bluuebunny/crossref_metadata_2025 huggingface dataset:
Longitudinal Point Prevalence Survey of Antimicrobial Consumption in Russian Hospitals: Results of the Global-PPS Project
Authors: Rachina Svetlana , Belkova Yuliya , Kozlov Roman , Versporten Ann , Pauwels Ines , Goossens Herman , Bochanova Elena , Domanskaya Olga , Elokhina Elena , Ezhova Ludmila , Mishchenko Vladimir , Ni Oksana , Popov Dmitry , Portnjagina Ulyana , Shchetinin Evgeny , Shegimova Vera , Strezh Yulia , Vityazeva Vera , Zubareva Nadezhda ,   Russian Global-PPS Project Study Group
Published: July 2020

Antimicrobial resistance is one of the key issues limiting the successful treatment of infectious diseases and associated with adverse medical, social and economic consequences on a global scale. The present study aims to evaluate antimicrobials prescribing patterns and assess progress in quality indicators in Russian multidisciplinary hospitals using three repetitive point prevalence studies (PPSs) over 4 years (Global-PPS 2015, 2017 and 2018). Out of 13,595 patients from 21 hospitals surveyed over the three time points, 3542 (26.14%) received antimicrobials, predominantly third-generation cephalosporins (44.7% in 2015, 34.1% in 2017 and 41.8% in 2018). Compliance with the hospital antibiotic guidelines was 74.8%, 66.8% and 74.3%, respectively. Indication for treatment was recorded in 72.6%, 84.1% and 82.6%, while stop/review date was documented only in 40.5%, 46.5% and 61.1% of cases. Perioperative antibiotic prophylaxis exceeded 1 day in 92%, 84% and 81% of cases. Targeted therapy rate at all time points did not exceed 15.1%, treatment based on the biomarkers rate—19.9%. For the part of PPS-2017 and 2018 analyzed in dynamics, no prominent trends were noted. The results of the project provide the basis for the development of appropriate antimicrobial stewardship programs tailored according to local practices for each hospital in the project.
Frog Skin-Derived Peptides Against Corynebacterium jeikeium: Correlation between Antibacterial and Cytotoxic Activities
Authors: Casciaro Bruno , Loffredo Maria Rosa , Cappiello Floriana , Verrusio Walter , Corleto Vito Domenico , Mangoni Maria Luisa
Published: July 2020

Corynebacterium jeikeium is a commensal bacterium that colonizes human skin, and it is part of the normal bacterial flora. In non-risk subjects, it can be the cause of bad body smell due to the generation of volatile odorous metabolites, especially in the wet parts of the body that this bacterium often colonizes (i.e., groin and axillary regions). Importantly, in the last few decades, there have been increasing cases of serious infections provoked by this bacterium, especially in immunocompromised or hospitalized patients who have undergone installation of prostheses or catheters. The ease in developing resistance to commonly-used antibiotics (i.e., glycopeptides) has made the search for new antimicrobial compounds of clinical importance. Here, for the first time, we characterize the antimicrobial activity of some selected frog skin-derived antimicrobial peptides (AMPs) against C. jeikeium by determining their minimum inhibitory and bactericidal concentrations (MIC and MBC) by a microdilution method. The results highlight esculentin-1b(1-18) [Esc(1-18)] and esculentin-1a(1-21) [Esc(1-21)] as the most active AMPs with MIC and MBC of 4–8 and 0.125–0.25 µM, respectively, along with a non-toxic profile after a short- and long-term (40 min and 24 h) treatment of mammalian cells. Overall, these findings indicate the high potentiality of Esc(1-18) and Esc(1-21) as (i) alternative antimicrobials against C. jeikeium infections and/or as (ii) additives in cosmetic products (creams, deodorants) to reduce the production of bad body odor.
Clinical Experience with High-Dose Polymyxin B against Carbapenem-Resistant Gram-Negative Bacterial Infections—A Cohort Study
Authors: Cai Yiying , Leck Hui , Tan Ray W. , Teo Jocelyn Q. , Lim Tze-Peng , Lee Winnie , Chlebicki Maciej Piotr , Kwa Andrea L.
Published: July 2020

Population pharmacokinetic studies have suggested that high polymyxin B (PMB) doses (≥30,000 IU/kg/day) can improve bacterial kill in carbapenem-resistant Gram-negative bacteria (CR-GNB). We aim to describe the efficacy and nephrotoxicity of patients with CR-GNB infections prescribed high-dose PMB. A single-centre cohort study was conducted from 2013 to 2016 on septic patients with CR-GNB infection and prescribed high-dose PMB (~30,000 IU/kg/day) for ≥72 h. Study outcomes included 30-day mortality and acute kidney injury (AKI) development. Factors associated with AKI were identified using multivariable regression. Forty-three patients with 58 CR-GNB received high-dose PMB; 57/58 (98.3%) CR-GNB were susceptible to PMB. The median daily dose and duration of high-dose PMB were 32,051 IU/kg/day (IQR, 29,340–34,884 IU/kg/day) and 14 days (IQR, 7–28 days), respectively. Thirty-day mortality was observed in 7 (16.3%) patients. AKI was observed in 25 (58.1%) patients with a median onset of 8 days (IQR, 6–13 days). Higher daily PMB dose (aOR,1.01; 95% CI, 1.00–1.02) and higher number of concurrent nephrotoxins (aOR, 2.14; 95% CI; 1.03–4.45) were independently associated with AKI. We observed that a sizable proportion developed AKI in CR-GNB patients described high-dose PMB; hence, the potential benefits must be weighed against increased AKI risk. Concurrent nephrotoxins should be avoided to reduce nephrotoxicity.
The Complex Relationship between Diabetic Retinopathy and High-Mobility Group Box: A Review of Molecular Pathways and Therapeutic Strategies
Authors: Nebbioso Marcella , Lambiase Alessandro , Armentano Marta , Tucciarone Giosuè , Bonfiglio Vincenza , Plateroti Rocco , Alisi Ludovico
Published: July 2020

High-mobility group box 1 (HMGB1) is a protein that is part of a larger family of non-histone nuclear proteins. HMGB1 is a ubiquitary protein with different isoforms, linked to numerous physiological and pathological pathways. HMGB1 is involved in cytokine and chemokine release, leukocyte activation and migration, tumorigenesis, neoangiogenesis, and the activation of several inflammatory pathways. HMGB1 is, in fact, responsible for the trigger, among others, of nuclear factor-κB (NF-κB), tumor necrosis factor-α (TNF-α), toll-like receptor-4 (TLR-4), and vascular endothelial growth factor (VEGF) pathways. Diabetic retinopathy (DR) is a common complication of diabetes mellitus (DM) that is rapidly growing in number. DR is an inflammatory disease caused by hyperglycemia, which determines the accumulation of oxidative stress and cell damage, which ultimately leads to hypoxia and neovascularization. Recent evidence has shown that hyperglycemia is responsible for the hyperexpression of HMGB1. This protein activates numerous pathways that cause the development of DR, and HMGB1 levels are constantly increased in diabetic retinas in both proliferative and non-proliferative stages of the disease. Several molecules, such as glycyrrhizin (GA), have proven effective in reducing diabetic damage to the retina through the inhibition of HMGB1. The main focus of this review is the growing amount of evidence linking HMGB1 and DR as well as the new therapeutic strategies involving this protein.
Functional Properties and Antioxidant Activity of Morus alba L. Leaves var. Zolwinska Wielkolistna (WML-P)—The Effect of Controlled Conditioning Process
Authors: Przeor Monika , Flaczyk Ewa , Kmiecik Dominik , Buchowski Maciej S. , Staniek Halina , Tomczak-Graczyk Aneta , Kobus-Cisowska Joanna , Gramza-Michałowska Anna , Foksowicz-Flaczyk Joanna
Published: July 2020

This study evaluated the effect of adding a new step, termed conditioning, to the traditional processing of leaves from Morus alba var. zolwinska wielkolistna grown in Poland (WML-P). This step, modeled on tea leaves processing, was conducted in a controlled environment on a semi-technical scale. The primary goal was to evaluate the effect of the WML-P conditioning for 1–4 h at 32–35 °C on the content of bioactive compounds (total phenolics, phenolic acids, flavonols, 1-deoxynojirimycin) and antioxidant activity (radical scavenging against DPPH, antioxidant capacity, chelating activity and ferric reducing antioxidant potential) of the lyophilized extracts. For the first time WML-P extracts content was comprehensively characterized by assessing dietary fiber fractions, fatty acids, amino acids, macro- and microelements and chlorophyll content. Compared to the traditional process, adding the conditioning step to WML-P processing resulted in an increased total phenolics content, radical scavenging capacity, ability to quench 2,2-diphenyl-1-picrylhydrazyl (DPPH•) and iron-chelating ability in the lyophilized extracts. The beneficial effect depended on conditioning time. The highest flavonols and phenolic acids content were found after 2-h conditioning. We concluded that adding a 2-h conditioning step to traditional WML-P processing results in getting WML-P lyophilized extract with increased bioactive compounds content and high antioxidant activity.
Ammonia Gas Sensors: Comparison of Solid-State and Optical Methods
Authors: Bielecki Zbigniew , Stacewicz Tadeusz , Smulko Janusz , Wojtas Jacek
Published: July 2020

High precision and fast measurement of gas concentrations is important for both understanding and monitoring various phenomena, from industrial and environmental to medical and scientific applications. This article deals with the recent progress in ammonia detection using in-situ solid-state and optical methods. Due to the continuous progress in material engineering and optoelectronic technologies, these methods are among the most perceptive because of their advantages in a specific application. We present the basics of each technique, their performance limits, and the possibility of further development. The practical implementations of representative examples are described in detail. Finally, we present a performance comparison of selected practical application, accumulating data reported over the preceding decade, and conclude from this comparison.
Optimal Design and Design Parameter Sensitivity Analyses of an eVTOL PAV in the Conceptual Design Phase
Authors: Lee Bong-Sul , Tullu Abera , Hwang Ho-Yon
Published: July 2020

An optimization study of an electric vertical takeoff and landing personal air vehicle (eVTOL PAV) was performed during the conceptual design stage using the design of experiments method. In defining the initial problem, a design target parameter was set. The PAV subsystem was based on a configuration tradeoff study matrix, which was used to effectively conduct configuration selection. Initial sizing was performed using the PAV sizing program developed by this research team using Microsoft Excel and Visual Basic for Application (VBA). A screening test was performed to find parameters with high sensitivity among independent design parameters. The response surface method was used to model design target parameters, and a regression equation was estimated using the experimental design method. A Monte Carlo simulation was performed to confirm the feasibility of the generated model. To optimize the design independent parameter, a satisfaction function was selected, and the appropriateness of the data was determined using a Pareto plot and p-value.
Thermal and Mechanical Characteristics of Okra (Abelmoschus esculentus) Fibers Obtained via Water- and Dew-Retting
Authors: Stawski Dawid , Çalişkan Ebru , Yilmaz Nazire , Krucińska Izabella
Published: July 2020

In this research, fibers were extracted from different parts of the okra plant (Abelmoschus esculentus) via water- and dew-retting methods. The fibers were subjected to physical and thermal analyses. The fibers obtained from the upper part of the okra plant showed higher breaking strength and lower linear density. Fibers obtained via water-retting exhibited higher breaking strength, higher elongation at break rates, and lower linear density values. The paper also presents the results of thermogravimetric analysis of the okra fibers. Tests were carried out in oxygen and inert gas atmospheres. Slight differences were found in the thermal resistance of the tested fibers, which was confirmed by an analysis using the αs-αr methodology. The calculated activation energy showed a widespread range of values.
Surface Quality of Wood Plastic Composites as Function of Water Exposure
Authors: Tasdemir Cagatay , Basboga Ibrahim Halil , Hiziroglu Salim
Published: July 2020

The objective of this study was to evaluate the surface quality of experimentally manufactured wood plastic composite (WPC) samples exposed to water soaking. Eastern redcedar (Juniperus virginiana L.), which is one of the invasive species in Oklahoma, USA, and recycled plastic were used to manufacture WPC samples. Three types of samples, namely with 0%, 3% and 6% nano-clay were soaked in water for up to one month. Stylus-type equipment was employed to evaluate their surface roughness as a function of water exposure. Two accepted roughness parameters, average roughness (Ra) and mean peak-to-valley (Rz), were used to determine changes in the surface quality of the specimens due to water exposure. Average roughness values of 1.5 µm and 4.1 µm were determined for the samples with no clay in dry conditions and those soaked for one month in water, respectively. Corresponding values were lower in the case of those with clay in their content. Based on the findings in this work, it appears that the stylus technique can be successfully applied to such samples to quantitatively evaluate their surface quality when they are exposed to water for an extended time span. It is expected that data from this work could help to produce a better understanding of the behavior of WPCs under environmental conditions.
X-ray Photoelectron Spectroscopy in Mineral Processing Studies
Authors: Mikhlin Yuri
Published: July 2020

Surface phenomena play the crucial role in the behavior of sulfide minerals in mineral processing of base and precious metal ores, including flotation, leaching, and environmental concerns. X-ray photoelectron spectroscopy (XPS) is the main experimental technique for surface characterization at present. However, there exist a number of problems related with complex composition of natural mineral systems, and instability of surface species and mineral/aqueous phase interfaces in the spectrometer vacuum. This overview describes contemporary XPS methods in terms of categorization and quantitative analysis of oxidation products, adsorbates and non-stoichiometric layers of sulfide phases, depth and lateral spatial resolution for minerals and ores under conditions related to mineral processing and hydrometallurgy. Specific practices allowing to preserve volatile species, e.g., elemental sulfur, polysulfide anions and flotation collectors, as well as solid/liquid interfaces are surveyed; in particular, the prospects of ambient pressure XPS and cryo-XPS of fast-frozen wet mineral pastes are discussed. It is also emphasized that further insights into the surface characteristics of individual minerals in technological slurries need new protocols of sample preparation in conjunction with high spatial resolution photoelectron spectroscopy that is still unavailable or unutilized in practice.
Knee-Assistive Robotic Exoskeleton (KARE-1) Using a Conditionally Singular Mechanism for Industrial Field Applications
Authors: Kim Hyung Joo , Noh Jaeho , Yang Woosung
Published: July 2020

With the aging demographic of today’s society, the need for robotic exoskeletons is expected to increase as they can compensate for declining physical strength in the physically impaired. In this study, an assistive robotic exoskeleton for the knee joint with fairly low energy consumption is proposed for industrial applications. The knee-assistive robotic exoskeleton (KARE-1) was designed to support a human body during production line tasks. The KARE-1 is based on a four-bar link mechanism with a rotary actuator and gas spring to accommodate a high power-to-weight ratio. By taking advantage of the utilized singular configuration of the four-bar linkage, this novel design is able to efficiently support the weight of the human body. The selected singular configuration allows this device to support the knee joint in the load-bearing stages of static sitting as well as during the motion between standing and sitting. The proposed device is further able to move freely along with the knee during walking movements. The proposed design was verified through a series of numerical simulations and through human subject testing at an industrial workplace.
A Novel Grid and Place Neuron’s Computational Modeling to Learn Spatial Semantics of an Environment
Authors: Shrivastava Rahul , Kumar Prabhat , Tripathi Sudhakar , Tiwari Vivek , Rajput Dharmendra Singh , Gadekallu Thippa Reddy , Suthar Bhivraj , Singh Saurabh , Ra In-Ho
Published: July 2020

Health-related limitations prohibit a human from working in hazardous environments, due to which cognitive robots are needed to work there. A robot cannot learn the spatial semantics of the environment or object, which hinders the robot from interacting with the working environment. To overcome this problem, in this work, an agent is computationally devised that mimics the grid and place neuron functionality to learn cognitive maps from the input spatial data of an environment or an object. A novel quadrant-based approach is proposed to model the behavior of the grid neuron, which, like the real grid neuron, is capable of generating periodic hexagonal grid-like output patterns from the input body movement. Furthermore, a cognitive map formation and their learning mechanism are proposed using the place–grid neuron interaction system, which is meant for making predictions of environmental sensations from the body movement. A place sequence learning system is also introduced, which is like an episodic memory of a trip that is forgettable based on their usage frequency and helps in reducing the accumulation of error during a visit to distant places. The model has been deployed and validated in two different spatial data learning applications, one being the 2D object detection by touch, and another is the navigation in an environment. The result analysis shows that the proposed model is significantly associated with the expected outcomes.
A Hybrid Weight Assignment Model for Urban Underground Space Resources Evaluation Integrated with the Weight of Time Dimension
Authors: Liu Dixu , Wu Lixin , Yang Yang
Published: July 2020

The utilization of urban underground space resources (UUSR) are important approaches to effectively save land resources, improve the living environment, expand the urban space, and achieve sustainable urban development. To obtain accurate UUSR evaluation results, the weight assignment of indicators plays an important role in the evaluation process and is an indispensable part of it. Reasonable weights of indicators can greatly improve the accuracy of the final UUSR evaluation results. Neither the basic characteristics of cross-section data and time series data of UUSR evaluation indicators are taken into consideration simultaneously, nor is the combination and cross application of different weighting methods in the previous weight assignment of UUSR evaluation indicators. Considering the influence of the time dimension, the weighting method of time dimension is introduced into the UUSR evaluation. Through integrating the classical entropy weight method, which is a frequently-used weighting method of indicator dimension with the weighting method of time dimension in two different approaches by time ordered weighted averaging (TOWA) operator, the hybrid weight assignment model named entropy and time weighting model (E-TW) for UUSR evaluation is proposed. The experimental calculation results show that the UUSR evaluation results using the E-TW model are significantly better than the results using the single classical entropy weight method, which means the hybrid weight assignment model is more suitable for UUSR evaluation than the single weighting method of indicator dimension.
The First Study of Irreversible Electroporation with Calcium Ions and Chemotherapy in Patients with Locally Advanced Pancreatic Adenocarcinoma
Authors: Rudno-Rudzińska Julia , Kielan Wojciech , Guziński Maciej , Płochocki Maciej , Kulbacka Julita
Published: July 2020

(1) Background: In the last two decades, anticancer treatment has been extensively developed based on various physical methods, including electroporation (EP). On the basis of many in vitro and in vivo studies, electroporation and further electrochemotherapy (ECT) have been established as a treatment method for cutaneous and subcutaneous lesions. In this procedure, after placing electrodes in the tumor mass and the generation of electrical pulses, a reversible or irreversible rearrangement of the cell membrane occurs. Calcium electroporation has already been applied to treat skin tumors and subcutaneous tissue tumors. Here, we demonstrate the first application of irreversible electroporation (IRE) in combination with calcium ions and chemotherapy for patients with cancer. (2) Methods: This study aimed to present and compare the findings and outcomes of patients with locally advanced pancreatic adenocarcinoma who were qualified for the procedure. Two patients were treated with IRE with calcium ions after chemotherapy (paclitaxel + Gemcitabine (GCB) or FOLOX) or only FOLFOX (folinic acid calcium folinate, fluorouracil, and oxaliplatin). The clinicopathological data, overall survival, and the safety of the procedure were analyzed. (3) Results: Two patients were treated with calcium electroporation. One of the patients developed pancreatitis and the second developed pancreatic fistula, but both of them continued standard systemic treatment. Overall survival was 9 months in the first case and 21 months in the second case (and the patient is still alive). Calcium electroporation had a good impact on QOL (Quality of Life). (4) Conclusions: IRE accompanied chemotherapy, and intratumoral calcium ions administration might represent an additional therapy to surgery and chemotherapy in patients with locally advanced pancreatic cancer (LAPC), particularly in unresectable cases. However, further studies of randomized trials should be undertaken to elucidate the role of chemotherapy in IRE protocols.
A Geological Perspective on Climate Change and Building Stone Deterioration in London: Implications for Urban Stone-Built Heritage Research and Management
Authors: Basu Sudeshna , Orr Scott Allan , Aktas Yasemin D.
Published: July 2020

The decay rates of building stones and, the processes leading to their deterioration is governed by intrinsic properties such as texture, mineralogy, porosity and pore size distribution, along with other extrinsic factors related to the climate and anthropogenic activities. For urban cities such as London, the influence of extrinsic factors like temperature and rainfall, as well as the concentrations of air pollutants, such as sulphur and nitrogen oxides, along with the emissions of carbonaceous aerosols, can be particularly significant. While considering the long-term preservation of building stones used in various heritage sites in the city, it is imperative to consider how the stone could be affected by the changing air pollutant concentrations, superimposed on the effects of climate change in the region, including rising average annual temperature and precipitation with a hotter, drier summer and, warmer, wetter winter months. This paper deals with the intrinsic rock properties of the common building stones of London, including limestone, marble, granite, sandstone, slate, flint as well as bricks, building on known characteristics including strength and durability that determine how and where they are placed in a building structure. The study reviews how these stones decay due to different processes such as salt weathering in sandstone, microcracking of quartz with kaolinisation of K-feldspar and biotite in granite and dissolution of calcite and dolomite, followed by precipitation of sulphate minerals in the carbonate rocks of limestone and marble. In the urban environment of London, with progressive build up in the concentration of atmospheric nitrogen oxides leading to an increasingly acidic environment and, with predicted climate change, the diverse stone-built heritage will be affected. For example, there can be enhanced carbonate dissolution in limestone with increased annual precipitation. Due to the prolonged wetter winter, any sandstone building stone will also undergo greater damage with a deeper wetting front. On the other hand, due to predicted wetter and warmer winter months, microcracking of any plagioclase in a granite is unlikely, thereby reducing the access of fluid and air pollutants to the Ca-rich core of the zoned crystals limiting the process of sericitisation. Management of the building stones in London should include routine expert visual inspection for signs of deterioration, along with mineralogical and compositional analyses and assessment of any recession rate.
Interplay among ATP-Dependent Chromatin Remodelers Determines Chromatin Organisation in Yeast
Authors: Prajapati Hemant K. , Ocampo Josefina , Clark David J.
Published: July 2020

Cellular DNA is packaged into chromatin, which is composed of regularly-spaced nucleosomes with occasional gaps corresponding to active regulatory elements, such as promoters and enhancers, called nucleosome-depleted regions (NDRs). This chromatin organisation is primarily determined by the activities of a set of ATP-dependent remodeling enzymes that are capable of moving nucleosomes along DNA, or of evicting nucleosomes altogether. In yeast, the nucleosome-spacing enzymes are ISW1 (Imitation SWitch protein 1), Chromodomain-Helicase-DNA-binding (CHD)1, ISW2 (Imitation SWitch protein 2) and INOsitol-requiring 80 (INO80); the nucleosome eviction enzymes are the SWItching/Sucrose Non-Fermenting (SWI/SNF) family, the Remodeling the Structure of Chromatin (RSC) complexes and INO80. We discuss the contributions of each set of enzymes to chromatin organisation. ISW1 and CHD1 are the major spacing enzymes; loss of both enzymes results in major chromatin disruption, partly due to the appearance of close-packed di-nucleosomes. ISW1 and CHD1 compete to set nucleosome spacing on most genes. ISW1 is dominant, setting wild type spacing, whereas CHD1 sets short spacing and may dominate on highly-transcribed genes. We propose that the competing remodelers regulate spacing, which in turn controls the binding of linker histone (H1) and therefore the degree of chromatin folding. Thus, genes with long spacing bind more H1, resulting in increased chromatin compaction. RSC, SWI/SNF and INO80 are involved in NDR formation, either directly by nucleosome eviction or repositioning, or indirectly by affecting the size of the complex that resides in the NDR. The nature of this complex is controversial: some suggest that it is a RSC-bound “fragile nucleosome”, whereas we propose that it is a non-histone transcription complex. In either case, this complex appears to serve as a barrier to nucleosome formation, resulting in the formation of phased nucleosomal arrays on both sides.
Radiation-Induced Senescence Bystander Effect: The Role of Exosomes
Authors: Elbakrawy Eman , Kaur Bains Savneet , Bright Scott , AL-Abedi Raheem , Mayah Ammar , Goodwin Edwin , Kadhim Munira
Published: July 2020

Ionizing Radiation (IR), especially at high doses, induces cellular senescence in exposed cultures. IR also induces “bystander effects” through signals released from irradiated cells, and these effects include many of the same outcomes observed following direct exposure. Here, we investigate if radiation can cause senescence through a bystander mechanism. Control cultures were exposed directly to 0, 0.1, 2, and 10 Gy. Unirradiated cells were treated with medium from irradiated cultures or with exosomes extracted from irradiated medium. The level of senescence was determined post-treatment (24 h, 15 days, 30 days, and 45 days) by β-galactosidase staining. Media from cultures exposed to all four doses, and exosomes from these cultures, induced significant senescence in recipient cultures. Senescence levels were initially low at the earliest timepoint, and peaked at 15 days, and then decreased with further passaging. These results demonstrate that senescence is inducible through a bystander mechanism. As with other bystander effects, bystander senescence was induced by a low radiation dose. However, unlike other bystander effects, cultures recovered from bystander senescence after repeated passaging. Bystander senescence may be a potentially significant effect of exposure to IR, and may have both beneficial and harmful effects in the context of radiotherapy.
Calcium Export from Neurons and Multi-Kinase Signaling Cascades Contribute to Ouabain Neuroprotection in Hyperhomocysteinemia
Authors: Ivanova Maria A. , Kokorina Arina D. , Timofeeva Polina D. , Karelina Tatiana V. , Abushik Polina A. , Stepanenko Julia D. , Sibarov Dmitry A. , Antonov Sergei M.
Published: July 2020

Pathological homocysteine (HCY) accumulation in the human plasma, known as hyperhomocysteinemia, exacerbates neurodegenerative diseases because, in the brain, this amino acid acts as a persistent N-methyl-d-aspartate receptor agonist. We studied the effects of 0.1–1 nM ouabain on intracellular Ca2+ signaling, mitochondrial inner membrane voltage (φmit), and cell viability in primary cultures of rat cortical neurons in glutamate and HCY neurotoxic insults. In addition, apoptosis-related protein expression and the involvement of some kinases in ouabain-mediated effects were evaluated. In short insults, HCY was less potent than glutamate as a neurotoxic agent and induced a 20% loss of φmit, whereas glutamate caused a 70% decrease of this value. Subnanomolar ouabain exhibited immediate and postponed neuroprotective effects on neurons. (1) Ouabain rapidly reduced the Ca2+ overload of neurons and loss of φmit evoked by glutamate and HCY that rescued neurons in short insults. (2) In prolonged 24 h excitotoxic insults, ouabain prevented neuronal apoptosis, triggering proteinkinase A and proteinkinase C dependent intracellular neuroprotective cascades for HCY, but not for glutamate. We, therefore, demonstrated here the role of PKC and PKA involving pathways in neuronal survival caused by ouabain in hyperhomocysteinemia, which suggests existence of different appropriate pharmacological treatment for hyperhomocysteinemia and glutamate excitotoxicity.
Targeting of BCL-2 Family Members during Anticancer Treatment: A Necessary Compromise between Individual Cell and Ecosystemic Responses?
Authors: Barillé-Nion Sophie , Lohard Steven , Juin Philippe P.
Published: July 2020

The imbalance between BCL-2 homologues and pro-death counterparts frequently noted in cancer cells endows them with a cell autonomous survival advantage. To eradicate ectopic cells, inhibitors of these homologues (BH3 mimetics) were developed to trigger, during anticancer treatment, full activation of the canonical mitochondrial apoptotic pathway and related caspases. Despite efficiency in some clinical settings, these compounds do not completely fulfill their initial promise. We herein put forth that a growing body of evidence indicates that mitochondrial integrity, controlled by BCL-2 family proteins, and downstream caspases regulate other cell death modes and influence extracellular signaling by committed cells. Moreover, intercellular communications play a key role in spreading therapeutic response across cancer cell populations and in engaging an immune response. We thus advocate that BH3 mimetics administration would be more efficient in the long term if it did not induce apoptosis in all sensitive cells at the same time, but if it could instead allow (or trigger) death signal production by non-terminally committed dying cell populations. The development of such a trade-off strategy requires to unravel the effects of BH3 mimetics not only on each individual cancer cell but also on homotypic and heterotypic cell interactions in dynamic tumor ecosystems.
More Than Resveratrol: New Insights into Stilbene-Based Compounds
Authors: Pecyna Paulina , Wargula Joanna , Murias Marek , Kucinska Malgorzata
Published: July 2020

The concept of a scaffold concerns many aspects at different steps on the drug development path. In medicinal chemistry, the choice of relevant “drug-likeness” scaffold is a starting point for the design of the structure dedicated to specific molecular targets. For many years, the chemical uniqueness of the stilbene structure has inspired scientists from different fields such as chemistry, biology, pharmacy, and medicine. In this review, we present the outstanding potential of the stilbene-based derivatives. Naturally occurring stilbenes, together with powerful synthetic chemistry possibilities, may offer an excellent approach for discovering new structures and identifying their therapeutic targets. With the development of scientific tools, sophisticated equipment, and a better understanding of the disease pathogenesis at the molecular level, the stilbene scaffold has moved innovation in science. This paper mainly focuses on the stilbene-based compounds beyond resveratrol, which are particularly attractive due to their biological activity. Given the “fresh outlook” about different stilbene-based compounds starting from stilbenoids with particular regard to isorhapontigenin and methoxy- and hydroxyl- analogues, the update about the combretastatins, and the very often overlooked and underestimated benzanilide analogues, we present a new story about this remarkable structure.
Mass-Spectrometry Based Proteome Comparison of Extracellular Vesicle Isolation Methods: Comparison of ME-kit, Size-Exclusion Chromatography, and High-Speed Centrifugation
Authors: Askeland Anders , Borup Anne , Østergaard Ole , Olsen Jesper V. , Lund Sigrid M. , Christiansen Gunna , Kristensen Søren R. , Heegaard Niels H. H. , Pedersen Shona
Published: July 2020

Extracellular vesicles (EVs) are small membrane-enclosed particles released by cells under various conditions specific to cells’ biological states. Hence, mass-spectrometry (MS) based proteome analysis of EVs in plasma has gained much attention as a method to discover novel protein biomarkers. MS analysis of EVs in plasma is challenging and EV isolation is usually necessary. Therefore, we compared differences in abundance, subtypes, and contamination for EVs isolated by high-speed centrifugation, size exclusion chromatography (SEC), and peptide-affinity precipitation (PAP/ME kit) for subsequent MS-based proteome analysis. Successful EV isolation was evaluated by nanoparticle-tracking analysis, immunoblotting, and transmission electron microscopy, while EV abundance, EV subtypes, and contamination was evaluated by label-free tandem MS. High-speed centrifugation and SEC isolates showed high EV abundance at the expense of contamination by non-EV proteins and lipoproteins, respectively. These two methods also resulted in EVs of a similar type, however, with smaller EVs in SEC isolates. PAP isolates had a relatively low EV abundance and high contamination. We consider high-speed centrifugation and SEC suitable as EV isolation for MS biomarker studies, where the choice between the two should depend on the scientific questions and whether the focus is on larger or smaller EVs or a combination of both.
Melatonin as a Radio-Sensitizer in Cancer
Authors: Alonso-González Carolina , González Alicia , Menéndez-Menéndez Javier , Martínez-Campa Carlos , Cos Samuel
Published: July 2020

Radiotherapy is one of the treatments of choice in many types of cancer. Adjuvant treatments to radiotherapy try, on one hand, to enhance the response of tumor cells to radiation and, on the other hand, to reduce the side effects to normal cells. Radiosensitizers are agents that increase the effect of radiation in tumor cells by trying not to increase side effects in normal tissues. Melatonin is a hormone produced mainly by the pineal gland which has an important role in the regulation of cancer growth, especially in hormone-dependent mammary tumors. Different studies have showed that melatonin administered with radiotherapy is able to enhance its therapeutic effects and can protect normal cells against side effects of this treatment. Several mechanisms are involved in the radiosensitization induced by melatonin: increase of reactive oxygen species production, modulation of proteins involved in estrogen biosynthesis, impairment of tumor cells to DNA repair, modulation of angiogenesis, abolition of inflammation, induction of apoptosis, stimulation of preadipocytes differentiation and modulation of metabolism. At this moment, there are very few clinical trials that study the therapeutic usefulness to associate melatonin and radiotherapy in humans. All findings point to melatonin as an effective adjuvant molecule to radiotherapy in cancer treatment.
How to Build a Biological Machine Using Engineering Materials and Methods
Authors: Ellery Alex
Published: July 2020

We present work in 3D printing electric motors from basic materials as the key to building a self-replicating machine to colonise the Moon. First, we explore the nature of the biological realm to ascertain its essence, particularly in relation to the origin of life when the inanimate became animate. We take an expansive view of this to ascertain parallels between the biological and the manufactured worlds. Life must have emerged from the available raw material on Earth and, similarly, a self-replicating machine must exploit and leverage the available resources on the Moon. We then examine these lessons to explore the construction of a self-replicating machine using a universal constructor. It is through the universal constructor that the actuator emerges as critical. We propose that 3D printing constitutes an analogue of the biological ribosome and that 3D printing may constitute a universal construction mechanism. Following a description of our progress in 3D printing motors, we suggest that this engineering effort can inform biology, that motors are a key facet of living organisms and illustrate the importance of motors in biology viewed from the perspective of engineering (in the Feynman spirit of “what I cannot create, I cannot understand”).
Piloting the UK’s First Home-Office-Licensed Pharmacist-Led Drug Checking Service at a Community Substance Misuse Service
Authors: Guirguis Amira , Gittins Rosalind , Schifano Fabrizio
Published: July 2020

(1) Introduction: Drug-related deaths in the UK are at concerning high levels. The unknown content and purity of illicit substances can cause unpredictable adverse effects and thus a public health risk with no sign of abating. On-site drug checking is a public health strategy that has previously been implemented, predominantly in festival settings, but without Home Office licensing. (2) Aims: The aim of this study was to pilot the UK’s first pharmacist-led, Home Office-licensed community drug checking service. (3) Methods: A bespoke protocol incorporating legally, professionally and ethically binding documents was implemented. This free, confidential service ran between February and March 2019, was available to anyone over 18 who were purposefully recruited, gave informed consent and agreed to relinquish their drug sample. Samples were checked on-site within an established Substance Misuse Service (SMS) using a handheld Raman spectrometer to determine likely drug content and adulterants. In parallel, participants completed a questionnaire about their substance use and the drug sample(s) being tested. A pharmacist-led multidisciplinary approach was adopted to discuss the analytical findings. Informed by the results of the analysis and the questionnaire, people who used the service received tailored harm reduction advice. (4) Results and Discussion: The pilot operated for a total of four days over four weeks. Eleven people visited and relinquished a total of thirteen samples. Half of the participants had previously overdosed and were known to the SMS. Seventy per cent were male, all were White British individuals, 30% were employed and two people disclosed visiting from another nearby town. Samples included what was thought to be heroin, synthetic cannabinoids, stimulants, benzodiazepines and LSD and none required activation of the “alerts cascade” process. Most participants drank alcohol regularly and the concomitant use of traditional illicit drugs and prescribed medication (including opioids, anxiolytics and antidepressants) with sedating profiles was common. Given some of the ethical decisions and interpretation of the results, specialist pharmacist involvement was deemed essential. (5) Conclusions: This pilot demonstrated the proof-of-concept that a pharmacist-led Home Office-licensed drug checking service can be successfully implemented in community SMSs.
Thermal Environment Perceptions from a Longitudinal Study of Indoor Temperature Profiles in Inpatient Wards
Authors: Alotaibi Badr , Lo Stephen
Published: July 2020

Inpatient wards in general have cooling systems with a “one-size-fits-all” approach, driven by a fixed set-point temperature (21–24 °C) that is flexible to lower limits down to 18 °C or less. This approach does not consider patients’ temperature demands, which vary due to thermo-physiology caused by medical conditions, and mixed demographics. It also causes additional cooling demands in hot climates that are infrequently utilized by patients, who tend to adopt warmer internal set temperatures. Thus, this research examined the indoor temperature profiles (distribution of shape) in patient rooms in fully air-conditioned inpatient wards over an extended period of time. During four months of summer, longitudinal monitoring of internal temperature and relative humidity was carried out in 18 patient rooms in the surgical, medical, cardiology, and oncology wards of two hospitals in Saudi Arabia. In parallel, 522 patients were surveyed to capture common subjective thermal indices. The findings revealed that the most frequently preferred temperature (peaks) varied significantly between wards; peaks (modes) were 20.1–21.8 °C in cardiology; 22.2–23.9 °C in the surgical ward; warmer 24.8–25.3 °C in medical ward; and 25.3–26.8 °C in oncology. Surveys also showed that patients were not satisfied with the indoor environment in both hospitals. Given the significant variance in temperature profiles between wards and patient dissatisfaction with the indoor environment, these results suggest that more appropriately designed zoned cooling strategies are needed in hospitals as per the nature of each ward. Besides its implications for benchmarking the HVAC system, this approach will substantially reduce energy loads and operational costs in hot-climate hospitals if patients desire warmer conditions than the set conditions provided by system.
Uncertainty in the Early Phase of a Municipal Building Refurbishment Project—A Case Study in Finland
Authors: Uotila Ulrika , Saari Arto , Junnonen Juha-Matti
Published: July 2020

Municipal building refurbishment projects are carried out under conditions of high uncertainty and complexity, which often result in unsatisfying outcomes. In this research, a case study approach is used to provide a holistic presentation of the sources of uncertainties in the early phase of a municipal school refurbishment project in Finland. The study also explores how these sources are treated in the case project. It is considered that the uncertainty in the case study originated from three key sources: from the project due to the characteristics of existing buildings; from the organization due to the separately operating municipal units; from the municipal environment due to the municipal policy, and decision-making process. This study shows that more emphasis should be laid on the sources of uncertainty in the early phases of a municipal building refurbishment project for reaching proper decisions. In addition, the study presents suggestions for improving the municipal process.
Effects of the Stacking Faults on the Electrical Resistance of Highly Ordered Graphite Bulk Samples
Authors: Hentrich Andreas , Esquinazi Pablo D.
Published: July 2020

High anisotropy and the existence of two-dimensional highly conducting interfaces at stacking faults parallel to the graphene planes of the graphite structure influence, in a non-simple way, the transport properties of highly oriented graphite. We report two related effects on the electrical resistance of highly oriented pyrolytic as well as of natural graphite bulk samples, measured with the four points method in the temperature range 300 K ≤T≤ 410 K. A qualitative and quantitative change in the temperature dependence of the resistance was obtained by simply enlarging the electrodes and contacting the edges of the internal interfaces on the same sample. Additionally, at temperatures T≳350 K the resistance can change with time. We show that this temperature-dependent annealing effect is related to the stacking faults and can irreversibly change the absolute value of the resistance and its temperature dependence. A partial recovery is obtained after leaving the sample at normal conditions for several days. The overall results stress the importance of the electrodes location on a bulk graphite sample, the contribution of the stacking faults in the interpretation of the measured transport properties and the need of systematic studies on the influence of high temperature annealing on the interfaces properties.
Downregulation of the DNA Repair Gene DDB2 by Arecoline Is through p53’s DNA-Binding Domain and Is Correlated with Poor Outcome of Head and Neck Cancer Patients with Betel Quid Consumption
Authors: Wang Yu-Chu , Huang Jau-Ling , Lee Ka-Wo , Lu Hsing-Han , Lin Yuan-Jen , Chen Long-Fong , Wang Chung-Sheng , Cheng Yun-Chiao , Zeng Zih-Ting , Chu Pei-Yi , Lin Chang-Shen
Published: July 2020

Arecoline is the principal alkaloid in the areca nut, a component of betel quids (BQs), which are carcinogenic to humans. Epidemiological studies indicate that BQ-chewing contributes to the occurrence of head and neck cancer (HNC). Previously, we have reported that arecoline (0.3 mM) is able to inhibit DNA repair in a p53-dependent pathway, but the underlying mechanism is unclear. Here we demonstrated that arecoline suppressed the expression of DDB2, which is transcriptionally regulated by p53 and is required for nucleotide excision repair (NER). Ectopic expression of DDB2 restored NER activity in arecoline-treated cells, suggesting that DDB2 downregulation was critical for arecoline-mediated NER inhibition. Mechanistically, arecoline inhibited p53-induced DDB2 promoter activity through the DNA-binding but not the transactivation domain of p53. Both NER and DDB2 promoter activities declined in the chronic arecoline-exposed cells, which were consistent with the downregulated DDB2 mRNA in BQ-associated HNC specimens, but not in those of The Cancer Genome Atlas (TCGA) cohort (no BQ exposure). Lower DDB2 mRNA expression was correlated with a poor outcome in HNC patients. These data uncover one of mechanisms underlying arecoline-mediated carcinogenicity through inhibiting p53-regulated DDB2 expression and DNA repair.