bluuebunny/crossref_metadata_2025 huggingface dataset:
The Dual Role of Macropinocytosis in Cancers: Promoting Growth and Inducing Methuosis to Participate in Anticancer Therapies as Targets
Authors: Song Shaojuan , Zhang Yanan , Ding Tingting , Ji Ning , Zhao Hang
Published: January 2021

Macropinocytosis is an important mechanism of internalizing extracellular materials and dissolved molecules in eukaryotic cells. Macropinocytosis has a dual effect on cancer cells. On the one hand, cells expressing RAS genes (such as K-RAS, H-RAS) under the stress of nutrient deficiency can spontaneously produce constitutive macropinocytosis to promote the growth of cancer cells by internalization of extracellular nutrients (like proteins), receptors, and extracellular vesicles(EVs). On the other hand, abnormal expression of RAS genes and drug treatment (such as MOMIPP) can induce a novel cell death associated with hyperactivated macropinocytosis: methuosis. Based on the dual effect, there is immense potential for designing anticancer therapies that target macropinocytosis in cancer cells. In view of the fact that there has been little review of the dual effect of macropinocytosis in cancer cells, herein, we systematically review the general process of macropinocytosis, its specific manifestation in cancer cells, and its application in cancer treatment, including anticancer drug delivery and destruction of macropinocytosis. This review aims to serve as a reference for studying macropinocytosis in cancers and designing macropinocytosis-targeting anticancer drugs in the future.
Highly Multiplexed Digital Spatial Profiling of the Tumor Microenvironment of Head and Neck Squamous Cell Carcinoma Patients
Authors: Kulasinghe Arutha , Taheri Touraj , O’Byrne Ken , Hughes Brett G. M. , Kenny Liz , Punyadeera Chamindie
Published: January 2021

Background

Immune checkpoint inhibitors (ICI) have shown durable and long-term benefits in a subset of head and neck squamous cell carcinoma (HNSCC) patients. To identify patient-responders from non-responders, biomarkers are needed which are predictive of outcome to ICI therapy. Cues in the tumor microenvironment (TME) have been informative in understanding the tumor-immune contexture.

Methods

In this preliminary study, the NanoString GeoMx™ Digital Spatial Profiling (DSP) technology was used to determine the immune marker and compartment specific measurements in a cohort of HNSCC tumors from patients receiving ICI therapy.

Results

Our data revealed that markers involved with immune cell infiltration (CD8 T-cells) were not predictive of outcome to ICI therapy. Rather, a number of immune cell types and protein markers (CD4, CD68, CD45, CD44, CD66b) were found to correlate with progressive disease. Cross platform comparison with the Opal Vectra (Perkin Elmer) for a number of markers across similar regions of interest demonstrated concordance for pan-cytokeratin, CD8, and PD-L1.

Conclusion

This study, to our knowledge, represents the first digital spatial analysis of HNSCC tumors. A larger cohort of HNSCC will be required to orthogonally validate the findings.
SGK1 in Human Cancer: Emerging Roles and Mechanisms
Authors: Sang Yiwen , Kong Piaoping , Zhang Shizhen , Zhang Lingyu , Cao Ying , Duan Xiuzhi , Sun Tao , Tao Zhihua , Liu Weiwei
Published: January 2021

Serum and glucocorticoid-induced protein kinase 1 (SGK1) is a member of the “AGC” subfamily of protein kinases, which shares structural and functional similarities with the AKT family of kinases and displays serine/threonine kinase activity. Aberrant expression of SGK1 has profound cellular consequences and is closely correlated with human cancer. SGK1 is considered a canonical factor affecting the expression and signal transduction of multiple genes involved in the genesis and development of many human cancers. Abnormal expression of SGK1 has been found in tissue and may hopefully become a useful indicator of cancer progression. In addition, SGK1 acts as a prognostic factor for cancer patient survival. This review systematically summarizes and discusses the role of SGK1 as a diagnostic and prognostic biomarker of diverse cancer types; focuses on its essential roles and functions in tumorigenesis, cancer cell proliferation, apoptosis, invasion, metastasis, autophagy, metabolism, and therapy resistance and in the tumor microenvironment; and finally summarizes the current understanding of the regulatory mechanisms of SGK1 at the molecular level. Taken together, this evidence highlights the crucial role of SGK1 in tumorigenesis and cancer progression, revealing why it has emerged as a potential target for cancer therapy.
Emodin Inhibits the Proliferation of MCF-7 Human Breast Cancer Cells Through Activation of Aryl Hydrocarbon Receptor (AhR)
Authors: Zhang Ning , Wang Jiawen , Sheng Aimin , Huang Shuo , Tang Yanyan , Ma Shitang , Hong Ge
Published: January 2021

Natural products have proved to be a promising source for the development of potential anticancer drugs. Emodin, a natural compound from Rheum palmatum, is used to treat several types of cancers, including lung, liver, and pancreatic. However, there are few reports regarding its use in the treatment of breast cancer. Thus, the therapeutic effect and mechanism of emodin on MCF-7 human breast cancer cells were investigated in this study. Morphological observations and cell viability were evaluated to determine the anti-proliferation activity of emodin. Network pharmacology and molecular docking were performed to screen the potential targets. Western blot analysis was used to explore a potential antitumor mechanism. The results showed that emodin (50–100 μmol/L) could significantly inhibit the proliferation of MCF-7 cells in a time and dose-dependent manner. Furthermore, virtual screening studies indicated that emodin was a potent aryl hydrocarbon receptor (AhR) agonist in chemotherapy for breast cancer. Finally, when MCF-7 cells were treated with emodin (100 μmol/L) for 24 h, the AhR and cytochrome P450 1A1 (CYP1A1) protein expression levels were significantly upregulated compared with the control group. Our study indicated that emodin exhibited promising antitumor activity in MCF-7 cells, likely through activation of the AhR-CYP1A1 signaling pathway. These findings lay a foundation for the application of emodin in breast cancer treatment.
Community Detection of Dynamic Complex Networks in Stock Markets Using Hybrid Methods (RMT‐CN‐LPAm+ and RMT‐BDM‐SA)
Authors: Purqon Acep , Jamaludin
Published: January 2021

A stock market represents a large number of interacting elements, leading to complex hidden interactions. It is very challenging to find a useful method to detect the detailed dynamical complex networks involved in the interactions. For this reason, we propose two hybrid methods called RMT-CN-LPAm+ and RMT-BDM-SA (RMT, random matrix theory; CN, complex network; LPAm+, advanced label propagation algorithm; BDM, block diagonal matrix; SA, simulated annealing). In this study, we investigated group mapping in the S&P 500 stock market using these two hybrid methods. Our results showed the good performance of the proposed methods, with both the methods demonstrating their own benefits and strong points. For example, RMT-CN-LPAm+ successfully identified six groups comprising 485 involved nodes and 17 isolated nodes, with a maximum modularity of 0.62 (identified more groups and displayed more maximum modularity). Meanwhile, RMT-BDM-SA provided useful detailed information through the decomposition of matrix C into Cm (market-wide), Cg (group), and Cr (noise). Both hybrid methods successfully performed very detailed community detection of dynamic complex networks in the stock market.
Possible Indications of Variations in the Directionality of Beta-Decay Products
Authors: Sturrock Peter A. , Fischbach Ephraim , Piatibratova Oksana , Scholkmann Felix
Published: January 2021

Some experiments seem to yield strong evidence of variability of beta-decay rates, but other experiments may show little or no such evidence. Some recent experiments help clarify the situation. In particular, a certain oscillation appears in neutrino measurements made at the Super-Kamiokande Neutrino Observatory and in radon beta-decay measurements made at the Geological Survey of Israel, with identical frequency (9.43 years−1), amplitude and phase, strengthening the case for an influence of neutrinos on beta decays. A review of current experimental information leads us to suggest that 1) beta-decay rates do not change, but 2) the angular distribution of decay products may be anisotropic, and 3) the angular distribution of decay products may be influenced by the ambient neutrino flux. It appears that experiments at standards laboratories tend to be insensitive to direction, and this may be the reason that they tend not to exhibit evidence of variability.
Control of THz Surface Plasmons by Geometric Phases
Authors: Hu Shulin , Wang Peng , Zhou Cai , Hu Min , Xiong Yuli , Xu Huanhuan , Li Xiaoyu , Xu Mingyao , Wang Shengxiang
Published: January 2021

Surface plasmons (SPs) are expected to have a wide range of applications in many fields, so they have recently attracted much attention. However, most of the previous studies achieved the manipulation of SPs through designing the structure of the individual meta-atom. When developing the next generation of integrated photonic devices and components, it is essential to seek out new methods of software control, which enable more diverse modulation and higher efficiency. Here, the tunable emission of SPs with metasurfaces is systematically studied. SPs are a source of on-chip plasmonic vortices (PVs). To verify the controllability of the directional excitation of SPs, we designed beam deflectors with different angles of surface waves (SWs). Furthermore, PVs with different topological charges were generated by arranging spatially varied microslits. The proposed control strategy provides a common platform for various promising applications, such as on-chip generation of the propagation control of SPs and PVs.
Rescuers at Risk: Posttraumatic Stress Symptoms Among Police Officers, Fire Fighters, Ambulance Personnel, and Emergency and Psychiatric Nurses
Authors: Soravia Leila M. , Schwab Simon , Walther Sebastian , Müller Thomas
Published: January 2021

Emergency personnel and rescue workers may be at a risk of posttraumatic stress symptoms (PTSS) due to exposure to trauma and work-related stressors. Though rescuers of different professions are often engaged in the same type of emergency, they have different tasks and responsibilities and receive different training in coping with traumatic events and stress; hence, we speculated that the salience of identified risk factors for PTSS vary across their respective professions. The present cross-sectional survey aimed to identify influencing variables on PTSS, well-being, and suicidal ideation that can act differently across professions of rescue workers and emergency personnel. In this anonymous online study, data from 1,002 rescue workers and emergency personnel in Switzerland, were collected: 499 police officers, 239 firefighters, 97 ambulance personnel, and 85 emergency and 82 psychiatric nurses. PTSS, coping strategies, well-being, suicidal ideation, previously experienced and work-related trauma, and self-efficacy were measured and analyzed using multiple regression and structural equation modeling (SEM). The prevalence of suspected posttraumatic stress disorder varied across the professions, ranged from 8% (firefighters) to 22% (psychiatric nurses), and was associated with psychological strain and suicidal ideation. The SEM showed that dysfunctional coping strategies, self-efficacy, previously experienced and work-related trauma, years on job, and female sex explained up to 78% of PTSS and that PTSS itself explained up to 68% of the psychological strain experienced in the different professions. Independent of the profession, dysfunctional coping such as alcohol use, avoidance, and distraction, as well as work-related trauma were the most robust predictors of PTSS. However, while self-efficacy was a risk factor for police officers, firefighters and ambulance personnel, it was a protective factor for emergency and psychiatric nurses. Furthermore, female sex was only a risk factor for ambulance personnel and emergency nurses. In agreement with prior research, emergency personnel and rescuers exhibited enhanced prevalence of PTSS and suspected PTSD, leading to significant psychological strain and suicidal ideation. However, risk factors varied across the professions. Thus, the development of profession-specific trainings to improve self-efficacy and coping with work-related stressors to reduce PTSS, and enhance quality of life, is needed for individuals in such high-risk professions.

Clinical Trial Registration:ClinicalTrials.gov Nr. NCT03842553.
Crowd Evacuation Guidance Based on Combined Action Reinforcement Learning
Authors: Xue Yiran , Wu Rui , Liu Jiafeng , Tang Xianglong
Published: January 2021

Existing crowd evacuation guidance systems require the manual design of models and input parameters, incurring a significant workload and a potential for errors. This paper proposed an end-to-end intelligent evacuation guidance method based on deep reinforcement learning, and designed an interactive simulation environment based on the social force model. The agent could automatically learn a scene model and path planning strategy with only scene images as input, and directly output dynamic signage information. Aiming to solve the “dimension disaster” phenomenon of the deep Q network (DQN) algorithm in crowd evacuation, this paper proposed a combined action-space DQN (CA-DQN) algorithm that grouped Q network output layer nodes according to action dimensions, which significantly reduced the network complexity and improved system practicality in complex scenes. In this paper, the evacuation guidance system is defined as a reinforcement learning agent and implemented by the CA-DQN method, which provides a novel approach for the evacuation guidance problem. The experiments demonstrate that the proposed method is superior to the static guidance method, and on par with the manually designed model method.
The Dynamic of Nitrogen Uptake from Different Sources by Pea (Pisum sativum L.)
Authors: Wysokinski Andrzej , Lozak Izabela
Published: January 2021

Nitrogen uptake from various sources by plants capable of biological reduction of N2 in symbiotic systems with root nodule bacteria is influenced by many factors. The aim of the study was to examine the influence of the development stage and variety of pea (Pisum sativum L.) cultivated in years with different temperature and precipitation conditions on the dynamics of nitrogen uptake from the atmosphere (Ndfa), fertilizer (Ndff), and soil (Ndfs). Pre-sowing nitrogen fertilization with the 15N isotope and the isotope dilution method were used in the research. The highest rate of Ndfa uptake was noted between the three-internode stage and the stage of the first visible flower buds outside the leaves, while Ndff and Ndfs uptake was highest between the 4-leaf stage and the 3-internode stage. The lowest rate of Ndfa uptake was noted from sowing to the four-leaf stage, while Ndff and Ndfs uptake was lowest between the stage when 50% of pods were of typical length and full maturity. Nitrogen uptake from all sources was similar for all pea cultivars, but significantly depended on the variable temperature and precipitation conditions (years of the study).
Review of Horseradish Breeding for Improved Root Quality and Yield in Illinois, USA
Authors: Walters Stuart Alan
Published: January 2021

Horseradish cultivars are highly heterozygous clones and are maintained through asexual propagation, using root cuttings. For many years, horseradish was believed to be sterile and therefore impossible to improve by traditional sexual crosses. Prior to the 20th century, the only way to improve horseradish was to select and plant root cuttings from the most desirable plants. Moreover, the development of new improved horseradish cultivars has also been somewhat limited by the lack of viable seed resulting from low fertility of horseradish flowers. However, in Illinois, USA, a horseradish breeding program was initiated in the 1950s to develop additional cultivars to widen the genetic base of the few cultivars being grown at the time. In more recent years, the proven cross breeding technique has been primarily used to obtain new genotypes of horseradish, since it is more efficient in producing new improved cultivars, compared to the polycross method that had been previously used for decades to obtain new genetic combinations. Since horseradish is a minor specialty crop with very little available information regarding breeding procedures, this review was developed to provide a better understanding of pollination barriers and methods for fertility improvement, traditional breeding procedures and cultivar development, and traditional breeding achievements and limitations. The development of new horseradish cultivars is essential for the sustained success of the Illinois, USA industry since it provides growers with a continuous supply of new selections that have increased vigor, outstanding root quality, and high yields.
Competition for Light Interception in Cotton Populations of Different Densities
Authors: Chen Huanxuan , Zhao Xinxin , Han Yingchun , Xing Fangfang , Feng Lu , Wang Zhanbiao , Wang Guoping , Yang Beifang , Lei Yaping , Xiong Shiwu , Li Xiaofei , Xin Minghua , An Jie , Du Wenli , Li Yabing
Published: January 2021

Modification of the cotton canopy results in shade avoidance and competition for light, which shows that density and spatial arrangement of cotton have a great impact on light interception. This experiment was conducted in 2018 and 2019 in the experimental field at the Institute of Cotton Research of Chinese Academy of Agricultural Science in Anyang city, Henan Province, China. Six plant densities of cotton variety SCRC28 were used to assess spatial competition for light in cotton populations during the whole growing period. Light interception data were collected and analyzed according to the spatial grid method and the extension of Simpson’s 3/8 rule. The results showed that at the bottom of the canopy, greater light interception was observed at high densities than at low densities, while in the external part of the layer of the canopy in the horizontal direction, low light interception was recorded at low densities. Leaf area, aboveground biomass and plant height were obviously correlated with light interception, and the cotton population with a higher density (8.7 plants m−2) performed best at the light interception competition, and with the highest yield. The results will provide guidance on light management through the optimization of the structure of the canopy to provide more solar radiation and a significant basis by which to improve the management of light and canopy architecture.
Reaction of Camelina (Camelina sativa (L.) Crantz) to Different Foliar Fertilization
Authors: Jarecki Wacław
Published: January 2021

Camelina (Camelina sativa (L.) Crantz) is an oil plant that can increase farmland biodiversity in many parts of the world. In addition to food importance, it is a good alternative in biofuel production. The aim of the experiment was to evaluate the response of camelina, the variety Śmiłowska (spring form), to various foliar fertilization. The combined application of three fertilizers had the most positive effect on the tested features and economic result: urea (46% N), magnesium sulfate (16% MgO + 32% SO3), and Plonvit R (multi-component fertilizer). The obtained increase in seed yield after the application of the above variant was 0.54 t ha−1, i.e., 37.5% compared to the control. The remaining fertilization combinations did not have a significant effect on seed yield, which amounted on average to 1.66 t ha−1. The yield of fat and protein amounted to 0.68 t·ha−1 and 0.42 t ha−1, respectively, and was strongly correlated with seed yield. The yielding of the variety Śmiłowska was stable over the years of the study. The combined use of three foliar fertilizers (variant H) increased the SPAD (soil plant analysis development) and LAI (leaf area index) values compared to the control. The application of urea alone reduced crude fat content in the seeds.
Evaluation of the Morphometry of Sperm from the Epididymides of Dogs Using Different Staining Methods
Authors: Wysokińska Anna , Wójcik Ewa , Chłopik Angelika
Published: January 2021

Evaluation of sperm morphometry is an important criterion in the diagnosis of a male animal’s suitability for breeding. The aim of the study was to evaluate the morphometry of sperm from the epididymides of dogs subjected to routine castration using various staining methods. The study was carried out on semen collected from ten healthy dogs. Gonads were obtained from each dog during routine castration at a veterinary surgery. Then, the epididymides (caput, corpus, cauda) were isolated from the gonads, semen was collected from them and microscope slides were prepared. The slides for evaluation of sperm morphometry were prepared by four methods: DiffQuik, SpermBlue, eosin-nigrosin and eosin-gentian. A total of 2400 sperm were analyzed (240 sperm from the dog). The sperm collected from the caput and corpus of the epididymis were found to have larger heads and tails than those collected from the cauda of the epididymis. The staining method was shown to affect the morphometry of sperm taken from the epididymides of dogs. The staining methods differentiate the dimensions of the head of sperm in different parts of the epididymis but do not affect the length of the sperm tail. The occurrence of differences in the head dimensions of sperm may be linked to the use of different fixatives and chemical reagents in the staining procedure. Sperm stained by the EN method had the smallest head and tail dimensions. The greatest head area was noted in the sperm stained by the EG method. In the slides stained by the SB method, the sperm heads were relatively long but narrow. The methods used are suitable for the evaluation of sperm structure, and the possibility of using all four methods enables a full characterization of sperm collected from the caput, corpus and cauda of the epididymides of dogs.
Endocrine Fertility Parameters—Genomic Background and Their Genetic Relationship to Boar Taint in German Landrace and Large White
Authors: Brinke Ines , Große-Brinkhaus Christine , Roth Katharina , Pröll-Cornelissen Maren Julia , Klein Sebastian , Schellander Karl , Tholen Ernst
Published: January 2021

The surgical castration of young male piglets without anesthesia is no longer allowed in Germany from 2021. One alternative is breeding against boar taint, but shared synthesis pathways of androstenone (AND) and several endocrine fertility parameters (EFP) indicate a risk of decreasing fertility. The objective of this study was to investigate the genetic background between AND, skatole (SKA), and six EFP in purebred Landrace (LR) and Large White (LW) populations. The animals were clustered according to their genetic relatedness because of their different origins. Estimated heritabilities (h2) of AND and SKA ranged between 0.52 and 0.34 in LR and LW. For EFP, h2 differed between the breeds except for follicle-stimulating hormone (FSH) (h2: 0.28–0.37). Both of the breeds showed unfavorable relationships between AND and testosterone, 17-β estradiol, and FSH. The genetic relationships (rg) between SKA and EFP differed between the breeds. A genome-wide association analysis revealed 48 significant associations and confirmed a region for SKA on Sus Scrofa chromosome (SSC) 14. For EFP, the results differed between the clusters. In conclusion, rg partly confirmed physiologically expected antagonisms between AND and EFP. Particular attention should be spent on fertility traits that are based on EFP when breeding against boar taint to balance the genetic progress in both of the trait complexes.
Facile In-Situ Fabrication of a Ternary ZnO/TiO2/Ag Nanocomposite for Enhanced Bactericidal and Biocompatibility Properties
Authors: Sakthi Mohan Priyadarshini , Sonsuddin Faridah , Mainal Azizah , Yahya Rosiyah , Venkatraman Gopinath , Vadivelu Jamuna , Al-Farraj Dunia , Al-Mohaimeed Amal , Alarjani Khaloud
Published: January 2021

This paper presents for the first time a successful fabrication of ternary ZnO/TiO2/Ag nanocomposites consisting of zinc oxide (ZnO), titania (TiO2) and silver (Ag) nanoparticles (NPs) synthesised using Morinda citrifolia fruit (MCF) extract. ZnONPs were synthesised using the co-precipitation method, and TiO2 and Ag were introduced into the precursor solutions under microwave irradiation to obtain ZnO/TiO2/Ag nanocomposites (NCs). This material demonstrated enhanced bactericidal effect towards bacterial pathogens compared to that of the binary TiO2/Ag, Ag and TiO2 alone. In vitro cytotoxicity results of the as-synthesised ZnO/TiO2/AgNCs on RAW 264.7 macrophages and A549 cell lines revealed a negative role in cytotoxicity, but contributed astoundingly towards antimicrobials as compared of Ag alone and binary Ag/TiO2. This study shows that the resultant ternary metal/bi-semiconductor nanocomposites may provide a therapeutic strategy for the eradication of bacterial pathogens without affecting the healthy mammalian cells.
Bistable Bacterial Growth Dynamics in the Presence of Antimicrobial Agents
Authors: Frenkel Nelly , Saar Dover Ron , Titon Eve , Shai Yechiel , Rom-Kedar Vered
Published: January 2021

The outcome of an antibiotic treatment on the growth capacity of bacteria is largely dependent on the initial population size (Inoculum Effect). We characterized and built a model of this effect in E. coli cultures using a large variety of antimicrobials, including conventional antibiotics, and for the first time, cationic antimicrobial peptides (CAMPs). Our results show that all classes of antimicrobial drugs induce an inoculum effect, which, as we explain, implies that the dynamic is bistable: For a range of anti-microbial densities, a very small inoculum decays whereas a larger inoculum grows, and the threshold inoculum depends on the drug concentration. We characterized three distinct classes of drug-induced bistable growth dynamics and demonstrate that in rich medium, CAMPs correspond to the simplest class, bacteriostatic antibiotics to the second class, and all other traditional antibiotics to the third, more complex class. These findings provide a unifying universal framework for describing the dynamics of the inoculum effect induced by antimicrobials with inherently different killing mechanisms.
Is the Antimicrobial Activity of Hydrolates Lower than That of Essential Oils?
Authors: Di Vito Maura , Smolka Antonina , Proto Maria Rita , Barbanti Lorenzo , Gelmini Fabrizio , Napoli Edoardo , Bellardi Maria Grazia , Mattarelli Paola , Beretta Giangiacomo , Sanguinetti Maurizio , Bugli Francesca
Published: January 2021

Among the top five human infections requiring medical treatment is dermatitis. Treatment of bacterial and fungal skin infections is usually based on antibiotic therapy, which is often ineffective due to the involvement of antibiotic-resistant microbial strains. The aim of this study was to compare the antimicrobial activity of essential oils (EOs) and hydrolates (Hys) extracted from six aromatic plants grown in Italy (Lavandula angustifolia, Lavandula intermedia, Origanum hirtum, Satureja montana, Monarda didyma, and Monarda fistulosa) towards fungal (Candida albicans, Candida parapsilosis, Candida glabrata and Candida tropicalis; Trichophyton soudanense, Trichophyton tonsurans, Trichophyton rubrum, Trichophyton violaceum and Microsporum canis) and bacterial strains (Staphylococcus aureus MRSA, Staphylococcus aureus MSSA, Streptococcus pyogenes, E. faecalis, Enterococcus faecalis VRE, and Enterococcus faecium) potentially pathogenic for human skin. The composition and antimicrobial activity of EOs and Hys were evaluated using the Gas-chromatography mass spectrometry and micro dilution-broth test, respectively. The volatiles’ conversion factors (CFs) were calculated to compare the activity of Hys with that of the corresponding EOs. Data show that, although the minimum inhibitory concentration values of EOs are lower than the corresponding Hys, the volatiles contained in Hys are more effective at inhibiting microbial growth because they are active at lower concentrations.
Diarylureas: Repositioning from Antitumor to Antimicrobials or Multi-Target Agents against New Pandemics
Authors: Catalano Alessia , Iacopetta Domenico , Pellegrino Michele , Aquaro Stefano , Franchini Carlo , Sinicropi Maria Stefania
Published: January 2021

Antimicrobials have allowed medical advancements over several decades. However, the continuous emergence of antimicrobial resistance restricts efficacy in treating infectious diseases. In this context, the drug repositioning of already known biological active compounds to antimicrobials could represent a useful strategy. In 2002 and 2003, the SARS-CoV pandemic immobilized the Far East regions. However, the drug discovery attempts to study the virus have stopped after the crisis declined. Today’s COVID-19 pandemic could probably have been avoided if those efforts against SARS-CoV had continued. Recently, a new coronavirus variant was identified in the UK. Because of this, the search for safe and potent antimicrobials and antivirals is urgent. Apart from antiviral treatment for severe cases of COVID-19, many patients with mild disease without pneumonia or moderate disease with pneumonia have received different classes of antibiotics. Diarylureas are tyrosine kinase inhibitors well known in the art as anticancer agents, which might be useful tools for a reposition as antimicrobials. The first to come onto the market as anticancer was sorafenib, followed by some other active molecules. For this interesting class of organic compounds antimicrobial, antiviral, antithrombotic, antimalarial, and anti-inflammatory properties have been reported in the literature. These numerous properties make these compounds interesting for a new possible pandemic considering that, as well as for other viral infections also for CoVID-19, a multitarget therapeutic strategy could be favorable. This review is meant to be an overview on diarylureas, focusing on their biological activities, not dwelling on the already known antitumor activity. Quite a lot of papers present in the literature underline and highlight the importance of these molecules as versatile scaffolds for the development of new and promising antimicrobials and multitarget agents against new pandemic events.
Implementation of Antibiotic Stewardship in a University Hospital Setting
Authors: Kolar Milan , Htoutou Sedlakova Miroslava , Urbanek Karel , Mlynarcik Patrik , Roderova Magdalena , Hricova Kristyna , Mezerova Kristyna , Kucova Pavla , Zapletalova Jana , Fiserova Katerina , Kurfurst Pavel
Published: January 2021

The article describes activities of an antibiotic center at a university hospital in the Czech Republic and presents the results of antibiotic stewardship program implementation over a period of 10 years. It provides data on the development of resistance of Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and Staphylococcus aureus to selected antibiotic agents as well as consumption data for various antibiotic classes. The genetic basis of resistance to beta-lactam antibiotics and its clonal spread were also assessed. The study showed significant correlations between aminoglycoside consumption and resistance of Escherichia coli and Klebsiella pneumoniae to gentamicin (r = 0.712, r = 0.869), fluoroquinolone consumption and resistance of Klebsiella pneumoniae to ciprofloxacin (r = 0.896), aminoglycoside consumption and resistance of Pseudomonas aeruginosa to amikacin (r = 0.716), as well as carbapenem consumption and resistance of Pseudomonas aeruginosa to meropenem (r = 0.855). Genotyping of ESBL- positive isolates of Klebsiella pneumoniae and Escherichia coli showed a predominance of CTX-M-type; in AmpC-positive strains, DHA, EBC and CIT enzymes prevailed. Of 19 meropenem-resistant strains of Klebsiella pneumoniae, two were identified as NDM-positive. Clonal spread of these strains was not detected. The results suggest that comprehensive antibiotic stewardship implementation in a healthcare facility may help to maintain the effectiveness of antibiotics against bacterial pathogens. Particularly beneficial is the work of clinical microbiologists who, among other things, approve administration of antibiotics to patients with bacterial infections and directly participate in their antibiotic therapy.
Comprehensive Review of Methodology to Detect Reactive Oxygen Species (ROS) in Mammalian Species and Establish Its Relationship with Antioxidants and Cancer
Authors: Fuloria Shivkanya , Subramaniyan Vetriselvan , Karupiah Sundram , Kumari Usha , Sathasivam Kathiresan , Meenakshi Dhanalekshmi Unnikrishnan , Wu Yuan Seng , Sekar Mahendran , Chitranshi Nitin , Malviya Rishabha , Sudhakar Kalvatala , Bajaj Sakshi , Fuloria Neeraj Kumar
Published: January 2021

Evidence suggests that reactive oxygen species (ROS) mediate tissue homeostasis, cellular signaling, differentiation, and survival. ROS and antioxidants exert both beneficial and harmful effects on cancer. ROS at different concentrations exhibit different functions. This creates necessity to understand the relation between ROS, antioxidants, and cancer, and methods for detection of ROS. This review highlights various sources and types of ROS, their tumorigenic and tumor prevention effects; types of antioxidants, their tumorigenic and tumor prevention effects; and abnormal ROS detoxification in cancer; and methods to measure ROS. We conclude that improving genetic screening methods and bringing higher clarity in determination of enzymatic pathways and scale-up in cancer models profiling, using omics technology, would support in-depth understanding of antioxidant pathways and ROS complexities. Although numerous methods for ROS detection are developing very rapidly, yet further modifications are required to minimize the limitations associated with currently available methods.
Catalytic Antioxidants in the Kidney
Authors: Hong Yu Ah , Park Cheol Whee
Published: January 2021

Reactive oxygen species and reactive nitrogen species are highly implicated in kidney injuries that include acute kidney injury, chronic kidney disease, hypertensive nephropathy, and diabetic nephropathy. Therefore, antioxidant agents are promising therapeutic strategies for kidney diseases. Catalytic antioxidants are defined as small molecular mimics of antioxidant enzymes, such as superoxide dismutase, catalase, and glutathione peroxidase, and some of them function as potent detoxifiers of lipid peroxides and peroxynitrite. Several catalytic antioxidants have been demonstrated to be effective in a variety of in vitro and in vivo disease models that are associated with oxidative stress, including kidney diseases. This review summarizes the evidence for the role of antioxidant enzymes in kidney diseases, the classifications of catalytic antioxidants, and their current applications to kidney diseases.
Oxidised LDL and Anti-Oxidised LDL Antibodies Are Reduced by Lipoprotein Apheresis in a Randomised Controlled Trial on Patients with Refractory Angina and Elevated Lipoprotein(a)
Authors: Khan Tina Z. , Hartley Adam , Haskard Dorian , Caga-Anan Mikhail , Pennell Dudley J. , Collins Peter , Barbir Mahmoud , Khamis Ramzi
Published: January 2021

Aims: An abundance of epidemiological evidence demonstrates that elevated lipoprotein(a) (Lp(a)) represents a significant contributing risk factor towards the development of cardiovascular disease. In particular, raised Lp(a) may play a mechanistic role in patients with refractory angina. Studies have also shown a correlation between oxidised LDL (oxLDL) levels and atherosclerotic burden as well as rates of cardiovascular events. Antibodies against oxLDL (anti-oxLDL) are involved in the removal of oxLDL. Lipoprotein apheresis (LA), which removes lipoproteins using extra-corporeal processes, is an established means of reducing Lp(a), and thereby reduces cardiovascular events. The aim of this study was to investigate the effect of LA on oxLDL and anti-oxLDL levels amongst those with refractory angina in the context of raised Lp(a). Methods: We performed a sub-study within a randomised controlled crossover trial involving 20 patients with refractory angina and raised Lp(a) > 500 mg/L, comparing the effect of three months of blinded weekly LA or sham, followed by crossover to the opposite study arm. We utilized enzyme-linked immunosorbent assays (ELISA) to quantify oxLDL and IgG/ IgM anti-oxLDL antibody levels at baseline and following three months of active LA or sham sessions. Results: Following three months of LA, there was a 30% reduction in oxLDL from 0.37 ± 0.06 to 0.26 ± 0.04 with a mean drop of −0.11 units (U) (95% CI −0.13, −0.09) compared to no significant change with sham therapy (p < 0.0001 between treatment arms). LA also led to a 22% reduction in levels of IgG and IgM anti-oxLDL, again with no significant change demonstrated during sham (p = 0.0036 and p = 0.012, respectively, between treatment arms). Conclusion: Amongst patients with refractory angina in the context of elevated Lp(a), LA significantly lowers levels of oxLDL and anti-oxLDL antibodies, representing potential mechanisms by which LA yields symptomatic and prognostic benefits in this patient cohort.
Pro-Resolving FPR2 Agonists Regulate NADPH Oxidase-Dependent Phosphorylation of HSP27, OSR1, and MARCKS and Activation of the Respective Upstream Kinases
Authors: Ammendola Rosario , Parisi Melania , Esposito Gabriella , Cattaneo Fabio
Published: January 2021

Background: Formyl peptide receptor 2 (FPR2) is involved in the pathogenesis of chronic inflammatory diseases, being activated either by pro-resolving or proinflammatory ligands. FPR2-associated signal transduction pathways result in phosphorylation of several proteins and in NADPH oxidase activation. We, herein, investigated molecular mechanisms underlying phosphorylation of heat shock protein 27 (HSP27), oxidative stress responsive kinase 1 (OSR1), and myristolated alanine-rich C-kinase substrate (MARCKS) elicited by the pro-resolving FPR2 agonists WKYMVm and annexin A1 (ANXA1). Methods: CaLu-6 cells or p22phoxCrispr/Cas9 double nickase CaLu-6 cells were incubated for 5 min with WKYMVm or ANXA1, in the presence or absence of NADPH oxidase inhibitors. Phosphorylation at specific serine residues of HSP27, OSR1, and MARCKS, as well as the respective upstream kinases activated by FPR2 stimulation was analysed. Results: Blockade of NADPH oxidase functions prevents WKYMVm- and ANXA1-induced HSP-27(Ser82), OSR1(Ser339) and MARCKS(Ser170) phosphorylation. Moreover, NADPH oxidase inhibitors prevent WKYMVm- and ANXA1-dependent activation of p38MAPK, PI3K and PKCδ, the kinases upstream to HSP-27, OSR1 and MARCKS, respectively. The same results were obtained in p22phoxCrispr/Cas9 cells. Conclusions: FPR2 shows an immunomodulatory role by regulating proinflammatory and anti-inflammatory activities and NADPH oxidase is a key regulator of inflammatory pathways. The activation of NADPH oxidase-dependent pro-resolving downstream signals suggests that FPR2 signalling and NADPH oxidase could represent novel targets for inflammation therapeutic intervention.
Microdose Lithium Protects against Pancreatic Islet Destruction and Renal Impairment in Streptozotocin-Elicited Diabetes
Authors: Zhang Jiahui , Anshul Fnu , Malhotra Deepak K. , Jaume Juan , Dworkin Lance D. , Gong Rujun
Published: January 2021

Psychiatric use of lithium has been associated with hypoglycemic effects, but its effect on type 1 diabetes mellitus (T1D) is unknown. In streptozotocin (STZ) induced murine models of T1D, microdose lithium therapy improved hyperglycemia, attenuated body weight loss and prevented early signs of diabetic kidney injury. This beneficial effect was associated with preservation of pancreatic islet histology and β-cell production of insulin as well as mitigated oxidative damage of islets. Mechanistically, lithium in islets cells induced inhibitory phosphorylation of glycogen synthase kinase 3β (GSK3β), the major molecular target of lithium that has been recently implicated in non-canonical regulation of Nrf2 activity. In turn, Nrf2 antioxidant response was potentiated in islets, marked by nuclear translocation of Nrf2 and augmented expression of its target antioxidant enzyme heme oxygenase 1 (HO-1). Conversely, cotreatment with trigonelline, a selective blockade of Nrf2, offset the lithium enhanced Nrf2 antioxidant response in islets, blunted the protective effect of lithium on pancreatic islets and β-cells, and abolished the hypoglycemic activity of lithium in STZ-injured mice. Collectively, our findings suggest that microdose lithium confers a protective effect on islet β-cells via targeting the GSK3β-regulated Nrf2 antioxidant response and thereby ameliorates T1D and its related kidney impairment.
An Improved Seismic Vulnerability Assessment Approach for Historical Urban Centres: The Case Study of Campi Alto di Norcia, Italy
Authors: Romis Federico , Caprili Silvia , Salvatore Walter , Ferreira Tiago M. , Lourenço Paulo B.
Published: January 2021

Seismic damage assessment is an extraordinary opportunity to evaluate the reliability of vulnerability and risk methodologies applied to historic masonry buildings, giving the possibility of enhancing and optimising mitigation and retrofit strategies. Vulnerability index methodologies are flexible and powerful tools for assessing seismic vulnerability on the urban scale, providing a first screening of the critical issues present in masonry buildings and a possible priority list for the following retrofit operations. Such approaches account for the buildings’ different structural characteristics, directly or indirectly influencing their seismic behaviour and measured through different weights and classes finally providing a vulnerability index. In this paper, we show the application of three well-known methodologies to Campi Alto di Norcia’s medieval city in Valnerina (Italy) stroke by the earthquakes of 24 August and 30 October 2016. The methodologies’ reliability is assessed, based on the observation of real seismic consequences and damages on the masonry buildings, and an optimised methodology is then proposed for the considered case study.
Deep-Learning-Based Pupil Center Detection and Tracking Technology for Visible-Light Wearable Gaze Tracking Devices
Authors: Ou Wei-Liang , Kuo Tzu-Ling , Chang Chin-Chieh , Fan Chih-Peng
Published: January 2021

In this study, for the application of visible-light wearable eye trackers, a pupil tracking methodology based on deep-learning technology is developed. By applying deep-learning object detection technology based on the You Only Look Once (YOLO) model, the proposed pupil tracking method can effectively estimate and predict the center of the pupil in the visible-light mode. By using the developed YOLOv3-tiny-based model to test the pupil tracking performance, the detection accuracy is as high as 80%, and the recall rate is close to 83%. In addition, the average visible-light pupil tracking errors of the proposed YOLO-based deep-learning design are smaller than 2 pixels for the training mode and 5 pixels for the cross-person test, which are much smaller than those of the previous ellipse fitting design without using deep-learning technology under the same visible-light conditions. After the combination of calibration process, the average gaze tracking errors by the proposed YOLOv3-tiny-based pupil tracking models are smaller than 2.9 and 3.5 degrees at the training and testing modes, respectively, and the proposed visible-light wearable gaze tracking system performs up to 20 frames per second (FPS) on the GPU-based software embedded platform.
Integrating Speculation Detection and Deep Learning to Extract Lung Cancer Diagnosis from Clinical Notes
Authors: Solarte Pabón Oswaldo , Torrente Maria , Provencio Mariano , Rodríguez-Gonzalez Alejandro , Menasalvas Ernestina
Published: January 2021

Despite efforts to develop models for extracting medical concepts from clinical notes, there are still some challenges in particular to be able to relate concepts to dates. The high number of clinical notes written for each single patient, the use of negation, speculation, and different date formats cause ambiguity that has to be solved to reconstruct the patient’s natural history. In this paper, we concentrate on extracting from clinical narratives the cancer diagnosis and relating it to the diagnosis date. To address this challenge, a hybrid approach that combines deep learning-based and rule-based methods is proposed. The approach integrates three steps: (i) lung cancer named entity recognition, (ii) negation and speculation detection, and (iii) relating the cancer diagnosis to a valid date. In particular, we apply the proposed approach to extract the lung cancer diagnosis and its diagnosis date from clinical narratives written in Spanish. Results obtained show an F-score of 90% in the named entity recognition task, and a 89% F-score in the task of relating the cancer diagnosis to the diagnosis date. Our findings suggest that speculation detection is together with negation detection a key component to properly extract cancer diagnosis from clinical notes.
The Use of Microalgae and Cyanobacteria in the Improvement of Agricultural Practices: A Review on Their Biofertilising, Biostimulating and Biopesticide Roles
Authors: Gonçalves Ana L.
Published: January 2021

The increase in worldwide population observed in the last decades has contributed to an increased demand for food supplies, which can only be attained through an improvement in agricultural productivities. Moreover, agricultural practices should become more sustainable, as the use of chemically-based fertilisers, pesticides and growth stimulants can pose serious environmental problems and lead to the scarcity of finite resources, such as phosphorus and potassium, thus increasing the fertilisers’ costs. One possible alternative for the development of a more sustainable and highly effective agriculture is the use of biologically-based compounds with known activity in crops’ nutrition, protection and growth stimulation. Among these products, microalgal and cyanobacterial biomass (or their extracts) are gaining particular attention, due to their undeniable potential as a source of essential nutrients and metabolites with different bioactivities, which can significantly improve crops’ yields. This manuscript highlights the potential of microalgae and cyanobacteria in the improvement of agricultural practices, presenting: (i) how these photosynthetic microorganisms interact with higher plants; (ii) the main bioactive compounds that can be isolated from microalgae and cyanobacteria; and (iii) how microalgae and cyanobacteria can influence plants’ growth at different levels (nutrition, protection and growth stimulation).