bluuebunny/crossref_metadata_2025 huggingface dataset:
Finite Element Analysis of Crack Propagation in Precise Separation Process of Tubing Eccentric Loading Fatigue Fracture
Authors: Zhao Renfeng , Pan Runze , Gao Weicheng , Zhang Dongya , Xiao Xudong , Zhao Pengkang , Zhu Xiaohuan
Published: May 2022

Aiming at the difficulties of efficient and precise separation of metal tubes. For tubing fatigue fracture precision separation, this paper proposes a tubing precision separation process under eccentric wheel rotational bending fatigue loading. Mechanical properties experiments for 304 stainless steel tubing are carried out. On this basis, the J-C constitutive model of 304 stainless steel tubing fatigue fracture is established. In addition, the tubing stress at different rotation angles of the eccentric wheel and the axial stress at four positions of the tubing V-groove section are analyzed, and the process of the tubing precision separation is simulated. According to the results, the axial stress of the tubing V-groove section changes basically symmetrically, and the stress is the largest at the smallest distance from the eccentric wheel excircle axis. During fatigue loading cycles from 0 to 500, the crack growth rate of tubing outer ring is greater than that of the inner ring. With the increase in loading cycles, the crack surface gradually changes from smooth to undulating. Finally, an obvious final fracture region appears, which is consistent with the experimental results.
Harvesting the Aggregate Computing Power of Commodity Computers for Supercomputing Applications
Authors: Regassa Dereje , Yeom Heonyoung , Son Yongseok
Published: May 2022

Distributed supercomputing is becoming common in different companies and academia. Most of the parallel computing researchers focused on harnessing the power of commodity processors and even internet computers to aggregate their computation powers to solve computationally complex problems. Using flexible commodity cluster computers for supercomputing workloads over a dedicated supercomputer and expensive high-performance computing (HPC) infrastructure is cost-effective. Its scalable nature can make it better employed to the available organizational resources, which can benefit researchers who aim to conduct numerous repetitive calculations on small to large volumes of data to obtain valid results in a reasonable time. In this paper, we design and implement an HPC-based supercomputing facility from commodity computers at an organizational level to provide two separate implementations for cluster-based supercomputing using Hadoop and Spark-based HPC clusters, primarily for data-intensive jobs and Torque-based clusters for Multiple Instruction Multiple Data (MIMD) workloads. The performance of these clusters is measured through extensive experimentation. With the implementation of the message passing interface, the performance of the Spark and Torque clusters is increased by 16.6% for repetitive applications and by 73.68% for computation-intensive applications with a speedup of 1.79 and 2.47 respectively on the HPDA cluster. We conclude that the specific application or job could be chosen to run based on the computation parameters on the implemented clusters.
Pilot Sequence Allocation Schemes in Massive MIMO Systems Using Heuristic Approaches
Authors: Matos Everton Alex , Parmezan Bonidia Robson , Sipoli Sanches Danilo , Santos Pozza Rogério , Dias Hiera Sampaio Lucas
Published: May 2022

This paper presents a comparison of different metaheuristic approaches applied to the pilot sequence allocation problem in Massive Multiple-Input Multiple-Output (MIMO) systems. A modified version of the Genetic Algorithm (GA) as well as different versions of the Particle Swarm Optimization (PSO) Algorithm are used to maximize the system spectral efficiency under an inter-cell interference regime. The metaheuristic parameters were optimized and computational simulations under different scenarios parameters were conducted to verify the system performance impact in terms of system spectral efficiency, minimum and maximum spectral efficiency per user and the cumulative distribution function (CDF) of the users spectral efficiencies. The main contributions of this work are: the creation of a public available dataset; heuristic parameters tuning; findings related to the impact of sub-optimal pilot sequence allocation to the users in terms of maximal and minimal achievable user spectral efficiency and the robustness of some algorithms in scenarios with different system loadings.
A Comparison of the Transglycosylation Capacity between the Guar GH27 Aga27A and Bacteroides GH36 BoGal36A α-Galactosidases
Authors: Wiemann Mathias , Axell Emil , Stålbrand Henrik
Published: May 2022

The transglycosylation behavior and capacity of two clan GH-D α-galactosidases, BoGal36A from the gut bacterium Bacteroides ovatus and Aga27A from the guar plant, was investigated and compared. The enzymes were screened for the ability to use para-nitrophenyl-α-galactoside (pNP-Gal), raffinose and locust bean gum (LBG) galactomannan as glycosyl donors with the glycosyl acceptors methanol, propanol, allyl alcohol, propargyl alcohol and glycerol using mass spectrometry. Aga27A was, in general, more stable in the presence of the acceptors. HPLC analysis was developed and used as a second screening method for reactions using raffinose or LBG as a donor substrate with methanol, propanol and glycerol as acceptors. Time-resolved reactions were set up with raffinose and methanol as the donor and acceptor, respectively, in order to develop an insight into the basic transglycosylation properties, including the ratio between the rate of transglycosylation (methyl galactoside synthesis) and rate of hydrolysis. BoGal36A had a somewhat higher ratio (0.99 compared to 0.71 for Aga27A) at early time points but was indicated to be more prone to secondary (product) hydrolysis in prolonged incubations. The methyl galactoside yield was higher when using raffinose (48% for BoGal36A and 38% for Aga27A) compared to LBG (27% for BoGal36A and 30% for Aga27A).
Numerical Computation of Sloshing-Induced Force in Complex Ship Tanks under the Excitation of Ship Rolling Motion Based on the MPS Method
Authors: Sun Xiaofeng , Zhong Yiping , Bian Feng , Liu Chunlei , Yin Yong
Published: May 2022

Liquid sloshing in ship tanks would have a direct effect on ship dynamic stability, and thus is of great importance for navigation safety. To calculate the sloshing-induced force on real ship tanks, this paper presents an approach to numerically simulate the liquid-sloshing in complex tanks using the moving particle semi-implicit (MPS) method. The sloshing-induced force is numerically calculated and used to investigate the effect of different excitation conditions in which the realistic ship motions under different loading conditions have been taken into account. Simulation results show that the maximum sloshing-induced force is much bigger than the corresponding static one. Meanwhile, both the rolling angle and period have significant effects on liquid sloshing.
Biomass Fly Ash Self-Hardened Adsorbent Monoliths for Methylene Blue Removal from Aqueous Solutions
Authors: Capela Marinélia N. , Cesconeto Francielly R. , Pinto Paula C. , Tarelho Luís A. C. , Seabra Maria P. , Labrincha João A.
Published: May 2022

The use of methylene blue (MB) by several industries generates contaminated industrial wastewaters that must be purified before discharge into the environment. Its removal can be achieved by adsorption, and low-cost and easily available materials should be used as adsorbents. Biomass fly ash (BFA) generated from biomass combustion, for heat and power generation, is increasing worldwide since the process is considered CO2 neutral. However, most of the ash is still landfilled. This study aims to evaluate the valorisation of BFA as a low-cost porous bulk adsorbent for MB removal from wastewaters. The monoliths were obtained after 14 days of curing just after adding water and a porogenic agent (aluminium powder) to the BFA, using the self-hardening ability of this waste. The BFA was characterised for chemical (XRF) and mineralogical (XRD) composition, particle size distribution (laser diffraction-COULTER) and morphology (SEM). The monolith sample cured for 14 days was characterised for density, porosity (total and open), microstructure, compressive strength, and MB removal ability (batch tests). The results showed that the addition of aluminium powder (0.09 wt.%) promoted an increase in interconnected porosity and the MB removal efficiency reached 80% for the most porous samples. The equilibrium data for the adsorption process were well characterised by a type 2 Langmuir isotherm equation with a monolayer adsorption capacity (qmax) that ranged from 0.22 to 0.66 mg/g.
Design and Verification of Large-Scaled Flapping Wings for High Altitude Environment
Authors: Zhu Zhichao , Song Bifeng , Xue Dong
Published: May 2022

Large-scaled flapping wings for high altitude environments have great potential for border patrol and biodiversity exploration due to their high flight efficiency and concealment. In this paper, wind tunnel experimental techniques, neural network models, and flight tests are implemented to optimize and validate the performance of flapping wings. Numerical simulation methods were used to give recommendations for the flight state of the vehicle at high altitudes. From sea level to 4000 m altitude, the Reynolds number was subsequently reduced by 27.98%, and the time-averaged lift, drag, and pitching moment decreased by 33.31%, 33.08%, and 33.33%, respectively. A combination of planform with an increase in the internal area of the wing, six wing ribs, and linen film material was selected for its moderate stiffness to generate at least 1300 g of lift and considerable positive thrust, making it easier to reach a trim state. For high altitude environments, the vehicle needs to increase its flight speed and frequency to compensate for the loss of lift and drag due to reduced air density, but this is at the cost of power consumption, which results in reduced endurance, as verified by flight tests. Finally, this study aims to provide guidance on the design of large-scaled flapping wings for high-altitude environments.
Bounds for the Neuman–Sándor Mean in Terms of the Arithmetic and Contra-Harmonic Means
Authors: Li Wen-Hui , Miao Peng , Guo Bai-Ni
Published: May 2022

In this paper, the authors provide several sharp upper and lower bounds for the Neuman–Sándor mean in terms of the arithmetic and contra-harmonic means, and present some new sharp inequalities involving hyperbolic sine function and hyperbolic cosine function.
Novel Approach to Ensure Safe Power Supply for Safety-Relevant Consumers
Authors: Braun Lars , Le Minh , Motz Jürgen , Birke Kai Peter
Published: May 2022

The 12 V powernet in vehicles must fulfill certain safety requirements due to the safety demand of consumers. A potential risk is undervoltage for a safety-relevant consumer, which leads to its fault. Therefore, a novel approach is presented in this study, which can predict the minimum terminal voltage for consumers. This consists of diagnostics of the wiring harness and of the lead-acid battery as well as predefined consumer currents. Using simulation, first the beginning of a drive cycle is simulated to determine the state of the powernet, and afterwards a critical driving maneuver is simulated to validate the predicted minimum terminal voltage. It demonstrates that the novel approach is able to predict a fault due to undervoltage. In addition to fulfilling safety requirements, the novel approach could be used to achieve additional availability and miniaturization of powernet components compared to the state of the art.
Reliability of the Fluoroscopic Assessment of Load-Induced Glenohumeral Translation during a 30° Shoulder Abduction Test
Authors: Croci Eleonora , Künzler Marina , Börlin Sean , Eckers Franziska , Nüesch Corina , Baumgartner Daniel , Müller Andreas , Mündermann Annegret
Published: May 2022

Rotator cuff tears are often linked to superior translational instability, but a thorough understanding of glenohumeral motion is lacking. This study aimed to assess the reliability of fluoroscopically measured glenohumeral translation during a shoulder abduction test. Ten patients with rotator cuff tears participated in this study. Fluoroscopic images were acquired during 30° abduction and adduction in the scapular plane with and without handheld weights of 2 kg and 4 kg. Images were labelled by two raters, and inferior–superior glenohumeral translation was calculated. During abduction, glenohumeral translation (mean (standard deviation)) ranged from 3.3 (2.2) mm for 0 kg to 4.1 (1.8) mm for 4 kg, and from 2.3 (1.5) mm for 0 kg to 3.8 (2.2) mm for 4 kg for the asymptomatic and symptomatic sides, respectively. For the translation range, moderate to good interrater (intra-class correlation coefficient ICC [95% confidence interval (CI)]; abduction: 0.803 [0.691; 0.877]; adduction: 0.705 [0.551; 0.813]) and intrarater reliabilities (ICC [95% CI]; abduction: 0.817 [0.712; 0.887]; adduction: 0.688 [0.529; 0.801]) were found. Differences in the translation range between the repeated measurements were not statistically significant (mean difference, interrater: abduction, −0.1 mm, p = 0.686; adduction, −0.1 mm, p = 0.466; intrarater: abduction 0.0 mm, p = 0.888; adduction, 0.2 mm, p = 0.275). This method is suitable for measuring inferior–superior glenohumeral translation in the scapular plane.
Distinct Cellular Tools of Mild Hyperthermia-Induced Acquired Stress Tolerance in Chinese Hamster Ovary Cells
Authors: Tiszlavicz Ádám , Gombos Imre , Péter Mária , Hegedűs Zoltán , Hunya Ákos , Dukic Barbara , Nagy István , Peksel Begüm , Balogh Gábor , Horváth Ibolya , Vígh László , Török Zsolt
Published: May 2022

Mild stress could help cells to survive more severe environmental or pathophysiological conditions. In the current study, we investigated the cellular mechanisms which contribute to the development of stress tolerance upon a prolonged (0–12 h) fever-like (40 °C) or a moderate (42.5 °C) hyperthermia in mammalian Chinese Hamster Ovary (CHO) cells. Our results indicate that mild heat triggers a distinct, dose-dependent remodeling of the cellular lipidome followed by the expression of heat shock proteins only at higher heat dosages. A significant elevation in the relative concentration of saturated membrane lipid species and specific lysophosphatidylinositol and sphingolipid species suggests prompt membrane microdomain reorganization and an overall membrane rigidification in response to the fluidizing heat in a time-dependent manner. RNAseq experiments reveal that mild heat initiates endoplasmic reticulum stress-related signaling cascades resulting in lipid rearrangement and ultimately in an elevated resistance against membrane fluidization by benzyl alcohol. To protect cells against lethal, protein-denaturing high temperatures, the classical heat shock protein response was required. The different layers of stress response elicited by different heat dosages highlight the capability of cells to utilize multiple tools to gain resistance against or to survive lethal stress conditions.
Thirty-Five-Year History of Desialylated Lipoproteins Discovered by Vladimir Tertov
Authors: Glanz Victor , Bezsonov Evgeny E. , Soldatov Vladislav , Orekhov Alexander N.
Published: May 2022

Atherosclerosis is one of the leading causes of death in developed and developing countries. The atherogenicity phenomenon cannot be separated from the role of modified low-density lipoproteins (LDL) in atherosclerosis development. Among the multiple modifications of LDL, desialylation deserves to be discussed separately, since its atherogenic effects and contribution to atherogenicity are often underestimated or, simply, forgotten. Vladimir Tertov is linked to the origin of the research related to desialylated lipoproteins, including the association of modified LDL with atherogenicity, autoimmune nature of atherosclerosis, and discovery of sialidase activity in blood plasma. The review will briefly discuss all the above-mentioned information, with a description of the current situation in the research.
A Very Rare Variant in SREBF2, a Possible Cause of Hypercholesterolemia and Increased Glycemic Levels
Authors: García-García Ana-Bárbara , Martínez-Hervás Sergio , Vernia Santiago , Ivorra Carmen , Pulido Inés , Martín-Escudero Juan-Carlos , Casado Marta , Carretero Julián , Real José T. , Chaves Felipe Javier
Published: May 2022

Patients with high cholesterol and glucose levels are at high risk for cardiovascular disease. The Sterol Regulatory Element Binding Protein (SREBP) system regulates genes involved in lipid, cholesterol and glucose pathways. Autosomal Dominant Hypercholesterolemias (ADHs) are a group of diseases with increased cholesterol levels. They affect 1 out of every 500 individuals. About 20–30% of patients do not present any mutation in the known genes (LDLR, APOB and PCSK9). ADHs constitute a good model to identify the genes involved in the alteration of lipid levels or possible therapeutic targets. In this paper, we studied whether a mutation in the SREBP system could be responsible for ADH and other metabolic alterations present in these patients. Forty-one ADH patients without mutations in the main responsible genes were screened by direct sequencing of SREBP system genes. A luciferase reporter assay of the found mutation and an oral glucose tolerance test in carriers and non-carriers were performed. We found a novel mutation in the SREBF2 gene that increases transcription levels and cosegregates with hypercholesterolemia, and we found increased glucose levels in one family. SREBP2 is known to be involved in cholesterol synthesis, plasma levels and glucose metabolism in humans. The found mutation may involve the SREBF2 gene in hypercholesterolemia combined with hyperglycemia.
Acetone Gas Sensor Based on SWCNT/Polypyrrole/Phenyllactic Acid Nanocomposite with High Sensitivity and Humidity Stability
Authors: Byeon Jun-Ho , Kim Ji-Sun , Kang Hyo-Kyung , Kang Sungmin , Kim Jin-Yeol
Published: May 2022

We synthesized core-shell-shaped nanocomposites composed of a single-walled carbon nanotube (SWCNT) and heptadecafluorooctanesulfonic acid-doped polypyrrole (C8F-doped-PPy)/phenyllatic acid (PLA), i.e., C8F-doped-PPy/PLA@SWCNT, for detecting acetone gas with high sensitivity and humidity stability. The obtained nanocomposites have the structural features of a sensing material as a C8F-doped-PPy layer surrounding a single-stranded SWCNT, and a PLA layer on the outer surface of the PPy as a specific sensing layer for acetone. PLA was chemically combined with the positively charged PPy backbone and provided the ability to reliably detect acetone gas at concentrations as low as 50 ppb even at 25 °C, which is required for medical diagnoses via human breath analysis. When C8F was contained in the pyrrole monomer in a ratio of 0.1 mol, it was able to stably detect an effective signal in a relative humidity (RH) of 0–80% range.
Eye Tracking in Patients with Parkinson’s Disease Treated with Nabilone–Results of a Phase II, Placebo-Controlled, Double-Blind, Parallel-Group Pilot Study
Authors: Ellmerer Philipp , Peball Marina , Carbone Federico , Ritter Marcel , Heim Beatrice , Marini Kathrin , Valent Dora , Krismer Florian , Poewe Werner , Djamshidian Atbin , Seppi Klaus
Published: May 2022

The topic of the therapeutic use of cannabinoids in Parkinson’s disease (PD) is broadly discussed and frequently comes up in the outpatient clinic. So far, there are only a few randomized clinical trials assessing the effects of cannabinoids in PD. We are able to demonstrate a reduction in non-motor symptom (NMS) burden after the administration of nabilone. As impairment of attention and working memory have been described earlier as possible side effects, we assess cognitive performance using saccadic paradigms measured by an eye tracker. We do not observe a significant difference in any of the saccadic paradigms between PD patients on placebo versus those treated with nabilone. We, therefore, conclude that top-down inhibitory control is not affected by the tetrahydrocannabinol analogue. Nabilone did not significantly worsen cognitive performance and appears to be safe to use in selected PD patients who suffer from disabling NMS.
Mindfulness-Enhanced Computerized Cognitive Training for Depression: An Integrative Review and Proposed Model Targeting the Cognitive Control and Default-Mode Networks
Authors: Bursky Mikell , Egglefield Dakota A. , Schiff Sophie G. , Premnath Pranitha , Sneed Joel R.
Published: May 2022

Depression is often associated with co-occurring neurocognitive deficits in executive function (EF), processing speed (PS) and emotion regulation (ER), which impact treatment response. Cognitive training targeting these capacities results in improved cognitive function and mood, demonstrating the relationship between cognition and affect, and shedding light on novel targets for cognitive-focused interventions. Computerized cognitive training (CCT) is one such new intervention, with evidence suggesting it may be effective as an adjunct treatment for depression. Parallel research suggests that mindfulness training improves depression via enhanced ER and augmentation of self-referential processes. CCT and mindfulness training both act on anti-correlated neural networks involved in EF and ER that are often dysregulated in depression—the cognitive control network (CCN) and default-mode network (DMN). After practicing CCT or mindfulness, downregulation of DMN activity and upregulation of CCN activity have been observed, associated with improvements in depression and cognition. As CCT is posited to improve depression via enhanced cognitive function and mindfulness via enhanced ER ability, the combination of both forms of training into mindfulness-enhanced CCT (MCCT) may act to improve depression more rapidly. MCCT is a biologically plausible adjunct intervention and theoretical model with the potential to further elucidate and target the causal mechanisms implicated in depressive symptomatology. As the combination of CCT and mindfulness has not yet been fully explored, this is an intriguing new frontier. The aims of this integrative review article are four-fold: (1) to briefly review the current evidence supporting the efficacy of CCT and mindfulness in improving depression; (2) to discuss the interrelated neural networks involved in depression, CCT and mindfulness; (3) to present a theoretical model demonstrating how MCCT may act to target these neural mechanisms; (4) to propose and discuss future directions for MCCT research for depression.
The Feasibility of Hydroxypropyl Methylcellulose as an Admixture for Porous Vegetarian Concrete Using Coarse Recycled Aggregates
Authors: Zhang Kun , Yin Wei , Chen Xi , Li Hui , Cao Mingxing , Zhu Shengxue
Published: May 2022

In this paper, hydroxypropyl methylcellulose (HPMC) is used as a new additive for porous vegetarian concrete (PVC) to improve its void structure and strength. The effect of the HPMC on the fluidity of the mortar was first investigated by a viscosity test. Then the cement hydration process was determined for analyzing the effect of the HPMC on the strength and durability of the hardened PVC. Subsequently, experiments to investigate the mass transport and compressive strength characteristics, as well as the vegetarian properties, of the concrete were carried out. The results show that the bonding forces between the recycled aggregates and packing layer are elevated by viscosity improvement. The viscocity and flowability are significantly related to the dosage of HPMC from 0.0‰ to 0.3‰. The harden time is also delayed while the content of HPMC increases.The segregation phenomenon caused by the recycled aggregate powder in porous concrete could also be relieved by adding HPMC. The durability of PVC in the wetting–drying cyclic test is significantly improved by incorporating HPMC. The results of the vegetarian test also prove that, with HPMC mixing, sufficient space would be created in porous concrete, which is more suitable for plant growth due to a large number of existing pore channels.
Three-Dimensional Organotypic Cultures Reshape the microRNAs Transcriptional Program in Breast Cancer Cells
Authors: Salinas-Vera Yarely M. , Valdés Jesús , Hidalgo-Miranda Alfredo , Cisneros-Villanueva Mireya , Marchat Laurence A. , Nuñez-Olvera Stephanie I. , Ramos-Payán Rosalio , Pérez-Plasencia Carlos , Arriaga-Pizano Lourdes A. , Prieto-Chávez Jessica L. , López-Camarillo César
Published: May 2022

The 3D organotypic cultures, which depend on the growth of cells over the extracellular matrix (ECM) used as a scaffold, can better mimic several characteristics of solid cancers that influence tumor biology and the response to drug therapies. Most of our current knowledge on cancer is derived from studies in 2D cultures, which lack the ECM-mediated microenvironment. Moreover, the role of miRNAs that is critical for fine-tuning of gene expression is poorly understood in 3D cultures. The aim of this study was to compare the miRNA expression profiles of breast cancer cells grown in 2D and 3D conditions. On an on-top 3D cell culture model using a basement membrane matrix enriched with laminin, collagen IV, entactin, and heparin-sulfate proteoglycans, the basal B (Hs578T) and luminal (T47D) breast cancer cells formed 3D spheroid-like stellate and rounded mass structures, respectively. Morphological changes in 3D cultures were observed as cell stretching, cell–cell, and cell–ECM interactions associated with a loss of polarity and reorganization on bulk structures. Interestingly, we found prolongations of the cytoplasmic membrane of Hs578T cells similar to tunneled nanotubes contacting between neighboring cells, suggesting the existence of cellular intercommunication processes and the possibility of fusion between spheroids. Expression profiling data revealed that 354 miRNAs were differentially expressed in 3D relative to 2D cultures in Hs578T cells. Downregulated miRNAs may contribute to a positive regulation of genes involved in hypoxia, catabolic processes, and focal adhesion, whereas overexpressed miRNAs modulate genes involved in negative regulation of the cell cycle. Target genes of the top ten modulated miRNAs were selected to construct miRNA/mRNA coregulation networks. Around 502 interactions were identified for downregulated miRNAs, including miR-935/HIF1A and miR-5189-3p/AKT that could contribute to cell migration and the response to hypoxia. Furthermore, the expression levels of miR-935 and its target HIF1A correlated with the expression found in clinical tumors and predicted poor outcomes. On the other hand, 416 interactions were identified for overexpressed miRNAs, including miR-6780b-5p/ANKRD45 and miR-7641/CDK4 that may result in cell proliferation inhibition and cell cycle arrest in quiescent layers of 3D cultures. In conclusion, 3D cultures could represent a suitable model that better resembles the miRNA transcriptional programs operating in tumors, with implications not only in the understanding of basic cancer biology in 3D microenvironments, but also in the identification of novel biomarkers of disease and potential targets for personalized therapies in cancer.
Antagonizing Glutamine Bioavailability Promotes Radiation Sensitivity in Prostate Cancer
Authors: Thiruvalluvan Manish , Billet Sandrine , Bhowmick Neil A.
Published: May 2022

Nearly half of localized prostate cancer (PCa) patients given radiation therapy develop recurrence. Here, we identified glutamine as a key player in mediating the radio-sensitivity of PCa. Glutamine transporters and glutaminase are upregulated by radiation therapy of PCa cells, but respective inhibitors were ineffective in radio-sensitization. However, targeting glutamine bioavailability by L-asparaginase (L-ASP) led to a significant reduction in clonogenicity when combined with irradiation. L-ASP reduced extracellular asparagine and glutamine, but the sensitization effects were driven through its depletion of glutamine. L-ASP led to G2/M cell cycle checkpoint blockade. As evidence, there was a respective delay in DNA repair associated with RAD51 downregulation and upregulation of CHOP, contributing to radiation-induced cell death. A radio-resistant PCa cell line was developed, was found to bypass radiation-induced mitotic catastrophe, and was sensitive to L-ASP/radiation combination treatment. Previously, PCa-associated fibroblasts were reported as a glutamine source supporting tumor progression. As such, glutamine-free media were not effective in promoting radiation-induced PCa cell death when co-cultured with associated primary fibroblasts. However, the administration L-ASP catalyzed glutamine depletion with irradiated co-cultures and catalyzed tumor volume reduction in a mouse model. The clinical history of L-ASP for leukemia patients supports the viability for its repurposing as a radio-sensitizer for PCa patients.
Studies of the Efficacy of Low-Dose Apatinib Monotherapy as Third-Line Treatment in Patients with Metastatic Colorectal Cancer and Apatinib’s Novel Anticancer Effect by Inhibiting Tumor-Derived Exosome Secretion
Authors: Zhao Lingying , Yu Qiang , Gao Chunyi , Xiang Jingzhou , Zheng Bowen , Feng Yujie , Li Runyang , Zhang Wenqing , Hong Xiaoting , Zhan Yan-yan , Xiao Li , Hu Tianhui
Published: May 2022

Antiangiogenic therapy is an important treatment strategy for metastatic colorectal cancer (mCRC). We carried out a clinical study of low-dose apatinib (250 mg) monotherapy as a third-line treatment in patients with mCRC and assessed its efficacy and safety. It demonstrated that low-dose apatinib had comparable survival outcomes, significantly improved the patient quality of life, and caused tolerable adverse reactions. To further investigate the underlying mechanism of the effects of apatinib in CRC besides angiogenesis, we performed RNA-seq, and our results suggested that apatinib may have other potential antitumor mechanisms in CRC through multiple pathways, including exosomes secretion. In RKO and HCT116 cells, apatinib significantly reduced exosomes secretion by targeting multivesicular body (MVB) transport. Further studies have indicated that apatinib not only promoted the degradation of MVBs via the regulation of LAMP2 but also interfered with MVB transport by inhibiting Rab11 expression. Moreover, apatinib inhibited MVB membrane fusion by reducing SNAP23 and VAMP2 expression. In vivo, apatinib inhibited orthotopic murine colon cancer growth and metastasis and reduced the serum exosomes amount. This novel regulatory mechanism provides a new perspective for the antitumor effect of apatinib beyond angiogenesis inhibition.
RON (MST1R) and HGFL (MST1) Co-Overexpression Supports Breast Tumorigenesis through Autocrine and Paracrine Cellular Crosstalk
Authors: Hunt Brian G. , Jones Angelle , Lester Carissa , Davis James C. , Benight Nancy M. , Waltz Susan E.
Published: May 2022

Background: Aberrant RON signaling is present in numerous cancers including breast cancer. Evidence suggests that the ligand, hepatocyte growth factor-like (HGFL), is also overexpressed in breast cancer. RON (MST1R) and HGFL (MST1) genes are located on human chromosome 3 and mouse chromosome 9 respectively and are found near each other in both species. Based on co-expression patterns, we posited that RON and HGFL are co-regulated and that coordinate upregulation drives aggressive tumorigenesis. Methods: Mouse models were used to establish the functional significance of RON and HGFL co-overexpression on the activation of tumor cells and tumor-associated macrophages in breast cancer. TCGA and METABRIC gene expression and alteration data were used to query the relationships between MST1R and MST1 in breast cancer. Results: In tumor models, physiologic sources of HGFL modestly improve Arginase-1+ (M2) macrophage recruitment to the tumor proper. Tumor-cell produced HGFL functions in autocrine to sustain tumor cell RON activation and MAPK-dependent secretion of chemotactic factors and in paracrine to activate RON on macrophages and to promote breast cancer stem cell self-renewal. In silico analyses support that RON and HGFL are co-expressed across virtually all cancer types including breast cancer and that common genomic alterations do not appear to be drivers of RON/HGFL co-overexpression. Conclusions: Co-overexpression of RON and HGFL in breast cancer cells (augmented by physiologic sources of HGFL) promotes tumorigenesis through autocrine-mediated RON activation/RON-dependent secretome changes and paracrine activation of macrophage RON to promote breast cancer stem cell self-renewal.
Management of Hematologic Malignancies in the Era of COVID-19 Pandemic: Pathogenetic Mechanisms, Impact of Obesity, Perspectives, and Challenges
Authors: Tsilingiris Dimitrios , Nasiri-Ansari Narjes , Spyrou Nikolaos , Magkos Faidon , Dalamaga Maria
Published: May 2022

The COVID-19 pandemic brought about an unprecedented societal and healthcare system crisis, considerably affecting healthcare workers and patients, particularly those with chronic diseases. Patients with hematologic malignancies faced a variety of challenges, pertinent to the nature of an underlying hematologic disorder itself as well as its therapy as a risk factor for severe SARS-CoV-2 infection, suboptimal vaccine efficacy and the need for uninterrupted medical observation and continued therapy. Obesity constitutes another factor which was acknowledged since the early days of the pandemic that predisposed people to severe COVID-19, and shares a likely causal link with the pathogenesis of a broad spectrum of hematologic cancers. We review here the epidemiologic and pathogenetic features that obesity and hematologic malignancies share, as well as potential mutual pathophysiological links predisposing people to a more severe SARS-CoV-2 course. Additionally, we attempt to present the existing evidence on the multi-faceted crucial challenges that had to be overcome in this diverse patient group and discuss further unresolved questions and future challenges for the management of hematologic malignancies in the era of COVID-19.
Clinical Landscape of PARP Inhibitors in Ovarian Cancer: Molecular Mechanisms and Clues to Overcome Resistance
Authors: Kyo Satoru , Kanno Kosuke , Takakura Masahiro , Yamashita Hitomi , Ishikawa Masako , Ishibashi Tomoka , Sato Seiya , Nakayama Kentaro
Published: May 2022

The survival of patients with advanced or recurrent ovarian cancer has improved tremendously in the past decade, mainly due to the establishment of maintenance therapy with poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis) after conservative chemotherapies. Despite their superior efficacy, resistance to PARPis has been reported, and patients with resistance have a much worse prognosis. Therefore, the development of novel treatment strategies to overcome PARPi resistance is urgently needed. The present review article focuses on the molecular mechanisms of how PARPis exert cytotoxic effects on cancer cells through DNA repair processes, especially the genetic background and tumor microenvironment favored by PARPis. Furthermore, currently available information on PARPi resistance mechanisms is introduced and discussed to develop a novel therapeutic approach against them.
Dynamic Visualization of TGF-β/SMAD3 Transcriptional Responses in Single Living Cells
Authors: Marvin Dieuwke L. , You Li , Bornes Laura , van Dinther Maarten , Peters Niek , Dang Hao , Hakuno Sarah K. , Hornsveld Marten , Kranenburg Onno , van Rheenen Jacco , Rohling Jos H. T. , Chien Miao-Ping , ten Dijke Peter , Ritsma Laila
Published: May 2022

Transforming growth factor-β (TGF-β) signaling is tightly controlled in duration and intensity during embryonic development and in the adult to maintain tissue homeostasis. To visualize the TGF-β/SMAD3 signaling kinetics, we developed a dynamic TGF-β/SMAD3 transcriptional fluorescent reporter using multimerized SMAD3/4 binding elements driving the expression of a quickly folded and highly unstable GFP protein. We demonstrate the specificity and sensitivity of this reporter and its wide application to monitor dynamic TGF-β/SMAD3 transcriptional responses in both 2D and 3D systems in vitro, as well as in vivo, using live-cell and intravital imaging. Using this reporter in B16F10 cells, we observed single cell heterogeneity in response to TGF-β challenge, which can be categorized into early, late, and non-responders. Because of its broad application potential, this reporter allows for new discoveries into how TGF-β/SMAD3-dependent transcriptional dynamics are affected during multistep and reversible biological processes.
Activation of MT1/MT2 to Protect Testes and Leydig Cells against Cisplatin-Induced Oxidative Stress through the SIRT1/Nrf2 Signaling Pathway
Authors: Zhang Junqiang , Fang Yuan , Tang Dongdong , Xu Xingyu , Zhu Xiaoqian , Wu Shusheng , Yu Hui , Cheng Huiru , Luo Ting , Shen Qunshan , Gao Yang , Ma Cong , Liu Yajing , Wei Zhaolian , Chen Xiaoyu , Tao Fangbiao , He Xiaojin , Cao Yunxia
Published: May 2022

There is growing concern that chemotherapy drugs can damage Leydig cells and inhibit the production of testosterone. Increasing evidence shows that melatonin benefits the reproductive process. This study mainly explores the protective effect and possible molecular mechanism of melatonin regarding cisplatin-induced oxidative stress in testicular tissue and Leydig cells. We found that there were only Leydig and Sertoli cells in the testes of gastrointestinal tumor patients with azoospermia caused by platinum chemotherapeutic drugs. Melatonin (Mel) receptor 1/melatonin receptor 2 (MT1/MT2) was mainly expressed in human and mouse Leydig cells of the testes. We also observed that the melatonin level in the peripheral blood decreased and oxidative stress occurred in mice treated with cisplatin or gastrointestinal tumor patients treated with platinum-based chemotherapeutic drugs. iTRAQ proteomics showed that SIRT1/Nrf2 signaling and MT1 proteins were downregulated in cisplatin-treated mouse testes. The STRING database predicted that MT1 might be able to regulate the SIRT1/Nrf2 signaling pathway. Melatonin reduced oxidative stress and upregulated SIRT1/Nrf2 signaling in cisplatin-treated mouse testes and Leydig cells. Most importantly, after inhibiting MT1/MT2, melatonin could not upregulate SIRT1/Nrf2 signaling in cisplatin-treated Leydig cells. The MT1/MT2 inhibitor aggravated the cisplatin-induced downregulation of SIRT1/Nrf2 signaling and increased the apoptosis of Leydig cells. We believe that melatonin stimulates SIRT1/Nrf2 signaling by activating MT1/MT2 to prevent the cisplatin-induced apoptosis of Leydig cells.
Role of Transcriptional and Epigenetic Regulation in Lymphatic Endothelial Cell Development
Authors: La Hyeonwoo , Yoo Hyunjin , Park Young Bin , Thang Nguyen Xuan , Park Chanhyeok , Yoo Seonho , Lee Hyeonji , Choi Youngsok , Song Hyuk , Do Jeong Tae , Hong Kwonho
Published: May 2022

The lymphatic system is critical for maintaining the homeostasis of lipids and interstitial fluid and regulating the immune cell development and functions. Developmental anomaly-induced lymphatic dysfunction is associated with various pathological conditions, including lymphedema, inflammation, and cancer. Most lymphatic endothelial cells (LECs) are derived from a subset of endothelial cells in the cardinal vein. However, recent studies have reported that the developmental origin of LECs is heterogeneous. Multiple regulatory mechanisms, including those mediated by signaling pathways, transcription factors, and epigenetic pathways, are involved in lymphatic development and functions. Recent studies have demonstrated that the epigenetic regulation of transcription is critical for embryonic LEC development and functions. In addition to the chromatin structures, epigenetic modifications may modulate transcriptional signatures during the development or differentiation of LECs. Therefore, the understanding of the epigenetic mechanisms involved in the development and function of the lymphatic system can aid in the management of various congenital or acquired lymphatic disorders. Future studies must determine the role of other epigenetic factors and changes in mammalian lymphatic development and function. Here, the recent findings on key factors involved in the development of the lymphatic system and their epigenetic regulation, LEC origins from different organs, and lymphatic diseases are reviewed.
Mediating EGFR-TKI Resistance by VEGF/VEGFR Autocrine Pathway in Non-Small Cell Lung Cancer
Authors: Osude Chike , Lin Leo , Patel Meet , Eckburg Adam , Berei Joseph , Kuckovic Adijan , Dube Namrata , Rastogi Aayush , Gautam Shruti , Smith Thomas J. , Sreenivassappa Shylendra B. , Puri Neelu
Published: May 2022

NSCLC treatment includes targeting of EGFR with tyrosine kinase inhibitors (TKIs) such as Erlotinib; however, resistance to TKIs is commonly acquired through T790M EGFR mutations or overexpression of vascular endothelial growth factor receptor-2 (VEGFR-2). We investigated the mechanisms of EGFR-TKI resistance in NSCLC cell lines with EGFR mutations or acquired resistance to Erlotinib. These studies showed upregulated gene and protein expression of VEGF, VEGFR-2, and a VEGF co-receptor neuropilin-1 (NP-1) in Erlotinib-resistant (1.4–5.3-fold) and EGFR double-mutant (L858R and T790M; 4.1–8.3-fold) NSCLC cells compared to parental and EGFR single-mutant (L858R) NSCLC cell lines, respectively. Immunofluorescence and FACS analysis revealed increased expression of VEGFR-2 and NP-1 in EGFR-TKI-resistant cell lines compared to TKI-sensitive cell lines. Cell proliferation assays showed that treatment with a VEGFR-2 inhibitor combined with Erlotinib lowered cell survival in EGFR double-mutant NSCLC cells to 9% compared to 72% after treatment with Erlotinib alone. Furthermore, Kaplan–Meier analysis revealed shorter median survival in late-stage NSCLC patients with high vs. low VEGFR-2 expression (14 mos vs. 21 mos). The results indicate that VEGFR-2 may play a key role in EGFR-TKI resistance and that combined treatment of Erlotinib with a VEGFR-2 inhibitor may serve as an effective therapy in NSCLC patients with EGFR mutations.
Why Do Young Adults in the United States Have Such Low Rates of Organ Donation Registration?
Authors: Wotring Amy J. , Jordan Timothy R. , Saltzman Barbara , Glassman Tavis , Holloway Jennifer , Khubchandani Jagdish
Published: May 2022

The demand for transplantable organs has outpaced the supply. Thus, 20 Americans die every day while waiting for an organ. Although most adults support organ donation, 42% are not registered. The rate is even lower among young adults who are not enrolled in/never graduated from college. The aim of this study was to use the Integrated Behavior Model (IBM) to identify factors that predicted organ donation registration among a racially diverse sample of non-student young adults. The study was observational and cross-sectional. Proportional allocation was used to identify a racially diverse sample of 550 non-student, young adults from ten states in the U.S. with the lowest registration rates. A valid and reliable survey was designed, pilot-tested, and administered. A total of 407 young adults completed the survey (74%). Only 19% were registered donors. Caucasians were more likely to be registered donors than racial minorities, χ² (3, N = 407) = 15.19, p = 0.002. Those with more positive direct attitudes toward registration were 1.5 times more likely to be registered than those who had negative direct attitudes. Among non-registrants, indirect descriptive norm and direct attitude were statistically significant predictors of behavioral intention. Moreover, those who knew someone who donated an organ and knew someone who needed a transplant were nearly three times more likely to intend to register in the next year. The IBM proved useful in elucidating factors that predicted intention to register among non-student young adults. The IBM should be used by those who desire to increase registration rates.
Sleep and Executive Functioning in Pediatric Traumatic Brain Injury Survivors after Critical Care
Authors: Williams Cydni N. , McEvoy Cindy T. , Lim Miranda M. , Shea Steven A. , Kumar Vivek , Nagarajan Divya , Drury Kurt , Rich-Wimmer Natalia , Hall Trevor A.
Published: May 2022

Over 50,000 children are hospitalized annually for traumatic brain injury (TBI) and face long-term cognitive morbidity. Over 50% develop sleep/wake disturbances (SWDs) that can affect brain development and healing. We hypothesized SWDs would portend worse executive function outcomes in children aged 3–18 years with TBI 1–3 months after hospital discharge. SWDs were defined using the Sleep Disturbances Scale for Children (t-scores ≥ 60). Outcomes included the Global Executive Composite (GEC, t-score) from the Behavior Rating Inventory of Executive Function, Second and Preschool Editions, and multiple objective executive function assessments combined through Principal Components Analysis into a Neurocognitive Index (NCI, z-score). Multiple linear regression evaluated associations between SWDs and executive function outcomes, controlling for covariates. Among 131 children, 68% had clinically significant SWDs, which were associated with significantly worse median scores on the GEC (56 vs. 45) and NCI (−0.02 vs. 0.42; both p < 0.05). When controlling for baseline characteristics and injury severity in multivariable analyses, SWDs were associated with worse GEC (β-coefficient = 7.8; 95% Confidence Interval = 2.5, 13.1), and worse NCI (β-coefficient = −0.4; 95% Confidence Interval = −0.8, −0.04). SWDs in children with TBI are associated with worse executive function outcomes after hospital discharge, and may serve as modifiable targets to improve outcomes.
Inclusive EFL Teaching for Young Students with Special Needs: A Case in China
Authors: Lu Jinjin , Jiang Han , Huang Yi
Published: May 2022

In China, English as a foreign language is important and compulsory from primary education to higher education, essentially because English has become a global language. The Ministry of Education emphasizes that school principals should attempt to train teachers in special education and in assisting students with special education needs (SEN) in regular classes via supportive services. However, EFL teachers usually have insufficient training and do not know how to adjust their teaching methods for students with SEN in regular classes. This study investigated 328 teachers’ teaching practices and their attitudes toward including students with SEN in K–12 English classes in the three largest provinces in east, south, and central China. The findings indicated that English teachers have not used specific teaching resources to teach students with SEN. Teachers noted that they were not provided with specialized training and there were not enough teaching assistants to help the students with SEN. There were significant statistical differences found between primary school teachers and middle school teachers with and without special education training regarding inclusion practices and their attitudes toward inclusion (regarding students with SEN). Most English teachers believe that students with SEN should be taught in special classes with specialized materials rather than in regular EFL classes.