bluuebunny/crossref_metadata_2025 huggingface dataset:
Physical Exercise as a Multimodal Tool for COVID-19: Could It Be Used as a Preventive Strategy?
Authors: Fernández-Lázaro Diego , González-Bernal Jerónimo J. , Sánchez-Serrano Nerea , Navascués Lourdes Jiménez , Ascaso-del-Río Ana , Mielgo-Ayuso Juan
Published: November 2020

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or coronavirus disease 2019 (COVID-19) is a novel coronavirus not previously recognized in humans until late 2019. On 31 December 2019, a cluster of cases of pneumonia of unspecified etiology was reported to the World Health Organization in China. The availability of adequate SARS-CoV-2 drugs is also limited, and the efficacy and safety of these drugs for COVID-2019 pneumonia patients need to be assessed by further clinical trials. For these reasons, there is a need for other strategies against COVID-19 that are capable of prevention and treatment. Physical exercise has proven to be an effective therapy for most chronic diseases and microbial infections with preventive/therapeutic benefits, considering that exercise involves primary immunological mediators and/or anti-inflammatory properties. This review aimed to provide an insight into how the implementation of a physical exercise program against COVID-19 may be a useful complementary tool for prevention, which can also enhance recovery, improve quality of life, and provide immune protection against SARS-CoV-2 virus infection in the long term. In summary, physical exercise training exerts immunomodulatory effects, controls the viral gateway, modulates inflammation, stimulates nitric oxide synthesis pathways, and establishes control over oxidative stress.
RoMoMatteR: Empowering Roma Girls’ Mattering through Reproductive Justice
Authors: Garcia-Ramirez Manuel , Soto-Ponce Belen , Albar-Marín María J. , Parra-Casado Daniel La , Popova Dena , Tomsa Raluca
Published: November 2020

Aim: To present a protocol study directed at tackling gender discrimination against Roma girls by empowering their mattering so they can envision their own futures and choose motherhood only if—and when—they are ready. Background: Motherhood among Roma girls (RGM) in Europe impoverishes their lives, puts them at risk of poor physical and mental health and precipitates school dropouts. Overwhelming evidence affirms that the conditions of poverty and the social exclusionary processes they suffer have a very important explanatory weight in their sexual and reproductive decisions. Methods: Through a Community-based Participatory Action Research design, 20–25 Roma girls will be recruited in each one of the four impoverished communities in Bulgaria, Romania and Spain. Data collection and analysis: Desk review about scientific evidences and policies will be carried out to frame the problem. Narratives of Roma women as well as baseline and end line interviews of girl participants will be collected through both qualitative and quantitative techniques. Quantitative data will be gathered through reliable scales of mattering, socio–political agency, satisfaction with life and self. A narrative analysis of the qualitative information generated in the interviews will be carried out. Expected results: (1) uncover contextual and psychosocial patterns of girl-motherhood among Roma women; (2) build critical thinking among Roma girls to actively participate in all decisions affecting them and advocate for their own gender rights within their communities; and (3) empower Roma girls and their significant adults to critically evaluate their own initiatives and provide feedback to their relevant stakeholders. Conclusions: Roma girls will improve their educational aspirations and achievements and their social status while respecting and enhancing Roma values.
Identifying the Factors That Affect Depressive Symptoms in Middle-Aged Menopausal Women: A Nationwide Study in Korea
Authors: Kim Kisook
Published: November 2020

Depressive symptoms do not persistently negatively affect functioning throughout the life span, but they may affect quality of life (QOL), especially in middle-aged women. Therefore, this study aimed to investigate the factors associated with depressive symptoms in premenopausal and postmenopausal women. This descriptive study was a secondary analysis of the data from the seventh Korea National Health and Nutrition Examination Survey that was conducted in 2016. Of the 8150 participants, the analysis included 644 premenopausal women and 459 postmenopausal women aged 40–60 years. The factors associated with depressive symptoms in the participants were examined using multivariate regression analysis. It was found that the depressive symptoms of postmenopausal middle-aged women were greater than those of premenopausal women. While a high perceived stress status and high pain-related discomfort were factors that influenced depressive symptoms among the premenopausal group, a high level of discomfort due to anxiety/depression, a poor perceived health status, shortened weekend sleep time, and smoking were associated with depressive symptoms in the postmenopausal group. Thus, it is necessary to develop an intervention to decrease depressive symptoms in postmenopausal women that considers their QOL, which is associated with depression, their subjective health status, sleep time, and smoking cessation.
The Direct and Indirect Influences of Adverse Childhood Experiences on Physical Health: A Cross-Sectional Study
Authors: Martín-Higarza Yolanda , Fontanil Yolanda , Méndez María Dolores , Ezama Esteban
Published: November 2020

A growing and significant body of research has documented the close relationship between adverse childhood experiences (ACEs) and health outcomes in adults. Less is known about the complex pathways through which ACEs exert their influence. This article examines the direct relationship between the quality of perceived physical health and childhood adversities. The association between the adversities and the physical health with other psychological and social variables is also analyzed. Data were collected from a sample of 170 subjects, using tools to assess adverse childhood experiences, physical health-related quality of life, socioeconomic vulnerability, emotion regulation, coping strategies, attachment, and social support. Results showed a high frequency of ACEs among the adult population, and the correlation with poor physical health was highly significant. Regression equations to predict physical health also revealed the following as significant variables: wishful thinking, social withdrawal, and cognitive restructuring as coping styles; reappraisal to achieve emotion regulation; fear of rejection or abandonment, and desire for closeness in relation to attachment figures; hardship; and poor financial support. The relationship between the different forms of ACE and social vulnerability identifies the important indirect contribution of childhood adversity to health and socioeconomic conditions in adulthood.
Stress-Related Responses to Alternations between Repetitive Physical Work and Cognitive Tasks of Different Difficulties
Authors: Mixter Susanna , Mathiassen Svend Erik , Lindfors Petra , Dimberg Kent , Jahncke Helena , Lyskov Eugene , Hallman David M.
Published: November 2020

Alternating between physical and cognitive tasks has been proposed as an alternative in job rotation, allowing workers to recover from the physical work while still being productive. However, effects of such alternations on stress have not been investigated. This controlled experiment aimed at determining the extent to which stress-related responses develop during alternating physical and cognitive work, and to determine the extent to which cognitive task (CT) difficulty influences these responses. Fifteen women performed three sessions of 10 consecutive work bouts each including a seven-minute repetitive physical task (pipetting) and a three-minute CT (n-back) at one of three difficulty levels. Stress was assessed in terms of changes in heart rate variability, blood pressure, salivary alpha-amylase, salivary cortisol, perceived stress, and cognitive performance. The work session did not result in any marked stress response, and CT difficulty did not significantly influence stress, apart from alpha-amylase being higher at the easiest CT (F = 5.34, p = 0.02). Thus, according to our results, alternating between repetitive physical tasks and cognitive tasks may be a feasible alternative to classic job rotation between physical tasks only, even if the cognitive task is quite difficult. Future studies should address possible effects of the temporal pattern of alternations, and combine even other occupationally relevant tasks, preferably for extended periods of time.
Development and External Validity of a Short-Form Version of the INICIARE Scale to Classify Nursing Care Dependency Level in Acute Hospitals
Authors: Porcel-Gálvez Ana María , Barrientos-Trigo Sergio , Fernández-García Elena , Allande-Cussó Regina , Quiñoz-Gallardo María Dolores , Morales-Asencio José Miguel
Published: November 2020

Background: The increasing dependence care in patients hospitalized in acute hospitals around the world entails classification systems heeding the wide range of care dependency levels generated by the many different types of dependent patients. This article is a report of a study assessing the validity and reliability of a short-from version of the instrument (Inventario del NIvel de Cuidados mediante Indicadores de Resultados de Enfermería (INICIARE)) used to classify inpatients according to their care dependency level. Methods: The validation, carried out in a multicenter longitudinal study, included three different samples: the first sample of 1800 patients to evaluate the reliability and validity, a second of 762 patients for confirmatory factor analysis, and a third of 762 to test the short-form version. Patients over 16 years of age, admitted to medical or surgical units at 11 public hospitals, were included. Results: The final sample included 3605 patients. Patients had a mean age of 64.5 years, 60% were admitted to medical units, with severe dependency. The validation process yielded two versions of the instrument: a 40-item version, with eight factors with 83.6% of total variance explained and Cronbach’s alpha values between 0.98 and 0.92, and a short-form with 26 items, with five factors and Cronbach’s alpha values between 0.96 and 0.90. The Confirmatory Factor Analysis yielded a good fit model to the 40-item version (Chi Square on Degrees of Freedom CMIN/DF) = 1.335; Normed Fit Index (NFI); Tucker–Lewis Index (TLI); Comparative Fit Index (CFI) > 0.90; Standardized Residual Root Mean Square (RMSEA) = 0.02; and Standardized Residual Root Mean Square (SRMR) = 0.027) and 26-item version (Chi Square on Degrees of Freedom CMIN/DF = 1.385; NFI = 0.998; CFI = 0.999; RMSEA = 0.02; and SRMR 0.02). Both INICIARE versions obtained a high correlation between them (r = 0.96; p < 0.001). Conclusion: INICIARE has proved to be a valid and reliable instrument for the assessment of the level of care dependency of acutely hospitalized patients.
Living with Restrictions. The Perspective of Nursing Students with Primary Dysmenorrhea
Authors: Fernández-Martínez Elia , Abreu-Sánchez Ana , Velarde-García Juan Francisco , Iglesias-López María Teresa , Pérez-Corrales Jorge , Palacios-Ceña Domingo
Published: November 2020

Primary dysmenorrhea (PD) affects a large number of female university students, diminishing their quality of life and hindering academic performance, representing a significant cause of absenteeism. The purpose of our study was to determine how nursing students experienced restrictions as a result of primary dysmenorrhea. A qualitative exploratory study was conducted among 33 nursing students with primary dysmenorrhea. A purposeful sampling strategy was applied. Data were collected from five focus groups (two sessions each) and the field notes of 10 researchers. A video meeting platform was used to conduct the focus groups. A thematic inductive analysis was performed. Thirty-three female nursing students participated in the study with a mean age of 22.72 (SD 3.46) years. Three broad themes emerged: (a) restrictions on daily activities and sports; (b) academic restrictions, and (c) restrictions on social and sexual relationships. The students described restrictions in performing everyday activities, such as carrying weight, and shopping. Some students even gave up the practice of sports and were absent from classes at the university, and from clinical practices at the hospital. The pain affected their ability to maintain and create new social relationships. Primary dysmenorrhea caused restrictions in the personal, social and academic life of the nursing students.
Feeding Arsenic-Containing Rice Bran to Growing Pigs: Growth Performance, Arsenic Tissue Distribution, and Arsenic Excretion
Authors: Liao Shengfa F. , Hasan M. Shamimul , Yang Zhongyue , Stevens Andrew W. , Brett James , Peng Zhaohua
Published: November 2020

This research was conducted to study the growth performance, arsenic (As) tissue distribution, and As excretion of pigs fed As-containing rice bran. Twenty gilts (26.3 kg) were randomly assigned to 3 dietary treatments (n = 6 or 7) with Diets I, II, and III containing 0, 36.7, and 73.5% rice bran and 0, 306, and 612 ppb As, respectively. Pigs were fed for 6 weeks, and their growth performance and daily activities were examined. Fecal, blood, and hair samples were collected immediately before and after the 6-weeks. At the end of the 6-weeks, pigs were slaughtered; the liver, kidney, muscle, and urine samples were collected. No pig showed any unhealthy signs throughout the trial. The average daily feed intake, average daily gain, and final body weight of Diet III pigs were lower (p ≤ 0.001) than Diet I pigs. The gain to feed ratios were not different among the treatments. The fecal, hair, kidney, and urinary As concentrations of both Diets II and III pigs were higher than Diet I pigs. The hair As concentration of Diet III pigs was higher than Diet II pigs, but no difference was found in the fecal, urinary, kidney, or muscle As concentrations between Diets II and III pigs. The blood and muscle As concentrations were below 10 ppb. These results suggest that 73.5% dietary rice bran inclusion compromised growth performance, whereas the 36.7% inclusion did not. The fecal As data imply that dietary As was poorly absorbed by the gastrointestinal tract. The tissue As data indicate that the absorbed As was rapidly cleared from the blood with some retained in various organs and others eliminated via urine. The hair As concentration was much higher than that of liver and kidney. The muscle As data suggest that the pork produced from the pigs fed a typical As-containing rice bran as used in this study is safe for human consumption.
The Role of Chemokine Receptor CXCR3 and Its Ligands in Renal Cell Carcinoma
Authors: Gudowska-Sawczuk Monika , Kudelski Jacek , Mroczko Barbara
Published: November 2020

The major invasive subtype of kidney cancer is renal cell carcinoma (RCC). The essential components of cancer development are chronic inflammation and neoangiogenesis. It has been suggested that the chemokine ligand 9, -10, –11 (CXCL9–11) and chemokine receptor 3 (CXCR3) chemokines receptor expressed on monocytes, T and NK cells may be involved in the inhibition of angiogenesis. However, to date, little is known about the potential clinical significance of these chemokines and their receptor in renal cell carcinoma. Therefore, in this review, we described the role of CXCR3 and its ligands in pathogenesis of RCC. We performed an extensive search of the current literature in our investigation, using the MEDLINE/PubMed database. The changes of chemokines and their specific receptor in renal cell carcinoma were observed. Published studies revealed an increased expression of CXCR3 and elevated concentration of its ligands in RCC. The association between treatment of RCC and CXCL9–11/CXCR3 concentration and expression was also observed. Moreover, CXCR3 and its ligands levels were related to patient’s prognosis, risk of metastasis and tumor growth. This review describes the potential role of CXCR3 and its ligands in pathogenesis of RCC, as well as their potential immune-therapeutic significance. However, future studies should aim to confirm the clinical and prognostic role of CXCL9–11/CXCR3 in renal cell carcinoma.
MicroRNA-23a-3p Down-Regulation in Active Pulmonary Tuberculosis Patients with High Bacterial Burden Inhibits Mononuclear Cell Function and Phagocytosis through TLR4/TNF-α/TGF-β1/IL-10 Signaling via Targeting IRF1/SP1
Authors: Chen Yung-Che , Lee Chiu Ping , Hsiao Chang-Chun , Hsu Po-Yuan , Wang Ting-Ya , Wu Chao-Chien , Chao Tung-Ying , Leung Sum-Yee , Chang Yu-Ping , Lin Meng-Chih
Published: November 2020

The aim of this study is to explore the role of microRNAs (miR)-21/23a/146a/150/155 targeting the toll-like receptor pathway in active tuberculosis (TB) disease and latent TB infection (LTBI). Gene expression levels of the five miRs and predicted target genes were assessed in peripheral blood mononuclear cells from 46 patients with active pulmonary TB, 15 subjects with LTBI, and 17 non-infected healthy subjects (NIHS). THP-1 cell lines were transfected with miR-23a-3p mimics under stimuli with Mycobacterium TB-specific antigens. Both miR-155-5p and miR-150-5p gene expressions were decreased in the active TB group versus the NIHS group. Both miR-23a-3p and miR-146a-5p gene expressions were decreased in active TB patients with high bacterial burden versus those with low bacterial burden or control group (LTBI + NIHS). TLR2, TLR4, and interleukin (IL)10 gene expressions were all increased in active TB versus NIHS group. MiR-23a-3p mimic transfection reversed ESAT6-induced reduction of reactive oxygen species generation, and augmented ESAT6-induced late apoptosis and phagocytosis, in association with down-regulations of the predicted target genes, including tumor necrosis factor (TNF)-α, TLR4, TLR2, IL6, IL10, Notch1, IL6R, BCL2, TGF-β1, SP1, and IRF1. In conclusion, the down-regulation of miR-23a-3p in active TB patients with high bacterial burden inhibited mononuclear cell function and phagocytosis through TLR4/TNF-α/TGF-β1/IL-10 signaling via targeting IRF1/SP1.
Potential Diagnostic and Prognostic Utility of miR-141, miR-181b1, and miR-23b in Breast Cancer
Authors: Taha Mohamed , Mitwally Noha , Soliman Ayman S. , Yousef Einas
Published: November 2020

miRNAs, a group of short noncoding RNAs, are key regulators of fundamental cellular processes and signaling pathways. Dysregulation of miRNA expression with known oncogenic or tumor suppressor functions has been associated with neoplastic transformation. Numerous studies have reported dysregulation of miRNA-141, miR-181b1, and miR-23b in a wide range of malignancies, including breast cancer. To the best of our knowledge, no previous study had demonstrated the expression of miR-141-3p, miR-181b1-5p, and miR-23b-3p in different histological grades and molecular subtypes of breast cancer. Here, we identified differential expression of these three miRNAs in breast cancer tissues compared with benign breast fibroadenomas. In addition, high expression levels of miR-141-3p and miR-181b1-5p are strongly associated with aggressive breast carcinomas. We also confirmed the clinical potential of using the three miRNAs individually or combined as diagnostic and prognostic markers in breast cancer. Using bioinformatics analyses, we identified 23 hub genes of these three miRNAs which are involved in key signaling pathways in breast cancer. Furthermore, the KM plotter online database analysis demonstrates the association between elevated expression of miR-141 and miR-181b and shorter overall survival of breast cancer patients. Together, our data suggest an oncogenic role of the studied miRNAs and highlight their molecular roles and potential clinical applications in breast cancer.
Genomics of Human Fibrotic Diseases: Disordered Wound Healing Response
Authors: Stone Rivka C. , Chen Vivien , Burgess Jamie , Pannu Sukhmani , Tomic-Canic Marjana
Published: November 2020

Fibrotic disease, which is implicated in almost half of all deaths worldwide, is the result of an uncontrolled wound healing response to injury in which tissue is replaced by deposition of excess extracellular matrix, leading to fibrosis and loss of organ function. A plethora of genome-wide association studies, microarrays, exome sequencing studies, DNA methylation arrays, next-generation sequencing, and profiling of noncoding RNAs have been performed in patient-derived fibrotic tissue, with the shared goal of utilizing genomics to identify the transcriptional networks and biological pathways underlying the development of fibrotic diseases. In this review, we discuss fibrosing disorders of the skin, liver, kidney, lung, and heart, systematically (1) characterizing the initial acute injury that drives unresolved inflammation, (2) identifying genomic studies that have defined the pathologic gene changes leading to excess matrix deposition and fibrogenesis, and (3) summarizing therapies targeting pro-fibrotic genes and networks identified in the genomic studies. Ultimately, successful bench-to-bedside translation of observations from genomic studies will result in the development of novel anti-fibrotic therapeutics that improve functional quality of life for patients and decrease mortality from fibrotic diseases.
Comparative Studies of Polysialic Acids Derived from Five Different Vertebrate Brains
Authors: Yang Yi , Murai Ryo , Takahashi Yuka , Mori Airi , Hane Masaya , Kitajima Ken , Sato Chihiro
Published: November 2020

Polysialic acid (polySia/PSA) is a linear homopolymer of sialic acid (Sia) that primarily modifies the neural cell adhesion molecule (NCAM) in mammalian brains. PolySia-NCAM not only displays an anti-adhesive function due to the hydration effect, but also possesses a molecule-retaining function via a direct binding to neurologically active molecules. The quality and quantity of polySia determine the function of polySia-NCAM and are considered to be profoundly related to the maintenance of normal brain functions. In this study, to compare the structures of polySia-NCAM in brains of five different vertebrates (mammals, birds, reptiles, amphibians, and fish), we adopted newly developed combinational methods for the analyses. The results revealed that the structural features of polySia considerably varied among different species. Interestingly, mice, as a mammal, possess eminently distinct types of polySia, in both quality and quantity, compared with those possessed by other animals. Thus, the mouse polySia is of larger quantities, of longer and more diverse chain lengths, and of a larger molecular size with higher negative charge, compared with polySia of other species. These properties might enable more advanced brain function. Additionally, it is suggested that the polySia/Sia ratio, which likely reflects the complexity of brain function, can be used as a new promising index to evaluate the intelligence of different vertebrate brains.
A Vismodegib Experience in Elderly Patients with Basal Cell Carcinoma: Case Reports and Review of the Literature
Authors: Passarelli Anna , Galdo Giovanna , Aieta Michele , Fabrizio Tommaso , Villonio Antonio , Conca Raffaele
Published: November 2020

Cutaneous basal cell carcinoma (BCC) is the most common type of human tumor, and its incidence rate is increasing worldwide. Up until a few years ago, therapeutic options have been limited for patients with advanced BCC (including metastatic and locally-advanced BCC). Over the last few years, promising systemic therapies have been investigated for the treatment of advanced BCC. In particular, the Hedgehog signaling inhibition has shown remarkable results for this population. Hedgehog inhibitors, represented by vismodegib and sonidegib, have been approved by the Food and Drug Administration and the European Medicines Agency for the treatment of both locally advanced and metastatic BCC, with, generally, a good safety profile. Notwithstanding the late onset of BCC in the global population, associated with life expectancy increase, only a few clinical trials have evaluated the efficacy and safety profile of Hedgehog inhibitors in this complex and neglected population. Herein, we review the major mechanisms implicated in the pathogenesis of BCC focusing on the Hedgehog signaling pathway and its therapeutic role in the elderly population. Finally, we report two case reports of BCC elderly patients in order to demonstrate both efficacy and safety of the Hedgehog inhibitors.
Mitochondrial Dynamics in Placenta-Derived Mesenchymal Stem Cells Regulate the Invasion Activity of Trophoblast
Authors: Seok Jin , Jun Sujin , Lee Jung Ok , Kim Gi Jin
Published: November 2020

Mitochondrial dynamics are involved in many cellular events, including the proliferation, differentiation, and invasion/migration of normal as well as cancerous cells. Human placenta-derived mesenchymal stem cells (PD-MSCs) were known to regulate the invasion activity of trophoblasts. However, the effects of PD-MSCs on mitochondrial function in trophoblasts are still insufficiently understood. Therefore, the objectives of this study are to analyze the factors related to mitochondrial function and investigate the correlation between trophoblast invasion and mitophagy via PD-MSC cocultivation. We assess invasion ability and mitochondrial function in invasive trophoblasts according to PD-MSC cocultivation by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and extracellular flux (XF) assay. Under PD-MSCs co-cultivation, invasion activity of a trophoblast is increased via activation of the Rho signaling pathway as well as Matrix metalloproteinases (MMPs). Additionally, the expression of mitochondrial function (e.g., reactive oxygen species (ROS), calcium, and adenosine triphosphate (ATP) synthesis) in trophoblasts are increased via PD-MSCs co-cultivation. Finally, PD-MSCs regulate mitochondrial autophagy factors in invasive trophoblasts via regulating the balance between PTEN-induced putative kinase 1 (PINK1) and parkin RBR E3 ubiquitin protein ligase (PARKIN) expression. Taken together, these results demonstrate that PD-MSCs enhance the invasion ability of trophoblasts via altering mitochondrial dynamics. These results support the fundamental mechanism of trophoblast invasion via mitochondrial function and provide a new stem cell therapy for infertility.
Effects of Chronic Intracerebroventricular Infusion of RFamide-Related Peptide-3 on Energy Metabolism in Male Mice
Authors: Moriwaki Shogo , Narimatsu Yuki , Fukumura Keisuke , Iwakoshi-Ukena Eiko , Furumitsu Megumi , Ukena Kazuyoshi
Published: November 2020

RFamide-related peptide-3 (RFRP-3), the mammalian ortholog of avian gonadotropin-inhibitory hormone (GnIH), plays a crucial role in reproduction. In the present study, we explored the other functions of RFRP-3 by investigating the effects of chronic intracerebroventricular infusion of RFRP-3 (6 nmol/day) for 13 days on energy homeostasis in lean male C57BL/6J mice. The infusion of RFRP-3 increased cumulative food intake and body mass. In addition, the masses of brown adipose tissue (BAT) and the liver were increased by the administration of RFRP-3, although the mass of white adipose tissue was unchanged. On the other hand, RFRP-3 decreased O2 consumption, CO2 production, energy expenditure, and core body temperature during a short time period in the dark phase. These results suggest that the increase in food intake and the decrease in energy expenditure contributed to the gain of body mass, including the masses of BAT and the liver. The present study shows that RFRP-3 regulates not only reproductive function, but also energy metabolism, in mice.
Cardiac ECM: Its Epigenetic Regulation and Role in Heart Development and Repair
Authors: Song Rui , Zhang Lubo
Published: November 2020

The extracellular matrix (ECM) is the non-cellular component in the cardiac microenvironment, and serves essential structural and regulatory roles in establishing and maintaining tissue architecture and cellular function. The patterns of molecular and biochemical ECM alterations in developing and adult hearts depend on the underlying injury type. In addition to exploring how the ECM regulates heart structure and function in heart development and repair, this review conducts an inclusive discussion of recent developments in the role, function, and epigenetic guidelines of the ECM. Moreover, it contributes to the development of new therapeutics for cardiovascular disease.
Antibacterial Effects of Bicarbonate in Media Modified to Mimic Cystic Fibrosis Sputum
Authors: Jaikumpun Pongsiri , Ruksakiet Kasidid , Stercz Balázs , Pállinger Éva , Steward Martin , Lohinai Zsolt , Dobay Orsolya , Zsembery Ákos
Published: November 2020

Cystic fibrosis (CF) is a hereditary disease caused by mutations in the gene encoding an epithelial anion channel. In CF, Cl− and HCO3− hyposecretion, together with mucin hypersecretion, leads to airway dehydration and production of viscous mucus. This habitat is ideal for colonization by pathogenic bacteria. We have recently demonstrated that HCO3− inhibits the growth and biofilm formation of Pseudomonas aeruginosa and Staphylococcus aureus when tested in laboratory culture media. Using the same bacteria our aim was to investigate the effects of HCO3− in artificial sputum medium (ASM), whose composition resembles CF mucus. Control ASM containing no NaHCO3 was incubated in ambient air (pH 7.4 or 8.0). ASM containing NaHCO3 (25 and 100 mM) was incubated in 5% CO2 (pH 7.4 and 8.0, respectively). Viable P. aeruginosa and S. aureus cells were counted by colony-forming unit assay and flow cytometry after 6 h and 17 h of incubation. Biofilm formation was assessed after 48 h. The data show that HCO3− significantly decreased viable cell counts and biofilm formation in a concentration-dependent manner. These effects were due neither to extracellular alkalinization nor to altered osmolarity. These results show that HCO3− exerts direct antibacterial and antibiofilm effects on prevalent CF bacteria.
PV1 Protein from Plasmodium falciparum Exhibits Chaperone-Like Functions and Cooperates with Hsp100s
Authors: Hakamada Kazuaki , Nakamura Manami , Midorikawa Rio , Shinohara Kyosuke , Noguchi Keiichi , Nagaoka Hikaru , Takashima Eizo , Morishima Ken , Inoue Rintaro , Sugiyama Masaaki , Kawamoto Akihiro , Yohda Masafumi
Published: November 2020

Plasmodium falciparum parasitophorous vacuolar protein 1 (PfPV1), a protein unique to malaria parasites, is localized in the parasitophorous vacuolar (PV) and is essential for parasite growth. Previous studies suggested that PfPV1 cooperates with the Plasmodium translocon of exported proteins (PTEX) complex to export various proteins from the PV. However, the structure and function of PfPV1 have not been determined in detail. In this study, we undertook the expression, purification, and characterization of PfPV1. The tetramer appears to be the structural unit of PfPV1. The activity of PfPV1 appears to be similar to that of molecular chaperones, and it may interact with various proteins. PfPV1 could substitute CtHsp40 in the CtHsp104, CtHsp70, and CtHsp40 protein disaggregation systems. Based on these results, we propose a model in which PfPV1 captures various PV proteins and delivers them to PTEX through a specific interaction with HSP101.
Large-Scale Plasma Analysis Revealed New Mechanisms and Molecules Associated with the Host Response to SARS-CoV-2
Authors: Barberis Elettra , Timo Sara , Amede Elia , Vanella Virginia V. , Puricelli Chiara , Cappellano Giuseppe , Raineri Davide , Cittone Micol G. , Rizzi Eleonora , Pedrinelli Anita R. , Vassia Veronica , Casciaro Francesco G. , Priora Simona , Nerici Ilaria , Galbiati Alessandra , Hayden Eyal , Falasca Marco , Vaschetto Rosanna , Sainaghi Pier Paolo , Dianzani Umberto , Rolla Roberta , Chiocchetti Annalisa , Baldanzi Gianluca , Marengo Emilio , Manfredi Marcello
Published: November 2020

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread to nearly every continent, registering over 1,250,000 deaths worldwide. The effects of SARS-CoV-2 on host targets remains largely limited, hampering our understanding of Coronavirus Disease 2019 (COVID-19) pathogenesis and the development of therapeutic strategies. The present study used a comprehensive untargeted metabolomic and lipidomic approach to capture the host response to SARS-CoV-2 infection. We found that several circulating lipids acted as potential biomarkers, such as phosphatidylcholine 14:0_22:6 (area under the curve (AUC) = 0.96), phosphatidylcholine 16:1_22:6 (AUC = 0.97), and phosphatidylethanolamine 18:1_20:4 (AUC = 0.94). Furthermore, triglycerides and free fatty acids, especially arachidonic acid (AUC = 0.99) and oleic acid (AUC = 0.98), were well correlated to the severity of the disease. An untargeted analysis of non-critical COVID-19 patients identified a strong alteration of lipids and a perturbation of phenylalanine, tyrosine and tryptophan biosynthesis, phenylalanine metabolism, aminoacyl-tRNA degradation, arachidonic acid metabolism, and the tricarboxylic acid (TCA) cycle. The severity of the disease was characterized by the activation of gluconeogenesis and the metabolism of porphyrins, which play a crucial role in the progress of the infection. In addition, our study provided further evidence for considering phospholipase A2 (PLA2) activity as a potential key factor in the pathogenesis of COVID-19 and a possible therapeutic target. To date, the present study provides the largest untargeted metabolomics and lipidomics analysis of plasma from COVID-19 patients and control groups, identifying new mechanisms associated with the host response to COVID-19, potential plasma biomarkers, and therapeutic targets.
Oncolytic Viruses and Immune Checkpoint Inhibitors: Preclinical Developments to Clinical Trials
Authors: Hwang June Kyu , Hong JinWoo , Yun Chae-Ok
Published: November 2020

Immuno-oncology (IO) has been an active area of oncology research. Following US FDA approval of the first immune checkpoint inhibitor (ICI), ipilimumab (human IgG1 k anti-CTLA-4 monoclonal antibody), in 2011, and of the first oncolytic virus, Imlygic (talimogene laherparepvec), in 2015, there has been renewed interest in IO. In the past decade, ICIs have changed the treatment paradigm for many cancers by enabling better therapeutic control, resuming immune surveillance, suppressing tumor immunosuppression, and restoring antitumor immune function. However, ICI therapies are effective only in a small subset of patients and show limited therapeutic potential due to their inability to demonstrate efficacy in ‘cold’ or unresponsive tumor microenvironments (TMEs). Relatedly, oncolytic viruses (OVs) have been shown to induce antitumor immune responses, augment the efficacy of existing cancer treatments, and reform unresponsive TME to turn ‘cold’ tumors ‘hot,’ increasing their susceptibility to checkpoint blockade immunotherapies. For this reason, OVs serve as ideal complements to ICIs, and multiple preclinical studies and clinical trials are demonstrating their combined therapeutic efficacy. This review will discuss the merits and limitations of OVs and ICIs as monotherapy then progress onto the preclinical rationale and the results of clinical trials of key combination therapies.
Technical and Methodological Aspects of Cell-Free Nucleic Acids Analyzes
Authors: Pös Zuzana , Pös Ondrej , Styk Jakub , Mocova Angelika , Strieskova Lucia , Budis Jaroslav , Kadasi Ludevit , Radvanszky Jan , Szemes Tomas
Published: November 2020

Analyzes of cell-free nucleic acids (cfNAs) have shown huge potential in many biomedical applications, gradually entering several fields of research and everyday clinical care. Many biological properties of cfNAs can be informative to gain deeper insights into the function of the organism, such as their different types (DNA, RNAs) and subtypes (gDNA, mtDNA, bacterial DNA, miRNAs, etc.), forms (naked or vesicle bound NAs), fragmentation profiles, sequence composition, epigenetic modifications, and many others. On the other hand, the workflows of their analyzes comprise many important steps, from sample collection, storage and transportation, through extraction and laboratory analysis, up to bioinformatic analyzes and statistical evaluations, where each of these steps has the potential to affect the outcome and informational value of the performed analyzes. There are, however, no universal or standard protocols on how to exactly proceed when analyzing different cfNAs for different applications, at least according to our best knowledge. We decided therefore to prepare an overview of the available literature and products commercialized for cfNAs processing, in an attempt to summarize the benefits and limitations of the currently available approaches, devices, consumables, and protocols, together with various factors influencing the workflow, its processes, and outcomes.
Platinum-Based Drugs Cause Mitochondrial Dysfunction in Cultured Dorsal Root Ganglion Neurons
Authors: Leo Markus , Schmitt Linda-Isabell , Küsterarent Patricia , Kutritz Andrea , Rassaf Tienush , Kleinschnitz Christoph , Hendgen-Cotta Ulrike B. , Hagenacker Tim
Published: November 2020

Cisplatin and oxaliplatin are treatment options for a variety of cancer types. While highly efficient in killing cancer cells, both chemotherapeutics cause severe side effects, e.g., peripheral neuropathies. Using a cell viability assay, a mitochondrial stress assay, and live-cell imaging, the effects of cis- or oxaliplatin on the mitochondrial function, reactive oxygen species (ROS) production, and mitochondrial and cytosolic calcium concentration of transient receptor potential ankyrin 1 (TRPA1)- or vanilloid 1 (TRPV1)-positive dorsal root ganglion (DRG) neurons of adult Wistar rats were determined. Mitochondrial functions were impaired after exposure to cis- or oxaliplatin by mitochondrial respiratory chain complex I-III inhibition. The basal respiration, spare respiratory capacity, and the adenosine triphosphate (ATP)-linked respiration were decreased after exposure to 10 µM cis- or oxaliplatin. The ROS production showed an immediate increase, and after reaching the peak, ROS production dropped. Calcium imaging showed an increase in the cytosolic calcium concentration during exposure to 10 µM cis- or oxaliplatin in TRPA1- or TRPV1-positive DRG neurons while the mitochondrial calcium concentration continuously decreased. Our data demonstrate a significant effect of cis- and oxaliplatin on mitochondrial function as an early event of platinum-based drug exposure, suggesting mitochondria as a potential target for preventing chemotherapy-induced neuropathy.
Whole Transcriptome Analysis of Myeloid Dendritic Cells Reveals Distinct Genetic Regulation in Patients with Allergies
Authors: Lee Kijeong , Han Mi-Ryung , Yeon Ji Woo , Kim Byoungjae , Kim Tae Hoon
Published: November 2020

Dendritic cells (DCs) play critical roles in atopic diseases, orchestrating both innate and adaptive immune systems. Nevertheless, limited information is available regarding the mechanism through which DCs induce hyperresponsiveness in patients with allergies. This study aims to reveal novel genetic alterations and future therapeutic target molecules in the DCs from patients with allergies using whole transcriptome sequencing. Transcriptome sequencing of human BDCA-3+/CD11c+ DCs sorted from peripheral blood monocytes obtained from six patients with allergies and four healthy controls was conducted. Gene expression profile data were analyzed, and an ingenuity pathway analysis was performed. A total of 1638 differentially expressed genes were identified at p-values < 0.05, with 11 genes showing a log2-fold change ≥1.5. The top gene network was associated with cell death/survival and organismal injury/abnormality. In validation experiments, amphiregulin (AREG) showed consistent results with transcriptome sequencing data, with increased mRNA expression in THP-1-derived DCs after Der p 1 stimulation and higher protein expression in myeloid DCs obtained from patients with allergies. This study suggests an alteration in the expression of DCs in patients with allergies, proposing related altered functions and intracellular mechanisms. Notably, AREG might play a crucial role in DCs by inducing the Th2 immune response.
High-Light versus Low-Light: Effects on Paired Photosystem II Supercomplex Structural Rearrangement in Pea Plants
Authors: Grinzato Alessandro , Albanese Pascal , Marotta Roberto , Swuec Paolo , Saracco Guido , Bolognesi Martino , Zanotti Giuseppe , Pagliano Cristina
Published: November 2020

In plant grana thylakoid membranes Photosystem II (PSII) associates with a variable number of antenna proteins (LHCII) to form different types of supercomplexes (PSII-LHCII), whose organization is dynamically adjusted in response to light cues, with the C2S2 more abundant in high-light and the C2S2M2 in low-light. Paired PSII-LHCII supercomplexes interacting at their stromal surface from adjacent thylakoid membranes were previously suggested to mediate grana stacking. Here, we present the cryo-electron microscopy maps of paired C2S2 and C2S2M2 supercomplexes isolated from pea plants grown in high-light and low-light, respectively. These maps show a different rotational offset between the two supercomplexes in the pair, responsible for modifying their reciprocal interaction and energetic connectivity. This evidence reveals a different way by which paired PSII-LHCII supercomplexes can mediate grana stacking at diverse irradiances. Electrostatic stromal interactions between LHCII trimers almost completely overlapping in the paired C2S2 can be the main determinant by which PSII-LHCII supercomplexes mediate grana stacking in plants grown in high-light, whereas the mutual interaction of stromal N-terminal loops of two facing Lhcb4 subunits in the paired C2S2M2 can fulfil this task in plants grown in low-light. The high-light induced accumulation of the Lhcb4.3 protein in PSII-LHCII supercomplexes has been previously reported. Our cryo-electron microscopy map at 3.8 Å resolution of the C2S2 supercomplex isolated from plants grown in high-light suggests the presence of the Lhcb4.3 protein revealing peculiar structural features of this high-light-specific antenna important for photoprotection.
Gestational Exposure to Bisphenol A Affects Testicular Morphology, Germ Cell Associations, and Functions of Spermatogonial Stem Cells in Male Offspring
Authors: Karmakar Polash Chandra , Ahn Jin Seop , Kim Yong-Hee , Jung Sang-Eun , Kim Bang-Jin , Lee Hee-Seok , Ryu Buom-Yong
Published: November 2020

Exposure to bisphenol A (BPA) in the gestational period damages the reproductive health of offspring; detailed evidence regarding BPA-induced damage in testicular germ cells of offspring is still limited. In this study, pregnant mice (F0) were gavaged with three BPA doses (50 μg, 5 mg, and 50 mg/kg body weight (bw)/day; tolerable daily intake (TDI), no-observed-adverse-effect-level (NOAEL), and lowest-observed-adverse-effect level (LOAEL), respectively) on embryonic days 7 to 14, followed by investigation of the transgenerational effects of such exposure in male offspring. We observed that the NOAEL- and LOAEL-exposed F1 offspring had abnormalities in anogenital distance, nipple retention, and pubertal onset (days), together with differences in seminiferous epithelial stages and testis morphology. These effects were eradicated in the next F2 and F3 generations. Moreover, there was an alteration in the ratio of germ cell population and the apoptosis rate in germ cells increased in F1 offspring at the LOAEL dose. However, the total number of spermatogonia remained unchanged. Finally, a reduction in the stemness properties of spermatogonial stem cells in F1 offspring was observed upon LOAEL exposure. Therefore, we provide evidence of BPA-induced disruption of physiology and functions in male germ cells during the gestational period. This may lead to several reproductive health issues and infertility in offspring.
Nanosystems Applied to HIV Infection: Prevention and Treatments
Authors: Macchione Micaela A. , Aristizabal Bedoya Dariana , Figueroa Francisco N. , Muñoz-Fernández María Ángeles , Strumia Miriam C.
Published: November 2020

Sexually-transmitted infections (STIs) are a global health concern worldwide as they cause acute diseases, infertility, and significant mortality. Among the bacterial, viral, and parasitic pathogens that can be sexually transmitted, human immunodeficiency virus (HIV) has caused one of the most important pandemic diseases, which is acquired immune deficiency syndrome (AIDS). 32.7 million people have died from AIDS-related illnesses since the start of the epidemic. Moreover, in 2019, 38 million people were living with HIV worldwide. The need to deal with this viral infection becomes more obvious, because it represents not only a problem for public health, but also a substantial economic problem. In this context, it is necessary to focus efforts on developing methods for prevention, detection and treatment of HIV infections that significantly reduce the number of newly infected people and provide a better quality of life for patients. For several decades, biomedical research has been developed allowing quick solutions through the contribution of effective tools. One of them is the use of polymers as vehicles, drug carrier agents, or as macromolecular prodrugs. Moreover, nanosystems (NSs) play an especially important role in the diagnosis, prevention, and therapy against HIV infection. The purpose of this work is to review recent research into diverse NSs as potential candidates for prevention and treatment of HIV infection. Firstly, this review highlights the advantages of using nanosized structures for these medical applications. Furthermore, we provide an overview of different types of NSs used for preventing or combating HIV infection. Then, we briefly evaluate the most recent developments associated with prevention and treatment alternatives. Additionally, the implications of using different NSs are also addressed.
Generation of Cochlear Hair Cells from Sox2 Positive Supporting Cells via DNA Demethylation
Authors: Deng Xin , Hu Zhengqing
Published: November 2020

Regeneration of auditory hair cells in adult mammals is challenging. It is also difficult to track the sources of regenerated hair cells, especially in vivo. Previous paper found newly generated hair cells in deafened mouse by injecting a DNA methyltransferase inhibitor 5-azacytidine into the inner ear. This paper aims to investigate the cell sources of new hair cells. Transgenic mice with enhanced green fluorescent protein (EGFP) expression controlled by the Sox2 gene were used in the study. A combination of kanamycin and furosemide was applied to deafen adult mice, which received 4 mM 5-azacytidine injection into the inner ear three days later. Mice were followed for 3, 5, 7 and 14 days after surgery to track hair cell regeneration. Immunostaining of Myosin VIIa and EGFP signals were used to track the fate of Sox2-expressing supporting cells. The results show that (i) expression of EGFP in the transgenic mice colocalized the supporting cells in the organ of Corti, and (ii) the cell source of regenerated hair cells following 5-azacytidine treatment may be supporting cells during 5–7 days post 5-azacytidine injection. In conclusion, 5-azacytidine may promote the conversion of supporting cells to hair cells in chemically deafened adult mice.