bluuebunny/crossref_metadata_2025 huggingface dataset:
Program and Results of Investigations Rapid Variability of the BL Lac Object 3C 371 in Radio and Optical Ranges
Authors: Sukharev Artem , Ryabov Michail , Bezrukovs Vladislavs , Orbidans Arturs , Bleiders Marcis , Udovichenko Sergei , Keir Leonid , Eglitis Ilgmars , Kudsey Igor , Dubovsky Pavol
Published: September 2020

BL Lac object 3C 371 is variable in optical and radio range, according to long-term monitoring data, for example AAVSO (American Association of Variable Star Observers) and OVRO (Owens Valley Radio Observatory). In addition, some authors note intra-night variability. However, in terms of access, just a few works are devoted to this topic, and questions remain about intra-day variability in radio range. The purpose of the work is to search for fast variability in radio (5, 6.1, 6.7 GHz) and optical bands (V, R, I) using international cooperation in 2019 and 2020 observation sessions. The 16-m radio telescope VIRAC, in Latvia, as well as optical telescopes AZT-3 (Mayaki, Ukraine), VNT (Vihorlat, Slovakia), and Schmidt camera (Baldone, Latvia) were used. To analyze variability, the STFT method of spectrograms and Lomb–Scargle periodograms for non-uniform time series were used. As result of the work, there is no correlation between optical and radio observations, and no significant quasi-harmonic variability was detected in radio range, but there is irregular low amplitude variability. In the optical range, there is variability with a characteristic time of about seven days and possibly less. Cyclical variability of 3C 371 was found in the optical range, and intra-day variability in radio range is most likely absent, as there are irregular variations and noise. It is planned to continue joint radio-optical observations 3C 371 to accumulate the necessary statistics.
Gene Polymorphisms of TLR4 and TLR9 and Haemophilus influenzae Meningitis in Angolan Children
Authors: Tenhu Elina , Teräsjärvi Johanna , Cruzeiro Manuel Leite , Savonius Okko , Rugemalira Emilie , Roine Irmeli , He Qiushui , Pelkonen Tuula
Published: September 2020

Bacterial meningitis (BM) is a severe disease caused by various bacterial pathogens. Toll-like receptors (TLRs) protect humans from invading pathogens. In this study, we determined whether single nucleotide polymorphisms (SNPs) of TLR4 and TLR9 are associated with susceptibility to and outcome of BM in Angolan children. Samples were taken from 241 patients and 265 age-matched ethnic controls. The SNPs TLR4 rs4986790 (896A > G) and TLR9 rs187084 (−1486T > C) were determined by high-resolution melting analysis (HRMA). The frequency of variant genotypes in TLR4 was significantly higher in patients with Haemophilus influenzae meningitis than controls (odds ratio (OR), 2.5; 95% confidence interval (CI), 1.2–5.4; p = 0.021), whereas the frequency of variant genotypes in TLR9 was significantly lower in patients with H. influenzae meningitis than controls (OR, 0.4; 95% CI, 0.2–0.9; p = 0.036). No such differences were found with other causative pathogens, such as Streptococcus pneumoniae and Neisseria meningitidis. At the time of discharge, patients with meningitis caused by Gram-negative bacteria who were carriers of variant TLR4 genotypes had a higher risk of ataxia (OR, 12.91; 95% CI, 1.52–109.80; p = 0.019) and other neurological sequelae (OR, 11.85; 95% CI, 1.07–131.49; p = 0.044) than those with the wild-type TLR4 genotype. Our study suggests an association between H. influenzae meningitis and genetic variation between TLR4 and TLR9 in Angolan children.
Origin of Genome Instability and Determinants of Mutational Landscape in Cancer Cells
Authors: Mehrotra Sonam , Mittra Indraneel
Published: September 2020

Genome instability is a crucial and early event associated with an increased predisposition to tumor formation. In the absence of any exogenous agent, a single human cell is subjected to about 70,000 DNA lesions each day. It has now been shown that physiological cellular processes including DNA transactions during DNA replication and transcription contribute to DNA damage and induce DNA damage responses in the cell. These processes are also influenced by the three dimensional-chromatin architecture and epigenetic regulation which are altered during the malignant transformation of cells. In this review, we have discussed recent insights about how replication stress, oncogene activation, chromatin dynamics, and the illegitimate recombination of cell-free chromatin particles deregulate cellular processes in cancer cells and contribute to their evolution. The characterization of such endogenous sources of genome instability in cancer cells can be exploited for the development of new biomarkers and more effective therapies for cancer treatment.
Natural Radioactivity of Laterite and Volcanic Rock Sample for Radioactive Mineral Exploration in Mamuju, Indonesia
Authors: Rosianna Ilsa , Nugraha Eka Djatnika , Syaeful Heri , Putra Sugili , Hosoda Masahiro , Akata Naofumi , Tokonami Shinji
Published: September 2020

Mamuju is a region of Indonesia with relatively high exposure to natural radiation. Since 2012, Mamuju has been a uranium and thorium exploration area. Several mapping studies of the region have been carried out to depict NORM (naturally occurring radioactive material) areas and areas with uranium anomalies. This paper is the first study to use radioactivity measurements of laterite and volcanic rocks to determine the characteristics of radionuclides and other mineral measurements, which are essential for categorising Mamuju rocks and exploring the region as a potential mining area. The radioactivity of the samples was measured using a high-purity germanium (HPGe) detector. Furthermore, we used X-ray fluorescence (XRF) to determine the rock mineral composition. Mamuju is anomalous due to its high content of 238U and 232Th concentrations of 539–128,699 Bq·kg−1 (average: 22,882 Bq·kg−1) and 471–288,639 Bq·kg−1 (average: 33,549 Bq·kg−1), respectively. The major elements are dominant, including Fe2O3, SiO2, Al2O3, and Na2O, with several other major elements such as MnO, TiO2, and CaO.
Testing the Strength of Hospital Accreditation as a Signal of the Quality of Care in Romania: Do Patients’ and Health Professionals’ Perceptions Align?
Authors: Druică Elena , Wu Bingyi , Cepoi Vasile , Mihăilă Viorel , Burcea Marin
Published: September 2020

Hospital accreditation, as a quality signal, is gaining its popularity among low- and middle-income countries, such as Romania, despite its costly nature. Nevertheless, its effectiveness as a quality signal in driving patients’ choice of hospital services remains unclear. In this study, we intend to empirically explore the perceptions of both healthcare professionals and patients toward Romanian hospital accreditation and identify perception gaps between the two parties. Exploratory and confirmatory factor analyses were carried out to extract the latent constructs of health professionals’ perceived effects of hospital accreditation. The Wilcoxon rank-sum test and Kruskal–Wallis test were used to identify correlations between patients’ sociodemographic characteristics and their behavioral intentions when confronted with low-quality services. We found that health professionals believe that hospital accreditation plays a positive role in improving patient satisfaction, institutional reputation, and healthcare services quality. However, we found a lack of awareness of hospital accreditation status among patients, indicating the existence of the perception gap of the accreditation effectiveness as a market signal. Our results suggest that the effect of interpersonal trust in current service providers may distract patients from the accreditation status. Our study provides important practical implications for Romanian hospitals on enhancing the quality of accreditation signal and suggests practical interventions.
Movement Behaviors and Perceived Loneliness and Sadness within Alaskan Adolescents
Authors: Burns Ryan D. , Bai Yang , Pfledderer Christopher D. , Brusseau Timothy A. , Byun Wonwoo
Published: September 2020

Physical activity, screen use, and sleep are behaviors that integrate across the whole day. However, the accumulative influence of meeting recommendations for these 24-h movement behaviors on the mental health of Alaskan adolescents has not been examined. The purpose of this study was to examine the associations between movement behaviors, loneliness, and sadness within Alaskan adolescents. Data were obtained from the 2019 Alaska Youth Risk Behavior Survey (YRBS). The number of adolescents participating in the 2019 Alaska YRBS was 1897. Associations between meeting recommendations for movement behaviors with loneliness and sadness were examined using weighted logistic regression models, adjusted for age, sex, race/ethnicity, and body mass index (BMI). Approximately 5.0% of the sample met recommendations for all three movement behaviors. Meeting 2 or 3 movement behavior recommendations was associated with lower odds of loneliness (odds ratio (OR) range = 0.23 to 0.44, p < 0.01). Additionally, meeting 1 to 3 movement behavior recommendations was associated with lower odds of sadness (OR range = 0.29 to 0.52, p < 0.05). Joint association analyses determined that these relationships were primarily driven by meeting the sleep recommendation for loneliness and meeting the screen use recommendation for sadness. The results support use of multiple movement-based behavior programming to attenuate feelings of loneliness and sadness within Alaskan adolescents.
Factors Associated with Latent Tuberculosis Infection among the Hospital Employees in a Tertiary Hospital of Northeastern Thailand
Authors: Chanpho Patimaporn , Chaiear Naesinee , Kamsa-ard Supot
Published: September 2020

Latent tuberculosis infection (LTBI) can develop into tuberculosis (TB). The WHO requires the discovery and management of LTBI among high-risk groups. Health care workers (HCWs) constitute a high-risk group. Factors associated with LTBI among HCWs in Thailand need further study. The current study aimed to explore the factors related to LTBI among Thai HCWs. A hospital-based, matched case-control study was conducted. All cases and controls were HCWs at a tertiary hospital in northeastern Thailand. Between 2017 and 2019, a total of 85 cases of interferon-γ release assays (IGRAs)-proven LTBI, and 170 control subjects were selected from a hospital (two controls per case). The two recruited controls were individually matched with LTBI cases by sex and age (±5 years). Secondary data were obtained from the occupational health and safety office. Case HCWs had a higher proportion of significant factors than control HCWs (i.e., working closely with pulmonary TB—94.1% vs. 88.8%, and working in the area of aerosol-generating procedures (AGPs) 81.2% vs. 69.4%). The bivariate conditional logistic regression showed that the occurrence of LTBI in HCWs was statistically significant (p-value < 0.05), particularly with respect to: workplaces of AGPs (crude OR = 1.90, 95% CI: 1.01–3.58, p = 0.041); among HCWs performing AGPs (crude OR = 2.04, 95% CI: 1.20, 3.48, p = 0.007); and, absent Bacille Calmette-Guérin (BCG) scar (crude OR = 2.59, 95% CI: 1.50–4.47, p = 0.001). Based on the multivariable conditional logistics analysis, HCWs who performed AGPs while contacting TB cases had a statistically significant association with LTBI (adjusted OR = 1.82, 95% CI: 1.04–3.20, p = 0.035). HCWs who reported the absence of a BCG scar had a statistically significant association with LTBI (adjusted OR = 2.49, 95% CI: 1.65–5.36, p = 0.001), whereas other factors including close contact with TB (adjusted OR = 2.44, 95% CI: 0.74, 8.09, p = 0.123) were not significantly associated with LTBI. In conclusion, HCWs who performed AGPs and were absent a BCG scar had a significant association with LTBI, while other factors played a less critical role.
Social Support and Well-Being of Chinese Special Education Teachers—An Emotional Labor Perspective
Authors: Wu Tung-Ju , Wang Lian-Yi , Gao Jia-Ying , Wei An-Pin
Published: September 2020

Due to their high expectations, teachers often hide their real emotions and play a role that conforms to public expectations of educational work. Special education teachers face a group of students with physical and mental disabilities who have high heterogeneity and require individualized services every day. Using social support theory, this study discusses special education teachers’ emotional labor and well-being. A total of 439 special education teachers in China participated in this study. We collected data at two different time-points and verified the research hypotheses with hierarchical regression and structural equation modeling analysis. The research findings show the mediating role of emotional labor in social support and well-being. It is, therefore, suggested that schools should pay more attention to special education teachers’ mental health and provide them with regular guidance and support.
Effects of Tetraselmis chuii Microalgae Supplementation on Ergospirometric, Haematological and Biochemical Parameters in Amateur Soccer Players
Authors: Toro Víctor , Siquier-Coll Jesús , Bartolomé Ignacio , Robles-Gil María , Rodrigo Javier , Maynar-Mariño Marcos
Published: September 2020

This study aimed to analyse the effects of Tetraselmis chuii (TC) microalgae supplementation during thirty days on ergospirometric, haematological and biochemical parameters in amateur soccer players. Thirty-two amateur soccer players divided into a control group (CG; n = 16; 22.36 ± 1.36 years; 68.36 ± 3.53 kg) and a supplemented group (SG; n = 16; 22.23 ± 2.19 years; 69.30 ± 5.56 kg) participated in the double-blind study. SG ingested 25 mg of the TC per day, while CG ingested 200 mg per day of lactose powder. Supplementation was carried out for thirty days. The participants performed a maximal treadmill test until exhaustion. The ergospirometric values at different ventilatory thresholds and haematological values were obtained after the test. Heart rate decreased after supplementation with TC (p < 0.05). Oxygen pulse, relative and absolute maximum oxygen consumption increased in SG (pre vs. post; 19.04 ± 2.53 vs. 22.08 ± 2.25; 53.56 ± 3.26 vs. 56.74 ± 3.43; 3.72 ± 0.35 vs. 3.99 ± 0.25; p < 0.05). Haemoglobin and mean corpuscular haemoglobin increased in SG (pre vs. post; 15.12 ± 0.87 vs. 16.58 ± 0.74 p < 0.01; 28.03 ± 1.57 vs. 30.82 ± 1.21; p < 0.05). On the other hand, haematocrit and mean platelet volume decreased in SG (p < 0.05). TC supplementation elicited improvements in ergospirometric and haematological values in amateur soccer players. TC supplementation could be valuable for improving performance in amateur athletes.
Daily Physical Activity and Sedentary Time Assessed by Acceleration Based on Mean Amplitude Deviation among Older People
Authors: Gao Ying , Rantalainen Timo , Finni Taija , Portegijs Erja , Eronen Johanna , Rantanen Taina , Rantakokko Merja
Published: September 2020

Accelerometer-derived estimates of physical activity (PA) and sedentary time have been an important methodological focus. However, little is known about the daily activities among older people during their normal lives. Furthermore, some older individuals would like to be more active, yet experience an unmet PA need, which is defined as the desire to engage in more PA but without the opportunity to act on the desire. This study examined the intensity of daily PA and sedentary behavior measured with accelerometers among older people, and whether PA differs between weekdays and weekends and those with and without the experience of unmet PA need, measured with self-reports. A total of 174 community-dwelling older people (64% female) aged 75 to 90 years used an accelerometer for 7 consecutive days during waking hours, and the results were classified for sedentary behavior (thresholds of 0.0167 g), light activity (0.091 g), and moderate-to-vigorous activity (MVPA, 0.414 g) based on mean amplitude deviation (g). We found that during weekdays, older people engaged slightly more in light activity and had less sedentary time than during weekends. In total, 7.6% of the participants perceived an unmet PA need. Accordingly, those with unmet PA needs spent less time in MVPA, especially during weekdays, and they might benefit from PA-enabling interventions.
Knowledge, Attitudes and Perceptions about Cervical Cancer Risk, Prevention and Human Papilloma Virus (HPV) in Vulnerable Women in Greece
Authors: Riza Elena , Karakosta Argiro , Tsiampalis Thomas , Lazarou Despoina , Karachaliou Angeliki , Ntelis Spyridon , Karageorgiou Vasilios , Psaltopoulou Theodora
Published: September 2020

Cervical cancer can be largely preventable through primary and secondary prevention activities. Following the financial crisis in Greece since 2011 and the increased number of refugees/migrants since 2015 the proportion of vulnerable population groups in Greece increased greatly and the ability of the healthcare sector to respond and to cover the health needs of the population is put under tremendous stress. A cross-sectional study was designed to assess the characteristics of vulnerable women in Greece regarding cervical cancer risk factors, prevention through screening activities and Human Papilloma Virus (HPV) knowledge. Two cohorts of women aged 18 to 70 years were studied (142 in 2012 and 122 in 2017) who completed an interviewer-administered questionnaire based on the behavioural model for vulnerable populations. According to this model, the factors that affect the behaviour of women in relation with their knowledge, attitudes and beliefs towards cervical cancer and the HPV vaccine in our study sample are categorised in predisposing factors (age, educational status, nationality menopausal status and housing) and enabling factors (lack of insurance coverage). Results from both univariate and multivariate analyses show that older age, low educational background, refugee/migrant or ethnic minority (Roma) background, menopausal status, housing conditions and lack of insurance coverage are linked with insufficient knowledge on risk factors for cervical cancer and false attitudes and perceptions on cervical cancer preventive activities (Pap smear and HPV vaccine). This is the first study in Greece showing the lack of knowledge and the poor attitudes and perceptions on cervical cancer screening and the HPV vaccine in various groups of vulnerable women. Our results indicate the need of health education and intervention activities according to the characteristics and needs of each group.
Social Determinants of Breastfeeding Preferences among Black Mothers Living with HIV in Two North American Cities
Authors: Etowa Josephine , Etowa Egbe , Nare Hilary , Mbagwu Ikenna , Hannan Jean
Published: September 2020

The study is motivated by the need to understand the social determinants of breastfeeding attitudes among HIV-positive African, Caribbean, and Black (ACB) mothers. To address the central issue identified in this study, analysis was conducted with datasets from two North American cities, where unique country-specific guidelines complicate infant feeding discourse, decisions, and practices for HIV-positive mothers. These national infant feeding guidelines in Canada and the US present a source of conflict and tension for ACB mothers as they try to navigate the spaces between contradictory cultural expectations and national guidelines. Analyses in this paper were drawn from a broader mixed methods study guided by a community-based participatory research (CBPR) approach to examine infant feeding practices among HIV-positive Black mothers in three countries. The survey were distributed through Qualtrics and SPSS was used for data cleaning and analysis. Results revealed a direct correlation between social determinants and breastfeeding attitude. Country of residence, relatives’ opinion, healthcare providers’ advice and HIV-related stigma had statistically significant association with breastfeeding attitude. While the two countries’ guidelines, which recommend exclusive formula feeding, are cardinal in preventing vertical transmission, they can also be a source of stress. We recommend due consideration of the cultural contexts of women’s lives in infant feeding guidelines, to ensure inclusion of diverse women.
Blood Lead Concentrations and Mortality in Korean Adults: the Korea National Health and Nutrition Examination Survey with Mortality Follow-Up
Authors: Byun Garam , Kim Sera , Kim Soo-Yeon , Park Dahyun , Shin Min-Jeong , Oh Hannah , Lee Jong-Tae
Published: September 2020

Previous studies have consistently reported an increase in mortality risk, even at low levels of blood lead. The average blood lead concentration in the Korean population has steadily decreased but is still higher than that of developed countries. The purpose of this study was to examine the associations between mortality and blood lead concentrations for adults in Korea. We used the Korea National Health and Nutrition Examination Survey (2008–2013) linked Cause of Death data, which are followed by 2018. A total of 7308 subjects who aged over 30 at the baseline examination were included in the analyses. Cox proportional hazard model was used to estimate the hazard ratios of mortality from non-accidental causes and cancer mortality. The estimated hazard ratios (95% CI) for comparison of the second and third tertile group with the lowest tertile group were 2.01 (1.20, 3.40) and 1.91 (1.13, 3.23) for non-accidental mortality and 3.42 (95% CI: 1.65, 7.08) and 2.27 (95% CI: 1.09, 4.70) for cancer mortality, respectively. The dose–response relationship also showed significant increase in the risk of mortality at blood lead level between 1.5 and 6.0 μg/dL. Our findings suggest that potent policies to lower lead exposure are required for the general Korean population.
Relationships between Exercise Modality and Activity Restriction, Quality of Life, and Hematopoietic Profile in Korean Breast Cancer Survivors
Authors: Kim MunHee , So Wi-Young , Kim Jiyoun
Published: September 2020

This study aimed to examine the relationships between activity restriction, quality of life (QoL), and hematopoietic profile in breast cancer survivors according to exercise modality. The subjects in this study were 187 female breast cancer survivors among a total of 32,631 participants in the Korea National Health and Nutrition Examination Survey, which was conducted from 2016 to 2018. The selected subjects participated in a questionnaire survey and blood analysis. A cross-analysis was conducted to determine the relationship between participation in various modality of exercise (e.g., aerobic exercise, resistance exercise, walking exercise). The phi coefficients or Cramer’s V value for activity restriction and QoL were calculated; an independent t-test was conducted to evaluate the differences between hematopoietic profiles based on the modality of exercise. Statistically significant correlations were seen between obesity and aerobic exercise and walking frequency, as well as between diabetes and aerobic exercise and activity restriction. With respect to QoL, there was a statistically significant correlation between participation in aerobic exercise and exercise ability, participation in aerobic exercise and anxiety/depression, participation in resistance exercise and subjective health status, participation in resistance exercise and exercise ability, and participation in weekly walking exercise and self-care ability. Regarding hemodynamic changes, red blood cells increased significantly in breast cancer survivors who participated in weekly resistance exercise compared to in those who did not. In conclusion, exercise participation had a positive effect on activity restriction, QoL, and hematopoietic profile in breast cancer survivors; in particular, some modalities of aerobic exercise were more effective.
Design and Validation of Linkers for Site-Specific Preparation of Antibody–Drug Conjugates Carrying Multiple Drug Copies Per Cysteine Conjugation Site
Authors: Kumar Amit , Mao Shenlan , Dimasi Nazzareno , Gao Changshou
Published: September 2020

First-generation cysteine-based site-specific antibody–drug conjugates (ADCs) are limited to one drug per cysteine. However, certain applications require a high drug to antibody ratio (DAR), such as when low-potency payloads are used. Higher drug load can be achieved using classical cysteine conjugation methods, but these result in heterogeneity, suboptimal efficacy and pharmacokinetics. Here, we describe the design, synthesis and validation of heterobifunctional linkers that can be used for the preparation of ADCs with a DAR of two, three and four in a site-specific manner per single cysteine conjugation site, resulting in site-specific ADCs with a DAR of four, six and eight. The designed linkers carry a sulfhydryl-specific iodoacetyl reactive group, and multiple cyclic diene moieties which can efficiently react with maleimide-carrying payloads through the Diels–Alder reaction. As a proof of concept, we synthesized site-specific DAR four, six and eight ADCs carrying tubulysin (AZ13601508) using engineered antibodies with a cysteine inserted after position 239 in the antibody CH2 domain. We evaluated and compared the in vitro cytotoxicity of ADCs obtained via the site-specific platform described herein, with ADCs prepared using classical cysteine conjugation. Our data validated a novel cysteine-based conjugation platform for the preparation of site-specific ADCs with high drug load for therapeutic applications.
miR-29a Modulates GSK3β/SIRT1-Linked Mitochondrial Proteostatic Stress to Ameliorate Mouse Non-Alcoholic Steatohepatitis
Authors: Yang Ya-Ling , Wang Pei-Wen , Wang Feng-Sheng , Lin Hung-Yu , Huang Ying-Hsien
Published: September 2020

MicroRNA-29a (miR-29a) has been shown to ameliorate hepatocellular damage, such as in the context of non-alcoholic fatty liver disease (NAFLD), steatohepatitis (NASH), and cholestatic injury. However, the mechanism mediating the hepatoprotective effect of miR-29a in diet-induced NASH remains elusive. In the present study, C57BL/6 mice of wild-type (WT) or miR-29a overexpression were fed with methionine–choline sufficient (MCS) or methionine–choline-deficient (MCD) diet for four weeks. The C57BL/6 mice harboring miR-29a overexpression presented reduced plasma AST, hepatic CD36, steatosis, and fibrosis induced by MCD. The TargetScan Release7.2-based bioinformatic analysis, KEGG pathway analysis, and luciferase reporter assay confirmed that miR-29a targets 3′UTR of glycogen synthase kinase 3 beta (Gsk3b) mRNA in the HepG2 hepatocyte cell line. Furthermore, miR-29a overexpression in the MCD-fed group resulted in inhibition of Gsk3b mRNA and GSK3β protein levels in the liver. GSK3β was notably expressed jointly with the extent of aggregated protein, which was then identified to be associated with mitochondrial unfolded protein response (UPRmt), but not with endoplasmic reticulum UPR (UPRER). Additionally, in silico analysis of protein–protein interaction, in vivo, and in vitro correlation analyses of protein expression demonstrated that GSK3β closely associated with sirtuin 1(SIRT1). Finally, the implication of SIRT1-mediated mitochondrial biogenesis in the perturbation of proteostasis was observed. We herein provide novel insight into a hepatoprotective pathway, whereby miR-29a inhibits GSK3β to repress SIRT1-mediated mitochondrial biogenesis, leading to alleviation of mitochondrial proteostatic stress and UPRmt in the context of NASH. miR-29a, GSK3β, and SIRT1 could thus serve as possible therapeutic targets to improve the treatment of NAFLD/NASH.
Targeting Molecular Mechanisms Underlying Treatment Efficacy and Resistance in Osteosarcoma: A Review of Current and Future Strategies
Authors: Lilienthal Ingrid , Herold Nikolas
Published: September 2020

Osteosarcoma is the most common primary malignant bone tumour in children and adolescents. Due to micrometastatic spread, radical surgery alone rarely results in cure. Introduction of combination chemotherapy in the 1970s, however, dramatically increased overall survival rates from 20% to approximately 70%. Unfortunately, large clinical trials aiming to intensify treatment in the past decades have failed to achieve higher cure rates. In this review, we revisit how the heterogenous nature of osteosarcoma as well as acquired and intrinsic resistance to chemotherapy can account for stagnation in therapy improvement. We summarise current osteosarcoma treatment strategies focusing on molecular determinants of treatment susceptibility and resistance. Understanding therapy susceptibility and resistance provides a basis for rational therapy betterment for both identifying patients that might be cured with less toxic interventions and targeting resistance mechanisms to sensitise resistant osteosarcoma to conventional therapies.
Dysregulated Autophagy Mediates Sarcopenic Obesity and Its Complications via AMPK and PGC1α Signaling Pathways: Potential Involvement of Gut Dysbiosis as a Pathological Link
Authors: Ryu Ji Yeon , Choi Hyung Muk , Yang Hyung-In , Kim Kyoung Soo
Published: September 2020

Sarcopenic obesity (SOB), which is closely related to being elderly as a feature of aging, is recently gaining attention because it is associated with many other age-related diseases that present as altered intercellular communication, dysregulated nutrient sensing, and mitochondrial dysfunction. Along with insulin resistance and inflammation as the core pathogenesis of SOB, autophagy has recently gained attention as a significant mechanism of muscle aging in SOB. Known as important cellular metabolic regulators, the AMP-activated protein kinase (AMPK) and the peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1α) signaling pathways play an important role in autophagy, inflammation, and insulin resistance, as well as mutual communication between skeletal muscle, adipose tissue, and the liver. Furthermore, AMPK and PGC-1α signaling pathways are implicated in the gut microbiome–muscle axis. In this review, we describe the pathological link between SOB and its associated complications such as metabolic, cardiovascular, and liver disease, falls and fractures, osteoarthritis, pulmonary disease, and mental health via dysregulated autophagy controlled by AMPK and/or PGC-1α signaling pathways. Here, we propose potential treatments for SOB by modulating autophagy activity and gut dysbiosis based on plausible pathological links.
Cell-Penetrable Peptide-Conjugated FADD Induces Apoptosis and Regulates Inflammatory Signaling in Cancer Cells
Authors: Ranjan Kishu , Waghela Bhargav N , Vaidya Foram U , Pathak Chandramani
Published: September 2020

Dysregulated expression of Fas-associated death domain (FADD) is associated with the impediment of various cellular pathways, including apoptosis and inflammation. The adequate cytosolic expression of FADD is critical to the regulation of cancer cell proliferation. Importantly, cancer cells devise mechanisms to suppress FADD expression and, in turn, escape from apoptosis signaling. Formulating strategies, for direct delivery of FADD proteins into cancer cells in a controlled manner, may represent a promising therapeutic approach in cancer therapy. We chemically conjugated purified FADD protein with cell permeable TAT (transactivator of transcription) peptide, to deliver in cancer cells. TAT-conjugated FADD protein internalized through the caveolar pathway of endocytosis and retained in the cytosol to augment cell death. Inside cancer cells, TAT-FADD rapidly constituted DISC (death inducing signaling complex) assembly, which in turn, instigate apoptosis signaling. The apoptotic competency of TAT-FADD showed comparable outcomes with the conventional apoptosis inducers. Notably, TAT-FADD mitigates constitutive NF-κB activation and associated downstream anti-apoptotic genes Bcl2, cFLIPL, RIP1, and cIAP2, independent of pro-cancerous TNF-α priming. In cancer cells, TAT-FADD suppresses the canonical NLRP3 inflammasome priming and restricts the processing and secretion of proinflammatory IL-1β. Our results demonstrate that TAT-mediated intracellular delivery of FADD protein can potentially recite apoptosis signaling with simultaneous regulation of anti-apoptotic and proinflammatory NF-κB signaling activation in cancer cells.
Dysmetria and Errors in Predictions: The Role of Internal Forward Model
Authors: Cabaraux Pierre , Gandini Jordi , Kakei Shinji , Manto Mario , Mitoma Hiroshi , Tanaka Hirokazu
Published: September 2020

The terminology of cerebellar dysmetria embraces a ubiquitous symptom in motor deficits, oculomotor symptoms, and cognitive/emotional symptoms occurring in cerebellar ataxias. Patients with episodic ataxia exhibit recurrent episodes of ataxia, including motor dysmetria. Despite the consensus that cerebellar dysmetria is a cardinal symptom, there is still no agreement on its pathophysiological mechanisms to date since its first clinical description by Babinski. We argue that impairment in the predictive computation for voluntary movements explains a range of characteristics accompanied by dysmetria. Within this framework, the cerebellum acquires and maintains an internal forward model, which predicts current and future states of the body by integrating an estimate of the previous state and a given efference copy of motor commands. Two of our recent studies experimentally support the internal-forward-model hypothesis of the cerebellar circuitry. First, the cerebellar outputs (firing rates of dentate nucleus cells) contain predictive information for the future cerebellar inputs (firing rates of mossy fibers). Second, a component of movement kinematics is predictive for target motions in control subjects. In cerebellar patients, the predictive component lags behind a target motion and is compensated with a feedback component. Furthermore, a clinical analysis has examined kinematic and electromyography (EMG) features using a task of elbow flexion goal-directed movements, which mimics the finger-to-nose test. Consistent with the hypothesis of the internal forward model, the predictive activations in the triceps muscles are impaired, and the impaired predictive activations result in hypermetria (overshoot). Dysmetria stems from deficits in the predictive computation of the internal forward model in the cerebellum. Errors in this fundamental mechanism result in undershoot (hypometria) and overshoot during voluntary motor actions. The predictive computation of the forward model affords error-based motor learning, coordination of multiple degrees of freedom, and adequate timing of muscle activities. Both the timing and synergy theory fit with the internal forward model, microzones being the elemental computational unit, and the anatomical organization of converging inputs to the Purkinje neurons providing them the unique property of a perceptron in the brain. We propose that motor dysmetria observed in attacks of ataxia occurs as a result of impaired predictive computation of the internal forward model in the cerebellum.
Freeze-Drying of Platelet-Rich Plasma: The Quest for Standardization
Authors: Andia Isabel , Perez-Valle Arantza , Del Amo Cristina , Maffulli Nicola
Published: September 2020

The complex biology of platelets and their involvement in tissue repair and inflammation have inspired the development of platelet-rich plasma (PRP) therapies for a broad array of medical needs. However, clinical advances are hampered by the fact that PRP products, doses and treatment protocols are far from being standardized. Freeze-drying PRP (FD-PRP) preserves platelet function, cytokine concentration and functionality, and has been proposed as a consistent method for product standardization and fabrication of an off-the-shelf product with improved stability and readiness for future uses. Here, we present the current state of experimental and clinical FD-PRP research in the different medical areas in which PRP has potential to meet prevailing medical needs. A systematic search, according to PRISMA (Preferred Reported Items for Systematic Reviews and Meta-Analyses) guidelines, showed that research is mostly focused on wound healing, i.e., developing combination products for ulcer management. Injectable hydrogels are investigated for lumbar fusion and knee conditions. In dentistry, combination products permit slow kinetics of growth factor release and functionalized membranes for guided bone regeneration.
Signalling Pathways Implicated in Alzheimer′s Disease Neurodegeneration in Individuals with and without Down Syndrome
Authors: Martínez-Cué Carmen , Rueda Noemí
Published: September 2020

Down syndrome (DS), the most common cause of intellectual disability of genetic origin, is characterized by alterations in central nervous system morphology and function that appear from early prenatal stages. However, by the fourth decade of life, all individuals with DS develop neuropathology identical to that found in sporadic Alzheimer’s disease (AD), including the development of amyloid plaques and neurofibrillary tangles due to hyperphosphorylation of tau protein, loss of neurons and synapses, reduced neurogenesis, enhanced oxidative stress, and mitochondrial dysfunction and neuroinflammation. It has been proposed that DS could be a useful model for studying the etiopathology of AD and to search for therapeutic targets. There is increasing evidence that the neuropathological events associated with AD are interrelated and that many of them not only are implicated in the onset of this pathology but are also a consequence of other alterations. Thus, a feedback mechanism exists between them. In this review, we summarize the signalling pathways implicated in each of the main neuropathological aspects of AD in individuals with and without DS as well as the interrelation of these pathways.
NOX1 Inhibition Attenuates Kidney Ischemia-Reperfusion Injury via Inhibition of ROS-Mediated ERK Signaling
Authors: Jung Hee-Yeon , Oh Se-Hyun , Ahn Ji-Sun , Oh Eun-Joo , Kim You-Jin , Kim Chan-Duck , Park Sun-Hee , Kim Yong-Lim , Cho Jang-Hee
Published: September 2020

The protective effects of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) 1 inhibition against kidney ischemia-reperfusion injury (IRI) remain uncertain. The bilateral kidney pedicles of C57BL/6 mice were clamped for 30 min to induce IRI. Madin–Darby Canine Kidney (MDCK) cells were incubated with H2O2 (1.4 mM) for 1 h to induce oxidative stress. ML171, a selective NOX1 inhibitor, and siRNA against NOX1 were treated to inhibit NOX1. NOX expression, oxidative stress, apoptosis assay, and mitogen-activated protein kinase (MAPK) pathway were evaluated. The kidney function deteriorated and the production of reactive oxygen species (ROS), including intracellular H2O2 production, increased due to IRI, whereas IRI-mediated kidney dysfunction and ROS generation were significantly attenuated by ML171. H2O2 evoked the changes in oxidative stress enzymes such as SOD2 and GPX in MDCK cells, which was mitigated by ML171. Treatment with ML171 and transfection with siRNA against NOX1 decreased the upregulation of NOX1 and NOX4 induced by H2O2 in MDCK cells. ML171 decreased caspase-3 activity, the Bcl-2/Bax ratio, and TUNEL-positive tubule cells in IRI mice and H2O2-treated MDCK cells. Among the MAPK pathways, ML171 affected ERK signaling by ERK phosphorylation in kidney tissues and tubular cells. NOX1-selective inhibition attenuated kidney IRI via inhibition of ROS-mediated ERK signaling.
Dim Light at Night Disturbs Molecular Pathways of Lipid Metabolism
Authors: Okuliarova Monika , Rumanova Valentina Sophia , Stebelova Katarina , Zeman Michal
Published: September 2020

Dim light at night (dLAN) is associated with metabolic risk but the specific effects on lipid metabolism have only been evaluated to a limited extent. Therefore, to explore whether dLAN can compromise lipid metabolic homeostasis in healthy individuals, we exposed Wistar rats to dLAN (~2 lx) for 2 and 5 weeks and analyzed the main lipogenic pathways in the liver and epididymal fat pad, including the control mechanisms at the hormonal and molecular level. We found that dLAN promoted hepatic triacylglycerol accumulation, upregulated hepatic genes involved in de novo synthesis of fatty acids, and elevated glucose and fatty acid uptake. These observations were paralleled with suppressed fatty acid synthesis in the adipose tissue and altered plasma adipokine levels, indicating disturbed adipocyte metabolic function with a potential negative impact on liver metabolism. Moreover, dLAN-exposed rats displayed an elevated expression of two peroxisome proliferator-activated receptor family members (Pparα and Pparγ) in the liver and adipose tissue, suggesting the deregulation of important metabolic transcription factors. Together, our results demonstrate that an impaired balance of lipid biosynthetic pathways caused by dLAN can increase lipid storage in the liver, thereby accounting for a potential linking mechanism between dLAN and metabolic diseases.
Selective Elimination of NG2-Expressing Hair Follicle Stem Cells Exacerbates the Sensitization Phase of Contact Dermatitis in a Transgenic Rat Model
Authors: Tamura Yasuhisa , Takata Kumi , Eguchi Asami , Kataoka Yosky
Published: September 2020

The hair cycle consists of three different phases: anagen (growth), catagen (regression), and telogen (resting). During the anagen phase, hair follicle stem cells (HFSCs) in the bulge and the secondary hair germ proliferate and generate the outer and inner root sheath cells and the hair shafts. We previously identified NG2-immunoreactive (NG2+) cells as HFSCs in both regions of the hair follicles. Recently, the interaction between the hair cycle and the cutaneous immune system has been re-examined under physiological and pathological conditions. However, the roles of NG2+ HFSCs in the skin’s immune system remain completely elucidated. In the present study, we investigated whether the elimination of NG2+ HFSCs affects the induction of allergic contact dermatitis, using a herpes simplex virus thymidine kinase (HSVtk)/ganciclovir (GCV) suicide gene system. When the GCV solution was applied to the skin of NG2-HSVtk transgenic (Tg) rats during the depilation-induced anagen phase, NG2+ HFSCs in the Tg rat skin induced apoptotic cell death. Under exposure of a hapten, the selective ablation of NG2+ HFSCs during the anagen phase aggravated the sensitization phase of allergic contact dermatitis. These findings suggest that NG2+ HFSCs and their progeny have immunosuppressive abilities during the anagen phase.
Diet Breadth Affects Bacterial Identity but Not Diversity in the Pollen Provisions of Closely Related Polylectic and Oligolectic Bees
Authors: Rothman Jason A. , Cox-Foster Diana L. , Andrikopoulos Corey , McFrederick Quinn S.
Published: September 2020

Mounting evidence suggests that microbes found in the pollen provisions of wild and solitary bees are important drivers of larval development. As these microbes are also known to be transmitted via the environment, most likely from flowers, the diet breadth of a bee may affect the diversity and identity of the microbes that occur in its pollen provisions. Here, we tested the hypothesis that, due to the importance of floral transmission of microbes, diet breadth affects pollen provision microbial community composition. We collected pollen provisions at four sites from the polylectic bee Osmia lignaria and the oligolectic bee Osmia ribifloris. We used high-throughput sequencing of the bacterial 16S rRNA gene to characterize the bacteria found in these provisions. We found minimal overlap in the specific bacterial variants in pollen provisions across the host species, even when the bees were constrained to foraging from the same flowers in cages at one site. Similarly, there was minimal overlap in the specific bacterial variants across sites, even within the same host species. Together, these findings highlight the importance of environmental transmission and host specific sorting influenced by diet breadth for microbes found in pollen provisions. Future studies addressing the functional consequences of this filtering, along with tests for differences between more species of oligoletic and polylectic bees will provide rich insights into the microbial ecology of solitary bees.
Beetle Species–Area Relationships and Extinction Rates in Protected Areas
Authors: Fattorini Simone
Published: September 2020

The species–area relationship (SAR, i.e., the increase in species richness with area) is one of the most general ecological patterns. SARs can be used to calculate expected extinction rates following area (habitat) loss. Here, using data from Italian reserves, extinction rates were calculated for beetle groups with different feeding habits: Carabidae (terrestrial predators), Hydradephaga (aquatic predators), coprophagous Scarabaeoidea (dung feeders), phytophagous Scarabaeoidea (herbivores), and Tenebrionidae (detritivores). The importance of other factors besides area (namely latitude and elevation) was investigated. Reserve area was recovered as an important predictor of species richness in all cases. For Carabidae, Hydradephaga, and Tenebrionidae, elevation exerted a negative influence, whereas latitude had a negative influence on coprophagous Scarabaeoidea and Tenebrionidae, as a consequence of current and historical biogeographical factors. Extinction rates were higher for dung beetles, due to their dependence on large grazing areas, and Tenebrionidae, due to their low dispersal capabilities. The lower extinction rates predicted for Carabidae, phytophagous Scarabaeoidea, and Hydradephaga can be explained by their higher dispersal power. If other variables besides area are considered, extinction rates became more similar among groups. Extinction rates by area loss are always relatively low. Thus, in reserves with few species, many local extinctions might be unnoticed.
Hypoxemia Index Associated with Prehospital Intubation in COVID-19 Patients
Authors: Jouffroy Romain , Kedzierewicz Romain , Derkenne Clement , Bertho Kilian , Scannavino Marine , Frattini Benoit , Lemoine Frederic , Jost Daniel , Prunet Bertrand
Published: September 2020

Background: There exists a need for prognostic tools for the early identification of COVID-19 patients requiring prehospital intubation. Here we investigated the association between a prehospital Hypoxemia Index (HI) and the need for intubation among COVID-19 patients in the prehospital setting. Methods: We retrospectively analyzed COVID-19 patients initially cared for by a Paris Fire Brigade advanced life support (ALS) team in the prehospital setting between 8th March and 18th April of 2020. We assessed the association between HI and prehospital intubation using receiver operating characteristic (ROC) curve analysis and logistic regression model analysis after propensity score matching. Results are expressed as odds ratio (OR) and 95% confidence interval (CI). Results: We analyzed 300 consecutive COVID-19 patients (166 males (55%); mean age, 64 ± 18 years). Among these patients, 45 (15%) were deceased on the scene, 34 (11%) had an active care restriction, and 18 (6%) were intubated in the prehospital setting. The mean HI value was 3.4 ± 1.9. HI was significantly associated with prehospital intubation (OR, 0.24; 95% CI: 0.12–0.41, p < 10−3) with a corresponding area under curve (AUC) of 0.91 (95% CI: 0.85–0.98). HI significantly differed between patients with and without prehospital intubation (1.0 ± 1.0 vs. 3.6 ± 1.8, respectively; p < 10−3). ROC curve analysis defined the optimal HI threshold as 1.3. Bivariate analysis revealed that HI <1.3 was significantly, positively associated with prehospital intubation (OR, 38.38; 95% CI: 11.57–146.54; p < 10−3). Multivariate logistic regression analysis demonstrated that prehospital intubation was significantly associated with HI (adjusted odds ratio (ORa), 0.20; 95% CI: 0.06–0.45; p < 10−3) and HI <3 (ORa, 51.08; 95% CI: 7.83–645.06; p < 10−3). After adjustment for confounders, the ORa between HI <1.3 and prehospital intubation was 3.6 (95% CI: 1.95–5.08; p < 10−3). Conclusion: An HI of <1.3 was associated with a 3-fold increase in prehospital intubation among COVID-19 patients. HI may be a useful tool to facilitate decision-making regarding prehospital intubation of COVID-19 patients initially cared for by a Paris Fire Brigade ALS team. Further prospective studies are needed to confirm these preliminary results.