bluuebunny/crossref_metadata_2025 huggingface dataset:
Factors Associated with Intention to Receive Vaccination against COVID-19 in Puerto Rico: An Online Survey of Adults
Authors: Melin Kyle , Zhang Cheyu , Zapata Juan P. , Rivera Yonaira M. , Fernandez Katie , Shacham Enbal , Malavé-Rivera Souhail M. , Rodriguez-Diaz Carlos E.
Published: July 2021

We conducted an online survey among adults in Puerto Rico to identify factors associated with the intention to receive vaccination against COVID-19. Sociodemographic variables were analyzed independently for association with intent to receive vaccination. Significant associations were included in the multivariate logistic regression analysis. A total of 1016 responses were available for analysis. In the bivariate analysis, younger age, higher education, pre-COVID-19 employment, male sex, gay/bisexual identity, and single marital status were associated with increased intent to receive the vaccination. In the multivariate logistic regression, younger, male respondents, and those with higher educational attainment reported higher intent to receive the vaccination. Lower-income and living outside the San Juan metro region were associated with lower intent to receive the vaccination. National and international health organizations were identified as the most reliable sources of information, followed by healthcare professionals. These findings highlight the importance of considering sociodemographic characteristics and using trusted sources of information when designing COVID-19 vaccination public messaging.
The Fabric of Aboriginal and Torres Strait Islander Wellbeing: A Conceptual Model
Authors: Garvey Gail , Anderson Kate , Gall Alana , Butler Tamara L. , Whop Lisa J. , Arley Brian , Cunningham Joan , Dickson Michelle , Cass Alan , Ratcliffe Julie , Tong Allison , Howard Kirsten
Published: July 2021

Wellbeing is culturally bound and is shaped by many aspects of life, including experiences, beliefs and values. As such, in order to accurately measure wellbeing for a specific cultural group, it is necessary to understand the experiences, beliefs and values that influence the conception and experience of wellbeing of that group. This paper presents a conceptual model of wellbeing for Aboriginal and Torres Strait Islander people, which was developed from a large national qualitative study that explored the views of 359 Aboriginal and Torres Strait Islander adults. An Aboriginal- and Torres Strait Islander-led research team used an Indigenist research approach to iteratively develop this conceptual model, called the Fabric of Aboriginal and Torres Strait Islander Wellbeing model, which takes inspiration from Aboriginal and Torres Strait Islander weaving traditions whereby individual strands are twined to create fabrics that are both beautiful and strong. This reflects our findings that the parts of life that are most important to wellbeing for many Aboriginal and Torres Strait Islander people are interwoven with their families, communities and culture.
COVID-19 Publications in Family Medicine Journals in 2020: A PubMed-Based Bibliometric Analysis
Authors: Liao Kuang-Yu , Wang Yueh-Hsin , Li Hui-Chun , Chen Tzeng-Ji , Hwang Shinn-Jang
Published: July 2021

Family medicine physicians have been on the front lines of the novel coronavirus disease 2019 (COVID-19) pandemic; however, research and publications in family medicine journals are rarely discussed. In this study, a bibliometric analysis was conducted on COVID-19-related articles published in PubMed-indexed English language family medicine journals in 2020, which recorded the publication date and author’s country and collected citations from Google Scholar. Additionally, we used LitCovid (an open database of COVID-19 literature from PubMed) to determine the content categories of each article and total number of global publications. We found that 33 family medicine journals published 5107 articles in 2020, of which 409 (8.0%) were COVID-19-related articles. Among the article categories, 107 were original articles, accounting for only 26.2% of the articles. In terms of content, the main category was prevention, with 177 articles, accounting for 43.3% of the articles. At the beginning of the epidemic, 10 articles were published in family medicine journals in January 2020, accounting for 11% of all COVID-19-related articles worldwide; however, this accounted for <0.5% of all disciplinary studies in the entire year. Therefore, family medicine journals indeed play a sentinel role, and the intensities and timeliness of COVID-19 publications deserve further investigation.
Water Yield Modelling, Sensitivity Analysis and Validation: A Study for Portugal
Authors: Almeida Bruna , Cabral Pedro
Published: July 2021

The spatially explicit assessment of freshwater is key to introduce the ecosystem services (ES) concept into decision-making processes. Many tools are being developed to model water balance and to analyze the effects of meteorological conditions on water ES behaviors at multiple spatial scales. The current study uses the InVEST Annual Water Yield Model (WYM) to assess water availability in watersheds of the mainland of Portugal. The methodology included sensitivity analysis to test different parameters of the model and validation using the European Environment Agency (EEA) database on the quantity of Europe’s water resources. To evaluate the models’ sensitivity, Pearson’s correlation coefficients and statistical methods were calculated for each simulation. Results at the national level show a correlation coefficient of 0.803 with statistical significance for 0.01 one-tail. Water yield was underestimated by 56.5 mm/ha/year in the North of the country and overestimated by 58.1 mm/ha/year in the South. This difference was explained through the spatial-temporal assessment of the main climatic variables used as input. This study contributes to a methodology to assess the level of confidence in the WYM outputs and can be used to support the trustworthiness of water availability studies, using open-access data and software.
Diabetic Nephropathy and COVID-19: The Potential Role of Immune Actors
Authors: Mourad Diane , Azar Nadim S. , Azar Sami T.
Published: July 2021

Nowadays, type II diabetes mellitus, more specifically ensuing diabetic nephropathy, and severe COVID-19 disease are known to be closely associated. The exact mechanisms behind this association are less known. An implication for the angiotensin-converting enzyme 2 remains controversial. Some researchers have started looking into other potential actors, such as neuropilin-1, mitochondrial glutathione, vitamin D, and DPP4. In particular, neuropilin-1 seems to play an important role in the underlying mechanism linking COVID-19 and diabetic nephropathy. We suggest, based on the findings in this review, that its up-regulation in the diabetic kidney facilitates viral entry in this tissue, and that the engagement of both processes leads to a depletion of neuropilin-1, which was demonstrated to be strongly associated with the pathogenesis of DN. More studies are needed to confirm this hypothesis, and research should be directed towards elucidating the potential roles of all these suggested actors and eventually discovering new therapeutic strategies that could reduce the burden of COVID-19 in patients with diabetic nephropathy.
Exosomes as New Biomarkers and Drug Delivery Tools for the Prevention and Treatment of Various Diseases: Current Perspectives
Authors: Liu Qi , Li Shiying , Dupuy Amandine , Mai Hoa le , Sailliet Nicolas , Logé Cédric , Robert J.-Michel H. , Brouard Sophie
Published: July 2021

Exosomes are nano-sized vesicles secreted by most cells that contain a variety of biological molecules, such as lipids, proteins and nucleic acids. They have been recognized as important mediators for long-distance cell-to-cell communication and are involved in a variety of biological processes. Exosomes have unique advantages, positioning them as highly effective drug delivery tools and providing a distinct means of delivering various therapeutic agents to target cells. In addition, as a new clinical diagnostic biomarker, exosomes play an important role in many aspects of human health and disease, including endocrinology, inflammation, cancer, and cardiovascular disease. In this review, we summarize the development of exosome-based drug delivery tools and the validation of novel biomarkers, and illustrate the role of exosomes as therapeutic targets in the prevention and treatment of various diseases.
Emerging Approaches to Understanding Microvascular Endothelial Heterogeneity: A Roadmap for Developing Anti-Inflammatory Therapeutics
Authors: Yang Qingliang , Wijerathne Harshani , Langston Jordan C. , Kiani Mohammad F. , Kilpatrick Laurie E.
Published: July 2021

The endothelium is the inner layer of all blood vessels and it regulates hemostasis. It also plays an active role in the regulation of the systemic inflammatory response. Systemic inflammatory disease often results in alterations in vascular endothelium barrier function, increased permeability, excessive leukocyte trafficking, and reactive oxygen species production, leading to organ damage. Therapeutics targeting endothelium inflammation are urgently needed, but strong concerns regarding the level of phenotypic heterogeneity of microvascular endothelial cells between different organs and species have been expressed. Microvascular endothelial cell heterogeneity in different organs and organ-specific variations in endothelial cell structure and function are regulated by intrinsic signals that are differentially expressed across organs and species; a result of this is that neutrophil recruitment to discrete organs may be regulated differently. In this review, we will discuss the morphological and functional variations in differently originated microvascular endothelia and discuss how these variances affect systemic function in response to inflammation. We will review emerging in vivo and in vitro models and techniques, including microphysiological devices, proteomics, and RNA sequencing used to study the cellular and molecular heterogeneity of endothelia from different organs. A better understanding of microvascular endothelial cell heterogeneity will provide a roadmap for developing novel therapeutics to target the endothelium.
Characterization of Temperature-Dependent Kinetics of Oculocutaneous Albinism-Causing Mutants of Tyrosinase
Authors: Wachamo Samuel A. , Patel Milan H. , Varghese Paul K. , Dolinska Monika B. , Sergeev Yuri V.
Published: July 2021

Human tyrosinase (Tyr) is a glycoenzyme that catalyzes the first and rate-limiting step in melanin production, and its gene (TYR) is mutated in many cases of oculocutaneous albinism type 1 (OCA1). The mechanisms by which individual mutations contribute to the diverse pigmentation phenotype in patients with OCA1 have only began to be examined and remain to be delineated. Here, we analyze the temperature-dependent kinetics of wild-type Tyr (WT) and two OCA1B mutant variants (R422Q and P406L) using Michaelis–Menten and Van’t Hoff analyses. Recombinant truncated human Tyr proteins (residues 19–469) were produced in the whole insect Trichoplusia Ni larvae. Proteins were purified by a combination of affinity and size-exclusion chromatography. The temperature dependence of diphenol oxidase protein activities and kinetic parameters were measured by dopachrome absorption. Using the same experimental conditions, computational simulations were performed to assess the temperature-dependent association of L-DOPA and Tyr. Our results revealed, for the first time, that the association of L-DOPA with R422Q and P406L followed by dopachrome formation is a complex reaction supported by enthalpy and entropy forces. We show that the WT has a higher turnover number as compared with both R422Q and P406L. Elucidating the kinetics and thermodynamics of mutant variants of Tyr in OCA1B helps to understand the mechanisms by which they lower Tyr catalytic activity and to discover novel therapies for patients.
Diabetes Mellitus and Cardiovascular Diseases: Nutraceutical Interventions Related to Caloric Restriction
Authors: Senesi Pamela , Ferrulli Anna , Luzi Livio , Terruzzi Ileana
Published: July 2021

Type 2 diabetes (T2DM) and cardiovascular disease (CVD) are closely associated and represent a key public health problem worldwide. An excess of adipose tissue, NAFLD, and gut dysbiosis establish a vicious circle that leads to chronic inflammation and oxidative stress. Caloric restriction (CR) is the most promising nutritional approach capable of improving cardiometabolic health. However, adherence to CR represents a barrier to patients and is the primary cause of therapeutic failure. To overcome this problem, many different nutraceutical strategies have been designed. Based on several data that have shown that CR action is mediated by AMPK/SIRT1 activation, several nutraceutical compounds capable of activating AMPK/SIRT1 signaling have been identified. In this review, we summarize recent data on the possible role of berberine, resveratrol, quercetin, and L-carnitine as CR-related nutrients. Additionally, we discuss the limitations related to the use of these nutrients in the management of T2DM and CVD.
Morphometric and Nanomechanical Features of Platelets from Women with Early Pregnancy Loss Provide New Evidence of the Impact of Inherited Thrombophilia
Authors: Andreeva Tonya , Komsa-Penkova Regina , Langari Ariana , Krumova Sashka , Golemanov Georgi , Georgieva Galya B. , Taneva Stefka G. , Giosheva Ina , Mihaylova Nikolina , Tchorbanov Andrey , Todinova Svetla
Published: July 2021

Pregnancy is associated with hypercoagulation states and increased thrombotic risk, especially in women with thrombophilia. We combine atomic force microscopy (AFM) and flow cytometry to examine the morphology and nanomechanics of platelets derived from women with early pregnancy loss (EPL) and control pregnant (CP) and non-pregnant (CNP) women. Both control groups exhibit similar morphometric parameters (height and surface roughness) and membrane stiffness of platelets. EPL patients’ platelets, on the other hand, are more activated than the control groups, with prominent cytoskeletal rearrangement. In particular, reduced membrane roughness (22.9 ± 6 nm vs. 39.1 ± 8 nm) (p < 0.05) and height (692 ± 128 nm vs. 1090 ± 131 nm) (p < 0.05), strong alteration in the membrane Young modulus, increased production of platelets’ microparticles, and higher expression of procoagulant surface markers, as well as increased occurrence of thrombophilia (FVL, FII20210A, PLA1/A2, MTHFR C677T or 4G/5G PAI-1) polymorphisms were found. We suggest that the carriage of thrombophilic mutations triggers structural and nanomechanical abnormalities in platelets, resulting in their increased activation. The activation state of platelets can be well characterized by AFM, and the morphometric and nanomechanical characteristics might serve as a new criterion for evaluation of the cause of miscarriage and offer the prospect of an innovative approach serving for diagnostic purposes.
Diverse Functions of Tim50, a Component of the Mitochondrial Inner Membrane Protein Translocase
Authors: Chaudhuri Minu , Tripathi Anuj , Gonzalez Fidel Soto
Published: July 2021

Mitochondria are essential in eukaryotes. Besides producing 80% of total cellular ATP, mitochondria are involved in various cellular functions such as apoptosis, inflammation, innate immunity, stress tolerance, and Ca2+ homeostasis. Mitochondria are also the site for many critical metabolic pathways and are integrated into the signaling network to maintain cellular homeostasis under stress. Mitochondria require hundreds of proteins to perform all these functions. Since the mitochondrial genome only encodes a handful of proteins, most mitochondrial proteins are imported from the cytosol via receptor/translocase complexes on the mitochondrial outer and inner membranes known as TOMs and TIMs. Many of the subunits of these protein complexes are essential for cell survival in model yeast and other unicellular eukaryotes. Defects in the mitochondrial import machineries are also associated with various metabolic, developmental, and neurodegenerative disorders in multicellular organisms. In addition to their canonical functions, these protein translocases also help maintain mitochondrial structure and dynamics, lipid metabolism, and stress response. This review focuses on the role of Tim50, the receptor component of one of the TIM complexes, in different cellular functions, with an emphasis on the Tim50 homologue in parasitic protozoan Trypanosoma brucei.
Glucose Variability: How Does It Work?
Authors: Klimontov Vadim V. , Saik Olga V. , Korbut Anton I.
Published: July 2021

A growing body of evidence points to the role of glucose variability (GV) in the development of the microvascular and macrovascular complications of diabetes. In this review, we summarize data on GV-induced biochemical, cellular and molecular events involved in the pathogenesis of diabetic complications. Current data indicate that the deteriorating effect of GV on target organs can be realized through oxidative stress, glycation, chronic low-grade inflammation, endothelial dysfunction, platelet activation, impaired angiogenesis and renal fibrosis. The effects of GV on oxidative stress, inflammation, endothelial dysfunction and hypercoagulability could be aggravated by hypoglycemia, associated with high GV. Oscillating hyperglycemia contributes to beta cell dysfunction, which leads to a further increase in GV and completes the vicious circle. In cells, the GV-induced cytotoxic effect includes mitochondrial dysfunction, endoplasmic reticulum stress and disturbances in autophagic flux, which are accompanied by reduced viability, activation of apoptosis and abnormalities in cell proliferation. These effects are realized through the up- and down-regulation of a large number of genes and the activity of signaling pathways such as PI3K/Akt, NF-κB, MAPK (ERK), JNK and TGF-β/Smad. Epigenetic modifications mediate the postponed effects of glucose fluctuations. The multiple deteriorative effects of GV provide further support for considering it as a therapeutic target in diabetes.
Single Nucleotide Polymorphism Induces Divergent Dynamic Patterns in CYP3A5: A Microsecond Scale Biomolecular Simulation of Variants Identified in Sub-Saharan African Populations
Authors: Othman Houcemeddine , da Rocha Jorge E. B. , Hazelhurst Scott
Published: July 2021

Pharmacogenomics aims to reveal variants associated with drug response phenotypes. Genes whose roles involve the absorption, distribution, metabolism, and excretion of drugs, are highly polymorphic between populations. High coverage whole genome sequencing showed that a large proportion of the variants for these genes are rare in African populations. This study investigated the impact of such variants on protein structure to assess their functional importance. We used genetic data of CYP3A5 from 458 individuals from sub-Saharan Africa to conduct a structural bioinformatics analysis. Five missense variants were modeled and microsecond scale molecular dynamics simulations were conducted for each, as well as for the CYP3A5 wildtype and the Y53C variant, which has a known deleterious impact on enzyme activity. The binding of ritonavir and artemether to CYP3A5 variant structures was also evaluated. Our results showed different conformational characteristics between all the variants. No significant structural changes were noticed. However, the genetic variability seemed to act on the plasticity of the protein. The impact on drug binding might be drug dependant. We concluded that rare variants hold relevance in determining the pharmacogenomics properties of populations. This could have a significant impact on precision medicine applications in sub-Saharan Africa.
Improving Consistency of Photobiomodulation Therapy: A Novel Flat-Top Beam Hand-Piece versus Standard Gaussian Probes on Mitochondrial Activity
Authors: Amaroli Andrea , Arany Praveen , Pasquale Claudio , Benedicenti Stefano , Bosco Alessandro , Ravera Silvia
Published: July 2021

The tremendous therapeutic potential of photobiomodulation therapy in different branches of medicine has been described in the literature. One of the molecular mechanisms for this treatment implicates the mitochondrial enzyme, cytochrome C oxidase. However, the efficacy and consistency of clinical outcomes with photobiomodulation treatments has been fiercely debated. This work was motivated by this need to improve photobiomodulation devices and delivery approaches. We designed a novel hand-piece with a flat-top beam profile of irradiation. We compared the beam profile versus a standard hand-piece and a fibre probe. We utilized isolated mitochondria and performed treatments at various spots within the beam, namely, the centre, left and right edge. We examined mitochondrial activity by assessing ATP synthesis with the luciferin/luciferase chemiluminescent method as a primary endpoint, while mitochondrial damage was assessed as the secondary endpoint. We observed a uniform distribution of the power density with the flat-top prototype compared to a wide Gaussian beam profile with the standard fibre and standard hand-piece. We noted increased production of ATP in the centre of all three beams with respect to the non-treated controls (p < 0.05). Both the fibre and standard hand-piece demonstrated less increase in ATP synthesis at the edges than the centre (p < 0.05). In contrast, ATP synthesis was increased homogenously in the flat-top handpiece, both in the centre and the edges of the beam. Fibre, standard hand-piece and the flat-top hand-piece prototype have discrete beam distribution characteristics. This significantly affected the mitochondrial activity with respect to their position within the treated areas. Flat-top hand-piece enhances the uniformity of photobiomodulation treatments and can improve the rigour and reproducibility of PBM clinical outcomes.
Mechanistic Insights of Aberrant Splicing with Splicing Factor Mutations Found in Myelodysplastic Syndromes
Authors: Kataoka Naoyuki , Matsumoto Eri , Masaki So
Published: July 2021

Pre-mRNA splicing is an essential process for gene expression in higher eukaryotes, which requires a high order of accuracy. Mutations in splicing factors or regulatory elements in pre-mRNAs often result in many human diseases. Myelodysplastic syndrome (MDS) is a heterogeneous group of chronic myeloid neoplasms characterized by many symptoms and a high risk of progression to acute myeloid leukemia. Recent findings indicate that mutations in splicing factors represent a novel class of driver mutations in human cancers and affect about 50% of Myelodysplastic syndrome (MDS) patients. Somatic mutations in MDS patients are frequently found in genes SF3B1, SRSF2, U2AF1, and ZRSR2. Interestingly, they are involved in the recognition of 3′ splice sites and exons. It has been reported that mutations in these splicing regulators result in aberrant splicing of many genes. In this review article, we first describe molecular mechanism of pre-mRNA splicing as an introduction and mainly focus on those four splicing factors to describe their mutations and their associated aberrant splicing patterns.
The Neurotrophin Receptor TrkC as a Novel Molecular Target of the Antineuroblastoma Action of Valproic Acid
Authors: Dedoni Simona , Marras Luisa , Olianas Maria C. , Ingianni Angela , Onali Pierluigi
Published: July 2021

Neurotrophins and their receptors are relevant factors in controlling neuroblastoma growth and progression. The histone deacetylase (HDAC) inhibitor valproic acid (VPA) has been shown to downregulate TrkB and upregulate the p75NTR/sortilin receptor complex. In the present study, we investigated the VPA effect on the expression of the neurotrophin-3 (NT-3) receptor TrkC, a favorable prognostic marker of neuroblastoma. We found that VPA induced the expression of both full-length and truncated (TrkC-T1) isoforms of TrkC in human neuroblastoma cell lines without (SH-SY5Y) and with (Kelly, BE(2)-C and IMR 32) MYCN amplification. VPA enhanced cell surface expression of the receptor and increased Akt and ERK1/2 activation by NT-3. The HDAC inhibitors entinostat, romidepsin and vorinostat also increased TrkC in SH-SY5Y, Kelly and BE(2)-C but not IMR 32 cells. TrkC upregulation by VPA involved induction of RUNX3, stimulation of ERK1/2 and JNK, and ERK1/2-mediated Egr1 expression. In SH-SY5Y cell monolayers and spheroids the exposure to NT-3 enhanced the apoptotic cascade triggered by VPA. Gene silencing of both TrkC-T1 and p75NTR prevented the NT-3 proapoptotic effect. Moreover, NT-3 enhanced p75NTR/TrkC-T1 co-immunoprecipitation. The results indicate that VPA upregulates TrkC by activating epigenetic mechanisms and signaling pathways, and sensitizes neuroblastoma cells to NT-3-induced apoptosis.
Sucrose Metabolism and Transport in Grapevines, with Emphasis on Berries and Leaves, and Insights Gained from a Cross-Species Comparison
Authors: Walker Robert P. , Bonghi Claudio , Varotto Serena , Battistelli Alberto , Burbidge Crista A. , Castellarin Simone D. , Chen Zhi-Hui , Darriet Philippe , Moscatello Stefano , Rienth Markus , Sweetman Crystal , Famiani Franco
Published: July 2021

In grapevines, as in other plants, sucrose and its constituents glucose and fructose are fundamentally important and carry out a multitude of roles. The aims of this review are three-fold. First, to provide a summary of the metabolism and transport of sucrose in grapevines, together with new insights and interpretations. Second, to stress the importance of considering the compartmentation of metabolism. Third, to outline the key role of acid invertase in osmoregulation associated with sucrose metabolism and transport in plants.
Expression Silencing of Glutathione Peroxidase 4 in Mouse Erythroleukemia Cells Delays In Vitro Erythropoiesis
Authors: Rademacher Marlena , Kuhn Hartmut , Borchert Astrid
Published: July 2021

Among the eight human glutathione peroxidase isoforms, glutathione peroxidase 4 (GPX4) is the only enzyme capable of reducing complex lipid peroxides to the corresponding alcohols. In mice, corruption of the Gpx4 gene leads to embryonic lethality and more detailed expression silencing studies have implicated the enzyme in several physiological processes (e.g., embryonal cerebrogenesis, neuronal function, male fertility). Experiments with conditional knockout mice, in which expression of the Gpx4 gene was silenced in erythroid precursors, indicated a role of Gpx4 in erythropoiesis. To test this hypothesis in a cellular in vitro model we transfected mouse erythroleukemia cells with a Gpx4 siRNA construct and followed the expression kinetics of erythropoietic gene products. Our data indicate that Gpx4 is expressed at high levels in mouse erythroleukemia cells and that expression silencing of the Gpx4 gene delays in vitro erythropoiesis. However, heterozygous expression of a catalytically inactive Gpx4 mutant (Gpx4+/Sec46Ala) did not induce a defective erythropoietic phenotype in different in vivo and ex vivo models. These data suggest that Gpx4 plays a role in erythroid differentiation of mouse erythroleukemia cells but that heterozygous expression of a catalytically inactive Gpx4 is not sufficient to compromise in vivo and ex vivo erythropoiesis.
Mechanisms of the Cytotoxic Effect of Selenium Nanoparticles in Different Human Cancer Cell Lines
Authors: Varlamova Elena G. , Goltyaev Mikhail V. , Mal’tseva Valentina N. , Turovsky Egor A. , Sarimov Ruslan M. , Simakin Alexander V. , Gudkov Sergey V.
Published: July 2021

In recent decades, studies on the functional features of Se nanoparticles (SeNP) have gained great popularity due to their high biocompatibility, stability, and pronounced selectivity. A large number of works prove the anticarcinogenic effect of SeNP. In this work, the molecular mechanisms regulating the cytotoxic effects of SeNP, obtained by laser ablation, were studied by the example of four human cancer cell lines: A-172 (glioblastoma), Caco-2, (colorectal adenocarcinoma), DU-145 (prostate carcinoma), MCF-7 (breast adenocarcinoma). It was found that SeNP had different concentration-dependent effects on cancer cells of the four studied human lines. SeNP at concentrations of less than 1 μg/mL had no cytotoxic effect on the studied cancer cells, with the exception of the A-172 cell line, for which 0.5 μg/mL SeNP was the minimum concentration affecting its metabolic activity. It was shown that SeNP concentration-dependently caused cancer cell apoptosis, but not necrosis. In addition, it was found that SeNP enhanced the expression of pro-apoptotic genes in almost all cancer cell lines, with the exception of Caco-2 and activated various pathways of adaptive and pro-apoptotic signaling pathways of UPR. Different effects of SeNP on the expression of ER-resident selenoproteins and selenium-containing glutathione peroxidases and thioredoxin reductases, depending on the cell line, were established. In addition, SeNP triggered Ca2+ signals in all investigated cancer cell lines. Different sensitivity of cancer cell lines to SeNP can determine the induction of the process of apoptosis in them through regulation of the Ca2+ signaling system, mechanisms of ER stress, and activation of various expression patterns of genes encoding pro-apoptotic proteins.
Novel N-Substituted Amino Acid Hydrazone-Isatin Derivatives: Synthesis, Antioxidant Activity, and Anticancer Activity in 2D and 3D Models In Vitro
Authors: Tumosienė Ingrida , Jonuškienė Ilona , Kantminienė Kristina , Mickevičius Vytautas , Petrikaitė Vilma
Published: July 2021

A series of novel mono and bishydrazones each bearing a 2-oxindole moiety along with substituted phenylaminopropanamide, pyrrolidin-2-one, benzimidazole, diphenylmethane, or diphenylamine fragments were synthesized, and their anticancer activities were tested by MTT assay against human melanoma A375 and colon adenocarcinoma HT-29 cell lines. In general, the synthesized compounds were more cytotoxic against HT-29 than A375. 3-((4-Methoxyphenyl)(3-oxo-3-(2-(2-oxoindolin-3-ylidene)hydrazinyl)propyl)amino)-N′-(2-oxoindolin-3-ylidene)propanehydrazide and (N′,N‴)-1,1′-(methylenebis(4,1-phenylene))bis(5-oxo-N′-(2-oxoindolin-3-ylidene)pyrrolidine-3-carbohydrazide) were identified as the most active compounds against HT-29 in 2D and 3D cell cultures. The same compounds showed the highest antioxidant activity among the synthesized compounds screened by ferric reducing antioxidant power assay (FRAP). Their antioxidant activity is on par with that of a well-known antioxidant ascorbic acid.
Hepatocellular Carcinoma Immunotherapy and the Potential Influence of Gut Microbiome
Authors: Temraz Sally , Nassar Farah , Kreidieh Firas , Mukherji Deborah , Shamseddine Ali , Nasr Rihab
Published: July 2021

Disruptions in the human gut microbiome have been associated with a cycle of hepatocyte injury and regeneration characteristic of chronic liver disease. Evidence suggests that the gut microbiota can promote the development of hepatocellular carcinoma through the persistence of this inflammation by inducing genetic and epigenetic changes leading to cancer. As the gut microbiome is known for its effect on host metabolism and immune response, it comes as no surprise that the gut microbiome may have a role in the response to therapeutic strategies such as immunotherapy and chemotherapy for liver cancer. Gut microbiota may influence the efficacy of immunotherapy by regulating the responses to immune checkpoint inhibitors in patients with hepatocellular carcinoma. Here, we review the mechanisms by which gut microbiota influences hepatic carcinogenesis, the immune checkpoint inhibitors currently being used to treat hepatocellular carcinoma, as well as summarize the current findings to support the potential critical role of gut microbiome in hepatocellular carcinoma (HCC) immunotherapy.
Directed Recovery and Molecular Characterization of Antibiotic Resistance Plasmids from Cheese Bacteria
Authors: Flórez Ana Belén , Vázquez Lucía , Rodríguez Javier , Mayo Baltasar
Published: July 2021

Resistance to antimicrobials is a growing problem of worldwide concern. Plasmids are thought to be major drivers of antibiotic resistance spread. The present work reports a simple way to recover replicative plasmids conferring antibiotic resistance from the bacteria in cheese. Purified plasmid DNA from colonies grown in the presence of tetracycline and erythromycin was introduced into plasmid-free strains of Lactococcus lactis, Lactiplantibacillus plantarum and Lacticaseibacillus casei. Following antibiotic selection, the plasmids from resistant transformants were isolated, analyzed by restriction enzyme digestion, and sequenced. Seven patterns were obtained for the tetracycline-resistant colonies, five from L. lactis, and one each from the lactobacilli strains, as well as a single digestion profile for the erythromycin-resistant transformants obtained in L. lactis. Sequence analysis respectively identified tet(S) and ermB in the tetracycline- and erythromycin-resistance plasmids from L. lactis. No dedicated resistance genes were detected in plasmids conferring tetracycline resistance to L. casei and L. plantarum. The present results highlight the usefulness of the proposed methodology for isolating functional plasmids that confer antibiotic resistance to LAB species, widen our knowledge of antibiotic resistance in the bacteria that inhabit cheese, and emphasize the leading role of plasmids in the spread of resistance genes via the food chain.
Skin Wound Healing Rate in Fish Depends on Species and Microbiota
Authors: Yun Tery , Shin Soeun , Bang Kyungwon , Lee Mugeun , Cho Jung-Ah , Baek Myungin
Published: July 2021

The skin is a barrier between the body and the environment that protects the integrity of the body and houses a vast microbiota. By interacting with the host immune system, the microbiota improves wound healing in mammals. However, in fish, the evidence of the role of microbiota and the type of species on wound healing is scarce. We aimed to examine the wound healing rate in various fish species and evaluate the effect of antibiotics on the wound healing process. The wound healing rate was much faster in two of the seven fish species selected based on habitat and skin types. We also demonstrated that the composition of the microbiome plays a role in the wound healing rate. After antibiotic treatment, the wound healing rate improved in one species. Through 16S rRNA sequencing, we identified microbiome correlates of varying responses on wound healing after antibiotic treatment. These findings indicate that not only the species difference but also the microbiota play a significant role in wound healing in fish.
Invadopodia Structure in 3D Environment Resolved by Near-Infrared Branding Protocol Combining Correlative Confocal and FIB-SEM Microscopy
Authors: Dalecká Markéta , Sabó Ján , Backová Lenka , Rösel Daniel , Brábek Jan , Benda Aleš , Tolde Ondřej
Published: July 2021

Cancer cell invasion through tissue barriers is the intrinsic feature of metastasis, the most life-threatening aspect of cancer. Detailed observation and analysis of cancer cell behaviour in a 3D environment is essential for a full understanding of the mechanisms of cancer cell invasion. The inherent limits of optical microscopy resolution do not allow to for in-depth observation of intracellular structures, such as invadopodia of invading cancer cells. The required resolution can be achieved using electron microscopy techniques such as FIB-SEM. However, visualising cells in a 3D matrix using FIB-SEM is challenging due to difficulties with localisation of a specific cell deep within the resin block. We have developed a new protocol based on the near-infrared branding (NIRB) procedure that extends the pattern from the surface grid deep inside the resin. This 3D burned pattern allows for precise trimming followed by targeted 3D FIB-SEM. Here we present detailed 3D CLEM results combining confocal and FIB-SEM imaging of cancer cell invadopodia that extend deep into the collagen meshwork.
Chronic Myeloid Leukemia in Children and Adolescents: The Achilles Heel of Oncogenesis and Tyrosine Kinase Inhibitors
Authors: Moschovi Maria , Kelaidi Charikleia
Published: July 2021

Chronic myeloid leukemia (CML) is a rare disease in children and adolescents [...]
Learning from High-Dimensional and Class-Imbalanced Datasets Using Random Forests
Authors: Pes Barbara
Published: July 2021

Class imbalance and high dimensionality are two major issues in several real-life applications, e.g., in the fields of bioinformatics, text mining and image classification. However, while both issues have been extensively studied in the machine learning community, they have mostly been treated separately, and little research has been thus far conducted on which approaches might be best suited to deal with datasets that are class-imbalanced and high-dimensional at the same time (i.e., with a large number of features). This work attempts to give a contribution to this challenging research area by studying the effectiveness of hybrid learning strategies that involve the integration of feature selection techniques, to reduce the data dimensionality, with proper methods that cope with the adverse effects of class imbalance (in particular, data balancing and cost-sensitive methods are considered). Extensive experiments have been carried out across datasets from different domains, leveraging a well-known classifier, the Random Forest, which has proven to be effective in high-dimensional spaces and has also been successfully applied to imbalanced tasks. Our results give evidence of the benefits of such a hybrid approach, when compared to using only feature selection or imbalance learning methods alone.
The Latent Digital Divide and Its Drivers in E-Learning among Bangladeshi Students during the COVID-19 Pandemic
Authors: Badiuzzaman Md , Rafiquzzaman Md. , Rabby Md Insiat Islam , Rahman Mohammad Mustaneer
Published: July 2021

The devastating COVID-19 pandemic forced academia to go virtual. Educational institutions around the world have stressed online learning programs in the aftermath of the pandemic. However, because of insufficient access to Information Communication Technology (ICT), a substantial number of students failed to harness the opportunity of online learning. This study explores the latent digital divide exhibited during the COVID-19 pandemic while online learning activities are emphasised among students of Bangladesh. It also investigates the digital divide exposure and the significant underlying drivers of the divide. In order to accomplish this, a cross-sectional survey was employed to collect quantitative data, mixed with open-ended questions were utilised to gather qualitative information from the student community. The findings revealed that despite the majority of students having physical access to ICT, only 32.5% of students could attend online classes seamlessly. In total, 34.1% reported data prices as the critical barrier, while 39.8% identified poor network infrastructure as the significant barrier preventing them from participating in online learning activities. Although most students possess physical access to various devices and the Internet, they face the first-level digital divide due to the quality of access and price of cellular Internet. Consequently, they fail to take advantage of physical access, resulting in the third-level digital divide (utility gap), which submerges them into a digital divide cycle. The primary objective of this study is to explore the underlying issues of the digital divide among Bangladeshi students. This will assist relevant stakeholders (e.g., the Bangladesh government, educational institutions, and researchers) to gain necessary insights and theoretical understanding of underlying limitations and emergent directions to arrange adequate support for underprivileged students to undertake essential online learning activities.
Susceptibility to Acaricides and the Frequencies of Point Mutations in Etoxazole- and Pyridaben-Resistant Strains and Field Populations of the Two-Spotted Spider Mite, Tetranychus urticae (Acari: Tetranychidae)
Authors: Koo Hyun-Na , Choi Jihye , Shin Eungyeong , Kang Wonjin , Cho Sun-Ran , Kim Hyunkyung , Park Bueyong , Kim Gil-Hah
Published: July 2021

The two-spotted spider mite Tetranychus urticae Koch is a major agricultural pest worldwide and is known to rapidly develop resistance to pesticides. In the present study, we explored a field strain that was collected in 2000 and 2003 and has been exhibiting resistance to etoxazole and pyridaben over the last 16 years. The resistance ratios of the etoxazole- and pyridaben-resistant strains (ER and PR) to etoxazole or pyridaben were more than 5,000,000- and 4109.6-fold higher than that of the susceptible strain, respectively. All field-collected populations showed resistance to etoxazole and pyridaben. The ER and PR strains showed cross-resistance to several acaricides. Both I1017F and H92R point mutations were detected in 7 out of 8 field groups. Spirodiclofen and spiromesifen resulted in more than 77.5% mortality in the 8 field groups. In addition, the genotype frequency of the I1017F point mutation was 100.0% in the ER strain, and that of the H92R point mutation was 97.0% in the PR strain. All of the field populations were found to have a high frequency of I1017F. These results suggest that the observation of resistance patterns will help in designing a sustainable IPM program for T. urticae.
Importance of Lung Ultrasound Follow-Up in Patients Who Had Recovered from Coronavirus Disease 2019: Results from a Prospective Study
Authors: Hernández-Píriz Alba , Tung-Chen Yale , Jiménez-Virumbrales David , Ayala-Larrañaga Ibone , Barba-Martín Raquel , Canora-Lebrato Jesús , Zapatero-Gaviria Antonio , Casasola-Sánchez Gonzalo García De
Published: July 2021

There is growing evidence regarding the imaging findings of coronavirus disease 2019 (COVID-19) in lung ultrasounds, however, their role in predicting the prognosis has yet to be explored. Our objective was to assess the usefulness of lung ultrasound in the short-term follow-up (1 and 3 months) of patients with SARS-CoV-2 pneumonia, and to describe the progression of the most relevant lung ultrasound findings. We conducted a prospective, longitudinal and observational study performed in patients with confirmed COVID-19 who underwent a lung ultrasound examination during hospitalization and repeated it 1 and 3 months after hospital discharge. A total of 96 patients were enrolled. In the initial ultrasound, bilateral involvement was present in 100% of the patients with mild, moderate or severe ARDS. The most affected lung area was the posteroinferior (93.8%) followed by the lateral (88.7%). Subpleural consolidations were present in 68% of the patients and consolidations larger than 1 cm in 24%. One month after the initial study, only 20.8% had complete resolution on lung ultrasound. This percentage rose to 68.7% at 3 months. Residual lesions were observed in a significant percentage of patients who recovered from moderate or severe ARDS (32.4% and 61.5%, respectively). In conclusion, lung injury associated with COVID-19 might take time to resolve. The findings in this report support the use of lung ultrasound in the short-term follow-up of patients recovered from COVID-19, as a radiation-sparing, easy to use, novel care path worth exploring.
The Paradoxical Effect Hypothesis of Abused Drugs in a Rat Model of Chronic Morphine Administration
Authors: Yu Yinghao , He Alan Bohan , Liou Michelle , Ou Chenyin , Kozłowska Anna , Chen Pingwen , Huang Andrew Chihwei
Published: July 2021

A growing body of studies has recently shown that abused drugs could simultaneously induce the paradoxical effect in reward and aversion to influence drug addiction. However, whether morphine induces reward and aversion, and which neural substrates are involved in morphine’s reward and aversion remains unclear. The present study first examined which doses of morphine can simultaneously produce reward in conditioned place preference (CPP) and aversion in conditioned taste aversion (CTA) in rats. Furthermore, the aversive dose of morphine was determined. Moreover, using the aversive dose of 10 mg/kg morphine tested plasma corticosterone (CORT) levels and examined which neural substrates were involved in the aversive morphine-induced CTA on conditioning, extinction, and reinstatement. Further, we analyzed c-Fos and p-ERK expression to demonstrate the paradoxical effect—reward and aversion and nonhomeostasis or disturbance by morphine-induced CTA. The results showed that a dose of more than 20 mg/kg morphine simultaneously induced reward in CPP and aversion in CTA. A dose of 10 mg/kg morphine only induced the aversive CTA, and it produced higher plasma CORT levels in conditioning and reacquisition but not extinction. High plasma CORT secretions by 10 mg/kg morphine-induced CTA most likely resulted from stress-related aversion but were not a rewarding property of morphine. For assessments of c-Fos and p-ERK expression, the cingulate cortex 1 (Cg1), prelimbic cortex (PrL), infralimbic cortex (IL), basolateral amygdala (BLA), nucleus accumbens (NAc), and dentate gyrus (DG) were involved in the morphine-induced CTA, and resulted from the aversive effect of morphine on conditioning and reinstatement. The c-Fos data showed fewer neural substrates (e.g., PrL, IL, and LH) on extinction to be hyperactive. In the context of previous drug addiction data, the evidence suggests that morphine injections may induce hyperactivity in many neural substrates, which mediate reward and/or aversion due to disturbance and nonhomeostasis in the brain. The results support the paradoxical effect hypothesis of abused drugs. Insight from the findings could be used in the clinical treatment of drug addiction.
Estimated Incidence of Sugammadex-Induced Anaphylaxis Using the Korea Adverse Event Reporting System Database
Authors: Ju Jae-Woo , Kim Nayoung , Yang Seong Mi , Kim Won Ho , Lee Ho-Jin
Published: July 2021

We aimed to investigate the incidence of sugammadex-induced anaphylaxis in a large Korean population. We retrospectively investigated the incidence of sugammadex-induced anaphylaxis between 2013 and 2019 from the database of the Korea Institute of Drug Safety-Risk Management-Korea Adverse Event Reporting System (KIDS-KAERS). We estimated the incidence of sugammadex-induced anaphylaxis from the KIDS-KAERS database, assuming that the reporting efficiency was 10%, 50%, and 100%, respectively. We also investigated its annual sales volume in Korea and assumed that the exposure to sugammadex was 95% of the estimated sales volume. During the study period, 1,401,630 sugammadex vials were sold, and 19 cases of sugammadex-induced anaphylaxis were identified in the KIDS-KAERS database. The estimated incidence of sugammadex-induced anaphylaxis was 0.0143%, 0.00279%, and 0.0014%, assuming a reporting efficiency of 10%, 50%, and 100%, respectively. All patients, except for one with a missing record, fully recovered after anaphylaxis. The incidence of sugammadex-induced anaphylaxis identified in the national pharmacovigilance database was lower than previously reported rates in other countries. Therefore, its use in general anesthesia should not be hindered by concerns about the resulting risk of anaphylaxis in Korea.