bluuebunny/crossref_metadata_2025 huggingface dataset:
Combined Method for Evaluating Accessibility in Serious Games
Authors: Salvador-Ullauri Luis , Acosta-Vargas Patricia , Gonzalez Mario , Luján-Mora Sergio
Published: September 2020

Nowadays, one of the learning resources in the educational area are serious games, also called training games; they are games designed with a different purpose than fun, whose main objective is to reinforce the new concepts more creatively. However, not all existing serious games are accessible in a way that allows access to a more significant number of users. Therefore, this research proposes to apply a combined method to evaluate accessibility in serious games, considering the Web Content Accessibility Guidelines (WCAG) 2.1. As a case study, we evaluated the accessibility of 82 serious games developed by Physical Education Technology Interactive Simulations at the University of Colorado. We propose to replicate this combined method for users with various types of disabilities, considering the various accessibility barriers. As future work, we suggest generating an accessibility heuristic evaluation focused on serious games, based on the accessibility issues identified. Finally, we believe it is essential to strengthen accessibility policies in each country, as well as implement best practices that generate innovation by incorporating diversity in building and designing more inclusive serious games.
Process Parameter Optimization When Preparing Ti(C, N) Ceramic Coatings Using Laser Cladding Based on a Neural Network and Quantum-Behaved Particle Swarm Optimization Algorithm
Authors: Deng Zixin , Chen Tao , Wang Haojun , Li Shengchen , Liu Defu
Published: September 2020

The formation process of surface coatings fabricated with laser cladding is very complicated and coating quality is closely related to laser cladding process parameters. Generally, the optimization and control of process parameters play key roles when preparing high-quality ceramic coating. In this paper, three reasonable parameters were selected for each process parameter based on the preliminary experiment. The experiment of Ti(C, N) ceramic coating prepared with laser cladding was designed via the Taguchi method. The laser power, spot diameter, overlapping ratio, and scanning velocity were selected as the main process parameters, and their effects on coating micro-hardness were analyzed using the signal-to-noise (S/N) ratio and analysis of variance (ANOVA). Then, based on the back-propagation neural network (BPNN) and quantum-behaved particle swarm optimization (QPSO) algorithm, we created the prediction model of BPNN-QPSO neural network for laser cladding Ti(C, N) ceramic coating. The mapping of process parameters to the micro-hardness of the coating was obtained according to the model and we analyzed the influence of process parameters that interacted with the coating’s micro-hardness. The results showed that the interaction of laser cladding process parameters had a significant effect on the micro-hardness of the coating. The established BPNN-QPSO neural network model was able to map the relationship between laser cladding process parameters and coating micro-hardness. The process parameters optimized by this model had similar results with ANOVA. This research provides guidance for the selection and control of ceramic coating process parameters Ti(C, N) prepared via laser cladding.
Practical Application of Plan–Do–Check–Act Cycle for Quality Improvement of Sustainable Packaging: A Case Study
Authors: Nguyen Vi , Nguyen Nam , Schumacher Bastian , Tran Thanh
Published: September 2020

The research aims to give practical instructions for applying Plan–Do–Check–Act (PDCA) cycle in a packaging process. Eco-friendly, recycled material and a new packaging method for quality improvement and cost efficiency of heavily fragile product packaging are studied in this paper. A case study was conducted at GPEM laboratory, Vietnamese German University, Vietnam. In this case study, the current packaging style with Styrofoam material was analyzed and replaced by new packaging material and methods after applying the PDCA cycle for continuous quality improvement. Targets of the research were to find the new packaging method using friendly environment materials, to improve the quality, and to reduce the defect ratio due to packaging for fine-stone round surface fountains. Moreover, the extra cost should not be higher than 20% compared with the current packaging cost. The article proposes a simplified way that focuses on the combination of quality tools in the PDCA multiple phases to solve these problems. The quality tools are applied effectively through the PDCA cycle from collecting data, defining, analysis, testing, evaluation, and making decisions. New packaging design was been produced and tested successfully. One hundred percent of new packaging boxes for the mid-weight fountains (under 15 kg) passed the dropping test condition. Nearly 10% of the heavier weight products (above 15 kg) still had some small cracks on their top and bottom due to drop tests. Another PDCA cycle is recommended to continue applying for achieving a thorough solution. The conducted results show that PDCA is an effective method to tackle the damage product issue due to inappropriate packaging material and technique. It also brings good solutions for balancing sustainable packaging improvement and reducing the cost to ensure profit for companies. Besides contributing a guide reference for PDCA deployment, the authors intend to inspire practitioners and researchers to broaden exploration of the PDCA applications for sustainable packaging methodology. The research analysis shows that the PDCA methodology should be applied for defect reduction and quality enhancement in the packaging field. The field currently lacks systematic guidance for continuous improvement.
Investigating the Effect of Cross-Modeling in Landslide Susceptibility Mapping
Authors: Pawluszek-Filipiak Kamila , Oreńczak Natalia , Pasternak Marta
Published: September 2020

To mitigate the negative effects of landslide occurrence, there is a need for effective landslide susceptibility mapping (LSM). The fundamental source for LSM is landslide inventory. Unfortunately, there are still areas where landslide inventories are not generated due to financial or reachability constraints. Considering this led to the following research question: can we model landslide susceptibility in an area for which landslide inventory is not available but where such is available for surrounding areas? To answer this question, we performed cross-modeling by using various strategies for landslide susceptibility. Namely, landslide susceptibility was cross-modeled by using two adjacent regions (“Łososina” and “Gródek”) separated by the Rożnów Lake and Dunajec River. Thus, 46% and 54% of the total detected landslides were used for the LSM in “Łososina” and “Gródek” model, respectively. Various topographical, geological, hydrological and environmental landslide-conditioning factors (LCFs) were created. These LCFs were generated on the basis of the Digital Elevation Model (DEM), Sentinel-2A data, a digitized geological and soil suitability map, precipitation, the road network and the Różnów lake shapefile. For LSM, we applied the Frequency Ratio (FR) and Landslide Susceptibility Index (LSI) methods. Five zones showing various landslide susceptibilities were generated via Natural Jenks. The Seed Cell Area Index (SCAI) and Relative Landslide Density Index were used for model validation. Even when the SCAI indicated extremely high values for “very low” susceptibility classes and very small values for “very high” susceptibility classes in the training and validation areas, the accuracy of the LSM in the validation areas was significantly lower. In the “Łososina” model, 90% and 57% of the landslides fell into the “high” and “very high” susceptibility zones in the training and validation areas, respectively. In the “Gródek” model, 86% and 46% of the landslides fell into the “high” and “very high” susceptibility zones in the training and validation areas, respectively. Moreover, the comparison between these two models was performed. Discrepancies between these two models exist in the areas of critical geological structures (thrust and fault proximity), and the reliability for such susceptibility zones can be low (2–3 susceptibility zone difference). However, such areas cover only 11% of the analyzed area; thus, we can conclude that in remaining regions (89%), LSM generated by the inventory for the surrounding area can be useful. Therefore, the low reliability of such a map in areas of critical geological structures should be borne in mind.
A Machine Learning Approach to Predicting Readmission or Mortality in Patients Hospitalized for Stroke or Transient Ischemic Attack
Authors: Hung Ling-Chien , Sung Sheng-Feng , Hu Ya-Han
Published: September 2020

Readmissions after stroke are not only associated with greater levels of disability and a higher risk of mortality but also increase overall medical costs. Predicting readmission risk and understanding its causes are thus essential for healthcare resource allocation and quality improvement planning. By using machine learning techniques on initial admission data, this study aimed to develop prediction models for readmission or mortality after stroke. During model development, resampling methods were implemented to balance the class distribution. Two-layer nested cross-validation was used to build and evaluate the prediction models. A total of 3422 patients were included for analysis. The 90-day rate of readmission or mortality was 17.6%. This study identified several important predictive factors, including age, prior emergency department visits, pre-stroke functional status, stroke severity, body mass index, consciousness level, and use of a nasogastric tube. The Naïve Bayes model with class weighting to compensate for class imbalance achieved the highest discriminatory capacity in terms of the area under the receiver operating characteristic curve (0.661). Despite having room for improvement, the prediction models could be used for early risk assessment of patients with stroke. Identification of patients at high risk for readmission or mortality immediately after admission has the potential of enabling early discharge planning and transitional care interventions.
Impacts of Compaction Load and Procedure on Stress-Deformation Behaviors of a Soil Geosynthetic Composite (SGC) Mass—A Case Study
Authors: Gui Meenwah , Phan Truc , Pham Thang
Published: September 2020

Fill compaction in the construction of Geosynthetic Reinforced Soil (GRS) mass is typically performed by operating a vibratory or roller compactor, which in turns imposed a compaction load in direction perpendicular to the wall face. The compaction process resulted in the development of the so-called compaction-induced stress (CIS), which may subsequently increase the stiffness and strength of the fill material. Compaction process is normally simulated using one of the following compaction procedures—(i) a uniformly distributed load acting on the top surface of each soil lift, (ii) a uniformly distributed load acting on the top and bottom surface of each soil lift, and (iii) a moving strip load with different width. Uncertainties such as compaction procedures, compaction and surcharge loads led to the disparity in studying the mechanism of GRS mass. This paper aimed to study the impact of compaction load, compaction procedure, surcharge load and CIS on the stress-deformation behavior of GRS mass via the simulation of a 2 m high Soil Geosynthetic Composite (SGC) mass and a 6 m high GRS mass. The results were examined in terms of reinforcement strains, wall lateral displacements, and net CIS. Results from the analysis show the important impacts of compaction conditions on the stress-deformation behavior of SGC mass and the CIS.
Integrated Flood Forecasting and Warning System against Flash Rainfall in the Small-Scaled Urban Stream
Authors: Lee Jung Hwan , Yuk Gi Moon , Moon Hyeon Tae , Moon Young-Il
Published: September 2020

The flood forecasting and warning system enable an advanced warning of flash floods and inundation depths for disseminating alarms in urban areas. Therefore, in this study, we developed an integrated flood forecasting and warning system combined inland-river that systematized technology to quantify flood risk and flood forecasting in urban areas. LSTM was used to predict the stream depth in the short-term inundation prediction. Moreover, rainfall prediction by radar data, a rainfall-runoff model combined inland-river by coupled SWMM and HEC-RAS, automatic simplification module of drainage networks, automatic calibration module of SWMM parameter by Dynamically Dimensioned Search (DDS) algorithm, and 2-dimension inundation database were used in very short-term inundation prediction to warn and convey the flood-related data and information to communities. The proposed system presented better forecasting results compared to the Seoul integrated disaster prevention system. It can provide an accurate water level for 30 min to 90 min lead times in the short-term inundation prediction module. And the very short-term inundation prediction module can provide water level across a stream for 10 min to 60 min lead times using forecasting rainfall by radar as well as inundation risk areas. In conclusion, the proposed modules were expected to be useful to support inundation forecasting and warning systems.
SlicerArduino: A Bridge between Medical Imaging Platform and Microcontroller
Authors: Zaffino Paolo , Merola Alessio , Leuzzi Domenico , Sabatino Virgilio , Cosentino Carlo , Spadea Maria Francesca
Published: September 2020

Interaction between medical image platform and external environment is a desirable feature in several clinical, research, and educational scenarios. In this work, the integration between 3D Slicer package and Arduino board is introduced, enabling a simple and useful communication between the two software/hardware platforms. The open source extension, programmed in Python language, manages the connection process and offers a communication layer accessible from any point of the medical image suite infrastructure. Deep integration with 3D Slicer code environment is provided and a basic input–output mechanism accessible via GUI is also made available. To test the proposed extension, two exemplary use cases were implemented: (1) INPUT data to 3D Slicer, to navigate on basis of data detected by a distance sensor connected to the board, and (2) OUTPUT data from 3D Slicer, to control a servomotor on the basis of data computed through image process procedures. Both goals were achieved and quasi-real-time control was obtained without any lag or freeze, thus boosting the integration between 3D Slicer and Arduino. This integration can be easily obtained through the execution of few lines of Python code. In conclusion, SlicerArduino proved to be suitable for fast prototyping, basic input–output interaction, and educational purposes. The extension is not intended for mission-critical clinical tasks.
A Glance of p53 Functions in Brain Development, Neural Stem Cells, and Brain Cancer
Authors: Xiong Yuqing , Zhang Yun , Xiong Shunbin , Williams-Villalobo Abie E.
Published: September 2020

p53 is one of the most intensively studied tumor suppressors. It transcriptionally regulates a broad range of genes to modulate a series of cellular events, including DNA damage repair, cell cycle arrest, senescence, apoptosis, ferroptosis, autophagy, and metabolic remodeling, which are fundamental for both development and cancer. This review discusses the role of p53 in brain development, neural stem cell regulation and the mechanisms of inactivating p53 in gliomas. p53 null or p53 mutant mice show female biased exencephaly, potentially due to X chromosome inactivation failure and/or hormone-related gene expression. Oxidative cellular status, increased PI3K/Akt signaling, elevated ID1, and metabolism are all implicated in p53-loss induced neurogenesis. However, p53 has also been shown to promote neuronal differentiation. In addition, p53 mutations are frequently identified in brain tumors, especially glioblastomas. Mechanisms underlying p53 inactivation in brain tumor cells include disruption of p53 protein stability, gene expression and transactivation potential as well as p53 gene loss or mutation. Loss of p53 function and gain-of-function of mutant p53 are both implicated in brain development and tumor genesis. Further understanding of the role of p53 in the brain may provide therapeutic insights for brain developmental syndromes and cancer.
From Seeds to Fibrils and Back: Fragmentation as an Overlooked Step in the Propagation of Prions and Prion-Like Proteins
Authors: Marrero-Winkens Cristóbal , Sankaran Charu , Schätzl Hermann
Published: September 2020

Many devastating neurodegenerative diseases are driven by the misfolding of normal proteins into a pathogenic abnormal conformation. Examples of such protein misfolding diseases include Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and prion diseases. The misfolded proteins involved in these diseases form self-templating oligomeric assemblies that recruit further correctly folded protein and induce their conversion. Over time, this leads to the formation of high molecular and mostly fibrillar aggregates that are increasingly inefficient at converting normal protein. Evidence from a multitude of in vitro models suggests that fibrils are fragmented to form new seeds, which can convert further normal protein and also spread to neighboring cells as observed in vivo. While fragmentation and seed generation were suggested as crucial steps in aggregate formation decades ago, the biological pathways involved remain largely unknown. Here, we show that mechanisms of aggregate clearance—namely the mammalian Hsp70–Hsp40–Hsp110 tri-chaperone system, macro-autophagy, and the proteasome system—may not only be protective, but also play a role in fragmentation. We further review the challenges that exist in determining the precise contribution of these mechanisms to protein misfolding diseases and suggest future directions to resolve these issues.
Inflammation in Dry Eye Syndrome: Identification and Targeting of Oxylipin-Mediated Mechanisms
Authors: Chistyakov Dmitry V. , Gancharova Olga S. , Baksheeva Viktoriia E. , Tiulina Veronika V. , Goriainov Sergei V. , Azbukina Nadezhda V. , Tsarkova Marina S. , Zamyatnin Andrey A. , Philippov Pavel P. , Sergeeva Marina G. , Senin Ivan I. , Zernii Evgeni Yu.
Published: September 2020

Dry eye syndrome (DES) is characterized by decreased tear production and stability, leading to desiccating stress, inflammation and corneal damage. DES treatment may involve targeting the contributing inflammatory pathways mediated by polyunsaturated fatty acids and their derivatives, oxylipins. Here, using an animal model of general anesthesia-induced DES, we addressed these pathways by characterizing inflammatory changes in tear lipidome, in correlation with pathophysiological and biochemical signs of the disease. The decline in tear production was associated with the infiltration of inflammatory cells in the corneal stroma, which manifested one to three days after anesthesia, accompanied by changes in tear antioxidants and cytokines, resulting in persistent damage to the corneal epithelium. The inflammatory response manifested in the tear fluid as a short-term increase in linoleic and alpha-linolenic acid-derived oxylipins, followed by elevation in arachidonic acid and its derivatives, leukotriene B4 (5-lipoxigenase product), 12-hydroxyeicosatetraenoic acid (12-lipoxigeanse product) and prostaglandins, D2, E2 and F2α (cyclooxygenase products) that was observed for up to 7 days. Given these data, DES was treated by a novel ophthalmic formulation containing a dimethyl sulfoxide-based solution of zileuton, an inhibitor of 5-lipoxigenase and arachidonic acid release. The therapy markedly improved the corneal state in DES by attenuating cytokine- and oxylipin-mediated inflammatory responses, without affecting tear production rates. Interestingly, the high efficacy of the proposed therapy resulted from the synergetic action of its components, namely, the general healing activity of dimethyl sulfoxide, suppressing prostaglandins and the more specific effect of zileuton, downregulating leukotriene B4 (inhibition of T-cell recruitment), as well as upregulating docosahexaenoic acid (activation of resolution pathways).
The Possible Neuroprotective Effect of Silymarin against Aluminum Chloride-Prompted Alzheimer’s-Like Disease in Rats
Authors: Aboelwafa Hanaa R. , El-kott Attalla F. , Abd-Ella Eman M. , Yousef Hany N.
Published: September 2020

Alzheimer’s disease (AD) is a worldwide rapidly growing neurodegenerative disease. Here, we elucidated the neuroprotective effects of silymarin (SM) on the hippocampal tissues of aluminum chloride (AlCl3)-induced Alzheimer-like disease in rats using biochemical, histological, and ultrastructural approaches. Forty rats were divided into control, SM, AlCl3, and AlCl3 + SM groups. Biochemically, AlCl3 administration resulted in marked elevation in levels of lipid peroxidation (LPO) and nitric oxide (NO) and decrease in levels of reduced glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD). Moreover, AlCl3 significantly increased tumor necrosis factor-α (TNF-α), interleukin-1beta (IL-1β), and acetylcholinesterase (AChE) activities. Furthermore, myriad histological and ultrastructural alterations were recorded in the hippocampal tissues of AlCl3-treated rats represented as marked degenerative changes of pyramidal neurons, astrocytes, and oligodendrocytes. Additionally, some myelinated nerve fibers exhibited irregular arrangement of their myelin coats, while the others revealed focal degranulation of their myelin sheaths. Severe defects in the blood–brain barrier (BBB) were also recorded. However, co-administration of SM with AlCl3 reversed most of the biochemical, histological, and ultrastructural changes triggered by AlCl3 in rats. The results of the current study indicate that SM can potentially mend most of the previously evoked neuronal damage in the hippocampal tissues of AlCl3-kindled rats.
Exhaustion of Protective Heat Shock Response Induces Significant Tumor Damage by Apoptosis after Modulated Electro-Hyperthermia Treatment of Triple Negative Breast Cancer Isografts in Mice
Authors: Danics Lea , Schvarcz Csaba András , Viana Pedro , Vancsik Tamás , Krenács Tibor , Benyó Zoltán , Kaucsár Tamás , Hamar Péter
Published: September 2020

Modulated electro-hyperthermia (mEHT) is a complementary antitumor therapy applying capacitive radiofrequency at 13.56 MHz. Here we tested the efficiency of mEHT treatment in a BALB/c mouse isograft model using the firefly luciferase-transfected triple-negative breast cancer cell line, 4T1. Tumors inoculated orthotopically were treated twice using a novel ergonomic pole electrode and an improved mEHT device (LabEHY 200) at 0.7 ± 0.3 W for 30 min. Tumors were treated one, two, or three times every 48 h. Tumor growth was followed by IVIS, caliper, and ultrasound. Tumor destruction histology and molecular changes using immunohistochemistry and RT-qPCR were also revealed. In vivo, mEHT treatment transitionally elevated Hsp70 expression in surviving cells indicating heat shock-related cell stress, while IVIS fluorescence showed a significant reduction of viable tumor cell numbers. Treated tumor centers displayed significant microscopic tumor damage with prominent signs of apoptosis, and major upregulation of cleaved/activated caspase-3-positive tumor cells. Serial sampling demonstrated substantial elevation of heat shock (Hsp70) response twelve hours after the treatment which was exhausted by twenty-four hours after treatment. Heat shock inhibitors Quercetin or KRIBB11 could synergistically amplify mEHT-induced tumor apoptosis in vitro. In conclusion, modulated electro-hyperthermia exerted a protective heat shock response as a clear sign of tumor cell stress. Exhaustion of the HSR manifested in caspase-dependent apoptotic tumor cell death and tissue damage of triple-negative breast cancer after mEHT monotherapy. Inhibiting the HSR synergistically increased the effect of mEHT. This finding has great translational potential.
Synergistic Anti-Tumor Activity by Targeting Multiple Signaling Pathways in Ovarian Cancer
Authors: Wen Wei , Han Ernest S. , Dellinger Thanh H. , Lu Leander X. , Wu Jun , Jove Richard , Yim John H.
Published: September 2020

More effective therapy is needed to improve the survival of patients with advanced and recurrent ovarian cancer. Preclinical and early clinical studies with single molecular targeted agents have shown limited antitumor activity in ovarian cancer, likely due to compensation by alternative growth/survival pathways. An emerging strategy in overcoming resistance is to combine inhibitors targeting multiple pathways. In this study, we used a novel strategy of combining several FDA-approved targeted drugs, including sunitinib, dasatinib, and everolimus, in human ovarian cancers. Combination of the tyrosine kinase inhibitor sunitinib with the SRC inhibitor dasatinib showed synergistic anti-tumor activity in human ovarian cancer cells. The increased activity was associated with inhibition of the STAT3, SRC, and MAPK signaling pathways, but not AKT signaling. To inhibit the PI3K/AKT/mTOR pathway, we added the mTOR inhibitor everolimus, which further increased anti-tumor activity in cells. Combined treatment with sunitinib, dasatinib, and everolimus also resulted in greater inhibition of human ovarian tumor growth in mice. Furthermore, the triple combination also synergistically increased the anti-tumor activity of paclitaxel, both in vitro and in vivo. Taken together, our results demonstrate that simultaneous inhibition of several signaling pathways results in better anti-tumor activity compared to inhibiting any of these signaling pathways alone.
Heat Shock Proteins and PD-1/PD-L1 as Potential Therapeutic Targets in Myeloproliferative Neoplasms
Authors: De Almeida Steven , Regimbeau Mathilde , Jego Gaëtan , Garrido Carmen , Girodon François , Hermetet François
Published: September 2020

Myeloproliferative neoplasms (MPN) are a group of clonal disorders that affect hematopoietic stem/progenitor cells. These disorders are often caused by oncogenic driver mutations associated with persistent Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling. While JAK inhibitors, such as ruxolitinib, reduce MPN-related symptoms in myelofibrosis, they do not influence the underlying cause of the disease and are not curative. Due to these limitations, there is a need for alternative therapeutic strategies and targets. Heat shock proteins (HSPs) are cytoprotective stress-response chaperones involved in protein homeostasis and in many critical pathways, including inflammation. Over the last decade, several research teams have unraveled the mechanistic connection between STAT signaling and several HSPs, showing that HSPs are potential therapeutic targets for MPN. These HSPs include HSP70, HSP90 (chaperoning JAK2) and both HSP110 and HSP27, which are key factors modulating STAT3 phosphorylation status. Like the HSPs, the PD-1/PD-L1 signaling pathway has been widely studied in cancer, but the importance of PD-L1-mediated immune escape in MPN was only recently reported. In this review, we summarize the role of HSPs and PD-1/PD-L1 signaling, the modalities of their experimental blockade, and the effect in MPN. Finally, we discuss the potential of these emerging targeted approaches in MPN therapy.
Genomic and Functional Regulation of TRIB1 Contributes to Prostate Cancer Pathogenesis
Authors: Shahrouzi Parastoo , Astobiza Ianire , Cortazar Ana R. , Torrano Verónica , Macchia Alice , Flores Juana M. , Niespolo Chiara , Mendizabal Isabel , Caloto Ruben , Ercilla Amaia , Camacho Laura , Arreal Leire , Bizkarguenaga Maider , Martinez-Chantar Maria L. , Bustelo Xose R. , Berra Edurne , Kiss-Toth Endre , Velasco Guillermo , Zabala-Letona Amaia , Carracedo Arkaitz
Published: September 2020

Prostate cancer is the most frequent malignancy in European men and the second worldwide. One of the major oncogenic events in this disease includes amplification of the transcription factor cMYC. Amplification of this oncogene in chromosome 8q24 occurs concomitantly with the copy number increase in a subset of neighboring genes and regulatory elements, but their contribution to disease pathogenesis is poorly understood. Here we show that TRIB1 is among the most robustly upregulated coding genes within the 8q24 amplicon in prostate cancer. Moreover, we demonstrate that TRIB1 amplification and overexpression are frequent in this tumor type. Importantly, we find that, parallel to its amplification, TRIB1 transcription is controlled by cMYC. Mouse modeling and functional analysis revealed that aberrant TRIB1 expression is causal to prostate cancer pathogenesis. In sum, we provide unprecedented evidence for the regulation and function of TRIB1 in prostate cancer.
Pt Deposites on TiO2 for Photocatalytic H2 Evolution: Pt Is Not Only the Cocatalyst, but Also the Defect Repair Agent
Authors: Shu Zhan , Cai Yandi , Ji Jiawei , Tang Changjin , Yu Shuohan , Zou Weixin , Dong Lin
Published: September 2020

Pt, as a common cocatalyst, has been widely used in photocatalytic H2 evolution. However, the specific role of Pt in photocatalytic H2 evolution has not been thoroughly studied. In this paper, by employing three Pt sources with different charges (positive, negative and neutral), we systematically studied the charge effect of Pt sources on photocatalytic H2 evolution via TiO2 catalyst. According to the results of Raman, X-ray photoelectron spectroscopy (XPS), recycle experiments and photocurrent characterizations, it was found that TiO2 would produce electropositive defects during photocatalytic H2 evolution, inevitably leading to the decline of H2 production activity. Thanks to the electrostatic interaction, the electronegative Pt source not only promoted charge separation, but preferential deposited on electropositive defects, which acted as the defect repair agent, and thus resulted in the increased photocatalytic stability. This work may provide a new perspective for enhancing photocatalytic stability of hydrogen production.
Selective Catalytic Reduction of NOx by CO over Doubly Promoted MeMo/Nb2O5 Catalysts (Me = Pt, Ni, or Co)
Authors: Nascimento João Pedro S. , Oton Lais F. , Oliveira Alcineia C. , Rodríguez-Aguado Elena , Rodríguez-Castellón Enrique , Araujo Rinaldo S. , Souza Monique S. , Lang Rossano
Published: September 2020

Doubly promoted MeMo/Nb2O5 catalysts, in which Me = Pt, Ni, or Co oxides were prepared for the selective catalytic reduction of NOx by CO reaction (CO-SCR). Comparable chemical, textural, and structural analyses revealed similarities between NiMo and CoMo impregnated on Nb2O5, in contrast to PtMo sites, which were not homogeneously dispersed on the support surface. Both the acid function and metal dispersion gave a synergistic effect for CO-SCR at moderate temperatures. The reactivity of PtMo catalysts towards NOx and CO chemisorption was at low reaction temperatures, whereas the NOx conversion over CoMo was greatly improved at relatively high temperatures. Careful XPS, NH3-TPD, and HRTEM analyses confirmed that the large amounts of strong and moderate acid sites from PtOx entrapped on MoO3 sites induced high NOx conversions. NiMo/Nb2O5 showed poor performance in all conditions. Poisoning of the MeMo sites with water vapor or SO2 (or both) provoked the decline of the NOx conversions over NiMo and PtMo sites, whereas the structure of CoMo ones remained very active with a maximum NOx conversion of 70% at 350 °C for 24 h of reaction. This was due to the interaction of the Co3+/Co2+ and Mo6+ actives sites and the weak strength Lewis acid Nb5+ ones, as well.
Evaluation of Priming Efficiency of Forskolin in Tissue-Specific Human Mesenchymal Stem Cells into Dopaminergic Neurons: An In Vitro Comparative Study
Authors: Singh Manisha , Vaishnav Pardeep Kumar , Dinda Amit Kumar , Mohanty Sujata
Published: September 2020

Background: Human mesenchymal stem cells (hMSC) can be derived from various tissue sources and differentiated into dopaminergic (DAergic) neurons using various types of inducers. There are several strategies that have been reported to generate functional dopaminergic neuronal cells from hMSCs in the most efficient manner possible. However, this area is still under extensive research. In this study, we aim to compare hMSCs derived from bone marrow (BM), adipose tissue (AD) and dental pulp (DP) to generate functional dopaminergic neurons, using FGF2 and forskolin. Post-differentiation, multiple factors were used to characterize the cells at morphological, morphometric, ultra-structural, mRNA and protein levels for various markers (Nestin, NF, MAP2, Tuj1, TH, DAT, PitX3, Ngn2, Kv4.2, SCN5A). Cells’ functionality was studied by calcium ion imaging, along with the amount of dopamine secreted by the cells in the culture medium. Results: Data analysis revealed that forskolin has comparable effect on BM- and AD-derived MSC (28.43% and 29.46% DAergic neurons, respectively), whereas DP-MSC (42.78 ± 1.248% DAergic neurons) show better outcome in terms of efficient generation of DAergic neuronal cells, expression of neuronal associated markers, dopamine release and calcium ion efflux. Ultra-structural studies by SEM and TEM also revealed a substantial change in both cellular morphology and composition of cellular organelles. It was observed that AD-MSCs showed the best neuronal features, at morphological, gene, and protein levels upon induction with the above-mentioned induction cocktail. Conclusion: It may be concluded that a combination of FGF2 and forskolin yields functionally active dopaminergic neuronal cells in vitro, with highest percentage of the same from AD-MSCs, as compared to that in BM-MSCs and DP-MSCs. The outcomes and comparative evaluation provide a substantial platform for further studies on molecular pathways involved in the process of DAergic neurogenesis in individual cases.
Nucleic Acid-Based Approaches for Tumor Therapy
Authors: Hager Simone , Fittler Frederic Julien , Wagner Ernst , Bros Matthias
Published: September 2020

Within the last decade, the introduction of checkpoint inhibitors proposed to boost the patients’ anti-tumor immune response has proven the efficacy of immunotherapeutic approaches for tumor therapy. Furthermore, especially in the context of the development of biocompatible, cell type targeting nano-carriers, nucleic acid-based drugs aimed to initiate and to enhance anti-tumor responses have come of age. This review intends to provide a comprehensive overview of the current state of the therapeutic use of nucleic acids for cancer treatment on various levels, comprising (i) mRNA and DNA-based vaccines to be expressed by antigen presenting cells evoking sustained anti-tumor T cell responses, (ii) molecular adjuvants, (iii) strategies to inhibit/reprogram tumor-induced regulatory immune cells e.g., by RNA interference (RNAi), (iv) genetically tailored T cells and natural killer cells to directly recognize tumor antigens, and (v) killing of tumor cells, and reprograming of constituents of the tumor microenvironment by gene transfer and RNAi. Aside from further improvements of individual nucleic acid-based drugs, the major perspective for successful cancer therapy will be combination treatments employing conventional regimens as well as immunotherapeutics like checkpoint inhibitors and nucleic acid-based drugs, each acting on several levels to adequately counter-act tumor immune evasion.
Using High-Content Screening to Generate Single-Cell Gene-Corrected Patient-Derived iPS Clones Reveals Excess Alpha-Synuclein with Familial Parkinson’s Disease Point Mutation A30P
Authors: Barbuti Peter , Antony Paul , Santos Bruno , Massart François , Cruciani Gérald , Dording Claire , Arias Jonathan , Schwamborn Jens , Krüger Rejko
Published: September 2020

The generation of isogenic induced pluripotent stem cell (iPSC) lines using CRISPR-Cas9 technology is a technically challenging, time-consuming process with variable efficiency. Here we use fluorescence-activated cell sorting (FACS) to sort biallelic CRISPR-Cas9 edited single-cell iPSC clones into high-throughput 96-well microtiter plates. We used high-content screening (HCS) technology and generated an in-house developed algorithm to select the correctly edited isogenic clones for continued expansion and validation. In our model we have gene-corrected the iPSCs of a Parkinson’s disease (PD) patient carrying the autosomal dominantly inherited heterozygous c.88G>C mutation in the SNCA gene, which leads to the pathogenic p.A30P form of the alpha-synuclein protein. Undertaking a PCR restriction-digest mediated clonal selection strategy prior to sequencing, we were able to post-sort validate each isogenic clone using a quadruple screening strategy prior to generating footprint-free isogenic iPSC lines, retaining a normal molecular karyotype, pluripotency and three germ-layer differentiation potential. Directed differentiation into midbrain dopaminergic neurons revealed that SNCA expression is reduced in the gene-corrected clones, which was validated by a reduction at the alpha-synuclein protein level. The generation of single-cell isogenic clones facilitates new insights in the role of alpha-synuclein in PD and furthermore is applicable across patient-derived disease models.
Truncated PPM1D Prevents Apoptosis in the Murine Thymus and Promotes Ionizing Radiation-Induced Lymphoma
Authors: Martinikova Andra S. , Burocziova Monika , Stoyanov Miroslav , Macurek Libor
Published: September 2020

Genome integrity is protected by the cell-cycle checkpoints that prevent cell proliferation in the presence of DNA damage and allow time for DNA repair. The transient checkpoint arrest together with cellular senescence represent an intrinsic barrier to tumorigenesis. Tumor suppressor p53 is an integral part of the checkpoints and its inactivating mutations promote cancer growth. Protein phosphatase magnesium-dependent 1 (PPM1D) is a negative regulator of p53. Although its loss impairs recovery from the G2 checkpoint and promotes induction of senescence, amplification of the PPM1D locus or gain-of-function truncating mutations of PPM1D occur in various cancers. Here we used a transgenic mouse model carrying a truncating mutation in exon 6 of PPM1D (Ppm1dT). As with human cell lines, we found that the truncated PPM1D was present at high levels in the mouse thymus. Truncated PPM1D did not affect differentiation of T-cells in the thymus but it impaired their response to ionizing radiation (IR). Thymocytes in Ppm1dT/+ mice did not arrest in the checkpoint and continued to proliferate despite the presence of DNA damage. In addition, we observed a decreased level of apoptosis in the thymi of Ppm1dT/+ mice. Moreover, the frequency of the IR-induced T-cell lymphomas increased in Ppm1dT/+Trp53+/− mice resulting in decreased survival. We conclude that truncated PPM1D partially suppresses the p53 pathway in the mouse thymus and potentiates tumor formation under the condition of a partial loss of p53 function.
Radiotherapy Scheme Effect on PD-L1 Expression for Locally Advanced Rectal Cancer
Authors: Boustani Jihane , Derangère Valentin , Bertaut Aurélie , Adotevi Olivier , Morgand Véronique , Charon-Barra Céline , Ghiringhelli François , Mirjolet Céline
Published: September 2020

In locally advanced rectal cancer, radiotherapy (RT) followed by surgery have improved locoregional control, but distant recurrences remain frequent. Although checkpoint inhibitors have demonstrated objective response in several cancers, the clinical benefit of PD-1/PD-L1 blockade remains uncertain in rectal cancer. We collected data from biopsies and surgical specimens in 74 patients. The main objective was to evaluate the impact of neoadjuvant RT and fractionation on PD-L1 expression. Secondary objectives were to study the relation between PD-L1 expression and tumor regression grade (TRG), progression-free survival (PFS), overall survival (OS), and CD8 TILs infiltration. Median rates of cells expressing PD-L1 pre- and post-RT were 0.15 (range, 0–17) and 0.5 (range, 0–27.5), respectively (p = 0.0005). There was no effect of RT fractionation on PD-L1+ cell rates. We found no relation between CD8+ TILs infiltration and PD-L1 expression and no difference between high-PD-L1 or low-PD-L1 expression and TRG. High-to-high PD-L1 expression profile had none significant higher OS and PFS compared to all other groups (p = 0.06). Median OS and PFS were higher in biopsies with >0.08 PD-L1+ cells. High-to-high PD-L1 profile and ypT0-2 were significantly associated with higher OS and PFS. This study did not show the differential induction of PD-L1 expression according to fractionation.
Stem Cell Repair of the Microvascular Damage in Stroke
Authors: Saft Madeline , Gonzales-Portillo Bella , Park You Jeong , Cozene Blaise , Sadanandan Nadia , Cho Justin , Garbuzova-Davis Svitlana , Borlongan Cesar V.
Published: September 2020

Stroke is a life-threatening disease that leads to mortality, with survivors subjected to long-term disability. Microvascular damage is implicated as a key pathological feature, as well as a therapeutic target for stroke. In this review, we present evidence detailing subacute diaschisis in a focal ischemic stroke rat model with a focus on blood–brain barrier (BBB) integrity and related pathogenic processes in contralateral brain areas. Additionally, we discuss BBB competence in chronic diaschisis in a similar rat stroke model, highlighting the pathological changes in contralateral brain areas that indicate progressive morphological brain disturbances overtime after stroke onset. With diaschisis closely approximating stroke onset and progression, it stands as a treatment of interest for stroke. Indeed, the use of stem cell transplantation for the repair of microvascular damage has been investigated, demonstrating that bone marrow stem cells intravenously transplanted into rats 48 h post-stroke survive and integrate into the microvasculature. Ultrastructural analysis of transplanted stroke brains reveals that microvessels display a near-normal morphology of endothelial cells and their mitochondria. Cell-based therapeutics represent a new mechanism in BBB and microvascular repair for stroke.
Retinoic Acid Improves the Recovery of Replication-Competent Virus from Latent SIV Infected Cells
Authors: Olwenyi Omalla A. , Acharya Arpan , Routhu Nanda Kishore , Pierzchalski Keely , Jones Jace W. , Kane Maureen A. , Sidell Neil , Mohan Mahesh , Byrareddy Siddappa N.
Published: September 2020

The accurate estimation and eradication of Human Immunodeficiency Virus (HIV) viral reservoirs is limited by the incomplete reactivation of cells harboring the latent replication-competent virus. We investigated whether the in vitro and in vivo addition of retinoic acid (RA) enhances virus replication and improves the detection of latent virus. Peripheral blood mononuclear cells (PBMCs) from naive and anti-retroviral therapy (ART)-treated SIV-infected rhesus macaques (RMs) were cultured in vitro with anti-CD3/CD28 + IL-2 in the presence/absence of RA. Viral RNA and p27 levels were quantified using RT-qPCR and ELISA, respectively. Viral reservoirs were estimated using the Tat/Rev-Induced Limited Dilution Assay (TILDA) and Quantitative Viral Outgrowth Assay (QVOA). In vitro and in vivo measures revealed that there was also an increase in viral replication in RA-treated versus without RA conditions. In parallel, the addition of RA to either CD3/CD28 or phorbol myristate acetate (PMA)/ionomycin during QVOA and TILDA, respectively, was shown to augment reactivation of the replication-competent viral reservoir in anti-retroviral therapy (ART)-suppressed RMs as shown by a greater than 2.3-fold increase for QVOA and 1 to 2-fold increments for multi-spliced RNA per million CD4+ T cells. The use of RA can be a useful approach to enhance the efficiency of current protocols used for in vitro and potentially in vivo estimates of CD4+ T cell latent reservoirs. In addition, flow cytometry analysis revealed that RA improved estimates of various viral reservoir assays by eliciting broad CD4 T-cell activation as demonstrated by elevated CD25 and CD38 but reduced CD69 and PD-1 expressing cells.
Annealing Temperature on Contact Properties between Nickel Film and Hydrogen-Terminated Single Crystal Diamond
Authors: Zhang Pengfei , Zhang Shaopeng , Chen Weidong , Yan Shufang , Ma Wen , Wang Hong-Xing
Published: September 2020

Ohmic contact of nickel on hydrogen-terminated single-crystal diamond film was investigated with an annealing temperature ranging from room temperature to 750 °C in hydrogen atmosphere. Nickel film was deposited on a hydrogen-terminated single-crystal diamond surface with gold film in order to protect it from oxidation. Contact properties between nickel and hydrogen-terminated single crystal diamond were measured by a circular transmission line model. The lowest specific contact resistivity was 7.82 × 10−5 Ω cm2 at annealing temperature of 750 °C, indicating good ohmic contact, which reveals improved thermal stability by increasing temperature.
DFT Study of Si/Al Ratio and Confinement Effects on the Energetics and Vibrational Properties of some Aza-Aromatic Molecules Adsorbed on H-ZSM-5 Zeolite
Authors: Castellà-Ventura Martine , Moissette Alain , Kassab Emile
Published: September 2020

The Si/Al ratio and confinement effects of zeolite framework on energetics and vibrational frequencies of pyridine and 4,4′-bipyridine adsorbed on Brønsted acid sites in the straight channel of H-ZSM-5 are investigated by DFT calculations at the B3LYP and M06-2X+D3 levels. The straight channel of H-ZSM-5 is simulated by a cluster of 32 tetrahedral centers covering the intersection between straight and zigzag channels. Pyridine and 4,4′-bipyridine adsorption at two different sites in the intersection (open region) and/or in the narrow region situated between two intersections (closed region) is studied. For two Si/Al ratios (31, 15), the ion pair complexes formed by proton transfer upon pyridine and 4,4′-bipyridine adsorption in the open region and for the first time in the closed region are characterized. Our results indicate: (i) the stability for all adsorption complexes is essentially governed by the dispersive van der Waals interactions and the open region is energetically more favorable than the closed region owing to the predominance of the dispersive interactions over the steric constraints exerted by the confinement effects; (ii) as the Al centers are sufficiently spaced apart, Si/Al ratio does not influence pyridine adsorption energy, but significantly affects the adsorption energies and the relative stability of 4,4′-bipyridine complexes; (iii) neither Si/Al ratio nor confinement significantly influence pyridine and 4,4′-bipyridine vibrational frequencies within their complexes.