bluuebunny/crossref_metadata_2025 huggingface dataset:
Numerical Modeling of Distortion of Ti-6Al-4V Components Manufactured Using Laser Powder Bed Fusion
Authors: Ninpetch Patiparn , Kowitwarangkul Pruet , Chalermkarnnon Prasert , Promoppatum Patcharapit , Chuchuay Piyapat , Rattanadecho Phadungsak
Published: September 2022

The laser powder bed fusion (L-PBF) process is a powder-based additive manufacturing process that can manufacture complex metallic components. However, when the metallic components are fabricated with the L-PBF process, they frequently encounter the residual stress and distortion that occurs due to the cyclic of rapid heating and cooling. The distortion detrimentally impacts the dimensional and geometrical accuracy of final built parts in the L-PBF process. The purpose of this research was to explore and predict the distortion of Ti-6Al-4V components manufactured using the L-PBF process by using numerical modeling in Simufact Additive 2020 FP1 software. Firstly, the numerical model validation was conducted with the twin-cantilever beam part. Later, studies were carried out to examine the effect of component sizes and support-structure designs on the distortion of tibial component produced by the L-PBF process. The results of this research revealed a good agreement between the numerical model and experiment data. In addition, the platform was extended to predict the distortion in the tibial component. Large distortion arose near the interface between the tibial tray and support structure due to the different stiffness between the solid bulk and support structure. The distortion of the tibial component increased with increasing component size according to the surface area of the tibial tray, and with increasing thickness of the tibial tray. Furthermore, the support-structure design plays an important role in distortion reduction in the L-PBF process. For example, the maximum distortion of the tibial component was minimized up to 44% when a block support-structure design with a height of 2.5 mm was used instead of the lattice-based support. The present study provides useful information to help the medical sector to manufacture effective medical components and reduce the chance of part failure from cracking in the L-PBF process.
Effect of Stress Ratio and Evaluation of Crack Sizes on Very-High-Cycle-Fatigue Crack Propagation Life Prediction of Carburized Cr-Ni Steel
Authors: Guo Yupeng , Chen Furong , Liu Bing , Yu Huan , Deng Hailong
Published: September 2022

Carburized Cr-Ni steel is widely used in the manufacture of components in many fields due to excellent performance, of which the service life has been a concern. In order to investigate the high-cycle-fatigue and very-high-cycle-fatigue properties of carburized Cr-Ni gear steel, axial loading fatigue tests were performed by QBG-100 with stress ratios of −1, 0 and 0.3. The Generalized Pareto distribution was used to evaluate the inclusion size of carburized Cr-Ni gear steel. Based on the stress ratio and the evaluated crack size, a new fatigue life prediction model for carburized Cr-Ni gear steels was constructed. The results show that the S–N characteristics of carburized Cr-Ni gear steel represent the continuously descending tendency. Based on the long crack propagation threshold and the instability propagation threshold of carburized Cr-Ni gear steel, the sizes of FGA, fisheye and surface smooth area (SSA) can be evaluated, respectively. In addition, the maximum size of surface and interior inclusion of carburized Cr-Ni gear steel are 17.50 μm and 6.46 μm with a cumulative probability of 99.9%. By validating the new established model, the prediction result is acceptable according to the good consistency between the predicted life and the experimental life.
Cold Laser Micro-Machining of PDMS as an Encapsulation Layer for Soft Implantable Neural Interface
Authors: Wang Minjie , Zhang Yuan , Bin Jianxiong , Niu Lan , Zhang Jing , Liu Lusheng , Wang Aiping , Tao Jin , Liang Jingqiu , Zhang Lihua , Kang Xiaoyang
Published: September 2022

PDMS (polydimethylsiloxane) is an important soft biocompatible material, which has various applications such as an implantable neural interface, a microfluidic chip, a wearable brain–computer interface, etc. However, the selective removal of the PDMS encapsulation layer is still a big challenge due to its chemical inertness and soft mechanical properties. Here, we use an excimer laser as a cold micro-machining tool for the precise removal of the PDMS encapsulation layer which can expose the electrode sites in an implantable neural interface. This study investigated and optimized the effect of excimer laser cutting parameters on the electrochemical impedance of a neural electrode by using orthogonal experiment design. Electrochemical impedance at the representative frequencies is discussed, which helps to construct the equivalent circuit model. Furthermore, the parameters of the equivalent circuit model are fitted, which reveals details about the electrochemical property of neural electrode using PDMS as an encapsulation layer. Our experimental findings suggest the promising application of excimer lasers in the micro-machining of implantable neural interface.
Thermal Performance Improvement of AlGaN/GaN HEMTs Using Nanocrystalline Diamond Capping Layers
Authors: Guo Huaixin , Li Yizhuang , Yu Xinxin , Zhou Jianjun , Kong Yuechan
Published: September 2022

Nanocrystalline diamond capping layers have been demonstrated to improve thermal management for AlGaN/GaN HEMTs. To improve the RF devices, the application of the technology, the technological approaches and device characteristics of AlGaN/GaN HEMTs with gate length less than 0.5 μm using nanocrystalline diamond capping layers have been studied systematically. The approach of diamond-before-gate has been adopted to resolve the growth of nanocrystalline diamond capping layers and compatibility with the Schottky gate of GaN HEMTs, and the processes of diamond multi-step etching technique and AlGaN barrier protection are presented to improve the technological challenge of gate metal. The GaN HEMTs with nanocrystalline diamond passivated structure have been successfully prepared; the heat dissipation capability and electrical characteristics have been evaluated. The results show the that thermal resistance of GaN HEMTs with nanocrystalline diamond passivated structure is lower than conventional SiN-GaN HEMTs by 21.4%, and the mechanism of heat transfer for NDC-GaN HEMTs is revealed by simulation method in theory. Meanwhile, the GaN HEMTs with nanocrystalline diamond passivated structure has excellent output, small signal gain and cut-off frequency characteristics, especially the current–voltage, which has a 27.9% improvement than conventional SiN-GaN HEMTs. The nanocrystalline diamond capping layers for GaN HEMTs has significant performance advantages over the conventional SiN passivated structure.
Performance Enhancement of Ytterbium-Doped Fiber Amplifier Employing a Dual-Stage In-Band Asymmetrical Pumping
Authors: Mirza Jawad , Ghafoor Salman , Armghan Ammar , Elhamrawy Osama I. , Jamal Laiq , Magam Musab , Sheikh Sharif Iqbal Mitu , Qureshi Khurram Karim
Published: September 2022

The performance of doped fiber amplifiers can be enhanced significantly with the help of multi-stage pumping technique provided that various critical parameters of pumps including their optical power and wavelength are optimized. We report the performance enhancement of a ytterbium doped fiber amplifier (YDFA) for a 1.02–1.08 μm spectral region with an optimized design based on a novel dual-stage in-band asymmetrical pumping scheme. By accurately adjusting the optical power and wavelength of pumps in both the stages, a record peak gain of around 62.5 dB and output power of 4.5 W are achieved for a signal wavelength of 1.0329 μm at an optimized length of Ytterbium-doped silica fiber and optimized doping concentration of Yb3+. Moreover, a minimum noise figure (NF) of 4 dB is observed for a signal wavelength of 1.0329 μm at the optimized parameters. Similarly, the effect of using high and low pump powers at the first and the second stage, respectively, on NF of the amplifier is also investigated at different values of signal powers. It is observed that the value of NF increases significantly by using high pump power at the first stage and low pump power at the second stage.
General Strategy toward Laser Single-Step Generation of Multiscale Anti-Reflection Structures by Marangoni Effect
Authors: Yin Jingbo , Yan Huangping , Dunzhu Gesang , Wang Rui , Cao Shengzhu , Zhou Rui , Li Yuanzhe
Published: September 2022

The anti-reflection of transparent material surfaces has attracted great attention due to its potential applications. In this paper, a single-step controllable method based on an infrared femtosecond laser is proposed for self-generation multiscale anti-reflection structures on glass. The multiscale composite structure with ridge structures and laser-induced nano-textures is generated by the Marangoni effect. By optimizing the laser parameters, multiscale structure with broadband anti-reflection enhancement is achieved. Meanwhile, the sample exhibits good anti-glare performance under strong light. The results show that the average reflectance of the laser-textured glass in the 300–800 nm band is reduced by 45.5% compared with the unprocessed glass. This work provides a simple and general strategy for fabricating anti-reflection structures and expands the potential applications of laser-textured glass in various optical components, display devices, and anti-glare glasses.
Laser Polishing Die Steel Assisted by Steady Magnetic Field
Authors: Zhao Zhenyu , Zeng Junyong , Lai Zhouyi , Yin Jie , Guo Ting
Published: September 2022

To improve the surface roughness of SKD61 die steel and reduce the secondary overflow of the molten pool, a steady magnetic field-assisted laser polishing method is proposed to study the effect of steady magnetic field on the surface morphology and melt pool flow behavior of SKD61 die steel. Firstly, a low-energy pulsed laser is used for the removal of impurities from the material surface; then, the CW laser, assisted by steady magnetic field, is used to polish the rough surface of SKD61 die steel to reduce the material surface roughness. The results show that the steady magnetic field-assisted laser polishing can reduce the surface roughness of SKD61 die steel from 6.1 μm to 0.607 μm, which is a 90.05% reduction compared with the initial surface roughness. Furthermore, a multi-physical-field numerical transient model involving heat transfer, laminar flow and electromagnetic field is established to simulate the flow state of the molten pool on the surface of the SKD61 die steel. This revealed that the steady magnetic field is able to inhibit the secondary overflow of the molten pool to improve the surface roughness of SKD61 slightly by reducing the velocity of the molten pool. Compared with the molten pool depth obtained experimentally, the molten pool depth simulation was 65 μm, representing an error 15.0%, thus effectively demonstrating the accuracy of the simulation model.
Modeling and Analysis of Radial Electromagnetic Force and Vibration Characteristics Based on Deflection Dual-Stator Switched Reluctance Generator
Authors: Li Zheng , Liu Libo , Wang Pengju , Liu Yu , Wei Xiaopeng , Xu Qianqian , Sun Hexu
Published: September 2022

In this paper, a mechanical model of the deflection dual-stator switched reluctance generator (DDSRG) is developed, and the advantages of the dual-stator structure for the deflecting motion are analyzed. Secondly, the spatio-temporal and spatial distribution characteristics of the inhomogeneous electromagnetic force are derived analytically and further verified by fast Fourier transform (FFT).Thirdly, the spatial and temporal distributions of electromagnetic forces of DDSRG are calculated based on finite element software, and the distributions of electromagnetic forces under different motion states are analyzed. By combining the analysis of modal analysis and harmonic response analysis, the free mode and vibration response acceleration variation laws of the internal and external stator are determined. The results show that the order of electromagnetic forces on the stator at rated speed is mainly 8 times the fundamental frequency, and the modal vibration order is more violent in the order of 2–7. Finally, the experimental platform of DDSRG is built, and the vibration characteristics are tested to verify the validity and accuracy of the proposed simulation results.
Optimizing Acetic Acid Application Strategy Can Effectively Promote the Remediation Performance of Oilseed Sunflower on Cd-Contaminated Soils
Authors: Wang Yadan , Qiao Dongmei , Han Yang , Zhang Dengmin
Published: September 2022

Applying exogenous organic acids is an effective method to improve the remediation efficiency of Cd-contaminated soils. To investigate the effects of exogenous acetic acid on Cd forms in rhizosphere soils and phytoremediation performance for Cd-contaminated soils, a potted experiment was performed with oilseed sunflower as the extractive plant. Acetic acid was applied at 1, 2, 3, 4, 5, and 6 mmol/kg at 20, 30, 40, and 50 days after seedling emergence. Soil without acetic acid was used as a control (CK). Emblematic chemical properties and different Cd forms in rhizosphere soils were inspected. Results showed that adding acetic acids improved the biomass of shoot and root; it increased firstly and then decreased with the increase of acetic acid concentrations. For all treatments, acetic acids increased sucrase activity and catalase activity but decreased amylase activity in rhizosphere soils. At 30 or 40 days after seedling emergence, the exchangeable Cd content, Fe-Mn oxide Cd content, and organic Cd content were lower, while the carbonate Cd content was greater. Adding acetic acids improved the removal rate of Cd, and when 1 mmol/kg acetic acid was applied at 40 days after seedling emergence, it was increased by 60%, which was the highest compared to CK. RDA showed that catalase activity, sucrase activity, carbonate Cd, and pH could promote the growth of oilseed sunflower, while organic Cd, Fe-Mn oxide Cd, total Cd, exchangeable Cd, and amylase activity inhibited the growth of oilseed sunflower. These findings suggest that acetic acid can improve the efficiency of phytoremediation in Cd-contaminated soils. In particular, the treatment with 1 mmol/kg acetic acid at 40 days after seedling emergence had the most obvious effect.
A Novel Fabrication of Single Electron Transistor from Patterned Gold Nanoparticle Array Template-Prepared by Polystyrene Nanospheres
Authors: Fang Jingyue , Li Xinxing , Xie Wenke , Sun Kehui
Published: September 2022

In this paper, polystyrene microspheres were firstly prepared by seeded emulsion polymerization, and the uniform monolayer of polystyrene microspheres was prepared on the substrate by the dipping method. Then, polystyrene monolayer film was used as a mask and a low dimensional array structure of gold was prepared by bottom-up self-assembly process. After that, the method of solution etching and annealing was used, and the gold nanoparticle array was post-processed. As a result, gold nanoparticles were recrystallized, with an average diameter of about 50 nm. Subsequently, the semiconductor process was adopted, with focused ion beams induced deposition and electron beam evaporation, and single electron transistors were fabricated, based on self-assembled gold nanoparticles. Finally, the devices were fixed in a liquid helium cryostat and Coulomb blockade was observed at 320 mK. It is a novel fabrication of a single electron transistor based on gold nanoparticle array template and prepared with polystyrene nanospheres.
Carbon Nanopowder-Based Stochastic Sensor for Ultrasensitive Assay of CA 15-3, CEA and HER2 in Whole Blood
Authors: Stefan-van Staden Raluca-Ioana , Musat Oana-Raluca , Gheorghe Damaris-Cristina , Ilie-Mihai Ruxandra-Maria , van Staden Jacobus (Koos) Frederick
Published: September 2022

Two microsensors obtained by the physical immobilization of 5,10,15,20-tetraphenyl-21H,23H-porphine (TPP) and 5,10,15,20-tetrakis (pentafluorophenyl chloride)-21H,23H-iron (III) porphyrin (Fe(TPFPP)Cl) in carbon nanopowder decorated with gold nanoparticles (AuNp) were designed, characterized, validated and used for the molecular recognition and simultaneous ultrasensitive determination of CEA, CA15-3 and HER2 in whole blood. High sensitivities were recorded for both microsensors. Low limits of quantification were recorded for all biomarkers: CEA (12.8 pg mL−1 by using Fe(TPFPP)Cl/AuNp, and 190 fg mL−1 by using TPP/AuNp), CA 15-3 (100 fU mL−1 for both microsensors) and HER2 (3.9 fg mL−1 by using Fe(TPFPP)Cl/AuNp, and 35 fg mL−1 by using TPP/AuNp). A very good correlation between the results obtained using the proposed microsensors and ELISA, certified by the Student t-test, proves that the screening test can be used for ultrasensitive assays of the three biomarkers in whole blood.
Development of Novel Colorful Electrorheological Fluids
Authors: Jekal Suk , Kim Jiwon , Lu Qi , Kim Dong-Hyun , Noh Jungchul , Kim Ha-Yeong , Kim Min-Jeong , Kim Min-Sang , Oh Won-Chun , Choi Hyoung-Jin , Yoon Chang-Min
Published: September 2022

Herein, the electrorheological (ER) performances of ER fluids were correlated with their colors to allow for the visual selection of the appropriate fluid for a specific application using naked eyes. A series of TiO2-coated synthetic mica materials colored white, yellow, red, violet, blue, and green (referred to as color mica/TiO2 materials) were fabricated via a facile sol–gel method. The colors were controlled by varying the thickness of the TiO2 coating layer, as the coatings with different thicknesses exhibited different light interference effects. The synthesized color mica/TiO2 materials were mixed with silicone oil to prepare colored ER fluids. The ER performances of the fluids decreased with increasing thickness of the TiO2 layer in the order of white, yellow, red, violet, blue, and green materials. The ER performance of differently colored ER fluids was also affected by the electrical conductivity, dispersion stability, and concentrations of Na+ and Ca2+ ions. This pioneering study may provide a practical strategy for developing new ER fluid systems in future.
Mesoscale Modeling of Phase Separation Controlled by Hydrosilylation in Polyhydromethylsiloxane (PHMS)-Containing Blends
Authors: Xiong Yao , Choudhury Chandan K. , Palkar Vaibhav , Wunderlich Raleigh , Bordia Rajendra K. , Kuksenok Olga
Published: September 2022

Controlling morphology of polysiloxane blends crosslinked by the hydrosilylation reaction followed by pyrolysis constitutes a robust strategy to fabricate polymer-derived ceramics (PDCs) for a number of applications, from water purification to hydrogen storage. Herein, we introduce a dissipative particle dynamics (DPD) approach that captures the phase separation in binary and ternary polymer blends undergoing hydrosilylation. Linear polyhydromethylsiloxane (PHMS) chains are chosen as preceramic precursors and linear vinyl-terminated polydimethylsiloxane (v-PDMS) chains constitute the reactive sacrificial component. Hydrosilylation of carbon–carbon unsaturated double bonds results in the formation of carbon–silicon bonds and is widely utilized in the synthesis of organosilicons. We characterize the dynamics of binary PHMS/v-PDMS blends undergoing hydrosilylation and ternary blends in which a fraction of the reactive sacrificial component (v-PDMS) is replaced with the non-reactive sacrificial component (methyl-terminated PDMS (m-PDMS), polyacrylonitrile (PAN), or poly(methyl methacrylate) (PMMA)). Our results clearly demonstrate that the morphology of the sacrificial domains in the nanostructured polymer network formed can be tailored by tunning the composition, chemical nature, and the degree of polymerization of the sacrificial component. We also show that the addition of a non-reactive sacrificial component introduces facile means to control the self-assembly and morphology of these nanostructured materials by varying the fraction, degree of polymerization, or the chemical nature of this component.
The Effect of Dietary Carbohydrate and Fat Manipulation on the Metabolome and Markers of Glucose and Insulin Metabolism: A Randomised Parallel Trial
Authors: McCullough Deaglan , Harrison Tanja , Boddy Lynne , Enright Kevin , Amirabdollahian Farzad , Schmidt Michael , Doenges Katrina , Quinn Kevin , Reisdorph Nichole , Mazidi Mohsen , Lane Katie , Stewart Claire , Davies Ian
Published: September 2022

High carbohydrate, lower fat (HCLF) diets are recommended to reduce cardiometabolic disease (CMD) but low carbohydrate high fat (LCHF) diets can be just as effective. The effect of LCHF on novel insulin resistance biomarkers and the metabolome has not been fully explored. The aim of this study was to investigate the impact of an ad libitum 8-week LCHF diet compared with a HCLF diet on CMD markers, the metabolome, and insulin resistance markers. n = 16 adults were randomly assigned to either LCHF (n = 8, <50 g CHO p/day) or HCLF diet (n = 8) for 8 weeks. At weeks 0, 4 and 8, participants provided fasted blood samples, measures of body composition, blood pressure and dietary intake. Samples were analysed for markers of cardiometabolic disease and underwent non-targeted metabolomic profiling. Both a LCHF and HCLF diet significantly (p < 0.01) improved fasting insulin, HOMA IR, rQUICKI and leptin/adiponectin ratio (p < 0.05) levels. Metabolomic profiling detected 3489 metabolites with 78 metabolites being differentially regulated, for example, an upregulation in lipid metabolites following the LCHF diet may indicate an increase in lipid transport and oxidation, improving insulin sensitivity. In conclusion, both diets may reduce type 2 diabetes risk albeit, a LCHF diet may enhance insulin sensitivity by increasing lipid oxidation.
Glucosamine Use Is Associated with a Higher Risk of Cardiovascular Diseases in Patients with Osteoarthritis: Results from a Large Study in 685,778 Subjects
Authors: Yu Huan , Wu Junhui , Chen Hongbo , Wang Mengying , Wang Siyue , Yang Ruotong , Zhan Siyan , Qin Xueying , Wu Tao , Wu Yiqun , Hu Yonghua
Published: September 2022

Glucosamine is widely used around the world and as a popular dietary supplement and treatment in patients with osteoarthritis in China; however, the real-world cardiovascular risk of glucosamine in long-term use is still unclear. A retrospective, population-based cohort study was performed, based on the Beijing Medical Claim Data for Employees from 1 January 2010 to 31 December 2017. Patients newly diagnosed with osteoarthritis were selected and divided into glucosamine users and non- glucosamine users. The glucosamine users group was further divided into adherent, partially adherent, and non-adherent groups according to the medication adherence. New-onset cardiovascular diseases (CVD) events, coronary heart diseases (CHD), and stroke, were identified during the observational period. COX proportional regression models were used to estimate the risks. Of the 685,778 patients newly diagnosed with osteoarthritis including 240,419 glucosamine users and 445,359 non-users, the mean age was 56.49 (SD: 14.45) years and 59.35% were females. During a median follow-up of 6.13 years, 64,600 new-onset CVD, 26,530 CHD, and 17,832 stroke events occurred. Glucosamine usage was significantly associated with CVD (HR: 1.10; 95% CI: 1.08–1.11) and CHD (HR: 1.12; 95% CI: 1.09–1.15), but not with stroke (HR: 1.03; 95% CI: 0.99–1.06). The highest CVD risk was shown in the adherent group (HR: 1.68; 95% CI: 1.59–1.78), followed by the partially adherent group (HR: 1.26, 95% CI: 1.22–1.30), and the non-adherent group (HR: 1.03; 95% CI: 1.02–1.05), with a significant dose–response relationship (p-trend < 0.001). In this longitudinal study, adherent usage of glucosamine was significantly associated with a higher risk for cardiovascular diseases in patients with osteoarthritis.
Mucosal Healing in Celiac Disease: Villous Architecture and Immunohistochemical Features in Children on a Long-Term Gluten Free Diet
Authors: Mandile Roberta , Maglio Mariantonia , Mosca Caterina , Marano Antonella , Discepolo Valentina , Troncone Riccardo , Auricchio Renata
Published: September 2022

Considerable heterogeneity exists across studies assessing intestinal mucosal recovery in celiac (CD) patients on a gluten-free diet (GFD). We aimed at investigating histological and immunohistochemical features in CD patients on a long-term GFD and to correlate them to the GFD duration. Morphometrical and immunohistochemical analysis were retrospectively performed on duodenal biopsies in three groups of children: 33 on a long-term (>2 years) GFD (GFD-group), four of which remained seropositive despite dietary adherence, 31 with villous atrophy (ACD-group) and 76 heathy, non-celiac (CTR-group). Moreover, in the GFD-group, we correlated immunohistochemical alterations to the GFD duration. The villous to crypt (V/C) ratio significantly improved after the GFD and completely normalized in all patients, becoming even higher than in the CTR-group (median value 3.2 vs. 3, p = 0.007). In parallel, the number of CD3+ and TCRγδ+ cells in the epithelium were significantly reduced in the GFD compared to ACD patients, even if they remained higher than in the CTR-group (p < 0.05). In contrast, CD25+ cells in the lamina propria significantly decreased after the GFD (p < 0.05) and become comparable to the CTR-group (p = 0.9). In the GFD-group there was no difference in the immunohistochemical parameters between seropositive and seronegative patients and alterations did not correlate to GFD length. In conclusion, a GFD is able to both restore a normal V/C ratio and reduce inflammation, but the epithelium maintains some stigmata of the disorder, such as an increased number of CD3+ and TCRγδ+ cells. These alterations persist regardless of the duration of the GFD.
Validation of a Smartphone Application for the Assessment of Dietary Compliance in an Intermittent Fasting Trial
Authors: Baum Martinez Isabella , Peters Beeke , Schwarz Julia , Schuppelius Bettina , Steckhan Nico , Koppold-Liebscher Daniela A. , Michalsen Andreas , Pivovarova-Ramich Olga
Published: September 2022

Accurate dietary analysis of energy, nutrient intake, and meal timing in human studies using traditional dietary assessment methods (e.g., food records) is challenging and time-consuming. The widespread use of smartphones, tablets, and nutrition applications (apps) can overcome some of these problems. The objective of this study was to evaluate the validity of an FDDB smartphone app and food database compared with PRODI®—a professional platform for nutritional counselling using the German Nutrient Database. Dietary records were collected from 10 subjects participating in the crossover intermittent fasting trial for 2 weeks at baseline and during the eating timeframe of 8 h (early or late in the course of the day). The FDDB app and database enabled a quicker and less sophisticated analysis of food composition and timing than the PRODI® software. Good agreement between the methods was found for energy and macronutrient intakes, while the FDDB data on most micronutrients and saturated/unsaturated fat intake were unreliable. In contrast to PRODI®, FDDB provided effective assessment of timely compliance, making it a promising tool for chrononutritional studies. Thus, the FDDB app is comparable to the traditional PRODI® dietary assessment method, and can be effectively used in human dietary trials and medical practice for specific goals.
Role of Postbiotics in Diet-Induced Metabolic Disorders
Authors: Park Miri , Joung Minji , Park Jae-Ho , Ha Sang Keun , Park Ho-Young
Published: September 2022

Although the prevalence of metabolic disorders has progressively increased over the past few decades, metabolic disorders can only be effectively treated with calorie restriction and improved physical activity. Recent research has focused on altering the gut microbiome using prebiotics, probiotics, and postbiotics because various metabolic syndromes are caused by gut microbial dysbiosis. Postbiotics, substances produced or released by microorganism metabolic activities, play an important role in maintaining and restoring host health. Because postbiotics have a small amount of literature on their consumption, there is a need for more experiments on short- and long-term intake. This review discusses current postbiotic research, categories of postbiotics, positive roles in metabolic syndromes, and potential therapeutic applications. It covers postbiotic pleiotropic benefits, such as anti-obesity, anti-diabetic, and anti-hypertensive qualities, that could aid in the management of metabolic disorders. Postbiotics are promising tools for developing health benefits and therapeutic goals owing to their clinical, technical, and economic properties. Postbiotic use is attractive for altering the microbiota; however, further studies are needed to determine efficacy and safety.
Evaluation of a Supervised Adapted Physical Activity Program Associated or Not with Oral Supplementation with Arginine and Leucine in Subjects with Obesity and Metabolic Syndrome: A Randomized Controlled Trial
Authors: Folope Vanessa , Meret Caroline , Castres Ingrid , Tourny Claire , Houivet Estelle , Grigioni Sébastien , Lelandais Hélène , Petit André , Coquard Aude , Guérin Charlène , Quillard Muriel , Bôle-Feysot Christine , Déchelotte Pierre , Achamrah Najate , Coëffier Moïse
Published: September 2022

Background: In patients with obesity and metabolic syndrome (MetS), lifestyle interventions combining diet, in particular, and physical exercise are recommended as the first line treatment. Previous studies have suggested that leucine or arginine supplementation may have beneficial effects on the body composition or insulin sensitivity and endothelial function, respectively. We thus conducted a randomized controlled study to evaluate the effects of a supervised adapted physical activity program associated or not with oral supplementation with leucine and arginine in MetS-complicated patients with obesity. Methods: Seventy-nine patients with obesity and MetS were randomized in four groups: patients receiving arginine and leucine supplementation (ALs group, n = 20), patients on a supervised adapted physical activity program (APA group, n = 20), patients combining ALs and APA (ALs+APA group, n = 20), and a control group (n = 19). After the baseline evaluation (m0), patients received ALs and/or followed the APA program for 6 months (m6). Body composition, MetS parameters, lipid and glucose metabolism markers, inflammatory markers, and a cardiopulmonary exercise test (CPET) were assessed at m0, m6, and after a 3-month wash-out period (m9). Results: After 6 months of intervention, we did not observe variable changes in body weight, body composition, lipid and glucose metabolism markers, inflammatory parameters, or quality of life scores between the four groups. However, during the CPET, the maximal power (Pmax and Ppeak), power, and O2 consumption at the ventilatory threshold (P(VT) and O2(VT)) were improved in the APA and ALs+APA groups (p < 0.05), as well as the forced vital capacity (FVC). Between m6 and m9, a gain in fat mass was only observed in patients in the APA and ALs+APA groups. Conclusion: In our randomized controlled trial, arginine and leucine supplementation failed to improve MetS in patients with obesity, as did the supervised adapted physical activity program and the combination of both. Only the cardiorespiratory parameters were improved by exercise training.
Recent Advances in the Neuroprotective Properties of Ferulic Acid in Alzheimer’s Disease: A Narrative Review
Authors: Di Giacomo Silvia , Percaccio Ester , Gullì Marco , Romano Adele , Vitalone Annabella , Mazzanti Gabriela , Gaetani Silvana , Di Sotto Antonella
Published: September 2022

Alzheimer’s disease (AD) is a progressive degenerative disorder of the central nervous system, characterized by neuroinflammation, neurotransmitter deficits, and neurodegeneration, which finally leads to neuronal death. Emerging evidence highlighted that hyperglycemia and brain insulin resistance represent risk factors for AD development, thus suggesting the existence of an additional AD form, associated with glucose metabolism impairment, named type 3 diabetes. Owing to the limited pharmacological options, novel strategies, especially dietary approaches based on the consumption of polyphenols, have been addressed to prevent or, at least, slow down AD progression. Among polyphenols, ferulic acid is a hydroxycinnamic acid derivative, widely distributed in nature, especially in cereal bran and fruits, and known to be endowed with many bioactivities, especially antioxidant, anti-inflammatory and antidiabetic, thus suggesting it could be exploited as a possible novel neuroprotective strategy. Considering the importance of ferulic acid as a bioactive molecule and its widespread distribution in foods and medicinal plants, the aim of the present narrative review is to provide an overview on the existing preclinical and clinical evidence about the neuroprotective properties and mechanisms of action of ferulic acid, also focusing on its ability to modulate glucose homeostasis, in order to support a further therapeutic interest for AD and type 3 diabetes.
Benzoic Acid Derivatives as Prodrugs for the Treatment of Tuberculosis
Authors: Pais João P. , Magalhães Marta , Antoniuk Olha , Barbosa Ivete , Freire Raquel , Pires David , Valente Emília , Testa Bernard , Anes Elsa , Constantino Luis
Published: September 2022

One interesting approach to fight tuberculosis is the use of prodrugs that often have shown improved biological activities over drugs with poor absorption or difficulty to cross membranes. Previous studies demonstrate that weak acids such as benzoic acid, present antimycobacterial activity. Moreover, esters of those acids revealed to be a viable alternative since they may diffuse more easily through the cell membranes. Previously we showed that mycobacteria can easily activate benzoic acid esters by conversion to the corresponding acid. Since Zhang postulated that the activity of the acids can be dependent on their pKa, we set up to synthesize a library of benzoates with different electron withdrawing groups (4-chloro, 2,6-dichloro, 3,5-dichloro, 4-nitro, and 3,5 dinitro), to modulate pKa of the liberated acid and different alkoxy substituents (propyl, hexyl, and phenyl) to modulate their lipophilicity, and tested the activity of the esters and the corresponding free acids against mycobacteria. We also studied the activation of the esters by mycobacterial enzymes and the stability of the compounds in buffer and plasma. We concluded that all the benzoates in our study can be activated by mycobacterial enzymes and that the phenyl and hexyl esters presented higher activity than the corresponding free acids, with the nitrobenzoates, and especially the dinitrobenzoates, showing very interesting antitubercular activity that deserve further exploration. Our results did not show a correlation between the activity and the pKa of the acids.
Why Multitarget Vasodilatory (Endo)cannabinoids Are Not Effective as Antihypertensive Compounds after Chronic Administration: Comparison of Their Effects on Systemic and Pulmonary Hypertension
Authors: Remiszewski Patryk , Malinowska Barbara
Published: September 2022

Systemic and pulmonary hypertension are multifactorial, high-pressure diseases. The first one is a civilizational condition, and the second one is characterized by a very high mortality rate. Searching for new therapeutic strategies is still an important task. (Endo)cannabinoids, known for their strong vasodilatory properties, have been proposed as possible drugs for different types of hypertension. Unfortunately, our review, in which we summarized all publications found in the PubMed database regarding chronic administration of (endo)cannabinoids in experimental models of systemic and pulmonary hypertension, does not confirm any encouraging suggestions, being based mainly on in vitro and acute in vivo experiments. We considered vasodilator or blood pressure (BP) responses and cardioprotective, anti-oxidative, and the anti-inflammatory effects of particular compounds and their influence on the endocannabinoid system. We found that multitarget (endo)cannabinoids failed to modify higher BP in systemic hypertension since they induced responses leading to decreased and increased BP. In contrast, multitarget cannabidiol and monotarget ligands effectively treated pulmonary and systemic hypertension, respectively. To summarize, based on the available literature, only (endo)cannabinoids with a defined site of action are recommended as potential antihypertensive compounds in systemic hypertension, whereas both mono- and multitarget compounds may be effective in pulmonary hypertension.
Combined Ramipril and Black Seed Oil Dosage Forms Using Bioactive Self-Nanoemulsifying Drug Delivery Systems (BIO-SNEDDSs)
Authors: Shahba Ahmad Abdul-Wahhab , Sherif Abdelrahman Y. , Elzayat Ehab M. , Kazi Mohsin
Published: September 2022

Purpose: Ramipril (RMP)—an angiotensin-converting enzyme (ACE) inhibitor—and thymoquinone (THQ) suffer from poor oral bioavailability. Developing a combined liquid SNEDDS that comprises RMP and black seed oil (as a natural source of THQ) could lead to several formulations and therapeutic benefits. Methods: The present study involved comprehensive optimization of RMP/THQ liquid SNEDDS using self-emulsification assessment, equilibrium solubility studies, droplet size analysis, and experimentally designed phase diagrams. In addition, the optimized RMP/THQ SNEDDS was evaluated against pure RMP, pure THQ, and the combined pure RMP + RMP-free SNEDDS (capsule-in-capsule) dosage form via in vitro dissolution studies. Results: The phase diagram study revealed that black seed oil (BSO) showed enhanced self-emulsification efficiency with the cosolvent (Transcutol P) and hydrogenated castor oil. The phase diagram studies also revealed that the optimized formulation BSO/TCP/HCO-30 (32.25/27.75/40 % w/w) showed high apparent solubility of RMP (25.5 mg/g), good THQ content (2.7 mg/g), and nanometric (51 nm) droplet size. The in-vitro dissolution studies revealed that the optimized drug-loaded SNEDDS showed good release of RMP and THQ (up to 86% and 89%, respectively). Similarly, the isolation between RMP and SNEDDS (pure RMP + RMP-free SNEDDS) using capsule-in-capsule technology showed >84% RMP release and >82% THQ release. Conclusions: The combined pure RMP + RMP-free SNEDDS (containing black seed oil) could be a potential dosage form combining the solubilization benefits of SNEDDSs, enhancing the release of RMP/THQ along with enhancing RMP stability through its isolation from lipid-based excipients during storage.
Synthesis and Structure–Activity Relationships for the Anti-Mycobacterial Activity of 3-Phenyl-N-(Pyridin-2-ylmethyl)Pyrazolo[1,5-a]Pyrimidin-7-Amines
Authors: Sutherland Hamish S. , Choi Peter J. , Lu Guo-Liang , Giddens Anna C. , Tong Amy S. T. , Franzblau Scott G. , Cooper Christopher B. , Palmer Brian D. , Denny William A.
Published: September 2022

Pyrazolo[1,5-a]pyrimidines have been reported as potent inhibitors of mycobacterial ATP synthase for the treatment of Mycobacterium tuberculosis (M.tb). In this work, we report the design and synthesis of approximately 70 novel 3,5-diphenyl-N-(pyridin-2-ylmethyl)pyrazolo[1,5-a]pyrimidin-7-amines and their comprehensive structure–activity relationship studies. The most effective pyrazolo[1,5-a]pyrimidin-7-amine analogues contained a 3-(4-fluoro)phenyl group, together with a variety of 5-alkyl, 5-aryl and 5-heteroaryl substituents. A range of substituted 7-(2-pyridylmethylamine) derivatives were also active. Some of these compounds exhibited potent in vitro M.tb growth inhibition, low hERG liability and good mouse/human liver microsomal stabilities, highlighting their potential as inhibitors of M.tb.
Testing the Protective Effects of Sulfobutylether-Βeta-Cyclodextrin (SBECD) and Sugammadex against Chlorpromazine-Induced Acute Toxicity in SH-SY5Y Cell Line and in NMRI Mice
Authors: Fliszár-Nyúl Eszter , Csepregi Rita , Benkovics Gábor , Szente Lajos , Poór Miklós
Published: September 2022

Chlorpromazine (CPZ) is an antipsychotic drug which can cause several adverse effects and drug poisoning. Recent studies demonstrated that CPZ forms highly stable complexes with certain cyclodextrins (CDs) such as sulfobutylether-β-CD (SBECD) and sugammadex (SGD). Since there is no available antidote in CPZ intoxication, and considering the good tolerability of these CDs even if when administered parenterally, we aimed to investigate the protective effects of SBECD and SGD against CPZ-induced acute toxicity employing in vitro (SH-SY5Y neuroblastoma cells) and in vivo (zebrafish embryo) models. Our major findings and conclusions are the following: (1) both SBECD and SGD strongly relieved the cytotoxic effects of CPZ in SH-SY5Y cells. (2) SGD co-treatment did not affect or increase the CPZ-induced 24 h mortality in NMRI mice, while SBECD caused a protective effect in a dose-dependent fashion. (3) The binding constants of ligand–CD complexes and/or the in vitro protective effects of CDs can help to estimate the in vivo suitability of CDs as antidotes; however, some other factors can overwrite these predictions.
Association between Genetic Polymorphisms and Bleeding in Patients on Direct Oral Anticoagulants
Authors: Yoon Ha-Young , Song Tae-Jin , Yee Jeong , Park Junbeom , Gwak Hye-Sun
Published: September 2022

Objectives: The purpose of our study is to investigate the effects of apolipoprotein B (APOB) and APOE gene polymorphisms on bleeding complications in patients receiving direct oral anticoagulants (DOACs). Methods: A total of 16 single nucleotide polymorphisms (SNPs) in 468 patients were genotyped. Six SNPs of ABCB1 (rs3842, rs1045642, rs2032582, rs1128503, rs3213619, and rs3747802), one SNP of CYP3A5 (rs776746), seven SNPs of APOB (rs1042034, rs2163204, rs693, rs679899, rs13306194, rs13306198, and rs1367117), and two SNPs of APOE (rs429358 and rs7412) were analyzed by a TaqMan genotyping assay. Multivariable logistic regression analysis with selected variables was performed for the construction of a risk scoring system. Two risk scoring systems were compared (demographic factors only vs. demographic factors and genetic factors). Results: In the multivariable analyses, two models were constructed; only demographic factors were included in Model I and both demographic factors and genetic factors in Model II. Rivaroxaban and anemia showed significant association with bleeding in both models. Additionally, ABCB1 rs3842 variant homozygote carriers (CC) and APOB rs13306198 variant allele carriers (AG, AA) had a higher risk of bleeding risk compared with that of wild-type allele carriers (TT, TC) and wild-type homozygote carriers (GG), respectively. Whereas the area under the receiver operating characteristic curve (AUROC) value using demographic factors only was 0.65 (95% confidence interval (CI): 0.56–0.74), the AUROC increased to 0.72 by adding genetic factors (95% CI: 0.65–0.80). The predicted bleeding risks of bleeding in patients with 0, 1, 2, 3, 4, 5, 6, 7 and 8 points from the logistic regression curve were 0.8%, 2.0%, 5.4%, 5.2%, 12.5%, 26.9%, 47.0%, 64.3% and 82.3%, respectively. Conclusions: The study results can be used for enhancing individualized treatment strategies in patients taking DOACs, helping clinicians predict the bleeding risk.
Mitotane Nanocarriers for the Treatment of Adrenocortical Carcinoma: Evaluation of Albumin-Stabilized Nanoparticles and Liposomes in a Preclinical In Vitro Study with 3D Spheroids
Authors: Langer Carolin , Köll-Weber Monika , Holzer Martin , Hantel Constanze , Süss Regine
Published: September 2022

Adrenocortical carcinoma (ACC) is a heterogeneous malignancy related to poor prognosis and limited treatment options. The orphan drug mitotane (MT) is still a cornerstone in ACC therapy, however, its application is characterized by low aqueous solubility, poor bioavailability, and unfavorable pharmacokinetics, often resulting in below-target plasma concentrations or toxic side effects. Throughout the last decades, nanoparticulate formulations have become attractive carriers to improve anticancer therapy. In this study, injectable MT liposomes (DOPC-MT) and albumin-stabilized MT nanoparticles (BSA-MT) were investigated in depth with respect to their physicochemical properties, and their colloidal and therapeutical stability upon storage. Furthermore, in vitro cytotoxicity was evaluated using the ACC model cell line NCI-H295R for preparing multicellular tumor spheroids, and was compared to non-malignant human dermal fibroblasts. Our results clearly demonstrate that BSA-MT, unlike DOPC-MT, represents a stable and storable MT formulation with a high drug concentration in an aqueous medium. Dual centrifugation was established as a reproducible method for nanoparticle preparation. Although an efficient cytotoxic effect on ACC tumor spheroids was demonstrated, concomitant low toxicity to fibroblasts suggests that higher drug concentrations may be tolerated in vivo. Consequently, BSA-MT is a novel and promising therapeutical approach to address key challenges in MT treatment.
Formulation and Evaluation of the In Vitro Performance of Topical Dermatological Products Containing Diclofenac Sodium
Authors: Manian Mahima , Jain Piyush , Vora Deepal , Banga Ajay K.
Published: September 2022

The selection of an appropriate vehicle in a semi-solid topical product is of utmost importance since the vehicle composition and microstructure can potentially cause changes in drug–vehicle or vehicle–skin interactions and affect drug release and subsequent permeation into and across skin. Hence, the aim of this study was to evaluate different semi-solid formulations containing diclofenac sodium for the physicochemical and structural performance of excipients used and various physiological factors governing permeation of drugs applied to skin. The formulations (emulsion, emulgel, gel, and ointment) were prepared using conventional excipients and were found to be homogenous and stable. Rheological analysis demonstrated characteristic shear-thinning and viscoelastic behavior of formulations. The mean release rate of the gel formulation (380.42 ± 3.05 µg/cm2/h0.5) was statistically higher compared to all other formulations. In vitro permeation using human skin showed a significantly greater extent of drug permeation and retention for the emulgel formulation (23.61 ± 1.03 µg/cm2 and 47.95 ± 2.47 µg/cm2, respectively). The results demonstrated that the different formulations influenced product performance due to their inherent properties. The findings of this study demonstrated that a comprehensive physicochemical and structural evaluation is required to optimize the in vitro performance for dermatological formulations depending on the intended therapeutic effect.