bluuebunny/crossref_metadata_2025 huggingface dataset:
Radio Frequency Reflectometry of Single-Electron Box Arrays for Nanoscale Voltage Sensing Applications
Authors: Zirkle Thomas A. , Filmer Matthew J. , Chisum Jonathan , Orlov Alexei O. , Dupont-Ferrier Eva , Rivard Joffrey , Huebner Matthew , Sanquer Marc , Jehl Xavier , Snider Gregory L.
Published: December 2020

Single-electron tunneling transistors (SETs) and boxes (SEBs) exploit the phenomenon of Coulomb blockade to achieve unprecedented charge sensitivities. Single-electron boxes, however, despite their simplicity compared to SETs, have rarely been used for practical applications. The main reason for that is that unlike a SET where the gate voltage controls conductance between the source and the drain, an SEB is a two terminal device that requires either an integrated SET amplifier or high-frequency probing of its complex admittance by means of radio frequency reflectometry (RFR). The signal to noise ratio (SNR) for a SEB is small, due to its much lower admittance compared to a SET and thus matching networks are required for efficient coupling ofSEBs to an RFR setup. To boost the signal strength by a factor of N (due to a random offset charge) SEBs can be connected in parallel to form arrays sharing common gates and sources. The smaller the size of the SEB, the larger the charging energy of a SEB enabling higher operation temperature, and using devices with a small footprint (<0.01 µm2), a large number of devices (>1000) can be assembled into an array occupying just a few square microns. We show that it is possible to design SEB arrays that may compete with an SET in terms of sensitivity. In this, we tested SETs using RF reflectometry in a configuration with no DC through path (“DC-decoupled SET” or DCD SET) along with SEBs connected to the same matching network. The experiment shows that the lack of a path for a DC current makes SEBs and DCD SETs highly electrostatic discharge (ESD) tolerant, a very desirable feature for applications. We perform a detailed analysis of experimental data on SEB arrays of various sizes and compare it with simulations to devise several ways for practical applications of SEB arrays and DCD SETs.
Quasi-Equilibrium and Unsteady Mass Transfer of Low-Grade Bloedite in the Process of Static Water Dissolution
Authors: Cheng Huaigang , Wei Lina , Cheng Fangqin
Published: December 2020

Hydrometallurgical extraction and treatment of bloedite waste is one necessity for the sustainable development of sodium sulfate subtype salt lake mining areas, but the industrial dissolution of bloedite is not stable. One of the reasons for this is the unsteady mass transfer of dissolved electrolytes in water according to the diffusion model and static water dissolution experiment in this work. The diffusion behaviors of aqueous Na2SO4 and MgSO4 released from bloedite in water are similar, and their mass transfer coefficients decrease in a nonlinear manner as the diffusion process continues. Within 720 h of dissolution time, there is a quasi-steady-state quasi-linear stage of rapid increase in the solute concentration of leaching water, and a water depth of 20–40 mm is recommended as the optimal dissolution depth. Under such operating conditions, the amount of evaporated water required for salt production decreases in a quasi-linear manner with respect to dissolution time. However, after 720 h of dissolution and extraction time, the growth rate of brine concentration slows. The information provided by the model can be used in practice as a quantitative reference for bloedite recycling.
Raman Analysis of E2 (High) and A1 (LO) Phonon to the Stress-Free GaN Grown on Sputtered AlN/Graphene Buffer Layer
Authors: Zeng Yu , Ning Jing , Zhang Jincheng , Jia Yanqing , Yan Chaochao , Wang Boyu , Wang Dong
Published: December 2020

The realization of high-speed and high-power gallium nitride (GaN)-based devices using high-quality GaN/Aluminum nitride (AlN) materials has become a hot topic. Raman spectroscopy has proven to be very useful in analyzing the characteristics of wide band gap materials, which reveals the information interaction of sample and phonon dynamics. Four GaN samples grown on different types of buffer layers were fabricated and the influence of graphene and sputtered AlN on GaN epitaxial layers were analyzed through the E2 (high) and A1 (LO) phonon. The relationship between the frequency shift of E2 (high) phonons and the biaxial stress indicated that the GaN grown on the graphene/sputtered AlN buffer layer was stress-free. Furthermore, the phonon lifetimes of A1 (LO) mode in GaN grown on graphene/sputtered AlN buffer layer suggested that carrier migration of GaN received minimal interference. Finally, the Raman spectra of graphene with the sputtered AlN interlayer has more disorder and the monolayer graphene was also more conducive to nucleation of GaN films. These results will have significant impact on the heteroepitaxy of high-quality thin GaN films embedded with a graphene/sputtered AlN buffer, and will facilitate the preparation of high-speed GaN-based optoelectronic devices.
Changes in Snow Depth, Snow Cover Duration, and Potential Snowmaking Conditions in Austria, 1961–2020—A Model Based Approach
Authors: Olefs Marc , Koch Roland , Schöner Wolfgang , Marke Thomas
Published: December 2020

We used the spatially distributed and physically based snow cover model SNOWGRID-CL to derive daily grids of natural snow conditions and snowmaking potential at a spatial resolution of 1 × 1 km for Austria for the period 1961–2020 validated against homogenized long-term snow observations. Meteorological driving data consists of recently created gridded observation-based datasets of air temperature, precipitation, and evapotranspiration at the same resolution that takes into account the high variability of these variables in complex terrain. Calculated changes reveal a decrease in the mean seasonal (November–April) snow depth (HS), snow cover duration (SCD), and potential snowmaking hours (SP) of 0.15 m, 42 days, and 85 h (26%), respectively, on average over Austria over the period 1961/62–2019/20. Results indicate a clear altitude dependence of the relative reductions (−75% to −5% (HS) and −55% to 0% (SCD)). Detected changes are induced by major shifts of HS in the 1970s and late 1980s. Due to heterogeneous snowmaking infrastructures, the results are not suitable for direct interpretation towards snow reliability of individual Austrian skiing resorts but highly relevant for all activities strongly dependent on natural snow as well as for projections of future snow conditions and climate impact research.
Transition from a Subaerial to a Subnival Permafrost Temperature Regime Following Increased Snow Cover (Livingston Island, Maritime Antarctic)
Authors: Ramos Miguel , Vieira Gonçalo , de Pablo Miguel Angel , Molina Antonio , Jimenez Juan Javier
Published: December 2020

The Antarctic Peninsula (AP) region has been one of the regions on Earth with strongest warming since 1950. However, the northwest of the AP showed a cooling from 2000 to 2015, which had local consequences with an increase in snow accumulation and a deceleration in the loss of mass from glaciers. In this paper, we studied the effects of increased snow accumulation in the permafrost thermal regime in two boreholes (PG1 and PG2) in Livingston Island, South Shetlands Archipelago, from 2009 to 2015. The two boreholes located c. 300 m apart but at similar elevation showed different snow accumulation, with PG2 becoming completely covered with snow all year long, while the other remained mostly snow free during the summer. The analysis of the thermal regimes and of the estimated soil surface energy exchange during the study period showed the effects of snow insulation in reducing the active layer thickness. These effects were especially relevant in PG2, which transitioned from a subaerial to a subnival regime. There, permafrost aggraded from below, with the active layer completely disappearing and the efficiency of thermal insulation by the snowpack prevailing in the thermal regime. This situation may be used as an analogue for the transition from a periglacial to a subglacial environment in longer periods of cooling in the paleoenvironmental record.
Evaluation of Sixteen Gridded Precipitation Datasets over the Caribbean Region Using Gauge Observations
Authors: Centella-Artola Abel , Bezanilla-Morlot Arnoldo , Taylor Michael A. , Herrera Dimitris A. , Martinez-Castro Daniel , Gouirand Isabelle , Sierra-Lorenzo Maibys , Vichot-Llano Alejandro , Stephenson Tannecia , Fonseca Cecilia , Campbell Jayaka , Alpizar Milena
Published: December 2020

The existence of several gridded precipitation products (GPP) has facilitated studies related to climate change, climate modeling, as well as a better understanding of the physical processes underpinning this key variable. Due to complexities in estimating rainfall, gridded datasets exhibit different levels of accuracy across regions, even when they are developed at relatively high resolution or using sophisticated procedures. The performance of 16 GPP are evaluated over the Caribbean region, which includes the Caribbean Islands, and portions of Central South America. Monthly data for sixty weather stations are used as a reference for the period 1983–2010. The 16 GPP include six products based on station data only, two that combine ground station and satellite information, two merging station and reanalysis information, four based on reanalysis, and two using multisource information. The temporal resolution of the GPP ranged between daily and monthly and spatial resolution from 0.033° to 0.5°. The methodological approach employed combined a comparison of regional and sub-regional precipitation annual cycles, the Kling–Gupta efficiency (KGE) index, as well as several metrics derived from the standardized precipitation index (SPI). Overall, the best performances were obtained from GPCC025 and MSWEP2, likely reflecting the positive impact of the large number of station data utilized in their development. It is also demonstrated that a higher spatial resolution does not always mean better accuracy. There is a need for this kind of assessment when undertaking climate studies in regions like the Caribbean where resolution is a significant consideration. ERA5 performed best among the reanalyses analyzed and has the potential to be used to develop regionally based GPP by applying bias correction or downscaling techniques. The methodological approach employed provides a comprehensive and robust evaluation of the relative strengths and weaknesses of GPP in the Caribbean region.
Future Changes of Agro-Climate and Heat Extremes over S. Korea at 2 and 3 °C Global Warming Levels with CORDEX-EA Phase 2 Projection
Authors: Jo Sera , Shim Kyo-Moon , Hur Jina , Kim Yong-Seok , Ahn Joong-Bae
Published: December 2020

The changes of agro-climate and heat extremes, and their impact on rice cultivation are assessed over South Korea in context of 2 and 3 °C global warming levels (GWL) compared to pre-industrial levels, with ensemble regional climate model projection produced under the Coordinated Regional Climate Downscaling Experiment–East Asia (CORDEX-EA) phase 2 protocols. It is found that the mean temperature increase under global warming has not only positive effects such as the extension of vegetable and crop periods and the widening of the cultivatable regions but also negative effects due to the shortening of the reproductive growth period. On the other hand, extreme heat changes in the future clearly show a negative effect on rice cultivation via the increase of hot days during heat-sensitive stages (27.16% under 2 °C GWL, 54.59% under 3 °C GWL) among rice phenology which determines the rice yield in tandem with rice flowering, ripening, and sterility problems. The major type of heat extreme is dominated by nationwide warm anomalies covering entire S. Korea, and the proportion of this type is projected to increase from 35.8% to 49.5% (57.4%) under 2 °C (3 °C) GWL in association with the thermal expansion of atmosphere which links to the favorable environment for occurring barotropic anti-cyclonic system.
Biomechanical Investigation of the Stomach Following Different Bariatric Surgery Approaches
Authors: Toniolo Ilaria , Fontanella Chiara Giulia , Foletto Mirto , Carniel Emanuele Luigi
Published: December 2020

Background: The stomach is a hollow organ of the gastrointestinal tract, on which bariatric surgery (BS) is performed for the treatment of obesity. Even though BS is the most effective treatment for severe obesity, drawbacks and complications are still present because the intervention design is largely based on the surgeon’s expertise and intraoperative decisions. Bioengineering methods can be exploited to develop computational tools for more rational presurgical design and planning of the intervention. Methods: A computational mechanical model of the stomach was developed, considering the actual complexity of the biological structure, as the nonhomogeneous and multilayered configuration of the gastric wall. Mechanical behavior was characterized by means of an anisotropic visco-hyperelastic constitutive formulation of fiber-reinforced conformation, nonlinear elastic response, and time-dependent behavior, which assume the typical features of gastric wall mechanics. Model applications allowed for an analysis of the influence of BS techniques on stomach mechanical functionality through different computational analyses. Results: Computational results showed that laparoscopic sleeve gastrectomy and endoscopic sleeve gastroplasty drastically alter stomach capacity and stiffness, while laparoscopic adjustable gastric banding modestly affects stomach stiffness and capacity. Moreover, the mean elongation strain values, which are correlated to the mechanical stimulation of gastric receptors, were elevated in laparoscopic adjustable gastric banding compared to other procedures. Conclusions: The investigation of stomach mechanical response through computational models provides information on different topics such as stomach capacity and stiffness and the mechanical stimulation of gastric receptors, which interact with the brain to control satiety. These data can provide reliable support to surgeons in the presurgical decision-making process.
Case Study upon Foliar Application of Biofertilizers Affecting Microbial Biomass and Enzyme Activity in Soil and Yield Related Properties of Maize and Wheat Grains
Authors: Latkovic Dragana , Maksimovic Jelena , Dinic Zoran , Pivic Radmila , Stanojkovic Aleksandar , Stanojkovic-Sebic Aleksandra
Published: December 2020

This study evaluated the effects of the application of microbial inoculants (N-fixing Klebsiella planticola and Enterobacter spp.), two rates of composite mineral fertilizers, and their combination on microbial biomass carbon (MBC), dehydrogenase (DHA), and proteinase activity (PTA) in Lessivated Cambisol and yield-related properties of maize and wheat grains in a two-year trial. Unfertilized soil was used as a control variant. MBC was measured using the chloroform fumigation-extraction method, DHA was determined spectrophotometrically by measuring the intensity of the formed red-colored triphenyl formazan, while PTA was determined using a titration method by measuring the degree of gelatine decomposition. In grain samples, P was determined spectrophotometrically, K—by flame emission photometry, N—on an elemental carbon/nitrogen/sulfur (CNS) analyzer, and crude proteins—by calculation of N content. Measuring both crops’ yield was carried out at the end of the vegetation. The results indicated that mineral fertilizers are not, in general, negative for soil microbiota when used in the context of sustainable agriculture without monoculture. There is a significant increase in the values of soil MBC, DHA, and PTA in the variants with combined application of bacterial inoculants and lower rates of mineral fertilizers. The highest values of these parameters were determined in the period with a better distribution of precipitation during the vegetation period of the year. The mentioned combination also resulted in a higher grain yield of maize and wheat comparing to the application of lower rates of the NPK nutrients solely. The combined application of high rates of mineral fertilizers and bacterial inoculants resulted in significantly increased N, P, K, and protein content in the grains of crops, and the same applied to yield. Concluding, studied bacterial inoculants can be used to specify the replacement of nitrogen fertilizers, stimulating the microbial biomass and enzyme activity in the soil, helping to ensure that the supply of nutrients contributing to an optimized yield of crops is maintained.
Literature on Applied Machine Learning in Metagenomic Classification: A Scoping Review
Authors: Tonkovic Petar , Kalajdziski Slobodan , Zdravevski Eftim , Lameski Petre , Corizzo Roberto , Pires Ivan Miguel , Garcia Nuno M. , Loncar-Turukalo Tatjana , Trajkovik Vladimir
Published: December 2020

Applied machine learning in bioinformatics is growing as computer science slowly invades all research spheres. With the arrival of modern next-generation DNA sequencing algorithms, metagenomics is becoming an increasingly interesting research field as it finds countless practical applications exploiting the vast amounts of generated data. This study aims to scope the scientific literature in the field of metagenomic classification in the time interval 2008–2019 and provide an evolutionary timeline of data processing and machine learning in this field. This study follows the scoping review methodology and PRISMA guidelines to identify and process the available literature. Natural Language Processing (NLP) is deployed to ensure efficient and exhaustive search of the literary corpus of three large digital libraries: IEEE, PubMed, and Springer. The search is based on keywords and properties looked up using the digital libraries’ search engines. The scoping review results reveal an increasing number of research papers related to metagenomic classification over the past decade. The research is mainly focused on metagenomic classifiers, identifying scope specific metrics for model evaluation, data set sanitization, and dimensionality reduction. Out of all of these subproblems, data preprocessing is the least researched with considerable potential for improvement.
Autophagy and Intracellular Membrane Trafficking Subversion by Pathogenic Yersinia Species
Authors: Lemarignier Marion , Pizarro-Cerdá Javier
Published: December 2020

Yersinia pseudotuberculosis, Y. enterocolitica and Y. pestis are pathogenic bacteria capable of causing disease in humans by growing extracellularly in lymph nodes and during systemic infections. While the capacity of these bacteria to invade, replicate, and survive within host cells has been known for long, it is only in recent years that their intracellular stages have been explored in more detail. Current evidence suggests that pathogenic Yersinia are capable of activating autophagy in both phagocytic and epithelial cells, subverting autophagosome formation to create a niche supporting bacterial intracellular replication. In this review, we discuss recent results opening novel perspectives to the understanding of intimate host-pathogens interactions taking place during enteric yersiniosis and plague.
Large Scale Conversion of Trilobolide into the Payload of Mipsagargin: 8-O-(12-Aminododecanoyl)-8-O-Debutanoylthapsigargin
Authors: Zimmermann Tomáš , Drašar Pavel , Rimpelová Silvie , Christensen Søren Brøgger , Khripach Vladimir A. , Jurášek Michal
Published: December 2020

In spite of the impressing cytotoxicity of thapsigargin (Tg), this compound cannot be used as a chemotherapeutic drug because of general toxicity, causing unacceptable side effects. Instead, a prodrug targeted towards tumors, mipsagargin, was brought into clinical trials. What substantially reduces the clinical potential is the limited access to Tg and its derivatives and cost-inefficient syntheses with unacceptably low yields. Laser trilobum, which contains a structurally related sesquiterpene lactone, trilobolide (Tb), is successfully cultivated. Here, we report scalable isolation of Tb from L. trilobum and a transformation of Tb to 8-O-(12-aminododecanoyl)-8-O-debutanoylthapsigargin in seven steps. The use of cultivated L. trilobum offers an unlimited source of the active principle in mipsagargin.
Extracellular Vesicles as Potential Biomarkers for Early Detection and Diagnosis of Pancreatic Cancer
Authors: Yee Nelson S. , Zhang Sheng , He Hong-Zhang , Zheng Si-Yang
Published: December 2020

Pancreatic carcinoma (PC) is highly metastatic, and it tends to be detected at advanced stages. Identifying and developing biomarkers for early detection of PC is crucial for a potentially curative treatment. Extracellular vesicles (EVs) are bilayer lipid membrane-structured nanovesicles found in various human bodily fluids, and they play important roles in tumor biogenesis and metastasis. Cancer-derived EVs are enriched with DNA, RNA, protein, and lipid, and they have emerged as attractive diagnostic biomarkers for early detection of PC. In this article, we provided an overview of the cell biology of EVs and their isolation and analysis, and their roles in cancer pathogenesis and progression. Multiplatform analyses of plasma-based exosomes for genomic DNA, micro RNA, mRNA, circular RNA, and protein for diagnosis of PC were critically reviewed. Numerous lines of evidence demonstrate that liquid biopsy with analysis of EV-based biomarkers has variable performance for diagnosis of PC. Future investigation is indicated to optimize the methodology for isolating and analyzing EVs and to identify the combination of EV-based biomarkers and other clinical datasets, with the goal of improving the predictive value, sensitivity, and specificity of screening tests for early detection and diagnosis of PC.
Dietary-Induced Low-Grade Inflammation in the Liver
Authors: Power Guerra Nicole , Müller Luisa , Pilz Kristin , Glatzel Annika , Jenderny Daniel , Janowitz Deborah , Vollmar Brigitte , Kuhla Angela
Published: December 2020

The literature describes a close correlation between metabolic disorders and abnormal immune responses, like low-grade inflammation (LGI), which may be one mechanistic link between obesity and various comorbidities, including non-alcoholic fatty liver disease (NAFLD). In our study, we investigated the influence of dietary composition on obesity-derived LGI in the liver. We used a dietary induced obesity mouse model of C57BL/6J mice fed with high fat diet (HFD, 60% fat, 20% protein, 20% carbohydrates) and two different controls. One was rich in carbohydrates (10% fat, 20% protein, 70% carbohydrates), further referred to as the control diet (CD), and the other one is referred to as the standard diet (SD), with a more balanced macronutrient content (9% fat, 33% protein, 58% carbohydrates). Our results showed a significant increased NAFLD activity score in HFD compared to both controls, but livers of the CD group also differed in their macroscopic appearance from healthy livers. Hepatic fat content showed significantly elevated cholesterol concentrations in the CD group. Histologic analysis of the cellular immune response in the liver showed no difference between HFD and CD and expression analysis of immunologic mediators like interleukin (IL)-1β, IL-6, IL-10 and tumor necrosis factor alpha also point towards a pro-inflammatory response to CD, comparable to LGI in HFD. Therefore, when studying diet-induced obesity with a focus on inflammatory processes, we encourage researchers to carefully select controls and not use a control diet disproportionally rich in carbohydrates.
Advances in Treatment of ATTRv Amyloidosis: State of the Art and Future Prospects
Authors: Russo Massimo , Gentile Luca , Toscano Antonio , Aguennouz M’Hammed , Vita Giuseppe , Mazzeo Anna
Published: December 2020

Hereditary amyloid transthyretin (ATTRv) amyloidosis with polyneuropathy is a progressive disease that is transmitted as an autosomal dominant trait and characterized by multiple organ failure, including axonal sensory-motor neuropathy, cardiac involvement, and autonomic dysfunction. Liver transplantation (LT) and combined heart–liver transplantation, introduced in the 1990s, have been the only therapies for almost two decades. In 2011, tafamidis meglumine became the first specific drug approved by regulatory agencies, since then the attention toward this disease has progressively increased and several drugs with different mechanisms of action are now available. This review describes the drugs already on the market, those that have shown interesting results although not yet approved, and those currently being tested.
Parental Education, Household Income, and Cortical Surface Area among 9–10 Years Old Children: Minorities’ Diminished Returns
Authors: Assari Shervin
Published: December 2020

Introduction: Although the effects of parental education and household income on children’s brain development are well established, less is known about possible variation in these effects across diverse racial and ethnic groups. According to the Minorities’ Diminished Returns (MDRs) phenomenon, due to structural racism, social stratification, and residential segregation, parental educational attainment and household income show weaker effects for non-White than White children. Purpose: Built on the MDRs framework and conceptualizing race as a social rather than a biological factor, this study explored racial and ethnic variation in the magnitude of the effects of parental education and household income on children’s whole-brain cortical surface area. Methods: For this cross-sectional study, we used baseline socioeconomic and structural magnetic resonance imaging (sMRI) data of the Adolescent Brain Cognitive Development (ABCD) study. Our analytical sample was 10,262 American children between ages 9 and 10. The independent variables were parental education and household income. The primary outcome was the children’s whole-brain cortical surface area. Age, sex, and family marital status were covariates. Race and ethnicity were the moderators. We used mixed-effects regression models for data analysis as participants were nested within families and study sites. Results: High parental education and household income were associated with larger children’s whole-brain cortical surface area. The effects of high parental education and high household income on children’s whole-brain cortical surface area were modified by race. Compared to White children, Black children showed a diminished return of high parental education on the whole-brain cortical surface area when compared to White children. Asian American children showed weaker effects of household income on the whole-brain cortical surface area when compared to White children. We could not find differential associations between parental education and household income with the whole-brain cortical surface area, when compared to White children, for non-Hispanic and Hispanic children. Conclusions: The effects of parental educational attainment and household income on children’s whole-brain cortical surface area are weaker in non-White than White families. Although parental education and income contribute to children’s brain development, these effects are unequal across racial groups.
EZH2 and KDM6B Expressions Are Associated with Specific Epigenetic Signatures during EMT in Non Small Cell Lung Carcinomas
Authors: Lachat Camille , Bruyère Diane , Etcheverry Amandine , Aubry Marc , Mosser Jean , Warda Walid , Herfs Michaël , Hendrick Elodie , Ferrand Christophe , Borg Christophe , Delage-Mourroux Régis , Feugeas Jean-Paul , Guittaut Michaël , Hervouet Eric , Peixoto Paul
Published: December 2020

The role of Epigenetics in Epithelial Mesenchymal Transition (EMT) has recently emerged. Two epigenetic enzymes with paradoxical roles have previously been associated to EMT, EZH2 (Enhancer of Zeste 2 Polycomb Repressive Complex 2 (PRC2) Subunit), a lysine methyltranserase able to add the H3K27me3 mark, and the histone demethylase KDM6B (Lysine Demethylase 6B), which can remove the H3K27me3 mark. Nevertheless, it still remains unclear how these enzymes, with apparent opposite activities, could both promote EMT. In this study, we evaluated the function of these two enzymes using an EMT-inducible model, the lung cancer A549 cell line. ChIP-seq coupled with transcriptomic analysis showed that EZH2 and KDM6B were able to target and modulate the expression of different genes during EMT. Based on this analysis, we described INHBB, WTN5B, and ADAMTS6 as new EMT markers regulated by epigenetic modifications and directly implicated in EMT induction.
TGF-β Mediated Immune Evasion in Cancer—Spotlight on Cancer-Associated Fibroblasts
Authors: Ghahremanifard Parisa , Chanda Ayan , Bonni Shirin , Bose Pinaki
Published: December 2020

Various components of the tumor microenvironment (TME) play a critical role in promoting tumorigenesis, progression, and metastasis. One of the primary functions of the TME is to stimulate an immunosuppressive environment around the tumor through multiple mechanisms including the activation of the transforming growth factor-beta (TGF-β) signaling pathway. Cancer-associated fibroblasts (CAFs) are key cells in the TME that regulate the secretion of extracellular matrix (ECM) components under the influence of TGF-β. Recent reports from our group and others have described an ECM-related and CAF-associated novel gene signature that can predict resistance to immune checkpoint blockade (ICB). Importantly, studies have begun to test whether targeting some of these CAF-associated components can be used as a combinatorial approach with ICB. This perspective summarizes recent advances in our understanding of CAF and TGF-β-regulated immunosuppressive mechanisms and ways to target such signaling in cancer.
Non-Coding RNAs as Mediators of Epigenetic Changes in Malignancies
Authors: Kumar Subhasree , Gonzalez Edward A. , Rameshwar Pranela , Etchegaray Jean-Pierre
Published: December 2020

Non-coding RNAs (ncRNAs) are untranslated RNA molecules that regulate gene expressions. NcRNAs include small nuclear RNAs (snRNAs), small nucleolar RNAs (snoRNAs), ribosomal RNAs (rRNAs), transfer RNAs (tRNAs), circular RNAs (cRNAs) and piwi-interacting RNAs (piRNAs). This review focuses on two types of ncRNAs: microRNAs (miRNAs) or short interfering RNAs (siRNAs) and long non-coding RNAs (lncRNAs). We highlight the mechanisms by which miRNAs and lncRNAs impact the epigenome in the context of cancer. Both miRNAs and lncRNAs have the ability to interact with numerous epigenetic modifiers and transcription factors to influence gene expression. The aberrant expression of these ncRNAs is associated with the development and progression of tumors. The primary reason for their deregulated expression can be attributed to epigenetic alterations. Epigenetic alterations can cause the misregulation of ncRNAs. The experimental evidence indicated that most abnormally expressed ncRNAs impact cellular proliferation and apoptotic pathways, and such changes are cancer-dependent. In vitro and in vivo experiments show that, depending on the cancer type, either the upregulation or downregulation of ncRNAs can prevent the proliferation and progression of cancer. Therefore, a better understanding on how ncRNAs impact tumorigenesis could serve to develop new therapeutic treatments. Here, we review the involvement of ncRNAs in cancer epigenetics and highlight their use in clinical therapy.
tRNA-Derived Fragments (tRFs) in Bladder Cancer: Increased 5′-tRF-LysCTT Results in Disease Early Progression and Patients’ Poor Treatment Outcome
Authors: Papadimitriou Maria-Alexandra , Avgeris Margaritis , Levis Panagiotis , Papasotiriou Evangelia Ch. , Kotronopoulos Georgios , Stravodimos Konstantinos , Scorilas Andreas
Published: December 2020

The heterogeneity of bladder cancer (BlCa) prognosis and treatment outcome requires the elucidation of tumors’ molecular background towards personalized patients’ management. tRNA-derived fragments (tRFs), although originally considered as degradation debris, represent a novel class of powerful regulatory non-coding RNAs. In silico analysis of the TCGA-BLCA project highlighted 5′-tRF-LysCTT to be significantly deregulated in bladder tumors, and 5′-tRF-LysCTT levels were further quantified in our screening cohort of 230 BlCa patients. Recurrence and progression for non-muscle invasive (NMIBC) patients, as well as progression and patient’s death for muscle-invasive (MIBC) patients, were used as clinical endpoint events. TCGA-BLCA were used as validation cohort. Bootstrap analysis was performed for internal validation and the clinical net benefit of 5′-tRF-LysCTT on disease prognosis was assessed by decision curve analysis. Elevated 5′-tRF-LysCTT was associated with unfavorable disease features, and significant higher risk for early progression (multivariate Cox: HR = 2.368; p = 0.033) and poor survival (multivariate Cox: HR = 2.151; p = 0.032) of NMIBC and MIBC patients, respectively. Multivariate models integrating 5′-tRF-LysCTT with disease established markers resulted in superior risk-stratification specificity and positive prediction of patients’ progression. In conclusion, increased 5′-tRF-LysCTT levels were strongly associated with adverse disease outcome and improved BlCa patients’ prognostication.
Pain Management in Childhood Leukemia: Diagnosis and Available Analgesic Treatments
Authors: Coluzzi Flaminia , Rocco Monica , Green Gladden Rula , Persiani Pietro , Thur Laurel A. , Milano Filippo
Published: December 2020

Pain is one of the most common symptoms in children suffering from leukemia, who are often misdiagnosed with other childhood painful diseases such as juvenile idiopathic arthritis. Corticosteroid-induced osteonecrosis (ON) and vincristine-induced peripheral neuropathy (VIPN) are the most common painful manifestations. Additionally, ongoing pain may continue to impact quality of life in survivorship. This narrative review focuses on the pathophysiological mechanisms of pain in childhood leukemia and current available indications for analgesic treatments. Pain management in children is often inadequate because of difficulties in pain assessment, different indications across countries, and the lack of specific pediatric trials. Analgesic drugs are often prescribed off-label to children by extrapolating information from adult guidelines, with possible increased risk of adverse events. Optimal pain management should involve a multidisciplinary team to ensure assessment and interventions tailored to the individual patient.
Genomic Fabric Remodeling in Metastatic Clear Cell Renal Cell Carcinoma (ccRCC): A New Paradigm and Proposal for a Personalized Gene Therapy Approach
Authors: Iacobas Dumitru A. , Mgbemena Victoria E. , Iacobas Sanda , Menezes Kareena M. , Wang Huichen , Saganti Premkumar B.
Published: December 2020

Published transcriptomic data from surgically removed metastatic clear cell renal cell carcinoma samples were analyzed from the genomic fabric paradigm (GFP) perspective to identify the best targets for gene therapy. GFP considers the transcriptome as a multi-dimensional mathematical object constrained by a dynamic set of expression controls and correlations among genes. Every gene in the chest wall metastasis, two distinct cancer nodules, and the surrounding normal tissue of the right kidney was characterized by three independent measures: average expression level, relative expression variation, and expression correlation with each other gene. The analyses determined the cancer-induced regulation, control, and remodeling of the chemokine and vascular endothelial growth factor (VEGF) signaling, apoptosis, basal transcription factors, cell cycle, oxidative phosphorylation, renal cell carcinoma, and RNA polymerase pathways. Interestingly, the three cancer regions exhibited different transcriptomic organization, suggesting that the gene therapy should not be personalized only for every patient but also for each major cancer nodule. The gene hierarchy was established on the basis of gene commanding height, and the gene master regulators DAPK3,TASOR, FAM27C and ALG13 were identified in each profiled region. We delineated the molecular mechanisms by which TASOR overexpression and ALG13 silencing would selectively affect the cancer cells with little consequences for the normal cells.
Liposome-Encapsulated Bacillus Calmette–Guérin Cell Wall Skeleton Enhances Antitumor Efficiency for Bladder Cancer In Vitro and In Vivo via Induction of AMP-Activated Protein Kinase
Authors: Whang Young Mi , Yoon Da Hyeon , Hwang Gwang Yong , Yoon Hoyub , Park Serk In , Choi Young Wook , Chang In Ho
Published: December 2020

The Mycobacterium Bacillus Calmette-Guérin cell wall skeleton (BCG-CWS), the main immune active center of BCG, is a potent candidate non-infectious immunotherapeutic drug and an alternative to live BCG for use against urothelial carcinoma. However, its application in anticancer therapy is limited, as BCG-CWS tends to aggregate in both aqueous and non-aqueous solvents. To improve the internalization of BCG-CWS into bladder cancer cells without aggregation, BCG-CWS was nanoparticulated at a 180 nm size in methylene chloride and subsequently encapsulated with conventional liposomes (CWS-Nano-CL) using an emulsified lipid (LEEL) method. In vitro cell proliferation assays showed that CWS-Nano-CL was more effective at suppressing bladder cancer cell growth compared to nonenveloped BCG-CWS. In an orthotopic implantation model of luciferase-tagged MBT2 bladder cancer cells, encapsulated BCG-CWS nanoparticles could enhance the delivery of BCG-CWS into the bladder and suppress tumor growth. Treatment with CWS-Nano-CL induced the inhibition of the mammalian target of rapamycin (mTOR) pathway and the activation of AMP-activated protein kinase (AMPK) phosphorylation, leading to apoptosis, both in vitro and in vivo. Furthermore, the antitumor activity of CWS-Nano-CL was mediated predominantly by reactive oxygen species (ROS) generation and AMPK activation, which induced endoplasmic reticulum (ER) stress, followed by c-Jun N-terminal kinase (JNK) signaling-mediated apoptosis. Therefore, our data suggest that the intravesical instillation of liposome-encapsulated BCG-CWS nanoparticles can facilitate BCG-CW cellular endocytosis and provide a promising drug-delivery system as a therapeutic strategy for BCG-mediated bladder cancer treatment.
Angiogenesis-Related Gene Expression Signatures Predicting Prognosis in Gastric Cancer Patients
Authors: Ren Haoyu , Zhu Jiang , Yu Haochen , Bazhin Alexandr , Westphalen Christoph , Renz Bernhard , Jacob Sven , Lampert Christopher , Werner Jens , Angele Martin , Bösch Florian
Published: December 2020

Increasing evidence indicates that angiogenesis is crucial in the development and progression of gastric cancer (GC). This study aimed to develop a prognostic relevant angiogenesis-related gene (ARG) signature and a nomogram. The expression profile of the 36 ARGs and clinical information of 372 GC patients were extracted from The Cancer Genome Atlas (TCGA). Consensus clustering was applied to divide patients into clusters 1 and 2. Least absolute shrinkage and selection operator (LASSO) Cox regression analyses were used to identify the survival related ARGs and establish prognostic gene signatures, respectively. The Asian Cancer Research Group (ACRG) (n = 300) was used for external validation. Risk score of ARG signatures was calculated, and a prognostic nomogram was developed. Gene set enrichment analysis of the ARG model risk score was performed. Cluster 2 patients had more advanced clinical stage and shorter survival rates. ARG signatures carried prognostic relevance in both cohorts. Moreover, ARG-risk score was proved as an independent prognostic factor. The predictive value of the nomogram incorporating the risk score and clinicopathological features was superior to tumor, lymph node, metastasis (TNM) staging. The high-risk score group was associated with several cancer and metastasis-related pathways. The present study suggests that ARG-based nomogram could serve as effective prognostic biomarkers and allow a more precise risk stratification.
Editorial Catalysts: Special Issue on “Biomass Derived Heterogeneous and Homogeneous Catalysts”
Authors: Encinar José María , Nogales-Delgado Sergio
Published: December 2020

The replacement of petrol products for environmentally-friendly ones is a reality today, as many governments and international organizations are promoting the implementation of renewable energy sources and natural feedstocks in industrial activity [...]
A CeO2 Semiconductor as a Photocatalytic and Photoelectrocatalytic Material for the Remediation of Pollutants in Industrial Wastewater: A Review
Authors: Kusmierek Elzbieta
Published: December 2020

The direct discharge of industrial wastewater into the environment results in serious contamination. Photocatalytic treatment with the application of sunlight and its enhancement by coupling with electrocatalytic degradation offers an inexpensive and green technology enabling the total removal of refractory pollutants such as surfactants, pharmaceuticals, pesticides, textile dyes, and heavy metals, from industrial wastewater. Among metal oxide—semiconductors, cerium dioxide (CeO2) is one of the photocatalysts most commonly applied in pollutant degradation. CeO2 exhibits promising photocatalytic activity. Nonetheless, the position of conduction bands (CB) and valence bands (VB) in CeO2 limits its application as an efficient photocatalyst utilizing solar energy. Its photocatalytic activity in wastewater treatment can be improved by various modification techniques, including changes in morphology, doping with metal cation dopants and non-metal dopants, coupling with other semiconductors, and combining it with carbon supporting materials. This paper presents a general overview of CeO2 application as a single or composite photocatalyst in the treatment of various pollutants. The photocatalytic characteristics of CeO2 and its composites are described. The main photocatalytic reactions with the participation of CeO2 under UV and VIS irradiation are presented. This review summarizes the existing knowledge, with a particular focus on the main experimental conditions employed in the photocatalytic and photoelectrocatalytic degradation of various pollutants with the application of CeO2 as a single and composite photocatalyst.
Assessment of the Impact of Trace Elements in FAME Biodiesel on Diesel Oxidation Catalyst Activity after Full Lifetime of Operation in A Heavy-Duty Truck
Authors: Granestrand Jonas , Suárez París Rodrigo , Nilsson Marita , Regali Francesco , Pettersson Lars
Published: December 2020

Fatty acid methyl ester (FAME) biodiesel contains some trace amounts of Na, K, P, Ca, and Mg. Our objective was to investigate whether the presence of such elements can poison a diesel oxidation catalyst that has been used for an entire regulatory lifetime in a heavy-duty truck fueled by FAME biodiesel. The investigated vehicle-aged catalyst contained high loadings of S, P, and Na, as well as a visible layer of soot. Activity in the NO oxidation reaction was severely decreased compared to a fresh catalyst of the same type, while the CO and C3H6 oxidation reactions were less affected. Subsequent selective trace element removal procedures, followed by activity tests, were used to decouple the effect of different poisons. Sintering was observed to be the main cause of catalyst deactivation. Of the trace elements present on the catalyst, P had the greatest effect on catalyst activity, while the other trace elements had little effect.
pH Mapping of Skeletal Muscle by Chemical Exchange Saturation Transfer (CEST) Imaging
Authors: Chen Yu-Wen , Liu Hong-Qing , Wu Qi-Xuan , Huang Yu-Han , Tung Yu-Ying , Lin Ming-Huang , Lin Chia-Huei , Chen Tsai-Chen , Lin Eugene C. , Hwang Dennis W.
Published: December 2020

Magnetic resonance imaging (MRI) is extensively used in clinical and basic biomedical research. However, MRI detection of pH changes still poses a technical challenge. Chemical exchange saturation transfer (CEST) imaging is a possible solution to this problem. Using saturation transfer, alterations in the exchange rates between the solute and water protons because of small pH changes can be detected with greater sensitivity. In this study, we examined a fatigued skeletal muscle model in electrically stimulated mice. The measured CEST signal ratio was between 1.96 ppm and 2.6 ppm in the z-spectrum, and this was associated with pH values based on the ratio between the creatine (Cr) and the phosphocreatine (PCr). The CEST results demonstrated a significant contrast change at the electrical stimulation site. Moreover, the pH value was observed to decrease from 7.23 to 7.15 within 20 h after electrical stimulation. This pH decrease was verified by 31P magnetic resonance spectroscopy and behavioral tests, which showed a consistent variation over time.
Prognostic Significance of Lymph Node Examination by the OSNA Method in Lung Cancer Patients—Comparison with the Standard Histopathological Procedure
Authors: Vodicka Josef , Pesta Martin , Kulda Vlastimil , Houfkova Katerina , Vankova Bohuslava , Sebek Jakub , Skala Martin , Fichtl Jakub , Prochazkova Kristyna , Topolcan Ondrej
Published: December 2020

The aim of the study was to compare the prognostic significance of lymph node status of patients with lung cancer analyzed by three different methods: hematoxylin and eosin (H&E), immunohistochemistry of cytokeratin 19 (IHC CK19), and One-Step Nucleic Acid Amplification (OSNA). The clinical relevance of the results was evaluated based on relation to prognosis; the disease-free interval (DFI) and overall survival (OS) were analyzed. During radical surgical treatment, a total of 1426 lymph nodes were obtained from 100 patients, creating 472 groups of nodes (4–5 groups per patient) and examined by H&E, IHC CK19 and OSNA. The median follow-up was 44 months. Concordant results on the lymph node status of the H&E, IHC CK19 and OSNA examinations were reported in 78% of patients. We recorded shorter OS in patients with positive results provided by both OSNA and H&E. The study demonstrated a higher percentage of detected micrometastases in lymph nodes by the OSNA method. However, the higher sensitivity of the OSNA, with the cut-off value 250 copies of mRNA of CK19/µL, resulted in a lower association of OSNA positivity with progress of the disease compared to H&E. Increasing the cut-off to 615 copies resulted in an increase in concordance between the OSNA and H&E, which means that the higher cut-off is more relevant in the case of lung tumors.
Understanding Pseudomonas aeruginosa–Host Interactions: The Ongoing Quest for an Efficacious Vaccine
Authors: Sainz-Mejías Maite , Jurado-Martín Irene , McClean Siobhán
Published: December 2020

Pseudomonas aeruginosa is a leading cause of chronic respiratory infections in people with cystic fibrosis (CF), bronchiectasis or chronic obstructive pulmonary disease (COPD), and acute infections in immunocompromised individuals. The adaptability of this opportunistic pathogen has hampered the development of antimicrobial therapies, and consequently, it remains a major threat to public health. Due to its antimicrobial resistance, vaccines represent an alternative strategy to tackle the pathogen, yet despite over 50 years of research on anti-Pseudomonas vaccines, no vaccine has been licensed. Nevertheless, there have been many advances in this field, including a better understanding of the host immune response and the biology of P. aeruginosa. Multiple antigens and adjuvants have been investigated with varying results. Although the most effective protective response remains to be established, it is clear that a polarised Th2 response is sub-optimal, and a mixed Th1/Th2 or Th1/Th17 response appears beneficial. This comprehensive review collates the current understanding of the complexities of P. aeruginosa-host interactions and its implication in vaccine design, with a view to understanding the current state of Pseudomonal vaccine development and the direction of future efforts. It highlights the importance of the incorporation of appropriate adjuvants to the protective antigen to yield optimal protection.