bluuebunny/crossref_metadata_2025 huggingface dataset:
Deep Theory of Functional Connections: A New Method for Estimating the Solutions of Partial Differential Equations
Authors: Leake Carl , Mortari Daniele
Published: March 2020

This article presents a new methodology called Deep Theory of Functional Connections (TFC) that estimates the solutions of partial differential equations (PDEs) by combining neural networks with the TFC. The TFC is used to transform PDEs into unconstrained optimization problems by analytically embedding the PDE’s constraints into a “constrained expression” containing a free function. In this research, the free function is chosen to be a neural network, which is used to solve the now unconstrained optimization problem. This optimization problem consists of minimizing a loss function that is chosen to be the square of the residuals of the PDE. The neural network is trained in an unsupervised manner to minimize this loss function. This methodology has two major differences when compared with popular methods used to estimate the solutions of PDEs. First, this methodology does not need to discretize the domain into a grid, rather, this methodology can randomly sample points from the domain during the training phase. Second, after training, this methodology produces an accurate analytical approximation of the solution throughout the entire training domain. Because the methodology produces an analytical solution, it is straightforward to obtain the solution at any point within the domain and to perform further manipulation if needed, such as differentiation. In contrast, other popular methods require extra numerical techniques if the estimated solution is desired at points that do not lie on the discretized grid, or if further manipulation to the estimated solution must be performed.
Dynamics Analysis and Chaotic Control of a Fractional-Order Three-Species Food-Chain System
Authors: Wang Lina , Chang Hui , Li Yuxia
Published: March 2020

Based on Hastings and Powell’s research, this paper extends a three-species food-chain system to fractional-order form, whose dynamics are analyzed and explored. The necessary conditions for generating chaos are confirmed by the stability theory of fractional-order systems, chaos is characterized by its phase diagrams, and bifurcation diagrams prove that the dynamic behaviors of the fractional-order food-chain system are affected by the order. Next, the chaotic control of the fractional-order system is realized by the feedback control method with a good effect in a relative short period. The stability margin of the controlled system is revealed by the theory and numerical analysis. Finally, the results of theory analysis are verified by numerical simulations.
The Homomorphism Theorems of M-Hazy Rings and Their Induced Fuzzifying Convexities
Authors: Mehmood Faisal , Shi Fu-Gui , Hayat Khizar , Yang Xiao-Peng
Published: March 2020

In traditional ring theory, homomorphisms play a vital role in studying the relation between two algebraic structures. Homomorphism is essential for group theory and ring theory, just as continuous functions are important for topology and rigid movements in geometry. In this article, we propose fundamental theorems of homomorphisms of M-hazy rings. We also discuss the relation between M-hazy rings and M-hazy ideals. Some important results of M-hazy ring homomorphisms are studied. In recent years, convexity theory has become a helpful mathematical tool for studying extremum problems. Finally, M-fuzzifying convex spaces are induced by M-hazy rings.
Influence of Friction Stir Processing on Mechanical Behavior of 2507 SDSS
Authors: Abubaker Hafiz M. , Merah Necar , Al-Badour Fadi A. , Albinmousa Jafar , Sorour Ahmad A.
Published: March 2020

Duplex stainless steel (DSS) is used for desalination equipment, pressure vessels, marine applications, offshore applications, and in oil/gas plants where a highly corrosive environment is present. Super duplex stainless steel (SDSS) 2507 has excellent mechanical properties, such as high strength, high toughness, high fatigue life, and high corrosion resistance. Friction stir processing (FSP) is used to refine the grain structure of the processed region such that properties like strength, hardness, fracture toughness, fatigue life, and corrosion resistance are enhanced. In this paper, an optimized friction stir process of 2507 SDSS is carried out to refine the microstructure of the material in order to improve its mechanical properties. Microstructure analysis revealed that grains were refined from a size of around 160 µm in the base material to 2–30 µm in the processed zone. This grain size reduction resulted in improved strength, hardness, and fracture toughness of the material by up to 14%, 11%, and 12%, respectively. However, FSP has reduced the fracture strain by about 30%.
Solderability, Microstructure, and Thermal Characteristics of Sn-0.7Cu Alloy Processed by High-Energy Ball Milling
Authors: Sharma Ashutosh , Oh Min Chul , Chae Myoung Jin , Seo Hyungtak , Ahn Byungmin
Published: March 2020

In this work, we have investigated the role of high-energy ball milling (HEBM) on the evolution of microstructure, thermal, and wetting properties of an Sn-0.7Cu alloy. We ball-milled the constituent Sn and Cu powders in eutectic composition for 45 h. The microstructural studies were carried out using optical and scanning electron microscopy. The melting behavior of the powder was examined using differential scanning calorimetry (DSC). We observed a considerable depression in the melting point of the Sn-0.7Cu alloy (≈7 °C) as compared to standard cast Sn-0.7Cu alloys. The resultant crystallite size and lattice strain of the ball-milled Sn-0.7Cu alloy were 76 nm and 1.87%, respectively. The solderability of the Sn-0.7Cu alloy was also improved with the milling time, due to the basic processes occurring during the HEBM.
Antifungal Drugs
Authors: Houšť Jiří , Spížek Jaroslav , Havlíček Vladimír
Published: March 2020

We reviewed the licensed antifungal drugs and summarized their mechanisms of action, pharmacological profiles, and susceptibility to specific fungi. Approved antimycotics inhibit 1,3-β-d-glucan synthase, lanosterol 14-α-demethylase, protein, and deoxyribonucleic acid biosynthesis, or sequestrate ergosterol. Their most severe side effects are hepatotoxicity, nephrotoxicity, and myelotoxicity. Whereas triazoles exhibit the most significant drug–drug interactions, echinocandins exhibit almost none. The antifungal resistance may be developed across most pathogens and includes drug target overexpression, efflux pump activation, and amino acid substitution. The experimental antifungal drugs in clinical trials are also reviewed. Siderophores in the Trojan horse approach or the application of siderophore biosynthesis enzyme inhibitors represent the most promising emerging antifungal therapies.
The Interrelations between Biological and Targeted Synthetic Agents Used in Inflammatory Joint Diseases, and Obesity or Body Composition
Authors: Toussirot Eric
Published: March 2020

Obesity is a comorbidity that plays a role in the development and severity of inflammatory joint diseases, including rheumatoid arthritis, psoriatic arthritis and axial spondyloarthritis. The relationships between obesity and adipose tissue and the treatments given for inflammatory joint diseases are bidirectional. In fact, biological agents (bDMARDs) and targeted synthetic agents (tsDMARDs) may influence body weight and body composition of treated patients, while obesity in turn may influence clinical response to these agents. Obesity is a prevalent comorbidity mainly affecting patients with rheumatoid arthritis (RA) and psoriatic arthritis (PsA) with specific phenotypes. Tumour necrosis factor alpha (TNFα) inhibitors have been associated with changes in body composition by improving lean mass, but also by significantly increasing fat mass, which localized toward the abdominal/visceral region. The IL-6 inhibitor tocilizumab is associated with an increase in lean mass without change in fat mass. The clinical response to TNFα inhibitors is attenuated by obesity, an effect that is less pronounced with IL-6 inhibitors and the B-cell depletion agent rituximab. Conversely, body weight has no influence on the response to the costimulation inhibitor abatacept. These effects may be of help to the physician in personalized medicine, and may guide the therapeutic choice in obese/overweight patients.
An Implanted Magnetic Microfluidic Pump for In Vivo Bone Remodeling Applications
Authors: Chen Ziyu , Noh Sunggi , Prisby Rhonda D. , Lee Jeong-Bong
Published: March 2020

Modulations of fluid flow inside the bone intramedullary cavity has been found to stimulate bone cellular activities and augment bone growth. However, study on the efficacy of the fluid modulation has been limited to external syringe pumps connected to the bone intramedullary cavity through the skin tubing. We report an implantable magnetic microfluidic pump which is suitable for in vivo studies in rodents. A compact microfluidic pump (22 mm diameter, 5 mm in thickness) with NdFeB magnets was fabricated in polydimethylsiloxane (PDMS) using a set of stainless-steel molds. An external actuator with a larger magnet was used to wirelessly actuate the magnetic microfluidic pump. The characterization of the static pressure of the microfluidic pump as a function of size of magnets was assessed. The dynamic pressure of the pump was also characterized to estimate the output of the pump. The magnetic microfluidic pump was implanted into the back of a Fischer-344 rat and connected to the intramedullary cavity of the femur using a tube. On-demand wireless magnetic operation using an actuator outside of the body was found to induce pressure modulation of up to 38 mmHg inside the femoral intramedullary cavity of the rat.
Metal-Assisted Chemical Etching and Electroless Deposition for Fabrication of Hard X-ray Pd/Si Zone Plates
Authors: Akan Rabia , Frisk Thomas , Lundberg Fabian , Ohlin Hanna , Johansson Ulf , Li Kenan , Sakdinawat Anne , Vogt Ulrich
Published: March 2020

Zone plates are diffractive optics commonly used in X-ray microscopes. Here, we present a wet-chemical approach for fabricating high aspect ratio Pd/Si zone plate optics aimed at the hard X-ray regime. A Si zone plate mold is fabricated via metal-assisted chemical etching (MACE) and further metalized with Pd via electroless deposition (ELD). MACE results in vertical Si zones with high aspect ratios. The observed MACE rate with our zone plate design is 700 nm/min. The ELD metallization yields a Pd density of 10.7 g/cm 3 , a value slightly lower than the theoretical density of 12 g/cm 3 . Fabricated zone plates have a grid design, 1:1 line-to-space-ratio, 30 nm outermost zone width, and an aspect ratio of 30:1. At 9 keV X-ray energy, the zone plate device shows a first order diffraction efficiency of 1.9%, measured at the MAX IV NanoMAX beamline. With this work, the possibility is opened to fabricate X-ray zone plates with low-cost etching and metallization methods.
Potential Effects of Indole-3-Lactic Acid, a Metabolite of Human Bifidobacteria, on NGF-Induced Neurite Outgrowth in PC12 Cells
Authors: Wong Chyn Boon , Tanaka Azusa , Kuhara Tetsuya , Xiao Jin-zhong
Published: March 2020

Gut microbiota-derived tryptophan metabolites such as indole derivatives are an integral part of host metabolome that could mediate gut–brain communication and contribute to host homeostasis. We previously reported that infant-type Human-Residential Bifidobacteria (HRB) produced higher levels of indole-3-lactic acid (ILA), suggesting the former might play a specific role in microbiota–host crosstalk by producing ILA in human infants. Nonetheless, the biological meaning of bifidobacteria-derived ILA in infant health development remains obscure. Here, we sought to explore the potential role of ILA in neuronal differentiation. We examined the neurite outgrowth and acetylcholinesterase (AchE) activity of PC12 cells following exposure to ILA and NGF induction. We found that ILA substantially enhanced NGF-induced neurite outgrowth of PC12 cells in a dose-dependent manner, and had the most prominent effect at 100 nM. Significant increases in the expression of TrkA receptor, ERK1/2 and CREB were observed in ILA-treated PC12 cells, suggesting ILA potentiated NGF-induced neurite outgrowth through the Ras/ERK pathway. Additionally, ILA was found to act as the aryl hydrocarbon receptor (AhR) agonist and evoked NGF-induced neurite outgrowth in an AhR-mediated manner. These new findings provide clues into the potential involvement of ILA as the mediator in bifidobacterial host–microbiota crosstalk and neuronal developmental processes.
Mineralogy and Zn Chemical Speciation in a Soil-Plant System from a Metal-Extreme Environment: A Study on Helichrysum microphyllum subsp. tyrrhenicum (Campo Pisano Mine, SW Sardinia, Italy)
Authors: Boi Maria Enrica , Medas Daniela , Aquilanti Giuliana , Bacchetta Gianluigi , Birarda Giovanni , Cappai Giovanna , Carlomagno Ilaria , Casu Maria Antonietta , Gianoncelli Alessandra , Meneghini Carlo , Piredda Martina , Podda Francesca , Porceddu Marco , Rimondi Valentina , Vaccari Lisa , De Giudici Giovanni
Published: March 2020

Environmental contamination due to human activities is a worldwide problem that has led to the development of different remediation techniques, including biotechnological approaches such as phytoextraction and phytostabilization. These techniques take advantage of pioneer plants that naturally develop tolerance mechanisms to survive in extreme environments. A multi-technique and multi-disciplinary approach was applied for the investigation of Helichrysum microphyllum subsp. tyrrhenicum samples, bulk soil, and rhizospheres collected from a metal-extreme environment (Zn-Pb mine of Campo Pisano, SW Sardinia, Italy). Zinc, Pb, and Cd are the most abundant metals, with Zn attaining 3 w/w% in the rhizosphere solid materials, inducing oxidative stress in the roots as revealed by infrared microspectroscopy (IR). X-ray diffraction (XRD), scanning electron microscopy (SEM), and chemical analysis coupled with synchrotron radiation-based (SR) techniques demonstrate that quartz, dolomite, and weddellite biominerals precipitate in roots, stems, and leaves, likely as a response to environmental stress. In the rhizosphere, Zn chemical speciation is mainly related to the Zn ore minerals (smithsonite and hydrozincite) whereas, in plant tissues, Zn is primarily bound to organic compounds such as malate, cysteine, and histidine molecules that act as metal binders and, eventually, detoxification agents for the Zn excess. These findings suggest that H. microphyllum subsp. tyrrhenicum has developed its own adaptation strategy to survive in polluted substrates, making it a potential candidate for phytostabilization aimed at mitigating the dispersion of metals in the surrounding areas.
UPLC-MS/MS Identification and Quantification of Withanolides from Six Parts of the Medicinal Plant Datura Metel L.
Authors: Yang Shi Hui , Liu Yan , Wang Qi , Sun Yan Ping , Guan Wei , Liu Yuan , Yang Bing You , Kuang Hai Xue
Published: March 2020

Withanolides from six parts (flower, leaf, stem, root, seed, and peel) of Datura metel L. (D metel L.) obtained from ten production areas in China were identified and quantified by UPLC-MS/MS. A total of 85 withanolides were characterized for the first time using the UPLC-Q-TOF-MS/MS system. Additionally, a simultaneous, rapid and accurate measurement method was developed for the determination of 22 bioactive withanolides from ten production areas with the UPLC-Q-TRAP-MS/MS system. The results show the total withanolide content is highest in the leaves (155640.0 ng/g) and lowest in the roots (14839.8 ng/g). Compared with other production areas, the total content of plants from Dujiangyan was the highest at 82013.9 ng/g (value range of ten areas: 82013.9–42278.5 ng/g). The results also show significant differences in the distribution of withanolides in the different plant parts, as well as across different production areas. This is a breakthrough report providing a simultaneous qualitative and quantitative analysis of 22 withanolides in D. metel L. It could be the basis for the more rational use of various parts of D. metel L., and the expansion of medicinal resources. This work also lays a solid foundation for research on the quality control of D. metel L.
Synthesis of Monolayer Gold Nanorings Sandwich Film and Its Higher Surface-Enhanced Raman Scattering Intensity
Authors: Zhang Liqiu , Zhu Tiying , Yang Cheng , Jang Ho Young , Jang Hee-Jeong , Liu Lichun , Park Sungho
Published: March 2020

Most previous studies relating to surface-enhanced Raman spectroscopy (SERS) signal enhancement were focused on the interaction between the light and the substrate in the x-y axis. 3D SERS substrates reported in the most of previous papers could contribute partial SERS enhancement via z axis, but the increases of the surface area were the main target for those reports. However, the z axis is also useful in achieving improved SERS intensity. In this work, hot spots along the z axis were specifically created in a sandwich nanofilm. Sandwich nanofilms were prepared with self-assembly and Langmuir-Blodgett techniques, and comprised of monolayer Au nanorings sandwiched between bottom Ag mirror and top Ag cover films. Monolayer Au nanorings were formed by self-assembly at the interface of water and hexane, followed by Langmuir-Blodgett transfer to a substrate with sputtered Ag mirror film. Their hollow property allows the light transmitted through a cover film. The use of a Ag cover layer of tens nanometers in thickness was critical, which allowed light access to the middle Au nanorings and the bottom Ag mirror, resulting in more plasmonic resonance and coupling along perpendicular interfaces (z-axis). The as-designed sandwich nanofilms could achieve an overall ~8 times SERS signals amplification compared to only the Au nanorings layer, which was principally attributed to enhanced electromagnetic fields along the created z-axis. Theoretical simulations based on finite-difference time-domain (FDTD) method showed consistent results with the experimental ones. This study points out a new direction to enhance the SERS intensity by involving more hot spots in z-axis in a designer nanostructure for high-performance molecular recognition and detection.
Probiotics Dietary Supplementation for Modulating Endocrine and Fertility Microbiota Dysbiosis
Authors: López-Moreno Ana , Aguilera Margarita
Published: March 2020

Human microbiota seems to play a key role in endocrine and reproductive systems. Fortunately, microbiota reproductive dysbiosis start to be treated by probiotics using typical species from genus Lactobacillus. This work presents the compiled and analysed results from the most up-to-date information from clinical trials regarding microbiota, fertility, probiotics and oral route administration, reviewing open access scientific documents. These studies analyse the clinical impact of probiotics administered on several endocrine disorders’ manifestations in women: mastitis; vaginal dysbiosis; pregnancy complication disorders; and polycystic ovary syndrome. In all cases, the clinical modulation achieved by probiotics was evaluated positively through the improvement of specific disease outcomes with the exception of the pregnancy disorders studies, where the sample sizes results were statistically insufficient. High amounts of studies were discarded because no data were provided on specific probiotic strains, doses, impact on the individual autochthon microbiota, or data regarding specific hormonal values modifications and endocrine regulation effects. However, most of the selected studies with probiotics contained no protocolised administration. Therefore, we consider that intervention studies with probiotics might allocate the focus, not only in obtaining a final outcome, but in how to personalise the administration according to the disorder to be palliated.
Gender-Related Determinants of Adherence to the Mediterranean Diet in Adults with Ischemic Heart Disease
Authors: Raparelli Valeria , Romiti Giulio , Spugnardi Valeria , Borgi Marco , Cangemi Roberto , Basili Stefania , Proietti Marco ,   the EVA Collaborative Group
Published: March 2020

Background: The reasons behind low adherence to the Mediterranean diet (Med-diet) are still not entirely known. We aimed to evaluate the effect of biological (i.e., sex-related) and psycho-socio-cultural (i.e., gender-related) factors on Med-diet adherence. Methods: Baseline Med-diet adherence was measured using a self-administered questionnaire among adults with ischemic heart disease (IHD) from the EVA (Endocrine Vascular Disease Approach) study. A multivariable analysis was performed to estimate the effect of sex- and gender-related factors (i.e., identity, roles, relations, and institutionalized gender) on low adherence. Results: Among 366 participants (66 ± 11 years, 31% women), 81 (22%) adults with low adherence demonstrated higher rates of diabetes, no smoking habit, lower male BSRI (Bem Sex Role Inventory) (median (IQR) 4.8 (4.1 to 5.5) vs. 5.1 (4.5 to 5.6) and p = 0.048), and higher Perceived Stress Scale 10 items (PSS-10) (median (IQR) 19 (11 to 23) vs. 15 (11 to 20) and p = 0.07) scores than those with medium-high adherence. In the multivariable analysis, only active smoking (odds ratio, OR = 2.10, 95% confidence interval, CI 1.14 to 3.85 and p = 0.017), PPS-10 (OR = 1.04, 95% CI 1.00 to 1.08, and p = 0.038) and male BSRI scores (OR = 0.70, 95% CI 0.52 to 0.95, and p = 0.021) were independently associated with low adherence. Conclusions: Male personality traits and perceived stress (i.e., gender identity) were associated with low Med-diet adherence regardless of the sex, age, and comorbidities. Therefore, gender-sensitive interventions should be explored to improve adherence in IHD.
A Guide to Human Zinc Absorption: General Overview and Recent Advances of In Vitro Intestinal Models
Authors: Maares Maria , Haase Hajo
Published: March 2020

Zinc absorption in the small intestine is one of the main mechanisms regulating the systemic homeostasis of this essential trace element. This review summarizes the key aspects of human zinc homeostasis and distribution. In particular, current knowledge on human intestinal zinc absorption and the influence of diet-derived factors on bioaccessibility and bioavailability as well as intrinsic luminal and basolateral factors with an impact on zinc uptake are discussed. Their investigation is increasingly performed using in vitro cellular intestinal models, which are continually being refined and keep gaining importance for studying zinc uptake and transport via the human intestinal epithelium. The vast majority of these models is based on the human intestinal cell line Caco-2 in combination with other relevant components of the intestinal epithelium, such as mucin-secreting goblet cells and in vitro digestion models, and applying improved compositions of apical and basolateral media to mimic the in vivo situation as closely as possible. Particular emphasis is placed on summarizing previous applications as well as key results of these models, comparing their results to data obtained in humans, and discussing their advantages and limitations.
Evaluations of Quality by Design (QbD) Elements Impact for Developing Niosomes as a Promising Topical Drug Delivery Platform
Authors: Shah Parinbhai , Goodyear Benjamin , Haq Anika , Puri Vinam , Michniak-Kohn Bozena
Published: March 2020

Topical corticosteroids are used to treat a variety of skin conditions such as allergic reactions, eczema, and psoriasis. Niosomes are a novel surfactant-based delivery system that may be used to deliver desoximetasone via topical product application in order to mitigate common side effects associated with traditional oral delivery routes. The aim of this research was to identify the critical material attributes (CMAs) and critical process parameters (CPPs) that impact key characteristics of drug-loaded niosomes using a systematic quality by design (QbD) approach. An organic phase injection method was developed and used to manufacture the niosomes. The CMAs were identified to be drug amount, concentrations of surfactant and cholesterol, and types of lipids. The CPPs were phase volumes, temperature, mixing parameters, and addition rate based on previous research. The quality attributes measured were entrapment efficiency, particle size distribution, PDI, and zeta potential. These were used to determine the quality target product profile (QTPP) of niosomes. The experimental data indicate that the critical impacting variables for niosomes are: surfactant and cholesterol concentrations, mixing parameters, and organic-phase addition rate. Based on the experimental results of this study methanol:diethyl ether (75:25) as the organic system, drug:surfactant:cholesterol in 1:2:1 concentration, stearic acid as the charge-inducing material, 20 mL external phase and 10 mL internal phase volume, 65 °C external phase temperature, 60 min mixing time, 650 RPM mixing speed and 1 mL/ml addition rate is the ideal combination to achieve desirable desoximetasone niosomes with optimum entrapment efficiency and particle size for topical application.
Lyophilized Iron Oxide Nanoparticles Encapsulated in Amphotericin B: A Novel Targeted Nano Drug Delivery System for the Treatment of Systemic Fungal Infections
Authors: Balabathula Pavan , Whaley Sarah Garland , Janagam Dileep R. , Mittal Nivesh K. , Mandal Bivash , Thoma Laura A. , Rogers P. David , Wood George C.
Published: March 2020

We formulated and tested a targeted nanodrug delivery system to help treat life-threatening invasive fungal infections, such as cryptococcal meningitis. Various designs of iron oxide nanoparticles (IONP) (34–40 nm) coated with bovine serum albumin and coated and targeted with amphotericin B (AMB-IONP), were formulated by applying a layer-by-layer approach. The nanoparticles were monodispersed and spherical in shape, and the lead formulation was found to be in an optimum range for nanomedicine with size (≤36 nm), zeta potential (−20 mV), and poly dispersity index (≤0.2), and the drug loading was 13.6 ± 6.9 µg of AMB/mg of IONP. The drug release profile indicated a burst release of up to 3 h, followed by a sustained drug release of up to 72 h. The lead showed a time-dependent cellular uptake in C. albicans and C. glabrata clinical isolates, and exhibited an improved efficacy (16–25-fold) over a marketed conventional AMB-deoxycholate product in susceptibility testing. Intracellular trafficking of AMB-IONP by TEM and confocal laser scanning microscopy confirmed the successful delivery of the AMB payload at and/or inside the fungal cells leading to potential therapeutic advantages over the AMB-deoxycholate product. A short-term stability study at 5 °C and 25 °C for up to two months showed that the lyophilized form was stable.
Technology of Orodispersible Polymer Films with Micronized Loratadine—Influence of Different Drug Loadings on Film Properties
Authors: Centkowska Katarzyna , Ławrecka Elżbieta , Sznitowska Malgorzata
Published: March 2020

The production of orodispersible films (ODFs) with suspended insoluble drug substances is still a challenge, mainly due to the difficulty associated with achieving a proper homogeneity and mechanical properties of the films. Hypromellose (HPMC) and a mixture of polyvinyl alcohol (AP) and povidone (PVP) were compared in terms of their suitability for ODFs incorporating suspended micronized loratadine (LO) in a concentration range of 10%–40%. In a planetary mixer (Thinky), a uniform dispersion of LO in an aqueous viscous casting solution was obtained. The suspended LO particles caused dose-dependent changes in the viscosity of the casting mass and affected the mechanical quality of ODFs. Drug concentrations higher than 30% reduced the film flexibility and tear resistance, depending on the polymer type. LO films with a thickness of 100 µm disintegrated within 60-100 s, with no significant influence of the LO content in the range 10%–30%. HPMC films, regardless of the drug concentration, met the pharmacopoeial requirements regarding the uniformity of the drug content. AP/PVP films were too elastic, and the drug content uniformity was not achieved. The conclusion is that, using an HPMC matrix, it is possible to obtain a high load of a poorly water-soluble drug (30% of dry film mass corresponds to a dose of 5 mg per 1.5 cm2) in ODFs characterized by proper physical characteristics.
Assembling Surfactants-Mucoadhesive Polymer Nanomicelles (ASMP-Nano) for Ocular Delivery of Cyclosporine-A
Authors: Terreni Eleonora , Chetoni Patrizia , Tampucci Silvia , Burgalassi Susi , Al-kinani Ali , Alany Raid , Monti Daniela
Published: March 2020

The physiological protective mechanisms of the eye reduce the bioavailability of topically administered drugs above all for those with high molecular weight and /or lipophilic characteristics, such as Cyclosporine A (CyA). The combined strategy based on the association of nanomicelles and mucoadhesive polymer seems promising since a limited number of commercial products containing CyA have been recently approved. The scope of this investigation was the design of Assembling Surfactants-Mucoadhesive Polymer Nanomicelles (ASMP-Nano), based on a binary system of two surfactants in combination with hyaluronic acid, and their biopharmaceutical evaluation. The optimisation of the ASMP-Nano in term of the amount of surfactants, CyA-loading and size determined the selection of the clear and stable Nano1HAB-CyA formulation containing 0.105% w/w CyA loaded-nanomicelles with a size of 14.41 nm. The nanostructured system had a protective effect towards epithelial corneal cells with a cell viability of more than 80%. It interacted with cellular barriers favouring the uptake and the accumulation of CyA into the cells as evidenced by fluorescent probe distribution, by hindering CyA permeation through reconstituted corneal epithelial tissue. In pharmacokinetics study on rabbits, the nanomicellar carrier prolonged the CyA retention time in the precorneal area mainly in presence of hyaluronic acid (HA), a mucoadhesive polymer.
Dual Peptide-Modified Nanoparticles Improve Combination Chemotherapy of Etoposide and siPIK3CA Against Drug-Resistant Small Cell Lung Carcinoma
Authors: Huang Hsin-Lin , Lin Wen Jen
Published: March 2020

Small cell lung carcinoma (SCLC) is a highly aggressive form of malignancy with rapid recurrence and poor prognosis. The dual peptide-modified nanoparticles (NPs) for improving chemotherapy against drug-resistant small cell lung carcinoma cells has been developed. In this study, the SCLC targeting ligand, antagonist G peptide (AG), and cell-penetrating peptide, TAT, modified NPs were used to encapsulate both anticancer drugs etoposide (ETP) and PIK3CA small-interfering RNA (siPIK3CA). The ETP@NPs and siRNA@NPs had particle size 201.0 ± 1.9–206.5 ± 0.7 nm and 155.3 ± 12.4–169.1 ± 11.2 nm, respectively. The lyophilized ETP@NPs and siRNA@NPs maintained their particle size and zeta potential during 28-day storage without severe aggregation or dissociation. Either ETP@NPs or siRNA@NPs significantly reduced the IC50 of drugs by 2.5–5.5 folds and 2.4–3.9 folds, respectively, as compared to free ETP and siRNA/PEI nanocomplex in drug-resistant CD133(+) H69 cells. Herein, the IC50 of dual-peptide modified ETP@NPs and siRNA@NPs were prominently lower than single-peptide modified NPs. The synergistic effect (CI < 1) was further observed in co-treatment of ETP and siPIK3CA particularly delivered by dual-peptide modified NPs.
In Vitro Performance of an Investigational Vibrating-Membrane Nebulizer with Surfactant under Simulated, Non-Invasive Neonatal Ventilation Conditions: Influence of Continuous Positive Airway Pressure Interface and Nebulizer Positioning on the Lung Dose
Authors: Bianco Federico , Pasini Elena , Nutini Marcello , Murgia Xabier , Stoeckl Carolin , Schlun Martin , Hetzer Uwe , Bonelli Sauro , Lombardini Marta , Milesi Ilaria , Pertile Marisa , Minocchieri Stefan , Salomone Fabrizio , Bucholski Albert
Published: March 2020

Non-invasive delivery of nebulized surfactant has been a long-pursued goal in neonatology. Our aim was to evaluate the performance of an investigational vibrating-membrane nebulizer in a realistic non-invasive neonatal ventilation circuit with different configurations. Surfactant (aerosols were generated with a nebulizer in a set-up composed of a continuous positive airway pressure (CPAP) generator with a humidifier, a cast of the upper airway of a preterm infant (PrINT), and a breath simulator with a neonatal breathing pattern. The lung dose (LD), defined as the amount of surfactant collected in a filter placed at the distal end of the PrINT cast, was determined after placing the nebulizer at different locations of the circuit and using either infant nasal mask or nasal prongs as CPAP interfaces. The LD after delivering a range of nominal surfactant doses (100–600 mg/kg) was also investigated. Surfactant aerosol particle size distribution was determined by laser diffraction. Irrespective of the CPAP interface used, about 14% of the nominal dose (200 mg/kg) reached the LD filter. However, placing the nebulizer between the Y-piece and the CPAP interface significantly increased the LD compared with placing it 7 cm before the Y-piece, in the inspiratory limb. (14% ± 2.8 vs. 2.3% ± 0.8, nominal dose of 200 mg/kg). The customized eFlow Neos showed a constant aerosol generation rate and a mass median diameter of 2.7 μm after delivering high surfactant doses (600 mg/kg). The customized eFlow Neos nebulizer showed a constant performance even after nebulizing high doses of undiluted surfactant. Placing the nebulizer between the Y-piece and the CPAP interface achieves the highest LD under non-invasive ventilation conditions.
An Enteric-Coated Polyelectrolyte Nanocomplex Delivers Insulin in Rat Intestinal Instillations When Combined with a Permeation Enhancer
Authors: Sladek Svenja , McCartney Fiona , Eskander Mena , Dunne David J. , Santos-Martinez Maria Jose , Benetti Federico , Tajber Lidia , Brayden David J.
Published: March 2020

The use of nanocarriers is being researched to achieve oral peptide delivery. Insulin-associated anionic polyelectrolyte nanoparticle complexes (PECs) were formed that comprised hyaluronic acid and chitosan in an optimum mass mixing ratio of 5:1 (MR 5), followed by coating with a pH-dependent polymer. Free insulin was separated from PECs by size exclusion chromatography and then measured by HPLC. The association efficiency of insulin in PECs was >95% and the loading was ~83 µg/mg particles. Dynamic light scattering and nanoparticle tracking analysis of PECs revealed low polydispersity, a negative zeta potential range of −40 to −50 mV, and a diameter range of 95–200 nm. Dissolution studies in simulated small intestinal fluid (FaSSIF-V2) revealed that the PECs were colloidally stable. PECs that were coated with Eudragit® L-100 delayed insulin release in FaSSIF-V2 and protected insulin against pancreatin attack more than uncoated PECs. Uncoated anionic PECs interacted weakly with mucin in vitro and were non-cytotoxic to Caco-2 cells. The coated and uncoated PECs, both concentrated further by ultrafiltration, permitted dosing of 50 IU/kg in rat jejunal instillations, but they failed to reduce plasma glucose or deliver insulin to the blood. When ad-mixed with the permeation enhancer (PE), sucrose laurate (100 mM), the physicochemical parameters of coated PECs were relatively unchanged, however blood glucose was reduced by 70%. In conclusion, the use of a PE allowed for the PEC-released bioactive insulin to permeate the jejunum. This has implications for the design of orally delivered particles that can release the payload when formulated with enhancers.
On-Chip Synthesis of Hyaluronic Acid-Based Nanoparticles for Selective Inhibition of CD44+ Human Mesenchymal Stem Cell Proliferation
Authors: Chiesa Enrica , Riva Federica , Dorati Rossella , Greco Antonietta , Ricci Stefania , Pisani Silvia , Patrini Maddalena , Modena Tiziana , Conti Bice , Genta Ida
Published: March 2020

In this study, an innovative microfluidics-based method was developed for one-step synthesis of hyaluronic acid (HA)-based nanoparticles (NPs), by exploiting polyelectrolytic interactions between HA and chitosan (CS), in order to improve reliability, reproducibility and possible scale-up of the NPs preparation. The on-chip synthesis, using a staggered herringbone micromixer, allowed to produce HA/CS NPs with tailored-made size and suitable for both parenteral (117.50 ± 4.51 nm) and loco-regional (349.15 ± 38.09 nm) administration, mainly composed by HA (more than 85% wt) with high negative surface charge (< −20 mV). HA/CS NPs were successfully loaded with a challenging water-insoluble molecule, Everolimus (EVE), an FDA- and EMA-approved anticancer drug able to lead to cell cycle arrest, reduced angiogenesis and promotion of apoptosis. HA/CS NPs resulted to be massively internalized in CD44+ human mesenchymal stem cells via CD44 receptor-mediated endocytosis. HA/CS NPs selectiveness towards CD44 was highlighted by blocking CD44 receptor by anti-CD44 primary antibody and by comparison to CS-based NPs cellular uptake. Eventually, high effectiveness in inhibiting cell proliferation was demonstrated on-chip synthetized EVE loaded HA/CS NPs by tracking in vitro DNA synthesis.
Characterization of the Auxin Efflux Transporter PIN Proteins in Pear
Authors: Qi Liying , Chen Ling , Wang Chuansen , Zhang Shaoling , Yang Yingjie , Liu Jianlong , Li Dingli , Song Jiankun , Wang Ran
Published: March 2020

PIN-FORMED (PIN) encodes a key auxin polar transport family that plays a crucial role in the outward transport of auxin and several growth and development processes, including dwarfing trees. We identified a dwarfing pear rootstock ‘OHF51’ (Pyrus communis), which limits the growth vigor of the ‘Xueqing’ (Pyrus bretschneideri × Pyrus pyrifolia) scion, and isolated 14 putative PbPINs from the pear Pyrus bretschneideri. The phylogenic relationships, structure, promoter regions, and expression patterns were analyzed. PbPINs were classified into two main groups based on the protein domain structure and categorized into three major groups using the neighbor-joining algorithm. Promoter analysis demonstrated that PbPINs might be closely related to plant growth and development. Through quantitative real-time PCR (qRT-PCR) analysis, we found that the expression patterns of 14 PbPINs varied upon exposure to different organs in dwarfing and vigorous stocks, ‘OHF51’ and ‘QN101’ (Pyrus betulifolia), indicating that they might play varying roles in different tissues and participated in the regulation of growth vigor. These results provide fundamental insights into the characteristics and evolution of the PINs family, as well as the possible relationship between dwarfing ability and auxin polar transport.
Comparative Metabolites and Citrate-Degrading Enzymes Activities in Citrus Fruits Reveal the Role of Balance between ACL and Cyt-ACO in Metabolite Conversions
Authors: Guo Lingxia , Liu Yongzhong , Luo Lijuan , Hussain Syed Bilal , Bai Yingxin , Alam Shariq Mahmood
Published: March 2020

Citric acid metabolism is considered to be the central cellular process of metabolite conversions. ATP-citrate lyase (ACL) and cytosolic aconitase (cyt-ACO) are the two citrate-degrading enzymes that decide the carbon flux towards different metabolite biosynthesis pathways. However, the correlation of their activities with metabolite concentrations in citrus fruits is still unclear. Here, the concentrations of soluble sugars, organic acids, acetyl-CoA, flavonoids, carotenoids, and γ-aminobutyric acid, as well as the activities of ACL, cyt-ACO, acetyl-CoA C-acetyltransferase, and acetyl-CoA carboxylase, were compared among the fruits of six citrus cultivars during fruit development and ripening. The results showed that the correlation between citrate concentration and cyt-ACO or ACL activity varied greatly among cultivars, while the activities of cyt-ACO and ACL had a significantly negative correlation (r = −0.4431). Moreover, ACL overexpression and RNA interference in the Citrus callus indicated that increasing and decreasing the ACL activity could reduce and induce cyt-ACO activity, respectively. In addition, significant correlation was only observed between the ACL activity and the concentration of acetyl-CoA (r = 0.4333). Taken together, the present study suggested that ACL and cyt-ACO synergistically control the citrate fate for the biosynthesis of other metabolites, but they are not the key determinants for the accumulation of citrate, as well as other metabolites in citrus fruits.
Effect of Plant Growth Regulators on Coloured Callus Formation and Accumulation of Azadirachtin, an Essential Biopesticide in Azadirachta indica
Authors: Ashokhan Sharmilla , Othman Rashidi , Abd Rahim Muhamad Hafiz , Karsani Saiful Anuar , Yaacob Jamilah Syafawati
Published: March 2020

For centuries, Azadirachta indica or neem has been utilized as a primary source of medicine due to its antimicrobial, larvacidal, antimalarial and antifungal properties. Recently, its potential as an effective biopesticide has garnered attention, especially towards efficient and continuous production of its bioactive compounds. The present study investigated the effect of the plant growth regulators (PGRs) thiadiazuron (TDZ) and 2,4-dichlorophenoxyacetic acid (2,4-D) on the induction of colored callus formation and subsequent accumulation of azadirachtin (AZA) in A. indica. An efficient protocol was established for micropropagation and colored callus production of this species, followed by quantification of AZA (a mixture of azadirachtin A and B) and its safety assessment. For induction of the callus, leaf and petiole explants obtained from a young growing neem plant were excised and cultured on Murashige and Skoog (MS) medium supplemented with TDZ (0.2–0.6 mg L−1) and 2,4-D (0.2–0.6 mg L−1), either applied singly or in combination. Callus was successfully induced from both explant types at different rates, where media with 0.6 mg L−1 of TDZ resulted in the highest fresh weight (3.38 ± 0.08 g). In general, media with a single hormone (particularly TDZ) was more effective in producing a high mass of callus compared to combined PGRs. A culture duration of six weeks resulted in the production of green, brown and cream colored callus. The highest callus weight and accumulation of AZA was recorded in green callus (214.53 ± 33.63 mg g−1 dry weight (DW)) induced using TDZ. On the other hand, small amounts of AZA were detected in both brown and cream callus. Further experimentation indicated that the green callus with the highest AZA was found to be non-toxic (LC50 at 4606 µg mL−1) to the zebrafish animal model. These results suggested that the addition of different PGRs during in vitro culture could prominently affect callus and secondary metabolite production and can further be manipulated as a sustainable method for the production of a natural and environmentally friendly pesticide.
Citrus Essential Oils (CEOs) and Their Applications in Food: An Overview
Authors: Bora Himashree , Kamle Madhu , Mahato Dipendra Kumar , Tiwari Pragya , Kumar Pradeep
Published: March 2020

Citrus is a genus belonging to the Rutaceae family and includes important crops like orange, lemons, pummelos, grapefruits, limes, etc. Citrus essential oils (CEOs) consist of some major biologically active compounds like α-/β-pinene, sabinene, β-myrcene, d-limonene, linalool, α-humulene, and α-terpineol belonging to the monoterpenes, monoterpene aldehyde/alcohol, and sesquiterpenes group, respectively. These compounds possess several health beneficial properties like antioxidant, anti-inflammatory, anticancer, etc., in addition to antimicrobial properties, which have immense potential for food applications. Therefore, this review focused on the extraction, purification, and detection methods of CEOs along with their applications for food safety, packaging, and preservation. Further, the concerns of optimum dose and safe limits, their interaction effects with various food matrices and packaging materials, and possible allergic reactions associated with the use of CEOs in food applications were briefly discussed, which needs to be addressed in future research along with efficient, affordable, and “green” extraction methods to ensure CEOs as an ecofriendly, cost-effective, and natural alternative to synthetic chemical preservatives.
Trends in Seaweed Extract Based Biostimulants: Manufacturing Process and Beneficial Effect on Soil-Plant Systems
Authors: EL Boukhari Mohammed EL Mehdi , Barakate Mustapha , Bouhia Youness , Lyamlouli Karim
Published: March 2020

The time when plant biostimulants were considered as “snake oil” is erstwhile and the skepticism regarding their agricultural benefits has significantly faded, as solid scientific evidences of their positive effects are continuously provided. Currently plant biostimulants are considered as a full-fledged class of agri-inputs and highly attractive business opportunity for major actors of the agroindustry. As the dominant category of the biostimulant segment, seaweed extracts were key in this growing renown. They are widely known as substances with the function of mitigating abiotic stress and enhancing plant productivity. Seaweed extracts are derived from the extraction of several macroalgae species, which depending on the extraction methodology lead to the production of complex mixtures of biologically active compounds. Consequently, plant responses are often inconsistent, and precisely deciphering the involved mechanism of action remains highly intricate. Recently, scientists all over the world have been interested to exploring hidden mechanism of action of these resources through the employment of multidisciplinary and high-throughput approaches, combining plant physiology, molecular biology, agronomy, and multi-omics techniques. The aim of this review is to provide fresh insights into the concept of seaweed extract (SE), through addressing the subject in newfangled standpoints based on current scientific knowledge, and taking into consideration both academic and industrial claims in concomitance with market’s requirements. The crucial extraction process as well as the effect of such products on nutrient uptake and their role in abiotic and biotic stress tolerance are scrutinized with emphasizing the involved mechanisms at the metabolic and genetic level. Additionally, some often overlooked and indirect effects of seaweed extracts, such as their influence on plant microbiome are discussed. Finally, the plausible impact of the recently approved plant biostimulant regulation on seaweed extract industry is addressed.
Somatic Embryogenesis and Plantlet Regeneration in the Carica papaya L. cv. Eksotika
Authors: Al-Shara Baker , Taha Rosna Mat , Mohamad Jamaludin , Elias Hashimah , Khan Asif
Published: March 2020

A highly efficient protocol for regeneration of Carica papaya L. cv. Eksotika somatic embryos from immature zygotic embryos was developed. This study was designed to overcome the obstacles in regeneration of somatic embryos from immature zygotic embryos of “Eksotika”, especially problems associated with formation of better root quality and callus formation at the base of somatic embryos. Somatic embryos were generated by incubation of immature zygotic embryos in half-strength salt Murashige and Skoog (MS) medium with full-strength vitamins supplemented with 7.5 mg L−1 2,4-D, 100 mg L−1 L-glutamine, 50 mg L−1 myo-inositol, 45 mg L−1 adenine sulphate, 0.33% gelrite, and 6% sucrose, followed by transfer to maturation medium consisting of ½ MS medium supplemented with 5 mg L−1 phloroglucinol, 100 mg L−1 L-glutamine, 100 mg L−1 myo-inositol, 68 mg L−1 adenine sulphate, 0.38% gelrite, and 3% sucrose. After that, well-formed somatic embryos were transferred to MS medium containing 3% sucrose and 0.8% agar for shoot production. The embryos were elongated in MS medium supplemented with 1 mg L−1 gibberellic acid, 0.5 mg L−1 indole-3-butyric acid, 100 mg L−1 myo-inositol, and 3.76 mg L−1 riboflavin. Root regeneration was achieved on MS medium containing 7.9 mg L−1 phloroglucinol and supported with vermiculite after 4 days of cultivation on ½ MS medium with 2 mg L−1 indole-3-butyric acid. After the rooting phase, in vitro plantlets were acclimatized in peat moss soil.