bluuebunny/crossref_metadata_2025 huggingface dataset:
Genomic Variations in Drug Resistant Mycobacterium tuberculosis Strains Collected from Patients with Different Localization of Infection
Authors: Chernyaeva Ekaterina , Rotkevich Mikhail , Krasheninnikova Ksenia , Lapidus Alla , Polev Dmitrii E. , Solovieva Natalia , Zhuravlev Viacheslav , Yablonsky Piotr , O’Brien Stephen J.
Published: December 2020

Mycobacterium tuberculosis is a highly studied pathogen due to public health importance. Despite this, problems like early drug resistance, diagnostics and treatment success prediction are still not fully resolved. Here, we analyze the incidence of point mutations widely used for drug resistance detection in laboratory practice and conduct comparative analysis of whole-genome sequence (WGS) for clinical M. tuberculosis strains collected from patients with pulmonary tuberculosis (PTB) and extra-pulmonary tuberculosis (XPTB) localization. A total of 72 pulmonary and 73 extrapulmonary microbiologically characterized M. tuberculosis isolates were collected from patients from 2007 to 2014 in Russia. Genomic DNA was used for WGS and obtained data allowed identifying major mutations known to be associated with drug resistance to first-line and second-line antituberculous drugs. In some cases previously described mutations were not identified. Using genome-based phylogenetic analysis we identified M. tuberculosis substrains associated with distinctions in the occurrence in PTB vs. XPTB cases. Phylogenetic analyses did reveal M. tuberculosis genetic substrains associated with TB localization. XPTB was associated with Beijing sublineages Central Asia (Beijing CAO), Central Asia Clade A (Beijing A) and 4.8 groups, while PTB localization was associated with group LAM (4.3). Further, the XPTB strain in some cases showed elevated drug resistance patterns relative to PTB isolates. HIV was significantly associated with the development of XPTB in the Beijing B0/W148 group and among unclustered Beijing isolates.
Aminoglycoside 6′-N-acetyltransferase Type Ib [AAC(6′)-Ib]-Mediated Aminoglycoside Resistance: Phenotypic Conversion to Susceptibility by Silver Ions
Authors: Reeves Craig M. , Magallon Jesus , Rocha Kenneth , Tran Tung , Phan Kimberly , Vu Peter , Yi Yang , Oakley-Havens Crista L. , Cedano José , Jimenez Verónica , Ramirez Maria S. , Tolmasky Marcelo E.
Published: December 2020

Clinical resistance to amikacin and other aminoglycosides is usually due to the enzymatic acetylation of the antimicrobial molecule. A ubiquitous resistance enzyme among Gram-negatives is the aminoglycoside 6′-N-acetyltransferase type Ib [AAC(6′)-Ib], which catalyzes acetylation using acetyl-CoA as a donor substrate. Therapies that combine the antibiotic and an inhibitor of the inactivation reaction could be an alternative to treat infections caused by resistant bacteria. We previously observed that metal ions such as Zn2+ or Cu2+ in complex with ionophores interfere with the AAC(6′)-Ib-mediated inactivation of aminoglycosides and reduced resistance to susceptibility levels. Ag1+ recently attracted attention as a potentiator of aminoglycosides′ action by mechanisms still in discussion. We found that silver acetate is also a robust inhibitor of the enzymatic acetylation mediated by AAC(6′)-Ib in vitro. This action seems to be independent of other mechanisms, like increased production of reactive oxygen species and enhanced membrane permeability, proposed to explain the potentiation of the antibiotic effect by silver ions. The addition of this compound to aac(6′)-Ib harboring Acinetobacter baumannii and Escherichia coli cultures resulted in a dramatic reduction of the resistance levels. Time-kill assays showed that the combination of silver acetate and amikacin was bactericidal and exhibited low cytotoxicity to HEK293 cells.
The Effect of Repeated Whole-Body Cryotherapy on Sirt1 and Sirt3 Concentrations and Oxidative Status in Older and Young Men Performing Different Levels of Physical Activity
Authors: Wojciak Gabriela , Szymura Jadwiga , Szygula Zbigniew , Gradek Joanna , Wiecek Magdalena
Published: December 2020

Background: The activity of antioxidant enzymes and sirtuins (Sirt) decreases along with age, which is counteracted by aerobic training. Sirtuins increase antioxidant defence. Whole-body cryotherapy (WBC) increases total antioxidant capacity (TAC) in young men. The aim of our study was to assess the impact of 24 WBC treatments on the blood concentration of selected sirtuins and the level of antioxidant defence as well as oxidative stress index of training and non-training men depending on age. Methods: The study involved 40 males. In each group, there were 10 non-training older and young men (60 NTR and 20 NTR), and 10 older and young long-distance runners (60 TR, 20 TR). During an 8-week period, participants underwent 24 WBC treatments (3 min −130 °C), which were performed three times a week (Monday, Wednesday, Friday). The concentrations of Sirt1, Sirt3, TAC, total oxidative status and the activity of superoxide dismutase (SOD), catalase and glutathione peroxidase (GPx) in the blood were determined before 1 WBC and after 1 WBC, 12 WBC and 24 WBC. Results: After 1 WBC, the activity of GPx and the concentration of Sirt1 and TAC in 60 TR and TAC in 60 NTR increased. After 12 WBC, the level of Sirt1 in 20 NTR and SOD in 20 TR increased. After 24 WBC, the level of Sirt1 increased in 60 TR and in 20 NTR, Sirt3 in 60 TR and SOD in 20 TR. Conclusions: Cryogenic temperatures increase blood levels of Sirt1 and Sirt3 and systemic antioxidant defence in men, but the effect is dependent on age, level of performed physical activity and the number of applied treatments.
Antioxidant and Hypolipidemic Activity of Açai Fruit Makes It a Valuable Functional Food
Authors: Pirozzi Anna Virginia Adriana , Imbimbo Paola , D’Agostino Antonella , Tirino Virginia , Finamore Rosario , Monti Daria Maria , Piccoli Renata , Schiraldi Chiara
Published: December 2020

Several plant extracts are acquiring increasing value because of their antioxidant activity and hypolipidemic properties. Among them, great interest has been recently paid to açai fruit as a functional food. The aim of this study was to test the ability of açai extract in reducing oxidative stress and modulating lipid metabolism in vitro using different cell models and different types of stress. In fact, lipid peroxidation as evaluated in a HepG2 model was reduced five-fold when using 0.25 µg/mL of extract, and it was further reduced (20-fold) with the concentration increase up to 2.5 µg/mL. With the nonalcoholic fatty liver disease (NAFLD)in vitro model, all concentrations tested showed at least a two-fold reduced fat deposit. In addition, primary adipocytes challenged with TNF-α under hypoxic conditions to mimic the persistent subcutaneous fat, treated with açai extract showed an approximately 40% reduction of fat deposit. Overall, our results show that açai is able to counteract oxidative states in all the cell models analysed and to prevent the accumulation of lipid droplets. No toxic effects and high stability overtime were highlighted at the concentrations tested. Therefore, açai can be considered a suitable support in the prevention of different alterations of lipid and oxidative metabolism responsible for fat deposition and metabolic pathological conditions.
Mechanistic Insight into the Regulation of Lipoxygenase-Driven Lipid Peroxidation Events in Human Spermatozoa and Their Impact on Male Fertility
Authors: Walters Jessica L. H. , Anderson Amanda L. , Martins da Silva Sarah J. , Aitken R. John , De Iuliis Geoffry N. , Sutherland Jessie M. , Nixon Brett , Bromfield Elizabeth G.
Published: December 2020

A prevalent cause of sperm dysfunction in male infertility patients is the overproduction of reactive oxygen species, an attendant increase in lipid peroxidation and the production of cytotoxic reactive carbonyl species such as 4-hydroxynonenal. Our previous studies have implicated arachidonate 15-lipoxygenase (ALOX15) in the production of 4-hydroxynonenal in developing germ cells. Here, we have aimed to develop a further mechanistic understanding of the lipoxygenase-lipid peroxidation pathway in human spermatozoa. Through pharmacological inhibition studies, we identified a protective role for phospholipase enzymes in the liberation of peroxidised polyunsaturated fatty acids from the human sperm membrane. Our results also revealed that arachidonic acid, linoleic acid and docosahexanoic acid are key polyunsaturated fatty acid substrates for ALOX15. Upon examination of ALOX15 in the spermatozoa of infertile patients compared to their normozoospermic counterparts, we observed significantly elevated levels of ALOX15 protein abundance in the infertile population and an increase in 4-hydroxynonenal adducts. Collectively, these data confirm the involvement of ALOX15 in the oxidative stress cascade of human spermatozoa and support the notion that increased ALOX15 abundance in sperm cells may accentuate membrane lipid peroxidation and cellular dysfunction, ultimately contributing to male infertility.
Viability of Creating an Offshore Wind Energy Cluster: A Case Study
Authors: Junqueira Helena , Robaina Margarita , Garrido Susana , Godina Radu , Matias João C. O.
Published: December 2020

Considering the advantages associated with the port sector concerning the potential of offshore wind energy, several international ports are aiming to achieve a solid integration in offshore wind energy clusters. This article performs an analysis of several seaports and offshore wind energy clusters in Europe to assess the feasibility of implementing an offshore wind energy cluster in the Port of Aveiro, Portugal. A deep literature review and a case study methodology were performed. Based on the analysis of the offshore energy market, and of the value chain of the company case study (ASM Offshore), it was concluded that the Portuguese market in this sector is not competitive, compared with other international markets. Nevertheless, the development of an offshore wind energy cluster could increase the included companie’s prospects, as well as dispute the growth of other companies associated with this sector. This research is relevant, because there is a lack of research that links the importance of seaports in offshore wind energy projects, in particular with a cluster structure, and because it contributes to knowledge for the development of the Aveiro region and Portugal, based on the exploitation of the renewable energy market and to the increase of related activities.
A Long-Term Analysis of the Possibility of Water Recovery for Hydroponic Lettuce Irrigation in an Indoor Vertical Farm. Part 2: Rainwater Harvesting
Authors: Jurga Anna , Pacak Anna , Pandelidis Demis , Kaźmierczak Bartosz
Published: December 2020

The aim of this study was to determine the suitability of a rainwater harvesting system to cover the water demand for indoor hydroponic lettuce cultivation located in Wrocław (Poland). The analysis was performed on the basis of the recorded rainfall in Wrocław in 2000–2019. The analyzed cultivation is located in a hall with an area of 300 m2, where the lettuce is grown vertically by the hydroponic method. The calculations of the rainwater harvesting (RWH) system were carried out considering the selection of the tank capacity for the collected water. The operation of the water storage is simulated using a yield after spillage (YAS) algorithm. It was evident that the proposed system might be an auxiliary system that relieves the water supply network or supports other water recovery systems (e.g., the water vapor condensation in a cross-flow heat exchanger operating as an element of the air conditioning system, proposed in Part 1 of this study). The harvesting system for the selected vertical farming indoor hall covers an average of 35.9% of water needs and allows a saving of 146,510 L of water annually for the cultivation. An average water demand coverage increases up to 90.4%, which allows a saving of 340,300 L per year when the RWH system is combined with water recovery from exhaust air from the hall.
Underwater Wireless Sensor Networks: An Energy-Efficient Clustering Routing Protocol Based on Data Fusion and Genetic Algorithms
Authors: Xiao Xingxing , Huang Haining , Wang Wei
Published: December 2020

Due to the limited battery energy of underwater wireless sensor nodes and the difficulty in replacing or recharging the battery underwater, it is of great significance to improve the energy efficiency of underwater wireless sensor networks (UWSNs). We propose a novel energy-efficient clustering routing protocol based on data fusion and genetic algorithms (GAs) for UWSNs. In the clustering routing protocol, the cluster head node (CHN) gathers the data from cluster member nodes (CMNs), aggregates the data through an improved back propagation neural network (BPNN), and transmits the aggregated data to a sink node (SN) through a multi-hop scheme. The effective multi-hop transmission path between the CHN and the SN is determined through the enhanced GA, thereby improving transmission efficiency and reducing energy consumption. This paper presents the GA based on a specific encoding scheme, a particular crossover operation, and an enhanced mutation operation. Additionally, the BPNN employed for data fusion is improved by adopting an optimized momentum method, which can reduce energy consumption through the elimination of data redundancy and the decrease of the amount of transferred data. Moreover, we introduce an optimized CHN selecting scheme considering residual energy and positions of nodes. The experiments demonstrate that our proposed protocol outperforms its competitors in terms of the energy expenditure, the network lifespan, and the packet loss rate.
Galactography Combined with Sonogalactography for Improving the Evaluation of Pathological Nipple Discharge
Authors: Berná-Serna Juan de Dios , Guzmán-Aroca Florentina , Leal-Costa César , Alcaraz Miguel , Berná-Mestre Juan de Dios
Published: December 2020

Diagnosing patients with pathological nipple discharge (PND) is controversial, and therefore a standardized diagnosis algorithm is needed. The objective of this study was to investigate the usefulness of galactography (GL) combined with sonogalactography (SGL) for the evaluation of PND patients. A retrospective study was conducted of 51 patients with PND who were evaluated with GL and SGL. The findings from the galactograms of the patients in this study were assigned to different categories of the Galactogram Image Classification System. Additionally, the sensitivity, specificity, and the positive predictive values and negative predictive values of the GL and SGL tests were calculated, considering the gold standard of pathology diagnosis. The results obtained show that GL combined with SGL improved the diagnostic efficiency of ductal lesions, especially for borderline and malignant lesions. Papilloma was diagnosed in 19 cases, and ductal carcinoma in situ in 8 patients. Conclusions: To the best of our knowledge, this is the first study in which the combination of GL and SGL improves the diagnostic efficiency of ductal lesions of patients with PND. A diagnosis algorithm is recommended for women with PND.
Literature Review of Digital Twins Applications in Construction Workforce Safety
Authors: Hou Lei , Wu Shaoze , Zhang Guomin (Kevin) , Tan Yongtao , Wang Xiangyu
Published: December 2020

For many decades, safety has been a challenge in the construction sector. Despite extensive efforts to improve overall safety, the sector’s casualty rate still remains high. In practice, dynamic and complex construction processes may lead to on-site risks and safety plans being overlooked, likely leading to a variety of safety accidents. Nowadays, under the guidance of the digital twins (DT) concept, the advent of state-of-the-art sensing and visualisation technologies has offered the possibility to improve construction health and safety in the workplace. To understand the research advances of these technologies, identify their gaps and challenges, and propose solutions to further advance the industry’s safety, we conducted and report a thorough review on the state-of-the-art technological studies, and elaborate upon the key findings in detail. For instance, despite DT being proven to be effective in improving construction workforce safety, the construction industry has yet to fully exploit and streamline these innovations in practice. Overall, this review provides insights into technological clustering, improvement strategies, as well as workforce safety, which can benefit from formulating effective digital technology paradigms.
An Assist-as-Needed Controller for Passive, Assistant, Active, and Resistive Robot-Aided Rehabilitation Training of the Upper Extremity
Authors: Zhang Leigang , Guo Shuai , Sun Qing
Published: December 2020

Clinical studies have demonstrated that robot-involved therapy can effectively improve the rehabilitation training effect of motor ability and daily behavior ability of subjects with an upper limb motor dysfunction. This paper presents an impedance-based assist-as-needed controller that can be used in robot-aided rehabilitation training for subjects with an upper extremity dysfunction. Then, the controller is implemented on an end-effector upper extremity rehabilitation robot which could assist subjects in performing training with a spatial trajectory. The proposed controller enables subjects’ arms to have motion freedom by building a fault-tolerant region around the rehabilitation trajectory. Subjects could move their upper limb without any assistance within the fault-tolerant region while the robot would provide assistance according to the subjects’ functional ability when deviating from the fault-tolerant region. Besides, we also put forward the stiffness field around the fault-tolerant region to increase the robot’s assistance when subjects’ hand is moving outside the fault-tolerant region. A series of columnar rigid walls would be constructed in the controller according to the subjects’ functional ability, and the stiffness of the wall increases as the motion performance deteriorates. Furthermore, the controller contains five adjustable parameters. The controller would show different performances by adjusting these parameters and satisfy the requirement of robot-aided rehabilitation training at different rehabilitation stages such as passive, assistant, active, and resistant training. Finally, the controller was tested with an elderly female participant with different controller parameters, and experimental results verified the correctness of the controller and its potential ability to satisfy the training requirements at different rehabilitation stages. In the close future, the proposed controller in this work is planned to be applied on more subjects and also patients who have upper limb motor dysfunctions to demonstrate performance of the controller with different parameters.
Virtual Reality Exposure Therapy for Driving Phobia Disorder (2): System Refinement and Verification
Authors: Trappey Amy , Trappey Charles V. , Chang Chia-Ming , Tsai Meng-Chao , Kuo Routine R. T. , Lin Aislyn P. C.
Published: December 2020

Driving phobia is a widespread anxiety disorder in modern society. Driving phobia disorders often cause difficulties in people’s professional and social activities. A growing trend for treating driving phobia is to apply virtual reality exposure therapy (VRET). We refined the system’s performance based on the previous research publication and have conducted a VRET pre-test research study with treatment and control group subjects to demonstrate the effectiveness of VRET. Some systemic problems were discovered in the first published experiment. For example, the experimental process and the virtual reality (VR) driving scenarios had to be modified to reflect realistic scenarios causing the fear of driving. These issues were identified and improvements made and verified in this research. A total of 130 subjects completed the driving behavior survey. Thirty subjects were randomly drawn from the subjects with high driving fear questionnaire scores and were invited to participate in the treatment experiments. The latest research presents the refined VRET for driving phobia disorders, including the revised system framework, the main modules and integration, and the subjects’ biodata collection, management, and analysis. The experiment results provide strong evidence that the refined VRET design helps subjects overcome driving phobias. The subjects’ subjective distress and fear of driving are reduced significantly through the implementation of VRET.
Microcystis aeruginosa and M. wesenbergii Were the Primary Planktonic Microcystin Producers in Several Bulgarian Waterbodies (August 2019)
Authors: Stoyneva-Gärtner Maya , Stefanova Katerina , Descy Jean-Pierre , Uzunov Blagoy , Radkova Mariana , Pavlova Vera , Mitreva Mariya , Gärtner Georg
Published: December 2020

The rising interest in harmful cyanoprokaryote blooms promotes an increase of phycological and ecological research on potentially toxic species and their hazardous substances. The present study aimed to identify the main microcystin (MC) producers and their contribution to the phytoplankton of shallow waterbodies in Bulgaria, applying different methods. The sampling was performed in August 2019 in nine lakes and reservoirs, two of which (reservoirs Kriva Reka and Izvornik 2) were studied for the first time. The high contribution of cyanoprokaryotes to the total species composition and phytoplankton abundance was proved by light microscopic (LM) observations and HPLC analysis of marker pigments. The LM identification of potential MC-producers was supported by PCR amplification of mcyE and mcyB genes. The MCs amounts, detected by HPLC-DAD, varied by sites with a range from undetectable concentrations to 0.46 µg L−1 with only one recorded variant, namely MC-LR. It was found only in the reservoirs Mandra and Durankulak, while toxigenic MC-strains were obtained by PCR from five more waterbodies. Both LM and PCR demonstrated that the MC-producers were Microcystis aeruginosa and M. wesenbergii, despite their occurrence in low amounts (<0.5–5% of the total biomass) when filamentous cyanoprokaryotes dominated.
Persistence of Ion Cyclotron Waves and Stochasticity of Kinetic Alfvén Waves in the Solar Wind
Authors: Telloni Daniele
Published: December 2020

This paper investigates the nature of the physical processes underlying the origin of the Ion Cyclotron Waves (ICWs) and Kinetic Alfvén Waves (KAWs) in the solar wind, by studying their Waiting Time Distributions (WTDs). The results show that ICWs and KAWs do not share common statistical properties: while KAWs independently occur as stochastic, uncorrelated wave packets governed by Poisson statistics, ICWs are highly correlated, thus departing from the Poisson hypothesis. The results based on the WTD analysis may cast more light on the mechanisms actively at work in the generation of the two wave modes. Specifically, while the stochastic character of KAWs may be reminiscent of the random convection-driven jostling of the flux-tube foot-points that generates the Alfvén waves in the lower solar atmosphere, the correlations among the ICW events can be effectively explained on the basis of the persistent nature of the mechanism underlying the local origin of ICWs, namely the proton cyclotron instability. Alternative explanations for the observed distribution of ICW waiting times, based on a piecewise-constant Poisson process involving time-varying rates, are also reported.
Global Air Quality: An Inter-Disciplinary Approach to Exposure Assessment for Burden of Disease Analyses
Authors: Shaddick Gavin , Salter James M. , Peuch Vincent-Henri , Ruggeri Giulia , Thomas Matthew L. , Mudu Pierpaolo , Tarasova Oksana , Baklanov Alexander , Gumy Sophie
Published: December 2020

Global assessments of air quality and health require comprehensive estimates of the exposures to air pollution that are experienced by populations in every country. However, there are many countries in which measurements from ground-based monitoring are sparse or non-existent, with quality-control and representativeness providing additional challenges. While ground-based monitoring provides a far from complete picture of global air quality, there are other sources of information that provide comprehensive coverage across the globe. The World Health Organization developed the Data Integration Model for Air Quality (DIMAQ) to combine information from ground measurements with that from other sources, such as atmospheric chemical transport models and estimates from remote sensing satellites in order to produce the information that is required for health burden assessment and the calculation of air pollution-related Sustainable Development Goals indicators. Here, we show an example of the use of DIMAQ with the Copernicus Atmosphere Monitoring Service Re-Analysis (CAMSRA) of atmospheric composition, which represents the best practices in meteorology and climate monitoring that were developed under the World Meteorological Organization’s Global Atmosphere Watch programme. Estimates of PM2.5 from CAMSRA are integrated within the DIMAQ framework in order to produce high-resolution estimates of air pollution exposure that can be aggregated in a coherent fashion to produce country-level assessments of exposures.
Investigation of Aerosol Direct Effect over China under El Niño and Its Spatial Distribution Using WRF-Chem
Authors: Li Fangzhou , Lin Wenshi , Jiang Baolin , Li Jiangnan
Published: December 2020

With rapid economic development and urbanization, the air pollution problem over China has drawn great attention. To explore the aerosol direct effect (ADE) over China, two simulations were conducted using WRF-Chem V3.5.1 in the summer of 2015. One was a control run (CTL) including aerosol effect and related physical and chemical processes, and the other one was a sensitivity simulation (SEN), the same as CTL except that aerosol-radiation interactions were turned off. The differences between two tests were analyzed, in particular over regions in South China (SC) and East China (EC). Results showed the following. (1) The large-scale circulation showed a strong El Niño signal, associated with cooling and wet anomalies over EC, while warming and dry anomalies over EC. (2) Due to ADE, there was a significant decrease in precipitation and an increase in AOD over SC and EC, albeit with different mechanisms. (3) In SC, ADE cooled the region reinforcing the El Niño impact and suppressing water vapor fluxes, which led to a more stable atmosphere and weakened water cycle. In EC, ADE caused vertical circulation anomalies opposing the El Niño impact. (4) ADE showed obvious land-sea difference in precipitation and shortwave radiation.
Susceptibility of Asialoglycoprotein Receptor-Deficient Mice to LPS/Galactosamine Liver Injury and Protection by Betaine Administration
Authors: Rasineni Karuna , Lee Serene M. L. , McVicker Benita L. , Osna Natalia A. , Casey Carol A. , Kharbanda Kusum K.
Published: December 2020

Background: Work from our laboratory has shown that the ethanol-induced increase in apoptotic hepatocellular death is closely related to the impairment in the ability of the asialoglycoprotein receptor (ASGP-R) to remove neighboring apoptotic cells. In this study, we assessed the role of ASGP-R in fulminant liver failure and investigated whether prior treatment with betaine (a naturally occurring tertiary amine) is protective. Methods: Lipopolysaccharide (LPS; 50 μg/kg BW) and galactosamine (GalN; 350 mg/kg BW) were injected together to wild-type and ASGP-R-deficient mice that were treated for two weeks prior with or without 2% betaine in drinking water. The mice were sacrificed 1.5, 3, or 4.5 h post-injection, and tissue samples were collected. Results: LPS/GalN injection generate distinct molecular processes, which includes increased production of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), thus causing apoptosis as evident by increased caspase-3 activity. ASGP-R deficient animals showed increased liver caspase activities, serum TNF-α and IL-6 levels, as well as more pronounced liver damage compared with the wild-type control animals after intraperitoneal injection of LPS/GalN. In addition, prior administration of betaine was found to significantly attenuate the LPS/GalN-induced increases in liver injury parameters. Conclusion: Our work underscores the importance of normal functioning of ASGP-R in preventing severe liver damage and signifies a therapeutic role of betaine in prevention of liver injuries from toxin-induced fulminant liver failure.
ADAMTS1 Supports Endothelial Plasticity of Glioblastoma Cells with Relevance for Glioma Progression
Authors: Serrano-Garrido Orlando , Peris-Torres Carlos , Redondo-García Silvia , Asenjo Helena G. , Plaza-Calonge María del Carmen , Fernandez-Luna José Luis , Rodríguez-Manzaneque Juan Carlos
Published: December 2020

Gliomas in general and the more advanced glioblastomas (GBM) in particular are the most usual tumors of the central nervous system with poor prognosis. GBM patients develop resistance to distinct therapies, in part due to the existence of tumor cell subpopulations with stem-like properties that participate in trans-differentiation events. Within the complex tumor microenvironment, the involvement of extracellular proteases remains poorly understood. The extracellular protease ADAMTS1 has already been reported to contribute to the plasticity of cancer cells. Accordingly, this basic knowledge and the current availability of massive sequencing data from human gliomas, reinforced the development of this work. We first performed an in silico study of ADAMTS1 and endothelial markers in human gliomas, providing the basis to further assess these molecules in several primary glioblastoma-initiating cells and established GBM cells with the ability to acquire an endothelial-like phenotype. Using a co-culture approach of endothelial and GBM cells, we noticed a relevant function of ADAMTS1 in GBM cells leading the organization of endothelial-like networks and, even more significantly, we found a blockade of the formation of tumor-spheres and a deficient response to hypoxia in the absence of ADAMTS1. Our data support a chief role of this protease modulating the phenotypic plasticity of GBM.
Molecular Targeting of VEGF with a Suramin Fragment–DOCA Conjugate by Mimicking the Action of Low Molecular Weight Heparins
Authors: Park Jooho , Kang Tae-Bong , Lim Ji-Hong , Won Hyung-Sik
Published: December 2020

Molecular targeting of growth factors has shown great therapeutic potential in pharmaceutical research due to their roles in pathological conditions. In the present study, we developed a novel suramin fragment and deoxycholic acid conjugate (SFD) that exhibited the potential to bind to the heparin-binding site (HBD) of vascular endothelial growth factor (VEGF) and to inhibit its pathogenic action for the first time. Notably, SFD was optimally designed for binding to the HBD of VEGF using the naphthalenetrisulfonate group, allowing to observe its excellent binding efficacy in a surface plasmon resonance (SPR) study, showing remarkable binding affinity (KD = 3.8 nM) as a small molecule inhibitor. In the tubular formation assay, it was observed that SFD could bind to HBD and exhibit antiangiogenic efficacy by inhibiting VEGF, such as heparins. The cellular treatment of SFD resulted in VEGF-inhibitory effects in human umbilical vein endothelial cells (HUVECs). Therefore, we propose that SFD can be employed as a novel drug candidate to inhibit the pathophysiological action of VEGF in diseases. Consequently, SFD, which has a molecular structure optimized for binding to HBD, is put forward as a new chemical VEGF inhibitor.
Micro- to Nanoscale Bio-Hybrid Hydrogels Engineered by Ionizing Radiation
Authors: Dispenza Clelia , Giacomazza Daniela , Jonsson Mats
Published: December 2020

Bio-hybrid hydrogels consist of a water-swollen hydrophilic polymer network encapsulating or conjugating single biomolecules, or larger and more complex biological constructs like whole cells. By modulating at least one dimension of the hydrogel system at the micro- or nanoscale, the activity of the biological component can be extremely upgraded with clear advantages for the development of therapeutic or diagnostic micro- and nano-devices. Gamma or e-beam irradiation of polymers allow a good control of the chemistry at the micro-/nanoscale with minimal recourse to toxic reactants and solvents. Another potential advantage is to obtain simultaneous sterilization when the absorbed doses are within the sterilization dose range. This short review will highlight opportunities and challenges of the radiation technologies to produce bio-hybrid nanogels as delivery devices of therapeutic biomolecules to the target cells, tissues, and organs, and to create hydrogel patterns at the nano-length and micro-length scales on surfaces.
Acriflavine, a Potent Inhibitor of HIF-1α, Disturbs Glucose Metabolism and Suppresses ATF4-Protective Pathways in Melanoma under Non-Hypoxic Conditions
Authors: Martí-Díaz Román , Montenegro María F. , Cabezas-Herrera Juan , Goding Colin R. , Rodríguez-López José Neptuno , Sánchez-del-Campo Luis
Published: December 2020

Hypoxia-inducible factor (HIF)-1α is constitutively expressed in melanoma cells under normoxic conditions and its elevated expression correlates with the aggressiveness of melanoma tumors. Here, we used acriflavine, a potent inhibitor of HIF-1α dimerization, as a tool to investigate whether HIF-1α-regulated pathways contribute to the growth of melanoma cells under normoxia. We observed that acriflavine differentially modulated HIF-1α-regulated targets in melanoma under normoxic conditions, although acriflavine treatment resulted in over-expression of vascular endothelial growth factor (VEGF), its action clearly downregulated the expression of pyruvate dehydrogenase kinase 1 (PDK1), a well-known target of HIF-1α. Consequently, downregulation of PDK1 by acrifavine resulted in reduced glucose availability and suppression of the Warburg effect in melanoma cells. In addition, by inhibiting the AKT and RSK2 phosphorylation, acriflavine also avoided protective pathways necessary for survival under conditions of oxidative stress. Interestingly, we show that acriflavine targets activating transcription factor 4 (ATF4) for proteasomal degradation while suppressing the expression of microphthalmia-associated transcription factor (MITF), a master regulator of melanocyte development and a melanoma oncogene. Since acriflavine treatment results in the consistent death of melanoma cells, our results suggest that inhibition of HIF-1α function in melanoma could open new avenues for the treatment of this deadly disease regardless of the hypoxic condition of the tumor.
Potentially Modifiable Factors Associated with Adherence to Adjuvant Endocrine Therapy among Breast Cancer Survivors: A Systematic Review
Authors: Toivonen Kirsti , Williamson Tamara , Carlson Linda , Walker Lauren , Campbell Tavis
Published: December 2020

Adjuvant endocrine therapy (AET) reduces risk of breast cancer recurrence. However, suboptimal adherence and persistence to AET remain important clinical issues. Understanding factors associated with adherence may help inform efforts to improve use of AET as prescribed. The present systematic review examined potentially modifiable factors associated with adherence to AET in accordance with PRISMA guidelines (PROSPERO registration ID: CRD42019124200). All studies were included, whether factors were significantly associated with adherence or results were null. This review also accounted for the frequency with which a potentially modifiable factor was examined and whether univariate or multivariate models were used. This review also examined whether methodological or sample characteristics were associated with the likelihood of a factor being associated with AET adherence. A total of 68 articles were included. Potentially modifiable factors were grouped into six categories: side effects, attitudes toward AET, psychological factors, healthcare provider-related factors, sociocultural factors, and general/quality of life factors. Side effects were less likely to be associated with adherence in studies with retrospective or cross-sectional than prospective designs. Self-efficacy (psychological factor) and positive decisional balance (attitude toward AET) were the only potentially modifiable factors examined ≥10 times and associated with adherence or persistence ≥75% of the time in both univariate and multivariate models. Self-efficacy and decisional balance (i.e., weight of pros vs. cons) were the potentially modifiable factors most consistently associated with adherence, and hence may be worth focusing on as targets for interventions to improve AET adherence among breast cancer survivors.
Reductive Catalytic Fractionation of Flax Shive over Ru/C Catalysts
Authors: Kazachenko Aleksandr S. , Tarabanko Valery E. , Miroshnikova Angelina V. , Sychev Valentin V. , Skripnikov Andrey M. , Malyar Yuriy N. , Mikhlin Yuriy L. , Baryshnikov Sergey V. , Taran Oxana P.
Published: December 2020

Flax shive is the main waste (up to 70 wt %) in the production of flax fiber. It represents the lignified parts of the flax stem mainly in the form of small straws. Complex processing of such wastes is a significant problem due to the heterogeneity of the chemical structure of lignin. This article presents the results of reductive catalytic fractionation (RCF) of flax shive in ethanol and isopropanol at elevated temperatures (225–250 °C) in the presence of a bifunctional catalyst (Ru/C) and molecular hydrogen. This provides solvolytic depolymerization of lignin and hemicelluloses presented in flax shive. Catalytic hydrogenation effectively stabilizes the formed lignin intermediates and prevents repolymerization reactions producing the lignin fraction with a high degree of depolymerization. RCF of flax shive produces solid products with a high cellulose content and liquid products consisting mainly of monophenolic compounds. Furthermore, the effect of different characteristics (the ruthenium content, particle size, and support acidity) of the bifunctional catalysts containing ruthenium nanoparticles supported on mesoporous, graphite-like carbon material Sibunit®-4 on the yield and composition of the products of hydrogenation of flax shive in sub- and super-critical ethanol has been studied. Bifunctional catalysts Ru/C used in the RCF of flax shive increase its conversion from 44 to 56 wt % and the yield of monophenols from 1.1 to 10.2 wt % (based on the weight of lignin in the sample). Using the best Ru/C catalyst containing 3% of Ru on oxidized at 400 °C carbon support, the high degree of delignification (up to 79.0%), cellulose yield (up to 67.2 wt %), and monophenols yield (up to 9.5 wt %) have been obtained.
Recent Advances in Microwave-Assisted Copper-Catalyzed Cross-Coupling Reactions
Authors: Baqi Younis
Published: December 2020

Cross-coupling reactions furnishing carbon–carbon (C–C) and carbon–heteroatom (C–X) bond is one of the most challenging tasks in organic syntheses. The early developed reaction protocols by Ullmann, Ullman–Goldberg, Cadiot–Chodkiewicz, Castro–Stephens, and Corey–House, utilizing elemental copper or its salts as catalyst have, for decades, attracted and inspired scientists. However, these reactions were suffering from the range of functional groups tolerated as well as severely restricted by the harsh reaction conditions often required high temperatures (150–200 °C) for extended reaction time. Enormous efforts have been paid to develop and achieve more sustainable reaction conditions by applying the microwave irradiation. The use of controlled microwave heating dramatically reduces the time required and therefore resulting in increase in the yield as well as the efficiency of the reaction. This review is mainly focuses on the recent advances and applications of copper catalyzed cross-coupling generation of carbon–carbon and carbon–heteroatom bond under microwave technology.
Circulating Non-Coding RNAs in Head and Neck Cancer: Roles in Diagnosis, Prognosis, and Therapy Monitoring
Authors: Diez-Fraile Araceli , Ceulaer Joke De , Derpoorter Charlotte , Spaas Christophe , Backer Tom De , Lamoral Philippe , Abeloos Johan , Lammens Tim
Published: December 2020

Head and neck cancer (HNC), the seventh most common form of cancer worldwide, is a group of epithelial malignancies affecting sites in the upper aerodigestive tract. The 5-year overall survival for patients with HNC has stayed around 40–50% for decades, with mortality being attributable mainly to late diagnosis and recurrence. Recently, non-coding RNAs, including tRNA halves, YRNA fragments, microRNAs (miRNAs), and long non-coding RNAs (lncRNAs), have been identified in the blood and saliva of patients diagnosed with HNC. These observations have recently fueled the study of their potential use in early detection, diagnosis, and risk assessment. The present review focuses on recent insights and the potential impact that circulating non-coding RNA evaluation may have on clinical decision-making in the management of HNC.
Gastrin-Releasing Peptide (GRP) Stimulates Osteoclastogenesis in Periodontitis
Authors: Choi YunJeong , Heo Soon Chul , Kim Yu Na , Joo Ji-Young , Hwang Jae Joon , Bae Moon-Kyoung , Kim Hyung Joon
Published: December 2020

Periodontitis is a chronic inflammatory disease with alveolar bone resorption and subsequent tooth loss as its ultimate outcomes. Gastrin-releasing peptide (GRP) is a neuropeptide with growth-stimulatory and tumorigenic properties, and neuropeptides have previously been suggested to play a role in the complex cascade of chemical activity associated with periodontal inflammation. In this study, GRP treatment enhanced the differentiation of bone marrow-derived macrophages (BMMs) into osteoclasts, and gastrin-releasing peptide receptor (GRPR) antagonists suppressed the pro-osteoclastogenic effect of GRP. Grpr-siRNA knockdown resulted in a significantly lower number of osteoclasts formed as compared with the control. Interestingly, gene expression analysis indicated downregulation of Grp and Grpr expressions in BMMs during osteoclastogenesis. Moreover, ligature-induced periodontitis model in mice and gingival samples from patients with periodontitis displayed increased immunostaining of GRP in the oral epithelium. Subsequently, stimulation of mouse primary epithelial cells (ECs) and HaCaT cells, human epidermal keratinocytes, with lipopolysaccharides (LPS) of Porphyromonas gingivalis or live P. gingivalis upregulated Grp and Grpr expressions. Finally, coculture of P. gingivalis-stimulated ECs and BMMs using Transwell system revealed that the differentiation of BMMs was induced when subjected to paracrine activation by LPS- as well as live-P. gingivalis stimulated ECs. Taken together, our results demonstrate that the pro-osteoclastogenic properties of BMMs may be modulated by GRP produced by ECs in the periodontal microenvironment.
Breakfast Food Advertisements in Mediterranean Countries: Products’ Sugar Content in the Adverts from 2015 to 2019
Authors: Montaña Blasco Mireia
Published: December 2020

Although Spain was considered to be the healthiest country in the world in 2019, some studies reported that Mediterranean diet (MD) adherence, especially for breakfast, is low among children in Mediterranean countries, where child obesity is increasing alarmingly. This study correlated longitudinally the sugar content of breakfast products with advertising strategies. The research design applied quantitative analysis to compile the advertising data from 2015 to 2019 for all media, qualitative analysis of the content, and the use of popular characters to promote the food purchase. Additionally, a nutritional analysis was used to determine the products’ sugar content. The results were analyzed according to the target they were aimed at (adults or children). Results showed that the Spanish food industry promoted unhealthy products for breakfast, especially those targeted to children, with very high sugar content. To improve the childhood obesity rate in Spain, greater involvement from the food industry is needed. The reformulation of breakfast products must be a priority along with additional sugar reduction strategies so as not to lose adherence to MD in younger generations. More nutrition education is necessary among children, especially on balanced breakfast consumption, a basic meal that helps children to concentrate better in class during the morning.
From SrTiO3 to Cuprates and Back to SrTiO3: A Way Along Alex Müller’s Scientific Career
Authors: Bussmann-Holder Annette , Keller Hugo
Published: December 2020

K.A. Müller took a long route in science leaving many traces and imprints, which have been and are still today initiations for further research activities. We “walk” along this outstanding path but are certainly not able to provide a complete picture of it, since the way was not always straight, often marked by unintended detours, which had novel impact on the international research society.
Top-Down Synthesis of a Lamivudine-Zidovudine Nano Co-Crystal
Authors: Witika Bwalya A. , Smith Vincent J. , Walker Roderick B.
Published: December 2020

Lamivudine (3TC) and zidovudine (AZT) are antiretroviral agents used to manage HIV/AIDS infection. A wet media milling top-down approach was used to develop and produce nano co-crystals of 3TC and AZT. Micro co-crystals were prepared by solvent evaporation and subsequently milled in the presence of two surfactants, viz., sodium lauryl sulfate (SLS) and α-tocopheryl polyethylene glycol succinate 1000 (TPGS 1000). Optimisation was undertaken using design of experiments (DoE) and response surface methodology (RSM) to establish and identify parameters that may affect the manufacturing of nano co-crystals. The impact of SLS and TPGS 1000 concentration, milling time, and number of units of milling medium on the manufacturing of nano co-crystals, was investigated. The critical quality attributes (CQA) monitored were particle size (PS), Zeta potential (ZP), and polydispersity index (PDI). Powder X-ray diffraction, Fourier transform infrared spectroscopy, differential scanning calorimetry, transmission electron microscopy, energy dispersive X-ray spectroscopy scanning electron microscopy, and cytotoxicity assays were used for additional characterization of the optimised nano co-crystal. The mean PS, PDI, and ZP of the optimised top-down nanocrystal were 271.0 ± 92.0 nm, 0.467 ± 0.073, and −41.9 ± 3.94 mV, respectively. In conclusion, a simple, inexpensive, rapid, and precise method of nano co-crystal manufacturing was developed, validated, and optimised using DoE and RSM, and the final product exhibited the target CQA.
Effect of Laser Beam Profile on Rotating Lattice Single Crystal Growth in Sb2S3 Model Glass
Authors: Au-Yeung Courtney , Savytskii Dmytro , Veenhuizen Keith , Dierolf Volkmar , Jain Himanshu
Published: December 2020

Laser heating of chalcogenide glasses has successfully produced rotating lattice single crystals through a solid-solid transformation. To better understand the nature of complex, orientation-dependent lattice rotation, we designed heat profiles of the continuous wave laser by beam shaping, fabricated larger Sb2S3 crystal dots in Sb2S3 glass, and investigated the lattice rotation where the crystal could grow in all radial directions under a circular thermal gradient. The results show that the rate of lattice rotation is highly anisotropic and depends on crystallographic direction. The nature of this rotation is the same in crystals of different orientation relative to the surface. The growth directions that align with the slip planes show the highest rate of rotation and the rotation rate gradually decreases away from this direction. Additionally, the presence of multiple growth directions results in a complicated rotation system. We suggest that the growth front influences the density of dislocations introduced during growth under confinement and thus affects the lattice rotation rate in these crystals.