bluuebunny/crossref_metadata_2025 huggingface dataset:
Burnout in International Medical Students: Characterization of Professionalism and Loneliness as Predictive Factors of Burnout
Authors: Gradiski Ivan P. , Borovecki Ana , Ćurković Marko , San-Martín Montserrat , Delgado Bolton Roberto C. , Vivanco Luis
Published: January 2022

Background: Burnout is a common mental problem in medical students. For those who are following medical studies abroad there is a higher risk of suffering this syndrome, due to the combination of academic stress and the stress derived from their new living situation. This study was performed with the purpose of testing the following hypothesis: in medical students enrolled in medical programs abroad, abilities associated with professionalism and family support play a protective role in the prevention of suffering burnout. Methods: A cross-sectional study was performed in the Faculty of Medicine of the University of Zagreb, where a fully English medical program is offered. The general version of the Maslach Burnout Inventory (MBI-GS) was used as a dependent variable, while Jefferson Scales of empathy, teamwork, and physician lifelong learning and the Social and Emotional Loneliness Scale for Adults were used as predictive variables. In addition, information related to sex, country of birth, native language, age, academic achievement, and living situation were collected in a socio-demographic form. Linear regression models were applied to identify predictors of burnout. Results: In a sample composed of 188 medical students (38 Croatians and 144 foreigners from 28 countries), 18% of the global score in the MBI-GS was explained by lifelong learning and family loneliness. A separate analysis for each domain of the MBI-GS allowed the creation of three models: the first model explained 19% of the variance of the “exhaustion” domain by “country of birth”, “living with parents”, “academic year”, and “cynicism”; a second model explained 24% of the variance of the “cynicism” domain by “academic year”, “empathy”, “lifelong learning”, and “exhaustion”; and finally, a third model explained 24% of the variance of the “professional efficacy” domain by “lifelong learning”, “family loneliness”, and “cynicism”. All obtained models presented an effect size between medium and large, as well as matching the required conditions for statistical inference. Conclusions: These findings confirm the important role that family plays as a source of support for medical students. Empathy and lifelong learning, two specific elements of medical professionalism, appear as protective factors in the prevention of burnout in international students.
The Effect of Exercise on Cardiometabolic Risk Factors in Women with Polycystic Ovary Syndrome: A Systematic Review and Meta-Analysis
Authors: Breyley-Smith Annabelle , Mousa Aya , Teede Helena J. , Johnson Nathan A. , Sabag Angelo
Published: January 2022

Background: Polycystic Ovary Syndrome (PCOS), a common endocrine disorder in women of reproductive age, increases the risk for cardiometabolic morbidity. While regular exercise is effective in reducing cardiometabolic risk, women with PCOS may experience condition-specific barriers to exercise thereby limiting its efficacy. Aim: To determine the effect of exercise on cardiometabolic risk factors in women with PCOS. Methods: Five databases (Cochrane, EMBASE, Medline, Scopus and SPORTDiscus) were searched up to December of 2021. Eligible studies included: a randomised controlled design; participants with a diagnosis of PCOS; aerobic and/or resistance exercise intervention lasting ≥4 weeks; cardiometabolic outcomes. Meta-analyses were performed to determine the effect of exercise versus non-exercising control on cardiometabolic outcomes. Results: Of the 4517 studies screened, 18 studies were analysed involving 593 participants. When compared with control, exercise significantly improved cardiorespiratory fitness (weighted mean difference {WMD} = 4.00 mL/kg/min, 95% CI: 2.61 to 5.40, p < 0.001) and waist circumference (WMD = −1.48 cm, 95% CI: −2.35 to −0.62, p = 0.001). Systolic blood pressure, fasting blood glucose, insulin resistance, and lipid profiles remained unchanged. Conclusions: Regular exercise may improve cardiorespiratory fitness and waist circumference in women with PCOS. Further large-scale studies are required to determine whether exercise interventions improve various biochemical and anthropometric parameters in women with PCOS and more severe cardiometabolic abnormalities.
Self-Reported Medication Use among Pregnant and Breastfeeding Women during the COVID-19 Pandemic: A Cross-Sectional Study in Five European Countries
Authors: Ceulemans Michael , Foulon Veerle , Panchaud Alice , Winterfeld Ursula , Pomar Léo , Lambelet Valentine , Cleary Brian , O’Shaughnessy Fergal , Passier Anneke , Richardson Jonathan Luke , Nordeng Hedvig
Published: January 2022

Insight into the epidemiology of perinatal medication use during the COVID-19 pandemic is scarce. Therefore, a cross-sectional study using an anonymous web survey was performed in Ireland, Norway, Switzerland, The Netherlands, and United Kingdom (UK) to investigate the prevalence and type of medications used by pregnant and breast-feeding women during the first pandemic wave. Factors associated with medication use were estimated by logistic regression. In total, 8378 women participated (i.e., 3666 pregnant and 4712 breastfeeding women). Most responses were collected in Norway (34%) and The Netherlands (28%), followed by Switzerland (19%), Ireland (17%) and UK (2%). Participants were more often professionally active and more often had a higher educational level compared to the general birthing population in each country. Overall, approximately 60% of women reported having used at least 1 medication in the preceding 3 months. Daily and occasional use was reported by 34% and 42% of pregnant and 29% and 44% of breastfeeding women. The most prevalent ATC (Anatomical Therapeutic Chemical) categories were the nervous system, the respiratory system, the alimentary tract/metabolism, and the musculo-skeletal system. Paracetamol, ibuprofen, antacids, and cetirizine were the most frequently used medications. The rate of antibacterial use was lower than previously reported. Having a chronic illness, country, maternal age, SARS-CoV-2 testing, professional status and time since delivery were associated with medication use. In conclusion, perinatal medication use was highly prevalent during the first pandemic wave, underlining the importance of maintaining counseling efforts on medication use, even in times of disrupted healthcare services and/or limited resources.
A Global Perspective of Racial–Ethnic Inequities in Dental Caries: Protocol of Systematic Review
Authors: Nath Sonia , Sethi Sneha , Bastos João L. , Constante Helena M. , Kapellas Kostas , Haag Dandara , Jamieson Lisa M.
Published: January 2022

Though current evidence suggests that racial–ethnic inequities in dental caries persist over time and across space, their magnitude is currently unknown from a global perspective. This systematic review aims to quantify the magnitude of racial/ethnic inequities in dental caries and to deconstruct the different taxonomies/concepts/methods used for racial/ethnic categorization across different populations/nations. This review has been registered in PROSPERO; CRD42021282771. An electronic search of all relevant databases will be conducted until December 2021 for both published and unpublished literature. Studies will be eligible if they include data on the prevalence or severity of dental caries assessed by the decayed, missing, filled teeth index (DMFT), according to indicators of race-ethnicity. A narrative synthesis of included studies and a random-effects meta-analysis will be conducted. Forest plots will be constructed to assess the difference in effect size for the occurrence of dental caries. Study quality will be determined via the Newcastle–Ottawa Scale and the GRADE approach will be used for assessing the quality of evidence. This systematic review will enhance knowledge of the magnitude of racial/ethnic inequities in dental caries globally by providing important benchmark data on which to base interventions to mitigate the problem and to visualize the effects of racism on oral health.
Health Effects of a 12-Week Web-Based Lifestyle Intervention for Physically Inactive and Overweight or Obese Adults: Study Protocol of Two Randomized Controlled Clinical Trials
Authors: Brame Judith , Kohl Jan , Wurst Ramona , Fuchs Reinhard , Tinsel Iris , Maiwald Phillip , Fichtner Urs , Armbruster Christoph , Bischoff Martina , Farin-Glattacker Erik , Lindinger Peter , Bredenkamp Rainer , Gollhofer Albert , König Daniel
Published: January 2022

Web-based lifestyle interventions have attracted considerable research interest. Available evidence on such interventions suggests health-promoting effects, but further research is needed. Therefore, this study aims to investigate short-, medium-, and long-term health effects of a web-based health program (“TK-HealthCoach”, TK-HC) offered by a national statutory health insurance fund (Techniker Krankenkasse, TK). The study comprises two randomized controlled clinical trials to evaluate the health goals “Increasing Fitness” (Fclin) and “Losing and Maintaining Weight” (Wclin). A total of n = 186 physically inactive (Fclin) and n = 150 overweight or obese (Wclin) adults will be randomly assigned to a 12-week interactive (TK-HC) or non-interactive web-based health program using permuted block randomization with a 1:1 allocation ratio. Primary outcomes include cardiorespiratory fitness (Fclin) and body weight (Wclin). Secondary outcomes comprise musculoskeletal fitness (Fclin), physical activity and dietary behavior, anthropometry, blood pressure, blood levels, and vascular health (Fclin, Wclin). All outcomes will be measured before and after the 12-week intervention and after a 6- and 12-month follow-up. Additionally, usage behavior data on the health programs will be assessed. Linear mixed models (LMMs) will be used for statistical analysis. Findings of this study will expand the available evidence on web-based lifestyle interventions.
Association between Self-Reported Childhood Difficulties and Obesity and Health-Related Behaviors in Adulthood—A Cross-Sectional Study among 28,047 Adults from the General Population
Authors: Stea Tonje Holte , Shatri Herolinda , Haugland Siri Håvås , Kleppang Annette Løvheim
Published: January 2022

The aim of the present study was to examine the associations between self-reported childhood difficulties, weight status, and lifestyle behaviors among a representative sample of Norwegian adults. This cross-sectional study included 28,047 adults (>18 years old) living in southern Norway. A self-report questionnaire was used to assess information about the overall quality of the respondents’ childhood retrospectively in addition to current weight status and current lifestyle behaviors. Multivariable logistic regression models adjusted for gender, age, and educational level showed that evaluating childhood as difficult was associated with increased odds of obesity (OR: 1.29; 95% CI; 1.16–1.44) in adulthood. Moreover, a difficult childhood was associated with increased odds of unhealthy lifestyle behaviors in adulthood, including low consumption of fruit and berries (1.21; 1.09–1.34) and fish (1.43; 1.30–1.57), high consumption of sugar-sweetened beverages (1.30; 1.14–1.48), low level of physical activity (1.10; 1.01–1.21), smoking cigarettes (1.78; 1.61–1.97), and using smokeless tobacco (1.20; 1.07–1.36). Overall, results from the present study suggest that experiencing childhood as difficult is associated with an increased risk of obesity and a range of unhealthy lifestyle behaviors in adulthood. Thus, our findings highlight the importance of identifying and providing support to children in difficult life circumstances in addition to customized and targeted public health efforts in adulthood.
Bringing Federated Semantic Queries to the GIS-Based Scenario
Authors: Páez Oswaldo , Vilches-Blázquez Luis M.
Published: January 2022

Geospatial data is increasingly being made available on the Web as knowledge graphs using Linked Data principles. This entails adopting the best practices for publishing, retrieving, and using data, providing relevant initiatives that play a prominent role in the Web of Data. Despite the appropriate progress related to the amount of geospatial data available, knowledge graphs still face significant limitations in the GIScience community since their use, consumption, and exploitation are scarce, especially considering that just a few developments retrieve and consume geospatial knowledge graphs from within GIS. To overcome these limitations and address some critical challenges of GIScience, standards and specific best practices for publishing, retrieving, and using geospatial data on the Web have appeared. Nevertheless, there are few developments and experiences that support the possibility of expressing queries across diverse knowledge graphs to retrieve and process geospatial data from different and distributed sources. In this scenario, we present an approach to request, retrieve, and consume (geospatial) knowledge graphs available at diverse and distributed platforms, prototypically implemented on Apache Marmotta, supporting SPARQL 1.1 and GeoSPARQL standards. Moreover, our approach enables the consumption of geospatial knowledge graphs through a lightweight web application or QGIS. The potential of this work is shown with two examples that use GeoSPARQL-based knowledge graphs.
Global Loss of Core 1-Derived O-Glycans in Mice Leads to High Mortality Due to Acute Kidney Failure and Gastric Ulcers
Authors: Suzuki Riku , Nakamura Yuki , Koiwai Rikako , Fuseya Sayaka , Murakami Yuka , Hagiwara Kozue , Sato Takashi , Takahashi Satoru , Kudo Takashi
Published: January 2022

The core 1 structure is the major constituent of mucin-type O-glycans, which are added via glycosylation—a posttranslational modification present on membrane-bound and secretory proteins. Core 1 β1,3-galactosyltransferase (C1galt1), an enzyme that synthesizes the core 1 structure, requires Cosmc, a C1galt1-specific molecular chaperone, for its enzymatic activity. Since Cosmc-knockout mice exhibit embryonic lethality, the biological role of core 1-derived O-glycans in the adult stage is not fully understood. We generated ubiquitous and inducible CAGCre-ERTM/Cosmc-knockout (iCAG-Cos) mice to investigate the physiological function of core 1-derived O-glycans. The iCAG-Cos mice exhibited a global loss of core 1-derived O-glycans, high mortality, and showed a drastic reduction in weights of the thymus, adipose tissue, and pancreas 10 days after Cosmc deletion. They also exhibited leukocytopenia, thrombocytopenia, severe acute pancreatitis, and atrophy of white and brown adipose tissue, as well as spontaneous gastric ulcers and severe renal dysfunction, which were considered the causes underlying the high mortality of the iCAG-Cos mice. Serological analysis indicated the iCAG-Cos mice have lower blood glucose and total blood protein levels and higher triglyceride, high-density lipoprotein, and total cholesterol levels than the controls. These data demonstrate the importance of core 1-derived O-glycans for homeostatic maintenance in adult mice.
microRNA-21 Regulates Stemness in Pancreatic Ductal Adenocarcinoma Cells
Authors: Mortoglou Maria , Miralles Francesc , Arisan Elif Damla , Dart Alwyn , Jurcevic Stipo , Lange Sigrun , Uysal-Onganer Pinar
Published: January 2022

Pancreatic ductal adenocarcinoma (PDAC) is the most common and aggressive type of pancreatic cancer (PCa) with a low survival rate. microRNAs (miRs) are endogenous, non-coding RNAs that moderate numerous biological processes. miRs have been associated with the chemoresistance and metastasis of PDAC and the presence of a subpopulation of highly plastic “stem”-like cells within the tumor, known as cancer stem cells (CSCs). In this study, we investigated the role of miR-21, which is highly expressed in Panc-1 and MiaPaCa-2 PDAC cells in association with CSCs. Following miR-21 knockouts (KO) from both MiaPaCa-2 and Panc-1 cell lines, reversed expressions of epithelial–mesenchymal transition (EMT) and CSCs markers were observed. The expression patterns of key CSC markers, including CD44, CD133, CX-C chemokine receptor type 4 (CXCR4), and aldehyde dehydrogenase-1 (ALDH1), were changed depending on miR-21 status. miR-21 (KO) suppressed cellular invasion of Panc-1 and MiaPaCa-2 cells, as well as the cellular proliferation of MiaPaCa-2 cells. Our data suggest that miR-21 is involved in the stemness of PDAC cells, may play roles in mesenchymal transition, and that miR-21 poses as a novel, functional biomarker for PDAC aggressiveness.
Anti-Obesity Efficacy of Pediococcus acidilactici MNL5 in Canorhabditis elegans Gut Model
Authors: Barathikannan Kaliyan , Chelliah Ramachandran , Elahi Fazle , Tyagi Akanksha , Selvakumar Vijayalakshmi , Agastian Paul , Valan Arasu Mariadhas , Oh Deog-Hawn
Published: January 2022

In the present study, thirty two lactic acid bacteria (LAB) were isolated from fermented Indian herbal medicine. In comparison to other strains, MNL5 had stronger bile salt hydrolase (BSH) and cholesterol-lowering properties. Furthermore, it can withstand the extreme conditions found in the GI tract, due to, e.g., pepsin, bile salts, pancreatin, and acids. Pediococcus acidilactici MNL5 was identified as a probiotic candidate after sequencing the 16S rRNA gene. The antibacterial activity of P. acidilactici MNL5 cell-free supernatants (CFS) against Escherichia coli, Staphylococcus aureus, Helicobacter pylori, Bacillus cereus, and Candida albicans was moderate. A Caenorhabditis elegans experiment was also performed to assess the effectiveness of P. acidilactici MNL5 supplementation to increase life span compared to E. coli supplementation (DAF-2 and LIU1 models) (p < 0.05). An immense reduction of the lipid droplets of C. elegans was identified through a fluorescent microscope. The drastic alteration of the expression of fat genes is related to obesity phenotypes. Hence, several paths are evolutionary for C. elegans; the results of our work highlight the nematode as an important model for obesity.
Protease Activated Receptors: A Pathway to Boosting Mesenchymal Stromal Cell Therapeutic Efficacy in Acute Respiratory Distress Syndrome?
Authors: Gupta Naveen
Published: January 2022

Acute Respiratory Distress Syndrome is the most common cause of respiratory failure among critically ill patients, and its importance has been heightened during the COVID-19 pandemic. Even with the best supportive care, the mortality rate in the most severe cases is 40–50%, and the only pharmacological agent shown to be of possible benefit has been steroids. Mesenchymal stromal cells (MSCs) have been tested in several pre-clinical models of lung injury and been found to have significant therapeutic benefit related to: (a) potent immunomodulation; (b) secretion of epithelial and endothelial growth factors; and (c) augmentation of host defense to infection. Initial translational efforts have shown signs of promise, but the results have not yielded the anticipated outcomes. One potential reason is the relatively low survival of MSCs in inflammatory conditions as shown in several studies. Therefore, strategies to boost the survival of MSCs are needed to enhance their therapeutic effect. Protease-activated receptors (PARs) may represent one such possibility as they are G-protein coupled receptors expressed by MSCs and control several facets of cell behavior. This review summarizes some of the existing literature about PARs and MSCs and presents possible future areas of investigation in order to develop potential, PAR-modified MSCs with enhanced therapeutic efficiency.
Chronic Systemic Dexamethasone Regulates the Mineralocorticoid/Glucocorticoid Pathways Balance in Rat Ocular Tissues
Authors: Zola Marta , Mejlachowicz Dan , Gregorio Raquel , Naud Marie-Christine , Jaisser Frédéric , Zhao Min , Behar-Cohen Francine
Published: January 2022

Central serous chorioretinopathy (CSCR) is a retinal disease affecting the retinal pigment epithelium (RPE) and the choroid. This is a recognized side-effect of glucocorticoids (GCs), administered through nasal, articular, oral and dermal routes. However, CSCR does not occur after intraocular GCs administration, suggesting that a hypothalamic-pituitary-adrenal axis (HPA) brake could play a role in the mechanistic link between CSCR and GS. The aim of this study was to explore this hypothesis. To induce HPA brake, Lewis rats received a systemic injection of dexamethasone daily for five days. Control rats received saline injections. Baseline levels of corticosterone were measured by Elisa at baseline and at 5 days in the serum and the ocular media and dexamethasone levels were measured at 5 days in the serum and ocular media. The expression of genes encoding glucocorticoid receptor (GR), mineralocorticoid receptors (MR), and the 11 beta hydroxysteroid dehydrogenase (HSD) enzymes 1 and 2 were quantified in the neural retina and in RPE/ choroid. The expression of MR target genes was quantified in the retina (Scnn1A (encoding ENac-α, Kir4.1 and Aqp4) and in the RPE/choroid (Shroom 2, Ngal, Mmp9 and Omg, Ptx3, Plaur and Fosl-1). Only 10% of the corticosterone serum concentration was measured in the ocular media. Corticosterone levels in the serum and in the ocular media dropped after 5 days of dexamethasone systemic treatment, reflecting HPA axis brake. Whilst both GR and MR were downregulated in the retina without MR/GR imbalance, in the RPE/choroid, both MR/GR and 11β-hsd2/11β-hsd1 ratio increased, indicating MR pathway activation. MR-target genes were upregulated in the RPE/ choroid but not in the retina. The psychological stress induced by the repeated injection of saline also induced HPA axis brake with a trend towards MR pathway activation in RPE/ choroid. HPA axis brake causes an imbalance of corticoid receptors expression in the RPE/choroid towards overactivation of MR pathway, which could favor the occurrence of CSCR.
Combined Transcriptomics and Metabolomics Analysis Reveals the Molecular Mechanism of Salt Tolerance of Huayouza 62, an Elite Cultivar in Rapeseed (Brassica napus L.)
Authors: Wan Heping , Qian Jiali , Zhang Hao , Lu Hongchen , Li Ouqi , Li Rihui , Yu Yi , Wen Jing , Zhao Lun , Yi Bin , Fu Tingdong , Shen Jinxiong
Published: January 2022

Soil salinity is one of the most significant abiotic stresses affecting crop yield around the world. To explore the molecular mechanism of salt tolerance in rapeseed (Brassica napus L.), the transcriptome analysis and metabolomics analysis were used to dissect the differentially expressed genes and metabolites in two rapeseed varieties with significant differences in salt tolerance; one is an elite rapeseed cultivar, Huayouza 62. A total of 103 key differentially expressed metabolites (DEMs) and 53 key differentials expressed genes (DEGs) that might be related to salt stress were identified through metabolomics and transcriptomics analysis. GO and KEGG analysis revealed that the DEGs were mainly involved in ion transport, reactive oxygen scavenging, osmotic regulation substance synthesis, and macromolecular protein synthesis. The DEMs were involved in TCA cycle, proline metabolism, inositol metabolism, carbohydrate metabolic processes, and oxidation-reduction processes. In addition, overexpression of BnLTP3, which was one of the key DEGs, could increase tolerance to salt stress in Arabidopsis plants. This study reveals that the regulation mechanism of salt tolerance in rapeseed at the transcriptome and metabolism level and provides abundant data for further in-depth identification of essential salt tolerance genes.
Floating Ricobendazole Delivery Systems: A 3D Printing Method by Co-Extrusion of Sodium Alginate and Calcium Chloride
Authors: Falcone Giovanni , Real Juan P. , Palma Santiago D. , Aquino Rita P. , Del Gaudio Pasquale , Garofalo Emilia , Russo Paola
Published: January 2022

At present, the use of benzimidazole drugs in veterinary medicine is strongly limited by both pharmacokinetics and formulative issues. In this research, the possibility of applying an innovative semi-solid extrusion 3D printing process in a co-axial configuration was speculated, with the aim of producing a new gastro-retentive dosage form loaded with ricobendazole. To obtain the drug delivery system (DDS), the ionotropic gelation of alginate in combination with a divalent cation during the extrusion was exploited. Two feeds were optimized in accordance with the printing requirements and the drug chemical properties: the crosslinking ink, i.e., a water ethanol mixture containing CaCl2 at two different ratios 0.05 M and 0.1 M, hydroxyethyl cellulose 2% w/v, Tween 85 0.1% v/v and Ricobendazole 5% w/v; and alginate ink, i.e., a sodium alginate solution at 6% w/v. The characterization of the dried DDS obtained from the extrusion of gels containing different amounts of calcium chloride showed a limited effect on the ink extrudability of the crosslinking agent, which on the contrary strongly influenced the final properties of the DDS, with a difference in the polymeric matrix toughness and resulting effects on floating time and drug release.
Role of eIF5A in Mitochondrial Function
Authors: Barba-Aliaga Marina , Alepuz Paula
Published: January 2022

The eukaryotic translation initiation factor 5A (eIF5A) is an evolutionarily conserved protein that binds ribosomes to facilitate the translation of peptide motifs with consecutive prolines or combinations of prolines with glycine and charged amino acids. It has also been linked to other molecular functions and cellular processes, such as nuclear mRNA export and mRNA decay, proliferation, differentiation, autophagy, and apoptosis. The growing interest in eIF5A relates to its association with the pathogenesis of several diseases, including cancer, viral infection, and diabetes. It has also been proposed as an anti-aging factor: its levels decay in aged cells, whereas increasing levels of active eIF5A result in the rejuvenation of the immune and vascular systems and improved brain cognition. Recent data have linked the role of eIF5A in some pathologies with its function in maintaining healthy mitochondria. The eukaryotic translation initiation factor 5A is upregulated under respiratory metabolism and its deficiency reduces oxygen consumption, ATP production, and the levels of several mitochondrial metabolic enzymes, as well as altering mitochondria dynamics. However, although all the accumulated data strongly link eIF5A to mitochondrial function, the precise molecular role and mechanisms involved are still unknown. In this review, we discuss the findings linking eIF5A and mitochondria, speculate about its role in regulating mitochondrial homeostasis, and highlight its potential as a target in diseases related to energy metabolism.
Exosomal miRNAs from Prostate Cancer Impair Osteoblast Function in Mice
Authors: Furesi Giulia , de Jesus Domingues Antonio Miguel , Alexopoulou Dimitra , Dahl Andreas , Hackl Matthias , Schmidt Johannes R. , Kalkhof Stefan , Kurth Thomas , Taipaleenmäki Hanna , Conrad Stefanie , Hofbauer Christine , Rauner Martina , Hofbauer Lorenz C.
Published: January 2022

Prostate cancer (PCa) is the most frequent malignancy in older men with a high propensity for bone metastases. Characteristically, PCa causes osteosclerotic lesions as a result of disrupted bone remodeling. Extracellular vesicles (EVs) participate in PCa progression by conditioning the pre-metastatic niche. However, how EVs mediate the cross-talk between PCa cells and osteoprogenitors in the bone microenvironment remains poorly understood. We found that EVs derived from murine PCa cell line RM1-BM increased metabolic activity, vitality, and cell proliferation of osteoblast precursors by >60%, while significantly impairing mineral deposition (−37%). The latter was further confirmed in two complementary in vivo models of ossification. Accordingly, gene and protein set enrichments of osteoprogenitors exposed to EVs displayed significant downregulation of osteogenic markers and upregulation of proinflammatory factors. Additionally, transcriptomic profiling of PCa-EVs revealed the abundance of three microRNAs, miR-26a-5p, miR-27a-3p, and miR-30e-5p involved in the suppression of BMP-2-induced osteogenesis in vivo, suggesting the critical role of these EV-derived miRNAs in PCa-mediated suppression of osteoblast activity. Taken together, our results indicate the importance of EV cargo in cancer-bone cross-talk in vitro and in vivo and suggest that exosomal miRNAs may contribute to the onset of osteosclerotic bone lesions in PCa.
Apoptosis during ZIKA Virus Infection: Too Soon or Too Late?
Authors: Turpin Jonathan , El Safadi Daed , Lebeau Grégorie , Krejbich Morgane , Chatelain Camille , Desprès Philippe , Viranaïcken Wildriss , Krejbich-Trotot Pascale
Published: January 2022

Cell death by apoptosis is a major cellular response in the control of tissue homeostasis and as a defense mechanism in the case of cellular aggression such as an infection. Cell self-destruction is part of antiviral responses, aimed at limiting the spread of a virus. Although it may contribute to the deleterious effects in infectious pathology, apoptosis remains a key mechanism for viral clearance and the resolution of infection. The control mechanisms of cell death processes by viruses have been extensively studied. Apoptosis can be triggered by different viral determinants through different pathways as a result of virally induced cell stresses and innate immune responses. Zika virus (ZIKV) induces Zika disease in humans, which has caused severe neurological forms, birth defects, and microcephaly in newborns during the last epidemics. ZIKV also surprised by revealing an ability to persist in the genital tract and in semen, thus being sexually transmitted. Mechanisms of diverting antiviral responses such as the interferon response, the role of cytopathic effects and apoptosis in the etiology of the disease have been widely studied and debated. In this review, we examined the interplay between ZIKV infection of different cell types and apoptosis and how the virus deals with this cellular response. We illustrate a duality in the effects of ZIKV-controlled apoptosis, depending on whether it occurs too early or too late, respectively, in neuropathogenesis, or in long-term viral persistence. We further discuss a prospective role for apoptosis in ZIKV-related therapies, and the use of ZIKV as an oncolytic agent.
Keep a Little Fire Burning—The Delicate Balance of Targeting Sphingosine-1-Phosphate in Cancer Immunity
Authors: Olesch Catherine , Brüne Bernhard , Weigert Andreas
Published: January 2022

The sphingolipid sphingosine-1-phosphate (S1P) promotes tumor development through a variety of mechanisms including promoting proliferation, survival, and migration of cancer cells. Moreover, S1P emerged as an important regulator of tumor microenvironmental cell function by modulating, among other mechanisms, tumor angiogenesis. Therefore, S1P was proposed as a target for anti-tumor therapy. The clinical success of current cancer immunotherapy suggests that future anti-tumor therapy needs to consider its impact on the tumor-associated immune system. Hereby, S1P may have divergent effects. On the one hand, S1P gradients control leukocyte trafficking throughout the body, which is clinically exploited to suppress auto-immune reactions. On the other hand, S1P promotes pro-tumor activation of a diverse range of immune cells. In this review, we summarize the current literature describing the role of S1P in tumor-associated immunity, and we discuss strategies for how to target S1P for anti-tumor therapy without causing immune paralysis.
Genome-Wide Characterization and Expression Analysis of Pathogenesis-Related 1 (PR-1) Gene Family in Tea Plant (Camellia sinensis (L.) O. Kuntze) in Response to Blister-Blight Disease Stress
Authors: Zhang Qiqi , Guo Nini , Zhang Yongheng , Yu Youben , Liu Shuyuan
Published: January 2022

Pathogenesis-related 1 (PR-1) proteins, which are defense proteins in plant–pathogen interactions, play an important role in the resistance and defense of plants against diseases. Blister blight disease is caused by Exobasidium vexans Massee and a major leaf disease of tea plants (Camellia sinensis (L.) O. Kuntze). However, the systematic characterization and analysis of the PR-1 gene family in tea plants is still lacking, and the defense mechanism of this family remains unknown. In this study, 17 CsPR-1 genes were identified from the tea plant genome and classified into five groups based on their signal peptide, isoelectric point, and C-terminus extension. Most of the CsPR-1 proteins contained an N-terminal signal peptide and a conserved PR-1 like domain. CsPR-1 genes comprised multiple cis-acting elements and were closely related to the signal-transduction pathways involving TCA, NPR1, EDS16, BGL2, PR4, and HCHIB. These characteristics imply an important role of the genes in the defense of the tea plant. In addition, the RNA-seq data and real-time PCR analysis demonstrated that the CsPR-1-2, -4, -6, -7, -8, -9, -10, -14, -15, and -17 genes were significantly upregulated under tea blister-blight stress. This study could help to increase understanding of CsPR-1 genes and their defense mechanism in response to tea blister blight.
Revisiting miRNA Association with Melanoma Recurrence and Metastasis from a Machine Learning Point of View
Authors: Korfiati Aigli , Grafanaki Katerina , Kyriakopoulos George C. , Skeparnias Ilias , Georgiou Sophia , Sakellaropoulos George , Stathopoulos Constantinos
Published: January 2022

The diagnostic and prognostic value of miRNAs in cutaneous melanoma (CM) has been broadly studied and supported by advanced bioinformatics tools. From early studies using miRNA arrays with several limitations, to the recent NGS-derived miRNA expression profiles, an accurate diagnostic panel of a comprehensive pre-specified set of miRNAs that could aid timely identification of specific cancer stages is still elusive, mainly because of the heterogeneity of the approaches and the samples. Herein, we summarize the existing studies that report several miRNAs as important diagnostic and prognostic biomarkers in CM. Using publicly available NGS data, we analyzed the correlation of specific miRNA expression profiles with the expression signatures of known gene targets. Combining network analytics with machine learning, we developed specific non-linear classification models that could successfully predict CM recurrence and metastasis, based on two newly identified miRNA signatures. Subsequent unbiased analyses and independent test sets (i.e., a dataset not used for training, as a validation cohort) using our prediction models resulted in 73.85% and 82.09% accuracy in predicting CM recurrence and metastasis, respectively. Overall, our approach combines detailed analysis of miRNA profiles with heuristic optimization and machine learning, which facilitates dimensionality reduction and optimization of the prediction models. Our approach provides an improved prediction strategy that could serve as an auxiliary tool towards precision treatment.
RT-qPCR Detection of SARS-CoV-2: No Need for a Dedicated Reverse Transcription Step
Authors: Bustin Stephen A. , Shipley Gregory L. , Kirvell Sara , Mueller Reinhold , Nolan Tania
Published: January 2022

Reverse transcription of RNA coupled to amplification of the resulting cDNA by the polymerase chain reaction (RT-PCR) is one of the principal molecular technologies in use today, with applications across all areas of science and medicine. In its real-time, fluorescence-based usage (RT-qPCR), it has long been a core technology driving the accurate, rapid and sensitive laboratory diagnosis of infectious diseases. However, RT-qPCR protocols have changed little over the past 30 years, with the RT step constituting a significant percentage of the time taken to complete a typical RT-qPCR assay. When applied to research investigations, reverse transcription has been evaluated by criteria such as maximum yield, length of transcription, fidelity, and faithful representation of an RNA pool. Crucially, however, these are of less relevance in a diagnostic RT-PCR test, where speed and sensitivity are the prime RT imperatives, with specificity contributed by the PCR component. We propose a paradigm shift that omits the requirement for a separate high-temperature RT step at the beginning of an RT-qPCR assay. This is achieved by means of an innovative protocol that incorporates suitable reagents with a revised primer and amplicon design and we demonstrate a proof of principle that incorporates the RT step as part of the PCR assay setup at room temperature. Use of this modification as part of a diagnostic assay will of course require additional characterisation, validation and optimisation of the PCR step. Combining this revision with our previous development of fast qPCR protocols allows completion of a 40 cycle RT-qPCR run on a suitable commercial instrument in approximately 15 min. Even faster times, in combination with extreme PCR procedures, can be achieved.
Protein Biochemistry and Molecular Modeling of the Intra-Melanosomal Domain of Human Recombinant Tyrp2 Protein and OCA8-Related Mutant Variants
Authors: Dolinska Monika B. , Woods Taariq , Osuna Isabella , Sergeev Yuri V.
Published: January 2022

Tyrosinase-related protein 2 (Tyrp2) is involved in the melanogenesis pathway, catalyzing the tautomerization of dopachrome to 5,6-dihydroxyindole-2-carboxylic acid (DHICA). Recently, a new type of albinism was discovered with disease-causing mutations in the TYRP2 gene. Here, for the first time, we characterized the intra-melanosomal protein domain of Tyrp2 (residues 1-474) and missense variants C40S and C61W, which mimic the alterations found in genetic studies. Recombinant proteins were produced in the Trichoplusia Ni (Ti. Ni) larvae, purified by a combination of immobilized metal affinity (IMAC) and gel-filtration (GF) chromatography, and biochemically characterized. The mutants showed the protein expression in the lysates such as the wild type; however, undetectable protein yield after two steps of purification exhibited their misfolding and instability. In addition, the misfolding effect of the mutations was confirmed computationally using homology modeling and molecular docking. Together, experiments in vitro and computer simulations indicated the critical role of the Cys-rich domain in the Tyrp2 protein stability. The results are consistent with molecular modeling, global computational mutagenesis, and clinical data, proving the significance of genetic alterations in cysteine residues, which could cause oculocutaneous albinism type 8.
Native Liquid Chromatography and Mass Spectrometry to Structurally and Functionally Characterize Endo-Xylanase Proteoforms
Authors: van Schaick Guusje , el Hajjouti Nadi , Nicolardi Simone , den Hartog Joost , Jansen Romana , van der Hoeven Rob , Bijleveld Wim , Abello Nicolas , Wuhrer Manfred , Olsthoorn Maurien M. A. , Domínguez-Vega Elena
Published: January 2022

Xylanases are of great value in various industries, including paper, food, and biorefinery. Due to their biotechnological production, these enzymes can contain a variety of post-translational modifications, which may have a profound effect on protein function. Understanding the structure–function relationship can guide the development of products with optimal performance. We have developed a workflow for the structural and functional characterization of an endo-1,4-β-xylanase (ENDO-I) produced by Aspergillus niger with and without applying thermal stress. This workflow relies on orthogonal native separation techniques to resolve proteoforms. Mass spectrometry and activity assays of separated proteoforms permitted the establishment of structure–function relationships. The separation conditions were focus on balancing efficient separation and protein functionality. We employed size exclusion chromatography (SEC) to separate ENDO-I from other co-expressed proteins. Charge variants were investigated with ion exchange chromatography (IEX) and revealed the presence of low abundant glycated variants in the temperature-stressed material. To obtain better insights into the effect on glycation on function, we enriched for these species using boronate affinity chromatography (BAC). The activity measurements showed lower activity of glycated species compared to the non-modified enzyme. Altogether, this workflow allowed in-depth structural and functional characterization of ENDO-I proteoforms.
Involvement of Fatty Acids and Their Metabolites in the Development of Inflammation in Atherosclerosis
Authors: Kotlyarov Stanislav , Kotlyarova Anna
Published: January 2022

Despite all the advances of modern medicine, atherosclerosis continues to be one of the most important medical and social problems. Atherosclerosis is the cause of several cardiovascular diseases, which are associated with high rates of disability and mortality. The development of atherosclerosis is associated with the accumulation of lipids in the arterial intima and the disruption of mechanisms that maintain the balance between the development and resolution of inflammation. Fatty acids are involved in many mechanisms of inflammation development and maintenance. Endothelial cells demonstrate multiple cross-linkages between lipid metabolism and innate immunity. In addition, these processes are linked to hemodynamics and the function of other cells in the vascular wall, highlighting the central role of the endothelium in vascular biology.
A Century of Fractionated Radiotherapy: How Mathematical Oncology Can Break the Rules
Authors: Ghaderi Nima , Jung Joseph , Brüningk Sarah C. , Subramanian Ajay , Nassour Lauren , Peacock Jeffrey
Published: January 2022

Radiotherapy is involved in 50% of all cancer treatments and 40% of cancer cures. Most of these treatments are delivered in fractions of equal doses of radiation (Fractional Equivalent Dosing (FED)) in days to weeks. This treatment paradigm has remained unchanged in the past century and does not account for the development of radioresistance during treatment. Even if under-optimized, deviating from a century of successful therapy delivered in FED can be difficult. One way of exploring the infinite space of fraction size and scheduling to identify optimal fractionation schedules is through mathematical oncology simulations that allow for in silico evaluation. This review article explores the evidence that current fractionation promotes the development of radioresistance, summarizes mathematical solutions to account for radioresistance, both in the curative and non-curative setting, and reviews current clinical data investigating non-FED fractionated radiotherapy.
The Versatility in the Applications of Dithiocarbamates
Authors: Ajiboye Timothy O. , Ajiboye Titilope T. , Marzouki Riadh , Onwudiwe Damian C.
Published: January 2022

Dithiocarbamate ligands have the ability to form stable complexes with transition metals, and this chelating ability has been utilized in numerous applications. The complexes have also been used to synthesize other useful compounds. Here, the up-to-date applications of dithiocarbamate ligands and complexes are extensively discussed. Some of these are their use as enzyme inhibitor and treatment of HIV and other diseases. The application as anticancer, antimicrobial, medical imaging and anti-inflammatory agents is examined. Moreover, the application in the industry as vulcanization accelerator, froth flotation collector, antifouling, coatings, lubricant additives and sensors is discussed. The various ways in which they have been employed in synthesis of other compounds are highlighted. Finally, the agricultural uses and remediation of heavy metals via dithiocarbamate compounds are comprehensively discussed.
Overexpression of Liriodendron tulipifera JAG Gene (LtuJAG) Changes Leaf Shapes in Transgenic Arabidopsis thaliana
Authors: Wei Lingmin , Wen Shaoying , Tu Zhonghua , Zhao Yanqing , Li Huogen
Published: January 2022

In Arabidopsis thaliana, JAGGED (JAG) is a transcription inhibitor that controls the development of leaf polarity and regulates the expression of genes controlling lateral organ formation. Liriodendron tulipifera is an ornamental tree with extraordinary tulip-shaped flowers and goose web-like leaves, this is one of the suitable plants for morphological development research. To investigate the potential functions of the LtuJAG gene, we isolated the full-length LtuJAG from L. tulipifera, transferred it into A. thaliana via agrobacterium-mediated transformation, and monitored its expression pattern. Subcellular localization showed that LtuJAG was located in the nucleus. RT-qPCR assays indicated that LtuJAG was expressed mainly in leaf buds and flowers, but not in mature leaves and stems. GUS staining results showed that LtuJAG was expressed in the shoot apical meristem (SAM). Overexpressing LtuJAG changed A. thaliana leaf shapes, causing a moderate serration and a slight asymmetric distribution in the medio-lateral and proximal-distal axes. Ectopic expression of LtuJAG induced the expression of lateral organ boundary suppressors JAGGED LATERAL ORGANS (JLO) and ARABIDOPSIS THALIANA HOMEOBOX1 (ATH1). It also repressed the expression of the apical meristem suppressor class-1 KNOX gene (KNOX I) and altered endogenous hormone levels. Our results suggest that LtuJAG plays a role in negatively regulating leaf polarity formation in L. tulipifera.
The Apoptosis Paradox in Cancer
Authors: Morana Ornella , Wood Will , Gregory Christopher D.
Published: January 2022

Cancer growth represents a dysregulated imbalance between cell gain and cell loss, where the rate of proliferating mutant tumour cells exceeds the rate of those that die. Apoptosis, the most renowned form of programmed cell death, operates as a key physiological mechanism that limits cell population expansion, either to maintain tissue homeostasis or to remove potentially harmful cells, such as those that have sustained DNA damage. Paradoxically, high-grade cancers are generally associated with high constitutive levels of apoptosis. In cancer, cell-autonomous apoptosis constitutes a common tumour suppressor mechanism, a property which is exploited in cancer therapy. By contrast, limited apoptosis in the tumour-cell population also has the potential to promote cell survival and resistance to therapy by conditioning the tumour microenvironment (TME)—including phagocytes and viable tumour cells—and engendering pro-oncogenic effects. Notably, the constitutive apoptosis-mediated activation of cells of the innate immune system can help orchestrate a pro-oncogenic TME and may also effect evasion of cancer treatment. Here, we present an overview of the implications of cell death programmes in tumour biology, with particular focus on apoptosis as a process with “double-edged” consequences: on the one hand, being tumour suppressive through deletion of malignant or pre-malignant cells, while, on the other, being tumour progressive through stimulation of reparatory and regenerative responses in the TME.