bluuebunny/crossref_metadata_2025 huggingface dataset:
Determination of Mohr-Coulomb Parameters for Modelling of Concrete
Authors: Lelovic Selimir , Vasovic Dejan
Published: September 2020

Cohesion is defined as the shear strength of material when compressive stress is zero. This article presents a new method for the experimental determination of cohesion at pre-set angles of shear deformation. Specially designed moulds are created to force deformation (close to τ-axis) at fixed pre-set values of angle with respect to normal stress σ. Testing is performed on series of concrete blocks of different strengths. From the compressive side, cohesion is determined from the extrapolation of the linear Mohr–Coulomb (MC) model, as the intercept on the shear stress axis. From the tensile stress side (from the left), cohesion is obtained using the Brazilian test results: first, indirect tensile strength of material σtBT is measured, then Mohr circle diagram values are calculated and cohesion is determined as the value of shear stress τBT on the Mohr circle where normal stress (σ)t = 0. A hypothesis is made that cohesion is the common point between two tests. In the numerical part, a theory of ultimate load is applied to model Brazilian test using the angle of shear friction from the MC model. Matching experimental and numerical results confirm that the proposed procedure is applicable in numerical analysis.
Modelling of Chaotic Processes with Caputo Fractional Order Derivative
Authors: Owolabi Kolade M. , Gómez-Aguilar José Francisco , Fernández-Anaya G. , Lavín-Delgado J. E. , Hernández-Castillo E.
Published: September 2020

Chaotic dynamical systems are studied in this paper. In the models, integer order time derivatives are replaced with the Caputo fractional order counterparts. A Chebyshev spectral method is presented for the numerical approximation. In each of the systems considered, linear stability analysis is established. A range of chaotic behaviours are obtained at the instances of fractional power which show the evolution of the species in time and space.
Origin, Impact and Control of Lignocellulosic Inhibitors in Bioethanol Production—A Review
Authors: Sjulander Nikki , Kikas Timo
Published: September 2020

Bioethanol production from lignocellulosic biomass is still struggling with many obstacles. One of them is lignocellulosic inhibitors. The aim of this review is to discuss the most known inhibitors. Additionally, the review addresses different detoxification methods to degrade or to remove inhibitors from lignocellulosic hydrolysates. Inhibitors are formed during the pretreatment of biomass. They derive from the structural polymers-cellulose, hemicellulose and lignin. The formation of inhibitors depends on the pretreatment conditions. Inhibitors can have a negative influence on both the enzymatic hydrolysis and fermentation of lignocellulosic hydrolysates. The inhibition mechanisms can be, for example, deactivation of enzymes or impairment of vital cell structures. The toxicity of each inhibitor depends on its chemical and physical properties. To decrease the negative effects of inhibitors, different detoxification methods have been researched. Those methods focus on the chemical modification of inhibitors into less toxic forms or on the separation of inhibitors from lignocellulosic hydrolysates. Each detoxification method has its limitations on the removal of certain inhibitors. To choose a suitable detoxification method, a deep molecular understanding of the inhibition mechanism and the inhibitor formation is necessary.
Enhancing the Protective Performance of Surge Arresters against Indirect Lightning Strikes via an Inductor-Based Filter
Authors: Pourakbari-Kasmaei Mahdi , Lehtonen Matti
Published: September 2020

Preventing the medium voltage (MV) transformer fault by protecting transformers against indirect lightning strikes plays a crucial role in enhancing the continuous service to electricity consumers. Surge arresters, if selected properly, are efficient devices in providing adequate protection for MV transformers against transient overvoltage impulses while preventing unwanted service interruptions. However, compared to other protective devices such as the spark gap, their prices are relatively high. The higher the surge arrester rating and energy absorption capacity are, the higher the prices go. This paper proposes an inductor-based filter to limit the energy pushed into the surge arrester, and consequently to prevent any unwanted failure. An energy-controlled switch is proposed to simulate the fault of the surge arrester. Surge arresters with different ratings, e.g., 12 kV, 18 kV, 24 kV, 30 kV, 36 kV, and 42 kV with two different classes of energy, namely, type a and type b, are tested under different indirect lightning impulses such as 100 kV, 125 kV, 150 kV, 175 kV, 200 kV, 250 kV, 300 kV, and 500 kV. Furthermore, these surge arresters are equipped with different filter sizes of 100 μH, 250 μH, 500 μH, and 1 mH. Results prove that equipping a surge arrester with a proper filter size enhances the performance of the surge arrester significantly such that a high rating and somewhat expensive surge arrester can be replaced by a low rating and cheap surge arrester while providing similar or even better protective performance for MV transformers. Therefore, such configurations not only enhance the protective capability of surge arrester, but also reduce the planning and operating costs of MV networks.
Steady-State Performance Prediction for a Variable Speed Direct Expansion Air Conditioning System Using a White-Box Based Modeling Approach
Authors: Xia Yudong , Jiangzhou Shu , Zhang Xuejun , Zhang Zhao
Published: September 2020

When using a certain type of Heating, Ventilation & Air Conditioning (HVAC) systems, it is primary to obtain their steady-state operating behaviors for achieving a better indoor thermal environment. This paper reports a development of a white-box-based dynamic model for a direct expansion (DX) air conditioning (A/C) system to predict its steady-state operating performance under variable speed operation. The established model consists of five sub-models, i.e., a compressor, an electronic expansion valve, an evaporator, a condenser and a conditioned space. Each sub-model was developed based on partial lumped parameter approach. Using the available data generated from an experimental DX A/C system, both transient and steady-state behaviors predictions agreed well with the experimental ones. With the help of the validated white-box model, the inherent steady-state operating performance expressed in terms of the relationship among total cooling capacity (TCC), equipment sensible heat ratio (E SHR) and coefficient of performance (COP) under various speed combinations of compressor and supply fan were further examined. The results show that a higher COP could be achieved when the DX A/C system was operated at a higher fan speed or a lower compressor speed for dealing with a larger required E SHR. This model could be helpful for A/C system design and controller development.
Multiple-Embedded-System Optimization Layout for Electromagnetic Wave Power Density in Complex Environments
Authors: Fan Yang-Hsin
Published: September 2020

Many embedded systems are implemented for healthcare, and smart homes and spaces. These devices are generally designed for elderly care, for monitoring, surveillance, and collection information. As embedded systems are ubiquitous and pervasive in a smart home, office, or space, different layout affects not only reduce the implementation cost but also the power density of electromagnetic waves. This study aimed to develop a multiple-embedded-system optimization layout to consume less electromagnetic wave power density and gain better communication strength. For smart offices, we analyzed the layout topology of n-shaped and n-shaped with door layout categories. On the basis of the location of each embedded system in a communication center via an n-shaped layout, we investigated the electromagnetic wave effect to the local, direct, and semidirect effects. Indirect and subindirect effects were also studied in the n-shaped layout with a door. In addition, we derived a set of formulas from the scope for the diverse effects to help users to quickly identify the scope of each effect. To verify the multiple-embedded-system optimization layout, 16 cooperating embedded systems with four test cases in a smart office were used to evaluate the diverse effects of electromagnetic wave power density and communication strength. Experiment results showed that the optimization layout consumed 3950 × 10−6 W/m2 electromagnetic wave power density.
Fast Transactive Control for Frequency Regulation in Smart Grids with Demand Response and Energy Storage
Authors: Ly Andrew , Bashash Saeid
Published: September 2020

This paper proposes a framework for controlling grid frequency by engaging the generation-side and demand-side resources simultaneously, via a fast transactive control approach. First, we use a proportional frequency-price relation to build and analyze a transactive frequency droop controller for a single-area power grid. Then, we develop a transactive demand response system by incorporating a large population of thermostatically controlled air conditioning loads. A proportional-integral controller is used to adjust the setpoint temperature of the air conditioners based on price variations. A battery storage system is then developed and augmented to the system to capture the energy arbitrage effects. A nonlinear price-responsive battery management system is developed to enable effective charging and discharging operations within the battery’s state-of-charge and power constraints. Simulation results indicate that the proposed transactive control system improves the steady-state and transient response of the grid to sudden perturbations in the supply and demand equilibrium. To decouple frequency from price during daily operation and maintain frequency near the nominal value, we propose adding a feedforward price broadcast signal to the control loop based on the net demand measurement. Through various simulations, we conclude that a combination of feedback transactive controller with feedforward price broadcast scheme provides an effective solution for the simultaneous generation-side and demand-side energy management and frequency control in smart power grids.
Demand-Response Application in Wastewater Treatment Plants Using Compressed Air Storage System: A Modelling Approach
Authors: Cottes Mattia , Mainardis Matia , Goi Daniele , Simeoni Patrizia
Published: September 2020

Wastewater treatment plants (WWTPs) are known to be one of the most energy-intensive industrial sectors. In this work, demand response was applied to the biological phase of wastewater treatment to reduce plant electricity cost, considering that the daily peak in flowrate typically coincides with the maximum electricity price. Compressed air storage system, composed of a compressor and an air storage tank, was proposed to allow energy cost reduction. A multi-objective modelling approach was applied by analyzing different scenarios (with and without anaerobic digestion, AD), considering both plant characteristics (in terms of treated flowrate and influent chemical oxygen demand, COD, concentration) and storage system properties (volume, air pressure), together with the current Italian market economic conditions. The results highlight that air tank volume has a strong positive influence on the obtainable economic savings, with a less significant impact held by air pressure, COD concentration and flowrate. In addition, biogas exploitation from AD led to an improvement in economic indices. The developed model is highly flexible and can be applied to different WWTPs and market conditions.
Quantifying Topological Flexibility of Active Distribution Networks Based on Community Detection
Authors: Gu Huizi , Chu Xiaodong
Published: September 2020

Active distribution networks (ADNs) provide a flexible platform to integrate various distributed generation sources, among which the intermittent renewable sources impose high operating uncertainty. Topological flexibility of ADNs should be exploited to counter the stochastic operating conditions by modifying the topologies of ADNs. Quantifying the topological flexibility is a vital step to utilize it, which is lacking in previous studies. A quantification method is proposed to measure the topological flexibility of ADNs in this paper. First, the community structures of ADNs are detected to achieve spatial partitions of the networks. Second, an improved spectral clustering algorithm is employed to significantly reduce the dimensionality of the partition space, in which the ADNs are further partitioned using the affinity propagation algorithm. Finally, a topological flexibility metric is defined based on the guiding role of sectionalizing and tie switches within and between communities. The proposed topological flexibility quantification method is a superb approach to the utilization of flexibility resources in distribution networks. Case study results of test ADNs demonstrate the effectiveness and efficiency of the proposed quantification method.
Model Based Optimisation Algorithm for Maximum Power Point Tracking in Photovoltaic Panels
Authors: Hamidi Faiçal , Olteanu Severus Constantin , Popescu Dumitru , Jerbi Houssem , Dincă Ingrid , Ben Aoun Sondess , Abbassi Rabeh
Published: September 2020

Extracting maximum energy from photovoltaic (PV) systems at varying conditions is crucial. It represents a problem that is being addressed by researchers who are using several techniques to obtain optimal outcomes in real-life scenarios. Among the many techniques, Maximum Power Point Tracking (MPPT) is one category that is not extensively researched upon. MPPT uses mathematical models to achieve gradient optimisation in the context of PV panels. This study proposes an enhanced maximisation problem based on gradient optimisation techniques to achieve better performance. In the context of MPPT in photovoltaic panels, an equality restriction applies, which is solved by employing the Dual Lagrangian expression. Considering this dual problem and its mathematical form, the Nesterov Accelerated Gradient (NAG) framework is used. Additionally, since it is challenging to ascertain the step size, its approximate value is taken using the Adadelta approach. A basic MPPT framework, along with a DC-to-DC convertor, was simulated to validate the results.
Time Series Analysis of Forest Dynamics at the Ecoregion Level
Authors: Rumyantseva Olga , Sarantsev Andrey , Strigul Nikolay
Published: September 2020

Forecasting of forest dynamics at a large scale is essential for land use management, global climate change and biogeochemistry modeling. We develop time series models of the forest dynamics in the conterminous United States based on forest inventory data collected by the US Forest Service over several decades. We fulfilled autoregressive analysis of the basal forest area at the level of US ecological regions. In each USA ecological region, we modeled basal area dynamics on individual forest inventory pots and performed analysis of its yearly averages. The last task involved Bayesian techniques to treat irregular data. In the absolute majority of ecological regions, basal area yearly averages behave as geometric random walk with normal increments. In California Coastal Province, geometric random walk with normal increments adequately describes dynamics of both basal area yearly averages and basal area on individual forest plots. Regarding all the rest of the USA’s ecological regions, basal areas on individual forest patches behave as random walks with heavy tails. The Bayesian approach allowed us to evaluate forest growth rate within each USA ecological region. We have also implemented time series ARIMA models for annual averages basal area in every USA ecological region. The developed models account for stochastic effects of environmental disturbances and allow one to forecast forest dynamics.
Modified Mittag-Leffler Functions with Applications in Complex Formulae for Fractional Calculus
Authors: Fernandez Arran , Husain Iftikhar
Published: September 2020

Mittag-Leffler functions and their variations are a popular topic of study at the present time, mostly due to their applications in fractional calculus and fractional differential equations. Here we propose a modification of the usual Mittag-Leffler functions of one, two, or three parameters, which is ideally suited for extending certain fractional-calculus operators into the complex plane. Complex analysis has been underused in combination with fractional calculus, especially with newly developed operators like those with Mittag-Leffler kernels. Here we show the natural analytic continuations of these operators using the modified Mittag-Leffler functions defined in this paper.
Fractal and Fractional Derivative Modelling of Material Phase Change
Authors: Esmonde Harry
Published: September 2020

An iterative approach is taken to develop a fractal topology that can describe the material structure of phase changing materials. Transfer functions and frequency response functions based on fractional calculus are used to describe this topology and then applied to model phase transformations in liquid/solid transitions in physical processes. Three types of transformation are tested experimentally, whipping of cream (rheopexy), solidification of gelatine and melting of ethyl vinyl acetate (EVA). A liquid-type model is used throughout the cream whipping process while liquid and solid models are required for gelatine and EVA to capture the yield characteristic of these materials.
Training Hospitalists in Negotiations to Address Conflicts with Older Adults around Their Social Needs
Authors: Campbell Mobola , Ramirez-Zohfeld Vanessa , Seltzer Anne , Lindquist Lee A.
Published: September 2020

Hospitalists care for a growing population of older patients with unique social needs that can often be addressed by providing caregiver help in the home. The importance of addressing social needs is well-recognized, yet older patients sometimes refuse these services. This refusal of services may result in rehospitalization and increased morbidity for patients. We aimed to overcome this refusal of social support through an innovative workshop training hospitalists in negotiation and dispute resolution. Hospitalists at a tertiary care, urban academic medical center completed a one-hour interactive workshop on negotiation and dispute resolution focused on addressing older patients’ refusal of social services. One month post workshop, participants reported increased confidence in engaging patients and families in conflicts and felt empowered to negotiate in both their clinical practice and personal lives. Training hospitalists to negotiate with older adults needing social services is feasible and positively impacts the ability to provide geriatric care.
Pneumonia: Does Age or Gender Relate to the Presence of an SLP Dysphagia Consultation?
Authors: Bolinger Christopher , Dembowski James , Mory Kimberly
Published: September 2020

A retrospective study of 1489 hospital records examined the relationship of speech-language pathologist (SLP) consults for dysphagia to age and gender in pneumonia patients from an acute care setting. Age and gender disparities exist in healthcare. The research sought to determine if disparities existed in the presence/absence of SLP dysphagia consults related to age and gender. Results suggested SLPs were consulted on a greater percentage of geriatric patients overall; however, there were differences in the number of consults for each pneumonia type. More males and geriatric patients were seen than females and non-geriatric adults, respectively. Results may be used to address local hospital policies and protocols and thus increase quality of care by improving morbidity and mortality outcomes of geriatric patients with pneumonia.
Does Focus Improve Performance in Elective Surgery? A Study of Obesity Surgery in Sweden
Authors: Svarts Anna , Urciuoli Luca , Thorell Anders , Engwall Mats
Published: September 2020

Recent studies have found positive effects from hospital focus on both quality and cost. Some studies indicate that certain patient segments benefit from focus, while others have worse outcomes in focused hospital departments. The aim of this study was to establish the relationship between hospital focus and performance in elective surgery. We studied obesity surgery procedures performed in Sweden in 2016 (5152 patients), using data from the Scandinavian Obesity Surgery Registry (SOReg) complemented by a survey of all clinics that performed obesity surgery. We examined focus at two levels of the organization: hospital level and department level. We hypothesized that higher proportions of obesity surgery patients in the hospital, and higher proportions of obesity surgery procedures in the department, would be associated with better performance. These hypotheses were tested using multilevel regression analysis, while controlling for patient characteristics and procedural volume. We found that focus was associated with improved outcomes in terms of reduced complications and shorter procedure times. These positive relationships were present at both hospital and department level, but the effect was larger at the department level. The findings imply that focus is a viable strategy to improve quality and reduce costs for patients undergoing elective surgery. For these patients, general hospitals should consider implementing organizationally separate units for patients undergoing elective surgery.
The Role of Tryptophan Metabolites in Musculoskeletal Stem Cell Aging
Authors: Anaya Jordan Marcano , Bollag Wendy B. , Hamrick Mark W. , Isales Carlos M.
Published: September 2020

Although aging is considered a normal process, there are cellular and molecular changes that occur with aging that may be detrimental to health. Osteoporosis is one of the most common age-related degenerative diseases, and its progression correlates with aging and decreased capacity for stem cell differentiation and proliferation in both men and women. Tryptophan metabolism through the kynurenine pathway appears to be a key factor in promoting bone-aging phenotypes, promoting bone breakdown and interfering with stem cell function and osteogenesis; however, little data is available on the impact of tryptophan metabolites downstream of kynurenine. Here we review available data on the impact of these tryptophan breakdown products on the body in general and, when available, the existing evidence of their impact on bone. A number of tryptophan metabolites (e.g., 3-hydroxykynurenine (3HKYN), kynurenic acid (KYNA) and anthranilic acid (AA)) have a detrimental effect on bone, decreasing bone mineral density (BMD) and increasing fracture risk. Other metabolites (e.g., 3-hydroxyAA, xanthurenic acid (XA), picolinic acid (PIA), quinolinic acid (QA), and NAD+) promote an increase in bone mineral density and are associated with lower fracture risk. Furthermore, the effects of other tryptophan breakdown products (e.g., serotonin) are complex, with either anabolic or catabolic actions on bone depending on their source. The mechanisms involved in the cellular actions of these tryptophan metabolites on bone are not yet fully known and will require further research as they are potential therapeutic targets. The current review is meant as a brief overview of existing English language literature on tryptophan and its metabolites and their effects on stem cells and musculoskeletal systems. The search terms used for a Medline database search were: kynurenine, mesenchymal stem cells, bone loss, tryptophan metabolism, aging, and oxidative stress.
Reply: “Comment on: Food for Bone: Evidence for a Role for Delta-Tocotrienol in the Physiological Control of Osteoblast Migration. Int. J. Mol. Sci. 2020, 21, 4661”
Authors: Casati Lavinia , Pagani Francesca , Maggi Roberto , Ferrucci Francesco , Sibilia Valeria
Published: September 2020

Dear Editor, [...]
Deleterious Alteration of Glia in the Brain of Alzheimer’s Disease
Authors: Kim Eunyoung , Otgontenger Undarmaa , Jamsranjav Ariunzaya , Kim Sang Seong
Published: September 2020

The deterioration of neurons in Alzheimer’s disease (AD) arises from genetic, immunologic, and cellular factors inside the cortex. The traditional consensus of the amyloid-beta (Aβ) paradigm as a singular cause of AD has been under revision, with the accumulation of exploding neurobiological evidence. Among the multifaceted casualties of AD, the involvement of glia gains significance for its dynamic contribution to neurons, either in a neuroprotective or neurotoxic fashion. Basically, microglia and astrocytes contribute to neuronal sustainability by releasing neuroprotective cytokines, maintaining an adequate amount of glutamate in the synapse, and pruning excessive synaptic terminals. Such beneficial effects divert to the other detrimental cascade in chronic neuroinflammatory conditions. In this change, there are new discoveries of specific cytokines, microRNAs, and complementary factors. Previously unknown mechanisms of ion channels such as Kv1.3, Kir2.1, and HCN are also elucidated in the activation of microglia. The activation of glia is responsible for the excitotoxicity through the overflow of glutamate transmitter via mGluRs expressed on the membrane, which can lead to synaptic malfunction and engulfment. The communication between microglia and astrocytes is mediated through exosomes as well as cytokines, where numerous pieces of genetic information are transferred in the form of microRNAs. The new findings tell us that the neuronal environment in the AD condition is a far more complicated and dynamically interacting space. The identification of each molecule in the milieu and cellular communication would contribute to a better understanding of AD in the neurobiological perspective, consequently suggesting a possible therapeutic clue.
Bioinformatic Characterization of Sulfotransferase Provides New Insights for the Exploitation of Sulfated Polysaccharides in Caulerpa
Authors: Landi Simone , Esposito Sergio
Published: September 2020

Caulerpa is an unusual algal genus from Caulerpaceae (Chlorophyta, Bryopsidales). Species from this family produce a wide range of metabolites suitable for biotechnology applications. Among these, sulfated polysaccharides (SPs) are often highly desirable for pharmaceutical and nutraceutical applications. Here, we provide a classification of sulfotransferases from Caulerpa; these important enzymes catalyze the nodal step for the biosynthesis of SPs. For this, we performed phylogenetic, genomic, expression analyses and prediction of the protein structure on sulfotransferases from Caulerpa. Sequences, domains and structures of sulfotransferases generally shared common characteristics with other plants and algae. However, we found an extensive duplication of sulfotransferase gene family, which is unique among the green algae. Expression analysis revealed specific transcript abundance in the pinnae and rachis of the alga. The unique genomic features could be utilized for the production of complex SPs, which require multiple and specific sulfation reactions. The expansion of this gene family in Caulerpaceae would have resulted in a number of proteins characterizing the unique SPs found in these algae. We provide a putative biosynthetic pathway of SPs, indicating the unique characteristics of this pathway in Caulerpa species. These data may help in the future selection of Caulerpa species for both commercial applications and genetic studies to improve the synthesis of valuable products from Caulerpa.
Mechanisms Underlying the Regulation of Mitochondrial Respiratory Chain Complexes by Nuclear Steroid Receptors
Authors: Kobayashi Ami , Azuma Kotaro , Ikeda Kazuhiro , Inoue Satoshi
Published: September 2020

Mitochondrial respiratory chain complexes play important roles in energy production via oxidative phosphorylation (OXPHOS) to drive various biochemical processes in eukaryotic cells. These processes require coordination with other cell organelles, especially the nucleus. Factors encoded by both nuclear and mitochondrial DNA are involved in the formation of active respiratory chain complexes and ‘supercomplexes’, the higher-order structures comprising several respiratory chain complexes. Various nuclear hormone receptors are involved in the regulation of OXPHOS-related genes. In this article, we review the roles of nuclear steroid receptors (NR3 class nuclear receptors), including estrogen receptors (ERs), estrogen-related receptors (ERRs), glucocorticoid receptors (GRs), mineralocorticoid receptors (MRs), progesterone receptors (PRs), and androgen receptors (ARs), in the regulatory mechanisms of mitochondrial respiratory chain complex and supercomplex formation.
Inhibition of DNA Repair in Cancer Therapy: Toward a Multi-Target Approach
Authors: Lodovichi Samuele , Cervelli Tiziana , Pellicioli Achille , Galli Alvaro
Published: September 2020

Alterations in DNA repair pathways are one of the main drivers of cancer insurgence. Nevertheless, cancer cells are more susceptible to DNA damage than normal cells and they rely on specific functional repair pathways to survive. Thanks to advances in genome sequencing, we now have a better idea of which genes are mutated in specific cancers and this prompted the development of inhibitors targeting DNA repair players involved in pathways essential for cancer cells survival. Currently, the pivotal concept is that combining the inhibition of mechanisms on which cancer cells viability depends is the most promising way to treat tumorigenesis. Numerous inhibitors have been developed and for many of them, efficacy has been demonstrated either alone or in combination with chemo or radiotherapy. In this review, we will analyze the principal pathways involved in cell cycle checkpoint and DNA repair focusing on how their alterations could predispose to cancer, then we will explore the inhibitors developed or in development specifically targeting different proteins involved in each pathway, underscoring the rationale behind their usage and how their combination and/or exploitation as adjuvants to classic therapies could help in patients clinical outcome.
Blocking ADAM17 Function with a Monoclonal Antibody Improves Sepsis Survival in a Murine Model of Polymicrobial Sepsis
Authors: Mishra Hemant K. , Ma Jing , Mendez Daniel , Hullsiek Robert , Pore Nabendu , Walcheck Bruce
Published: September 2020

Sepsis is the culmination of hyperinflammation and immune suppression in response to severe infection. Neutrophils are critical early responders to bacterial infection but can become highly dysfunctional during sepsis and other inflammatory disorders. The transmembrane protease ADAM17 (a disintegrin and metalloproteinase 17) is expressed by leukocytes and most other cells and has many substrates that regulate inflammation. We have reported that conditional knockout mice lacking ADAM17 in all leukocytes had a survival advantage during sepsis, which was associated with improved neutrophil effector functions. These and other findings indicate aberrant ADAM17 activity during sepsis. For this study, we evaluated for the first time the effects of an ADAM17 function blocking monoclonal antibody (mAb) on the pathogenesis of polymicrobial sepsis. Mice treated with the ADAM17 mAb MEDI3622 prior to sepsis induction exhibited significantly decreased mortality. When the ADAM17 mAb was combined with antibiotic administration, sepsis survival was markedly enhanced compared to either intervention alone, which was associated with a significant reduction in plasma levels of various inflammation-related factors. MEDI3622 and antibiotic administration after sepsis induction also significantly improved survival. Our results indicate that the combination of blocking ADAM17 as an immune modulator and appropriate antibiotics may provide a new therapeutic avenue for sepsis treatment.
Pre-Operative Evaluation of DNA Methylation Profile in Oral Squamous Cell Carcinoma Can Predict Tumor Aggressive Potential
Authors: Gissi Davide , Fabbri Viscardo , Gabusi Andrea , Lenzi Jacopo , Morandi Luca , Melotti Sofia , Asioli Sofia , Tarsitano Achille , Balbi Tiziana , Marchetti Claudio , Montebugnoli Lucio
Published: September 2020

Background: Prognosis of oral squamous cell carcinoma (OSCC) is difficult to exactly assess on pre-operative biopsies. Since OSCC DNA methylation profile has proved to be a useful pre-operative diagnostic tool, the aim of the present study was to evaluate the prognostic impact of DNA methylation profile to discriminate OSCC with high and low aggressive potential. Methods: 36 OSCC cases underwent neoplastic cells collection by gentle brushing of the lesion, before performing a pre-operative biopsy. The CpG islands methylation status of 13 gene (ZAP70, ITGA4, KIF1A, PARP15, EPHX3, NTM, LRRTM1, FLI1, MiR193, LINC00599, MiR296, TERT, GP1BB) was studied by bisulfite Next Generation Sequencing (NGS). A Cox proportional hazards model via likelihood-based component-wise boosting was used to evaluate the prognostic power of the CpG sites. Results: The boosting estimation identified five CpGs with prognostic significance: EPHX3-24, EPHX3-26, ITGA4-3, ITGA4-4, and MiR193-3. The combination of significant CpGs provided promising results for adverse events prediction (Brier score = 0.080, C-index = 0.802 and AUC = 0.850). ITGA4 had a strong prognostic power in patients with early OSCC. Conclusions: These data confirm that the study of methylation profile provides new insights into the molecular mechanisms of OSCC and can allow a better OSCC prognostic stratification even before surgery.
Downregulation of CDC20 Increases Radiosensitivity through Mcl-1/p-Chk1-Mediated DNA Damage and Apoptosis in Tumor Cells
Authors: Gao Yang , Wen Pengbo , Chen Bin , Hu Guanshuo , Wu Lijun , Xu An , Zhao Guoping
Published: September 2020

Radiotherapy is an important modality for the local control of human cancers, but the radioresistance induced by aberrant apoptotic signaling is a hallmark of cancers. Restoring the aberrant apoptotic pathways is an emerging strategy for cancer radiotherapy. In this study, we determined that targeting cell division cycle 20 (CDC20) radiosensitized colorectal cancer (CRC) cells through mitochondrial-dependent apoptotic signaling. CDC20 was overexpressed in CRC cells and upregulated after radiation. Inhibiting CDC20 activities genetically or pharmacologically suppressed the proliferation and increased radiation-induced DNA damage and intrinsic apoptosis in CRC cells. Mechanistically, knockdown of CDC20 suppressed the expression of antiapoptotic protein Mcl-1 but not other Bcl-2 family proteins. The expressions of CDC20 and Mcl-1 respond to radiation simultaneously through direct interaction, as evidenced by immunoprecipitation and glutathione S-transferase (GST) pull-down assays. Subsequently, decreased Mcl-1 expression inhibited the expression level of phosphorylated checkpoint kinase 1 (p-Chk1), thereby resulting in impaired DNA damage repair through downregulating the homologous recombination repair protein Rad51 and finally causing apoptotic signaling. In addition, both CDC20 and Chk1 inhibitors together, through in vivo studies, confirmed the radiosensitizing effect of CDC20 via inhibiting Mcl-1 and p-Chk1 expression. In summary, our results indicate that targeting CDC20 is a promising strategy to improve cancer radiotherapy.
Insights into the Selectivity Mechanisms of Grapevine NIP Aquaporins
Authors: Sabir Farzana , Di Pizio Antonella , Loureiro-Dias Maria C. , Casini Angela , Soveral Graça , Prista Catarina
Published: September 2020

Nodulin 26-like intrinsic proteins (NIPs) of the plant aquaporin family majorly facilitate the transport of physiologically relevant solutes. The present study intended to investigate how substrate selectivity in grapevine NIPs is influenced by the aromatic/arginine (ar/R) selectivity filter within the pore and the possible underlying mechanisms. A mutational approach was used to interchange the ar/R residues between grapevine NIPs (VvTnNIP1;1 with VvTnNIP6;1, and VvTnNIP2;1 with VvTnNIP5;1). Their functional characterization by stopped-flow spectroscopy in Saccharomyces cerevisiae revealed that mutations in residues of H2/H5 helices in VvTnNIP1;1 and VvTnNIP6;1 caused a general decline in membrane glycerol permeability but did not impart the expected substrate conductivity in the mutants. This result suggests that ar/R filter substitution could alter the NIP channel activity, but it was not sufficient to interchange their substrate preferences. Further, homology modeling analyses evidenced that variations in the pore radius combined with the differences in the channel’s physicochemical properties (hydrophilicity/hydrophobicity) may drive substrate selectivity. Furthermore, yeast growth assays showed that H5 residue substitution alleviated the sensitivity of VvTnNIP2;1 and VvTnNIP5;1 to As, B, and Se, implying importance of H5 sequence for substrate selection. These results contribute to the knowledge of the overall determinants of substrate selectivity in NIPs.
Genetic and Methylome Variation in Turkish Brachypodium Distachyon Accessions Differentiate Two Geographically Distinct Subpopulations
Authors: Skalska Aleksandra , Stritt Christoph , Wyler Michele , Williams Hefin W. , Vickers Martin , Han Jiwan , Tuna Metin , Savas Tuna Gulsemin , Susek Karolina , Swain Martin , Wóycicki Rafał K. , Chaudhary Saurabh , Corke Fiona , Doonan John H. , Roulin Anne C. , Hasterok Robert , Mur Luis A. J.
Published: September 2020

Brachypodium distachyon (Brachypodium) is a non-domesticated model grass species that can be used to test if variation in genetic sequence or methylation are linked to environmental differences. To assess this, we collected seeds from 12 sites within five climatically distinct regions of Turkey. Seeds from each region were grown under standardized growth conditions in the UK to preserve methylated sequence variation. At six weeks following germination, leaves were sampled and assessed for genomic and DNA methylation variation. In a follow-up experiment, phenomic approaches were used to describe plant growth and drought responses. Genome sequencing and population structure analysis suggested three ancestral clusters across the Mediterranean, two of which were geographically separated in Turkey into coastal and central subpopulations. Phenotypic analyses showed that the coastal subpopulation tended to exhibit relatively delayed flowering and the central, increased drought tolerance as indicated by reduced yellowing. Genome-wide methylation analyses in GpC, CHG and CHH contexts also showed variation which aligned with the separation into coastal and central subpopulations. The climate niche modelling of both subpopulations showed a significant influence from the “Precipitation in the Driest Quarter” on the central subpopulation and “Temperature of the Coldest Month” on the coastal subpopulation. Our work demonstrates genetic diversity and variation in DNA methylation in Turkish accessions of Brachypodium that may be associated with climate variables and the molecular basis of which will feature in ongoing analyses.
A Possible Role of FZD10 Delivering Exosomes Derived from Colon Cancers Cell Lines in Inducing Activation of Epithelial–Mesenchymal Transition in Normal Colon Epithelial Cell Line
Authors: Scavo Maria Principia , Rizzi Federica , Depalo Nicoletta , Fanizza Elisabetta , Ingrosso Chiara , Curri Maria Lucia , Giannelli Gianluigi
Published: September 2020

Exosomes belong to the family of extracellular vesicles released by every type of cell both in normal and pathological conditions. Growing interest in studies indicates that extracellular vesicles, in particular, the fraction named exosomes containing lipids, proteins and nucleic acid, represent an efficient way to transfer functional cargoes between cells, thus combining all the other cell–cell interaction mechanisms known so far. Only a few decades ago, the involvement of exosomes in the carcinogenesis in different tissues was discovered, and very recently it was also observed how they carry and modulate the presence of Wnt pathway proteins, involved in the carcinogenesis of gastrointestinal tissues, such as Frizzled 10 protein (FZD10), a membrane receptor for Wnt. Here, we report the in vitro study on the capability of tumor-derived exosomes to induce neoplastic features in normal cells. Exosomes derived from two different colon cancer cell lines, namely the non-metastatic CaCo-2 and the metastatic SW620, were found to deliver, in both cases, FZD10, thus demonstrating the ability to reprogram normal colonic epithelial cell line (HCEC-1CT). Indeed, the acquisition of specific mesenchymal characteristics, such as migration capability and expression of FZD10 and markers of mesenchymal cells, was observed. The exosomes derived from the metastatic cell line, characterized by a level of FZD10 higher than the exosomes extracted from the non-metastatic cells, were also more efficient in stimulating EMT activation. The overall results suggest that FZD10, delivered by circulating tumor-derived exosomes, can play a relevant role in promoting the CRC carcinogenesis and propagation.
Functional Characterization of a Putative RNA Demethylase ALKBH6 in Arabidopsis Growth and Abiotic Stress Responses
Authors: Huong Trinh Thi , Ngoc Le Nguyen Tieu , Kang Hunseung
Published: September 2020

RNA methylation and demethylation, which is mediated by RNA methyltransferases (referred to as “writers”) and demethylases (referred to as “erasers”), respectively, are emerging as a key regulatory process in plant development and stress responses. Although several studies have shown that AlkB homolog (ALKBH) proteins are potential RNA demethylases, the function of most ALKBHs is yet to be determined. The Arabidopsis thaliana genome contains thirteen genes encoding ALKBH proteins, the functions of which are largely unknown. In this study, we characterized the function of a potential eraser protein, ALKBH6 (At4g20350), during seed germination and seedling growth in Arabidopsis under abiotic stresses. The seeds of T-DNA insertion alkbh6 knockdown mutants germinated faster than the wild-type seeds under cold, salt, or abscisic acid (ABA) treatment conditions but not under dehydration stress conditions. Although no differences in seedling and root growth were observed between the alkbh6 mutant and wild-type under normal conditions, the alkbh6 mutant showed a much lower survival rate than the wild-type under salt, drought, or heat stress. Cotyledon greening of the alkbh6 mutants was much higher than that of the wild-type upon ABA application. Moreover, the transcript levels of ABA signaling-related genes, including ABI3 and ABI4, were down-regulated in the alkbh6 mutant compared to wild-type plants. Importantly, the ALKBH6 protein had an ability to bind to both m6A-labeled and m5C-labeled RNAs. Collectively, these results indicate that the potential eraser ALKBH6 plays important roles in seed germination, seedling growth, and survival of Arabidopsis under abiotic stresses.
Regulation of microRNAs in Satellite Cell Renewal, Muscle Function, Sarcopenia and the Role of Exercise
Authors: Fochi Stefania , Giuriato Gaia , De Simone Tonia , Gomez-Lira Macarena , Tamburin Stefano , Del Piccolo Lidia , Schena Federico , Venturelli Massimo , Romanelli Maria Grazia
Published: September 2020

Sarcopenia refers to a condition of progressive loss of skeletal muscle mass and function associated with a higher risk of falls and fractures in older adults. Musculoskeletal aging leads to reduced muscle mass and strength, affecting the quality of life in elderly people. In recent years, several studies contributed to improve the knowledge of the pathophysiological alterations that lead to skeletal muscle dysfunction; however, the molecular mechanisms underlying sarcopenia are still not fully understood. Muscle development and homeostasis require a fine gene expression modulation by mechanisms in which microRNAs (miRNAs) play a crucial role. miRNAs modulate key steps of skeletal myogenesis including satellite cells renewal, skeletal muscle plasticity, and regeneration. Here, we provide an overview of the general aspects of muscle regeneration and miRNAs role in skeletal mass homeostasis and plasticity with a special interest in their expression in sarcopenia and skeletal muscle adaptation to exercise in the elderly.
IKKγ/NEMO Is Required to Confer Antimicrobial Innate Immune Responses in the Yellow Mealworm, Tenebrio Molitor
Authors: Ko Hye Jin , Jo Yong Hun , Patnaik Bharat Bhusan , Park Ki Beom , Kim Chang Eun , Keshavarz Maryam , Jang Ho Am , Lee Yong Seok , Han Yeon Soo
Published: September 2020

IKKγ/NEMO is the regulatory subunit of the IκB kinase (IKK) complex, which regulates the NF-κB signaling pathway. Within the IKK complex, IKKγ/NEMO is the non-catalytic subunit, whereas IKKα and IKKβ are the structurally related catalytic subunits. In this study, TmIKKγ was screened from the Tenebrio molitor RNA-Seq database and functionally characterized using RNAi screening for its role in regulating T. molitor antimicrobial peptide (AMP) genes after microbial challenges. The TmIKKγ transcript is 1521 bp that putatively encodes a polypeptide of 506 amino acid residues. TmIKKγ contains a NF-κB essential modulator (NEMO) and a leucine zipper domain of coiled coil region 2 (LZCC2). A phylogenetic analysis confirmed its homology to the red flour beetle, Tribolium castaneum IKKγ (TcIKKγ). The expression of TmIKKγ mRNA showed that it might function in diverse tissues of the insect, with a higher expression in the hemocytes and the fat body of the late-instar larvae. TmIKKγ mRNA expression was induced by Escherichia coli, Staphylococcus aureus, and Candida albicans challenges in the whole larvae and in tissues such as the hemocytes, gut and fat body. The knockdown of TmIKKγ mRNA significantly reduced the survival of the larvae after microbial challenges. Furthermore, we investigated the tissue-specific induction patterns of fourteen T. molitor AMP genes in TmIKKγ mRNA-silenced individuals after microbial challenges. In general, the mRNA expression of TmTenecin1, -2, and -4; TmDefensin1 and -2; TmColeoptericin1 and 2; and TmAttacin1a, 1b, and 2 were found to be downregulated in the hemocytes, gut, and fat body tissues in the TmIKKγ-silenced individuals after microbial challenges. Under similar conditions, TmRelish (NF-κB transcription factor) mRNA was also found to be downregulated. Thus, TmIKKγ is an important factor in the antimicrobial innate immune response of T. molitor.
The Effects of Cannabidiol, a Non-Intoxicating Compound of Cannabis, on the Cardiovascular System in Health and Disease
Authors: Kicman Aleksandra , Toczek Marek
Published: September 2020

Cannabidiol (CBD) is a non-intoxicating and generally well-tolerated constituent of cannabis which exhibits potential beneficial properties in a wide range of diseases, including cardiovascular disorders. Due to its complex mechanism of action, CBD may affect the cardiovascular system in different ways. Thus, we reviewed the influence of CBD on this system in health and disease to determine the potential risk of cardiovascular side effects during CBD use for medical and wellness purposes and to elucidate its therapeutic potential in cardiovascular diseases. Administration of CBD to healthy volunteers or animals usually does not markedly affect hemodynamic parameters. Although CBD has been found to exhibit vasodilatory and antioxidant properties in hypertension, it has not affected blood pressure in hypertensive animals. Hypotensive action of CBD has been mainly revealed under stress conditions. Many positive effects of CBD have been observed in experimental models of heart diseases (myocardial infarction, cardiomyopathy, myocarditis), stroke, neonatal hypoxic ischemic encephalopathy, sepsis-related encephalitis, cardiovascular complications of diabetes, and ischemia/reperfusion injures of liver and kidneys. In these pathological conditions CBD decreased organ damage and dysfunction, oxidative and nitrative stress, inflammatory processes and apoptosis, among others. Nevertheless, further clinical research is needed to recommend the use of CBD in the treatment of cardiovascular diseases.