials with light-controllable birefringence and dichroism.
The Glass-Transition Temperature of Supported PMMA Thin Films with Hydrogen Bond/Plasmonic Interface
Authors: Chen Jiayao , Li Jing , Xu Lirong , Hong Wei , Yang Yuzhao , Chen Xudong
Published: April 2019

The interfacial effect is one of the significant factors in the glass-transition temperature (Tg) of the polymeric thin film system, competing against the free surface effect. Herein, the Tgs of poly (methyl methacrylate) (PMMA) films with different thicknesses and substrates are studied by fluorescence measurements, focusing on the influence of interfacial effects on the Tgs. The strong interaction between PMMA and quartz substrate leads to increased Tgs with the decreased thickness of the film. The plasmonic silver substrate causes enhanced fluorescence intensity near the interface, resulting in the delayed reduction of the Tgs with the increasing film thickness. Moreover, as a proof of the interface-dependent Tgs, hydrogen bonds of PMMA/quartz and molecules orientation of PMMA/silver are explored by the Raman spectroscopy, and the interfacial interaction energy is calculated by the molecular dynamics simulation. In this study, we probe the inter-relationship between the interfacial interactions arising from the different substrates and the Tg behavior of polymer thin films.